CBL-B inhibitors

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Z, M, R1, R2 and R3 are as defined in claim 1. Compounds of formula (I) have utility as inhibitors of Cbl-b. These compounds are useful as medicaments for the treatment of diseases or conditions in which inhibition of CBl-b is desired, such as cancer.

Description

TECHNICAL FIELD

[0001] The present invention relates to therapeutically active compounds useful for the inhibition of the E3 ligase Casitas B-lineage lymphoma b enzyme (also known as Cbl-b), and to pharmaceutical compositions containing such compounds. These compounds are useful, for example, in modulating the immune system in the treatment of various diseases and disorders such as cancer. BACKGROUND

[0002] Maintaining immune tolerance and inducing T cell anergy are essential for preventing autoimmunity. However, in the case of malignancies, tumor-induced T cell anergy leads to cancer-associated immunoparalysis, resulting in uncontrolled tumor growth and metastasis. Proteins that negatively regulate the amplitude and duration of TCR signaling will play a key role in determining the induction of T cell anergy. The Cbl family of E3 ubiquitin ligases, which includes Cbl-b and c-Cbl, has been identified as a key protein that regulates several signaling pathways in T cells, NK cells, and B cells through ubiquitination of several activated tyrosine kinases (Bachmaier, K. et al., Nature, 403, 6766, 211-216, 2000).

[0003] Ubiquitination is an important post-translational mechanism that regulates cellular function through proteasomal degradation of proteins involved in several signaling pathways. Ubiquitination of a target protein occurs in steps with three enzymes. Ubiquitination is initiated by catalysis of ubiquitin activation by a first enzyme (El). Activated ubiquitin is then transferred from El to a ubiquitin-conjugating enzyme (E2). Finally, a third enzyme (E3 ligase) confers substrate specificity and catalyzes the transfer of ubiquitin from E2 into the target protein substrate. The addition of polyubiquitin chains to a protein marks it for degradation by the proteasomal degradation machinery (Staub, O. et al., Physiological Reviews, 86, 2, 669-707, 2006).

[0004] Ubiquitination regulates a variety of biological functions, including cell division, DNA repair, and cell signaling. Molecules that can modulate components of the ubiquitin proteasome system can be useful as therapeutics for a wide range of disorders, including cancer and autoimmune diseases.

[0005] E3 ubiquitin ligases have recently been described to confer specificity and their role in the fine-tuning of the immune response. Casitas B-lineage lymphoma b (Cbl-b) stands out due to its function as a non-redundant negative regulator of immune activation and is one of the most important “gatekeepers” of immune activation (Chiang, Y. et al., Nature, 403, 6766, 16-220, 2000).

[0006] The Cbl family of E3 ligases selectively modulates activated PTKs by recognizing specific phosphotyrosine-containing motifs. Cbl-b also downregulates signaling from antigen and cytokine receptors through ubiquitination of receptor chains and associated cytoplasmic tyrosine kinases, leading to inactivation and / or proteasomal degradation of target proteins (Schmidt. H. et al., Nat Rev Mol Cell Biol, 2005, 6(12):907-918).

[0007] Cbl-b is preferentially expressed in peripheral lymphoid organs and acts as a major regulator of immune cell activation and maintenance of peripheral tolerance. Cbl-b-deficient immune cells show a lower activation threshold and Cbl-b knockout mice reject tumors mediated by cytotoxic T cells and NK cells (Loeser, S. et al., Journal of Experimental Medicine, 204, 4, 879-891, 2007).

[0008] Cbl proteins not only regulate adaptive immune cell functions but also critically participate in the regulation of innate lymphocyte populations such as NK cells, dendritic cells and myeloid cells. Therefore, targeting Cbl-b offers an opportunity to enhance anti-cancer immunity.

[0009] Compounds having Cbl-b inhibitory activity have been disclosed in, for example, WO 2019 / 148005, WO 2020 / 210508, WO 2020 / 236654, WO 2020 / 264398, WO 2022 / 169997, WO 2022 / 217276 and WO 2022 / 272248. SUMMARY

[0010] It has been found that compounds of Formula (I) are potent inhibitors of the E3 ligase Casitas B-lineage lymphoma b enzyme (Cbl-b). Therefore, these compounds are useful in the treatment of conditions and diseases in which inhibition of Cbl-b is desirable. Such conditions and diseases include, but are not limited to, cancer.

[0011] The present invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof

[0012]

[0013] wherein

[0014] Z is CH2or NH;

[0015] M is C or N;

[0016] when M is C, then R2is hydrogen, halogen, C 1-7 alkoxy, cyano, halogen C 1-7 alkyl or -NH-C 1-7 alkyl;

[0017] when M is N, then R2is absent;

[0018] R1is any one of the following groups:

[0019] , , ,

[0020] or ;

[0021] R4, R5, R6, R7, R8and R9are independently hydrogen, C 1-7 alkyl, halogen or halogen C 1-7 alkyl, or R4and R5, or R6and R7, or R8and R9together with the carbon atom to which they are attached form an optionally substituted C 3-7 cycloalkyl ring or an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms, independently selected from O, S and N;

[0022] R’4and R’5together with the carbon atom to which they are attached form an optionally substituted C3-C6cycloalkyl ring or an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms, independently selected from O, S and N;

[0023] B1, B2, B3and B4are independently an optionally substituted 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring atoms, independently selected from O, S and N;

[0024] B5is an optionally substituted phenyl ring or an optionally substituted 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring atoms, independently selected from O, S and N;

[0025] B6 is an optionally substituted 5-10 membered monocyclic, bicyclic, or spiro bicyclic heterocycle containing 1-4 heteroatoms as ring atoms independently selected from O, S, and N;

[0026] R3 is any one of the following groups:

[0027] , or

[0028] Z1, Z2, Z3, and Z4 are independently CH, CX, C-CF3, or N;

[0029] X is halogen;

[0030] Y1and Y2are independently a 3-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring atoms independently selected from O, S, and N;

[0031] R 11 , R 13 , and R 15 are independently hydrogen, C 1-7 1-6 alkyl, C 2-7 2-6 alkenyl, C 3-7 3-6 cycloalkyl, C 3-7 3-6 cycloalkyl C 1-7 1-6 alkyl, halogen, C 1-7 1-6 alkoxy, halogen C 1-7 1-6 alkyl, or a 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms independently selected from O, S, and N;

[0032] R 12 is hydrogen, C 1-7 1-6 alkyl, or -C 1-7 1-6 alkyl-NR 16 R 17 ;

[0033] R 10 and R 14 are independently -C(O)O-C 1-7 1-6 alkyl, hydroxy C 1-7 1-6 alkyl, halogen C 1-7 1-6 alkyl, -NR 21 R 22 , -C 1-7 1-6 alkyl-NR 21 R 22 , -hydroxy C 1-7 1-6 alkyl-NR 21 R 22 , or a group

[0034] ;

[0035] L is a bond, -CH2-, -CH-, -CH(CH3)-, -C(CH2)-, or -C(O)-;

[0036] A is a 5-10 membered monocyclic, bicyclic, or spiro bicyclic heterocycle containing 1-4 heteroatoms as ring members, the heteroatoms being independently selected from O, S, and N;

[0037] R 16 and R 17 are independently hydrogen or C 1-7 alkyl;

[0038] R 18 , R 19 , and R 20 are independently absent, hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, cyano, halogen C 1-7 alkyl, hydroxy, hydroxy C 1-7 alkyl, or oxo;

[0039] R 21 and R 22 are independently hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl, (C 3-7 cycloalkyl)2C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, C 3-7 cycloalkyl halogen C 1-7 alkyl, halogen C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, halogen C 1-7 alkyl, halogen C 3-7 cycloalkyl, halogen C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 1-7 alkyl, hydroxy C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 3-7 cycloalkyl, C 1-7 alkoxy C 3-7 cycloalkyl, cyano C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkoxy C 3-7Cycloalkyl C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, Amino hydroxy C 1-7 Alkyl, C 1-7 Alkyl amide C 1-7 Alkyl, -SO2-C 1-7 Alkyl, -S(O)-C 1-7 Alkyl, -C 1-7 Alkyl-(O-C 1-7 alkyl) 1-3 -NH2, -C 1-7 alkyl(C 3-7 cycloalkyl)(OH), or a group

[0040] ;

[0041] L' is a bond, C 1-7 alkyl or C 2-7 alkenyl;

[0042] A' is an optionally substituted 3-6 membered heterocycle having 1-3 heteroatoms as ring atoms, independently selected from O, S and N;

[0043] R 23 is independently hydrogen, C 1-7 alkyl or halogen;

[0044] n is 0, 1 or 2;

[0045] wherein the optional substitution is 1-2 substituents independently selected from C 1-7 alkyl, C 3-7 cycloalkyl, halogen, hydroxyl, C 1-7 alkoxy, halogen C 1-7 alkyl and cyano.

[0046] According to one embodiment, the present application provides a method for treating a disease or disorder in which inhibition of Cbl-b is desired, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof

[0047]

[0048] wherein

[0049] Z is CH2or NH;

[0050] M is C or N;

[0051] when M is C, then R2is hydrogen, halogen, C 1-7 alkoxy, cyano, halogen C 1-7 alkyl or -NH-C1-7 alkyl;

[0052] When M is N, then R2 does not exist;

[0053] R1 is any one of the following groups:

[0054] , , ,

[0055] or ;

[0056] R4, R5, R6, R7, R8, and R9 are independently hydrogen and C. 1-7 Alkyl, halogen or halogen C 1-7 Alkyl groups, or R4 and R5, or R6 and R7, or R8 and R9, together with the carbon atoms to which they are attached, form optionally substituted C atoms. 3-7 Cycloalkyl rings or optional substituted 3-6 membered heterocycles having 1-3 heteroatoms as ring atoms, the heteroatoms being independently selected from O, S and N;

[0057] R'4 and R'5, together with the carbon atoms to which they are attached, form optionally substituted C3-C6 cycloalkyl rings or optionally substituted 3-6 membered heterocycles having 1-3 heteroatoms as ring atoms, the heteroatoms being independently selected from O, S and N;

[0058] B1, B2, B3 and B4 are independently substituted 5-6 membered heterocycles having 1-4 heteroatoms as ring atoms, the heteroatoms being independently selected from O, S and N;

[0059] B5 is an optionally substituted benzene ring or an optionally substituted 5-6 membered heterocycle having 1-4 heteroatoms as ring atoms, the heteroatoms being independently selected from O, S and N;

[0060] B6 is a 5-10 membered monocyclic, bicyclic, or spirobicyclic heterocycle containing 1-4 heteroatoms as ring atoms, which are optionally substituted, and the heteroatoms are independently selected from O, S, and N;

[0061] R3 is any one of the following groups:

[0062] , or

[0063] Z1, Z2, Z3 and Z4 are independently CH, CX, C-CF3 or N;

[0064] X is a halogen;

[0065] Y1and Y2are independently a 3-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring members independently selected from O, S, and N;

[0066] R 11 , R 13 , and R 15 are independently hydrogen, C 1-7 1-6 alkyl, C 2-7 2-6 alkenyl, C 3-7 3-6 cycloalkyl, C 3-7 3-6 cycloalkyl C 1-7 1-6 alkyl, halogen, C 1-7 1-6 alkoxy, halogen C 1-7 1-6 alkyl, or a 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring members independently selected from O, S, and N;

[0067] R 12 is hydrogen, C 1-7 1-6 alkyl, or -C 1-7 1-6 alkyl-NR 16 R 17 ;

[0068] R 10 and R 14 are independently -C(O)O-C 1-7 1-6 alkyl, hydroxy C 1-7 1-6 alkyl, halogen C 1-7 1-6 alkyl, -NR 21 R 22 , -C 1-7 1-6 alkyl-NR 21 R 22 , -hydroxy C 1-7 1-6 alkyl-NR 21 R 22 , or a group

[0069] ;

[0070] L is a bond, -CH2-, -CH-, -CH(CH3)-, -C(CH2)-, or -C(O)-;

[0071] A is a 5-10 membered monocyclic, bicyclic, or spiro bicyclic heterocyclic ring containing 1-4 heteroatoms as ring members independently selected from O, S, and N;

[0072] R 16 and R 17 are independently hydrogen or C 1-7 1-6 alkyl;

[0073] R 18 , R 19 , and R 20 are independently absent, hydrogen, C1-7 Alkyl, C 1-7 Alkoxy, halogen, cyano, halogen C 1-7 Alkyl, hydroxyl, hydroxyl C 1-7 Alkyl or oxo group;

[0074] R 21 and R 22 Independently, it is hydrogen and C 1-7 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 Alkyl, C 1-7 Alkyl C 3-7 cycloalkyl, (C 3-7 cycloalkyl)2C 1-7 Alkyl, C 1-7 Alkyl C 3-7 cycloalkyl C 1-7 Alkyl, C 3-7 cycloalkyl halogen C 1-7 Alkyl, Halogen C 1-7 Alkyl C 3-7 cycloalkyl C 1-7 Alkyl, Halogen C 1-7 Alkyl, Halogen C 3-7 cycloalkyl, halogen C 3-7 cycloalkyl C 1-7 Alkyl, hydroxyl C 1-7 Alkyl, hydroxyl C 1-7 Alkyl C 3-7 cycloalkyl C 1-7 Alkyl, hydroxyl C 3-7 cycloalkyl, C 1-7 Alkoxy C 3-7 cycloalkyl, cyano C 3-7 cycloalkyl C 1-7 Alkyl, hydroxyl C 3-7 cycloalkyl C 1-7 Alkyl, C 1-7 Alkoxy C 3-7 cycloalkyl C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, aminohydroxy C 1-7 Alkyl, C 1-7 Alkylamide C 1-7 Alkyl group, -SO2-C 1-7 Alkyl, -S(O)-C 1-7 Alkyl, -C 1-7 Alkyl-(OC) 1-7 alkyl) 1-3 -NH2, -C 1-7 Alkyl (C) 3-7 cycloalkyl (OH) or groups

[0075] ;

[0076] L' is a bond, C 1-7 alkyl or C 2-7 alkenyl;

[0077] A' is an optionally substituted 3-6 membered heterocycle having 1-3 heteroatoms as ring atoms, independently selected from O, S and N;

[0078] R 23 is independently hydrogen, C 1-7 alkyl or halogen;

[0079] n is 0, 1 or 2;

[0080] wherein the optional substitution is 1-2 substituents independently selected from C 1-7 alkyl, C 3-7 cycloalkyl, halogen, hydroxyl, C 1-7 alkoxy, halogen C 1-7 alkyl and cyano.

[0081] According to one embodiment, the disease or disorder in which inhibition of Cbl-b is desired is a cancer, such as squamous cell carcinoma, bladder cancer, gastric cancer, liver cancer, lung cancer and colon cancer, bone cancer, pancreatic cancer, melanoma, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, testicular cancer, uterine cancer, endometrial cancer, non-Hodgkin's lymphoma or leukemia.

[0082] According to one embodiment, the present application provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. DETAILED DESCRIPTION

[0083] The present application provides novel compounds of Formula (I) or a pharmaceutically acceptable salt thereof useful as Cbl-b inhibitors.

[0084] One of the embodiments of the present application provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof

[0085]

[0086] wherein

[0087] Z is CH2or NH;

[0088] M is C or N;

[0089] when M is C, then R2is hydrogen, halogen, C 1-7 alkoxy, cyano, halogen C 1-7 alkyl or -NH-C 1-7alkyl;

[0090] when M is N, then R2is absent;

[0091] R1is any one of the following groups:

[0092] , , ,

[0093] or ;

[0094] R4, R5, R6, R7, R8and R9are independently hydrogen, C 1-7 alkyl, halogen or halogen C1-7alkyl, or R4and R5, or R6and R7, or R8and R9together with the carbon atoms to which they are attached form an optionally substituted C 3-7 cycloalkyl ring or an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms independently selected from O, S and N;

[0095] R’4and R’5together with the carbon atom to which they are attached form an optionally substituted C3-C6cycloalkyl ring or an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms independently selected from O, S and N;

[0096] B1, B2, B3and B4are independently an optionally substituted 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring atoms independently selected from O, S and N;

[0097] B5is an optionally substituted phenyl ring or an optionally substituted 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring atoms independently selected from O, S and N;

[0098] B6is an optionally substituted 5-10 membered monocyclic, bicyclic or spiro bicyclic heterocyclic ring containing 1-4 heteroatoms as ring atoms independently selected from O, S and N;

[0099] R3is any one of the following groups:

[0100] , or

[0101] Z1, Z2, Z3and Z4are independently CH, CX, C-CF3or N;

[0102] X is halogen;

[0103] Y1and Y2are independently a 3-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring members independently selected from O, S, and N;

[0104] R 11 , R 13 , and R 15 are independently hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, halogen, C 1-7 alkoxy, halogen C 1-7 alkyl, or a 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring members independently selected from O, S, and N;

[0105] R 12 is hydrogen, C 1-7 alkyl, or -C 1-7 alkyl-NR 16 R 17 ;

[0106] R 10 and R 14 are independently -C(O)O-C 1-7 alkyl, hydroxy C 1-7 alkyl, halogen C 1-7 alkyl, -NR 21 R 22 , -C 1-7 alkyl-NR 21 R 22 , -hydroxy C 1-7 alkyl-NR 21 R 22 , or a group

[0107] ;

[0108] L is a bond, -CH2-, -CH-, -CH(CH3)-, -C(CH2)-, or -C(O)-;

[0109] A is a 5-10 membered monocyclic, bicyclic, or spiro bicyclic heterocyclic ring containing 1-4 heteroatoms as ring members independently selected from O, S, and N;

[0110] R 16 and R 17 are independently hydrogen or C 1-7 alkyl;

[0111] R 18 , R 19 , and R 20 are independently absent, hydrogen, C1-7 alkyl, C 1-7 alkoxy, halogen, cyano, halogen C 1-7 alkyl, hydroxy, hydroxy C 1-7 alkyl or oxo;

[0112] R 21 and R 22 are independently hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl, (C 3-7 cycloalkyl)2C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, C 3-7 cycloalkyl halogen C 1-7 alkyl, halogen C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, halogen C 1-7 alkyl, halogen C 3-7 cycloalkyl, halogen C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 1-7 alkyl, hydroxy C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 3-7 cycloalkyl, C 1-7 alkoxy C 3-7 cycloalkyl, cyano C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkoxy C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkoxy C 1-7 alkyl, amino hydroxy C 1-7 alkyl, C 1-7 alkyl amide C 1-7 alkyl, -SO2-C 1-7 alkyl, -S(O)-C 1-7 alkyl, -C 1-7 alkyl-(O-C 1-7 alkyl) 1-3 -NH2, -C 1-7 alkyl(C 3-7 cycloalkyl)(OH), or a group

[0113] ;

[0114] L' is a bond, C 1-7 alkyl or C 2-7 alkenyl;

[0115] A' is an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms independently selected from O, S and N;

[0116] R 23 independently is hydrogen, C 1-7 alkyl or halogen;

[0117] n is 0, 1 or 2;

[0118] wherein the optional substitution is 1-2 substituents independently selected from C 1-7 alkyl, C 3-7 cycloalkyl, halogen, hydroxyl, C 1-7 alkoxy, halogen C 1-7 alkyl and cyano.

[0119] According to one embodiment, specifically provided are compounds according to formula (I), wherein R1is a group (1) or (5):

[0120]

[0121] According to yet another embodiment, specifically provided are compounds, wherein Z is CH2. According to yet another embodiment, specifically provided are compounds, wherein M is C. According to yet another embodiment, specifically provided are compounds, wherein R2is hydrogen.

[0122] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments, wherein R4and R5are independently hydrogen or C 1-7 alkyl. According to yet another embodiment, specifically provided are compounds according to any of the above embodiments, wherein R4is hydrogen and R5is or C 1-7 alkyl.

[0123] According to yet another embodiment, R4and R5together with the carbon atom to which they are attached form an optionally substituted C3-C6cycloalkyl ring or an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms independently selected from O, S and N. Within the subgroup of the foregoing embodiments are compounds, wherein R4and R5together with the carbon atom to which they are attached form an optionally substituted oxetanyl ring or an optionally substituted C3-C6cycloalkyl ring, such as an optionally substituted cyclobutyl ring.

[0124] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments, wherein B6 is an optionally substituted 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring atoms, independently selected from O, S and N.

[0125] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments, wherein B1, B2, B3, B4 and B6 are independently an optionally substituted triazolyl ring, optionally substituted with one C 1-7 alkyl substituent. In a subgroup of the foregoing embodiments are compounds, wherein B1, B2, B3, B4 and B6 are independently an optionally substituted triazolyl ring, optionally substituted with one C 1-7 alkyl substituent. In a subgroup of the foregoing embodiments are compounds, wherein B1, B2, B3, B4 and B6 are independently an optionally substituted triazolyl ring, optionally substituted with one C

[0126] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments, wherein R 23 is hydrogen.

[0127] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments, wherein B5 is an optionally substituted phenyl ring. According to yet another embodiment, specifically provided are compounds according to any of the above embodiments, wherein B6 is an optionally substituted triazolyl ring, optionally substituted with one C 1-7 alkyl substituent. In a subgroup of the foregoing embodiments are compounds, wherein B1, B2, B3, B4 and B6 are independently an optionally substituted triazolyl ring, optionally substituted with one C

[0128] Specifically provided are compounds according to any of the above embodiments, wherein n is 0.

[0129] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments, wherein R3 is any one of the following groups:

[0130] , , , , , or .

[0131] In a subgroup of the foregoing embodiments are compounds, wherein R3 is group (1a'), (1b') or (1c'). In a subgroup of the foregoing embodiments are compounds, wherein R3 is group (1b').

[0132] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments, wherein R 10 and R 14 are groups

[0133] , wherein -L- is -CH2- or -CH(CH3)-.

[0134] In a subgroup of this embodiment are compounds in which L is -CH2-.

[0135] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments, wherein A is a 5-10 membered monocyclic ring containing 1-4 heteroatoms as ring members, independently selected from O, S and N. In a subgroup of the foregoing embodiment, A is any one of the following groups:

[0136] , , , , , ,

[0137] , or .

[0138] In a subgroup of the foregoing embodiment are compounds in which A is group (2a'), (2b') or (2l'). In a subgroup of the foregoing embodiment are compounds in which A is group (2a').

[0139] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments, wherein A is a 5-10 membered bicyclic or spirobicyclic ring containing 1-4 heteroatoms as ring members, independently selected from O, S and N. In a subgroup of the foregoing embodiment, A is any one of the following groups:

[0140] , , , , , , , , , , ,

[0141] , or .

[0142] According to one embodiment, specifically provided are compounds according to any of the above embodiments, wherein R 10 is -C 1-7 alkyl-NR 21 R 22 . In a subgroup of this embodiment are compounds in which -C 1-7 alkyl- is -CH2- or -CH(CH3)-.

[0143] Specifically provided are compounds according to any of the above embodiments, wherein R 21 is hydrogen.

[0144] Specifically provided are compounds according to any of the above embodiments, wherein R 22 is C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, halogen C 1-7 alkyl, halogen C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkoxy C 3-7 cycloalkyl, hydroxy C 3-7 cycloalkyl, hydroxy C 3-7 cycloalkyl C 1-7 alkyl or the group

[0145] ;

[0146] wherein

[0147] L' is a bond or C 1-7 alkyl; and

[0148] A' is an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms, independently selected from O, S and N.

[0149] In a subgroup of any of the above embodiments are compounds, wherein R 21 is hydrogen and R 22 is C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, halogen C 1-7 alkyl, halogen C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkoxy C 3-7 cycloalkyl, hydroxy C 3-7 cycloalkyl or hydroxy C 3-7 cycloalkyl C 1-7 alkyl. In a subgroup of this embodiment are compounds, wherein C 3-7 cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl and C 1-7 alkyl is C1-3 alkyl, e.g. -CH2- or -CH(CH3)-. In one embodiment, compounds are provided in which halo C 1-7 alkyl is -CH2-CH2-CF3. In one embodiment, compounds are provided in which C 3-7 cycloalkyl C 1-7 alkyl is -CH2-cyclopropyl.

[0150] In particular, compounds according to any one of the above embodiments are provided, wherein the compound is represented by formula (Ia)

[0151]

[0152] wherein Z1and Z2are independently CH, CX, or N;

[0153] R4and R5are independently hydrogen or C 1-7 alkyl, or R4and R5together with the carbon atom to which they are attached form an optionally substituted cyclobutyl ring or an optionally substituted oxetane ring, wherein the optional substitution is 1-2 substituents independently selected from C 1-7 alkyl, halo, and cyano at each occurrence;

[0154] R 11 is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, halo, C 1-7 alkoxy, or halo C 1-7 alkyl;

[0155] L is -CH2- or -CH(CH3)-;

[0156] R 24 is -NR 21 R 22 or a group

[0157] ;

[0158] wherein A is a 5-10 membered monocyclic or bicyclic or spiro bicyclic heterocycle containing 1-4 heteroatoms as ring atoms, independently selected from O, S, and N;

[0159] R 18 , R 19 , and R 20 are independently hydrogen, C 1-7 alkyl, halo, cyano, halo C 1-7 alkyl, hydroxyl, hydroxyl C 1-7 alkyl, or oxo;

[0160] R 21 and R 22 independently hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl, C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, halogen C 1-7 alkyl, halogen C 3-7 cycloalkyl or halogen C 3-7 cycloalkyl C 1-7 alkyl, hydroxyl C 1-7 alkoxy C 1-7 alkoxy C 3-7 cycloalkyl, hydroxyl C 3-7 cycloalkyl C 1-7 alkyl or hydroxyl C 3-7 cycloalkyl.

[0161] In a subgroup of the above embodiments are compounds wherein R4and R5together with the carbon atom to which they are attached form an optionally substituted cyclobutyl ring or an optionally substituted oxetane ring, wherein the optional substitution is 1-2 substituents independently selected from C 1-7 alkyl, halogen and cyano.

[0162] In a subgroup of the above embodiments are compounds of formula (Ia) wherein A is any one of groups (2a'), (2b'), (2c'), (2d'), (2e'), (2f'), (2g'), (2h') or (2i') as defined above. In particular, compounds of formula (Ia) are provided wherein A is group (2a').

[0163] According to yet another embodiment, specifically provided are compounds according to any one of the above embodiments wherein R4is hydrogen and R5is C 1-7 alkyl, or R4and R5together with the carbon atom to which they are attached form a group of formula (3a) or (3b),

[0164]

[0165] These groups can be optionally substituted with 1-2 substituents independently selected from C 1-7 alkyl, halogen and cyano.

[0166] According to a further embodiment, specifically provided are compounds according to any of the above embodiments, wherein R 18 is hydrogen, and R 19 and R 20 are independently hydrogen, C 1-7 alkyl or halogen. In a subgroup of the foregoing embodiments are compounds, wherein the C 1-7 alkyl is methyl. In a subgroup of the foregoing embodiments are compounds, wherein R 18 and R 19 are hydrogen, and R 20 is C 1-7 alkyl, in particular methyl. In another subgroup are compounds, wherein R 18 is hydrogen, and R 19 and R 20 are C 1-7 alkyl, in particular methyl.

[0167] Specifically provided are compounds according to any of the above embodiments, wherein the compound is represented by formula (Ib)

[0168]

[0169] wherein

[0170] R 25 and R 26 are independently hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen or cyano;

[0171] R 11 is hydrogen, C 1-7 alkyl or halogen;

[0172] R 22 is C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl, (C 3-7 cycloalkyl)2C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, C 3-7 cycloalkyl halogen C 1-7 alkyl, halogen C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, halogen C 1-7 alkyl, halogen C 3-7 cycloalkyl, halogen C 3-7 cycloalkyl C1-7 alkyl, hydroxyC 1-7 alkyl, hydroxyC 1-7 alkylC 3-7 cycloalkylC 1-7 alkyl, hydroxyC 3-7 cycloalkyl, C 1-7 alkoxyC 3-7 cycloalkyl, cyanoC 3-7 cycloalkylC 1-7 alkyl, hydroxyC 3-7 cycloalkylC 1-7 alkyl, C 1-7 alkoxyC 3-7 cycloalkylC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, aminohydroxyC 1-7 alkyl, C 1-7 alkylamideC 1-7 alkyl, -SO2-C 1-7 alkyl, -S(O)-C 1-7 alkyl, -C 1-7 alkyl-(O-C 1-7 alkyl) 1-3 -NH2, -C 1-7 alkyl(C 3-7 cycloalkyl)(OH), or a group

[0173] ;

[0174] L' is a bond or C 1-7 alkyl;

[0175] A' is an optionally substituted 3-6 membered heterocycle having 1-3 heteroatoms as ring atoms, independently selected from O, S and N,

[0176] wherein the optional substitution is 1-2 substituents independently selected from C 1-7 alkyl, C 3-7 cycloalkyl, halogen, hydroxy, C 1-7 alkoxy, halogenC 1-7 alkyl and cyano.

[0177] In a sub-group, R 22 is C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-7 alkyl, halogenC 1-7 alkyl, halogenC 3-7 cycloalkyl, halogenC 3-7 cycloalkylC 1-7 alkyl, C 1-7 alkoxyC 3-7cycloalkyl, hydroxy C 3-7 cycloalkyl or the group

[0178] ;

[0179] L' is a bond or C 1-7 alkyl;

[0180] A' is an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms, independently selected from O, S and N,

[0181] wherein the optional substitution is 1-2 substituents independently selected from C 1-7 alkyl, C 3-7 cycloalkyl, halogen, hydroxy, C 1-7 alkoxy, halogen C 1-7 alkyl and cyano.

[0182] In a subgroup of any of the above embodiments are compounds, wherein A' is a furanyl, tetrahydrofuranyl, thiazolyl, pyrazolyl, oxazolyl, oxetanyl, piperidinyl or pyridinyl ring.

[0183] According to yet another embodiment, the present application provides a method for the treatment of a disease or disorder in which inhibition of Cbl-b is desired, such as cancer, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as defined in any of the above embodiments.

[0184] According to one embodiment, the present application provides a method wherein a therapeutically effective amount of a compound of formula (I) is administered in addition to one or more anti-cancer agents.

[0185] The compounds of the present application can be prepared using appropriate starting materials by a variety of synthetic routes analogous to those known in the literature. Compounds according to formula (I) can for example be prepared analogously or according to the following reaction schemes. Some of the compounds included in formula (I) can be obtained by transformation of functional groups of other compounds of formula (I) obtained according to the following schemes via well-known reaction steps such as oxidation, reduction, hydrolysis, acylation, alkylation, amidation, amination, sulfonation and the like. It should be noted that any appropriate leaving group, for example an N-protecting group such as a tert-butoxycarbonyl (t-BOC) group or a phenylsulfonyl group, can be used in well-known manner during the synthesis in order to improve the selectivity of the reaction steps.

[0186] Compounds of formula (I) can for example be prepared according to Scheme 1, wherein Z, M, R1, R 2、R3is as defined above, and X is a halogen, such as chlorine, bromine, or iodine. In the method of Scheme 1, a compound of formula [1] is reacted with a halogen compound of formula [2] in a suitable solvent, such as DMF or DMSO, in the presence of a base, such as cesium carbonate, and a suitable catalyst system, such as a combination of Pd(OAc)2and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), or copper(I) iodide and potassium iodide, to produce a compound of formula (I).

[0187]

[0188] Intermediate compounds can be prepared according to methods disclosed in the literature or as disclosed in the present disclosure.

[0189] For example, an intermediate compound of formula [1] wherein R1is a group of formula (1)

[0190]

[0191] and B1is a triazolyl ring optionally substituted with one C 1-7 alkyl substituent can be prepared according to Scheme 2, wherein Z, M, R2, R4, R5, and R 23 is as defined above, and X is a halogen, such as chlorine or bromine. In the method of Scheme 2, the nitrogen of a compound of formula [2a] is first protected with a BOC-group to produce a compound of formula [2b]. The compound of formula [2b] is then reacted with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in a suitable solvent, such as 1,4-dioxane, in the presence of potassium acetate and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex. The resulting compound of formula [2c] is then coupled with a compound of formula [2d] in a suitable solvent, such as a 1,4-dioxane:water mixture, in the presence of N,N-diethylethanamine and a suitable catalyst, such as [Rh(COD)Cl]2, to produce a compound of formula [2e]. The protecting group is removed, and the resulting compound of formula [2f] is treated with hydrazine hydrate. The compound of formula [2g] is reacted with methyl isothiocyanate to produce a compound of formula [2h], which can be treated with NaOH to produce a compound of formula [2i]. Finally, treatment with hydrogen peroxide in the presence of acetic acid in a suitable solvent, such as DCM, produces the intermediate of formula [1’].

[0192]

[0193] Alternatively, intermediates of formula [1'] can be prepared according to Scheme 3, wherein Z, M, R2, R4, R5and R 23 are as defined above. In the method of Scheme 3, a compound of formula [3a] is treated with LiOH in a suitable solvent, such as a mixture of THF, MeOH and water, to yield a compound of formula [3b], which can then be reacted with N-methylhydrazine thioformamide in the presence of DIPEA and HATU in a suitable solvent, such as DMF, to yield a compound of formula [2h]. Following Scheme 2, intermediate [1'] is then obtained.

[0194]

[0195] Intermediate compounds R3-X [2] (wherein R3is a group of formula (1'), wherein R 10 is a group of formula (1'')

[0196]

[0197] may be prepared, for example, according to Scheme 4, wherein A, Z1, Z2, R 11 , R 18 , R 19 and R 20 are as defined above, L is -CH2- and X is halogen. In the method of Scheme 4, a cyclic compound of formula [4a] is coupled with an aldehyde compound of formula [4b] in the presence of DIPEA and sodium triacetoxyborohydride (STAB) in a suitable solvent, such as DCM, to yield intermediate [2'].

[0198]

[0199] Alternatively, intermediate compounds R3-X [2] (wherein R3is a group of formula (1'), wherein R 10 is a group of formula (1''),

[0200]

[0201] and L is -CH2-) can be prepared according to Scheme 5, wherein A, Z1, Z2, R 11 , R 18 , R 19 and R 20is as defined above, and X is halogen. In the method of Scheme 5, the aldehyde compound of formula [4b] is reduced with sodium borohydride in a suitable solvent such as THF to yield a compound of formula [5a], which is then reacted with methanesulfonyl chloride in the presence of triethylamine in a suitable solvent such as DCM to yield a compound of formula [5b]. Coupling of the compound of formula [5b] with the compound of formula [4a] in the presence of cesium carbonate in a suitable solvent such as THF yields the intermediate [2'].

[0202]

[0203] The intermediate compound R3-X [2] (where R3is a group of formula (1') wherein R 10 is -C 1-7 alkyl-NR 21 R 22 )

[0204]

[0205] may be prepared, for example, according to Scheme 6, wherein Z1, Z2, R 11 , R 21 and R 22 are as defined above, and X is halogen. In the method of Scheme 6, the amine compound of formula [6a] is coupled with the aldehyde compound of formula [4b] in the presence of acetic acid and sodium triacetoxyborohydride (STAB) in a suitable solvent such as DCM to yield the intermediate [3'].

