Pyrazolopyrazine compounds as SHP2 inhibitors

Abstract

Provided herein are compounds and pharmaceutical compositions thereof for modulating SHP2, and their use in the treatment of diseases.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 291,012, filed December 17, 2021, and U.S. Provisional Application No. 63 / 431,260, filed December 8, 2022, the disclosures of each of which are incorporated by reference in their entireties herein.

[0002] The present disclosure relates to inhibitors of the protein tyrosine phosphatase SHP2 that are useful for treating diseases or disorders, such as cancer. Specifically, the disclosure describes compounds and compositions that inhibit SHP2, methods of treating diseases associated with SHP2, and methods of synthesizing these compounds. [Background technology]

[0003] SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is involved in signal transduction through the Ras-mitogen-activated protein kinase, JAK-STAT, or phosphoinositol 3-kinase-AKT pathways.

[0004] Mutations in the PTPN11 gene and subsequently SHP2 have been identified in several human diseases, such as Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, melanoma, neuroblastoma, acute myeloid leukemia, and breast, lung, colon, and brain cancers, including glioblastoma (Chan, G. et al., Cancer Metastasis Rev. 2008, 27, 179-192; Zhang, J. et al., J. Cell. Mol. Med. 2015, 19, 2075-2083; Roccograndi L. et al., J. Neuro-Oncol. 2017, 135, 487-496; Mitra R. et al., ChemMedChem 2021, 16, 777-787). Thus, SHP2 represents a highly attractive target for the development of novel therapies for the treatment of various diseases, including cancer. For treating or preventing brain-related cancers, SHP2 inhibitors with brain-penetrating capabilities are particularly attractive.

[0005] Accordingly, in one aspect, there is provided herein compounds that are modulators of SHP2 for use in treating diseases such as cancer. Summary of the Invention

[0006] Described herein, in certain embodiments, are compounds and compositions thereof for modulating SHP2 to treat diseases such as cancer.

[0007] The following embodiments are included:

[0008] Embodiment 1 is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, Ring A is C 3 -C 6cycloalkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, where heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O, and S; Each R 1 are independently halo, cyano, -NR 2a R 2b , C 1 -C 6 Alkyl, oxo, hydroxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-OH, C 1 -C 6 Alkyl-CN, -C(O)NR 2a R 2b , -C(O)(C 1 -C 6 Alkyl), -CO 2 H, -CO 2 (C 1 -C 6 alkyl), -Si(R a )(R b )(R c ), -P(O)(R a )(R b ), -OP(O)(R a )(R b ), C 3 -C 6 cycloalkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, where heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O, and S; or two R's 1 The groups, together with the carbon atom or heteroatom to which they are attached, form a fused phenyl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which may be selected from 1 to 4 R 6 groups, and the fused heterocycloalkyl and heteroaryl contain 1 to 3 heteroatoms selected from N, O, and S; Each R a , R b , and Rc are independently hydroxy, C 1 -C 6 Alkyl, or C 1 -C 6 is alkoxy; Each R 2a and R 2b are independently H, C 1 -C 6 Alkyl, or C 3 -C 6 is cycloalkyl; L is a bond, S, O, C(O), or N(R d ) and; R d is H or C 1 -C 6 is alkyl; X is CR 3a R 3b , N.R. 3a , or O; R 3a and R 3b are independently H or C 1 -C 6 is alkyl; R 4 , H, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-OH, C 1 -C 6 Haloalkyl, or -NH 2 and; Each R 5 Independently, Halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -(C 1 -C 6 Alkylene)(C 1 -C 6 alkoxy), or C 1 -C 6 is alkyl-OH; Ring B is a fused phenyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Each R 6is independently 1 -C 6 Alkyl, halo, or C 1 -C 6 is haloalkyl; Each R 7 is independently 1 -C 6 Alkyl, halo, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-OH, hydroxy, cyano, -Si(R a )(R b )(R c ), -P(O)(R a )(R b ), -OP(O)(R a )(R b ), -NR 2a R 2b , or C 1 -C 6 is haloalkyl; x is 0 to 5; y is 0 to 2; z is 0 to 4; One or more hydrogen atoms in the compound are optionally replaced by deuterium).

[0009] Embodiment 2 is a compound according to embodiment 1, or a pharma- ceutically acceptable salt thereof; Ring A is C 3 -C 5 cycloalkyl, phenyl, a 6-membered heterocycloalkyl, or a 5-6 membered heteroaryl, where the heterocycloalkyl and heteroaryl contain 1-2 heteroatoms selected from N, O, and S.

[0010] Embodiment 3 is a compound according to embodiment 1 or 2, or a pharma- ceutically acceptable salt thereof; Ring A is cyclopropyl, phenyl, dihydropyridinyl, dihydropyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, isoxazolyl, or thiophenyl.

[0011] Embodiment 4 is a compound according to any one of embodiments 1 to 3, or a pharma- ceutically acceptable salt thereof; [ka] teeth, [ka] It is.

[0012] Embodiment 5 is a compound according to any one of embodiments 1 to 4, or a pharma- ceutically acceptable salt thereof; x is 0, 1, 2, or 3; Each R 1 -, if present, independently represents halo, cyano, -NR 2a R 2b , C 1 -C 3 Alkyl, oxo, hydroxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Alkyl-OH, C 1 -C 3 Alkyl-CN, -C(O)NR 2a R 2b , -C(O)(C 1 -C 3 Alkyl), -CO 2 H, -CO 2 (C 1 -C 3 alkyl), -Si(R a )(R b )(R c ), -P(O)(R a )(R b ), -OP(O)(R a )(R b ), C 3 -C 5 cycloalkyl, phenyl, or 6-membered heterocycloalkyl, where heterocycloalkyl contains 1-2 heteroatoms selected from N and O; or two R's 1 The groups, together with the carbon atom or heteroatom to which they are attached, form a fused phenyl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which may be selected from 1 to 2 R 6 groups, and the fused heterocycloalkyl and heteroaryl contain 1-2 heteroatoms selected from N, O, and S; Each R a , R b , and R c is independently 1 -C 3 Alkyl or C 1 -C 3 is alkoxy; Each R 2a and R 2b are independently H, C 1 -C 3 Alkyl, or C 3 -C 5 is cycloalkyl; Each R 6 is independently 1 -C 3 Alkyl, halo, or C 1 -C 3 It is haloalkyl.

[0013] Embodiment 6 is a compound according to any one of embodiments 1 to 5, or a pharma- ceutically acceptable salt thereof; Each R 1 When present, each independently represents F, Cl, -CN, -CH 2 CN, -NH 2 , -N(H)CH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , oxo, -CF 3 , -OCH 3 , -CH 2 OH, -C(O)N(CH 3 ) 2 , -C(O)CH3 , cyclopropyl, or [ka] and; or two R's 1 Groups, together with the carbon atom or heteroatom to which they are attached, [ka] The condensation group is selected from the group consisting of:

[0014] Embodiment 7 is a compound according to any one of embodiments 1 to 6, or a pharma- ceutically acceptable salt thereof; [ka] teeth, [ka] [ka] It is.

[0015] Embodiment 8 is a compound according to any one of embodiments 1 to 7, or a pharma- ceutically acceptable salt thereof; L is a bond, O, C(O), or N(R d ) and; R d is H or C 1 -C 3 It is an alkyl.

[0016] Embodiment 9 is a compound according to any one of embodiments 1 to 8, or a pharma- ceutically acceptable salt thereof; X is CR 3a R 3b , N.R. 3a , or O; R 3a and R 3b are independently H or C1 -C 3 It is an alkyl.

[0017] Embodiment 10 is a compound according to embodiment 9, or a pharma- ceutically acceptable salt thereof; X is CH 2 , N(H), N(CH 3 ), or O.

[0018] Embodiment 11 is a compound according to any one of embodiments 1 to 10, or a pharma- ceutically acceptable salt thereof; R 4 , H, C 1 -C 3 Alkyl, C 1 -C 3 Alkyl-OH, C 1 -C 3 Haloalkyl, or -NH 2 It is.

[0019] Embodiment 12 is a compound according to embodiment 11, or a pharma- ceutically acceptable salt thereof; R 4 H, CH 3 , -CH 2 OH, -CH 2 F, or -CHF 2 It is.

[0020] Embodiment 13 is a compound according to any one of embodiments 1 to 12, or a pharma- ceutically acceptable salt thereof; y is 0 or 1; Each R 5 If present, independently, halo, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, -(C 1 -C 3 Alkylene)(C 1 -C 3 alkoxy), or C 1 -C 3 It is alkyl-OH.

[0021] Embodiment 14 is a compound according to embodiment 13, or a pharma- ceutically acceptable salt thereof; Each R 5 When present, each independently represents Cl, F, -CH 2 F, -CHF 2 , -CH 2 OCH 3 , or -CH 2 It is OH.

[0022] Embodiment 15 is a compound according to any one of embodiments 1 to 14, or a pharma- ceutically acceptable salt thereof; Ring B is a fused phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O, and S.

[0023] Embodiment 16 is a compound according to embodiment 15, or a pharma- ceutically acceptable salt thereof; Ring B is a fused phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, or oxazolyl.

[0024] Embodiment 17 is a compound according to any one of embodiments 1 to 16, or a pharma- ceutically acceptable salt thereof; z is 0, 1, or 2; Each R 7 If present, independently, C 1 -C 3 Alkyl, halo, C 1 -C 3 Alkoxy, C 1 -C 3 Alkyl-OH, hydroxy, cyano, -Si(R a )(R b )(R c ), -P(O)(R a )(R b ), -OP(O)(R a )(R b ), -NR 2a R 2b , or C 1 -C 3 is haloalkyl; Each R a , Rb , and R c are independently hydroxy, C 1 -C 3 Alkyl, or C 1 -C 3 is alkoxy; Each R 2a and R 2b are independently H, C 1 -C 3 Alkyl, or C 3 -C 5 It is cycloalkyl.

[0025] Embodiment 18 is a compound according to embodiment 17, or a pharma- ceutically acceptable salt thereof; Each R 7 is, if present, independently CH 3 , F, -OCH 3 , -CH 2 OH, hydroxy, -CN, -N(CH 3 ) 2 , or -CHF 2 It is.

[0026] Embodiment 19 is a compound according to any one of embodiments 1 to 18, or a pharma- ceutically acceptable salt thereof; [ka] teeth, [ka] It is.

[0027] Embodiment 20 is a compound of any one of embodiments 1-19, or a pharma- ceutically acceptable salt thereof, wherein the compound has formula (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIf): [ka] [ka] It is of the following.

[0028] Embodiment 21 is a compound according to embodiment 20, or a pharma- ceutically acceptable salt thereof, wherein the compound has the formula (IIa-1): [ka] It is of the following.

[0029] Embodiment 22 is a compound according to embodiment 21, or a pharma- ceutically acceptable salt thereof; x is 0, 1, or 2; Each R 1 is, when present, independently halo; R 4 is C 1 -C 6 It is an alkyl.

[0030] Embodiment 23 is a compound according to embodiment 22, or a pharma- ceutically acceptable salt thereof; x is 0 or 1; R 1 is F, if present; R 4 is -CH 3 It is.

[0031] Embodiment 24 is a compound according to any one of embodiments 1-19, or a pharma- ceutically acceptable salt thereof, wherein the compound has formula (IVa), (IVb), (IVc), (IVd), or (IVe): [ka] It is.

[0032] Embodiment 25 is a compound selected from the compounds in Table 1, or a pharma- ceutically acceptable salt thereof.

[0033] Embodiment 26 is a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 25, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0034] Embodiment 27 is a method of inhibiting SHP2, comprising contacting SHP2 with an effective amount of a compound of any one of embodiments 1 to 25, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 26.

[0035] Embodiment 28 is a method for treating a disease associated with SHP2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of embodiments 1 to 25, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 26.

[0036] Embodiment 29 is the method of embodiment 28, wherein the disease is Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, lung cancer, colon cancer, or brain cancer, optionally wherein the brain cancer is glioblastoma. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and do not limit any claimed subject matter. In the event that any material incorporated herein by reference conflicts with the language of this disclosure, the language shall control. In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. In this application, the use of "or" means "and / or" unless the context requires otherwise. Additionally, the use of the term "including" and other forms, such as "include," "includes," and "included," is not limiting.

[0038] References herein to "some embodiments," "one embodiment," "one embodiment," or "other embodiments" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least some embodiments of the invention, but not necessarily in all embodiments.

[0039] As used herein, ranges and amounts may be expressed as "about" a particular value or range. About also includes the exact amount. Thus, "about 5 μL" means "about 5 μL" and also "5 μL". In general, the term "about" includes amounts that would be expected to be within experimental error, such as within 15%, 10%, or 5%.

[0040] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0041] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1 -C 20 alkyl), 1 to 10 carbon atoms (i.e., C 1 -C 10 alkyl), 1 to 6 carbon atoms (i.e., C 1 -C 6 alkyl) or 1 to 3 carbon atoms (i.e., C 1 -C 3 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbons is named by a chemical name or specified by a molecular formula, all positional isomers having that number of carbons can be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH 2 ) 3 CH 3 ), isobutyl (i.e., -CH 2 CH(CH 3 ) 2 ), sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 ), and tert-butyl (i.e., -C(CH 3 ) 3 ); "propyl" includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ) and isopropyl (i.e., -CH(CH 3 ) 2 ) are included.

[0042] "Alkyl-CN" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by -CN. For example, "C 1 -C 6"Alkyl-CN" refers to a C alkyl group substituted with one or more -CN groups. 1 -C 6 Alkyl-CN may contain multiple cyano groups attached to the same carbon atom or multiple carbon atoms.

[0043] "Alkyl-OH" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by -OH. For example, "C 1 -C 6 "Alkyl-OH" refers to a C alkyl group substituted with one or more -OH groups. 1 -C 6 An alkyl-OH may contain multiple hydroxy groups attached to the same carbon atom or to multiple carbon atoms.

[0044] An "alkoxy" group refers to an --O-(alkyl), where alkyl is defined above.

[0045] An "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms (C 6 -C 14 aryl) with a single ring (e.g., phenyl or C 6 aryl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups have 6 to 14 carbons (C 6 -C 14 aryl), and in other embodiments, 6 to 12 (C 6 -C 12 aryl) or further 6 to 10 carbon atoms (C 6 -C 10 aryl). Particular aryl include phenyl, biphenyl, naphthyl, etc. The aryl group may be substituted or unsubstituted.

[0046] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to cyclic groups having 3 to 20 ring carbon atoms (i.e., C 3 -C 20 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3 -C 10 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3 -C 6 Cycloalkyl also includes "spirocycloalkyl" when the two positions for substitution are on the same carbon atom. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Additionally, the term cycloalkyl is intended to encompass any non-aromatic ring that may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule.

[0047] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more hydrogen atoms are replaced by halogen. For example, "C 1 -C 6 "Haloalkyl" means a C alkyl group substituted with one or more halogen atoms. 1 -C 6 Refers to alkyl. 1 Haloalkyl refers to a methyl group which may be substituted by 1 to 3 halo groups; 2 Haloalkyl refers to an ethyl group which may be substituted by 1 to 5 halo groups; 3Haloalkyl refers to a propyl group which may be substituted by 1-7 halo groups, etc. Examples of haloalkyl include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Haloalkyl can contain one or more halo atoms which are the same (i.e., all fluoro) or a mixture of halo atoms (i.e., chloro and fluoro).

[0048] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings (e.g., a 5-14 membered ring system) having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1-10 ring carbon atoms and 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur in the ring. Examples of heteroaryl groups include pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).

[0049] "Heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. Heterocyclyl can be a single ring or multiple rings, which may be fused, bridged, or spiro, and may contain one or more oxo (C=O) or N-oxide (NO-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the bond (i.e., it may be bonded through a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which may be fused to an aryl or heteroaryl ring, regardless of the bond to the remainder of the molecule. As used herein, a heterocyclyl has 1 to 10 ring carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms, and 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Examples of heterocyclyl groups include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0050] "Cyano" refers to the group --CN.

[0051] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo.

[0052] "Hydroxy" refers to the group --OH.

[0053] "Oxo" refers to the atom (=O) or (O).

[0054] Certain commonly used alternative chemical nomenclature may be used, for example, a divalent group, such as a divalent "alkyl" group, a divalent "phenyl" group, a divalent "heteroaryl" group, a divalent "heterocyclyl" group, may also be referred to as an "alkylene" group, a "phenylene" group, a "heteroarylene" group, or a "heterocyclylene" group, respectively.

[0055] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which said event or circumstance occurs and instances in which said event or circumstance does not occur.

[0056] Also, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group that may or may not be replaced by a moiety other than hydrogen. A substituent may be substituted with one or more substituents, such as 1, 2, 3, 4, or 5 substituents. In some embodiments, the substituents are selected from the functional groups provided herein. In some embodiments, the substituents are selected from oxo, halo, -CN, NO 2 , -CO 2 R x , -OR x , -SR x , -SOR x , -SO 2 R x , -NR y R z , -CONR y R z , -SO 2 NR y R z , C 1 -C 6 Alkyl, C 1 -C6 Alkoxy, -CR x =C(R x ) 2 , -CCR x , C 3 -C 10 Cycloalkyl, C 4 -C 10 Heterocyclyl, C 6 -C 14 Aryl and C 5 -C 12 heteroaryl, and each R x are independently hydrogen, C 1 -C 6 Alkyl, C 3 -C 12 Cycloalkyl, C 4 -C 10 Heterocyclyl, C 6 -C 14 Aryl, or C 2 -C 12 and heteroaryl; each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 3 halo, 1 to 3 C 1 -C 6 Alkyl, 1-3 C 1 -C 6 Haloalkyl, or 1-3 C 1 -C 6 Optionally substituted with an alkoxy group. In some embodiments, the substituents are chloro, fluoro, -OCH 3 , methyl, ethyl, isopropyl, cyclopropyl, -OCF 3 , -CF 3 and -OCHF 2 Selected from: R y and R z are independently hydrogen; -CO 2 C optionally substituted with H or its ester 1 -C 6 Alkyl;C 1 -C 6 Alkoxy;Oxo;-CR w =C(R w ) 2 ; -CCR w ;C 3 -C10 Cycloalkyl;C 3 -C 10 Heterocyclyl;C 6 -C 14 Aryl; or C 5 -C 12 heteroaryl; each R w are independently hydrogen, C 1 -C 6 Alkyl, C 3 -C 12 Cycloalkyl, C 4 -C 10 Heterocyclyl, C 6 -C 14 Aryl, or C 5 -C 12 each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 3 alkyl groups or 1 to 3 halo groups, or R y and R z form a 5- to 7-membered heterocyclic ring together with the nitrogen atom to which they are attached.

[0057] Any compound or formula described herein is intended to represent unlabeled forms of the compound as well as isotopically labeled forms. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125Various isotopically labeled compounds of the present disclosure include, for example, 2 H, 3 H, 13 C, and 14 Included in the present disclosure are compounds that incorporate radioactive isotopes such as C. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radioactive treatment of patients.

[0058] The present disclosure also includes "deuterated analogs" of the compounds described herein in which 1 to n hydrogens bonded to a carbon atom have been replaced by deuterium, where n is the number of hydrogens in the molecule. When multiple deuterium atoms are present in a compound, the deuterium atoms may be on the same part of the molecule (e.g., on a single alkyl group or on a single ring) or on different parts of the molecule (e.g., on separate alkyl groups or separate rings). Such compounds may exhibit increased resistance to metabolism and thus may be useful for extending the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol.Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0059] "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for animal or human pharmaceutical use.

[0060] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. Also, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. It will be understood that a reference to a particular salt, e.g., a hydrochloride or formate salt, may refer to a single salt, e.g., the monohydrochloride or monoformate salt, or may refer to multiple salts, e.g., the dihydrochloride or diformate salts.

[0061] The compounds disclosed herein, or their pharma- ceutically acceptable salts, may contain asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomers that may be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemates (or racemates of salts or derivatives) using, e.g., chiral high pressure liquid chromatography (HPLC).

[0062] "Tautomer" refers to alternating forms of a compound that differ in the location of a proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups that contain ring atoms attached to both the ring -NH- and =N moieties, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. All tautomeric forms of the compounds described herein are intended to be included.

[0063] "Stereoisomers" refer to compounds composed of the same atoms linked by the same bonds, but with different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0064] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0065] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" or "excipient" includes any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the compositions.

[0066] An "effective amount" or dose of a compound or composition refers to that amount of a compound or composition that produces the intended results, as desired, based on the disclosure herein. An effective amount includes, but is not limited to, LD 50 (the dose lethal to 50% of the population) and ED 50 This can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including determining the dose that is therapeutically effective in 50% of the population.

[0067] A "therapeutically effective amount" or dose of a compound or composition refers to that amount of the compound or composition that results in a reduction or inhibition of symptoms or prolongation of survival in a subject (i.e., a human patient). The result may require multiple doses of the compound or composition.

[0068] "Treating" or "treatment" of a disease in a subject refers to 1) preventing the disease from occurring in a patient who is susceptible to or who does not yet exhibit symptoms of the disease; 2) inhibiting or halting the progression of the disease; or 3) improving or causing regression of the disease. As used herein, "treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: reducing one or more symptoms caused by a disease or disorder, attenuating the extent of a disease or disorder, stabilizing a disease or disorder (e.g., preventing or delaying the worsening of a disease or disorder), delaying the onset or recurrence of a disease or disorder, delaying or slowing the progression of a disease or disorder, improving a disease or disorder condition, providing remission (whether partial or total) of a disease or disorder, reducing the dose of one or more other pharmaceutical agents required to treat a disease or disorder, improving the effectiveness of another pharmaceutical agent used to treat a disease or disorder, delaying the progression of a disease or disorder, improving the quality of life, and / or prolonging the survival of a subject. Reduction of the pathological consequences of a disease or disorder is also encompassed by "treatment". The method of the present invention contemplates any one or more of these aspects of treatment.

[0069] As used herein, the terms "subject(s)" and "patient(s)" refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human, e.g., a primate, dog, cat, rabbit, or rodent. None of these terms require or are limited to a situation characterized by the supervision (e.g., constant or intermittent) of a health care worker (e.g., a physician, registered nurse, nursing practitioner, physician's assistant, handyman, or hospice worker).

[0070] As used herein, the term "pharmaceutical composition" or "medicament" refers to a composition suitable for pharmaceutical use in a subject, e.g., as an SHP2 inhibitor.

[0071] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may for clarity be described herein in the context of separate embodiments, the invention may also be practiced in a single embodiment.

[0072] compound In one aspect, provided herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, Ring A is C 3 -C 6 cycloalkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, where heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O, and S; Each R 1 i is independently halo, cyano, -NR 2a R 2b , C 1 -C 6 Alkyl, oxo, hydroxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-OH, C 1 -C 6 Alkyl-CN, -C(O)NR 2a R 2b , -C(O)(C 1 -C 6 Alkyl), -CO 2 H, -CO 2 (C 1 -C 6 alkyl), -Si(R a )(Rb )(R c ), -P(O)(R a )(R b ), -OP(O)(R a )(R b ), C 3 -C 6 cycloalkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, where heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O, and S; or two R's 1 The groups, together with the carbon atom or heteroatom to which they are attached, form a fused phenyl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which may be selected from 1 to 4 R 6 groups, and the fused heterocycloalkyl and heteroaryl contain 1 to 3 heteroatoms selected from N, O, and S; Each R a , R b , and R c are independently hydroxy, C 1 -C 6 Alkyl, or C 1 -C 6 is alkoxy; Each R 2a and R 2b are independently H, C 1 -C 6 Alkyl, or C 3 -C 6 is cycloalkyl; L is a bond, S, O, C(O), or N(R d ) and; R d is H or C 1 -C 6 is alkyl; X is CR 3a R 3b , N.R. 3a , or O; R 3a and R 3b are independently H or C 1 -C 6 is alkyl; R 4 , H, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-OH, C 1 -C 6 Haloalkyl, or -NH 2 and; Each R 5 Independently, Halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -(C 1 -C 6 Alkylene)(C 1 -C 6 alkoxy), or C 1 -C 6 is alkyl-OH; Ring B is a fused phenyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Each R 6 is independently 1 -C 6 Alkyl, halo, or C 1 -C 6 is haloalkyl; Each R 7 is independently 1 -C 6 Alkyl, halo, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-OH, hydroxy, cyano, -Si(R a )(R b )(R c ), -P(O)(R a )(R b ), -OP(O)(R a )(R b ), -NR 2a R 2b , or C 1 -C 6 is haloalkyl; x is 0 to 5; y is 0 to 2; z is 0 to 4; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

[0073] In some embodiments, ring A is C 3 -C 6 In some embodiments, ring A is selected from C. 3 -C 5 cycloalkyl, phenyl, 6-membered heterocycloalkyl, or 5-6-membered heteroaryl, where heterocycloalkyl and heteroaryl contain 1-2 heteroatoms selected from N, O, and S. In some embodiments, Ring A is cyclopropyl, phenyl, dihydropyridinyl, dihydropyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, isoxazolyl, or thiophenyl. In some embodiments, Ring A is optionally substituted.

[0074] In some embodiments, ring A is C 3 -C 6 In some embodiments, ring A is C 3 -C 5 In some embodiments, ring A is C 3 -C 4 In some embodiments, the ring A is cycloalkyl. In some embodiments, the ring A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the ring A is cyclopropyl. In some embodiments, the ring A is cyclobutyl. In some embodiments, the ring A is cyclopentyl. In some embodiments, the ring A is cyclohexyl.

[0075] In some embodiments, ring A is phenyl.

[0076] In some embodiments, ring A is a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, ring A is a 5 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, ring A is a 6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, the heterocycloalkyl contains 1-2 unsaturated bonds. In some embodiments, the heterocycloalkyl contains 1 unsaturated bond. In some embodiments, the heterocycloalkyl contains 2 unsaturated bonds. In some embodiments, the heterocycloalkyl contains 1-2 heteroatoms selected from N, O, and S. In some embodiments, the heterocycloalkyl contains 1-2 heteroatoms selected from N and O. In some embodiments, the heterocycloalkyl contains 1 heteroatom selected from N and O. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom. In some embodiments, the heterocycloalkyl contains 1 oxygen atom. In some embodiments, ring A is dihydropyridinyl, dihydropyranyl, piperidinyl, or tetrahydropyranyl.

[0077] In some embodiments, ring A is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, ring A is a 5 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, ring A is a 6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, the heteroaryl contains 1-2 heteroatoms selected from N, O, and S. In some embodiments, ring A is a 5 membered heteroaryl containing 1-2 nitrogen atoms. In some embodiments, ring A is a 5 membered heteroaryl containing 1 nitrogen atom. In some embodiments, ring A is a 5 membered heteroaryl containing 2 nitrogen atoms. In some embodiments, ring A is a 5 membered heteroaryl containing 1 nitrogen atom and 1 sulfur atom. In some embodiments, ring A is a 5 membered heteroaryl containing 1 nitrogen atom and 1 oxygen atom. In some embodiments, ring A is a 5 membered heteroaryl containing 1 sulfur atom. In some embodiments, ring A is a 6-membered heteroaryl containing 1-2 nitrogen atoms. In some embodiments, ring A is a 6-membered heteroaryl containing 1 nitrogen atom. In some embodiments, ring A is a 6-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, ring A is pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, or thiophenyl.

[0078] In some embodiments, [ka] teeth, [ka] It is.

[0079] In some embodiments, x is 0 to 5. In some embodiments, x is 0 to 4. In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5.

[0080] In some embodiments, ring A is unsubstituted. In some embodiments, ring A is selected from 1 to 5 R 1 Ring A is substituted with a C group. 3 -C 6 In some variations where Ring A is cycloalkyl, Ring A is substituted. In some variations where Ring A is pyrimidinyl, Ring A is substituted. In some variations where Ring A is pyridazinyl, Ring A is substituted.

[0081] In some embodiments, each R 1 are independently halo, cyano, -NR 2a R 2b , C 1 -C 6 Alkyl, oxo, hydroxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-OH, C 1 -C 6 Alkyl-CN, -C(O)NR 2a R 2b , -C(O)(C 1 -C 6 Alkyl), -CO 2 H, -CO 2 (C 1 -C 6 alkyl), -Si(R a )(R b )(R c ), -P(O)(R a )(R b ), -OP(O)(Ra )(R b ), C 3 -C 6 cycloalkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, where the heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O, and S. In some embodiments, each R 1 are independently halo, cyano, -NR 2a R 2b , C 1 -C 3 Alkyl, oxo, hydroxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Alkyl-OH, C 1 -C 3 Alkyl-CN, -C(O)NR 2a R 2b , -C(O)(C 1 -C 3 Alkyl), -CO 2 H, -CO 2 (C 1 -C 3 alkyl), -Si(R a )(R b )(R c ), -P(O)(R a )(R b ), -OP(O)(R a )(R b ), C 3 -C 5 cycloalkyl, phenyl, or a 6-membered heterocycloalkyl, where the heterocycloalkyl contains 1 to 2 heteroatoms selected from N and O. In some embodiments, each R a , R b , and R c is independently 1 -C 3 Alkyl or C 1 -C 3 In some embodiments, each R 2a and R 2b are independently H, C 1 -C3 Alkyl, or C 3 -C 5 In some embodiments, R 1 Any of the groups disclosed herein for are optionally substituted.

[0082] In some embodiments, R 1 is halo. In some embodiments, R 1 is F, Cl, Br, or I. In some embodiments, R 1 is F, Cl, or Br. In some embodiments, R 1 is F or Cl. In some embodiments, R 1 is F. In some embodiments, R 1 is Cl.

[0083] In some embodiments, R 1 is cyano. In some embodiments, R 1 is oxo. In some embodiments, R 1 is hydroxy. In some embodiments, R 1 -CO 2 It's H.

[0084] In some embodiments, R 1 -NR 2a R 2b and R 2a and R 2b are independently H, C 1 -C 6 Alkyl, or C 3 -C 6 In some embodiments, R 2a and R 2b are independently H, C 1 -C 3 Alkyl, or C 3 -C 5 In some embodiments, R 2a and R 2b are both H. In some embodiments, R 2aand R 2b Both are C 1 -C 3 In some embodiments, R 2a and R 2b One of them is H and the other is C 1 -C 3 In some embodiments, R 2a and R 2b One of them is H and the other is C 3 -C 6 In some embodiments, R 2a and R 2b One of them is C 1 -C 3 alkyl, and the other is C 3 -C 6 In some embodiments, R 1 is -NH 2 , -N(H)CH 3 , or -N(CH 3 ) 2 In some embodiments, R 1 is -NH 2 In some embodiments, R 1 is -N(H)CH 3 In some embodiments, R 1 is -N(CH 3 ) 2 In some embodiments, R 2a and R 2b Any of the groups disclosed herein for are optionally substituted.

[0085] In some embodiments, R 1 is C 1 -C 6 In some embodiments, R 1 is C 1 -C 3 In some embodiments, R 1 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 1is methyl, ethyl, or isopropyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is isopropyl.

[0086] In some embodiments, R 1 is C 1 -C 6 In some embodiments, R 1 is a C containing 1 to 13 halogen atoms 1 -C 6 In some embodiments, R 1 is C 1 -C 3 In some embodiments, R 1 is a C containing 1 to 7 halogen atoms 1 -C 3 In some embodiments, R 1 -CF 3 , -CHF 2 , -CH 2 F, -CCl 3 , -CHCl 2 , -CH 2 Cl, -CF 2 Cl, -CFCl 2 , -CH 2 CF 3 , -CH 2 CHF 2 , or -CH 2 CCl 3 In some embodiments, R 1 -CF 3 It is.

