TREM2 modulators

Abstract

The present invention relates to compounds useful for modulating trigger receptor 2 ('TREM2') expressed on myeloid cells. The present invention also relates to compounds useful in the treatment of diseases associated with loss of TREM2 function, such as neurodegenerative diseases, and pharmaceutical compositions comprising the same.

Description

Technical Field

[0001] The present invention relates to compounds that can be used to modulate triggering receptor expressed on myeloid cells-2 ("TREM2"). The present invention also relates to compounds for treating diseases associated with loss of TREM2 function (e.g., neurodegenerative diseases) and pharmaceutical compositions containing the compounds. Background Art

[0002] Triggering receptor expressed on myeloid cells-2 (TREM2) is a transmembrane receptor belonging to the immunoglobulin superfamily and is encoded by the TREM2 gene, which is located on human chromosome 6p21. TREM2 consists of an extracellular portion including a single immunoglobulin domain and a short extracellular domain, a single transmembrane helix, and a short cytoplasmic tail (Colonna, M. et al. (2016)).

[0003] The restricted expression pattern of TREM2 provides insight into its role. It is expressed only in myeloid cells (such as macrophages, microglia, dendritic cells, and osteoclasts). It plays a role in tissue maintenance as a pathology sensor and inducer of innate immune signaling in specific tissues. In the brain, TREM2 is expressed only in microglia and is functionally required for processes such as phagocytosis of cell debris, but is also thought to play a role in limiting inflammation and promoting cell survival (Deczkowska, A. et al. (2020)).

[0004] TREM2 has a wide range of ligands, such as bacterial anionic molecules / endotoxins, phospholipids (including phosphatidylserine), lipoproteins and apolipoproteins (including ApoE), and oligomeric Aβ (Hammond, TR (2019)).

[0005] Signaling through TREM2 is best described through the co-receptor DAP12. The adaptor molecule DAP 12 is expressed as a homodimer on the surface of a variety of cells involved in the innate immune response, including microglia, macrophages, granulocytes, NK cells, and dendritic cells. Following ligation of TREM2, tyrosine phosphorylation of DAP 12 by SRC family kinases drives the recruitment and activation of Syk kinase and / or ZAP70 kinase. Downstream of TREM2 / DAP12 / Syk, several signaling pathways have been described that are involved in cell survival, cell activation and differentiation, and control of the actin cytoskeleton.

[0006] Proteolytic cleavage of the TREM2 extracellular domain by metalloproteinases (including ADAM10 and ADAM17 and possibly matrix metalloproteinases) leads to the shedding of soluble TREM2 (sTREM2), which can be detected in human cerebrospinal fluid (CSF). sTREM2 is considered a potential biomarker of microglial activity in early Alzheimer's disease (Suárez-Calvet, M. et al. (2016)).

[0007] Deficiency of either TREM2 or DAP12 results in a blunted response of microglia to pathological factors. The effects of TREM2 deficiency have been demonstrated in vitro in the context of stimulation with canonical TLR ligands, such as LPS. Loss-of-function genetic variants of TREM2 have been associated with neurodegenerative diseases and support a central role for microglial function in disease pathogenesis. Homozygous loss-of-function TREM2 variants cause Nasu-Hakola disease (Yamazaki, K. et al. (2015); Paloneva BM, J. et al. (2001); Ulrich JD et al. (2017)), while heterozygous loss-of-function TREM2 variants are associated with an increased risk of multiple neurological and neurodegenerative diseases, such as Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), Parkinson's disease, FTLD-like syndrome, and amyotrophic lateral sclerosis (ALS). The most prevalent mutation associated with AD is the loss-of-function mutation R47H, which has been shown to abrogate ligand binding and phagocytosis (Atagi, Y. et al. (2015); Kleinberger, G. et al (2014)).

[0008] Neurodegenerative diseases that can be treated by modulating TREM2 activity and / or signaling include, but are not limited to, Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), FTLD-like syndromes, Parkinson's disease, Huntington's disease, Nasu-Hakola disease (also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), multiple sclerosis (MS), Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease, and amyotrophic lateral sclerosis (ALS). There is a high and unmet medical need for TREM2 modulators to address these indications. Summary of the Invention

[0009] The present invention relates to compounds that modulate TREM2.

[0010] In one aspect, the present invention relates to compounds of formula LXI:

[0011]

[0012] in

[0013] X 1 Is N or C (R 42 );

[0014] R 42 is H or halogen;

[0015] X 2 is N or CH;

[0016] X 14 is N or CH;

[0017] R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 independently selected substituents R 10 replace;

[0018] R a Is H or C 1-6 alkyl;

[0019] R b Is H or C 1-6 alkyl;

[0020] R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace;

[0021] R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 Tricycloalkyl, C 5-8 Bicycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl),

[0022] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl or 5-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and CN substituents;

[0023] wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace;

[0024] R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0025] and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents;

[0026] R 10 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and halogen;

[0027] R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 Substitution of alkyl groups;

[0028] R 23 Having the formula XLVI:

[0029]

[0030] in

[0031] X 3 Is N or C (R 8 );

[0032] X 4 It is C(R 38 )(R 39 ), O, NH, NR 9 or key;

[0033] X 10 C(R 37 )(R 7 ) or C(O);

[0034] X 11 It is C(R 4 ) or N;

[0035] X 12 It is C(R 6 )(R 6b );

[0036] X 13 It is C(R 40 )(R 41 );

[0037] R 4 Is H or C 1-3 alkyl;

[0038] R 5 Selected from C 1-6 Alkyl, C1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein

[0039] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution;

[0040] (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 Substituents of heterocycloalkyl, wherein (b) a small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein (b) a small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent;

[0041] (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent;

[0042] R 6 is H, halogen or C 1-3 alkyl;

[0043] R 6b is H, halogen or C 1-3 alkyl;

[0044] When R6 and R 6b It is C 1-3 When alkyl, R 6 and R 6b are optionally linked together to form a 3-6 membered ring; and / or

[0045] When R 6 and R 6b It is C 1-3 When alkyl, a methylene group is optionally replaced by -O- or

[0046] -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0047] R 7 H, C alone 1-3 alkyl or bond;

[0048] When R 7 When it is a key, R 6 It is C 1-3 Alkyl, and R 7 and R 6 Connected together to form a 3-5 membered ring;

[0049] R 37 H or C alone 1-3 alkyl;

[0050] R 8 is selected from H, -OH, -O-alkyl and halogen;

[0051] R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups;

[0052] R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution;

[0053] R 29is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain;

[0054] R 30 Is H or C 1-3 alkyl;

[0055] R 31 Is H or C 1-3 alkyl;

[0056] R 38 is H or F;

[0057] R 39 is H or F;

[0058] R 40 H, C alone 1-3 alkyl or bond;

[0059] When R 40 When it is a key, then R 8 It is C 1-3 Alkyl, and R 8 and R 40 Connected together to form a 3-5 membered ring;

[0060] R 41 H or C alone 1-3 alkyl;

[0061] n is 0, 1, or 2; and

[0062] v is 0, 1, or 2,

[0063] or a pharmaceutically acceptable salt thereof.

[0064] In one aspect, the invention relates to a compound of formula LXI as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases associated with loss of TREM2 function, such as neurodegenerative diseases.

[0065] definition

[0066] As used herein, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0067] As used herein, the terms "approximately" and "about" are synonymous. In some embodiments, "about" refers to a recited amount, value, or duration ±20%, ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, or ±0.5%.

[0068] Unless otherwise indicated, the term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure.

[0069] The term "C 1-3 Alkyl", "C 1-5 Alkyl" and "C 1-6 "Alkyl" refers to a straight or branched hydrocarbon chain containing 1 to 3, 1 to 5 and 1 to 6 carbon atoms, respectively. 1-3 Alkyl, C 1-5 Alkyl and C 1-6 Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0070] The term "C 2-4 "Alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. Alkenyl includes straight chain and branched chain portions. 2-4 Representative examples of alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.

[0071] The term "C 3-6 "Cycloalkyl" refers to a saturated carbocyclic molecule in which the cyclic backbone has 3 to 6 carbon atoms. 3-6 Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0072] The term "diC 1-3 "Alkylamino" refers to -NR*R**, wherein R* and R** independently represent C as defined herein. 1-3 Alkyl. DiC 1-3 Representative examples of alkylamino include, but are not limited to, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -N(CH2CH2CH3)2, and -N(CH(CH3)2)2.

[0073] The term "C 1-3 Alkoxy" and "C 1-6 "Alkoxy" refers to -OR # , where R # Represents C as defined in this article 1-3 Alkyl and C 1-6 Alkyl. C 1-3 Alkoxy and C 1-6 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0074] As used herein, the term "halogen" refers to -F, -Cl, -Br, or -I. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl.

[0075] The term "halo" as used herein as a prefix to another term for a chemical group refers to a modification of a chemical group wherein one or more hydrogen atoms are replaced by a halogen as defined herein. Halogen is selected independently at each occurrence. For example, the term "C 1-6 "Haloalkyl" refers to a C 1-6 Alkyl groups in which one or more hydrogen atoms are replaced by halogen. 1-6 Representative examples of haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCl, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3). In addition, for example, the term "C 1-6 "Haloalkoxy" refers to a C 1-6 Alkoxy, in which one or more hydrogen atoms are replaced by halogen. 1-6 Representative examples of haloalkoxy include, but are not limited to, -OCH2F, -OCHF2, -OCF3, -OCHFCl, -OCH2CF3, -OCFHCF3, -OCF2CF3, -OCH(CF3)2, -OCF(CHF2)2, and -OCH(CH2F)(CF3).

[0076] The term "CN" is used herein to represent a cyano group.

[0077] As used herein, the term "5-membered heteroaryl" or "6-membered heteroaryl" refers to a 5- or 6-membered carbocyclic ring having two or three double bonds, containing one ring heteroatom selected from N, S, and O and optionally one or two additional ring N atoms in place of one or more ring carbon atoms. Representative examples of 5-membered heteroaryl groups include, but are not limited to, furanyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and oxazolyl. Representative examples of 6-membered heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

[0078] The term "C 3-6 "Heterocycloalkyl" refers to a saturated carbocyclic molecule wherein the cyclic backbone has 3 to 6 carbons and wherein one or more carbon atoms are substituted with a heteroatom selected from N, O, and S. In some embodiments, "C 3-6 "Heterocycloalkyl" refers to a saturated carbocyclic molecule in which the cyclic backbone has 3 to 6 carbon atoms and one of the carbon atoms is replaced by a heteroatom selected from N, O and S. If C 3-6 Heterocycloalkyl is C6 heterocycloalkyl, then one or two carbon atoms are substituted by heteroatoms independently selected from N, O and S. 3-6Representative examples of heterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0079] The term "spirocyclic compound" as used herein refers to a compound having one atom (usually a quaternary carbon) as the only common member of two rings. 5-8 "Spirocycloalkyl" refers to a bicyclic ring system containing 5 to 8 carbon atoms, wherein the two rings are linked by a single common carbon atom. 5-8 Representative examples of spirocycloalkyl include, but are not limited to, spiro[2.2]pentyl, spiro[3.2]hexyl, spiro[3.3]heptyl, spiro[3.4]octyl, and spiro[2.5]octyl.

[0080] The term "C 5-8 "Tricycloalkyl" refers to a tricyclic ring system in which all three cycloalkyl rings share the same two ring atoms. 5-8 Representative examples of tricycloalkyl groups include, but are not limited to, tricyclo[1.1.1.0 1,3 ]pentyl, tricyclic [2.1.1.0 1,4 ] hexyl, tricyclic [3.1.1.0 1,5 ] hexyl and tricyclic [3.2.1.0 1,5 ]Hinky.

[0081] The term "C 5-8 "Bicycloalkyl" refers to a bicyclic ring system in which the two cycloalkyl rings share the same two ring atoms. The term "C 5-8 "Bicycloalkyl" includes bridged bicyclic compounds, ie, wherein the two rings share three or more atoms and the two bridgehead atoms are separated by a bridge containing at least one atom. For example, the term "C 5-8 "Bicycloalkyl" includes bicyclo[1.1.1]pentyl. For example, the term "C 5-8 "Bicycloalkyl" includes

[0082] The term "aryl" used alone or as part of a larger moiety, such as in "aralkyl," "aralkyloxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 4 to 14 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains three to seven ring members. The term "aryl" can be used interchangeably with the term "aromatic ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may carry one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimido, naphthalimido, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0083] The terms "heteroaryl" and "heteroar" used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy") refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic arrangement; and having from one to five heteroatoms in addition to carbon atoms. The term "heteroatom" in the context of "heteroaryl" specifically includes, but is not limited to, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, "heteroaryl" and "heteroaromatic" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings, wherein the free radical or point of attachment is located on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido [2,3-b] -1,4-oxazine -3 (4H) -one. The heteroaryl group can be monocyclic or bicyclic. The heteroaromatic ring can include one or more oxo (=O) or thio (=S) substituents. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0084] As described herein, the compounds of the present invention may contain "substituted" moieties. In general, the term "substituted" means that one or more hydrogens of a designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted by more than one substituent selected from a particular group, the substituent may be the same or different at each position, i.e., the substituent may be individually / independently selected from a group of substituents. The combination of substituents contemplated by the present invention is preferably a combination that results in the formation of a stable or chemically feasible compound.

[0085] As used herein, the term "stable" refers to a compound that is not substantially altered when subjected to conditions that allow for its production, detection, and, in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0086] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. Detailed Description of the Invention

[0088] In one aspect, the present invention relates to compounds of formula LXI:

[0089]

[0090] in

[0091] X 1 Is N or C (R 42 );

[0092] R 42 is H or halogen;

[0093] X 2 is N or CH;

[0094] X 14 is N or CH;

[0095] R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 independently selected substituents R 10 replace;

[0096] R aIs H or C 1-6 alkyl;

[0097] R b Is H or C 1-6 alkyl;

[0098] R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace;

[0099] R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 Tricycloalkyl, C 5-8 Bicycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl),

[0100] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl or 5-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and CN substituents;

[0101] wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace;

[0102] R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0103] and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexane

[0104] -3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents;

[0105] R 10 Individually selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and halogen;

[0106] R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 Substitution of alkyl groups;

[0107] R 23 Having the formula XLVI:

[0108]

[0109] in

[0110] X 3 Is N or C (R 8 );

[0111] X 4 It is C(R 38 )(R 39 ), O, NH, NR 9 or key;

[0112] X 10 C(R 37 )(R 7 ) or C(O);

[0113] X 11 It is C(R 4 ) or N;

[0114] X 12 It is C(R 6 )(R 6b );

[0115] X 13 It is C(R 40 )(R 41 );

[0116] R 4 Is H or C 1-3 alkyl;

[0117] R 5 Selected from C 1-6 Alkyl, C 1-6Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein

[0118] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution;

[0119] (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 Substituents of heterocycloalkyl, wherein (b) a small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein (b) a small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent;

[0120] (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent;

[0121] R 6 is H, halogen or C 1-3 alkyl;

[0122] R 6b is H, halogen or C 1-3 alkyl;

[0123] When R 6and R 6b It is C 1-3 When it is an alkyl group, R 6 and R 6b are optionally linked together to form a 3-6 membered ring; and / or

[0124] When R 6 and R 6b It is C 1-3 When alkyl, a methylene group is optionally replaced by -O- or

[0125] -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0126] R 7 H, C alone 1-3 alkyl or bond;

[0127] When R 7 When it is a key, then R 6 It is C 1-3 Alkyl, and R 7 and R 6 Connected together to form a 3-5 membered ring;

[0128] R 37 H or C alone 1-3 alkyl;

[0129] R 8 is selected from H, -OH, -O-alkyl and halogen;

[0130] R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups;

[0131] R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution;

[0132] R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O-1-6 hydrocarbon chain;

[0133] R 30 Is H or C 1-3 alkyl;

[0134] R 31 Is H or C 1-3 alkyl;

[0135] R 38 is H or F;

[0136] R 39 is H or F;

[0137] R 40 H, C alone 1-3 alkyl or bond;

[0138] When R 40 When it is a key, then R 8 It is C 1-3 Alkyl, and R 8 and R 40 Connected together to form a 3-5 membered ring;

[0139] R 41 H or C alone 1-3 alkyl;

[0140] n is 0, 1, or 2; and

[0141] v is 0, 1, or 2,

[0142] or a pharmaceutically acceptable salt thereof.

[0143] In one aspect, the present invention relates to compounds of formula LXI:

[0144]

[0145] in

[0146] X 1 Is N or C (R 42 );

[0147] R 42 is H or halogen;

[0148] X 2 is N or CH;

[0149] X 14 is N or CH;

[0150] R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 independently selected substituents R 10 replace;

[0151] R a Is H or C 1-6 alkyl;

[0152] R b Is H or C 1-6 alkyl;

[0153] R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace;

[0154] R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl),

[0155] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl or 5-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 The substituent of haloalkyl is substituted; wherein said C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace;

[0156] R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0157] and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexane

[0158] -3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents;

[0159] R 10 Individually selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and halogen;

[0160] R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 Substitution of alkyl groups;

[0161] R 23 Having the formula XLVI:

[0162]

[0163] in

[0164] X 3 Is N or C (R 8 );

[0165] X 4 It is C(R 38 )(R 39 ), O, NH, NR 9 or key;

[0166] X 10 C(R 37 )(R 7 ) or C(O);

[0167] X 11 It is C(R 4 ) or N;

[0168] X 12 It is C(R 6 )(R 6b );

[0169] X 13 It is C(R 40 )(R 41 );

[0170] R 4 Is H or C 1-3 alkyl;

[0171] R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein

[0172] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution;

[0173] (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 Substituents of heterocycloalkyl, wherein (b) a small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein (b) a small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent;

[0174] (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent;

[0175] R 6 is H, halogen or C 1-3 alkyl;

[0176] R6b is H, halogen or C 1-3 alkyl;

[0177] When R 6 and R 6b It is C 1-3 When it is an alkyl group, R 6 and R 6b are optionally linked together to form a 3-6 membered ring; and / or

[0178] When R 6 and R 6b It is C 1-3 When alkyl, a methylene group is optionally replaced by -O- or

[0179] -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0180] R 7 H or C alone 1-3 alkyl;

[0181] R 37 H or C alone 1-3 alkyl;

[0182] R 8 is selected from H, -OH, -O-alkyl and halogen;

[0183] R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups;

[0184] R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution;

[0185] R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain;

[0186] R30 Is H or C 1-3 alkyl;

[0187] R 31 Is H or C 1-3 alkyl;

[0188] R 38 is H or F;

[0189] R 39 is H or F;

[0190] R 40 H, C alone 1-3 alkyl or bond;

[0191] When R 8 is a bond and R 40 It is C 1-3 When it is an alkyl group, R 8 and R 40 are optionally linked together to form a 3-5 membered ring;

[0192] R 41 H or C alone 1-3 alkyl;

[0193] n is 0, 1, or 2; and

[0194] v is 0, 1, or 2,

[0195] or a pharmaceutically acceptable salt thereof.

[0196] In one aspect, the present invention relates to compounds of formula LXI:

[0197]

[0198] in

[0199] X 1 Is N or C (R 42 );

[0200] R 42 is H or halogen;

[0201] X 2 is N or CH;

[0202] X 14 is N or CH;

[0203] R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6The cycloalkyl group is optionally substituted with 1 to 3 independently selected substituents R 10 replace;

[0204] R a Is H or C 1-6 alkyl;

[0205] R b Is H or C 1-6 alkyl;

[0206] R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace;

[0207] R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl),

[0208] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl or 5-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 The substituent of haloalkyl is substituted; wherein said C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace;

[0209] R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0210] and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexane

[0211] -3-yl, piperidin-1-yl or -OCH2-(C 3-6Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents;

[0212] R 10 Individually selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and halogen;

[0213] R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 Substitution of alkyl groups;

[0214] R 23 Having the formula XLVI:

[0215]

[0216] in

[0217] X 3 Is N or C (R 8 );

[0218] X 4 It is C(R 38 )(R 39 ), O, NH, NR 9 or key;

[0219] X 10 C(R 37 )(R 7 ) or C(O);

[0220] X 11 It is C(R 4 ) or N;

[0221] X 12 It is C(R 6 )(R 6b );

[0222] X 13 It is C(R 40 )(R 41 );

[0223] R 4 Is H or C 1-3 alkyl;

[0224] R 5Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein

[0225] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution;

[0226] (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 Substituents of heterocycloalkyl, wherein (b) a small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein (b) a small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent;

[0227] (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent;

[0228] R 6 is H, halogen or C 1-3 alkyl;

[0229] R 6b is H, halogen or C 1-3 alkyl;

[0230] When R 6 and R 6b It is C 1-3 When it is an alkyl group, R 6 and R 6b are optionally linked together to form a 3-6 membered ring; and / or

[0231] When R 6 and R 6b It is C 1-3 When alkyl, a methylene group is optionally replaced by -O- or

[0232] -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0233] R 7 H or C alone 1-3 alkyl;

[0234] R 37 H or C alone 1-3 alkyl;

[0235] R 8 is selected from H, -OH, -O-alkyl and halogen;

[0236] R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups;

[0237] R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution;

[0238] R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain;

[0239] R 30 Is H or C 1-3 alkyl;

[0240] R 31 Is H or C 1-3 alkyl;

[0241] R 38 is H or F;

[0242] R 39 is H or F;

[0243] R 40 H, C alone 1-3 alkyl or bond;

[0244] When R 8 is a bond and R 40 It is C 1-3 When it is an alkyl group, R 8 and R 40 are optionally linked together to form a 3-5 membered ring;

[0245] R 41 H or C alone 1-3 alkyl;

[0246] n is 0, 1, or 2; and

[0247] v is 1 or 2,

[0248] or a pharmaceutically acceptable salt thereof.

[0249] In one aspect, the present invention relates to compounds of formula IX:

[0250]

[0251] in

[0252] X 1 is N or CH;

[0253] X 2 is N or CH;

[0254] R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 independently selected substituents R 10 replace;

[0255] R a Is H or C 1-6 alkyl;

[0256] R b Is H or C 1-6 alkyl;

[0257] R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace;

[0258] R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl),

[0259] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl or 5-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 The substituent of haloalkyl is substituted; wherein said C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace;

[0260] R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0261] and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexane

[0262] -3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents;

[0263] R 10 Individually selected from -OC 1-6Alkyl, C 3-6 Cycloalkyl and halogen;

[0264] R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 Substitution of alkyl groups;

[0265] R 23 Having the formula XX:

[0266]

[0267] in

[0268] X 3 Is N or C (R 8 );

[0269] X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key;

[0270] X 10 is C(H)(R 7 ) or C(O);

[0271] X 11 It is C(R 4 ) or N;

[0272] X 12 It is C(R 6 )(R 6b );

[0273] R 4 Is H or C 1-3 alkyl;

[0274] R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein

[0275] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3Alkoxy and halogen substituents substitution;

[0276] (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 Substituents of heterocycloalkyl, wherein (b) a small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein (b) a small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent;

[0277] (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent;

[0278] R 6 is H, halogen or C 1-3 alkyl;

[0279] R 6b is H, halogen or C 1-3 alkyl;

[0280] When R 6 and R 6b It is C 1-3 When it is an alkyl group, R 6 and R 6b are optionally linked together to form a 3-6 membered ring; and / or

[0281] When R 6 and R 6b It is C 1-3 When alkyl, a methylene group is optionally replaced by -O- or

[0282] -N(R 35 )-replacement, where R35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0283] R 7 Is H or C 1-3 alkyl;

[0284] R 8 is selected from H, -OH, -O-alkyl and halogen;

[0285] R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups;

[0286] R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution;

[0287] R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain;

[0288] R 30 Is H or C 1-3 alkyl;

[0289] R 31 Is H or C 1-3 alkyl;

[0290] n is 0, 1, or 2; and

[0291] v is 1 or 2,

[0292] or a pharmaceutically acceptable salt thereof.

[0293] In one aspect, the present invention relates to compounds of formula IX:

[0294]

[0295] in

[0296] X 1 is N or CH;

[0297] X 2 is N or CH;

[0298] R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 10 replace;

[0299] R a Is H or C 1-6 alkyl;

[0300] R b Is H or C 1-6 alkyl;

[0301] R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace;

[0302] R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl),

[0303] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl or 6-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 Substitution of haloalkyl groups;

[0304] wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace;

[0305] R 28Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0306] and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl or -OCH2-(C 3-6 cycloalkyl) is optionally substituted by 1 to 4 independently selected halogen,

[0307] C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents;

[0308] R 10 Selected from -OC 1-6 Alkyl and C 3-6 Cycloalkyl;

[0309] R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 Substitution of alkyl groups;

[0310] R 23 Having the formula XX:

[0311]

[0312] in

[0313] X 3 Is N or C (R 8 );

[0314] X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key;

[0315] X 10 is C(H)(R 7 ) or C(O);

[0316] X 11 It is C(R 4 ) or N;

[0317] X 12 It is C(R 6 )(R 6b );

[0318] R 4 Is H or C 1-3alkyl;

[0319] R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein

[0320] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution;

[0321] (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 Substituents of heterocycloalkyl, wherein (b) a small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein (b) a small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent;

[0322] (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent;

[0323] R 6 is H, halogen or C 1-3 alkyl;

[0324] R6b is H, halogen or C 1-3 alkyl;

[0325] When R 6 and R 6b It is C 1-3 When it is an alkyl group, R 6 and R 6b are optionally linked together to form a 3-6 membered ring; and / or

[0326] When R 6 and R 6b It is C 1-3 When alkyl, a methylene group is optionally replaced by -O- or

[0327] -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0328] R 7 Is H or C 1-3 alkyl;

[0329] R 8 is selected from H, -OH, -O-alkyl and halogen;

[0330] R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups;

[0331] R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution;

[0332] R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain;

[0333] R 30 Is H or C 1-3 alkyl;

[0334] R 31Is H or C 1-3 alkyl;

[0335] n is 0, 1, or 2; and

[0336] v is 1 or 2,

[0337] or a pharmaceutically acceptable salt thereof.

[0338] In one aspect, the present invention relates to compounds of formula IX:

[0339]

[0340] in

[0341] X 1 is N or CH;

[0342] X 2 is N or CH;

[0343] R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 10 replace;

[0344] R a Is H or C 1-6 alkyl;

[0345] R b Is H or C 1-6 alkyl;

[0346] R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace;

[0347] R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl),

[0348] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl or 6-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 Substitution of haloalkyl groups;

[0349] wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace;

[0350] R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0351] and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexane

[0352] -3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents;

[0353] R 10 Selected from -OC 1-6 Alkyl and C 3-6 Cycloalkyl;

[0354] R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 alkyl halide;

[0355] R 23 Having the formula XVI:

[0356]

[0357] in

[0358] X 3 Is N or C (R 8 );

[0359] X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key;

[0360] X 10 is C(H)(R 7 ) or C(O);

[0361] X 11 It is C(R 4 ) or N;

[0362] R 4 Is H or C 1-3 alkyl;

[0363] R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein

[0364] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution;

[0365] (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted,

[0366] (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and

[0367] (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent;

[0368] (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent;

[0369] R 6 Is H or C 1-3 alkyl;

[0370] R 7 Is H or C 1-3 alkyl;

[0371] R 8 is selected from H, -OH, -O-alkyl and halogen;

[0372] R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups;

[0373] R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution;

[0374] R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain;

[0375] R 30 Is H or C 1-3 alkyl;

[0376] R 31 Is H or C 1-3 alkyl;

[0377] n is 0, 1, or 2; and

[0378] v is 1 or 2,

[0379] or a pharmaceutically acceptable salt thereof.

[0380] In one aspect, the present invention relates to compounds of formula IX:

[0381]

[0382] in

[0383] X 1 is N or CH;

[0384] X 2 is N or CH;

[0385] R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 10 Replacement; R a Is H or C 1-6 alkyl;

[0386] R b Is H or C 1-6 alkyl;

[0387] R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace;

[0388] R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl),

[0389] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl or 6-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3Substitution of haloalkyl groups;

[0390] wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace;

[0391] R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0392] and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexane

[0393] -3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents;

[0394] R 10 Selected from -OC 1-6 Alkyl and C 3-6 Cycloalkyl;

[0395] R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 alkyl halide;

[0396] R 23 With formula X:

[0397]

[0398] in

[0399] X 3 Is N or C (R 8 );

[0400] X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key;

[0401] X 10 is C(H)(R 7 ) or C(O);

[0402] R 4 Is H or C 1-3 alkyl;

[0403] R 5 Selected from C1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein

[0404] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted with oxo (=O), and

[0405] (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 Substituents of heterocycloalkyl, wherein (b) a small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein (b) a small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent;

[0406] (c) C 1-6 The alkyl group is optionally replaced by -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 )replace;

[0407] R 6 Is H or C 1-3 alkyl;

[0408] R 7 Is H or C 1-3 alkyl;

[0409] R 8 is selected from H, -OH, -O-alkyl and halogen;

[0410] R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl;

[0411] R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substituted; and

[0412] n is 0, 1, or 2,

[0413] or a pharmaceutically acceptable salt thereof.