[0206]

[0207] Alternatively, the intermediate compound R3-X [2] (where R3is a group of formula (1') wherein R 10 is -C 1-7 alkyl-NR 21 R 22 )

[0208]

[0209] may be prepared, for example, according to Scheme 7, wherein Z1, Z2, R 11 , R 21 and R 22is as defined above, and X is halogen. In the method of Scheme 7, an amine compound of formula [6a] is coupled with a carboxylic acid compound of formula [7a] in the presence of 1-hydroxybenzotriazole (HOBT) and 1-ethyl-3-[3- dimethylaminopropyl]carbodiimide (EDCI) in a suitable solvent such as ACN to yield a compound of formula [7b] which can be treated with borane dimethyl sulfide complex in a suitable solvent such as THF to yield intermediate [4'].

[0210]

[0211] Intermediate compounds R3-X [2] (wherein R3is a group of formula (2'),

[0212]

[0213] wherein Y1is a 1H-pyrazolyl ring) can be prepared, for example, according to Scheme 8, wherein Z3and R 13 is as defined above, R 12 is hydrogen and X is halogen. In the method of Scheme 8, an aldehyde compound of formula [8a] is reacted with hydrazine in a suitable solvent such as DMSO at elevated temperature to obtain intermediate [5'].

[0214]

[0215] Intermediate compounds R3-X [2] (wherein R3is a group of formula (3') wherein Y2is a furanyl ring, and R 14 is a group of formula (1'') wherein L is -CH2-)

[0216]

[0217] can be prepared, for example, according to Scheme 9, wherein A, Z4, R 18 , R 19 , and R 20is as defined above, L is -CH2- and X is halogen. In the method of Scheme 9, the carboxylic acid compound of formula [9a] is treated with H2SO4 in MeOH to yield the compound of formula [9b], which is reacted with 2-bromo-1,1 -diethoxyethane in the presence of cesium carbonate in a suitable solvent such as DMF to yield the compound of formula [9c]. The compound of formula [9c] is treated with polyphosphoric acid in a suitable solvent such as toluene to yield the compound of formula [9d]. Subsequent reduction with LiBH4 in a suitable solvent such as THF yields the compound of formula [9e], which is then reacted with Dess-Martin periodinane (DMP) in a suitable solvent such as DCM to yield the compound of formula [9f]. Coupling of the compound of formula [4a] with the compound of formula [9f] as described in Scheme 4 yields the intermediate [6'].

[0218]

[0219] The intermediate compound R3-X [2] (wherein R3is a group of formula (2'),

[0220]

[0221] wherein Y1is a 1,2,3,6-tetrahydropyridyl ring) can be prepared, for example, according to Scheme 10, wherein Z3, R 12 and R 13 are as defined above, and X is halogen. In the method of Scheme 10, the amine compound of formula [10a] is reacted with formaldehyde in the presence of sulfuric acid in a suitable solvent such as acetic acid to yield the intermediate of formula [7'].

[0222]

[0223] The intermediate compound R3-X [2] (wherein R3is a group of formula (1'), 10 is a group of formula (1 "),

[0224]

[0225] wherein L is -C(O)-) can be prepared, for example, according to Scheme 11, wherein A, Z1, Z2, R 11 , R 18 , R 19 and R 20is as defined above, and X is halogen. In the method of Scheme 11, the carboxylic acid compound of formula [11a] is first treated with thionyl chloride in a suitable solvent such as DCM to yield the acyl chloride compound of formula [11b], which is then reacted with the hydroxyl compound of formula [11c] in the presence of triethylamine in a suitable solvent such as DCM to yield the intermediate of formula [8'].

[0226]

[0227] The intermediate compound R3-X [2] (where R3is a group of formula (1'), wherein R 10 is a group of formula (1"), wherein R

[0228]

[0229] wherein L is -CH(CH3)-) can be prepared, for example, according to Scheme 12, wherein A, Z1, Z2, R 11 , R 18 , R 19 and R 20 are as defined above, and X is halogen. In the method of Scheme 12, the aldehyde compound of formula [4b] is reacted with methylmagnesium bromide in a suitable solvent such as THF to yield the hydroxyl compound of formula [12a], which is then brominated with CBr4in the presence of triphenylphosphine in a suitable solvent such as DCM to yield the compound of formula [12b]. Coupling of the compound of formula [4a] with the compound of formula [12b] in the presence of tetrabutylammonium iodide (TBAI) and DIPEA in a suitable solvent such as DCM yields the intermediate of formula [9'].

[0230]

[0231] The intermediate compound of formula [1] (wherein R1is a group of formula (5),

[0232]

[0233] wherein B5is phenyl optionally substituted with, for example, a chloro substituent, B6is optionally substituted with one C 1-7triazolyl ring substituted with an alkyl substituent, and n is 0) can be prepared according to Scheme 13, wherein Z, M, R2 are as defined above, and X is a halogen, such as chloro, bromo or iodo. In the method of Scheme 13, a compound of formula [13a] is first treated with hydrazine hydrate to yield a compound of formula [13b], which is then reacted with methyl isothiocyanate in a suitable solvent, such as THF. Treatment of the obtained compound of formula [13c] with a base, such as NaOH, yields a thiol compound of formula [13d]. Treatment with hydrogen peroxide in the presence of acetic acid in a suitable solvent, such as DCM, yields a compound of formula [13e]. Coupling of this compound with an isoindolinone compound of formula [13f] in the presence of a base, such as K2CO3, and a suitable catalyst, such as Pd(amphos)Cl2, in a suitable solvent, such as a 1,4-dioxane:water mixture, yields an intermediate compound of formula [1-a].

[0234]

[0235] An intermediate compound of formula [1] (wherein R1 is a group of formula (5),

[0236]

[0237] wherein B5 is an optionally substituted phenyl, B6 is an optionally substituted C 1-7 triazolyl ring substituted with an alkyl substituent, and n is 1) can be prepared according to Scheme 14, wherein Z, M, R2 are as defined above, and X is a halogen, such as chloro, bromo or iodo. In the method of Scheme 14, a compound of formula [14a] is first coupled with an isoindolinone compound of formula [14b] in the presence of a base, such as Cs2CO3, and a suitable catalyst, such as Pd(dppf)Cl2, in a suitable solvent, such as a 1,4-dioxane:water mixture, to yield a compound of formula [14c]. Treatment of this compound with hydrazine hydrate yields a compound of formula [14d]. Further reaction with methyl isothiocyanate in a suitable solvent, such as THF, yields a compound of formula [14e]. Treatment of a compound of formula [14e] with a base, such as NaOH, followed by reaction of the obtained compound of formula [14f] with hydrogen peroxide in the presence of acetic acid in a suitable solvent, such as DCM, yields an intermediate compound of formula [1-b].

[0238]

[0239] Alternatively, compounds of formula (I) can be prepared as disclosed in the specific examples of the present disclosure.

[0240] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs. As used herein, the following definitions are provided to facilitate understanding of the present application.

[0241] As used herein, the term "subject" refers to humans and animals.

[0242] As used herein by itself or as part of another group, the term "halo" or "halogen" refers to chloro, bromo, fluoro or iodo. Preferred halogens are chloro and bromo and fluoro.

[0243] As used herein by itself or as part of another group, the term "C 1-7 "alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms. Representative examples of "C 1-7 "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, and n-hexyl. A preferred embodiment of "C 1-7 "alkyl" is C 1-3 "alkyl". The term "C 1-3 "alkyl" refers to "C 1-7 "alkyl" having 2, 3, or 4 carbon atoms. Representative examples include, but are not limited to, ethenyl, propenyl, and butenyl. A preferred "C 1-3 "alkyl" is a -CH=CH2group. 1-7 "alkyl" is methyl.

[0244] As used herein by itself or as part of another group, the term "C 2-7 "alkenyl" refers to an aliphatic hydrocarbon group having 2, 3, 4, 5, 6, or 7 carbon atoms and containing one or more double bonds. Representative examples include, but are not limited to, ethenyl, propenyl, and hexenyl. A preferred embodiment of "C 2-7 "alkenyl" is C 2-4 "alkenyl". The term "C 2-4 "alkenyl" refers to "C 2-7 "alkenyl" having 2, 3, or 4 carbon atoms. Representative examples include, but are not limited to, ethenyl, propenyl, and butenyl. A preferred "C 2-7 "alkenyl" is a -CH=CH2group.

[0245] As used herein, the term "3-6 membered carbocyclic ring" refers to a saturated, partially saturated, or aromatic ring having 3 to 6 ring atoms composed solely of carbon atoms. Representative examples of 3-6 membered carbocyclic rings include, but are not limited to, phenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, and cyclobutyl rings.

[0246] The term "C 3-7 Cycloalkyl" refers to a saturated monocyclic or bicyclic (fused, bridged or in the spiro configuration) hydrocarbon ring containing 3, 4, 5, 6 or 7 ring atoms composed only of carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and spiro(3,3)heptane. One preferred C 3-7 Cycloalkyl" refers to a saturated monocyclic or bicyclic (fused, bridged or in the spiro configuration) hydrocarbon ring containing 3, 4, 5, 6 or 7 ring atoms composed only of carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and spiro(3,3)heptane. One preferred C 3-7 Cycloalkyl" refers to a saturated monocyclic or bicyclic (fused, bridged or in the spiro configuration) hydrocarbon ring containing 3, 4, 5, 6 or 7 ring atoms composed only of carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and spiro(3,3)heptane. One preferred C

[0247] The term "C 3-6 Cycloalkyl" refers to a saturated monocyclic or bicyclic (fused, bridged or in the spiro configuration) hydrocarbon ring containing 3, 4, 5, 6 or 7 ring atoms composed only of carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and spiro(3,3)heptane. One preferred C 1-7 Alkyl" refers to a C 3-6 Cycloalkyl group, as defined herein, attached to the parent molecular moiety through a C 1-7 Alkyl group, as defined herein.

[0248] The term "C 1-7 Cycloalkyl" refers to a saturated monocyclic or bicyclic (fused, bridged or in the spiro configuration) hydrocarbon ring containing 3, 4, 5, 6 or 7 ring atoms composed only of carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and spiro(3,3)heptane. One preferred C 3-7 Cycloalkyl" refers to a saturated monocyclic or bicyclic (fused, bridged or in the spiro configuration) hydrocarbon ring containing 3, 4, 5, 6 or 7 ring atoms composed only of carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and spiro(3,3)heptane. One preferred C 1-7 Cycloalkyl group, as defined herein, attached to the parent molecular moiety through a C 3-7 Alkyl group, as defined herein.

[0249] The term "halo" as used herein by itself or as part of another group, refers to a -F, -Cl, -Br or -I group. 3-7 Cycloalkyl" refers to a saturated monocyclic or bicyclic (fused, bridged or in the spiro configuration) hydrocarbon ring containing 3, 4, 5, 6 or 7 ring atoms composed only of carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and spiro(3,3)heptane. One preferred C 3-7 Cycloalkyl group, as defined herein, attached to the parent molecular moiety through a C

[0250] The term "halo" as used herein by itself or as part of another group, refers to a -F, -Cl, -Br or -I group. 3-7 Cycloalkyl" refers to a saturated monocyclic or bicyclic (fused, bridged or in the spiro configuration) hydrocarbon ring containing 3, 4, 5, 6 or 7 ring atoms composed only of carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and spiro(3,3)heptane. One preferred C 1-7 Alkyl" refers to a C 3-7 Cycloalkyl" refers to a saturated monocyclic or bicyclic (fused, bridged or in the spiro configuration) hydrocarbon ring containing 3, 4, 5, 6 or 7 ring atoms composed only of carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and spiro(3,3)heptane. One preferred C 1-7 Alkyl group, as defined herein, attached to the parent molecular moiety.

[0251] The term "hydroxyl" as used herein by itself or as part of another group, refers to an -OH group.

[0252] The term "cyano" as used herein by itself or as part of another group, refers to a -CN group.

[0253] The term "carboxyl" as used herein by itself or as part of another group, refers to a -COOH group.

[0254] The term "carbonyl" as used herein by itself or as part of another group, refers to a carbon atom double bonded to an oxygen atom (C=0).

[0255] The term "oxo" as used herein by itself or as part of another group, refers to an oxygen atom connected to another atom through a double bond (=0).

[0256] The term "C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-3 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-3 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-3 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C

[0257] The term "hydroxy C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C

[0258] The term "halo C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C

[0259] The term "halo C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C 1-7 alkyl, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, isobutoxyl, sec-butoxyl, and tert-butoxyl. A preferred "C

[0260] The term "C1-C6alkyl" as used herein, by itself or as part of another group, refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1-7 The term "C1-C6alkoxy" as used herein, by itself or as part of another group, refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, attached to the parent molecular moiety through an oxygen atom. 1-7 The term "C1-C6alkyl" as used herein, by itself or as part of another group, refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1-7 The term "C1-C6alkoxy" as used herein, by itself or as part of another group, refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, attached to the parent molecular moiety through an oxygen atom. 1-7 The term "C1-C6alkyl" as used herein, by itself or as part of another group, refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms.

[0261] The term "3-6 membered carbocycle" as used herein refers to a saturated, partially saturated, or aromatic ring having 3 to 6 ring atoms composed solely of carbon atoms. Representative examples of 3-6 membered carbocycles include, but are not limited to, phenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, and cyclobutyl rings.

[0262] The term "3-6 membered heterocycle" as used herein refers to a saturated, partially saturated, or aromatic ring having 3-6 ring atoms, wherein 1-3 atoms are heteroatoms selected from the group consisting of N, O, and S. Representative examples of 3-6 membered heterocycles include, but are not limited to, oxetanyl, azetidinyl, oxiranyl, pyrazolyl, pyrimidinyl, pyridyl, piperidinyl, piperazinyl, furanyl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,4-oxadiazolyl, morpholinyl, pyrrolidinyl, thiazolyl, isoxazolyl, pyrazinyl, tetrahydropyranyl, oxazolyl, and imidazolyl rings.

[0263] The term "5-6 membered heterocycle" as used herein refers to a saturated, partially saturated, or aromatic ring having 5-6 ring atoms, wherein 1-4 atoms are heteroatoms selected from the group consisting of N, O, and S. Representative examples of 5-6 membered heterocycles include, but are not limited to, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,4-oxadiazolyl, tetrazolyl, pyrazolyl, pyrimidinyl, pyridyl, piperidinyl, piperazinyl, furanyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, thiazolyl, isoxazolyl, pyrazinyl, tetrahydropyranyl, oxazolyl, and imidazolyl rings.

[0264] As used herein, the term "5-10 membered monocyclic, bicyclic or spiro bicyclic heterocycle" refers to a saturated, partially saturated or aromatic monocyclic or bicyclic (fused, bridged or in a spiro conformation) ring system having 5 to 10 ring atoms, of which 1-4 atoms are heteroatoms selected from the group consisting of N, O and S. Representative examples of "5-10 membered monocyclic, bicyclic or spiro bicyclic heterocycle" include, but are not limited to, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, 3-azabicyclo[3.1.0]hexan-3-yl, 5-azaspiro[2.4]heptan-5-yl, 2-azaspiro[3.3]heptan-2-yl, 3,4-dihydroisoquinolin-2(lH)-yl, l-oxa-8-azaspiro[4.5]dec-8-yl, l-oxa-7-azaspiro[4.4]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, hexahydrocyclopenta[c]pyrrol-2(lH)-yl, hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, l,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl, l,2,4-triazol-l-yl, l,2,3-triazol-l-yl, pyrimidinyl, pyridinyl, tetrazolyl, furanyl, tetrahydrofuranyl, thiazolyl, isoxazolyl, pyrazinyl, tetrahydropyranyl, l,2,4-oxadiazolyl, oxazolyl, indolyl and 4,5-dihydroimidazolyl rings.

[0265] As used herein, the term "spiro bicyclic" refers to a ring system in which two rings have one common carbon atom.

[0266] As used herein, the term "bicyclic" refers to a saturated, partially saturated or aromatic ring system in which two rings are fused (having two common ring atoms) or bridged (sharing three or more common ring atoms).

[0267] The term "substituted" as used herein in connection with various residues, if not otherwise defined, means halogen substituents (such as fluoro, chloro, bromo, iodo), or C 1-7 alkyl, C 3-7 cycloalkyl, hydroxy, amino, nitro, cyano, thiol 1-7 alkyl, methylsulfonyl, C 1-7 alkoxy, halo 1-7 alkyl, hydroxy 1-7 alkyl or amino 1-7 alkyl substituents. Preferred are halogen, C 1-7 alkyl, hydroxy, amino, halo 1-7 alkyl, C 1-7 alkoxy and methylsulfonyl substituents. In one preferred substituent group are 1-2 substituents selected from C 1-7 alkyl or halo substituents, in particular C1-3 alkyl or halo substituents, in particular methyl, ethyl, chloro, fluoro or bromo substituents.

[0268] A "substituted" group can contain 1 to 3, preferably 1 or 2, of the above substituents, unless otherwise defined.

[0269] Optically active enantiomeric or diastereomeric forms of the compounds of formula (I) can be prepared, for example, by resolution of a racemic final product by known methods or by using suitable optically active starting materials. Similarly, racemic compounds of formula (I) can be prepared by using racemic starting materials. Resolution of racemic compounds of formula (I) or their racemic starting materials can be carried out, for example, by converting the racemic compound into a mixture of diastereomeric salts with an optically active acid and then separating the diastereomeric salts by crystallization or other techniques. Representative examples of the optically active acids include, but are not limited to, D-tartaric acid and dibenzoyl-D-tartaric acid. Alternatively, preparative chiral chromatography can be used to resolve racemic mixtures.

[0270] Pharmaceutically acceptable salts are well known in the pharmaceutical art. Non-limiting examples of suitable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Non-limiting examples of metal salts include alkali metal salts, such as sodium and potassium salts, and alkaline earth metal salts, such as calcium and magnesium salts. Non-limiting examples of salts with inorganic or organic acids include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methanesulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates, acetates, oxalates, fumarates, hemifumarates, and succinates. Pharmaceutically acceptable esters, when applicable, can be prepared by known methods using pharmaceutically acceptable acids, which are conventional in the pharmaceutical art and which retain the pharmacological properties of the free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl esters. Phosphates and carbonates are also within the scope of the present application.

[0271] The above definition of formula (I) includes all possible isotopes and isomers of the compounds, such as stereoisomers, including geometric isomers, such as Z and E isomers (cis and trans isomers), and optical isomers, such as diastereomers and enantiomers, as well as prodrug esters, such as phosphates and carbonates.

[0272] Those skilled in the art will appreciate that the compounds of the present application can contain at least one chiral center. Thus, these compounds can exist as optically active or racemic forms. It should be understood that formula (I) includes any racemic or optically active form, or mixtures thereof. In one embodiment, the compounds are pure (R)-isomers. In another embodiment, the compounds are pure (S)-isomers. In another embodiment, the compounds are a mixture of (R) and (S) isomers. In another embodiment, the compounds are a racemic mixture comprising equal amounts of (R) and (S) isomers. The compounds can contain two chiral centers. In such cases, according to one embodiment, the compounds are a mixture of diastereomers. According to another embodiment, the compounds of the present application are a mixture of enantiomers. According to still another embodiment, the compounds are pure enantiomers. The individual isomers can be obtained using the corresponding isomeric forms of starting materials, or they can be separated from mixtures of compounds following preparation of the final compound, according to conventional methods of separation. To separate optical isomers, e.g., enantiomers or diastereomers, from mixtures thereof, conventional resolution methods can be employed, e.g., fractional crystallization, distillation or chromatography, e.g., HPLC.

[0273] The compounds of the present application can also exist as tautomers or equilibrium mixtures thereof, wherein a proton of a compound is shifted from one atom to another. Examples of tautomers include, but are not limited to, amide-imine, ketone-enol, phenol-keto, oxime-nitroso, nitro-acidic, imine-enamine, cyclic tautomers of heterocyclic rings such as pyrazole ring, and the like. The compounds of formula (I) are intended to encompass the tautomeric forms, even if only one tautomeric form can be depicted.

[0274] Examples of a group of preferred compounds of formula (I) include

[0275] (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)isoindolin-l-one (Compound 1);

[0276] (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((3- methylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-l-one (Compound 2);

[0277] (S)-2-(3-fluoro-5-((3-methylpiperidin-l-yl)methyl)phenyl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 3);

[0278] (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)phenyl)isoindolin-l-one (Compound 4);

[0279] (S)-2-(3-methoxy-5-((3-methylpiperidin-l-yl)methyl)phenyl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 5);

[0280] (S)-2-(3-chloro-5-((3-methylpiperidin-l-yl)methyl)phenyl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 6);

[0281] (S)-2-(3-cyclopropyl-5-((3-methylpiperidin-l-yl)methyl)phenyl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 7);

[0282] (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)phenyl)isoindolin-l-one (Compound 8);

[0283] (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)-5-vinylphenyl)isoindolin-l-one (Compound 9);

[0284] (S)-2-(3-bromo-5-((3-methylpiperidin-l-yl)methyl)phenyl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 10);

[0285] (S)-2-(3-ethyl-5-((3-methylpiperidin-l-yl)methyl)phenyl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 11);

[0286] 6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-methyl-5- (l-((S)-3-methylpiperidin-l-yl)ethyl)phenyl)isoindolin-l-one (Compound 12);

[0287] 2-(3-(((cyclopropylmethyl)amino)methyl)-5-(trifluoromethyl)phenyl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 13);

[0288] (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)-5-(piperidin-l-yl)phenyl)isoindolin-l-one (Compound 14);

[0289] (S)-2-(3-isopropyl-5-((3-methylpiperidin-l-yl)methyl)phenyl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 15);

[0290] (S)-2-(3-(tert-butyl)-5-((3-methylpiperidin-l-yl)methyl)phenyl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 16);

[0291] (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(2-((3- methylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl)isoindolin-l-one (Compound 17);

[0292] 2-(3-(((cyclopropylmethyl)amino)methyl)-5-methylphenyl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 18);

[0293] 6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-methyl-5- (((3,3,3-trifluoropropyl)amino)methyl)phenyl)isoindolin-l-one (Compound 19);

[0294] 2-(3-((((2,2-difluorocyclopropyl)methyl)amino)methyl)-5-methylphenyl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 20);

[0295] (S)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3-methylpiperidin-1-yl)methyl)-5-(pyrrolidin-1-yl)phenyl)isoindolin-1-one (Compound 21);

[0296] 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-methyl-5-(((2,2,2-trifluoroethyl)amino)methyl)phenyl)isoindolin-1-one (Compound 22);

[0297] (S)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(2-methyl-6-((3-methylpiperidin-1-yl)methyl)pyridin-4-yl)isoindolin-1-one (Compound 23);

[0298] (S)-2-(3-(azetidin-1-yl)-5-((3-methylpiperidin-1-yl)methyl)phenyl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 24);

[0299] 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(6-(trifluoromethyl)-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)isoindolin-1-one (Compound 25);

[0300] (S)-2-(6-methyl-4-((3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 26);

[0301] (S)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(6-(trifluoromethyl)-4-((3-(trifluoromethyl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-1-one (Compound 27);

[0302] 2-(4-((4,4-difluoro-3-methylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 28);

[0303] 1-((2-(6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-l-oxoisoindolin-2-yl)-6- (trifluoromethyl)pyridin-4-yl)methyl)piperidine-3-carbonitrile (Compound 29);

[0304] (S)-2-(4-((3-hydroxypiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 30);

[0305] 2-(4-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 31);

[0306] 2-(4-((l-oxa-8-azaspiro[4.5]dec-8-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 32);

[0307] 2-(4-((3-fluoropiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 33);

[0308] (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((3-methylpyrrolidin-l- yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-l-one (Compound 34);

[0309] 2-(4-((hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 35);

[0310] (S)-2-(4-(3-hydroxypyrrolidine-l-carbonyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 36);

[0311] 2-(4-((3-(hydroxymethyl)piperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 37);

[0312] 6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(6-(trifluoromethyl)-4-((4- (trifluoromethyl)piperidin-l-yl)methyl)pyridin-2-yl)isoindolin-l-one (Compound 38);

[0313] 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 39);

[0314] (S)-2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 40);

[0315] (R)-2-(4-((hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)- 6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 41);

[0316] 2-(4-(((3S,5S)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 42);

[0317] 2-(4-((4-hydroxypiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H- l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 43);

[0318] 2-(4-((6-azaspiro[2.5]octan-6-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 44);

[0319] 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((2-methylpiperidin-1-yl)methyl)-6- (trifluoromethyl)pyridin-2-yl)isoindolin-1-one (Compound 45);

[0320] (R)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((2-methylmorpholino)methyl)-6- (trifluoromethyl)pyridin-2-yl)isoindolin-1-one (Compound 46);

[0321] 2-(4-((3,3-difluoropiperidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 47);

[0322] 2-(4-((4,4-difluoropiperidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 48);

[0323] (S)-2-(3-(cyclopropylmethyl)-5-((3-methylpiperidin-1-yl)methyl)phenyl)-6-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 49);

[0324] 2-(4-((1-oxa-7-azaspiro[4.4]nonan-7-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 50);

[0325] 2-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 51);

[0326] 2-(6-chloro-4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 52);

[0327] (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(2-methyl-6-((3- methylpiperidin-l-yl)methyl)pyrimidin-4-yl)isoindolin-l-one (Compound 53);

[0328] 2-(4-((2-methyl-lH-imidazol-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 54);

[0329] 2-(4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3- ((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 55);

[0330] 2-(3-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-5-methylphenyl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 56);

[0331] 2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 57);

[0332] 2-(6-chloro-4-(((S)-3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-((ls,3R)-3-methyl- 1-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)isoindolin-l-one (Compound 58);

[0333] 2-(3-(((3S,5S)-3,5-dimethylpiperidin-l-yl)methyl)-5-methylphenyl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 59);

[0334] 2-(6-chloro-4-(((3S,5S)-3,5-dimethylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 60);

[0335] (S)-2-(4-((3-fluoropyrrolidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 61);

[0336] 2-(4-((5-azaspiro[2.4]heptan-5-yl)methyl)-6-chloropyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 62);

[0337] 2-(4-((4-methyl-3-oxopiperazin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 63);

[0338] 2-(6-chloro-4-(piperidin-l-ylmethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3- yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 64);

[0339] 2-(3-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 65);

[0340] 2-(6-chloro-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 66);

[0341] (S)-2-(6-chloro-4-((3-methylpyrrolidin-l-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 67);

[0342] (R)-2-(6-chloro-4-((3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 68);

[0343] 2-(4-((5-methyl-1 H-imidazol-1 -yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 69);

[0344] 2-(4-((4-methyl-1 H-imidazol-1 -yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 70);

[0345] 2-(4-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 71 );

[0346] 2-(4-(((2R,6S)-2,6-dimethylmorpholino)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 72);

[0347] (S)-2-(6-cyclopropyl-4-((3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 73);

[0348] 2-(4-(((3,3-difluorocyclobutyl)amino)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 74);

[0349] 2-(3-(2-(ethylamino)ethyl)-5-(trifluoromethyl)phenyl)-6-(3-((4-methyl-4H-1,2,4-triazol- 3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 75);

[0350] 2-(l-(2-(dimethylamino)ethyl)-4-methyl-lH-indazol-6-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3- yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 76);

[0351] 2-(2-ethyl-5-(trifluoromethyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3- yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 77);

[0352] 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-methylpyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 78);

[0353] 2-(6-chloro-4-((diethylamino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan- 3-yl)isoindolin-l-one (Compound 79);

[0354] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 80);

[0355] 2-(4-((5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 81);

[0356] 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(l-((4-methyl-4H- l,2,4-triazol-3-yl)methyl)cyclobutyl)isoindolin-l-one (Compound 82);

[0357] 2-(6-chloro-4-(((S)-3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(l-(4-methyl-4H-l,2,4-triazol-3- yl)propan-2-yl)isoindolin-l-one (Compound 83);

[0358] 2-(6-chloro-4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)pyridin-2-yl)-6- ( 1 -(4-methyl-4H- 1,2,4-triazol-3 -yl)propan-2-yl)isoindolin- 1 -one (Compound 84);

[0359] 2-(6-chloro-4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)pyridin-2-yl)-6- ( 1 -(4-methyl-4H- 1,2,4-triazol-3 -yl)propan-2-yl)isoindolin- 1 -one (Compound 84);

[0360] 2-(6-chloro-4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)pyridin-2-yl)-6- ( 1 -(4-methyl-4H- 1,2,4-triazol-3 -yl)propan-2-yl)isoindolin- 1 -one (Compound 84);

[0361] 2-(6-chloro-4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)pyridin-2-yl)-6- ( 1 -(4-methyl-4H- 1,2,4-triazol-3 -yl)propan-2-yl)isoindolin- 1 -one (Compound 84);

[0362] 6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-(((l- methylcyclobutyl)amino)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-l- one (Compound 88);

[0363] (S)-2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(l-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)isoindolin-l-one (Compound 89);

[0364] 2-(6-chloro-4-(((S)-3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-((R)-l-(4- methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 90);

[0365] 2-(6-chloro-4-(((S)-3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-((S)-l-(4- methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 91);

[0366] 2-(4-((1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methyl)-6- (trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3- yl)isoindolin-1-one (Compound 92);

[0367] 2-(4-((2,5-dimethylpiperidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 93);

[0368] (S)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((3- methylpiperidin-1-yl)methyl)benzofuran-6-yl)isoindolin-1-one (Compound 94);

[0369] 2-(4-(1H-pyrazol-4-yl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 95);

[0370] (R)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((3- methylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-1-one (Compound 96);

[0371] (R)-2-(4-((3,4-dimethylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3- ((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 97);

[0372] 2-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6- (3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 98);

[0373] 2-(4-(13-amino-5,8,11-trioxa-2-azatridecyl)-6-chloropyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 99);

[0374] 2-(3-(1 -hydroxy-2-(isopropylamino)ethyl)-5-(trifluoromethyl)phenyl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 100);

[0375] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(((cyclopropylmethyl)amino)methyl)- 6-methylpyridin-2-yl)isoindolin-1 -one (Compound 101 );

[0376] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)isoindolin-1 -one (Compound 102);

[0377] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(1 -((cyclopropylmethyl)amino)ethyl)- 6-methylpyridin-2-yl)isoindolin-1 -one (Compound 103);

[0378] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(1 -(cyclopentylamino)ethyl)pyridin-2-yl)isoindolin-1 -one [enantiomer 1 ] (Compound 104);

[0379] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(1 -(cyclopentylamino)ethyl)pyridin-2-yl)isoindolin-1 -one, enantiomer 2 (Compound 105);

[0380] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((cyclopentylamino)methyl)pyridin-2-yl)isoindolin-1 -one (Compound 106);

[0381] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(1 -((cyclobutylmethyl)amino)ethyl)pyridin-2-yl)isoindolin-1 -one (Compound 107);

[0382] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(((l- cyclopropylethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 109);

[0383] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(((l- cyclopropylethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 109);

[0384] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(((l- cyclopropylethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 109);

[0385] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(((l- cyclopropylethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 109);

[0386] (S)-4-(2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-3- oxoisoindolin-5-yl)-3-(4-methyl-4H-l,2,4-triazol-3-yl)benzonitrile (Compound 112);

[0387] (S)-6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((3- methylpiperidin-l-yl)methyl)pyridin-2-yl)isoindolin-l-one (Compound 113);

[0388] (S)-2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(2-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)phenyl)isoindolin-l-one (Compound 115);

[0389] (S)-2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(2-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)phenyl)isoindolin-l-one (Compound 115);

[0390] 2-(6-chloro-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-6-(2-(4-methyl- 4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 116);

[0391] 2-(4-(((3S,5R)-3,5-dimethylpiperidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6- (2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 117);

[0392] (S)-2-(6-chloro-4-((3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-6-(2-(4-methyl-4H- 1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 118);

[0393] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(3-chloro-5-(((cyclopropyl- methyl)amino)methyl)phenyl)isoindolin-1 -one (Compound 119);

[0394] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-methyl-3-(4- methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 120);

[0395] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(1 -(((3,3- difluorocyclobutyl)methyl)amino)ethyl)pyridin-2-yl)isoindolin-1 -one (Compound 121);

[0396] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(((1 - cyclopropylethyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-1 -one (Compound 122);

[0397] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((((tetrahydro- furan-2-yl)methyl)amino)methyl)pyridin-2-yl)isoindolin-1 -one [enantiomer 1] (Compound 123);

[0398] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((((tetrahydrofuran-2-yl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 124);

[0399] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(l-(cyclopentyl- amino)ethyl)-6-methylpyridin-2-yl)isoindolin-l-one [enantiomer 1] (Compound 125);

[0400] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(l-(cyclopentyl- amino)ethyl)-6-methylpyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 126);

[0401] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 127);

[0402] and tautomers and pharmaceutically acceptable salts thereof.

