Dihydropyrrolopyrimidinone compounds as TREM2 modulators

Abstract

The present invention relates to compounds useful for modulating Triggering Receptor Expressed on Myeloid Cells-2 ("TREM2"). The invention also relates to the compounds for use in treatment of conditions related to loss of function of TREM2, such as neurodegenerative diseases, and to pharmaceutical compositions comprising the compounds.

Description

[0001] DIHYDROPYRROLOPYRIMIDINONE COMPOUNDS AS TREM2 MODULATORS

[0002] Technical field

[0003] The present invention relates to compounds useful for modulating Triggering Receptor Expressed on Myeloid Cells-2 (“TREM2”). The invention also relates to the compounds for use in treatment of conditions related to loss of function of TREM2, such as neurodegenerative diseases, and to pharmaceutical compositions comprising the compounds.

[0004] Background

[0005] Triggering receptor expressed on myeloid cells-2 (TREM2) is a transmembrane receptor belonging to the immunoglobulin superfamily and is encoded by the TREM2 gene, which maps to human chromosome 6p21. TREM2 consists of an extracellular part that includes a single immunoglobulin domain and a short ectodomain, a single transmembrane helix and a short cytosolic tail (Colonna, M. et al. (2016))).

[0006] Insight to the role of TREM2 is provided by its restricted expression pattern. It is expressed exclusively on myeloid lineage cells, such as macrophages, microglia, dendritic cells and osteoclasts. It plays a role in tissue maintenance, as a sensor of pathology and inducer of innate immune signalling in specific tissues. In the brain TREM2 is exclusively expressed in microglia and is functionally required e.g. in phagocytosis of cellular debris, but has also been assigned roles in restricting inflammation as well as promoting cell survival (Deczkowska, A. et al. (2020)).

[0007] TREM2 has a wide range of ligands such as bacterial anionic molecules / endotoxins, phospholipids incl. phosphatidylserine, lipoproteins and apolipoproteins incl ApoE, as well as oligomeric Aβ (Hammond, T. R. (2019)).

[0008] Signalling via TREM2 is well described through co-receptor DAP12. The adaptor molecule DAP 12 is expressed as a homodimer at the surface of a variety of cells participating in the innate immune response, including microglia, macrophages, granulocytes, NK cells, and dendritic cells. After ligation of TREM2, ITAM (immunoreceptor tyrosine-based activation motif) tyrosine phosphorylation of DAP12 by SRC-family kinases drive the recruitment and activation of the Syk kinase and / or ZAP70 kinase. Downstream of TREM2 / DAP12 / Syk several signalling pathways have been described involved in cell survival, cell activation and differentiation, and in the control of the actin cytoskeleton.

[0009] Proteolytic cleavage of the ectodomain of TREM2 by metalloproteinases, including ADAM 10 and ADAM 17 and possibly matrix metalloproteinases, leads to the shedding of soluble TREM2 (sTREM2), which can be detected in human cerebrospinal fluid (CSF). sTREM2 has been suggested as a potential biomarker for microglia activity in early-stage Alzheimer’s disease (Suárez-Calvet, M. et al. (2016)).

[0010] Deficiency of either TREM2 or DAP12 leads to a blunted microglial response to pathological agents. The impact of TREM2-deficiency in vitro has been shown in the context of stimulation with typical TLR ligands, such as LPS. Loss-of-function genetic variants of TREM2 are associated with neurodegenerative diseases and supports a central role of microglial function in disease pathogenesis. Homozygous loss-of-function TREM2 variants cause Nasu-Hakola disease (Yamazaki, K. et al. (2015); Paloneva BM, J. et al. (2001); Ulrich J. D. et al. (2017)), whereas heterozygous loss-of-function TREM2 variants are associated with an increased risk for several neurological and neurodegenerative disorders such as Alzheimer's disease (AD), Frontotemporal lobar degeneration (FTLD), Parkinson's disease, FTLD-like syndrome, and Amyotrophic lateral sclerosis (ALS). The most prevalent mutation associated with AD is the loss-of-function mutation R47H, which has been shown to abrogate ligand binding and phagocytosis (Atagi, Y. et al. (2015); Kleinberger, G. et al (2014)).

[0011] Neurodegenerative disorders that may be treated by modulation of TREM2 activity and / or signaling include, but is not limited to, Alzheimer's disease (AD), Frontotemporal lobar degeneration (FTLD), FTLD-like syndrome, Parkinson's disease, Huntington disease, Nasu-Hakola disease (also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), Multiple sclerosis (MS), Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease andAmyotrophic lateral sclerosis (ALS). Thus, there is a high and unmet medical need for TREM2 modulators to address these indications.

[0012] Summary

[0013] The present invention relates to compounds that modulates TREM2. In one aspect, the present invention relates to a compound of Formula (I):

[0014]

[0015] wherein:

[0016] - X1is N or C(H);

[0017] - X2is N or C(H);

[0018] - R1is 5- to 6-membered heteroaryl optionally substituted with one or more, identical or different, R16; phenyl optionally substituted with one or more, identical or different, R16; or of Formula (III):

[0019]

[0020] Formula (III)

[0021] wherein

[0022] X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[0023] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[0024] X7is O, C(R9)(R10), or N(R11);

[0025] R9is F or H;

[0026] R10is F or H;

[0027] R11is C1-3 alkyl optionally substituted with one or more F;

[0028] R8is individually H, F or CH3, and m is 0, 1 or 2;

[0029] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2;

[0030] - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[0031]

[0032]

[0033] Formula (II)

[0034] wherein

[0035] - X3is N or C(H);

[0036] - X4is O or N(R22);

[0037] or X3is N and X4is C(F)2;

[0038] - R22is H or C1-3 alkyl;

[0039] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[0040] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0041] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0042] - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0043] with the proviso that the compound is not 6-((2S,6R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6-methylmorpholino)-4-(2-fluoro-4-(trifluoromethyl)phenyl)-2-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one,

[0044] or a pharmaceutically acceptable salt thereof.

[0045] In one aspect, the present invention relates a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with loss-of-function of TREM2, such as a neurodegenerative disease.

[0046] Definitions

[0047] As used herein, the singular forms “a,” “an” and “the” include plural referents unless the content clearly dictates otherwise. The terms “approximately” and “about” as referred herein are synonymous. In some embodiments, “about” refer to the recited amount, value, or duration ±20%, ±10%, ± 5%, ± 4%, ±3%, ±2%, ±1%, or ± 0.5%.

[0048] The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified.

[0049] The terms “C1-3 alkyl”, “C1-5 alkyl” and “C1-6 alkyl” as used herein refer to a straight or branched hydrocarbon chains containing from 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively. Representative examples of C1-3 alkyl, C1-5 alkyl and C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tertbutyl, pentyl and hexyl.

[0050] The term “C1-3 alkoxy” and “C1-6 alkoxy” as used herein refer to -OR#, wherein R#represents a C1-3 alkyl and C1-6 alkyl group, respectively, as defined herein.

[0051] Representative examples of C1-3 alkoxy and C1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy.

[0052] The term “C3-6 cycloalkyl” as used herein refers to a saturated carbocyclic moiety wherein the cyclic framework has 3 to 6 carbon atoms. Representative examples of C3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0053] The term “halogen” as used herein refers to -F, -Cl, -Br, or -I. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl.

[0054] The term “halo” as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with a halogen as defined herein. The halogen is independently selected at each occurrence. For example, the term “C1-6 haloalkyl” refers to a C1-6 alkyl as defined herein, wherein one or more hydrogen atoms are substituted with a halogen.

[0055] Representative examples of C1-6 haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCl, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3). The term “CN” is used herein to indicate a cyano group ( (-C≡N )

[0056] The term “C5-8 bicycloalkyl” as used herein refers a bicyclic ring system, wherein both cycloalkyl rings share the same two ring atoms. The term “C5-8 bicycloalkyl” includes bridged bicyclic compounds, i.e. wherein the two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom. For example, the term “C5-8 bicycloalkyl” includes bicyclo[1.1.1]pentyl. For example, the

[0057] term “C5-8 bicycloalkyl” includes

[0058]

[0059] The term "heteroaryl" refers to a mono- or multivalent, monocyclic or bicyclic ring system having a total of 5 to 10 ring members, preferably 5 to 8 ring members, more preferably 5 to 6 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms selected from N, S, and O. Preferably, the system contains one heteroatom selected from N, S, and O and optionally one or two further ring N atoms. Representative examples of a 5-membered heteroaryl include, but are not limited to, furyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and oxazolyl. Representative examples of a 6-membered heteroaryl include, but are not limited to, pyridyl, pyrimidyl, pyrazyl, and pyridazyl.

[0060] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of 4 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0061] As described herein, compounds of the present invention may contain “substituted” moieties. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at one or more substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position, i.e. the substituent may be individually / independently selected from a group of substituents. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds.

[0062] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0063] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio.

[0064] Pharmaceutically acceptable salts are well known in the art.

[0065] Detailed description

[0066] In one aspect, the present invention relates to a compound of Formula (I):

[0067]

[0068] Formula (I)

[0069] wherein:

[0070] - X1is N or C(H);

[0071] - X2is N or C(H);

[0072] - R1is 5- to 6-membered heteroaryl optionally substituted with one or more, identical or different, R16; phenyl optionally substituted with one or more, identical or different, R16; or of Formula (III):

[0073]

[0074] Formula (III)

[0075] wherein

[0076] X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[0077] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[0078] X7is O, C(R9)(R10), or N(R11);

[0079] R9is F or H;

[0080] R10is F or H;

[0081] R11is C1-3 alkyl optionally substituted with one or more F;

[0082] R8is individually H, F or CH3, and m is 0, 1 or 2;

[0083] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2;

[0084] - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[0085] - R2is of Formula (II):

[0086]

[0087] Formula (II)

[0088] wherein

[0089] - X3is N or C(H);

[0090] - X4is O or N(R22);

[0091] or X3is N and X4is C(F)2;

[0092] - R22is H or C1-3 alkyl;

[0093] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0094] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0095] - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0096] or a pharmaceutically acceptable salt thereof.

[0097] In one aspect, the present invention relates to a compound of Formula (I):

[0098]

[0099] Formula (I)

[0100] wherein:

[0101] - X1is N or C(H);

[0102] - X2is N or C(H);

[0103] - R1is 5- to 6-membered heteroaryl optionally substituted with one or more, identical or different, R16; phenyl optionally substituted with one or more, identical or different, R16; or of Formula (III):

[0104]

[0105] Formula (III)

[0106] wherein

[0107] X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[0108] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[0109] X7is O, C(R9)(R10), or N(R11);

[0110] R9is F or H;

[0111] R10is F or H;

[0112] R11is C1-3 alkyl optionally substituted with one or more F;

[0113] R8is individually H, F or CH3, and m is 0, 1 or 2; or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2;

[0114] - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[0115] - R2is of Formula (II):

[0116]

[0117] Formula (II)

[0118] wherein

[0119] - X3is N or C(H);

[0120] - X4is O or N(R22);

[0121] - R22is H or C1-3 alkyl;

[0122] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[0123] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0124] or n is 2 and the two R6are each -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0125] - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0126] or a pharmaceutically acceptable salt thereof.

[0127] In one aspect, the present invention relates to a compound of Formula (I):

[0128]

[0129] wherein: - X1is N or C(H);

[0130] - X2is N or C(H);

[0131] - R1is of Formula (III):

[0132]

[0133] Formula (III)

[0134] wherein

[0135] • X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[0136] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[0137] • X7is O, C(R9)(R10), or N(R11);

[0138] • R9is F or H;

[0139] • R10is F or H;

[0140] • R11is C1-3 alkyl optionally substituted with one or more F;

[0141] • R8is individually H, F or CH3, and m is 0, 1 or 2;

[0142] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2; - R2is of Formula (II):

[0143]

[0144] Formula (II)

[0145] wherein

[0146] - X3is N or C(H);

[0147] - X4is O or N(R22);

[0148] or X3is N and X4is C(F)2;

[0149] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[0150] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0151] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0152] - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0153] or a pharmaceutically acceptable salt thereof.

[0154] In one aspect, the present invention relates to a compound of Formula (I):

[0155]

[0156] Formula (I)

[0157] wherein:

[0158] - X1is N or C(H);

[0159] - X2is N or C(H);

[0160] - R1is of Formula (XI):

[0161]

[0162] Formula (XI)

[0163] wherein

[0164] - R12is H or F;

[0165] - R14is H or F;

[0166] - X7is O, C(R9)(R10), or N(R11);

[0167] - R9is F or H;

[0168] - R10is F or H;

[0169] R11is C1-3 alkyl optionally substituted with one or more F; and

[0170] R8is individually H, F or CH3, and m is 0, 1 or 2;

[0171] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2; - R2is of Formula (II):

[0172]

[0173] Formula (II)

[0174] wherein

[0175] - X3is N or C(H);

[0176] - X4is O or N(R22);

[0177] or X3is N and X4is C(F)2;

[0178] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[0179] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[0180] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0181] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0182] - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0183] or a pharmaceutically acceptable salt thereof.

[0184] In one aspect, the present invention relates to a compound of Formula (la):

[0185]

[0186] Formula (la)

[0187] wherein:

[0188] - R1is a 6-membered heteroaryl optionally substituted with one or more, identical or different, R16;

[0189] - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl; - R2is of Formula (II):

[0190]

[0191] Formula (II)

[0192] wherein

[0193] - X3is N or C(H);

[0194] - X4is O or N(R22);

[0195] or X3is N and X4is C(F)2;

[0196] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[0197] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[0198] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0199] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0200] - R3is phenyl optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0201] or a pharmaceutically acceptable salt thereof.

[0202] In one aspect, the present invention relates to a compound of Formula (XXI):

[0203]

[0204] Formula (XXI)

[0205] wherein:

[0206] - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[0207] - R2is of Formula (II):

[0208]

[0209] Formula (II)

[0210] wherein

[0211] - X3is N or C(H);

[0212] - X4is O or N(R22);

[0213] or X3is N and X4is C(F)2;

[0214] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[0215] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[0216] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0217] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0218] - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0219] or a pharmaceutically acceptable salt thereof.

[0220] In one aspect, the present invention relates to a compound of Formula (XXII):

[0221]

[0222] Formula (XXII)

[0223] wherein:

[0224] - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[0225] - R2is of Formula (II):

[0226]

[0227] Formula (II)

[0228] wherein

[0229] - X3is N or C(H);

[0230] - X4is O or N(R22);

[0231] or X3is N and X4is C(F)2;

[0232] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[0233] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[0234] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0235] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0236] - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0237] or a pharmaceutically acceptable salt thereof.

[0238] In one aspect, the present invention relates to a compound of Formula (la):

[0239]

[0240] Formula (la)

[0241] wherein:

[0242] - R1is phenyl optionally substituted with one or more, identical or different, R16;

[0243] - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[0244] - R2is of Formula (II):

[0245]

[0246] Formula (II)

[0247] wherein

[0248] - X3is N or C(H);

[0249] - X4is O or N(R22);

[0250] or X3is N and X4is C(F)2;

[0251] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[0252] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[0253] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0254] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0255] - R3is phenyl optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy; or a pharmaceutically acceptable salt thereof.

[0256] In one aspect, the present invention relates to a compound of Formula (la):

[0257]

[0258] Formula (la)

[0259] wherein:

[0260] - R1is of Formula (XI):

[0261]

[0262] Formula (XI)

[0263] wherein

[0264] • R12is H or F; • R14is H or F;

[0265] • X7is O, C(R9)(R10), or N(R11);

[0266] • R9is F or H;

[0267] • R10is F or H;

[0268] • R11is C1-3 alkyl optionally substituted with one or more F; and

[0269] • R8is individually H, F or CH3, and m is 0, 1 or 2;

[0270] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2;

[0271] - R2is of Formula (II):

[0272]

[0273] Formula (II)

[0274] wherein

[0275] - X3is N or C(H);

[0276] - X4is O or N(R22);

[0277] or X3is N and X4is C(F)2;

[0278] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[0279] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[0280] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0281] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0282] - R3is phenyl optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0283] or a pharmaceutically acceptable salt thereof.

[0284] In one aspect, the present invention relates to a compound of Formula (I):

[0285]

[0286] wherein:

[0287] - X1is N or C(H);

[0288] - X2is N or C(H);

[0289] - R1is a 6-membered heteroaryl optionally substituted with one or more, identical or different, R16; phenyl optionally substituted with one or more, identical or different, R16; or of Formula (III):

[0290]

[0291] Formula (III)

[0292] wherein

[0293] • X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[0294] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[0295] • X7is O, C(R9)(R10), or N(R11);

[0296] • R9is F or H;

[0297] • R10is F or H;

[0298] • R11is C1-3 alkyl optionally substituted with one or more F;

[0299] • R8is individually H, F or CH3, and m is 0, 1 or 2;

[0300] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2; - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[0301] - R2is of Formula (II):

[0302]

[0303] Formula (II)

[0304] wherein

[0305] - X3and X4are N, or X3is C(H) and X4is N;

[0306] - R5is pyrazolyl or pyridinyl, each of which is substituted with 1 to 3 substituents individually selected from C1-3 alkyl, C1-3 haloalkyl, cyclopropyl, and C1-3 alkoxy; and

[0307] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0308] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0309] - R3is phenyl substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0310] or a pharmaceutically acceptable salt thereof.

[0311] In one aspect, the present invention relates to a compound of Formula (I):

[0312]

[0313] Formula (I)

[0314] wherein:

[0315] - X1is N or C(H);

[0316] - X2is N or C(H);

[0317] - R1is

[0318]

[0319] 1

[0320]

[0321]

[0322]

[0323]

[0324]

[0325] In some embodiments, X3is N or C(H), and X4is O or N(R22). In some embodiments, X1is N. In some embodiments, X1is C(H). n some embodiments, X2is N. In some embodiments, X2is C(H). In some embodiments, X1is N and X2is C(H). In some embodiments, X1is N and X2is N.

[0326] Thus, in some embodiments, the compound is of Formula (la):

[0327]

[0328] Formula (la) In some embodiments, X1is N, X2is N, R1is pyridinyl substituted with R16, and R16is C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl. In some embodiments, the compound is of Formula (XXI):

[0329] In some embodiments, the comp

[0330]

[0331] ound is of Formula (XXI) and R3is

[0332]

[0333] In some embodiments, the compound is of Formula (XXIa). In some embodiments, the compound is of Formula (XXIb).

[0334]

[0335] Formula (XXIa) Formula (XXIb)

[0336]

[0337] embodiments, the compound is of Formula (XXIb) and R3is

[0338]

[0339]

[0340] In some embodiments, X1is N, X2is N, R1is pyrimidinyl substituted with R16, and R16is C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl. In some embodiments, the compound is of Formula (XXII). In some embodiments, the compound is of Formula (XXIIa).

[0341]

[0342] In some embodiments, the compound is of Formula (XXII) and R3is

[0343]

[0344] In some embodiments, X1is N, X2is N, R1is phenyl substituted with R16, and R16is C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl. In some embodiments, the compound is of Formula (XXIIIa). In some embodiments, the compound is of Formula (XXIIIb).

[0345]

[0346] In some embodiments, the compound is of Formula (XXIIIa) and R3is

[0347]

[0348] In some embodiments, the compound is of Formula (XXIV):

[0349] In some embodiments, the comp

[0350]

[0351] ound is of Formula (XXIV) and R3is

[0352]

[0353] In some embodiments, X1is C(H) and X2is N. Thus, in some embodiments, the compound is of Formula (lb):

[0354]

[0355] Formula (lb)

[0356] In some embodiments, R2is of Formula (Ila). In some embodiments, R2is of Formula (IIb).

[0357]

[0358] Formula (Ila) Formula (lib)

[0359] In some embodiments, R2is of Formula (IV):

[0360]

[0361] Formula (IV)

[0362] wherein

[0363] X3, X4, and R5are as defined in classes and subclasses herein, both singly and in combination;

[0364] R6ais H, F or CH3, and R6bis H, F or CH3;

[0365] or R6aand R6bare linked together to form a ring together with the intervening atom, and R6aand R6bare each individually –(CH2)2- or -CH2-.

[0366] In some embodiments, R2is of Formula (IVa):

[0367]

[0368] Formula (IVa)

[0369] In some embodiments, R2is of Formula (IVb):

[0370]

[0371] Formula (IVb)

[0372] wherein

[0373] X3, X4, and R5are as defined in classes and subclasses herein, both singly and in combination;

[0374] R6ais H, F or CH3, and R6bis H, F or CH3;

[0375] or R6aand R6bare linked together to form a ring together with the intervening atom, and R6aand R6bare each individually –(CH2)2- or -CH2-.

[0376] wherein

[0377] X3, X4, and R5are as defined in classes and subclasses herein, both singly and in combination;

[0378] R6ais H, F or CH3, and R6bis H, F or CH3;

[0379] or R6aand R6bare linked together to form a ring together with the intervening atom, and R6aand R6bare each individually –(CH2)2- or -CH2-.

[0380] In some embodiments, R2is of Formula (IVc):

[0381]

[0382] Formula (IVc)

[0383] wherein

[0384] R6ais H, F or CH3, and R6bis H, F or CH3;

[0385] or R6aand R6bare linked together to form a ring together with the intervening atom, and R6aand R6bare each individually –(CH2)2- or -CH2-.

[0386] In some embodiments, X3is N. In some embodiments, X4is O. In some embodiments, X3is N and X4is O. In some embodiments, R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, and X4is O. In some embodiments, R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais H, and R6bis H. In some embodiments, R2is of Formula (XIX):

[0387]

[0388] Formula (XIX)

[0389]

[0390] In some embodiments, R2of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais CH3, and R6bis H. In some embodiments, R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais H, and R6bis CH3. In some embodiments, R2is of Formula (XX):

[0391]

[0392] Formula (XX)

[0393] wherein R5is as defined herein. In some embodiments, R2is

[0394]

[0395]

[0396] In some embodiments, R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais CH3, and R6bis CH3. In some embodiments, R2is of Formula (XVI):

[0397]

[0398] Formula (XVI)

[0399] wherein R5is as defined herein. In some embodiments,

[0400]

[0401]

[0402] In some embodiments, R6ais F, and R6bis F. In some embodiments, R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais F, and R6bis F. In some embodiments, R2is of Formula (XV):

[0403]

[0404] Formula (XV) wherein R5is as defined herein. In some embodiments, R2is

[0405]

[0406]

[0407] In some embodiments, n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s). In some embodiments, R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais -CH2-, and R6bis -CH2- and R6aand R6bare linked together to form a ring. In some embodiments, R2is of Formula (XVII):

[0408]

[0409] In some embodiments, R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais –(CH2)2-, and R6bis -CH2- and R6aand R6bare linked together to form a ring. In some embodiments, R2is of Formula (XVIII):

[0410]

[0411] Formula (XVIII)

[0412] wherein R5is as defined herein. In some embodiments, R2is

[0413]

[0414]

[0415] In some embodiments, R2is of Formula (V):

[0416]

[0417] Formula (V)

[0418] wherein R6is as defined herein. In some embodiments, R2is of Formula (Va), wherein R5is as defined herein. In some embodiments, R2is of Formula (Vb), wherein R5is as defined herein. In some embodiments, R2is of Formula (Vc), wherein R5is as defined herein. In some embodiments, R2is of Formula (Vd), wherein R5is as defined herein.

[0419]

[0420] Formula (Va) Formula (Vb) Formula (Vc) Formula (Vd) In some embodiments, R2is of Formula (Va), (Vb), (Vc), or (Vd), R6is CH3 or H, and R5is as defined herein. In some embodiments, R2is of Formula (V), Formula (Va), Formula (Vb), Formula (Vc), or Formula (Vd), and R6is H. In some embodiments, R2is of Formula (V), Formula (Va), Formula (Vb), Formula (Vc), or Formula (Vd), and R6is CH3.

[0421] In some embodiments, X3is C(H). In some embodiments, X3is C(H) and X4is O. In some embodiments, R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is C(H), and X4is O. In some embodiments, R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is C(H), X4is O, R6ais H, and R6bis H. In some embodiments, R2is of Formula (VI):

[0422]

[0423] Formula (VI)

[0424] wherein R5is as defined herein. In some embodiments, R2is of Formula (VIa), wherein R5is as defined herein. In some embodiments, R2is of Formula (VIb), wherein R5is as defined herein. In some embodiments, R2is of Formula (VIc), wherein R5is as defined herein. In some embodiments, R2is of Formula (VId), wherein R5is as defined herein.

[0425]

[0426] Formula (VIa) Formula (VIb) Formula (VIc) Formula (VId)

[0427]

[0428] , or

[0429] In some embodiments, R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is C(H), X4is O, R6ais H, and R6bis CH3. In some embodiments, R2is of Formula (XIV):

[0430]

[0431] Formula (XIV)

[0432] wherein R5is as defined herein. In some embodiments, R2is of Formula (XIVa):

[0433]

[0434] Formula (XIVa)

[0435]

[0436] In some embodiments, X4is N(R22). In some embodiments, X3is N and X4is N(R22). In some embodiments, R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, and X4is N(R22). In some embodiments, R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is N(R22), R6ais H, and R6bis H. In some embodiments, R2is of Formula (XII), wherein R5and R22are as defined herein. In some embodiments, R2is of Formula (XIIa), wherein R5and R22are as defined herein. In some embodiments, R2is of Formula (XIIb), wherein R5and R22are as defined herein.

[0437]

[0438] Formula (XII) Formula (XIIa)

[0439] Formula (XIIb)

[0440] In some embodiments, R22is H. In some embodiments, R22is C1-3 alkyl substituted with one or more F. In some embodiments, R22is C1-3 alkyl. In some embodiments, R22is

[0441]

[0442] CH3. In some embodiments, R2is

[0443]

[0444] In some embodiments, X3is N and X4is C(F)2. In some embodiments, R2is of Formula (XIII):

[0445]

[0446] Formula (XIII)

[0447]

[0448] wherein R5is as defined herein. In some embodiments, R2is

[0449]

[0450] In some embodiments, R5is pyrazolyl or pyridinyl, each of which is substituted with 1 to 3 substituents individually selected from C1-3 alkyl, C1-3 haloalkyl, cyclopropyl, and C1-3 alkoxy.

[0451] In some embodiments, R5is a 5-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-3 alkyl, C1-3 haloalkyl, cyclopropyl, and C1-3 alkoxy. In some embodiments, R5is pyrazolyl optionally substituted with 1 to 3 individually selected substituents R7, wherein R7is individually selected from C1-3 alkyl, C1-3 haloalkyl, and cyclopropyl.

[0452] In some embodiments, R5is of Formula (VII):

[0453]

[0454] Formula (VII)

[0455] wherein R7is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl or H.

[0456] In some embodiments, R5is of Formula (VIII):

[0457]

[0458] Formula (VIII)

[0459] wherein R7is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl or H.

[0460] In some embodiments, R5is

[0461]

[0462] In some embodiments, R5is

[0463]

[0464] ,

[0465] In some embodiments, R2is of Formula (IX):

[0466]

[0467] Formula (IX)

[0468] wherein

[0469] X3is N or C(H);

[0470] R6ais H, F, or C1-3 alkyl; R6bis H, F, or C1-3 alkyl; and

[0471] R7is C1-3 alkyl or cyclopropyl.