[0414] In some embodiments, the compound has Formula I:

[0415]

[0416] in

[0417] X 1 is N or CH;

[0418] X 2 is N or CH;

[0419] X 3 Is N or C (R 8 );

[0420] X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key;

[0421] X 10 is C(H)(R 7 ) or C(O);

[0422] R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 10 replace;

[0423] R a Is H or C 1-6 alkyl;

[0424] R b Is H or C 1-6 alkyl;

[0425] R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace;

[0426] R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl),

[0427] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl or 6-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 The substituent of the haloalkyl group is substituted,

[0428] and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexane

[0429] -3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents;

[0430] R 4 Is H or C 1-3 alkyl;

[0431] R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6Heterocycloalkyl, phenyl, 5-membered heteroaryl and 6-membered heteroaryl, wherein

[0432] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted with oxo (=O), and

[0433] (b) the phenyl, 5-membered heteroaryl or 6-membered heteroaryl is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted,

[0434] (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein (b) a small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent;

[0435] R 6 Is H or C 1-3 alkyl;

[0436] R 7 Is H or C 1-3 alkyl;

[0437] R 8 is selected from H, -OH, -O-alkyl and halogen;

[0438] R 9 It is C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl or C 1-6 alkyl halide;

[0439] R 10 Selected from -OC 1-6 Alkyl and C 3-6 Cycloalkyl;

[0440] R 11 Selected from -OC 1-6 Alkyl and C3-6 Cycloalkyl;

[0441] n is 0, 1, or 2,

[0442] or a pharmaceutically acceptable salt thereof.

[0443] In some embodiments, R 23 having the formula XLVII, wherein R 5 、R 8 、R 29 、X 4 、X 10 、X 11 、X 12 , n and v are as defined herein. In some embodiments, R 23 having the formula XLVIII, wherein R 5 、R 8 、R 29 、X 4 、X 10 、X 11 、X 12 , n and v are as defined herein. In some embodiments, R 23 Having the formula XLIX, wherein R 4 、R 5 、R 29 、X 4 、X 10 、X 12 、X 13 , n and v are as defined herein.

[0444] In some embodiments, R 23 Having the formula L, where R 4 、R 5 、R 29 、X 4 、X 10 、X 12 、X 13 , n and v are as defined herein. In some embodiments, R 23 Having the formula LI, wherein R 4 、R 5 、R 8 、R 29 、X 4 、X 10 、X 12 、X 13 , n and v are as defined herein. In some embodiments, R 23 Having the formula LII, wherein R 4 、R 5 、R 8 、R 29 、X 4 、X10 、X 12 、X 13 , n and v are as defined herein.

[0445] In some embodiments, R 23 Having the formula LIII, wherein R 4 、R 5 、R 8 、R 29 、X 4 、X 10 、X 12 、X 13 , n and v are as defined herein. In some embodiments, R 23 Having the formula LIV, wherein R 4 、R 5 、R 8 、R 29 、X 4 、X 10 、X 12 、X 13 , n and v are as defined herein.

[0446]

[0447]

[0448] In some embodiments, R 23 Having the formula Xa, wherein R 4 、R 5 、R 6 、X 3 、X 4 、X 10 and n are as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, R 23 Having the formula Xb, wherein R 4 、R 5 、R 6 、X 3 、X 4 、X 10 and n are as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, R 23 Having the formula XXa,

[0449] where R 4 、R 5 、R 29 、X 3 、X 4 、X 10 、X 12 , n and v are as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, R 23 Having the formula XXb,

[0450] where R 4 、R 5 、R 29 、X 3 、X 4 、X 10 、X 12 , n and v are as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, R 23 Having the formula XXc,

[0451] where R 4 、R 5 、R 8 、R 29 、X 4 、X 10 、X 12 , n and v are as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, R 23 Having the formula XXd,

[0452] where R 4 、R 5 、R 8 、R 29 、X 4 、X 10 、X 12 , n and v are as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, R 23 Having the formula XXe,

[0453] where R 4 、R 5 、R 8 、R 29 、X 4 、X 10 、X 12 , n and v are as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, R 23 Having the formula XXf,

[0454] where R 4 、R 5 、R 8 、R 29 、X 4 、X 10 、X 12 , n and v are as defined herein, or a pharmaceutically acceptable salt thereof.

[0455]

[0456] In some embodiments, the compound has Formula Ia or Formula Ib:

[0457]

[0458] where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 3 、X 4 、X 10 and n are as defined herein, or a pharmaceutically acceptable salt thereof.

[0459] In some embodiments, X 1 Is N. In some embodiments, X 1 It is C(R 42 ), where R 42 Is H or halogen. In some embodiments, R 42 It is H, that is, X 1 is CH. In some embodiments, R 42 In some embodiments, R 42 It is F, that is, X 1 In some embodiments, X 1 In some embodiments, X 2 Is N. In some embodiments, X 2 In some embodiments, X 14 Is N. In some embodiments, X 14 In some embodiments, X 1 is N and X 2 In some embodiments, X 1 is CH and X 2 Is N. In some embodiments, X 1 is CH and X 2 In some embodiments, X 1 is N and X 2 Is N. In some embodiments, X 1 It is N, X 2 is N and X 14 Is N. In some embodiments, X 1 It is N, X 2 is N and X 14 In some embodiments, X 1 It is N, X 2 is CH and X 14 Is N. In some embodiments, X 1 It is CH, X 2 is N and X 14 Is N. In some embodiments, X 1It is CH, X 2 is CH and X 14 Is N. In some embodiments, X 1 It is CH, X 2 is N and X 14 In some embodiments, X 1 It is N, X 2 is CH and X 14 In some embodiments, X 1 It is CH, X 2 is CH and X 14 In some embodiments, X 1 It's CF, X 2 is N and X 14 It's N.

[0460] In some embodiments, the compound has Formula II:

[0461]

[0462] where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 3 、X 4 、X 10 and n are as defined herein, or a pharmaceutically acceptable salt thereof.

[0463] In some embodiments, the compound has Formula II, wherein

[0464] X 1 is N or CH;

[0465] X 2 is N or CH;

[0466] R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 10 replace;

[0467] R a Is H or C 1-6 alkyl;

[0468] R b Is H or C 1-6 alkyl;

[0469] R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace;

[0470] R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl),

[0471] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl or 6-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 Substitution of haloalkyl groups;

[0472] wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace;

[0473] R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0474] and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexane

[0475] -3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents;

[0476] R 10 Selected from -OC 1-6Alkyl and C 3-6 Cycloalkyl;

[0477] R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 alkyl halide;

[0478] X 3 Is N or C (R 8 );

[0479] X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key;

[0480] X 10 It is CH2;

[0481] R 4 Is H or C 1-3 alkyl;

[0482] R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein

[0483] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted with oxo (=O), and

[0484] (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 Substituents of heterocycloalkyl, wherein (b) a small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein (b) a small portion of C3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent;

[0485] (c) C 1-6 The alkyl group is optionally replaced by -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 )replace;

[0486] R 6 Is H or C 1-3 alkyl;

[0487] R 8 is selected from H, -OH, -O-alkyl and halogen;

[0488] R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl;

[0489] R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substituted; and

[0490] n is 1,

[0491] or a pharmaceutically acceptable salt thereof.

[0492] In some embodiments, R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 independently selected substituents R 10 Replacement; R a Is H or C 1-6 Alkyl; R b Is H or C 1-6 alkyl; and R 10 Selected from -OC 1-6 Alkyl, C 3-6 In some embodiments, R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NRa R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 10 Replacement; R a Is H or C 1-6 Alkyl; R b Is H or C 1-6 alkyl; and R 10 Selected from -OC 1-6 Alkyl, C 3-6 In some embodiments, R 1 It is C 1-6 Alkyl, optionally substituted by 1 to 3 independently selected substituents R 10 In some embodiments, R 1 It is C 1-6 Alkyl, which is optionally replaced by R as defined herein 10 In some embodiments, R 1 It is C 1-3 Alkyl, optionally substituted by 1 to 3 independently selected substituents R 10 In some embodiments, R 1 It is C 1-3 Alkyl, which is optionally replaced by R as defined herein 10 In some embodiments, R 1 is -CH3. In some embodiments, R 10 Individually selected from -OC 1-6 Alkyl, C 3-6 In some embodiments, R 10 is a halogen, such as F. In some embodiments, R 1 In some embodiments, R 1 It is C 3-6 Cycloalkyl, which is optionally substituted by R as defined herein 10 In some embodiments, R 1 It’s H.

[0493] In some embodiments, R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 Substituted, where R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 In some embodiments, R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 In some embodiments, R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 In some embodiments, R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 Substituted, where R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 In some embodiments, R 2 It is C 1-6 Alkyl, which is optionally replaced by R as defined herein 11 In some embodiments, R 2 It is C 1-3 Alkyl, which is optionally replaced by R as defined herein 11 In some embodiments, R 2 is -CH3. In some embodiments, R 2 It is C 3-6 Cycloalkyl, which is optionally substituted by R as defined herein 11 In some embodiments, R 11 Yes-OC 1-6 In some embodiments, R 2 is H. In some embodiments, R 2 Is R 11 Substituted C 1-3 Alkyl, and R 11 Yes-OC 1-6 In some embodiments, R 2 In some embodiments, R 2 is C substituted by phenyl 1-6 Alkyl, wherein the phenyl group is optionally replaced by -OC 1-6 In some embodiments, R2 is a C1 alkyl substituted by a phenyl group, wherein the phenyl group is replaced by -OC 1-6 Alkyl groups such as -OC 1-3 Alkyl groups such as -O-C1 alkyl groups are substituted.

[0494] In some embodiments, R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl),

[0495] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl or 5-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and CN substituents;

[0496] wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace;

[0497] R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0498] and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 The substituents of the haloalkoxy group are substituted.

[0499] In some embodiments, R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl),

[0500] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl or 6-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, -CN, C 1-3 Alkyl and C 1-3 Substitution of haloalkyl groups;

[0501] wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace;

[0502] R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0503] and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 The substituents of the haloalkoxy group are substituted.

[0504] In some embodiments, R 3 is phenyl, which is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 and a pharmaceutically acceptable salt thereof.

[0505] In some embodiments, R 3 is phenyl, which is optionally substituted by 1 to 4 independently selected from halogen, -CN, C 1-3 Alkyl and C 1-3 The substituents of the haloalkyl group are substituted.

[0506] In some embodiments, R 3 Having formula III:

[0507]

[0508] in

[0509] X 5 It is C(R 15 ) or N;

[0510] X 6 is CH or N;

[0511] R 12 It is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or CN;

[0512] R 13 It is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or CN;

[0513] R 14 It is H, halogen, C 1-3 Alkyl, C 1-3 haloalkyl or CN; and

[0514] R 15 It is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or CN,

[0515] or a pharmaceutically acceptable salt thereof.

[0516] In some embodiments, R 3 Having formula III, wherein X 5 It is C(R 15 ) or N; X 6 is CH or N; R 12 It is H, halogen, C 1-3 Alkyl or C 1-3 Haloalkyl; R 13 It is H, halogen, C 1-3 Alkyl or C 1-3 Haloalkyl; R 14 It is H, halogen, C 1-3 Alkyl or C 1-3 haloalkyl; and R 15 It is H, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0517] In some embodiments, R 3 Having formula III, wherein X 5 It is C(R 15 ) or N; X 6 It is CH; R12 is H or halogen; R 13 is H or halogen; R 14 is H, halogen or C 1-3 haloalkyl; and R 15 is H or halogen, or a pharmaceutically acceptable salt thereof.

[0518] In some embodiments, X 5 It is C(R 15 ) and X 6 is CH. Thus, in some embodiments, R 3 Having formula IV:

[0519]

[0520] in

[0521] R 12 It is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or CN;

[0522] R 13 It is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or CN;

[0523] R 14 It is H, halogen, C 1-3 Alkyl, C 1-3 haloalkyl or CN; and

[0524] R 15 It is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or CN,

[0525] or a pharmaceutically acceptable salt thereof.

[0526] In some embodiments, R 3 It has the formula IV, wherein R 12 It is H, halogen, C 1-3 Alkyl or C 1-3 Haloalkyl; R 13 It is H, halogen, C 1-3 Alkyl or C 1-3 Haloalkyl; R 14 It is H, halogen, C 1-3 Alkyl or C 1-3 haloalkyl; and R 15 It is H, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0527] In some embodiments, X 5is N and X 6 In some embodiments, X 5 is CH and X 6 It's N.

[0528] In some embodiments, R 12 is H. In some embodiments, R 12 is a halogen, such as F or Cl. In some embodiments, R 12 It is C 1-3 In some embodiments, R 12 It is CN.

[0529] In some embodiments, R 13 is H. In some embodiments, R 13 is a halogen, such as F.

[0530] In some embodiments, R 14 is a halogen, such as F or Cl. In some embodiments, R 14 It is C 1-3 In some embodiments, R 14 It is C 1-3 In some embodiments, R 14 In some embodiments, R 14 is -CHF2. In some embodiments, R 14 It is CN.

[0531] In some embodiments, R 15 is H. In some embodiments, R 15 is a halogen, such as F.

[0532] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes

[0533] In some embodiments, R 3 is a 5-membered heteroaryl group optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl and C 1-3 In some embodiments, R 3 is a 5-membered heteroaryl group, which is optionally substituted by 1 to 3 independently selected halogen, C 1-3 Alkyl and C 1-3 In some embodiments, R 3 is pyrazolyl, which is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and C 1-3 In some embodiments, R 3 yes

[0534] In some embodiments, R 3 It is C 3-6 Cycloalkyl, which is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl and C 1-3 The substituents of the haloalkyl group are substituted.

[0535] In some embodiments, R 3 Having formula V:

[0536]

[0537] in

[0538] R 16 It is H, halogen, C 1-3 Alkyl and C1-3 alkyl halide;

[0539] R 17 It is H, halogen, C 1-3 Alkyl and C 1-3 alkyl halide;

[0540] m is 1, 2, or 3; and

[0541] p is 1, 2, or 3.

[0542] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, R 16 is H. In some embodiments, R 16 is a halogen, such as F. In some embodiments, R 16 It is C 1-3 In some embodiments, R 16 It is C 1-3 In some embodiments, R 17 is H. In some embodiments, R 17 is a halogen, such as F. In some embodiments, R 17 It is C 1-3 In some embodiments, R 17 It is C 1-3 In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes

[0543] In some embodiments, R 3 It is C 1-3 Haloalkyl, for example -(CH2)2CF3.

[0544] In some embodiments, R 3 It is C 5-8 Spirocycloalkyl, which is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl and C 1-3 In some embodiments, R 3 yes

[0545]

[0546] In some embodiments, R 3 It is C 5-8 tricycloalkyl, which is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl and C 1-3 In some embodiments, R 3 It is C 5-8 Bicycloalkyl, which is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl and C 1-3 In some embodiments, R 3 is bicyclo[1.1.1]pentyl, which is optionally substituted with CF3 or C1 alkyl, or a pharmaceutically acceptable salt thereof. 3 yes

[0547]

[0548] In some embodiments, R 3 Having formula VI:

[0549]

[0550] in

[0551] R 18 It is H, halogen, C 1-3 Alkyl and C 1-3 alkyl halide;

[0552] R 19 It is H, halogen, C 1-3 Alkyl and C 1-3 alkyl halide;

[0553] q is 1, 2, or 3; and

[0554] r is 1, 2, or 3.

[0555] In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, r is 1. In some embodiments, r is 2.

[0556] In some embodiments, R 18 is H. In some embodiments, R 18 is a halogen, such as F. In some embodiments, R 18 It is C 1-3 In some embodiments, R 18 It is C 1-3 Haloalkyl, such as -CF3 or -CHF2.

[0557] In some embodiments, R 19 is H. In some embodiments, R 19 is a halogen, such as F. In some embodiments, R 19 It is C 1-3 In some embodiments, R 19 It is C 1-3 Haloalkyl, such as -CF3 or -CHF2.

[0558] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes

[0559] In some embodiments, R 3 It is -OCH2-(C 3-6 cycloalkyl), which is optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 The substituents of the haloalkoxy group are substituted.

[0560] In some embodiments, R 3 yes

[0561]

[0562] In some embodiments, R3 It is C 3-6 Cycloalkyl, wherein one or more methylene groups are replaced by -O-. In some embodiments, R 3 yes

[0563] In some embodiments, R 3 It is C 3-6 Cycloalkyl, in which one or more methylene groups are replaced by -N(R 28 )-replacement, where R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 In some embodiments, R 3 Having formula XV:

[0564]

[0565] where R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0566] In some embodiments, R 3 Selected from:

[0567]

[0568] In some embodiments, R 23 Having the formula XLVI:

[0569]

[0570] in

[0571] X 3 Is N or C (R 8 );

[0572] X 4 It is C(R 38 )(R 39 ), O, NH, NR 9 or key;

[0573] X 10 C(R 37 )(R 7 ) or C(O);

[0574] X 11 It is C(R 4 ) or N;

[0575] X 12 It is C(R 6 )(R 6b);

[0576] X 13 It is C(R 40 )(R 41 );

[0577] R 4 Is H or C 1-3 alkyl;

[0578] R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein

[0579] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution;

[0580] (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 Substituents of heterocycloalkyl, wherein (b) a small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein (b) a small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent;

[0581] (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent;

[0582] R 6 is H, halogen or C 1-3 alkyl;

[0583] R 6b is H, halogen or C 1-3 alkyl;

[0584] When R 6 and R 6b It is C 1-3 When it is an alkyl group, R 6 and R 6b are optionally linked together to form a 3-6 membered ring; and / or

[0585] When R 6 and R 6b It is C 1-3 When alkyl, a methylene group is optionally replaced by -O- or

[0586] -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0587] R 7 H, C alone 1-3 alkyl or bond;

[0588] When R 7 When it is a key, then R 6 It is C 1-3 Alkyl, and R 7 and R 6 Connected together to form a 3-5 membered ring;

[0589] R 37 H or C alone 1-3 alkyl;

[0590] R 8 is selected from H, -OH, -O-alkyl and halogen;

[0591] R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups;

[0592] R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution;

[0593] R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain;

[0594] R 30 Is H or C 1-3 alkyl;

[0595] R 31 Is H or C 1-3 alkyl;

[0596] R 38 is H or F;

[0597] R 39 is H or F;

[0598] R 40 H, C alone 1-3 alkyl or bond;

[0599] When R 40 When it is a key, then R 8 It is C 1-3 Alkyl, and R 8 and R 40 Connected together to form a 3-5 membered ring;

[0600] R 41 H or C alone 1-3 alkyl;

[0601] n is 0, 1, or 2; and

[0602] v is 0, 1, or 2.

[0603] In some embodiments, R 23 Is a 6-membered ring, that is, X 3 、(X 13 ) v 、X 11 、X 4 、X 12 and (X 10 ) n Together they form a 6-membered ring. For example, in some embodiments, R 23Of Formula XLVI, wherein n is 1, v is 1 and is not a bond. In some embodiments, R 23 Having the formula XLVI, wherein X 3 It is N; X 4 It is O; X 10 It is C(R 37 )(R 7 );X 11 It is C(R 4 );X 12 It is C(R 6 )(R 6b );X 13 It is C(R 40 )(R 41 ); n is 1; and v is 1. In some embodiments, R 23 Having the formula XLVI, wherein X 3 It is N; X 4 Is NH or NR 9 ;X 10 It is C(R 37 )(R 7 );X 11 It is C(R 4 );X 12 It is C(R 6 )(R 6b );X 13 It is C(R 40 )(R 41 ); n is 1; and v is 1. In some embodiments, R 23 Having the formula XLVI, wherein X 3 It is N; X 4 It is C(R 38 )(R 39 );X 10 It is C(R 37 )(R 7 );X 11 It is C(R 4 );X 12 It is C(R 6 )(R 6b );X 13 It is C(R 40 )(R 41 ); n is 1; and v is 1. In some embodiments, R 23 Having the formula XLVI, wherein X 3 It is N; X 4 Yes key; X 10 It is C(R 37 )(R 7 );X 11 It is C(R 4 );X 12It is C(R 6 )(R 6b );X 13 It is C(R 40 )(R 41 ); n is 1; and v is 2. In some embodiments, R 23 Having the formula XLVI, wherein X 3 It is C(R 8 );X 4 It is O; X 10 It is C(R 37 )(R 7 );X 11 It is C(R 4 );X 12 It is C(R 6 )(R 6b );X 13 It is C(R 40 )(R 41 ); n is 1; and v is 1.

[0604] In some embodiments, R 23 Is a 5-membered ring, that is, X 3 、(X 13 ) v 、X 11 、X 4 、X 12 and (X 10 ) n Together they form a 5-membered ring. For example, in some embodiments, R 23 having the formula XLVI, wherein n is 1, v is 1 and X 4 is a bond; or n is 0, v is 1 and X 4 In some embodiments, R 23 Having the formula XLVI, wherein X 3 It is N; X 13 It is C(R 40 )(R 41 );X 11 It is C(R 4 );X 4 It is C(R 38 )(R 39 );X 12 It is C(R 6 )(R 6b ); and n is 0.

[0605] In some embodiments, R 23 Is a 4-membered ring, that is, X 3 、(X 13 ) v 、X 11 、X 4、X 12 and (X 10 ) n Together they form a 4-membered ring. For example, in some embodiments, R 23 having the formula XLVI, wherein n is 0, v is 1 and X 4 is a bond; or n is 1, v is 0 and X 4 In some embodiments, R 23 Having the formula XLVI, wherein X 3 It is N; X 4 is a key; n is 0; X 11 It is C(R 4 );X 12 It is C(R 6 )(R 6b );X 13 It is C(R 40 )(R 41 ); and v is 1.

[0606] In some embodiments, X 3 Is N. In some embodiments, X 3 It is C(R 8 ), where R 8 is selected from H, -OH, -O-alkyl and halogen. In some embodiments, R 8 is H. In some embodiments, X 3 It is C(H).

[0607] In some embodiments, X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key, where R 9 As defined herein. In some embodiments, X 4 is CH2, O, CHF, NH or NR 9 , where R 9 As defined herein. In some embodiments, X 4 Is O. In some embodiments, X 4 In some embodiments, X 4 is CH2. In some embodiments, X 4 is CHF. In some embodiments, X 4 It is NR 9 , where R 9 As defined herein. In some embodiments, R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0608] In some embodiments, X 4 It is C(R 38 )(R 39 ), where R 38 is H or F, and R 39 is H or F. In some embodiments, R 38 is H. In some embodiments, R 38 is F. In some embodiments, R 39 is F. In some embodiments, R 39 is F. In some embodiments, R 38 is H and R 39 is H. In some embodiments, R 38 is F and R 39 is F. In some embodiments, R 38 is H and R 39 It's F.

[0609] In some embodiments, R 4 It is C 1-3 In some embodiments, R 4 It’s H.

[0610] In some embodiments, R 23 Has the formula XVI, wherein X 3 It is N; X 10 is CH2; n is 1; v is 1; R 6 It is H; X 4 is O; and X 11 is C(H). In some embodiments, R 23 Having the formula XX, where X 3 It is N; X 10 is CH2; n is 1; v is 1; X 4 is O; and X 11 is C(H). In some embodiments, R 23 Having the formula XX, where X 3 It is N; X 10 is CH2; n is 1; v is 1; X 4 It is O; X 11 is C(H); X 12 It is C(R 6 )(R 6b ). In some embodiments, R 23 Having the formula XXXIV:

[0611]

[0612] where R 5 、R 6 、R6b and R 29 As defined herein. In some embodiments, R 23 Having the formula XXXIV, R 6 is H and R 6b is H. In some embodiments, R 23 Having the formula XXXIV, R 6 is H and R 6b It is C 1-3 In some embodiments, R 23 Having the formula XXXIV, R 6 It is C 1-3 Alkyl and R 6b is H. In some embodiments, R 23 Having the formula XXXIV, R 6 It is C 1-3 Alkyl and R 6b It is C 1-3 In some embodiments, R 23 Having the formula XXXIV, R 6 is H and R 6b In some embodiments, R 23 Having the formula XXXIV, R 6 is a halogen and R 6b In some embodiments, R 23 Having the formula XXXIV, R 6 is H and R 6b is H. In some embodiments, R 23 Having the formula XXXIV, R 6 is F and R 6b is F. In some embodiments, R 23 Having the formula XXXIV, R 6 is CH3 and R 6b is CH3. In some embodiments, R 23 Having the formula XXXIV, R 6 is CH3 and R 6b It’s H.

[0613] In some embodiments, R 23 Having the formula XXXIV, R 6 It is C 1-3 Alkyl and R 6b It is C 1-3 Alkyl, and R 6 and R 6b are linked together to form a 3 to 6 membered ring. 23 Having the formula XXXIV, R 6 It is C 1-3 Alkyl and R6b It is C 1-3 Alkyl, and R 6 and R 6b connected together to form a 4-membered ring, such as R 6 is a C1 alkyl group and R 6b is a C2 alkyl group, or R 6 is a C2 alkyl group and R 6b In some embodiments, R 23 Having the formula XXXIV, R 6 It is C 1-3 Alkyl and R 6b It is C 1-3 Alkyl, and R 6 and R 6b connected together to form a 3-membered ring, such as R 6 is a C1 alkyl group and R 6b is C1 alkyl. In some embodiments, R 6 and R 6b It is C 1-3 Alkyl, R 6 and R 6b are linked together to form a 3-6 membered ring, and one methylene group is optionally replaced by -O-. In some embodiments, R 6 and R 6b It is C 1-3 Alkyl, R 6 and R 6b are linked together to form a 3-6 membered ring, and one methylene group is optionally replaced by -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 In some embodiments, R 35 is H. In some embodiments, R 35 It is C 1-3 In some embodiments, R 35 Yes-C(O)C 1-3 In some embodiments, R 23 With formula XLV:

[0614]

[0615] wherein k is 1, 2, 3, or 4. In some embodiments, R 23 having the formula XLV, wherein k is 1. In some embodiments, R 23 Has the formula XLV, where k is 2.

[0616] In some embodiments, R 23 Having the formula XLVI, wherein X3 It is C(R 8 );R 8 is a C1 alkyl group; X 13 It is C(R 40 )(R 41 );R 40 is a key; R 8 and R 40 Connected together to form a 3-membered ring; R 41 is H; and v is 1. In some embodiments, R 23 With formula LV:

[0617]

[0618] where R 5 、R 29 、X 4 、X 10 、X 12 and n are as defined herein.

[0619] In some embodiments, R 23 Having the formula LVI, wherein R 5 、R 29 、X 4 、X 10 、X 12 and n are as defined herein. In some embodiments, R 23 Having the formula LVI, wherein R 5 、R 29 、X 4 、X 10 、X 12 and n are as defined herein. In some embodiments, R 23 having the formula LVIII, wherein R 5 、R 29 、X 4 、X 10 、X 12 and n are as defined herein. In some embodiments, R 23 Having the formula LIX, where R 5 、R 29 、X 4 、X 10 、X 12 and n are as defined herein.

[0620]

[0621] In some embodiments, R 23 Having the formula XLVI, wherein X 3 It is C(R 8 );R 8 Yes key; X13 It is C(R 40 )(R 41 );R 40 is a C1 alkyl group; R 8 and R 40 Connected together to form a 3-membered ring; R 41 is H; v is 1; X 11 is C(H), X 4 It is O; X 12 is CH2; X 10 is CH2; and n is 1. In some embodiments, R 23 With the formula LX:

[0622]

[0623] where R 5 and R 29 As defined herein.

[0624] In some embodiments, R 23 Having the formula XLVI, wherein X 12 It is C(R 6 )(R 6b );R 6b It is H; R 6 It is C 1-3 Alkyl; n is 1; X 10 It is C(R 37 )(R 7 );R 37 is H; and R 7 is with R 6 In some embodiments, R 23 Having the formula XLVI, wherein X 3 It is N; X 13 is CH2; v is 1; X 11 is C(H); X 4 It is O; X 12 It is C(R 6 )(R 6b );R 6b It is H; R 6 is a C1 alkyl group; n is 1; X 10 It is C(R 37 )(R 7 );R 37 is H; and R 7 is with R 6 In some embodiments, R 23 Having the formula LXIII:

[0625]

[0626] where R 5 and R 29 As defined herein.

[0627] In some embodiments, R 23 Has the formula XVI, wherein X 3 It is N; X 10 is CH2; n is 1; v is 1; R 6 It is H; X 4 It is C(R 33 )(R 34 );R 33 Is H or F; R 34 is H or F; and X 11 is C(H). In some embodiments, R 23 Having the formula XXXV:

[0628]

[0629] where R 5 and R 29 As defined herein, R 33 is H or F, and R 34 is H or F. In some embodiments, R 23 Having the formula XXXV, R 33 is H and R 34 is H. In some embodiments, R 23 Having the formula XXXV, R 33 is F and R 34 It's F.

[0630] In some embodiments, R 23 Has the formula XVI, wherein X 3 is N; n is 0; v is 1; R 6 It is H; X 4 is CH2; and X 11 is C(H). In some embodiments, R 23 Having the formula XXXVI:

[0631]

[0632] where R 5 and R 29 As defined herein.

[0633] In some embodiments, R 23 Has the formula XVI, wherein X 3 It is N; X 10 is CH2; n is 1; v is 1; R 6 It is H; X 4It is N(R 9 ); and X 11 is C(H). In some embodiments, R 23 Having the formula XXXVII:

[0634]

[0635] where R 5 、R 9 and R 29 As defined herein.

[0636] In some embodiments, R 23 Has the formula XVI, wherein X 3 is C(H); X 10 is CH2; n is 1; v is 1; R 6 It is H; X 4 is O; and X 11 is C(H). In some embodiments, R 23 Having the formula XXXVIII:

[0637]

[0638] where R 5 and R 29 As defined herein.

[0639] In some embodiments, R 23 Has the formula XVI, wherein X 3 is C(H); X 10 is CH2; n is 1; v is 1; R 6 It is H; X 4 It is C(R 33 )(R 34 );R 33 Is H or F; R 34 is H or F; and X 11 is N. In some embodiments, R 23 Having the formula XXXIX:

[0640]

[0641] where R 5 and R 29 As defined herein, R 33 is H or F, and R 34 is H or F. In some embodiments, R 23 Having the formula XXXIX, R 33 is H and R 34 is H. In some embodiments, R 23 Having the formula XXXIX, R 33is F and R 34 It's F.

[0642] In some embodiments, R 23 Has the formula XVI, wherein X 3 is N; n is 0; v is 1; R 6 It is H; X 4 is a key; and X 11 is C(H). In some embodiments, R 23 With Formula XL:

[0643]

[0644] where R 5 and R 29 As defined herein.