[0403] Examples of a particularly preferred group of compounds of Formula (I) include

[0404] (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((3- methylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-l-one (Compound 2);

[0405] (S)-2-(3-fluoro-5-((3-methylpiperidin-l-yl)methyl)phenyl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 3);

[0406] (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-methyl-5-((3- methylpiperidin-l-yl)methyl)phenyl)isoindolin-l-one (Compound 4);

[0407] (S)-2-(3-chloro-5-((3-methylpiperidin-1-yl)methyl)phenyl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 6);

[0408] (S)-2-(3-chloro-5-((3-methylpiperidin-1-yl)methyl)phenyl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 6);

[0409] 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-methyl-5-(((3,3,3- trifluoropropyl)amino)methyl)phenyl)isoindolin-1 -one (Compound 19);

[0410] 2-(3-(((cyclopropylmethyl)amino)methyl)-5-methylphenyl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 18);

[0411] 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-methyl-5-(((3,3,3- trifluoropropyl)amino)methyl)phenyl)isoindolin-1 -one (Compound 19);

[0412] 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-methyl-5-(((3,3,3- trifluoropropyl)amino)methyl)phenyl)isoindolin-1 -one (Compound 19);

[0413] (S)-2-(3-chloro-5-((3-methylpiperidin-1-yl)methyl)phenyl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 6);

[0414] (S)-2-(3-chloro-5-((3-methylpiperidin-1-yl)methyl)phenyl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 6);

[0415] 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 39);

[0416] (S)-2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 40);

[0417] 2-(4-(((3S,5S)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 42);

[0418] 2-(6-chloro-4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 52);

[0419] (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(2-methyl-6-((3-methylpiperidin-l-yl)methyl)pyrimidin-4-yl)isoindolin-l-one (Compound 53);

[0420] 2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 57);

[0421] 2-(6-chloro-4-(((3S,5S)-3,5-dimethylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 60);

[0422] 2-(6-chloro-4-(piperidin-l-ylmethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 64);

[0423] 2-(6-chloro-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 66);

[0424] 2-(4-(((3S,5R)-3,5-dimethylpiperidin-1-yl)methyl)-6-methylpyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 78);

[0425] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 80);

[0426] 2-(4-(((3S,5R)-3,5-dimethylpiperidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6- (1 -((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)isoindolin-1 -one (Compound 82);

[0427] 2-(6-chloro-4-(((S)-3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-6-(1-(4-methyl-4H- 1,2,4-triazol-3-yl)propan-2-yl)isoindolin-1 -one (Compound 83);

[0428] 2-(6-chloro-4-(((3S,5R)-3,5-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-6-(1-(4-methyl- 4H-1,2,4-triazol-3-yl)propan-2-yl)isoindolin-1 -one (Compound 85);

[0429] 2-(4-(((3S,5R)-3,5-dimethylpiperidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6- ((S)-1 -(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)isoindolin-1 -one (Compound 86);

[0430] (S)-2-(6-chloro-4-((3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-6-(1-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)cyclobutyl)isoindolin-1 -one (Compound 89);

[0431] 2-(6-chloro-4-(((S)-3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-((R)- 1 -(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin- 1 -one (Compound 90);

[0432] 2-(6-chloro-4-(((S)-3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-((S)- 1 -(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin- 1 -one (Compound 91);

[0433] (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((3- methylpiperidin- 1 -yl)methyl)benzofuran-6-yl)isoindolin- 1 -one (Compound 94);

[0434] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin- 1 -one (Compound 101);

[0435] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)isoindolin- 1 -one (Compound 102);

[0436] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(l-((cyclopropylmethyl)amino)ethyl)-6-methylpyridin-2-yl)isoindolin- 1 -one (Compound 103);

[0437] (R)-6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(l- (cyclopentylamino)ethyl)pyridin-2-yl)isoindolin- 1 -one (Compound 104);

[0438] (S)-6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(l- (cyclopentylamino)ethyl)pyridin-2-yl)isoindolin- 1 -one (Compound 105);

[0439] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(l-((cyclobutylmethyl)amino)ethyl)pyridin-2-yl)isoindolin- 1 -one (Compound 107);

[0440] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(((l- cyclopropylethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 109);

[0441] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(((l- cyclopropylethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 109);

[0442] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(((l- cyclopropylethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 109);

[0443] 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(((l- cyclopropylethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 109);

[0444] (S)-4-(2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-3- oxoisoindolin-5-yl)-3-(4-methyl-4H-l,2,4-triazol-3-yl)benzonitrile (Compound 112);

[0445] (S)-6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((3- methylpiperidin-l-yl)methyl)pyridin-2-yl)isoindolin-l-one (Compound 113);

[0446] 2-(6-chloro-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-6-(2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 116);

[0447] (S)-2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 118);

[0448] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(3-chloro-5-(((cyclopropylmethyl)amino)methyl)phenyl)isoindolin-1 -one (Compound 119);

[0449] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(1 -(((3,3- difluorocyclobutyl)methyl)amino)ethyl)pyridin-2-yl)isoindolin-1 -one (Compound 121 );

[0450] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(((1 - cyclopropylethyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-1 -one (Compound 122);

[0451] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((((tetrahydrofuran-2-yl)methyl)amino)methyl)pyridin-2-yl)isoindolin-1 -one [Enantiomer 1] (Compound 123);

[0452] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((((tetrahydrofuran-2-yl)methyl)amino)methyl)pyridin-2-yl)isoindolin-1 -one [Enantiomer 2] (Compound 124);

[0453] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(1 -(cyclopentyl- amino)ethyl)-6-methylpyridin-2-yl)isoindolin-1 -one [Enantiomer 1] (Compound 125);

[0454] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(1 -(cyclopentyl- amino)ethyl)-6-methylpyridin-2-yl)isoindolin-1 -one [Enantiomer 2] (Compound 126);

[0455] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 127);

[0456] 2-(6-chloro-4-(((1-cyclopropylethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 131 );

[0457] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(((cyclopropylmethyl) amino)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-1 -one (Compound 132);

[0458] 2-(6-(((cyclopropylmethyl)amino)methyl)-2-methylpyrimidin-4-yl)-6-(4-fluoro-2-(4- methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 133);

[0459] 2-(4-(((cyclobutylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 134);

[0460] 2-(6-chloro-4-(((cyclobutylmethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 144);

[0461] 2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(1 -((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)isoindolin-1 -one (Compound 145);

[0462] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 147);

[0463] 2-(6-chloro-4-((3-ethylpiperidin-1 -yl)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 148);

[0464] 2-(6-chloro-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-6-(1 -((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)isoindolin-1 -one (Compound 151 );

[0465] (S)-2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(3,3-difluoro-l- ((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)isoindolin-l-one (Compound 152);

[0466] 3-(2-(6-chloro-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-3-oxoisoindolin-5- yl)-3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutane-l-carbonitrile (Compound 158);

[0467] 2-(6-chloro-4-(((cyclopentylmethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 159);

[0468] (S)-2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(l-(4-methyl-4H-l,2,4- triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 160);

[0469] (R)-2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(l-(4-methyl-4H-l,2,4- triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 161);

[0470] 2-(4-(((cyclobutylmethyl)amino)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 162);

[0471] (S)-2-(6-chloro-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-6-(l-(4-methyl-4H-l,2,4- triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 163);

[0472] (R)-2-(6-chloro-4-(l-((cyclopropylmethyl)amino)ethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 166);

[0473] (S)-2-(6-chloro-4-(1-((cyclopropylmethyl)amino)ethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 167);

[0474] 3-(2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-3-oxoisoindolin-5- yl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1 -carbonitrile (Compound 168);

[0475] 2-(6-chloro-4-((((3,3-difluorocyclobutyl)methyl)amino)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 169);

[0476] (R)-2-(6-chloro-4-(((cyclobutylmethyl)amino)methyl)pyridin-2-yl)-6-(1-(4-methyl-4H- 1,2,4-triazol-3-yl)propan-2-yl)isoindolin-1 -one (Compound 170);

[0477] (S)-2-(6-chloro-4-(((cyclobutylmethyl)amino)methyl)pyridin-2-yl)-6-(1-(4-methyl-4H- 1,2,4-triazol-3-yl)propan-2-yl)isoindolin-1 -one (Compound 171);

[0478] 2-(6-chloro-4-((((1 -methylcyclobutyl)methyl)amino)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 172);

[0479] 2-(6-chloro-4-((((2,2-difluorocyclopropyl)methyl)amino)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 175);

[0480] (1 S,3r)-3-(2-(6-chloro-4-(((S)-3-methylpiperidin-1 -yl)methyl)pyridin-2-yl)-3-oxoisoindolin- 5-yl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1 -carbonitrile (Compound 179);

[0481] 2-(6-chloro-4-(((S)-3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-((S)-l,l,l- trifluoro-3-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 181);

[0482] 3-(2-(6-chloro-4-(((cyclobutylmethyl)amino)methyl)pyridin-2-yl)-3-oxoisoindolin-5-yl)- 3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutane-l-carbonitrile (Compound 182);

[0483] 2-(6-chloro-4-((((tetrahydrofuran-2-yl)methyl)amino)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 188);

[0484] 2-(6-chloro-4-(((2-hydroxycyclopentyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 193);

[0485] (S)-2-(6-chloro-4-((((tetrahydrofuran-2-yl)methyl)amino)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 196);

[0486] 2-(6-chloro-4-(l-(((2,2-difluorocyclopropyl)methyl)amino)ethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 199);

[0487] 2-(6-chloro-4-((cyclopentylamino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 201);

[0488] 2-(6-chloro-4-(((3,3,3-trifluoro-2-methylpropyl)amino)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 202);

[0489] 2-(6-chloro-4-(((2-hydroxycyclopentyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 209);

[0490] 2-(6-chloro-4-(((2-hydroxycyclopentyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 209);

[0491] 2-(6-chloro-4-(((2-hydroxycyclopentyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 209);

[0492] 2-(6-chloro-4-(((2-hydroxycyclopentyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 209);

[0493] 2-(6-chloro-4-(((2-hydroxycyclopentyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 209);

[0494] 2-(6-chloro-4-(((2-hydroxycyclopentyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 209);

[0495] 2-(6-chloro-4-(((2-hydroxycyclopentyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 209);

[0496] 2-(6-chloro-4-(((2-hydroxycyclopentyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 209);

[0497] 3-(2-(6-chloro-4-((((2,2-difluorocyclopropyl)methyl)amino)methyl)pyridin-2-yl)-3- oxoisoindolin-5-yl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1 - carbonitrile (Compound 230);

[0498] (R)-2-(6-chloro-4-(1-(cyclopentylamino)ethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 231);

[0499] (S)-2-(6-chloro-4-(1-(cyclopentylamino)ethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 232);

[0500] (1r,3r)-3-(2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-3-oxoisoindolin- 5-yl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1-carbonitrile (Compound 233);

[0501] (1s,3s)-3-(2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-3-oxoisoindolin- 5-yl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1-carbonitrile (Compound 234);

[0502] 2-(6-chloro-4-((R)-1-(((S)-1-cyclopropylethyl)amino)ethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 239);

[0503] (1r,3r)-3-(2-(6-chloro-4-(((cyclobutylmethyl)amino)methyl)pyridin-2-yl)-3-oxoisoindolin- 5-yl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1-carbonitrile (Compound 244);

[0504] 2-(6-chloro-4-(1-((2-cyclopropylpropan-2-yl)amino)ethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 247);

[0505] 2-(6-chloro-4-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 252);

[0506] 2-(6-chloro-4-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 252);

[0507] 2-(6-chloro-4-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 252);

[0508] 2-(6-chloro-4-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 252);

[0509] 2-(6-chloro-4-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 252);

[0510] 2-(6-chloro-4-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 252);

[0511] 2-(6-chloro-4-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 252);

[0512] 2-(6-chloro-4-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 252);

[0513] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-methoxy-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindoline-1-one (compound 273);

[0514] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(((cyclobutylmethyl)amino)methyl)-6-methylpyridin-2-yl)isoindoline-1-one (compound 274);

[0515] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(2-((cyclopropylmethyl)amino)propane-2-yl)pyridin-2-yl)isoindoline-1-one (compound 275);

[0516] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindoline-1-one (compound 277);

[0517] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(1-((cyclobutylmethyl)amino)ethyl)-6-methylpyridin-2-yl)isoindoline-1-one (compound 278);

[0518] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-((((3,3-difluorocyclobutyl)methyl)amino)methyl)-6-methylpyridin-2-yl)isoindoline-1-one (compound 279);

[0519] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(3-(((cyclopropylmethyl)amino)methyl)-5-methylphenyl)isoindoline-1-one (compound 280);

[0520] 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(1-(((3,3-difluorocyclobutyl)methyl)amino)ethyl)-6-methylpyridin-2-yl)isoindoline-1-one (compound 281);

[0521] 2-(4-(1-((cyclopropylmethyl)amino)ethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindoline-1-one (compound 282);

[0522] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 295);

[0523] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 295);

[0524] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 295);

[0525] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 295);

[0526] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 295);

[0527] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 295);

[0528] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 295);

[0529] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 295);

[0530] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 295);

[0531] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((2-hydroxy-2- methylpropyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 309);

[0532] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- (methyl-d3)-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 310);

[0533] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-((((lR,2R)-2- hydroxycyclopentyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 314);

[0534] (R)-6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((l-hydroxy-3- methylbutan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 315);

[0535] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-((((l-hydroxycyclopentyl) methyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 319);

[0536] 6-(2-(4-Cyclopropyl-4H-l,2,4-triazol-3-yl)-4-fluorophenyl)-2-(4-(((cyclopropylmethyl) amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 320);

[0537] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-((propylamino) methyl)pyridin-2-yl)isoindolin-l-one (Compound 323);

[0538] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(((oxetan-2- ylmethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 325);

[0539] 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(((3,3,3- trifluoropropyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 328);

[0540] 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(((3,3,3- trifluoropropyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 328);

[0541] 2-(4-(((cyclopentylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 329);

[0542] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6- (4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 337);

[0543] and tautomers and pharmaceutically acceptable salts thereof.

[0544] The compounds of the present application can be administered to a patient at therapeutically effective amounts, which typically range from about 0.5 to about 2000 mg, more typically about 1 to about 500 mg, for example about 2 to about 100 mg, per day, depending on the age, sex, weight, condition of the patient, the disorder to be treated, the route of administration and the active ingredient employed. The compounds of the present application can be formulated into dosage forms using principles known in the art. The compounds can be administered to a patient as they are or in combination with suitable pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, emulsions, suspensions or solutions. Suitable carriers, solvents, gel-forming excipients, dispersion-forming excipients, antioxidants, coloring agents, sweetening agents, wetting compounds and other ingredients commonly used in the art can also be used. The compositions containing the active compounds can be administered enterally or parenterally, with the oral route being the preferred mode. The active compounds are present in the compositions in amounts of about 0.5% to 100%, typically about 0.5% to about 20%, by weight of the total composition.

[0545] The compounds of the present application can be administered to a subject as the sole active ingredient or in combination with one or more other active ingredients used in the treatment of a particular disease.

[0546] In the treatment of diseases and conditions in which inhibition of Cbl-b is desirable, such as various cancers, it is often advantageous to combine a therapeutic agent and / or other therapy (e.g., radiation therapy). The second (or third) agent to be administered can have the same or a different mechanism of action as the primary therapeutic agent.

[0547] Accordingly, the compounds of the application can be administered in combination with other anticancer treatments useful in the treatment of cancer. For example, the compounds of the application can be packaged with instructions that the compound is to be used in combination with other anticancer agents and therapies for the treatment of cancer. The application further includes combinations of a compound of the application and one or more additional agents in the form of a kit, e.g., where they are packaged together or in separate packages for sale as a kit, or where they are packaged to be formulated together.

[0548] According to one embodiment of the application, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is co-administered with one or more anticancer agents or analgesic agents.

[0549] In addition to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, optional additional anticancer agents that can be administered include, but are not limited to:

[0550] - chemotherapeutic agents (e.g., docetaxel and paclitaxel),

[0551] - tyrosine kinase inhibitors, including EGFR inhibitors (e.g., gefitinib and osimertinib), VEGFR inhibitors (e.g., bevacizumab), and FGFR inhibitors (e.g., erdafitinib);

[0552] - immune checkpoint inhibitors (e.g., PD-1, PD-L1, or CTLA-4 antagonists, such as nivolumab and pembrolizumab),

[0553] - epigenetic modulators (e.g., BET inhibitors and HDAC inhibitors),

[0554] - mTOR inhibitors (e.g., everolimus);

[0555] - AKT inhibitors (e.g., ipatasertib);

[0556] - radiopharmaceuticals (e.g., alpharadin);

[0557] - GnRH / LHRH analogues (such as leuprolide);

[0558] - PI3K inhibitors (e.g., idelalisib); and

[0559] - CDK4 / 6 inhibitors (e.g., ribocyclib)

[0560] - Steroidogenesis inhibitors (e.g., CYP17A1 inhibitors, such as abiraterone acetate and seviteronel); and

[0561] - Non-steroidal androgen receptor antagonists (e.g., enzalutamide, apalutamide, and darolutamide).

[0562] The other therapeutic agents described above, when used in combination with the compounds of the present application, can be used, for example, in amounts as indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

[0563] The compounds of the present application can be prepared using appropriate starting materials by a variety of synthetic routes analogous to those in the literature. The present application will be more fully understood from the following experiments and examples. These experiments and examples are intended merely to be illustrative of the present application and are not limiting thereof.

[0564] Example:

[0565] Intermediate 1. 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one

[0566]

[0567] a) tert-Butyl 6-bromo-1-oxoisoindoline-2-carboxylate (1b)

[0568] To a stirred solution of 6-bromoisoindolin-1-one (70.0 g, 330.11 mmol) and 4-dimethylaminopyridine (4.066 g, 33.01 mmol) in THF (700.0 mL) was added di-tert-butyl dicarbonate (180.12 g, 825.27 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude mixture was dissolved in DCM and triturated with pentane to get a precipitate. The precipitate was filtered, dried under vacuum to get the title compound (84.0 g, 81.52%). 1H NMR (400 MHz, CDCl3) δ: 8.02 (d, 1H), 7.74 (dd, 1H), 7.36(d, 1H), 4.70 (s, 2H), 1.62 (s, 9H)。

[0569] b) tert-Butyl 1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2- carboxylate (1c)

[0570] To a degassed solution of tert-butyl 6-bromo-1-oxoisoindoline-2-carboxylate (30.0 g, 96.11 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (29.286 g, 115.32 mmol) and potassium acetate (12.26 g, 124.9 mmol) in 1,4-dioxane (300.0 mL) was added [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (3.921 g, 4.8 mmol) followed by stirring the mixture at 80 °C for 2 h. The reaction mixture was then cooled to room temperature, filtered through a pad of celite followed by washing the celite pad with ethyl acetate. The filtrate was concentrated, diluted with water and extracted with 40% ethyl acetate in hexane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was dissolved in DCM and triturated with a mixture of methyl tert-butyl ether (MTBE) and pentane to obtain a precipitate. The filtered precipitate was dried under vacuum to get the title compound (23.0 g, 66.62%). 1 H NMR (400 MHz, CDCl3) δ: 8.39 (s, 1H), 8.06 (dd, 1H),7.48 (dd, 1H), 4.78 (s, 2H), 1.63 (s, 9H), 1.37 (s, 12H)。

[0571] c) tert-Butyl 6-(3-(2-ethoxy-2-oxoethyl)oxetan-3-yl)-1-oxoisoindoline-2- carboxylate (1d)

[0572] To a degassed solution of tert-butyl 1-oxo-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindoline-2-carboxylate (45.0 g, 125.26 mmol), ethyl 2-(oxetan-3- ylidene)acetate (26.7 g, 187.9 mmol) and N,N-diethylethanamine (25.35 g, 250.05 mmol) in 1,4-dioxane (450.0 mL) and water (400.0 mL) was added [Rh(COD)Cl]2(3.09 g, 6.26 mmol) followed by stirring the mixture at room temperature for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 20-40% ethyl acetate in hexanes as eluent to afford the title compound (29.0 g, 61.67%). 1 H NMR (400 MHz, CDCl3) δ: 7.66 (s, 1H), 7.52-7.45 (m,2H), 4.99 (d, 2H), 4.87 (d, 2H), 4.73 (s, 2H), 4.02-3.96 (m, 2H), 3.15 (s,2H), 1.60 (s, 9H), 1.12 (t, 3H).

[0573] d) Ethyl 2-(3-(3-oxoisoindolin-5-yl)oxetan-3-yl)acetate (1e)

[0574] To a solution of tert-butyl 6-(3-(2-ethoxy-2-oxoethyl)oxetan-3-yl)-1-oxoisoindoline- 2-carboxylate (13.5 g, 35.96 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (135.0 mL) was added HCl (5.40 mL, 4 M in dioxane) at 0 °C. The mixture was then slowly warmed to room temperature and stirred for 4 h. The mixture was then concentrated and purified by silica gel flash column chromatography using 0-2.5% methanol in dichloromethane as eluent to afford the title compound as an off-white solid (6.0 g, 60.61%). LCMS: 276.1 [M+H] + .

[0575] e) 2-(3-(3-oxoisoindolin-5-yl)oxetan-3-yl)acetic hydrazide (1f)

[0576] To a solution of ethyl 2-(3-(3-oxoisoindolin-5-yl)oxetan-3-yl)acetate (14.0 g, 50.85 mmol) in ethanol (70.0 mL) was added hydrazine hydrate (38.18 g, 762.8 mmol) followed by stirring the mixture at 75 °C for 24 h. The mixture was concentrated and triturated with 5% methanol in dichloromethane to get the title compound as off white solid (8.9 g, 66.98%). LCMS: 262.1 [M+H] + .

[0577] f) N-methyl-2-(2-(3-(3-oxoisoindolin-5-yl)oxetan-3-yl)acetyl)hydrazine-1- thioformamide (1g)

[0578] To a solution of 2-(3-(3-oxoisoindolin-5-yl)oxetan-3-yl)hydrazinecarboxylic acid (12.50 g, 47.84 mmol) in THF (120.0 mL) was added methyl isothiocyanate (8.74 g, 119.59 mmol) followed by stirring at 70 °C for 6 h. The precipitated solid was filtered, washed with cold THF and dried under vacuum to get the title compound as off white solid (14.0 g, 87.51%). LCMS: 335.1 [M+H] + .

[0579] g) 6-(3-((5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin- 1-one (1h)

[0580] N-methyl-2-(2-(3-(3-oxoisoindolin-5-yl)oxetan-3-yl)acetyl)hydrazine-1- thioformamide (5.8 g, 17.344 mmol) in 1 N NaOH (29.0 mL) was stirred at room temperature for 4 h. The reaction mixture was then quenched with ice cold water and pH was adjusted to ~4 with 1 N HCI. The precipitate was filtered and dried under vacuum to get the title compound as off white solid (4.70 g, 85.65 %), LCMS: 317.1 [M+H] + .

[0581] h) 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Intermediate-1)

[0582] Hydrogen peroxide (6.6 mL) was added to a solution of 6-(3-((5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetane-3-yl)isoindoline-1-one (4.70 g, 14.86 mmol) and acetic acid (7.8 mL) in dichloromethane (32.0 mL) at 0°C. The mixture was slowly heated to room temperature and stirred for 1 h. The mixture was concentrated and co-evaporated twice with toluene. The resulting semi-solid was ground with methanol, filtered, and dried under reduced pressure to give the title compound (3.5 g, 82.87%) as an off-white solid, LCMS: 285.1 [M+H]. + .

[0583] The following intermediates were prepared from the starting materials indicated in the table according to the procedure described for intermediate-1, with appropriate variations in the amounts of reactants, reagents, coupling methods, and solvents. Characterization data for the compounds are also summarized in the table.

[0584]

[0585] Intermediate - 4.(S)-1-(3-bromo-5-(trifluoromethyl)benzyl)-3-methylpiperidine (Procedure A)

[0586]

[0587] DIPEA (1.70 mL, 9.75 mmol) was added to a solution of (S)-3-methylpiperidine hydrochloride (0.67 g, 4.94 mmol) in DCM (10 mL), followed by stirring for 30 min. 3-Bromo-5-(trifluoromethyl)benzaldehyde (0.50 g, 1.98 mmol) was added to the mixture at 0°C, followed by sodium triacetoxyborohydride (STAB) (1.69 g, 7.99 mmol). The mixture was then stirred at room temperature for 12 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel rapid column chromatography using 0%–30% ethyl acetate in hexane as eluent to give the title compound (0.6 g, 90%). LCMS: 338.0 [M+2+H] + .

[0588] Intermediate 5. N-(3-bromo-5-(methyl)benzyl)-1-cyclopropylmethylamine (Program B)

[0589]

[0590] To a solution of cyclopropylmethanamine (0.36 g, 5.02 mmol) and 3-bromo-5- methylbenzaldehyde (0.40 g, 2.01 mmol) in DCM (10 mL) was added catalytic amount of acetic acid followed by stirring for 30 min. STAB (2.56 g, 12.06 mmol) was added at 0 °C and the mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography using 3-5% MeOH in DCM as eluent to afford the title compound (0.35 g, 68%). LCMS: 256.0 [M+2+H] + .

[0591] Intermediate 6. (S)-1-(3-bromo-5-(piperidin-1-yl)benzyl)-3-methylpiperidine

[0592]

[0593] a) 3-bromo-5-(piperidin-1-yl)benzonitrile (6b)

[0594] A mixture of 3-bromo-5-fluorobenzonitrile (0.5 g, 2.5 mmol), piperidine (0.63 g, 7.5 mmol) and K2CO3 (1.0 g, 7.50 mmol) in DMSO (2 mL) was stirred at 120 °C for 16 h. The mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography using 10% ethyl acetate in hexane as eluent to afford the title compound (0.6 g, 90.51%). LCMS: 267.0 [M+H] + .

[0595] b) 3-bromo-5-(piperidin-1-yl)benzaldehyde (6c)

[0596] To a solution of 3-bromo-5-(piperidin-1-yl)benzonitrile (0.47 g, 1.80 mmol) in DCM (5 mL) was added diisobutylaluminum hydride (DIBAL-H) (2.7 mL, 2.7 mmol, 1 M in THF) at 0 °C followed by stirring at room temperature for 4 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated. The obtained crude product was purified by silica gel flash column chromatography using 10% ethyl acetate in hexane as eluent to afford the title compound (0.28 g, 58.36%). LCMS: 268.0 [M+H]+ .

[0597] c) (S)-1-(3-bromo-5-(piperidin-l-yl)benzyl)-3-methylpiperidine (Intermediate-6)

[0598] The compound was prepared according to the procedure described for Intermediate-2 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 353.1 [M+2+H]+.

[0599] The following intermediate was prepared according to the procedure described for Intermediate-6 from the starting material indicated in the table with appropriate changes in the amount of reactants, reagents, coupling method and solvents. Characterization data of the compounds are also summarized in the table.

[0600]

[0601] Intermediate 9. (S)-2-chloro-4-((3-methylpiperidin-l-yl)methyl)-6- (trifluoromethyl)pyridine

[0602]

[0603] a) 2-chloro-6-(trifluoromethyl)isonicotinaldehyde (9b)

[0604] To a solution of 2-chloro-6-(trifluoromethyl)pyridine (5.0 g, 27.42 mmol) in dry THF (100 mL) was added 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (13.3 g, 55.080 mmol) dropwise at 0 °C followed by stirring at room temperature for 1 h. The mixture was then cooled to -78 °C and added dry DMF (4.2 mL in 25 mL THF). The mixture was slowly warmed to room temperature and stirred for 16 h. The mixture was cooled to 0 °C, quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, concentrated. The crude product was purified by silica gel flash column chromatography using 0-10% ethyl acetate in hexane as eluent to afford the title compound as a liquid (0.9 g, 15%). 1 H NMR (CDC13, 400 MHz) δ: 10.11 (s, 1H), 8.03 (s, 1H), 7.95 (s, 1H).

[0605] b) (S)-2-chloro-4-((3-methylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridine (Intermediate-9)

[0606] The compound was prepared according to the procedure described for Intermediate-4 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 293.0 [M+H] + .

[0607] Intermediate 10 and 11. (S)-1-(3-bromo-5-vinylbenzyl)-3-methylpiperidine (Intermediate-10) and (S)-1-(3-bromo-5-(cyclopropylmethyl)benzyl)-3-methylpiperidine (Intermediate-11)

[0608]

[0609] a) 3-bromo-5-vinylbenzaldehyde (10b)

[0610] To a degassed solution of 3-bromo-5-iodobenzaldehyde (2.70 g, 8.68 mmol), potassium trifluoro(vinyl)borate (1.40 g, 10.42 mmol), and sodium carbonate (1.38 g, 13.02 mmol) in 1,4-dioxane (30.0 mL) and water (18.0 mL) was added bis(triphenylphosphine)palladium(II) chloride (0.61 g, 0.86 mmol) followed by stirring at 70 °C for 2 h. The mixture was cooled to room temperature, filtered through a pad of celite followed by washing the celite pad with ethyl acetate. The filtrate was concentrated, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography using 8-10% ethyl acetate in hexanes as the eluent to afford the title compound as a colorless liquid (1.50 g, 81%). 1 H NMR (400MHz, CDCl3) δ: 10.00 (s, 1H), 7.90(dd, 1H), 7.84 (dd, 1H), 7.80 (dd, 1H), 6.77 - 6.69 (m, 1H), 5.89 (d, 1H),5.45 (d, 1H).

[0611] b) (S)-1-(3-bromo-5-vinylbenzyl)-3-methylpiperidine (Intermediate-10)

[0612] The compound was prepared according to the procedure described for Intermediate-4 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 293.0 [M+H] + .

[0613] c) (S)-3-bromo-5-((3-methylpiperidin-1-yl)methyl)benzaldehyde (11a)

[0614] To a solution of (S)-l-(3-bromo-5-ethenylbenzyl)-3-methylpiperidine (1.50 g, 5.10 mmol) and sodium periodate (2.18 g, 10.19 mmol) in THF (20.0 mL) and water (10.0 mL) was added osmium tetroxide (0.97 mL, 0.15 mmol, 4 wt-% in H20) dropwise at 0 °C. The mixture was slowly warmed to room temperature and stirred for 4 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography using 8-9% ethyl acetate in hexanes as eluent to give the title compound (0.90 g, 59%) as a liquid. LCMS: 295.95 [M+H] + .

[0615] d) (3-bromo-5-(((S)-3-methylpiperidin-l-yl)methyl)phenyl)(cyclopropyl)methanol (lib)

[0616] To a solution of (S)-3-bromo-5-((3-methylpiperidin-l-yl)methyl)benzaldehyde (1.20 g, 4.05 mmol) in THF (4.0 mL) was added cyclopropylmagnesium bromide solution (19.50 mL, 9.72 mmol, 0.5 M in THF) at 0 °C. The mixture was then slowly warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous NH4C1 solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography using 20-25% ethyl acetate in hexanes as eluent to give the title compound (0.60 g, 43%) as a liquid. LCMS: 338.10 [M+H] + .

[0617] e) (S)-l-(3-bromo-5-(cyclopropylmethyl)benzyl)-3-methylpiperidine (Intermediate-11)

[0618] To a solution of (3-bromo-5-(((S)-3-methylpiperidin-l-yl)methyl)phenyl)(cyclopropyl)methanol (0.45 g, 1.33 mmol) in dichloroethane at 0 °C was added trifluoroacetic acid (0.15 g, 1.35 mmol) and triethylsilane (0.16 g, 1.35 mmol). The resulting mixture was slowly warmed to room temperature and then stirred at 70 °C for 16 h. The mixture was then concentrated. The crude product was purified by reverse phase HPLC [mobile phase: 0.05% TFA in water and MeCN, 0-80%, column: LUNA OMEG PS C-18 (250 x 21.2 mm) 5µ] to give the title compound (0.20 g, 46%) as a colorless liquid. LCMS: 324.10 [M+H] + .

[0619] Intermediate 12. (S)-l-(3-bromo-5-ethylbenzyl)-3-methylpiperidine

[0620]

[0621] To a solution of (S)-l-(3-bromo-5-vinylbenzyl)-3-methylpiperidine (0.22 g, 0.75 mmol) and sodium acetate trihydrate (0.51 g, 3.74 mmol) in THF was added p-toluenesulfonylhydrazide (0.70 g, 3.74 mmol) followed by stirring at 75 °C for 12 h. The mixture was filtered and washed with diethyl ether:hexanes (1 :2). The filtrate was concentrated. The crude product was purified by silica gel flash column chromatography using 6% ethyl acetate in hexanes as eluent to give the title compound (0.17 g, 76%) as a colorless liquid. LCMS: 296.10 [M+H] + .

[0622] Intermediate-13. (S)-4-chloro-2-methyl-6-((3-methylpiperidin-l-yl)methyl)pyrimidine

[0623]

[0624] a) 4-chloro-2-methyl-6-vinylpyrimidine (13b)

[0625] The compound was prepared according to the procedure described for Intermediate-10b with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 155.10 [M+H] + .

[0626] b) 6-chloro-2-methylpyrimidine-4-carbaldehyde (13c)

[0627] The compound was prepared according to the procedure described for Intermediate-11a with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 157.10 [M+H] + .

[0628] c) (S)-4-chloro-2-methyl-6-((3-methylpiperidin-l-yl)methyl)pyrimidine (Intermediate-13)

[0629] The compound was prepared according to the procedure described for Intermediate-4 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 240.1 [M+H] + .

[0630] Intermediate 14. (S)-l-(3-bromo-5-cyclopropylbenzyl)-3-methylpiperidine

[0631]

[0632] a) 3-bromo-5-cyclopropylbenzaldehyde (14a)

[0633] The compound was prepared according to the procedure described for Intermediate-11 with appropriate changes in the amount of reactants, reagents and solvents. 1 H NMR (400MHz, CDCl3) δ: 9.93 (s, 1H), 7.99 - 7.98 (m, 1H), 7.51 - 7.48(m, 1H), 2.00 -1.93 (m, 1H), 1.11 - 1.06 (m, 2H), 0.81 - 0.77 (m, 2H).

[0634] b) (S)-l-(3-bromo-5-cyclopropylbenzyl)-3-methylpiperidine (Intermediate-14)

[0635] The compound was prepared according to the procedure described for Intermediate-4 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 310.1 [M+2+H] + 。

[0636] Intermediate-15. (S)-4-bromo-2-methyl-6-((3-methylpiperidin-l-yl)methyl)pyridine

[0637]

[0638] a) (4-bromo-6-methylpyridin-2-yl)methanol (15b)

[0639] To a solution of 4-bromo-2-methylpyridine (3.0 g, 17.44 mmol) and sulfuric acid (0.15 mL) in methanol (75.0 mL) was added ammonium peroxydisulfate (3.979 g, 17.430 mmol) in water (6.6 mL) followed by stirring at 70 °C for 2 h. The mixture was concentrated, diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography using 0-50% ethyl acetate in hexane as eluent to afford the title compound (0.950 g, 26.96%). LCMS: 203.9 [M+H] + .

[0640] b) 4-bromo-6-methylpyridinecarboxaldehyde (15c)

[0641] To a solution of (4-bromo-6-methylpyridin-2-yl)methanol (0.90 g, 4.45 mmol) in dichloromethane (10.0 mL) was added Dess-Martin Oxidizing reagent (DMP) (2.456 g, 5.790 mmol) at 0 °C. The mixture was slowly warmed to room temperature and stirred for 4 h. The mixture was diluted with hexane, filtered through a pad of celite, then the celite pad was washed with diethyl ether. The combined organic layers were washed with aqueous sodium thiosulfate and aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a crude product (0.600 g) which was used as such in the next step. LCMS: 201.9 [M+H] + .

[0642] c) (S)-4-bromo-2-methyl-6-((3-methylpiperidin-l-yl)methyl)pyridine (Intermediate-15)

[0643] The compound was prepared according to the procedure described for Intermediate-4 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 285.1 [M+2+H] + 。

[0644] Intermediate 16. (S)-4-bromo-2-((3-methylpiperidin-l-yl)methyl)-6- (trifluoromethyl)pyridine

[0645]

[0646] a) 4-bromo-6-(trifluoromethyl)pyridinecarboxaldehyde (16b)

[0647] This compound was prepared from 4-bromo-6-(trifluoromethyl)picolinonitrile (prepared according to WO 2010 / 100050) according to the procedure described for Intermediate-6c with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 255.0 [M+H] + .