[0087] In some embodiments, R 1 is C 1 -C 6 In some embodiments, R 1 is C 1 -C 3 In some embodiments, R 1 -OCH3 , -OCH 2 CH 3 , or -OCH(CH 3 ) 2 In some embodiments, R 1 -OCH 3 In some embodiments, R 1 -OCH 2 CH 3 It is.

[0088] In some embodiments, R 1 is C 1 -C 6 In some embodiments, R 1 is C 1 -C 3 In some embodiments, R 1 is -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH(OH)CH 3 , -CH(OH)CH 2 OH, or -CH 2 CH(OH)CH 3 In some embodiments, R 1 is -CH 2 In some embodiments, R 1 is -CH 2 CH 2 It is OH.

[0089] In some embodiments, R 1 is C 1 -C 6 In some embodiments, R 1 is C 1 -C 3 In some embodiments, R 1 is -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CH2 CN, -CH(CN)CH 3 , -CH(CN)CH 2 OH, or -CH 2 CH(CN)CH 3 In some embodiments, R 1 is -CH 2 CN. In some embodiments, R 1 is -CH 2 CH 2 It is CN.

[0090] In some embodiments, R 1 is -C(O)NR 2a R 2b and R 2a and R 2b are independently H, C 1 -C 6 Alkyl, or C 3 -C 6 In some embodiments, R 2a and R 2b are independently H, C 1 -C 3 Alkyl, or C 3 -C 5 In some embodiments, R 2a and R 2b are both H. In some embodiments, R 2a and R 2b Both are C 1 -C 3 In some embodiments, R 2a and R 2b One of them is H and the other is C 1 -C 3 In some embodiments, R 2a and R 2b One of them is H and the other is C 3 -C 6 In some embodiments, R 2a and R 2b One of them is C 1 -C 3 alkyl, and the other is C 3-C 6 In some embodiments, R 1 is -C(O)NH 2 , -C(O)N(CH 3 ) 2 , or -C(O)N(H)(CH 3 In some embodiments, R 1 teeth, -C(O)N(CH 3 ) 2 In some embodiments, R 1 is -C(O)NH 2 In some embodiments, R 1 is -C(O)N(H)(CH 3 ).

[0091] In some embodiments, R 1 is -C(O)(C 1 -C 6 In some embodiments, R 1 is -C(O)(C 1 -C 3 In some embodiments, R 1 is -C(O)CH 3 , -C(O)CH 2 CH 3 , or -C(O)CH(CH 3 In some embodiments, R 1 is -C(O)CH 3 It is.

[0092] In some embodiments, R 1 -CO 2 (C 1 -C 6 In some embodiments, R 1 -CO 2 (C 1 -C 3 In some embodiments, R 1 -CO 2 CH 3 , -CO 2 CH 2 CH 3, or -CO 2 CH(CH 3 ) 2 It is.

[0093] In some embodiments, R 1 is -Si(R a )(R b )(R c ) and R a , R b , and R c are independently hydroxy, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R a , R b , and R c are independently hydroxy, C 1 -C 3 Alkyl, or C 1 -C 3 In some embodiments, R a , R b , and R c is independently hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, or isopropoxy. 1 is -Si(CH 3 ) 3 or -Si(CH 3 ) 3 In some embodiments, R a , R b , and R c Any of the groups disclosed herein for are optionally substituted.

[0094] In some embodiments, R 1 is -P(O)(R a )(R b ) and R a and R b are independently hydroxy, C 1 -C 6 Alkyl, or C 1 -C 6In some embodiments, R a and R b are independently hydroxy, C 1 -C 3 Alkyl, or C 1 -C 3 In some embodiments, R a and R b is independently hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, or isopropoxy. 1 is -P(O)(OH) 2 , -P(O)(CH 3 ) 2 , -P(O)(OH)(OCH 3 ), or -P(O)(OCH 3 ) 2 It is.

[0095] In some embodiments, R 1 -OP(O)(R a )(R b ) and R a and R b are independently hydroxy, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R a and R b are independently hydroxy, C 1 -C 3 Alkyl, or C 1 -C 3 In some embodiments, R a and R b is independently hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, or isopropoxy. 1 is -OP(O)(OH) 2 , -OP(O)(CH 3 ) 2 , -OP(O)(OH)(OCH 3 ), or -OP(O)(OCH 3 )2 It is.

[0096] In some embodiments, R 1 is C 3 -C 6 In some embodiments, R 1 is C 3 -C 5 In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 1 is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 1 is cyclopropyl.

[0097] In some embodiments, R 1 is phenyl.

[0098] In some embodiments, R 1 is a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, R 1 is a 5-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 1 is a 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, the heterocycloalkyl contains 1-2 heteroatoms selected from N and O. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom and 1 oxygen atom. In some embodiments, the heterocycloalkyl contains 2 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 2 oxygen atoms. In some embodiments, R 1 is morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, or tetrahydrofuranyl.

[0099] In some embodiments, R1 is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, R 1 is a 5-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, R 1 is a 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, the heteroaryl contains 1-2 heteroatoms selected from N and O. In some embodiments, the heteroaryl contains 1 nitrogen atom and 1 oxygen atom. In some embodiments, the heteroaryl contains 2 nitrogen atoms. In some embodiments, R 1 is pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, or thiophenyl.

[0100] In some embodiments, each R 1 are independently F, Cl, -CN, -CH 2 CN, -NH 2 , -N(H)CH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , oxo, -CF 3 , -OCH 3 , -CH 2 OH, -C(O)N(CH 3 ) 2 , -C(O)CH 3 , cyclopropyl, or [ka] It is.

[0101] In some embodiments, two R 1 The groups, together with the carbon or heteroatom to which they are attached, may consist of 1 to 4 R6 The aryl group forms a fused phenyl optionally substituted with a group.

[0102] In some embodiments, two R 1 The groups, together with the carbon or heteroatom to which they are attached, may consist of 1 to 4 R 6 In some embodiments, the fused heterocycloalkyl comprises one or more heteroatoms selected from N, O, and S. In some embodiments, the fused heterocycloalkyl comprises one or more heteroatoms selected from N, O, and S. In some embodiments, the fused heterocycloalkyl comprises one or more heteroatoms selected from N, O, and S. 6 In some embodiments, the fused heterocycloalkyl contains 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, two R 1 The groups, together with the carbon or heteroatom to which they are attached, may consist of 1 to 4 R 6 In some embodiments, two R 1 The groups, together with the carbon or heteroatom to which they are attached, may consist of 1 to 4 R 6 In some embodiments, two R 1 The groups, together with the carbon atom or heteroatom to which they are attached, form a fused pyranyl, dihydrodioxinyl, or dihydrofuranyl.

[0103] In some embodiments, two R 1 The group may be composed of 1 to 4 R 6 In some embodiments, the fused heteroaryl comprises one or more heteroatoms selected from N, O, and S. In some embodiments, the fused heteroaryl comprises one or two R 6 In some embodiments, the heteroaryl contains 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, two R 1 The groups, together with the carbon or heteroatom to which they are attached, may consist of 1 to 4 R6 In some embodiments, two R 1 The groups, together with the carbon or heteroatom to which they are attached, may consist of 1 to 4 R 6 In some embodiments, two R 1 The groups together with the carbon atom or heteroatom to which they are attached form a fused pyridyl, pyrazinyl, pyrrolyl, or thiazolyl.

[0104] In some embodiments, two R 1 Groups, together with the carbon atom or heteroatom to which they are attached, [ka] The condensation group is selected from the group consisting of:

[0105] In some embodiments, each R 6 is independently 1 -C 6 Alkyl, halo, or C 1 -C 6 In some embodiments, each R 6 is independently 1 -C 3 Alkyl, halo, or C 1 -C 3 It is haloalkyl.

[0106] In some embodiments, R 6 is C 1 -C 6 In some embodiments, R 6 is C 1 -C 3 In some embodiments, R 6 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 6 is methyl, ethyl, or isopropyl. In some embodiments, R 6is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 Any of the groups disclosed herein for are optionally substituted.

[0107] In some embodiments, R 6 is halo. In some embodiments, R 6 is F, Cl, Br, or I. In some embodiments, R 6 is F, Cl, or Br. In some embodiments, R 6 is F or Cl. In some embodiments, R 6 is F. In some embodiments, R 6 is Cl.

[0108] In some embodiments, R 6 is C 1 -C 6 In some embodiments, R 6 is a C containing 1 to 13 halogen atoms 1 -C 6 In some embodiments, R 6 is C 1 -C 3 In some embodiments, R 6 is a C containing 1 to 7 halogen atoms 1 -C 3 In some embodiments, R 6 -CF 3 , -CHF 2 , -CH 2 F, -CCl 3 , -CHCl 2 , -CH 2 Cl, -CF 2 Cl, -CFCl 2 , -CH 2 CF 3 , -CH 2 CHF 2 , or -CH2 CCl 3 In some embodiments, R 6 -CF 3 It is.

[0109] In some embodiments, [ka] teeth, [ka] [ka] It is.

[0110] In some embodiments, L is a bond. In some embodiments, L is S. In some embodiments, L is O. In some embodiments, L is C(O). In some embodiments, L is N(R d ) and R d is H or C 1 -C 6 In some embodiments, R d is H. In some embodiments, R d is C 1 -C 6 In some embodiments, R d is C 1 -C 3 In some embodiments, L is NH. In some embodiments, L is N(CH 3 In some embodiments, R d Any of the groups disclosed herein for are optionally substituted.

[0111] In some embodiments, X is CR 3a R 3b , N.R. 3a , or O and R3a and R 3b are independently H or C 1 -C 6 In some embodiments, X is CR 3a R 3b , N.R. 3a , or O and R 3a and R 3b are independently H or C 1 -C 3 In some embodiments, R 3a and R 3b Any of the groups disclosed herein for are optionally substituted.

[0112] In some embodiments, X is O.

[0113] In some embodiments, X is CR 3a R 3b and R 3a and R 3b are independently H or C 1 -C 6 In some embodiments, R 3a and R 3b are independently H or C 1 -C 3 In some embodiments, R 3a and R 3b are both H. In some embodiments, R 3a and R 3b Both are C 1 -C 3 alkyl, e.g., methyl, ethyl, or propyl. In some embodiments, R 3a and R 3b One of them is H and the other is C 1 -C 3 In some embodiments, X is CH 2 , CH(CH 3 ), or C(CH 3 ) 2 In some embodiments, X is CH 2 It is.

[0114] In some embodiments, X is NR 3a and R 3a is H or C 1 -C 6 In some embodiments, R 3a is H or C 1 -C 3 In some embodiments, R 3a is H. In some embodiments, R 3a is C 1 -C 3 In some embodiments, X is N(H) or N(CH 3 In some embodiments, X is N(H). In some embodiments, X is N(CH 3 ).

[0115] In some embodiments, R 4 , H, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-OH, C 1 -C 6 Haloalkyl, or -NH 2 In some embodiments, R 4 , H, C 1 -C 3 Alkyl, C 1 -C 3 Alkyl-OH, C 1 -C 3 Haloalkyl, or -NH 2 In some embodiments, R 4 Any of the groups disclosed herein for are optionally substituted.

[0116] In some embodiments, R 4 is H.

[0117] In some embodiments, R 4 is C 1 -C 6In some embodiments, R 4 is C 1 -C 3 In some embodiments, R 4 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 4 is methyl, ethyl, or isopropyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is isopropyl.

[0118] In some embodiments, R 4 is C 1 -C 6 In some embodiments, R 4 is C 1 -C 3 In some embodiments, R 4 is -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH(OH)CH 3 , -CH(OH)CH 2 OH, or -CH 2 CH(OH)CH 3 In some embodiments, R 4 is -CH 2 In some embodiments, R 4 is -CH 2 CH 2 It is OH.

[0119] In some embodiments, R 4 is C 1 -C 6 In some embodiments, R 4 is a C containing 1 to 13 halogen atoms 1 -C 6 In some embodiments, R4 is C 1 -C 3 In some embodiments, R 4 is a C containing 1 to 7 halogen atoms 1 -C 3 In some embodiments, R 4 -CF 3 , -CHF 2 , -CH 2 F, -CCl 3 , -CHCl 2 , -CH 2 Cl, -CF 2 Cl, -CFCl 2 , -CH 2 CF 3 , -CH 2 CHF 2 , or -CH 2 CCl 3 In some embodiments, R 4 -CF 3 , -CHF 2 , or -CH 2 F. In some embodiments, R 4 -CHF 2 In some embodiments, R 4 is -CH 2 It's F.

[0120] In some embodiments, R 4 is -NH 2 It is.

[0121] In some embodiments, each R 5 Independently, Halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -(C 1 -C 6 Alkylene)(C 1 -C 6 alkoxy), or C 1 -C 6 In some embodiments, each R 5 Independently, Halo, C 1-C 3 Alkyl, C 1 -C 3 Haloalkyl, -(C 1 -C 3 Alkylene)(C 1 -C 3 alkoxy), or C 1 -C 3 In some embodiments, each R 5 are independently Cl, F, -CH 2 F, -CHF 2 , -CH 2 OCH 3 , or -CH 2 In some embodiments, R 5 Any of the groups disclosed herein for are optionally substituted.

[0122] In some embodiments, R 5 is halo. In some embodiments, R 5 is F, Cl, Br, or I. In some embodiments, R 5 is F, Cl, or Br. In some embodiments, R 5 is F or Cl. In some embodiments, R 5 is F. In some embodiments, R 5 is Cl.

[0123] In some embodiments, R 5 is C 1 -C 6 In some embodiments, R 5 is C 1 -C 3 In some embodiments, R 5 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 5 is methyl, ethyl, or isopropyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5is isopropyl.

[0124] In some embodiments, R 5 is C 1 -C 6 In some embodiments, R 5 is a C containing 1 to 13 halogen atoms 1 -C 6 In some embodiments, R 5 is C 1 -C 3 In some embodiments, R 5 is a C containing 1 to 7 halogen atoms 1 -C 3 In some embodiments, R 5 -CF 3 , -CHF 2 , -CH 2 F, -CCl 3 , -CHCl 2 , -CH 2 Cl, -CF 2 Cl, -CFCl 2 , -CH 2 CF 3 , -CH 2 CHF 2 , or -CH 2 CCl 3 In some embodiments, R 5 -CF 3 , -CHF 2 , or -CH 2 F. In some embodiments, R 5 -CHF 2 In some embodiments, R 5 is -CH 2 It's F.

[0125] In some embodiments, R 5 is -(C 1 -C 6 Alkylene)(C 1 -C 6 In some embodiments, R 5 is -(C1 -C 3 Alkylene)(C 1 -C 3 In some embodiments, R 5 is -(C 1 -alkylene)(C 1 -C 3 Alkoxy), for example, -CH 2 OCH 3 , -CH 2 COH 2 CH 3 , or -CH 2 COH 2 CH 2 CH 3 In some embodiments, R 5 is -(C 2 -alkylene)(C 1 -C 3 Alkoxy), for example, -CH 2 CH 2 COH 3 , -CH 2 CH 2 COH 2 CH 3 , or -CH 2 CH 2 COH 2 CH 2 CH 3 In some embodiments, R 5 is -(C 3 -alkylene)(C 1 -C 3 Alkoxy), for example, -CH 2 CH 2 CH 2 COH 3 , -CH 2 CH 2 CH 2 COH 2 CH 3 , or -CH 2 CH 2 CH 2 COH 2 CH 2 CH 3 In some embodiments, R 5 is -CH 2 COH 3 It is.

[0126] In some embodiments, R 5 is C 1 -C 6 In some embodiments, R 5 is C 1 -C 3 In some embodiments, R 5 is -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH(OH)CH 3 , -CH(OH)CH 2 OH, or -CH 2 CH(OH)CH 3 In some embodiments, R 5 is -CH 2 In some embodiments, R 5 is -CH 2 CH 2 It is OH.

[0127] In some embodiments, y is 0 to 2. In some embodiments, y is 0 or 1. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.

[0128] In some embodiments, ring B is a fused phenyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, ring B is a fused phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O, and S. In some embodiments, ring B is a fused phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, or oxazolyl. In some embodiments, ring B is optionally substituted.

[0129] In some embodiments, ring B is a fused phenyl.

[0130] In some embodiments, ring B is a fused 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, ring B is a fused 5 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, ring B is a fused 6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, the fused heteroaryl contains 1-2 heteroatoms selected from N, O, and S. In some embodiments, ring B is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, or oxazolyl.

[0131] In some embodiments, each R 7 is independently 1 -C 6 Alkyl, halo, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-OH, hydroxy, cyano, -Si(R a )(R b )(R c ), -P(O)(R a )(R b ), -OP(O)(R a )(R b ), -NR 2a R 2b , or C 1 -C 6 In some embodiments, each R 7 is independently 1 -C 3 Alkyl, halo, C 1 -C 3 Alkoxy, C 1 -C 3 Alkyl-OH, hydroxy, cyano, -Si(R a )(R b )(R c ), -P(O)(R a )(R b ), -OP(O)(R a )(Rb ), -NR 2a R 2b , or C 1 -C 3 In some embodiments, each R 7 are independently 3 , F, -OCH 3 , -CH 2 OH, hydroxy, -CN, -N(CH 3 ) 2 , or -CHF 2 In some embodiments, R 7 Any of the groups disclosed herein for are optionally substituted.

[0132] In some embodiments, R 7 is C 1 -C 6 In some embodiments, R 7 is C 1 -C 3 In some embodiments, R 7 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 7 is methyl, ethyl, or isopropyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is ethyl. In some embodiments, R 7 is isopropyl.

[0133] In some embodiments, R 7 is halo. In some embodiments, R 7 is F, Cl, Br, or I. In some embodiments, R 7 is F, Cl, or Br. In some embodiments, R 7 is F or Cl. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl.

[0134] In some embodiments, R7 is C 1 -C 6 In some embodiments, R 7 is C 1 -C 3 In some embodiments, R 7 -OCH 3 , -OCH 2 CH 3 , or -OCH(CH 3 ) 2 In some embodiments, R 7 -OCH 3 In some embodiments, R 7 -OCH 2 CH 3 It is.

[0135] In some embodiments, R 7 is C 1 -C 6 In some embodiments, R 7 is C 1 -C 3 In some embodiments, R 7 is -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH(OH)CH 3 , -CH(OH)CH 2 OH, or -CH 2 CH(OH)CH 3 In some embodiments, R 7 is -CH 2 In some embodiments, R 7 is -CH 2 CH 2 It is OH.

[0136] In some embodiments, R 7 is hydroxy. In some embodiments, R 7 is cyano.

[0137] In some embodiments, R 7 is -Si(R a )(R b )(R c ) and R a , R b , and R c are independently hydroxy, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R a , R b , and R c are independently hydroxy, C 1 -C 3 Alkyl, or C 1 -C 3 In some embodiments, R a , R b , and R c is independently hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, or isopropoxy. 7 is -Si(CH 3 ) 3 or Si(OCH 3 ) 3 It is.

[0138] In some embodiments, R 7 is -P(O)(R a )(R b ) and R a and R b are independently hydroxy, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R a and R b are independently hydroxy, C 1 -C 3 Alkyl, or C 1 -C 3 In some embodiments, R a and R bis independently hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, or isopropoxy. 7 is -P(O)(OH) 2 , -P(O)(CH 3 ) 2 , -P(O)(OH)(OCH 3 ), or -P(O)(OCH 3 ) 2 It is.

[0139] In some embodiments, R 7 -OP(O)(R a )(R b ) and R a and R b are independently hydroxy, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R a and R b are independently hydroxy, C 1 -C 3 Alkyl, or C 1 -C 3 In some embodiments, R a and R b is independently hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, or isopropoxy. 7 is -OP(O)(OH) 2 , -OP(O)(CH 3 ) 2 , -OP(O)(OH)(OCH 3 ), or -OP(O)(OCH 3 ) 2 It is.

[0140] In some embodiments, R 7 -NR 2a R 2b and R 2a and R 2b are independently H, C 1 -C6 Alkyl, or C 3 -C 6 In some embodiments, R 2a and R 2b are independently H, C 1 -C 3 Alkyl, or C 3 -C 5 In some embodiments, R 2a and R 2b are both H. In some embodiments, R 2a and R 2b Both are C 1 -C 3 In some embodiments, R 2a and R 2b One of them is H and the other is C 1 -C 3 In some embodiments, R 2a and R 2b One of them is H and the other is C 3 -C 6 In some embodiments, R 2a and R 2b One of them is C 1 -C 3 alkyl, and the other is C 3 -C 6 In some embodiments, R 7 is -NH 2 , -N(H)CH 3 , or -N(CH 3 ) 2 In some embodiments, R 7 is -N(CH 3 ) 2 It is.

[0141] In some embodiments, R 7 is C 1 -C 6 In some embodiments, R 7 is a C containing 1 to 13 halogen atoms 1 -C 6In some embodiments, R 7 is C 1 -C 3 In some embodiments, R 7 is a C containing 1 to 7 halogen atoms 1 -C 3 In some embodiments, R 7 -CF 3 , -CHF 2 , -CH 2 F, -CCl 3 , -CHCl 2 , -CH 2 Cl, -CF 2 Cl, -CFCl 2 , -CH 2 CF 3 , -CH 2 CHF 2 , or -CH 2 CCl 3 In some embodiments, R 7 -CF 3 , -CHF 2 , or -CH 2 F. In some embodiments, R 4 -CHF 2 In some embodiments, R 7 is -CH 2 It's F.

[0142] In some embodiments, z is 0 to 4. In some embodiments, z is 0 to 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4.

[0143] In some embodiments, [ka] teeth, [ka] It is.

[0144] In some embodiments, each R a , R b , and R c are independently hydroxy, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, each R a , R b , and R c are independently hydroxy, C 1 -C 3 Alkyl, or C 1 -C 3 It is an alkoxy.

[0145] In some embodiments, R a is hydroxy.

[0146] In some embodiments, R a is C 1 -C 6 In some embodiments, R a is C 1 -C 3 In some embodiments, R a -OCH 3 , -OCH 2 CH 3 , or -OCH(CH 3 ) 2 In some embodiments, R a -OCH 3 In some embodiments, R a -OCH 2 CH 3 It is.

[0147] In some embodiments, R a is C 1 -C 6 In some embodiments, R a is C1 -C 3 In some embodiments, R a is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R a is methyl, ethyl, or isopropyl. In some embodiments, R a is methyl. In some embodiments, R a is ethyl. In some embodiments, R a is isopropyl.

[0148] In some embodiments, R b is hydroxy.

[0149] In some embodiments, R b is C 1 -C 6 In some embodiments, R b is C 1 -C 3 In some embodiments, R b -OCH 3 , -OCH 2 CH 3 , or -OCH(CH 3 ) 2 In some embodiments, R b -OCH 3 In some embodiments, R b -OCH 2 CH 3 It is.

[0150] In some embodiments, R b is C 1 -C 6 In some embodiments, R b is C 1 -C 3 In some embodiments, R b is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R bis methyl, ethyl, or isopropyl. In some embodiments, R b is methyl. In some embodiments, R b is ethyl. In some embodiments, R b is isopropyl.

[0151] In some embodiments, R c is hydroxy.

[0152] In some embodiments, R c is C 1 -C 6 In some embodiments, R c is C 1 -C 3 In some embodiments, R c -OCH 3 , -OCH 2 CH 3 , or -OCH(CH 3 ) 2 In some embodiments, R c -OCH 3 In some embodiments, R c -OCH 2 CH 3 It is.

[0153] In some embodiments, R c is C 1 -C 6 In some embodiments, R c is C 1 -C 3 In some embodiments, R c is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R c is methyl, ethyl, or isopropyl. In some embodiments, R c is methyl. In some embodiments, R c is ethyl. In some embodiments, R c is isopropyl.

[0154] In some embodiments, each R 2a and R 2b are independently H, C 1 -C 6 Alkyl, or C 3 -C 6 In some embodiments, each R 2a and R 2b are independently H, C 1 -C 3 Alkyl, or C 3 -C 5 It is cycloalkyl.

[0155] In some embodiments, R 2a is H.

[0156] In some embodiments, R 2a is C 1 -C 6 In some embodiments, R 2a is C 1 -C 3 In some embodiments, R 2a is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 2a is methyl, ethyl, or isopropyl. In some embodiments, R 2a is methyl. In some embodiments, R 2a is ethyl. In some embodiments, R 2a is isopropyl.

[0157] In some embodiments, R 2a is C 3 -C 6 In some embodiments, R 2a is C 3 -C 5 In some embodiments, R 2ais cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 2a is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 2a is cyclopropyl.

[0158] In some embodiments, R 2b is H.

[0159] In some embodiments, R 2b is C 1 -C 6 In some embodiments, R 2b is C 1 -C 3 In some embodiments, R 2b is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 2b is methyl, ethyl, or isopropyl. In some embodiments, R 2b is methyl. In some embodiments, R 2b is ethyl. In some embodiments, R 2b is isopropyl.

[0160] In some embodiments, R 2b is C 3 -C 6 In some embodiments, R 2b is C 3 -C 5 In some embodiments, R 2b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 2b is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 2b is cyclopropyl.

[0161] In some embodiments, R 2a and R2b are both H. In some embodiments, R 2a and R 2b Both are C 1 -C 3 In some embodiments, R 2a and R 2b One of them is H and the other is C 1 -C 3 In some embodiments, R 2a and R 2b One of them is H and the other is C 3 -C 6 In some embodiments, R 2a and R 2b One of them is C 1 -C 3 alkyl, and the other is C 3 -C 6 It is cycloalkyl.

[0162] In some embodiments, the compound of formula (I) is a compound of formula (Ia): [ka] (In the formula, rings A, R 1 , R 4 , R 5 , R 7 , x, y, z, X, L, and ring B are as described for formula (I).

[0163] In some embodiments, the compound of formula (I) is a compound of formula (Ib): [ka] (In the formula, rings A, R 1 , R 4 , R 5 , R 7 , x, y, z, X, L, and ring B are as described for formula (I).

[0164] In some embodiments, the compound of formula (I) is a compound of formula (IA): [ka] (In the formula, rings A, R 1 , R 4 , R 5 , R 7 , x, y, z, X, and ring B are as described for formula (I); L is a bond, O, C(O), or N(R d ) and R d is as described for formula (I). In some embodiments, L is a bond. In some embodiments, L is O. In some embodiments, L is C(O). In some embodiments, L is N(R d ).

[0165] In some embodiments, the compound of formula (I) is a compound of formula (IIa), (IIb), (IIc), or (IId): [ka] (In the formula, rings A, R 1 , R 4 , R 5 , R 7 , x, y, z, X, and L are as described for formula (I). In some embodiments, the compound is of formula (IIa). In some embodiments, the compound is of formula (IIb). In some embodiments, the compound is of formula (IIc). In some embodiments, the compound is of formula (IId). In some embodiments, L is a bond.

[0166] In some embodiments, the compound of formula (I) is a compound of formula (IIa-1): [ka] (In the formula, R 1 , R 4and x is as described for formula (I). In some embodiments, each R 1 is independently halo; x is 0, 1, or 2; R 4 is C 1 -C 6 In some embodiments, R 1 is F; x is 0 or 1; R 4 is -CH 3 It is.

[0167] In some embodiments, the compound of Formula (I) is a compound of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIf): [ka] (In the formula, rings A, R 1 , R 4 , R 5 , R 7 , x, y, z, X, and L are as described for formula (I). In some embodiments, the compound is of formula (IIIa). In some embodiments, the compound is of formula (IIIb). In some embodiments, the compound is of formula (IIIc). In some embodiments, the compound is of formula (IIId). In some embodiments, the compound is of formula (IIIe). In some embodiments, the compound is of formula (IIIf).

[0168] In some embodiments, the compound of formula (I) is a compound of formula (IVa): [ka] (In the formula, rings A, R 1 , R 4 , R 5 , R 7 , x, y, z, X, and ring B are as described for formula (I).

[0169] In some embodiments, the compound of formula (I) is a compound of formula (IVb), (IVc), (IVd), or (IVe): [ka] (In the formula, rings A, R 1 , R 4 , R 5 , R 7 , R d , x, y, z, X, and ring B are as described for formula (I). In some embodiments, the compound is of formula (IVb). In some embodiments, the compound is of formula (IVc). In some embodiments, the compound is of formula (IVd). In some embodiments, the compound is of formula (IVe).

[0170] In any of the embodiments or variations described herein, the -NH 2 The stereochemistry at the carbon atom attached to the group is understood to be in either the (R) or (S) configuration. [ka] In some embodiments, the -NH of the spirocyclyl ring 2 The carbon atom (*) attached to the group has the (R) configuration. In another embodiment, the -NH 2 The carbon atom (*) attached to the group has the (S) configuration. In some embodiments, the -NH 2 The configuration of the carbon atoms bonded to the group is [ka] In some embodiments, the spirocyclyl ring is -NH 2 The configuration of the carbon atoms bonded to the group is [ka] In any of the pharmaceutical compositions described herein, the compound of formula (I) may be present as an enantiomerically pure compound or as a racemic mixture. In some embodiments, the pharmaceutical composition contains the (S)-isomer of the compound of formula (I) (i.e., the -NH 2 In some embodiments, the pharmaceutical composition comprises the (S) isomer of the compound of formula (I) at at least about 50%, 60%, 70%, 80%, or 90% of the total amount of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises the (S) isomer of the compound of formula (I) at at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the total amount of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises the (R) isomer of the compound of formula (I) (i.e., the -NH of the spirocyclyl ring as shown above). 2 In some embodiments, the pharmaceutical composition comprises a small amount of the (R)-isomer of the compound of formula (I) at less than about 50%, 40%, 30%, 20%, or 10% of the total amount of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises at least about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the total amount of the compound of formula (I) at less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the total amount of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises the (S)-isomer of the compound of formula (I) but not the (R)-isomer.

[0171] It is understood that in the specification herein, all descriptions, variations, embodiments, or aspects of a moiety may be combined with all descriptions, variations, embodiments, or aspects of other moieties, as if each and every combination of descriptions were specifically and individually recited. For example, all descriptions, variations, embodiments, or aspects provided herein with respect to ring A of formula (I) may be combined with R 1 , R a , R b , Rc , R d , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , L, X, ring B, x, y, and z. It is also understood that all descriptions, variations, embodiments, or aspects of formula (I) apply equally to other formulas detailed herein, where applicable, and that each and every description, variation, embodiment, or aspect is equally described as if it were listed separately and individually for every formula. For example, every statement, variation, embodiment, or aspect of formula (I), where applicable, applies equally to any of the formulas detailed herein, e.g., formulas (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIa-1), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVb), (IVc), (IVd), and (IVe), and is equally described as if each and every statement, variation, embodiment, or aspect was listed separately and individually for every formula.

[0172] In any of the foregoing embodiments of formula (I) and its variations, the substituent R 1 , R a , R b , R c , R d , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 It is understood that any one or more of L, X, ring A, and ring B can be optionally substituted.