[0645] In some embodiments, R 23 Has the formula XVI, wherein X 3 It is N; X 10 is CH2; n is 1; v is 2; R 6 It is H; X 4 is a key; and X 11 is C(H). In some embodiments, R 23 With formula XLI:

[0646]

[0647] where R 5 and R 29 As defined herein.

[0648] In some embodiments, R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein

[0649] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution;

[0650] (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted,

[0651] (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and

[0652] (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent;

[0653] (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O) and -N(R 30 )(R 31 ) is substituted by a substituent,

[0654] where R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution;

[0655] R 30 Is H or C 1-3 alkyl; and

[0656] R 31 Is H or C 1-3 alkyl.

[0657] In some embodiments, R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein

[0658] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted with oxo (=O), and

[0659] (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted,

[0660] (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and

[0661] (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent; and

[0662] (c) C 1-6 The alkyl group is optionally replaced by -N(H)C(O)R 24 Substituted, where R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substituted.

[0663] In some embodiments, R 5 It is C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl, wherein the C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents are substituted.

[0664] In some embodiments, R 5 It is C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl, and the C 3-6 Cycloalkyl or C 3-6Heterocycloalkyl is optionally substituted with oxo (=O), or a pharmaceutically acceptable salt thereof. 5 It is C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally replaced by -N(H)C(O)R 24 Substituted, where R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 In some embodiments, R 5 It is C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally substituted with oxo (=O). In some embodiments, R 5 It is C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally replaced by -N(R 30 )(R 31 ) substituted, wherein R 30 Is H or C 1-3 Alkyl, and R 31 Is H or C 1-3 In some embodiments, R 30 is H. In some embodiments, R 30 It is C 1-3 In some embodiments, R 31 is H. In some embodiments, R 31 It is C 1-3 In some embodiments, R 30 It is C 1-3 Alkyl, such as C1 alkyl, and R 31 is H. In some embodiments, R 30 It is C 1-3 Alkyl, such as C1 alkyl, and R 31 It is C 1-3 Alkyl, for example C1 alkyl.

[0665] In some embodiments, R 5 It is C 3-6 Heterocycloalkyl, optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 In some embodiments, R 5 is C4 heterocycloalkyl, which is optionally substituted by 1 to 3 independently selected 1-3 In some embodiments, R 5 is an azetidine, which is optionally replaced by 1 to 3 independently selected1-3 In some embodiments, R 5 yes In some embodiments, R 5 yes

[0666] In some embodiments, R 5 is selected from phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl and -O-(6-membered heteroaryl), wherein the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected from halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted,

[0667] wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and

[0668] wherein the C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent.

[0669] In some embodiments, R 5 is a 5-membered heteroaryl group, which is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted,

[0670] wherein the C 1-6 Alkyl or C 1-6 Haloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl, C 1-6Alkoxy, halogen and -OH substituents,

[0671] And wherein said C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent.

[0672] In some embodiments, R 5 is a 5-membered heteroaryl group, which is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted,

[0673] wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein the C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent.

[0674] In some embodiments, R 5 Having the formula XXI:

[0675]

[0676] in

[0677] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0678] In some embodiments, R 5 Having the formula XXII:

[0679]

[0680] in

[0681] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl, C 1-6 Substituents include alkoxy, halogen and -OH.

[0682] In some embodiments, R 5 Having the formula XXII:

[0683]

[0684] in

[0685] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0686] In some embodiments, R 5 Having the formula XXIII:

[0687]

[0688] in

[0689] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0690] In some embodiments, R 5 Having the formula XXIV:

[0691]

[0692] in

[0693] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0694] In some embodiments, R 5 Having the formula XLIII:

[0695]

[0696] in

[0697] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0698] In some embodiments, R 5 yes In some embodiments, R 5 yes

[0699] In some embodiments, R 5 Having formula VII:

[0700]

[0701] in

[0702] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl C 1-6 Substituents include alkoxy, halogen and -OH.

[0703] In some embodiments, R 5 Having formula VII:

[0704]

[0705] in

[0706] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0707] In some embodiments, R 5 Having formula VII:

[0708]

[0709] in

[0710] R 20 It is C 1-3 Alkyl, such as -CH3, or C 3-6 Cycloalkyl, for example C3 cycloalkyl.

[0711] In some embodiments, R 5 Having formula XXV:

[0712]

[0713] in

[0714] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0715] In some embodiments, R 5 Having the formula XXVI:

[0716]

[0717] in

[0718] R20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0719] In some embodiments, R 5 Having the formula XXVII:

[0720]

[0721] in

[0722] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0723] In some embodiments, R 5 Having the formula XXVIII:

[0724]

[0725] in

[0726] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0727] In some embodiments, R 5 Having the formula XXIX:

[0728]

[0729] in

[0730] R20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0731] In some embodiments, R 5 With the formula XXX:

[0732]

[0733] in

[0734] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent; and

[0735] R 32 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0736] In one embodiment, R 5 Having the formula XLII:

[0737]

[0738] in

[0739] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0740] In some embodiments, R 5 Having the formula XXXI:

[0741]

[0742] in

[0743] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0744] In some embodiments, R 5 Having the formula XXXII:

[0745]

[0746] in

[0747] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0748] In some embodiments, R 5 Having the formula XXXIII:

[0749]

[0750] in

[0751] R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0752] In some embodiments, R 20 It is C 1-3 In some embodiments, R 20 Is C 1-6 Alkoxy-substituted C 1-3 In some embodiments, R 20 It is C 1-2 In some embodiments, R 20 In some embodiments, R 20 It is C 3-6 In some embodiments, R 20 is H. In some embodiments, R 20 It is C 1-3 Alkyl, which is optionally substituted with 1 to 3 halogens such as F. In some embodiments, R 20 is methyl, which is optionally substituted with 1 to 3 halogens, such as F. In some embodiments, R 20 Yes -CF3.

[0753] In some embodiments, R 5 yes In some embodiments, R 5 yes

[0754] In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes

[0755] In some embodiments, R 5 yes In some embodiments, R 5 yes

[0756] In some embodiments, R 5 yes In some embodiments, R 5 yes

[0757] In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes

[0758] In some embodiments, R 5 yes In some embodiments, R 5 yes

[0759] In some embodiments, R 5 yes

[0760] In some embodiments, R 5 is a 6-membered heteroaryl group, which is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted,

[0761] wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein the C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent.

[0762] In some embodiments, X 12 It is CH2, R 29 is a bond and R 5 is optionally C 1-6 Alkyl or C 3-6 In some embodiments, X 12 It is CH2, R 29 is a bond and R5 Is C 3-6 Cycloalkyl groups such as cyclopropyl-substituted pyrazolyl groups.

[0763] In some embodiments, R 5 Having the formula XLIV:

[0764]

[0765] in

[0766] X 7 is N or CH;

[0767] X 8 Is N or C (R 21 );

[0768] X 9 Is N or C (R 22 );

[0769] R 21 It is C 1-3 Alkyl groups, such as -CH3;

[0770] R 22 It is C 1-3 an alkyl group, such as -CH3, and

[0771] R 36 Is H or C 1-3 Alkyl, such as -CH3.

[0772] In some embodiments, R 5 Having the formula VIII:

[0773]

[0774] in

[0775] X 7 is N or CH;

[0776] X 8 Is N or C (R 21 );

[0777] X 9 Is N or C (R 22 );

[0778] R 21 It is C 1-3 an alkyl group, such as -CH3; and

[0779] R 22 It is C 1-3 Alkyl, such as -CH3.

[0780] In some embodiments, R5 Selected from

[0781]

[0782] In some embodiments, R 5 It is C 1-6 Alkyl, optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O) and -N(R 30 )(R 31 ) is substituted by a substituent,

[0783] where R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution;

[0784] R 30 Is H or C 1-3 alkyl; and

[0785] R 31 Is H or C 1-3 alkyl.

[0786] In some embodiments, R 5 Having the formula XIII:

[0787]

[0788] in

[0789] R 27 It is C 1-6 alkyl; and

[0790] u is 1, 2, or 3.

[0791] In some embodiments, R 4 and R 5 are linked together to form a ring, thereby producing a spirocyclic compound. In some embodiments, R 4 It is C 1-3 Alkyl and R 5 It is C 1-3 In some embodiments, R 4 It is C 1-3 Alkyl and R 5 It is C 1-3 Alkyl, and R 4 and R 5 are linked together to form a 3 to 6 membered ring. 4 is a C2 alkyl group and R 5 is a C2 alkyl group, and R 4 and R5 Connected together to form a 4-membered ring.

[0792] In some embodiments, R 6 It is C 1-3 In some embodiments, R 6 is H. In some embodiments, R 6 In some embodiments, R 6b It is C 1-3 In some embodiments, R 6b is H. In some embodiments, R 6b In some embodiments, R 6 and R 6b is H. In some embodiments, R 6 is a halogen and R 6b In some embodiments, R 6 is H and R 6b In some embodiments, R 6 and R 6b It is C 1-3 In some embodiments, R 6 and R 6b are linked together to form a ring, thereby producing a spirocyclic compound. In some embodiments, R 6 and R 6b It is C 1-3 Alkyl, and R 6 and R 6b are linked together to form a 3-6 membered ring, such as a 4 membered ring or a 3 membered ring. 6 and R 6b is a C1 alkyl group, and R 6 and R 6b are linked together to form a 3-membered ring. In some embodiments, R 6 is a C1 alkyl group and R 6b is a C2 alkyl group, or R 6 is a C2 alkyl group and R 6b is a C1 alkyl group, and R 6 and R 6b are linked together to form a 4-membered ring. In some embodiments, R 6 and R 6b It is C 1-3 Alkyl, R 6 and R 6b are linked together to form a 3-6 membered ring, and one methylene group is optionally replaced by -O-. In some embodiments, R 6 and R 6b It is C 1-3 Alkyl, R 6and R 6b are linked together to form a 3-6 membered ring, and one methylene group is optionally replaced by -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 In some embodiments, R 35 is H. In some embodiments, R 35 It is C 1-3 In some embodiments, R 35 Yes-C(O)C 1-3 alkyl.

[0793] In some embodiments, X 10 is C(H)(R 7 ) or C(O). In some embodiments, X 10 is C(H)(R 7 ), where R 7 Is H or C 1-3 In some embodiments, X 10 C(R 37 )(R 7 ), where R 7 H or C alone 1-3 Alkyl, and R 37 H or C alone 1-3 In some embodiments, R 7 is H. In some embodiments, R 37 is H. In some embodiments, R 7 is H and R 37 is H. In some embodiments, X 10 is C(H)2. When R 7 When it is a key, it is in X 10 C and another atom (such as R 6 In some embodiments, R 7 is a bond and R 6 It is C 1-3 Alkyl, and R 7 and R 6 Connected together to form a 3-5 membered ring.

[0794] In some embodiments, X 13 It is C(R 40 )(R 41 ), where R 40 H, C alone 1-3 alkyl or bond, and R 41 H or C alone 1-3 In some embodiments, R40 is H. In some embodiments, R 41 is H. In some embodiments, R 40 is H and R 41 is H. In some embodiments, X 13 is CH2. When R 40 When it is a key, it is in X 13 C and another atom (such as R 8 In some embodiments, when R 40 When it is a key, then R 8 It is C 1-3 Alkyl, and R 8 and R 40 Connected together to form a 3-5 membered ring.

[0795] In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes

[0796] In some embodiments, R 23 Selected from:

[0797]

[0798] In some embodiments, R 23 Selected from:

[0799]

[0800] or a pharmaceutically acceptable salt thereof.

[0801] In some embodiments, R 23 Has the formula XVI, wherein X 3 It is N, X 4 It's O, R 4 It's H, R 6 It is H, X 10 is C(H)(R 7 ), R 7 is H and n is 1. In some embodiments, R 23 Has the formula XVI, wherein X 3 It is CH, X 4 It's O, R 4 It's H, R 6 It is H, X 10 is C(H)(R 7 ), R 7 is H and n is 1. In some embodiments, R 23 Has the formula XVI, wherein X 3 It is N, X 4 It is a key, R 4 It's H, R 6 is H and n is 0.

[0802] In some embodiments, R 23 Having the formula XI:

[0803]

[0804] in

[0805] R 25 Select C alone 1-6 Alkyl, -OC 1-6 Alkyl, halogen, C 1-6 haloalkyl and -CN; and

[0806] t is 0, 1, 2, or 3.

[0807] In some embodiments, R 23 Having the formula XIX:

[0808]

[0809] in

[0810] R 26 is a 5-membered or 6-membered heteroaryl group, which is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted,

[0811] wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and

[0812] wherein the C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent; and

[0813] R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain;

[0814] or a pharmaceutically acceptable salt thereof.

[0815] In some embodiments, R 23 Having the formula XII:

[0816]

[0817] in

[0818] R 26 is a 5-membered or 6-membered heteroaryl group, which is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted,

[0819] wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and

[0820] wherein the C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) or a pharmaceutically acceptable salt thereof.

[0821] In some embodiments, R 26 It is R 5 In some embodiments, R 26 is a 5-membered heteroaryl group, which is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted,

[0822] wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein the C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent.

[0823] In some embodiments, R 26 Having formula VII:

[0824]

[0825] in

[0826] R 20 It is C 1-3 Alkyl, such as -CH3, or C 3-6 Cycloalkyl, for example C3 cycloalkyl.

[0827] In some embodiments, R 23 yes In some embodiments, R 23 Having the formula XIV:

[0828]

[0829] in

[0830] R 27 It is C 1-6 alkyl; and

[0831] u is 1, 2, or 3.

[0832] In some embodiments, R 23 Having the formula XVII:

[0833]

[0834] in

[0835] X 3 Is N or C (R 8 );

[0836] X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key;

[0837] X 10 is C(H)(R 7 ) or C(O);

[0838] X 11 It is C(R 4 ) or N;

[0839] R 4 Is H or C 1-3 alkyl;

[0840] R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein

[0841] (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution;

[0842] (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted,

[0843] (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and

[0844] (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent;

[0845] (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O) and -N(R 30 )(R 31 ) is substituted with a substituent;

[0846] R 6 Is H or C 1-3 alkyl;

[0847] R 7 Is H or C 1-3 alkyl;

[0848] R 8 is selected from H, -OH, -O-alkyl and halogen;

[0849] R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C1-3 Substitution of alkoxy groups;

[0850] R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution;

[0851] R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain;

[0852] R 30 Is H or C 1-3 alkyl;

[0853] R 31 Is H or C 1-3 alkyl;

[0854] n is 0, 1, or 2; and

[0855] v is 1 or 2,

[0856] or a pharmaceutically acceptable salt thereof.

[0857] In some embodiments, v is 0. In some embodiments, v is 2. In some embodiments, v is 1. In some embodiments, X 11 It is C(R 4 ). In some embodiments, R 23 Having the formula XVIII:

[0858]

[0859] where X 3 、X 4 、X 10 、R 4 、R 5 、R 6 、R 29 and n are as defined herein, or a pharmaceutically acceptable salt thereof.

[0860] In some embodiments, R 23 Is a 3-membered ring, that is, X 3 、(X 13 ) v 、X 11 、X 4 、X 12 and (X 10 ) n Together they form a 3-membered ring. For example, in some embodiments, R 23 having the formula XLVI, wherein n is 0, v is 0 and X4 In some embodiments, R 23 Having the formula XLVI, wherein X 3 It is C(R 8 );X 4 is a key; n is 0; X 11 It is C(R 4 );X 12 It is C(R 6 )(R 6b ); and v is 0.

[0861] In some embodiments, X 3 is C(H), X 12 is C(H)2, X 4 Yes key, X 11 is C(H), n is 0 and v is 0. In some embodiments, R 23 Having the formula LXII:

[0862]

[0863] In some embodiments, R 23 Having formula LXIIa or formula LXIIb:

[0864]

[0865] In some embodiments, R 23 yes

[0866] In some embodiments, R 29 is the key, i.e. R 29 Does not exist.

[0867] In some embodiments, R 23 With formula X:

[0868]

[0869] where X 3 、X 4 、X 10 、R 4 、R 5 、R 6 and n are as defined herein, or a pharmaceutically acceptable salt thereof.

[0870] In some embodiments, R 29 It is C 1-3 In some embodiments, R 29 Yes-OC 1-3 In some embodiments, R 29It is -OCH2-, -CH2O-, -CH2- or O.

[0871] In some embodiments, X 11 Is N. In some embodiments, X 11 It is C(R 4 ). In some embodiments, X 11 is C(H). In some embodiments, X 11 It is C(CH3).

[0872] In some embodiments, n is 0. In some embodiments, n is 1.

[0873] In some embodiments, v is 1. In some embodiments, v is 2.

[0874] In some embodiments, the compound has the formula LXI, wherein

[0875] X 1 It is N;

[0876] X 2 It is N;

[0877] X 14 It is N;

[0878] R 1 Yes -CF3,

[0879] R 2 It is C 1-6 Alkyl, such as CH3,

[0880] R 3 Having formula IV:

[0881]

[0882] in

[0883] R 12 It is H, halogen, C 1-3 Alkyl or C 1-3 alkyl halide;

[0884] R 13 It is H, halogen, C 1-3 Alkyl or C 1-3 alkyl halide;

[0885] R 14 It is H, halogen, C 1-3 Alkyl or C 1-3 haloalkyl; and

[0886] R 15 It is H, halogen, C 1-3 Alkyl or C1-3 Halogenated alkyl.

[0887] In some embodiments, R 12 is a halogen, R 13 It's H, R 14 is a halogen and R 15 is H. For example, R 12 is F and R 14 Is Cl. In some embodiments, R 23 Having the formula XXXIV:

[0888]

[0889] in

[0890] R 6 is H, halogen or C 1-3 alkyl;

[0891] R 6b is H, halogen or C 1-3 alkyl; and

[0892] R 29 It is a key.

[0893] In some embodiments, R 6 is H and R 6b is H. In some embodiments, R 5 Having the formula XXII:

[0894]

[0895] in

[0896] R 20 It is C 1-3 Alkyl or C 3-6 In some embodiments, R 5 Having formula VII:

[0897]

[0898] in

[0899] R 20 It is C 1-3 Alkyl or C 3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0900] In some embodiments, R 23 yes For example

[0901] In some embodiments, the compound has the formula LXI, wherein

[0902] X 1 It is N;

[0903] X 2 It is N;

[0904] X 14 It is N;

[0905] R 1 It is -CH3,

[0906] R 2 It is C 1-6 Alkyl, such as CH3,

[0907] R 3 Having formula IV:

[0908]

[0909] in

[0910] R 12 It is H, halogen, C 1-3 Alkyl or C 1-3 alkyl halide;

[0911] R 13 It is H, halogen, C 1-3 Alkyl or C 1-3 alkyl halide;

[0912] R 14 It is H, halogen, C 1-3 Alkyl, -CN or C 1-3 haloalkyl; and

[0913] R 15 It is H, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0914] In some embodiments, R 12 is a halogen, R 13 It's H, R 14 is a haloalkyl group and R 15 is H. In some embodiments, R 12 is F and R 14 is CF3. In some embodiments, R 23 Having the formula XXXIV:

[0915]

[0916] in

[0917] R 6 is H, halogen or C 1-3 alkyl;

[0918] R 6b is H, halogen or C 1-3 alkyl; and

[0919] R 29 Yes key,

[0920] or a pharmaceutically acceptable salt thereof.

[0921] In some embodiments, R 6 is H and R 6b is H. In some embodiments, R 5 is Formula VIII:

[0922]

[0923] in

[0924] X 7 is N or CH;

[0925] X 8 Is N or C (R 21 );

[0926] X 9 Is N or C (R 22 );

[0927] R 21 It is C 1-3 an alkyl group, such as -CH3; and

[0928] R 22 It is C 1-3 Alkyl groups, such as -CH 3。

[0929] In some embodiments, R 5 yes In some embodiments, R 23 yes For example

[0930] In one aspect, the present invention relates to compounds of formula LXI:

[0931]

[0932] in

[0933] X 1 Is N or C (R 42 );

[0934] R 42 is H or halogen;

[0935] X 2 is N or CH;

[0936] X 14 is N or CH;

[0937] R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 independently selected substituents R 10 replace;

[0938] R a Is H or C 1-6 alkyl;

[0939] R b Is H or C 1-6 alkyl;

[0940] R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace;

[0941] R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl),

[0942] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl or 5-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and CN substituents;

[0943] wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28)-replace;

[0944] R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl;

[0945] and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexane

[0946] -3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents;

[0947] R 10 Individually selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and halogen;

[0948] R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 The alkyl group is substituted with a substituent; and

[0949] R 23 Selected from:

[0950]

[0951] or a pharmaceutically acceptable salt thereof.

[0952] In some embodiments, the compound is selected from:

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974] or a pharmaceutically acceptable salt thereof.

[0975] In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methylpyridin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methylpyridin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methylpyrimidin-5-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methylpyrimidin-5-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(6-methylpyridazin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(6-methylpyridazin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(3R)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(3S)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4S)-2-(1-methyl-1H-pyrazol-4-yl)oxane-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(2R,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(2S,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4S)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(2-methylpyrimidin-5-yl)oxane-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4S)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-{6,6-difluorospiro[3.3]hept-2-yl}-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-{6,6-difluorospiro[3.3]hept-2-yl}-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,3r)-3-(trifluoromethyl)cyclobutyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,3r)-3-(trifluoromethyl)cyclobutyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[6-(trifluoromethyl)pyridin-3-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[6-(trifluoromethyl)pyridin-3-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,3,4-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,3,4-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(3,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(3,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(3,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(3,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,4r)-4-methylcyclohexyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,4r)-4-methylcyclohexyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(oxan-4-yl)-3H,4H,4aH,8aH-[1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(oxan-4-yl)-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4,4-difluoropiperidin-1-yl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4,4-difluoropiperidin-1-yl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-{3-[(1-methyl-1H-pyrazol-4-yl)oxy]azetidin-1-yl}-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(3R)-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(3S)-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(3R)-4-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(3S)-4-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1s,4s)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1r,4r)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)azetidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)azetidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)methoxy)azetidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)--6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(4-ethyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(4-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(4-(2,2-difluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-(1-methyl-1H-pyrazol-4-yl)-4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(4-(2-methoxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyrimidin-5-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-3-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1H-pyrazol-4-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-5-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(4-methylthiazol-2-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(3-methyl-1H-1,2,4-triazol-5-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1H-pyrazol-3-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(thiazol-2-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 4-(4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-2-yl)-N-methylmorpholine-2-carboxamide, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 4-(4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-2-yl)-N,N-dimethylmorpholine-2-carboxamide, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2-(methoxymethyl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2-((dimethylamino)methyl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-oxa-9-azaspiro[4.5]dec-9-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-methyl-2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(9-methyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1,2,4-oxadiazol-3-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-3-(4-methoxybenzyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-3-(2-methoxyethyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)pyrrolidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2-chloro-4-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-((R)-2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1r,4R)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-((S)-2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1r,4S)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(6,6-difluorospiro[3.3]hept-2-yl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-1,2,3-triazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)pyrrolidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-morpholinopiperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(3-(3-methoxyazetidin-1-yl)piperidin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(3-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1H-imidazol-2-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-imidazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(4-((3-methylpyridin-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2,3-dihydrospiro[indene-1,2'-morpholino]-4'-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5,6,7,9-tetrahydro-8H-pyrido[3,4-c]azepine-8-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(piperidin-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro(3,5)nonan-8-yl)pyrimido(5,4-d)pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methyl-2H-1,2,3-triazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoro-15-methyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S) -6- (2,2-dimethyl-6- (1-methyl-1H-pyrazol-4-yl) morpholino) -8- (2-fluoro-4- (trifluoro-15-methyl) phenyl) -2,3-dimethyl pyrimido [5,4-d] pyrimidin-4 (3H) -one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R) -6- (2,2-dimethyl-6- (1-methyl-1H-pyrazol-4-yl) morpholino) -2,3-dimethyl-8- (2,4,5-trifluorophenyl) pyrimido [5,4-d] pyrimidin-4 (3H) -one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-3-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,2-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,2-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)quinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro(2,5)octan-7-yl)pyrimido(5,4-d)pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]non-8-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]non-8-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-dimethylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-dimethylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((4S,6S)-2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((4R,6R)-2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)(R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-8(7H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-3-oxabicyclo[4.1.0]hept-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((1S,2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-3-oxabicyclo[4.1.0]hept-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((1R,2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-3-oxabicyclo[4.1.0]hept-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(2-methylpyridin-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(2-methylpyridin-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,2-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S) 8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,2-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]non-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]non-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methyl-2H-1,2,3-triazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methyl-2H-1,2,3-triazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((1R,2S)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((1R,2R)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]non-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]non-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-5-fluoro-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-5-fluoro-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-5-fluoro-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-5-fluoro-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-5-fluoro-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-5-fluoro-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-5-fluoro-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. Methyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (trans-racemate), or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (trans-racemate), or a pharmaceutically acceptable salt thereof. ]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(6-(difluoromethyl)pyridin-3-yl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(6-(difluoromethyl)pyridin-3-yl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2R,4S,6R)-2-methyl-6-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-3-methyl-2-(trifluoromethyl)-8-(2,4 In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-3-methyl-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-3-methyl-6- (2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-dichlorophenyl)-2,3-dimethyl-6-(2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-3-methyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-3-methyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 5-chloro-2-(6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 4-(6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 4-(6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2-(6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2-(6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2-(6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-(trifluoromethyl)benzonitrile, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2-(6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-(trifluoromethyl)benzonitrile, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.

[0976] The compounds of the present invention also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton. Tautomeric forms include proton transfer tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary proton transfer tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic ring system, such as 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or spatially locked into one form by appropriate substitution. Tautomeric forms can also include methyl transfer tautomers, which are produced by the exchange of a single bond with an adjacent double bond accompanied by the migration of a methyl group.

[0977] The compounds of the present invention also include all isotopes of the atoms occurring in the intermediates or final compounds. Isotopes include those atoms with the same atomic number but different mass numbers. In some embodiments, the compounds of the present invention include one or more isotopes of atoms in an amount greater than the natural abundance of the isotope. For example, the isotope of hydrogen includes tritium and deuterium. In some embodiments, the compounds of the present invention include at least one deuterium atom (for example, the compound is rich in deuterium) in an amount greater than the natural abundance of deuterium.

[0978] All compounds described herein and their pharmaceutically acceptable salts may exist together with other substances such as water and solvents (eg, in the form of hydrates and solvates).

[0979] In one aspect, the present invention relates to an intermediate compound or a pharmaceutically acceptable salt thereof, which can be used to synthesize the compounds of the present invention. For example, in some embodiments, the intermediate compound is one of the intermediate compounds of any one of Examples 1 to 203 disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present invention is selected from any intermediate compound disclosed in any one of Examples 1 to 203 herein, or a pharmaceutically acceptable salt thereof.

[0980] The compounds of the present invention may contain, for example, one or more asymmetric carbon atoms and may therefore exist as stereoisomers, enantiomers, and diastereoisomers. Therefore, unless stereochemistry is specifically indicated, the scope of the present invention should be understood to encompass all possible stereoisomers of the compounds shown, including stereoisomerically pure forms and stereoisomeric mixtures of any chemical structure disclosed herein. If the stereochemistry of a structure or a portion of a structure is not indicated by, for example, bold or dashed lines, then the structure or portion of the structure should be interpreted as encompassing all stereoisomers thereof. If the stereochemistry of a structure or a portion of a structure is indicated by, for example, bold or dashed lines, then the structure or portion of the structure should be interpreted as encompassing only the indicated stereoisomers.

[0981] As used herein, the terms "stereoisomer" or "stereomerically pure" compound refer to one stereoisomer of a compound that is substantially free of other stereoisomers of the compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound, while a stereomerically pure compound having two chiral centers will be substantially free of the other enantiomer and diastereomers of the compound. Typical stereomerically pure compounds contain greater than about 80% by weight of one stereoisomer of the compound and equal to or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal to or less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal to or less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal to or less than about 3% by weight of other stereoisomers of the compound.

[0982] In some embodiments, the compounds as defined herein are stereomerically pure.

[0983] Mixtures of stereoisomers can be resolved using standard techniques, such as chiral columns or chiral resolving agents, for example as outlined in the Examples section.

[0984] Pharmaceutical composition

[0985] The present invention also relates to a pharmaceutical composition comprising, for example, a pharmaceutically effective amount of a compound disclosed herein as an active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient, and / or diluent.

[0986] While the compounds disclosed herein for use in therapy can be administered as the raw chemical compound, it is often preferred to incorporate the active ingredient (optionally in the form of a pharmaceutically acceptable salt) into a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and / or other conventional pharmaceutical auxiliaries.

[0987] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, and optionally other therapeutic and / or prophylactic ingredients known and used in the art. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.

[0988] A therapeutic amount or therapeutically effective amount or dosage refers to an amount of the active ingredient (i.e., a compound or composition disclosed herein) that treats, alleviates, lessens, or reduces the severity of the symptoms of a subject's disease, such as improving one or more symptoms of the condition or the condition itself. A therapeutic amount of a compound described herein can improve a patient's chance of survival, increase survival time or survival rate, alleviate symptoms, make an injury, disease, or condition (e.g., a neurodegenerative disease) more tolerable, slow the rate of degeneration or decline, or improve the patient's physical or mental well-being.

[0989] Treatment efficacy and toxicity, such as ED 50 , which can be determined by standard pharmacological procedures in cell culture or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index, which can be expressed as the ratio between the plasma level that produces therapeutic effects and the plasma ratio that produces toxic effects. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. In some embodiments, the therapeutically effective dose of the compounds disclosed herein is in the range of about 0.01 mg / kg to about 100 mg / kg body weight / day.

[0990] The dosage administered must, of course, be carefully adjusted according to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the desired result, and the exact dosage will, of course, be determined by the physician.

[0991] Administration refers to the method of delivering a medicament, compound or composition to a desired biological site of action. These methods include, but are not limited to, enteral delivery, oral delivery, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colon delivery, rectal delivery or intraperitoneal delivery.