[0472] In some embodiments, R5is triazolyl substituted with C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy or C1-6 haloalkoxy. In some embodiments, R5is triazolyl substituted with C1-3 alkyl. In some embodiments, R5is triazolyl substituted with CH3. In

[0473] some embodiments, R5is

[0474]

[0475] . In some embodiments, R5is triazolyl substituted with C3-6 cycloalkyl. In some embodiments, R5is triazolyl substituted with

[0476] cyclopropyl. In some embodiments, R5is

[0477]

[0478] In some embodiments, R5is a 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy. In some embodiments, R5is a 6-membered heteroaryl substituted with 1 to 3 substituents individually selected from C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, C1-3 alkoxy and C1-3 haloalkoxy. In some embodiments, R5is a 6-membered heteroaryl substituted with 1 to 3 substituents individually selected from C1-3 alkyl and C1-3 alkoxy. In some embodiments, R5is a 6-membered heteroaryl substituted with C1-3 alkyl or C1-3 alkoxy. In some embodiments, R5is a 6-membered heteroaryl substituted with -CH3 or -OCH3. In some embodiments, R5is a 6-membered heteroaryl substituted with C1-6 alkoxy. In some embodiments, R5is a 6-membered heteroaryl substituted with C1-3 alkoxy. In some embodiments, R5is a 6-membered heteroaryl substituted with methoxy.

[0479] In some embodiments, R5is a 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-3 alkyl, C1-3 haloalkyl, cyclopropyl, and C1-3 alkoxy. In some embodiments, R5is pyridinyl optionally substituted with 1 to 3 individually selected substituents R7, wherein R7is individually selected from C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy. In some embodiments, R5is pyridinyl optionally substituted with -CH3 or -OCH3.

[0480] In some embodiments, R5is pyridinyl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy. In some embodiments, R5is a pyridinyl substituted with C1-3 alkyl or C1-3 alkoxy. In some embodiments, R5is pyridinyl substituted with -CH3 or-OCH3. In some embodiments, R5is pyridinyl substituted with C1-6 alkoxy. In some embodiments, R5is pyridinyl substituted with C1-3 alkoxy. In some embodiments, R5is pyridinyl substituted

[0481] with methoxy. In some embodiments, R5is

[0482]

[0483] . In some embodiments, R5is pyridinyl substituted with C1-6 alkyl. In some embodiments, R5is pyridinyl substituted with C1-3 alkyl. In some embodiments, R5is pyridinyl substituted with -CH3. In some

[0484] embodiments,

[0485]

[0486] In some embodiments, R6is individually H, F or CH3, and n is 0, 1 or 2. In some embodiments, R6is individually F or CH3, and n is 0, 1 or 2. In some embodiments, R6is individually H. In some embodiments, R6is individually F. In some embodiments, R6is individually CH3. In some embodiments, R6is individually F or CH3. In some embodiments, R6ais R6. In some embodiments, R6ais H. In some embodiments, R6ais F. In some embodiments, R6ais CH3. In some embodiments, R6bis R6. In some embodiments, R6bis H. In some embodiments, R6bis F. In some embodiments, R6bis CH3. In some embodiments, R6ais H, and R6bis H. In some embodiments, R6ais H, and R6bis CH3. In some embodiments, R6ais CH3, and R6bis H. In some embodiments, R6ais CH3, and R6bis CH3.

[0487] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0488] In some embodiments, n is 2 and the two R6are attached to the same carbon atom in the ring. In some embodiments, n is 2 and the two R6are attached to different carbon atoms in the ring. In some embodiments, n is 2 and the two R6are -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s).

[0489] In some embodiments, R7is C3-6 cycloalkyl. In some embodiments, R7is C1-6 alkyl. In some embodiments, R7is C1-3 alkyl. In some embodiments, R7is -CH3. In some embodiments, R7is cyclopropyl.

[0490] In some embodiments, R2is

[0491]

[0492] embodiments,

[0493]

[0494] some embodiments, R2is

[0495]

[0496] some embodiments,

[0497]

[0498] some embodiments, R2is

[0499]

[0500] embodiments,

[0501]

[0502] In some embodiments, R2is

[0503]

[0504]

[0505] embodiments, R2is

[0506] In some embodiments, R2is

[0507]

[0508] . In some embodiments, R2is

[0509]

[0510] F F. In some embodiments, R2is F F. In some

[0511]

[0512]

[0513] ,

[0514] embodiments,

[0515]

[0516] some embodiments, R2is

[0517]

[0518] In some embodiments, R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy.

[0519] In some embodiments, R3is of Formula (X):

[0520]

[0521] Formula (X) wherein

[0522] R17is H, halogen, C1-3 alkyl, C1-3 haloalkyl, or C1-3 alkoxy;

[0523] R18is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN;

[0524] R19is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN;

[0525] R20is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN, and

[0526] R21is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN.

[0527] In some embodiments, R3is of Formula (X):

[0528]

[0529] Formula (X)

[0530] wherein R17is H or halogen; R18is H or halogen; R19is halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN; R20is H or halogen; and R21is H or halogen.

[0531] In some embodiments, R3is of Formula (X):

[0532]

[0533] Formula (X)

[0534] wherein R17is H or halogen; R18is H; R19is halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN; R20is H; and R21is H or halogen.

[0535] In some embodiments, R17is halogen; R18is H; R19is halogen; R20is H; and R21is H. In some embodiments, R17is H. In some embodiments, R17is halogen. In some embodiments, R17is C1-3 alkyl. In some embodiments, R17is -CH3.

[0536] In some embodiments, R18is H. In some embodiments, R18is halogen. In some embodiments, R18is F. In some embodiments, R19is halogen. In some embodiments, R19is F or Cl. In some embodiments, R19is C1-3 alkyl. In some embodiments, R19is -CH3. In some embodiments, R19is C1-3 haloalkyl, such as –CF3or –CHF2. In some embodiments, R19is CN. In some embodiments, R19is C1-3 alkoxy. In some embodiments, R19is -OCH3.

[0537] In some embodiments, R20is H. In some embodiments, R20is halogen. In some embodiments, R20is F.

[0538] In some embodiments, R21is H. In some embodiments, R21is halogen. In some embodiments, R21is F.

[0539] In some embodiments, R18is H and R20is H. In some embodiments, R18, R20, and R21are H.

[0540] In some embodiments, R3is phenyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN. In some embodiments, R3is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN.

[0541] In some embodiments, R3is selected from the group consisting of:

[0542]

[0543] e

[0544]

[0545] embodiments, R3is

[0546]

[0547] embodiments,

[0548]

[0549] embodiments,

[0550]

[0551] some embodiments,

[0552]

[0553] embodiments,

[0554]

[0555] . In some embodiments,

[0556]

[0557] someCl

[0558] embodiments,

[0559]

[0560] some embodiments, R3is

[0561]

[0562] . In some

[0563] embodiments, R3is

[0564]

[0565] . In some embodiments,

[0566]

[0567] some

[0568] embodiments,

[0569]

[0570] In some embodiments, R3is C5-8 bicycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl and C1-3 haloalkyl.

[0571] In some embodiments, R3is bicyclo[1.1.1]pentyl optionally substituted with CF3 or CH3.

[0572] In some embodiments,

[0573]

[0574] In some embodiments, R1is a 5- to 6-membered heteroaryl optionally substituted with one or more, identical or different, R16.

[0575] In some embodiments, R1is a 6-membered heteroaryl optionally substituted with one or more, identical or different, R16. In some embodiments, the 6-membered heteroaryl is pyridinyl. In some embodiments, the 6-membered heteroaryl is pyridin-4-yl. In some embodiments, the 6-membered heteroaryl is pyridin-3-yl. In some embodiments, the 6-membered heteroaryl is pyrimidinyl. In some embodiments, the 6-membered heteroaryl is pyrazinyl. In some embodiments, the 6-membered heteroaryl is 2-pyridone.

[0576] In some embodiments, R1is phenyl optionally substituted with one or more, identical or different, R16. In some embodiments, R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl. In some embodiments, R16is individually C1-3 alkoxy, C1-3 alkyl optionally substituted with C1-3 alkoxy, or-CN. In some embodiments, R16is C1-6 alkoxy. In some embodiments, R16is C1-3 alkoxy. In some embodiments, R16is -OCH3. In some embodiments, R16is C1-6 alkyl substituted with C1-3 alkoxy. In some embodiments, R16is -CH2CH2OCH3. In some embodiments, R16is C1-6 alkyl. In some embodiments, R16is C1-3 alkyl. In some embodiments, R16is -CH3. In some embodiments, R16is halogen. In some embodiments, R16is C1-6 haloalkoxy. In some embodiments, R16is -CN. In some embodiments, R16is C3-6 cycloalkyl. In some embodiments, R16is azetidinyl optionally substituted with C1-3 alkyl. In some embodiments, R16is -O-azetidinyl optionally

[0577] substituted with C1-3 alkyl. In some embodiments,

[0578]

[0579]

[0580]

[0581] In some embodiments, R1is

[0582]

[0583] . In some embodiments, R1is

[0584]

[0585] In some embodiments, R1is. In some embodiments, R1is

[0586]

[0587] In some embodiments,

[0588]

[0589] some embodiments, R1is

[0590]

[0591]

[0592] In some embodiments,

[0593]

[0594] some embodiments, R1is —O

[0595]

[0596] In some embodiments, R1is of Formula (III):

[0597]

[0598] Formula (III)

[0599] wherein

[0600] X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[0601] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[0602] X7is O, C(R9)(R10), or N(R11);

[0603] R9is F or H;

[0604] R10is F or H;

[0605] R11is C1-3 alkyl optionally substituted with one or more F; and

[0606] R8is individually H, F or CH3, and m is 0, 1 or 2;

[0607] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2.

[0608] In some embodiments, X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F. In some embodiments, X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together. In some embodiments, R1is of Formula (XI):

[0609]

[0610] Formula (XI)

[0611] wherein

[0612] R12is H or F;

[0613] R14is H or F;

[0614] X7is O, C(R9)(R10), or N(R11);

[0615] R9is F or H;

[0616] R10is F or H;

[0617] R11is C1-3 alkyl optionally substituted with one or more F; and

[0618] R8is individually H, F or CH3, and m is 0, 1 or 2;

[0619] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2.

[0620]

[0621] In some embodiments, the moiety of Formula (XI) is, such as preferably

[0622]

[0623] In some embodiments, R8is individually H, F or CH3, and m is 0, 1 or 2. In some embodiments, m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2.

[0624] In some embodiments, R8is H. In some embodiments, R8is F. In some embodiments, m is 0. In some embodiments, R12is H. In some embodiments, R13is H. In some embodiments, X5is CH2. In some embodiments, R14is H. In some embodiments, R15is H. In some embodiments, R15is C1-3 alkyl. In some embodiments, R15is CH3. In some embodiments, X6is CH2. In some embodiments, R12and R14are H. In some embodiments, X7is O. In some embodiments, X7is C(R9)(R10). In some embodiments, R9is H. In some embodiments, R10is H. In some embodiments, X7is CH2. In some embodiments, R9is F. In some embodiments, R10is F. In some embodiments, X7is CF2. In some embodiments, X7is N(R11). In some embodiments, R11is CH3.

[0625] In some embodiments,

[0626]

[0627] . In some embodiments, R1is

[0628]

[0629] some embodiments,

[0630]

[0631] some embodiments, R1is

[0632]

[0633] In some embodiments,

[0634]

[0635] some embodiments, R1is

[0636]

[0637] In one aspect, the present invention relates to a compound selected from Group A, wherein Group A consists of:

[0638]

[0639] 5

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646] or a pharmaceutically acceptable salt thereof.

[0647] In some embodiments, the compound is selected from Group A.

[0648] In some embodiments, when R1is a 5-membered heteroaryl, then X1is N. In some embodiments, the compound is not 6-(-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2-fluoro-4-(trifluoromethyl)phenyl)-2-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one. In some embodiments, the compound is not 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2-fluoro-4-(trifluoromethyl)phenyl)-2-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one.

[0649] In one aspect, the present invention relates to a compound selected from the list consisting of:

[0650] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0651] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methylpyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;

[0652] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(3-methoxyphenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-methylpyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(4-methoxyphenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-(3-oxabicyclo[3.1.0]hexan-6-yl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(4-fluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0653] 4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0654] 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0655] (S)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0656] (R)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0657] 4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0658] (S)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0659] (R)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0660] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,5-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0661] 4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0662] (S)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0663] (R)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,5-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0664] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,6-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0665] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0666] 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,6-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0667] 2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methylpiperazin-1-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0668] (S)-2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methylpiperazin-1-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0669] (R)-2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methylpiperazin-1-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0670] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0671] 4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0672] (S)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0673] (R)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0674] 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0675] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 3-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;

[0676] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(5-methylpyrazin-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 5-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)picolinonitrile;

[0677] 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)picolinonitrile;

[0678] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0679] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-methylpyrimidin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methylpyrimidin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(4-chloro-2-fluorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0680] 4-(4-chloro-2-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile;

[0681] 3-fluoro-4-(2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)benzonitrile; 4-(4-chlorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0682] 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)benzonitrile; 4-(4-chlorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)- 6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0683] 4-(4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-7-oxo-5, 7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile; (S)-4-(4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)- 7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;

[0684] (R)-4-(4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)- 7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;

[0685] 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-7-oxo-4-(2,4,6-trifluorophenyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;

[0686] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(4-fluorophenyl)-6- (2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0687] 4-(2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-7-oxo-4-(2,4,6-trifluorophenyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;

[0688] 4-(2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin- 5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)benzonitrile;

[0689] 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-2-(2-methylpyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-2-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 4-(4-fluorophenyl)-6-(6-methoxypyridin-3-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0690] 4-(4-fluorophenyl)-6-(2-methoxypyridin-4-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0691] 4-(2,4-difluorophenyl)-6-(2-methoxypyridin-4-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0692] 4-(2,4-difluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6- (2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0693] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(4-fluorophenyl)-6- (2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0694] 4-(4-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0695] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methoxy-3-methylpyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0696] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2,4-dimethylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0697] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-(methoxymethyl)pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0698] 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2-(2-methylpyrimidin-5-yl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

[0699] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0700] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(4,4-difluorocyclohexyl)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(4-chloro-2-fluorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin- 7-one;

[0701] 4-(4-chloro-2-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0702] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-((1-methylazetidin-3-yl)oxy)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0703] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(2,4-difluorophenyl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0704] 4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0705] 4-(2,4-difluorophenyl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0706] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((S)-2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((R)-2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin- 7-one;

[0707] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0708] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((R)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0709] (S)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0710] (R)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0711] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0712] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((R)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[0713] (S)-4-(4-chloro-2-fluorophenyl)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; and

[0714] (R)-4-(4-chloro-2-fluorophenyl)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one,

[0715] or a pharmaceutically acceptable salt thereof.

[0716] In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methylpyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin- 6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(3-methoxyphenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-methylpyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(4-methoxyphenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-(3-oxabicyclo[3.1.0]hexan-6-yl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(4-fluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(6- methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)- 4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin- 5-yl)-4-(2,4,5-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)- 4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,5-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin- 5-yl)-4-(2,4,6-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,6-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methylpiperazin-1-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methylpiperazin-1-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methylpiperazin-1-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0717] (S)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6- methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin- 6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(5-methylpyrazin-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 5-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)picolinonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)- 7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)picolinonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)- 6-(6-methylpyrimidin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methylpyrimidin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(4-chloro-2-fluorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(4-chloro-2-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1 H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-((2S,6R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(4-chlorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(4-chlorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-4-(4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-4-(4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-7-oxo-5, 7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-7-oxo-4-(2,4,6-trifluorophenyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(4-fluorophenyl)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-7-oxo-4-(2,4,6-trifluorophenyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile, ora pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-2-(2-methylpyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-2-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4- (4-fluorophenyl)-6-(6-methoxypyridin-3-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(4-fluorophenyl)-6-(2-methoxypyridin-4-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2,4-difluorophenyl)-6-(2-methoxypyridin-4-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2,4-difluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(4-fluorophenyl)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(4-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methoxy-3-methylpyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2,4-dimethylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin- 3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-(methoxymethyl)pyridin- 4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2-(2-methylpyrimidin-5-yl)-4-(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(4,4-difluorocyclohexyl)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(4-chloro-2-fluorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(4-chloro-2-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1 H-pyrazol-4-yl)morpholino)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-((2S,6R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-((1-methylazetidin-3-yl)oxy)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(2,4-difluorophenyl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2,4-difluorophenyl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.

[0718] In some embodiments, the compound is 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((S)-2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((R)-2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((R)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4- d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((R)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-4-(4-chloro-2-fluorophenyl)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-4-(4-chloro-2-fluorophenyl)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.

[0719] Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. Tautomeric forms can also include methyltropic tautomers, which result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a methyl group.

[0720] Compounds of the invention also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. In some embodiments, the compounds of the invention include one or more isotopes of atoms in an amount greater than the natural abundance of the isotope. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, a compound of the invention includes at least one deuterium atom in an amount that is greater than the natural abundance of deuterium (e.g., the compound is enriched in deuterium).

[0721] All compounds described herein, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates).

[0722] In one aspect, the present invention is directed to an intermediate compound, or a pharmaceutically acceptable salt thereof, which can be used in the synthesis of the compounds of the present invention. For example, said intermediate compound is in some embodiments one of the intermediate compounds, or a pharmaceutically acceptable salt thereof, of any one of examples 1 to 73 disclosed herein. In some embodiments the compound of the present invention is selected from any of the intermediate compounds, or a pharmaceutically acceptable salt thereof, described in the example section herein.

[0723] The compounds of the present invention may contain, for example, one or more asymmetric carbon atoms, and therefore may exist as stereoisomers, enantiomers and diastereomers. Accordingly, the scope of the instant invention is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form and stereoisomeric mixtures of any chemical structures disclosed herein, unless the stereochemistry is specifically identified. If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated.

[0724] The term “stereoisomer” or “stereoisomerically pure” compound as used herein refers to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of the other enantiomer and diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal or less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of the other stereoisomers of the compound.

[0725] In some embodiments, the compound as defined herein is stereoisomerically pure.

[0726] Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents, for example as outlined in the example section.

[0727] Pharmaceutical composition

[0728] The present invention also relates to a pharmaceutical composition comprising, for example as an active ingredient, a pharmaceutically effective amount of a compound as disclosed herein. In some embodiments, said pharmaceutical composition comprises a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient and / or diluent.

[0729] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of Formula (I):

[0730]

[0731] Formula (I) wherein:

[0732] - X1is N or C(H);

[0733] - X2is N or C(H);

[0734] - R1is 5- to 6-membered heteroaryl optionally substituted with one or more, identical or different, R16; phenyl optionally substituted with one or more, identical or different, R16; or of Formula (III):

[0735]

[0736] Formula (III)

[0737] wherein

[0738] X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[0739] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[0740] X7is O, C(R9)(R10), or N(R11);

[0741] R9is F or H;

[0742] R10is F or H;

[0743] R11is C1-3 alkyl optionally substituted with one or more F;

[0744] R8is individually H, F or CH3, and m is 0, 1 or 2;

[0745] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2;

[0746] - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[0747] - R2is of Formula (II):

[0748] Y"’

[0749] yx4

[0750] ( 'R6')n

[0751] Formula (II)

[0752] wherein

[0753] - X3is N or C(H); - X4is O or N(R22);

[0754] or X3is N and X4is C(F)2;

[0755] - R22is H or C1-3 alkyl;

[0756] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[0757] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0758] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0759] - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0760] or a pharmaceutically acceptable salt thereof.

[0761] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of selected from:

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768] pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0769] While a compound as disclosed herein for use in therapy may be administered in the form of the raw chemical compound, it is often preferred to introduce the active ingredient, optionally in the form of a pharmaceutically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries. In some embodiments, the invention provides pharmaceutical compositions comprising a compound as disclosed herein or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, and, optionally, other therapeutic and / or prophylactic ingredients, known and used in the art. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. Examples of excipients and their use may be found in Remington’s Pharmaceutical Sciences 20th Edition (Lippincott Williams & Wilkins, 2000).

[0770] A therapeutic amount or therapeutically effective amount or dose refers to that amount of active ingredient, i.e. the compounds or compositions as disclosed herein, which treats, alleviates, abates, or reduces the severity of symptoms of a disease in a subject, such as ameliorates one or more symptoms of the condition or the condition itself. A therapeutic amount of a compound as described herein may improve patient survival, increase survival time or rate, diminish symptoms, make an injury, disease, or condition (e.g, a neurodegenerative disease) more tolerable, slow the rate of degeneration or decline, or improve a patient’s physical or mental well-being.

[0771] Therapeutic efficacy and toxicity, e.g. ED50, may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by ratio between plasma levels resulting in therapeutic effects and plasma ratios resulting in toxic effects. Pharmaceutical compositions exhibiting large therapeutic indexes are preferred. In some embodiments, the therapeutically effective dose of a compound as disclosed herein is in the range of about 0.01 mg / kg to about 100 mg / kg bodyweight / day.

[0772] The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.

[0773] To administer refers to a method of delivering agents, compounds, or compositions to the desired site of biological action. These methods include, but are not limited to, enteral delivery, oral delivery, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery.

[0774] Biological activity

[0775] As demonstrated in Example 74 compounds of the present invention are capable of modulating TREM2. Thus, in some embodiments, the compound of the present invention is a TREM2 modulator, such as a TREM2 agonist. The assay described in Example 74 may be used to assess and characterize a compound’s ability to act as an agonist of TREM2. In some embodiments the compounds of the present invention are useful for the activation of TREM2. In some embodiments the compounds of the present invention activates TREM2. In some embodiments the compounds of the present invention enhances TREM2 activity. In some embodiments, a compound of the present invention induces phosphorylation of a kinase that interacts with the TREM2 / DAP12 signalling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b. In some embodiments the compounds of the present invention enhances or activates TREM2 signalling through DAP12. In some embodiments the compounds of the present invention enhances or activates TREM2-induced phosphorylation levels of the Syk kinase. In some embodiments, a compound of the present invention induces or enhances phosphorylation of Syk if the level of Syk phosphorylation in a sample treated with the compound is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more as compared to a control value; such as is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more as compared to a control value.

[0776] The potency of compounds of the present invention are in some embodiments expressed as ECso corresponding to the concentration of compound able to activate the phospho-Syk AlphaScreen signal to 50% of the maximal response. In some embodiments the compounds of the present invention has an ECso value of less than 1000 nM, such as an ECso value between 100 nM and 1000 nM, such as an ECso value between 10 nM and 100 nM, such as an an EC50 value between 1 nM and 10 nM, such as an ECso value <1 nM. The ECso value may be determined as described in Example 74. In some embodiments the compounds of the present invention are capable of increasing the expression of one or more TREM2 regulated genes. In some embodiments the compounds of the present invention increases the expression of one or more TREM2 regulated genes. In some embodiments the compounds of the present invention are capable or increasing one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119. In some embodiments the compounds of the present invention increases expression levels, such as brain expression levels, of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119.

[0777] In some embodiments, a compound of the present invention increases expression levels, such as brain expression levels, if the level expression of the gene in a sample treated with the compound is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more as compared to a control value; such as is increased by at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 5-fold, or more as compared to a control value (e.g. untreated control / vehicle).

[0778] In some embodiments, the compound of the present invention is suitable for use as a pharmaceutical agent. Hence, in some embodiments, the compound has suitable pharmacological activity, such as target efficacy, affinity and / or selectivity. In some embodiments, the compound has suitable Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. For example, in some embodiments, the compound has acceptable levels of off-target effects, including low hERG channel (human Ether-a-go-go-Related Gene) inhibition, low off-target toxicity, genotoxicity, carcinogenicity, and / or hepatotoxicity. In some embodiments, the compound demonstrates suitable pharmacokinetics, such as bioavailability, half-life, and / or clearance. In some embodiments, the compound demonstrates suitable pharmacodynamics, such as efficacy and / or potency. In some embodiments, the compound demonstrates chemical stability and / or metabolic stability. Said parameters may be assessed by conventional in vitro tests, animal studies and / or clinical trials known by the skilled person. In some embodiments, the compound demonstrates suitable characteristics for oral formulation using pharmaceutically acceptable excipients. For example, the compound demonstrates suitable solubility in relevant media. Medical use

[0779] Being modulators of TREM2, the compounds of the present invention are of use in the treatment of diseases and disorders of a living body, including human. As used herein, the term “treatment” includes treatment, prevention, and / or alleviation or amelioration of one or more diseases and disorders or one or more symptoms of a disease or disorder. In one aspect, the compound as described herein is for use as a medicament.

[0780] In one aspect, the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a condition associated with a loss of function of TREM2. In one aspect, the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a condition associated with a mutation in TREM2.

[0781] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a neurodegenerative disease.

[0782] In some embodiments, a compound as described herein is used in treating a neurodegenerative disease that is characterized by a loss of function of TREM2. In some embodiments, a compound as described herein is used in treating a neurodegenerative disease that is characterized by a mutation in TREM2.

[0783] In one aspect, the present invention relates to a method for enhancing or increasing TREM2 activity in a subject in need thereof, such as in a subject having a neurodegenerative disease, said method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0784] In one aspect, the present invention relates to method for one or more of i) enhancing or activating TREM2 signaling through DAP12, ii) inducing phosphorylation of a kinase that interacts with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b, iii) enhancing TREM2-induced phosphorylation levels of the Syk kinase, Iv) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes, and / or v) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119; in a subject in need thereof, such as in a subject having a neurodegenerative disease, said method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0785] In some embodiments, the neurodegenerative disease is a tauopathy. Tautopathies depicts some neurodegenerative disorders characterized by tau deposits in the brain, with symptoms of dementia and parkinsonism. In some embodiments, the neurodegenerative disease is a tauopathy selected from the group consisting of Primary age related tauopathy (PART), globular glial tauopathy, Chronic traumatic encephalopathy (CTE), Progressive supranuclear palsy, Corticobasal degeneration, diffuse neurofibrillary tangles with calcification (DNTC), Frontotemporal dementia (FTD), and FTD with parkinsonism-17 (FTD with parkinsonism linked to chromosome 17; FTDP-17).

[0786] In some embodiments, the neurodegenerative disease is a neurodegenerative disorders associated with TDP-43 (TDP-43 proteinopathies or TDP-43-opathies).

[0787] Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases.

[0788] In some embodiments, the neurodegenerative disease is a TDP-43 proteinopathy selected from the group consisting of amyotrophic lateral sclerosis (ALS), sporadic amyotrophic lateral sclerosis (sALS), familial amyotrophic lateral sclerosis (fALS), frontotemporal lobar degeneration / disease (FTLD), Primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), FTLD-tau, FTLD-FUS (bvFTLD), FTLD-TDP-43 or FTLD-ll (types a, b and c), Facial onset sensory and motor neuronopathy (FOSMN), Limbic-predominant age-related TDP-43 encephalopathy (LATE), cerebral age-related TDP-43 with sclerosis (CARTS), Guam Parkinson-dementia complex (G-PDC) and ALS (G-ALS), Kii ALS / PDC, amyotrophic lateral sclerosis / parkinsonism-dementia complex of Guam (ALS-PDC), Multisystem proteinopathy (MSP; also referred to as inclusion body myopathy, IBM, associated with early-onset Paget disease of the bone and FTLD dementia), Perry disease, and disorders with concomitant TDP-43 pathology, including Alzheimer’s disease (AD) and Chronic traumatic encephalopathy (CTE).

[0789] In some embodiments, the neurodegenerative disease is Multisystem proteinopathy (MSP). MSP is a dominantly inherited, pleiotropic, degenerative disorder of humans that can affect muscle, bone, and / or the central nervous system. MSP can manifest clinically as classical amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Paget's disease of bone (PDB), or as a combination of these disorders (IBMPFD, IBMPFD / ALS).