[0173] In some embodiments, a compound is provided that is selected from the compounds in Table 1 or a pharma- ceutically acceptable salt thereof. Certain compounds described in this disclosure, including those in Table 1, are presented as specific stereoisomers and / or in non-stereochemical form, but it is understood that any enantiomeric or diastereomeric form, and any tautomeric or other form, of any of the compounds of this disclosure, including those in Table 1, are described herein. Similarly, certain compounds described in this disclosure, including those in Table 1, are presented as specific salts, but it is understood that any pharma- ceutically acceptable salt of any of the compounds of this disclosure, including those in Table 1, are described herein. Certain compounds described in this disclosure, including those in Table 1, are presented as specific salts, but it is further understood that the free form of the compounds of this disclosure, including those in Table 1, are also described herein. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

[0174] In some embodiments, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, does not include compound numbers 33, 129, 145, 146, 147, 172, 210, 225, 226, and 227.

[0175] It is understood that combinations of substituents and / or variables of the depicted formulae herein are permissible only if such contributions result in stable compounds.

[0176] In addition, all compounds of formula (I) that exist in free base or acid form can be converted to their pharma- ceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of compounds of formula (I) can be converted to their free base or acid form by standard techniques.

[0177] Synthesis method In a further aspect, provided herein is a process for preparing a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0178] Compounds of formula (I) or any variation thereof may be prepared according to the general reactions depicted in Schemes 1 and 2.

[0179] Scheme 1. [ka] The general synthesis of certain compounds of formula (I) (L is a bond or S) is outlined in Scheme 1. Coupling of 7-bromo-4-chloro (or 4-bromo)pyrazolo[1,5-a]pyrazine (intermediate A) to a substituted secondary amine (intermediate B) provides 7-bromo-pyrazolo[1,5-a]pyrazine-4-amine (intermediate D). In some cases, the substituted secondary amine (intermediate B) may bear an optionally protected (PG=protecting group) primary amine or a ketone that is subsequently converted to a primary amine. Intermediate D may be coupled to a substituted aryl, heteroaryl, or alkyl boronic acid / ester (R is H or alkyl), stannane, or substituted heteroaryl-thiol (intermediate C) in the presence of a palladium catalyst, and additional deprotection and / or functionalization steps may be performed to generate the final compound of formula (I).

[0180] Scheme 2. [ka] Scheme 2 provides a general synthesis of certain additional compounds of formula (I), for example, where L is CO. Intermediate D can be coupled to a substituted aryl, heteroaryl, or alkyl boronic acid / ester (where R is H or alkyl) in the presence of a palladium catalyst and a CO source, followed by additional deprotection and / or functionalization steps to generate the final compound of formula (I).

[0181] In some embodiments of the methods described herein, compounds of formula (I) are synthesized via a reduction step (e.g., sulfinium reduction using DIBAL-H) ​​to provide the (S) configuration at the carbon atom indicated below with an "*" in high purity. [ka]

[0182] It is understood that the synthetic processes disclosed herein can be modified to arrive at various compounds of the present disclosure by selection of the appropriate reagents and starting materials.

[0183] All compounds of formula (I) or any variation thereof described herein, which may exist in free base or acid form, can be converted to their pharma- ceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of the compounds of the present disclosure can be converted to their free base or acid form by standard techniques.

[0184] Also provided herein are intermediate compounds useful for preparing compounds of formula (I) or a pharma- ceutically acceptable salt thereof.

[0185] Pharmaceutical Compositions In another aspect, provided herein is a pharmaceutical composition of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. Thus, the present disclosure includes a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient. The pharmaceutical composition according to the present disclosure may be in a form suitable for oral, buccal, sublingual, parenteral (subcutaneous, intramuscular, intravenous, or intrathecal), nasal, topical, vaginal, rectal, intracerebral, intradermal, intravitreal, intraosseous injection, intraperitoneal, or inhalation administration. The pharmaceutical composition of the present disclosure includes a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or excipient.

[0186] The compounds described herein can be used in the preparation of pharmaceutical compositions by combining the compounds as active ingredients with pharma- ceutically acceptable excipients.Some examples of substances that can function as pharma-ceutically acceptable excipients include sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; surfactants, such as polysorbate 80 (i.e., Tween 80); powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil. , olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffers; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances used in pharmaceutical preparations. Pharmaceutical preparations can be prepared by known pharmaceutical methods. Suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st ed. (2005), incorporated herein by reference.

[0187] Wetting agents, emulsifying agents and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0188] Examples of pharma- ceutically acceptable antioxidants include water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0189] The pharmaceutical compositions may be conveniently provided in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will usually be that amount of the compound that produces a therapeutic effect. Usually, this amount will be in the range of about 1% to about 99% active ingredient, preferably about 5% to about 70%, most preferably about 10% to about 30%.

[0190] In certain embodiments, the pharmaceutical composition of the present disclosure comprises an excipient selected from the group consisting of cyclodextrins, liposomes, micelle forming agents, such as bile acids, and polymeric carriers, such as polyesters and polyanhydrides; and a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition renders the compound of formula (I) or a pharma- ceutically acceptable salt thereof orally bioavailable.

[0191] Pharmaceutical compositions of the disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powder, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a troche (using an inert base, such as gelatin and glycerin or sucrose and acacia), and / or as a mouthwash or the like, each containing a predetermined amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, as the active ingredient. The compound of formula (I), or a pharma- ceutically acceptable salt thereof, may also be administered as a bolus, electuary, or paste.

[0192] In solid dosage forms of the present disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants, such as glycerol; disintegrating agents, such as glycerol; Agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; dissolution retarders such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate and non-ionic surfactants; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard shelled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0193] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, and dispersants. Molded tablets can be made in a suitable machine in which a mixture of powdered compounds is infiltrated with an inert liquid diluent.

[0194] Tablets and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide slow or controlled release of the active ingredient therein, using, for example, hydroxypropylmethylcellulose, in various proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They can be formulated for rapid release, for example, lyophilized. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can be of a composition that they release the active ingredient(s) only or preferentially, optionally in a delayed manner, in a desired part of the digestive tract. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0195] The liquid dosage form for oral administration of the compound of formula (I) or its pharma- ceutically acceptable salt includes pharma-ceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof.

[0196] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0197] Suspensions may contain, in addition to the active compounds, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0198] Pharmaceutical compositions of the disclosure for rectal or vaginal administration can be prepared by mixing one or more compounds of the disclosure with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and can be provided as a suppository which is solid at room temperature but liquid at body temperature and will therefore melt in the rectal or vaginal cavity and release the active compound.

[0199] Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound (i.e., a compound of formula (I) or a pharma- ceutically acceptable salt thereof) may be mixed under sterile conditions with a pharma- ceutically acceptable carrier and any preservatives, buffers or propellants which may be required.

[0200] The ointments, pastes, creams, and gels may contain, in addition to a compound of formula (I), or a pharma- ceutically acceptable salt thereof, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0201] Powders and sprays can contain, in addition to a compound of formula (I), or a pharma- ceutically acceptable salt thereof, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0202] Pharmaceutical compositions of the disclosure suitable for parenteral administration comprise one or more compounds of formula (I), or pharma- ceutically acceptable salts thereof, in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes or suspending or thickening agents that render the formulation isotonic with the blood of the intended recipient, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use.

[0203] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0204] The pharmaceutical compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms on the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenylsorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the compositions. Prolonged absorption of the injectable pharmaceutical form may also be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0205] In some cases, it is desirable to slow down the absorption of drug from subcutaneous or intramuscular injection in order to prolong the effect of drug.This can be achieved by using liquid suspension of crystalline or amorphous substance with poor water solubility.The absorption rate of drug then depends on the dissolution rate, which in turn can depend on crystal size and crystalline form.Alternatively, the delayed absorption of parenterally administered drug form can be achieved by dissolving or suspending drug in oil vehicle.

[0206] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0207] In some embodiments of the pharmaceutical compositions described herein, the pharmaceutical compositions contain the (S)-isomer of the compound of formula (I) (i.e., the -NH 2 It contains a high purity of (S) configuration at the carbon atom (*) bonded to the group. [ka] In some embodiments, the pharmaceutical composition comprises the (S) isomer of the compound of formula (I) at at least about 50%, 60%, 70%, 80%, or 90% of the total amount of the compounds of formula (I). In some embodiments, the pharmaceutical composition comprises the (S) isomer of the compound of formula (I) at at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the total amount of the compounds of formula (I). In some embodiments, the pharmaceutical composition comprises the (S) isomer of the compound of formula (I) at at least about 95% of the total amount of the compounds of formula (I). In some embodiments, the pharmaceutical composition comprises the (S) isomer of the compound of formula (I) as about 100% of the total amount of the compounds of formula (I). In some embodiments, the pharmaceutical composition comprises the (R) isomer of the compound of formula (I) (i.e., the -NH of the spirocyclyl ring shown above). 2In some embodiments, the pharmaceutical composition comprises the (R) isomer of the compound of formula (I) in less than about 50%, 40%, 30%, 20%, or 10% of the total amount of the compounds of formula (I). In some embodiments, the pharmaceutical composition comprises the (R) isomer of the compound of formula (I) in less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the total amount of the compounds of formula (I). In some embodiments, the pharmaceutical composition comprises the (R) isomer of the compound of formula (I) in less than about 5% of the total amount of the compounds of formula (I). In some embodiments, the pharmaceutical composition does not include the (R) isomer of the compound of formula (I).

[0208] Treatment The compounds of formula (I), or pharma- ceutically acceptable salts thereof, and pharmaceutical compositions comprising the compounds of formula (I), or pharma- ceutically acceptable salts thereof, may be used in the methods of administration and treatment provided herein. The compounds and pharmaceutical compositions may also be used in in vitro methods, such as in vitro methods in which the compounds or pharmaceutical compositions are administered to cells for screening purposes and / or to perform quality control assays.

[0209] In one aspect, provided herein is a method of modulating SHP2, comprising contacting SHP2 with an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or an effective amount of any of the pharmaceutical compositions provided herein. Modulation (e.g., inhibition or activation) of SHP2 can be assessed and demonstrated by a variety of methods known in the art. Kits and commercially available assays can be utilized to determine whether and to what extent SHP2 is modulated (e.g., inhibited or activated). In certain embodiments, the compounds of the present disclosure are allosteric modulators of SHP2.

[0210] In some embodiments, provided herein are methods of inhibiting SHP2, comprising contacting SHP2 with an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or an effective amount of any of the pharmaceutical compositions provided herein. In certain embodiments, the compounds of the present disclosure are allosteric inhibitors of SHP2.

[0211] In some embodiments, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, modulates the activity of SHP2 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the compound of formula (I) enhances the activity of SHP2 by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 100-100%, 100-100%, 110-100%, 120-100%, 130-100%, 140-100%, 150-100%, 160-100%, 170-100%, 180-100%, 190-100%, 200-100%, 210-100%, 220-100%, 230-100%, 240-100%, 250-100%, 260-100%, 270-100%, 280-100%, 290-100%, 300-100%, 310-100%, 320-100%, 330-100%, 340-100%, 350-100%, 360-100%, 370-100%, 380-100%, 390-100%, 400-100%, 410-100%, 420-100%, 430-100%, 440-100%, 450-100 Adjust from 5~100%, 90~100%, 95~100%, 5~95%, 5~90%, 5~85%, 5~80%, 5~75%, 5~70%, 5~65%, 5~60%, 5~55%, 5~50%, 5~45%, 5~40%, 5~35%, 5~30%, 5~25%, 5~20%, 5~15%, 5~10%, 10~90%, 20~80%, 30~70%, or 40~60%.

[0212] In some embodiments, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, inhibits the activity of SHP2 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the compound of formula (I) enhances the activity of SHP2 by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 100-100%, 100-100%, 110-100%, 120-100%, 130-100%, 140-100%, 150-100%, 160-100%, 170-100%, 180-100%, 190-100%, 200-100%, 210-100%, 220-100%, 230-100%, 240-100%, 250-100%, 260-100%, 270-100%, 280-100%, 290-100%, 300-100%, 310-100%, 320-100%, 330-100%, 340-100%, 350-100%, 360-100%, 370-100%, 380-100%, 390-100%, 400-100%, 410-100%, 420-100%, 430-100%, 440-100%, 450-100 Inhibits by 5-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0213] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, crosses the blood-brain barrier. Thus, in some embodiments, the compound of formula (I) is useful in treating a disease associated with SHP2 regulation in a subject in need of such treatment, the disease being a brain disease, for example, brain cancer. Without wishing to be bound by theory, the pyrazolopyrazine core of formula (I), including the relative position of the nitrogen atom in the fused bicyclic ring, promotes desirable brain-crossing properties (improved blood-brain barrier crossing). In some embodiments, the compound of formula (I) has improved blood-brain barrier crossing ability compared to compounds having a core ring structure other than pyrazolopyrazine. Those skilled in the art are familiar with methods of measuring brain crossing, such as measuring blood-brain barrier crossing.

[0214] In another aspect, provided herein is a method for treating a disease associated with SHP2 regulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein is a method for preventing a disease associated with SHP2 regulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I). Non-limiting examples of diseases associated with SHP2 regulation include Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, lung cancer, colon cancer, or brain cancer. In some embodiments, the brain cancer is glioblastoma. In some embodiments, the disease associated with SHP2 regulation is a genetic disorder. In some embodiments, the disease associated with SHP2 regulation is Noonan syndrome. In some embodiments, the disease associated with SHP2 regulation is Leopard syndrome. In some embodiments, the disease associated with SHP2 regulation is cancer. In some embodiments, the disease associated with SHP2 regulation is juvenile myelomonocytic leukemia. In some embodiments, the disease associated with SHP2 regulation is neuroblastoma. In some embodiments, the disease associated with SHP2 regulation is melanoma. In some embodiments, the disease associated with SHP2 regulation is acute myeloid leukemia. In some embodiments, the disease associated with SHP2 regulation is breast cancer. In some embodiments, the disease associated with SHP2 regulation is lung cancer. In some embodiments, the disease associated with SHP2 regulation is colon cancer. In some embodiments, the disease associated with SHP2 regulation is brain cancer, e.g., glioblastoma.

[0215] In some embodiments, the disease associated with SHP2 regulation includes brain metastasis or glioblastoma that is EGFR / RAS pathway dependent.In some variations, brain metastasis may develop in non-small cell lung cancer (NSCLC) patients treated with EGFR inhibitors.In some embodiments, the treatment of brain metastasis or glioblastoma that is EGFR / RAS pathway dependent comprises administering to a subject a compound of formula (I) or its pharmacologic acceptable salt in combination with an ALK inhibitor.

[0216] Additional non-limiting examples of diseases associated with SHP2 regulation include: hematopoietic cancers; lymphoid system; myeloproliferative syndromes; myelodysplastic syndromes; leukemia; acute myeloid leukemia; juvenile myelomonocytic leukemia; esophageal cancer; breast cancer; lung cancer; colon cancer; gastric cancer; neuroblastoma; bladder cancer; prostate cancer; glioblastoma; urothelial carcinoma; uterine cancer; adenoid and ovarian serous cystadenocarcinoma; paraganglioma; pheochromocytoma; pancreatic cancer; adrenocortical carcinoma; gastric adenocarcinoma; sarcoma. ;rhabdomyosarcoma;lymphoma;head and neck cancer;skin cancer;peritoneal cancer;intestinal cancer (small and large intestine);thyroid cancer;endometrial cancer;cancer of the biliary tract;soft tissue cancer;ovarian cancer;cancer of the central nervous system (e.g., primary CNS lymphoma);gastric cancer;pituitary cancer;reproductive tract cancer;urinary tract cancer;salivary gland cancer;cervical cancer;liver cancer;eye cancer;cancer of the adrenal gland;cancer of the autonomic ganglia;cancer of the upper aerodigestive tract;bone cancer;testicular cancer;pleural cancer;kidney cancer;penile cancer;parathyroid cancer;cancer of the meninges;vulvar cancer and melanoma.

[0217] In some embodiments, the disease associated with SHP2 modulation is a cancer selected from the following: lung (e.g., NSCLC), colon, esophageal, rectal, breast, melanoma, pancreatic, juvenile myelomonocytic leukemia, and schwannoma. In some embodiments, the disease associated with SHP2 modulation is uterine cancer, endometrial cancer, or ovarian cancer.

[0218] In some embodiments, the disease associated with SHP2 regulation is a Ras mutation-induced cancer (e.g., KRAS G12C, KRAS G12D, or KRAS G12V).

[0219] In some embodiments, the disease associated with SHP2 modulation is a cancer selected from EGFR mutant non-small cell lung cancer, KRAS mutant non-small cell lung cancer (NSCLC), head and neck squamous cell lung cancer, melanoma, gastrointestinal stromal tumor, colorectal cancer, medullary thyroid carcinoma, and ALK rearranged NSCLC. In some embodiments, the disease associated with SHP2 modulation is a cancer selected from epithelial cancer (e.g., respiratory cancer, gastrointestinal cancer, reproductive cancer, endocrine cancer, breast cancer), mesothelioma, sarcoma, hematopoietic tumor, retinoblastoma, or tumor of the central or peripheral nervous system.

[0220] In some embodiments, administering a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof reduces the extent of a disease associated with SHP2 modulation in the subject (e.g., tumor size, tumor growth rate, metastasis). In some embodiments, administering a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof stabilizes a disease associated with SHP2 modulation (e.g., prevents or delays the progression of a cancer). In some embodiments, administering a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof delays the onset or recurrence of a disease associated with SHP2 modulation. In some embodiments, administering a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof slows the progression of a disease associated with SHP2 modulation. In some embodiments, administering a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof provides a partial remission of a disease associated with SHP2 modulation (e.g., cancer). In some embodiments, administering a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof provides overall remission of a disease associated with SHP2 modulation (e.g., cancer). In some embodiments, administering a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof reduces the dose of one or more other pharmaceutical agents required to treat a disease associated with SHP2 modulation (e.g., cancer). In some embodiments, administering a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof improves the efficacy of another pharmaceutical agent used to treat a disease associated with SHP2 modulation (e.g., cancer). In some embodiments, administering a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof delays the progression of a disease associated with SHP2 modulation (e.g., cancer). In some embodiments, administering a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof improves the quality of life of a subject having a disease associated with SHP2 modulation (e.g., cancer).In some embodiments, administering a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof prolongs survival of the subject having a disease associated with SHP2 modulation (e.g., cancer).

[0221] In some aspects, provided herein is a method of slowing the progression of a disease associated with SHP2 modulation (e.g., cancer) in a subject, the method comprising administering to the subject a compound of Formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein is a method of stabilizing a disease associated with SHP2 modulation (e.g., cancer) in a subject, the method comprising administering to the subject a compound of Formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the method prevents the progression of a disease associated with SHP2 modulation (e.g., cancer). In some embodiments, the method delays the progression of a disease associated with SHP2 modulation (e.g., cancer). In some embodiments, the method provides partial or total remission of a disease associated with SHP2 modulation (e.g., cancer).

[0222] In another aspect, provided herein is a method of delaying the onset or recurrence of a disease associated with SHP2 modulation (e.g., cancer) in a subject, the method comprising administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0223] In a further aspect, provided herein is a method of reducing the dosage of one or more other pharmaceutical agents required to treat a disease associated with SHP2 modulation (e.g., cancer) in a subject, the method comprising administering to the subject a compound of Formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein is a method of improving the effect of another pharmaceutical agent used to treat a disease associated with SHP2 modulation (e.g., cancer) in a subject, the method comprising administering to the subject a compound of Formula (I), or a pharma- ceutically acceptable salt thereof.

[0224] Also provided herein is a method of delaying progression of a disease associated with SHP2 modulation (e.g., cancer) in a subject, the method comprising administering to the subject a compound of Formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the method improves the quality of life of a subject having a disease associated with SHP2 modulation (e.g., cancer). In some embodiments, the method prolongs survival of a subject having a disease associated with SHP2 modulation (e.g., cancer).

[0225] In some aspects, provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use in treating a disease associated with SHP2 modulation. In other aspects, provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for treating a disease associated with SHP2 modulation.

[0226] Dosage and Administration The phrases "parenteral administration" and "administered parenterally", as used herein, mean modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0227] The phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally," as used herein, refer to the administration of a compound, drug, or other substance other than directly to the central nervous system, e.g., subcutaneous administration, so that it enters the patient's system and is thereby subject to metabolic and other similar processes.

[0228] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, e.g., nasally by spray, rectally, intravaginally, parenterally, intravesically, and topically (including buccal and sublingually) by powders, ointments or drops.

[0229] Regardless of the route of administration selected, the compounds of the present disclosure, or pharmaceutical compositions of the present disclosure, are formulated into pharma- ceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0230] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be modified to obtain an amount of the active ingredient that is not toxic to the patient and is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0231] The dosage level selected will depend on a variety of factors, including the activity of the particular compound of the present disclosure or its esters, salts or amides employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound employed, the duration of treatment, other drugs, compounds and / or substances used in combination with the particular compound employed, the age, sex, weight, condition, general health and medical history of the patient being treated, and similar factors well known in the medical arts. Daily, weekly or monthly dosing (or other time intervals) may be used.

[0232] A physician or veterinarian having ordinary skill in the art can easily determine and prescribe the effective amount of pharmaceutical composition required.For example, a physician or veterinarian can start the dose of the compound of the present disclosure used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and then gradually increase the dosage until the desired effect is achieved.

[0233] Typically, a suitable daily dose of a compound of the present disclosure will be that amount of compound that is the minimum dose effective to produce a therapeutic effect (e.g., inhibit necrosis). Such an effective dose will typically depend on the factors discussed above. Typically, the dose of a compound of the present disclosure for a patient, when used for the indicated effect, will range from about 0.0001 to about 100 mg per kg of body weight per day. Preferably, the daily dosage will range from 0.001 to 50 mg of compound per kg of body weight, and even more preferably, from 0.01 to 10 mg of compound per kg of body weight.

[0234] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms.

[0235] In some embodiments, the present disclosure relates to a compound for modulating SHP2, or a pharma- ceutically acceptable salt thereof, the compound being represented by formula (I). In some embodiments, the compounds of the present disclosure are allosteric regulators of SHP2. In any event, the compounds of the present disclosure preferably exert their effect on modulating SHP2 at a concentration of less than about 50 micromolar, for example, less than about 10 micromolar or less than 1 micromolar.

[0236] When the compounds of the present disclosure are administered to humans and animals as pharmaceuticals, they may be given by themselves or in combination with a pharma- ceutical carrier, for example, as a pharmaceutical composition containing 0.1% to 99.5% (e.g., 0.5% to 90%) of the active ingredient.

[0237] The compounds of the present application or pharmaceutical compositions thereof may be administered once, twice, three times, or four times a day using any suitable embodiment described above. Also, administration of the compounds or treatment may continue for a number of days; for example, treatment will generally continue for at least 7, 14, or 28 days between cycles of treatment. Treatment cycles are well known and are frequently alternated with rest periods of about 1 to 28 days, generally about 7 days or about 14 days, between cycles. Treatment cycles may also be continuous in certain embodiments.

[0238] When administered orally, the total daily dosage for a human subject can be about 1 mg to 1,000 mg, about 1,000 to 2,000 mg per day, about 10 to 500 mg per day, about 50 to 300 mg per day, about 75 to 200 mg per day, or about 100 to 150 mg per day.

[0239] The daily dosage may also be expressed as the total amount of the compound described herein administered per dose or per day. The daily dosage of the compound may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0240] In certain embodiments, the method includes administering to the subject an initial daily dose of about 1-800 mg of a compound described herein and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. Dosage can be increased daily, every other day, twice per week, or once per week.

[0241] In certain embodiments, the compound or pharmaceutical preparation is administered orally. In certain embodiments, the compound or pharmaceutical preparation is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0242] The preparations of the present disclosure may be given orally, parenterally, topically, or rectally. They are, of course, given in a form suitable for each administration route. For example, they are given in tablet or capsule form; by injection, inhalation, eye lotion, ointment, suppository, injection, inhalation, etc.; topically by lotion or ointment; and rectally by suppository. In some embodiments, administration is oral.

[0243] Combination therapy The disclosed method may include a compound of formula (I), or a pharma- ceutically acceptable salt thereof, used alone or in combination with one or more additional therapies (e.g., non-drug treatments or therapeutic agents). The dosage of one or more of the additional therapies (e.g., non-drug treatments or therapeutic agents) may be reduced from the standard dosage when administered alone. For example, dosage may be empirically determined from drug combinations and modifications, or estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6(2005)).

[0244] The compound of formula (I), or its pharmaceutically acceptable salt, can be administered before, after, or simultaneously with one or more of such additional therapies. When combined, the dosage of the compound of formula (I), or its pharmaceutically acceptable salt, and the dosage of one or more additional therapies (e.g., non-drug treatments or therapeutic agents) provide a therapeutic effect (e.g., synergistic or additive therapeutic effect). The compound of formula (I), or its pharmaceutically acceptable salt, and the additional therapies, e.g., anticancer drugs, can be administered together, e.g., in a single pharmaceutical composition, or separately, and when administered separately, this can be done simultaneously or sequentially. Such sequential administration can be close or distant in time.

[0245] In some embodiments, the additional therapy is the administration of a side effect limiting agent (e.g., an agent intended to reduce the occurrence or severity of side effects of treatment). For example, in some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may also be used in combination with a therapeutic agent that treats nausea. Examples of agents that may be used to treat nausea include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, the one or more additional therapies include a non-drug treatment (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies include a therapeutic agent (e.g., a compound or biological agent that is an anti-angiogenic agent, a signal transduction inhibitor, an anti-proliferative agent, a glycolysis inhibitor, or an autophagy inhibitor). In some embodiments, the one or more additional therapies include a non-drug treatment (e.g., surgery or radiation therapy) and a therapeutic agent (e.g., a compound or biological agent that is an anti-angiogenic agent, a signal transduction inhibitor, an anti-proliferative agent, a glycolysis inhibitor, or an autophagy inhibitor). In other embodiments, the one or more additional therapies include two therapeutic agents. In yet other embodiments, the one or more additional therapies include three therapeutic agents. In some embodiments, the one or more additional therapies include four or more therapeutic agents.

[0247] In this Combination Therapy section, all references are incorporated by reference for the agents described, or for any pharma- ceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers thereof, whether or not expressly described as such.

[0248] Nonpharmacological treatments Examples of non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (eg, surgical removal of tumor tissue), and T cell adoptive transfer (ACT) therapy.

[0249] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, may be used as an adjuvant therapy after surgery. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, may be used as a neoadjuvant therapy before surgery.

[0250] Radiation therapy can be used to inhibit abnormal cell growth or treat hyperproliferative disorders, such as cancer, in a subject (e.g., a mammal, e.g., a human). Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered via one of several methods, or a combination of methods, including, but not limited to, external beam therapy, internal radiation therapy, implanted radiation, stereotactic radiotherapy, systemic radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. The term "brachytherapy," as used herein, refers to radiation therapy delivered by a spatially restricted radioactive material inserted into the body at or near the site of a tumor or other proliferative tissue disease. The term is intended to include, but is not limited to, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioisotopes of Lu). Suitable sources of radiation for use as the cell conditioner of the present disclosure include both solid and liquid. As a non-limiting example, the source of radiation can be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclide that emits photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be any solution of radionuclide(s), such as a fluid made from a solution of I-125 or I-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclide, such as Au-198, or Y-90. Moreover, the radionuclide(s) can be embedded in a gel or radioactive microspheres.

[0251] In some embodiments, the compound of formula (I), or its pharmaceutically acceptable salt, can make abnormal cells more sensitive to treatment with radiation for the purpose of killing or inhibiting the growth of such cells. Thus, the present disclosure further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation, comprising administering to the mammal an amount of the compound of formula (I), or its pharmaceutically acceptable salt, which amount is effective for sensitizing abnormal cells to treatment with radiation. The amount of the compound in this method can be determined according to the average to confirm the effective amount of such compound as described herein. In some embodiments, the compound of formula (I), or its pharmaceutically acceptable salt, can be used as an adjuvant therapy after radiation therapy or as a neoadjuvant therapy before radiation therapy.

[0252] In some embodiments, the non-drug treatment is T cell adoptive transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells can be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. Prior to expansion and genetic modification of T cells, a source of T cells is obtained from the subject. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present disclosure, any number of T cell lines available in the art can be used. In some embodiments, the T cells are autologous T cells. Whether before or after genetic modification of the T cells to express a desired protein (e.g., a CAR), the T cells can be activated and expanded using methods described, for example, in U.S. Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041.

[0253] Therapeutic Agents The therapeutic agent may be a compound used in the treatment of cancer or a condition related thereto.

[0254] For example, the therapeutic agent may be a steroid. Thus, in some embodiments, the one or more additional therapies include a steroid. Suitable steroids include 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurand. These may include, but are not limited to, lenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarb, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednibar, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof.

[0255] Further examples of therapeutic agents that may be used in combination therapy with the compounds of Formula (I), or pharma- ceutically acceptable salts thereof, include those described in the following patents: U.S. Patent Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, and International Patent Application Publication No. These include compounds described in WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089, and WO00 / 02871.

[0256] The therapeutic agent may be a biologic (e.g., a cytokine (e.g., an interferon or an interleukin, e.g., IL-2)) used in the treatment of cancer or a condition associated therewith. In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important to cancer. Antibody-drug conjugates are also included.

[0257] The therapeutic agent can be a T cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, e.g., a monoclonal antibody). The antibody can be, e.g., humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-L1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, or combinations thereof.In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibodies such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene) or Preusser, M. et al. (2015) Nat. Rev. Neurol. (including, but not limited to, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDl4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002).

[0258] The therapeutic agent can be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A or OMP-313M32 (etigilimab).

[0259] The therapeutic agent may be an agent that treats cancer or a condition related thereto (e.g., a cytotoxic agent, a non-peptide small molecule, or other compound useful in the treatment of cancer or a condition related thereto, collectively, an "anti-cancer agent"). The anti-cancer agent may be, for example, a chemotherapeutic agent or a targeted therapy agent.

[0260] Anticancer drugs include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenal cortical suppressants, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Further anticancer drugs include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, the one or more additional therapies include two or more anticancer drugs. Two or more anticancer drugs can be used in a cocktail that is administered in combination or separately. Suitable dosing regimens for combinations of anticancer drugs are known in the art and described in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0261] Other non-limiting examples of anti-cancer drugs include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex™ (bicalutamide); Iressa® (gefitinib); alkylating agents such as thiotepa and cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethylenimines and methylamelamines (including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine); acetogenins (especially bullatacin and butaracinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its adzelesin, carzelesin and cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); erytherobin; pancratistatin; sarcodictyin A; spongistatins; nitrogen mustards, e.g., chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mec loretamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosurea, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicins, such as calicheamicin gamma ll and calicheamicin omega ll (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicins, such as dynemicin A; bisphosphonates, such as clodronate; esperamicin;Neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxol Bicine, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, pteropterin, trimethothrexate ... oxalates;purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone;antiadrenergic agents such as aminoglutethimide, mitotane, trilostane;folic acid supplements such as floric acid;aceglatate amines;aldophosphamide glycosides;aminolevulinic acid;eniluracil;amsacrine;bestrabucil;bisantrene;edatraxate;defofamine;demecolcine;diaziquone;elfomitine;elliptinium acetate;epothilones, e.g. epothilone B;etoglucide;gallium nitrate;hydroxyurea;lentinan;lonidamine;maytansinoids, e.g. maytansine and ansamitocin;mitoguazone;mitoxantrone;mopidamol;nitracrine;pentostatin;fenameth;pirarubicin;rosoxantrone;Podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; schizophyllan; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes, such as T-2 toxin, veracrine A, roridin A, and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphatase amides; thiotepa; taxoids such as Taxol® (paclitaxel), Abraxane® (a cremophor-free albumin engineered nanoparticle formulation of paclitaxel), and Taxotere® (doxetaxel); chlorambucil; tamoxifen (Nolvadex®); raloxifene; aromatase-inhibiting 4(5)-imidazoles; 4-hydroxytamoxifen; trioxyphene; ketoxifene; LY 117018; Onapristone; Toremifene (Fareston®); Flutamide, nilutamide, bicalutamide, leuprolide, goserelin; Chlorambucil; Gemzar® gemcitabine; 6-thioguanine; Mercaptopurine; Platinum coordination complexes, such as cisplatin, oxaliplatin and carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Na velbine® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitors RFS2000; difluoromethylornithine (DMFO); retinoids, e.g., retinoic acid; esperamicin; capecitabine (e.g., Xeloda®); and pharmaceutically acceptable salts of any of the above.