[0992] Biological activity

[0993] As demonstrated in Example 204, the compounds of the present invention are capable of regulating TREM2. Therefore, in some embodiments, the compounds of the present invention are TREM2 modulators, such as TREM2 agonists. The assays described in Example 204 can be used to evaluate and characterize the ability of a compound to act as a TREM2 agonist. In some embodiments, the compounds of the present invention can be used to activate TREM2. In some embodiments, the compounds of the present invention activate TREM2. In some embodiments, the compounds of the present invention enhance the activity of TREM2. In some embodiments, the compounds of the present invention induce phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, and GSK3b. In some embodiments, the compounds of the present invention enhance or activate TREM2 signaling through DAP12. In some embodiments, the compounds of the present invention enhance or activate the phosphorylation level of TREM2-induced Syk kinase. In some embodiments, a compound induces or enhances phosphorylation of Syk if the level of Syk phosphorylation in a sample treated with a compound of the invention is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more compared to a control value; for example, by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more compared to a control value.

[0994] In some embodiments, the potency of the compounds of the invention is measured using EC 50 In some embodiments, the EC50 value of the compound of the present invention is less than 1000 nM, such as an EC50 value between 100 nM and 1000 nM, such as an EC50 value between 10 nM and 100 nM, such as an EC50 value between 1 nM and 10 nM, such as an EC50 value between 1 nM and 10 nM, such as an EC50 value <1 nM.

[0995] In some embodiments, the compounds of the present invention can increase the expression of one or more TREM2-regulated genes. In some embodiments, the compounds of the present invention increase the expression of one or more TREM2-regulated genes. In some embodiments, the compounds of the present invention can increase the gene (see Example 205) regulated by one or more TREM2 selected from CXCL10, CCL2, CST7 and TMEM119. In some embodiments, the compounds of the present invention increase the expression level of genes regulated by one or more TREM2 selected from CXCL10, CCL2, CST7 and TMEM119, such as brain expression levels.

[0996] In some embodiments, a compound of the invention increases expression levels, e.g., brain expression levels, if the gene expression level in a sample treated with the compound of the invention is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more compared to a control value; e.g., by at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 5-fold, or more compared to a control value (e.g., an untreated control / vehicle).

[0997] Medical uses

[0998] As modulators of TREM2, the compounds of the present invention can be used to treat diseases and conditions in living organisms (including humans). As used herein, the term "treating" includes treating, preventing, and / or alleviating or ameliorating one or more diseases and conditions or one or more symptoms of a disease or condition. In one aspect, the compounds described herein can be used as pharmaceuticals.

[0999] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in treating a condition associated with loss of function of TREM2. In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in treating a condition associated with a TREM2 mutation.

[1000] In one aspect, the invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease.

[1001] In some embodiments, the compounds described herein are used to treat a neurodegenerative disease characterized by loss of function of TREM2. In some embodiments, the compounds described herein are used to treat a neurodegenerative disease characterized by a TREM2 mutation.

[1002] In one aspect, the present invention relates to a method of enhancing or increasing TREM2 activity in a subject in need thereof (e.g., a subject suffering from a neurodegenerative disease), comprising administering to the subject a compound as defined herein or a pharmaceutically acceptable salt thereof.

[1003] In one aspect, the present invention relates to a method for one or more of: i) enhancing or activating TREM2 signaling through DAP12, ii) inducing phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, and GSK3b, iii) enhancing the level of TREM2-induced phosphorylation of Syk kinase, iv) increasing the expression level of one or more TREM2-regulated genes, e.g., brain expression level, and / or v) increasing the expression level of one or more TREM2-regulated genes selected from CXCL10, CCL2, CST7, and TMEM119, e.g., brain expression level, in a subject in need thereof, e.g., a subject suffering from a neurodegenerative disease; the method comprising administering to the subject a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[1004] In some embodiments, the neurodegenerative disease is a tauopathy, which describes a group of neurodegenerative diseases characterized by tau deposits in the brain and associated symptoms of dementia and Parkinson's disease. In some embodiments, the neurodegenerative disease is a tauopathy selected from primary age-related tauopathy (PART), globular glial tauopathy, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy, corticobasal degeneration, diffuse neurofibrillary tangles with calcification (DNTC), frontotemporal dementia (FTD), and FTD with parkinsonism-17 (FTD with parkinsonism linked to chromosome 17; FTDP-17).

[1005] In some embodiments, the neurodegenerative disease is a neurodegenerative disorder associated with TDP-43 (TDP-43 proteinopathies or TDP-43-opathies). Pathogenic deposits containing TAR DNA binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients with a range of neurodegenerative diseases.

[1006] In some embodiments, the neurodegenerative disease is a TDP-43 proteinopathy selected from the group consisting of amyotrophic lateral sclerosis (ALS), sporadic amyotrophic lateral sclerosis (sALS), familial amyotrophic lateral sclerosis (fALS), frontotemporal lobar degeneration / disease (FTLD), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), FTLD-tau, FTLD-FUS (bvFTLD), FTLD-TDP-43 or FTLD-U (types a, b, and c), facial onset sensory and motor neuron disease (FSN), and FTLD-Tau. neuronopathy (FOSMN), limbic-predominant age-related TDP-43 encephalopathy (LATE), cerebral age-related TDP-43 with sclerosis (CARTS), Guam Parkinson-dementia complex (G-PDC) and ALS (G-ALS), Kii ALS / PDC, amyotrophic lateral sclerosis / parkinsonism-dementia complex of Guam (ALS-PDC), multisystem proteinopathy (MSP; also known as inclusion body myopathy (IBM), associated with early-onset Paget disease of bone and FTLD dementia), Perry disease disease) and conditions accompanied by TDP-43 pathology, including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE).

[1007] In some embodiments, the neurodegenerative disease is a multisystem proteinopathy (MSP). MSP is a dominantly inherited, pleiotropic degenerative disorder in humans that affects the muscles, bones, and / or central nervous system. MSP can clinically manifest as classic amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Paget's disease of bone (PDB), or a combination of these disorders (IBMPFD, IBMPFD / ALS).

[1008] In some embodiments, the neurodegenerative disease is a synucleinopathy. Synucleinopathy (also known as α-synucleinopathy) is a neurodegenerative disease characterized by the abnormal accumulation of α-synuclein aggregates in neurons, nerve fibers, or glial cells.

[1009] In some embodiments, the neurodegenerative disease is a synucleinopathy selected from the group consisting of Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple systematrophy (MSA), neuroaxonal dystrophies, and Alzheimer's Disease with Amygdalar Restricted Lewy Bodies (AD / ALB).

[1010] In some embodiments, the neurodegenerative disease is cognitive impairment and / or memory loss. In some embodiments, the neurodegenerative disease is dementia. In some embodiments, the neurodegenerative disease is a dementia selected from the group consisting of Alzheimer's disease, Parkinson's disease dementia, Huntington's disease dementia, vascular dementia, HIV dementia, frontotemporal dementia, dementia with lewy bodies, prion disease dementia, argyrophilic grain dementia, dementia pugilistica, Guadeloupean parkinsonism with dementia, neurofibrillary tangle-predominant dementia, tangle-only dementia, Down's syndrome, semantic dementia, and schizophrenia. dementia, familial British dementia, familial Danish dementia, and other dementias caused by another medical condition, such as brain tumor, subdural hematoma, endocrine disorders, nutritional deficiencies, infection, immune disorders, liver or kidney failure, metabolic disorders (such as Kufs disease), certain leukodystrophies, certain nervous system diseases (such as epilepsy), and multiple sclerosis.

[1011] Disorders of the peripheral nerves (peripheral neuropathy) are the most common neurological complication of systemic amyloidosis. In some embodiments, the neurodegenerative disease is peripheral amyloidosis (peripheral neuropathy in systemic amyloidosis).

[1012] In some embodiments, neurodegenerative disease is demyelinating disorder (demyelinating disorder).In some embodiments, neurodegenerative disease is the demyelinating disorder of central nervous system CNS.In some embodiments, demyelinating disorder is myelin destructive or demyelinating disorder, for example, selected from multiple sclerosis, neuromyelitis optica (neuromyelitis optica) (Devic disease (Devic's disease)) and idiopathic inflammatory demyelinating disease.In some embodiments, demyelinating disorder is leukodystrophy or myelination disorder, for example, selected from CNS neuropathy (such as vitamin B12 deficiency (vitamin B12 deficiency), central pontine myelinolysis (centralpontine myelinolysis), myelopathy (myelopathies) (such as tabes dorsalis (syphilitic myelopathy (syphilitic myelopathy))), leukoencephalopathy (leukoencephalopathies) and leukodystrophy (leukodystrophies).

[1013] In some embodiments, the neurodegenerative disease is a demyelinating disorder of the peripheral nervous system (PNS). In some embodiments, the demyelinating disorder is selected from Guillain–Barré syndrome and its chronic counterpart, chronic inflammatory demyelinating polyneuropathy; Anti-MAG peripheral neuropathy; Charcot–Marie–Tooth disease and its counterpart, hereditary neuropathy with liability to pressure palsy; copper deficiency-related diseases (peripheral neuropathies, myelopathy, and rare optic neuropathy); and progressive inflammatory neuropathy.

[1014] In some embodiments, the neurodegenerative disease is Alzheimer's disease (AD). In some embodiments, the neurodegenerative disease is Alzheimer's disease (AD) with an R47H mutation. In some embodiments, the neurodegenerative disease is early Alzheimer's disease. In some embodiments, the neurodegenerative disease is frontotemporal lobar degeneration (FTLD). In some embodiments, the neurodegenerative disease is frontotemporal dementia. In some embodiments, the neurodegenerative disease is Parkinson's disease. In some embodiments, the neurodegenerative disease is Nasu-Hakola disease (NHD). In some embodiments, the neurodegenerative disease is FTLD-like syndrome. In some embodiments, the neurodegenerative disease is Huntington's disease. In some embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS). In some embodiments, the neurodegenerative disease is multiple sclerosis (MS). In some embodiments, the neurodegenerative disease is Guillain-Barre syndrome. In some embodiments, the neurodegenerative disease is chronic inflammatory demyelinating polyneuropathy. In some embodiments, the neurodegenerative disease is progressive subcortical gliosis. In some embodiments, the neurodegenerative disease is Charcot-Marie-Tooth disease. In some embodiments, the neurodegenerative disease is a prion disease, such as prion protein cerebral amyloid angiopathy. In some embodiments, the neurodegenerative disease is stroke. In some embodiments, the neurodegenerative disease is cerebral amyloid angiopathy (CAA). In some embodiments, the neurodegenerative disease is fragile X-associated tremor ataxia syndrome (FXTAS). In some embodiments, the neurodegenerative disease is herpes simplex virus (HSV) encephalitis. In some embodiments, the neurodegenerative disease is HIV-associated neurocognitive disorders (HAND). In some embodiments, the neurodegenerative disease is progressive supranuclear palsy (PSP). In some embodiments, the neurodegenerative disease is corticobasal degeneration. In some embodiments, the neurodegenerative disease is Hallevorden-Spatz disease.In some embodiments, the neurodegenerative disease is pallido-ponto-nigral degeneration. In some embodiments, the neurodegenerative disease is postencephalitic parkinsonism. In some embodiments, the neurodegenerative disease is subacute sclerosing panencephalitis (SSPE). In some embodiments, the neurodegenerative disease is retinal degeneration (e.g., macular degeneration).

[1015] In some embodiments, the neurodegenerative disease is a leukoencephalopathy. Leukoencephalopathy (leukodystrophy-like diseases) is a term that describes all diseases of the white matter of the brain, regardless of whether their molecular cause is known. In some embodiments, the neurodegenerative disease is a leukoencephalopathy selected from the group consisting of progressive multifocal leukoencephalopathy, toxic leukoencephalopathy, leukoencephalopathy with vanishing white matter, leukoencephalopathy with neuroaxonal spheroids, reversible posterior leukoencephalopathy syndrome, megalencephalicleukoencephalopathy with subcortical cysts, and hypertensive leukoencephalopathy. In some embodiments, the neurodegenerative disease is ALSP (Adult-onset leukoencephalopathy with axonalspheroids and pigmented glia).

[1016] In some embodiments, the neurodegenerative disease is selected from cerebral autosomal dominant arteriopathy with subcortical infarcts or leukoencephalopathy; cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; and retinal vasculopathy with cerebral leukoencephalopathy (or cerebroretinal vasculopathy).

[1017] In some embodiments, the neurodegenerative disease is a leukodystrophy. In some embodiments, the neurodegenerative disease is vanishing white matter disease (VWM). Leukodystrophies are a group of rare genetic disorders that affect the white matter of the brain. In some embodiments, the neurodegenerative disease is a leukodystrophy selected from the group consisting of metachromatic leukodystrophy (MLD), also known as globoid cell leukodystrophy, Krabbe disease, Canavan disease, X-linked adrenoleukodystrophy, Alexander disease, hypomyelinating leukodystrophy type 7 (4H syndrome), Pelizaeus-Merzbacher disease, cerebrotendineous xanthomatosis, and leukodystrophy with white matter ablation. In some embodiments, the neurodegenerative disease is adult-onset autosomal dominant leukodystrophy (ADLD). In some embodiments, the neurodegenerative disease is X-linked adrenoleukodystrophy (X-ALD). In some embodiments, the neurodegenerative disease is Nasu-Hakola disease, also known as polycystic lipomembranousosteodysplasia with sclerosing leukoencephalopathy (PLOSL).

[1018] In some embodiments, the neurodegenerative disease is a transmissible spongiform encephalopathy (TSE), including Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease (GSS), kuru disease, and fatal familial insomnia.

[1019] In one aspect, the present invention relates to a method of treating a neurodegenerative disease, comprising administering to a subject in need thereof a compound as described herein or a pharmaceutically acceptable salt thereof.

[1020] In one aspect, the present invention relates to a method of treating a neurodegenerative disease comprising one or more steps of administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof.

[1021] In some embodiments, the subject is a mammal, such as a human.

[1022] In one aspect, the present invention relates to the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a neurodegenerative disease.

[1023] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition associated with dysfunction of the colony stimulating factor 1 receptor (CSF1R, also known as macrophage colony stimulating factor receptor / M-CSFR, or cluster of differentiation 115 / CD115). In some embodiments, the disease or condition associated with CSF1R dysfunction is a neurodegenerative disease associated with CSF1R dysfunction.

[1024] In some embodiments, the disease or disorder is caused by a heterozygous CSF1R mutation, a homozygous CSF1R mutation, a splicing mutation in the csf1r gene, a missense mutation in the csf1r gene, a mutation in the catalytic kinase domain of CSF1R, a mutation in the immunoglobulin domain of CSF1R, a mutation in the extracellular domain of CSF1R, or a loss-of-function mutation in CSF1R. In some embodiments, the disease or disorder is caused by a change (e.g., an increase, decrease, or cessation) in CSF1R activity and / or a decrease or cessation in CSF1R activity.

[1025] In some embodiments, the neurodegenerative disease associated with CSF1R dysfunction is a leukoencephalopathy.

[1026] In some embodiments, the neurodegenerative disease associated with CSF1R dysfunction is selected from:

[1027] Adult-onset leukoencephalopathy with axonal spheroids and pigmented glial cells (ALSP)

[1028] CSF1R-related leukoencephalopathy,

[1029] hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS)

[1030] pigmentary orthochromatic leukodystrophy (POLD)

[1031] Childhood-onset leukoencephalopathy,

[1032] Congenital absence of microglia,

[1033] brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS), and

[1034] Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

[1035] In some embodiments, the neurodegenerative disease is a disease associated with dysfunction of ATP-binding cassette transporter 1 (ABCD1).

[1036] In one aspect, the present invention relates to a compound as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of lysosomal storage disorders (LSDs).Most lysosomal storage disorders lead to progressive neurodegeneration, resulting in premature death.

[1037] In some embodiments, the LSD is a lipidoses, such as a lipidoses selected from the group consisting of cholesterol ester storage disease, fucosidosis, Schindler disease, and Wolman disease.

[1038] In some embodiments, the LSD is a sphingolipidoses, such as a sphingolipidoses selected from Fabry disease, Gaucher disease, Krabbe disease (globoid cell leukodystrophy), metachromatic leukodystrophy (MLD), Niemann-Pick disease (types A, B, and C), Sandhoff disease, Farmer disease, multiple sulfatase deficiency, and Tay-Sachs disease.

[1039] In some embodiments, the LSD is a mucopolysaccharidoses, such as a mucopolysaccharidoses selected from Hunter syndrome, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, Sanfilippo syndrome (A, B, C, D), Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, and Natowicz syndrome.

[1040] In some embodiments, the LSD is selected from Batten disease, cyctinosis, Danon disease, and Pompe disease.

[1041] In one aspect, the invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition of the bone and / or joints. In some embodiments, the disease or condition is selected from arthritis, rheumatoid arthritis, pyle disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, and dysosteoplasia.

[1042] In one aspect, the invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of autism spectrum disorders, autism and Aspergers syndrome.

[1043] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of traumatic brain injuries (TBI) and spinal cord injuries. Traumatic brain injury (TBI) may also be referred to as intracranial injury. Traumatic brain injury occurs when an external force causes traumatic damage to the brain. Spinal cord injury (SCI) includes any spinal cord injury caused by trauma rather than disease. In some embodiments, TBI is chronic traumatic encephalopathy (CTE).

[1044] In one aspect, the invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of muscular dystrophy, such as myotonic dystrophy (DM), including type 1 DM (DM1) and type 2 DM (DM2).

[1045] In one aspect, the invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammation. In some embodiments, the inflammation is selected from inclusion-body myositis, systemic lupus erythematosus (SLE), RA, gout, and certain intestinal conditions including inflammatory bowel disease (IBD).

[1046] A reduction in TREM2 functional levels can lead to an imbalance in lipid metabolism. In one aspect, the present invention relates to a compound as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of dysregulated lipid metabolism. In certain embodiments, the dysregulated lipid metabolism comprises an increased accumulation of one or more lipids within and / or outside the cell. In some embodiments, the dysregulated lipid metabolism is atherosclerosis.

[1047] In one aspect, the invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of metabolic syndrome and conditions associated with metabolic syndrome, such as obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver disease and alcoholic and non-alcoholic steatohepatitis.

[1048] In one aspect, the invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of amyloidosis, including AL amyloidosis (immunoglobulin light chain amyloidosis), AA amyloidosis (secondary amyloidosis), familial amyloidosis, familial systemic amyloidosis, wild-type amyloidosis (senile systemic amyloidosis), and localized amyloidosis.

[1049] In some embodiments, the neurodegenerative disease is Alzheimer's disease. In some embodiments, the neurodegenerative disease is Nasu-Hakola disease. In some embodiments, the neurodegenerative disease is frontotemporal dementia. In some embodiments, the method comprises administering to the subject a compound as described herein or a pharmaceutical composition comprising a compound as described herein.

[1050] Unless otherwise indicated, the term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structure shown. Therefore, the scope of the methods and uses herein should be understood to encompass methods and uses employing all of these forms.

[1051] Depending on the specific condition or disease to be treated, additional therapeutic agents that are typically administered to treat the condition can be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents that are typically administered to treat a specific disease or condition are referred to as "suitable for the disease or condition being treated." In some embodiments, the provided combination or its composition is administered in combination with another therapeutic agent. In some embodiments, the present invention provides a method for treating a disclosed disease or condition, comprising administering an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof to a patient in need thereof, and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents. In some embodiments, the method includes co-administering one or more additional therapeutic agents. Examples of therapeutic agents that the combinations of the present invention can also be combined with include, but are not limited to, for the treatment of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke. In some embodiments, the example of the therapeutic agent that the combination of the present invention can also be combined with it includes but is not limited to: for the treatment of following disease: tau disease, TDP-43 protein disease, synuclein disease, dementia, amyloidosis, demyelinating disease of CNS, demyelinating disease of PNS, leukoencephalopathy, leukodystrophy, transmissible spongiform encephalopathy (TSE) and lysosomal storage disease (LSD).Term used herein " combination (combination) ", " combined (combined) " and related terms refer to the therapeutic agent according to the present invention simultaneously or sequentially.For example, the combination of the present invention can be used simultaneously or sequentially with another therapeutic agent in the unit dosage form separated, or is used together with single unit dosage form.

[1052] Manufacturing method

[1053] Generally, compounds of formula LXI as described herein can be synthesized according to the following scheme.

[1054] All starting materials are commercially available or known in the art and can be synthesized using known procedures. Starting materials can also be synthesized using procedures disclosed herein. The reaction conditions of the scheme in this section, such as reaction temperature, solvent and reagent, can be found in the experimental section in this article.

[1055] Option 1:

[1056]

[1057] As shown in Scheme 1, (R 1 CO)2O is an anhydride that can condense with 5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid to form 2-substituted pyrimido[5,4-d][1,3]oxazine-4,6,8-trione. 2 NH2 reagents are added and cyclized to give [1,3]diazin-[5,4-d]pyrimidine-2,4,8-trione. Activation with POCl3 or POBr3, for example, gives 6,8-dihalogeno-pyrimido[5,4-d][1,3]diazin-4-one, where Y is a Cl or Br leaving group. 3 Substituents are added by cross-coupling reactions, for example where W is a boronic acid, boronic ester or other organometallic coupling reagent such as an organomagnesium, organotin or organozinc reagent. 3 It can also be introduced by nucleophilic displacement of the Y leaving group. R can then be introduced by a second cross-coupling reaction or a second nucleophilic displacement reaction. 23 substituent.

[1058] In one aspect, the present invention provides a method for preparing a compound of formula IX as described herein, comprising the steps of:

[1059] (a) Make the formula (R 1 The compound of CO)2O reacts with 5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid to produce a compound of formula A1

[1060]

[1061] (b) the compound of formula A1 produced in a) and the compound of formula R 2 The compound of formula A2 is generated by reacting with NH2:

[1062]

[1063] (c) activating the compound of formula A2 generated in b) with POY3 (wherein Y is Cl or Br) to generate a compound of formula A3:

[1064]

[1065] (d) reacting the compound of formula A3 produced in c) with R 3 W 1 (wherein W is B(OH)2, OH or NH) to produce a compound of formula A4:

[1066]

[1067] as well as

[1068] (e) reacting the compound of formula A4 produced in step d) with R 23 W 2 (wherein W is B(OH)2, OH or NH) to produce a compound of formula IX.

[1069] Option 2:

[1070]

[1071] As shown in Scheme 2, R1COCl is an acyl chloride that reacts with an amino-substituted aryl starting material to form an amide. Ester hydrolysis is followed by treatment with an amine R2NH2 to form an intermediate amide, which then undergoes cyclization. X and Y are Cl or Br leaving groups and can be the same or different. R 3 Substituents are added by cross-coupling reactions, for example where W is a boronic acid, boronic ester or other organometallic coupling reagent such as an organomagnesium, organotin or organozinc reagent. 3 It can also be introduced by nucleophilic displacement of the X leaving group. R can then be subsequently introduced by a second cross-coupling reaction or a second nucleophilic displacement reaction of the Y leaving group. 23 substituent.

[1072] In one aspect, the present invention relates to a method for preparing a compound of formula B6, comprising the following steps:

[1073] (a) Make R 1 COCl reacts with the compound of formula B1 to form a compound of formula B2:

[1074]

[1075] (b) hydrolyzing the ester of B2 to form a compound of formula B3:

[1076]

[1077] (c) Compound B3 and R 2 NH2 reacts to form a compound of formula B4:

[1078]

[1079] (d) Compound B4 and R 3 W 1(W 1 It is the reaction of B(OH)2, OH or NH) to produce compound B5:

[1080]

[1081] as well as

[1082] (e) Compound B5 and R 23 W 2 (W 2 It is the reaction of B(OH)2, OH or NH) to produce compound B6:

[1083]

[1084] where R 1 、R 2 、R 3 and R 23 As defined herein, and R is alkyl, such as C 1-6 alkyl; A is N, CH, or CF; Q is N or CH; X is Cl or Br; and Y is Cl or Br.

[1085] Alternatively, as shown in Scheme 3, amino-amide substituted aryl starting materials can be cyclized in the presence of an orthoacetate reagent such as R1C(OEt)3. X and Y are Cl or Br leaving groups and can be the same or different from each other. 3 Substituents. For example, where W is boronic acid, boric acid ester or other organometallic coupling reagents, such as organomagnesium, organotin or organozinc reagents. R can also be introduced by nucleophilic displacement of the leaving group X. 3 R can then be subsequently introduced via a second cross-coupling reaction or a second nucleophilic displacement reaction of the Y leaving group. 23 substituent.

[1086] Option 3:

[1087]

[1088] In one aspect, the present invention relates to a method for preparing a compound of formula C4, comprising the following steps:

[1089] (a) reacting a compound of formula C1 with an orthoacetic acid ester reagent (e.g., R 1 C (OEt) 3) reaction to form a compound of formula C2:

[1090]

[1091] (b) Compound C2 and R 3 W 1 (W 1It is the reaction of B(OH)2, OH or NH) to produce compound C3:

[1092]

[1093] as well as

[1094] (c) Compound C3 and R 23 W 2 (W 2 It is the reaction of B(OH)2, OH or NH) to produce the compound C4:

[1095]

[1096] where R 1 、R 2 、R 3 and R 23 As defined herein, and A is CH, CF, or N; Q is N or CH; X is Cl or Br; and Y is Cl or Br.

[1097] In another alternative approach, as shown in Scheme 4, R can be introduced via a cross-coupling reaction or a nucleophilic displacement reaction of the Y leaving group. 23 Substituents. Then, R is added by a second cross-coupling reaction. 3 Substituents, for example, where W is a boronic acid, a boronate ester or other organometallic coupling reagent, such as an organomagnesium, an organotin or an organozinc reagent. R can also be introduced by a second nucleophilic displacement of the X leaving group. 3 Subsequent reduction, hydrolysis, treatment with anhydride (R1CO)2O, and cyclization with R2NH2 can afford the desired compound.

[1098] Option 4:

[1099]

[1100] In one aspect, the present invention relates to a method for preparing a compound of formula D6, comprising the following steps:

[1101] (a) Compound D1 and R 23 W 2 (W 2 It is the reaction of B(OH)2, OH or NH) to produce compound D2:

[1102]

[1103] (b) Compound D2 and R 3 W 1 (W 1 It is the reaction of B(OH)2, OH or NH) to produce compound D3:

[1104]

[1105] (c) reducing and hydrolyzing the compound of formula D3 to produce a compound of formula D4:

[1106]

[1107] (d) making the compound of formula D4 and (R 1 CO)2O reaction to generate compound D5:

[1108]

[1109] as well as

[1110] (e) Compound D5 and R 2 NH2 reaction, generating compound D6:

[1111]

[1112] where R 1 、R 2 、R 3 and R 23 As defined herein, and X is Cl or Br; and Y is Cl or Br, and R is an alkyl group, such as C 1-6 alkyl.

[1113] As shown in Scheme 5, metal-catalyzed coupling with alkynes R1CCH and halogen-substituted heterocyclic substituents can be followed by ester hydrolysis and cyclization. Further treatment with amines R2NH2 and deprotection of the R group can provide pyrido[3,4-d]pyrimidine-2,4,8-trione. Activation with, for example, POCl3 or POBr3 gives 2,4-dihalo-pyrido[3,4-d]pyrimidin-8-one, where X is a Cl or Br leaving group. Addition of R by cross-coupling reaction 3 Substituents, for example, where W is a boronic acid, a boronic ester or other organometallic coupling reagent, such as an organomagnesium, an organotin or an organozinc reagent. R can also be introduced by nucleophilic displacement of the X leaving group. 3 R can then be subsequently introduced via a second cross-coupling reaction or a second nucleophilic displacement reaction. 23 substituent.

[1114] Option 5:

[1115]

[1116] In one aspect, the present invention relates to a method for preparing a compound of formula E7, comprising the following steps:

[1117] (a) Compound E1 and R 1CCH reaction to generate compound E2:

[1118]

[1119] (b) hydrolyzing the compound of formula E2 to generate a compound of formula E3:

[1120]

[1121] (c) Compound E3 and R 2 NH2 reacts and removes the R group to generate the compound of formula E4:

[1122]

[1123] (d) reacting the compound of formula E4 with POCl3 or POBr3 to produce a compound of formula E5:

[1124]

[1125] (e) Compound E5 and R 3 W 1 (W 1 It is B (OH) 2, OH or NH) reaction, generating formula E6 compound:

[1126]

[1127] as well as

[1128] (f) Compound E6 and R 23 W 2 (W 2 It is B (OH) 2, OH or NH) reaction, generating formula E7 compound:

[1129]

[1130] where R 1 、R 2 、R 3 and R 23 As defined herein, and R is a suitable protecting group, such as PMB; and X is I, Cl or Br. Example

[1131] List of abbreviations

[1132]

[1133]

[1134] Some of the compounds in the examples were obtained as mixtures of stereoisomers and subsequently separated by chiral preparative HPLC. As described in some examples, the assignment of stereochemistry is arbitrary. Therefore, in the examples, the compounds obtained after chiral preparative HPLC are annotated in order. For example, in Example 19, two stereoisomers were obtained. These are annotated as "19A," i.e., Peak 1, and "19B," i.e., Peak 2. The structure of 19A has been arbitrarily designated as (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one and the structure of 19B has been arbitrarily designated as (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one. These are labeled "absolute stereochemistry unknown" in Example 19. However, since the stereochemical designation is arbitrary ("absolute stereochemistry unknown"), the stereochemistry may be reversed, i.e., for example, 19A is (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, while 19B is (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one. Importantly, the numbering was retained in the biological evaluation (e.g., Peak 1 in Example 19 is numbered 19A).