[0790] In some embodiments, the neurodegenerative disease is a synucleinopathy.

[0791] Synucleinopathies (also called a-Synucleinopathies) are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells.

[0792] In some embodiments, the neurodegenerative disease is a synucleinopathy selected from the group consisting of Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), neuroaxonal dystrophies, Alzheimer's Disease with Amygdalar Restricted Lewy Bodies (AD / ALB).

[0793] In some embodiments, the neurodegenerative disease is cognitive deficit and / or memory loss. In some embodiments, the neurodegenerative disease is dementia. In some embodiments, the neurodegenerative disease is dementia selected from the group consisting of Alzheimer’s disease, Parkinson’s disease dementia, Huntingtons disease dementia, vascular dementia, HIV dementia, frontotemporal dementia, dementia with lewy bodies, prion disease dementia, argyrophilic grain dementia, dementia pugilistica, Guadeloupean parkinsonism with dementia, neurofibrillary tangle-predominant dementia, tangle only dementia, Down’s syndrome, semantic dementia, familial British dementia, familial Danish dementia, and other dementias caused by another medical condition such as brain tumors, subdural hematoma, endocrine disorders, nutritional deficiencies, infections, immune disorders, liver or kidney failure, metabolic disorders such as Kufs disease, some leukodystrophies, some neurological disorders such as epilepsy, and multiple sclerosis.

[0794] Disorders of peripheral nerves (peripheral neuropathy) are the most common neurological complications of systemic amyloidosis. In some embodiments, the neurodegenerative disease is peripheral amyloidosis (peripheral neuropathy in systemic amyloidosis).

[0795] In some embodiments, the neurodegenerative disease is a demyelinating disorder. In some embodiments, the neurodegenerative disease is a demyelinating disorder of the central nervous system, CNS. In some embodiments, the demyelinating disorder is a myelinoclastic or demyelinating disorder, such as selected from the group consisting of multiple sclerosis, neuromyelitis optica (Devic’s disease) and idiopathic inflammatorydemyelinating diseases. In some embodiments, the demyelinating disorder is a leukodystrophic or dysmyelinating disorder, such as selected from the group consisting of CNS neuropathies such as vitamin B12 deficiency, central pontine myelinolysis, myelopathies such as tabes dorsalis (syphilitic myelopathy), leukoencephalopathies and leukodystrophies.

[0796] In some embodiments, the neurodegenerative disease is a demyelinating disorder of the peripheral nervous system, PNS. In some embodiments, the demyelinating disorder is selected from the group consisting of Guillain-Barre syndrome and its chronic counterpart, chronic inflammatory demyelinating polyneuropathy; Anti-MAG peripheral neuropathy; Charcot-Marie-Tooth disease and its counterpart Hereditary neuropathy with liability to pressure palsy; Copper deficiency-associated conditions (peripheral neuropathy, myelopathy, and rarely optic neuropathy); and Progressive inflammatory neuropathy.

[0797] In some embodiments, the neurodegenerative disease is Alzheimer’s disease (AD). In some embodiments, the neurodegenerative disease is Alzheimer’s disease (AD) with the R47H mutation. In some embodiments, the neurodegenerative disease is early Alzheimer’s disease. In some embodiments, the neurodegenerative disease is Frontotemporal lobar degeneration (FTLD). In some embodiments, the neurodegenerative disease is frontotemporal dementia. In some embodiments, the neurodegenerative disease is Parkinson’s disease. In some embodiments, the neurodegenerative disease is Nasu-Hakola disease (NHD). In some embodiments, the neurodegenerative disease is FTLD-like syndrome. In some embodiments, the neurodegenerative disease is Huntington disease. In some embodiments, the neurodegenerative disease is Amyotrophic lateral sclerosis (ALS). In some embodiments, the neurodegenerative disease is multiple sclerosis (MS). In some embodiments, the neurodegenerative disease is Guillain-Barre syndrome. In some embodiments, the neurodegenerative disease is chronic inflammatory demyelinating polyneuropathies. In some embodiments, the neurodegenerative disease is progressive subcortical gliosis. In some embodiments, the neurodegenerative disease is Charcot-Marie-Tooth disease. In some embodiments, the neurodegenerative disease is prion disease, such as prion protein cerebral amyloid angiopathy. In some embodiments, the neurodegenerative disease is stroke. In some embodiments, the neurodegenerative disease is cerebral amyloid angiopathy (CAA). In some embodiments the neurodegenerative disease is fragile X-associated tremor ataxia syndrome (FXTAS). In some embodiments the neurodegenerative disease is herpes simplex virus (HSV) encephalitis. In some embodiments the neurodegenerative disease is HIV-associated neurocognitive disorders (HAND). In some embodiments the neurodegenerative disease is progressive supranuclear palsy (PSP). In some embodiments the neurodegenerative disease is corticobasal degeneration. In some embodiments the neurodegenerative disease is Hallevorden-Spatz disease. In some embodiments the neurodegenerative disease is pallido-ponto-nigral degeneration. In some embodiments the neurodegenerative disease is postencephalitic parkinsonism. In some embodiments the neurodegenerative disease is subacute sclerosing panencephalitis (SSPE). In some embodiments the neurodegenerative disease is retinal degeneration (e.g., macular degeneration).

[0798] In some embodiments the neurodegenerative disease is a Leukoencephalopathy. Leukoencephalopathy (leukodystrophy-like diseases) is a term that describes all of the brain white matter diseases, whether their molecular cause is known or unknown. In some embodiments the neurodegenerative disease is a Leukoencephalopathy selected from the group consisting of Progressive multifocal leukoencephalopathy, Toxic leukoencephalopathy, Leukoencephalopathy with vanishing white matter, Leukoencephalopathy with neuroaxonal spheroids, Reversible posterior leukoencephalopathy syndrome, Megalencephalic leukoencephalopathy with subcortical cysts, and Hypertensive leukoencephalopathy. In some embodiments, the neurodegenerative disease is ALSP (Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia).

[0799] In some embodiments the neurodegenerative disease is selected from the group consisting of cerebral autosomal dominant arteriopathy with subcortical infarcts or leukoencephalopathy; cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; and retinal vasculopathy with cerebral leukoencephalopathy (or cerebroretinal vasculopathy).

[0800] In some embodiments the neurodegenerative disease is a leukodystrophy. In some embodiments the neurodegenerative disease is vanishing white matter disease (VWM). Leukodystrophies are a group of rare, genetic disorders that affect the white matter of the brain. In some embodiments the neurodegenerative disease is a leukodystrophy selected from the group consisting of metachromatic leukodystrophy (MLD, also known as globoid cell leukodystrophy), Krabbe disease, Canavan disease, X-linked adrenoleukodystrophy, Alexander disease, hypomyelinating leukodystrophy type 7 (4H syndrome), Pelizaeus-Merzbacher disease, cerebrotendineous xanthomatosis and leukoendephalopathy with vanishing white matter. In some embodiments the neurodegenerative disease is adult-onset autosomal dominant leukodystrophy (ADLD). In some embodiments the neurodegenerative disease is X-linked adrenoleukodystrophy (X-ALD). In some embodiments the neurodegenerative disease is Nasu-Hakola disease also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL).

[0801] In some embodiments, the neurodegenerative disease is a transmissible spongiform encephalopathy (TSE), including Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease (GSS), kuru, and fatal familial insomnia.

[0802] In one aspect, the present invention relates to a method for treatment of a neurodegenerative disease comprising administering a compound, ora pharmaceutically acceptable salt thereof, as described herein to a subject in need thereof.

[0803] In one aspect, the present invention relates to a method for treatment of a neurodegenerative disease comprising one or more steps of administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein to a subject in need thereof.

[0804] In some embodiments, the subject is a mammal, such as a human.

[0805] In one aspect, the present invention relates to use of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the manufacture of a medicament for treatment of a neurodegenerative disease.

[0806] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a disease or disorder associated with dysfunction of Colony stimulating factor 1 receptor (CSF1R, also known as macrophage colony-stimulating factor receptor / M- CSFR, or cluster of differentiation 115 / CD115). In some embodiments the disease or disorder associated with dysfunction of CSF1R is a neurodegenerative disease associated with dysfunction of CSF1R.

[0807] In some embodiments the disease or disorder is caused by a heterozygous CSF1 R mutation, a homozygous CSF1R mutation, a splice mutation in the csf1r gene, a missense mutation in the csf1r gene, a mutation in the catalytic kinase domain of CSF1R, a mutation in an immunoglobulin domain of CSF1R, a mutation in the ectodomain of CSF1R, a loss-of-function mutation in CSF1R. In some embodiments the disease or disorder result from a change (e.g. increase, decrease or cessation) in the activity of CSF1 R and / or a decrease or cessation in the activity of CSF 1 R.

[0808] In some embodiments the neurodegenerative disease associated with dysfunction of CSF1R is a Leukoencephalopathy.

[0809] In some embodiments the neurodegenerative disease associated with dysfunction of CSF1R is selected from the group consisting of:

[0810] adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), CSF1 R-related leukoencephalopathy,

[0811] hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmentary orthochromatic leukodystrophy (POLD),

[0812] pediatric-onset leukoencephalopathy,

[0813] congenital absence of microglia,

[0814] brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS), and Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

[0815] In some embodiments the neurodegenerative disease is a condition associated with dysfunction of ATP- binding cassette transporter 1 (ABCD1).

[0816] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a lysosomal storage disorder (LSD). Most lysosomal storage disorders cause progressive neurodegeneration leading to early death. In some embodiments the LSD is a lipidoses, such as a lipidoses selected from the group consisting of cholesteryl ester storage disease, fucosidosis, Schindler disease and Wolman disease.

[0817] In some embodiments the LSD is a sphingolipidoses, such as a sphingolipidoses selected from the group consisting of Fabry disease, Gaucher disease, Krabbe disease (globoid cell leukodystrophy), metachromatic leukodystrophy (MLD), Niemann-Pick disease (Types A, B and C), Sandhoff disease, Farmer disease, multiple sulfatase deficiency and Tay-Sachs disease.

[0818] In some embodiments the LSD is a mucopolysaccharidoses, such as a mucopolysaccharidoses selected from the group consinting of Hunter syndrome, Hurler syndomre, Hurler-Scheie syndrome, Scheie syndrome, Sanfilippo syndrome (A, B, C, D), Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome and Natowicz syndrome.

[0819] In some embodiments the LSD is selected from the group consisting of Batten disease, cyctinosis, Danon disease and Pompe disease.

[0820] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a disease or disorder of the bones and / or joints. In some embodiments said disease or disorder is selected from the group consisting of arthritis, rheumatoid arthritis, pyle disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia and dysosteoplasia.

[0821] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of autism spectrum disorders, autism and Aspergers syndrome.

[0822] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of traumatic brain injuries (TBI) and spinal cord injuries. Traumatic brain injuries (TBI), may also be known as intracranial injuries. Traumatic brain injuries occur when an external force traumatically injures the brain. Spinal cord injuries (SCI) include any injury to the spinal cord that is caused by trauma instead of disease. In some embodiments the TBI is chronic traumatic encephalopathy (CTE). In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of muscular dystrophy such as myotonic dystrophy (DM) including Type 1 DM (DM1) and Type 2 DM (DM2).

[0823] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of inflammation. In some embodiments said inflammation is selected from the group consisting of inclusion-body myositis, systemic lupus erythematosus (SLE), RA, gout, and certain bowel conditions including Inflammatory bowel disease (IBD).

[0824] A reduction in the functional levels of TREM2 results in dysregulation of lipid metabolism. In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of dysregulated lipid metabolism. In certain embodiments, the dysregulated lipid metabolism comprises increased intracellular and / or extracellular accumulation of one or more lipids. In some embodiments said dysregulated lipid metabolism is atherosclerosis.

[0825] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of metabolic syndrome and conditions associated with metabolic syndrome, such as obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver disease, and alcoholic and non-alcoholic steatohepatitis,

[0826] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of Amyloidosis, including AL amyloidosis (immunoglobulin light chain amyloidosis), AA amyloidosis (secondary amyloidosis), familial amyloidosis, familial systemic amyloidosis, Wild-type amyloidosis (senile systemic amyloidosis) and Localized amyloidosis.

[0827] In some embodiments, the neurodegenerative disease is Alzheimer’s disease. In some embodiments, the neurodegenerative disease is Nasu-Hakola disease. In some embodiments, the neurodegenerative disease is frontotemporal dementia. In some embodiments, the method comprises administering to the subject a compound as described herein, or a pharmaceutical composition comprising a compound as described herein.

[0828] The compounds of the present invention may be used to treat an animal patient belonging to any classification. Examples of such animals include mammals such as humans, rodents, dogs, cats, zoo animals and farm animals. In some embodiments, the subject referred to herein is a mammal, such as a human.

[0829] The term “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified. Accordingly, the scope of the methods and uses herein is to be understood to encompass methods and uses employing all such forms.

[0830] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of the present invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” In some embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent. In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents. In some embodiments, the method includes coadministering one or more additional therapeutic agent. Examples of therapeutic agents the combinations of the present invention may also be combined with include, without limitation: treatments for Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, Nasu- Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke. In some embodiments, the therapeutic agents the combinations of the present invention may also be combined with include, without limitation: treatments for a disease selected from the group consisting of a tauopathy, a TDP-43 proteinopathy, a synucleinopathy, dementia, amyloidosis, a demyelinating disorder of the CNS, a demyelinating disorder of the PNS, a Leukoencephalopathy, a leukodystrophy, a transmissible spongiform encephalopathy (TSE) and a lysosomal storage disorder (LSD). As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with the present invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.

[0831] In one aspect, the present invention relates to a method of treating a condition associated with a loss of function of TREM2 comprising administering to a subject a therapeutically effective amount of a compound selected from:

[0832] wherein Group A consists of:

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839] some embodiments, the condition is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), Parkinson’s disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington disease, Amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease, prion disease and stroke. In some embodiments, the neurodegenerative disease is Alzheimer’s Disease.

[0840] Methods of manufacturing

[0841] Compounds of the present invention may be prepared according to any conventional methods of chemical synthesis known by the skilled person, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods known by the skilled artisan from commercially available chemicals. The end products of the reactions described herein may be isolated by conventional technique such as extraction, crystallisation, distillation, chromatography etc.

[0842] Generally, the compounds of the current invention may be synthesised according to the following schemes.

[0843] All starting materials are either commercially available or known in the art and may be synthesised by using known procedures. Starting materials may also be synthesised using the procedures disclosed herein. Reaction conditions such as reaction temperature, solvent and reagents for the Schemes in this section may be found in the experimental section herein.

[0844] As shown in Scheme 1, a suitably protected dihalo-substituted 5H,6H,7H-pyrrolo[3,4-d]pyrimidine can be functionalised to deliver the desired compounds. For example, the R3group can be introduced first via a cross coupling reaction (e.g. a Suzuki coupling with a suitable boronic acid) which is then oxidised to give a 2-halo-4-substituted 5H,6H,7H-pyrrolo[3,4-d]pyrimidin-7-one. Addition of the R2substituent is then carried out via nucleophilic displacement or a metal-catalysed coupling reaction. The protecting group (PG) is then cleaved (e.g. using HCI in dioxane) to give a N-H intermediate which undergoes a final cross coupling reaction to introduce the R1substituent. Metal-catalysed

[0845] coupling

[0846]

[0847] e.g. with R3B(OH)2

[0848]

[0849] talysed

[0850]

[0851] lic displacement

[0852] i) deprotection

[0853] ii) metal-catalysed

[0854]

[0855] coupling

[0856]

[0857] Scheme 1. Examples of synthetic routes for compounds of Formula I. PG is a protecting group such as Boc; W is halogen; Y is halogen; R1, R2and R3are as defined herein.

[0858] In one aspect, the present invention relates to a method for synthesizing a compound of Formula (I) comprising one or more steps described above. In one aspect, the present invention relates to a method for manufacturing a compound of Formula (la) as defined herein, said method comprising the steps of:

[0859] a) Reacting a compound of Formula (S-a1):

[0860]

[0861] wherein PG is a protecting group, such as Boc; W is halogen; and Y is halogen, with a cross coupling reagent, such as R3B(OH)2, wherein R3is as defined herein, to generate a compound of Formula (S-a2):

[0862]

[0863] b) Oxidizing the compound of Formula (S-a2), for example with NaIO2 / RuCl3, to generate a compound of Formula (S-a3):

[0864]

[0865] c) Reacting the compound of Formula (S-a3) with a cross coupling agent, such as R2B(OH)2, wherein R2is as defined herein:

[0866]

[0867] and

[0868] d) Removing PG from the compound of Formula (S-a4), and reacting the formed compound with a cross coupling agent, such as R1B(OH)2, wherein R1is as defined herein, to generate a compound of Formula (la):

[0869]

[0870] Formula (la) Alternatively, when R2is N-linked (i.e. X3is N), step c) above may be replaced by reacting the compound of Formula (S-a3) with the corresponding amine via nucleophilic displacement to generate a compound of Formula (S-a4).

[0871] Other examples can be made as shown in Scheme 2. A suitably protected dihalo-substituted 1H,2H,3H-pyrrolo[3,4-c]pyridin-1-one can be functionalised to deliver the desired compounds. For example, the R3group can be introduced first via a cross coupling reaction (e.g. a Suzuki coupling with a suitable boronic acid). Addition of the R2substituent is then carried out via nucleophilic displacement or a metal-catalysed coupling reaction. The protecting group is then cleaved (e.g. using HCI in dioxane) to give a N-H intermediate which undergoes a final cross coupling reaction to introduce the R1substituent.

[0872] Metal-catalysed Metal-catalysed coupling

[0873] coupling

[0874] e.g. with R3B(OH)2or

[0875]

[0876] nucleohilic displacement

[0877] i) deprotection

[0878] ii) metal-catalysed coupling

[0879]

[0880]

[0881] Scheme 2. Examples of synthetic routes for further compounds of Formula I. PG is a protecting group such as Boc; W is halogen; Y is halogen; R1, R2and R3are as defined herein.

[0882] In one aspect, the present invention relates to a method for manufacturing a compound of Formula (lb) as defined herein, said method comprising the steps of:

[0883] 1. Reacting a compound of Formula (S-b1):

[0884]

[0885] wherein PG is a protecting group, such as Boc; W is halogen; and Y is halogen, with a cross coupling reagent, such as R3B(OH)2, wherein R3is as defined herein, to generate a compound of Formula (S-b2):

[0886]

[0887] 2. Reacting the compound of Formula (S-b2) with a cross coupling agent, such as R2B(OH)2, wherein R2is as defined herein, to generate a compound of Formula (S-b3):

[0888]

[0889] and

[0890] 3. Removing PG from the compound of Formula (S-b3), and reacting the formed compound with a cross coupling agent, such as R1B(OH)2, wherein R1is as defined herein, to generate a compound of Formula (lb):

[0891]

[0892] Formula (lb)

[0893] Alternatively, when R2is linked N-linked (i.e. X3is N), step b) above may be replaced by reacting the compound of Formula (S-a3) with the corresponding amine via nucleophilic displacement to generate a compound of Formula (S-a4). Items

[0894] 1. A compound of Formula (I):

[0895]

[0896] Formula (I)

[0897] wherein:

[0898] - X1is N or C(H);

[0899] - X2is N or C(H);

[0900] - R1is 5- to 6-membered heteroaryl optionally substituted with one or more, identical or different, R16; phenyl optionally substituted with one or more, identical or different, R16; or of Formula (III):

[0901]

[0902] Formula (III)

[0903] wherein

[0904] • X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[0905] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[0906] • X7is O, C(R9)(R10), or N(R11);

[0907] • R9is F or H;

[0908] • R10is F or H;

[0909] • R11is C1-3 alkyl optionally substituted with one or more F;

[0910] • R8is individually H, F or CH3, and m is 0, 1 or 2;

[0911] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2; - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[0912] - R2is of Formula (II):

[0913]

[0914] Formula (II)

[0915] wherein

[0916] - X3is N or C(H);

[0917] - X4is O or N(R22);

[0918] or X3is N and X4is C(F)2;

[0919] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[0920] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[0921] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0922] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0923] - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0924] or a pharmaceutically acceptable salt thereof.

[0925] A compound of Formula (I):

[0926]

[0927] Formula (I)

[0928] wherein:

[0929] - X1is N or C(H);

[0930] - X2is N or C(H); - R1is 5- to 6-membered heteroaryl optionally substituted with one or more, identical or different, R16; phenyl optionally substituted with one or more, identical or different, R16; or of Formula (III):

[0931]

[0932] Formula (III)

[0933] wherein

[0934] • X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[0935] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[0936] • X7is O, C(R9)(R10), or N(R11);

[0937] • R9is F or H;

[0938] • R10is F or H;

[0939] • R11is C1-3 alkyl optionally substituted with one or more F;

[0940] • R8is individually H, F or CH3, and m is 0, 1 or 2;

[0941] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2; - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[0942] - R2is of Formula (II):

[0943]

[0944] Formula (II)

[0945] wherein

[0946] - X3is N or C(H);

[0947] - X4is O or N(R22);

[0948] - R22is H or C1-3 alkyl optionally substituted with one or more F; - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[0949] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0950] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0951] - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0952] or a pharmaceutically acceptable salt thereof.

[0953] A compound of Formula (I):

[0954]

[0955] wherein:

[0956] - X1is N or C(H);

[0957] - X2is N or C(H);

[0958] - R1is of Formula (III):

[0959]

[0960] Formula (III)

[0961] wherein

[0962] • X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[0963] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[0964] • X7is O, C(R9)(R10), or N(R11);

[0965] • R9is F or H;

[0966] • R10is F or H; • R11is C1-3 alkyl optionally substituted with one or more F;

[0967] • R8is individually H, F or CH3, and m is 0, 1 or 2;

[0968] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2; - R2is of Formula (II):

[0969]

[0970] Formula (II)

[0971] wherein

[0972] - X3is N or C(H);

[0973] - X4is O or N(R22);

[0974] or X3is N and X4is C(F)2;

[0975] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[0976] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[0977] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[0978] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[0979] - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0980] or a pharmaceutically acceptable salt thereof.

[0981] 4. A compound of Formula (I):

[0982]

[0983] Formula (I)

[0984] wherein: - X1is N or C(H);

[0985] - X2is N or C(H);

[0986] - R1is of Formula (XI):

[0987]

[0988] Formula (XI)

[0989] wherein

[0990] - R12is H or F;

[0991] - R14is H or F;

[0992] - X7is O, C(R9)(R10), or N(R11);

[0993] - R9is F or H;

[0994] - R10is F or H;

[0995] R11is C1-3 alkyl optionally substituted with one or more F; and

[0996] R8is individually H, F or CH3, and m is 0, 1 or 2;

[0997] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2;

[0998] - R2is of Formula (II):

[0999]

[1000] Formula (II)

[1001] wherein

[1002] - X3is N or C(H);

[1003] - X4is O or N(R22);

[1004] or X3is N and X4is C(F)2;

[1005] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[1006] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[1007] - R6is individually H, F or CH3, and n is 0, 1 or 2; or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[1008] - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[1009] or a pharmaceutically acceptable salt thereof.

[1010] A compound of Formula (la):

[1011]

[1012] Formula (la)

[1013] wherein:

[1014] - R1is a 6-membered heteroaryl optionally substituted with one or more, identical or different, R16;

[1015] - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[1016] - R2is of Formula (II):

[1017]

[1018] Formula (II)

[1019] wherein

[1020] - X3is N or C(H);

[1021] - X4is O or N(R22);

[1022] or X3is N and X4is C(F)2;

[1023] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[1024] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[1025] - R6is individually H, F or CH3, and n is 0, 1 or 2; or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[1026] - R3is phenyl optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[1027] or a pharmaceutically acceptable salt thereof.

[1028] A compound of Formula (XXI):

[1029]

[1030] wherein:

[1031] - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[1032] - R2is of Formula (II):

[1033]

[1034] Formula (II)

[1035] wherein

[1036] - X3is N or C(H);

[1037] - X4is O or N(R22);

[1038] or X3is N and X4is C(F)2;

[1039] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[1040] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[1041] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[1042] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s); - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[1043] or a pharmaceutically acceptable salt thereof.

[1044] A compound of Formula (XXII):

[1045]

[1046] Formula (XXII)

[1047] wherein:

[1048] - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[1049] - R2is of Formula (II):

[1050]

[1051] Formula (II)

[1052] wherein

[1053] - X3is N or C(H);

[1054] - X4is O or N(R22);

[1055] or X3is N and X4is C(F)2;

[1056] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[1057] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[1058] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[1059] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s); - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[1060] or a pharmaceutically acceptable salt thereof.

[1061] A compound of Formula (la):

[1062]

[1063] Formula (la)

[1064] wherein:

[1065] - R1is phenyl optionally substituted with one or more, identical or different, R16; - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[1066] - R2is of Formula (II):

[1067]

[1068] Formula (II)

[1069] wherein

[1070] - X3is N or C(H);

[1071] - X4is O or N(R22);

[1072] or X3is N and X4is C(F)2;

[1073] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[1074] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[1075] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[1076] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s); - R3is phenyl optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[1077] or a pharmaceutically acceptable salt thereof.

[1078] 9. A compound of Formula (la):

[1079]

[1080] Formula (la)

[1081] wherein:

[1082] - R1is of Formula (XI):

[1083]

[1084] Formula (XI)

[1085] wherein

[1086] • R12is H or F;

[1087] • R14is H or F;

[1088] • X7is O, C(R9)(R10), or N(R11);

[1089] • R9is F or H;

[1090] • R10is F or H;

[1091] • R11is C1-3 alkyl optionally substituted with one or more F; and

[1092] • R8is individually H, F or CH3, and m is 0, 1 or 2;

[1093] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2;

[1094] - R2is of Formula (II):

[1095]

[1096] Formula (II) wherein

[1097] - X3is N or C(H);

[1098] - X4is O or N(R22);

[1099] or X3is N and X4is C(F)2;

[1100] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[1101] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[1102] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[1103] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[1104] - R3is phenyl optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[1105] or a pharmaceutically acceptable salt thereof.

[1106] A compound of Formula (I):

[1107]

[1108] Formula (I)

[1109] wherein:

[1110] - X1is N or C(H);

[1111] - X2is N or C(H);

[1112] - R1is a 6-membered heteroaryl optionally substituted with one or more, identical or different, R16; phenyl optionally substituted with one or more, identical or different, R16; or of Formula (III):

[1113]

[1114] Formula (III)

[1115] wherein • X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[1116] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[1117] • X7is O, C(R9)(R10), or N(R11);

[1118] • R9is F or H;

[1119] • R10is F or H;

[1120] • R11is C1-3 alkyl optionally substituted with one or more F;

[1121] • R8is individually H, F or CH3, and m is 0, 1 or 2;

[1122] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2; - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[1123] - R2is of Formula (II):

[1124]

[1125] Formula (II)

[1126] wherein

[1127] - X3and X4are N, or X3is C(H) and X4is N;

[1128] - R5is pyrazolyl or pyridinyl, each of which is substituted with 1 to 3 substituents individually selected from C1-3 alkyl, C1-3 haloalkyl, cyclopropyl, and C1-3 alkoxy; and

[1129] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[1130] or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[1131] - R3is phenyl substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy; or a pharmaceutically acceptable salt thereof.