[0648] b) (S)-4-bromo-2-((3-methylpiperidin-l-yl)methyl)-6- (trifluoromethyl)pyridine (Intermediate 16)

[0649] The compound was prepared according to the procedure described for Intermediate-4 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 339.0 [M+2+H] + 。

[0650] Intermediate-17. (S)-2-chloro-6-methyl-4-((3-methylpiperidin-l- yl)methyl)pyridine

[0651]

[0652] a) (2-chloro-6-methylpyridin-4-yl)methanol (17b)

[0653] To a solution of 2-chloro-6-methylisonicotinic acid (5.0 g, 29.14 mmol) in THF (50 ml) was added BH3*THF (50 mL, 1 M in THF) drop wise at 0 °C. The mixture was then slowly warmed to room temperature and stirred for 16 h. The mixture was cooled to 0 °C, quenched with water and extracted with ethyl acetate. The combined organic layers were then washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel flash column chromatography using 10-20% ethyl acetate in hexane as eluent to obtain the title product (4.0 g, 87.10%). LCMS: 158.1 [M+H] + .

[0654] b) 2-chloro-6-methylisonicotinaldehyde (17c)

[0655] The compound was prepared according to the procedure described for the preparation of Intermediate-15c with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 156.0 [M+H] + .

[0656] c) (S)-2-chloro-6-methyl-4-((3-methylpiperidin-l-yl)methyl)pyridine (Intermediate-17)

[0657] The compound was prepared according to the procedure described for Intermediate-4 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 239.1 [M+H] + .

[0658] Intermediate-18 and Intermediate-19. (S)-2,6-dichloro-4-((3-methylpiperidin-l- yl)methyl)pyridine (Intermediate 18) and (S)-2-chloro-6-cyclopropyl-4-((3- methylpiperidin- 1 -yl)methyl)pyridine (Intermediate 19)

[0659]

[0660] a) (S)-2,6-dichloro-4-((3-methylpiperidin-l-yl)methyl)pyridine (Intermediate-18)

[0661] The compound was prepared according to the procedure described for Intermediate-4 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 261.1 [M+H] + .

[0662] b) (S)-2-chloro-6-cyclopropyl-4-((3-methylpiperidin-l-yl)methyl)pyridine (Intermediate-19)

[0663] The compound was prepared according to the procedure described for the preparation of Intermediate-11 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 265.10 [M+H] + .

[0664] Intermediate-20. 2-(6-bromo-4-methyl-lH-indazol-l-yl)-N,N-dimethylethan-l-amine

[0665]

[0666] a) (4-bromo-2-fluoro-6-methylphenyl)methanol (20b)

[0667] The compound was prepared according to the procedure described for Intermediate- 17b with appropriate changes in the amount of reactants, reagents and solvents. 1 H-NMR (400 MHz, CDC13) δ: 7.18 (brs, 1H) 7.12 (dd, 1H), 4.72 (s, 2H), 2.45 (s, 3H).

[0668] b) 4-bromo-2-fluoro-6-methylbenzaldehyde (20c)

[0669] The compound was prepared according to the procedure described for Intermediate- 15c with appropriate changes in the amount of reactants, reagents and solvents.1 H-NMR (400 MHz, CDCl3) δ 10.48 (s, 1H) 7.31 - 7.21 (m, 2H), 2.62 (s,3H)。

[0670] c) 6-bromo-4-methyl-1H-indazole (20d)

[0671] A mixture of 4-bromo-2-fluoro-6-methylbenzaldehyde (2.85 g, 13.13 mmol) and NH2NH2*H2O (6.57 g, 131.31 mmol) in DMSO (20.0 mL) was stirred at 110 °C for 16 h. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the title compound. (2.83 g, 97.88 %). LCMS: 211.0 [M+H] + .

[0672] d) 6-bromo-1-(2-bromoethyl)-4-methyl-1H-indazole (20e)

[0673] To a solution of 6-bromo-4-methyl-1H-indazole (0.50 g, 2.37 mmol) and 1,2- dibromoethane (0.89 g, 4.74 mmol) in DMF (5.0 mL) was added CS2CO3 (1.16 g, 3.55 mmol) followed by stirring at room temperature for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (0.450 g, 59.73 %). LCMS: 320.9 [M+H] + .

[0674] e) 2-(6-bromo-4-methyl-1H-indazol-1-yl)-N,N-dimethylethan-1-amine (Intermediate-20)

[0675] To a solution of 6-bromo-1-(2-bromoethyl)-4-methyl-1H-indazole (0.45 g, 1.42 mmol) and dimethylamine (0.64 g, 14.15 mmol) in DMF (5.0 mL) was added NaI (0.12 g, 1.41 mmol) followed by stirring at 70 °C for 5 h. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography using 10% MeOH in DCM as eluent to afford the title compound. LCMS: 284.0 [M+H] + .

[0676] Intermediate-21 and Intermediate-22. l-(7-bromo-5-(trifluoromethyl)-3,4- dihydroisoquinolin-2(lH)-yl)ethan-l-one (Intermediate-21) and 7-bromo-2-ethyl-5- (trifluoromethyl)-l,2,3,4-tetrahydroisoquinoline (Intermediate-22)

[0677]

[0678] a) N-(4-bromo-2-(trifluoromethyl)phenethyl)acetamide (21b)

[0679] To a solution of 2-(4-bromo-2-(trifluoromethyl)phenyl)ethan-l -amine (1.8 g, 6.71 mmol, prepared according to WO2021 / 032148) and triethylamine (1.36 g, 13.42 mmol) in dichloromethane (20.0 mL) was added acetyl chloride (0.53 g, 6.71 mmol) at 0 °C followed by stirring for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography using 40% ethyl acetate in hexanes as eluent to afford the title compound (1.5 g, 72%). LCMS: 311.9 [M+2+H] + .

[0680] b) l-(7-bromo-5-(trifluoromethyl)-3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-one (Intermediate-21)

[0681] To a solution of N-(4-bromo-2-(trifluoromethyl)phenethyl)acetamide (1.45 g, 4.68 mmol) and formaldehyde (1.4 g, 46.7 mmol) in acetic acid (16.0 mL) was added sulfuric acid (0.45 mL) followed by stirring at 80 °C for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography using 30% ethyl acetate in hexanes as eluent to afford the title compound (0.650 g, 43%). LCMS: 323.9 [M+2+H] + .

[0682] c) 7-bromo-2-ethyl-5-(trifluoromethyl)-l,2,3,4-tetrahydroisoquinoline (Intermediate-22)

[0683] To a solution of l-(7-bromo-5-(trifluoromethyl)-3,4-dihydroisoquinolin-2(lH)- yl)ethan-l-one (0.05 g, 0.16 mmol) in anhydrous THF (0.5 mL) was added BH3* SMe2 (0.18 mL, 0.38 mmol, 2.0 M in THF) at 0 °C. The mixture was then slowly warmed to room temperature and stirred for 2 h. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (0.04 g). LCMS: 310.9 [M+2+H] + .

[0684] Intermediate 23. 3-((4-Methyl-4H-l,2,4-triazol-3-yl)methyl)-3-(3-oxoisoindolin-5- yl)cyclobutane-l-carbonitrile

[0685]

[0686] a) Ethyl 2-(3-cyano cyclobutyl)acetate (23b)

[0687] To a solution of 3-oxocyclobutane-l-carbonitrile (3.00 g, 31.545 mmol) in DCM (30.0 mL) was added ethyl 2-(triphenyl-l5-phosphoranyl)acetate (10.990 g, 31.545 mmol) and the mixture was stirred at room temperature for 15 h. The reaction was quenched with hexane and stirred for 10 min to get white precipitate. The precipitate was filtered and the filtrate was dried under vacuum to get the title product (2.72 g, 52.20%). 1 H-NMR (400 MHz, CDCl3) δ: 5.73 - 5.72 (br m, 1H), 4.18 (q, 2H), 3.68 - 3.55 (m, 1H), 3.48 - 3.54 (m, 1H), 3.34 - 3.22 (m, 3H), 1.29 (t, 3H).

[0688] b) tert-Butyl 6-(3-cyano-l-(2-ethoxy-2-oxoethyl)cyclobutyl)-l-oxoisoindoline-2- carboxylate (23c)

[0689] The compound was prepared according to the procedure described for Intermediate-Id with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 343.0 [M-56] + .

[0690] c) 2-(3-cyano-l-(3-oxoisoindolin-5-yl)cyclobutyl)acetic acid ethyl ester (23d)

[0691] The compound was prepared according to the procedure described for Intermediate- le with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 297.1 [M-H] -

[0692] d) 2-(3-cyano-l-(3-oxoisoindolin-5-yl)cyclobutyl)acetic acid (23e)

[0693] To a solution of 2-(3-cyano-l-(3-oxoisoindolin-5-yl)cyclobutyl)acetic acid ethyl ester (2.64 g, 8.85 mmol) in THF (12.0 mL), MeOH (2.5 mL) and water (4.7 mL) was added LiOH (0.46 mg, 11.06 mmol) followed by stirring at room temperature for 4 h. The mixture was concentrated, the residue was dissolved in water and pH was adjusted to acidic using 0.5 N HC1. The precipitate was filtered, dried under vacuum to afford the title compound as a white solid. LCMS: 271.1 [M+H] + .

[0694] e) 2-(2-(3-cyano-l-(3-oxoisoindolin-5-yl)cyclobutyl)acetyl)-N-methylhydrazine- 1 -carbothioamide (23f)

[0695] To a solution of 2-(3-cyano-l-(3-oxoisoindolin-5-yl)cyclobutyl)acetic acid (1.35 g, 4.99 mmol), N-methylhydrazine carbothioamide (0.63 g, 5.99 mmol) and DIPEA (1.291 g, 9.990 mmol) in DMF (13.0 mL) was added HATU (1.41 g, 5.99 mmol) and the mixture was stirred at room temperature for 5 h. The reaction was quenched with ice cold water and stirred for 10 min to get a brown precipitate. The precipitate was filtered and dried under vacuum to obtain the title product. LCMS: 358.1 [M+H] + .

[0696] f) 3-((5-mercapto-4-methyl-4H-l,2,4-triazol-3-yl)methyl)-3-(3-oxoisoindolin-5- yl)cyclobutane-l-carbonitrile (23g)

[0697] The compound was prepared according to the procedure described for Intermediate- lh with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 340.0 [M+H] + .

[0698] g) 3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)-3-(3-oxoisoindolin-5-yl)cyclobutane- 1-carbonitrile (Intermediate-23)

[0699] The compound was prepared according to the procedure described for Intermediate-1 (last step) with appropriate changes in the reactants, amount of reagents and solvents. LCMS: 308.1 [M+H] + .

[0700] Intermediate-24. 6-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)isoindolin- 1-one

[0701]

[0702] a) 6-iodo-2-(4-methoxybenzyl)isoindolin-l-one (24b)

[0703] To a solution of 6-iodoisoindolin-l-one (27 g, 104.23 mmol) and CS2CO3 (67.92 g, 208.45 mmol) in acetonitrile (270 mL) was added p-methoxychlorobenzene (PMBC1) (27 g, 104.23 mmol) dropwise over 30 min followed by stirring at 60 °C for 12 h. The mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated and purified by silica gel flash column chromatography using 20% ethyl acetate in hexane as eluent to afford the title compound (21 g, 53.13%). LCMS: 379.9 [M+H] + .

[0704] b) tert-butyl 2-cyano-2-(2-(4-methoxybenzyl)-3-oxoisoindolin-5-yl)acetate (24c)

[0705] To a degassed solution of 6-iodo-2-(4-methoxybenzyl)isoindolin-l-one (19.6 g, 51.69 mmol), tert-butyl 2-cyanoacetate (14.59 g, 103.38 mmol), picolinic acid (0.636 g, 5.160 mmol) and CS2CO3 (33.68 g, 103.37 mmol) in dioxane (200 mL) was added Cul (0.492 g, 2.580 mmol) followed by stirring at 80 °C for 12 h. The mixture was cooled to room temperature, filtered through a pad of celite and concentrated. The product was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography using 30% ethyl acetate in hexanes as eluent to afford the title compound (17 g, 83.81%). LCMS: 393.2 [M-H] + .

[0706] c) 2-(2-(4-methoxybenzyl)-3-oxoisoindolin-5-yl)acetonitrile (24d)

[0707] To a solution of tert-butyl 2-cyano-2-(2-(4-methoxybenzyl)-3-oxoisoindolin-5- yl)acetate (17.00 g, 43.317 mmol) in hexafluoroisopropanol (HFIP) (170.0 mL) was added 4M HC1 in dioxane (69 ml, 281.55 mmol) at 0 °C. The mixture was slowly heated to 50 °C and stirred for 12 h. The mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography using 50% ethyl acetate in hexanes as eluent to afford the title compound (8.4 g, 66.34%). LCMS: 293.1 [M+H] + .

[0708] d) l-(2-(4-methoxybenzyl)-3-oxoisoindolin-5-yl)-3-methylcyclobutane-l- carbonitrile (24e)

[0709] To a solution of 2-(2-(4-methoxybenzyl)-3-oxoisoindolin-5-yl)acetonitrile (4.00 g, 13.68 mmol) and KOH (1.919 g, 34.20 mmol) in DMSO (40.0 mL) was added 1,3-dibromo-2-methylpropane (2.95 g, 13.68 mmol) at 0 °C. The mixture was slowly warmed to room temperature and stirred for 8 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography using 40% ethyl acetate in hexanes as eluent to afford the title compound (2.7 g, 56.97%). LCMS: 347.1 [M+H] + .

[0710] e) 1-(2-(4-methoxybenzyl)-3-oxoisoindolin-5-yl)-3-methylcyclobutane-1-carboxylic acid (24f)

[0711] To a solution of 1-(2-(4-methoxybenzyl)-3-oxoisoindolin-5-yl)-3-methylcyclobutane-1- carbonitrile (1.7 g, 4.91 mmol) and KOH (2.49 g, 44.16 mmol) in EtOH (10.0 mL) was added water (2.5 mL) followed by stirring at 110 °C for 12 h. The mixture was cooled to room temperature, quenched with ice-cold water and extracted with 20% MeOH in DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (1.5 g, 83.65 %). LCMS: 366.1 [M+H] + .

[0712] f) 2-(1-(2-(4-methoxybenzyl)-3-oxoisoindolin-5-yl)-3-methylcyclobutane-1-carbonyl)-N- methylhydrazine-1-carbothioamide (24g)

[0713] The compound was prepared according to the procedure described for Intermediate-23f with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 453.1 [M+H] + .

[0714] g) 6-(1-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)-3-methylcyclobutyl)-2-(4- methoxybenzyl)isoindolin-1-one (24h)

[0715] The compound was prepared according to the procedure described for Intermediate-1h with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 435.2 [M+H] +.

[0716] h) 2-(4-methoxybenzyl)-6-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3- yl)cyclobutyl)isoindolin-l-one (24i)

[0717] The compound was prepared according to the procedure described for Intermediate-1 (last step) with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 403.2 [M+H] + .

[0718] i) 6-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)isoindolin-l-one (Intermediate 24)

[0719] A solution of 2-(4-methoxybenzyl)-6-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3- yl)cyclobutyl)isoindolin-l-one (0.5 g, 1.24 mmol) in TFA (10.0 mL) was irradiated in microwave at 100 °C for 4 h. The mixture was concentrated, diluted with DCM, added solid NaHC03and stirred for 2 h. The organic layer was filtered through sintered funnel, dried over anhydrous sodium sulfate, filtered and concentrated to get the title compound. LCMS: 283.1 [M+H] + .

[0720] Intermediate-25. 2-chloro-4-((4,4-difluoro-3-methylpiperidin-l-yl)methyl)-6- (trifluoromethyl)pyridine

[0721]

[0722] a) l-benzyl-4,4-difluoro-3-methylpiperidine (25b)

[0723] To a solution of l-benzyl-3-methylpiperidin-4-one (1.0 g, 4.918 mmol) in dichloromethane (10 mL) was added (diethylamino)sulfur trifluoride (3.96 g, 24.59 mmol) followed by stirring at room temperature for 16 h. The reaction mixture was quenched by saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography using 10-20% ethyl acetate in hexane as eluent to obtain the title product (0.9 g, 81.22%). LCMS: 226.1 [M+H] + .

[0724] b) 4,4-difluoro-3-methylpiperidine (25c)

[0725] To a solution of l-benzyl-4,4-difluoro-3-methylpiperidine (0.9 g, 3.995 mmol) in ethanol (10 ml) was added Pd / C (0.43 g, 0.400 mmol) followed by stirring at room temperature under hydrogen atmosphere for 24 h. The mixture was filtered through a pad of celite followed by washing the celite pad with dichloromethane. The filtrate was concentrated to get the title product (0.750 g, 75%). LCMS: 136.1 [M+H] + .

[0726] c) 2-chloro-4-((4,4-difluoro-3-methylpiperidin-l-yl)methyl)-6- (trifluoromethyl)pyridine (Intermediate-25)

[0727] The compound was prepared according to the procedure described for Intermediate-5 with appropriate changes in the amount of reactants, reagents and solvents. LC-MS: 331.0 [M+2+H] + .

[0728] Intermediate-26. (S)-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)(3- hydroxypyrrolidin-l-yl)methanone

[0729]

[0730] a) 2-chloro-6-(trifluoromethyl)isonicotinic acid (26b)

[0731] To a solution of 2-chloro-6-(trifluoromethyl)pyridine (5.0 g, 27.542 mmol) in dry THF (100.0 ml) was added 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (1.0 M solution in THF, 33.0 ml, 33.05 mmol) at room temperature followed by stirring for 1 h. The mixture was cooled to -78 °C and dry ice (16.0 g) was added portion wise. The mixture was slowly allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with water at 0 °C and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 5-10% methanol in dichloromethane as eluent to get the title compound (0.700 g, 11.27%); LCMS: 225.9 [M+H] + .

[0732] b) (S)-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)(3-hydroxypyrrolidin-l- yl)methanone (Intermediate-26)

[0733] To a solution of 2-chloro-6-(trifluoromethyl)isonicotinic acid (0.60 g, 2.66 mmol) in DCM (1.0 ml) was added thionyl chloride (0.949 g, 7.98 mmol). The mixture was refluxed at 55 °C for 2 h. Then the mixture was cooled to room temperature and evaporated under argon. The obtained crude acid chloride was dissolved in dichloromethane (6.0 ml) and added triethylamine (0.251 g, 2.47 mmol) followed by (S)-pyrrolidin-3-ol (0.157 g, 1.80 mmol). The mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 0%-5% methanol in dichloromethane as eluent to afford the title compound (0.230 g, 34.63%); LCMS: 295.0 [M+H] + .

[0734] Intermediate-27. (3S)-1-(1-(3-bromo-5-methylphenyl)ethyl)-3-methylpiperidine

[0735]

[0736] a) 1-(3-bromo-5-methylphenyl)ethan-1-ol (27a)

[0737] To a solution of 3-bromo-5-methylbenzaldehyde (3.0 g, 15.07 mmol) in THF (30 mL) was added methylmagnesium bromide (60.28 ml, 60.28 mmol, 1 M in THF) drop wise at -78 °C followed by stirring for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography using 20%-30% ethyl acetate in hexane as eluent to afford the title compound (1.3 g, 40%). 1 H NMR (DMSO, 400 MHz): 7.31 (s, 1H), 7.25 - 7.21 (m, 1H), 7.14 (d, 1H), 5.24 (d, 1H), 4.69 - 4.64 (m, 1H), 2.29 (s, 3H),1.99 (d, 3H).

[0738] b) 1-bromo-3-(1-bromoethyl)-5-methylbenzene (27b)

[0739] To a solution of 1-(3-bromo-5-methylphenyl)ethan-1-ol (0.65 g, 3.02 mmol) and triphenylphosphine (0.95 g, 3.62 mmol) in DCM (10 mL) was added CBr4(1.0 g, 3.62 mmol) followed by stirring at room temperature for 3 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography using 5% ethyl acetate in hexanes as the eluent to afford the title compound (0.5 g, 59%). 1 H NMR (CDCl3, 400 MHz): 7.38 (s, 1H), 7.26 (d, 1H), 7.16 (s, 1H),5.01 (q, 1H), 2.33 (s, 3H), 2.01 (d, 3H).

[0740] c) (3S)-1-(1-(3-bromo-5-methylphenyl)ethyl)-3-methylpiperidine (Intermediate-27)

[0741] To a solution of (S)-3-methylpiperidine hydrochloride (0.220 g, 1.61 mmol), tetrabutylammonium iodide (0.399 g, 1.07 mmol) and DIPEA (0.558 g, 4.31 mmol) in DCM (6 mL) was added 1-bromo-3-(1-bromoethyl)-5-methylbenzene (0.3 g, 1.07 mmol) followed by stirring at room temperature for 12 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography using 10% ethyl acetate in hexanes as the eluent to afford the title compound (0.16 g, 50%). LCMS: 298.1 [M+H] + .

[0742] Intermediate-28. 2-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)-6- (trifluoromethyl)pyridine

[0743]

[0744] a) (2-chloro-6-(trifluoromethyl)pyridin-4-yl)methanol (28a)

[0745] Sodium borohydride (0.36 g, 9.54 mmol) was added fractionally to a solution of 2-chloro-6-(trifluoromethyl)isoniaaldehyde (1.0 g, 4.77 mmol) in THF (10 mL) at 0°C. The mixture was slowly heated to room temperature and stirred for 2 h. The reaction was quenched with an aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel rapid column chromatography using 20%–30% ethyl acetate in hexane as the eluent to give the title compound (0.97 g, 96.08%). LCMS: 212.0 [M+H] + .

[0746] b) (2-Chloro-6-(trifluoromethyl)pyridin-4-yl)methylmethanesulfonate (28b)

[0747] In 0 ° Methanesulfonyl chloride (0.26 mL, 3.37 mmol) was added to a solution of (2-chloro-6-(trifluoromethyl)pyridin-4-yl)methanol (0.35 g, 1.68 mmol) and triethylamine (0.51 g, 5.06 mmol) in DCM (6 mL), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (0.6 g) as a crude product, which was used as is in the next step. LCMS: 289.9 [M+H] + .

[0748] c) 2-Chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)-6-(trifluoromethyl)pyridine (intermediate 28)

[0749] Cesium carbonate (1.12 g, 3.45 mmol) and 2-methyl-1H-imidazolium (0.42 g, 5.17 mmol) were added to a solution of (2-chloro-6-(trifluoromethyl)pyridin-4-yl)methylmethanesulfonate (0.50 g, 1.72 mmol) in THF (7 mL), followed by stirring at room temperature for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography using 5%–10% methanol in dichloromethane as eluent to give the title compound (0.21 g, 44%). LCMS: 276.0 [M+H] + .

[0750] The following intermediates were prepared according to the procedure described for Intermediate-28 from the starting materials indicated in the table with appropriate changes in the amount of reactants, reagents, coupling method and solvent. Characterization data of the compounds are also summarized in the table.

[0751]

[0752] Intermediate-36. 2-chloro-4-((2,5-dimethylpiperidin-l-yl)methyl)-6- (trifluoro-methyl)pyridine

[0753]

[0754] a) 2,5-dimethylpiperidine (36b)

[0755] To a solution of 2,5-dimethylpyridine (0.5 g, 4.66 mmol) in TFA (10 mL) was added platinum oxide (0.10 g, 0.46 mmol) in a pressure vessel and stirred at room temperature under 80 psi pressure of hydrogen for 12 h. The mixture was filtered through a pad of celite and concentrated. The pH of the crude was adjusted to 7 with 7 M methanolic ammonia solution, then concentrated and purified by preparative HPLC to afford the title compound (0.4 g, 75.73%) LCMS: 114.1 [M+H] + .

[0756] b) 2-chloro-4-((2,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridine (Intermediate-36)

[0757] The compound was prepared according to the procedure described for Intermediate-28 with appropriate changes in the amount of reactants, reagents and solvent. LCMS: 307.2 [M+H] + .

[0758] Intermediate-37. 2-(3-bromo-5-(trifluoromethyl)phenyl)-N-ethyl ethan-l-amine

[0759]

[0760] a) 2-(3-bromo-5-(trifluoromethyl)phenyl) ethyl 2-cyanoacetate (37b)

[0761] To a solution of sodium hydride (1.2 g, 53.08 mmol) in N-methyl-2-pyrrolidinone (NMP) (12 mL) was added ethyl 2-cyanoacetate (6.00 g, 53.08 mmol) followed by 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (4.3 g, 17.69 mmol). The mixture was stirred at 110 °C for 12 h. The mixture was cooled to 0 °C, quenched with 2 N HC1 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 3-4% ethyl acetate in hexane as eluent to afford the title compound (3.5 g, 58.85%); LCMS: 335.9 [M+H] + .

[0762] b) 2-(3-bromo-5-(trifluoromethyl)phenyl)acetic acid (37c)

[0763] To a solution of ethyl 2-(3-bromo-5-(trifluoromethyl)phenyl)-2-cyanoacetate (3.4 g, 10.11 mmol) in water (35 mL) was added aqueous sodium hydroxide (2.0 g, 50.58 mmol) followed by stirring at 95 °C for 6 h. The mixture was concentrated and the pH was adjusted to 3-4 using 1 N HC1. The obtained precipitate was filtered through a sintered funnel and dried under vacuum to afford the title compound (1.8 g, 62.8%). 1 H NMR (DMSO-d6, 400 MHz): 12.80 - 12.50 (bs, 1H), 7.85 (s, 1H), 7.84 (s, 1H), 7.69 (s, 1H), 3.75 (s, 2H).

[0764] c) 2-(3-bromo-5-(trifluoromethyl)phenyl)-N-ethylacetamide (37d)

[0765] To a solution of ethylamine (0.08 g, 1.766 mmol) and 2-(3-bromo-5-(trifluoromethyl)phenyl)acetic acid (0.5 g, 1.76 mmol) in MeCN (6 mL) was added 1-hydroxybenzotriazole (HOBT) (0.26 g, 1.76 mmol) and 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDCI) (0.33 g, 1.76 mmol) followed by stirring at room temperature for 16 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with 1 N HC1 and sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (0.4 g). LCMS: 312.0 [M+H]+ .

[0766] d) 2-(3-bromo-5-(trifluoromethyl)phenyl)-N-ethylacetamide (Intermediate-37)

[0767] To a solution of 2-(3-bromo-5-(trifluoromethyl)phenyl)-N-ethylacetamide (0.25 g, 0.80 mmol) in dry THF (3 mL) was added borane dimethyl sulfide complex (1.61 mL, 3.22 mmol, 2 M in THF) at 0 °C. The mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 5% MeOH in DCM as eluent to get the title compound (0.18 g, 75%). LCMS: 298.0 [M+H] + .

[0768] Intermediate-38. (S)-1-((6-bromobenzofuran-4-yl)methyl)-3-methylpiperidine

[0769]

[0770] a) Methyl 3-bromo-5-hydroxybenzoate (38b)

[0771] To a solution of 3-bromo-5-hydroxybenzoic acid (10 g, 46.08 mmol) in MeOH (50 mL) was added H2SO4(18.06 g, 184.30 mmol) followed by stirring at 70 °C for 12 h. The mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography using 0-30% ethyl acetate in hexane as eluent to get the title compound (10 g, 93.93%). LCMS: 233.1 [M+H] + .

[0772] b) Methyl 3-bromo-5-(2,2-diethoxyethoxy)benzoate (38c)

[0773] To a solution of methyl 3-bromo-5-hydroxybenzoate (9.0 g, 38.95 mmol) and 2-bromo-l,l-diethoxyethane (15.3 g, 77.92 mmol) in DMF (60 mL) was added cesium carbonate (25.38 g, 77.90 mmol) followed by stirring at 95 °C for 12 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography using 0-30% ethyl acetate in hexane as eluent to afford the title compound (8.0 g, 59.15%). LCMS: 347.2 [M+H] + .

[0774] c) Methyl 6-bromobenzofuran-4-carboxylate (38d)

[0775] To a solution of methyl 3-bromo-5-(2,2-diethoxyethoxy)benzoate (4.0 g, 11.51 mmol) in toluene (30 mL) was added polyphosphoric acid (PPA) (3.38 g, 34.56 mmol) followed by stirring at 115 °C for 6 h. The mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography using 10-30% ethyl acetate in hexane as eluent to afford the title compound (2.5 g, 85.08%). 1 H NMR (400 MHz, CDCl3) δ: 8.13 (s, 1H), 7.88 (s, 1H), 7.73 (d, 1 H), 7.37 (d, 1H), 4.07 (s, 3H).

[0776] d) (6-Bromobenzofuran-4-yl)methanol (38e)

[0777] To a solution of methyl 6-bromobenzofuran-4-carboxylate (1.5 g, 5.88 mmol) in anhydrous THF (10 mL) was added LiBH4(11.7 mL, 11.760 mmol, 1 M in THF) at -78 °C followed by stirring for 3 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography using 10-30% ethyl acetate in hexane as eluent to afford the title compound (1.2 g, 88.97%). 1H NMR (400 MHz, DMSO-d6) δ: 8.03 (s, 1H), 7.84(s, 1H), 7.55 (d, 1 H), 7.01 (d, 1H), 5.47 (t, 1H), 4.88 (d, 2H).

[0778] e) 6-bromobenzofuran-4-carbaldehyde (38f)

[0779] To a solution of (6-bromobenzofuran-4-yl)methanol (1.00 g, 4.40 mmol) in dichloromethane (20.0 mL) was added Dess-Martin Oxidizing reagent (DMP) (3.76 g, 8.80 mmol) at 0 °C. The mixture was slowly warmed to room temperature and stirred for 4 h. The mixture was diluted with hexane, filtered through a pad of celite, then the celite pad was washed with diethyl ether. The combined organic layers were washed with aqueous sodium thiosulfate and aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a crude product (1.0 g) which was used as such in the next step. 1 H NMR (400 MHz, DMSO-d6) δ: 10.17 (s, 1H), 7.99 (s, 1H), 7.89 (d, 1H), 7.71 (d, 1H), 5.51 (d, 1H).

[0780] f) (S)-1-((6-bromobenzofuran-4-yl)methyl)-3-methylpiperidine (Intermediate-38)

[0781] The compound was prepared according to the procedure described for Intermediate-2 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 309.23 [M+H] + .

[0782] The following intermediates were prepared according to the procedures described for Intermediate 4 (Procedure A) and 5 (Procedure B) with appropriate starting materials, changes in the amount of reactants, reagents, coupling method and solvents. Characterization data of the compounds are also summarized in the table.

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789] Intermediate-93. 6-(4-Chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l- one

[0790]

[0791] a) 2-Bromo-5-chlorobenzohydrazide (93b)

[0792] To a solution of methyl 2-bromo-5-chlorobenzoate (50.0 g, 200.41 mmol) in ethanol (500.0 mL) was added hydrazine hydrate (50.16 g, 1002.04 mmol) followed by stirring at room temperature for 12 h. The mixture was concentrated and triturated with pentane to afford the title compound (49.0 g, 98%) as off-white solid. LCMS: 250.9 [M+2+H] + .

[0793] b) 2-(2-Bromo-5-chlorobenzoyl)-N-methylhydrazine-l-carbothioamide (93c)

[0794] To a solution of 2-bromo-5-chlorobenzohydrazide (26 g, 104.21 mmol) in THF (150.0 mL) was added methyl isothiocyanate (11.43 g, 156.32 mmol) followed by stirring at room temperature for 12 h. The precipitated solid was filtered, washed with cold THF and dried under vacuum to afford the title compound (28.0 g, 83%) as off-white solid. LCMS: 324.0 [M+2+H] + .

[0795] c) 5-(2-Bromo-5-chlorophenyl)-4-methyl-4H-l,2,4-triazole-3-thiol (93d)

[0796] 2-(2-Bromo-5-chlorobenzoyl)-N-methylhydrazine-l-carbothioamide (27.5 g, 85.24 mmol) in 2 N NaOH (137.5 mL) was stirred at 60 °C for 6 h. The mixture was cooled to room temperature and quenched with ice water. The pH was adjusted to ~4 with 1 N HC1. The precipitate was filtered and dried under vacuum to afford the title compound (25.0 g, 96%) as off-white solid, LCMS: 305.9 [M+2+H] + .

[0797] d) 3-(2-Bromo-5-chlorophenyl)-4-methyl-4H-l,2,4-triazole (93e)

[0798] To a solution of 5-(2-bromo-5-chlorophenyl)-4-methyl-4H-l,2,4-triazole-3- thiol (20.0 g, 65.66 mmol) and acetic acid (40 mL) in DCM (200 mL) was added hydrogen peroxide (20 mL) at 0 °C. The mixture was slowly warmed to room temperature and stirred for 1 h. The mixture was concentrated and co-evaporated with toluene twice. The obtained semi-solid was triturated with methanol, filtered, and dried under vacuum to afford the title compound as off-white solid (16.0 g. 89%). LCMS: 273.9 [M+2+H] + .

[0799] e) 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Intermediate-93)

[0800] To a degassed solution of 3-(2-bromo-5-chlorophenyl)-4-methyl-4H-l,2,4-triazole (0.5 g, 1.83 mmol), 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoindolin-l- one (0.713 g, 2.75 mmol), K2CO3(0.76 g, 5.5 mmol) in dioxane (8.0 mL) and water (2.0 mL) was added Pd(amphos)Cl2(0.065 g, 0.09 mmol) followed by stirring at 100 °C for 4 h. The mixture was cooled to room temperature, filtered through a pad of celite and washed with ethyl acetate. The filtrate was dried over anhydrous sodium sulfate and concentrated. The obtained crude was purified by silica gel flash column chromatography using 6-7% MeOH in DCM as eluent to afford the title compound as light brown solid (0.3 g, 50%). LCMS: 325.0 [M+H] + .

[0801] Intermediate-94. 6-(2-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)phenyl)isoindolin-l- one

[0802]

[0803] a) 2-(2-(3-oxoisoindolin-5-yl)phenyl)acetic acid methyl ester (94b)

[0804] To a degassed solution of 2-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetic acid methyl ester (0.2 g, 0.724 mmol), 6-iodoisoindolin-l-one (0.19 g, 0.724 mmol) and Cs2CO3(0.47 g , 1.440 mmol) in dioxane (1.3 mL) and water (0.3 mL) was added Pd(dppf)Cl2in DCM (0.06 g, 0.070 mmol) followed by stirring at 100 °C for 4 h. The mixture was cooled to room temperature, filtered through a pad of celite and washed with ethyl acetate. The filtrate was dried over anhydrous sodium sulfate, concentrated and purified by silica gel flash column chromatography using 5-6% MeOH in DCM as eluent to afford the title compound as a light brown solid (0.065 g, 31%), LCMS: 282.1 [M+H] + .

[0805] b) 2-(2-(3-oxoisoindolin-5-yl)phenyl)acethydrazide (94c)

[0806] The compound was prepared according to the procedure described for intermediate 93b with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 282.2 [M+H] + .

[0807] c) N-methyl-2-(2-(2-(3-oxoisoindolin-5-yl)phenyl)acetyl)hydrazine-1- thioformamide (94d)

[0808] The compound was prepared according to the procedure described for intermediate 93c with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 355.1 [M+H] + .