[0262] Additional non-limiting examples of anti-cancer drugs include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicin, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadishtin ... , alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 antitoxin, antineoplastic agents (e.g., cell cycle non-specific antineoplastic agents, and other antineoplastic agents described herein), antineoplastic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, biricoderm, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), Calyculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanton, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortatat These include, but are not limited to, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0263] Further non-limiting examples of anti-cancer drugs include natural products, such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., enzymes that systemically replace L-asparagine, L-asparaginase, which inhibits mitochondrial function and does not render cells without the ability to synthesize their own asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents, such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., CDK4 / 6 inhibitors, e.g., abemaciclib, ribociclib, palbociclib;seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), trazenes-dacarbazine (DTIC), antiproliferative / antimitotic antimetabolites, e.g., folic acid analogs, pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin, and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoylanilide hydroamic acid, vorinostat, LBH589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., bistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array520), DNA binders (e.g., Zalypsis®), PI3K inhibitors such as PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (e.g., CAL-130), copanlisib, alpelisib, and idelalisib;Multikinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen) and hormone agonists, such as luteinizing hormone releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN163L), Aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CSl (e.g., elotuzumab), HSP90 inhibitors ( For example, 17AAG and KOS953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra™), anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists;

[0264] In some embodiments, the anticancer drug is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analog or derivative variant of the foregoing.

[0265] In some embodiments, the anti-cancer drug is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors such as gefitinib (Iressa®), erlotinib (Tarceva®), piritinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW2992, ARRY-334543, and JNJ-26483327.

[0266] In some embodiments, the anticancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib; brigatinib; entrectinib; ensartinib (X-396); lorlatinib; ASP3026; CEP-37440; 4SC-203; TL-398; PLB1003; TSR-011; CT-707; TPX-0005, and AP26113. Additional examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894.

[0267] In some embodiments, the anti-cancer agent is an inhibitor of a downstream member of a receptor tyrosine kinase (RTK) / growth factor receptor (e.g., an SOS1 inhibitor (e.g., BI-1701963, BI-3406, SDR5, BAY-293, or RMC-5845, or a pharma- ceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof), a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., an mTORC1 inhibitor or an mTORC2 inhibitor). In some embodiments, the anti-cancer agent is JAB-3312.

[0268] In some embodiments, the anticancer agent is an SOS1 inhibitor. In some embodiments, the SOS1 inhibitor is selected from those disclosed in WO2021173524, WO2021130731, WO2021127429, WO2021092115, WO2021105960, WO2021074227, WO2020180768, WO2020180770, WO2020173935, WO2020146470, WO2019201848, WO2019122129, WO2018172250, and WO2018115380, or a pharma- ceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0269] In some embodiments, the anti-cancer agent is an additional Ras inhibitor or a Ras vaccine, or another therapeutic modality designed to directly or indirectly reduce the oncogenic activity of Ras. In some embodiments, the anti-cancer agent is an additional Ras inhibitor. In some embodiments, the Ras inhibitor targets Ras in its active or GTP-bound state. In some embodiments, the Ras inhibitor targets Ras in its inactive or GDP-bound state. In some embodiments, the Ras inhibitor is, for example, an inhibitor of K-Ras G12C, such as AMG 510 (sotorasib), MRTX1257, MRTX849 (adagrasib), JNJ-74699157, LY3499446, ARS-1620, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-21000, IBI351, ERAS-3490, RMC-6291, ASP2453, or GDC-6036, or a pharma- ceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the Ras inhibitor is an inhibitor of K-Ras G12D, such as MRTX1133 or JAB-22000, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the Ras inhibitor is an inhibitor of K-Ras G12V, such as JAB-23000, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the Ras inhibitor is RMC-6236, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the Ras inhibitor is selected from the Ras(ON) inhibitors disclosed in the following, which are incorporated by reference in their entireties, or a pharma- ceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof: WO2021091982, WO2021091967, WO2021091956, and WO2020132597. Other examples of Ras inhibitors that may be combined with the Ras inhibitors of the present disclosure include:The present invention is provided in the following, which are incorporated by reference in their entireties: WO20220133038, WO2022133345, WO2022132200, WO2022119748, WO2022109485, WO2022109487, WO2022066805, WO2021239058, WO2021236920, WO2021231526, WO2021228161, WO2021222333, WO2021219091, WO2021219090, WO2021219072, WO202121893 9, WO2021217019, WO2021216770, WO2021215545, WO2021215544, WO2021211864, WO2021197499, WO2021190467, WO2021185233, WO2021180181, WO202 1175199, WO2021173923, WO2021169990, WO2021169963, WO2021168193, WO2021158071, WO2021155716, WO2021152149, WO2021150613, WO2021147967 , WO2021147965, WO2021143693, WO2021142252, WO2021141628, WO2021139748, WO2021139678, WO2021129824, WO2021129820, WO2021127404, WO202 1126816, WO2021126799, WO2021124222, WO2021121371, WO2021121367, WO2021121330, WO2020050890, WO2020047192, WO2020035031, WO2020028706 , WO2019241157, WO2019232419, WO2019217691, WO2019217307, WO2019215203, WO2019213526, WO2019213516, WO2019155399, WO2019150305, WO2019 110751, WO2019099524, WO2019051291, WO2018218070, WO2018217651, WO2018218071, WO2018218069, WO2018206539, WO2018143315, WO2018140600,WO2018140599, WO2018140598, WO2018140514, WO2018140513, WO2018140512, WO2018119183, WO2018112420, WO2018068017, WO20 18064510, WO2017201161, WO2017172979, WO2017100546, WO2017087528, WO2017058807, WO2017058805, WO2017058728, WO201705 8902, WO2017058792, WO2017058768, WO2017058915, WO2017015562, WO2016168540, WO2016164675, WO2016049568, WO2016049524, WO2015054572, WO2014152588, WO2014143659, and WO2013155223, or a pharma- ceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0270] In some embodiments, a therapeutic agent that may be combined with a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is an inhibitor of the MAP kinase (MAPK) pathway (or "MAPK inhibitor"). MAPK inhibitors include, but are not limited to, one or more MAPK inhibitors described in Cancers (Basel) 2015 Sep;7(3):1758-1784. For example, MAPK inhibitors include trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132; vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA119 / BAY86-9766); GDC-0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (Roche, described in PLoS One. 2014 Nov 25; 9(11)); and GSK1120212 (or JTP-74057, Clin Cancer Res. 2011 Mar 1;17(5):989-1000). The MAPK inhibitor may be PLX8394, LXH254, GDC-5573, or LY3009120.

[0271] In some embodiments, the anticancer drug is an inhibitor or disruptor of RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathway.The PI3K / AKT inhibitor can include, but is not limited to, one or more of the PI3K / AKT inhibitors described in Cancers (Basel) 2015 Sep; 7 (3): 1758-1784.For example, the PI3K / AKT inhibitor can be selected from one or more of NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.

[0272] In some embodiments, the anti-cancer agent is a PD-1 or PD-L1 antagonist.

[0273] In some embodiments, the additional therapeutic agent includes an ALK inhibitor, a HER2 inhibitor, an EGFR inhibitor, an IGF-1R inhibitor, a MEK inhibitor, a PI3K inhibitor, an AKT inhibitor, a TOR inhibitor, an MCL-1 inhibitor, a BCL-2 inhibitor, a proteasome inhibitor, and an immunotherapy. In some embodiments, the therapeutic agent can be a pan-RTK inhibitor, e.g., afatinib.

[0274] IGF-1R inhibitors include linsitinib, or a pharma- ceutically acceptable salt thereof.

[0275] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Further antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res. 1999, 59:1236-1243. The EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.

[0276] Small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®), and lapatinib (TykerB®). See, e.g., Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (Tagrisso®). Further non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications, and all pharma- ceutically acceptable salts of such EGFR inhibitors: EP0520722; EP0566226; WO96 / 33980; U.S. Patent No. 5,747,498; WO96 / 30347; EP0787772; WO97 / 30034; WO97 / 30044; WO97 / 38994; WO97 / 49688; EP837063; WO98 / 02434; WO97 / 38983; WO95 / 19774; WO95 / 19970; WO97 / 13771; WO98 / 02437; WO98 / 02438. ;WO97 / 32881;DE19629652;WO98 / 33798;WO97 / 32880;WO97 / 32880;EP682027;WO97 / 02266;WO97 / 27199;WO98 / 07726;WO97 / 34895;WO96 / 31510;WO98 / 14449;WO98 / 1445 0;WO98 / 14451;WO95 / 09847;WO97 / 19065;WO98 / 17662;U.S. Patent No. 5,789,427;U.S. Patent No. 5,650,415;U.S. Patent No. 5,656,643;WO99 / 35146;WO99 / 35132;WO99 / 07701; and WO92 / 20642.Additional non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998,8(12):1599-1625. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family contains HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0277] MEK inhibitors include, but are not limited to, pimasertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation that is a class I MEK1 mutation selected from D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is a class II MEK1 mutation selected from ΔE51-Q58; ΔF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N.

[0278] PI3K inhibitors include wortmannin; the 17-hydroxywortmannin analogs described in WO06 / 044453; 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941, and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4 ,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ235 or NVP-BEZ235 and described in WO06 / 122806); (S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (Axon available from Medchem; PI103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride (available from Axon Medchem); PIK75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid, monohydrochloride) (available from Axon Medchem); PIK90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)-nicotinamide (available from Axon available from Medchem); AS-252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione (available from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrilnidin-4-one (available from Axon Medchem); XL-765;and XL-147. Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0279] AKT inhibitors include Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem. J. 2005, 385(Pt. 2):399-408); Akt-1-1,2 (inhibits Akl and 2) (Barnett et al., Biochem. J. 2005, 385(Pt. 2):399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91:1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05 / 011700); indole-3-carbinol and its derivatives (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li J Nutr. 2004, 134(12) Suppl):3493S-3498S); perifosine (e.g., disrupts Akt membrane localization; Dasmahapatra et al. Clin. Cancer Res. 2004, 10(15):5242-52); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and triciribine (TCN or API-2 or NCI identifier: NSC154020; Yang et al., Cancer Res. 2004, 64:4394-9).

[0280] mTOR inhibitors include ATP-competitive mTORC1 / mTORC2 inhibitors, e.g., PI-103, PP242, PP30; torin1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, such as temsirolimus (Torisel®); everolimus (Afinitor®; WO 94 / 09010); ridaforolimus (also known as deforolimus or AP23573); rapalogs disclosed, for example, in WO 98 / 02441 and WO 01 / 14387, e.g., AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(temsirolimus) 32-deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapamycin; derivatives disclosed in WO 05 / 005434; U.S. Patent Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, and WO 94 / 090 101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, e.g., WO2018204416, WO2019212990, and WO2019212991), such as a compound having the structure [ka] The RMC-5552 has the following features.

[0281] BRAF inhibitors that may be used in combination with the compound of formula (I), or a pharma- ceutically acceptable salt thereof, include, for example, vemurafenib, dabrafenib, and encorafenib. BRAF may include a class 3 BRAF mutation. In some embodiments, the class 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R, and A762E.

[0282] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the essential anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely related to tumor progression and resistance to not only conventional chemotherapy but also targeted therapeutic agents, including BCL-2 inhibitors such as ABT-263.

[0283] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0284] Immunotherapies include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, engineered T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTEs), and anti-PD-1, anti-PD-L1, anti-CTLA4, anti-LAG1, and anti-OX40 agents.

[0285] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs (drugs that modify the immune response) that contain an imide group. The IMiD class includes thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0286] Exemplary anti-PD-1 antibodies and methods for their use are described by Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168A1), and elsewhere herein.

[0287] GITR agonists include GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), e.g., the GITR fusion proteins described in U.S. Patent No. 6,111,090, U.S. Patent No. 8,586,023, WO2010 / 003118 and WO2011 / 090754; or, e.g., U.S. Patent No. 7,025,962, EP1947183, U.S. Patent No. 7,812,135, U.S. Patent No. 8,388,967, U.S. Patent No. 8 No. 7,618,632, EP 1866339, and the anti-GITR antibodies described in WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726.

[0288] Another example of a therapeutic agent that can be used in combination with the compound of formula (I) or its pharma- ceutically acceptable salt is an antiangiogenic agent.Antiangiogenic agents include, but are not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof.Antiangiogenic agents can be agonists, antagonists, allosteric regulators, toxins, or more generally act to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), thereby promoting cell death or halting cell growth.In some embodiments, one or more additional therapies include antiangiogenic agents.

[0289] Antiangiogenic agents can be MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of antiangiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 5 2889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US20090012085, as well as US Patent Nos. 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 or MMP-9 over other matrix-metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors are AG-3340, RO32-3555, and RS13-0830.

[0290] Further exemplary anti-angiogenesis agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen binding regions that specifically bind to VEGF (e.g., bevacizumab), or soluble VEGF receptors or ligand binding regions thereof), such as VEGF-TRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen binding regions that specifically bind thereto), EGFR inhibitors (e.g., antibodies or antigen binding regions that specifically bind thereto), such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Angl and anti-Ang2 agents (e.g., antibodies or antigen binding regions that specifically bind thereto or to their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind thereto). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen binding regions, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM disintegrin domains to antagonize binding of integrins to their ligands (US2002 / 0042368), specifically binding anti-eph receptor or Anti-ephrin antibodies or antigen binding regions (U.S. Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and patent family members thereof), and anti-PDGF-BB antagonists (e.g., antibodies or antigen binding regions that specifically bind) as well as antibodies or antigen binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind thereto). Additional anti-angiogenic agents include SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO0770622); pegaptanib octasodium (Gilead Sciences, USA); alphastatin (BioActa, UK);M-PGA (Celgene, USA, US5712291); Ilomastat (Arriva, USA, US5892112); Emaxanib (Pfizer, USA, US5792783); Vatalanib (Novartis, Switzerland); 2-Methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); Anecortave acetate (Alcon, USA); Alpha-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); Anti-Vn Mab (Crucell, Netherlands), DAC antiangiogenic agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan; SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); Fibrinogen-E fragment (BioActa, UK); Angiogenesis inhibitors (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); Maspin (Sosei, Japan); 2-Methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (Lane Labs,USA);Tz-93(Tsumura,Japan);TAN-1120(Takeda,Japan);FR-111142(Fujisawa,Japan,JP02233610);Platelet factor 4(RepliGen,USA,EP407122);Vascular endothelial growth factor antagonist(Borean,Denmark);Bevacizumab (pINN)(Genentech,USA);Angiogenesis inhibitor(SUGEN,USA);XL784(Exelixis,USA);XL647(Exelixis,USA);MAb, alpha5beta3 integrin, second generation (Applied Molecular Evolution, USA and MedImmune, USA); enzastaurin hydrochloride (Lilly, USA); CEP7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC1 (Genoa Institute of Cancer Research, Italy); rBPI21 and BPI-derived antiangiogenic agents (XOMA, USA); PI88 (Progen, Australia); cilengitide (Merck KGaA, German; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); AVE8062 (Ajinomoto, Japan); AS1404 (Cancer Research Laboratory, New Zealand); SG292 (Telios, USA); endostatin (Boston Children's Hospital, USA); ATN161 (Attenuon, USA); 2-methoxyestradiol (Boston Children's ZD6474 (AstraZeneca, UK); ZD6126 (Angiogene Pharmaceuticals, UK); PPI2458 (Praecis, USA); AZD9935 (AstraZeneca, UK); AZD2171 (AstraZeneca, UK); vatalanib (pINN) (Novartis, Switzerland and Schering AG, Germany); Tissue factor pathway inhibitor (EntreMed, USA); pegaptanib (Pinn) (Gilead Sciences, USA); xanthrulizole (Yonsei University, South Korea); vaccine, gene-based, VEGF-2 (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX103 (University of California at San Diego, USA); PX478 (ProlX, USA); metastatin (EntreMed, USA); troponin I (Harvard University, USA); SU6668 (SUGEN, USA); OXI4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, Canada); CDP791 (Celltech Group, UK); Atiprimod (pINN) (GlaxoSmithKline, UK); E7820 (Eisai, Japan); CYC381 (Harvard University, USA); AE941 (Aeterna, Canada); Vaccines, Angiogenesis (EntreMed, USA); Urokinase Plasminogen Activator Inhibitor (Dendreon, USA); Oglufanide (pINN) (Melmotte, USA); HIF-ralpha Inhibitor (Xenova, UK); CEP5214 (Cephalon, USA); BAY RES2622 (Bayer, Germany); Angiocidin (InKine, USA); A6 (Angstrom, USA); KR31372 (Korea Research Institute of Chemical Technology, South Korea);GW2286(GlaxoSmithKline,UK);EHT0101(ExonHit,France);CP868596(Pfizer,USA);CP564959(OSI,USA);CP547632(Pfizer,USA);786034(GlaxoSmithKline,UK);KRN633(Kirin Brewery,Japan);Drug delivery system, intraocular, 2-methoxyestradiol; Anginex (Maastricht University, Netherlands, and University of Minnesota, USA); ABT510 (Abbott, USA); AAL993 (Novartis, Switzerland); VEGI (ProteomTech, USA); Tumor necrosis factor-alpha inhibitors; SU11248 (Pfizer, USA, and SUGEN USA); ABT518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA, and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, alpha5beta (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK, and Johnson & Johnson, USA); GFB116 (University of South Florida, USA, and Yale University, USA); CS706 (Sankyo, Japan); combrestatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES2690 (Bayer, Germany); AGM1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG13925 (Agouron, USA); tetrathiomolybdate (University of Michigan, USA); GCS100 (Wayne State University, USA) CV247 (Ivy Medical, UK); CKD732 (Chong Kun Dang, South Korea); irsogladine (Nippon Shinyaku, Japan); RG13577 (Aventis, France); WX360 (Wilex, Germany); Squalamine (Genaera, USA); RPI4610 (Sirna, USA); Heparanase inhibitor (InSight, Israel); KL3106 (Kolon, South Korea);These include honokiol (Emory University, USA); ZKCDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK229561 (Novartis, Switzerland, and Schering AG, Germany); XMP300 (XOMA, USA); VGA1102 (Taisho, Japan); VE-cadherin-2 antagonist (ImClone Systems, USA); vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, USA); truncated soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA). ;

[0291] Further examples of therapeutic agents that may be used in combination with the compounds of Formula (I), or pharma- ceutically acceptable salts thereof, include agents (e.g., antibodies, antigen-binding regions, or soluble receptors) that specifically bind to and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen-binding regions that specifically bind to its receptor, c-Met.

[0292] Another example of a therapeutic agent that can be used in combination with the compound of formula (I), or its pharma- ceutically acceptable salt, is an autophagy inhibitor. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, analogs of cAMP, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Antisense or siRNA that inhibits the expression of proteins, including, but not limited to, ATG5 (involved in autophagy), can also be used. In some embodiments, one or more additional therapies include an autophagy inhibitor.

[0293] Another example of a therapeutic agent that may be used in combination with the compound of formula (I) or a pharma- ceutically acceptable salt thereof is an anti-neoplastic agent. In some embodiments, one or more additional therapies include an anti-neoplastic agent. Non-limiting examples of anti-neoplastic agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ansar, ancestim, aruglavin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosphe. DA3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emiteflu, epirubicin, epoetin beta , etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumabzogamicin, gimeracil / oteracil / tegafur combination, glycopin, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronate, idarubicin, (imiquimod, interferon alfa, interferon alfa Lufa, Natural, Interferon Alpha-2, Interferon Alpha-2a, Interferon Alpha-2b, Interferon Alpha-Nl, Interferon Alpha-n3, Interferon Alphacon-1, Interferon Alpha, Natural, Interferon Beta, Interferon Beta-la, Interferon Beta-lb, Interferon Gamma, Natural Interferon Gamma-la, Interferon Gamma-lb, Interleukin-1 Beta, Iobenguane,Irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, millimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, Nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis stimulating protein, NSC631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon alpha-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alpha-2a, porfimer sodium, raloxifene, raltitrexed, rasbriembodiment, Rhenium Re186 etidronate, RII retinamide, rituximab, romurtide, samarium (153Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimethoprim Rexart, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulidizin, zinostatin stimalamer, or zoledronic acid; abarelix; AE941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), decitabine, dexaminoglutethimide, diazicon, EL532 (Elan), EM800 (Endorecherche),Eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran), interleukin-2, iproxifen, LDI200 (Milkhaus), religistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techni clone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafingadolinium, MX6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital), or Valspodar.

[0294] Additional examples of therapeutic agents that may be used in combination with the compounds of Formula (I), or pharma- ceutical acceptable salts thereof, include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services;huMAbOX40L;Atacicept;CP-870893;Lucatumumab;Dacetuzumab;Muromonab-CD3;Ipilumumab;MEDI4736 (Imfinzi®);MSB0010718C;AMP224;Adalimumab (Humira®);Ado-trastuzumab emtansine (Kadcyla®);Aflibercept (Eylea®);Alemtuzumab (Campath®);Basiliximab (Simulect®);Belimumab (Benlysta®);Basiliximab (Simulect®);Belimumab (Benlysta®);Brentuximab vedotin (Adcetris®);Canakinumab (Ilaris®) );Certolizumab pegol (Cimzia®);Daclizumab (Zenapax®);Daratumumab (Darzalex®);Denosumab (Prolia®);Eculizumab (Soliris®);Efalizumab (Raptiva®);Gemtuzumab ozogamicin (Mylotarg®);Golimumab (Simponi®);Ibritumomab tiuxetan (Zevalin®);Infliximab (Remicade®);Motavizumab (Numax®);Natalizumab (Tysabri®);Obinutuzumab (Gazyva®);Ofatumumab (Arzerra®);Omalizumab (Xolair®);These include palivizumab (Synagis®); pertuzumab (Perjeta®); ranibizumab (Lucentis®); raxibacumab (Abthrax®); tocilizumab (Actemra®); tositumomab; tositumomab-i-131; ustekinumab (Stelara®); AMG102; AMG386; AMG479; AMG655; AMG706; AMG745; and AMG951.

[0295] In some embodiments, a compound of formula (I), or a pharma- ceutically acceptable salt thereof, may be used in combination with one or more of the following: an SOS1 inhibitor, a Ras inhibitor (e.g., a Ras(ON) inhibitor, such as RMC-6291 or RMC-6236, or a Ras(OFF) inhibitor, such as adagrasib or sotorasib), a MEK inhibitor, an EGFR inhibitor, or an immune checkpoint inhibitor (e.g., an anti-PD1 inhibitor, such as pembrolizumab).

[0296] In some embodiments, a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is used in combination with an ERK inhibitor and a BRAF inhibitor (i.e., as part of a triple combination therapy).

[0297] The compounds described in this disclosure may be used in combination with the agents disclosed herein or other suitable agents depending on the condition being treated. Thus, in some embodiments, one or more compounds of formula (I), or a pharma- ceutically acceptable salt thereof, will be co-administered with other therapies described herein. When used in combination therapy, the compounds described herein may be administered simultaneously or separately with the second agent. This combined administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds of formula (I), or a pharma- ceutically acceptable salt thereof, and any of the agents described herein may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of formula (I), or a pharma- ceutically acceptable salt thereof, and any of the therapies described herein may be administered simultaneously, where both agents are in separate formulations. In another alternative, the compounds of formula (I), or a pharma- ceutically acceptable salt thereof, may be administered, followed by any of the therapies described herein, or vice versa. In some embodiments of the separate administration protocol, a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, and any of the therapies described herein are administered minutes apart, or hours apart, or days apart.

[0298] In some embodiments of any of the methods described herein, the first therapy (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt thereof) and the one or more additional therapies are administered simultaneously or sequentially, in any order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7, 1-14, 1-21, or 1-30 days before or after the one or more additional therapies.

[0299] Kit / manufactured product Disclosed herein, in certain embodiments, are kits and articles of manufacture for use with one or more compounds, compositions, or methods described herein. Such kits include carriers, packages, or containers that are compartmentalized to receive one or more containers, such as vials, tubes, etc., each of the containers (or containers) containing one of the other elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials, such as glass or plastic.

[0300] The kit typically includes a label listing the contents and / or instructions for use, and a package insert having instructions for use. A set of instructions will also typically be included.

[0301] In one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container when the letters, numbers, or other features that form the label are bonded, molded, or inscribed on the container itself, and the label is associated with the container when it is present in a receptacle or carrier that also holds the container, for example, as a package insert. In one embodiment, the label is used to indicate that the contents should be used for a specific therapeutic application. The label also indicates instructions for the use of the contents, such as in the methods described herein.

[0302] In certain embodiments, pharmaceutical compositions are provided in a pack or dispenser device that contains one or more unit dosage forms containing the compound provided herein. The pack contains, for example, metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied by a warning associated with the container in a form prescribed by a government agency that regulates the manufacture, specification, or sale of pharmaceuticals, which reflects the approval by the agency of the form of the drug for human or animal administration. Such a warning is, for example, a label approved by the U.S. Food and Drug Administration for a drug, or an approved product insert. In one embodiment, a composition containing the compound provided herein formulated in a compatible pharmaceutical carrier is also prepared and placed in a suitable container, and labeled for the treatment of an indicated condition.

[0303] Exemplary embodiments The present disclosure is further illustrated by the following embodiments, the features of each of which may be combined with any of the other embodiments where appropriate and practical.

[0304] Embodiment P1. A compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, Ring A is C 3 -C 6 cycloalkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, where heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O, and S; Each R 1 are independently halo, cyano, -NR 2a R 2b , C 1 -C 6 Alkyl, oxo, hydroxy, C 1 -C 6Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-OH, C 1 -C 6 Alkyl-CN, -C(O)NR 2a R 2b , -C(O)(C 1 -C 6 Alkyl), -CO 2 H, -CO 2 (C 1 -C 6 alkyl), -Si(R a )(R b )(R c ), -P(O)(R a )(R b ), -OP(O)(R a )(R b ), C 3 -C 6 cycloalkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein said heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O, and S; or two R's 1 The groups, together with the carbon atom or heteroatom to which they are attached, form a fused phenyl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which may be selected from 1 to 4 R 6 groups, wherein the fused heterocycloalkyl and heteroaryl contain 1 to 3 heteroatoms selected from N, O, and S; Each R a , R b , and R c are independently hydroxy, C 1 -C 6 Alkyl, or C 1 -C 6 is alkoxy; Each R 2a and R 2b are independently H, C 1 -C 6 Alkyl, or C 3 -C 6 is cycloalkyl; L is a bond, S, O, C(O), or N(R d ) and; R d is H or C 1 -C 6 is alkyl; X is CR 3a R 3b , N.R. 3a , or O; R 3a and R 3b are independently H or C 1 -C 6 is alkyl; R 4 , H, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-OH, C 1 -C 6 Haloalkyl, or -NH 2 and; Each R 5 Independently, Halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -(C 1 -C 6 Alkylene)(C 1 -C 6 alkoxy), or C 1 -C 6 is alkyl-OH; Ring B is a fused phenyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Each R 6 is independently 1 -C 6 Alkyl, halo, or C 1 -C 6 is haloalkyl; Each R 7 is independently 1 -C 6 Alkyl, halo, C 1 -C 6 Alkoxy, C 1 -C 6Alkyl-OH, hydroxy, cyano, -Si(R a )(R b )(R c ), -P(O)(R a )(R b ), -OP(O)(R a )(R b ), -NR 2a R 2b , or C 1 -C 6 is haloalkyl; x is 0 to 5; y is 0 to 2; z is 0 to 4; One or more hydrogen atoms in said compounds are optionally replaced by deuterium).

[0305] Embodiment P2. Ring A is C 3 -C 5 cycloalkyl, phenyl, 6-membered heterocycloalkyl, or 5-6-membered heteroaryl, wherein the heterocycloalkyl and heteroaryl contain 1-2 heteroatoms selected from N, O, and S; A compound according to embodiment P1, or a pharma- ceutically acceptable salt thereof.

[0306] Embodiment P3. Ring A is cyclopropyl, phenyl, dihydropyridinyl, dihydropyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, isoxazolyl, or thiophenyl; A compound according to embodiment P1 or P2, or a pharma- ceutically acceptable salt thereof.

[0307] Embodiment P4. [ka] teeth, [ka] That is, A compound according to any one of embodiments P1 to P3, or a pharma- ceutically acceptable salt thereof.

[0308] Embodiment P5. x is 0, 1, 2, or 3; A compound according to any one of embodiments P1 to P4, or a pharma- ceutically acceptable salt thereof.

[0309] Embodiment P6. Each R 1 are independently halo, cyano, -NR 2a R 2b , C 1 -C 3 Alkyl, oxo, hydroxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Alkyl-OH, C 1 -C 3 Alkyl-CN, -C(O)NR 2a R 2b , -C(O)(C 1 -C 3 Alkyl), -CO 2 H, -CO 2 (C 1 -C 3 alkyl), -Si(R a )(R b )(R c ), -P(O)(R a )(R b ), -OP(O)(R a )(R b ), C 3 -C 5 cycloalkyl, phenyl, or 6-membered heterocycloalkyl, said heterocycloalkyl containing 1-2 heteroatoms selected from N and O; or two R's 1 The groups, together with the carbon atom or heteroatom to which they are attached, form a fused phenyl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which may be selected from 1 to 2 R 6groups, and the fused heterocycloalkyl and heteroaryl contain 1-2 heteroatoms selected from N, O, and S; Each R a , R b , and R c is independently 1 -C 3 Alkyl or C 1 -C 3 is alkoxy; Each R 2a and R 2b are independently H, C 1 -C 3 Alkyl, or C 3 -C 5 is cycloalkyl; Each R 6 is independently 1 -C 3 Alkyl, halo, or C 1 -C 3 haloalkyl, A compound according to any one of embodiments P1 to P5, or a pharma- ceutically acceptable salt thereof.

[0310] Embodiment P7. Each R 1 are independently F, Cl, -CN, -CH 2 CN, -NH 2 , -N(H)CH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , oxo, -CF 3 , -OCH 3 , -CH 2 OH, -C(O)N(CH 3 ) 2 , -C(O)CH 3 , cyclopropyl, or [ka] and; or two R's1 Groups, together with the carbon atom or heteroatom to which they are attached, [ka] forming a condensation group selected from A compound according to any one of embodiments P1 to P6, or a pharma- ceutically acceptable salt thereof.

[0311] Embodiment P8. [ka] teeth, [ka] [ka] That is, A compound according to any one of embodiments P1 to P7, or a pharma- ceutically acceptable salt thereof.

[0312] Embodiment P9. The compound according to any one of embodiments P1 to P8, or a pharma- ceutically acceptable salt thereof, wherein L is a bond.

[0313] Embodiment P10. L is S, A compound according to any one of embodiments P1 to P8, or a pharma- ceutically acceptable salt thereof.