[1132] 11. A compound of Formula (I):

[1133]

[1134]

[1135]

[1136]

[1137] or a pharmaceutically acceptable salt thereof.

[1138] The compound or salt according to item 11, wherein

[1139]

[1140]

[1141] 13. The compound according to any one of the preceding items, wherein X1is N. 14. The compound according to any one of the preceding items, wherein X1is C(H).

[1142] 15. The compound according to any one of the preceding items, wherein X2is N. 16. The compound according to any one of the preceding items, wherein X2is C(H).

[1143] 17. The compound according to any one of the preceding items, wherein X1is N and X2is N.

[1144] 18. The compound according to any one of the preceding items, wherein the compound is of Formula (la):

[1145]

[1146] Formula (la)

[1147] 19. The compound according to any one of the preceding items, wherein X1is N, X2is N, R1is pyridinyl substituted with R16, and R16is C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl.

[1148] 20. The compound according to any one of the preceding items, wherein the compound is of Formula (XXI):

[1149]

[1150] Formula (XXI)

[1151] The compound according to any one of the preceding items, wherein the compound is of Formula (XXIa):

[1152]

[1153] Formula (XXIa)

[1154] The compound according to any one of the preceding items, wherein the compound is of Formula (XXIb):

[1155]

[1156] Formula (XXIb)

[1157] The compound according to any one of the preceding items, wherein X1is N, X2is N, R1is pyrimidinyl substituted with R16, and R16is C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl.

[1158] The compound according to any one of the preceding items, wherein the compound is of Formula (XXII):

[1159]

[1160] Formula (XXII) 25. The compound according to any one of the preceding items, wherein the compound is of Formula (XXIIa):

[1161]

[1162] Formula (XXIIa)

[1163] 26. The compound according to any one of the preceding items, wherein X1is N, X2is N, R1is phenyl substituted with R16, and R16is C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl.

[1164] 27. The compound according to any one of the preceding items, wherein the compound is of Formula (XXIIIa):

[1165]

[1166] Formula (XXIIIa)

[1167] 28. The compound according to any one of the preceding items, wherein the compound is of Formula (XXIIIb):

[1168]

[1169] Formula (XXIIIb)

[1170] 29. The compound according to any one of the preceding items, wherein the compound is of Formula (XXIV):

[1171]

[1172] Formula (XXIV)

[1173] 30. The compound according to any one of the preceding items, wherein X1is C(H) and X2is N.

[1174] 31. The compound according to any one of the preceding items, wherein the compound is of Formula (lb):

[1175]

[1176] Formula (lb)

[1177] 32. The compound according to any one of the preceding items, wherein X1is N and X2is C(H).

[1178] 33. The compound according to any one of the preceding items, wherein R2is of Formula (Ila):

[1179]

[1180] Formula (Ila)

[1181] 34. The compound according to any one of the preceding items, wherein R2is of Formula (lib):

[1182]

[1183] Formula (lib)

[1184] 35. The compound according to any one of the preceding items, wherein R2is of Formula (IV):

[1185]

[1186] Formula (IV)

[1187] wherein

[1188] R6ais H, F or CH3, and R6bis H, F or CH3;

[1189] or R6aand R6bare linked together to form a ring together with the intervening atom, and R6aand R6bare each individually -(CH2)2- or -CH2-.

[1190] The compound according to any one of the preceding items, wherein R2is of Formula (IVa):

[1191]

[1192] Formula (IVa)

[1193] wherein

[1194] R6ais H, F or CH3, and R6bis H, F or CH3;

[1195] or R6aand R6bare linked together to form a ring together with the intervening atom, and R6aand R6bare each individually -(CH2)2- or -CH2-.

[1196] The compound according to any one of the preceding items, wherein R2is of Formula (IVb):

[1197]

[1198] Formula (IVb)

[1199] wherein

[1200] R6ais H, F or CH3, and R6bis H, F or CH3;

[1201] or R6aand R6bare linked together to form a ring together with the intervening atom, and R6aand R6bare each individually -(CH2)2- or -CH2-. 38. The compound according to any one of the preceding items, wherein X3is N or C(H), and X4is O or N(R22).

[1202] 39. The compound according to any one of the preceding items, wherein X3is N.

[1203] 40. The compound according to any one of the preceding items, wherein X4is O.

[1204] 41. The compound according to any one of the preceding items, wherein X3is N and X4is O.

[1205] 42. The compound according to any one of the preceding items, wherein R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, and X4is O.

[1206] 43. The compound according to any one of the preceding items, wherein R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais H, and R6bis H.

[1207] 44. The compound according to any one of the preceding items, wherein R2of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais CH3, and R6bis H.

[1208] 45. The compound according to any one of the preceding items, wherein R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais H, and R6bis CH3.

[1209] 46. The compound according to any one of the preceding items, wherein R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais CH3, and R6bis CH3.

[1210] 47. The compound according to any one of the preceding items, wherein R2is of Formula (IVc):

[1211]

[1212] Formula (IVc)

[1213] wherein

[1214] R6ais H, F or CH3, and R6bis H, F or CH3;

[1215] or R6aand R6bare linked together to form a ring together with the intervening atom, and R6aand R6bare each individually -(CH2)2- or -CH2-.

[1216] 48. The compound according to any one of the preceding items, wherein R2is of Formula (XVI):

[1217]

[1218] Formula (XVI)

[1219] 49. The compound according to any one of the preceding items, wherein R2is of Formula (V):

[1220]

[1221] Formula (V)

[1222] 50. The compound according to any one of the preceding items, wherein R2is of Formula (Va), (Vb), (Vc) or (Vd):

[1223]

[1224] 51. The compound according to any one of the preceding items, wherein R2is of Formula (V), Formula (Va), Formula (Vb), Formula (Vc), or Formula (Vd), and R6is H.

[1225] 52. The compound according to any one of the preceding items, wherein R2is of Formula (XIX):

[1226]

[1227] Formula (XIX)

[1228] 53. The compound according to any one of the preceding items, wherein R2is of Formula (V), Formula (Va), Formula (Vb), Formula (Vc), or Formula (Vd), and R6is CH3. 54. The compound according to any one of the preceding items, wherein R2is of Formula (XX):

[1229]

[1230] Formula (XX)

[1231] 55. The compound according to any one of the preceding items, wherein R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais F, and R6bis F.

[1232] 56. The compound according to any one of the preceding items, wherein R2is of Formula (XV):

[1233]

[1234] Formula (XV)

[1235] 57. The compound according to any one of the preceding items, wherein R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais -CH2-, and R6bis -CH2- and R6aand R6bare linked together to form a ring.

[1236] 58. The compound according to any one of the preceding items, wherein R2is of Formula (XVII):

[1237]

[1238] Formula (XVII)

[1239] 59. The compound according to any one of the preceding items, wherein R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is O, R6ais - (CH2)2-, and R6bis -CH2- and R6aand R6bare linked together to form a ring. 60. The compound according to any one of the preceding items, wherein R2is of Formula (XVIII):

[1240]

[1241] Formula (XVIII)

[1242] 61. The compound according to any one of the preceding items, wherein X3is C(H).

[1243] 62. The compound according to any one of the preceding items, wherein X3is C(H) and X4is O.

[1244] 63. The compound according to any one of the preceding items, wherein R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is C(H), and X4is O.

[1245] 64. The compound according to any one of the preceding items, wherein R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is C(H), X4is O, R6ais H, and R6bis H.

[1246] 65. The compound according to any one of the preceding items, wherein R2is of Formula (VI):

[1247]

[1248] Formula (VI)

[1249] 66. The compound according to any one of the preceding items, wherein R2is of

[1250]

[1251] Formula (VIa) Formula (VIb) Formula (VIc) Formula (VId)

[1252] 67. The compound according to any one of the preceding items, wherein R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is C(H), X4is O, R6ais H, and R6bis CH3.

[1253] 68. The compound according to any one of the preceding items, wherein R2is of Formula (XIV):

[1254]

[1255] Formula (XIV)

[1256] 69. The compound according to any one of the preceding items, wherein R2is of Formula (XIVa):

[1257]

[1258] Formula (XIVa)

[1259] 70. The compound according to any one of the preceding items, wherein X4is N(R22).

[1260] 71. The compound according to any one of the preceding items, wherein X3is N and X4is N(R22).

[1261] 72. The compound according to any one of the preceding items, wherein R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, and X4is N(R22). 73. The compound according to any one of the preceding items, wherein R2is of Formula (IV), Formula (IVa) or Formula (IVb), and X3is N, X4is N(R22), R6ais H, and R6bis H.

[1262] 74. The compound according to any one of the preceding items, wherein R2is of Formula (XII):

[1263]

[1264] Formula (XII)

[1265] 75. The compound according to any one of the preceding items, wherein R2is of Formula (XIIa) or (XI lb):

[1266]

[1267] Formula (XIIa) Formula (XIIb)

[1268] 76. The compound according to any one of the preceding items, wherein R22is H.

[1269] 77. The compound according to any one of the preceding items, wherein R22is C1-3 alkyl substituted with one or more F.

[1270] 78. The compound according to any one of the preceding items, wherein R22is C1-3 alkyl.

[1271] 79. The compound according to any one of the preceding items, wherein R22is CH3. 80. The compound according to any one of the preceding items, wherein X3is N and X4is C(F)2.

[1272] 81. The compound according to any one of the preceding items, wherein R2is of Formula (XIII):

[1273]

[1274] Formula (XIII)

[1275] 82. The compound according to any one of the preceding items, wherein R5is pyrazolyl or pyridinyl, each of which is substituted with 1 to 3 substituents individually selected from C1-3 alkyl, C1-3 haloalkyl, cyclopropyl, and C1-3 alkoxy.

[1276] 83. The compound according to any one of the preceding items, wherein R5is a 5- membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-3 alkyl, C1-3 haloalkyl, cyclopropyl, and C1-3 alkoxy.

[1277] 84. The compound according to any one of the preceding items, wherein R5is pyrazolyl optionally substituted with 1 to 3 individually selected substituents R7, wherein R7is individually selected from C1-3 alkyl, C1-3 haloalkyl, and cyclopropyl.

[1278] 85. The compound according to any one of the preceding items, wherein R5is of Formula (VII):

[1279]

[1280] Formula (VII)

[1281] wherein

[1282] R7is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl or H.

[1283] 86. The compound according to any one of the preceding items, wherein R5is of Formula (VIII):

[1284]

[1285] Formula (VIII)

[1286] wherein

[1287] R7is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl or H. 87. The compound according to any one of the preceding items, wherein R7is C3-6 cycloalkyl.

[1288] 88. The compound according to any one of the preceding items, wherein R7is C1-6 alkyl.

[1289] 89. The compound according to any one of the preceding items, wherein R2is of Formula (IX):

[1290]

[1291] Formula (IX)

[1292] wherein

[1293] X3is N or C(H);

[1294] R6ais H, F, or C1-3 alkyl;

[1295] R6bis H, F, or C1-3 alkyl; and

[1296] R7is C1-3 alkyl or cyclopropyl.

[1297] 90. The compound according to any one of the preceding items, wherein R7is C1-3 alkyl.

[1298] 91. The compound according to any one of the preceding items, wherein R7is - CH3.

[1299] 92. The compound according to any one of the preceding items, wherein R7is cyclopropyl.

[1300] 93. The compound according to any one of the preceding items, wherein R5is

[1301]

[1302] 94. The compound according to any one of the preceding items, wherein R5is

[1303]

[1304] 95. The compound according to any one of the preceding items, wherein R5is

[1305]

[1306] 96. The compound according to any one of the preceding items, wherein R5is triazolyl substituted with C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy or C1-6 haloalkoxy.

[1307] 97. The compound according to any one of the preceding items, wherein R5is triazolyl substituted with C1-3 alkyl.

[1308] 98. The compound according to any one of the preceding items, wherein R5is triazolyl substituted with CH3.

[1309] 99. The compound according to any one of the preceding items, wherein R5is triazolyl substituted with C3-6 cycloalkyl.

[1310] 100. The compound according to any one of the preceding items, wherein R5is triazolyl substituted with cyclopropyl.

[1311] 101. The compound according to any one of the preceding items, wherein R5

[1312]

[1313] 102. The compound according to any one of the preceding items, wherein R5

[1314]

[1315] 103. The compound according to any one of the preceding items, wherein R5is a 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy.

[1316] 104. The compound according to any one of the preceding items, wherein R5is a 6-membered heteroaryl substituted with 1 to 3 substituents individually selected from C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, C1-3 alkoxy and C1-3 haloalkoxy.

[1317] 105. The compound according to any one of the preceding items, wherein R5is a 6-membered heteroaryl substituted with 1 to 3 substituents individually selected from C1-3 alkyl and C1-3 alkoxy.

[1318] 106. The compound according to any one of the preceding items, wherein R5is a 6-membered heteroaryl substituted with C1-3 alkyl or C1-3 alkoxy.

[1319] 107. The compound according to any one of the preceding items, wherein R5is a 6-membered heteroaryl substituted with -CH3 or -OCH3. 108. The compound according to any one of the preceding items, wherein R5is a 6-membered heteroaryl substituted with C1-6 alkoxy.

[1320] 109. The compound according to any one of the preceding items, wherein R5is a 6-membered heteroaryl substituted with C1-3 alkoxy.

[1321] 110. The compound according to any one of the preceding items, wherein R5is a 6-membered heteroaryl substituted with methoxy.

[1322] 111. The compound according to any one of the preceding items, wherein R5is pyridinyl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy.

[1323] 112. The compound according to any one of the preceding items, wherein R5is pyridinyl substituted with C1-6 alkoxy.

[1324] 113. The compound according to any one of the preceding items, wherein R5is pyridinyl substituted with C1-3 alkoxy.

[1325] 114. The compound according to any one of the preceding items, wherein R5is pyridinyl substituted with methoxy.

[1326] 115. The compound according to any one of the preceding items, wherein R5

[1327]

[1328] 116. The compound according to any one of the preceding items, wherein R5is a pyridinyl substituted with C1-3 alkyl or C1-3 alkoxy.

[1329] 117. The compound according to any one of the preceding items, wherein R5is pyridinyl substituted with -CH3 or -OCH3.

[1330] 118. The compound according to any one of the preceding items, wherein R5is pyridinyl substituted with C1-6 alkyl.

[1331] 119. The compound according to any one of the preceding items, wherein R5is pyridinyl substituted with C1-3 alkyl.

[1332] 120. The compound according to any one of the preceding items, wherein R5is pyridinyl substituted with -CH3.

[1333] 121. The compound according to any one of the preceding items, wherein R5

[1334]

[1335] 122. The compound according to any one of the preceding items, wherein R6is individually H, F or CH3, and n is 0, 1 or 2. 123. The compound according to any one of the preceding items, wherein R6is individually F or CH3, and n is 0, 1 or 2.

[1336] 124. The compound according to any one of the preceding items, wherein R6is individually H.

[1337] 125. The compound according to any one of the preceding items, wherein R6is individually F.

[1338] 126. The compound according to any one of the preceding items, wherein R6is individually CH3.

[1339] 127. The compound according to any one of the preceding items, wherein R6ais R6.

[1340] 128. The compound according to any one of the preceding items, wherein R6ais H.

[1341] 129. The compound according to any one of the preceding items, wherein R6ais F.

[1342] 130. The compound according to any one of the preceding items, wherein R6ais CH3.

[1343] 131. The compound according to any one of the preceding items, wherein R6bis R6.

[1344] 132. The compound according to any one of the preceding items, wherein R6bis H.

[1345] 133. The compound according to any one of the preceding items, wherein R6bis F.

[1346] 134. The compound according to any one of the preceding items, wherein R6bis CH3.

[1347] 135. The compound according to any one of the preceding items, wherein R6ais H, and R6bis H.

[1348] 136. The compound according to any one of the preceding items, wherein R6ais H, and R6bis CH3.

[1349] 137. The compound according to any one of the preceding items, wherein R6ais CH3, and R6bis H.

[1350] 138. The compound according to any one of the preceding items, wherein R6ais CH3, and R6bis CH3.

[1351] 139. The compound according to any one of the preceding items, wherein R6ais F, and R6bis F. 140. The compound according to any one of the preceding items, wherein n is 0.

[1352] 141. The compound according to any one of the preceding items, wherein n is 1.

[1353] 142. The compound according to any one of the preceding items, wherein n is 2.

[1354] 143. The compound according to any one of the preceding items, wherein n is 2 and the two R6are attached to the same carbon atom in the ring.

[1355] 144. The compound according to any one of the preceding items, wherein n is 2 and the two R6are attached to different carbon atoms in the ring.

[1356] 145. The compound according to any one of the preceding items, wherein n is 2 and the two R6are -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s).

[1357] 146. The compound according to any one of the preceding items, wherein R2

[1358]

[1359] 147. The compound according to any one of the preceding items, wherein R2

[1360]

[1361]

[1362] The compound according to any one of the preceding items, wherein R2

[1363]

[1364] The compound according to any one of the preceding items, wherein R2

[1365]

[1366]

[1367] 157. The compound according to any one of the preceding items, wherein R2is

[1368]

[1369] 158. The compound according to any one of the preceding items, wherein R2

[1370]

[1371] 159. The compound according to any one of the preceding items, wherein R2

[1372]

[1373] 160. The compound according to any one of the preceding items, wherein R2

[1374]

[1375] 161. The compound according to any one of the preceding items, wherein R2

[1376]

[1377] 162. The compound according to any one of the preceding items, wherein R2

[1378]

[1379] 163. The compound according to any one of the preceding items, wherein R2

[1380]

[1381] 164. The compound according to any one of the preceding items, wherein R2

[1382]

[1383] 165. The compound according to any one of the preceding items, wherein R2

[1384]

[1385] 166. The compound according to any one of the preceding items, wherein R2

[1386]

[1387] 167. The compound according to any one of the preceding items, wherein R2

[1388]

[1389] 168. The compound according to any one of the preceding items, wherein R2

[1390]

[1391] 169. The compound according to any one of the preceding items, wherein R2

[1392]

[1393] 170. The compound according to any one of the preceding items, wherein R2

[1394]

[1395] 171. The compound according to any one of the preceding items, wherein R2

[1396]

[1397] 172. The compound according to any one of the preceding items, wherein R2

[1398]

[1399] 173. The compound according to any one of the preceding items, wherein R2

[1400]

[1401] 174. The compound according to any one of the preceding items, wherein R2

[1402]

[1403] is

[1404] 175. The compound according to any one of the preceding items, wherein R2

[1405]

[1406] 176. The compound according to any one of the preceding items, wherein R2

[1407]

[1408] 177. The compound according to any one of the preceding items, wherein R2

[1409]

[1410] 178. The compound according to any one of the preceding items, wherein R2

[1411] is

[1412]

[1413] 179. The compound according to any one of the preceding items, wherein R2

[1414]

[1415] 180. The compound according to any one of the preceding items, wherein R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy.

[1416] 181. The compound according to any one of the preceding items, wherein R3is phenyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN. 182. The compound according to any one of the preceding items, wherein R3is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN.

[1417] 183. The compound according to any one of the preceding items, wherein R3is of Formula (X):

[1418]

[1419] Formula (X)

[1420] wherein

[1421] R17is H, halogen, C1-3 alkyl, C1-3 haloalkyl, or C1-3 alkoxy;

[1422] R18is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN;

[1423] R19is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN;

[1424] R20is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN, and

[1425] R21is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN.

[1426] 184. The compound according to any one of the preceding items, wherein R3is of Formula (X):

[1427]

[1428] Formula (X)

[1429] wherein

[1430] R17is H or halogen;

[1431] R18is H or halogen;

[1432] R19is halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN;

[1433] R20is H or halogen; and

[1434] R21is H or halogen.

[1435] 185. The compound according to any one of the preceding items, wherein R3is of Formula (X):

[1436]

[1437] Formula (X)

[1438] wherein

[1439] R17is H or halogen;

[1440] R18is H;

[1441] R19is halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN;

[1442] R20is H; and

[1443] R21is H or halogen.

[1444] 186. The compound according to any one of the preceding items, wherein R17is halogen; R18is H; R19is halogen; R20is H; and R21is H.

[1445] 187. The compound according to any one of the preceding items, wherein R17is H.

[1446] 188. The compound according to any one of the preceding items, wherein R17is halogen.

[1447] 189. The compound according to any one of the preceding items, wherein R17is C1-3 alkyl.

[1448] 190. The compound according to any one of the preceding items, wherein R17is -CH3.

[1449] 191. The compound according to any one of the preceding items, wherein R18is H.

[1450] 192. The compound according to any one of the preceding items, wherein R18is halogen.

[1451] 193. The compound according to any one of the preceding items, wherein R18is F.

[1452] 194. The compound according to any one of the preceding items, wherein R19is halogen.

[1453] 195. The compound according to any one of the preceding items, wherein R19is F or Cl.

[1454] 196. The compound according to any one of the preceding items, wherein R19is C1-3 alkyl. 197. The compound according to any one of the preceding items, wherein R19is -CH3.

[1455] 198. The compound according to any one of the preceding items, wherein R19is C1-3 haloalkyl, such as –CF3or –CHF2.

[1456] 199. The compound according to any one of the preceding items, wherein R19is CN.

[1457] 200. The compound according to any one of the preceding items, wherein R19is C1-3 alkoxy.

[1458] 201. The compound according to any one of the preceding items, wherein R19is -OCH3.

[1459] 202. The compound according to any one of the preceding items, wherein R20is H.

[1460] 203. The compound according to any one of the preceding items, wherein R20is halogen.

[1461] 204. The compound according to any one of the preceding items, wherein R20is F.

[1462] 205. The compound according to any one of the preceding items, wherein R21is H.

[1463] 206. The compound according to any one of the preceding items, wherein R21is halogen.

[1464] 207. The compound according to any one of the preceding items, wherein R21is F.

[1465] 208. The compound according to any one of the preceding items, wherein R18is H and R20is H.

[1466] 209. The compound according to any one of the preceding items, wherein R18, R20, and R21are H.

[1467] 210. The compound according to any one of the preceding items, wherein R3is selected from the group consisting of:

[1468]

[1469] . The compound according to any one of the preceding items, wherein the compound is of Formula (XXIa) and R3is

[1470]

[1471]

[1472] . The compound according to any one of the preceding items, wherein the

[1473]

[1474] . The compound according to any one of the preceding items, wherein the compound is of Formula (XXII) and R3is

[1475]

[1476]

[1477] . The compound according to any one of the preceding items, wherein the

[1478]

[1479] . The compound according to any one of the preceding items, wherein the compound is of Formula (XXIIIa) and R3is

[1480]

[1481]

[1482] . The compound according to any one of the preceding items, wherein the

[1483]

[1484] . The compound according to any one of the preceding items, wherein the compound is of Formula (XXIV) and R3is

[1485]

[1486]

[1487] 219. The compound according to any one of the preceding items, wherein R3is selected from the group consisting of:

[1488]

[1489] 220. The compound according to any one of the preceding items, wherein R3is selected from the group consisting of:

[1490]

[1491] 221. The compound according to any one of the preceding items, wherein R3

[1492]

[1493] 229. The compound according to any one of the preceding items, wherein R3

[1494]

[1495] 230. The compound according to any one of the preceding items, wherein R3

[1496]

[1497] 231. The compound according to any one of the preceding items, wherein R3

[1498]

[1499] 232. The compound according to any one of the preceding items, wherein R3

[1500]

[1501] 233. The compound according to any one of the preceding items, wherein R3

[1502]

[1503] 234. The compound according to any one of the preceding items, wherein R3

[1504]

[1505] 235. The compound according to any one of the preceding items, wherein R3

[1506]

[1507] . The compound according to any one of the preceding items, wherein R3

[1508]

[1509] . The compound according to any one of the preceding items, wherein R3is C5-8 bicycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl and C1-3 haloalkyl.. The compound according to any one of the preceding items, wherein R3is bicyclo[1.1.1]pentyl optionally substituted with CF3 or CH3.

[1510] . The compound according to any one of the preceding items, wherein R3

[1511]

[1512] . The compound according to any one of the preceding items, wherein R1is a 6-membered heteroaryl optionally substituted with one or more, identical or different, R16; phenyl optionally substituted with one or more, identical or different, R16; or of Formula (III):

[1513]

[1514] Formula (III)

[1515] wherein

[1516] • X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[1517] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[1518] • X7is O, C(R9)(R10), or N(R11);

[1519] • R9is F or H;

[1520] • R10is F or H;

[1521] • R11is C1-3 alkyl optionally substituted with one or more F;

[1522] • R8is individually H, F or CH3, and m is 0, 1 or 2; or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2; and

[1523] R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl.

[1524] 241. The compound according to any one of the preceding items, wherein R1is a 5- to 6-membered heteroaryl optionally substituted with one or more, identical or different, R16.

[1525] 242. The compound according to any one of the preceding items, wherein R1is a 6-membered heteroaryl optionally substituted with one or more, identical or different, R16.

[1526] 243. The compound according to any one of the preceding items, wherein the 6-membered heteroaryl is pyridinyl.

[1527] 244. The compound according to any one of the preceding items, wherein the 6-membered heteroaryl is pyridin-4-yl.

[1528] 245. The compound according to any one of the preceding items, wherein the 6-membered heteroaryl is pyridin-3-yl.

[1529] 246. The compound according to any one of the preceding items, wherein the 6-membered heteroaryl is pyrimidinyl.

[1530] 247. The compound according to any one of the preceding items, wherein the 6-membered heteroaryl is pyrazinyl.

[1531] 248. The compound according to any one of the preceding items, wherein the 6-membered heteroaryl is 2-pyridone.

[1532] 249. The compound according to any one of the preceding items, wherein R1is phenyl optionally substituted with one or more, identical or different, R16. 250. The compound according to any one of the preceding items, wherein R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl.

[1533] 251. The compound according to any one of the preceding items, wherein R16is individually C1-3 alkoxy, C1-3 alkyl optionally substituted with C1-3 alkoxy, or - CN. 252. The compound according to any one of the preceding items, wherein R16is C1-6 alkoxy.

[1534] 253. The compound according to any one of the preceding items, wherein R16is C1-3 alkoxy.

[1535] 254. The compound according to any one of the preceding items, wherein R16is -OCH3.

[1536] 255. The compound according to any one of the preceding items, wherein R16is C1-6 alkyl substituted with C1-3 alkoxy.

[1537] 256. The compound according to any one of the preceding items, wherein R16is -CH2CH2OCH3.

[1538] 257. The compound according to any one of the preceding items, wherein R16is C1-6 alkyl.

[1539] 258. The compound according to any one of the preceding items, wherein R16is C1-3 alkyl.

[1540] 259. The compound according to any one of the preceding items, wherein R16is -CH3.

[1541] 260. The compound according to any one of the preceding items, wherein R16is halogen.

[1542] 261. The compound according to any one of the preceding items, wherein R16is C1-6 haloalkoxy.

[1543] 262. The compound according to any one of the preceding items, wherein R16is -CN.

[1544] 263. The compound according to any one of the preceding items, wherein R16is C3-6 cycloalkyl.

[1545] 264. The compound according to any one of the preceding items, wherein R16is azetidinyl optionally substituted with C1-3 alkyl.

[1546] 265. The compound according to any one of the preceding items, wherein R16is -O-azetidinyl optionally substituted with C1-3 alkyl.