[0809] d) 6-(2-((5-mercapto-4-methyl-4H-l,2,4-triazol-3-yl)methyl)phenyl)isoindolin- 1-one (94e)

[0810] The compound was prepared according to the procedure described for intermediate 93d with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 337.1 [M+H] + .

[0811] e) 6-(2-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)phenyl)isoindolin-l-one (Intermediate-94)

[0812] The compound was prepared according to the procedure described for Intermediate-93 (last step) with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 305.1 [M+H] + .

[0813] The following intermediates were prepared according to the procedure described for Intermediate-93 from the starting materials indicated in the table with appropriate changes in the amount of reactants, reagents, coupling method and solvent. Characterization data of the compounds are also summarized in the table.

[0814]

[0815] Intermediate-100. l-(2-chloro-6-methylpyridin-4-yl)-N-(cyclopropylmethyl)methanamine

[0816]

[0817] a) (2-chloro-6-methylpyridin-4-yl)methanol (100b)

[0818] To a solution of 2-chloro-6-methylisonicotinic acid (7.0 g, 40.80 mmol) in THF (70 mL) was added BH3.THF (81.59 mL, 1 M in THF) dropwise at 0 °C. The mixture was then slowly warmed to room temperature and stirred for 16 h. The mixture was cooled to 0 °C, quenched with methanol (50.0 mL), followed by water (250.0 mL), and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel flash column chromatography using 15-30% ethyl acetate in hexanes as eluent to obtain the title product (5.0 g, 77.10%). LCMS: 158.1 [M+H] + .

[0819] b) 2-chloro-6-methylisonicotinaldehyde (100c)

[0820] To a solution of (2-chloro-6-methylpyridin-4-yl)methanol (5.0 g, 31.725 mmol) in DCM (100 mL) was added Dess-Martin Oxidizing Reagent (20.19 g, 47.58 mmol) portionwise at 0 °C. The mixture was then slowly warmed to room temperature and stirred for 2 h. The mixture was cooled to 0 °C, quenched with sodium thiosulfate solution (100 mL), followed by aqueous sodium bicarbonate solution (100 mL), and extracted with DCM. The combined organic layers were dried over sodium sulfate, concentrated, and purified by silica gel flash column chromatography using 10-30% ethyl acetate in hexanes as eluent to obtain the title product (4.0 g, 81%). LCMS: 156.0 [M+H] + .

[0821] c) l-(2-chloro-6-methylpyridin-4-yl)-N-(cyclopropylmethyl)methanamine (Intermediate-100)

[0822] To a solution of 2-chloro-6-methylisonicotinaldehyde (2 g, 12.86 mmol) and cyclopropylmethanamine (2.29 g, 32.14 mmol) in DCM (20 mL) was added catalytic acetic acid at room temperature followed by stirring for 1 h. STAB (5.45 g, 25.71 mmol) was added to the mixture at 0 °C followed by stirring at room temperature for 16 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 0-30% ethyl acetate in hexane as eluent to afford the title compound (2 g, 73.84%). LCMS: 211.1 [M+H] + .

[0823] Intermediate-103. N-(cyclopropylmethyl)-1-(2,6-dichloropyridin-4-yl)ethan-1- amine (Procedure C)

[0824]

[0825] a) 1-(2,6-dichloropyridin-4-yl)ethan-1-ol (103a)

[0826] To a solution of 2,6-dichloroisonicotinaldehyde (3.0 g, 17.04 mmol) in THF (30 mL) was added methylmagnesium bromide (8.13 g, 68.18 mmol) dropwise at -78 °C followed by stirring at the same temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 0-5% ethyl acetate in hexane as eluent to afford the title compound (3.5 g, 76.38%) LCMS: 192.0 [M+H] + .

[0827] b) 4-(1-bromoethyl)-2,6-dichloropyridine (103b)

[0828] To a solution of 1-(2,6-dichloropyridin-4-yl)ethan-1-ol (0.3 g, 1.56 mmol) in DCM (5 mL) was added triphenylphosphine (0.49 g, 1.87 mmol) and carbon tetrabromide (0.62 g, 1.87 mmol) at 0 °C followed by stirring at room temperature for 3 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 0-5% ethyl acetate in hexane as eluent to afford the title compound (0.23 g, 57.76%).1 H NMR (CDCl3, 400 MHz): δ 7.30 (s, 2H), 4.99 (q,1H), 2.01 (d, 3H).

[0829] c) N-(Cyclopropylmethyl)-1-(2,6-dichloropyridin-4-yl)ethan-1-amine (Intermediate-103)

[0830] To a solution of 4-(1-bromoethyl)-2,6-dichloropyridine (0.18 g, 0.70 mmol) and cyclopropylmethylamine (0.06 g, 0.84 mmol) in MeCN (3 mL) was added K2CO3(0.24 g, 1.76 mmol) followed by stirring at room temperature for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 15-30% ethyl acetate in hexane as eluent to afford the title compound (0.19 g). LCMS: 245.0 [M+H] + .

[0831] Intermediate-104. 1-(2-Chloro-6-methylpyridin-4-yl)-N-(cyclopropylmethyl)ethan-1- amine (Procedure D)

[0832]

[0833] a) 1-(2-Chloro-6-methylpyridin-4-yl)ethan-1-ol (104a)

[0834] To a solution of 2-chloro-6-methylisonicotinaldehyde (2.0 g, 12.855 mmol) in THF (20 mL) was added methylmagnesium bromide (6.13 g, 51.420 mmol) dropwise at -78 °C followed by stirring at same temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted by ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 0-30% ethyl acetate-hexane as eluent to afford the title compound (1.6 g, 72.5%); LCMS: 172.1 [M+H] + .

[0835] b) 4-(1-Bromoethyl)-2-chloro-6-methylpyridine (104b)

[0836] To a solution of 1-(2-chloro-6-methylpyridin-4-yl ethan-1 -ol (1.60 g, 9.32 mmol) in DCM (50.0 mL) was added triphenylphosphine (2.93 g, 11.18 mmol) and carbon tetrabromide (3.71 g, 11.18 mmol) at 0 °C followed by stirring at room temperature for 3 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 0-1% ethyl acetate in hexane as eluent to afford the title compound (1.4 g, 64.03%); LCMS: 233.9 [M+H] + .

[0837] c) 1-(2-chloro-6-methylpyridin-4-yl)-N-(cyclopropylmethyl)ethan-1 -amine (Intermediate-104)

[0838] To a solution of 4-(1-bromoethyl)-2-chloro-6-methylpyridine (0.50 g, 2.13 mmol) and cyclopropylmethylamine (0.30 g, 4.26 mmol) in MeCN (5.0 mL) was added K2CO3(0.74 g, 5.33 mmol) followed by stirring at room temperature for 12 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 15-30% ethyl acetate in hexane as eluent to afford the title compound (0.450 g, 93.92%) LCMS: 225.1 [M+H] + .

[0839] The following intermediates were prepared according to the procedure described for Intermediate-76 (Procedure A) or Intermediate-18 (Procedure B) from the starting materials indicated in the table with appropriate changes in the amount of reactants, reagents, coupling method and solvent. Characterization data of the compounds are also summarized in the table.

[0840]

[0841] The following intermediates were prepared according to the procedure described for Intermediate-103 (Procedure C) or Intermediate-104 (Procedure D) from the starting materials indicated in the table with appropriate changes in the amount of reactants, reagents, coupling method and solvent. Characterization data of the compounds are also summarized in the table.

[0842]

[0843] The following intermediates were prepared according to the procedure described for Intermediate-1 from the starting materials indicated in the table with appropriate changes in the amount of reactants, reagents, coupling method and solvent. Characterization data of the compounds are also summarized in the table.

[0844]

[0845] Intermediate 124. 6-(3,3-difluoro-1-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)cyclobutyl)isoindolin-1-one

[0846]

[0847] a) Ethyl 2-(3-(benzyloxy)cyclobutylidene)acetate (124b)

[0848] To a stirred solution of 3-(benzyloxy)cyclobutan-1-one (25.0 g, 141.87 mmol) in DCM was added (triphenylphosphoranylidene)acetic acid ethyl ester (64.25 g, 184.43 mmol) portion wise and stirred for 20 h at room temperature. The mixture was concentrated, the crude mixture was triturated with hexane and filtered. The organic layer was evaporated and purified by silica gel flash column chromatography using 0-5% ethyl acetate in hexane as eluent to get the title compound (21.5 g, 61.53%) LCMS: 247.2 [M+H] + .

[0849] b) tert-Butyl 6-(3-(benzyloxy)-1-(2-ethoxy-2-oxoethyl)cyclobutyl)-1-oxoisoindoline- 2-carboxylate (124c)

[0850] To a degassed solution of tert-butyl 1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindoline-2-carboxylate (29.17 g, 81.20 mmol), compound 124b (10.00 g, 40.60 mmol) and N,N-diethylethanamine (8.22 g, 81.19 mmol) in 1,4-dioxane (110.00 mL) and water (66.0 mL) was added [Rh(COD)Cl]2(1.001 g, 2.03 mmol) followed by stirring for 3 h at room temperature. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were worked up as in Example Intermediate-1, step c using 15-25% ethyl acetate in hexane as eluent to get the title compound (8.0 g, 41.08%). 1HNMR: NMR (400 MHz, CDCl3): δ 7.7(d, 1H), 7.50 - 7.43 (m, 1H), 7.41-7.28 (m, 6H), 4.74 (s, 2H), 4.45 (s, 2H),4.31 - 4.23 (m, 1H), 3.99 - 3.90 (m, 2H), 2.94 - 2.87 (m, 2H), 2.72 (s, 2H), 2.43 - 2.38 (m, 2H), 1.26 (s, 9H), 1.09 (t, 3H).

[0851] c) Ethyl 2-(3-hydroxy-1-(3-oxoisoindoline-5-yl)cyclobutyl)ethyl acetate (124d)

[0852] Concentrated boron tribromide (16.72 g, 66.72 mmol) was added to a solution of compound 124c (8.0 g, 16.68 mmol) in DCM (400.0 mL) at -78°C. The mixture was slowly warmed to room temperature and stirred for 3 h. The mixture was poured into ice-cold water and diluted with an aqueous sodium bicarbonate solution and extracted with DCM. The combined organic layers were treated with 0%–10% MeOH in DCM as the eluent as in step c of Example Int-1 to give the title compound (3.5 g, 72.52%). LCMS: 290.1 ​​[M+H] + .

[0853] d) Ethyl 2-(3-oxo-1-(3-oxoisoindoline-5-yl)cyclobutyl)acetate (124e)

[0854] At 0°C, a solution of compound 124d (1.5 g, 5.18 mmol) in DCM (20.0 mL) was added with Dys-Martin oxidant (3.30 g, 7.77 mmol). The mixture was slowly warmed to room temperature and stirred for 5 h. The reaction was quenched with an aqueous sodium thiosulfate solution, followed by the addition of an aqueous sodium bicarbonate solution. The mixture was stirred for 10 min and extracted with ethyl acetate. The combined organic layers were treated using 0%–5% methanol in DCM as the eluent as in step c of Example Int-1 to give the title compound (1.20 g, 80.57%). LCMS: 288.2 [M+H] + .

[0855] e) 2-(3,3-difluoro-1-(3-oxoisoindoline-5-yl)cyclobutyl)ethyl acetate (124f)

[0856] To a solution of compound 124e (2.8 g, 9.74 mmol) in DCM (100.0 mL) was added diethylaminosulfur trifluoride (9.42 g, 58.47 mmol) at -40 °C. Then the mixture was slowly warmed to room temperature and stirred for 6 h. The mixture was poured into ice-cold water and diluted with aqueous sodium bicarbonate solution and extracted with DCM. The combined organic layers were worked up as in example Int-124, step d to afford the title compound (2.0 g, 66.36 %). LCMS: 310.1 [M+H] +

[0857] f) 2-(3,3-difluoro-l-(3-oxoisoindolin-5-yl)cyclobutyl)acetic acid hydrazide (124g)

[0858] The compound was prepared according to the procedure described for Intermediate- If with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 296.1 [M+H] + .

[0859] g) 2-(2-(3,3-difluoro-l-(3-oxoisoindolin-5-yl)cyclobutyl)acetyl)-N-methylhydrazine- 1 -carbothioamide (124h)

[0860] The compound was prepared according to the procedure described for Intermediate- Ig with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 369.1 [M+H] + .

[0861] h) 6-(3,3-difluoro-l-((5-mercapto-4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl) isoindolin-l-one (124i)

[0862] The compound was prepared according to the procedure described for Intermediate- Ih with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 351.1 [M+H] + .

[0863] i) 6-(3,3-difluoro-l-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)isoindolin- 1 -one (Intermediate-124)

[0864] The compound was prepared according to the procedure described for Intermediate- 1 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 351.1 [M+H] + .

[0865] Intermediate 125. 6-(3-methoxy-l-((4-methyl-4H-l,2,4-triazol-3- yl)methyl)cyclobutyl)isoindolin-l-one

[0866]

[0867] a) 6-(l-(2-ethoxy-2-oxoethyl)-3-hydroxycyclobutyl)-l-oxoisoindoline-2- carboxylic acid tert-butyl ester (125a)

[0868] To a solution of tert-butyl 6-(3-(benzyloxy)-l-(2-ethoxy-2-oxoethyl)cyclobutyl)-l- oxoisoindoline-2-carboxylate (5.9 g, 12.30 mmol) in ethanol (250.0 mL) was added wet activated carbon supported palladium (0.66 g, 6.15 mmol) at room temperature followed by stirring for 12 h at room temperature. The mixture was filtered through celite, concentrated and purified by silica gel flash column chromatography using 0-15% MeOH in DCM as eluent to afford the title compound (4.5 g, 93.92%). LCMS: 290.1 [M-100+H] +

[0869] b) 6-(l-(2-ethoxy-2-oxoethyl)-3-methoxycyclobutyl)-l-oxoisoindoline-2- carboxylic acid tert-butyl ester (125b)

[0870] To a solution of compound 125a (3.00 g, 7.70 mmol) in dry THF (30.0 mL) was added sodium hydride (0.22 g, 9.24 mmol) at 0 °C followed by stirring for 30 min. Iodomethane (1.64 g, 11.55 mmol) was added to the mixture and stirred for 1 h at 0 °C. The mixture was quenched with aqueous NH4CI solution and extracted with ethyl acetate. The combined organic layers were worked up as in example intermediate-1 step c using 0-60% ethyl acetate in hexane as eluent to afford the title compound (1.1 g, 35.39%). LCMS: 404.3 [M+H] + .

[0871] c) 2-(3-methoxy-l-(3-oxoisoindolin-5-yl)cyclobutyl)ethyl acetate (125c)

[0872] The compound was prepared according to the procedure described for intermediate- le with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 304.4 [M+H] + .

[0873] d) 2-(3-methoxy-l-(3-oxoisoindolin-5-yl)cyclobutyl)acethydrazide (125d)

[0874] The compound was prepared according to the procedure described for Intermediate- 1f with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 290.1 [M+H] + .

[0875] e) 2-(2-(3-methoxy-l-(3-oxoisoindolin-5-yl)cyclobutyl)acetyl)-N-methylhydrazine- 1 -carbthioamide (125e)

[0876] The compound was prepared according to the procedure described for Intermediate- 1g with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 363.05 [M+H] + .

[0877] f) 6-(l-((5-mercapto-4-methyl-4H-l,2,4-triazol-3-yl)methyl)-3-methoxycyclobutyl) isoindolin-l-one (125f)

[0878] The compound was prepared according to the procedure described for Intermediate- 1h with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 345.1 [M+H] + .

[0879] h) 6-(3-methoxy-l-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)isoindolin- 1 -one (Intermediate-125)

[0880] The compound was prepared according to the procedure described for Intermediate- 1 (last step) with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 313.2 [M+H] + .

[0881] Intermediate 127. 6-(2-(4-methyl-4H-l,2,4-triazol-3-yl)ethyl)isoindolin-l-one

[0882]

[0883] a) (E)-3-(3-oxoisoindolin-5-yl)propenoic acid ethyl ester (127c)

[0884] To a degassed solution of 6-iodoisoindolin-1-one (3.8 g, 14.67 mmol), triethylamine and ethyl acrylate (4.406 g, 44.0 mmol) in DMF (35 ml) was added palladium acetate (0.17 g, 0.73 mmol) and tris(2-methylphenyl)phosphine (0.45 g, 1.46 mmol) followed by stirring at 90 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were worked up using 80% ethyl acetate in hexane as eluent as in example intermediate-1 step c to get the title compound (0.9 g, 26.53%), LCMS: 232.1 [M+H] + .

[0885] b) 3-(3-oxoisoindolin-5-yl)propionic acid ethyl ester (127d)

[0886] To a stirred solution of compound 127c (0.9 g, 3.89 mmol) in EtOAc (100 ml) was added Pd-carbon and the mixture was stirred in a Parr shaker under hydrogen (80 psi) at room temperature for 12 h. The mixture was filtered through celite and concentrated to get the title compound (0.8 g, 88.2%), LCMS: 234.1 [M+H] + .

[0887] c) 3-(3-oxoisoindolin-5-yl)propanohydrazide (127e)

[0888] The compound was prepared according to the procedure described for intermediate-1f with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 220.1 [M+H] + .

[0889] d) N-methyl-2-(3-(3-oxoisoindolin-5-yl)propanoyl)hydrazine-1-carbothioic acid amide (127f)

[0890] The compound was prepared according to the procedure described for intermediate-1g with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 293.0 [M+H] + .

[0891] e) 6-(2-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)ethyl)isoindolin-1-one (127g)

[0892] The compound was prepared according to the procedure described for intermediate-1h with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 275.1 [M+H] + .

[0893] f) 6-(2-(4-methyl-4H-l,2,4-triazol-3-yl)ethyl)isoindolin-l-one (Intermediate-127)

[0894] The compound was prepared according to the procedure described for Intermediate- 1 (last step) with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 243.1 [M+H] + .

[0895] Intermediate 128. 6-((l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)amino)isoindolin- 1-one

[0896]

[0897] a) 3-((3-oxoisoindolin-5-yl)amino)butanoic acid ethyl ester (128c)

[0898] To a stirred solution of 3-oxo butanoic acid ethyl ester (2.50 g, 19.1 mmol) and 6- aminoisoindolin-l-one (2.85 g, 19.21 mmol) in 1,2-dichloroethylene was added 2.5 ml of acetic acid followed by stirring at room temperature for 20 min. Then STAB (8.14 g, 38.42 mmol) was added portion wise to the mixture at 0 °C. The mixture was slowly warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated to get the title compound (4.6 g). LC-MS: 263.1 [M+H] + .

[0899] b) 3-((3-oxoisoindolin-5-yl)amino)butanoic acid (128d)

[0900] The compound was prepared according to the procedure described for Intermediate- 23e with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 235.1 [M+H] + .

[0901] c) N-methyl-2-(3-((3-oxoisoindolin-5-yl)amino)butanoyl)hydrazine-l- thioformamide (128e)

[0902] To a stirred solution of compound 128d (1.0 g, 4.27 mmol) and N-methylhydrazinecarbothioamide (0.67 g, 6.4 mmol) in acetonitrile (15.0 mL) was added 1-methylimidazole (1.75 g, 21.34 mmol) followed by stirring for 10 min. Chloro-dimethylaminomethylene)-dimethylazanium (1.74 g, 12.80 mmol) was then added to the mixture followed by stirring at room temperature for 12 h. The mixture was concentrated and purified by silica gel flash column chromatography using 15% methanol in DCM as eluent to afford the title compound (0.90 g). LCMS: 322.1 [M+H] + .

[0903] d) 6-((1-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)amino)isoindolin-1-one (128f)

[0904] The compound was prepared according to the procedure described for Intermediate-1h with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 304.1 [M+H] + .

[0905] e) 6-((1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)amino)isoindolin-1-one (Intermediate-128)

[0906] The compound was prepared according to the procedure described for Intermediate-1 (last step) with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 272.2 [M+H] + .

[0907] The following intermediates were prepared according to the procedure described for Intermediate-93 from the starting materials indicated in the table with appropriate changes in the amount of reactants, reagents, coupling method and solvents. Characterization data of the compounds are also summarized in the table.

[0908]

[0909] Intermediate 139. 6-(3,4-difluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1-one

[0910]

[0911] a) 2-(2-bromo-5-fluorophenyl)-4,5-dihydro-1H-imidazole (139b)

[0912] To a solution of 6-bromo-2,3-difluorobenzoic acid (4.0 g, 16.88 mmol), N- methylhydrazinecarboxamidine (2.13 g, 20.54 mmol) and DIPEA (4.36 g, 33.75 mmol) in DMF (30.0 mL) was added HATU (4.77 g, 20.25 mmol) followed by stirring at room temperature for 12 h. The mixture was concentrated and ice was added to get solid precipitate. The solid was then filtered and triturated with pentane and MTBE and purified by silica gel flash column chromatography using 15% MeOH in DCM as eluent to get the title compound as off-white solid (2.15 g, 39.30%). LCMS: 323.9 [M+H] + .

[0913] b) 5-(6-bromo-2,3-difluorophenyl)-4-methyl-4H-1,2,4-triazole-3-thiol (139c)

[0914] The compound was prepared according to the procedure described for Intermediate-93d with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 305.9 [M+H] + .

[0915] c) 3-(6-bromo-2,3-difluorophenyl)-4-methyl-4H-1,2,4-triazole (139d)

[0916] The compound was prepared according to the procedure described for Intermediate-93e with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 274.0 [M+H] + .

[0917] d) 6-(3,4-difluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1-one (Intermediate-139)

[0918] The compound was prepared according to the procedure described for Intermediate-93 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 327.0 [M+H] + .

[0919] The following intermediates were prepared according to the procedure described for Intermediate-139 from the starting materials indicated in the table with appropriate changes in the amount of reactants, reagents, coupling method and solvents. Characterization data of the compounds are also summarized in the table.

[0920]

[0921] Intermediate-142. 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4- (trifluoromethyl)isoindolin-l-one

[0922]

[0923] a) Methyl 2-methyl-3-(trifluoromethyl)benzoate (142b)

[0924] To a stirred suspension of 2-methyl-3-(trifluoromethyl)benzoic acid (4.0 g, 19.593 mmol) in MeOH (24.0 mL) was added dropwise concentrated H2SO4 (1.922 g, 19.59 mmol) at 0 °C followed by stirring overnight at 80 °C. The reaction mixture was quenched with aqueous NaHCO3 solution and extracted with hexane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to get the title compound as crude (3.4 g) which was used as such for the next step. LCMS: 218.9 [M+H] + .

[0925] b) Methyl 5-bromo-2-methyl-3-(trifluoromethyl)benzoate (142c)

[0926] To a stirred solution of compound 142b (3.4 g, 15.58 mmol) in acetic acid (35.0 mL) and nitric acid (10.41 g, 165.18 mmol) was added dropwise bromine (2.86 g, 35.84) at 0 °C. Then silver nitrate (3.63 g, 21.34 mmol) dissolved in 8.0 mL of water was added dropwise followed by stirring at room temperature for 12 h. The mixture was filtered through filter paper. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were worked up using 0-5% ethyl acetate in hexane as eluent as in example intermediate-1 step c to get the desired product (3.2 g, 69.13%). 1 H-NMR (400MHz, CDCl3): δ 8.08 (d, 1H), 7.91 (d, 1H), 3.95 (s, 3H), 2.61 (s, 3H).

[0927] c) Methyl 5-bromo-2-(bromomethyl)-3-(trifluoromethyl)benzoate (142d)

[0928] To a solution of compound 142c (3.2 g, 10.77 mmol) in CCI4(32.0 mL) was added N-bromosuccinimide (2.88 g, 16.15 mmol) followed by benzoyl peroxide (0.26 g, 1.07 mmol) and the mixture was stirred in dark at 80 °C for 12 h. The mixture was concentrated. The crude product was diluted with water and extracted with hexane. The combined organic layers were worked up using 0-2% ethyl acetate in hexane as eluent as in example intermediate-1 step c to get the desired product (3.0 g, 74.08%). LCMS: 375.3 [M+H] + .

[0929] d) 6-Bromo-4-(trifluoromethyl)isoindolin-l-one (142e)

[0930] To a solution of compound 142d (3.0 g, 7.98 mmol) in DCM (30.0 mL) was added 7 M methanolic-ammonia solution (15.0 mL) at 0 °C followed by stirring at room temperature for 16 h. The mixture was concentrated and the crude product was diluted with water and extracted with ethyl acetate. The combined organic layers were worked up using 30-50% ethyl acetate in hexane as eluent as in example intermediate-1 step c to get the desired product (2.2 g, 98.46%). LCMS: 280.0 [M+H] + .

[0931] e) 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4- (trifluoromethyl)isoindolin-l-one (Intermediate-142)

[0932] To a degassed solution of compound 142e (0.05 g, 0.18 mmol), 3-(2-bromo-5- fluorophenyl)-4-methyl-4H-l,2,4-triazole (0.06 g, 0.21 mol), bis(pinacolato)diboron (0.07 g, 0.26 mmol) and CsF (0.13 g, 0.85 mmol) in MeOH was added a mixture of cataCXium-A (0.016 g, 0.04 mmol) and Pd(OAc)2(0.008 g, 0.03 mmol) in toluene at 50 °C. The mixture was heated at 80 °C for 12 h. The mixture was filtered through celite and washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were worked up using 0% to 7% MeOH in DCM as eluent as in Example Intermediate-124, step d to afford the title compound as a yellow solid (0.017 g, 25%). LCMS: 377.1 [M+H] + .

[0933] The following intermediates were prepared according to the procedure described for Intermediate-142 from the starting materials indicated in the table with appropriate changes in the amount of reactants, reagents, coupling method and solvent. Characterization data of the compounds are also summarized in the table.

[0934]

[0935] Intermediate-146. 6-(4-Chloro-2-(lH-pyrazol-3-yl)phenyl)isoindolin-l-one

[0936]

[0937] a) 1-(2-Bromo-5-chlorophenyl)ethan-l-ol (146b)

[0938] To a solution of 2-bromo-5-chlorobenzaldehyde (1.0 g, 4.56 mmol) in THF (15.0 mL) was added methylmagnesium bromide (6.07 mL, 18.21 mmol, 3.0 M in diethyl ether) at -78 °C followed by stirring at -78 °C for 1 h. The reaction mixture was quenched by saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were worked up using 0% to 10% ethyl acetate in hexanes as eluent as in Example Intermediate-1, step c to obtain the title product (0.90 g, 83.86%). 1H-NMR: NMR (400 MHz, DMSO-d6): δ 7.59 (s, 1H), 7.57 (d, 1H), 7.27(dd, 1H), 5.56 (d, 1H), 4.93 - 4.88 (m, 1H), 1.3 (d, 3H).

[0939] b) 1-(2-bromo-5-chlorophenyl)ethyl-1-one (146c)

[0940] DMP (2.16 g, 5.09 mmol) was added to a solution of compound 146b (0.80 g, 3.40 mmol) in DCM (15.0 mL) at 0°C. The mixture was slowly warmed to room temperature and stirred for 2 h. The mixture was diluted with hexane, filtered through a diatomaceous earth pad, washed with diethyl ether, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (0.700 g, 88.28% g). 1 H-NMR: NMR (400 MHz, DMSO-d6): δ 7.77 (d, 1H), 7.73 (d, 1H), 7.50 (dd, 1H), 2.50 (s, 3H).

[0941] c) (E)-1-(2-bromo-5-chlorophenyl)-3-(dimethylamino)prop-2-en-1-one (146d)

[0942] A mixture of compound 146c (8.60 g, 36.832 mmol) and dimethoxymethyl-dimethylazaium (6.72 g, 55.91 mmol) in a sealed tube was heated at 120°C for 12 h. The mixture was concentrated and diluted with water, then extracted with ethyl acetate. The combined organic layers were treated using 10%–30% ethyl acetate in hexane as the eluent as in step c of Example Intermediate-1 to obtain the title compound (9.0 g, 84.68%). LCMS: 288.0 [M+H] + .

[0943] d) 3-(2-bromo-5-chlorophenyl)-1H-pyrazole (146e)

[0944] To a stirred solution of compound 146d (9.00 g, 31.19 mmol) in EtOH (90.0 mL) was added hydrazine hydrate (2.34 g, 46.78 mmol) at room temperature followed by stirring for 12 h. The mixture was concentrated and diluted with water and extracted with ethyl acetate. The combined organic layer was worked up using 10-15% ethyl acetate in hexane as eluent as in example intermediate-1 step c to get the title compound (8.0 g, 99.61%). LCMS: 257.0 [M+H] + .

[0945] e) 6-(4-Chloro-2-(1H-pyrazol-3-yl)phenyl)isoindolin-1-one (Intermediate-146)

[0946] The compound was prepared according to the procedure described for Intermediate-139 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 310.1 [M+H] + .

[0947] Intermediate-147. 6-(4-Fluoro-2-(oxazol-2-yl)phenyl)isoindolin-1-one

[0948]

[0949] a) 2-(2-Bromo-5-fluorophenyl)oxazole (147b)

[0950] A mixture of 2-bromo-5-fluorobenzamide (7.0 g, 32.00 mmol) and 2-chloroacetaldehyde (3.02 g, 38.53 mmol) in acetic acid (15.0 mL) was heated at 120 °C for 8 h. The mixture was diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was worked up using 50% ethyl acetate in hexane as eluent as in example intermediate-1 step c to get the title compound (0.7 g, 9.01%). LCMS: 244.0 [M+2+H] + 。

[0951] b) 6-(4-Fluoro-2-(oxazol-2-yl)phenyl)isoindolin-1-one (Intermediate-147)

[0952] The compound was prepared according to the procedure described for Intermediate-146 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 295.0 [M+H] + .

[0953] Intermediate-148. 6-(4-Fluoro-2-(4-(methyl-d3)-4H-l,2,4-triazol-3-yl)phenyl)isoindolin- 1-one

[0954]

[0955] a) 2-Bromo-5-fluorobenzohydrazide (148a)

[0956] The compound was prepared according to the procedure described for Intermediate-93b with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 232.9 [M+H] + .

[0957] b) (E)-N'-(2-Bromo-5-fluorobenzoyl)-N,N-dimethylhydrazinecarboxamide (148b)

[0958] To a solution of compound 148a (5.0 g, 21.45 mmol) in DCM (50.0 mL) was added DMF-DMA (10.2 g, 85.82 mmol) followed by stirring at 40 °C for 4 h. The mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to get the crude compound. The crude product was washed with diethyl ether to get the title compound (6.1 g, 98.68 %). LCMS: 290.0 [M+2+H] + .

[0959] c) 3-(2-Bromo-5-fluorophenyl)-4-(methyl-d3)-4H-l,2,4-triazole (148c)

[0960] To a solution of compound 148b (5.0 g, 17.35 mmol) and CD3NH2.HCI (9.79 g, 138.83 mmol) in THF (100.0 mL) was added AcOH (20 ml) and stirred at 80 °C for 12 h. The mixture was cooled to room temperature, quenched with water and extracted with 20% MeOH in DCM. The combined organic layers were worked up using 5% MeOH in DCM as eluent as in Example Intermediate-124, step d to get the title compound (1.9 g, 42.26 %). LCMS: 261.0 [M+2+H] + .

[0961] d) 6-(4-Fluoro-2-(4-(methyl-d3)-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Intermediate-148)

[0962] The compound was prepared according to the procedure described for Intermediate-93 with appropriate variation in the reactants, amount of reagents and solvent. LCMS: 312.1 [M+H] + .

[0963] Intermediate-149. 6-(4-Fluoro-2-(4-methylisoxazol-3-yl)phenyl)isoindolin-1-one

[0964]

[0965] a) (E)-2-Bromo-5-fluorobenzaldehyde oxime (149a)

[0966] To a solution of 2-bromo-5-fluorobenzaldehyde (2.0 g, 9.85 mmol) and NH2OH.HC1 (1.03 g, 14.77 mmol) in EtOH (20 mL) was added NaHC03(0.99 g, 11.82 mmol) in water (10 mL) at 0 °C. The mixture was stirred at room temperature for 12 h. The mixture was concentrated, diluted with brine and extracted with DCM. The combined organic layers were worked up as in Example Intermediate-128, step a to afford the title compound as off-white solid (2.0 g, 93.1%). LCMS: 218.0 [M+H] + .

[0967] b) (Z)-2-Bromo-5-fluoro-N-hydroxybenzimidoyl chloride (149b)

[0968] To a solution of compound 149a (1.6 g, 7.34 mmol) in DMF (20 mL) was added NCS (0.98 g, 7.33 mmol) at 0 °C. The mixture was stirred at 40 °C for 2 h. The mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were worked up as in Example Intermediate-128, step a to afford the title compound as yellow liquid (1.6 g, 86.36%). The crude product was used as such for the next step.

[0969] c) 3-(2-Bromo-5-fluorophenyl)-5-ethoxy-4-methyl-4,5-dihydroisoxazole (149c)

[0970] To a solution of compound 149b (1.6 g, 6.33 mmol) and (E)-1- methoxyprop-1 -ene (1.09 g, 12.67 mmol) in DMF (20 mL) was added sodium bicarbonate (1.06 g, 12.67 mmol) at 0 °C. The mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were worked up as in example Int-128, step a to afford the title compound (1.5 g, 78.36%) as off-white solid. LCMS: 302.0 [M+H] + .

[0971] d) 3-(2-bromo-5-fluorophenyl)-4-methylisoxazole (149d)

[0972] A mixture of compound 149c (1.4 g, 4.63 mmol) and TFA (2.0 mL) was heated at 80 °C for 10 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were worked up using 10-15% ethyl acetate in hexane as eluent as in example Intermediate-1, step c to afford the title compound (1 g, 84.27%) as off-white solid. LCMS: 258.0 [M+2+H] + .

[0973] e) 6-(4-fluoro-2-(4-methylisoxazol-3-yl)phenyl)isoindolin-1-one (Intermediate-149)

[0974] The compound was prepared according to the procedure described for Intermediate-93 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 309.1 [M+H] + .

[0975] Intermediate-150. 6-(4-fluoro-2-(1-methyl-1H-imidazol-2-yl)phenyl)isoindolin-1-one

[0976]

[0977] a) 2-(2-bromo-5-fluorophenyl)-4,5-dihydro-1H-imidazole (150a)

[0978] To a solution of 2-bromo-5-fluorobenzaldehyde (3.0 g, 14.77 mmol) in t-BuOH (10 mL) was added ethylenediamine (0.98 g, 16.25 mmol) followed by stirring at room temperature for 30 min. Then K2CO3 (0.99 g, 11.82 mmol) and I2 (0.99 g, 11.82 mmol) were added followed by stirring at 70 °C for 12 h. The reaction mixture was quenched with saturated aqueous Na2SO3 until the iodine color disappeared and then extracted with ethyl acetate. The combined organic layers were worked up as in example intermediate-128, step a to afford the title compound as a yellow solid (3.50 g, 97.4%), LCMS: 245.0 [M+2+H] + .