[1135] LCMS conditions:

[1136] Condition A

[1137] LCMS column: Acquity BEH C18 (50x2.1mm, 1.7u), initial (90% [water containing 0.05% HCOOH] and 10% [CH3CN containing 0.05% HCOOH:water (90:10)] until 0.75min, then reaching 50% [water containing 0.05% HCOOH] and 50% [CH3CN containing 0.05% HCOOH:water (90:10)] in 1.00min, then reaching 2% [water containing 0.05% HCOOH] and 98% [CH3CN containing 0.05% HCOOH:water (90:10)] in 2.00min, maintaining this mobile phase composition until 2.25min, finally returning to the initial conditions in 2.60min and maintaining until 3.00min). Flow rate: 0.60ml / min.

[1138] Condition B

[1139] LCMS column: YMC Triart C18 (33x2.1mm, 3u), initial (98% [water containing 0.05% HCOOH] and 2% [CH3CN containing 0.05% HCOOH:water (90:10)] until 0.75min, then reaching 90% [water containing 0.05% HCOOH] and 10% [CH3CN containing 0.05% HCOOH:water (90:10)] in 1.00min, then reaching 2% [water containing 0.05% HCOOH] and 98% [CH3CN containing 0.05% HCOOH:water (90:10)] in 2.00min, maintaining this mobile phase composition until 2.25min, and finally returning to the initial conditions in 2.90min and maintaining until 3.00min). Flow rate: 1.00ml / min.

[1140] Condition C

[1141] LCMS column: Acquity BEH C18 (50x2.1mm, 1.7u), initial (95% [water containing 0.05% HCOOH] and 5% [CH3CN containing 0.05% HCOOH:water (90:10)] until 0.75min, then reaching 75% [water containing 0.05% HCOOH] and 25% [CH3CN containing 0.05% HCOOH:water (90:10)] in 1.50min, then reaching 5% [water containing 0.05% HCOOH] and 95% [CH3CN containing 0.05% HCOOH:water (90:10)] in 3.00min, maintaining this mobile phase composition until 4.00min, finally returning to the initial conditions in 4.50min and maintaining until 5.10min). Flow rate: 0.80ml / min.

[1142] Condition D

[1143] LCMS column - YMC Triart C18 (33x2.1mm, 3u), initial (95% [water containing 0.05% HCOOH] and 5% [CH3CN containing 0.05% HCOOH: water (90:10)] maintained until 0.75min, then reached 50% [water containing 0.05% HCOOH] and 50% [CH3CN containing 0.05% HCOOH: water (90:10)] in 1.20min, then reached 2% [water containing 0.05% HCOOH] and 98% [CH3CN containing 0.05% HCOOH: water (90:10)] in 2.00min, and maintained this mobile phase composition until 2.25min, and finally returned to the initial conditions in 2.60min and maintained until 3.00min). Flow rate: 0.60ml / min.

[1144] Condition E

[1145] Column: YMC TRIART C18 (33 x 2.1 mm, 3 u), (mobile phase: 98% [water containing 0.05% HCOOH] and 2% [CH3CN] for 0.75 min, then reaching 90% [water containing 0.05% HCOOH] and 10% [CH3CN] within 1.0 min, further reaching 2% [water containing 0.05% HCOOH] and 98% [CH3CN] within 2.0 min, maintaining this mobile phase composition until 2.25 min, and finally returning to the initial conditions within 3.0 min). Flow rate = 1.5 ml / min.

[1146] Condition F

[1147] Column: Acquity BEH C18 (2.1×50 mm, 1.7 u) (mobile phase: 90% [water containing 0.05% HCOOH] and 10% [CH3CN with 0.05% HCOOH:water (90:10)], maintained for 0.75 min, then reaching 50% [water containing 0.05% HCOOH] and 50% [CH3CN with 0.05% HCOOH:water (90:10)] within 1.0 min, further reaching 2% [water containing 0.05% HCOOH] and 98% [CH3CN with 0.05% HCOOH:water (90:10)] within 2.0 min, maintaining this mobile phase composition until 2.25 min, finally returning to the initial conditions within 2.60 min, and maintaining this composition until 3.00 min). Flow rate = 0.60 ml / min.

[1148] Condition G

[1149] Column: Xbridge C18 (4.6 x 50 mm, 5 u). Mobile phase: 90% [10 mM ammonium acetate in water] and 10% [CH3CN]. The mixture reached 70% [10 mM ammonium acetate in water] and 30% [CH3CN] over 1.5 min, then 10% [10 mM ammonium acetate in water] and 90% [CH3CN] over 3.00 min. This mobile phase composition was maintained until 4.00 min, and finally returned to the initial conditions over 5.00 min. Flow rate: 1.20 ml / min.

[1150] Condition H

[1151] Column: Acquity BEH C8 (2.1×50 mm, 1.7 u) (mobile phase: 95% [water containing 0.05% HCOOH] and 5% [CH 3 CN containing 0.05% HCOOH:water (90:10)] for 0.75 min, then reaching 75% [water containing 0.05% HCOOH] and 25% [CH 3 CN containing 0.05% HCOOH:water (90:10)] within 1.5 min, further reaching 5% [water containing 0.05% HCOOH] and 95% [CH 3 CN containing 0.05% HCOOH:water (90:10)] within 3.00 min, maintaining this mobile phase composition until 4.00 min, finally returning to the initial conditions within 4.50 min, and maintaining this composition until 5.10 min). Flow rate = 0.80 ml / min.

[1152] Condition I

[1153] Column: Acquity BEH C8 (2.1x50mm, 1.7u) (mobile phase: 90% [water containing 0.05% HCOOH] and 10% [CH3CN containing 0.05% HCOOH:water (90:10)], maintained for 0.75min, then reaching 50% [water containing 0.05% HCOOH] and 50% [CH3CN containing 0.05% HCOOH:water (90:10)] within 1.0min, further reaching 2% [water containing 0.05% HCOOH] and 98% [CH3CN containing 0.05% HCOOH:water (90:10)] within 2.0min, maintaining this mobile phase composition until 2.25min, finally returning to the initial conditions within 2.60min, and maintaining this composition until 3.00min). Flow rate = 0.80ml / min.

[1154] Condition J

[1155] LCMS column: Acquity BEH C8 (50x2.1mm, 1.7u), initial (90% [water containing 0.05% HCOOH] and 10% [CH3CN containing 0.05% HCOOH: water (90:10)] until 0.75min, then reach 50% [water containing 0.05% HCOOH] and 50% [CH3CN containing 0.05% HCOOH: water (90:10)] in 1.00min, then reach 2% [water containing 0.05% HCOOH] and 98% [CH3CN containing 0.05% HCOOH: water (90:10)] in 2.00min, maintain this mobile phase composition until 2.25min, finally return to the initial conditions in 2.60min and maintain until 3.00min). Flow rate: 0.80ml / min.

[1156] Condition K

[1157] LCMS column: Acquity BEH C8 (50x2.1mm, 1.7u), initial (95% [water containing 0.05% HCOOH] and 5% [CH3CN containing 0.05% HCOOH:water (90:10)] until 0.75min, then reaching 75% [water containing 0.05% HCOOH] and 25% [CH3CN containing 0.05% HCOOH:water (90:10)] in 1.50min, then reaching 5% [water containing 0.05% HCOOH] and 95% [CH3CN containing 0.05% HCOOH:water (90:10)] in 3.00min, maintaining this mobile phase composition until 4.00min, finally returning to the initial conditions in 4.50min and maintaining until 5.10min). Flow rate: 0.80ml / min.

[1158] Condition L

[1159] LCMS column: YMC Triart C18 column (3 μm, 33×2.1 mm), initial (95% [water containing 0.05% HCOOH] and 5% [CH 3 CN containing 0.05% HCOOH:water (90:10)] maintained until 0.75 min, then reaching 70% [water containing 0.05% HCOOH] and 30% [CH 3 CN containing 0.05% HCOOH:water (90:10)] within 1.00 min, then reaching 2% [water containing 0.05% HCOOH] and 98% [CH 3 CN containing 0.05% HCOOH:water (90:10)] within 2.00 min, maintaining this mobile phase composition until 2.25 min, and finally returning to the initial conditions within 2.50 min and maintaining until 3.00 min). Flow rate: 1.00 ml / min.

[1160] Condition M

[1161] LCMS column: Acquity BEH C8 (50x2.1mm, 1.7u), initial (90% [water containing 0.05% HCOOH] and 10% [CH3CN containing 0.05% HCOOH:water (90:10)] until 0.75min, then reaching 50% [water containing 0.05% HCOOH] and 50% [CH3CN containing 0.05% HCOOH:water (90:10)] in 1.00min, then reaching 2% [water containing 0.05% HCOOH] and 98% [CH3CN containing 0.05% HCOOH:water (90:10)] in 2.00min, maintaining this mobile phase composition until 2.25min, finally returning to the initial conditions in 2.60min and maintaining until 3.00min). Flow rate: 0.60ml / min.

[1162] ConditionN

[1163] Column: Xbridge C18 (50 x 4.6 mm, 5 u), (mobile phase: from 90% [10 mM NH4OAc aqueous solution] and 10% [CH3CN] to 70% [10 mM NH4OAc aqueous solution] and 30% [CH3CN] in 1.5 min, further to 10% [10 mM NH4OAc aqueous solution] and 90% [CH3CN] in 3.0 min, maintaining this mobile phase composition until 4.0 min, and finally returning to the initial conditions in 5.0 min). Flow rate = 1.20 ml / min.

[1164] Condition O

[1165] Column: YMC Triart C18 (33x2.1mm, 3u), (initial 98% [water containing 0.05% HCOOH] and 2% [ACN containing 0.05% HCOOH:water (90:10)], maintained for 0.75min, then reaching 90% [water containing 0.05% HCOOH] and 10% [ACN containing 0.05% HCOOH:water (90:10)] within 1.0min, further reaching 2% [water containing 0.05% HCOOH] and 98% [ACN containing 0.05% HCOOH:water (90:10)] within 2.00min, maintaining this mobile phase composition until 2.50min, finally returning to the initial conditions within 4.90min, and maintaining this composition until 3.0min). Flow rate: 1.0ml / min.

[1166] Condition P

[1167] Column: Xbridge C18 column (3.5 μm, 50×3 mm), (initial 95% [5 mM NH4OAc aqueous solution] and 5% [ACN containing 5 mM NH4OAc: water (90:10)] maintained for 0.75 min, then reaching 70% [5 mM NH4OAc aqueous solution] and 30% [ACN containing 5 mM NH4OAc: water (90:10)] within 1.00 min, and finally reaching 2% [5 mM NH4OAc aqueous solution] and 98% [ACN containing 5 mM NH4OAc: water (90:10)] within 2.00 min, maintaining this mobile phase composition until 2.50 min, and finally returning to the initial conditions within 2.75 min, and maintaining this composition until 3.0 min). Flow rate: 1.20 ml / min.

[1168] Condition Q

[1169] LCMS column: Xbridge C18 column (5 μm, 100 x 4.6 mm). The mobile phase composition initially consisted of 95% [10 mM aqueous NH4OAc] and 5% [ACN], maintained for 1.50 min, then increased to 60% [10 mM aqueous NH4OAc] and 40% [ACN] over 5.00 min, further increased to 5% [10 mM aqueous NH4OAc] and 95% [ACN] over 2.50 min, and finally increased to 2% [10 mM aqueous NH4OAc] and 98% ACN over 9.50 min. This mobile phase composition was maintained until 12.50 min, and finally returned to the initial conditions over 14.00 min, where it was maintained until 15.00 min. Flow rate: 1.00 ml / min.

[1170] Condition R

[1171] Column: Gemini NX C18 (4.6 x 100 mm, 3 u). Mobile phase: 98% [10 mM ammonium acetate in water] and 2% [ACN] for 0.50 min, then reaching 50% [10 mM ammonium acetate in water] and 50% [ACN] over 6.50 min, then further reaching 5% [10 mM ammonium acetate in water] and 95% [ACN] over 9.50 min. This mobile phase composition was maintained until 13.00 min, and finally returned to the initial conditions within 14.00 min, and this composition was maintained until 15.00 min. Flow rate = 1.00 ml / min.

[1172] Example 1

[1173] 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one

[1174] Example 1A: Enantiomer Peak 1, Example 1B: Enantiomer Peak 2

[1175] Step 1-Preparation of 2-methyl-4H-pyrimido[5,4-d][1,3]oxazine-4,6,8(5H,7H)-trione

[1176]

[1177] To a stirred solution of 5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (2 g, 11.70 mmol) in acetic anhydride (20.17 mL, 213.45 mmol) was added pyridine (3.96 mL, 49.12 mmol) dropwise at room temperature. The resulting mixture was heated at 120 ° C for 2 h. It was cooled to ambient temperature and concentrated under reduced pressure. The crude material was diluted with chloroform and concentrated under reduced pressure again. The residue thus obtained was triturated with ether, acetonitrile and dried to give 2-methyl-4H-pyrimido[5,4-d][1,3]oxazine-4,6,8(5H,7H)-trione (2 g, 87.63% yield) as a brown solid.

[1178] 1H NMR(400MHz,DMSO D6)δ11.7(1H,s),11.55(1H,s),2.34(3H,s)

[1179] LCMS conditions A: Rt = 0.28 min. m / z 196.1 [M+H] + .

[1180] Step 2-Preparation of 6,7-dimethyl-1,7-dihydropyrimido[5,4-d]pyrimidine-2,4,8(3H)-trione

[1181]

[1182] To a stirred solution of 2-methyl-4H-pyrimido[5,4-d][1,3]oxazine-4,6,8(5H,7H)-trione (2 g, 10.26 mmol) in acetic acid (20 mL) was added sodium acetate (840 mg, 10.26 mmol) at room temperature, followed by the dropwise addition of MeNH2 [2(M) in THF, 5.13 mL, 10.26 mmol]. The resulting mixture was heated at 120°C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water, and the precipitate formed was collected and dried. It was then triturated with diethyl ether, followed by ethyl acetate, and dried under high vacuum to afford 6,7-dimethyl-1,7-dihydropyrimido[5,4-d]pyrimidine-2,4,8(3H)-trione (1.35 g, 63.2% yield) as a light brown solid.

[1183] 1H NMR(400MHz,DMSO D6)δ11.51(1H,s),10.98(1H,s),3.50(3H,s),2.50(3H,s)

[1184] LCMS condition B: Rt = 0.62 min. m / z 209.38 [M+H] + .

[1185] Step 3 - Preparation of 6,8-dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one

[1186]

[1187] To a stirred solution of 6,7-dimethyl-1,7-dihydropyrimido[5,4-d]pyrimidine-2,4,8(3H)-trione (600 mg, 2.88 mmol) in POCl3 (12.028 mL, 128.654 mmol) was added DIPEA (2.01 mL, 11.538 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for 15 min, then heated to 100°C and maintained for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was cooled to 0°C, quenched with saturated NaHCO3 aqueous solution and extracted with ethyl acetate. The combined organic fractions were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (50% ethyl acetate-hexanes) to afford 6,8-dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (400 mg, 56.58% yield) as a yellow solid.

[1188] 1H NMR(400MHz,DMSO D6)δ3.56(3H,s),2.66(3H,s)

[1189] LCMS conditions A: Rt = 1.68 min. m / z 245.2 [M+H] + .

[1190] Step 4- Preparation of 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one

[1191]

[1192] To a stirred solution of 6,8-dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (200 mg, 0.816 mmol) and (4-chloro-2-fluorophenyl)boronic acid (127.83 mg, 0.735 mmol) in dioxane (6 mL) and water (2 mL) was added sodium carbonate (128.571 mg, 1.224 mmol) and degassed with argon. PdCl2(dppf) (59.673 mg, 0.082 mmol) was added under an inert atmosphere. The resulting mixture was heated at 90 ° C for 16 h. The reaction mixture was diluted with ethyl acetate, filtered through a short pad of celite and washed with ethyl acetate. The combined organic fractions were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (35% ethyl acetate-hexanes) to give 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (200 mg, 72% yield). LCMS: m / z 339.2 [M+H] + .

[1193] 1H NMR (400MHz, DMSO D6) δ7.72-7.68(2H,m),7.52(1H,d,J=8.32Hz),3.56(3H,s),2.54(3H,s)

[1194] LCMS conditions A: Rt = 2.14 min. m / z 339.2 [M+H] + .

[1195] Step 5 - Preparation of 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one

[1196]

[1197] To a stirred solution of 2-(1-methyl-1H-pyrazol-4-yl)morpholine (HCl salt, 141.593 mg, 0.59 mmol) in DMSO (2 mL) was added DIPEA (0.206 mL, 1.18 mmol) and stirred for 15 min at room temperature. 6-Chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (100 mg, 0.295 mmol) was added at room temperature. The resulting mixture was heated at 100 ° C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC to afford 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one (40 mg, 60.94 mmol, 29% yield) as a yellow solid.

[1198] Preparative HPLC was performed on a Waters automated purification instrument. Column name: YMC-Actus C18 (250 x 20 mm, 5 μ), operated at ambient temperature, flow rate: 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate solution, B = acetonitrile; Gradient profile: mobile phase composition initially 60% A and 40% B, then reaching 40% A and 60% B over 3 min, then 20% A and 80% B over 20 min, then 5% A and 95% B over 21 min, maintaining this composition until 22 min for column cleaning, then returning to the initial composition over 23 min and maintaining this composition for 25 min.

[1199] 1H NMR (400MHz, DMSO D6)δ7.74(1H,s)7.68-7.64(1H,m)7.61-7.59(1H,m),7.45-7.44(2H,m),4.63-4.60(1H,m),4.52-4.49( 2H,m),4.01-3.99(1H,m),3.81(3H,s),3.66-3.63(1H,m),3.51(3H,s),3.18-3.12(2H,m),2.44(3H,s).

[1200] LCMS conditions C: Rt = 2.86 min. m / z 470.27 [M+H] + .

[1201] Step Preparation of 6-(R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one [Example 1A] and (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one [Example 1B]

[1202]

[1203] Chiral separation of 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one (30 mg, 0.064 mmol) was performed by normal phase chiral preparative HPLC to afford Example 1A (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one (8 .9 mg, 29.6% yield; eluted first and designated as Peak 1 with arbitrary stereochemical assignment) as a light yellow solid, and Example 1B (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one (9.6 mg, 3.95 mmol, 31.9% yield, eluted later and designated as Peak 2 with arbitrary stereochemical assignment) as a light yellow solid.

[1204] Details of the chiral preparative HPLC method for separation of enantiomers:

[1205] Instrument: Agilent 1200 Series Instrument / Column: CHIRALPAK IC (250X 21mm) 5u / Flow rate: 21.0ml / min / Mobile phase: Hexane / dichloromethane / Ethanol: 65 / 17.5 / 17.5 / Solubility: A mixture of acetonitrile and dichloromethane / Wavelength: 295nm / Run time: 36min

[1206] Example 1A (peak 1): HNMR: 1H NMR (400 MHz, DMSO D6) δ 7.74 (1H, s) 7.67 (1H, t, J = 7.96 Hz) 7.62-7.59 (1H, m), 7.46-7.44 (2H, m), 4.62 (1H, br d, J = 13.08 Hz), 4.52-4.59 (2H, m), 4.01-3.99 (1H, m), 3.81 (3H, s), 3.66-3.65 (1H, m), 3.51 (3H, s), 3.18-3.12 (2H, m), 2.44 (3H, s).

[1207] LCMS conditions D: Rt = 1.87 min. m / z 470 [M+H] + .

[1208] Example 1B (peak 2) HNMR: 1H NMR (400 MHz, DMSO D6) δ 7.74 (1H, s) 7.67 (1H, t, J = 7.96 Hz) 7.62-7.59 (1H, m), 7.45-7.44 (2H, m), 4.62 (1H, br d, J = 13.08 Hz), 4.52-4.59 (2H, m), 4.01-3.99 (1H, m), 3.81 (3H, s), 3.66-3.65 (1H, m), 3.51 (3H, s), 3.18-3.12 (2H, m), 2.44 (3H, s).

[1209] LCMS conditions D: Rt = 3.03 min, m / z 470.3 [M+H] + .

[1210] Analytical chiral HPLS: Chiralpak IC (4.6x250mm), 5μ, mobile phase: hexane / DCM / EtOH / IPAmine: 60 / 20 / 20 / 0.1, flow rate: 1.0 ml / min, solubility: MeOH, Rt of peak 1 = 12.62 min, Rt of peak 2 = 14.95 min.

[1211] Example 2

[1212] 8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one

[1213] Step 1-Preparation of 1-benzyl-4-bromo-1H-pyrazole

[1214]

[1215] To a stirred solution of 4-bromo-1H-pyrazole (5 g, 34.02 mmol) in DMF (60 mL) at 0° C., sodium hydride (60% in oil, 2.04 g, 51.03 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 0.5 h. Benzyl bromide (6.06 mL, 51.03 mmol) was added dropwise at 0° C. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was cooled to 0° C., quenched with crushed ice and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by combiflash chromatography (20-30% ethyl acetate-hexane) to give 1-benzyl-4-bromo-1H-pyrazole (7.5 g, 92.9% yield) as a colorless liquid.

[1216] 1H NMR (400MHz, DMSO-d6) δ8.09(s,1H),7.57(s,1H),7.36-7.23(m,5H),5.31(s,2H).

[1217] LCMS Conditions F: Rt = 2.07 min. m / z 237.1 [M+H] + .

[1218] Step 2- Preparation of 1-benzyl-4-(1-ethoxyvinyl)-1H-pyrazole

[1219]

[1220] To a stirred solution of 1-benzyl-4-bromo-1H-pyrazole (3.3 g, 13.92 mmol) in toluene (70 mL) was added tributyl (1-ethoxyvinyl) stannane (5.2 mL). The resulting mixture was degassed with argon and Pd (PPh 3 ) 4 (805 mg, 0.69 mmol) was added under an inert atmosphere. The resulting mixture was heated to 110° C. for 16 h. The reaction mixture was filtered through a short diatomaceous earth pad and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to give 1-benzyl-4-(1-ethoxyvinyl)-1H-pyrazole (3.1 g, crude product) as a black liquid. The crude material was used in the next step without further purification.

[1221] Step 3- Preparation of 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethane-1-one

[1222]

[1223] To a stirred solution of 1-benzyl-4-(1-ethoxyvinyl)-1H-pyrazole (3.15 g, 13.82 mmol) in THF (90 mL) and water (25 mL) at 0°C was added NBS (2.95 g, 16.58 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (25-40% ethyl acetate-hexane) to give 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethane-1-one (960 mg, 24.3% yield) as a colorless liquid.

[1224] 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.04(s,1H),7.36-7.28(m,5H),5.39(s,2H),4.59(s,2H).

[1225] LCMS Conditions F: Rt = 1.91 min. m / z 279.2 [M+H] + .

[1226] Step 4- Preparation of 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one

[1227]

[1228] To a stirred solution of 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethane-1-one (940 mg, 3.37 mmol) in acetonitrile (20 mL) was added potassium carbonate (1.16 g, 8.42 mmol) and 2-(benzylamino)ethane-1-ol (661.4 mg, 4.38 mmol) at room temperature. The resulting mixture was heated to 70° C. and maintained for 4 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by combiflash chromatography (50-80% ethyl acetate in hexane) to give 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethane-1-one (1.1 g, 93.4% yield) as a yellow liquid.

[1229] 1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.96(s,1H),7.37-7.23(m,10H),5.36(s,2H) ,4.44(t,J=5.12Hz,1H),3.69-3.68(m,4H),3.51-3.46(m,2H),2.61-2.58(m,2H).

[1230] LCMS conditions E: Rt = 1.51 min. m / z 350.41 [M+H] + .

[1231] Step 5 - Preparation of 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-ol

[1232]

[1233] To a stirred solution of 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethane-1-one (500 mg, 1.43 mmol) in methanol (10 mL) was added sodium borohydride (108.4 mg, 2.86 mmol) in portions at 0°C. The resulting mixture was stirred at 0°C for 0.5 h and then at room temperature for 2 h. The reaction mixture was quenched with ice-cold water and extracted with dichloromethane. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was triturated with diethyl ether to give 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethane-1-ol (470 mg, 93.3% yield) as a colorless, sticky solid.

[1234] 1H NMR (400MHz, DMSO-d6) δ7.62 (s, 1H), 7.33-7.19 (m, 11H), 5.25 (s, 2H), 4.81 (d, J = 3.68Hz, 1H), 4. 63-4.61(m,1H),4.37(t,J=5.04Hz,1H),3.71-3.64(m,2H),3.46-3.78(m,2H),2.64-2.55(m,4H).

[1235] LCMS Conditions F: Rt = 1.61 min. m / z 352.4 [M+H] + .

[1236] Step 6- Preparation of 4-benzyl-2-(1-benzyl-1H-pyrazol-4-yl)morpholine HCl salt

[1237]

[1238] 6(N)HCl (5.0 mL) was added to 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-ol (470 mg, 1.34 mmol). The resulting mixture was heated at 110°C for 2 h. The reaction mixture was concentrated under reduced pressure, triturated with diethyl ether, and dried to provide 4-benzyl-2-(1-benzyl-1H-pyrazol-4-yl)morpholine (430.0 mg, 96.3% yield, HCl salt) as a gum.

[1239] 1H NMR(400MHz,DMSO-d6)δ11.6(s,1H),7.87(s,1H),7.63-7.61(m,2H),7.48-4.46(m,4H),7.35-7.28(m,3H),7.22-7.20(m,2H),5.3 0(s,2H),4.93-4.91(m,2H),4.34-4.32(m,2H),4.01-3.98(m,2H),3.39(d,J=11.56Hz,1H),3.23-3.20(m,1H),3.16-3.10(m,1H).

[1240] LCMS Conditions F: Rt = 1.67 min. m / z 334.4 [M+H] + .

[1241] Step 7- Preparation of 2-(1H-pyrazol-4-yl)morpholine

[1242]

[1243] To the degassed solution of 4-benzyl-2-(1-benzyl-1H-pyrazoles-4-yl) morpholine (500mg, 1.23mmol, HCl salt) in ethanol (20mL), add palladium hydroxide (150mg, 0.25mmol).At room temperature under 30psi pressure in Parr Shaker, gained mixture is hydrogenated 16h.Reaction mixture is filtered through short diatomaceous earth pad and washed with ethanol.The filtrate decompression merging is concentrated, obtain 2-(1H-pyrazoles-4-yl) morpholine (180mg, productive rate 95.6%, HCl salt), is jelly.

[1244] 1H NMR (400MHz, DMSO-d6) δ9.74(bs,1H),9.61(bs,1H),7.71(s,2H),4.79(d,J=9.24Hz,1H),4. 01-3.98(m,1H),3.93-3.87(m,2H),3.36-3.33(m,1H),3.21-3.16(m,2H),3.10-2.99(m,2H).

[1245] LCMS Conditions F: Rt = 0.23 min. m / z 154.2 [M+H] + .

[1246] Step 8- Preparation of tert-butyl 2-(1H-pyrazol-4-yl)morpholine-4-carboxylate

[1247]

[1248] To a stirred solution of 2-(1H-pyrazol-4-yl)morpholine HCl salt (300 mg, 1.33 mmol) in dioxane (3 ml) and water (1 mL) was added triethylamine (0.37 mL, 2.67 mmol), 4-dimethylaminopyridine (8.1 mg, 0.07 mmol) and di-tert-butyl dicarbonate (0.15 mL, 0.67 mmol) in dioxane (2 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (60-70% ethyl acetate in hexane) to give tert-butyl 2-(1H-pyrazol-4-yl)morpholine-4-carboxylate (190 mg, 56.3% yield) as a white solid.

[1249] 1H NMR (400MHz, DMSO) δ12.79(s,1H),7.72(s,1H),7.47(s,1H),4.38-4.35(m,1H),3.85-3.72(m,3H),3.51-3.46(m,1H),2.95(bs,2H),1.41(s,9H).

[1250] LCMS Conditions G: Rt = 2.63 min. m / z 254.1 [M+H] + .

[1251] Step 9- Preparation of tert-butyl 2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholine-4-carboxylate

[1252]

[1253] To a stirred solution of tert-butyl 2-(1-cyclopropyl-1H-pyrazole-4-yl)morpholine-4-carboxylate (190 mg, 0.75 mmol) and cyclopropylboronic acid (141.92 mg, 1.65 mmol) in dichloroethane (4 mL) was added sodium carbonate (174.9 mg, 1.65 mmol). The resulting solution was purged with oxygen for 10 min, and 2,2'-bipyridine (129.03 mg, 0.83 mmol) and cupric acetate (150.04 mg, 0.83 mmol) were added. The resulting mixture was heated at 70 ° C for 16 h under an oxygen atmosphere. The reaction mixture was filtered through a short celite pad and washed with dichloromethane. The combined filtrate was washed with 2N HCl, water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (20-50% ethyl acetate in hexanes) to afford tert-butyl 2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholine-4-carboxylate (100.0 mg, 45.3% yield) as a colorless gum.

[1254] 1H NMR(400MHz,DMSO)δ7.76(s,1H),7.39(s,1H),4.33-4.30(m,1H),3.83-3.81(m,2H),3.74-3.6 5(m,2H),3.51-3.45(m,1H),2.91(bs,2H),1.41(s,9H),0.99-0.98(m,2H),0.94-0.92(m,2H).

[1255] LCMS Conditions G: Rt = 2.99 min. m / z 294.0 [M+H] + .

[1256] Step 10- Preparation of 2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholine

[1257]

[1258] To a stirred solution of tert-butyl 2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholine-4-carboxylate (100 mg, 0.34 mmol) in dichloromethane (3 mL) at 0°C was added TFA (2 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, triturated with diethyl ether, and dried to afford 2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholine (60 mg, 90.9% yield, TFA salt) as a gum.

[1259] LCMS Conditions G: Rt = 0.79 min. m / z 194.1 [M+H] + .

[1260] Step 11- Preparation of 8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one

[1261]

[1262] To a stirred solution of 2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholine TFA salt (60 mg, 0.31 mmol) and 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (105.08 mg, 0.31 mmol) in DMSO (3 mL) was added DIPEA (0.27 mL, 1.55 mmol). The resulting mixture was heated at 100 °C for 16 h. The reaction was purified by reverse phase preparative HPLC to afford 8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (50 mg, 32.4% yield) as a yellow solid.