[1547] 266. The compound according to any one of the preceding items, wherein R16

[1548]

[1549] 267. The compound according to any one of the preceding items, wherein R1

[1550]

[1551] 268. The compound according to any one of the preceding items, wherein R1

[1552]

[1553] 269. The compound according to any one of the preceding items, wherein R1

[1554]

[1555] 270. The compound according to any one of the preceding items, wherein R1

[1556]

[1557] 271. The compound according to any one of the preceding items, wherein R1

[1558]

[1559] 272. The compound according to any one of the preceding items, wherein R1

[1560]

[1561] 273. The compound according to any one of the preceding items, wherein R1

[1562]

[1563] is

[1564] 274. The compound according to any one of the preceding items, wherein R1

[1565]

[1566] 275. The compound according to any one of the preceding items, wherein R1

[1567]

[1568] 276. The compound according to any one of the preceding items, wherein R1

[1569]

[1570] 277. The compound according to any one of the preceding items, wherein R1

[1571]

[1572] 278. The compound according to any one of the preceding items, wherein R1

[1573]

[1574] 279. The compound according to any one of the preceding items, wherein R1

[1575]

[1576] is

[1577] 280. The compound according to any one of the preceding items, wherein R1

[1578]

[1579] is

[1580] 281. The compound according to any one of the preceding items, wherein R1

[1581]

[1582] 284. The compound according to any one of the preceding items, wherein R1

[1583]

[1584] 287. The compound according to any one of the preceding items, wherein R1

[1585]

[1586] 288. The compound according to any one of the preceding items, wherein R1

[1587]

[1588] 289. The compound according to any one of the preceding items, wherein R1is of Formula (III):

[1589]

[1590] Formula (III)

[1591] wherein

[1592] - X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[1593] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[1594] - X7is O, C(R9)(R10), or N(R11);

[1595] - R9is F or H;

[1596] - R10is F or H;

[1597] R11is C1-3 alkyl optionally substituted with one or more F; and

[1598] R8is individually H, F or CH3, and m is 0, 1 or 2;

[1599] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2.

[1600] 290. The compound according to any one of the preceding items, wherein X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F.

[1601] 291. The compound according to any one of the preceding items, wherein X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together.

[1602] 292. The compound according to any one of the preceding items, wherein R1is of Formula (XI):

[1603]

[1604] Formula (XI)

[1605] wherein

[1606] - R12is H or F;

[1607] - R14is H or F;

[1608] - X7is O, C(R9)(R10), or N(R11);

[1609] - R9is F or H;

[1610] - R10is F or H;

[1611] R11is C1-3 alkyl optionally substituted with one or more F; and

[1612] R8is individually H, F or CH3, and m is 0, 1 or 2;

[1613] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2.

[1614] 293. The compound according to any one of the preceding items, wherein R8is individually H, F or CH3, and m is 0, 1 or 2.

[1615] 294. The compound according to any one of the preceding items, wherein m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2.

[1616] 295. The compound according to any one of the preceding items, wherein R8is H.

[1617] 296. The compound according to any one of the preceding items, wherein R8is F.

[1618] 297. The compound according to any one of the preceding items, wherein m is 0.

[1619] 298. The compound according to any one of the preceding items, wherein R12is H.

[1620] 299. The compound according to any one of the preceding items, wherein R13is H.

[1621] 300. The compound according to any one of the preceding items, wherein X5is CH2. 301. The compound according to any one of the preceding items, wherein R14is H.

[1622] 302. The compound according to any one of the preceding items, wherein R15is H.

[1623] 303. The compound according to any one of the preceding items, wherein R15is C1-3 alkyl.

[1624] 304. The compound according to any one of the preceding items, wherein R15is CH3.

[1625] 305. The compound according to any one of the preceding items, wherein R12and R14are H.

[1626] 306. The compound according to any one of the preceding items, wherein X6is CH2.

[1627] 307. The compound according to any one of the preceding items, wherein X7is O.

[1628] 308. The compound according to any one of the preceding items, wherein X7is C(R9)(R10).

[1629] 309. The compound according to any one of the preceding items, wherein R9is H.

[1630] 310. The compound according to any one of the preceding items, wherein R10is H.

[1631] 311. The compound according to any one of the preceding items, wherein X7is CH2.

[1632] 312. The compound according to any one of the preceding items, wherein R9is F.

[1633] 313. The compound according to any one of the preceding items, wherein R10is F.

[1634] 314. The compound according to any one of the preceding items, wherein X7is CF2.

[1635] 315. The compound according to any one of the preceding items, wherein X7is N(R11).

[1636] 316. The compound according to any one of the preceding items, wherein R11is CH3.

[1637] 317. The compound according to any one of the preceding items, wherein R1

[1638]

[1639] is 318. The compound according to any one of the preceding items, wherein R1

[1640]

[1641] 319. The compound according to any one of the preceding items, wherein R1

[1642]

[1643] 320. The compound according to any one of the preceding items, wherein R1

[1644]

[1645] 321. The compound according to any one of the preceding items, wherein R1

[1646]

[1647] 322. The compound according to any one of the preceding items, wherein R1

[1648]

[1649] 323. The compound according to any one of the preceding items, wherein the halogen is individually F.

[1650] 324. The compound according to any one of the preceding items, wherein the halogen is individually Cl.

[1651] 325. The compound according to any one of the preceding items, provided that when R1is a 5-membered heteroaryl, then X1is N.

[1652] 326. The compound according to any one of the preceding items, wherein the compound is not 6-(-2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6-methylmorpholino)-4- (2-fluoro-4-(trifluoromethyl)phenyl)-2-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-1-one.

[1653] 327. The compound according to any one of the preceding items, wherein the compound is not 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6- methylmorpholino)-4-(2-fluoro-4-(trifluoromethyl)phenyl)-2-(1-methyl-1H- pyrazol-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one.

[1654] 328. A compound of Formula (I):

[1655]

[1656] Formula (I)

[1657] wherein:

[1658] - X1is N or C(H);

[1659] - X2is N or C(H);

[1660] - R1is 5- to 6-membered heteroaryl optionally substituted with one or more, identical or different, R16; phenyl optionally substituted with one or more, identical or different, R16; or of Formula (III):

[1661]

[1662] Formula (III)

[1663] wherein

[1664] • X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or

[1665] X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;

[1666] • X7is O, C(R9)(R10), or N(R11);

[1667] • R9is F or H;

[1668] • R10is F or H;

[1669] • R11is C1-3 alkyl optionally substituted with one or more F;

[1670] • R8is individually H, F or CH3, and m is 0, 1 or 2;

[1671] or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2; - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl;

[1672] - R2is of Formula (II):

[1673]

[1674] Formula (II)

[1675] wherein

[1676] - X3is N or C(H);

[1677] - X4is O or N(R22);

[1678] - R22is H or C1-3 alkyl optionally substituted with one or more F;

[1679] - R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and

[1680] - R6is individually H, F or CH3, and n is 0, 1 or 2;

[1681] or n is 2 and the two R6are each -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);

[1682] - R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[1683] or a pharmaceutically acceptable salt thereof.

[1684] . The compound according to item 328, wherein X1is N and X2is N, or a pharmaceutically acceptable salt thereof.

[1685] . The compound according to item 328, wherein X1is C(H) and X2is N, or a pharmaceutically acceptable salt thereof.

[1686] . The compound according to any one of items 328 to 330, wherein R1is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or 2-pyridone, each of which is optionally substituted with one or more, identical or different, substituents selected from the group consisting of C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, and -O-azetidinyl optionally substituted with C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[1687] . The compound according to any one of items 328 to 331, wherein R1is

[1688]

[1689]

[1690] pharmaceutically acceptable salt thereof

[1691] . The compound according to any one of items 328 to 330, wherein R1is of Formula (XI):

[1692]

[1693] Formula (XI)

[1694] wherein

[1695] - R12is H or F;

[1696] - R14is H or F;

[1697] - X7is O, C(R9)(R10), or N(R11);

[1698] - R9is F or H;

[1699] - R10is F or H;

[1700] R11is C1-3 alkyl optionally substituted with one or more F;

[1701] R8is individually H, F or CH3; and

[1702] m is 0, 1 or 2,

[1703] or a pharmaceutically acceptable salt thereof. . The compound according to any one of items 328 to 330, wherein R1is

[1704]

[1705] pharmaceutically acceptable salt thereof.

[1706] . The compound according to any one of items 328 to 334, wherein R2is of Formula (V):

[1707]

[1708] Formula (V)

[1709] or a pharmaceutically acceptable salt thereof.

[1710] . The compound according to any one of items 328 to 334, wherein R2is of Formula (VI):

[1711]

[1712] Formula (VI)

[1713] or a pharmaceutically acceptable salt thereof.

[1714] . The compound according to any one of items 328 to 334, wherein R2is of Formula (XII):

[1715]

[1716] Formula (XII)

[1717] or a pharmaceutically acceptable salt thereof.

[1718] . The compound according to any one of items 328 to 337, wherein R5is of Formula (VIII):

[1719]

[1720] Formula (VIII) wherein R7is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl or H, or a pharmaceutically acceptable salt thereof.

[1721] . The compound according to any one of items 328 to 334, wherein R2is

[1722]

[1723] acceptable salt thereof.

[1724] . The compound according to any one of items 328 to 334, wherein R2is

[1725]

[1726] acceptable salt thereof. 341. The compound according to any one of items 328 to 340, wherein R3is

[1727]

[1728]

[1729]

[1730] ptable salt thereof.

[1731] 342. The compound according to any one of the preceding items, wherein the compound is

[1732] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1733] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methylpyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;

[1734] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(3-methoxyphenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-methylpyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(4-methoxyphenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-(3-oxabicyclo[3.1.0]hexan-6-yl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(4-fluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1735] 4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1736] 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1737] (S)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1738] (R)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1739] 4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1740] (S)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1741] (R)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1742] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,5-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1743] 4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1744] (S)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1745] (R)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1746] 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,5-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1747] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,6-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1748] 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,6-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1749] 2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methylpiperazin-1-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1750] (S)-2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methylpiperazin-1-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1751] (R)-2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methylpiperazin-1-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1752] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1753] 4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1754] (S)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1755] (R)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1756] 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1757] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1758] 3-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;

[1759] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(5-methylpyrazin-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 5-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)picolinonitrile;

[1760] 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)picolinonitrile;

[1761] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1762] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-methylpyrimidin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methylpyrimidin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(4-chloro-2-fluorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1763] 4-(4-chloro-2-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile;

[1764] 3-fluoro-4-(2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)benzonitrile; 4-(4-chlorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1765] 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)benzonitrile; 4-(4-chlorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)- 6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1766] 4-(4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-7-oxo-5, 7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;

[1767] (S)-4-(4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)- 7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;

[1768] (R)-4-(4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)- 7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;

[1769] 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-7-oxo-4-(2,4,6-trifluorophenyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(4-fluorophenyl)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1770] 4-(2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-7-oxo-4-(2,4,6-trifluorophenyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;

[1771] 4-(2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin- 5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)benzonitrile;

[1772] 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-2-(2-methylpyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-2-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 4-(4-fluorophenyl)-6-(6-methoxypyridin-3-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1773] 4-(4-fluorophenyl)-6-(2-methoxypyridin-4-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1774] 4-(2,4-difluorophenyl)-6-(2-methoxypyridin-4-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1775] 4-(2,4-difluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1776] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(4-fluorophenyl)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1777] 4-(4-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1778] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methoxy-3-methylpyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1779] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2,4-dimethylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1780] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1781] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-(methoxymethyl)pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2-(2-methylpyrimidin-5-yl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

[1782] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1783] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(4,4-difluorocyclohexyl)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(4-chloro-2-fluorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin- 7-one;

[1784] 4-(4-chloro-2-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1785] 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-((1-methylazetidin-3-yl)oxy)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1786] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(2,4-difluorophenyl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1787] 4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1788] 4-(2,4-difluorophenyl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1789] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((S)-2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((R)-2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin- 7-one;

[1790] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((R)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1791] (S)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1792] (R)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1793] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1794] 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((R)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;

[1795] (S)-4-(4-chloro-2-fluorophenyl)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; or

[1796] (R)-4-(4-chloro-2-fluorophenyl)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one,

[1797] or a pharmaceutically acceptable salt thereof.

[1798] 343. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is a TREM2 modulator, such as a TREM2 activator, such as a TREM2 agonist.

[1799] 344. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound enhances or activates TREM2 signaling through DAP12; and / or wherein the compound induces phosphorylation of a kinase that interacts with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b; and / or wherein the compound enhances TREM2-induced phosphorylation levels of the Syk kinase.

[1800] 345. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound increases the expression of one or more TREM2 regulated genes, such as wherein the compound increases the expression of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119. 346. A pharmaceutical composition comprising a compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[1801] 347. The compound according to any one of items 1 to 345, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 346, for use as a medicament.

[1802] 348. The compound according to any one of items 1 to 345, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 346, for use in the treatment of a condition associated with a loss of function of TREM2, such as for use in the treatment of a condition associated with a mutation of TREM2.

[1803] 349. The compound according to any one of items 1 to 345, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 346, for use in the treatment of a neurodegenerative disease.

[1804] 350. The compound according to any one of items 1 to 345, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 346, wherein said neurodegenerative disease is selected from the group consisting of a tauopathy, a TDP-43 proteinopathy, a synucleinopathy, dementia, amyloidosis, a demyelinating disorder of the CNS, a demyelinating disorder of the PNS, a Leukoencephalopathy, a leukodystrophy, a transmissible spongiform encephalopathy (TSE) and a lysosomal storage disorder (LSD).

[1805] 351. The compound according to any one of items 1 to 345, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 346, for use in the treatment of a neurodegenerative disease selected from the group consisting of Alzheimer’s disease, Frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), Parkinson’s disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington disease, Amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease, prion disease and stroke.

[1806] 352. The compound according to any one of items 1 to 345, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 346, for use in the treatment of a disease selected from the group consisting of arthritis, rheumatoid arthritis, pyle disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, dysosteoplasia, autism spectrum disorders, autism and Aspergers syndrome, traumatic brain injuries (TBI), spinal cord injuries, muscular dystrophy, myotonic dystrophy, inclusionbody myositis, systemic lupus erythematosus (SLE), RA, gout, bowel conditions, Inflammatory bowel disease (IBD), metabolic syndrome, obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver disease, alcoholic and non-alcoholic steatohepatitis, Amyloidosis.

[1807] . The compound or pharmaceutical composition for use according to any one of items 347 to 352, wherein said compound is administered in an amount of about 0.01 mg / kg to about 100 mg / kg bodyweight / day.

[1808] . The compound or pharmaceutical composition for use according to any one of items 347 to 352, wherein said compound is administered via enteral delivery, oral delivery, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery.

[1809] . A method for treatment of a condition associated with a loss of function of TREM2, such as a neurodegenerative disease, said method comprising administering a therapeutically effective amount of a compound according to any one of items 1 to 345, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 346, to a subject in need thereof.. Use of a compound according to any one of items 1 to 345, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 346, for the manufacture of a medicament for the treatment of a condition associated with a loss of function of TREM2, such as a neurodegenerative disease.

[1810] . A method of enhancing or increasing TREM2 activity, such as a method of one or more of i) enhancing or activating TREM2 signaling through DAP12, ii) inducing phosphorylation of a kinase that interacts with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b, iii) enhancing TREM2-induced phosphorylation levels of the Syk kinase, Iv) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes, and / or v) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119; in a subject in need thereof, such as in a subject having a neurodegenerative disease, said method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, according to any one of items 1 to 345.

[1811] Examples

[1812] Abbreviations

[1813] ACN Acetonitrile

[1814] DCM Dichloromethane

[1815] DME Dimethoxyethane

[1816] DCE Dichloroethane

[1817] EA Ethyl acetate

[1818] HPLC High performance liquid chromatography

[1819] MeCN Acetonitrile

[1820] MeOH Methanol

[1821] EtOH Ethanol

[1822] THF Tetrahydrofuran

[1823] DMF Dimethyl formamide

[1824] TFA Trifluoroacetic Acid

[1825] TEA Triethyl amine

[1826] DIPEA Diisopropylethylamine

[1827] NBS N-bromo succinimide

[1828] Pd / C Palladium on carbon

[1829] NH4OAc Ammonium acetate

[1830] dba Dibenzylideneacetone

[1831] dppf [1,1'-Bis(diphenylphosphino) ferrocene

[1832] Pd-118 Dichloro[1, 1 ’-bis(di-tert-butylphosphino)ferrocene]palladium(l I) rt Room temperature

[1833] Rt Retention time

[1834] mL millilitre

[1835] mg milligram

[1836] g gram

[1837] mmol millimole mol mole

[1838] DMAP 4-dimethylaminopiridine

[1839] AIBN Azobisisobutyronitrile

[1840] LCMS Liquid chromatography mass spectrometry

[1841] TMEDA Tetramethylethylenediamine

[1842] LCMS conditions

[1843] Condition A

[1844] LCMS Column- Acquity BEH C18 (50 x 2.1 mm, 1.7u), Initially (90% [0.05% HCOOH in water] and 10% [0.05% HCOOH in CH3CN: water (90:10)] is held up to 0.75 min, then to 50% [0.05% HCOOH in water] and 50% [0.05% HCOOH in CH3CN: water (90:10)] in 1.00 min, then to 2% [0.05% HCOOH in water] and 98% [0.05% HCOOH in CH3CN: water (90:10)] in 2.00 min held this mobile phase composition up to 2.25 min and finally back to initial condition in 2.60 min and held up to 3.00 min). Flow: 0.60 ml / min.

[1845] Condition B

[1846] Column -Xbridge C18 (4.6x50 mm, 5 u) mobile phase: 90 % [10 mM Ammonium Acetate in Water] and 10 % [CH3CN] to 70% [10 mM Ammonium Acetate in Water] and 30% [CH3CN] in 1.5 min, further to 10% [10 mM Ammonium Acetate in Water] and 90% [CH3CN] in 3.00 min, held this mobile phase composition up to 4.00 min and finally back to initial condition in 5.00 min. Flow =1.20 ml / min

[1847] Condition C

[1848] LCMS Column- Acquity BEH C8 (50 x 2.1 mm, 1.7u), Initially (95% [0.05% HCOOH in water] and 5% [0.05% HCOOH in CH3CN: water (90:10)] is held up to 0.75 min, then to 75% [0.05% HCOOH in water] and 25% [0.05% HCOOH in CH3CN: water (90:10)] in 1.50 min, then to 5% [0.05% HCOOH in water] and 95% [0.05% HCOOH in CH₃CN: water (90:10)] in 3.00 min held this mobile phase composition up to 4.00 min and finally back to initial condition in 4.50 min and held up to 5.10 min). Flow: 0.80 ml / min.

[1849] Condition D

[1850] Column- Xbridge C18 column (3.5 pm, 50 x 3 mm), (initially 95% [5 mM NH4OAc in water] and 5% [5 mM NH4OAc in ACN: Water (90:10)] held for 0.75 min, then to 70% [5 mM NH4OAc in water] and 30% [5 mM NH4OAc in ACN: Water (90:10) ] in 1.00 min, and finally 2% [5 mM NH4OAc in water] and 98% [5 mM NH4OAc in ACN: Water (90:10) ] in 2.00 min, held this mobile phase composition up to 2.50 min and finally back to initial condition in 2.75 min and held this composition up to 3.0 min). Flow: 1.20 ml / min. Condition E Column- YMC Triart C18 (33 x 2.1 mm, 3u), (initially 98% [0.05% HCOOH in water] and 2% [0.05% HCOOH in ACN: Water (90:10)] held for 0.75 min, then to 90% [0.05% HCOOH in water] and 10% [0.05% HCOOH in ACN: Water (90:10) ] in 1.0 min, further to 2% [0.05% HCOOH in water] and 98% [0.05% HCOOH in ACN: Water (90:10) ] in 2.00 min, held this mobile phase composition up to 2.50 min and finally back to initial condition in 4.90 min and held this composition up to 3.0 min). Flow: 1.0 ml / min.

[1851] Reverse Phase Prep-Purification method

[1852] Unless stated otherwise, preparative HPLC was done on Waters auto purification instrument operating at ambient temperature and flow rate of 16 mL / min

[1853] Prep-A

[1854] Column name: YMC-Actus C18 (250 x20 mm, 5p). Mobile phase: A = 20Mm Ammonium bicarbonate in water, B = Acetonitrile; Gradient Profile: Mobile phase initial composition of 60% A and 40% B, then 40% A and 60% B in 3 min, then to 20% A and 80% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min

[1855] Prep-B

[1856] Column name: Chromcore C18 (250 x 21.2 mm, 5p). Mobile phase: A = 20mM Ammonium Bicarbonate in water, B=Acetonitrile: Methanol(50:50); Gradient Profile: Mobile phase initial composition of 60% A and 40% B, then 35% A and 65% B in 3 min, then to 5% A and 95% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min.

[1857] Prep-C

[1858] Column name: CHROMCORE 120 C18,5 pm (21.2 x 250mm). Mobile phase: A=Acetonitrile, B = 20mM Ammonium Bicarbonate in water; Gradient Profile: Mobile phase initial composition of 30% A and 70% B, then 50% A and 50% B in 3 min, then to 61.6% A and 38.4% B in 14 min., then to 100% A and 0% B in 14.1 min., held this composition up to 18 min. for column washing, then returned to initial composition in 18.1 min. and held till 21 min.

[1859] Prep-D

[1860] Preparative HPLC was done on Gilson auto purification instrument equipped with DAD Detector. Column name: Column name: YMC (150 x 20 mm, 5pm) at ambient temperature and flow rate of 18mL / min. Mobile phase: A= 20mM Ammonium Bicarbonate, B= ACN. Gradient profile: Mobile phase initial composition of 50% A and 50% B, then 25% A and 75% B in 10 min, then to 5% A and 95% B in 10.5min, held in this composition up to 13 min for column washing, then returned to initial composition in 13.5 min and held till 15 min.

[1861] Prep-E

[1862] Column name: GEMINI-NX C18 (250 X 21.2 mm, 5 p). Mobile phase: A = Acetonitrile, B=20mM Ammonium Bicarbonate in water; Gradient Profile: Mobile phase initial composition of 25% A and 75% B, then 50% A and 50% B in 3 min, then to 56.8% A and 43.2% B in 16 min., then to 100% A and 0% B in 16.5 min., held this composition up to 20.5 min. for column washing, then returned to initial composition in 21 min. and held till 24 min.

[1863] Prep-F

[1864] Preparative HPLC was done on Gilson auto purification instrument equipped with UV Detector set to 220nm. Column name: Column name: LYMC C-18 (250 x 20 mm, 5pm) at ambient temperature and flow rate of 16mL / min. Mobile phase: A = 20mM Ammonium bicarbonate in water, B= ACN. Gradient profile: Mobile phase initial composition of 40% A and 60% B, then 40% A and 60% B in 3 min, then 10% A and 90% B in 18 min, then to 5% A and 95% B in 19 min, held in this composition up to 22 min for column washing, then returned to initial composition in 22.5 min and held till 26min.

[1865] Prep-G

[1866] Preparative HPLC Was done in WATERS BGM 2545 EQUIPPED with WATERS PDA detector 2998 set to multiple-wavelength UV (200-400nm) detection. Column name: Atlantis T3 (250 x 19 mm, 10p) operating at ambient temperature and flow rate of 16 mL / min. Mobile phase: A= 0.1% Trifluoroacetic acid in water, B=Acetonitrile. Gradient profile: Mobile phase initial composition of 98% A and 2% B and held for 5 min, then to 5% A and 95% B in 6 min,, held in this composition up to 10 min for column washing, then returned to initial composition in 10.5min and held till 12 min.

[1867] Prep-H

[1868] Column name: Column name: YMC Actus triart C18 (100 x 20 mm, 3p). Mobile phase: Mobile phase: A= 20mM Ammonium bicarbonate in water, B= Acetonitrile. Gradient profile: Mobile phase initial composition of 70% A and 30% B, then to 50% A and 50% B in 2 min, then to 35% A and 65% B in 13 min, then 5% A and 95% B in 13.5 min, held in this composition up to 16 min for column washing with flow rate of 24 mL / min, then returned to initial composition in 16.5 min and held till 18 min. Normal Phase Chiral Prep Methods

[1869] NP Chiral Method-1:

[1870] Chiral separation was done on Agilent 1200 series instrument. Column name: CHIRALPAK IG (250 X 30 mm) 5. Operating at ambient temperature and flow rate is 27.0 mL / min. Mobile phase was mixture of 70% Hexane, 15% DCM, 15% EtOH, held this isocratic mixture run up to 30 min with wavelength of 318 nm.

[1871] NP Chiral Method-2

[1872] Chiral separation was done on Agilent 1200 series instrument. Column name: CHIRALPAK IC (250 X 20 mm) 5. Operating at ambient temperature and flow rate is 18.0 mL / min. Mobile phase was mixture of 80% Hexane, 10% DCM and 10% EtOH held this isocratic mixture run up to 22 min with wavelength of 316 nm.

[1873] Chiral SFC Prep Methods:

[1874] SFC Chiral Method-1

[1875] HPLC SFC Prep Purification of CR635-23702-16-F (T. N-117) (3677 mg) is currently running on Waters SFC PREP 150 instruments equipped with Waters 2489 UV / Visible Detector by using CHIRALPAK IG (30.0 mm x 250 mm), 5p Column operating at 35°C temperature, maintaining flow rate of 90 ml / min, using 75% CO2 in super critical state & 25% of 100% MeOH as Mobile phase. Run this isocratic mixture up to 8.0 minutes and also maintained isobaric condition of 100 bar at 220 nm wavelength.

[1876] Synthesis of Intermediates

[1877] Synthesis of (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine (Intermediate 1-1)

[1878] Step-1 - Preparation of 4-bromo-1-cyclopropyl-1H-pyrazole:

[1879]

[1880] To a stirred solution of 4-bromo-1H-pyrazole (10 g, 68.02 mmol) in dichloroethane (200 mL) were added cyclopropyl boronic acid (11.7 g, 137.9 mmol), 2,2- bipyridyl (11.7 g, 74.8 mmol) and sodium carbonate (15.9 g, 149.7 mmol), purged with oxygen and copper acetate (13.6 g, 74.8 mmol) was added. Resulting mixture was heated at 65 °C for 16 h under oxygen atmosphere. Reaction mixture was filtered through a pad of celite bed, washed with methanol and concentrated under reduced pressure. Concentrated mass was diluted with ethyl acetate, washed with brine, dried over sodium sulphate, and concentrated under reduced pressure. Crude product was purified by combi-flash chromatography using 10-15% ethyl acetate in hexane to afford 4-bromo-1-cyclopropyl- 1H-pyrazole (6.5 g, 51% yield) as colourless liquid.

[1881] LCMS Condition D: Rt = 1.91 min. m / z 187.2 [M+H]+.

[1882] Step-2 - Preparation of 2-chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)ethan-1-one:

[1883]

[1884] To a stirred solution of 4-bromo-1-cyclopropyl-1H-pyrazole (5 g, 26.7 mmol) in dry THF (75 mL) at -78 °C, n-BuLi (1.8 M in hexane; 22 mL, 40.1 mmol) was added dropwise under argon atmosphere. Resulting mixture was continued at -78 °C for 1 h. A solution of 2-chloro-N-methoxy-N-methylacetamide (5.5 g, 40.1 mmol) in THF (25 mL) was then slowly added to it and reaction was prolonged for another 1 h at -78 °C. Reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. Combined organic layer was dried over sodium sulphate and concentrated under reduced pressure. Crude material was purified by column chromatography using 20-50% ethyl acetate in hexane to afford 2-chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)ethan-1-one (2.5 g, 50% yield) as off-white solid.