[0979] b) 2-(2-bromo-5-fluorophenyl)-1H-imidazole (150b)

[0980] To a solution of compound 150a (2.8 g, 11.58 mmol) in DMSO (20.0 mL) was added K2CO3 (1.07 g, 12.67 mmol) and iodo phenyl diacetate (4.08 g, 12.67 mmol) and stirred at room temperature for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were worked up using 50% ethyl acetate in hexane as eluent as in example intermediate-1, step a to afford the title compound as off white solid (1.0 g, 36%). LCMS: 241.0 [M+H] + .

[0981] c) 2-(2-bromo-5-fluorophenyl)-1-methyl-1H-imidazole (150c)

[0982] To a solution of compound 150b (1.0 g, 4.16 mmol) in THF (10 mL) was added NaH (0.11 g, 4.56 mmol) followed by iodomethane (0.65 g, 4.56 mmol) at 0 °C. The mixture was stirred at room temperature for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were worked up as in example intermediate-128, step a to afford the title compound as a clear liquid. (0.80 g, 75.6%), LCMS: 255.0 [M+H] + .

[0983] d) 6-(4-fluoro-2-(1-methyl-1H-imidazol-2-yl)phenyl)isoindolin-1-one (Intermediate-150)

[0984] The compound was prepared according to the procedure described for Intermediate-93 with appropriate variation in the amount of reactants, reagents and solvent. LCMS: 308.1 [M+H] + .

[0985] Intermediate-151. 1-(2-Bromo-6-methylpyridin-4-yl)-N- (cyclopropylmethyl)methanamine (Procedure A')

[0986]

[0987] a) (2-Bromo-6-methylpyridin-4-yl)methanol (151b)

[0988] To a solution of methyl 2-bromo-6-methylisonicotinate (25 g, 108.67 mmol) in THF (250 mL) was added LiBH4 (217.34 mL, 434.68 mmol, 2 M in THF) dropwise at -78 °C. The mixture was slowly warmed to room temperature and stirred for 4 h. The mixture was cooled to 0 °C, quenched with saturated aqueous ammonium chloride, followed by water (250.0 mL), and extracted with ethyl acetate. The combined organic layers were then worked up as in Example Intermediate-128, step a, to give the title compound (22.0 g). 1 H - NMR (400 MHz, DMSO-d6): 7.34 (d, 1H), 7.22 (d, 1H), 5.51 (t,1H), 4.49 (d, 2H), 2.43 (s, 3H).

[0989] b) 2-Bromo-6-methylisonicotinaldehyde (151c)

[0990] To a solution of compound 151b (22.0 g, 108 mmol) in DCM (200 mL) was added Dess-Martin Oxidizing Reagent (69 g, 163.32 mmol) portion wise at 0 °C. The mixture was slowly warmed to room temperature and stirred for 6 h. The mixture was cooled to 0 °C, quenched with aqueous sodium thiosulfate and aqueous sodium bicarbonate, and extracted with DCM. The combined organic layers were worked up using 10-30% ethyl acetate in hexanes as eluent as in Example Intermediate-1, step c, to give the title compound (18.0 g). 1 H-NMR (400 MHz, DMSO-d6): 10.0 (s, 1H), 7.86 (d, 1H), 7.71 (d,1H), 2.57 (s, 3H).

[0991] c) 1-(2-bromo-6-methylpyridin-4-yl)-N-(cyclopropylmethyl)methanamine (Intermediate-151)

[0992] To a solution of cyclopropylmethylamine (3.73 g, 52.49 mmol) and compound 151c (7.0 g, 34.99 mmol) in DCM (100 mL) was added catalytic amount of acetic acid and stirred for 1 h. STAB (14.83 g, 69.98 mmol) was added at 0 °C and then stirred at room temperature for 12 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were worked up using 60% ethyl acetate in hexane as eluent as in Example Intermediate-1 step c to get the title compound (4.1 g, 46%). LCMS: 255.1 [M+H] + .

[0993] Intermediate-152. 1-(2-bromo-6-methylpyridin-4-yl)-N-(cyclobutylmethyl)methanamine (Procedure B')

[0994]

[0995] To a solution of cyclobutylmethylamine hydrochloride (0.28 g, 2.25 mmol) in DCM (10 mL) was added DIPEA (0.58 mL, 4.50 mmol) and stirred for 30 min. To this mixture was added 2-bromo-6-methylisonicotinaldehyde (0.30 g, 1.50 mmol) at 0 °C followed by STAB (0.64 g, 3.00 mmol) and stirred at room temperature for 12 h. The mixture was quenched with water and extracted with DCM. The combined organic layers were worked up using 0-30% ethyl acetate in hexane as eluent as in Example Intermediate-1 step c to get the title compound (0.33 g, 82%). LCMS: 271.1 [M+2+H] + .

[0996] Intermediate-155. 1-(2,6-dichloropyridin-4-yl)-N-((1-methylcyclobutyl)methyl)methanamine (Procedure C')

[0997]

[0998] a) (2,6-dichloropyridin-4-yl)methanol (155a)

[0999] NaBH4 (1.26 g, 34.09 mmol) was added to a solution of 2,6-dichloroisononial (3.0 g, 17.04 mmol) in MeOH (20 mL) at 0°C and stirred for 1 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were treated with 0%–5% ethyl acetate in hexane as the eluent as in step c of Example Intermediate-1 to give the title compound (2.7 g, 90%). LCMS: 178.0 [M+H] + .

[1000] b) 4-(bromomethyl)-2,6-dichloropyridine (155b)

[1001] Triphenylphosphine (4.77 g, 18.2 mmol) and carbon tetrabromide (6.03 g, 18.2 mmol) were added to a solution of compound 155a (2.7 g, 15.16 mmol) in DCM (30 mL) at 0°C and stirred at room temperature for 3 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were treated with 0%–5% ethyl acetate in hexane as the eluent as in step c of Example Intermediate-1 to give the title compound. LCMS: 242.0 [M+2+H] + .

[1002] c) 1-(2,6-dichloropyridin-4-yl)-N-((1-methylcyclobutyl)methyl)methylamine (intermediate-155)

[1003] K₂CO₃ (0.86 g, 6.22 mmol) was added to a solution of compound 155b (0.6 g, 2.49 mmol) and (1-methylcyclobutyl)hexamethylenetetramine (0.45 g, 2.98 mmol) in MeCN (3 mL), followed by stirring at room temperature for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were treated as in step a of Example Intermediate-128 to give the title compound (0.6 g, 92%). LCMS: 259.9 [M+H] + .

[1004] Intermediate - 156. 4-((2-chloro-6-(trifluoromethyl)pyridin-4-yl)methyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine

[1005]

[1006] a) (2-chloro-6-(trifluoromethyl)pyridin-4-yl)methanol (156b)

[1007] Sodium borohydride (0.36 g, 9.54 mmol) was added fractionally to a solution of 2-chloro-6-(trifluoromethyl)isoniazol (1.0 g, 4.77 mmol) in THF (10 mL) at 0°C. The mixture was slowly warmed to room temperature, followed by stirring for 2 h. The reaction mixture was quenched with an aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were treated with 20%–30% ethyl acetate in hexane as the eluent as in step c of Example Intermediate-1 to give the title compound (0.97 g, 96.08%). LCMS: 212.0 [M+H] + .

[1008] b) (2-Chloro-6-(trifluoromethyl)pyridin-4-yl)methylmethanesulfonate (156c)

[1009] In 0 ° C. A solution of compound 156b (0.35 g, 1.68 mmol) and triethylamine (0.51 g, 5.06 mmol) in DCM (6 mL) was added to a solution of methanesulfonyl chloride (0.26 mL, 3.37 mmol), followed by stirring at room temperature for 1 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were treated as in step a of Example Intermediate-128 to give the title compound (0.6 g) as a crude product, which was used as is in the next step. LCMS: 289.9 [M+H] + .

[1010] c) 4-((2-chloro-6-(trifluoromethyl)pyridin-4-yl)methyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine (intermediate-156)

[1011] Cesium carbonate (0.5 g, 1.82 mmol) was added to a stirred solution of 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine (0.1 g, 0.73 mmol) in THF (5 ml) at 0°C, followed by stirring for 30 min. Compound 156c (0.27 g, 0.87 mmol) was added to the reaction mixture at 0°C, and then stirred at room temperature for 12 h. The reaction mixture was quenched with brine and extracted with ethyl acetate. The combined organic layers were treated with 50% ethyl acetate in hexane as eluent as in step c of Example Intermediate-1 to give the title compound (0.050 g, 20%). LCMS: 332.1 [M+2+H] + .

[1012] Intermediate-157. 2,6-dichloro-4-((4,4-difluoro-3-methylpiperidin-l- yl)methyl)pyridine

[1013]

[1014] a) 1 -benzyl-4,4-difluoro-3-methylpiperidine (157b)

[1015] To a solution of 1 -benzyl-3-methylpiperidin-4-one (1.0 g, 4.918 mmol) in DCM (10 mL) was added (diethylamino)sulfur trifluoride (3.96 g, 24.59 mmol) followed by stirring at room temperature for 16 h. The reaction mixture was quenched by saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to get crude material. The crude was purified by silica gel flash column chromatography using 10-20% ethyl acetate in hexane as eluent to obtain the title product (0.9 g, 81 %). LCMS: 226.1 [M+H] + .

[1016] b) 4,4-difluoro-3-methylpiperidine (157c)

[1017] To a solution of compound 157b (0.9 g, 3.995 mmol) in ethanol (10 ml) was added Pd / C (0.43 g, 0.400 mmol) followed by stirring at room temperature under hydrogen atmosphere for 24 h. The mixture was filtered through a pad of celite and washed with DCM. The filtrate was concentrated to get the title product (0.750 g, 75 %). LCMS: 136.1 [M+H] + .

[1018] c) 2,6-dichloro-4-((4,4-difluoro-3-methylpiperidin-l-yl)methyl)pyridine (Intermediate-157)

[1019] The compound was prepared according to the procedure described for Intermediate 152 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 295.0 [M+H] + .

[1020] Intermediate-158. 2,6-dichloro-4-((3-fluoro-3-methylpyrrolidin-l- yl)methyl)pyridine

[1021]

[1022] a) 3-hydroxy-3-methylpyrrolidine-1 -carboxylic acid tert-butyl ester (158b)

[1023] To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (2 g, 10.81 mmol) in ethyl ether (20 mL) was added methyl magnesium bromide (7.2 mL, 21.59 mmol, 3 M in ethyl ether) drop wise at 0 °C followed by stirring at 0 °C for 2 h. The reaction mixture was quenched by saturated aqueous ammonium chloride and extracted by ethyl acetate. The combined organic layers were worked up using 0-5% ethyl acetate in hexane as eluent as in example intermediate-1 step c to get the title compound (1.4 g, 64%). LCMS: 102.0 [M-100+H] + .

[1024] b) tert-butyl 3-fluoro-4-methylpyrrolidine-1-carboxylate (158c)

[1025] To a solution of compound 158b (1.2 g, 5.96 mmol) in dry DCM was added diethylaminosulfur trifluoride (1.92 g, 11.92 mmol) at 0 °C under argon atmosphere. The mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM. The combined organic layers were worked up using 15-17% ethyl acetate in hexane as eluent as in example intermediate-1 step c to obtain the desired product (0.8 g, 66%).

[1026] c) 3-fluoro-4-methylpyrrolidine (158d)

[1027] To a solution of compound 158c (0.1 g, 0.49 mmol) in DCM (0.3 mL) was added TFA (0.5 mL) at 5 °C followed by stirring at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM. The combined organic layers were worked up as in example intermediate-128 step a to get the title compound as crude (0.08 g) which was used as such in the next step. LCMS: 104.2 [M+H] + .

[1028] d) 2,6-dichloro-4-(3-fluoro-4-methylpyrrolidin-1-yl)pyridine (Intermediate-158)

[1029] The compound was prepared according to the procedure described for Intermediate-152 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 263.0 [M+H] + .

[1030] Intermediate-159. 2,6-dichloro-4-((3-fluoro-4-methylpyrrolidin-1-yl)methyl)pyridine

[1031]

[1032] a) 3-Fluoro-4-methylpyrrolidine (159b)

[1033] To a solution of tert-butyl 3-fluoro-4-methylpyrrolidine-l-carboxylate (1.60 g, 7.87 mmol) (prepared according to WO2014 / 177060) in dioxane (5.0 mL) was added 4 M HC1 in dioxane (15.0 mL) at 0 °C, followed by stirring at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NaHC03solution and extracted with DCM. The combined organic layers were worked up as in Example-Intermediate-128, step a to give the title compound as a crude product (1.10 g) which was used as such in the next step. LCMS: 104.2 [M+H] + .

[1034] b) 2,6-Dichloro-4-((3-fluoro-4-methylpyrrolidin-l-yl)methyl)pyridine (Intermediate-159)

[1035] The compound was prepared according to the procedure described for Intermediate-152 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 263.0 [M+H] + .

[1036] Intermediate-160. l-(6-Chloro-3-fluoro-2-methylpyridin-4-yl)-N- (cyclopropylmethyl)methanamine

[1037]

[1038] a) 2,6-Dichloro-3-fluoroisonicotinaldehyde (45b)

[1039] To a solution of 6-chloro-3-fluoro-2-methylpyridine (5.0 g, 34.35 mmol) in anhydrous THF (100 mL) was added 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (16.65 g, 68.70 mmol) dropwise at 0 °C, followed by stirring at room temperature for 1 h. The mixture was cooled to -78 °C and anhydrous DMF (5.0 mL in 25 mL THF) was added. The mixture was slowly warmed to room temperature and stirred for 16 h. The mixture was cooled to 0 °C, quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined ethyl acetate layers were worked up as in Example-Intermediate- 1, step c using 0-10% ethyl acetate in hexanes as eluent to give the title compound as a liquid (2.70 g, 45.29%). LCMS: 172.2 [M-H]- .

[1040] b) 1-(6-chloro-3-fluoro-2-methylpyridin-4-yl)-N-(cyclopropylmethyl)methanamine (Intermediate-160)

[1041] The compound was prepared according to the procedure described for Intermediate-151 with appropriate changes in the reactants, amount of reagents and solvents. LCMS: 229.1 [M+H] + .

[1042] Intermediate-161. 2,6-dichloro-4-(4-methylpiperidin-2-yl)pyridine

[1043]

[1044] a) 4-methyl-2-oxopiperidine-1-carboxylic acid tert-butyl ester (161b)

[1045] To a solution of 4-methylpiperidin-2-one (5.00 g, 44.19 mmol) and 4-dimethylaminopyridine (5.43 g, 44.18 mmol) in DCM (50.0 mL) was added DIPEA (6.16 mL, 88.37 mmol) and di-tert-butyl dicarbonate (19.5 mL, 88.37 mmol) dropwise at 0 °C followed by stirring at room temperature for 12 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were worked up as in Example Intermediate-1, step c to afford the title compound (8.4 g, 89.14 %). LCMS: 214.1 [M+H] + .

[1046] b) 4-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (161c)

[1047] To a stirred solution of compound 161b (8.4 g, 39.38 mmol) in THF (80.0 mL) was added LDA (5.06 g, 47.26 mmol) dropwise at -78 °C followed by dropwise addition of N-phenyl-bis(trifluoromethylsulfonimide) (16.88 g, 47.26 mmol) in THF (20 mL). The mixture was slowly allowed to warm to room temperature and stirred for 7 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were worked up using 10-20% ethyl acetate in hexanes as eluent as in Example Intermediate-1, step c to afford the title compound (2.5 g, 18.38 %). LCMS: 346.1 [M+H]+ .

[1048] c) tert-Butyl 2',6'-dichloro-4-methyl-5,6-dihydro-[2,4'-bipyridine]- 1 (4H)-carboxylate (161e)

[1049] To a degassed solution of compound 161c (2.3 g, 6.66 mmol), 2,6-dichloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.18 g, 7.99 mmol) and K2CO3 (1.41 g, 13.32 mmol) in dioxane (30.0 mL) and water (10.0 mL) was added Pd(dppf)Cl2 (0.244 g, 0.33 mmol) followed by stirring at 100 °C for 4 h. The mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic layers were worked up using 10% ethyl acetate in hexane as eluent as in Example Intermediate-1 step c to get the title compound (2.0 g, 87.49%). LCMS: 345.1 [M+H] + .

[1050] d) 2',6'-Dichloro-4-methyl-1,4,5,6-tetrahydro-2,4'-bipyridine (161f)

[1051] To a solution of compound 161e (0.81 g, 2.37 mmol) in DCM (10.0 mL) was added TFA (1.08 g, 9.49 mmol) and stirred at room temperature for 2 h. The mixture was concentrated to dryness and the obtained solid was washed with diethyl ether to get the title compound (0.55 g, 95.29%) LCMS: 243.1 [M+H] + .

[1052] e) 2,6-Dichloro-4-(4-methylpiperidin-2-yl)pyridine (Intermediate-161)

[1053] To a solution of compound 161f (0.550 g, 2.26 mmol) in THF (10.0 mL) was added TEA (1.33 g, 13.16 mmol) and sodium cyanoborohydride (0.413 g, 6.58 mmol) followed by stirring at room temperature for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were worked up using 30% ethyl acetate in hexane as eluent as in Example Intermediate-1 step c to get the title compound (0.250 g, 45.08%). LCMS: 245.0 [M+H] + .

[1054] Intermediate-162. l-(2,6-dichloropyridin-4-yl)-N-((5-methyltetrahydrofuran-2- yl)methyl)methanamine

[1055]

[1056] a) (5-methyltetrahydrofuran-2-yl)methanamine (162b)

[1057] To a solution of (5-methylfuran-2-yl)methanamine (0.80 g, 7.19 mmol) in ethyl acetate (30 mL) was added palladium on carbon (0.077 g, 0.720 mmol, 10 wt%) and stirred under hydrogen gas (50 psi) at room temperature for 12 h. The mixture was filtered through a pad of celite. The filtrate was concentrated to afford the title compound (0.60 g, 72%).

[1058] b) l-(2,6-dichloropyridin-4-yl)-N-((5-methyltetrahydrofuran-2-yl)methyl)methanamine (Intermediate-162)

[1059] The compound was prepared according to the procedure described for Intermediate-151 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 275.0 [M+H] + .

[1060] Intermediate-163. 2-(2-chloro-6-methylpyridin-4-yl)-N-(cyclopropylmethyl)propan-2- amine

[1061]

[1062] a) 2-(2-chloro-6-methylpyridin-4-yl)propan-2-amine (163b)

[1063] To a solution of 2-chloro-6-methylisonicotinonitrile (0.3 g, 1.62 mmol) in diethyl ether (10 mL) was added methylmagnesium bromide (0.73 g, 6.55 mmol) dropwise at 0 °C followed by Ti(OiPr)4(1.86, 6.55 mmol) dropwise followed by stirring for 1 h. The mixture was heated at 60 °C for 12 h. The reaction mixture was quenched by saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were worked up using 0-5% ethyl acetate in hexanes as eluent as in Example Intermediate-1, step c to afford the title compound (0.3 g, 49.57%) LCMS: 185.1 [M+H] + .

[1064] b) 2-(2-chloro-6-methylpyridin-4-yl)-N-(cyclopropylmethyl)propan-2-amine (Intermediate-163)

[1065] To a solution of compound 163b (0.3 g, 1.62 mmol) in MeOH (50 mL) was added cyclopropanecarboxaldehyde (0.34 g, 4.87 mmol) and stirred at room temperature for 3 h. NaBH4(0.037 g, 0.970 mmol) was added at 0 °C followed by stirring at room temperature for 16 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layer was worked up using 15-20% ethyl acetate in hexane as eluent as in example intermediate-1 step c to get the title compound (0.3 g, 77.32%). LCMS: 239.1 [M+H] + .

[1066] Intermediate-164. N-(cyclopropylmethyl)-2-(2,6-dichloropyridin-4-yl)propan-2-amine

[1067]

[1068] a) 2-(2,6-dichloropyridin-4-yl)propan-2-amine

[1069] The compound was prepared according to the procedure described for Intermediate-163b with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 205.1 [M+H] + .

[1070] b) N-(cyclopropylmethyl)-2-(2,6-dichloropyridin-4-yl)propan-2-amine (Intermediate-164)

[1071] The compound was prepared according to the procedure described for Intermediate-163 with appropriate changes in the amount of reactants, reagents and solvents. LC-MS: 259.1 [M+H] + .

[1072] Intermediate-165. 1-(6-chloro-2-methylpyrimidin-4-yl)-N-(cyclopropylmethyl)methanamine

[1073]

[1074] a) 4-chloro-2-methyl-6-vinylpyrimidine (165b)

[1075] To a degassed solution of 4,6-dichloro-2-methylpyrimidine (10.00 g, 61.35 mmol), potassium trifluoro(vinyl)borate (4.10 g, 30.67 mmol), and sodium carbonate (9.75 g, 92.02 mmol) in 1,4-dioxane (45.0 mL) and water (30.0 mL) was added bis(triphenylphosphine)palladium(II) chloride (2.50 g, 3.06 mmol) followed by stirring at 70 °C for 2 h. The mixture was cooled to room temperature, filtered through a pad of celite and washed with ethyl acetate. The filtrate was concentrated, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and purified by silica gel flash column chromatography using 8-10% ethyl acetate in hexanes as eluent to give the title compound (1.50 g, 15%) as a colorless liquid. LCMS: 155.1 [M+H] + .

[1076] b) 6-Chloro-2-methylpyrimidine-4-carbaldehyde (165c)

[1077] To a solution of compound 165b (1.50 g, 9.70 mmol) and sodium periodate (3.87 g, 18.11 mmol) in THF (20.0 mL) and water (10.0 mL) was added osmium tetroxide (0.069 mL, 0.27 mmol, 4 wt-% in H2O) dropwise at 0 °C. The mixture was slowly warmed to room temperature and stirred for 4 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography using 8-9% ethyl acetate in hexanes as eluent to give the title compound (0.60 g, 39%) as a liquid. LCMS: 157.0 [M+H] + .

[1078] c) -(6-Chloro-2-methylpyrimidin-4-yl)-N-(cyclopropylmethyl)methanamine (Intermediate-165)

[1079] The compound was prepared according to the procedure described for Intermediate-151 with appropriate changes in the amount of reactants, reagents, and solvents. LCMS: 212.1 [M+H] + .

[1080] Intermediate-166. 4-((2,6-Dichloropyridin-4-yl)methyl)hexahydro-2H-furo[3,2-b]pyrrole

[1081]

[1082] a) Hexahydro-2H-furo[3,2-b]pyrrole (166b)

[1083] To a solution of hexahydro-2H-furo[3,2-b]pyrrole-5-carboxylic acid (0.45 g, 2.86 mmol) (prepared according to WO 2022 / 217276) in cyclohexanol (4 mL) was added 4'-methylacetophenone (0.04 g, 0.28 mmol) followed by stirring at 160 °C for 4 h. The mixture was diluted with ethyl acetate and extracted with 1 N HC1. The combined aqueous layer was concentrated to get brown oil. The crude mixture was washed with diethyl ether and dried to get the title compound as HC1 salt (0.22 g, 50%) as brown oil. LCMS: 114.1 [M+H] + .

[1084] b) 4-((2,6-Dichloropyridin-4-yl)methyl)hexahydro-2H-furo[3,2-b]pyrrole (Intermediate-166)

[1085] The compound was prepared according to the procedure described for Intermediate-152 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 273.0 [M+H] + .

[1086] Intermediate 167 and 168. N-((2-Bromo-6-methylpyridin-4-yl)methyl)-2- methylpropane-2-sulfmamide (Int-167) and N-((2-bromo-6-methylpyridin-4- yl)methyl)methanesulfonamide (Int-168)

[1087]

[1088] a) (E)-N-((2-Bromo-6-methylpyridin-4-yl)methylene)-2-methylpropane-2- sulfmamide (167a)

[1089] To a solution of 2-bromo-6-methylisonicotinaldehyde (1.0 g, 4.99 mmol) and 2-methylpropane-2-sulfmamide (0.636 g, 5.25 mmol) in DCM (30.0 mL) was added titanium ethoxide (2.28 g, 9.99 mmol) at 0 °C followed by stirring at room temperature for 12 h. The reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to get the title compound (0.54 g, 35.7%) as off white solid; LCMS: 303.0 [M+H] + .

[1090] b) N-((2-bromo-6-methylpyridin-4-yl)methyl)-2-methylpropane-2- sulfinamide (Intermediate-167)

[1091] To a solution of compound 167a (0.4 g, 1.32 mmol) in MeOH (4.0 mL) was added sodium borohydride (0.1 g, 2.63 mmol) at 0 °C followed by stirring at room temperature for 4 h. The reaction mixture was quenched with 1 N HCI and extracted with ethyl acetate. The combined organic layers were worked up as in Example Intermediate-128, step a to afford the title compound as off-white solid (0.54 g, 35.7%); LCMS: 305.0 [M+H] + .

[1092] c) (2-bromo-6-methylpyridin-4-yl)methanamine (167b)

[1093] To a solution of Intermediate-167 (0.4 g, 1.31 mmol) in 1,4-dioxane was added 4 N HCI in 1,4-dioxane (2 mL) at 0 °C followed by stirring at room temperature for 6 h. The mixture was concentrated and triturated with diethyl ether to afford the title compound (0.20 g) as a white solid which was used as such in the next step.

[1094] d) N-((2-bromo-6-methylpyridin-4-yl)methyl)methanesulfonamide (Intermediate-168)

[1095] To a solution of compound 167b (0.3 g, 1.49 mmol) and triethylamine (0.45 g, 4.47 mmol) in DCM (5 mL) was added MsCI (0.21 g, 1.79 mmol) followed by stirring at room temperature for 12 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 20% ethyl acetate in hexanes as an eluent to afford the title compound (0.40 g, 96%) as a liquid. LCMS: 279.0 [M+H] + .

[1096] The following intermediates were prepared according to the procedures described for Intermediate-151 (Procedure A’), Intermediate 152 (Procedure B’), Intermediates 103, 104 and 155 (Procedure C’) with variations in appropriate starting materials, amounts of reactants, reagents, coupling methods and solvents. Characterization data of the compounds are also summarized in the table.

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103]

[1104]

[1105]

[1106] Intermediate-248. 6-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-chlorophenyl)- isoindolin-1-one

[1107]

[1108] a) (E)-2-(2-(2-bromo-5-chlorobenzylidene)hydrazinyl)pyridine (248b)

[1109] To a solution of 2-bromo-5-chlorobenzaldehyde (5 g, 22.78 mmol) and 2- hydrazinylpyridine (2.74 g, 25.06 mmol) in MeOH (30 mL) was added AcOH (0.08 g, 1.38) followed by stirring at room temperature for 16 h. The precipitated solid was filtered, triturated with MeOH and dried to obtain the title compound (6.8 g). LCMS: 310.0 [M+H] + .

[1110] b) 3-(2-bromo-5-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridine (248c)

[1111] To a solution of compound 248b (6 g, 19.32 mmol) in DCM (20 mL) was added [bis(trifluoroacetoxy)iodo]benzene (9.15 g, 21.27 mmol) at 0 °C. The mixture was slowly warmed to room temperature and stirred for 16 h. The mixture was concentrated and purified by silica gel flash column chromatography using 65% ethyl acetate in hexane as eluent to obtain the title compound (2.2 g, 37%). LCMS: 307.9 [M+H] + .

[1112] c) 6-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-chlorophenyl)isoindolin-1-one (Intermediate-248)

[1113] The compound was prepared according to the procedure described for Intermediate-93 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 361.1 [M+H] + .

[1114] Intermediate-249. 3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one

[1115]

[1116] a) (E)-3-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)but-2-enoic acid ethyl ester (249c)

[1117] To a degassed solution of 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (4.5 g, 21.12 mmol) (prepared according to WO2021 / 143927), triethylamine (3.21 g, 31.68 mmol) and (E)-but-2-enoic acid ethyl ester (7.23 g, 63.37 mmol) in DMF (50 ml) was added palladium acetate (0.24 g, 1.05 mmol) and tris(2-methylphenyl)phosphine (0.64 g, 2.11 mmol) followed by stirring at 90 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were worked up using 5% MeOH in DCM as eluent as in Example Intermediate-124, step d to get the title compound (3.5 g, 67.3%). LCMS: 245.0 [M-H] - .

[1118] b) 3-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)butanoic acid ethyl ester (249d)

[1119] The compound was prepared according to the procedure described for Intermediate-127c with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 249.1 [M+H] + .

[1120] c) 3-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)butyric hydrazide (249e)

[1121] The compound was prepared according to the procedure described for Intermediate-1f with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 235.1 [M+H] + .

[1122] d) N-methyl-2-(3-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)butanoyl)hydrazine-1- carbothioamide (249f)

[1123] The compound was prepared according to the procedure described for Intermediate-1g with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 308.1 [M+H] + .

[1124] e) 3-(1-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one (249g)

[1125] The compound was prepared according to the procedure described for Intermediate-1h with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 290.1 [M+H] + .

[1126] f) 3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5- one (Intermediate-249)

[1127] The compound was prepared according to the procedure described for Intermediate-1 (last step) with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 258.1 [M+H] + .

[1128] Example 1. (S)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)isoindolin-1-one (Compound 1)

[1129]

[1130] Condition A: To 6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)-methyl)oxetan-3-yl)isoindolin- 1-one (0.10 g, 0.35 mmol), (S)-l-(3-bromo-5-(trifluoromethyl)benzyl)-3-methylpiperidine (0.142 g, 0.42 mmol), cesium carbonate (0.23 g, 0.70 mmol), potassium iodide (0.12 g, 0.70 mmol) and N,N 1 - To a degassed solution of dimethyl ethylenediamine (40.0 μL, 0.35 mmol) in DMF (4.0 mL) was added copper(I) iodide (6.67 mg, 0.035 mmol) followed by stirring at 90 °C for 16 h. The mixture was cooled to room temperature, filtered through a pad of celite followed by washing the celite pad with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude was purified by silica gel preparative thin layer chromatography (TLC) using 5% MeOH in DCM as eluent to afford the title compound as off-white solid (0.025 g, 13%). LCMS: 540.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ: 8.25 (brs, 2H), 8.05 (s, 1H), 7.58 (d, 1H), 7.50(s, 1H), 7.43 (s, 1H), 7.33 (d, 1H), 5.06 (s, 2H), 4.97 (d, 2H), 4.90 (d,2H), 3.58 (s, 2H), 3.55 (s, 2H), 3.02 (s, 3H), 2.80 - 2.70 (m, 2H), 1.95 -1.89 (m, 1H), 1.73 - 1.45 (m, 5H), 0.95 - 0.85 (m, 1H), 0.83 (d, 3H).

[1131] Example 2. ((S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((3- methylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-l-one (Compound 2)

[1132]

[1133] Condition B: To a degassed solution of (S)-2-chloro-4-((3-methylpiperidin-l- yl)methyl)-6-(trifluoromethyl)pyridine (0.10 g, 0.34 mmol), 6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (0.10 g, 0.34 mmol), dicesium carbonate (0.33 g, 1.03 mmol) and Xantphos (0.04 g, 0.07 mmol) in DMSO (1.0 ml) was added Pd(OAc)2(0.008 g, 0.030 mmol) and heated at 100 °C for 1 h. The mixture was cooled to room temperature, passed through a bed of celite, followed by washing the celite pad with 10% methanol in DCM. The filtrate was diluted with water and extracted with 10% methanol in DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative TLC using 7% methanol in DCM as eluent to get the title compound (0.0198 g, 10.71%); LCMS: 542.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ: 8.81 (s, 1H),8.20 (s, 1H), 7.64 (dd, 1H), 7.60 (d, 1H), 7.50 (d, 1H), 7.27 (dd, 1H), 5.16(s, 2H), 5.13 (d, 2H), 5.09 (d, 2H), 3.70 (s, 2H), 3.67 (s, 2H), 2.96 (s,3H), 2.90 - 2.80 (m, 2H), 2.10 - 2.05 (m, 1H), 1.76 - 1.69 (m, 5H), 1.00 -0.90 (m, 1H), 0.90 (d, 3H).

[1134] The following compounds were prepared according to the procedure described for Compound 1 (= Condition A) and Compound 2 (= Condition B) with appropriate changes in the reactants, amount of reagents, coupling method and solvent. The characterization data of the compounds are summarized in the table.

[1135]

[1136]

[1137]

[1138]

[1139]

[1140]

[1141]

[1142]

[1143]

[1144]

[1145]

[1146]

[1147]

[1148]

[1149]

[1150]

[1151]

[1152]

[1153]

[1154]

[1155]

[1156]

[1157]

[1158]

[1159] Example 3. 2-(4-(lH-pyrazol-4-yl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 95)

[1160]

[1161] a) 2-chloro-4-(lH-pyrazol-4-yl)-6-(trifluoromethyl)pyridine (95c)

[1162] To a degassed solution of 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (1.0 g, 3.25 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-tert-butyl carboxylate (1.05 g, 3.57 mmol) and sodium carbonate (0.86 g, 8.13 mmol) in 1,4 dioxane (20 mL) and water (5 mL) was added Pd(dppf)Cl2*DCM (0.265 g, 0.325 mmol) followed by stirring at 80 °C for 4 h. The mixture was cooled to room temperature and filtered through a pad of celite followed by washing the celite pad with ethyl acetate and the filtrate was concentrated. The crude product was purified by silica gel flash column chromatography to get the title compound (0.5 g, 62.08 %). LCMS: 248.2 [M+H] + .

[1163] b) 2-chloro-6-(trifluoromethyl)-4-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4- yl)pyridine (95d)

[1164] To a solution of 2-chloro-4-(lH-pyrazol-4-yl)-6-(trifluoromethyl)pyridine (0.4 g, 1.62 mmol) and N,N-diisopropylethylamine (0.41 g, 2.42 mmol) in DCM (8 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (0.42 mL, 2.42 mmol) at 0 °C followed by stirring at room temperature for 4 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to get the title compound. (0.4 g, 65.55 %). LCMS: 278.2 [M+H] + .

[1165] c) 6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(6-(trifluoromethyl)-4-(l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)pyridin-2-yl)isoindolin-l-one (95e)

[1166] The compound was prepared according to the procedure described in example 2 with appropriate changes in the coupling method, amount of reactants, reagents and solvents. LCMS: 626.7 [M+H] + .