[0314] Embodiment P11. The compound according to any one of embodiments P1 to P8, wherein L is O, or a pharma- ceutically acceptable salt thereof.

[0315] Embodiment P12. The compound according to any one of embodiments P1 to P8, wherein L is C(O), or a pharma- ceutically acceptable salt thereof.

[0316] Embodiment P13. L is N(R d ) and; R d is H or C 1 -C 3 is alkyl, A compound according to any one of embodiments P1 to P8, or a pharma- ceutically acceptable salt thereof.

[0317] Embodiment P14. X is CR 3a R 3b , N.R. 3a , or O; R 3a and R 3b are independently H or C 1 -C 3 is alkyl, A compound according to any one of embodiments P1 to P13, or a pharma- ceutically acceptable salt thereof.

[0318] Embodiment P15. X is CH 2 , N(H), N(CH 3 ), or O, or a pharma- ceutically acceptable salt thereof.

[0319] Embodiment P16. R 4 , H, C 1 -C 3 Alkyl, C 1 -C 3 Alkyl-OH, C 1 -C 3 Haloalkyl, or -NH 2 That is, A compound according to any one of embodiments P1 to P15, or a pharma- ceutically acceptable salt thereof.

[0320] Embodiment P17. R 4 H, CH 3 , -CH 2 OH, -CH 2 F, or -CHF 2 That is, A compound according to embodiment P16, or a pharma- ceutically acceptable salt thereof.

[0321] Embodiment P18. y is 0 or 1; A compound according to any one of embodiments P1 to P17, or a pharma- ceutically acceptable salt thereof.

[0322] Embodiment P19. Each R 5 Independently, Halo, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, -(C 1 -C 3 Alkylene)(C 1 -C 3 alkoxy), or C 1 -C 3 is alkyl-OH; A compound according to any one of embodiments P1 to P18, or a pharma- ceutically acceptable salt thereof.

[0323] Embodiment P20. Each R 5 are independently Cl, F, -CH 2 F, -CHF 2 , -CH 2 OCH 3 , or -CH 2 OH, A compound according to embodiment P19, or a pharma- ceutically acceptable salt thereof.

[0324] Embodiment P21. Ring B is a fused phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O, and S; A compound according to any one of embodiments P1 to P20, or a pharma- ceutically acceptable salt thereof.

[0325] Embodiment P22. Ring B is a fused phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, or oxazolyl; A compound according to embodiment P21, or a pharma- ceutically acceptable salt thereof.

[0326] Embodiment P23. z is 0, 1, or 2; A compound according to any one of embodiments P1 to P22, or a pharma- ceutically acceptable salt thereof.

[0327] Embodiment P24. Each R 7 is independently 1 -C 3 Alkyl, halo, C 1 -C 3 Alkoxy, C 1 -C 3 Alkyl-OH, hydroxy, cyano, -Si(R a )(R b )(R c ), -P(O)(R a )(R b ), -OP(O)(R a )(R b ), -NR 2a R 2b , or C 1 -C 3 is haloalkyl; Each R a , R b , and R c are independently hydroxy, C 1 -C 3 Alkyl, or C 1 -C 3 is alkoxy; Each R 2a and R 2b are independently H, C 1 -C 3 Alkyl, or C 3 -C 5 is cycloalkyl, A compound according to any one of embodiments P1 to P23, or a pharma- ceutically acceptable salt thereof.

[0328] Embodiment P25. Each R 7 are independently 3 , F, -OCH 3 , -CH 2 OH, hydroxy, -CN, -N(CH 3 ) 2 , or -CHF 2 or a pharma- ceutically acceptable salt thereof.

[0329] Embodiment P26. [ka] teeth, [ka] That is, A compound according to any one of embodiments P1 to P25, or a pharma- ceutically acceptable salt thereof.

[0330] Embodiment P27. The compound has formula (IIa), (IIb), (IIc), or (IId): [ka] It is of A compound according to any one of embodiments P1 to P26, or a pharma- ceutically acceptable salt thereof.

[0331] Embodiment P28. The compound according to embodiment P27, wherein L is a bond, or a pharma- ceutically acceptable salt thereof.

[0332] Embodiment P29. The compound has formula (IIa-1): [ka] It is of The compound according to embodiment P27 or P28, or a pharma- ceutically acceptable salt thereof.

[0333] Embodiment P30. Each R 1 is, independently, a halo; x is 0, 1, or 2; R 4 is C 1 -C 6 is alkyl, A compound according to embodiment P29, or a pharma- ceutically acceptable salt thereof.

[0334] Embodiment P31. R 1 is F; x is 0 or 1; R 4 is -CH 3 That is, A compound according to embodiment P30, or a pharma- ceutically acceptable salt thereof.

[0335] Embodiment P32. The compound has formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIf): [ka] or a pharma- ceutically acceptable salt thereof.

[0336] Embodiment P33. The compound has formula (IVa): [ka] or a pharma- ceutically acceptable salt thereof.

[0337] Embodiment P34. The compound has formula (IVb), (IVc), (IVd), or (IVe): [ka] or a pharma- ceutically acceptable salt thereof.

[0338] Embodiment P35. A compound selected from the compounds of Table 1, or a pharma- ceutically acceptable salt thereof.

[0339] Embodiment P36. A pharmaceutical composition comprising a compound according to any one of embodiments P1 to P35, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0340] Embodiment P37. A method of inhibiting SHP2 comprising contacting SHP2 with an effective amount of a compound according to any one of embodiments P1 to P35, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment P36.

[0341] Embodiment P38. A method for treating a disease associated with SHP2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of embodiments P1 to P35, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment P36.

[0342] Embodiment P39. The method of embodiment P38, wherein the disease is Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, lung cancer, colon cancer, or brain cancer.

[0343] Embodiment P40. The method of embodiment P39, wherein the brain cancer is glioblastoma. EXAMPLES

[0344] The examples and preparations provided below further illustrate and exemplify the compounds of the present disclosure and methods for testing such compounds. It is understood that the scope of the present disclosure is not in any way limited to the scope of the following examples.

[0345] The chemical reactions in the examples described can be easily adapted to prepare many other compounds disclosed herein, and alternative methods for preparing the compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of compounds not exemplified according to the present disclosure can be carried out by modifications obvious to those skilled in the art, such as by suitable protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions, reagents, and starting materials. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure.

[0346] The following abbreviations may be relevant for purposes of this application: Abbreviation ACN or MeCN: Acetonitrile AcOH: acetic acid AIBN: Azobisisobutyronitrile aq: water-based BF 3 .Et 2 O: Boron trifluoride etherate Bis-pin: Bis(pinacolato)diboron Boc: tert-butoxycarbonyl Boc 2 O: Di-tert-butyl decarbonate BSA: bovine serum albumin conc.:concentration DAST: Diethylaminosulfur trifluoride DCM: dichloromethane DIBAL-H: Diisobutylaluminum hydride DIEA or DIPEA: Diisopropylethylamine DiFMUP: 6,8-difluoro-4-methylumbelliferyl phosphate Dioxane: 1,4-dioxane DMA: N,N-Dimethylacetamide DMF: Dimethylformamide DMSO: Dimethyl sulfoxide DTT: Dithiothreitol EDTA: Ethylenediaminetetraacetic acid Et 2 O: Diethyl ether Et 3 N: Triethylamine EtOAc: ethyl acetate EtOH: Ethanol h: hour(s) HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HPLC: High-performance liquid chromatography IBX: 2-iodoxybenzoic acid iPr 2 O: Diisopropyl ether iPrOH: Isopropyl alcohol KOAc: Potassium acetate L: Liters LCMS: Liquid chromatography / mass spectrometry LDA: Lithium diisopropylamide m-CPBA: 3-chloroperbenzoic acid mCPBA: meta-chloroperoxybenzoic acid Max: Maximum 2-MeTHF: 2-methyltetrahydrofuran MeOH: Methanol min:minutes Min:Minimum MTBE: tert-butyl methyl ether NBS: N-bromosuccinimide n-BuLi: n-butyl lithium NMP: N-methylpyrrolidinone NMR: nuclear magnetic resonance Pd(AmPhos) 2 Cl 2 :Dichlorobis(p-methylaminophenyl-di-tert-butylphosphine)palladium(II) Pd(dba) 2 Palladium(0) bis(dibenzylideneacetone) Pd(dppf)Cl 2:Dichlorobis(1,1'-diphenylphosphinoferrocene)-palladium(ll) Pd(PPh 3 ) 4 :Tetrakis(triphenylphosphine)palladium(0) Pd 2 (dba) 3 : Tris(dibenzylideneacetone)dipalladium(0) PPTS: Pyridinium p-toluenesulfonate psi: pounds per square inch Py.HBr 3 Pyridinium hydrobromide perbromide rt: retention time RT: room temperature SFC: Supercritical Fluid Chromatography SPhos Pd G2: Chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) SPhos Pd G4: Methanesulfonato(2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl TBAB: Tetrabutylammonium bromide TBS: tert-butyldimethylsilyl t-BuOK: Potassium tert-butoxide TEA: Triethylamine TFA: Trifluoroacetic acid TFAA: Trifluoroacetic anhydride THF: tetrahydrofuran Ti(OEt) 4 Titanium(IV) ethoxide TIPS: Triisopropylsilyl TIPSCl: Triisopropylsilyl chloride XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos Pd G4: Methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0347] Synthesis Example intermediate compound Example i-1. Intermediate A-1 (7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazine) [ka] Step a: To a solution of ethyl pyrazole-3-carboxylate (510 g, 3.64 mol) in DMF (3 L), 1-chloropropan-2-one (504 g, 5.46 mol) and potassium carbonate (1005 g, 7.27 mol) were added at room temperature with N 2 The mixture was stirred for 2 hours. The residue was poured into water (7.00L). The aqueous phase was extracted with ethyl acetate (3.00L*3). The combined organic phase was washed with brine (3.00L) and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50 / 1 to 1 / 1) to give ethyl 2-acetonylpyrazole-3-carboxylate (139 g, 680 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d7.56(d,J = 2.0 Hz, 1H), 6.91 (d, J=2.0Hz,1H),5.36(s,2H),4.31(q,J = 7.2 Hz, 2H), 2.20 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H).

[0348] Process b:CH 3 CO 2A solution of ethyl 2-acetonylpyrazole-3-carboxylate (139 g, 708 mmol) in H (690 mL) was added to CH 3 CO 2 NH 4 (273g, 3.54mol) at room temperature with N 2 The reaction was stirred at 130° C. for 16 h. The solution was concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50 / 1 to 1 / 1) to give 6-methylpyrazolo[1,5-a]pyrazin-4(5H)-one (68.0 g, 433 mmol) as a brown solid. 1 HNMR (400MHz, CDCl 3 )d10.8(s,1H),7.79(d,J = 2.4 Hz, 1H), 7.33 (s, 1H), 7.06 (d, J=2.0Hz,1H),2.31(d,J = 1.2 Hz, 3H).

[0349] Step c: To a solution of 6-methylpyrazolo[1,5-a]pyrazin-4(5H)-one (68.0 g, 455 mmol) in DMF (340 mL) was added NBS (89.2 g, 501 mmol) at 0 °C. 2 The reaction was stirred at 0° C. for 5 min. The residue was diluted with a saturated aqueous solution of sodium sulfite (2.00 L) and H 2 The combined organic phase was washed with brine (2.00L) and poured into 2.00 mL of anhydrous NaCl. The aqueous phase was extracted with ethyl acetate (1.50L*3). The combined organic phase was washed with brine (2.00L) and 2 SO 4 The crude product was triturated with MTBE (80.0 mL) at room temperature for 30 min to give 7-bromo-6-methyl-pyrazolo[1,5-a]pyrazin-4(5H)-one (43.0 g, 182 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3 )d11.1(s,1H),7.90(d,J = 2.0Hz, 1H), 7.22(d, J=2.0Hz,1H),2.49(s,3H).

[0350] Process d: PCl3 A solution of 7-bromo-6-methyl-pyrazolo[1,5-a]pyrazin-4(5H)-one (43.0 g, 188 mmol) in 215 mL of N 2 The mixture was stirred under reduced pressure. The residue was carefully poured into water (1.50L) ​​and stirred for 5 minutes. The pH value of the aqueous phase was adjusted to about 7 with a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (1.00L*2). The combined organic phase was washed with brine (1.00L) and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50 / 1 to 1 / 1) to give 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazine (33.0 g, 131 mmol) as an off-white solid. 1 HNMR (400MHz, CDCl 3 )d8.09(d,J = 2.0 Hz, 1H), 6.98 (d, J=2.4Hz,1H),2.68(s,3H). LCMS m / z[M+H] + 245.9.

[0351] Example i-2. Intermediate A-2 (4,7-dibromo-6-methyl-pyrazolo[1,5-a]pyrazine) [ka] To a solution of 7-bromo-6-methyl-pyrazolo[1,5-a]pyrazin-4(5H)-one (19.0 g, 83.3 mmol) in DCM (200 mL) was added phosphoryl bromide (11 mL, 108 mmol) and DMF (6 mL). The mixture was stirred at 40° C. for 6 h. The mixture was poured slowly into water (200 mL) and extracted with ethyl acetate (200 mL*2). The combined organic phase was washed with brine (100 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to obtain 4,7-dibromo-6-methyl-pyrazolo[1,5-a]pyrazine (15.0 g, 51.5 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3 )d8.06(d,J = 2.40Hz, 1H), 6.92 (d, J=2.40Hz,1H),2.67(s,3H).

[0352] Example i-3. Intermediate A-3 (7-bromo-4-chloro-pyrazolo[1,5-a]pyrazine) [ka] Step a: To a mixture of pyrazole-3-carboxylic acid (200 g, 1.78 mol) in dioxane (1400 mL) was added 1,1′-carbonyldiimidazole (318 g, 1.96 mol) in one portion at room temperature. The reaction mixture was stirred at 50° C. for 30 minutes. To the mixture was then added aminoacetaldehyde dimethyl acetal (214 mL, 1.96 mol) in one portion at 50° C. The reaction mixture was stirred at 50° C. for 30 minutes. To the mixture was then added an aqueous solution of HCl (12 M, 743 mL) in one portion at 50° C. The reaction mixture was stirred at 100° C. for 16 hours. The mixture was then concentrated under vacuum. To the residue was added water (2.00 L) and the mixture was stirred for 30 minutes. The solid was collected by filtration and washed with water (500 mL*2) to give crude pyrazolo[1,5-a]pyrazin-4(5H)-one (100 g) as a brown solid, which was used in the next step further without purification.

[0353] Step b: To a solution of the crude pyrazolo[1,5-a]pyrazin-4(5H)-one obtained above (100 g) in DMF (700 mL) was added AcOH (127 mL, 2.22 mol) and NBS (132 g, 0.74 mol) at 0 °C with N 2 The reaction was stirred at 0° C. for 5 min and then poured into ice water. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine and anhydrous Na 2 SO 4Drying at 40° C., filtering and concentrating in vacuo gave crude 7-bromopyrazolo[1,5-a]pyrazin-4(5H)-one (80 g), which was used in the next step without further purification.

[0354] Process c: PCl 3 A solution of crude 7-bromopyrazolo[1,5-a]pyrazin-4(5H)-one (80 g) in 1,5-dichloropyrazine-4(5H)-one (800 mL, 8.61 mol) was stirred at 100° C. for 2 h. The residue was carefully poured into water (500 mL). The pH value of the aqueous phase was adjusted with NaHCO 3 The pH was adjusted to about 7 with a saturated solution of 100%. The aqueous phase was extracted with ethyl acetate (300 mL*2). The combined organic phase was washed with brine (200 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50 / 1 to 1 / 1) followed by prep-HPLC (neutral conditions) to give 7-bromo-4-chloro-pyrazolo[1,5-a]pyrazine (30.0 g, 128 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3 )d 8.39 (d, J=2.4Hz,1H),8.11(s,1H),7.27(d,J = 1.2 Hz, 1H). LCMS m / z[M+H] + 233.9.

[0355] Example i-4. Intermediate A-4 (Ethyl 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazine-2-carboxylate) [ka] Step a: To a mixture of diethyl 3,5-pyrazoledicarboxylate (4.4 g, 21 mmol) in acetone (100 mL) was added potassium carbonate (3.9 g, 28.2 mmol) followed by 1-chloropropan-2-one (1.8 mL, 23.0 mmol) at room temperature. The reaction mixture was stirred at 55° C. for 3 h. The mixture was then concentrated under vacuum. To the residue was added water (100 mL) and the aqueous phase was extracted with ethyl acetate (150 mL*2). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 Drying at 40° C., filtering and concentrating in vacuo afforded ethyl 4-hydroxy-6-methyl-pyrazolo[1,5-a]pyrazine-2-carboxylate (5.83 g) as a brown oil which was used in the next step without further purification.

[0356] Step b: To a mixture of the crude diethyl 3,5-pyrazoledicarboxylate obtained above (5.83 g) in AcOH (90 mL) was added ammonium acetate (33.5 g, 435.0 mmol). The reaction mixture was stirred at 120° C. for 20 h. The mixture was cooled to room temperature and then poured into water (300 mL) and stirred for 15 min. The precipitate was collected by filtration and washed with water to obtain crude ethyl 7-bromo-4-hydroxy-6-methyl-pyrazolo[1,5-a]pyrazine-2-carboxylate (2.01 g) as a brown solid, which was used in the next step without further purification.

[0357] Step c: To a mixture of the crude ethyl 7-bromo-4-hydroxy-6-methyl-pyrazolo[1,5-a]pyrazine-2-carboxylate (2.01 g) obtained above in dichloromethane (40 mL) cooled to 0° C., NBS (1.95 g, 11.0 mmol) was added. The reaction was then stirred at 0° C. for 1 h. Dichloromethane (120 mL) and a saturated aqueous solution of sodium thiosulfate (200 mL) were added, and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration and washed with water to give crude ethyl 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazine-2-carboxylate (2.43 g) as a brown solid, which was used in the next step without further purification.

[0358] Process d: PCl 3 A solution of crude ethyl 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazine-2-carboxylate (2.43 g) in ethyl acetate (38 mL, 408 mmol) was stirred at 120° C. for 2 h. The residue was carefully poured into water (500 mL). The pH value of the aqueous phase was adjusted using NaHCO 3 The pH was adjusted to about 7 with a saturated solution of 100 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (300 mL*2). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 Drying at 40° C., filtering and concentrating in vacuo gave ethyl 7-bromo-6-methyl-4-(5-oxospiro[7H-cyclopenta[b]pyridine-6,4′-piperidine]-1′-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (2.18 g, 6.84 mmol) as a light brown solid. 1 HNMR(400MHz,DMSO-d6) d 7.60 (s, 1H), 4.41 (d, J = 7.1 Hz, 3H), 2.61 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). LCMS m / z[M+H] + 320.0.

[0359] Example i-5. Intermediate A-5 (Ethyl 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazine-2-carboxylate) [ka] Step a: To a mixture of ethyl 7-bromo-6-methyl-4-(5-oxospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (1 g, 3.14 mmol) in anhydrous THF (40 mL) cooled at -78°C, DIBAL-H (1 M in toluene, 7 mL, 7 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 1.5 h and then warmed to 0°C. A saturated aqueous solution of Rochelle's salt (10 mL) was added, followed by water (40 mL) and ethyl acetate (40 mL). The mixture was stirred at room temperature for 16 h. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (40 mL). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , cyclohexane / ethyl acetate = 8 / 2 to 6 / 4) to obtain 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazin-2-yl)methanol (535 mg, 1.93 mmol) as a white solid. 1 HNMR(400MHz,DMSO-d6) d 6.97 (s, 1H), 5.42 (t, J = 5.9 Hz, 1H), 4.64 (d, J = 5.9 Hz, 2H), 3.21 (s, 3H). LCMS m / z[M+H] + 277.9.

[0360] Step b: Dess-Martin periodinane (1.0 g, 2.36 mmol) was added portionwise to a mixture of 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazin-2-yl)methanol (0.53 g, 1.92 mmol) in dichloromethane (20 mL) cooled to 0° C. The reaction was stirred at 0° C. for 45 min and then at room temperature for 45 min. A saturated aqueous solution of sodium thiosulfate (20 mL), sodium bicarbonate (20 mL) and dichloromethane (20 mL) was added and the mixture was stirred for 1 h. The mixture was filtered through a hydrophobic cartridge (liquid / liquid extraction column, Radleys®) and then concentrated in vacuo to give crude 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazine-2-carbaldehyde (0.82 g) as a brown solid, which was used in the next step without further purification.

[0361] Step c: Diethylaminosulfur trifluoride (1.6 mL, 12.1 mmol) was added dropwise to a mixture of crude 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazine-2-carbaldehyde (0.82 g) in dichloromethane (20 mL) cooled at -20°C. The reaction mixture was stirred at -20°C for 2 h and then at room temperature for 2 h. The mixture was cooled to 0°C and a saturated aqueous solution of sodium bicarbonate (20 mL) was added slowly, followed by solid sodium bicarbonate to adjust the pH value of the aqueous phase to about 8. Water (20 mL) and dichloromethane (30 mL) were added and the mixture was filtered through a hydrophobic cartridge (liquid / liquid extraction column, Radleys®) and then concentrated in vacuum. The residue was purified by column chromatography (SiO 2 , cyclohexane / ethyl acetate = 100 / 0 to 95 / 5) to give 7-bromo-4-chloro-2-(difluoromethyl)-6-methyl-pyrazolo[1,5-a]pyrazine (437 mg, 1.47 mmol) as a white solid. 1 HNMR (400MHz, DMSO-d6) d 7.48 (br s, 1H), 7.37 (t, J = 53.7 Hz, 1H), 3.61 (s, 3H). LCMS m / z[M+H] + 297.9.

[0362] Example i-6. Intermediate A-6 (7-bromo-4-chloro-3-fluoro-6-methyl-pyrazolo[1,5-a]pyrazine) [ka] Step a: To a mixture of 4-fluoro-1H-pyrazole (5 g, 58 mmol) in DMSO (110 mL) was added cesium carbonate (2.8 g, 87 mmol) followed by 1-bromo-2,2-dimethoxy-propane (11 g, 8.2 mL, 61 mmol) at room temperature. The reaction mixture was stirred at 120° C. for 5 days. The reaction mixture was poured into water (600 mL) and the aqueous phase was extracted with ethyl acetate (2*150 mL). The combined organic phase was washed with water, brine and anhydrous Na 2 SO 4 The mixture was dried over 400° C., filtered and concentrated in vacuo to give a yellow oil which was purified by column chromatography (SiO 2 , heptane / ethyl acetate=85 / 15) to give 1-(2,2-dimethoxypropyl)-4-fluoro-pyrazole (7.69 g) as a colorless oil. 1 HNMR(400MHz,DMSO-d6) d 7.76 (dd, J=4.4Hz,J =0.8 Hz 1H), 7.46 (dd, J=4.4Hz,J =0.8 Hz 1H), 4.13 (s, 2H), 3.18 (s, 6H), 1.08 (s, 3H).

[0363] Step b: A solution of 1-(2,2-dimethoxypropyl)-4-fluoro-pyrazole (7.69 g, 40.9 mmol) in dry THF (150 mL) was cooled to -70 °C with N 2 The reaction mixture was stirred at -70°C for 1 h, then ethyl chloroformate (6.65 g, 61.3 mmol) was added dropwise at -70°C. The reaction mixture was stirred for 30 min, then warmed to room temperature. The reaction mixture was diluted with NH 4The combined organic phase was washed with brine and anhydrous NaCl. 2 SO 4 The mixture was dried over 400° C., filtered and concentrated in vacuo to give an orange oil which was purified by column chromatography (SiO 2 , heptane / ethyl acetate=9 / 1) to give ethyl 2-(2,2-dimethoxypropyl)-4-fluoro-pyrazole-3-carboxylate (9.73 g) as a pale yellow oil. 1 HNMR(400MHz,DMSO-d6) d 7.72 (d, J=4.4Hz,1H),4.59(s,2H),4.33(d,J = 7.2 Hz, 2H), 3.15 (s, 6H), 1.30 (m, 3H), 1.03 (s, 3H). LCMS m / z[M+Na] + 283.2.

[0364] Step c: To a solution of ethyl 2-(2,2-dimethoxypropyl)-4-fluoro-pyrazole-3-carboxylate (9.73 g, 37.4 mmol) in the mixture THF / water 1 / 1 (25 mL) was added trifluoroacetic acid (4.26 g, 28.6 mL, 374 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure to give crude ethyl 2-acetonyl-4-fluoro-pyrazole-3-carboxylate as a white solid (7.95 g), which was used without further purification. 1 HNMR(400MHz,DMSO-d6) d 7.74 (s, 1H), 5.35 (s, 2H), 4.28 (m, 2H), 2.18 (s, 3H), 1.26 (m, 3H). LCMS m / z[M+H] + 215.1.

[0365] Step d: To a mixture of ethyl 2-acetonyl-4-fluoro-pyrazole-3-carboxylate (7.95 g, 37.1 mmol) in AcOH (10.6 mL) was added ammonium acetate (14.3 g, 186 mmol). The reaction mixture was stirred under reflux for 15 h. The mixture was concentrated in vacuo. Water (300 mL) and ethyl acetate (300 mL) were added, the aqueous layer was separated and extracted with DCM (300 mL). The combined organic phase was diluted with Na 2 SO 4 Drying at 40° C., filtering and concentrating to dryness gave the crude product which was triturated in diisopropyl ether (40 mL) and ethyl acetate (2 mL), cooled in ice and filtered to give 3-fluoro-6-methyl-5H-pyrazolo[1,5-a]pyrazin-4-one (5.03 g, 30.1 mmol) as a beige solid. 1 HNMR(400MHz,DMSO-d6) d 11.24 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.41 (s, 1H), 2.08 (s, 3H). LCMS m / z[M+H] + 168.1.

[0366] Step e: To a mixture of 3-fluoro-6-methyl-5H-pyrazolo[1,5-a]pyrazin-4-one (5.03 g, 30.1 mmol) in DMF (150 mL) cooled to 0° C., NBS (5.62 g, 31.6 mmol) was added. The reaction was stirred at 0° C. for 1 h. The reaction mixture was diluted with ethyl acetate (150 mL). A saturated aqueous solution of sodium thiosulfate (700 mL) was added and the mixture was stirred at room temperature for 30 min, then extracted with ethyl acetate (3*200 mL). The solid was filtered from the interphase to provide the crude product (1.1 g). The combined organic phase was washed with Na 2 SO 4 The resulting combined crude products were triturated in acetonitrile (20 mL), cooled on ice, and filtered to give 7-bromo-3-fluoro-6-methyl-5H-pyrazolo[1,5-a]pyrazin-4-one (5.17 g, 21 mmol). 1HNMR (400MHz, DMSO-d6) d 11.63 (s, 1H), 8.03 (s, 1H), 2.25 (s, 3H). LCMS m / z[M+H] + 246.0.

[0367] Process f: PCl 3 A solution of ethyl 7-bromo-3-fluoro-6-methyl-5H-pyrazolo[1,5-a]pyrazin-4-one (5.3 g, 22 mmol) in ethyl 7-bromo-3-fluoro-6-methyl-5H-pyrazolo[1,5-a]pyrazin-4-one (66 g, 40 mL, 430 mmol) was heated to reflux for 2 h. The residue was cooled to room temperature and carefully poured into ice-cold water (800 mL) and the resulting mixture was stirred for 45 min. The aqueous phase was extracted with ethyl acetate (2*200 mL). The pH value of the aqueous phase was measured using NaHCO 3 The pH was adjusted to about 7 with a saturated solution of 100 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (300 mL*2). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 Drying at 40° C., filtering and concentrating in vacuo gave the crude product which was triturated in diisopropyl ether (40 mL), cooled in ice and filtered to give 7-bromo-4-chloro-3-fluoro-6-methyl-pyrazolo[1,5-a]pyrazine (4.95 g, 18.7 mmol) as a beige powder. 1 HNMR (400MHz, DMSO-d6) d 8.44 (s, 1H), 2.57 (s, 3H). LCMS m / z[M+H] + 264.0.

[0368] Example i-7. Intermediate A-7 (Ethyl 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazine-3-carboxylate) [ka] Step a: To a mixture of ethyl 1H-pyrazole-4-carboxylate (15 g, 107.0 mmol) in DMSO (210 mL) was added potassium carbonate (5.2 g, 161 mmol) followed by 1-bromo-2,2-dimethoxy-propane (21 g, 15.90 mL, 117.7 mmol) at room temperature. The reaction mixture was stirred at 120° C. for 24 h. The reaction mixture was poured into water (500 mL) and the aqueous phase was extracted with ethyl acetate (2*400 mL). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The mixture was dried over 400° C., filtered and concentrated in vacuo to give an orange oil which was purified by column chromatography (SiO 2 , heptane / ethyl acetate=7 / 3) to give ethyl 1-(2,2-dimethoxypropyl)pyrazole-4-carboxylate (17.5 g) as a yellow oil. 1 HNMR(400MHz,DMSO-d6) d 8.21 (s, 1H), 7.85 (s, 1H), 4.28 (s, 2H), 4.21 (q, J=7.1Hz,2H),3.20(s,6H),1.27(t,J = 7.1 Hz, 3H), 1.12 (s, 3H). LCMS m / z[M+H] + 243.2.

[0369] Step b: A solution of ethyl 1-(2,2-dimethoxypropyl)pyrazole-4-carboxylate (8.5 g, 35.1 mmol) in dry THF (130 mL) was treated with LDA (2 M in THF, 23 mL, 46 mmol) at −70 °C with N 2 The reaction mixture was stirred for 30 min at -70°C, then ethyl chloroformate (5.71 g, 52.6 mmol) was added dropwise at -70°C. The reaction mixture was stirred for 30 min, then warmed to room temperature. The reaction mixture was poured into a solution of brine and extracted with ethyl acetate (2*150 mL). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The mixture was dried over 400° C., filtered and concentrated in vacuo to give an orange oil which was purified by column chromatography (SiO 2, heptane / ethyl acetate=8 / 2) to give diethyl 2-(2,2-dimethoxypropyl)pyrazole-3,4-dicarboxylate (3.67 g, 11.7 mmol) as a yellow liquid. 1 HNMR(400MHz,DMSO-d6) d 7.92 (s, 1H), 4.43 (s, 2H), 4.34 (q, J=7.1Hz,2H),4.21(q,J = 7.1 Hz, 2H), 3.11 (s, 6H), 1.32 (t, J=7.1Hz,3H),1.25(t,J = 7.1Hz, 3H), 1.05 (s, 3H).

[0370] Step c: To a solution of diethyl 2-(2,2-dimethoxypropyl)pyrazole-3,4-dicarboxylate (3.67 g, 11.7 mmol) in the mixture THF / water 1 / 1 (20 mL) was added trifluoroacetic acid (2.66 g, 17.9 mL, 234 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , heptane / ethyl acetate=6 / 4) to give diethyl 2-acetonylpyrazole-3,4-dicarboxylate as a colorless oil (2.18 g). 1 HNMR(400MHz,DMSO-d6) d 7.92 (s, 1H), 5.37 (s, 2H), 4.21-4.31(m,4H),2.17(s,3H),1.24-1.28(m,6H). LCMS m / z[M+H] + 269.2.