[1885] LCMS Condition A: Rt = 1.53 min. m / z 185.2 [M+H]+.

[1886] Step-3 - Preparation of (R)-2-(benzyl(2-hydroxypropyl)amino)-1-(1-cyclopropyl-1H- pyrazol-4-yl)ethan-1 -one:

[1887]

[1888] To a suspension of 2-chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)ethan-1-one (5 g, 31.6 mmol) in acetonitrile (50 mL) were added (R)-1-(benzylamino)propan-2-ol (5.7 g, 38.3 mmol) and potassium carbonate (8.8 g, 63.2 mmol). Resulting mixture was heated at 60 °C for 16 h. Reaction mixture was concentrated under reduced pressure. Concentrated mass was diluted with cold water and extracted with ethyl acetate. Combined organic layer was dried over sodium sulphate and concentrated under vacuo. Crude material was purified by column chromatography using 40-60% ethyl acetate in hexane to afford (R)-2-(benzyl(2-hydroxypropyl)amino)-1-(1-cyclopropyl-1H-pyrazol-4-yl)ethan-1-one (6 g, 69% yield) as yellow oil.

[1889] LCMS Condition E: Rt = 3.12 min. m / z 314.2 [M+H]+.

[1890] Step-4 - Preparation of (2R)-1-(benzyl(2-(1-cyclopropyl-1H-pyrazol-4-yl)-2-hydroxyethyl)amino)propan-2-ol:

[1891]

[1892] To a stirred solution of (R)-2-(benzyl(2-hydroxypropyl)amino)-1-(1-cyclopropyl-1H-pyrazol-4-yl)ethan-1-one (4 g, 14.6 mmol) in methanol (50 mL) was portion-wise added NaBH4 (1.2 g, 29.3 mmol) at 0 °C over a period of 20 min and reaction was kept stirring for additional 20 min at 0 °C. Resulting mixture was then warmed to rt and stirred for 2 h. Reaction mixture was quenched with cold water and concentrated under reduced pressure. Residual mass was diluted with dichloromethane, washed with water, brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. Crude material was purified by column chromatography using 5-7% methanol in dichloromethane to afford (2R)-1-(benzyl(2-(1-cyclopropyl-1H-pyrazol-4-yl)-2-hydroxyethyl)amino)propan-2-ol (2.3 g, 59% yield) as yellow sticky oil.

[1893] LCMS Condition A: Rt = 1.29 min. m / z 317.2 [M+H]+.

[1894] Step-5 - Preparation of (2S,6R)-4-benzyl-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine:

[1895]

[1896] To a stirred solution of (2R)-1-(benzyl(2-(1-cyclopropyl-1H-pyrazol-4-yl)-2-hydroxyethyl)amino)propan-2-ol (10 g, 31.7 mmol) in 1,4-dioxane (30 mL) was added aqueous HCI (6N, 30.0 mL). Resulting mixture was heated at 120 °C for 4 h. Reaction mixture was evaporated under reduced pressure. Crude mass was neutralized with saturated NaHCO3solution under cold condition and extracted with ethyl acetate. Organic portion was dried over Na2SO4 and concentrated under reduced pressure. Crude mass was purified by combiflash chromatography (10-30% ethyl acetate in hexane) to get (2R,6R)-4-benzyl-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine (eluted earlier [Peak-1], 2.8 g, 29.7% yield) as colourless gum and (2S,6R)-4-benzyl-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine (eluted latter [Peak-2], 4.2 g, 44% yield) as yellow gum. Structure was confirmed by 2D NMR.

[1897] Peak-1: 1H NMR (400 MHz, DMSO D6) 57.68 (s, 1H), 7.40 (s, 1H), 7.36-7.24 (m, 5H), 4.77-4.75 (m, 1H), 3.75-3.63 (m, 2H), 3.49-3.38 (m, 2H), 2.66-2.55 (m, 2H), 2.43-2.33 (m, 1H), 1.98-1.94 (m, 1H), 1.05 (d, J= 6.36 Hz, 3H), 0.96-0.89 (m, 4H).

[1898] LCMS Condition A: Rt = 1.42 min. m / z 298.2 [M+H]+.

[1899] Peak-2: 1H NMR (400 MHz, DMSO D6) 57.67 (s, 1H), 7.32-7.25 (m, 6H), 4.46-4.44 (m, 1H), 3.66-3.62 (m, 2H), 3.48 (s, 2H), 2.77-2.67 (m, 2H), 2.03-1.99 (m, 1H), 1.77-1.71 (m, 1H), 1.04 (d, J= 6.12 Hz, 3H), 0.96-0.88 (m, 4H).

[1900] LCMS Condition A: Rt = 1.42 min. m / z 298.2 [M+H]+.

[1901] Step-6 - Preparation of (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine (Intermediate 1-1):

[1902]

[1903] To a stirred solution of (2S,6R)-4-benzyl-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine (1 g, 3.4 mmol) in methanol (15 mL) was added ammonium formate (1.6 g,16.8 mmol). Reaction mixture was degassed with argon. Pd(OH)2 (0.3 g, 2.02 mmol) was added to reaction mixture under inert atmosphere. Resulting mixture was heated at 80 °C for 30 min. Reaction mixture was filtered through celite bed and washed with methanol. Filtrate portion was concentrated under reduced pressure. Concentrated mass was purified by combiflash chromatography (2-5% methanol in DCM) to get (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine (450 mg, 64% yield) as light-yellow liquid.

[1904] 1H NMR (400 MHz, DMSO-d6) 57.66 (s, 1H), 7.32 (s, 1H), 4.29 (d, J= 8.4 Hz, 1H), 3.64-3.53 (m, 2H), 2.80-2.76 (m, 2H), 2.67 (br s, 1 H), 2.32-2.26 (m, 1 H) 1.06-0.94 (m, 7H). LCMS Condition A: Rt = 0.53 min. m / z 208.3 [M+H]+.

[1905] Intermediate 1-1-1 and 1-1-2 were synthesized by using similar procedures described in Intermediate 1-1 in five steps (Step-2 to 6) (Table 1)

[1906] Table 1

[1907]

[1908] Table 2 describes analytical data analysis and information of Intermediates 1-1-1 & 1-1-

[1909] 2.

[1910] Table 2

[1911]

[1912] Synthesis of 1-methyl-2-(1-methyl-1H-pyrazol-4-yl)piperazine, TFA salt (Intermediate 1-1-3)

[1913] Step-1 - Preparation of 2-(1-methyl-1H-pyrazol-4-yl)pyrazine:

[1914]

[1915] To a stirred solution of 2-chloropyrazine (5 gm, 43.66 mmol) and 2-methyl-4-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.9 gm, 52.39 mmol) in DME (100 mL) and water (20 mL) was added Na2CO3 (11.5 g, 109.14 mmol) at rt and degassed with argon. PdCl2(dppf). DCM (1.8 g, 2.18 mmol) was added under inert atmosphere. Resulting mixture was stirred at 90°C for 6 h. Reaction mixture was diluted with ethyl acetate, filtered through a short pad of celite and washed with ethyl acetate. Combined organic part was washed with water, brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. Crude mass was purified by combi flash chromatography using 80-85% ethyl acetate in hexane to afford 2-(1- methyl-1H-pyrazol-4-yl)pyrazine (3 g, 42% yield) as white solid.

[1916] LCMS Condition C: Rt = 0.86 min. m / z 161.1 [M+H]+.

[1917] Step-2 - Preparation of 2-(1-methyl-1H-pyrazol-4-yl)piperazine:

[1918]

[1919] To a degassed solution of 2-(1-methyl-1H-pyrazol-4-yl)pyrazine (300 mg, 1.87 mmol) in ethanol (20 mL) and acetic acid (2 mL) was added PtO2 (510 mg, 2.25 mmol) under nitrogen atmosphere. Resulting mixture was shaken in a Parr shaker at rt under 50 psi hydrogen pressure for 16 h. Reaction was filtered through a pad of celite bed, washed with ethanol and concentrated under reduced pressure. Crude material was triturated with diethyl ether to afford 2-(1-methyl-1H-pyrazol-4-yl)piperazine (270 mg, 86% yield) as white solid.

[1920] LCMS Condition C: Rt = 0.27 min. m / z 167.1 [M+H]+.

[1921] Step-3 - Preparation of tert-butyl 3-(1-methyl-1H-pyrazol-4-yl)piperazine-1- carboxylate

[1922]

[1923] To a stirred solution of 2-(1-methyl-1H-pyrazol-4-yl)piperazine (500 mg, 3.01 mmol) in Dioxane (15 mL) and H2O (1.5 mL) at rt were added TEA (0.84 mL, 6.02 mmol), DMAP (183.49 mg, 1.5 mmol) followed by Boc-anhydride (0.35 mL, 1.5 mmol). Resulting mixture was stirred at RT for 16 h. Reaction mass was diluted with cold water and extracted with ethyl acetate. Combined organic part was washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Crude mass was purified by column chromatography using 5-10% methanol in DCM to afford tert-butyl 3-(1-methyl-1H-pyrazol-4-yl)piperazine-1 -carboxylate (600 mg, 74% yield) as off-white solid.

[1924] LCMS Condition D: Rt = 2.41 min. m / z 267.0 [M+H]+.

[1925] Step-4 - Preparation of tert-butyl 4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazine- 1 -carboxylate

[1926]

[1927] To a stirred solution of tert-butyl 3-(1-methyl-1H-pyrazol-4-yl)piperazine-1 -carboxylate (310 mg, 1.16 mmol) in methanol (1 mL) and water (0.2 mL), paraformaldehyde (19.6 mg, 0.65 mmol) was added. Resulting mixture and heated at 60°C for 1 h. It was then cooled to rt, sodium cyanoborohydride (100 mg, 0.47 mmol) and acetic acid (0.2 mL) was added. Resulting mixture was again heated at 60°C for 16 h. Reaction mixture was quenched with saturated NaHCO3 solution and concentrated under reduced pressure. It was diluted with cold water and extracted with 10% methanoldichloromethane. Combined organic part was washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Crude mass was purified by column chromatography (5% MeOH in DCM) to afford tert-butyl 4- methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazine-1 -carboxylate (302 mg, 92% yield) as colourless gum. LCMS Condition D: Rt = 2.70 min. m / z 281.0 [M+H]+.

[1928] Step-5 - Preparation of 1-methyl-2-(1-methyl-1H-pyrazol-4-yl)piperazine, TFA salt (Intermediate 1-1-3)

[1929]

[1930] To a stirred solution of tert-butyl 4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazine-1- carboxylate (530 mg, 1.89 mmol) in DCM (10 mL) at 0 °C was added TFA (3 mL). Reaction mixture was slowly warmed up to rt and stirred for 3 h. Reaction mixture was concentrated under reduced pressure. Residue was triturated with diethyl ether / pentane (1:1) to afford 1-methyl-2-(1-methyl-1H-pyrazol-4-yl)piperazine, TFA salt [Intermediate I- 1-3] (300 mg, 88% yield) as a colourless gum.

[1931] LCMS Condition A: Rt = 0.22 min. m / z 181.2 [M+H]+.

[1932] Intermediate 1-1-4 was synthesized by using similar procedures described in Intermediate 1-1-3 (Table 3)

[1933] Table 3

[1934]

[1935] Table 4 describes analytical data analysis and information of Intermediate 1-1-4 Table 4

[1936]

[1937] Synthesis of (2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholine (Intermediate 1-1-5)

[1938] Step-1 - Preparation of 4-(1-ethoxyvinyl)-2-methoxypyridine

[1939]

[1940] To a stirred solution of 4-bromo-2-methoxypyridine (10 g, 53.2 mmol) in toluene (70 mL) was added tributyl(1-ethoxyvinyl)stannane (17.9 mL, 53.2 mmol). Solution was degassed with argon and Pd(PPh3)4(3.07 g, 2.7 mmol) was added under inert atmosphere. Resulting mixture was heated to 110 °C for 16 h. Reaction mixture was filtered through a short pad of celite and washed with ethyl acetate. Combined filtrate was concentrated under reduced pressure. Crude material was purified by column chromatography using 10-20% ethyl acetate in hexane to afford 4-(1-ethoxyvinyl)-2-methoxypyridine (6 g, 63% yield) as colourless liquid.

[1941] LCMS Condition A: Rt = 2.21 min. m / z 180.1 [M+H]+.

[1942] Step-2 - Preparation of 2-bromo-1-(2-methoxypyridin-4-yl)ethan-1-one

[1943]

[1944] To a stirred solution of 4-(1-ethoxyvinyl)-2-methoxypyridine (8.5 g, 47.4 mmol) in THF (80 mL) and water (20 mL) at 0 °C was added NBS (10.9 g, 61.6 mmol). Resulting solution was stirred at RT for 2 h. Reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Crude mass was purified by column chromatography using 25-40% ethyl acetate-hexane to afford 2-bromo-1-(2-methoxypyridin-4-yl)ethan-1 -one (4 g, 36.3% yield) as colourless liquid. LCMS Condition A: Rt = 1.87 min. m / z 230.1 [M+H]+.

[1945] Step-3 - Preparation of (R)-2-(benzyl(2-hydroxypropyl)amino)-1-(2-methoxypyridin-4-yl)ethan-1 -one

[1946]

[1947] To a stirred solution of 2-bromo-1-(2-methoxypyridin-4-yl)ethan-1-one (11 g, 47.8 mmol) in acetonitrile (100 mL) were added potassium carbonate (19.8 g, 143.4 mmol) and (R)-1-(benzylamino)propan-2-ol (9.5 g, 57.4 mmol). Resulting mixture was stirred at RT for 3 h. Reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Crude mass was purified by combi-flash chromatography using 50-80% ethyl acetate in hexane to afford (R)-2-(benzyl(2-hydroxypropyl)amino)-1-(2-methoxypyridin-4-yl)ethan-1-one (8.2 g, 53% yield) as yellow liquid. LCMS Condition A: Rt = 1.59 min. m / z 315.31 [M+H]+.

[1948] Step-4 - Preparation of (R)-4-benzyl-6-(2-methoxypyridin-4-yl)-2-methyl-3,4-dihydro-2H-1,4-oxazine

[1949]

[1950] To a stirred solution of (R)-2-(benzyl(2-hydroxypropyl)amino)-1-(2-methoxypyridin-4-yl)ethan-1-one (8.2 g, 26.08 mmol) in DCE (100 mL) was added TMSOTf (133.7 mL, 782.4 mmol) at 0 °C. Resulting mixture was heated at 70 °C for 8 h. Reaction mixture was quenched with aqueous NaHCO3 solution and extracted with dichloromethane. Combined organic layer was dried over sodium sulphate and concentrated into vacuo and purified by column chromatography using 20-30% ethyl acetate in hexane to afford (R)-4-benzyl-6-(2-methoxypyridin-4-yl)-2-methyl-3,4-dihydro-2H-1,4-oxazine (4.8 g, 63% yield) as yellow sticky oil. LCMS Condition A: Rt = 1.67 min. m / z 297.3 [M+H]+.

[1951] Step-5 - Preparation of (2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholine (Intermediate 1-1-5)

[1952]

[1953] To a stirred solution of (R)-4-benzyl-6-(2-methoxypyridin-4-yl)-2-methyl-3,4-dihydro-2H-1,4-oxazine (2.3 g, 7.7 mmol) in methanol (30 mL) was added ammonium formate (2.5 g, 38.8 mmol) and Pd(OH)2 (1.6 g, 20% on carbon) under nitrogen atmosphere. Resulting mixture was refluxed at 70 °C for 2 h. Reaction mixture was filtered through a pad of celite bed, washed with methanol and concentrated. Crude residue was quenched with sodium bicarbonate solution, extracted with 10% methanol-dichloromethane mixture, dried over sodium sulphate and concentrated. Crude mass was purified by combi flash chromatography using 5% MeOH-DCM to afford (2S,6R)-2-(2- methoxypyridin-4-yl)-6-methylmorpholine (1.1 g, 70% yield) as gum. LCMS Condition A: Rt = 0.66 min. m / z 209.17 [M+H]+.

[1954] Synthesis of Intermediate 1-1-6

[1955] Synthesis of 6-( 1 -cyclopropyl-1H-pyrazol-4-yl)-2, 2-difluoromorpholine (Intermediate 1-1-6)

[1956] Step-1 - Preparation of 1-cyclopropyl-1H-pyrazole-4-carbaldehyde:

[1957]

[1958] To a stirred solution of 1 H-pyrazole-4-carbaldehyde (50 g, 520.35 mmol) in DCE (1000 mL) were added cyclopropyl boronic acid (17.8 g, 208.1 mmol), 2,2- bipyridyl (16.2 g, 104.07 mmol) and sodium carbonate (36.4 g, 343.4 mmol) under oxygen atmosphere. Copper acetate (18.9 g, 104.07 mmol)) was added to the reaction mixture. Resulting mixture was heated to 70 °C for 16 h. Reaction mixture was filtered through a short pad of celite, washed with methanol and concentrated under reduced pressure. Crude residue was extracted with ethyl acetate, washed with brine, dried over sodium sulphate, and concentrated under reduced pressure. Crude product was purified by combi-flash chromatography using 10% ethyl acetate-hexane to afford 1 -cyclopropyl- 1 H-pyrazole-4-carbaldehyde (16 g, 56% yield) as colourless liquid.

[1959] LCMS Condition A: Rt = 0.68 min. m / z 137.2 [M+H]+.

[1960] Step-2 - Preparation of 1-(1-cyclopropyl-1H-pyrazol-4-yl)-2-nitroethan-1-ol:

[1961]

[1962] To a stirred solution of 1-cyclopropyl-1H-pyrazole-4-carbaldehyde (30 g, 220.34 mmol) in CH3NO2 (300 mL) was added Triethyl amine (45 ml, 330.51 mmol) at 0 °C. Resulting mixture was stirred at room temperature for 6 h. Reaction mixture was evaporated under reduced pressure. Crude product was purified by combi-flash chromatography using 70% ethyl acetate-hexane to afford 1-(1-cyclopropyl-1H-pyrazol-4-yl)-2-nitroethan-1-ol (21 g, 47% yield) as light-yellow liquid.

[1963] LCMS Condition C: Rt = 0.94 min. m / z 198.2 [M+H]+.

[1964] Step-3 - Preparation of 2-amino-1-(1-cyclopropyl-1H-pyrazol-4-yl)ethan-1-ol:

[1965]

[1966] To a stirred solution of 1-(1-cyclopropyl-1H-pyrazol-4-yl)-2-nitroethan-1-ol (21 g, 106.49 mmol) in Methanol (200 mL) were added acetic acid (2 mL) and Pd / C (10.2 g, 10 % on charcoal) under nitrogen atmosphere. Finally, under vacuum condition the reaction mixture was charged with hydrogen gas pressure. Resulting mixture was stirred at room temperature for 16 h. Reaction mixture was filtered through a pad of celite bed, washed with methanol and concentrated under reduced pressure to afford 2-amino-1-(1-cyclopropyl-1H-pyrazol-4-yl)ethan-1-ol (17 g, 95% yield ) as gummy liquid.

[1967] LCMS Condition A: Rt = 0.23 min. m / z 168.1 [M+H]+.

[1968] Step-4 - Preparation of 2-bromo-N-[2-(1-cyclopropyl-1H-pyrazol-4-yl)-2-hydroxyethyl]-2,2-difluoroacetamide:

[1969]

[1970] To a stirred solution of 2-amino-1-(1-cyclopropyl-1H-pyrazol-4-yl)ethan-1-ol (7 g, 41.86 mmol) in DMF (50 mL) was added ethyl bromodifluoroacetate (5.35 mL, 41.86 mmol). Resulting mixture was stirred at room temperature for 16 h. Reaction mixture was quenched with crushed ice and extracted with ethyl acetate (100 mL). Combined organic layer was washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. Crude product was purified by combi-flash chromatography using 80% ethyl acetate-hexane to afford 2-bromo-N-[2-(1-cyclopropyl- 1 H-pyrazol-4-yl)-2-hydroxyethyl]-2,2-difluoroacetamide (4.6 g, 34% yield) as white solid. LCMS Condition C: Rt = 1.38 min. m / z 324.2 [M+H]+.

[1971] Step-5 - Preparation of 6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholin-3-one:

[1972]

[1973] To a stirred solution of 2-bromo-N-[2-(1-cyclopropyl-1H-pyrazol-4-yl)-2-hydroxyethyl]-2,2-difluoroacetamide (1 g, 3.08 mmol) in THF (40 mL) was added 2M NaOtBu in THF (6.2 mL, 12.34 mmol) at 0 °C. Resulting mixture was stirred at room temperature for 16 h. Crude LCMS indicated desired product formed and SM present. Again, 2M NaOtBu in THF (6.2 mL, 12.34 mmol) was added and stirred at room temperature for another 20 h. Reaction mixture was quenched with sat. NH4Cl solution and extracted with ethyl acetate (100 mL). Combined organic layer was dried over sodium sulphate, filtered, and evaporated under reduced pressure. Crude product was purified by combi-flash chromatography using 90% ethyl acetate-hexane to afford 6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholin-3-one (200 mg, 27% yield) as white solid.

[1974] LCMS Condition A: Rt = 1.55 min. m / z 244.1 [M+H]+.

[1975] Step-6 - Preparation of 6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholine (Intermediate 1-1-6):

[1976]

[1977] To a stirred solution of 6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholin-3-one (200 mg, 0.82 mmol) in THF (5 mL) was added 2M BH3. DMS (1.2 mL, 2.47 mmol) at 0 °C. Resulting mixture was stirred at room temperature for 16 h. Reaction mixture was quenched with methanol and extracted with 20% Methanol in DCM (50 mL). Combined organic layer was washed with brine, dried over sodium sulphate, filtered, and evaporated under reduced pressure to afford 6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholine (100 mg, crude) as light-yellow liquid.

[1978] This compound was used to the next step without purification.

[1979] LCMS Condition A: Rt = 1.71 min. m / z 230.1 [M+H]+.

[1980] Synthesis of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5, 6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (Intermediate I-2)

[1981] Step-1 - Preparation of tert-butyl 2-chloro-4-(2,4-difluorophenyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate:

[1982]

[1983] To a stirred solution of tert-butyl 2,4-dichloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (1 g, 3.14 mmol) and 2,4-difluorophenyl boronic acid (496 mg, 3.14 mmol) in toluene (20 mL) and 1,4-dioxane (10 mL) was added 3M K3PO4(3 mL) at 10 °C and degassed with argon. PdCl₂(dppf).DCM (128.3 mg, 0.16 mmol) was added under inert atmosphere. Resulting mixture was stirred at rt for 2 h. Reaction mixture was diluted with ethyl acetate, filtered through a short pad of celite and washed with ethyl acetate. Combined organic part was washed with water, brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. Crude mass was purified by combi flash chromatography (20-25% ethyl acetate in hexane) to afford tertbutyl 2-chloro-4-(2,4-difluorophenyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (657 mg, 52.1% yield) as off-white solid.

[1984] LCMS Condition C: Rt = 3.19 min. m / z 368.1 [M+H]+.

[1985] Step-2 - Preparation of tert-butyl 2-chloro-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[1986]

[1987] To a stirred solution of tert-butyl 2-chloro-4-(2,4-difluorophenyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (5 g, 13.6 mmol) in ethyl acetate (80 mL), were added aq. solution of NaIO4(8.7 g, 40.8 mmol) in 80 mL water, and RuCl3.3H2O (3.6 g, 13.6 mmol) at rt. Resulting mixture was stirred at rt for 3 h. Reaction mixture was filtered through celite bed and washed with ethyl acetate. Combined organic part and evaporated under reduced pressure. Crude was purified by combi flash chromatography using 25-35% ethyl acetate in hexane to afford tert-butyl 2-chloro-4-(2,4-difluorophenyl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (eluted earlier, [Fraction-1], 1.4 g, 32% yield) as off-white solid and tert-butyl 2-chloro-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (eluted latter, [Fraction-2], 1.2 g, 29% yield) as white solid.

[1988] Fraction!1H NMR (400 MHz, DMSO-d6) δ 7.78-7.72 (m, 1H), 7.53-7.48 (m, 1H), 7.34-7.29 (m, 1H), 4.88 (s, 2H), 1.52 (s, 9H)

[1989] LCMS condition A: Rt= 2.19 min. m / z 382.2 [M+H]+.

[1990] Fraction-2:1H NMR (400 MHz, DMSO-d6) δ 7.94-7.88 (m, 1H), 7.63-7.57 (m, 1H), 7.40-7.35 (m, 1H), 4.85 (s, 2H), 1.53 (s, 9H)

[1991] LCMS condition A: Rt= 2.14 min. m / z 382.2 [M+H]+.

[1992] Step-3 - Preparation of tert-butyl 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate:

[1993]

[1994] To a stirred solution of (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine (Intermediate 1-1) (270.7 mg, 1.3 mmol) in DMSO (20 mL) was added DIPEA (0.9 mL, 5.2 mmol) at rt and stirred for 15 min. To it was added tert-butyl 2-chloro-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (500 mg, 1.3 mmol) at rt. Resulting mixture was stirred at rt for 16 h. Reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. Crude mass was purified by combi flash chromatography (35-55% ethyl acetate in hexane) to afford tert-butyl 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (500 mg, 69% yield) as yellow solid. LCMS Condition C: Rt = 3.94 min. m / z 553.2 [M+H]+.

[1995] Step-4 - Preparation of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin- 7-one (Intermediate I-2).

[1996]

[1997] To a stirred solution of tert-butyl 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (500.0 mg, 0.9 mmol) in DCM (15 mL) at 0 °C was slowly added HCI in Dioxane (4M, 15 mL). Resulting mixture was stirred at rt for 1 h. Reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate, washed with sodium bicarbonate, brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. Crude mass was purified by combi flash chromatography (4-7% methanol in DCM) to afford 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (300 mg, 73% yield) as off-white solid.

[1998] LCMS Condition C: Rt = 2.72 min. m / z 453.2 [M+H]+ Intermediates 1-2-1 to I-2-22 were synthesized by using similar procedures described in Intermediate I-2 (Table 5)

[1999] Table 5

[2000]

[2001]

[2002]

[2003]

[2004]

[2005]

[2006] Table 6 describes analytical data and description of Intermediates from 1-2-1 to I-2-22

[2007] Table 6

[2008]

[2009]

[2010] Synthesis of 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Intermediate 1-3)

[2011] Step-1 - Preparation of ethyl 3-(bromomethyl)-2,6-dichloroisonicotinate

[2012]

[2013] To a stirred solution of ethyl 2,6-dichloro-3-methylpyridine-4-carboxylate (2 g, 8.5 mmol) in DCE (80 mL) was added NBS (2.2 g, 12.8 mmol) and AIBN (0.2 g, 1.3 mmol) at rt. Resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. Reaction mixture was concentrated, and residue was purified by column chromatography using 7% ethyl acetate in hexane to afford ethyl 3-(bromomethyl)-2,6-dichloropyridine-4-carboxylate (2.6 g, 93.5% yield) as a light-yellow oil. LCMS Condition A: Rt = 2.29 min. m / z 312.2 [M+H]+.