[1167] d) 2-(4-(1H-Pyrazol-4-yl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 95)

[1168] To a solution of 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(6- (trifluoromethyl)-4-(1 -(2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-4-yl)isoindolin- 1 -one (0.05 g, 0.08 mmol) in DCM (5 mL) was added TFA followed by stirring at room temperature for 12 h. The mixture was concentrated and purified by silica gel flash column chromatography using 10% methanol in chloroform as eluent to afford the title compound (0.033 g, 83.26%); LCMS: 496.05 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ 13.37(s, 1H), 8.92 (d, 1H), 8.60. (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 7.93 (d,1H), 7.67 (d, 1H), 7.52 (d, 1H), 7.40 (dd, 1H), 5.09 (s, 2H), 4.99 (d, 2H),4.92 (d, 2H), 3.58 (s, 2H), 3.03 (s, 3H).

[1169] Example 4. (R)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((3- methylpiperazin-1 -yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-1 -one (Compound 96) and (R)-2-(4-((3,4-dimethylpiperazin-1 -yl)methyl)-6- (trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan- 3-yl)isoindolin-1 -one (Compound 97)

[1170]

[1171] a) (R)-2-methyl-4-((2-(6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-l- oxoisoindolin-2-yl)-6-(trifluoromethyl)pyridin-4-yl)methyl)piperazine-l-carboxylic acid tert-butyl ester (96a)

[1172] The compound was prepared according to the procedure described in example 2 with appropriate changes in the coupling method, amount of reactants, reagents and solvents. LCMS: 642.2 [M+H] + .

[1173] b) (R)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((3-methylpiperazin- 1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-l-one (Compound 96)

[1174] To a solution of (R)-2-methyl-4-((2-(6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan- 3-yl)-l-oxoisoindolin-2-yl)-6-(trifluoromethyl)pyridin-4-yl)methyl)piperazine-l-carboxylic acid tert-butyl ester (0.23 g, 0.35 mmol) in DCM (2 mL) at 0 °C was added TFA (0.5 mL). The mixture was slowly warmed to room temperature and stirred for 1 h. The mixture was concentrated, basified with aqueous bicarbonate solution and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel preparative TLC to afford the title compound (0.19 g, 98%). LCMS: 542.2 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ 8.79 (s, 1H), 8.22 (s,1H), 7.66(d, 1H), 7.58 (s, 1H), 7.53 (d, 1H), 7.38 (dd, 1H), 5.07 (s, 2H), 4.98 (d,2H), 4.91 (d, 2H), 3.63 (s, 2H), 3.58 (s, 2H), 3.03 (s, 3H), 2.85 - 2.81 (m,1H), 2.78 - 2.72 (m, 2H), 2.71 - 2.63 (m, 2H), 2.01 - 1.98 (m, 1H), 1.68 (t,1H), 0.92 (d, 3H).

[1175] c) (R)-2-(4-((3,4-dimethylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetane-3-yl)isoindoline-1-one (Compound 97)

[1176] A solution of (R)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetane-3-yl)-2-(4-(((3-methylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindoline-1-one (0.1 g, 0.18 mmol) in MeOH (3 mL) was added with formic acid (0.03 g, 0.74 mmol) and formaldehyde (0.05 g, 1.85 mmol), followed by stirring at 70°C for 6 h. The mixture was cooled to room temperature, concentrated, alkalized with aqueous bicarbonate solution, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative TLC on silica gel using 7% MeOH in DCM to give the title compound (0.018 g, 17.51%). LCMS: 556.2 [M+H]+. 1 H NMR (DMSO-d6, 400 MHz): δ 8.80 (s, 1H), 8.22 (s, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 7.54 (d, 1H), 7.38 (dd, 1H), 5.07 (s, 2H), 4.98 (d, 2H), 4.91 (d, 2H), 3.70 -3.61 (m, 2H), 3.57 (s, 2H), 3.03 (s, 3H), 2.69 - 2.66 (m, 3H), 2.22 - 2.18(m, 5H), 2.02 - 1.98 (m, 1H), 1.89 (t, 1H), 0.95 (d, 3H).

[1177] Example 5. 2-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetane-3-yl)isoindoline-1-one (Compound 98)

[1178]

[1179] a) (2R,6S)-2,6-Dimethyl-4-((2-(6-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)-1-oxoisoindolin-2-yl)-6-(trifluoromethyl)pyridin-4- yl)methyl)piperazin-1-yl)acetic acid tert-butyl ester (98a)

[1180] The compound was prepared according to the procedure described in example 2 with appropriate changes in coupling method, amount of reactants, reagents and solvents. LCMS: 656.2 [M+H] + .

[1181] b) 2-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)-6- (trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan- 3-yl)isoindolin-1-one (Compound 98)

[1182] The compound was prepared according to the procedure described in example 4 with appropriate changes in coupling method, amount of reactants, reagents and solvents. LCMS: 556.2 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ 8.78 (s, 1H), 8.22 (s,1H), 7.66 (d, 1H), 7.57 (s, 1H), 7.53 (d, 1H), 7.38 (dd, 1H), 5.07 (s, 2H),4.98 (d, 2H), 4.91 (d, 2H), 3.63 (s, 2H), 3.58 (s, 2H), 3.03 (s, 3H), 2.88 -2.75 (m, 2H), 2.72 - 2.62 (m, 2H), 1.61 (t, 2H), 0.92 (d, 6H).

[1183] Example 6. 2-(4-(13-amino-5,8,11-trioxa-2-azatridecyl)-6-chloropyridin-2-yl)-6-(3- ((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 99)

[1184]

[1185] a) (1-(2,6-dichloropyridin-4-yl)-5,8,11-trioxa-2-azatridec-13-yl)carbamic acid tert-butyl ester (99b)

[1186] To a solution of tert-butyl (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)carbamate (0.40 g, 1.37 mmol) and 2,6-dichloroisonicotinaldehyde (0.60 g, 3.42 mmol) in DCM (4.0 mL) was added acetic acid (0.1 mL) at 0 °C. The mixture was warmed to room temperature and then stirred for 12 h. Then STAB (0.58 g, 2.73 mmol) was added to the mixture followed by stirring for 6 h. The mixture was diluted with aqueous sodium bicarbonate and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 0-20% methanol in DCM as eluent to give the title compound (0.390 g, 63.02%). LCMS: 454.0 [M+H] + .

[1187] b) tert-Butyl (1-(2-chloro-6-(6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-1- oxoisoindolin-2-yl)pyridin-4-yl)-5,8,11-trioxa-2-azatridecan-13-yl)carbamate (99c)

[1188] To a degassed solution of tert-butyl (1-(2,6-dichloropyridin-4-yl)-5,8,11-trioxa-2- azatridecan-13-yl)carbamate (0.33 g, 0.73 mmol), 6-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)isoindolin-1-one (0.21 g, 0.73 mmol), Cs2CO3 (0.71 g, 2.18 mmol) and Xantphos (0.084 g, 0.140 mmol) in DMSO (3.3 mL) was added Pd(OAc)2 (0.016 g, 0.07 mmol) followed by stirring at 80 °C for 1 h. The mixture was cooled to room temperature and passed through a bed of celite which was washed with 10% methanol in DCM. The filtrate was diluted with water and extracted with 10% methanol in DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 0-20% methanol in DCM as eluent to give the title compound (0.135 g, 26.45%). LCMS: 701.3 [M+H] + .

[1189] c) 2-(4-(13-amino-5,8,11-trioxa-2-azatridecyl)-6-chloropyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 99)

[1190] To a solution of tert-butyl (l-(2-chloro-6-(6-(3-((4-methyl-4H-l,2,4-triazol-3- yl)methyl)oxetan-3-yl)-l-oxoisoindolin-2-yl)pyridin-4-yl)-5,8,11-trioxa-2- azatridec-13-yl)carbamate (0.065 g, 0.093 mmol) in DCM (2.0 mL) at 0 °C was added trifluoroacetic acid (0.11 g, 0.93 mmol). The mixture was slowly warmed to room temperature then stirred for 4 h. The mixture was concentrated and triturated with diethyl ether. The crude mixture was dissolved in 10% MeOH in DCM and added carbonic bicarbonate anion exchange resin then stirred at room temperature for 12 h. The resin was filtered, concentrated and purified by preparative HPLC to give the title compound (0.019 g, yield: 34.04%). LCMS: 600.15 [M+H] + . 1 H NMR ((400 MHz, DMSO): δ 8.47 (d, 1H), 8.30 (s, 2H), 8.22(s, 1H), 7.63 (d, 1H), 7.49 (d, 1H), 7.40 (dd, 1H), 7.26 (d, 1H), 5.03 (s,2H), 4.98 (d, 2H), 4.91 (d, 2H), 3.82 (s, 2H), 3.58 - 3.54 (m, 9H), 3.51 (t,3H), 3.04 (s, 3H), 2.90 (t, 2H), 2.68 - 2.66 (m, 2H).

[1191] Example 7. 2-(3-(l-hydroxy-2-(isopropylamino)ethyl)-5-(trifluoromethyl)phenyl)-6-(3- ((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 100)

[1192]

[1193] a) 3-(trifluoromethyl)-5-vinylaniline [100b]

[1194] To a degassed solution of 3-bromo-5-(trifluoromethyl)aniline (15.0 g, 62.49 mmol), vinylpotassium trifluoroborate (7.88 g, 187.48 mmol) and Cs2CO3(50.90 g, 156.23 mmol) in 1,4-dioxane (100 mL) and water (20 mL) was added Pd(dppf)Cl 2* DCM, followed by stirring at 100 °C for 6 h. The mixture was cooled to room temperature, quenched with water and extracted with DCM. The organic layer was then dried over sodium sulfate, filtered and concentrated to get the crude product. The crude product was purified by silica gel flash column chromatography using 10-20% ethyl acetate in hexane as eluent to get the title compound (8.0 g, 68.40%) LCMS: 188.0 [M+H] + .

[1195] b) 1 -Bromo-3-(trifluoromethyl)-5-vinylbenzene [100c]

[1196] To a solution of 3-(trifluoromethyl)-5-vinylaniline (0.5 g, 2.67 mmol) and copper bromide (0.60 g, 2.67 mmol) in acetonitrile (8 mL) was added tert-butylnitrite at 0 °C followed by stirring for 30 min. The mixture was filtered through celite and the filtrate was concentrated to get the crude product. The crude product was purified by silica gel flash column chromatography using 5-20% ethyl acetate in hexane as eluent to get the title compound (0.2 g, 29.83%). 1 H NMR ((400 MHz, DMSO): δ 8.06 (s, 1H), 7.87 (s, 1H), 7.85 (s, 1H), 6.79 (dd, 1H), 6.09 (d, 1H), 5.43 (d, 1H).

[1197] c) 2-(3-Bromo-5-(trifluoromethyl)phenyl)oxirane [100d]

[1198] To a solution of l-bromo-3-(trifluoromethyl)-5-vinylbenzene (0.25 g, 1.0 mmol) in DCM (2 mL) was added meta-chloroperoxybenzoic acid (MCPBA) (0.26 g, 1.4 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 16 h. The mixture was quenched by saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to get the crude product. The crude product was purified by silica gel flash column chromatography using 10-30% ethyl acetate in hexane as eluent to get the title compound (0.170 g, 63.92%).1 H NMR ((400 MHz, DMSO): δ 7.92(s, 1H), 7.82 (s, 1H), 7.69 (s, 1H), 4.12 - 4.10 (m, 1H), 3.19 - 3.16 (m,1H), 2.99 - 2.96 (m, 1H).

[1199] e) 1-(3-bromo-5-(trifluoromethyl)phenyl)-2-(isopropylamino)ethane-1-ol [100e]

[1200] Isopropylamine (0.022 g, 0.37 mmol) was added to a solution of 2-(3-bromo-5-(trifluoromethyl)phenyl)ethylene oxide (0.10 g, 0.37 mmol) in methanol (2 mL), followed by stirring at 80°C for 1 h. The mixture was concentrated to give the title compound (0.095 g, 77.88%). LC-MS: 328.0 [M+2+H] + .

[1201] f) 2-(3-(1-hydroxy-2-(isopropylamino)ethyl)-5-(trifluoromethyl)phenyl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetane-3-yl)isoindoline-1-one (Compound 100)

[1202] The compound was prepared according to the procedure described in Example 2, with appropriate variations in the coupling method, reactants, reagent amounts, and solvent. LCMS: 530.2 [M+H] + . 1 ¹H NMR (400 MHz, CD3OD): δ 8.67 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.67 - 7.64 (m, 2H), 7.54 (s, 1H), 7.39 (dd, 1H), 5.07 - 5.14 (m, 7H), 3.80 (s, 2H), 3.54 - 3.47 (m, 1H), 3.37 - 3.35 (m, 2H), 3.25 - 3.15 (m, 1H), 3.17 (s, 3H), 1.40 (t, 6H, two peaks partially overlap).

[1203] Example 8. 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)isoindoline-1-one (Compound 101)

[1204]

[1205] To a degassed solution of 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3- yl)phenyl)isoindolin-l-one (0.30 g, 0.92 mmol), l-(2-chloro-6-methylpyridin-4-yl)-N- (cyclopropylmethyl)methanamine (0.234 g, 1.11 mmol), Cs2CO3(0.90 g, 2.77 mmol) and XantPhos (0.08 g, 0.14 mmol) in DMSO (3.0 mL) was added Pd(OAc)2(0.02 g, 0.09 mmol) followed by stirring at 100 °C for 6 h. The mixture was cooled to rt, filtered through a pad of celite and washed with 10% MeOH in DCM. The filtrate was washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel flash column chromatography using 8% MeOH in DCM as eluent to afford the title compound as off-white solid (0.024 g). LCMS: 499.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.44 (s,1H), 8.31 (s, 1H), 7.79 (dd, 1H), 7.72 - 7.70 (m, 2H), 7.65 (d, 1H), 7.52 (d,1H), 7.39 (dd, 1H), 7.04 (s, 1H), 5.09 (s, 2H), 3.76 (s, 2H), 3.12 (s, 3H),2.45 (s, 3H), 2.39 (d, 2H), 0.92 - 0.86 (m, 1H), 0.43 - 0.38 (m, 2H), 0.13 - 0.09 (m, 2H).

[1206] Example 9. 6-(4-Chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4- (((cyclopropylmethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 102)

[1207]

[1208] To a degassed solution of 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3- yl)phenyl)isoindolin-l-one (0.30 g, 0.94 mmol), l-cyclopropyl-N-((2,6-dichloropyridin- 4-yl)methyl)methanamine (0.28 g, 1.20 mmol), Cs2CO3(0.90 g, 2.78 mmol) and Xantphos (0.05 g, 0.09 mmol) in dioxane (5 ml) was added Pd2(dba)3(0.08 g, 0.09 mmol) followed by stirring at 90 °C for 6 h. The mixture was cooled to rt, filtered through a pad of celite and washed with 10% MeOH in DCM. The filtrate was washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel flash column chromatography using 8% MeOH in DCM as eluent to afford the title compound (0.03 g) as off-white solid. LCMS: 519.2 [M+H] + .

[1209] Example 10. 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(l-((cyclopropylmethyl)amino)ethyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 103)

[1210]

[1211] To a degassed solution of 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3- yl)phenyl)isoindolin-l-one (0.30 g, 0.92 mmol), l-(2-chloro-6-methylpyridin-4-yl)-N- (cyclopropylmethyl)ethan-l-amine (0.31 g, 1.38 mmol), Cs2CO3(0.90 g, 2.77 mmol) and DavePhos (0.07 g, 0.18 mmol) in DMSO (6.0 mL) was added Pd(OAc)2(0.02 g, 0.09 mmol) followed by stirring at 100 °C for 2 h. The mixture was cooled to rt, filtered through a pad of celite and washed with DCM. The filtrate was washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel flash column chromatography using 5% MeOH in DCM as eluent to afford the title compound as off-white solid. The mixture was further purified by preparative TLC using 5% methanol in dichloromethane as eluent to afford the title compound (0.05 g, 10.63%). LCMS: 513.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.44 (s,1H), 8.30 (s, 1H), 7.80 (dd, 1H), 7.72 - 7.70 (m, 2H), 7.66 (dd, 1H), 7.51(d, 1H), 7.40 (dd, 1H), 7.05 (s, 1H), 5.08 (s, 2H), 3.75 (q, 1H), 3.11 (s,3H), 2.45 (s, 3H), 2.27 - 2.17 (m, 2H), 1.26 (d, 3H), 0.90 - 0.82 (m, 1H),0.41 - 0.32 (m, 2H), 0.07 - 0.03 (m, 2H)..

[1212] The following examples were prepared according to the procedure described for Example 8 (Reaction Condition A’), Example 9 (Reaction Condition B’), or Example 10 (Reaction Condition C’), with appropriate changes in the amount of reactants, reagents, coupling method, and solvent. Characterization data for the compounds are also summarized in the table.

[1213]

[1214]

[1215]

[1216]

[1217]

[1218]

[1219]

[1220] Example 11. 2-(4-((2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methyl)-6- (trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin- 1-one (Compound 128)

[1221]

[1222] To a degassed solution of 4-((2-chloro-6-(trifluoromethyl)pyridin-4-yl)methyl)-2- methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine (0.1 g, 0.30 mmol), 6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (0.103 g, 0.36 mmol), Cs2CO3(0.25 g, 0.75 mmol) and Xantphos (0.03 g, 0.06 mmol) in DMSO (5.0 ml) was added Pd(OAc)2(0.014 g, 0.06 mmol) and heated at 100 °C for 1 h. The mixture was cooled to room temperature, passed through a bed of celite, followed by washing the celite pad with 10% methanol in DCM. The filtrate was diluted with water and extracted with 10% methanol in DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative TLC using 7% methanol in DCM as eluent to get the title compound (0.035 g, 20%). LCMS: 579.4 [M+H] + . 1 HNMR (400 MHz, DMSO-d6): δ 8.81 (s, 1H), 8.61 (bs, 1H), 7.68 (d, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.43 (dd, 1H), 6.93 (s, 1H), 5.08 (s, 2H), 4.95 (d, 2H), 4.92 (d, 2H), 4.22 (s, 2H), 3.67 (s, 2H), 3.48 (s, 3H), 3.15 (s, 3H), 2.94 - 2.90 (m, 2H), 2.60 - 2.56 (m, 2H), 1.97 - 1.95 (m, 2H).

[1223] Example 12. 2-(6-chloro-4-((((2-methylthiazol-4-yl)methyl)amino)methyl)pyridin-2-yl)-6- (3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 129)

[1224]

[1225] To a degassed solution of 6-(3-((4-methyl-4H-l,2,4-triazol-3- yl)methyl)oxetan-3-yl)isoindolin-l-one (0.2 g, 0.70 mmol), l-(2,6-dichloropyridin-4- yl)-N-((2-methylthiazol-4-yl)methyl)methanamine (0.24 g, 0.84 mmol), Cs2CO3(0.69 g, 2.10 mmol) and Xantphos (0.041 g, 0.07 mmol) in dioxane (5.0 ml) was added Pd(OAc)2(0.016 g, 0.07 mmol) and heated at 90 °C for 2 h. The mixture was cooled to rt, passed through a bed of celite, followed by washing the celite pad with 10% methanol in DCM. The filtrate was diluted with water and extracted with 10% methanol in DCM. The combined organic layer was worked up as in example 11 to get the title compound (0.006 g, 15%); LCMS: 536.1 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 8.21 (s,1H), 7.62 (d, 1H), 7.50 (s, 1H), 7.37 (dd, 1H), 7.28 (d, 1H), 7.27 (s, 1H),5.03 (s, 2H), 4.97 (d, 2H), 4.91 (d, 2H), 3.84 (s, 2H), 3.76 (s, 2H), 3.57(s, 2H), 3.02 (s, 3H), 2.63 (s, 3H)。

[1226] Example 13: 2-(6-chloro-4-((((l-fluorocyclopropyl)methyl)amino)methyl)pyridin-2-yl)-6- (3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 130)

[1227]

[1228] To a degassed solution of 6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (0.15 g, 0.53 mmol), l-(2,6-dichloropyridin-4-yl)-N-((l-fluorocyclopropyl)methyl)methanamine (0.16 g, 0.63 mmol), Cs2CO3(0.34 g, 1.05 mmol) and Xantphos (0.06 g, 0.10 mmol) in dioxane (5.0 ml) was added Pd2(dba)3(0.05 g, 0.05 mmol) and heated at 90 °C for 2 h. The mixture was cooled to rt, passed through a bed of celite, followed by washing the celite pad with 10% methanol in DCM. The filtrate was diluted with water and extracted with 10% methanol in DCM. The combined organic layers were worked up using 5% methanol in DCM as eluent as in Example 11 to give the title compound (0.02 g, 7.62%). LCMS: 497.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d6): δ 8.49 (s, 1H), 8.21 (s, 1H), 7.62 (dd, 1H), 7.51 (s, 1H), 7.36 (dd, 1H), 7.28(s, 1H), 5.05 (s, 2H), 4.97 (d, 2H), 4.92 (d, 2H), 3.89 (s, 2H), 3.57 (s,2H), 3.03 (s, 3H), 2.90 (d, 2H), 2.65 - 2.58 (m, 1H), 0.90 - 1.01 (m, 2H),0.71 - 0.65 (m, 2H).

[1229] Example 14. 2-(6-chloro-4-(((l-cyclopropylethyl)amino)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 131)

[1230]

[1231] To a degassed solution of 6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin- 1-one (0.20 g, 0.70 mmol), l-cyclopropyl-N-((2,6-dichloropyridin-4-yl)methyl)ethan-l-amine (0.224 g, 0.91 mmol), Cs2CO3(0.46 g, 1.40 mmol) and DavePhos (0.055 g, 0.14 mmol) in DMSO (2.0 ml) was added Pd(OAc)2(0.016 g, 0.07 mmol) and heated at 90 °C for 2 h. The mixture was cooled to rt, passed through a bed of celite, followed by washing the celite pad with 10% methanol in DCM. The filtrate was diluted with water and extracted with 10% methanol in DCM. The combined organic layer was worked up using 5% methanol in DCM as eluent as in Example 11 to give the title compound (0.075 g, 22%). LCMS: 493.15 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ 8.50 (s, 1H), 8.21 (s, 1H), 7.62 (d, 1H), 7.51 (s, 1H), 7.36 (dd, 1H), 7.29(d, 1H), 5.02 (s, 2H), 4.97 (d, 2H), 4.91 (d, 2H), 3.88 (s, 2H), 3.57 (s,2H), 3.03 (s, 3H), 1.92 - 1.85 (m, 1H), 1.09 (d, 3H), 0.70 - 0.65 (m, 1H),0.49 - 0.42 (m, 1H), 0.40 - 0.30 (m, 1H), 0.29 - 0.19 (m, 1H).

[1232] Example 15. 6-(4-Chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((cyclopropylmethyl)amino)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-l-one (Compound 132)

[1233]

[1234] To a degassed solution of 1-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-N- (cyclopropylmethyl)methanamine (0.21 g, 0.80 mmol), 6-(4-chloro-2-(4-methyl-4H- 1,2,4-triazol-3-yl)phenyl)isoindolin-1-one (0.20 g, 0.62 mmol), Cs2CO3(0.50 g, 1.54 mmol) and Xantphos (0.07 g, 0.12 mmol) in DMSO (2.0 ml) was added Pd(OAc)2(0.014 g, 0.06 mmol) and heated at 80 °C for 1 h. The mixture was cooled to room temperature, passed through a bed of celite, followed by washing the celite pad with 10% methanol in DCM. The filtrate was diluted with water and extracted with 9% methanol in DCM. The combined organic layer was worked up as in Example 11 to give the title compound (0.053 g, 16%). LC-MS: 553.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ 8.78 (s, 1H), 8.45 (s, 1H), 7.8(dd, 1H), 7.26-7.66 (m, 4H), 7.55 (d, 1H), 7.43 (dd, 1H), 5.11 (s, 2H), 3.90(s, 2H), 3.13 (s, 3H), 2.41 (s, 2H), 0.92-0.87 (m, 1H), 0.44-0.39 (m, 2H),0.14-0.10 (m, 2H).

[1235] Example 16. 2-(6-(((Cyclopropylmethyl)amino)methyl)-2-methylpyrimidin-4-yl)-6-(4- fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1-one (Compound 133)

[1236]

[1237] To a degassed solution of 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3- yl)phenyl)isoindolin-l-one (0.15 g, 0.49 mmol), l-(6-chloro-2-methylpyrimidin-4-yl)- N-(cyclopropylmethyl)methanamine (0.13 g, 0.63 mmol), Cs2CO3(0.48 g, 1.46 mmol) and Xantphos (0.014 g, 0.02 mmol) in dioxane (3.0 ml) was added Pd(OAc)2(0.003 g, 0.01 mmol) and heated at 65 °C for 4 h. The mixture was cooled to rt, passed through a bed of celite, followed by washing the celite pad with 10% methanol in DCM. The filtrate was diluted with water and extracted with 10% methanol in DCM. The combined organic layers were worked up using 8% methanol in DCM as eluent as in Example 11 to give the title compound (0.06 g, 25%). LC-MS: 484.30 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ 8.45 (s,1H), 8.41 (s, 1H), 7.75 - 7.71 (m, 1H), 7.69 (d, 1H), 7.61 - 7.50 (m, 3H),7.43 (dd, 1H), 5.07 (s, 2H), 3.79 (s, 2H), 3.16 (s, 3H), 2.67 (s, 3H), 2.44(d, 2H), 0.95 - 0.90 (m, 1H), 0.44 - 0.40 (m, 2H), 0.15 - 0.13 (m, 2H).

[1238] Example 17. 2-(4-(((Cyclobutylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 134)

[1239]

[1240] To a degassed solution of 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3- yl)phenyl)isoindolin-l-one (0.15 g, 0.49 mmol), l-(2-bromo-6-methylpyridin-4-yl)-N- (cyclobutylmethyl)methanamine (0.17 g, 0.63 mmol), Cs2CO3(0.48 g, 1.46 mmol) and Xantphos (0.014 g, 0.02 mmol) in dioxane (5.0 ml) was added Pd2(dba)3(0.022 g, 0.02 mmol) and heated at 60 °C for 6 h. The mixture was cooled to rt, passed through a bed of celite, followed by washing the celite pad with 10% methanol in DCM. The filtrate was diluted with water and extracted with 10% methanol in DCM. The combined organic layer was worked up using 5% methanol in DCM as eluent as in Example 11 to give the title compound (0.08 g, 33%). LCMS: 497.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H),8.30 (s, 1H), 7.72 (dd, 1H), 7.64 (d, 1H), 7.62 -7.55 (m, 1H), 7.54 - 7.48(m, 2H), 7.38 (dd, 1H), 7.03 (s, 1H), 5.08 (s, 2H), 3.71 (s, 2H), 3.13 (s,3H), 2.54 - 2.51 (m, 2H), 2.45 (s, 3H), 2.45 -2.38 (m, 1H), 2.05 - 1.95 (m,2H), 1.90 -1.78 (m, 2H), 1.73 -1.59 (m, 2H).

[1241] Example 18. 6-(4-Chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(l- ((cyclopropylmethyl)amino)ethyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 135)

[1242]

[1243] To a degassed solution of 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3- yl)phenyl)isoindolin-l-one (0.30 g, 0.92 mmol), l-(2-chloro-6-methylpyridin-4-yl)-N- (cyclopropylmethyl)ethan-l -amine (0.31 g, 1.34 mmol), Cs2C03(0.90 g, 2.77 mmol) and DavePhos (0.073 g, 0.18 mmol) in DMSO (6.0 ml) was added Pd(OAc)2(0.021 g, 0.09 mmol) and heated at 100 °C for 2 h. The mixture was cooled to room temperature, passed through a bed of celite, followed by washing the celite pad with 10% methanol in DCM. The filtrate was diluted with water and extracted with 10% methanol in DCM. The combined organic layer was worked up using 5% methanol in DCM as eluent as in Example 11 to give the title compound (0.05 g, 12%). LCMS: 513.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H),8.30 (s, 1H), 7.80 (dd, 1H), 7.72 - 7.70 (m, 2H), 7.66 (d, 1H), 7.50 (d, 1H),7.40 (dd, 1H), 7.05 (s, 1H), 5.08 (s, 2H), 3.75 (q, 1H), 3.11 (s, 3H), 2.45(s, 3H), 2.28 - 2.18 (m, 2H), 1.26 (d, 3H), 0.88 - 0.80 (m, 1H), 0.40 - 0.32(m, 2H), 0.08 - 0.02 (m, 2H).

[1244] Example 19. 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(hydroxymethyl)- 6-methylpyridin-2-yl)isoindolin-l-one (Compound 136)

[1245]

[1246] To a degassed solution of 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3- yl)phenyl)isoindolin-l-one (3.00 g, 9.73 mmol), (2-bromo-6-methylpyridin-4- yl)methanol (2.36 g, 11.68 mmol) and Cs2CO3(9.51 g, 29.19 mmol) in 1,4- dioxane (60.0 mL) was added Xantphos-Pd-G3 (0.93 g, 0.97 mmol) and stirred at 100 °C for 6 h. The mixture was cooled to rt, filtered through a pad of celite, followed by washing with 10% MeOH in DCM. The filtrate was washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel flash column chromatography using 6% MeOH in DCM as eluent to give the title compound as off-white solid (3.00 g, 72%). LCMS: 430.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ 8.45 (s, 1H), 8.32 (s, 1H), 7.73(dd, 1H), 7.64 (d, 1H), 7.58 (dt, 1H), 7.55 - 7.50 (m, 2H), 7.38 (dd, 1H),7.00 (s, 1H), 5.46 (t, 1H), 5.09 (s, 2H), 4.55 (d, 2H), 3.15 (s, 3H), 2.46(s, 3H).

[1247] Example 20: 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-((((l- methoxycyclopropyl)methyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 137)

[1248]

[1249] a) 2-(4-(chloromethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4- triazol-3-yl)phenyl)isoindolin-l-one (Compound 137a)

[1250] To a solution of 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4- (hydroxymethyl)-6-methylpyridin-2-yl)isoindolin-l-one (2.40 g, 5.58 mmol) in DCM (20.0 mL) was added thionyl chloride (1.60 mL, 21.80 mmol) at 0 °C and then stirred at room temperature for 16 h. The mixture was concentrated, diluted with saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 4% MeOH in DCM as eluent to afford the title compound (2.1 g, 83.91 %). LCMS: 448.1 [M+H] + .

[1251] b) 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-((((l- methoxycyclopropyl)methyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 137)

[1252] To a solution of Compound 137a (0.070 g, 0.15 mmol) and (l-methoxycyclopropyl)methanamine hydrochloride (0.032 g, 0.234 mmol) in acetonitrile was added K2CO3(0.108 g, 0.78 mmol) and the mixture was stirred at room temperature for 12 h. The mixture was diluted with water and extracted with 10% methanol in DCM. The combined organic layers were worked up as in Example 11 using 5% MeOH in DCM as eluent to afford the title compound as off-white solid (0.020 g, 25.01 %). LCMS: 513.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.33 (s,1H), 7.73 (dd, 1H), 7.64 (d, 1H), 7.58 (td, 1H), 7.55 - 7.48 (m, 2H), 7.38(dd, 1H), 7.05 (s, 1H), 5.08 (s, 2H), 3.81 (s, 2H), 3.22 (s, 3H), 3.14 (s,3H), 2.68 (s, 2H), 2.46 (s, 3H), 0.68 - 0.64 (m, 2H), 0.52 - 0.48 (m, 2H).

[1253] The following compounds were prepared according to the procedures described for Examples 11 and 15 (= Condition A"), Examples 12 and 16 (= Condition B"), Examples 13 and 17 (= Condition C"), Examples 14 and 18 (= Condition D"), and Example 20 (= Condition E) with appropriate variations in the reactants, amount of reagents, coupling method, and solvent. Characterization data for the compounds are summarized in the table.

[1254]

[1255]

[1256]

[1257]

[1258]

[1259]

[1260]

[1261]

[1262]

[1263]

[1264]

[1265]

[1266]

[1267]

[1268]

[1269]

[1270]

[1271]

[1272]

[1273]

[1274]

[1275]

[1276]

[1277]

[1278]

[1279]

[1280]

[1281]

[1282]

[1283]

[1284]

[1285]

[1286]

[1287]

[1288]

[1289]

[1290]

[1291]

[1292]

[1293]

[1294]

[1295]

[1296]

[1297]

[1298]

[1299]

[1300]

[1301]

[1302]

[1303]

[1304]

[1305]

[1306]

[1307]

[1308] Example 21. 2-(4-(Aminomethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-1,2,4- triazol-3-yl)phenyl)isoindolin-1-one (Compound 331)

[1309]

[1310] To a solution of N-((2-(6-(4-fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-1- oxisoindolin-2-yl)-6-methylpyridin-4-yl)methyl)-2-methylpropane-2-sulfmamide (0.29 g, 0.54 mmol) in 1,4-dioxane was added 4 N HC1 in 1,4-dioxane (0.54 mL, 2.16 mmol) at 0 °C, followed by stirring at room temperature for 2 h. The mixture was concentrated and purified by preparative HPLC using water and acetonitrile as eluents to afford the title compound (0.060 g, 25.74%) as a white solid; LCMS: 429.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.29 (s, 1H), 7.73 (dd, 1H), 7.64 (d, 1H), 7.58 (td,1H), 7.54 - 7.50 (m, 2H), 7.39 (dd, 1H), 7.06 (s, 1H), 5.08 (s, 2H), 3.76 (s,2H), 3.15 (s, 3H), 2.45 (s, 3H).

[1311] Example 22. 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(l-(l- methyl-lH-pyrazol-4-yl)vinyl)pyridin-2-yl)isoindolin-l-one (Compound 332) and 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(l-(l-methyl-lH- pyrazol-4-yl)ethyl)pyridin-2-yl)isoindolin-l-one (Compound 333)

[1312]

[1313] a) 4-(l-Bromo vinyl)-l-methyl-lH-pyrazole (332b)

[1314] To a solution of l-(l-methyl-lH-pyrazol-4-yl)ethan-l-one (5.0 g, 40.28 mmol) in DCM (100.0 mL) was added triethylamine (8.5 mL, 61.09 mmol) and triphenyl phosphite (12.5 g, 40.27 mmol) at -78 °C followed by dropwise addition of bromine (3.86 g, 48.33 mmol). The solution was stirred at room temperature for 12 h. The reaction was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated and purified by silica gel column chromatography on silica using 20-40% ethyl acetate in hexanes as eluent to afford the title compound (2.0 g, 26.55%). LCMS: 187.0 [M+H] + .

[1315] b) 2-Chloro-6-methyl-4-(l-(l-methyl-lH-pyrazol-4-yl)vinyl)pyridine (332c)

[1316] To a degassed solution of 2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (2.0 g, 7.89 mmol), compound 332b (1.92 g, 10.26 mmol) and K2CO3(3.27 g, 23.66 mmol) in dioxane (20.0 mL) and water (5.0 mL) was added Pd(amphos)Cl2(0.56 g, 0.78 mmol) followed by stirring at 80 °C for 6 h. The mixture was filtered through a bed of celite followed by washing with ethyl acetate. The filtrate was extracted with water. The combined organic layer was dried over sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 20-40% ethyl acetate in hexane as eluent to obtain the desired product (1.6 g, 86.78%). LCMS: 234.1 [M+H] + .