[1263] Preparative HPLC was performed on a Waters automated purification instrument. Column name: YMC-Actus C18 (250 x 20 mm, 5μ), operated at ambient temperature, flow rate: 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate, B = acetonitrile; Gradient profile: Mobile phase composition initially 40% A and 60% B, then reaching 20% ​​A and 80% B over 20 min, then 5% A and 95% B over 21 min, maintained at this composition for 22 min for column cleaning, then returned to the initial composition over 23 min and maintained for 25 min.

[1264] 1H NMR (400MHz, DMSO-d6) δ7.83 (s, 1H), 7.66-7.59 (m, 2H), 7.45-7.44 (m, 2H), 4.61 (d, J = 13.3Hz, 1H), 4.50-4.47 (m, 2H), 4.0 0(d,J=11.4Hz,1H),3.69-3.67(m,2H),3.50(s,3H),3.18-3.13(m,2H),2.44(s,3H),1.02-1.00(m,2H),0.94-0.92(m,2H).

[1265] LCMS conditions H: Rt = 2.94 min. m / z 496.32 [M+H] + .

[1266] Example 3

[1267] 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one

[1268] Step 1: Preparation of tert-butyl 2-(2-methylpyridin-4-yl)morpholine-4-carboxylate

[1269]

[1270] To a stirred solution of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (600 mg, 2.59 mmol) and 4-bromo-2-methylpyridine (444.15 mg, 2.59 mmol) in DMF (30 mL) was added cesium carbonate (2.5 g, 7.79 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (104.42 mg, 0.39 mmol) and degassed with argon. Under an inert atmosphere, nickel(II) chloride ethylene glycol dimethyl ether complex (57.07 mg, 0.26 mmol) and 4,4-bis(tert-butyl)-2,2-bipyridyl]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate (29.12 mg, 0.03 mmol) were added to the reaction mass. In 4-nitro-2-nitropropene-1-one (90mg, 1.74mmol) in 4-nitro-2-nitropropene-1-one (5.5mmol) in 4-nitro-2-nitropropene-1-one (5.5mmol) in 4-nitro-2-nitropropene-1-one (6.5mmol) in 4-nitro-2-nitropropene-1-one (7 ...

[1271] 1H NMR (400MHz, DMSO) δ8.39 (d, J = 22.2Hz, 1H), 7.25 (s, 1H), 7.17-7.11 (m, 1H), 4.3 8-4.23(m,1H),3.96-3.56(m,4H),2.50(s,3H),2.46-2.39(m.2H),1.42(s,9H).

[1272] LCMS conditions E: Rt = 1.65 min. m / z 279.3 [M+H] + .

[1273] Step 2: Preparation of 2-(2-methylpyridin-4-yl)morpholine

[1274]

[1275] To a stirred solution of tert-butyl 2-(2-methylpyridin-4-yl)morpholine-4-carboxylate (90 mg, 0.32 mmol) in dioxane (2 mL) at 0°C was added dioxane-HCl (4 M solution, 2 mL, 7.68 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and triturated with diethyl ether and pentane to afford 2-(2-methylpyridin-4-yl)morpholine (50 mg, 86.6% yield, HCl salt) as a gum.

[1276] LCMS conditions E: Rt = 1.65 min. m / z 279.3 [M+H] + .

[1277] Step 3: Preparation of 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one

[1278]

[1279] To a stirred solution of 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (80 mg, 0.24 mmol) and 2-(2-methylpyridin-4-yl)morpholine (46.34 mg, 0.26 mmol, HCl salt) in DMSO (2 mL) was added DIPEA (0.21 mL, 1.18 mmol). The resulting mixture was heated at 100 °C for 16 h. The reaction mixture was purified by reverse phase preparative HPLC to afford 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one (75 mg, 65.8% yield) as a yellow solid.

[1280] Preparative HPLC was performed on a Waters automated purification instrument. Column name: YMC-Actus C18 (250 x 20 mm, 5 μ), operated at ambient temperature, and a flow rate of 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate solution, B = acetonitrile; Gradient profile: mobile phase initial composition was 70% A and 30% B, then reached 40% A and 60% B within 3 min, then reached 30% A and 70% B within 20 min, then reached 5% A and 95% B within 21 min, maintained at this composition until 22 min for column cleaning, then returned to the initial composition within 23 min and maintained for 25 min.

[1281] 1H NMR (400MHz, DMSO) δ8.44(d,J=4.9Hz,1H),7.68(t,J=7.9Hz,1H),7.61(d,J= 8.7Hz,1H),7.46(d,J=8.1Hz,1H),7.30(s,1H),7.23(d,J=4.6Hz,1H),4.70( d,J=13.0Hz,1H),4.68-4.57(m,2H),4.15-4.09(m,1H),3.76-3.71(m,1H),3 .51(s,3H),3.23-3.18(m,1H),3.00-2.94(m,1H),2.49(s,3H),2.44(s,3H).

[1282] LCMS conditions H: Rt = 1.65 min. m / z 279.3 [M+H] + .

[1283] Examples 4 to 10

[1284]

[1285] Boric acid used in the synthesis of Examples 4 to 10:

[1286]

[1287] General Procedure for Step 1

[1288] Condition A:

[1289] To a stirred solution of 6,8-dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (1 mmol) and the corresponding boronic acid (0.9 mmol) in dioxane (6 mL) and water (2 mL) was added sodium carbonate (1.5 mmol) and degassed with argon. PdCl2(dppf) (0.1 mmol) was added under an inert atmosphere. The resulting mixture was heated at 60°C for 1 h. The reaction mixture was diluted with ethyl acetate, filtered through a short celite pad and washed with ethyl acetate. The combined organic fractions were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (20-40% ethyl acetate-hexane) to give the corresponding desired products 3a-3f.

[1290] Condition B:

[1291] To a stirred solution of 6,8-dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (1mmol) and the corresponding boronic acid (0.9mmol) in dioxane (6mL) and water (2mL) was added sodium carbonate (1.5mmol) and degassed with argon. PdCl2(dppf) (0.1mmol) was added under an inert atmosphere. The resulting mixture was stirred at room temperature for 16h. The reaction mixture was diluted with ethyl acetate, filtered through a short diatomaceous earth pad and washed with ethyl acetate. The combined organic portions were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (20-40% ethyl acetate-hexane) to obtain the corresponding desired product 3g.

[1292] Preparative HPLC method (Using Waters automated purification instrument) ：

[1293] Example 4: Column name: YMC-Actus C18 (250x20mm, 5μ), operated at ambient temperature, and flow rate: 16mL / min. Mobile phase: A = 20mM ammonium bicarbonate aqueous solution, B = acetonitrile; Gradient profile: mobile phase initial composition is 70% A and 30% B, then reaches 45% A and 55% B in 3 minutes, then reaches 20% A and 80% B in 20 minutes, then reaches 5% A and 95% B in 21 minutes, maintains this composition until 22 minutes for column cleaning, then returns to the initial composition in 23 minutes and maintains it for 25 minutes.

[1294] Example 5: Column name: YMC-Actus C18 (250x20mm, 5μ), operated at ambient temperature, and flow rate: 16mL / min. Mobile phase: A = 20mM ammonium bicarbonate aqueous solution, B = acetonitrile; Gradient profile: mobile phase initial composition is 70% A and 30% B, then reaches 50% A and 50% B in 3 minutes, then reaches 30% A and 70% B in 20 minutes, then reaches 5% A and 95% B in 21 minutes, maintains this composition until 22 minutes for column cleaning, then returns to the initial composition in 23 minutes and maintains it for 25 minutes.

[1295] Example 6:Column name: YMC-Actus C18 (250x20mm, 5μ), operated at ambient temperature, and a flow rate of 16mL / min. Mobile phase: A = 20mM ammonium bicarbonate aqueous solution, B = acetonitrile; Gradient curve: mobile phase initial composition is 60% A and 40% B, then reaches 45% A and 55% B in 3min, then reaches 20% A and 80% B in 20min, then reaches 5% A and 95% B in 21min, maintains this composition until 22min for column cleaning, then returns to the initial composition in 23min and maintains it for 25min.

[1296] Example 7: Column name: YMC-Actus C18 (250x20mm, 5μ), operated at ambient temperature, and a flow rate of 16mL / min. Mobile phase: A = 20mM ammonium bicarbonate aqueous solution, B = acetonitrile; Gradient curve: mobile phase initial composition is 60% A and 40% B, then reaches 50% A and 50% B in 3min, then reaches 25% A and 75% B in 20min, then reaches 5% A and 95% B in 21min, maintains this composition until 22min for column cleaning, then returns to the initial composition in 23min and maintains it for 25min.

[1297] Example 8: Column name: YMC-Actus C18 (250x20mm, 5μ), operated at ambient temperature with a flow rate of 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate, B = acetonitrile; Gradient profile: Mobile phase composition initially 50% A and 50% B, then reaching 40% A and 60% B over 20 min, then 5% A and 95% B over 21 min, maintaining this composition until 22 min for column cleaning, then returning to the initial composition over 23 min and maintaining it for 25 min.

[1298] Example 9: Column name: YMC-Actus C18 (250x20mm, 5μ), operated at ambient temperature with a flow rate of 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate, B = acetonitrile; Gradient profile: Mobile phase composition initially 50% A and 50% B, then reaching 20% ​​A and 80% B over 20 min, then 5% A and 95% B over 21 min, maintaining this composition until 22 min for column cleaning, then returning to the initial composition over 23 min and maintaining it for 25 min.

[1299] Example 10:Column name: YMC-Actus C18 (250x20mm, 5μ), operated at ambient temperature, and flow rate: 16mL / min. Mobile phase: A = 20mM ammonium bicarbonate aqueous solution, B = acetonitrile; Gradient profile: mobile phase initial composition is 60% A and 40% B, then reaches 50% A and 50% B in 3 minutes, then reaches 30% A and 70% B in 20 minutes, then reaches 5% A and 95% B in 21 minutes, maintains this composition until 22 minutes for column cleaning, then returns to the initial composition in 23 minutes and maintains it for 25 minutes.

[1300] General procedure for step 2:

[1301] To a stirred solution of 2-(1-methyl-1H-pyrazol-4-yl)morpholine HCl salt (0.59 mmol) in DMSO (2 mL) was added DIPEA (1.18 mmol) at room temperature and stirred for 15 min. The corresponding compound 3a to 3g (0.29 mmol) was added thereto at room temperature. The resulting mixture was heated at 100 ° C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC to obtain the corresponding target compound.

[1302] The HNMR, LCMS and yield percentage information of compounds 3a to 3g and Examples 4 to 10 are listed in...

Claims

1. A compound of formula LXI: in X 1 Is N or C (R 42 ); R 42 is H or halogen; X 2 is N or CH; X 14 is N or CH; R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 independently selected substituents R 10 replace; R a Is H or C 1-6 alkyl; R b Is H or C 1-6 alkyl; R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace; R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 Tricycloalkyl, C 5-8 Bicycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl or 5-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and CN substituents; wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace; R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl; and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents; R 10 Individually selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and halogen; R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 Substitution of alkyl groups; R 23 Having the formula XLVI: in X 3 Is N or C (R 8 ); X 4 It is C(R 38 )(R 39 ), O, NH, NR 9 or key; X 10 C(R 37 )(R 7 ) or C(O); X 11 It is C(R 4 ) or N; X 12 It is C(R 6 )(R 6b ); X 13 It is C(R 40 )(R 41 ); R 4 Is H or C 1-3 alkyl; R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent; (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 、-oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent; R 6 is H, halogen or C 1-3 alkyl; R 6b is H, halogen or C 1-3 alkyl; When R 6 and R 6b It is C 1-3 When alkyl, R 6 and R 6b are optionally linked together to form a 3-6 membered ring; and / or When R 6 and R 6b It is C 1-3 When alkyl, a methylene group is optionally replaced by -O- or -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl; R 7 H, C alone 1-3 alkyl or bond; When R 7 When it is a key, R 6 It is C 1-3 Alkyl, and R 7 and R 6 Connected together to form a 3-5 membered ring; R 37 H or C alone 1-3 alkyl; R 8 is selected from H, -OH, -O-alkyl and halogen; R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups; R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution; R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain; R 30 Is H or C 1-3 alkyl; R 31 Is H or C 1-3 alkyl; R 38 is H or F; R 39 is H or F; R 40 H, C alone 1-3 alkyl or bond; When R 40 When it is a key, R 8 It is C 1-3 Alkyl, and R 8 and R 40 Connected together to form a 3-5 membered ring; R 41 H or C alone 1-3 alkyl; n is 0, 1, or 2; and v is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound has the formula LXI: in X 1 Is N or C (R 42 ); R 42 is H or halogen; X 2 is N or CH; X 14 is N or CH; R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 independently selected substituents R 10 replace; R a Is H or C 1-6 alkyl; R b Is H or C 1-6 alkyl; R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace; R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl or 5-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 Substitution of haloalkyl groups; wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace; R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl; and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents; R 10 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and halogen; R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 Substitution of alkyl groups; R 23 Having the formula XLVI: in X 3 Is N or C (R 8 ); X 4 It is C(R 38 )(R 39 ), O, NH, NR 9 or key; X 10 C(R 37 )(R 7 ) or C(O); X 11 It is C(R 4 ) or N; X 12 It is C(R 6 )(R 6b ); X 13 It is C(R 40 )(R 41 ); R 4 Is H or C 1-3 alkyl; R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent; (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent; R 6 is H, halogen or C 1-3 alkyl; R 6b is H, halogen or C 1-3 alkyl; When R 6 and R 6b It is C 1-3 When alkyl, R 6 and R 6b are optionally linked together to form a 3-6 membered ring; and / or When R 6 and R 6b It is C 1-3 When alkyl, a methylene group is optionally replaced by -O- or -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl; R 7 H or C alone 1-3 alkyl; R 37 H or C alone 1-3 alkyl; R 8 is selected from H, -OH, -O-alkyl and halogen; R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups; R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution; R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain; R 30 Is H or C 1-3 alkyl; R 31 Is H or C 1-3 alkyl; R 38 is H or F; R 39 is H or F; R 40 H, C alone 1-3 alkyl or bond; When R 8 is a bond and R 40 It is C 1-3 When alkyl, R 8 and R 40 are optionally linked together to form a 3-5 membered ring; R 41 H or C alone 1-3 alkyl; n is 0, 1, or 2; and v is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound has the formula LXI: in X 1 Is N or C (R 42 ); R 42 is H or halogen; X 2 is N or CH; X 14 is N or CH; R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 independently selected substituents R 10 replace; R a Is H or C 1-6 alkyl; R b Is H or C 1-6 alkyl; R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace; R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl or 5-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 Substitution of haloalkyl groups; wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace; R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl; and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents; R 10 Individually selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and halogen; R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 Substitution of alkyl groups; R 23 Having the formula XLVI: in X 3 Is N or C (R 8 ); X 4 It is C(R 38 )(R 39 ), O, NH, NR 9 or key; X 10 C(R 37 )(R 7 ) or C(O); X 11 It is C(R 4 ) or N; X 12 It is C(R 6 )(R 6b ); X 13 It is C(R 40 )(R 41 ); R 4 Is H or C 1-3 alkyl; R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent; (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent; R 6 is H, halogen or C 1-3 alkyl; R 6b is H, halogen or C 1-3 alkyl; When R 6 and R 6b It is C 1-3 When alkyl, R 6 and R 6b are optionally linked together to form a 3-6 membered ring; and / or When R 6 and R 6b It is C 1-3 When alkyl, a methylene group is optionally replaced by -O- or -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl; R 7 H or C alone 1-3 alkyl; R 37 H or C alone 1-3 alkyl; R 8 is selected from H, -OH, -O-alkyl and halogen; R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups; R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution; R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain; R 30 Is H or C 1-3 alkyl; R 31 Is H or C 1-3 alkyl; R 38 is H or F; R 39 is H or F; R 40 H, C alone 1-3 alkyl or bond; When R 8 is a bond and R 40 It is C 1-3 When alkyl, R 8 and R 40 are optionally linked together to form a 3-5 membered ring; R 41 H or C alone 1-3 alkyl; n is 0, 1, or 2; and v is 1 or 2, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound has the formula IX: in X 1 is N or CH; X 2 is N or CH; R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 independently selected substituents R 10 replace; R a Is H or C 1-6 alkyl; R b Is H or C 1-6 alkyl; R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace; R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl or 5-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 Substitution of haloalkyl groups; wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace; R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl; and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents; R 10 Individually selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and halogen; R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 Substitution of alkyl groups; R 23 Having the formula XX: in X 3 Is N or C (R 8 ); X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key; X 10 is C(H)(R 7 ) or C(O); X 11 It is C(R 4 ) or N; X 12 It is C(R 6 )(R 6b ); R 4 Is H or C 1-3 alkyl; R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent; (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent; R 6 is H, halogen or C 1-3 alkyl; R 6b is H, halogen or C 1-3 alkyl; When R 6 and R 6b It is C 1-3 When alkyl, R 6 and R 6b are optionally linked together to form a 3-6 membered ring; and / or When R 6 and R 6b It is C 1-3 When alkyl, a methylene group is optionally replaced by -O- or -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl; R 7 Is H or C 1-3 alkyl; R 8 is selected from H, -OH, -O-alkyl and halogen; R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups; R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution; R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain; R 30 Is H or C 1-3 alkyl; R 31 Is H or C 1-3 alkyl; n is 0, 1, or 2; and v is 1 or 2, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound has the formula IX: in X 1 is N or CH; X 2 is N or CH; R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 10 replace; R a Is H or C 1-6 alkyl; R b Is H or C 1-6 alkyl; R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace; R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl or 6-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 Substitution of haloalkyl groups; wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace; R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl; and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents; R 10 Individually selected from -OC 1-6 Alkyl and C 3-6 Cycloalkyl; R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted by 1 to 5 independently selected from -OC 1-6 Substitution of alkyl groups; R 23 Having the formula XX: in X 3 Is N or C (R 8 ); X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key; X 10 is C(H)(R 7 ) or C(O); X 11 It is C(R 4 ) or N; X 12 It is C(R 6 )(R 6b ); R 4 Is H or C 1-3 alkyl; R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent; (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent; R 6 is H, halogen or C 1-3 alkyl; R 6b is H, halogen or C 1-3 alkyl; When R 6 and R 6b It is C 1-3 When alkyl, R 6 and R 6b are optionally linked together to form a 3-6 membered ring; and / or When R 6 and R 6b It is C 1-3 When alkyl, a methylene group is optionally replaced by -O- or -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl; R 7 Is H or C 1-3 alkyl; R 8 is selected from H, -OH, -O-alkyl and halogen; R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups; R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution; R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain; R 30 Is H or C 1-3 alkyl; R 31 Is H or C 1-3 alkyl; n is 0, 1, or 2; and v is 1 or 2, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound has the formula IX: in X 1 is N or CH; X 2 is N or CH; R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 10 replace; R a Is H or C 1-6 alkyl; R b Is H or C 1-6 alkyl; R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace; R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl or 6-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 Substitution of haloalkyl groups; wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace; R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl; and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents; R 10 Individually selected from -OC 1-6 Alkyl and C 3-6 Cycloalkyl; R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 alkyl halide; R 23 Having the formula XVI: in X 3 Is N or C (R 8 ); X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key; X 10 is C(H)(R 7 ) or C(O); X 11 It is C(R 4 ) or N; R 4 Is H or C 1-3 alkyl; R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent; (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ) is substituted with a substituent; R 6 Is H or C 1-3 alkyl; R 7 Is H or C 1-3 alkyl; R 8 is selected from H, -OH, -O-alkyl and halogen; R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl is optionally substituted by 1 to 3 independently selected halogen and C 1-3 Substitution of alkoxy groups; R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substitution; R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain; R 30 Is H or C 1-3 alkyl; R 31 Is H or C 1-3 alkyl; n is 0, 1, or 2; and v is 1 or 2, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound has the formula IX: in X 1 is N or CH; X 2 is N or CH; R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 10 replace; R a Is H or C 1-6 alkyl; R b Is H or C 1-6 alkyl; R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace; R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl or 6-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 Substitution of haloalkyl groups; wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace; R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl; and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents; R 10 Individually selected from -OC 1-6 Alkyl and C 3-6 Cycloalkyl; R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 alkyl halide; R 23 With formula X: in X 3 Is N or C (R 8 ); X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key; X 10 is C(H)(R 7 ) or C(O); R 4 Is H or C 1-3 alkyl; R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted with oxo (=O), and (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent; (c) C 1-6 The alkyl group is optionally replaced by -N(H)C(O)R 24 replace; R 6 Is H or C 1-3 alkyl; R 7 Is H or C 1-3 alkyl; R 8 is selected from H, -OH, -O-alkyl and halogen; R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl; R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substituted; and n is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

8. A compound according to any one of the preceding claims, wherein the compound has formula I: in X 1 is N or CH; X 2 is N or CH; X 3 Is N or C (R 8 ); X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key; X 10 is C(H)(R 7 ) or C(O); R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 10 replace; R a Is H or C 1-6 alkyl; R b Is H or C 1-6 alkyl; R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace; R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl or 6-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 The substituent of the haloalkyl group is substituted, and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents; R 4 Is H or C 1-3 alkyl; R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, phenyl, 5-membered heteroaryl and 6-membered heteroaryl, wherein (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted with oxo (=O), and (b) the phenyl, 5-membered heteroaryl or 6-membered heteroaryl is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent; R 6 Is H or C 1-3 alkyl; R 7 Is H or C 1-3 alkyl; R 8 is selected from H, -OH, -O-alkyl and halogen; R 9 It is C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl or C 1-6 alkyl halide; R 10 Selected from -OC 1-6 Alkyl and C 3-6 Cycloalkyl; R 11 Selected from -OC 1-6 Alkyl and C 3-6 Cycloalkyl; n is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

9. A compound according to any one of the preceding claims, wherein R 23 Having the formula Xa: or a pharmaceutically acceptable salt thereof.

10. A compound according to any one of the preceding claims, wherein R 23 Having the formula Xb: or a pharmaceutically acceptable salt thereof.

11. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXa: or a pharmaceutically acceptable salt thereof.

12. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXb: or a pharmaceutically acceptable salt thereof.

13. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXc: or a pharmaceutically acceptable salt thereof.

14. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXd: or a pharmaceutically acceptable salt thereof.

15. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXe: or a pharmaceutically acceptable salt thereof.

16. A compound according to any one of the preceding claims, wherein R 23 With the formula XXf: or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of the preceding claims, wherein the compound has Formula Ia or Formula Ib: or a pharmaceutically acceptable salt thereof.

18. A compound according to any one of the preceding claims, wherein X 1 is N, or a pharmaceutically acceptable salt thereof.

19. A compound according to any one of the preceding claims, wherein X 1 It is C(R 42 ), or a pharmaceutically acceptable salt thereof.

20. A compound according to any one of the preceding claims, wherein R 42 is H, or a pharmaceutically acceptable salt thereof.

21. A compound according to any one of the preceding claims, wherein R 42 is a halogen, or a pharmaceutically acceptable salt thereof.

22. A compound according to any one of the preceding claims, wherein R 42 is F, or a pharmaceutically acceptable salt thereof.

23. A compound according to any one of the preceding claims, wherein X 1 is CH, or a pharmaceutically acceptable salt thereof.

24. A compound according to any one of the preceding claims, wherein X 1 is CF, or a pharmaceutically acceptable salt thereof.

25. A compound according to any one of the preceding claims, wherein X 2 is N, or a pharmaceutically acceptable salt thereof.

26. A compound according to any one of the preceding claims, wherein X 2 is CH, or a pharmaceutically acceptable salt thereof.

27. A compound according to any one of the preceding claims, wherein X 14 is N, or a pharmaceutically acceptable salt thereof.

28. A compound according to any one of the preceding claims, wherein X 14 is CH, or a pharmaceutically acceptable salt thereof.

29. A compound according to any one of the preceding claims, wherein X 1 is N and X 2 is N, or a pharmaceutically acceptable salt thereof.

30. A compound according to any one of the preceding claims, wherein X 1 is N and X 2 is CH, or a pharmaceutically acceptable salt thereof.

31. A compound according to any one of the preceding claims, wherein X 1 is CH and X 2 is N, or a pharmaceutically acceptable salt thereof.

32. A compound according to any one of the preceding claims, wherein X 1 is CH and X 2 is CH, or a pharmaceutically acceptable salt thereof.

33. A compound according to any one of the preceding claims, wherein X 1 It is N, X 2 is N and X 14 is N, or a pharmaceutically acceptable salt thereof.

34. A compound according to any one of the preceding claims, wherein X 1 It is N, X 2 is N and X 14 is CH, or a pharmaceutically acceptable salt thereof.

35. A compound according to any one of the preceding claims, wherein X 1 It is N, X 2 is CH and X 14 is N, or a pharmaceutically acceptable salt thereof.

36. A compound according to any one of the preceding claims, wherein X 1 It is CH, X 2 is N and X 14 is N, or a pharmaceutically acceptable salt thereof.

37. A compound according to any one of the preceding claims, wherein X 1 It is CH, X 2 is CH and X 14 is N, or a pharmaceutically acceptable salt thereof.

38. A compound according to any one of the preceding claims, wherein X 1 It is CH, X 2 is N and X 14 is CH, or a pharmaceutically acceptable salt thereof.

39. A compound according to any one of the preceding claims, wherein X 1 It is N, X 2 is CH and X 14 is CH, or a pharmaceutically acceptable salt thereof.

40. A compound according to any one of the preceding claims, wherein X 1 It is CH, X 2 is CH and X 14 is CH, or a pharmaceutically acceptable salt thereof.

41. A compound according to any one of the preceding claims, wherein X 1 It's CF, X 2 is N and X 14 is N, or a pharmaceutically acceptable salt thereof.

42. A compound according to any one of the preceding claims, wherein the compound has Formula II: or a pharmaceutically acceptable salt thereof.

43. A compound according to any one of the preceding claims, wherein the compound has Formula II: in R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, H and NR a R b , wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 10 replace; R a Is H or C 1-6 alkyl; R b Is H or C 1-6 alkyl; R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and H, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by R 11 replace; R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hex-3-yl, piperidin-1-yl and -OCH2-(C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl or 6-membered heteroaryl are optionally substituted by 1 to 4 independently selected halogen, C 1-3 Alkyl and C 1-3 Substitution of haloalkyl groups; wherein the C 3-6 A methylene group of the cycloalkyl group is optionally replaced by -O- or -N(R 28 )-replace; R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl; and wherein the azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl or -OCH2-(C 3-6 Cycloalkyl) is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 Substitution of haloalkoxy substituents; R 10 Selected from -OC 1-6 Alkyl and C 3-6 Cycloalkyl; R 11 Selected from -OC 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 alkyl halide; X 3 Is N or C (R 8 ); X 4 It is CH2, O, CHF, CF2, NH, NR 9 or key; X 10 It is CH2; R 4 Is H or C 1-3 alkyl; R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted with oxo (=O), and (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent; (c) C 1-6 The alkyl group is optionally replaced by -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 )replace; R 6 Is H or C 1-3 alkyl; R 8 is selected from H, -OH, -O-alkyl and halogen; R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 Cycloalkyl; R 24 It is C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl group is optionally replaced by a C 1-3 Alkoxy or halogen substituted; and n is 1, or a pharmaceutically acceptable salt thereof.

44. A compound according to any one of the preceding claims, wherein R 1 is optionally replaced by R 10 Substituted C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

45. A compound according to any one of the preceding claims, wherein R 1 is optionally replaced by R 10 Substituted C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

46. ​​A compound according to any one of the preceding claims, wherein R 1 is -CH3, or a pharmaceutically acceptable salt thereof.

47. A compound according to any one of the preceding claims, wherein R 1 is optionally substituted by 1 to 3 independently selected substituents R 10 Substituted C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

48. A compound according to any one of the preceding claims, wherein R 1 is optionally substituted by 1 to 3 independently selected substituents R 10 Substituted C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

49. A compound according to any one of the preceding claims, wherein R 10 is a halogen, such as F, or a pharmaceutically acceptable salt thereof.

50. A compound according to any one of the preceding claims, wherein R 1 is -CF3, or a pharmaceutically acceptable salt thereof.

51. A compound according to any one of the preceding claims, wherein R 1 is optionally replaced by R 10 Substituted C 3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

52. A compound according to any one of the preceding claims, wherein R 1 is H, or a pharmaceutically acceptable salt thereof.

53. A compound according to any one of the preceding claims, wherein R 2 is optionally replaced by R 11 Substituted C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

54. A compound according to any one of the preceding claims, wherein R 2 is optionally replaced by R 11 Substituted C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

55. A compound according to any one of the preceding claims, wherein R 2 is -CH3, or a pharmaceutically acceptable salt thereof.

56. A compound according to any one of the preceding claims, wherein R 2 It’s H.

57. A compound according to any one of the preceding claims, wherein R 2 is optionally replaced by R 11 Substituted C 3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

58. A compound according to any one of the preceding claims, wherein R 11 Yes-OC 1-6 Alkyl, such as -O-CH3, or a pharmaceutically acceptable salt thereof.

59. A compound according to any one of the preceding claims, wherein R 2 Is R 11 Substituted C 1-3 Alkyl, and R 11 Yes-OC 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

60. A compound according to any one of the preceding claims, wherein R 2 is -CH2CH2OCH3, or a pharmaceutically acceptable salt thereof.

61. A compound according to any one of the preceding claims, wherein R 2 is C substituted by phenyl 1-6 Alkyl, the phenyl group is optionally replaced by -OC 1-6 Alkyl substituted, or a pharmaceutically acceptable salt thereof.

62. A compound according to any one of the preceding claims, wherein R 2 is a C1 alkyl group substituted with a phenyl group, wherein the phenyl group is replaced with -OC 1-6 Alkyl groups such as -OC 1-3 The alkyl group is substituted with -O-C1 alkyl, or a pharmaceutically acceptable salt thereof.