[2014] Step-2 - Preparation of 4,6-dichloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[2015]

[2016] To a stirred solution of ethyl 3-(bromomethyl)-2,6-dichloropyridine-4-carboxylate (4 g, 12.8 mmol) in THF (30 mL), and ammonium hydroxide (90 mL of 28-30% ammonia) was stirred at room temperature for 18 h. Reaction mixture was concentrated under reduced pressure. Concentrated mass was diluted with water and extracted with ethyl acetate. Combined organic part was washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Crude mass was purified by column chromatography using 5-10% ethyl acetate in hexane to afford 4,6-dichloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one as light brown solid (2 g,77%): LCMS Condition A: Rt = 1.54 min. m / z 203.2 [M+H] Step-3 - Preparation of tert-butyl 4,6-dichloro-1-oxo-1,3-dihydro-2H-pyrrolo[3,4- c]pyridine-2-carboxylate

[2017]

[2018] To a stirred solution of4,6-dichloro-1H,2H,3H-pyrrolo[3,4-c]pyridin-1-one (900 mg, 4.43 mmol) in DCM (50 mL) at rtwas added DMAP (27.04 mg, 0.22 mmol) followed by Boc- anhydride (1.53 mL, 6.65 mmol). Resulting mixture was stirred at rt for 16 h. Reaction mass was diluted with cold water and extracted with 10% methanol-dichloromethane. Combined organic part was washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Crude mass was purified by column chromatography using 5-10% ethyl acetate in hexane to afford tert-butyl 4,6- dichloro-1-oxo-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxylate (900 mg, 67% yield) as white solid. LCMS Condition B: Rt = 3.88 min. m / z 303.2 [M+H]+.

[2019] Step-4 - Preparation of tert-butyl 6-chloro-4-(2,4-difluorophenyl)-1-oxo-1,3- dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate

[2020]

[2021] To a stirred solution of tert-butyl-4,6-dichloro-1-oxo-1H,2H,3H-pyrrolo[3,4-c]pyridine-2- carboxylate (500 mg, 1.65 mmol) and 2,4-difluorophenyl boronic acid (312 mg, 1.98 mmol) in 1,4-dioxane (20 mL) at rt was added aqueous sodium acetate solution (270 mg, 0.33 mmol dissolved in 1.5 mL water) and degassed with argon. PdCl2(dppf). DCM (128.3 mg, 0.16 mmol) was added under inert atmosphere. Resulting mixture was stirred at rt for 2 h. Reaction mixture was diluted with ethyl acetate, filtered through a short pad of celite and washed with ethyl acetate. Combined organic part was washed with water, brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. Crude mass was purified by combi flash chromatography using 20-25% ethyl acetate in hexane to afford tert-butyl 6-chloro-4- (2,4-difluorophenyl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate (250 mg, 40% yield) as off-white solid.

[2022] LCMS Condition C: Rt = 2.20 min. m / z 381.2 [M+H] +.

[2023] Step-5 - Preparation of tert-butyl 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate

[2024]

[2025] Tert-butyl 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-1 -oxo-1, 3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate was synthesized (40% yield; off-white solid) using tert-butyl 6-chloro-4-(2,4-difluorophenyl)-1 -oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate and (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine (Intermediate 1-1) according to similar procedure mentioned in Step-3, Intermediate I-2. LCMS Condition C: Rt = 3.56 min. m / z 552.2 [M+H]+.

[2026] Step-6 - Preparation of 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Intermediate I-3)

[2027]

[2028] 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Intermediate I-3) was synthesized (56% yield; yellow solid) according to similar procedure mentioned in Step- 4, Intermediate I-2. LCMS Condition C: Rt = 1.98 min. m / z 452.2 [M+H]+.

[2029] Synthesis of 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4- (3-(trifluoromethyl)bicyclo[1.1.1 ]pentan-1-yl)-2,3-dihydro-1H-pyrrolo[3,4- c]pyridin-1-one (Intermediate 1-3-1)

[2030] Step-1- Preparation of ethyl 2,6-dibromo-3-methylisonicotinate

[2031]

[2032] A suspension of ethyl 2,6-dichloro-3-methylpyridine-4-carboxylate (500 mg, 2.14 mmol) and HBr in acetic acid (5 mL) was heated at 80°C in a sealed tube for 16 h. Reaction mixture was concentrated, quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate. Organic part was dried over Na2SO4 and concentrated under reduced pressure. Crude was purified by combi flash chromatography using 0- 10% ethyl acetate in hexane to afford ethyl 2,6-dibromo-3-methylisonicotinate (450 mg, 65% yield) as colourless liquid.

[2033] LCMS Condition C: Rt = 2.17 min. m / z 322.2 [M+H]+.

[2034] Step-2- Preparation of ethyl 2,6-dibromo-3-(bromomethyl)isonicotinate

[2035]

[2036] Ethyl 2,6-dibromo-3-(bromomethyl)isonicotinate was synthesized (76% yield; colourless gum) according to similar procedure mentioned in Step-1, Intermediate I-3.

[2037] LCMS Condition C: Rt = 2.37 min. m / z 400.2 [M+H]+.

[2038] Step-3- Preparation of 4,6-dibromo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[2039]

[2040] 4,6-dibromo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one was synthesized (66% yield; off- white solid) according to similar procedure mentioned in Step-2, Intermediate I-3.

[2041] LCMS Condition C: Rt = 2.67 min. m / z 293.0 [M+H]+.

[2042] Step-4- Preparation of tert-butyl 4,6-dibromo-1-oxo-1,3-dihydro-2H-pyrrolo[3,4- c]pyridine-2-carboxylate

[2043]

[2044] tert-butyl 4,6-dibromo-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate was synthesized (54% yield; off-white solid) according to similar procedure mentioned in Step-3, Intermediate I-3.

[2045] 1H NMR (400 MHz, DMSO-d6) 58.08 (s, 1H), 4.71-4.67 (s, 2H), 1.52 (s, 9H),

[2046] Step-5- Preparation of tert-butyl 6-bromo-1-oxo-4-(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine- 2-carboxylate

[2047]

[2048] To a degassed solution of 1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl 3- (trifluoromethyl)bicyclo[1.1.1]pentane-1 -carboxylate [prepared from 3- (trifluoromethyl)bicyclo[ 1.1.1]pentane-1 -carboxylic acid; procedure provided below] (80 mg, 0.25 mmol), tert-butyl 4,6-dibromo-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2- carboxylate (135 mg, 0.34 mmol), NiCl2·6H2O (23.39 mg, 0.1 mmol), 2,2'- bipyridine (15.37 mg, 0.1 mmol) in dry DMF (3 mL) in a 20 mL ElectraSyn 2.0 vial was added AgNO3 (41.81 mg, 0.25 mmol). Vial was closed with an ElectraSyn 2.0 vial cap with a magnesium sacrificial anode and a 100 ppi RVC cathode (3 mm x 7 mm x 51 mm). Then vial was then placed on an IKA ElectraSyn 2.0 stir plate and electrolysis was set to 12 mA, 0.25 mmol, 4.0 F / mol. Reaction underwent programmed electrolysis open to air for 3 h. Reaction mixture was diluted with ethyl acetate, filtered through a short pad of celite and washed with ethyl acetate. Combined organic part was washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Crude mass was purified by column chromatography using 20% ethyl acetate in hexane to afford tert-butyl 6-bromo-1-oxo-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate (45 mg, 41% yield) as off-white solid.

[2049] LCMS Condition C: Rt = 2.38 min. m / z 447.2 [M+H]+.

[2050] Preparation of 1,3-dioxoisoindolin-2-yl 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylate:

[2051]

[2052] To a stirred solution of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylicacid (200 mg, 1.11 mmol) and N-hydroxy phthalimide (199.23 mg, 1.22 mmol) and DMAP (13.6 mg, 0.11 mmol) in DCM (7 mL) was added dicyclohexylcarbodiimide (0.19 mL, 1.22 mmol). Reaction mixture stirred at rt for 16 h. Reaction mass was evaporated to dryness under reduced pressure. Crude mass was purified by chromatography (silica gel; 50% ethyl acetate-hexane) to afford 1,3-dioxoisoindolin-2-yl 3- (trifluoromethyl)bicyclo[1.1.1]pentane-1 -carboxylate (250 mg, 69% yield) as white solid. LCMS Condition A: Rt = 2.18 min. m / z 326.1 [M+H]+.

[2053] Step-6- Preparation of tert-butyl 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-1 -oxo-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1 -y I )-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate

[2054]

[2055] Tert-butyl 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-1-oxo-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate was synthesized (61% yield; yellow solid) using tert-butyl 6-bromo-1-oxo-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate and (2S,6R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6-methylmorpholine (Intermediate 1-1) according to similar procedure mentioned in Step-3, Intermediate I-2. LCMS Condition C: Rt = 3.51 min. m / z 574.2 [M+H]+.

[2056] Step-7- Preparation of 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Intermediate 1-3-1)

[2057]

[2058] 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Intermediate 1-3-1) was synthesized (96% yield; yellow solid) according to similar procedure mentioned in Step-4, Intermediate I-2.

[2059] LCMS Condition C: Rt = 2.16 min. m / z 474.1 [M+H]+.

[2060] Synthesis of (R)-1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (Intermediate 1-4)

[2061] Step-1- Preparation of 1-cyclopropyl-1H-pyrazole-4-carbaldehyde:

[2062]

[2063] To a stirred solution of 1 H-pyrazole-4-carbaldehyde (20 g, 208.1 mmol) in DCE (400 mL) were added cyclopropyl boronic acid (17.8 g, 208.1 mmol), 2,2- bipyridyl (16.2 g, 104.07 mmol) and sodium carbonate (36.4 g, 343.4 mmol) under oxygen atmosphere. Copper acetate (18.9 g, 104.07 mmol)) was added to the reaction mixture. Resulting mixture was heated to 70 °C for 16 h. Reaction mixture was filtered through a short pad of celite, washed with methanol and concentrated under reduced pressure. Crude residue was extracted with ethyl acetate, washed with brine, dried over sodium sulphate, and concentrated under reduced pressure. Crude product was purified by combi-flash chromatography using 10% ethyl acetate-hexane to afford 1 -cyclopropyl- 1 H-pyrazole-4- carbaldehyde (16 g, 56% yield) as colourless liquid.

[2064] LCMS Condition A: Rt = 0.93 min. m / z 137.2 [M+H]+.

[2065] Step-2- Preparation of 6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate

[2066]

[2067] To a stirred solution of 1-cyclopropyl-1H-pyrazole-4-carbaldehyde (18.5 g, 135.8 mmol) in DCM (185 mL) at 0°C was added but-3-yn-1-ol (17 mL, 203.8 mmol) followed by addition of triflic acid (30 mL, 339.7 mmol). Resulting mixture was stirred at rt for 16h. Reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with DCM and concentrated under reduced pressure. Crude material was purified by column chromatography using 20-40% EA in hexane to afford 6-(1-cyclopropyl-1H- pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (14 g, 30% yield) as sticky liquid.

[2068] 1H NMR (400 MHz, DMSO-d6) 57.74 (s, 1H), 7.36 (s, 1H), 6.20 (s, 1H), 5.32 (s, 1H), 3.91 - 3.64 (m, 3H), 2.49 -2.42 (m, 2H), 1.11 - 0.88 (m, 4H).

[2069] LCMS Condition D: Rt = 1.82 min. m / z 339.1 [M+H]+.

[2070] Step-3- Preparation of 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole

[2071]

[2072] To a stirred solution of 6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (12.9 g, 38.1 mmol) and Bis(pinacolato)diboron (14.5 g, 57.1 mmol) in dioxane (60 mL) was added potassium acetate (14.9 g, 152.5 mmol) and degassed with argon. PdCl2(dppf).DCM (3.1 g, 3.8 mmol) was added under inert atmosphere. Resulting mixture was heated at 80°C for 3 h. Reaction mixture was diluted with ethyl acetate, filtered through a short pad of celite and washed with ethyl acetate. Combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Crude product was purified by column chromatography using 30% EA in Hexane to afford 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (6.8 g, 56% yield) as gum.

[2073] 1H NMR (400 MHz, DMSO-d6) 57.67 (s, 1H), 7.31 (s, 1H), 6.43 (d, J =2.2 Hz, 1H), 5.16 - 5.01 (m, 1H), 3.82 - 3.63 (m, 2H), 3.63 - 3.53 (m, 1H), 2.20 - 2.00 (m, 2H), 1.15 -0.96 (m, 16H).

[2074] LCMS Condition D: Rt = 3.25 min. m / z 316.9 [M+H]+.

[2075] Step-4- Preparation of (R)-1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1 H-pyrazole (Intermediate I-4)

[2076]

[2077] Chiral separation of 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (3.7 g, 11.7 mmol) was done by chiral SFC method-1 to afford (S)-1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (490 mg, 29.6% yield; eluted first, assigned as Peak 1 with arbitrary assignment of stereochemistry) and (R)-1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (Intermediate I-4) (472 mg, 25% yield, eluted later, assigned as Peak 2 with arbitrary assignment of stereochemistry) both as white solid.

[2078] Peak 1:1 H NMR (400 MHz, DMSO-d6) 57.67 (s, 1H), 7.31 (s, 1H), 6.43 (d, J = 2.2 Hz, 1H), 5.16 - 5.01 (m, 1H), 3.82 - 3.63 (m, 2H), 3.63 - 3.53 (m, 1H), 2.20 - 2.00 (m, 2H), 1.15 - 0.96 (m, 16H).

[2079] LCMS Condition D: Rt = 3.25 min. m / z 316.9 [M+H]+. Peak 2 [Intermediate I-4]: 1H NMR (400 MHz, DMSO-d6) 57.67 (s, 1H), 7.31 (s, 1H), 6.43 (d, J = 2.2 Hz, 1 H), 5.16 - 5.01 (m, 1H), 3.82 - 3.63 (m, 2H), 3.63 - 3.53 (m, 1H), 2.20 - 2.00 (m, 2H), 1.15 - 0.96 (m, 16H).

[2080] LCMS Condition D: Rt = 3.25 min. m / z 316.9 [M+H]+.

[2081] Synthesis of (3-oxabicyclo[3.1,0]hexan-6-yl)boronic acid (Intermediate-I-4-1)

[2082] Step-1- Preparation of 2-(3-oxabicyclo[3.1.0]hexan-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[2083]

[2084] To a stirred solution of CrCI2 (3.6 g, 29.9 mmol) in THF (50 mL) was added TMEDA (4.5 mL, 29.9 mmol) slowly at rt under nitrogen atmosphere. Resulting mixture was stirred at rt for20 min to give a thick blue suspension. 2-(diiodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.6 g, 8.9 mmol) was added and resulting mixture was stirred at same temperature for 30 min. To this solution was added 2, 5-di hydrofuran (700 mg, 9.9 mmol) and resulting mixture was stirred at 50°C for 20 h. Mixture was filtered through celite pad; filtrate was diluted with water and extracted with ethyl acetate. Organic part was dried over Na2SO4 and concentrated under reduced pressure. Crude was purified by combi flash chromatography using 5% ethyl acetate in hexane to get2-(3-oxabicyclo[3.1.0]hexan-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 57% yield) as yellow liquid.

[2085] 1H NMR (400 MHz, DMSO-d6) 5 3.89-3.87 (m, 1H), 3.81-3.79 (m, 1H), 3.69-3.67 (m, 1H), 3.52-3.50 (m, 1H), 1.75-1.71 (m, 1H), 1.66-1.64 (m, 1H), 1.23-1.21 (m, 12H), -0.08 (m, 1H)

[2086] Step-2- Preparation of (3-oxabicyclo[3.1.0]hexan-6-yl)boronic acid (Intermediate-1-4-1)

[2087]

[2088] To a stirred solution of 2-(3-oxabicyclo[3.1.0]hexan-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 5.7 mmol) in THF (15 mL) and H2O (3 mL), at rt was added NalO4 (3.6 g, 17.1 mmol). Reaction mixture was stirred at rt for 15 min and HCI [2(N), 10 mL] was added. Resulting mixture was stirred at rt for 1 h. Reaction mixture was diluted with ethyl acetate, washed with water and brine. Organic part was separated, dried over Na2SO4 and concentrated under reduced pressure to afford (3-oxabicyclo[3.1.0]hexan- 6-yl)boronic acid (Intermediate-I-4-1) (500 mg, 68% yield) as light yellow solid.

[2089] 1H NMR (400 MHz, DMSO-d6) δ7.40 (br s, 2H), 3.65-3.63 (m, 2H), 3.56-3.54 (m, 2H), 1.60-1.58 (m, 2H), -0.38 (m, 1H).

[2090] Synthesis of (6-(methoxymethyl)pyridin-3-yl)boronic acid (lntermediate-l-4-2)

[2091] Step-1- Preparation of 2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine

[2092]

[2093] 2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was synthesized (58% yield; brown liquid) according to similar procedure mentioned in Step- 3, Intermediate I-4.

[2094] LCMS Condition B: Rt = 1.09 min. m / z 250.2 [M+H]+.

[2095] Step-2- Preparation of (6-(methoxymethyl)pyridin-3-yl)boronic acid (lntermediate- l-4-2)

[2096]

[2097] (6-(methoxymethyl)pyridin-3-yl)boronic acid (lntermediate-l-4-2) was synthesized (15% yield; white solid) according to similar procedure mentioned in Step-2, Intermediate I-4- 1. Purification was done by reverse phase prep HPLC using prep G method.

[2098] LCMS Condition D: Rt = 1.29 min. m / z 167.9 [M+H]+.

[2099] Synthesis of 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4- yl)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (Intermediate 1-5)

[2100] Step-1- Preparation of (tert-butyl (R)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6- dihydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidine-6-carboxylate

[2101]

[2102] To a stirred solution of tert-butyl 2-chloro-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate [synthesized in Step-2 of Intermediate 1-2] (300 mg, 0.79 mmol) and (R)-1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole [Intermediate I-4] (248.48 mg, 0.79 mmol) in 1,4-dioxane (7 mL) was added K3PO4(706 mg, 5.12 mmol; 2M aqueous solution) and degassed with argon. Pd-118 (51.22 mg, 0.08 mmol) was added under inert atmosphere. The resulting mixture was stirred at 80°C for 2 h. Reaction mixture was diluted with ethyl acetate, filtered through a short pad of celite and washed with ethyl acetate. Combined organic part was washed with water, brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. Crude mass was purified by column chromatography using 35-50% ethyl acetate in hexane to afford (tertbutyl (R)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (160 mg, 32% yield) as brown solid.

[2103] LCMS Condition C: Rt = 3.32 min. m / z 536.1 [M+H]+.

[2104] Step-2- Preparation of tert-butyl 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[2105]

[2106] To a degassed solution (tert-butyl (R)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (150 mg, 0.28 mmol) in THF (7 mL) was added Pd(OH)2 (1:1 w / w, 150 mg) under inert atmosphere and degassed again. The resulting mixture was stirred under hydrogen balloon pressure at rt for 16 h. Reaction mixture was filtered through a short pad of celite and washed with ethyl acetate. Combined filtrate was concentrated under reduced pressure and crude product was purified by column chromatography using 60% ethyl acetate in hexane to afford 4 tert-butyl 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (65 mg, 43% yield) as off-white solid.

[2107] LCMS Condition C: Rt = 3.09 min. m / z 538.1 [M+H]+.

[2108] Step-3- Preparation of 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (Intermediate I-5)

[2109]

[2110] 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (Intermediate I-5) was synthesized (81% yield; yellow solid) according to similar procedure mentioned in Step-4, Intermediate I-2.

[2111] LCMS Condition C: Rt = 2.66 min. m / z 438.1 [M+H]+.

[2112] Example 1

[2113] Synthesis of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4- (2,4-difluorophenyl)-6-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[2114] Step-1 - Preparation of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one:

[2115]

[2116] To a stirred solution of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6- methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [I-2] (40 mg, 0.09 mmol) and pyridin-4-ylboranediol (10.9 mg, 0.09 mmol) in DCE (3 mL) was added Na2CO3 (20.6 mg, 0.2 mmol). Solution was purged with oxygen for 10 mins and 2,2'-Bipyridyl (15.189 mg, 0.097 mmol) and copper acetate (17.6 mg, 0.097 mmol) were added. Resulting mixture was heated at 60 °C for 16 h under oxygen atmosphere. Reaction mixture was filtered through celite bed and washed with DCM. Combined organic part was evaporated under reduced pressure and purified by reverse phase prep HPLC using Prep-B method to afford 2-((2S,6R)-2-(1-cyclopropyl- 1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(pyridin-4-yl)-5,6- dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (20 mg, 46.8% yield) as light-yellow solid.1H NMR (400 MHz, DMSO-d6) δ8.58 (br s, 2H), 7.94-7.86 (m, 4H), 7.55-7.48 (m, 2H), 7.34-7.30 (m, 1H), 4.97 (s, 2H), 4.71-4.65 (m, 2H), 4.54-4.52 (m, 1H), 3.74-3.68 (m, 2H), 3.10-3.04 (m, 1H), 2.81-2.75 (m, 1H), 1.22 (d, J=5.96 Hz, 3H), 1.03-0.99 (m, 2H), 0.95-0.94 (m, 2H).

[2117] LCMS Condition C: Rt = 2.71 min. m / z 530.4 [M+H]+

[2118] Examples 2-26

[2119] Examples 2-26 were synthesized by using similar procedures to those described in Example 1 (Table 7).

[2120] Table 7

[2121]

[2122]

[2123]

[2124]

[2125]

[2126]

[2127] Table 8 describes analytical data analysis and information of examples 2-26:

[2128] Table 8

[2129]

[2130]

[2131]

[2132]

[2133]

[2134] Table 9 describes information regarding separation of enantiomers for required examples from the above table. Absolute stereochemistry was not determined and was assigned arbitrarily.

[2135] Table 9

[2136]

[2137]

[2138]

[2139] Table 10 describes analytical data analysis and yield information of enantiomers of the above table:

[2140] Table 10

[2141]

[2142]

[2143]

[2144]

[2145] Example 27

[2146] Synthesis of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(( 1 R, 5S, 6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)-5, 6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one:

[2147] Step-1- Preparation of tert-butyl (1R,5S,6s)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[2148]

[2149] Tert-butyl (1R,5S,6s)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was synthesized (32% yield; yellow solid) according to similar procedure mentioned in Step-1, Intermediate 1-4-1.

[2150] 1H NMR (400 MHz, DMSO-d6) δ 3.54 (br s, 2H), 3.34-3.31 (m, 2H), 1.69-1.62 (m, 3H), 1.41 (s, 9H), 1.26-1.24 (m, 12H)

[2151] Step-2- Preparation of ((1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)boronic acid

[2152]

[2153] ((1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)boronic acid was synthesized (32% yield; yellow solid) according to similar procedure mentioned in Step-2, Intermediate 1-4-1.

[2154] 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.37 (s, 1H), 3.52-3.28 (m, 4H), 1.49-1.48 (m, 2H), 1.36 (s, 9H), -0.04 (m, 1H)

[2155] Step-3- Preparation of tert-butyl (1R,5S,6s)-6-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[2156]

[2157] To a stirred solution of 2-[(2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholin-4-yl]-4-(2,4-difluorophenyl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-7-one[l-2] (60 mg, 0.13 mmol ) and ((1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)boronic acid (60.22 mg, 0.27 mmol) in DCE (5 mL) was added pyridine (0.11 mL, 1.33 mmol) and sodium carbonate (30.9 mg, 0.29 mmol) and resultant solution was degassed with oxygen. To this solution were added copper acetate (24 mg, 0.13 mmol) and 2,2 - Bipyridine (20.7 mg, 0.13 mmol). Resulting solution was heated at 80 °C for 16 h under oxygen atmosphere. Reaction mixture was filtered through celite pad, and filtrate was diluted with water and extracted with ethyl acetate. Organic portion was dried over Na2SO4 and concentrated under reduced pressure. Crude was purified by reverse phase prep HPLC using Prep-E method to tert-butyl (1R,5S,6s)-6-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-3-azabicyclo[3.1,0]hexane-3-carboxylate (25 mg, 29% yield) as yellow solid.

[2158] LCMS Condition C: Rt = 3.32 min. m / z 634.1 [M+H]+.

[2159] Step-4- Preparation of 6-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[2160]

[2161] To a stirred solution of tert-butyl (1R,5S,6s)-6-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol- 4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.16 mmol) in DCM (4 mL) at 0 °C was slowly added HCI in Dioxane (4M, 6 mL). Resulting mixture was stirred at rt for 2 h. Reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate, washed with sodium bicarbonate, brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. Crude mass was purified by combi flash chromatography (4-7% methanol in DCM) to afford 6-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (60 mg, 71% yield) as light yellow solid.

[2162] LCMS Condition A: Rt = 1.64 min. m / z 534.2 [M+H]+.

[2163] Step-5- Preparation of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (Example 27)

[2164]

[2165] To a stirred solution of 6-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (60 mg, 0.11 mmol) in DCE (3 mL), paraformaldehyde (20 mg, 0.66 mmol) was added followed by TEA (0.016 mL, 0.11 mmol) and sodium triacetoxyborohydride (35 mg, 0.17 mmol). Resulting mixture was stirred at rt for 4 h. Reaction mixture was diluted with DCM and washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Crude mass was purified by reverse phase prep HPLC using Prep-E method to afford 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-((1 R,5S,6s)-3-methyl-3-azabicyclo[3.1,0]hexan-6-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (Example 27) (10 mg, 16% yield) as yellow solid.

[2166] 1H NMR (400 MHz, DMSO-d6) 67.84-7.82 (m, 2H), 7.50-7.46 (m, 2H), 7.30-7.26 (m, 1 H), 4.67-4.61 (m, 2H), 4.51-4.48 (m, 1H), 4.33 (s, 2H), 3.71-3.68 (m, 2H), 3.14 (brs, 1H), 3.05-2.99 (m, 3H), 2.75-2.67 (m, 1H), 2.31-2.29 (m, 2H), 2.22 (s, 3H), 1.92 (s, 2H), 1.21 (d, J=5.9 Hz, 3H), 1.03-1.02 (m, 2H), 0.96-0.93 (m, 2H).

[2167] LCMS Condition C: Rt = 2.56 min. m / z 548.4 [M+H]+

[2168] Example 28

[2169] Synthesis of 3-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)- 4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile:

[2170] Step-1 - Preparation of 3-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile

[2171]

[2172] To a stirred solution of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [I-2] (100 mg, 0.2 mmol) and 3-bromobenzonitrile (81 mg, 0.44 mmol) in DMSO (5 mL) was added K3PO4(94 mg, 0.44 mmol) and degassed with argon. Cui (85 mg, 0.44 mmol) and 1,2-transcyclohexane diamine (0.05 ml, 0.44 mmol) were added under inert atmosphere. Resulting mixture was heated at 80 °C for 16 h. Reaction mixture was filtered through celite bed and washed with ethyl acetate. Combined organic part was evaporated under reduced pressure and purified by reverse phase prep HPLC using Prep-B method to afford 3-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile (20 mg, 16.3% yield) as yellow solid.

[2173] 1H NMR (400 MHz, DMSO-d6) 68.35 (s, 2H), 7.91-7.86 (m, 2H), 7.69-7.65 (m, 2H), 7.547-7.48 (m, 2H), 7.34-7.29 (m, 1H), 5.00 (s, 2H), 4.72-4.66 (m, 2H), 4.55-4.52 (m, 1H), 3.75-3.70 (m, 2H), 3.10-3.04 (m, 1H), 2.81-2.75 (m, 1H), 1.22 (d, J=5.96 Hz, 3H), 1.03-0.96 (m, 2H), 0.95-0.94 (m, 2H).