[0371] Step d: To a mixture of diethyl 2-acetonylpyrazole-3,4-dicarboxylate (1.62 g, 4.7 mmol) in AcOH (1.34 mL) was added ammonium acetate (1.8 g, 23.4 mmol). The reaction mixture was stirred under reflux for 5 h. The mixture was cooled to room temperature and then poured into water (300 mL) and stirred for 15 min. The solid was collected by filtration and washed with water to give crude ethyl 6-methyl-4-oxo-5H-pyrazolo[1,5-a]pyrazine-3-carboxylate (1.1 g) as a beige solid, which was used in the next step without further purification. 1 HNMR(400MHz,DMSO-d6) d 11.5 (s, 1H), 8.18 (s, 1H), 7.58 (s, 1H), 4.24 (q, J=7.1Hz,2H),2.12(s,3H),1.28(t,J = 7.1 Hz, 3H). LCMS m / z[M+H] + 222.1.

[0372] Step e: To a mixture of the previously obtained ethyl 6-methyl-4-oxo-5H-pyrazolo[1,5-a]pyrazine-3-carboxylate (1.1 g) in DMF (25 mL) cooled to 0° C., NBS (929 mg, 5.2 mmol) was added. The reaction was stirred at 0° C. for 1 h. A saturated aqueous solution of ethyl acetate and sodium thiosulfate was added, and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration and washed with water to give crude ethyl 7-bromo-6-methyl-4-oxo-5H-pyrazolo[1,5-a]pyrazine-3-carboxylate (1 g) as a pink solid, which was used in the next step without further purification. 1 HNMR(400MHz,DMSO-d6) d 11.9 (s, 1H), 8.28 (s, 1H), 4.26 (q, J=7.1Hz,2H),2.29(s,3H),1.30(t,J = 7.1 Hz, 3H). LCMS m / z[M+H] + 300.0.

[0373] Process f: PCl 3A solution of crude ethyl 7-bromo-6-methyl-4-oxo-5H-pyrazolo[1,5-a]pyrazine-3-carboxylate (1.14 g) in (16.4 g, 10 mL, 106.2 mmol) was heated to reflux for 2 h. The residue was carefully poured into ice-cold water (500 mL). The pH value of the aqueous phase was adjusted to 0.01 with saturated NaHCO 3 The pH was adjusted to about 7 with ethyl acetate (300 mL*2). The aqueous phase was extracted with ethyl acetate (300 mL*2). The combined organic phase was washed with NaHCO 3 Wash with a saturated aqueous solution of NaCl, brine, and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo The residue was triturated in diisopropyl ether, cooled in ice and filtered to give ethyl 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazine-3-carboxylate (1.11 g, 3.5 mmol) as a beige powder. 1 HNMR(400MHz,DMSO-d6) d 8.68 (s, 1H), 4.35 (q, J = 7.1 Hz, 3H), 2.62 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). LCMS m / z[M+H] + 318.0.

[0374] Example i-8. Intermediate A-8 ((7-Bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazin-3-yl)methanol) [ka] To a solution of intermediate A-7 (980 mg, 3.47 mmol) in anhydrous THF (40 mL) cooled at -78°C was added DIBAL-H (1 M in toluene, 6.9 mL, 6.9 mmol) dropwise. The reaction mixture was stirred at -78°C for 1.5 h and then warmed to 0°C. A saturated aqueous solution of Rochelle's salt (10 mL) was added, followed by water (40 mL) and ethyl acetate (40 mL). The mixture was stirred at room temperature for 10 min. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (40 mL). The combined organic phase was washed with brine and anhydrous Na 2 SO 4Drying at 40° C., filtering and concentrating in vacuo to give 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazin-2-yl)methanol (980 mg, 3.47 mmol) as a white solid, which was used in the next step without any further purification. 1 HNMR(400MHz,DMSO-d6) d 8.24 (s, 1H), 5.28 (t, J = 5.4 Hz, 1H), 4.85 (d, J = 5.4 Hz, 2H), 2.57 (s, 3H). LCMS m / z[M+H] + 276.0.

[0375] Example i-9. Intermediate A-9 (7-bromo-4-chloro-3-(difluoromethyl)-6-methyl-pyrazolo[1,5-a]pyrazine) [ka] Step a: To a mixture of intermediate A-8 (400 mg, 1.45 mmol) in dichloromethane (20 mL) cooled to 0° C., Dess-Martin periodinane (736 mg, 1.74 mmol) was added portionwise. The reaction was stirred at 0° C. for 10 min and then at room temperature for 1 h. An additional portion of Dess-Martin periodinane (150 mg) was added. A saturated aqueous solution of sodium thiosulfate (20 mL), sodium bicarbonate (20 mL) and dichloromethane (20 mL) was added and the mixture was stirred for 1 h. The mixture was filtered through a hydrophobic PTFE cartridge (liquid / liquid extraction column, Radleys®) and then concentrated in vacuo to give crude 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazine-3-carbaldehyde (506 mg) as a beige solid, which was used in the next step without further purification. 1 HNMR (400MHz, DMSO-d6) d 10.48 (s, 1H), 8.80 (s, 1H), 2.65 (s, 3H). LCMS m / z[M+H] + 276.0.

[0376] Step b: Diethylaminosulfur trifluoride (1.2 mL, 8.66 mmol) was added dropwise to a mixture of the crude 7-bromo-4-chloro-6-methyl-pyrazolo[1,5-a]pyrazine-3-carbaldehyde obtained above in dichloromethane (20 mL) cooled at -20°C. The reaction mixture was stirred at -20°C for 2 h and then at room temperature for 48 h. The mixture was poured into an ice-cold saturated aqueous solution of sodium bicarbonate (20 mL) under vigorous stirring to adjust the pH value of the aqueous phase to about 8. Water (20 mL) and dichloromethane (30 mL) were added and the mixture was filtered through a hydrophobic PTFE cartridge (liquid / liquid extraction column, Radleys®) and then concentrated in vacuum. The residue was purified by column chromatography (SiO 2 , heptane / ethyl acetate=90 / 10) to give 7-bromo-4-chloro-3-(difluoromethyl)-6-methyl-pyrazolo[1,5-a]pyrazine (345 mg, 1.16 mmol) as a white powder. 1 HNMR (400MHz, DMSO-d6) d 8.61 (s, 1H), 7.55 (t, J = 54.7 Hz, 1H), 2.61 (s, 3H). LCMS m / z[M+H] + 298.0.

[0377] Example i-10. Intermediate B-1 (spiro[7H-cyclopenta[b]pyridine-6,4'-piperidin]-5-one hydrochloride) [ka] To a mixture of tert-butyl 5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (Labnetwork, 20 g, 66.14 mmol) in dichloromethane (200 mL) and methanol (100 mL) was added a solution of HCl (4 M in dioxane, 165.3 mL, 661.4 mmol) dropwise at room temperature. The mixture was stirred for 18 h and then concentrated under vacuum. The residue was taken up in ethyl acetate (50 mL) and stirred for 5 min. The precipitate was collected by filtration and washed with pentane (50 mL) to give spiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-5-one hydrochloride (18.1 g) as a white solid, which was used without further purification. 1 HNMR(400MHz,DMSO-d6) d 9.43 (s, 1H), 9.12 (s, 1H), 8.92 (d, J=3.2Hz,1H),8.17(d,J = 8.0 Hz, 1H), 7.58 (dd, J=8.0,5.2Hz,1H),3.30-3.37(m,4H),3.01-3.10(m,2H),1.95-2.03(m,2H),1.67-1.70(m,2H).

[0378] Example i-11. Intermediate B-2 (tert-butyl (5S)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate) [ka] Step a: To a solution of tert-butyl 5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (Labnetwork, 14 g, 46.30 mmol) in 2-methyltetrahydrofuran (100 mL) was added (R)-2-methylpropane-2-sulfinamide (11.45 g, 92.59 mmol). The mixture was heated at 60 °C and Ti(OEt) 4(58 mL, 185.2 mmol) was added dropwise. The mixture was stirred at 80° C. for 18 h. The mixture was cooled to room temperature and diluted with 2-methyltetrahydrofuran (150 mL), Na 2 SO 4 A 5% aqueous solution of (100 mL) and dicalite (15 g) were added. The mixture was stirred for 30 min, then filtered and the solid was washed with 2-methyltetrahydrofuran. The filtrate was then washed with water (6*300 mL), brine (200 mL) and Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , heptane / ethyl acetate = 1 / 0 to 0 / 1) to give tert-butyl (5Z)-5-[(R)-tert-butylsulfinyl]iminospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (15.42 g, 38.02 mmol) as an off-white solid. LCMS m / z [M+H] + 406.2.

[0379] Step b: DIBAL-H (1M in toluene, 17 mL, 17 mmol) was added dropwise to a mixture of tert-butyl (5Z)-5-[(R)-tert-butylsulfinyl]iminospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (5.7 g, 14.07 mmol) in anhydrous THF (115 mL) cooled at -78 °C. The reaction mixture was stirred at -78 °C for 15 min and ethyl acetate (140 mL) was added, followed by a saturated aqueous solution of Rochelle's salt (100 mL). The cooling batch was removed and the mixture was stirred at room temperature for 1 h. The aqueous layer was separated and then extracted with ethyl acetate (50 mL). The combined organic phases were washed with brine and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2, dichloromethane / methanol = 100 / 0 to 95 / 5) to give tert-butyl (5S)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (5.2 g, 12.8 mmol) as a white solid. LCMS m / z [M+H] + 408.2.

[0380] Example i-12. Intermediate B-3 ((R)-2-methyl-N-[(5S)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-yl]propane-2-sulfinamide) [ka] To a solution of intermediate B-2 (0.7 g, 1.71 mmol) in dichloromethane (5 mL) was added TFA (1.5 mL, 20 mmol). The mixture was stirred at room temperature for 3 h. Dichloromethane (10 mL) and water (10 mL) were added, the pH value of the aqueous phase was adjusted to 11-12 with 1N aqueous NaOH solution, the mixture was filtered through a hydrophobic cartridge (liquid / liquid extraction column, Radleys®) and then concentrated in vacuum to give (R)-2-methyl-N-[(5S)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidin]-5-yl]propane-2-sulfinamide (0.34 g, 1.12 mmol) as a beige solid. LCMS m / z[M+H] + 308.2.

[0381] Example i-13. Intermediate B-4 ((5S)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-amine hydrochloride) [ka] A mixture of intermediate B-2 (2.35 g, 5.77 mmol) in a solution of HCl (2.5 M in ethanol, 30 mL, 75 mmol) was stirred at room temperature for 3 h. The reaction mixture was then concentrated under vacuum. The residue was taken up in ethyl acetate (50 mL) and diisopropyl ether (50 mL), triturated, filtered, washed with diisopropyl ether (2*50 mL), pentane (50 mL) to give (5S)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-amine hydrochloride (1.8 g, crude) as a white solid, which was used without further purification.

[0382] Example i-14. Intermediate B-5 (3-chlorospiro[7H-cyclopenta[b]pyridine-6,4'-piperidin]-5-one hydrochloride) [ka] Step a: To a solution of (3-bromo-5-chloropyridin-2-yl)methanol (1.25 g, 5.62 mmol) in anhydrous dichloromethane (15 mL) was added triethylamine (1.7 mL, 12.2 mmol) followed by methanesulfonyl chloride (0.5 mL, 6.4 mmol) at -15°C. After addition, the mixture was stirred at this temperature for 1 h, water (20 mL) was added and the mixture was filtered through a hydrophobic cartridge (liquid / liquid extraction column, Radleys®) and then concentrated in vacuo to give (3-bromo-5-chloro-2-pyridyl)methyl methanesulfonate (1.2 g, 3.99 mmol) as an oil. LCMS m / z [M+H] + =301.8.

[0383] Step b: To a solution of ethyl N-Boc-piperidine-4-carboxylate (2.48 g, 9.64 mmol) in anhydrous THF (15 mL) was added LDA (2 M, 6 mL, 12 mmol) dropwise at -78°C. After addition, the mixture was stirred at this temperature for 1.5 h and (3-bromo-5-chloro-2-pyridyl)methyl methanesulfonate (2.85 g, 9.48 mmol) in anhydrous THF (6 mL) was added dropwise. The resulting mixture was then gradually warmed to 0°C. The reaction mixture was diluted with NH 4 The mixture was quenched by the addition of a saturated aqueous solution of Cl (10 mL). Water (30 mL) was added and the mixture was extracted with EtOAc (40 mL*2). The combined organic layers were washed with brine and Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , cyclohexane / ethyl acetate=95 / 5) to give O1-tert-butyl O4-ethyl 4-[(3-bromo-5-chloro-2-pyridyl)methyl]piperidine-1,4-dicarboxylate (3.23 g, 6.99 mmol) as an orange oil. LCMS m / z [M-56+H] + =406.9.

[0384] Step c: To a solution of O1-tert-butyl O4-ethyl 4-[(3-bromo-5-chloro-2-pyridyl)methyl]piperidine-1,4-dicarboxylate (3.22 g, 6.97 mmol) in methanol (30 mL) and water (6 mL) was added an aqueous solution of sodium hydroxide (35%, 6 mL, 72.12 mmol) at room temperature. The mixture was stirred at 65° C. for 18 hours and then cooled to room temperature. Water was added and the mixture was filtered; the precipitate was washed with acetonitrile to give the sodium salt of 4-[(3-bromo-5-chloro-2-pyridyl)methyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylate (1.96 g, 4.30 mmol) as a white solid.

[0385] Step d: To a suspension of 4-[(3-bromo-5-chloro-2-pyridyl)methyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylate sodium salt (1.96 g, 4.30 mmol) in anhydrous THF (10 mL) was added n-BuLi (2.1 M in hexanes, 3 mL, 6.3 mmol) dropwise at -20°C. At the end of the addition, the mixture was stirred at this temperature for 1 h, and the reaction mixture was quenched by the addition of water (40 mL) and then extracted with EtOAc (40 mL x 2). The combined organic layers were washed with brine and Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , cyclohexane / ethyl acetate=8 / 2) to give tert-butyl 3-chloro-5-oxo-spiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (175 mg, 0.52 mmol) as a white solid. LCMS m / z[M+H] + =337.1.

[0386] Step e: To a mixture of tert-butyl 3-chloro-5-oxo-spiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (390 mg, 1.16 mmol) in methanol (10 mL) was added dropwise a solution of HCl (4 M in dioxane, 1.5 mL, 6 mmol). The mixture was stirred at room temperature for 16 h and then concentrated in vacuo to give crude 3-chlorospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-5-one hydrochloride (352 mg) as a pink solid, which was used without further purification.

[0387] Example i-15. Intermediate B-6 ((5S)-3-Methoxyspiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-amine hydrochloride) [ka] Step a: To a solution of 3-bromo-2-chloro-5-methoxypyridine (15.0 g, 67.4 mmol) in THF (150 mL), i-PrMgCl (2 M in THF, 40.5 mL, 91 mmol) was added at 0 °C with N 2 The solution was then added dropwise at 0° C. under reduced pressure. The reaction was stirred at room temperature for 2 hours. To the solution was then added a solution of tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (23.0 g, 101 mmol) in THF (75 mL) dropwise at 0° C. The reaction was stirred at room temperature for 30 minutes. The mixture was then poured into water (200 mL). The aqueous phase was extracted with ethyl acetate (80 mL*3). The combined organic phase was washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50 / 1 to 1 / 1) to give crude tert-butyl 4-((2-chloro-5-methoxypyridin-3-yl)(hydroxy)methyl)-4-methylpiperidine-1-carboxylate (26.0 g) as a yellow oil, which was used without further purification.

[0388] Step b: To a solution of crude tert-butyl 4-((2-chloro-5-methoxypyridin-3-yl)(hydroxy)methyl)-4-methylpiperidine-1-carboxylate (26.0 g) in DCM (260 mL) was added Dess-Martin periodinane (59.5 g, 140 mmol) at 0 °C with N 2 The mixture was poured into a saturated aqueous solution of sodium sulfite (300 mL). The aqueous phase was extracted with ethyl acetate (80 mL*3). The combined organic phase was washed with brine (100 mL) and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50 / 1 to 1 / 1) to give tert-butyl 4-(2-chloro-5-methoxynicotinoyl)-4-methylpiperidine-1-carboxylate (22.0 g, 59.6 mmol) as a yellow oil.1 HNMR (400MHz, CDCl 3 )d8.10(d,J = 3.2 Hz, 1H), 6.99(d, J=2.8Hz,1H),3.88(s,3H),3.69-3.75(m,2H),3.21-3.28(m,2H),1.96-2.03(m,2H),1.57-1.61(m,2H),1.45(s,9H),1.36(s,3H).

[0389] Step c: To a solution of tert-butyl 4-(2-chloro-5-methoxynicotinoyl)-4-methylpiperidine-1-carboxylate (22.0 g, 59.6 mmol) in mesitylene (220 mL), Pd(OAc) 2 (670mg, 2.98mmol), Cs 2 CO 3 (23.4 g, 71.6 mmol), tricyclohexylphosphonium tetrafluoroborate (2.20 g, 5.96 mmol) and pivalic acid (2.06 mL, 17.9 mmol) were added at room temperature under N 2 The solution was diluted with N 2 The mixture was degassed at 40° C. for 10 minutes. The reaction was then stirred at 160° C. for 4 hours. The reaction was cooled to room temperature and then poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (150 mL*3). The combined organic phase was washed with brine (150 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50 / 1 to 1 / 1) to obtain tert-butyl 3-methoxy-5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (15.0 g, 45.1 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d8.57(d,J = 2.8 Hz, 1H), 7.43(d, J=2.8Hz,1H),4.15(s,2H),3.89(s,3H),3.12(s,2H),3.02(s,2H),1.90-1.98(m,2H),1.41-1.49(m,11H).

[0390] Process d:Ti(OEt) 4 To a solution of tert-butyl 3-methoxy-5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (14.0 g, 21.1 mmol) in 100 mL of ethyl acetate (70.0 mL), (R)-2-methylpropane-2-sulfinamide (12.7 g, 105.0 mmol) was added at room temperature with N 2 The reaction was stirred at 110° C. for 13 hours. The mixture was poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (200 mL*3). The combined organic phase was washed with brine (200 mL) and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give tert-butyl (R,Z)-5-((tert-butylsulfinyl)imino)-3-methoxy-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (6.80 g, 15.6 mmol) as a yellow oil. 1 HNMR (400MHz, CDCl 3 )d8.41-8.42(m,2H),4.09-4.17(m,2H),3.90(s,3H),3.09(s,2H),2.94(s,2H),1.94-1.97(m,2H),1.39-1.57(m,11H),1.35(s,9H).

[0391] Step e: To a solution of tert-butyl (R,Z)-5-((tert-butylsulfinyl)imino)-3-methoxy-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (6.8 g, 15.6 mmol) in THF (50 mL) was added DIBAL-H (1 M, 62.4 mL, 62.4 mmol) at -78 °C with N 2 The reaction was stirred at -78°C for 1 h. Water (40 mL) was then added slowly and the mixture was stirred for 15 min. Anhydrous Na 2 SO 4(100 g) was added and the mixture was stirred for 5 min and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give tert-butyl 5-[[(R)-tert-butylsulfinyl]amino]-3-methoxy-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (3.40 g, 7.72 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d8.11-8.14(m,1H),7.26(s,1H),4.50(d,J = 8.8 Hz, 1H), 4.01-4.04(m,2H),3.86(s,3H),3.63(s,1H),2.81-3.14(m,4H),2.05(s,1H),1.46-1.73(m,11H),1.23-1.45(m,10H). LCMS m / z[M+H] + =438.2.

[0392] Step f: To a solution of tert-butyl 5-[[(R)-tert-butylsulfinyl]amino]-3-methoxy-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (0.4 g, 0.91 mmol) in dichloromethane (6 mL) and methanol (2 mL) was added a solution of HCl (4 M in dioxane, 2 mL, 8 mmol) dropwise at room temperature. The mixture was stirred for 4 h and then concentrated under vacuum. The residue was taken up in diethyl ether (40 mL) and stirred for 5 min. The solid was collected by filtration and washed with diethyl ether to give 3-methoxyspiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-amine hydrochloride (0.32 g, crude) as a yellow solid, which was used without further purification.

[0393] Example i-16. Intermediate B-7 ((5S)-3-fluorospiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-amine hydrochloride) [ka] Step a: To a solution of 3-bromo-2-chloro-5-fluoropyridine (21.0 g, 99.8 mmol) in THF (420 mL) was added i-PrMgCl-LiCl (1.30 M in THF, 92.1 mL, 119.7 mmol) dropwise at 0 °C with N 2 The reaction mixture was stirred at room temperature for 2 hours, then a solution of tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (29.5 g, 130 mmol) in THF (210 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 30 minutes, then poured into saturated aqueous ammonium chloride solution (800 mL). The aqueous phase was extracted with ethyl acetate (300 mL*3). The combined organic phase was washed with brine (800 mL) and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 10 / 1) to give tert-butyl 4-((2-chloro-5-fluoropyridin-3-yl)(hydroxy)methyl)-4-methylpiperidine-1-carboxylate (26.7 g, 74.4 mmol) as a yellow oil. 1 HNMR (400MHz, CDCl 3 )d8.19-8.21(m,1H),7.67(dd,J = 12 Hz, 1H), 4.91 (s, 1H), 3.95 (s, 2H), 2.86-2.94(m,3H),1.79-1.80(m,1H),1.54-1.61(m,3H),1.45-1.46(m,11H),1.04-1.05(m,3H). LCMS m / z[M- t Bu+H] + =303.0.

[0394] Step b: To a stirred solution of tert-butyl 4-((2-chloro-5-fluoropyridin-3-yl)(hydroxy)methyl)-4-methylpiperidine-1-carboxylate (26.7 g, 74.4 mmol) in DCM (160 mL) was added Dess-Martin periodinane (58.1 g, 137 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h and then added Na 2 SO 3 (200 mL) and then diluted with DCM (150 mL). The suspension was filtered and the filtrate was extracted with DCM (100 mL*3). The combined organic layers were washed with brine (300 mL) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 10 / 1) to give tert-butyl 4-(2-chloro-5-fluoronicotinoyl)-4-methylpiperidine-1-carboxylate (13.9 g, 38.9 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3 )d8.33(d,J = 2.8 Hz 1H), 7.27-7.30(m,1H),3.72-3.78(m,2H),3.25-3.31(m,2H),1.98-2.05(m,2H),1.59-1.65(m,2H),1.48(s,9H),1.39(s,3H).

[0395] Step c: To a stirred solution of tert-butyl 4-(2-chloro-5-fluoronicotinoyl)-4-methylpiperidine-1-carboxylate (6.50 g, 18.2 mmol) in mesitylene (80 mL) was added tricyclohexylphosphonium tetrafluoroborate (671 mg, 1.82 mmol), pivalic acid (0.63 mL, 5.46 mmol) and Cs 2 CO 3 (7.12 g, 21.9 mmol) was added and the mixture was treated with N 2 The mixture was degassed for 5 minutes with Pd(OAc) 2 (204 mg, 0.91 mmol) was added to the reaction mixture and N 2The mixture was degassed at 160° C. for 2 h. The reaction mixture was stirred at 160° C. for 2 h. The reaction was cooled to room temperature and then poured into water (150 mL). The aqueous phase was extracted with ethyl acetate (60 mL*3). The combined organic phase was washed with brine (150 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 10 / 1) to obtain 3-fluoro-5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1-carboxylate (4.50 g, 14.1 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d8.71(d,J = 3.6 Hz, 1H), 7.68 (s, J=9.6Hz1H),4.11-4.15(m,2H),3.16(s,2H),3.00-3.07(m,2H),1.90-1.97(m,2H),1.44-1.48(m,12H).

[0396] Process d:Ti(OEt) 4 To a stirred solution of 3-fluoro-5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1-carboxylate (5.00 g, 15.6 mmol) in (25.0 mL) was added (R)-2-methylpropane-2-sulfinamide (3.78 g, 31.2 mmol) at room temperature, and the reaction mixture was then stirred at 100°C for 16 hours. The reaction mixture was poured into water (100 mL), then diluted with 80 mL of ethyl acetate, and the suspension was filtered. The filtrate was extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with 150 mL of brine and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give tert-butyl (R,Z)-5-((tert-butylsulfinyl)imino)-3-fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1-carboxylate (5.80 g, 13.7 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d 8.65 (s, 1H), 8.56 (d, J=2.8Hz,1H),4.12-4.17(m,2H),3.14(s,2H),2.95-3.05(m,2H),1.92-1.97(m,2H),1.50(s,11H),1.36(s,9H).

[0397] Step e: To a stirred solution of tert-butyl (R,Z)-5-((tert-butylsulfinyl)imino)-3-fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1-carboxylate (5.10 g, 12.0 mmol) in THF (26.0 mL) was added DIBAL-H (1 M, 48 mL, 48 mmol) at -70°C and the mixture was stirred for 1 h. The reaction mixture was poured into water (100 mL) and the suspension was filtered. The filtrate was extracted with ethyl acetate (40 mL*3). The combined organic layers were washed with brine (50 mL) and concentrated to dryness with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 10 / 1) to give tert-butyl (5S)-5-(tert-butylsulfinylamino)-3-fluoro-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (2.5 g, 5.87 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3)d8.31(s,1H),7.40(d,J=5.6Hz1H),4.54(d,J = 9.2 Hz 1H), 4.04-4.15(m,2H),3.68(s,1H),3.18(s,1H),2.87-2.96(m,3H),2.05-2.13(m,1H),1.45-1.73(m,12H),1.29-1.49(m,9H). LCMS m / z[M+H] + =426.2.

[0398] Step f: To a mixture of tert-butyl (5S)-5-(tert-butylsulfinylamino)-3-fluoro-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (1.5 g, 3.53 mmol) in methanol (10 mL) was added dropwise a solution of HCl (4 M in dioxane, 8.8 mL, 35.3 mmol) at 0° C. The mixture was stirred for 1 h at room temperature, methanol (14 mL) was added, and the mixture was stirred for 16 h. The mixture was then concentrated under vacuum to give crude (5S)-3-fluorospiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-amine hydrochloride (1.24 g, crude) as a yellow solid, which was used without further purification.

[0399] Example i-17. Intermediate B-8 ((1S)-5-Methoxyspiro[indan-2,4'-piperidine]-1-amine hydrochloride) [ka] Step a: To a solution of 1-boc-4-cyanopiperidine (3.0 g, 14.27 mmol) in anhydrous THF (60 mL) was added LDA (2 M, 10 mL, 20 mmol) dropwise at -78 °C under Ar. After addition, the mixture was stirred at this temperature for 1 h, and 2-bromo-5-methoxybenzyl bromide (4.8 g, 17.27 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for 3 h, and then warmed to 0 °C. The reaction mixture was quenched by the addition of water (100 mL * 2) and then extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine and Na2 SO 4 The residue was purified by column chromatography (SiO 2 , cyclohexane / ethyl acetate = 95 / 5 to 80 / 20) to give tert-butyl 4-[(2-bromo-5-methoxy-phenyl)methyl]-4-cyano-piperidine-1-carboxylate (4.93 g, 12.0 mmol) as a yellow wax. LCMS m / z [M-100+H] + =309.0.

[0400] Step b: DMA (80mL) and H 2 tert-Butyl 4-[(2-bromo-5-methoxy-phenyl)methyl]-4-cyano-piperidine-1-carboxylate (4.93 g, 12 mmol), DIPEA (10 mL, 57.4 mmol), Pd(AmPhos) in O (15 mL) 2 Cl 2 A mixture of (0.86 g, 1.21 mmol) was degassed with Ar for 3 min, then the mixture was stirred at 140° C. for 2 h. The reaction was cooled to room temperature and water (350 mL) and EtOAc (350 mL) were added followed by an aqueous solution of HCl (37%, 3 mL) to reach a pH of about 2. The organic layer was separated and the aqueous layer was extracted with EtOAc (350 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The residue was taken up in diethyl ether (50 mL), the ether layer was washed with water (50 mL*3), and the aqueous layer was washed with Na 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure to give crude methoxy-1-oxo-spiro[indane-2,4′-piperidine]-1′-carboxylate (3.72 g) as an orange solid which was used without further purification.

[0401] Step c: Crude methoxy-1-oxo-spiro[indan-2,4'-piperidine]-1'-carboxylate (3.72 g), Ti(OEt) 4A mixture of (13.0 mL, 62.01 mmol) and (R)-2-methylpropane-2-sulfinamide (3.0 g, 24.75 mmol) was stirred at 105 °C for 16 h. 4 (3.0 mL, 14.31 mmol) was added and the mixture was stirred at 105° C. for 24 h, then cooled to room temperature. Water (150 mL) and ethyl acetate (100 mL) were added and the mixture was filtered. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine and Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , cyclohexane / ethyl acetate = 8 / 2 to 6 / 4) to give crude tert-butyl (1Z)-1-[(R)-tert-butylsulfinyl]imino-5-methoxy-spiro[indan-2,4'-piperidine]-1'-carboxylate (1.01 g) as a yellow solid. LCMS m / z [M+H] + =435.3.

[0402] Step d: To a mixture of crude tert-butyl (1Z)-1-[(R)-tert-butylsulfinyl]imino-5-methoxy-spiro[indane-2,4'-piperidine]-1'-carboxylate (1.0 g) in anhydrous THF (35 mL) cooled at -78°C was added DIBAL-H (1 M in toluene, 6 mL, 6 mmol) dropwise. The reaction mixture was stirred at -78°C for 45 min and then warmed to -20°C. A saturated aqueous solution of Rochelle's salt (10 mL) was added and the mixture was stirred at room temperature for 1 h. Water and ethyl acetate were added. The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine and anhydrous Na 2 SO 4 Drying at 40° C., filtering and concentrating in vacuo afforded crude tert-butyl (1S)-1-[[(R)-tert-butylsulfinyl]amino]-5-methoxy-spiro[indan-2,4′-piperidine]-1′-carboxylate (984 mg) as a yellow solid. LCMS m / z [M+H] + =437.3.

[0403] Step e: To a mixture of crude tert-butyl (1S)-1-[[(R)-tert-butylsulfinyl]amino]-5-methoxy-spiro[indan-2,4'-piperidine]-1'-carboxylate (984 mg) in dichloromethane (12 mL) and methanol (4 mL) was added dropwise a solution of HCl (4 M in dioxane, 3.5 mL, 14 mmol). The mixture was stirred at room temperature for 16 hours and then concentrated under vacuum. The residue was taken up in diethyl ether (40 mL) and filtered to give crude (1S)-5-methoxyspiro[indan-2,4'-piperidine]-1-amine hydrochloride (755 mg) as a yellow solid which was used without further purification.

[0404] Example i-18. Intermediate B-9 (2-Methoxy-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-7-amine hydrochloride) [ka] Step a: A solution of 2-bromo-6-methoxynicotinaldehyde (42.0 g, 194 mmol) in MeOH (294 mL) was treated with NaBH 4 (3.64 g, 96.2 mmol) at room temperature with N 2 The mixture was added under reduced pressure. The reaction was then stirred for 30 minutes at room temperature. The residue was poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (200 mL*3). The combined organic phase was washed with brine (200 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give (2-bromo-6-methoxypyridin-3-yl)methanol (42.0 g, 193 mmol) as a colorless oil. 1 HNMR(400MHz,DMSO-d6) d 7.76-7.80(m,1H),6.87(d,J = 8.0 Hz, 1H), 5.44 (t, J=5.6Hz,1H),4.43(d,J = 5.6 Hz, 2H), 3.83 (s, 3H).