63. A compound according to any one of the preceding claims, wherein R 3 is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 phenyl substituted with a haloalkyl group and a CN substituent, or a pharmaceutically acceptable salt thereof.

64. A compound according to any one of the preceding claims, wherein R 3 is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl and C 1-3 The substituent of the haloalkyl group is phenyl substituted with a haloalkyl group, or a pharmaceutically acceptable salt thereof.

65. A compound according to any one of the preceding claims, wherein R 3 Having formula III: in X 5 It is C(R 15 ) or N; X 6 is CH or N; R 12 It is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or CN; R 13 It is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or CN; R 14 It is H, halogen, C 1-3 Alkyl, C 1-3 haloalkyl or CN; and R 15 It is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or CN, or a pharmaceutically acceptable salt thereof.

66. A compound according to any one of the preceding claims, wherein R 3 Having formula III: in X 5 It is C(R 15 ) or N; X 6 is CH or N; R 12 It is H, halogen, C 1-3 Alkyl or C 1-3 alkyl halide; R 13 It is H, halogen, C 1-3 Alkyl or C 1-3 alkyl halide; R 14 It is H, halogen, C 1-3 Alkyl or C 1-3 haloalkyl; and R 15 It is H, halogen, C 1-3 Alkyl or C 1-3 haloalkyl, or a pharmaceutically acceptable salt thereof.

67. A compound according to any one of the preceding claims, wherein X 5 It is C(R 15 ) or N; X 6 It is CH; R 12 is H or halogen; R 13 is H or halogen; R 14 is H, halogen or C 1-3 haloalkyl; and R 15 is H or halogen, or a pharmaceutically acceptable salt thereof.

68. A compound according to any one of the preceding claims, wherein X 5 is N and X 6 is CH, or a pharmaceutically acceptable salt thereof.

69. A compound according to any one of the preceding claims, wherein X 5 is CH and X 6 It's N.

70. A compound according to any one of the preceding claims, wherein R 3 Having formula IV: in R 12 It is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or CN; R 13 It is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or CN; R 14 It is H, halogen, C 1-3 Alkyl, C 1-3 haloalkyl or CN; and R 15 It is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or CN, or a pharmaceutically acceptable salt thereof.

71. A compound according to any one of the preceding claims, wherein R 3 Has formula IV: in R 12 It is H, halogen, C 1-3 Alkyl or C 1-3 alkyl halide; R 13 It is H, halogen, C 1-3 Alkyl or C 1-3 alkyl halide; R 14 It is H, halogen, C 1-3 Alkyl or C 1-3 haloalkyl; and R 15 It is H, halogen, C 1-3 Alkyl or C 1-3 haloalkyl, or a pharmaceutically acceptable salt thereof.

72. A compound according to any one of the preceding claims, wherein R 12 is H, or a pharmaceutically acceptable salt thereof.

73. A compound according to any one of the preceding claims, wherein R 12 is a halogen, such as F or Cl, or a pharmaceutically acceptable salt thereof.

74. A compound according to any one of the preceding claims, wherein R 12 It is C 1-3 Alkyl, such as -CH3, or a pharmaceutically acceptable salt thereof.

75. A compound according to any one of the preceding claims, wherein R 12 is CN, or a pharmaceutically acceptable salt thereof.

76. A compound according to any one of the preceding claims, wherein R 13 is H, or a pharmaceutically acceptable salt thereof.

77. A compound according to any one of the preceding claims, wherein R 13 is a halogen, such as F, or a pharmaceutically acceptable salt thereof.

78. A compound according to any one of the preceding claims, wherein R 14 is a halogen, such as F or Cl, or a pharmaceutically acceptable salt thereof.

79. A compound according to any one of the preceding claims, wherein R 14 It is C 1-3 Alkyl, such as -CH3, or a pharmaceutically acceptable salt thereof.

80. A compound according to any one of the preceding claims, wherein R 14 It is C 1-3 Haloalkyl, such as -CF3, or a pharmaceutically acceptable salt thereof.

81. A compound according to any one of the preceding claims, wherein R 14 It is C 1-3 Haloalkyl, such as -CHF2, or a pharmaceutically acceptable salt thereof.

82. A compound according to any one of the preceding claims, wherein R 14 is CN, or a pharmaceutically acceptable salt thereof.

83. A compound according to any one of the preceding claims, wherein R 15 is H, or a pharmaceutically acceptable salt thereof.

84. A compound according to any one of the preceding claims, wherein R 15 is a halogen, such as F, or a pharmaceutically acceptable salt thereof.

85. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from:

86. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 yes 87. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from:

88. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 yes 89. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from:

90. A compound according to any one of the preceding claims, wherein R 3 is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl and C 1-3 a 5-membered heteroaryl group substituted with a haloalkyl substituent, or a pharmaceutically acceptable salt thereof.

91. A compound according to any one of the preceding claims, wherein R 3 is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and C 1-3 a 5-membered heteroaryl substituted with a haloalkyl substituent, or a pharmaceutically acceptable salt thereof.

92. A compound according to any one of the preceding claims, wherein R 3 is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and C 1-3 The substituent of the haloalkyl group is pyrazolyl substituted with a haloalkyl group, or a pharmaceutically acceptable salt thereof.

93. A compound according to any one of the preceding claims, wherein R 3 yes or a pharmaceutically acceptable salt thereof.

94. A compound according to any one of the preceding claims, wherein R 3 is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl and C 1-3 The substituent of haloalkyl is substituted with C 3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

95. A compound according to any one of the preceding claims, wherein R 3 Having formula V: in R 16 It is H, halogen, C 1-3 Alkyl and C 1-3 alkyl halide; R 17 It is H, halogen, C 1-3 Alkyl and C 1-3 alkyl halide; m is 1, 2, or 3; and p is 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

96. The compound of any one of the preceding claims, wherein m is 1, or a pharmaceutically acceptable salt thereof.

97. The compound of any one of the preceding claims, wherein m is 2, or a pharmaceutically acceptable salt thereof.

98. The compound of any one of the preceding claims, wherein p is 1, or a pharmaceutically acceptable salt thereof.

99. The compound of any one of the preceding claims, wherein p is 2, or a pharmaceutically acceptable salt thereof.

100. A compound according to any one of the preceding claims, wherein R 16 is H, or a pharmaceutically acceptable salt thereof.

101. A compound according to any one of the preceding claims, wherein R 16 is a halogen, such as F, or a pharmaceutically acceptable salt thereof.

102. A compound according to any one of the preceding claims, wherein R 16 It is C 1-3 Alkyl, such as -CH3, or a pharmaceutically acceptable salt thereof.

103. A compound according to any one of the preceding claims, wherein R 16 It is C 1-3 Haloalkyl, such as -CF3 or -CHF2, or a pharmaceutically acceptable salt thereof.

104. A compound according to any one of the preceding claims, wherein R 17 is H, or a pharmaceutically acceptable salt thereof.

105. A compound according to any one of the preceding claims, wherein R 17 is a halogen, such as F, or a pharmaceutically acceptable salt thereof.

106. A compound according to any one of the preceding claims, wherein R 17 It is C 1-3 Alkyl, such as -CH3, or a pharmaceutically acceptable salt thereof.

107. A compound according to any one of the preceding claims, wherein R 17 It is C 1-3 Haloalkyl, such as -CF3 or -CHF2, or a pharmaceutically acceptable salt thereof.

108. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from:

109. A compound according to any one of the preceding claims, wherein R 3 It is C 1-3 Haloalkyl, for example -(CH2)2CF3, or a pharmaceutically acceptable salt thereof.

110. A compound according to any one of the preceding claims, wherein R 3 is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl and C 1-3 The substituent of haloalkyl is substituted with C 5-8 Spirocycloalkyl, or a pharmaceutically acceptable salt thereof.

111. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 yes 112. A compound according to any one of the preceding claims, wherein R 3 is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl and C 1-3 The substituent of haloalkyl is substituted with C 5-8 tricycloalkyl, or a pharmaceutically acceptable salt thereof.

113. A compound according to any one of the preceding claims, wherein R 3 is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl and C 1-3 The substituent of haloalkyl is substituted with C 5-8 A bicycloalkyl group, or a pharmaceutically acceptable salt thereof.

114. A compound according to any one of the preceding claims, wherein R 3 is a bicyclo[1.1.1]pentyl group optionally substituted by CF3 or C1 alkyl, or a pharmaceutically acceptable salt thereof.

115. A compound according to any one of the preceding claims, wherein R 3 yes or a pharmaceutically acceptable salt thereof.

116. A compound according to any one of the preceding claims, wherein R 3 Having formula VI: in R 18 It is H, halogen, C 1-3 Alkyl and C 1-3 alkyl halide; R 19 It is H, halogen, C 1-3 Alkyl and C 1-3 alkyl halide; q is 1, 2, or 3; and r is 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

117. The compound of any one of the preceding claims, wherein q is 1, or a pharmaceutically acceptable salt thereof.

118. A compound according to any one of the preceding claims, wherein q is 2, or a pharmaceutically acceptable salt thereof.

119. The compound of any one of the preceding claims, wherein r is 1, or a pharmaceutically acceptable salt thereof.

120. The compound of any one of the preceding claims, wherein r is 2, or a pharmaceutically acceptable salt thereof.

121. A compound according to any one of the preceding claims, wherein R 18 is H, or a pharmaceutically acceptable salt thereof.

122. A compound according to any one of the preceding claims, wherein R 18 is a halogen, such as F, or a pharmaceutically acceptable salt thereof.

123. A compound according to any one of the preceding claims, wherein R 18 It is C 1-3 Alkyl, such as -CH3, or a pharmaceutically acceptable salt thereof.

124. A compound according to any one of the preceding claims, wherein R 18 It is C 1-3 Haloalkyl, such as -CF3 or -CHF2, or a pharmaceutically acceptable salt thereof.

125. A compound according to any one of the preceding claims, wherein R 19 is H, or a pharmaceutically acceptable salt thereof.

126. A compound according to any one of the preceding claims, wherein R 19 is a halogen, such as F, or a pharmaceutically acceptable salt thereof.

127. A compound according to any one of the preceding claims, wherein R 19 It is C 1-3 Alkyl, such as -CH3, or a pharmaceutically acceptable salt thereof.

128. A compound according to any one of the preceding claims, wherein R 19 It is C 1-3 Haloalkyl, such as -CF3 or -CHF2, or a pharmaceutically acceptable salt thereof.

129. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from:

130. A compound according to any one of the preceding claims, wherein R 3 is optionally substituted by 1 to 4 independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 1-3 -OCH2-(C 3-6 cycloalkyl), or a pharmaceutically acceptable salt thereof.

131. A compound according to any one of the preceding claims, wherein R 3 yes or a pharmaceutically acceptable salt thereof.

132. A compound according to any one of the preceding claims, wherein R 3 It is C 3-6 A cycloalkyl group in which one or more methylene groups is replaced by -O-, or a pharmaceutically acceptable salt thereof.

133. A compound according to any one of the preceding claims, wherein R 3 yes or a pharmaceutically acceptable salt thereof.

134. A compound according to any one of the preceding claims, wherein R 3 It is C 3-6 Cycloalkyl, in which one or more methylene groups are replaced by -N(R 28 )-replacement, where R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

135. A compound according to any one of the preceding claims, wherein R 3 Having formula XV: where R 28 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

136. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from:

137. A compound according to any one of the preceding claims, wherein R 23 Having the formula XLVII: or a pharmaceutically acceptable salt thereof.

138. A compound according to any one of the preceding claims, wherein R 23 Having the formula XLVIII: or a pharmaceutically acceptable salt thereof.

139. A compound according to any one of the preceding claims, wherein R 23 Having formula XLIX: or a pharmaceutically acceptable salt thereof.

140. A compound according to any one of the preceding claims, wherein R 23 With the formula L: or a pharmaceutically acceptable salt thereof.

141. A compound according to any one of the preceding claims, wherein R 23 With formula LI: or a pharmaceutically acceptable salt thereof.

142. A compound according to any one of the preceding claims, wherein R 23 Having formula LII: or a pharmaceutically acceptable salt thereof.

143. A compound according to any one of the preceding claims, wherein R 23 Having the formula LIII: or a pharmaceutically acceptable salt thereof.

144. A compound according to any one of the preceding claims, wherein R 23 Having the formula XLVI, wherein X 3 It is C(R 8 );R 8 Yes key; X 13 It is C(R 40 )(R 41 );R 40 is a C1 alkyl group; R 8 and R 40 Connected together to form a 3-membered ring; R 41 is H; and v is 1.

145. A compound according to any one of the preceding claims, wherein R 23 With formula LIV: or a pharmaceutically acceptable salt thereof.

146. A compound according to any one of the preceding claims, wherein R 23 With formula LV: or a pharmaceutically acceptable salt thereof.

147. A compound according to any one of the preceding claims, wherein R 23 Having the formula LVI: or a pharmaceutically acceptable salt thereof.

148. A compound according to any one of the preceding claims, wherein R 23 Having the formula LVII: or a pharmaceutically acceptable salt thereof.

149. A compound according to any one of the preceding claims, wherein R 23 Having the formula LVIII: or a pharmaceutically acceptable salt thereof.

150. A compound according to any one of the preceding claims, wherein R 23 With formula LIX: or a pharmaceutically acceptable salt thereof.

151. A compound according to any one of the preceding claims, wherein R 23 is a 6-membered ring, or a pharmaceutically acceptable salt thereof.

152. A compound according to any one of the preceding claims, wherein X 3 It is N; X 4 It is O; X 10 It is C(R 37 )(R 7 );X 11 It is C(R 4 );X 12 It is C(R 6 )(R 6b );X 13 It is C(R 40 )(R 41 ); n is 1; and v is 1, or a pharmaceutically acceptable salt thereof.

153. A compound according to any one of the preceding claims, wherein X 3 It is N; X 4 Is NH or NR 9 ;X 10 It is C(R 37 )(R 7 );X 11 It is C(R 4 );X 12 It is C(R 6 )(R 6b );X 13 It is C(R 40 )(R 41 ); n is 1; and v is 1, or a pharmaceutically acceptable salt thereof.

154. A compound according to any one of the preceding claims, wherein X 3 It is N; X 4 It is C(R 38 )(R 39 );X 10 It is C(R 37 )(R 7 );X 11 It is C(R 4 );X 12 It is C(R 6 )(R 6b );X 13 It is C(R 40 )(R 41 ); n is 1; and v is 1, or a pharmaceutically acceptable salt thereof.

155. A compound according to any one of the preceding claims, wherein X 3 It is N; X 4 Yes key; X 10 It is C(R 37 )(R 7 );X 11 It is C(R 4 );X 12 It is C(R 6 )(R 6b );X 13 It is C(R 40 )(R 41 ); n is 1; and v is 2, or a pharmaceutically acceptable salt thereof.

156. A compound according to any one of the preceding claims, wherein X 3 It is C(R 8 );X 4 It is O; X 10 It is C(R 37 )(R 7 );X 11 It is C(R 4 );X 12 It is C(R 6 )(R 6b );X 13 It is C(R 40 )(R 41 ); n is 1; and v is 1, or a pharmaceutically acceptable salt thereof.

157. A compound according to any one of the preceding claims, wherein X 3 is N, or a pharmaceutically acceptable salt thereof.

158. A compound according to any one of the preceding claims, wherein X 3 It is C(R 8 ), or a pharmaceutically acceptable salt thereof.

159. A compound according to any one of the preceding claims, wherein R 8 is H, or a pharmaceutically acceptable salt thereof.

160. A compound according to any one of the preceding claims, wherein X 4 is O, or a pharmaceutically acceptable salt thereof.

161. A compound according to any one of the preceding claims, wherein X 4 is CF2, or a pharmaceutically acceptable salt thereof.

162. A compound according to any one of the preceding claims, wherein X 4 is CH2, or a pharmaceutically acceptable salt thereof.

163. A compound according to any one of the preceding claims, wherein X 4 is CHF, or a pharmaceutically acceptable salt thereof.

164. A compound according to any one of the preceding claims, wherein R 38 is H, or a pharmaceutically acceptable salt thereof.

165. A compound according to any one of the preceding claims, wherein R 38 is F, or a pharmaceutically acceptable salt thereof.

166. A compound according to any one of the preceding claims, wherein R 39 is F, or a pharmaceutically acceptable salt thereof.

167. A compound according to any one of the preceding claims, wherein R 39 is F, or a pharmaceutically acceptable salt thereof.

168. A compound according to any one of the preceding claims, wherein R 38 is H and R 39 is H, or a pharmaceutically acceptable salt thereof.

169. A compound according to any one of the preceding claims, wherein R 38 is F and R 39 is F, or a pharmaceutically acceptable salt thereof.

170. A compound according to any one of the preceding claims, wherein R 38 is H and R 39 is F, or a pharmaceutically acceptable salt thereof.

171. A compound according to any one of the preceding claims, wherein R 4 is H, or a pharmaceutically acceptable salt thereof.

172. A compound according to any one of the preceding claims, wherein R 4 and R 5 are linked together to form a ring, or a pharmaceutically acceptable salt thereof.

173. A compound according to any one of the preceding claims, wherein R 23 Having the formula XLVI, wherein X 3 It is C(R 8 );R 8 Yes key; X 13 It is C(R 40 )(R 41 );R 40 is a C1 alkyl group; R 8 and R 40 Connected together to form a 3-membered ring; R 41 is H; v is 1; X 11 is C(H), X 4 It is O; X 12 is CH2; X 10 is CH2; and n is 1; or a pharmaceutically acceptable salt thereof.

174. A compound according to any one of the preceding claims, wherein R 23 With the formula LX: or a pharmaceutically acceptable salt thereof.

175. A compound according to any one of the preceding claims, wherein X 12 It is C(R 6 )(R 6b );R 6b It is H; R 6 It is C 1-3 Alkyl; n is 1; X 10 It is C(R 37 )(R 7 );R 37 is H; and R 7 is with R 6 A bond connected thereto, or a pharmaceutically acceptable salt thereof.

176. A compound according to any one of the preceding claims, wherein R 23 Having the formula XLVI, wherein X 3 It is N; X 13 is CH2; v is 1; X 11 is C(H); X 4 It is O; X 12 It is C(R 6 )(R 6b );R 6b It is H; R 6 is a C1 alkyl group; n is 1; X 10 It is C(R 37 )(R 7 );R 37 is H; and R 7 is with R 6 A bond connected thereto, or a pharmaceutically acceptable salt thereof.

177. A compound according to any one of the preceding claims, wherein R 23 Having the formula LXIII: or a pharmaceutically acceptable salt thereof.

178. A compound according to any one of the preceding claims, wherein R 23 Has the formula XVI, wherein X 3 It is N; X 10 is CH2; n is 1; v is 1; R 6 It is H; X 4 is O; and X 11 is C(H), or a pharmaceutically acceptable salt thereof.

179. A compound according to any one of the preceding claims, wherein R 23 Having the formula XX, where X 3 It is N; X 10 is CH2; n is 1; v is 1; X 4 is O; and X 11 is C(H), or a pharmaceutically acceptable salt thereof.

180. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXXIV: or a pharmaceutically acceptable salt thereof.

181. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXXIV, R 6 is H and R 6b is H, or a pharmaceutically acceptable salt thereof.

182. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXXIV, R 6 Yes and R 6b is F, or a pharmaceutically acceptable salt thereof.

183. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXXIV, R 6 is CH3 and R 6b is CH3, or a pharmaceutically acceptable salt thereof.

184. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXXIV, R 6 is CH3 and R 6b is H, or a pharmaceutically acceptable salt thereof.

185. A compound according to any one of the preceding claims, wherein R 23 With formula XLV: wherein k is 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof.

186. The compound of any one of the preceding claims, wherein k is 1, or a pharmaceutically acceptable salt thereof.

187. The compound of any one of the preceding claims, wherein k is 2, or a pharmaceutically acceptable salt thereof.

188. A compound according to any one of the preceding claims, wherein R 23 Has the formula XVI, wherein X 3 It is N; X 10 is CH2; n is 1; v is 1; R 6 It is H; X 4 It is C(R 33 )(R 34 );R 33 is H or F; R 34 is H or F; and X 11 is C(H), or a pharmaceutically acceptable salt thereof.

189. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXXV: where R 33 is H or F, and R 34 is H or F, or a pharmaceutically acceptable salt thereof.

190. A compound according to any one of the preceding claims, wherein R 23 Has the formula XVI, wherein X 3 is N; n is 0; v is 1; R 6 It is H; X 4 is CH2; and X 11 is C(H), or a pharmaceutically acceptable salt thereof.

191. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXXVI: or a pharmaceutically acceptable salt thereof.

192. A compound according to any one of the preceding claims, wherein R 23 Has the formula XVI, wherein X 3 It is N; X 10 is CH2; n is 1; v is 1; R 6 It is H; X 4 It is N(R 9 ); and X 11 is C(H), or a pharmaceutically acceptable salt thereof.

193. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXXVII: or a pharmaceutically acceptable salt thereof.

194. A compound according to any one of the preceding claims, wherein R 23 Has the formula XVI, wherein X 3 is C(H); X 10 is CH2; n is 1; v is 1; R 6 It is H; X 4 is O; and X 11 is C(H), or a pharmaceutically acceptable salt thereof.

195. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXXVIII: or a pharmaceutically acceptable salt thereof.

196. A compound according to any one of the preceding claims, wherein R 23 Has the formula XVI, wherein X 3 is C(H); X 10 is CH2; n is 1; v is 1; R 6 It is H; X 4 It is C(R 33 )(R 34 );R 33 is H or F; R 34 is H or F; and X 11 is N, or a pharmaceutically acceptable salt thereof.

197. A compound according to any one of the preceding claims, wherein R 23 Having the formula XXXIX: where R 33 is H or F, and R 34 is H or F, or a pharmaceutically acceptable salt thereof.

198. A compound according to any one of the preceding claims, wherein R 33 is H and R 34 is H, or a pharmaceutically acceptable salt thereof.

199. A compound according to any one of the preceding claims, wherein R 33 is F and R 34 is F, or a pharmaceutically acceptable salt thereof.

200. A compound according to any one of the preceding claims, wherein R 23 Has the formula XVI, wherein X 3 is N; n is 0; v is 1; R 6 It is H; X 4 is a key; and X 11 is C(H), or a pharmaceutically acceptable salt thereof.

201. A compound according to any one of the preceding claims, wherein R 23 With Formula XL: or a pharmaceutically acceptable salt thereof.

202. A compound according to any one of the preceding claims, wherein R 23 Has the formula XVI, wherein X 3 It is N; X 10 is CH2; n is 1; v is 2; R 6 It is H; X 4 is a key; and X 11 is C(H), or a pharmaceutically acceptable salt thereof.

203. A compound according to any one of the preceding claims, wherein R 23 With formula XLI: or a pharmaceutically acceptable salt thereof.

204. A compound according to any one of the preceding claims, wherein R 23 is a 5-membered ring, or a pharmaceutically acceptable salt thereof.

205. A compound according to any one of the preceding claims, wherein n is 1, v is 1 and X 4 is a bond; or n is 0, v is 1 and X 4 is not a bond, or a pharmaceutically acceptable salt thereof.

206. A compound according to any one of the preceding claims, wherein X 3 It is N; X 13 It is C(R 40 )(R 41 );X 11 It is C(R 4 );X 4 It is C(R 38 )(R 39 );X 12 It is C(R 6 )(R 6b ); and n is 0, or a pharmaceutically acceptable salt thereof.

207. A compound according to any one of the preceding claims, wherein R 23 is a 4-membered ring, or a pharmaceutically acceptable salt thereof.

208. A compound according to any one of the preceding claims, wherein n is 0, v is 1 and X 4 is a key, n is 1, v is 0 and X 4 is a bond, or a pharmaceutically acceptable salt thereof.

209. A compound according to any one of the preceding claims, wherein X 3 It is N; X 4 is a key; n is 0; X 11 It is C(R 4 );X 12 It is C(R 6 )(R 6b );X 13 It is C(R 40 )(R 41 ); and v is 1, or a pharmaceutically acceptable salt thereof. A compound according to any one of the preceding claims, wherein R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein (a) C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 Alkoxy and halogen substituents substitution; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, (b) A small portion of C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and (b) A small portion of C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent; (c) C 1-6 Alkyl is optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O) and -N(R 30 )(R 31 ) is substituted with a substituent; or a pharmaceutically acceptable salt thereof.

210. A compound according to any one of the preceding claims, wherein R 5 is a 5-membered heteroaryl group, which is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, wherein the C 1-6 Alkyl or C 1-6 Haloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, halogen and -OH substituents, And wherein said C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

211. A compound according to any one of the preceding claims, wherein R 5 is a 5-membered heteroaryl group, which is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein the C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

212. A compound according to any one of the preceding claims, wherein R 5 Having the formula XXI: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

213. A compound according to any one of the preceding claims, wherein R 5 Having the formula XXII: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl, C 1-6 The substituents are substituted with alkoxy, halogen and -OH, or a pharmaceutically acceptable salt thereof.

214. A compound according to any one of the preceding claims, wherein R 5 Having the formula XXII: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

215. A compound according to any one of the preceding claims, wherein R 5 Having the formula XXIII: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

216. A compound according to any one of the preceding claims, wherein R 5 Having the formula XXIV: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

217. A compound according to any one of the preceding claims, R 5 Having the formula XLIII: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

218. A compound according to any one of the preceding claims, R 5 yes or a pharmaceutically acceptable salt thereof.

219. A compound according to any one of the preceding claims, wherein R 5 yes or a pharmaceutically acceptable salt thereof.

220. A compound according to any one of the preceding claims, wherein R 5 Having formula VII: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl, C 1-6 The substituents are substituted with alkoxy, halogen and -OH, or a pharmaceutically acceptable salt thereof.

221. A compound according to any one of the preceding claims, wherein R 5 Having formula VII: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

222. A compound according to any one of the preceding claims, wherein R 5 Having formula XXV: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

223. A compound according to any one of the preceding claims, wherein R 5 Having the formula XXVI: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

224. A compound according to any one of the preceding claims, wherein R 5 Having the formula XXVII: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

225. A compound according to any one of the preceding claims, wherein R 5 Having the formula XXVIII: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

226. A compound according to any one of the preceding claims, wherein R 5 Having the formula XXIX: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

227. A compound according to any one of the preceding claims, wherein R 5 With the formula XXX: in R 32 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy substituent is substituted, and R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

228. A compound according to any one of the preceding claims, wherein R 5 Having the formula XLII: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

229. A compound according to any one of the preceding claims, wherein R 5 Having the formula XXXI: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

230. A compound according to any one of the preceding claims, wherein R 5 Having the formula XXXII: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

231. A compound according to any one of the preceding claims, wherein R 5 Having the formula XXXIII: in R 20 It is C 1-3 Alkyl, C 3-6 Cycloalkyl, H or C 3-6 Heterocycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

232. A compound according to any one of the preceding claims, wherein R 20 It is C 1-3 Alkyl, such as -CH3, or a pharmaceutically acceptable salt thereof.

233. A compound according to any one of the preceding claims, wherein R 20 is optionally C 1-6 Alkoxy-substituted C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

234. A compound according to any one of the preceding claims, wherein R 20 is C optionally substituted by C1 alkoxy 1-2 alkyl, or a pharmaceutically acceptable salt thereof.

235. A compound according to any one of the preceding claims, wherein R 20 is C optionally substituted by 1 to 3 halogens such as F 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

236. A compound according to any one of the preceding claims, wherein R 20 is methyl optionally substituted by 1 to 3 halogens such as F, or a pharmaceutically acceptable salt thereof.

237. A compound according to any one of the preceding claims, wherein R 20 is -CF3, or a pharmaceutically acceptable salt thereof.

238. A compound according to any one of the preceding claims, wherein R 20 is -CH2CH2OCH3, or a pharmaceutically acceptable salt thereof.

239. A compound according to any one of the preceding claims, wherein R 20 It is C 3-6 Cycloalkyl, for example, C3 cycloalkyl, or a pharmaceutically acceptable salt thereof.

240. A compound according to any one of the preceding claims, wherein R 20 is H, or a pharmaceutically acceptable salt thereof.

241. A compound according to any one of the preceding claims, wherein R 5 Selected from: or a pharmaceutically acceptable salt thereof.

242. A compound according to any one of the preceding claims, wherein R 5 yes or a pharmaceutically acceptable salt thereof.

243. A compound according to any one of the preceding claims, wherein R 5 yes or a pharmaceutically acceptable salt thereof.

244. A compound according to any one of the preceding claims, wherein R 5 Selected from or a pharmaceutically acceptable salt thereof.

245. A compound according to any one of the preceding claims, wherein R 5 Selected from or a pharmaceutically acceptable salt thereof.

246. A compound according to any one of the preceding claims, wherein R 5 Selected from or a pharmaceutically acceptable salt thereof.

247. A compound according to any one of the preceding claims, wherein R 5 yes or a pharmaceutically acceptable salt thereof.

248. A compound according to any one of the preceding claims, wherein R 5 is a 6-membered heteroaryl group, which is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein the C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent, or a pharmaceutically acceptable salt thereof.

249. A compound according to any one of the preceding claims, wherein R 5 Having the formula XLIV: in X 7 is N or CH; X 8 Is N or C (R 21 ); X 9 Is N or C (R 22 ); R 21 It is C 1-3 Alkyl groups, such as -CH3; R 22 It is C 1-3 an alkyl group, such as -CH3, and R 36 Is H or C 1-3 Alkyl, such as -CH3, or a pharmaceutically acceptable salt thereof.

250. A compound according to any one of the preceding claims, wherein R 5 Having the formula VIII: in X 7 is N or CH; X 8 Is N or C (R 21 ); X 9 Is N or C (R 22 ); R 21 It is C 1-3 an alkyl group, such as -CH3; and R 22 is C 1-3 Alkyl, such as -CH3, or a pharmaceutically acceptable salt thereof.

251. A compound according to any one of the preceding claims, wherein R 5 Selected from or a pharmaceutically acceptable salt thereof.