[2174] LCMS Condition C: Rt = 3.29 min. m / z 554.2 [M+H]+ Examples 29-60

[2175] Examples 29-60 were synthesized by using similar procedure described in Example 28 (Table 11).

[2176] Table 11

[2177]

[2178]

[2179]

[2180]

[2181]

[2182]

[2183]

[2184]

[2185]

[2186] Table 12 describes analytical data analysis and information of examples 29-60:

[2187] Table 12

[2188]

[2189]

[2190]

[2191]

[2192]

[2193]

[2194] Table 13 describes information regarding separation of enantiomers of Example 43A and 43B. Absolute stereochemistry was not determined and was assigned arbitrarily.

[2195] Table 13

[2196]

[2197] Following table describes analytical data analysis and yield information of examples Example 43A and 43B

[2198] Table 14

[2199]

[2200] Example 61

[2201] Synthesis of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4- (2,4-difluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4- d]pyrimidin-7-one: Step-1- Preparation of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(3,6-dihydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[2202]

[2203] Synthesis of 2-((2S,6R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(3,6-dihydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one was done using 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)- 4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [I-2] (100 mg, 0.22 mmol) and 4-bromo-3,6-dihydro-2H-pyran (72 mg, 0.44 mmol) according to similar protocol mentioned in Example-8 ( Step-1) and obtained as yellow solid (50 mg, 42.3% yield).

[2204] Note: K2CO3 (2 eq and dimethyl ethylene diamine (10 eq were used instead of K3PO4and 1,2-transcyclohexane diamine.

[2205] LCMS Condition C: Rt = 2.91 min. m / z 535.3 [M+H]+

[2206] Step-2- Preparation of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[2207]

[2208] To a degassed solution of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(3,6-dihydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (45 mg, 0.08 mmol) in ethyl acetate (5.0 mL) was added Pd / C (20 mg, 10 % on charcoal) under nitrogen atmosphere. Reaction mixture was stirred at rt for 16 h under hydrogen balloon pressure. Reaction was filtered through a pad of celite bed, washed with ethyl acetate and concentrated under reduced pressure. Crude material was purified by reverse phase prep HPLC to afford 2-((2S,6R)-2-(1- cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(tetrahydro- 2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (11 mg, 25% yield) as off- white solid.

[2209] 1H NMR (400 MHz, DMSO-d6) 5 7.89-7.84 (m, 2H), 7.50-7.46 (m, 2H), 7.31-7.27 (m, 1H), 4.69-4.63 (m, 2H), 4.52-4.49 (m, 1H), 4.42 (br s, 2H), 4.31-4.26 (m, 1H), 3.93-3.90 (m, 2H), 3.74-3.66 (m, 2H), 3.46-3.41 (m, 2H), 3.06-2.99 (m, 1H), 2.76-2.71 (m, 1H), 1.85-1.76 (m, 2H), 1.67-1.65 (m, 2H), 1.21 (d, J=6.08 Hz, 3H), 1.05-0.98 (m, 2H), 0.96- 0.93 (m, 2H).

[2210] LCMS Condition C: Rt = 2.99 min. m / z 537.2 [M+H]+

[2211] Examples 62-64

[2212] Examples 62-64 were synthesized by using similar procedures described in Example 61 (Table 15).

[2213] Table 15

[2214]

[2215]

[2216]

[2217] Table 16 describes analytical data analysis and information of Examples 62-64

[2218] Table 16

[2219]

[2220] Example 65

[2221] Synthesis of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-((1-methylazetidin-3-yl)oxy)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one:

[2222] Step-1 - Preparation of tert-butyl 3-((5-bromopyridin-2-yl)oxy)azetidine-1-carboxylate

[2223]

[2224] To a stirred solution of tert-butyl (3-hydroxyazetidin-1-yl) carbamate (1 g, 5.74 mmol) in DMF (10 mL) at 0 °C was added sodium hydride (60% in oil, 206.6 mg, 8.61 mmol). Resulting suspension was stirred for 10 min and a solution of 5-bromo-2-iodopyridine (1.6 g, 5.74 mmol) in DMF (5 mL) was added dropwise. Resulting mixture was heated at 70 °C for 5 h. Reaction mixture was cooled to ambient temperature, diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Crude mass was purified by column chromatography using 8-10% ethyl acetate in hexane to afford tert-butyl 3-((5-bromopyridin-2-yl)oxy)azetidine-1 -carboxylate (1 g, 53% yield) as a yellow solid.

[2225] LCMS Condition C: Rt = 3.97 min. m / z 331.1 [M+H]+

[2226] Step-2 - Preparation of tert-butyl 3-((5-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)pyridin-2-yl)oxy)azetidine-1 -carboxylate

[2227]

[2228] To a stirred solution of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [I-2] (200 mg, 0.44 mmol) and tert-butyl 3-[(5-bromopyridin-2-yl)oxy]azetidine-1-carboxylate (145.51 mg, 0.44 mmol) in dioxane (5 mL) was added K2CO3 (122 mg, 0.88 mmol) and degassed with argon. CuI (168 mg, 0.88 mmol) and 1,2-transcyclohexane diamine (0.09 ml, 0.88 mmol) were added under inert atmosphere. Resulting mixture was heated at 80 °C for 3 h. Reaction mixture was filtered through celite bed and washed with ethyl acetate. Combined organic part was evaporated under reduced pressure and purified by column chromatography using 60% ethyl acetate in hexane to afford tert-butyl 3-((5-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)pyridin-2-yl)oxy)azetidine-1 -carboxylate (130 mg, 42% yield) as yellow solid.

[2229] LCMS Condition B: Rt = 2.16 min. m / z 701.6 [M+H]+

[2230] Step-3 - Preparation of 6-(6-(azetidin-3-yloxy)pyridin-3-yl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[2231]

[2232] To a stirred solution of tert-butyl 3-((5-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)pyridin-2-yl)oxy)azetidine-1-carboxylate ((200 mg, 0.28 mmol) in DCM (4 mL) at 0 °C was added TFA (1 mL). Reaction mixture was slowly warmed up to rt and stirred for 2 h. Reaction mixture was concentrated under reduced pressure. Residue was neutralized with saturated aqueous NaHCO3 solution and extracted with 5% methanol in DCM solution. Combined organic part was evaporated under reduced pressure to afford 6-(6-(azetidin-3-yloxy)pyridin-3-yl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (160 mg, crude) which was used in next step without purification.

[2233] LCMS Condition B: Rt = 3.08 min. m / z 601.4 [M+H]+.

[2234] Step-4 - Preparation of 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-((1-methylazetidin-3-yl)oxy)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[2235]

[2236] To a stirred solution of 6-(6-(azetidin-3-yloxy)pyridin-3-yl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (80 mg, 0.13 mmol) in DCE (3 mL), paraformaldehyde (20 mg, 0.66 mmol) was added followed by TEA (0.019 mL, 0.13 mmol) and sodium triacetoxyborohydride (42 mg, 0.25 mmol). Resulting mixture was stirred at rt for 4 h. Reaction mixture was diluted with DCM and washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Crude mass was purified by reverse phase prep HPLC using Prep-D method to afford 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-((1-methylazetidin-3-yl)oxy)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (Example 65, 25 mg, 24% yield) as yellow solid.

[2237] 1H NMR (400 MHz, DMSO-d6) 68.59 (s, 1 H), 8.26-8.23 (m, 1 H), 7.91-7.86 (m, 2H), 7.51-7.48 (m, 2H), 7.30 (t, J=7.9 Hz, 1H), 6.96-6.94 (m, 1H), 5.10-5.08 (m, 1H), 4.94 (s, 2H), 4.72-4.66 (m, 2H), 4.54-4.52 (m, 1H), 3.74-3.68 (m, 4H), 3.09-3.03 (m, 1H), 2.99-2.95 (m, 2H), 2.79-2.67 (m, 1H), 2.28 (s, 3H), 1.21 (d, J=5.9 Hz, 3H), 1.03-0.93 (m, 4H). LCMS Condition C: Rt = 2.68 min. m / z 615.4 [M+H]+ Example 66

[2238] Synthesis of 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(2,4-difluorophenyl)-2- ((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one:

[2239] Step-1 - Preparation of 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(2,4-difluorophenyl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[2240]

[2241] To a stirred solution of 4-(2,4-difluorophenyl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [1-2-19] (100 mg, 0.22 mmol) and (3-oxabicyclo[3.1.0]hexan-6-yl)boronic acid [1-4-1] (42.3 mg, 0.33 mmol) in toluene (5 mL) was added Cs2CO3 (35.9 mg, 0.11 mmol). Solution was purged with oxygen for 10 mins and pyridine (0.053 mL, 0.66 mmol) and copper acetate (40 mg, 0.22 mmol) were added. Resulting mixture was heated at 110 °C for 2 h under oxygen atmosphere. Reaction mixture was filtered through celite bed and washed with DCM. Combined organic part was evaporated under reduced pressure and purified by reverse phase prep HPLC using Prep-F method to afford 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(2,4-difluorophenyl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (42 mg, 35.5% yield) as off-white solid.

[2242] 1H NMR (400 MHz, DMSO-d6) 68.18-8.17 (m, 1H), 7.89-7.83 (m, 1H), 7.50 (t, J=9.2 Hz, 1H), 7.30 (t, J=7.7 Hz, 1H), 7.05-7.04 (m, 1H), 6.86 (s, 1H), 4.75-4.63 (m, 3H), 4.39 (s, 2H), 3.92-3.85 (m, 2H), 3.86 (m, 3H), 3.82-3.80 (m, 1H), 3.67-3.66 (m, 2H), 2.87-2.76 (m, 2H), 2.86 (s, 1H), 2.22 (s, 2H), 1.28 (d, J=6 Hz, 3H).

[2243] LCMS Condition C: Rt = 3.17 min. m / z 536.4 [M+H]+ Examples 67-68

[2244] Examples 67 and 68 were synthesized by using similar procedure described in Example 28 (Table 17).

[2245] Table 17

[2246]

[2247] Table 18 describes analytical data analysis and information of Examples 67-68

[2248] Table 18

[2249]

[2250]

[2251] Examples 69-73

[2252] Examples 69-73 were synthesized by using similar procedures described in Example 27 and Example 28 (Table 19).

[2253] Table 19

[2254]

[2255]

[2256]

[2257] Table 20 describes analytical data analysis and information of examples 69-73:

[2258] Table 20

[2259]

[2260]

[2261] Table 21 describes information regarding separation of enantiomers of Example 69 / 69B to 73A / 73B. Absolute stereochemistry was not determined and was assigned arbitrarily.

[2262] Table 21

[2263]

[2264]

[2265]

[2266]

[2267]

[2268] The following table describes analytical data analysis and yield information of examples Example 69A & B to 73A & B

[2269] Table 22

[2270]

[2271]

[2272]

[2273]

[2274]

[2275] Example 74

[2276] Human TREM2, in vitro Measurement of Triggering Receptor Expressed on Myeloid Cells 2 activity using cellular phosphorylation of Spleen Tyrosine Kinase (“Syk”) Assay Cell line:

[2277] HEK-293 cells were co-transfected with separate plasmids encoding TREM2 and DAP12 to generate a stable cell line. After antibiotic selection, functional clone pool analysis and two successive limiting dilutions, the final clone “HEK293 / DAP12+TREM2” underwent a qPCR analysis and a pharmacological validation.

[2278] Assay

[2279] TREM2 signalling through DAP12 was monitored in the HEK293 / DAP12+TREM2 stable cell line by measuring the phosphorylation levels of the Syk kinase using the commercially available AlphaLISA SureFire Ultra p-SYK (Tyr525 / 526) Assay Kit (Revvity, Revvity, lot:8220-24305, cat:6005350), based on the Perkin Elmer AlphaScreen / AlphaLISA technology.

[2280] Compound stock solutions were prepared at 20 mM in 100% DMSO. Compound serial dilutions were performed in 384 well plates (SPTLabtech, SPTLabtech, lot:3138848, cat: 4150-05828) by hand at 10-fold assay concentration in Eagle medium supplemented with 0.1 % Pluronic-F68 and 5 % DMSO thus generating 12 points in triplicates at 1:4 titrations steps. For each plate, 15 replicates of 100 % stimulation (MTX00041305 10 uM final assay concentration) and 12 replicates of 0% stimulation (0.5 % DMSO mock final assay concentration) controls were included.

[2281] Finally, 5 uL from each well containing the serial dilution or controls were transferred to a 384 well plate (Greiner, VWR, lot: E22103UP, cat:737-0080) prefilled with HEK293 / DAP12+TREM2 cells and 45 uL Eagle medium supplemented with 0.1 % Pluronic-F68 and incubated 30 min at 37 °C with 5 % CO2.

[2282] After 30 min, media was removed from each well and 10 uL Lysis buffer (Revvity, Revvity, lot:U18368, cat:#ALSU-PSYK-A10k) was added. The plate was then sealed and incubated 10 min. at RT before freezing at -80 °C. Next day, the plate was thawed and 5 uL lysate transferred to an alpha plate (Revvity, Revvity, lot:8220-24305, cat:6005350) together with 2.5 uL Acceptor mix (Revvity, Revvity, lot: U18368, cat:#ALSU-PSYK-A10k). The plate is now spun down 30 sec to sediment the reaction, shaken for 2 min at 450 rpm and shielded from sunlight with tinfoil before incubation for 1 hrs. at RT. After 1 hrs., 2.5 uL Donor mix (Revvity, Revvity, lot: U18368, cat:#ALSU-PSYK-A10k) was added to each well in a dark room and the plate is spun down for 30 sec to sediment the reaction and shaken at 450 rpm for 2 min before incubating 1 hrs at RT. At the end of the incubation, AlphaLISA signal was measured using a ClarioSTAR plate reader.

[2283] Data analysis was performed in Excel and GraphPad Prism (Version 10.0.3.). Data was normalized to 0-100 % activity based on signal intensity from control measurements. EC50 curves were estimated in GraphPad Prism by fitting a sigmoidal dose-response curve against normalized data after transforming compound concentration to logarithmic values.

[2284] The potency of the test compounds was expressed as EC₅₀ corresponding to the test compound concentration able to activate the phospho-Syk AlphaScreen signal to 50% of the maximal response.

[2285] The EC₅₀ values measured in this assay for the exemplified compounds is set out in the table below:

[2286]

[2287]

[2288]

[2289]

[2290] wherein “A “denotes an ECso value <1 nM, “B” denotes an ECso value between 1 nM and 10 nM, “C” denotes an ECso value between 10 and 100 nM, “D” denotes an ECso value between 100 and 1000 nM and “E” denotes an ECso value greater than 1000 nM. Regarding Emaxvalues, “+” denotes < 75%, “++” denotes 75-110% and “+++” denotes >110% maximal response relative to the maximal response of the reference agonist (8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-[1,3]diazino[5,4-d]pyrimidin-4-one).

[2291] References

[2292] Colonna, M. et al. (2016) Nat Rev Neurosci 17, 201–207

[2293] Deczkowska, A. et al. (2020) Perspective, 181, 6, 1207-1217

[2294] Hammond, T. R. (2019) Immunity, 50, 45955-974

[2295] Suarez-Calvet, M. et al. (2016) EMBO Mol Med, 8, 466-476

[2296] Yamazaki, K. et al. (2015) Clinical psychopharmacology and neuroscience: the official scientific journal of the Korean College of Neuropsychopharmacology, 13(3), 324–326 Paloneva BM, J. et al. (2001) Neurology, 56 (11) 1552-1558;

[2297] Ulrich J. D. et al. (2017) Neuron., 19;94(2):237-248)

[2298] Atagi, Y. et al. (2015) J Biol Chem., 290(43), 26043-50

[2299] Kleinberger, G. et al (2014) Sci Transl Med., 2, 6 (243):243

Claims

1. Claims1. A compound of Formula (I):

4. 6.Formula (I)7.wherein:8.- X1is N or C(H);9.- X2is N or C(H);10.- R1is 5- to 6-membered heteroaryl optionally substituted with one or more, identical or different, R16; phenyl optionally substituted with one or more, identical or different, R16; or of Formula (III):

12. 14.Formula (III)15.wherein16.• X5is C(R12)(R13) and X6is C(R14)(R15), wherein R12is H or F, R13is H or F, R14is H or F, and R15is H or F, or17.X5is C(R12) and X6is C(R14), wherein R12is H or F, R14is H or F, and X5and X6are linked together;18.• X7is O, C(R9)(R10), or N(R11);19.• R9is F or H;20.• R10is F or H;21.• R11is C1-3 alkyl optionally substituted with one or more F;22.• R8is individually H, F or CH3, and m is 0, 1 or 2;23.or m is 2 and the two R8are linked together to form a ring together with the intervening atom(s), and the two R8are together -(CH2)p-Oq-(CH2)y-, wherein p is 0, 1 or 2, q is 0 or 1, and y is 0, 1, or 2; - R16is individually C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, or -O-azetidinyl optionally substituted with C1-3 alkyl; - R2is of Formula (II):

25. 27.Formula (II)28.wherein29.- X3is N or C(H);30.- X4is O or N(R22);31.or X3is N and X4is C(F)2;32.- R22is H or C1-3 alkyl optionally substituted with one or more F;33.- R5is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; and34.- R6is individually H, F or CH3, and n is 0, 1 or 2;35.or n is 2 and the two R6are each -(CH2)2- or -CH2-, and the two R6are linked together to form a ring together with the intervening atom(s);36.- R3is phenyl or C5-8 bicycloalkyl, each of which is optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, CN, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;37.with the proviso that the compound is not 6-((2S,6R)-2-(1-cyclopropyl-1 H- pyrazol-4-yl)-6-methylmorpholino)-4-(2-fluoro-4-(trifluoromethyl)phenyl)-2-(1- methyl-1H-pyrazol-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one,38.or a pharmaceutically acceptable salt thereof.

2. The compound or salt according to claim 1, wherein X1is N and X2is N.

3. The compound or salt according to claim 1, wherein X1is C(H) and X2is N.

4. The compound or salt according to any one of the preceding claims, wherein R1is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or 2-pyridone, each of which is optionally substituted with one or more, identical or different, substituents selected from the group consisting of C1-6 alkoxy, C1-6 alkyl optionally substituted with C1-3 alkoxy, halogen, C1-6 haloalkoxy, -CN, C3-6 cycloalkyl, azetidinyl optionally substituted with C1-3 alkyl, and -O-azetidinyl optionally substituted with C1-3 alkyl.

5. The compound or salt according to any one of the preceding claims, wherein R143.

44.

6. The compound or salt according to any one of claims 1 to 3, wherein R1is of Formula (XI):

47. 49.Formula (XI)50.wherein51.- R12is H or F;52.- R14is H or F;53.- X7is O, C(R9)(R10), or N(R11);54.- R9is F or H;55.- R10is F or H;56.R11is C1-3 alkyl optionally substituted with one or more F;57.R8is individually H, F or CH3; and m is 0, 1 or 2.

7. The compound or salt according to any one of claims 1 to 3, wherein R1is60.

8. The compound according to any one of the preceding claims, wherein R2is of Formula (IVc):

64. 66.Formula (IVc)67.wherein68.R6ais H, F or CH3, and R6bis H, F or CH3;69.or R6aand R6bare linked together to form a ring together with the intervening atom, and R6aand R6bare each individually -(CH2)2- or -CH2-.

9. The compound or salt according to claim 8, wherein R6ais H and R6bis CH3.

10. The compound or salt according to claim 8, wherein R6ais CH3and R6bis CH3.

11. The compound or salt according to claim 8, wherein R6ais F and R6bis F.

12. The compound or salt according to claim 8, wherein R6ais H and R6bis H.

13. The compound or salt according to any one of claims 1 to 7, wherein R2is of Formula (V):

74. 76.Formula (V)14. The compound or salt according to any one of claims 1 to 7, wherein R2is of Formula (VI):

79. 81.Formula (VI) 15. The compound or salt according to any one of claims 1 to 7, wherein R2is of Formula (XII):

83. 85.Formula (XII)16. The compound or salt according to any one of the preceding claims, wherein R5is pyrazolyl or pyridinyl, each of which is optionally substituted with 1 to 3 substituents individually selected from C1-3 alkyl, C1-3 haloalkyl, cyclopropyl, and C1-3 alkoxy.

17. The compound or salt according to any one of the preceding claims, wherein R5is of Formula (VIII):

89. 91.Formula (VIII)92.wherein R7is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl or H.

18. The compound or salt according to any one of claims 1 to 7, wherein R2is95.

96.

19. The compound or salt according to any one of claims 1 to 7, wherein R2is98.

20. The compound or salt according to any one of claims 1 to 11, wherein R5is pyridinyl optionally substituted with 1 to 3 substituents individually selected from C1-3 alkyl, C1-3 haloalkyl, cyclopropyl, and C1-3 alkoxy.

21. The compound or salt according to any one of claims 1 to 7, wherein R2is103.

22. The compound or salt according to any one of the preceding claims, wherein R3107.

109.

110.

23. The compound or salt according to any one of the preceding claims, wherein R3111.

24. The compound or salt according to claim 1, wherein115.

117.

25. The compound according to claim 1, wherein the compound is120.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;121.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methylpyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;122.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(3-methoxyphenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-methylpyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(4-methoxyphenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-(3-oxabicyclo[3.1.0]hexan-6-yl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(4-fluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;123.4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;124.2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;125.(S)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;126.(R)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;127.4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;128.(S)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;129.(R)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;130.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,5-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;131.(S)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;132.(R)-4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;133.2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,5-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;134.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,6-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;135.6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;136.2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-4-(2,4,6-trifluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;137.2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methylpiperazin-1-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;138.(S)-2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methylpiperazin-1-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;139.(R)-2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methylpiperazin-1-yl)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;140.6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;141.4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;142.(S)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;143.(R)-4-(2,4-difluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;144.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;145.3-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;146.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(5-methylpyrazin-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 5-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)picolinonitrile;147.4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)picolinonitrile;148.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;149.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-methylpyrimidin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methylpyrimidin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(4-chloro-2-fluorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;150.4-(4-chloro-2-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile;151.3-fluoro-4-(2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)benzonitrile; 4-(4-chlorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)benzonitrile; 4-(4-chlorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)- 6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;152.4-(4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-7-oxo-5, 7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;153.(S)-4-(4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)- 7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;154.(R)-4-(4-(2,4-difluorophenyl)-2-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)- 7-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;155.4-(2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-7-oxo-4-(2,4,6-trifluorophenyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;156.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(4-fluorophenyl)-6- (2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;157.4-(2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-7-oxo-4-(2,4,6-trifluorophenyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)benzonitrile;158.4-(2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin- 5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)benzonitrile;159.6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-2-(2-methylpyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-2-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 4-(4-fluorophenyl)-6-(6-methoxypyridin-3-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;160.4-(4-fluorophenyl)-6-(2-methoxypyridin-4-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;161.4-(2,4-difluorophenyl)-6-(2-methoxypyridin-4-yl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;162.4-(2,4-difluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6- (2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;163.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(4-fluorophenyl)-6- (2-methoxypyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;164.4-(4-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-methoxy-3-methylpyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;165.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2,4-dimethylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;166.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;167.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(2-(methoxymethyl)pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;168.6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2-(2-methylpyrimidin-5-yl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;169.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;170.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(4,4-difluorocyclohexyl)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(4-chloro-2-fluorophenyl)-2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin- 7-one;171.4-(4-chloro-2-fluorophenyl)-2-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-6-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;172.2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2,4-difluorophenyl)-6-(6-((1-methylazetidin-3-yl)oxy)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;173.6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(2,4-difluorophenyl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;174.4-(2,4-difluorophenyl)-6-(6-(methoxymethyl)pyridin-3-yl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(2,4-difluorophenyl)-2-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-6-(2-methylpyrimidin-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;175.6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((S)-2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((R)-2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin- 7-one;176.6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)- 2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;177.6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-((R)-6-(1-cyclopropyl-1H-pyrazol-4-yl)- 2,2-difluoromorpholino)-4-(2,4-difluorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;178.(S)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)- 6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;179.(R)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-4-(2,4-difluorophenyl)- 6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;180.6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;181.6-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-(4-chloro-2-fluorophenyl)-2-((R)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;182.(S)-4-(4-chloro-2-fluorophenyl)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; or183.(R)-4-(4-chloro-2-fluorophenyl)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-difluoromorpholino)-6-(6-(methoxymethyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one,184.or a pharmaceutically acceptable salt thereof.

26. The compound or salt according to any one of the preceding claims, wherein the compound is a TREM2 modulator, such as a TREM2 activator, such as a TREM2 agonist.

27. A pharmaceutical composition comprising a compound or salt according to any one of the preceding claims and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

28. The compound or salt according to any one of claims 1 to 26, or the pharmaceutical composition according to claim 27, for use as a medicament.

29. The compound or salt according to any one of claims 1 to 26, or the pharmaceutical composition according to claim 27, for use in the treatment of a condition associated with a loss of function of TREM2, such as for use in the treatment of a condition associated with a mutation of TREM2.

30. The compound or salt according to any one of claims 1 to 26, or the pharmaceutical composition according to claim 27, for use in the treatment of a neurodegenerative disease.

31. The compound, salt, or pharmaceutical composition for use according to claim 30, wherein said neurodegenerative disease is selected from the group consisting of a tauopathy, a TDP-43 proteinopathy, a synucleinopathy, dementia, amyloidosis, a demyelinating disorder of the CNS, a demyelinating disorder of the PNS, a Leukoencephalopathy, a leukodystrophy, a transmissible spongiform encephalopathy (TSE) and a lysosomal storage disorder (LSD).

32. The compound or salt according to any one of claims 1 to 26, or the pharmaceutical composition according to claim 27, for use in the treatment of a neurodegenerative disease selected from the group consisting of Alzheimer’s disease, Frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), Parkinson’s disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington disease, Amyotrophic lateral sclerosis, multiple sclerosis, Guillain- Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease, prion disease and stroke.

33. The compound or salt according to any one of claims 1 to 26, or the pharmaceutical composition according to claim 27, for use in the treatment of a disease selected from the group consisting of arthritis, rheumatoid arthritis, pyle disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, dysosteoplasia, autism spectrum disorders, autism and Aspergers syndrome, traumatic brain injuries (TBI), spinal cord injuries, muscular dystrophy, myotonic dystrophy, inclusion-body myositis, systemic lupus erythematosus (SLE), RA, gout, bowel conditions, Inflammatory bowel disease (IBD), metabolic syndrome,obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver disease, alcoholic and non-alcoholic steatohepatitis, Amyloidosis.

34. A method for treatment of a condition associated with a loss of function of TREM2, such as a neurodegenerative disease, said method comprising administering a therapeutically effective amount of a compound or salt according to any one of claims 1 to 26, or the pharmaceutical composition according to claim 27, to a subject in need thereof.

35. Use of a compound or salt according to any one of claims 1 to 26, or the pharmaceutical composition according to claim 27, for the manufacture of a medicament for the treatment of a condition associated with a loss of function of TREM2, such as a neurodegenerative disease.

36. A method of enhancing or increasing TREM2 activity, such as a method of one or more of i) enhancing or activating TREM2 signaling through DAP12, ii) inducing phosphorylation of a kinase that interacts with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b, iii) enhancing TREM2-induced phosphorylation levels of the Syk kinase, Iv) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes, and / or v) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119; in a subject in need thereof, such as in a subject having a neurodegenerative disease, said method comprising administering to the subject a compound or salt according to any one of claims 1 to 26, or the pharmaceutical composition according to claim 27.

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