[0405] Step b: (2-bromo-6-methoxypyridin-3-yl)methanol (42.0 g, 193 mmol) and CBr in DCM (210 mL). 4 A solution of (76.7 g, 231 mmol) of PPh in DCM (126 mL) 3 A solution of (60.6 g, 231 mmol) was heated at room temperature with N 2 The mixture was added under reduced pressure. The reaction was then stirred at room temperature for 30 minutes. The residue was poured into water (500 mL). The aqueous phase was extracted with DCM (200 mL*3). The combined organic phase was washed with brine (200 mL) and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50 / 1 to 0 / 1) to obtain 2-bromo-3-(bromomethyl)-6-methoxypyridine (43.0 g, 153 mmol) as a white solid. 1 HNMR (400MHz, DMSO-d6) d 7.91-7.94(m,1H),6.89-6.93(m,1H),4.69(s,2H),3.86(s,3H).

[0406] Step c: To a solution of 1-boc-4-cyanopiperidine (35.4 g, 168 mmol) in THF (215 mL) was added LDA (2.00 M, 153 mL, 306 mmol) at 0 °C with N 2 The reaction was stirred at 0° C. for 30 min. The reaction was then treated with a solution of 2-bromo-3-(bromomethyl)-6-methoxypyridine (43.0 g, 153 mmol) in THF (215 mL) at 0° C. with N 2 The reaction was stirred at room temperature for 2 hours. The residue was diluted with NH 4 The aqueous phase was extracted with ethyl acetate (500 mL*3). The combined organic phase was washed with brine (100 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2The solid was stirred with petroleum ether (100 mL) at room temperature for 1 h. The suspension was filtered and the filter cake was dried under vacuum to give tert-butyl 4-[(2-bromo-6-methoxypyridin-3-yl)methyl]-4-cyanopiperidine-1-carboxylate (17.0 g, 41.4 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3 )d7.69(d,J=8.4Hz,1H),6.74(t,J=8.4Hz,1H),4.16(s,2H),3.94(s,3H ),2.96-3.03(m,4H),1.72-1.89(m,2H),1.64-1.71(m,2H),1.47(s,9H).

[0407] Step d: DMA (170mL) and H 2 A solution of tert-butyl 4-[(2-bromo-6-methoxypyridin-3-yl)methyl]-4-cyanopiperidine-1-carboxylate (17.0 g, 41.4 mmol) in 20O (17 mL) was diluted with Pd(AmPhos) 2 Cl 2 (2.93 g, 4.14 mmol, 2.93 mL) and TEA (16.8 g, 166 mmol, 23.1 mL) were dissolved in N at room temperature. 2 The reaction was heated at 120 °C for 12 h under N 2 The mixture was stirred under reduced pressure. The residue was poured into water (600 mL). The aqueous phase was extracted with ethyl acetate (300 mL*3). The combined organic phase was washed with brine (200 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50 / 1 to 1 / 1) to obtain tert-butyl 2-methoxy-7-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (12.0 g, 36.1 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3)d7.70(d,J=8.4Hz,1H),6.98(d,J=8.4Hz,1H),4.23(s,2H),4.03(s,3H),2.99 -3.06(m,2H),2.95(s,2H),1.91-1.99(m,2H),1.48(s,9H),1.38-1.43(m,2H).

[0408] Step e: tert-Butyl 2-methoxy-7-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (12.0 g, 36.1 mmol) and Ti(OEt) in 2-MeTHF (84 mL) 4 (71.9 mL, 347 mmol) was diluted with (R)-2-methylpropane-2-sulfinamide (17.5 g, 144 mmol) at room temperature with N 2 The mixture was added under reduced pressure. The reaction was stirred at 90° C. for 16 hours. The residue was poured into water (300 mL). The suspension was filtered and the filtrate was extracted with ethyl acetate (150 mL*3). The combined organic phase was washed with brine (100 mL) and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl (7Z)-2-methoxy-7-{[(R)-2-methylpropane 2-sulfinyl]imino}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (8.00 g, 18.4 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d7.61-7.64(m,1H),6.86-6.89(m,1H),4.12(s,2H),4.03(s,3H),2.89-3.00(m, 4H), 2.10-2.17 (m, 1H), 1.90-1.98 (m, 1H), 1.44-1.43 (m, 12H), 1.25-1.32 (m, 9H).

[0409] Step f: To a solution of tert-butyl (7Z)-2-methoxy-7-{[(R)-2-methylpropane 2-sulfinyl]imino}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (8.00 g, 18.4 mmol) in THF (56 mL) was added NaBH 4 (2.08 g, 55.1 mmol) was dissolved in N at 0 °C. 2 The reaction was stirred at room temperature for 1 hour. The residue was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (75 mL*3). The combined organic phase was washed with brine (75 mL) and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give tert-butyl 2-methoxy-7-{[(R)-2-methylpropane-2-sulfinyl]amino}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (2.00 g, 4.55 mmol) as a yellow solid and as a 3 / 2 mixture of diastereoisomers, which was used without further purification. LCMS m / z [M+H] + =438.1.

[0410] Step g: To a 3 / 2 mixture of diastereoisomers of tert-butyl 2-methoxy-7-{[(R)-2-methylpropane-2-sulfinyl]amino}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (875 mg, 2 mmol) in methanol (20 mL) was added a solution of HCl (4 M in dioxane, 3 mL, 12 mmol) dropwise at room temperature. The mixture was stirred for 4 h and then concentrated under vacuum to give 2-methoxy-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-7-amine hydrochloride (800 mg, crude) as a yellow solid and as a mixture of enantiomers, which was used without further purification. LCMS m / z [M+H] + =234.2.

[0411] Example i-19. Intermediate B-10 (3-aminospiro[indan-2,4'-piperidine]-5-carbonitrile hydrochloride) [ka] Step a: To a solution of 1-boc-4-cyanopiperidine (2.0 g, 9.51 mmol) in anhydrous THF (20 mL) was added LDA (2 M, 7 mL, 14 mmol) dropwise at -78 °C under Ar. After addition, the mixture was stirred at this temperature for 1 h and 3-bromo-4-(bromomethyl)benzonitrile (2.65 g, 9.64 mmol) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 3 h and then warmed to 0 °C. The reaction mixture was diluted with NH 4 The mixture was quenched by the addition of a saturated aqueous solution of Cl (10 mL) and then extracted with EtOAc (50 mL*2). The combined organic layers were washed with brine and 2 SO 4 The residue was purified by column chromatography (SiO 2 , cyclohexane / ethyl acetate = 95 / 5 to 80 / 20) to give tert-butyl 4-[(2-bromo-4-cyano-phenyl)methyl]-4-cyano-piperidine-1-carboxylate (2.1 g, crude) as a white solid, which was used without further purification.

[0412] Step b: DMA (30mL) and H 2 Crude tert-butyl 4-[(2-bromo-4-cyano-phenyl)methyl]-4-cyano-piperidine-1-carboxylate (2.1 g), DIPEA (4.5 mL, 26 mmol), Pd(AmPhos) in O (5 mL). 2 Cl 2(0.35 g, 0.5 mmol) was degassed with Ar for 3 min, then the mixture was stirred at 140° C. for 2 h. The reaction was cooled to room temperature, water (100 mL) and EtOAc (100 mL) were added followed by an aqueous solution of HCl (37%, 3 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , cyclohexane / ethyl acetate = 95 / 5 to 80 / 20) to obtain tert-butyl 6-cyano-1-oxo-spiro[indane-2,4'-piperidine]-1'-carboxylate (1.14 g, 3.49 mmol) as a white solid.

[0413] Step c: tert-Butyl 6-cyano-1-oxo-spiro[indan-2,4'-piperidine]-1'-carboxylate (680 mg, 2.08 mmol), Ti(OEt) 4 A mixture of (R)-2-methylpropane-2-sulfinamide (6.0 mL, 28.62 mmol) and (R)-2-methylpropane-2-sulfinamide (770 mg, 6.35 mmol) was stirred at 100° C. for 1 h and then at room temperature for 16 h. Water and dichloromethane were added and the mixture was filtered through a hydrophobic cartridge (liquid / liquid extraction column, Radleys®) and then concentrated in vacuo. The residue was taken up in diethyl ether and water, the organic layer was separated, washed with brine and sodium 2 SO 4 It was dried at 40° C., filtered and concentrated in vacuo to give crude tert-butyl (1Z)-1-[(R)-tert-butylsulfinyl]imino-6-cyano-spiro[indan-2,4′-piperidine]-1′-carboxylate (806 mg) as a yellow solid which was used without further purification.

[0414] Step d: To a mixture of crude tert-butyl (1Z)-1-[(R)-tert-butylsulfinyl]imino-6-cyano-spiro[indan-2,4'-piperidine]-1'-carboxylate (250 mg) in anhydrous THF (7 mL) cooled at -50 °C, NaBH 4 (45 mg, 1.19 mmol) was added in one portion. The reaction mixture was stirred at -50 °C for 30 min and then warmed to 0 °C. NH 4 A saturated aqueous solution of Cl (3 mL) was slowly added, followed by water (20 mL) and ethyl acetate (20 mL). The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine and anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated in vacuo to give crude tert-butyl 1-[[(R)-tert-butylsulfinyl]amino]-6-cyano-spiro[indane-2,4′-piperidine]-1′-carboxylate (260 mg) as a mixture of diastereoisomers which was not further purified.

[0415] Step e: To a mixture of crude tert-butyl 1-[[(R)-tert-butylsulfinyl]amino]-6-cyano-spiro[indane-2,4'-piperidine]-1'-carboxylate (260 mg) in dichloromethane (4 mL) and methanol (1 mL) was added a solution of HCl (4 M in dioxane, 0.85 mL, 3.4 mmol) dropwise at 0° C. The mixture was stirred for 16 h at room temperature, diethyl ether was added, and the mixture was filtered to give 3-aminospiro[indane-2,4'-piperidine]-5-carbonitrile hydrochloride (140 mg, crude) as a white solid as a mixture of enantiomers, which was used without further purification.

[0416] Example i-20. Intermediate B-11 ((R)-2-methyl-N-[(7S)-spiro[5,7-dihydrocyclopenta[c]pyridine-6,4'-piperidine]-7-yl]propane-2-sulfinamide) [ka] Step a: To a solution of 3-bromo-4-pyridinemethanol (40.0 g, 212 mmol) in DCM (200 mL) was added DMF (1.64 mL, 21.2 mmol) followed by SOCl 2 (dropwise) (30.8 mL, 425 mmol) at room temperature with N 2 The mixture was stirred at 35° C. for 4 h. The reaction mixture was diluted with NaHCO 3 The mixture was quenched at 10° C. by the addition of an aqueous solution of (500 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with brine (200 mL) and diluted with Na 2 SO 4 The mixture was evaporated, dried at 40° C., filtered, and concentrated under reduced pressure to give 3-bromo-4-(chloromethyl)pyridine (35.4 g, 171 mmol) as a yellow oil. 1 HNMR (400MHz, CDCl 3 )d8.72(s,1H),8.54(d,J=4.8Hz,1H),7.46(d,J=4.8Hz,1H),4.63(s,2H).

[0417] Step b: To a solution of 1-boc-4-cyanopiperidine (36.0 g, 171 mmol) in THF (720 mL) was added LDA (2 M, 111 mL, 222 mmol) dropwise at -78 °C. After the addition, the mixture was stirred at this temperature for 1 h, and 3-bromo-4-(chloromethyl)pyridine (35.4 g, 171 mmol) was then added dropwise. The resulting mixture was stirred at -78 °C for 2 h. The reaction mixture was cooled to 0 °C with NH 4 The mixture was quenched by the addition of an aqueous solution of Cl (500 mL) and extracted with EtOAc (200 mL*3). The combined organic layers were washed with brine (200 mL) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50 / 1 to 0 / 1) to give tert-butyl 4-[(3-bromo-4-pyridinyl)methyl]-4-cyanopiperidine-1-carboxylate (32.2 g, 84.6 mmol) as an off-white solid. 1 HNMR (400MHz, CDCl3 )d8.76(s,1H),8.51(d,J=4.8Hz,1H),7.46(d,J=4.8Hz,1H),4.17(s,2H),3 .10(s,2H),2.99(s,2H),1.85-1.88(m,2H),1.64-1.71(m,2H),1.46(s,9H).

[0418] Step c: DMA (436mL) and H 2 tert-Butyl 4-[(3-bromo-4-pyridinyl)methyl]-4-cyanopiperidine-1-carboxylate (32.0 g, 84.1 mmol), DIPEA (58.6 mL, 336 mmol), Pd(AmPhos) in O (44 mL) 2 Cl 2 A mixture of (5.96 g, 8.41 mmol) was added to N 2 Degass with N for 18 h at 100 °C. 2 The reaction mixture was stirred under atmospheric pressure. 2 The mixture was quenched by the addition of O (700 mL) and extracted with EtOAc (200 mL*7). The combined organic layers were washed with brine (200 mL*3) and diluted with Na 2 SO 4 The crude product was triturated with MTBE (80 mL) at room temperature for 1 h and filtered to give tert-butyl 7-oxo-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidine]-1'-carboxylate (21.0 g, 69.4 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3 )d8.99(s,1H),8.72(d,J=4.8Hz,1H),7.43(d,J=4.8Hz,1H),4.09(s,2H),3.08 (s,2H),2.97-3.03(m,2H),1.85-1.92(m,2H),1.46(s,9H),1.36-1.40(m,2H).

[0419] Step d: To a solution of tert-butyl 7-oxo-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidine]-1'-carboxylate (18.5 g, 61.2 mmol) in 2-MeTHF (130 mL) was added Ti(OEt) 4 (76.1 mL, 367 mmol) and (R)-2-methylpropane-2-sulfinamide (29.6 g, 244 mmol) were added. The mixture was stirred at 80° C. for 16 h. The reaction mixture was stirred at H 2 The mixture was quenched by the addition of 200 mL of O and filtered. The filter cake was washed with EtOAc (2.0 L) and the aqueous phase was extracted with EtOAc (200 mL*3). The combined organic layers were washed with brine (200 mL) and diluted with Na 2 SO 4 The crude product was dried at 40° C., filtered, and concentrated under reduced pressure. The crude product was triturated with MTBE (100 mL) at room temperature for 30 min to give tert-butyl 7-{[(R)-2-methylpropane-2-sulfinyl]imino}-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidine]-1′-carboxylate (20.0 g, 49.3 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d9.59(s,1H),8.64(d,J=4.8Hz,1H),7.36(d,J=4.8Hz,1H),4.13(s,2H),3.06(s, 2H), 2.94 (s, 2H), 1.94-1.99 (m, 2H), 1.47 (s, 9H), 1.39-1.42 (m, 2H), 1.33 (s, 9H).

[0420] Step e: A solution of tert-butyl 7-{[(R)-2-methylpropane-2-sulfinyl]imino}-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidine]-1'-carboxylate (20.0 g, 49.3 mmol) in THF (140 mL) was treated with DIBAL-H (1 M in toluene, 98.6 mL, 98.6 mmol) at -78 °C with N 2 The resulting mixture was stirred at -78 °C for 3 h. The reaction mixture was cooled to 0 °C with NH 4The mixture was quenched by the addition of an aqueous solution of Cl (200 mL) and stirred at room temperature for 30 min, followed by filtration. The filter cake was washed with EtOAc (500 mL) and the aqueous phase was extracted with EtOAc (100 mL*3). The combined organic layers were washed with brine (200 mL) and Na 2 SO 4 The crude product was dried at 40° C., filtered, and concentrated under reduced pressure. The crude product was triturated with MTBE (80 mL) at room temperature for 1 h and filtered to give tert-butyl (7S)-7-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[c]pyridine-6,4'-piperidine]-1'-carboxylate (14.0 g, 33.8 mmol) as an off-white solid. 1 HNMR (400MHz, CDCl 3 )d8.55(s,1H),8.45-8.48(m,1H),7.17(s,1H),4.58(d,J=9.6Hz,1H),4.02(d,J=13.6Hz,1H) ,3.58(s,1H),2.68-3.07(m,4H),2.11(s,1H),1.74(s,2H),1.44-1.60(m,11H),1.28(s,9H).

[0421] Step f: To a mixture of tert-butyl (7S)-7-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[c]pyridine-6,4'-piperidine]-1'-carboxylate (900 mg, 2.14 mmol) in dichloromethane (7 mL) was added TFA (1.64 mL, 21.4 mmol) at room temperature. The mixture was stirred for 1 h and the mixture was poured into a 2N aqueous solution of NaOH. The mixture was filtered through a hydrophobic cartridge (liquid / liquid extraction column, Radleys®) and then concentrated in vacuo to give (R)-2-methyl-N-[(7S)-spiro[5,7-dihydrocyclopenta[c]pyridine-6,4'-piperidine]-7-yl]propane-2-sulfinamide (663 mg, 2.09 mmol) as a white solid. 1HNMR(400MHz,DMSO-d6) d 8.43 (s, 1H), 8.37 (d, J = 4.9 Hz, 1H), 7.25 (d, J = 4.8 Hz, 1H), 5.67 (d, J = 10.2 Hz, 1H), 4.42 (d, J = 10.2 Hz, 1H), 3.04 (d, J = 16.6 Hz, 1H), 2.85-2.89(m,2H),2.60-2.70(m,3H),1.78-1.85(m,1H),1.58-1.65(m,1H),1.37-1.40(m,1H),1.13-1.21(m,10H). LCMS m / z[M+H] + =308.1.

[0422] Example i-21. Intermediate B-12 ((R)-2-methyl-N-[(3R)-spiro[3H-benzofuran-2,4'-piperidin]-3-yl]propane-2-sulfinamide) [ka] Step a: To a solution of 2-fluorobenzaldehyde (45.0 g, 362 mmol) in DCM (225 mL) was added 1,3-propanedithiol (36.3 mL, 362 mmol) and I 2 (2.76 g, 10.9 mmol) was added. The mixture was stirred at room temperature for 4 h. The residue was dissolved in Na 2 S 2 O 3 (180mL) and NaOH (150mL). The mixture was extracted with DCM (180mL*3), and the organic layer was diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 The mixture was purified by elution with hexane / ethyl acetate (petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give 2-(2-fluorophenyl)-1,3-dithiolane (41.0 g, 191 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3)d7.62-7.63(m,1H),7.28-7.30(m,1H),7.17-7.19(m,1H),7.07-7.09(m,1H),5.57 (s,1H),3.11-3.17(m,2H),2.92-2.97(m,2H),2.18-2.22(m,1H),1.95-1.99(m,1H).

[0423] Step b: A mixture of 2-(2-fluorophenyl)-1,3-dithiolane (18.0 g, 84.0 mmol) in THF (90 mL) was treated with LDA (2 M in heptane / THF, 84.0 mL, 168 mmol) at −78 °C with N 2 The mixture was then stirred at -20°C for 30 min, then cooled to -78°C, and tert-butyl 4-oxopiperidine-1-carboxylate (16.7 g, 84.0 mmol) was added. The mixture was stirred at -78°C for 2 h. The mixture was diluted with NH 4 The mixture was quenched by the addition of an aqueous solution of NaCl (180 mL). The mixture was extracted with EtOAc (180 mL*3). The organic layer was 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=30 / 1 to 0 / 1) to give tert-butyl 4-[2-(2-fluorophenyl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylate (16.0 g, 38.7 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d8.04-8.08(m,1H),7.34-7.36(m,1H),7.19-7.22(m,1H),7.09-7.13(m,1H),3.92(d,J = 12 Hz, 2H), 2.99-3.00(m,2H),2.82-2.86(m,2H),2.64-2.68(m,2H),2.60(s,1H),1.85-1.90(m,2H),1.77(s,4H),1.42(s,9H).

[0424] Step c: DCM (10 mL) and H 2tert-Butyl 4-[2-(2-fluorophenyl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylate (10.0 g, 24.2 mmol), TBAB (2.34 g, 7.25 mmol), Py.HBr in 2H2O (2.5 mL). 3 A mixture of 11.6 g (36.3 mmol) and pyridine (5.85 mL, 72.5 mmol) was stirred at room temperature for 8 h. Water (50 mL) was added and the mixture was extracted with DCM (50 mL*3), and the organic layer was diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50 / 1 to 0 / 1) to give tert-butyl 4-(2-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate (7.5 g, 23.2 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3 )d7.36-7.50(m,1H),7.35-7.36(m,1H),7.23-7.25(m,1H),7.15-7.17(m,1H),4.04(d,J = 12 Hz, 2H), 3.31 (s, 1H), 3.12-3.20(m,2H),1.98-2.03(m,2H),1.64(d,J=12.0Hz,2H),1.45(s,9H).

[0425] Step d: A mixture of tert-butyl 4-(2-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate (13.0 g, 40.2 mmol) and t-BuOK (4.96 g, 44.2 mmol) in dioxane (65 mL) was heated at room temperature for 2 h with N 2 Water (65 mL) was added and the mixture was extracted with EtOAc (65 mL*3), and the organic layer was washed with Na 2 SO 4The crude product was triturated with petroleum ether / ethyl acetate=50 / 1, filtered, and the filter cake was dried under reduced pressure to give tert-butyl 3-oxo-3H-spiro[1-benzofuran-2,4'-piperidine]-1'-carboxylate (5.80 g, 19.1 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3 )d7.36-7.507.63-7.69(m,2H),7.08-7.14(m,2H),4.15(d,J = 12 Hz, 2H), 3.21-3.28(m,2H),1.91-1.99(m,2H),1.58(d,J=12Hz,2H),1.49(s,9H).

[0426] Process e:Ti(OEt) 4 A mixture of tert-butyl 3-oxo-3H-spiro[1-benzofuran-2,4'-piperidine]-1'-carboxylate (4.78 g, 15.8 mmol) and (R)-2-methylpropane-2-sulfinamide (11.5 g, 94.5 mmol) in 23.9 mL of N 2 The mixture was extracted with water (75 mL) and EtOAc (30 mL*3), and the organic layer was diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to give tert-butyl (3R)-3-[[(R)-tert-butylsulfinyl]imino]spiro[3H-benzofuran-2,4'-piperidine]-1'-carboxylate (4.68 g, 11.53 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3 )d8.33(d,J = 8 Hz, 1H), 7.51-7.55(m,1H),7.03-7.08(m,2H),4.17(s,1H),3.20(s,2H),1.93-1.96(m,2H),1.71-1.74(m,1H),1.64(d,J = 12 Hz, 1H), 1.50 (s, 9H), 1.31 (s, 9H).

[0427] Step f: To a mixture of tert-butyl (3R)-3-[[(R)-tert-butylsulfinyl]imino]spiro[3H-benzofuran-2,4'-piperidine]-1'-carboxylate (7.50 g, 18.5 mmol) in THF (40 mL) was added DIBAL-H (1 M, 73.8 mL, 73.8 mmol) dropwise. The mixture was incubated at -78 °C for 45 min with N 2 The mixture was stirred under reduced pressure, then quenched by the addition of water (120 mL) at -78°C, and then warmed to room temperature. The mixture was extracted with EtOAc (40 mL*3), and the organic layer was washed with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 The crude product was purified by hexane distillation (petroleum ether / ethyl acetate = 15 / 1 to 0 / 1), then the crude product was triturated with petroleum ether / ethyl acetate = 15 / 1 at room temperature, filtered, and the filter cake was dried under reduced pressure to give tert-butyl (3R)-3-[[(R)-tert-butylsulfinyl]amino]spiro[3H-benzofuran-2,4'-piperidine]-1'-carboxylate (2.26 g, 5.55 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3 )d7.23-7.29(m,2H),6.90-6.94(m,1H),6.82(d,J = 8 Hz, 1H), 4.63 (d, J=8.0Hz,1H),4.10(s,2H),3.66(s,1H),3.17(s,2H),1.69-2.01(m,4H),1.47(s,9H),1.26(s,9H).

[0428] Step g: To a mixture of tert-butyl (3R)-3-[[(R)-tert-butylsulfinyl]amino]spiro[3H-benzofuran-2,4'-piperidine]-1'-carboxylate (1.5 g, 3.67 mmol) in dichloromethane (10 mL) was added TFA (2.81 mL, 36.7 mmol) at room temperature. The mixture was stirred for 2 h and the mixture was poured into a 2N aqueous solution of NaOH. The mixture was filtered through a hydrophobic cartridge (liquid / liquid extraction column, Radleys®) and then concentrated in vacuo to give (R)-2-methyl-N-[(3R)-spiro[3H-benzofuran-2,4'-piperidine]-3-yl]propane-2-sulfinamide (1.13 g, 3.66 mmol) as an off-white solid. 1 HNMR(400MHz,DMSO-d6) d 7.25 (d, J=7.4Hz,1H),7.16-7.20(m,1H),6.85-6.89(m,1H),6.78(d,J = 8.0 Hz, 1H), 5.97 (d, J=10.3Hz,1H),4.52(d,J = 10.3 Hz, 1H), 2.75-2.90(m,4H),1.58-1.85(m,4H),1.18(s,9H). LCMS m / z[M+H] + =309.5.

[0429] Example i-22. Intermediate B-13 ((R)-2-methyl-N-[(3R)-spiro[3H-furo[2,3-b]pyridine-2,4'-piperidine]-3-yl]propane-2-sulfinamide) [ka] Step a: To a solution of 2-fluoronicotinaldehyde (48.0 g, 384 mmol) and 1,3-propanedithiol (42.4 mL, 422 mmol) in DCM (240 mL) was added BF 3 .Et 2 O (47.0% purity, 31.2 mL, 119 mmol) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction was cooled to 37° C. with NaHCO 3The mixture was quenched with a saturated aqueous solution of (300 mL) and extracted with DCM (150 mL*3). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to give 3-(1,3-dithian-2-yl)-2-fluoropyridine (46.0 g, 214 mmol) as a colorless oil. 1 HNMR (400MHz, CDCl 3 )d8.15(d,J = 4.0 Hz, 1H), 8.01-8.05(m,1H),7.20-7.27(m,1H),5.44(s,1H),3.09-3.16(m,2H),2.92-2.96(m,2H)2.18-2.23(m,1H),1.93-1.96(m,1H).

[0430] Step b: To a solution of 3-(1,3-dithian-2-yl)-2-fluoropyridine (30.0 g, 138.9 mmol) in THF (150 mL) was added LDA (2 M, 146.4 mL, 292.8 mmol) dropwise at -78°C. The mixture was stirred for 1 h at -20°C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (55.5 g, 278.7 mmol) in THF (60 mL) was added at -78°C. The reaction was stirred for 1 h at -78°C. The reaction mixture was diluted with NH 4 The aqueous solution of Cl (300 mL) was poured into the solution at 0° C. The aqueous phase was extracted with ethyl acetate (200 mL*3). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to give tert-butyl 4-[2-(2-fluoropyridin-3-yl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylate (21.0 g, 50.7 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3)d8.49-8.54(m,1H),8.21(d,J = 4.0 Hz, 1H), 7.27-7.31(m,1H),3.94(d,J = 12 Hz, 2H), 2.98-2.99(m,2H),2.84-2.88(m,2H),2.57-2.61(m,2H),1.88-1.92(m,2H),1.74-1.81(m,4H),1.43(s,9H).

[0431] Process c:H 2 To a solution of tert-butyl 4-[2-(2-fluoropyridin-3-yl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylate (13.5 g, 32.6 mmol) in 2H2O (14.0 mL) and DCM (70.0 mL) was added TBAB (3.15 g, 9.77 mmol), pyridine (3.15 mL, 39.1 mmol) and PyHBr. 3 (12.5 g, 39.1 mmol) was added. The mixture was stirred at room temperature for 10 h. The residue was 2 The combined organic phase was washed with brine and poured into 200 mL of anhydrous NaCl. The aqueous phase was extracted with DCM (150 mL*3). 2 SO 4 The residue was purified by silica gel chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to give tert-butyl 4-(2-fluoropyridine-3-carbonyl)-4-hydroxypiperidine-1-carboxylate (14.3 g, 44.1 mmol) as a yellow oil. 1 HNMR (400MHz, CDCl 3 )d8.34(d,J = 4.0 Hz, 1H), 7.88-7.92(m,1H),7.30-7.33(m,1H),4.03(d,J=12.0Hz,2H),3.11-3.19(m,2H),1.98-2.02(m,2H),1.68(d,J = 12.0 Hz, 2H), 1.45 (s, 9H).

[0432] Step d: To a solution of tert-butyl 4-(2-fluoropyridine-3-carbonyl)-4-hydroxypiperidine-1-carboxylate (14.3 g, 44.1 mmol) in dioxane (70 mL) was added t-BuOK (5.44 g, 48.5 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours. The residue was purified by H 2 The combined organic phase was washed with brine and poured into 200 mL of ethyl acetate (100 mL*3) at 0° C. The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with brine and 2 SO 4 The crude product was dried at 40° C., filtered, and concentrated in vacuo. The crude product was triturated with petroleum ether / ethyl acetate=50 / 1 (25.0 mL) at room temperature for 30 min to give tert-butyl 3-oxospiro[furo[2,3-b]pyridine-2,4′-piperidine]-1′-carboxylate (9.20 g, 30.2 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d8.61-8.62(m,1H),8.04-8.06(m,1H),7.13-7.16(m,1H),4.16(s,2H),3.27-3.33(m,2H),1.95-2.04(m,2H),1.65(d,J = 12 Hz, 2H), 1.49 (s, 9H).

[0433] Step e: To a mixture of tert-butyl 3-oxospiro[furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (9.2 g, 30.2 mmol) in 2-MeTHF (94 mL) was added (R)-2-methylpropane-2-sulfinamide (22.0 g, 181.4 mmol) and Ti(OEt). 4 (25 mL, 121 mmol) at room temperature with N 2 The mixture was stirred at 85° C. for 2 hours. The reaction was poured into water (80 mL). The suspension was filtered and the filtrate was extracted with ethyl acetate (30.0 mL*3). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (SiO 2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give tert-butyl (3R)-3-[[(R)-tert-butylsulfinyl]imino]spiro[3H-furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (10.2 g, 25.0 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d8.79(d,J = 4 Hz, 1H), 8.43-8.44(m,1H),7.06-7.09(m,1H),4.11-4.19(m,2H),3.26(s,2H),1.89-2.04(m,2H),1.77-1.81(m,2H),1.50(s,9H),1.33(s,9H).

[0434] Step f: To a solution of tert-butyl (3R)-3-[[(R)-tert-butylsulfinyl]imino]spiro[3H-furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (6.00 g, 14.7 mmol) in THF (30.0 mL) was added DIBAL (1 M, 58.9 mL, 58.9 mmol) dropwise at -78°C. The mixture was stirred at -78°C for 1 h. The mixture was then cooled to -78°C for 1 h. 2 The combined organic phase was washed with brine and poured into 20.0 mL of ethyl acetate (50 mL) at -20°C. The aqueous phase was extracted with ethyl acetate (30.0 mL*3). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give tert-butyl (3R)-3-[[(R)-tert-butylsulfinyl]amino]spiro[3H-furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (3.07 g, 7.51 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3)d8.12(d,J = 4.0 Hz, 1H), 7.63 (d, J=8.0Hz,1H),6.86-6.89(m,1H),4.66(d,J = 8.0 Hz, 1H), 4.11 (s, 2H), 3.76 (d, J=8.0Hz,1H),3.23(s,2H),1.89-1.99(m,2H),1.71-1.79(m,2H),1.46(s,9H),1.25(s,9H).