252. A compound according to any one of the preceding claims, wherein R 5 Having the formula XIII: in R 27 It is C 1-6 alkyl; and u is 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

253. A compound according to any one of the preceding claims, wherein R 5 It is C 1-6 Alkyl, optionally substituted by 1 to 3 independently selected -N(H)C(O)R 24 , -oxo (=O), -OC 1-3 Alkyl and -N(R 30 )(R 31 ), or a pharmaceutically acceptable salt thereof.

254. A compound according to any one of the preceding claims, wherein R 5 It is C 1-3 Alkyl, which is optionally replaced by -OC 1-3 The alkyl group is substituted with -O-C1 alkyl, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

255. A compound according to any one of the preceding claims, wherein R 5 is optionally replaced by -N(R 30 )(R 31 ) substituted C 1-3 Alkyl, where R 30 and R 31 Individually selected from H and C 1-3 Alkyl, for example, C1 alkyl, or a pharmaceutically acceptable salt thereof.

256. A compound according to any one of the preceding claims, wherein R 5 Selected from: or a pharmaceutically acceptable salt thereof.

257. A compound according to any one of the preceding claims, wherein R 5 It is C 3-6 Heterocycloalkyl, optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 substituted with alkoxy and halogen, or a pharmaceutically acceptable salt thereof.

258. A compound according to any one of the preceding claims, wherein R 5 is C4 heterocycloalkyl, which is optionally substituted by 1 to 3 independently selected 1-3 substituted with alkoxy and halogen, or a pharmaceutically acceptable salt thereof.

259. A compound according to any one of the preceding claims, wherein R 5 It is C 3-6 Heterocycloalkyl, optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 substituted with alkoxy and halogen, or a pharmaceutically acceptable salt thereof.

260. A compound according to any one of the preceding claims, wherein R 5 is C4 heterocycloalkyl, which is optionally substituted by 1 to 3 independently selected 1-3 substituted with alkoxy and halogen, or a pharmaceutically acceptable salt thereof.

261. A compound according to any one of the preceding claims, wherein R 5 is an azetidine, which is optionally replaced by 1 to 3 independently selected 1-3 substituted with alkoxy and halogen, or a pharmaceutically acceptable salt thereof.

262. A compound according to any one of the preceding claims, wherein R 5 yes It is optionally substituted by 1 or 2 independently selected from C 1-3 The present invention is substituted with a substituent selected from the group consisting of alkoxy such as C1 alkoxy and halogen such as F, or a pharmaceutically acceptable salt thereof.

263. A compound according to any one of the preceding claims, wherein R 5 yes: or a pharmaceutically acceptable salt thereof.

264. A compound according to any one of the preceding claims, wherein R 5 is a C6 heterocycloalkyl group, which is optionally substituted by 1 to 3 independently selected from oxo (=O), C 1-3 substituted with alkoxy and halogen, or a pharmaceutically acceptable salt thereof.

265. A compound according to any one of the preceding claims, wherein R 5 yes: or a pharmaceutically acceptable salt thereof.

266. A compound according to any one of the preceding claims, wherein the C 3-6 Heterocycloalkyl is selected from: or a pharmaceutically acceptable salt thereof.

267. A compound according to any one of the preceding claims, wherein R 6 is H, or a pharmaceutically acceptable salt thereof.

268. A compound according to any one of the preceding claims, wherein R 6 It is C 1-3 Alkyl, for example, C1 alkyl, or a pharmaceutically acceptable salt thereof.

269. A compound according to any one of the preceding claims, wherein R 6 It's a halogen.

270. A compound according to any one of the preceding claims, wherein R 6b is H, or a pharmaceutically acceptable salt thereof.

271. A compound according to any one of the preceding claims, wherein R 6b It is C 1-3 Alkyl, for example, C1 alkyl, or a pharmaceutically acceptable salt thereof.

272. A compound according to any one of the preceding claims, wherein R 6b It's a halogen.

273. A compound according to any one of the preceding claims, wherein R 6 and R 6b is H, or a pharmaceutically acceptable salt thereof.

274. A compound according to any one of the preceding claims, wherein R 6 and R 6b It is C 1-3 Alkyl, for example, C1 alkyl, or a pharmaceutically acceptable salt thereof.

275. A compound according to any one of the preceding claims, wherein R 6 and R 6b It is C 1-3 Alkyl, and R 6 and R 6b are linked together to form a 3- to 6-membered ring, for example, a 4-membered ring or a 3-membered ring, or a pharmaceutically acceptable salt thereof.

276. A compound according to any one of the preceding claims, wherein R 6 and R 6b It is C 1-3 Alkyl, and R 6 and R 6b are linked together to form a 3- to 6-membered ring, and one methylene group is replaced by -O-, or a pharmaceutically acceptable salt thereof.

277. A compound according to any one of the preceding claims, wherein R 6 and R 6b It is C 1-3 Alkyl, and R 6 and R 6b are linked together to form a 3- to 6-membered ring, and one methylene group is replaced by -N(R 35 )-replacement, where R 35 Selected from H, C 1-3 Alkyl and -C(O)C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

278. A compound according to any one of the preceding claims, wherein X 10 is C(H)(R 7 ), or a pharmaceutically acceptable salt thereof.

279. A compound according to any one of the preceding claims, wherein R 7 is H, or a pharmaceutically acceptable salt thereof.

280. A compound according to any one of the preceding claims, wherein R 37 is H, or a pharmaceutically acceptable salt thereof.

281. A compound according to any one of the preceding claims, wherein R 7 is H and R 37 is H, or a pharmaceutically acceptable salt thereof.

282. A compound according to any one of the preceding claims, wherein X 10 is C(H)2, or a pharmaceutically acceptable salt thereof.

283. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

284. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

285. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

286. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

287. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

288. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

289. A compound according to any one of the preceding claims, wherein R 23 yes or a pharmaceutically acceptable salt thereof.

290. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

291. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

292. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

293. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

294. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

295. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

296. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

297. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

298. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

299. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 23 Selected from:

300. A compound according to any one of the preceding claims, wherein R 23 Selected from: or a pharmaceutically acceptable salt thereof.

301. A compound according to any one of the preceding claims, wherein X 3 It is N, X 4 It's O, R 4 It's H, R 6 It's H, X 10 is C(H)(R 7 ), R 7 is H and n is 1, or a pharmaceutically acceptable salt thereof.

302. A compound according to any one of the preceding claims, wherein X 3 It is CH, X 4 It's O, R 4 It's H, R 6 It's H, X 10 is C(H)(R 7 ), R 7 is H and n is 1, or a pharmaceutically acceptable salt thereof.

303. A compound according to any one of the preceding claims, wherein X 3 It is N, X 4 It is a key, R 4 It's H, R 6 is H and n is 0, or a pharmaceutically acceptable salt thereof.

304. A compound according to any one of the preceding claims, wherein R 23 Having the formula XI: in R 25 Select C alone 1-6 Alkyl, -OC 1-6 Alkyl, halogen, C 1-6 haloalkyl and -CN; and t is 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

305. A compound according to any one of the preceding claims, wherein R 23 Having the formula XIX: in R 26 is a 5-membered or 6-membered heteroaryl group, which is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein the C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) is substituted with a substituent; and R 29 is a bond, -O- or a C in which one methylene group is optionally replaced by -O- 1-6 hydrocarbon chain; or a pharmaceutically acceptable salt thereof.

306. A compound according to any one of the preceding claims, wherein R 23 Having the formula XII: in R 26 is a 5-membered or 6-membered heteroaryl group, which is optionally substituted by 1 to 3 independently selected halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl and C 3-6 The substituent of the heterocycloalkyl group is substituted, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with -OH, and wherein the C 3-6 Heterocycloalkyl is optionally substituted by 1 to 3 independently selected from halogen, C 1-3 Alkyl and -C(O)O(C 1-6 alkyl) or a pharmaceutically acceptable salt thereof.

307. A compound according to any one of the preceding claims, wherein R 26 It is R 5 .

308. A compound according to any one of the preceding claims, wherein R 23 yes or a pharmaceutically acceptable salt thereof.

309. A compound according to any one of the preceding claims, wherein R 23 Having the formula XIV: in R 27 It is C 1-6 alkyl; and u is 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

310. A compound according to any one of the preceding claims, wherein R 23 is a 3-membered ring, or a pharmaceutically acceptable salt thereof.

311. A compound according to any one of the preceding claims, wherein X 3 It is C(R 8 );X 4 is a key; n is 0; X 11 It is C(R 4 );X 12 It is C(R 6 )(R 6b ); and v is 0, or a pharmaceutically acceptable salt thereof.

312. A compound according to any one of the preceding claims, wherein X 3 is C(H), X 12 is C(H)2, X 4 Yes key, X 11 is C(H), n is 0 and v is 0, or a pharmaceutically acceptable salt thereof.

313. A compound according to any one of the preceding claims, wherein R 23 Having the formula LXII: or a pharmaceutically acceptable salt thereof.

314. A compound according to any one of the preceding claims, wherein R 23 Having formula LXIIa or formula LXIIb: or a pharmaceutically acceptable salt thereof.

315. A compound according to any one of the preceding claims, wherein R 23 yes or a pharmaceutically acceptable salt thereof.

316. A compound according to any one of the preceding claims, wherein R 23 Having the formula XVII: or a pharmaceutically acceptable salt thereof.

317. A compound according to any one of the preceding claims, wherein R 23 Having the formula XVIII: or a pharmaceutically acceptable salt thereof.

318. A compound according to any one of the preceding claims, wherein R 23 With formula X: or a pharmaceutically acceptable salt thereof.

319. A compound according to any one of the preceding claims, wherein R 29 is a bond, or a pharmaceutically acceptable salt thereof.

320. A compound according to any one of the preceding claims, wherein R 29 It is C 1-3 Alkoxy, or a pharmaceutically acceptable salt thereof.

321. A compound according to any one of the preceding claims, wherein R 29 Yes-OC 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

322. A compound according to any one of the preceding claims, wherein X 11 It is C(R 4 ), or a pharmaceutically acceptable salt thereof.

323. A compound according to any one of the preceding claims, wherein X 11 is N, or a pharmaceutically acceptable salt thereof.

324. A compound according to any one of the preceding claims, wherein X 13 is CH2, or a pharmaceutically acceptable salt thereof.

325. A compound according to any one of the preceding claims, wherein R 40 is H, or a pharmaceutically acceptable salt thereof.

326. A compound according to any one of the preceding claims, wherein R 41 is H, or a pharmaceutically acceptable salt thereof.

327. A compound according to any one of the preceding claims, wherein R 40 is H and R 41 is H, or a pharmaceutically acceptable salt thereof.

328. A compound according to any one of the preceding claims, wherein v is 1, or a pharmaceutically acceptable salt thereof.

329. A compound according to any one of the preceding claims, wherein v is 0, or a pharmaceutically acceptable salt thereof.

330. A compound according to any one of the preceding claims, wherein v is 2, or a pharmaceutically acceptable salt thereof.

331. A compound according to any one of the preceding claims, wherein R 5 It is C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl, and the C 3-6 Cycloalkyl or C 3-6 The heterocycloalkyl group is optionally substituted with oxo (=O), or a pharmaceutically acceptable salt thereof.

332. A compound according to any one of the preceding claims, wherein R 5 It is C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally replaced by -N(H)C(O)R 24 replace.

333. A compound according to any one of the preceding claims, wherein R 9 It is C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or -C(O)-C 3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

334. A compound according to any one of the preceding claims, wherein R 29 is a bond, or a pharmaceutically acceptable salt thereof.

335. A compound according to any one of the preceding claims, wherein R 29 is O, or a pharmaceutically acceptable salt thereof.

336. A compound according to any one of the preceding claims, wherein R 30 is H, or a pharmaceutically acceptable salt thereof.

337. A compound according to any one of the preceding claims, wherein R 30 It is C 1-3 Alkyl, for example, C1 alkyl, or a pharmaceutically acceptable salt thereof.

338. A compound according to any one of the preceding claims, wherein R 31 is H, or a pharmaceutically acceptable salt thereof.

339. A compound according to any one of the preceding claims, wherein R 31 It is C 1-3 Alkyl, for example, C1 alkyl, or a pharmaceutically acceptable salt thereof.

340. A compound according to any one of the preceding claims, wherein R 30 It is C 1-3 Alkyl, such as C1 alkyl, and R 31 is H, or a pharmaceutically acceptable salt thereof.

341. A compound according to any one of the preceding claims, wherein R 30 It is C 1-3 Alkyl, such as C1 alkyl, and R 31 It is C 1-3 Alkyl, for example, C1 alkyl, or a pharmaceutically acceptable salt thereof.

342. A compound according to any one of the preceding claims, wherein v is 1, or a pharmaceutically acceptable salt thereof.

343. A compound according to any one of the preceding claims, wherein v is 2, or a pharmaceutically acceptable salt thereof.

344. A compound according to any one of the preceding claims, wherein n is 0, or a pharmaceutically acceptable salt thereof.

345. A compound according to any one of the preceding claims, wherein n is 1, or a pharmaceutically acceptable salt thereof.

346. A compound according to any one of the preceding claims, wherein X 12 It is CH2, R 29 is a bond and R 5 is optionally C 1-6 Alkyl or C 3-6 Cycloalkyl-substituted pyrazolyl, or a pharmaceutically acceptable salt thereof.

347. A compound according to any one of the preceding claims, wherein X 12 It is CH2, R 29 is a bond and R 5 It is C 3-6 Pyrazolyl substituted with a cycloalkyl group such as cyclopropyl, or a pharmaceutically acceptable salt thereof.

348. A compound according to any one of the preceding claims, wherein the halogen is F, or a pharmaceutically acceptable salt thereof.

349. A compound according to any one of the preceding claims, wherein the halogen is Cl, or a pharmaceutically acceptable salt thereof.

350. The compound of claim 1, wherein the compound has the formula LXI, wherein X 1 It is N; X 2 It is N; X 14 It is N; R 1 Yes -CF3, R 2 It is C 1-6 Alkyl, such as CH3, R 3 Having formula IV: in R 12 It is H, halogen, C 1-3 Alkyl or C 1-3 alkyl halide; R 13 It is H, halogen, C 1-3 Alkyl or C 1-3 alkyl halide; R 14 It is H, halogen, C 1-3 Alkyl or C 1-3 haloalkyl; and R 15 It is H, halogen, C 1-3 Alkyl or C 1-3 haloalkyl, or a pharmaceutically acceptable salt thereof.

351. The compound according to claim 350, wherein R 12 is a halogen, R 13 It's H, R 14 is a halogen and R 15 is H, or a pharmaceutically acceptable salt thereof.

352. The compound of claim 351, wherein R 12 is F and R 14 is Cl, or a pharmaceutically acceptable salt thereof.

353. A compound according to any one of claims 350 to 352, wherein R 23 Having the formula XXXIV: in R 6 is H, halogen or C 1-3 alkyl; R 6b is H, halogen or C 1-3 alkyl; and R 29 It's the key. or a pharmaceutically acceptable salt thereof.

354. The compound according to claim 353, wherein R 6 is H and R 6b It’s H.

355. A compound according to any one of claims 350 to 354, wherein R 5 Having the formula XXII: in R 20 It is C 1-3 Alkyl or C 3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

356. A compound according to any one of claims 350 to 355, wherein R 5 Having formula VII: in R 20 It is C 1-3 Alkyl or C 3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

357. A compound according to any one of claims 350 to 356, wherein R 23 yes or a pharmaceutically acceptable salt thereof.

358. A compound according to any one of claims 350 to 356, wherein R 23 yes or a pharmaceutically acceptable salt thereof.

359. The compound of claim 1, wherein the compound has the formula LXI, wherein X 1 It is N; X 2 It is N; X 14 It is N; R 1 It is -CH3, R 2 It is C 1-6 Alkyl, such as CH3, R 3 Having formula IV: in R 12 It is H, halogen, C 1-3 Alkyl or C 1-3 alkyl halide; R 13 It is H, halogen, C 1-3 Alkyl or C 1-3 alkyl halide; R 14 It is H, halogen, C 1-3 Alkyl or C 1-3 haloalkyl; and R 15 It is H, halogen, C 1-3 Alkyl or C 1-3 haloalkyl, or a pharmaceutically acceptable salt thereof.

360. The compound according to claim 359, wherein R 12 is a halogen, R 13 It's H, R 14 is a haloalkyl group and R 15 is H, or a pharmaceutically acceptable salt thereof.

361. The compound according to claim 360, wherein R 12 is F and R 14 is CF3, or a pharmaceutically acceptable salt thereof.

362. according to the compound described in any one of claims 359 to 361, wherein R 23 Having the formula XXXIV: in R 6 is H, halogen or C 1-3 alkyl; R 6b is H, halogen or C 1-3 alkyl; and R 29 It's the key. or a pharmaceutically acceptable salt thereof.

363. The compound according to claim 362, wherein R 6 is H and R 6b It’s H.

364. according to the compound described in any one of claim 359 to 363, wherein R 5 is Formula VIII: in X 7 is N or CH; X 8 Is N or C (R 21 ); X 9 Is N or C (R 22 ); R 21 It is C 1-3 an alkyl group, such as -CH3; and R 22 It is C 1-3 Alkyl, such as -CH3, or a pharmaceutically acceptable salt thereof.

365. according to the compound described in any one of claim 359 to 364, wherein R 5 yes or a pharmaceutically acceptable salt thereof.

366. A compound according to any one of claims 359 to 365, wherein R 23 yes or a pharmaceutically acceptable salt thereof.

367. A compound according to any one of claims 359 to 366, wherein R 23 yes or a pharmaceutically acceptable salt thereof.

368. The compound of any one of the preceding claims, wherein the compound is selected from: 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methylpyridin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methylpyridin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methylpyrimidin-5-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methylpyrimidin-5-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(6-methylpyridazin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(6-methylpyridazin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(3R)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(3S)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4S)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4S)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4S)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-{6,6-difluorospiro[3.3]hept-2-yl}-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-{6,6-difluorospiro[3.3]hept-2-yl}-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,3r)-3-(trifluoromethyl)cyclobutyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,3r)-3-(trifluoromethyl)cyclobutyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[6-(trifluoromethyl)pyridin-3-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[6-(trifluoromethyl)pyridin-3-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,3,4-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,3,4-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(3,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(3,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(3,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(3,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,4r)-4-methylcyclohexyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,4r)-4-methylcyclohexyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-[2-Fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-[2-Fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(oxan-4-yl)-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one; 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(oxan-4-yl)-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one; 8-(4,4-difluoropiperidin-1-yl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one; 8-(4,4-difluoropiperidin-1-yl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-{3-[(1-methyl-1H-pyrazol-4-yl)oxy]azetidin-1-yl}-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(3R)-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(3S)-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(3R)-4-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(3S)-4-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1s,4s)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1r,4r)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-(4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)azetidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)azetidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)methoxy)azetidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (S)--6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-(4-ethyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-(4-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-(4-(2,2-difluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-(1-methyl-1H-pyrazol-4-yl)-4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-(4-(2-methoxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyrimidin-5-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-3-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 2,3-Dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 2,3-Dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-(2-(1H-pyrazol-4-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-(2-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-5-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(4-methylthiazol-2-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(3-methyl-1H-1,2,4-triazol-5-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-(2-(1H-pyrazol-3-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(thiazol-2-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 4-(4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-2-yl)-N-methylmorpholine-2-carboxamide; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 4-(4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-2-yl)-N,N-dimethylmorpholine-2-carboxamide; 8-(4-chloro-2-fluorophenyl)-6-(2-(methoxymethyl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-(2-((dimethylamino)methyl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-oxa-9-azaspiro[4.5]dec-9-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-methyl-2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(9-methyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 6-(2-(1,2,4-oxadiazol-3-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-3-(4-methoxybenzyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-3-(2-methoxyethyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one; (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)pyrrolidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(2-chloro-4-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 2,3-Dimethyl-6-((R)-2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1r,4R)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 2,3-Dimethyl-6-((S)-2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1r,4S)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(6,6-difluorospiro[3.3]hept-2-yl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-1,2,3-triazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)pyrrolidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-morpholinopiperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-(3-(3-methoxyazetidin-1-yl)piperidin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-(3-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 6-(2-(1H-imidazol-2-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-imidazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(4-((3-methylpyridin-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-(2,3-dihydrospiro[indene-1,2'-morpholino]-4'-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5,6,7,9-tetrahydro-8H-pyrido[3,4-c]azepine-8-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(piperidin-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 2,3-Dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 2,3-Dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro(3,5)nonan-8-yl)pyrimido(5,4-d)pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methyl-2H-1,2,3-triazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-6-(4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-6-(4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoro-15-methyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoro-15-methyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-3-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,2-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,2-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)quinazolin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro(2,5)octan-7-yl)pyrimido(5,4-d)pyrimidin-4(3H)-one; (S)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-8(7H)-one; 8-(4-chloro-2-fluorophenyl)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-3-oxabicyclo[4.1.0]hept-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-((1S,2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-3-oxabicyclo[4.1.0]hept-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-((1R,2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-3-oxabicyclo[4.1.0]hept-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylquinazolin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylquinazolin-4(3H)-one; 6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one; 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one; 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylquinazolin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylquinazolin-4(3H)-one; 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one; 8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one (S)-2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; 2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(2-methylpyridin-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(2-methylpyridin-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (R)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R) 8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,2-d]pyrimidin-4(3H)-one; (S) 8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,2-d]pyrimidin-4(3H)-one; (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-2,3-Dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methyl-2H-1,2,3-triazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methyl-2H-1,2,3-triazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((1R,2S)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((1R,2R)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-2,3-Dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(2,4-difluorophenyl)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(2,4-difluorophenyl)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-5-fluoro-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 8-(2,4-difluorophenyl)-5-fluoro-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-8-(2,4-difluorophenyl)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(2,4-difluorophenyl)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; 6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-5-fluoro-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (S)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(4-chloro-2-fluorophenyl)-5-fluoro-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(4-chloro-2-fluorophenyl)-5-fluoro-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (R)-8-(2,4-difluorophenyl)-5-fluoro-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(2,4-difluorophenyl)-5-fluoro-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; (8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (trans racemate); 8-(4-chloro-2-fluorophenyl)-6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; (R)-8-(6-(difluoromethyl)pyridin-3-yl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (S)-8-(6-(difluoromethyl)pyridin-3-yl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (R)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; (S)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; 8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; 8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2R,4S,6R)-2-methyl-6-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-3-methyl-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-3-methyl-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(2,4-difluorophenyl)-3-methyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 8-(2,4-difluorophenyl)-3-methyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; 8-(2,4-difluorophenyl)-3-methyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; 8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one; 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one dimethylpyrido[3,4-d]pyrimidin-4(3H)-one; 5-chloro-2-(6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)benzonitrile; 2,3-Dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 2,3-Dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 4-(6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile; 4-(6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile; 2-(6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-fluorobenzonitrile; 2-(6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-fluorobenzonitrile; 2-(6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-(trifluoromethyl)benzonitrile; 2-(6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-(trifluoromethyl)benzonitrile; (R)-8-(4-chloro-2-fluorophenyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one; and (S)-8-(4-chloro-2-fluorophenyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.

369. A compound according to any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a TREM2 modulator, e.g., a TREM2 activator, e.g., a TREM2 agonist.

370. A compound according to any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound enhances or activates TREM2 signaling through DAP12; and / or wherein the compound induces phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex, such as but not limited to Syk, ZAP70, PI3K, Erk, AKT and GSK3b; and / or wherein the compound enhances the level of phosphorylation of TREM2-induced Syk kinase.

371. A compound according to any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound increases the expression of one or more TREM2-regulated genes, for example, wherein the compound increases the expression of one or more TREM2-regulated genes selected from CXCL10, CCL2, CST7 and TMEM119.

372. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

373. A compound according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 372 for use as a medicament.

374. A compound according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 372, for use in treating a condition associated with loss of TREM2 function, such as for treating a condition associated with a TREM2 mutation.

375. A compound according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 372 for use in treating a neurodegenerative disease.

376. A compound for use according to any one of claims 1 to 371368, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 372, wherein the neurodegenerative disease is selected from tauopathy, TDP-43 proteinopathy, synucleinopathy, dementia, amyloidosis, demyelinating disorders of the CNS, demyelinating disorders of the PNS, leukoencephalopathy, leukodystrophy, transmissible spongiform encephalopathy (TSE) and lysosomal storage disease (LSD).

377. A compound for use according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 372, for treating a neurodegenerative disease selected from the group consisting of Alzheimer's disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), Parkinson's disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth disease, prion disease and stroke.

378. A compound for use according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 372, for treating a disease selected from the group consisting of arthritis, rheumatoid arthritis, pyle's disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, bone dysplasia, autism spectrum disorder, autism and Aspergers syndrome, traumatic brain injury (TBI), spinal cord injury, muscular dystrophy, myotonic dystrophy, inclusion body myositis, systemic lupus erythematosus (SLE), RA, gout, intestinal conditions, inflammatory bowel disease (IBD), metabolic syndrome, obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver disease, alcoholic and non-alcoholic steatohepatitis, and amyloidosis.

379. The compound for use according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 372, wherein the compound is administered in an amount of about 0.01 mg / kg to about 100 mg / kg body weight per day.

380. The compound for use according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 372, wherein the compound is administered enterally, orally, topically, parenterally, intravenously, intradermally, intramuscularly, intrathecally, colonically, rectally or intraperitoneally.

381. A method of treating a condition associated with loss of TREM2 function, such as a neurodegenerative disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 372.

382. Use of a compound according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 372, in the manufacture of a medicament for treating a condition associated with loss of TREM2 function, such as a neurodegenerative disease.

383. A method of enhancing or increasing TREM2 activity in a subject in need thereof, e.g., a subject with a neurodegenerative disease, e.g., one or more of the following methods: i) enhancing or activating TREM2 signaling through DAP12, ii) inducing phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, and GSK3b, iii) enhancing the level of TREM2-induced phosphorylation of Syk kinase, iv) increasing the expression level of one or more TREM2-regulated genes, e.g., brain expression level, and / or v) increasing the expression level of one or more TREM2-regulated genes selected from CXCL10, CCL2, CST7, and TMEM119, e.g., brain expression level; the method comprising administering to the subject a compound according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof.

384. A process for preparing a compound of formula IX according to any one of claims 1 to 371, comprising the steps of: a. Make (R 1 CO)2O compound reacts with 5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid to generate compound A1 b. the compound of formula A1 generated in a) and formula R 2 NH2 compound reacts to produce compound A2: c. Activating the compound of formula A2 generated in b) with POY3, wherein Y is Cl or Br, to produce a compound of formula A3: d. making the compound of formula A3 generated in c) with R 3 W 1 Reaction, wherein W is B(OH)2, OH or NH, to produce a compound of formula A4: and e. the compound of formula A4 generated in d) and R 23 W 2 Reaction, wherein W is B(OH)2, OH or NH, produces a compound of formula IX.

385. A method for preparing a compound of formula B6, comprising the following steps: a. Make R 1 COCl reacts with the compound of formula B1 to form a compound of formula B2: b. hydrolyzing the ester of B2 to form a compound of formula B3: c. Make the compound of formula B3 and R 2 NH2 reacts to form a compound of formula B4: d. Make the compound of formula B4 and R 3 W 1 reaction, where W 1 It is B(OH)2, OH or NH, generating compound B5: and e. Make the compound of formula B5 and R 23 W 2 reaction, where W 2 It is B(OH)2, OH or NH, generating compound B6: where R 1 、R 2 、R 3 and R 23 As defined in any one of claims 1 to 371, and R is an alkyl group, such as C 1-6 alkyl; A is N, CH, or CF; Q is N or CH; X is Cl or Br; and Y is Cl or Br.

386. A method for preparing a compound of formula C4, comprising the steps of: a. Make the compound of formula C1 and the original acetate reagent (eg R 1 C (OEt) 3) reaction to form a compound of formula C2: b. Make the compound of formula C2 and R 3 W 1 reaction, where W 1 It is B(OH)2, OH or NH, generating compound C3: and c. Make the compound of formula C3 and R 23 W 2 reaction, where W 2 It is B(OH)2, OH or NH, and the formula is C4 compound: where R 1 、R 2 、R 3 and R 23 As defined in any one of claims 1 to 371, and A is CH, CF or N; Q is N or CH; X is Cl or Br; and Y is Cl or Br.

387. A method for preparing a compound of formula D6, comprising the following steps: a. Make the compound of formula D1 and R 23 W 2 reaction, where W 2 It is B(OH)2, OH or NH, and the compound of formula D2 is: b. Make the compound of formula D2 and R 3 W 1 reaction, where W 1 It is B(OH)2, OH or NH, and the compound of formula D3 is: c. The compound of formula D3 is reduced and hydrolyzed to produce a compound of formula D4: d. Make the compound of formula D4 and (R 1 CO)2O reaction to generate compound D5: and e. Make the compound of formula D5 and R 2 NH2 reaction, generating compound D6: where R 1 、R 2 、R 3 and R 23 As defined in any one of claims 1 to 371, wherein X is Cl or Br; and Y is Cl or Br, and R is an alkyl group, such as C 1-6 alkyl.

388. A method for preparing a compound of formula E7, comprising the following steps: a. Make the compound of formula E1 and R 1 CCH reaction to generate compound E2: b. The compound of formula E2 is hydrolyzed to produce a compound of formula E3: c. Make the compound of formula E3 and R 2 NH2 reacts and removes the R-group to generate a compound of formula E4: d. The compound of formula E4 is reacted with POCl3 or POBr3 to produce a compound of formula E5: e. Make the compound of formula E5 and R 3 W 1 reaction, where W 1 is B(OH)2, OH or NH, generating compound E6: and f. Make the compound of formula E6 and R 23 W 2 reaction, where W 2 is B(OH)2, OH or NH, generating compound E7: where R 1 、R 2 、R 3 and R 23 As defined in any one of claims 1 to 371, wherein R is a suitable protecting group, such as PMB; and X is I, Cl or Br.

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