[0435] Step g: To a mixture of tert-butyl (3R)-3-[[(R)-tert-butylsulfinyl]amino]spiro[3H-furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (300 mg, 0.73 mmol) in dichloromethane (2 mL) was added TFA (0.56 mL, 7.33 mmol) at room temperature. The mixture was stirred for 2 h and the mixture was poured into a 2N aqueous solution of NaOH. The mixture was filtered through a hydrophobic cartridge (liquid / liquid extraction column, Radleys®) and then concentrated in vacuo to give (R)-2-methyl-N-[(3R)-spiro[3H-furo[2,3-b]pyridine-2,4'-piperidine]-3-yl]propane-2-sulfinamide (225 mg, 0.73 mmol) as a white solid. 1 HNMR(400MHz,DMSO-d6) d 8.04 (m, 1H), 7.65 (m, 1H), 6.92 (m, 1H), 6.10 (d, J=10.3Hz,1H),4.57(d,J = 10.3 Hz, 1H), 2.78-2.94(m,4H),1.65-1.88(m,4H),1.17(s,9H). LCMS m / z[M+H] + =310.5.

[0436] Example i-23. Intermediate B-14 (tert-butyl (4S)-4-(tert-butylsulfinylamino)-2-chloro-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate) [ka] Step a: To a solution of 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (90 g, 350 mmol) in THF (500 mL) was added LDA (2M, 192.4 mL, 384.8 mmol) dropwise at -78°C. The mixture was stirred at -78°C for 1 h. Then 2-chloro-5-(chloromethyl)-1,3-thiazole (58.8 g, 350 mmol) was added dropwise at -78°C. The reaction was stirred at -78°C for 1 h. Then the reaction was stirred at room temperature for 12 h. The reaction was poured into water (800 mL) and extracted with petroleum ether / ethyl acetate (1 / 1, 500 mL*3), the combined organic layer was washed with brine (500 mL) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50 / 1 to 0 / 1) to give 1-(tert-butyl) 4-ethyl 4-((2-chlorothiazol-5-yl)methyl)piperidine-1,4-dicarboxylate (50.0 g, 129 mmol) as a yellow oil. 1 HNMR (400MHz, CDCl 3 )dδ7.14(s,1H),4.10(q,J = 6.8 Hz, 2H), 3.80 (d, J=11.2Hz,2H),2.88-2.93(m,4H),2.04(d,J = 13.6 Hz, 2H), 1.38 (s, 9H), 1.33-1.36(m,2H),1.19(t,J = 7.2 Hz, 3H).

[0437] Step b: To a solution of 1-(tert-butyl) 4-ethyl 4-((2-chlorothiazol-5-yl)methyl)piperidine-1,4-dicarboxylate (50.0 g, 128.6 mmol) in THF (500 mL) was added LDA (2M, 160.8 mL, 321.6 mmol) at -78°C. The mixture was stirred at -78°C for 1 h. The reaction was poured into water (1.0 L) slowly and extracted with EtOAc (200 mL*3), the combined organic layer was washed with brine (500 mL) and diluted with Na 2 SO 4The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=20 / 1 to 0 / 1) to obtain tert-butyl 2-chloro-4-oxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (14.0 g, 40.8 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d4.08-4.16(m,2H),3.10(s,2H),2.97(t,J = 12.4 Hz, 2H), 1.92-2.00(m,2H),1.43-1.47(m,12H).

[0438] Process c:Ti(OEt) 4 A mixture of tert-butyl 2-chloro-4-oxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (10.0 g, 29.2 mmol) and (R)-2-methylpropane-2-sulfinamide (10.6 g, 87.5 mmol) in 10 mL of N 2 The mixture was then degassed at 100 °C for 16 h with N 2 The reaction was poured into water (200 mL) and EtOAc (200 mL), the suspension was filtered, the filtrate was extracted with EtOAc (200 mL*3), the combined organic layers were washed with brine (200 mL) and added Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 30 / 1 to 0 / 1) to give tert-butyl (R,Z)-4-((tert-butylsulfinyl)imino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (10.72 g, 24.03 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3)d4.02-4.11(m,2H),3.02(d,J = 4.8 Hz, 2H), 2.85 (br s, 2H), 2.03-2.11(m,1H),1.92-1.96(m,1H),1.45-1.57(m,2H),1.41(s,9H),1.20(s,9H).

[0439] Step d: To a solution of tert-butyl (R,Z)-4-((tert-butylsulfinyl)imino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (10.0 g, 22.4 mmol) in THF (50 mL) was added DIBAL-H (1 M, 89.7 mL, 89.7 mmol) dropwise at -78 °C. The mixture was stirred at -78 °C for 1 h. The reaction was cooled to below 0 °C and cooled to H 2 The mixture was quenched by dropwise addition of 2H2O (30 mL) and stirred at room temperature for 12 h. The suspension was filtered, the filtrate was extracted with EtOAc (30 mL*2), and the combined organic layers were washed with brine (50 mL) and added with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=5 / 1 to 0 / 1) to give tert-butyl (4S)-4-(tert-butylsulfinylamino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (6.0 g, 13.4 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d4.32(d,J = 9.2 Hz, 1H), 3.84(d, J=13.6Hz,2H),2.96-3.03(m,2H),2.69-2.78(m,2H),1.79-1.92(m,2H),1.44-1.55(m,2H),1.39(s,9H),1.18(s,9H).

[0440] Example i-24. Intermediate B-15 ((4S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-4-amine hydrochloride) [ka] Step a: To a solution of intermediate B-14 (6.0 g, 13.4 mmol) in MeOH (30 mL) and TEA (6 mL), Pd / C (10%, 3 g) was added with N 2 The suspension was degassed under vacuum and H 2 The mixture was purged with H several times. 2 The mixture was stirred under reduced pressure (40 psi) at 50° C. for 2 h. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give tert-butyl (4S)-4-((R)-tert-butylsulfinylamino)spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (2.74 g, 6.47 mmol) as an off-white solid. 1 HNMR(400MHz,MeOD)d8.87(s,1H),4.37(s,1H),3.87-3.98(m,2H),3.09-3.19(m,2H),2.94(q,J = 9.2 Hz, 2H), 1.89-1.93 (m, 1H), 1.47-1.76 (m, 3H), 1.26 (s, 9H), 1.23 (s, 9H).

[0441] Step b: To a mixture of tert-butyl (4S)-4-((R)-tert-butylsulfinylamino)spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (1.5 g, 3.6 mmol) in dichloromethane (25 mL) was added a solution of HCl (2.5 M in ethanol, 25 mL, 62.5 mmol) dropwise at room temperature. The mixture was stirred for 3 h and then concentrated under vacuum. The residue was taken up in dichloromethane (50 mL), filtered, washed with diisopropyl ether (30 mL) and then pentane (30 mL) to give (4S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-4-amine hydrochloride (1.2 g, crude), which was used without further purification.

[0442] Example i-25. Intermediate B-16 ((4S)-2-chlorospiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-4-amine hydrochloride) [ka] A mixture of intermediate B-14 (1.5 g, 3.3 mmol) in a solution of HCl (2.5 M in ethanol, 15 mL, 37.5 mmol) was stirred for 3 h and then concentrated under vacuum. The residue was taken up in EtOAc (10 mL) and diisopropyl ether (10 mL), filtered, and washed with diisopropyl ether and then pentane to give ((4S)-2-chlorospiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-4-amine hydrochloride (1.04 g, crude), which was used without further purification.

[0443] Example i-26. Intermediate B-17 (tert-butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]-2-chloro-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate) [ka] Step a: To a solution of 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (50.0 g, 194 mmol) in THF (350 mL) was added LDA (2M, 117 mL, 234 mmol) dropwise at -78°C. The mixture was stirred at -78°C for 1 h. Then 2-chloro-4-(chloromethyl)thiazole (31.0 g, 185 mmol) was added dropwise at -78°C. The reaction was stirred at -78°C for 1 h. Then the reaction was stirred at room temperature for 12 h. The reaction was poured into water (100 mL) and extracted with petroleum ether / ethyl acetate (1 / 1, 50 mL*3), the combined organic layer was washed with brine (100 mL) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate=50 / 1 to 0 / 1) to give 1-(tert-butyl) 4-ethyl 4-((2-chlorothiazol-4-yl)methyl)piperidine-1,4-dicarboxylate (20.0 g, 51.5 mmol) as a yellow oil. 1 HNMR (400MHz, CDCl 3 )d6.80(s,1H),4.15(q,J = 7.2 Hz, 2H), 3.89 (br s, 2H), 2.80-2.94(m,3H),2.11(d,J = 13.2 Hz, 2H), 1.50-1.52(m,2H),1.45(s,9H),1.24(t,J = 7.2 Hz, 3H).

[0444] Step b: To a solution of 1-(tert-butyl) 4-ethyl 4-((2-chlorothiazol-4-yl)methyl)piperidine-1,4-dicarboxylate (30 g, 77.14 mmol) in THF (210 mL) was added LDA (2M, 57.9 mL, 115.8 mmol) dropwise at -78 °C. The mixture was stirred at -78 °C for 1 h. The reaction was poured into brine (200 mL) slowly and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to obtain tert-butyl 2-chloro-6-oxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (13.0 g, 37.9 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d4.09(d,J = 13.2 Hz, 2H), 2.98 (s, 2H), 2.88 (t, J=8.0Hz,2H),1.86-1.93(m,2H),1.41-1.44(m,10H).

[0445] Process c:Ti(OEt) 4To a solution of tert-butyl 2-chloro-6-oxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (13.0 g, 37.9 mmol) in (65 mL) was added (R)-2-methylpropane-2-sulfinamide (13.8 g, 114 mmol). The mixture was stirred at 100°C for 16 h and then cooled to room temperature. The reaction was poured into water (50 mL) and EtOAc (50 mL), the suspension was filtered, the filtrate was extracted with EtOAc (20 mL*3), the combined organic layers were washed with brine (50 mL) and Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give tert-butyl (R,Z)-6-((tert-butylsulfinyl)imino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (11.0 g, 24.7 mmol) as a yellow oil. 1 HNMR (400MHz, CDCl 3 )d4.06-4.13(m,2H),2.80-2.92(m,4H),1.84-2.01(m,3H),1.41(s,9H),1.16(s,9H).

[0446] Step d: To a solution of tert-butyl 6-(((R)-tert-butylsulfinyl)imino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (12.0 g, 26.9 mmol) in THF (60 mL) was added DIBAL-H (1 M, 108 mL, 108 mmol) dropwise at -78 °C. The mixture was stirred at -78 °C for 1 h. The reaction was cooled to below 0 °C and cooled to H 2 The mixture was quenched by dropwise addition of 2,4-dichlorophenyl ether (50 mL) and stirred at room temperature for 12 h. The suspension was filtered, the filtrate was extracted with EtOAc (50 mL*2), and the combined organic layers were washed with brine (50 mL) and added with Na 2 SO 4 The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give tert-butyl (6S)-6-(((R)tert-butylsulfinyl)amino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (7.00 g, 15.6 mmol) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )d4.49(d,J = 8.8 Hz, 1H), 3.95-3.98(m,2H),3.61(d,J = 7.2 Hz, 1H), 2.79-3.30(m,4H),1.73-1.84(m,2H),1.54-1.61(m,2H),1.44(s,9H),1.19(s,9H).

[0447] Example i-27. Intermediate B-18 ((6S)-2-chlorospiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-6-amine hydrochloride) [ka] A mixture of intermediate B-17 (0.81 g, 2.3 mmol) in a solution of HCl (4 M in dioxane, 15 mL, 60 mmol) was stirred at room temperature for 24 h. The mixture was then filtered and washed with diisopropyl ether to give (6S)-2-chlorospiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-6-amine hydrochloride (813 mg, crude) as a yellow solid, which was used without further purification.

[0448] Example i-28. Intermediate B-19 ((6S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-6-amine hydrochloride) [ka] Step a: To a solution of intermediate B-17 (7.00 g, 15.6 mmol) in MeOH (35 mL) and TEA (7 mL) was added Pd / C (10%, 3.00 g, 15.6 mmol) with N 2The suspension was degassed under vacuum and H 2 The mixture was purged with H several times. 2 The mixture was stirred under reduced pressure (40 psi) at 50° C. for 5 h. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give tert-butyl (6S)-6-(((R)tert-butylsulfinyl)amino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (4.5 g, 10.8 mmol) as a white solid. 1 HNMR(400MHz,MeOD)d8.98(s,1H),4.57(s,1H),3.94-4.03(m,2H),3.04-3.13(m,2H),2.90(q,J = 15.6 Hz, 2H), 1.86-1.91(m,1H),1.76-1.77(m,1H),1.64-1.68(m,2H),1.47(s,9H),1.24(s,9H).

[0449] Step b: A mixture of tert-butyl (6S)-6-(((R)tert-butylsulfinyl)amino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (500 mg, 1.21 mmol) in a solution of HCl (2.5 M in ethanol, 10 mL, 25 mmol) was stirred at room temperature for 3 h. The mixture was then concentrated under vacuum. The residue was taken up in ethyl acetate (30 mL), filtered, and washed with diisopropyl ether (30 mL) and then pentane (30 mL) to give (6S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-6-amine hydrochloride (320 mg, crude), which was used without further purification.

[0450] Example i-29. Intermediate B-20 ((6S)-2-Methylspiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-6-amine hydrochloride) [ka] Step a: Mix intermediate B-17 (2.50 g, 5.58 mmol), trimethylboroxine (50% purity, 2.34 mL, 8.37 mmol) and K in dioxane (5 mL). 2 CO 3 A mixture of (1.54 g, 11.2 mmol) Pd(dppf)Cl 2 .CH 2 Cl 2 (227 mg, 0.28 mmol) 2 The mixture was stirred at 115° C. for 2 h. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give tert-butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]-2-methyl-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (3.00 g, 7.02 mmol) as a pale yellow solid. 1 HNMR (400MHz, CDCl 3 )d4.49(d,J = 8.4 Hz, 1H), 3.99 (s, 2H), 3.54 (s, 1H), 2.96-3.04(m,2H),2.81(s,2H),2.73(s,3H),1.73-1.84(m,2H),1.58-1.63(m,2H),1.46(s,9H),1.21(s,9H).

[0451] Step b: A mixture of tert-butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]-2-methyl-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (1.0 g, 2.3 mmol) in a solution of HCl (4 M in dioxane, 15 mL, 60 mmol) was stirred at room temperature for 24 h. The mixture was then filtered and washed with diisopropyl ether to give (6S)-2-methylspiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-6-amine hydrochloride (763 mg, crude) as a white solid, which was used without further purification.

[0452] Example i-30. Intermediate B-21 ((5S)-2-Methylspiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-amine hydrochloride) [ka] Step a: N at 75°C 2 CHCl below 3 To a solution of 3-bromo-2,6-dimethylpyridine (160 g, 860 mmol) in (1.12 L) was added NBS (184 g, 1.03 mol) and AIBN (42.4 g, 258 mmol) and the mixture was stirred for 4 h. The residue was poured into water (500 mL). The aqueous phase was extracted with DCM (350 mL*3). The combined organic phase was washed with brine (200 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 0-0 / 1) to obtain the compound 3-bromo-2-(bromomethyl)-6-methylpyridine (33.3 g, 119.5 mmol) as a brown oil. 1 HNMR (400MHz, CDCl 3 )d7.74(d,J=8.4Hz,1H),6.98(d,J=8.4Hz,1H),4.68(s,2H),2.53(s,3H).

[0453] Step b: N at -78°C 2 To the mixture of 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (21.0 g, 86.3 mmol) in THF (91.0 mL) below, LDA (2.00 M, 64.7 mL, 129.4 mmol) was added dropwise. The mixture was then stirred at room temperature for 1 h. 3-Bromo-2-(bromomethyl)-6-methylpyridine (32.3 g, 104 mmol) was added and the mixture was stirred for 2 h. The reaction mixture was poured into water (200 mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with brine (100 mL) and anhydrous Na 2 SO4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to give 1-(tert-butyl) 4-methyl 4-((3-bromo-6-methyl-2-pyridinyl)methyl)piperidine-1,4-dicarboxylate (17.0 g, 39.0 mmol) as a yellow oil. 1 HNMR (400MHz, CDCl 3 )d7.66(d,J=8.4Hz,1H),6.85(d,J=8.4Hz,1H),3.82(s,2H),3.72(s,3H),3.23(s,2H),3.03(t,J = 12 Hz, 2H), 2.43 (s, 3H), 2.09 (d, J = 7.6 Hz, 2H), 1.61 (t, J=2Hz,2H),1.46(s,9H).

[0454] Process c:H 2 To a mixture of 1-(tert-butyl) 4-methyl 4-((3-bromo-6-methyl-2-pyridinyl)methyl)piperidine-1,4-dicarboxylate (66.9 g, 157 mmol) in 2H2O (134 mL) and MeOH (468 mL) was added NaOH (31.3 g, 783 mmol) at room temperature. The mixture was stirred at 65 °C for 16 h. The mixture was concentrated to dryness and the crude was dissolved in water (50 mL) and washed with MTBE (20 mL). The aqueous layer was separated and brought to pH 6-7 by addition of a 2N aqueous solution of HCl. The compound was extracted with EtOAc (25 mL*2). The combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO 4 Drying at 40° C., filtering and concentrating in vacuo afforded 1-(tert-butoxycarbonyl)-4-((3-bromo-6-methyl-2-pyridinyl)methyl)piperidine-4-carboxylic acid (75.0 g, crude) as a white solid.

[0455] Step d: To a mixture of crude 1-(tert-butoxycarbonyl)-4-((3-bromo-6-methyl-2-pyridinyl)methyl)piperidine-4-carboxylic acid (75.0 g) in THF (105 mL) was added NaH (60%, 6.97 g, 174 mmol) in one portion at −15 °C with N 2 The mixture was stirred at -15°C for 15 min, then cooled to -60°C, n-BuLi (1.79M, 114mL, 204mmol) was added dropwise, and the temperature was then allowed to rise to -20°C over 30 min. The reaction mixture was quenched at 0°C by the addition of water (350mL) and extracted with ethyl acetate (400mL*2). The combined organic layers were washed with brine (200mL) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to give tert-butyl 2-methyl-5-oxo-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (11.0 g, 34.8 mmol) as a yellow oil. 1 HNMR (400MHz, CDCl 3 )d7.91(d,J=3.2,1H),7.20(d,J=4Hz,1H),4.12(s,2H),3.12(s,2H),3.01(t,J=10.4Hz,2H),2.67(s,3H),1.92(t,J = 12 Hz, 2H), 1.47 (s, 9H), 1.41 (d, J=5.8Hz,2H).

[0456] Process e:Ti(OEt) 4A mixture of tert-butyl 2-methyl-5-oxo-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (12.5 g, 39.5 mmol) and (R)-2-methylpropane-2-sulfinamide (14.4 g, 119 mmol) in (87.5 mL) was stirred at 110°C for 11 hours and then cooled to room temperature. The reaction mixture was quenched by the addition of water (100 mL), then filtered and extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with brine (100 mL*2) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to give tert-butyl (5S)-5-((tert-butylsulfinyl)imino)-2-methyl-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (18.5 g, crude) as a white solid, which was used without further purification.

[0457] Step f: To a mixture of tert-butyl (5S)-5-((tert-butylsulfinyl)imino)-2-methyl-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (18.5 g, crude) in THF (116 mL) was added DIBAL-H (1.00 M, 172 mL, 172 mmol) dropwise at -78°C. The mixture was stirred at -78°C for 1 h. The reaction mixture was quenched by the addition of water (300 mL) at 0°C, stirred for 40 min, then filtered and extracted with ethyl acetate (200 mL*2). The combined organic layers were washed with brine (100 mL*2) and concentrated to dryness with NaCl. 2 SO 4The crude product was triturated with MTBE (100 mL) at room temperature for 20 min and filtered to give tert-butyl (5S)-5-((tert-butylsulfinyl)amino)-2-methyl-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (2.90 g, 6.81 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3 )d7.55(d,J=3.6Hz,1H),7.01(d,J=4Hz,1H),4.48(d,J=4.4Hz,1H),4.01(d,J=8.8Hz,2H),3.55(s,1H),3.11(s,1H),2.945(t,J = 10.4 Hz, 2H), 2.84 (d, J=7.2Hz,1H),2.561(s,3H),2.03-2.05(m,1H),1.53(s,1H),1.49(s,1H),1.46(s,9H),1.35(s,1H),1.26(s,9H).

[0458] Step g: To a mixture of tert-butyl (5S)-5-((tert-butylsulfinyl)amino)-2-methyl-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (1.0 g, 2.37 mmol) in dichloromethane (5 mL) was added a solution of HCl (2.5 M in ethanol, 15 mL, 38 mmol). The mixture was stirred at room temperature for 3 h and then concentrated in vacuo to give (5S)-2-methylspiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-amine hydrochloride (1.045 g, crude) as a yellow solid, which was used without further purification.

[0459] Example i-31. Intermediate B-22 (1-(triisopropylsilyloxymethyl)spiro[7H-cyclopenta[c]pyridine-6,4'-piperidin]-5-one) [ka] Step a: To a solution of (3-chloro-2-pyridinyl)methanol (24.0 g, 167 mmol) and TIPSCl (39.3 mL, 184 mmol) in DCM (120 mL) was added imidazole (22.7 g, 334 mmol) at 0° C., then the mixture was stirred at room temperature for 2 h. Water was added (100 mL) and the mixture was extracted with DCM. The combined organic layers were washed with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0-0 / 1) to give 3-chloro-2-(triisopropylsilyloxymethyl)pyridine (50.0 g, 167 mmol) as a colorless oil. 1 HNMR (400MHz, CDCl 3 )d8.48(dd,J = 4.4 Hz, 1.2 Hz, 1H), 7.67 (dd, J=8.0Hz,1.2Hz,1H),7.17(dd,J = 8.0 Hz, 4.8 Hz, 1H), 4.99 (s, 2H), 1.16-1.22(m,3H),1.08-1.10(m,18H).

[0460] Step b: A solution of 3-chloro-2-(triisopropylsilyloxymethyl)pyridine (30.0 g, 100 mmol) in THF (600 mL) was treated with LDA (2 M, 60.0 mL, 120 mmol) at −78 °C with N 2 The mixture was stirred at -78°C for 1.5 h. tert-Butyl 4-formyl-4-methylpiperidine-1-carboxylate (22.7 g, 100 mmol) in THF (30 mL) was added dropwise to the mixture, and the mixture was stirred at -78°C for 1 h. The mixture was quenched with water (1000 mL), extracted with EtOAc (500 mL*2), and the organic layer was washed with Na 2 SO 4 The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate=1 / 0-0 / 1) to give tert-butyl 4-[[3-chloro-2-(triisopropylsilyloxymethyl)-4-pyridyl]-hydroxy-methyl]-4-methyl-piperidine-1-carboxylate (19.0 g, 36.0 mmol) as a white solid. 1 HNMR (400MHz, CDCl 3 )d8.45(d,J = 4.8 Hz, 1H), 7.40(d, J=5.2Hz,1H),4.96-5.05(m,3H),3.92(m,2H),2.81-2.89(m,2H),2.23(s,1H),1.79-1.82( m, 1H), 1.55-1.61 (m, 2H), 1.45 (s, 9H), 1.17-1.20 (m, 4H), 1.06-1.09 (m, 18H), 1.03 (s, 3H).

[0461] Step c: To a solution of tert-butyl 4-[[3-chloro-2-(triisopropylsilyloxymethyl)-4-pyridyl]-hydroxy-methyl]-4-methyl-piperidine-1-carboxylate (10.0 g, 19.0 mmol) in MeCN (150 mL) and DCM (50 mL) was added IBX (10.6 g, 37.9 mmol) and ...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein Ring A is C 3 -C 6 cycloalkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein said heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O, and S; Each R 1 are independently halo, cyano, -NR 2a R 2b , C 1 -C 6 Alkyl, oxo, hydroxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-OH, C 1 -C 6 Alkyl-CN, —C(O)NR 2a R 2b , -C(O)(C 1 -C 6 alkyl), —CO 2 H, -CO 2 (C 1 -C 6 alkyl), -Si(R a ) (R b ) (R c ), -P(O)(R a ) (R b ), -OP(O)(R a ) (R b ), C 3 -C 6 cycloalkyl, phenyl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein said heterocycloalkyl and heteroaryl contain 1 to 3 heteroatoms selected from N, O, and S; or two R 1 The groups are fused together with the carbon atom or heteroatom to which they are attached. phenyl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which is selected from 1 to 4 R 6 wherein said fused heterocycloalkyl and heteroaryl contain 1 to 3 heteroatoms selected from N, O, and S; Each R a , R b , and R c are independently hydroxy, C 1 -C 6 Alkyl, or C 1 -C 6 is alkoxy; Each R 2a and R 2b are independently H, C 1 -C 6 Alkyl, or C 3 -C 6 is cycloalkyl; L is a bond, S, O, C(O), or N(R d ) and R d is H or C 1 -C 6 is alkyl; X is CR 3a R 3b , N.R. 3a or O; R 3a and R 3b are independently H or C 1 -C 6 is alkyl; R 4 is H, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-OH, C 1 -C 6 Haloalkyl, or —NH 2 and Each R 5 are independently halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -(C 1 -C 6 alkylene) (C 1 -C 6 alkoxy), or C 1 -C 6 alkyl-OH; Ring B is a fused phenyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Each R 6 are independently 1 -C 6 Alkyl, halo, or C 1 -C 6 haloalkyl; Each R 7 are independently 1 -C 6 Alkyl, halo, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-OH, hydroxy, cyano, -Si(R a ) (R b ) (R c ), -P(O)(R a ) (R b ), -OP(O)(R a ) (R b ), -NR 2a R 2b , or C 1 -C 6 haloalkyl; x is 0 to 5; y is 0 to 2; z is 0 to 4; One or more hydrogen atoms in said compounds are optionally replaced by deuterium).

2. Ring A is C 3 -C 5 cycloalkyl, phenyl, 6-membered heterocycloalkyl, or 5-6-membered heteroaryl, wherein said heterocycloalkyl and heteroaryl contain 1-2 heteroatoms selected from N, O, and S; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclopropyl, phenyl, dihydropyridinyl, dihydropyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, isoxazolyl, or thiophenyl. 【Request Item 4】 【Chemistry 2】 teeth, 【Transformation 3】 That is, 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

5. x is 0, 1, 2, or 3; Each R 1 is, if present, independently selected from halo, cyano, -NR 2a R 2b , C 1 -C 3 Alkyl, oxo, hydroxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Alkyl-OH, C 1 -C 3 Alkyl-CN, —C(O)NR 2a R 2b , -C(O)(C 1 -C 3 alkyl), —CO 2 H, -CO 2 (C 1 -C 3 alkyl), -Si(R a ) (R b ) (R c ), -P(O)(R a ) (R b ), -OP(O)(R a ) (R b ), C 3 -C 5 cycloalkyl, phenyl, or 6-membered heterocycloalkyl, said heterocycloalkyl containing 1 to 2 heteroatoms selected from N and O; or two R's 1 The groups, together with the carbon atom or heteroatom to which they are attached, form a fused phenyl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which may be joined by one to two R 6 wherein said fused heterocycloalkyl and heteroaryl contain 1 to 2 heteroatoms selected from N, O, and S; Each R a , R b , and R c are independently 1 -C 3 Alkyl or C 1 -C 3 is alkoxy; Each R 2a and R 2b are independently H, C 1 -C 3 Alkyl, or C 3 -C 5 is cycloalkyl; Each R 6 are independently 1 -C 3 Alkyl, halo, or C 1 -C 3 haloalkyl, 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

6. Each R 1 is, if present, independently F, Cl, —CN, —CH 2 CN, -NH 2 , -N(H)CH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , oxo, -CF 3 , -OCH 3 , -CH 2 OH, -C(O)N(CH 3 ) 2 , —C(O)CH 3 , cyclopropyl, or 【Chemistry 4】 and or two R's 1 Groups, together with the carbon atoms or heteroatoms to which they are attached, 【Transformation 5】 forming a condensation group selected from 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof. 【Request Item 7】 【Transformation 6】 teeth, 【Chemistry 7-1】 【Chemistry 7-2】 That is, 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

8. L is a bond, O, C(O), or N(R d ) and R d is H or C 1 -C 3 is alkyl, 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

9. X is CR 3a R 3b , N.R. 3a or O; R 3a and R 3b are independently H or C 1 -C 3 is alkyl, 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

10. X is CH 2 , N(H), N(CH 3 ), or O; 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof.

11. R 4 is H, C 1 -C 3 Alkyl, C 1 -C 3 Alkyl-OH, C 1 -C 3 Haloalkyl, or —NH 2 That is, 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

12. R 4 is H, CH 3 , -CH 2 OH, -CH 2 F, or -CHF 2 That is, 12. The compound of claim 11 or a pharmaceutically acceptable salt thereof.

13. y is 0 or 1; Each R 5 is, if present, independently selected from halo, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, -(C 1 -C 3 alkylene) (C 1 -C 3 alkoxy), or C 1 -C 3 alkyl-OH; 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

14. Each R 5 is, if present, independently Cl, F, —CH 2 F, -CHF 2 , -CH 2 OCH 3 , or -CH 2 OH, 14. The compound of claim 13 or a pharmaceutically acceptable salt thereof.

15. Ring B is a fused phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O, and S; 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

16. Ring B is a fused phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, or oxazolyl; 16. The compound of claim 15 or a pharmaceutically acceptable salt thereof.

17. z is 0, 1, or 2; Each R 7 is, if present, independently 1 -C 3 Alkyl, halo, C 1 -C 3 Alkoxy, C 1 -C 3 Alkyl-OH, hydroxy, cyano, -Si(R a ) (R b ) (R c ), -P(O)(R a ) (R b ), -OP(O)(R a ) (R b ), -NR 2a R 2b , or C 1 -C 3 haloalkyl; Each R a , R b , and R c are independently hydroxy, C 1 -C 3 Alkyl, or C 1 -C 3 is alkoxy; Each R 2a and R 2b are independently H, C 1 -C 3 Alkyl, or C 3 -C 5 is cycloalkyl, 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

18. Each R 7 is, if present, independently CH 3 , F, -OCH 3 , -CH 2 OH, hydroxy, -CN, -N(CH 3 ) 2 , or -CHF 2 That is, 18. The compound of claim 17 or a pharmaceutically acceptable salt thereof. 【Request Item 19】 【Chemistry 8】 teeth, 【Chemistry 9】 That is, 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

20. The compound has the formula (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIf): 【Chemistry 10-1】 【Chemistry 10-2】 It is of 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

21. The compound has the formula (IIa-1): 【Chemistry 11】 It is of 21. The compound of claim 20 or a pharmaceutically acceptable salt thereof.

22. x is 0, 1, or 2; Each R 1 is, if present, independently halo; R 4 is C 1 -C 6 22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein:

23. x is 0 or 1; R 1 is F, if present; R 4 is -CH 3 That is, 23. The compound of claim 22 or a pharmaceutically acceptable salt thereof.

24. The compound has the formula (IVa), (IVb), (IVc), (IVd), or (IVe): 【Chemistry 12】 2. The compound of claim 1, wherein:

25. A compound selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

27. 26. A method of inhibiting SHP2, comprising contacting SHP2 with an effective amount of a compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof.

28. 26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for use in a method for treating a disease associated with SHP2 modulation in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions.

29. 29. The pharmaceutical composition of claim 28, wherein the disease is Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, lung cancer, colon cancer, or brain cancer, optionally wherein the brain cancer is glioblastoma.

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