[1317] c) 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(l-(l-methyl- lH-pyrazol-4-yl)vinyl)pyridin-2-yl)isoindolin-l-one (Compound 332)

[1318] Compound was prepared according to the procedure described for Example-17 with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 506.2 [M+H] + . 1 H-NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 8.02 (s, 1H),7.93 (d, 1H), 7.62 - 7.58 (m, 2H), 7.43 - 7.38 (m, 4H), 7.29 (dd, 1H), 7.00(s, 1H), 5.56 (s, 1H), 5.40 (s, 1H), 5.16 (s, 2H), 3.94 (s, 3H), 3.02 (s,3H), 2.55 (s, 3H).

[1319] d) 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(l-(l-methyl- lH-pyrazol-4-yl)ethyl)pyridin-2-yl)isoindolin-l-one (Compound 333)

[1320] To a solution of compound 332 (0.07 g, 0.138 mmol) in EtOH (2 mL) was added Pd-carbon (10 wt%) (0.029 g, 0.27 mmol) followed by stirring the mixture under hydrogen at room temperature for 3 h. The mixture was filtered through a bed of celite followed by washing with EtOH. The filtrate was concentrated and triturated with pentane to afford the title compound as a white solid (0.055 g, 78.5%). LCMS: 508.2 [M+H] + . 1 H-NMR (400 MHz, CDCl3): δ 8.38 (s, 1H), 8.01 (s,1H), 7.92 (s, 1H), 7.61 (dd, 1H), 7.42 - 7.35 (m, 4H), 7.27 (dd, 1H), 7.20(s, 1H), 6.80 (s, 1H), 5.12 (s, 2H), 4.07 (q, 1H), 3.88 (s, 3H), 3.00 (s,3H), 2.49 (s, 3H), 1.63 (d, 3H).

[1321] Example 23. 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(l-(l- methyl-lH-imidazol-2-yl)ethyl)pyridin-2-yl)isoindolin-l-one (Compound 334)

[1322]

[1323] a) 2-(l-Bromoethenyl)-l-methyl-lH-imidazole (334b)

[1324] The compound was prepared according to the procedure described for compound 332b with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 187.0 [M+H] + .

[1325] b) 2-Chloro-6-methyl-4-(l-(l-methyl-lH-imidazol-2-yl)ethenyl)pyridine (334c)

[1326] The compound was prepared according to the procedure described for compound 332c with appropriate changes in the amount of reactants, reagents and solvents. LCMS: 234.1 [M+H] + .

[1327] c) 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(l-(l- methyl-lH-imidazol-2-yl)vinyl)pyridin-2-yl)isoindolin-l-one (334d)

[1328] Compound was prepared according to the procedure described for compound 332 with appropriate changes in reactants, amounts of reagents and solvents. LCMS: 506.2 [M+H]+. + .

[1329] d) 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(l-(l- methyl-lH-imidazol-2-yl)ethyl)pyridin-2-yl)isoindolin-l-one (Compound 334)

[1330] Compound was prepared according to the procedure described for compound 333 with appropriate changes in reactants, amounts of reagents and solvents. LCMS: 508.2 [M+H]+.1H-NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.19 (s, 1H), 7.72 (dd, 1H), 7.64 (d, 1H), 7.59 (td, 1H), 7.52 (dd, 1H), 7.47 (d, 1H), 7.40 (dd, 1H), 7.05 (d, 1H), 6.86 (d, 1H), 6.85 (d, 1H), 5.06 (s, 2H), 4.34 (q, 1H), 3.43 (s, 3H), 3.13 (s, 3H), 2.42 (s, 3H), 1.59 (d, 3H).

[1331] Example 24. (Z)-2-(6-Chloro-4-((l-methylpiperidin-3-ylidene)methyl)pyridin-2-yl)-6-(3- ((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 335)

[1332]

[1333] a) ((2,6-Dichloropyridin-4-yl)methyl)diethyl phosphonate (335a)

[1334] To compound 4-(bromomethyl)-2,6-dichloropyridine (2.0 g, 8.30 mmol) was added triethyl phosphite (12 mL) followed by heating to 80 °C for 12 h. After 12 h, the mixture was concentrated to get the title compound as crude (2.4 g) which was used as such for the next step. LCMS: 298.0 [M+H] + .

[1335] b) (Z)-3-((2,6-dichloropyridin-4-yl)methylene)piperidine-1-carboxylic acid tert-butyl ester (335b)

[1336] To a solution of diisopropylamine (1.07 g, 10.60 mmol) in dry THF was added n-butyllithium (0.67 g, 10.60 mmol) at -78 °C followed by stirring for 1 h. The resulting light yellow solution was added to compound 335a (1.89 g, 6.36 mmol) in dry THF followed by stirring for 1 h. Then tert-butyl 3-oxopiperidine-1-carboxylate (0.84 g, 4.24 mmol) was added to the mixture followed by stirring for 3 h. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 10-30% ethyl acetate in hexanes as eluent to get the title compound (1.0 g, 68.69%). LCMS: 343.1 [M+H] +

[1337] c) (Z)-3-((2-chloro-6-(6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-1-oxoisoindolin-2-yl)pyridin-4-yl)methylene)piperidine-1-carboxylic acid tert-butyl ester (335c)

[1338] To a degassed solution of compound 335b (0.19 g, 0.56 mmol), 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (016 g, 0.56 mmol), cesium carbonate (0.36 g, 1.12 mmol) and Xantphos (0.06 g, 0.11 mmol) in DMSO (4.0 ml) was added Pd(OAc)2(0.01 g, 0.05 mmol) followed by heating at 90 °C for 3 h. The mixture was cooled to room temperature, passed through a bed of celite followed by washing the celite pad with 10% methanol in DCM. The filtrate was diluted with water and extracted with 10% methanol in DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 8% MeOH in DCM as eluent to get the title compound (0.15 g, 45.07%). LCMS: 591.4 [M+H] + .

[1339] d) (Z)-2-(6-chloro-4-(piperidin-3-ylidenemethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (335d)

[1340] To a stirred solution of compound 335c (0.13 g, 0.22 mmol) in DCM (1.7 ml) was added TFA (0.3 ml) followed by stirring at room temperature for 1 h. The mixture was concentrated, basified with saturated aqueous sodium bicarbonate solution and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to get the title compound as crude (0.11 g) which was used as such for the next step. LCMS: 491.3 [M+H] + .

[1341] e) (Z)-2-(6-chloro-4-((1 -methylpiperidin-3-ylidene)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 335)

[1342] To a solution of compound 335d (0.10 g, 0.20 mmol) and formaldehyde (0.06 g, 2.04 mmol) in MeOH was added formic acid (0.03 g, 0.81 mmol) and heated at 70 °C for 6 h. The mixture was concentrated, basified with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative TLC method using 8% MeOH-DCM as eluent to get the title compound (0.029 g, 2.81%). LCMS: 505.20 [M+H] + . 1 HNMR (400 MHz, DMSO-d6): δ 8.37 (d, 1H), 8.21 (s, 1H),7.62 (d, 1H), 7.49 ( s, 1H), 7.36 (dd, 1H), 7.13 (s, 1H), 5.58 (s, 1H), 5.02(s, 2H), 4.98 (d, 2H), 4.90 (d, 2H), 3.57 (s, 2H), 3.34 (s, 2H), 3.01 (s,3H), 2.70 - 2.65 (m, 3H), 2.38 - 2.35 (m, 2H), 2.12 (bm, 2H), 2.01 - 1.99 (m,2H).

[1343] Example 25. 2-(6-methyl-4-((pyrrolidin-2-ylmethyl)amino)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 336)

[1344]

[1345] a) tert-Butyl 2-formylpyrrolidine-l-carboxylate (336b)

[1346] To a stirred suspension of oxalyl chloride (15.76 g, 124.21 mmol) and 3A° molecular sieves in DCM (125.0 mL) was added DMSO (19.40 g, 248.42 mmol) in DCM (25.0 ml) at -78 °C. tert-Butyl 2-(hydroxymethyl)pyrrolidine-1 -carboxylate (5.0 g, 24.84 mmol) in DCM (75.0 mL) was added dropwise followed by stirring for 30 min. Triethylamine (37.70 g, 372.6 mmol) was added dropwise to the mixture followed by stirring for 1 h at -78 °C. The mixture was slowly warmed to room temperature and stirred for 12 h. The reaction mixture was quenched by saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 10-20% ethyl acetate in hexanes as eluent to afford the title compound (4.0 g, 80%). LCMS: 144 [M-56 H] + .

[1347] b) tert-Butyl 2-(((2-bromo-6-methylpyridin-4-yl)amino)methyl)pyrrolidine-1- carboxylate (336c)

[1348] To a solution of 2-bromo-6-methylpyridin-4-amine (1.10 g, 5.88 mmol) and compound 336b (2.92 g, 14.7 mmol) in DCM (50.0 mL) was added acetic acid (0.5 ml) followed by stirring at room temperature for 12 h. STAB (3.11 g, 14.71 mmol) was added to the mixture followed by stirring at room temperature for 16 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were worked up as in the previous step using 15-20% ethyl acetate in hexanes as eluent to afford the title compound (1.0 g, 45.92%). LCMS: 372.1 [M+H] + .

[1349] c) tert-Butyl 2-(((2-methyl-6-(6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-1- oxoisoindolin-2-yl)pyridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (336d)

[1350] Compound was prepared according to the procedure described for compound 128 with appropriate changes in the amounts of reactants, reagents. LCMS: 574.3 [M+H] + .

[1351] e) 2-(6-methyl-4-((pyrrolidin-2-ylmethyl)amino)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 336)

[1352] To a solution of compound 336d (0.04 g, 0.49 mmol) in DCM (1.35 ml) was added TFA (0.45 ml) at 5 °C followed by stirring at room temperature for 16 h. The mixture was concentrated and purified by passing through bicarbonate resin using 5% water in ACN (5.0 ml) as eluent to get the title compound (0.009 g, 24.36%). LCMS: 474.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d6): δ 8.21(s, 1H), 7.60 - 7.57 (m, 2H), 7.42 (d,1H), 7.29 (dd, 1H), 6.55 (t, 1H), 6.25 (d, 1H), 4.98 - 4.96 (m, 4H), 4.90 (d,2H), 3.56 (s, 2H), 3.25 - 3.18 (m, 1H), 3.05 - 2.97( m, 5H), 2.84 - 2.73 (m,2H), 2.27 (s, 3H), 1.85 - 1.75 (m, 1H), 1.75 - 1.58 (m, 2H), 1.40 - 1.30 (m,1H).

[1353] Example 26. 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methyl-5- (trifluoromethyl)pyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3- yl)phenyl)isoindolin-l-one (Compound 337)

[1354]

[1355] a) Methyl 6-chloro-3-iodo-2-methylisonicotinate (337b)

[1356] To a solution of methyl 3-amino-6-chloro-2-methylisonicotinate (3.0 g, 14.95 mmol) (prepared according to WO 2008 / 130021) in acetonitrile (12.5 mL) was added potassium iodide (12.41 g, 74.77 mmol), tert-butylnitrite (7.71 g, 74.77 mmol) and copper iodide (3.41 g, 17.94 mmol) followed by heating at 80 °C for 12 h. The mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated and purified by silica gel flash column chromatography using 0-10% ethyl acetate in hexane as eluent to obtain the title compound (1.7 g, 36.50%). LCMS: 311.9 [M+H] + .

[1357] b) Methyl 6-chloro-2-methyl-3-(trifluoromethyl)isonicotinate (337c)

[1358] To a solution of compound 337b (0.60 g, 1.92 mmol) in DMF (3.0 mL) was added copper(I) iodide (0.55 g, 2.88 mmol) and methyl 2,2-difluoro-2-fluorosulfonylacetate (0.55 g, 2.88 mmol) followed by stirring at 70 °C for 12 h. The reaction mixture was quenched with brine and extracted with hexane. The combined organic layers were dried over sodium sulfate, filtered, concentrated to get crude (0.45 g) which was used as such in the next step. LCMS: 254.0 [M+H] + .

[1359] c) (6-Chloro-2-methyl-3-(trifluoromethyl)pyridin-4-yl)methanol (337d)

[1360] The compound was prepared according to the procedure described for intermediate-151b with appropriate changes in the amount of reactants, reagents. LCMS: 226.0 [M+H] + .

[1361] d) 6-(4-Fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(hydroxymethyl)-6- methyl-5-(trifluoromethyl)pyridin-2-yl)isoindolin-1-one (337e)

[1362] The compound was prepared according to the procedure described for compound 136 with appropriate changes in the amount of reactants, reagents. LCMS: 498.1 [M+H] + .

[1363] e) 2-(4-(chloromethyl)-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (337f)

[1364] Compound was prepared according to the procedure described for compound 137a with appropriate changes in the amount of reactants, reagents. LCMS: 516.1 [M+H] + .

[1365] f) 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 337)

[1366] Compound was prepared according to the procedure described for compound 137 with appropriate changes in the amount of reactants, reagents. LCMS: 551.0 [M+H] + . 1 H-NMR (400 MHz, DMSO): δ 8.85 (s, 1H), 8.45 (s, 1H), 7.74(dd, 1H), 7.67 (d, 1H), 7.61 - 7.50 (m, 3H), 7.42 (dd, 1H), 5.12 (s, 2H),3.93 (s, 2H), 3.17 (s, 3H), 2.68 - 2.61 (m, 3H), 2.44 (d, 2H), 0.98 - 0.90(m, 1H), 0.45 - 0.40 (m, 2H), 0.20 - 0.12 (m, 2H).

[1367] Example 27. 2-(4-(((l-cyclopropyl-3-hydroxy-3-methylbutyl)amino)methyl)-6- methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l- one (Compound 338)

[1368]

[1369] a) (E)-N-(cyclopropylmethylidene)-2-methylpropane-2-sulfmamide (338b)

[1370] To a solution of cyclopropanecarboxaldehyde (5.0 g, 71.33 mmol) in THF (100.0 mL) was added 2-methyl-2-propanesulfmide (8.64 g, 71.33 mmol) followed by heating to 40 °C for 14 h. The reaction mixture was quenched with brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography using 5-10% ethyl acetate in hexanes as eluent to give the title compound (2.0 g, 16.18%). LCMS: 174.1 [M+H] + .

[1371] b) 3-((tert-Butylsulfinyl)amino)-3-cyclopropylpropanoic acid ethyl ester (338c)

[1372] To a stirred suspension of activated zinc (12.83 g, 196.22 mmol) in anhydrous THF (17.0 ml) under argon atmosphere was added copper(l) chloride (1.94 g, 19.62 mmol) followed by heating at 50 °C for 30 min. The resulting mixture was cooled to 0 °C. Ethyl 2-bromoacetate (3.27 g, 19.62 mmol) was added dropwise followed by heating the mixture at 50 °C for 30 min. The mixture was cooled to 0 °C and compound 338b in THF (8.0 mL) was added followed by stirring at room temperature for 14 h. The mixture was filtered through a pad of celite, washing with ethyl acetate. The organic layer was washed with 0.25 M aqueous citric acid and 1 M aqueous sodium bicarbonate. The combined organic layers were worked up as in the previous step using 0-50% ethyl acetate in hexanes as eluent to give the title compound (1.7 g, 66.29%). LCMS: 262.2 [M+H] + .

[1373] c) N-(l-cyclopropyl-3-hydroxy-3-methylbutyl)-2-methylpropane-2-sulfmide (338d)

[1374] To a solution of compound 338c (1.5 g, 5.74 mmol) in anhydrous THF (20.0 mL) at room temperature was added methylmagnesium bromide (3.0 M in diethyl ether, 19.13 mL, 57.39 mmol) followed by stirring for 14 h. The reaction mixture was quenched at 0 °C by saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were worked up as in the previous step using 40-50% ethyl acetate in hexanes as eluent to give the title compound (0.60 g, 42.27%). LCMS: 248.2 [M+H] + .

[1375] d) 4-amino-4-cyclopropyl-2-methylbutan-2-ol (338e)

[1376] To a solution of compound 338d (0.54 g, 2.18 mmol) in MeOH (1.35 mL) was added 4 M HC1 in 14-dioxane (0.54 ml, 2.16 mmol) at 0 °C, followed by stirring at room temperature for 30 min. The mixture was concentrated, neutralized by saturated NaHC03solution, and extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a solid. The solid was triturated with diethyl ether to give the title compound (0.33 g) which was used as such in the next step. LCMS: 144.2 [M+H] + .

[1377] f) 2-(4-(((1-cyclopropyl-3-hydroxy-3-methylbutyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1-one (Compound 338)

[1378] Compound was prepared according to the procedure described for Compound 137 with appropriate changes in the amounts of reactants, reagents. LCMS: 555.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ 8.45 (s, 1H), 8.30 (s, 1H),7.73 (dd, 1H), 7.64 (d, 1H), 7.59 (td, 1H), 7.54 - 7.50 (m, 2H), 7.39 (dd,1H), 7.04 (s, 1H), 5.09 (s, 2H), 4.03 (d, 1H), 3.80 (d, 1H), 3.15 (s, 3H),2.46 (s, 3H), 2.11 - 2.04 (m, 1H), 1.65 (dd, 1H), 1.55 (dd, 1H), 1.11 (s,3H), 1.07 (s, 3H), 0.80 - 0.70 (m, 1H), 0.62 - 0.55 (m, 1H), 0.43 - 0.31 (m,2H), -0.066 - -0.012 (m, 1H).

[1379] Example 28. 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4- (((piperidin-2-ylmethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 339)

[1380]

[1381] a) 2-((((2-(6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin-2- yl)-6-methylpyridin-4-yl)methyl)amino)methyl)piperidine-l -carboxylate (339a)

[1382] Compound was prepared according to the procedure described for Compound 137 with appropriate changes in the amount of reactants, reagents. LCMS: 626.20 [M+H] + .

[1383] b) 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(((piperidin-2- ylmethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 339)

[1384] Compound was prepared according to the procedure described for Compound 336 with appropriate changes in the amount of reactants, reagents. LCMS: 526.20 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.30 (s, 1H),7.73 (dd, 1H), 7.64 (d, 1H), 7.58 (dt, 1H), 7.54 - 7.49 (m, 2H), 7.39 (dd,1H), 7.05 (s, 1H), 5.08 (s, 2H), 3.71 (s, 2H), 3.16 (s, 3H), 2.99 - 2.94 m,1H), 2.60 - 2.53 (m, 2H), 2.46 (brs, 4H), 2.42 - 2.36 (m, 1H), 1.74 - 1.68(m, 1H), 1.60 - 1.48 (m, 2H), 1.33 - 1.23 (m, 2H), 1.08 - 0.95 (m, 1H).

[1385] Example 29. 2-(6-chloro-4-((methyl(3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-6- (3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 340)

[1386]

[1387] a) 2-(6-chloro-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (340a)

[1388] Compound was prepared according to the procedure described for Compound 128 with appropriate changes in the amount of reactants, reagents. LCMS: 521.1 [M+H] + .

[1389] b) 2-(6-chloro-4-((methyl(3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 340)

[1390] Compound was prepared according to the procedure described for Compound 335 with appropriate changes in the amount of reactants, reagents. LCMS: 535.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d6): δ 8.47 (d, 1H), 8.21 (s, 1H), 7.62(d, 1H), 7.51 (d, 1H), 7.37 (dd, 1H), 7.22 (d, 1H), 5.03 (s, 2H), 4.98 (d,2H), 4.91 (d, 2H), 3.63 (s, 2H), 3.57 (s, 2H), 3.02 (s, 3H), 2.68 - 2.63 (m,2H), 2.58 - 2.54 (m, 2H), 2.21 (s, 3H).

[1391] Abbreviations

[1392] BOC - tert-butyloxycarbonyl

[1393] DCM - dichloromethane

[1394] DIPAL-H - diisobutylaluminum hydride

[1395] DIPEA - N,N-diisopropylethylamine

[1396] DMA-dimethylacetamide

[1397] DMF - N,N-dimethylformamide

[1398] DMSO - Dimethyl sulfoxide

[1399] EDCl - 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide

[1400] HATU-2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate

[1401] HOBT-1-hydroxybenzotriazole

[1402] HPLC - High Performance Liquid Chromatography

[1403] LCMS - Liquid Chromatography-Mass Spectrometry

[1404] MTBE - Methyl tert-butyl ether

[1405] NCS - N-chlorosuccinimide

[1406] Pd(amphos)Cl2 - bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)

[1407] Pd(dppf)Cl2 - [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[1408] Pd2(dba)3-tris(dibenzylacetone)dipalladium(0)

[1409] [Rh(COD)Cl]2-cyclooctadiene rhodium chloride dimer

[1410] RT - Room temperature

[1411] STAB - Sodium Triacetoxyborohydride

[1412] TFA - Trifluoroacetic acid

[1413] THF - Tetrahydrofuran

[1414] TLC - Thin-layer chromatography

[1415] XantPhos - 4,5-bis(diphenylphosphino)-9,9-dimethylxanthones

[1416] experiment

[1417] Experiment 1. Biochemical assay for CBL-b inhibition

[1418] Inhibition activity of test compounds was assessed by a ligand displacement TR-FRET assay. Human recombinant CBL-b (human biotin CBL-b recombinant protein a.a. 39 - 426; in-house synthesis) was diluted in a volume of 10 μΐ in enzyme assay buffer (20 mM HEPES, 150 mM NaCl, 0.01% Triton X, 0.01% BSA, 0.5 mM TCEP) and plated in a 384 well plate (cat. no. 781075, Greiner) to a final concentration of 50 nM. The enzyme / compound mixture was incubated for 60 min at room temperature. Bodipy FL-probe described in WO 2020 / 210508 (in-house synthesis) diluted in enzyme assay buffer was added to the plate and incubated for 60 min at room temperature, final probe concentration 0.3 μΜ. After 60 min of incubation, 10 μΐ of detection mixture (Tb-streptavidin, (cat. no. PV3576, Invitrogen), diluted in IX Lance buffer) was added and incubated for 60 min at room temperature. Time resolved fluorescence (excitation, 320 nm; emission donor, 615 nm; emission acceptor, 665 nm) was monitored by using a 2030 Multilabel Reader Victor 5 (PerkinElmer). IC 50 values and % maximum inhibition were estimated by fitting the dose response data to a sigmoidal curve fit equation using Graph pad Prism software V. 8.

[1419] Compounds of the present application were screened in the above mentioned assay and IC 50 values of these compounds are set out in Table 1 below, where “A” refers to a group of compounds having an IC 50 value of less than 0.08 μΜ, “B” refers to a group of compounds having an IC 50 value in the range of 0.08 to 0.3 μΜ, and “C” refers to a group of compounds having an IC 50 value in the range of 0.3 μΜ to 5.0 μΜ.

[1420] Table 1.

[1421]

[1422] Experiment 2. Jurkat NFAT reporter assay protocol

[1423] The human T lymphocyte Jurkat reporter cell line was further used to assess the activation of the nuclear factor (NFAT) signaling pathway of activated T cells by Cbl-b inhibitors. The reporter cell line is a genetically engineered Jurkat T cell line that expresses a luciferase reporter gene driven by NFAT-responsive elements (NFAT-RE). Cbl-b inhibitors were incubated with 1 x 10 5 Jurkat NFAT reporter cells per well for 30 minutes. Subsequently, the cells were stimulated with soluble anti-human CD3 / CD28 antibodies for 6 hours, resulting in NFAT-RE-mediated luminescence. The bioluminescence signal was detected and quantified using the Bio-Glo™ Luciferase Assay System. The readout is reported as fold change relative to baseline. Here, the baseline is the measurement obtained from Jurkat NFAT reporter cells stimulated with anti-CD3 and anti-CD28 antibodies, wherein the cells were not incubated with a Cbl-b inhibitor.

[1424] The compounds of the present application were screened in the above-mentioned assay, and the EC 50 values of these compounds are set out in Table 2 below, wherein “A” refers to a group of compounds having an EC 50 value of less than 0.3 µM, “B” refers to a group of compounds having an EC 50 value in the range of 0.3 to 1.0 µM, and “C” refers to a group of compounds having an EC 50 value in the range of 1.0 µM to 10.0 µM.

[1425] Table 2.

[1426]

[1427] Example 3. Human PBMC cytokine release assay

[1428] Peripheral blood mononuclear cells (PBMCs) were isolated from healthy human donors using Histopaque (Sigma). Cbl-inhibitors were added to 1 x 10 5In the presence of Cbl-b inhibitors, the cells were stimulated with Dynabeads™ Human T-Activator CD3 / CD28 (Thermo Fisher Scientific) for 48 hours. At the end of the incubation, cell-free supernatants were collected and analyzed for cytokine secretion, including IL-2, by ELISA (R&D Systems). Readouts are reported as fold change relative to baseline. Here, baseline is the measurement obtained from human PBMCs stimulated with Dynabeads™ Human T-Activator CD3 / CD28, where the cells were not incubated with a Cbl-b inhibitor.

[1429] Some compounds of the application were screened in the above-mentioned assay and the EC 50 values of these compounds are set forth in Table 3 below, where “A” refers to a group of compounds having an EC 50 value of less than 5.0 µM.

[1430] .

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein Z is CH2or NH; M is C or N; when M is C, then R2is hydrogen, halo, C 1-7 alkoxy, cyano, halo C 1-7 alkyl; or -NH-C 1-7 alkyl; or -NH-C when M is N, then R2is absent; R1is any one of the following groups: 、 、 、 or ; R4, R5, R6, R7, R8, and R9are independently hydrogen, C 1-7 alkyl, halogen, or halogen C 1-7 alkyl, or R4and R5, or R6and R7, or R8and R9together with the carbon atoms to which they are attached form an optionally substituted C 3-7 cycloalkyl ring or an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms independently selected from O, S, and N; R’4and R’5together with the carbon atom to which they are attached form an optionally substituted C3-C6cycloalkyl ring or an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms independently selected from O, S and N; B1, B2, B3and B4are independently an optionally substituted 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring atoms independently selected from O, S and N; B5is an optionally substituted phenyl ring or an optionally substituted 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring atoms independently selected from O, S and N; B6is an optionally substituted 5-10 membered monocyclic, bicyclic or spiro bicyclic heterocyclic ring containing 1-4 heteroatoms as ring atoms independently selected from O, S and N; R3is any one of the following groups: , or Z1, Z2, Z3and Z4are independently CH, CX, C-CF3or N; X is halogen; Y1and Y2are independently a 3-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring atoms independently selected from O, S and N; R 11 , R 13 , and R 15 are independently hydrogen, C 1-7 1-6 alkyl, C 2-7 2-6 alkenyl, C 3-7 3-6 cycloalkyl, C 3-7 3-6 cycloalkyl C 1-7 1-6 alkyl, halogen, C 1-7 1-3 alkoxy, halogen C 1-7 1-3 alkyl, or a 3-6 membered heterocycle with 1-3 heteroatoms as ring atoms, independently selected from O, S and N; R 12 is hydrogen, C 1-7 alkyl or -C 1-7 alkyl-NR 16 R 17 ; R 10 and R 14 are independently -C(O)O-C 1-7 alkyl, hydroxyC 1-7 alkyl, haloC 1-7 alkyl, -NR 21 R 22 , -C 1-7 alkyl-NR 21 R 22 , -hydroxyC 1-7 alkyl-NR 21 R 22 , or a group ； L is a bond, -CH2-, -CH-, -CH(CH3)-, -C(CH2)- or -C(O)-; A is a 5-10 membered monocyclic, bicyclic or spiro bicyclic heterocyclic ring containing 1-4 heteroatoms as ring atoms independently selected from O, S and N; R 16 and R 17 are independently hydrogen or C 1-7 alkyl; R 18 , R 19 , and R 20 are independently absent, hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, cyano, halogen C 1-7 alkyl, hydroxy, hydroxy C 1-7 alkyl, or oxo; R 21 and R 22 independently are hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl, (C 3-7 cycloalkyl)2C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, C 3-7 cycloalkyl halogen C 1-7 alkyl, halogen C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, halogen C 1-7 alkyl, halogen C 3-7 cycloalkyl, halogen C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 1-7 alkyl, hydroxy C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 3-7 cycloalkyl, C 1-7 alkoxy C 3-7 cycloalkyl, cyano C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkoxy C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkoxy C 1-7 alkyl, amino hydroxy C 1-7 alkyl, C 1-7 alkyl amide C 1-7 alkyl, -SO2-C 1-7 alkyl, -S(O)-C 1-7 alkyl, -C 1-7 alkyl-(O-C 1-7 alkyl) 1-3 -NH2, -C 1-7 alkyl(C 3-7 cycloalkyl)(OH), or a group ； L' is a bond, C 1-7 alkyl or C 2-7 alkenyl; A’ is an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms independently selected from O, S and N; R 23 independently hydrogen, C 1-7 alkyl or halogen; n is 0, 1 or 2; wherein the optional substituents are 1-2 substituents independently selected at each occurrence from C 1-7 alkyl, C 3-7 cycloalkyl, halogen, hydroxy, C 1-7 alkoxy, halogen C 1-7 alkyl and cyano.

2. The compound of claim 1, wherein, R1is group (1) or (5).

3. The compound according to any one of the preceding claims, wherein, Z is CH2.

4. The compound according to any one of the preceding claims, wherein, M is C.

5. The compound according to any one of the preceding claims, wherein, R2is hydrogen.

6. The compound according to any one of the preceding claims, wherein, R4and R5are independently hydrogen or C 1-7 alkyl.

7. The compound of claim 6, wherein, R4 is hydrogen and R5 is C 1-7 alkyl.

8. The compound according to any one of the preceding claims, wherein, R4and R5together with the carbon atom to which they are attached form an optionally substituted C3-C6cycloalkyl ring or an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms independently selected from O, S and N.

9. The compound of claim 8, wherein, R4and R5together with the carbon atom to which they are attached form an optionally substituted oxetanyl ring.

10. The compound of claim 8, wherein, R4and R5together with the carbon atom to which they are attached form an optionally substituted C3-C6cycloalkyl ring.

11. The compound of claim 10, wherein, R4and R5together with the carbon atom to which they are attached form an optionally substituted cyclobutanyl ring.

12. The compound according to any one of the preceding claims, wherein, B6is an optionally substituted 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring atoms independently selected from O, S and N.

13. The compound according to any one of the preceding claims, wherein, B1, B2, B 3、 B4and B6are independently triazolyl rings optionally substituted with one C 1-7 alkyl substituent.

14. The compound of claim 13, wherein, C 1-7 The alkyl substituent is methyl.

15. The compound according to any one of the preceding claims, wherein, R 23 is hydrogen.

16. The compound according to any one of the preceding claims, wherein, B5is an optionally substituted phenyl ring.

17. The compound according to any one of the preceding claims, wherein, B6 is optionally substituted by one C 1-7 triazolyl ring substituted by an alkyl substituent.

18. The compound according to any one of the preceding claims, wherein, n is 0.

19. The compound according to any one of the preceding claims, wherein, R3is any one of the following groups: , , , , , or .

20. The compound of claim 19, wherein, R3is group (1b’).

21. The compound of claim 19 or 20, wherein, R 10 and R 14 is a group wherein -L- is -CH2- or -CH(CH3)-.

22. The compound of claim 21, wherein, A is a 5-10 membered monocyclic heterocyclic ring containing 1-4 heteroatoms as ring atoms independently selected from O, S and N.

23. The compound of claim 22, wherein, A is any one of the following groups: 、 、 、 、 、 、 、 or .

24. The compound of claim 22, wherein, A is group (2a’).

25. The compound of claim 21, wherein, A is a 5-10 membered bicyclic or spiro bicyclic heterocyclic ring containing 1-4 heteroatoms as ring atoms independently selected from O, S and N.

26. The compound of claim 25, wherein, A is any one of the following groups: 、 、 、 、 、 、 、 、 、 、 、 、 or .

27. The compound of claim 19 or 20, wherein, R 10 is -C 1-7 alkyl-NR 21 R 22 .

28. The compound of claim 27, wherein, R 21 is hydrogen.

29. The compound of claim 27 or 28, wherein, R 22 is C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, halogen C 1-7 alkyl, halogen C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkoxy C 3-7 cycloalkyl, hydroxy C 3-7 cycloalkyl or hydroxy C 3-7 cycloalkyl C 1-7 alkyl or the group ； wherein L' is a bond or C 1-7 alkyl; and A' is an optionally substituted 3-6 membered heterocycle having 1-3 heteroatoms as ring atoms, independently selected from O, S, and N.

30. The compound of claim 1 having the structure (Ia) wherein Z1and Z2are independently CH, CX, or N; R4and R5are independently hydrogen or C 1-7 alkyl, or R4and R5together with the carbon atom to which they are attached form an optionally substituted cyclobutyl ring or an optionally substituted oxetane ring, wherein the optional substitution is 1-2 substituents per occurrence independently selected from C 1-7 alkyl, halogen, and cyano; R 11 is hydrogen, C1-7alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, halogen, C 1-7 alkoxy or halogen C 1-7 alkyl; L is -CH2- or -CH(CH3)-; R 24 is -NR 21 R 22 or group ； wherein A is a 5-10 membered monocyclic or bicyclic or spiro bicyclic heterocycle containing 1-4 heteroatoms as ring atoms, independently selected from O, S, and N; R 18 , R 19 , and R 20 are independently hydrogen, C 1-7 1-6alkyl, halo, cyano, haloC 1-7 1-6alkyl, hydroxy, hydroxyC 1-7 1-6alkyl, or oxo; R 21 and R 22 independently hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl, C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, halogen C 1-7 alkyl, halogen C 3-7 cycloalkyl or halogen C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 1-7 alkyl, C 1-7 alkoxy C 3-7 cycloalkyl, hydroxy C 3-7 cycloalkyl C 1-7 alkyl or hydroxy C 3-7 cycloalkyl.

31. The compound of claim 30, wherein, R4and R5together with the carbon atom to which they are attached form an optionally substituted cyclobutyl ring or an optionally substituted oxetane ring, wherein the optional substitution is 1-2 substituents per occurrence independently selected from C 1-7 alkyl, halo, and cyano.

32. The compound according to any one of the preceding claims, wherein, R4is hydrogen and R5is C 1-7 alkyl, or R4and R5together with the carbon atom to which they are attached form a group of formula (3a) or (3b) These groups can be optionally substituted with 1-2 substituents independently selected from C 1-7 substituted with 1-2 substituents independently selected from C alkyl, halo, and cyano.

33. The compound of claim 32, wherein, R4and R5together with the carbon atom to which they are attached form a group of formula (3a) or (3b) These groups can be optionally substituted with 1-2 substituents independently selected from C 1-7 substituted with 1-2 substituents independently selected from C alkyl, halo, and cyano.

34. The compound according to any one of the preceding claims, wherein, R 21 is hydrogen and R 22 is C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, halogen C 1-7 alkyl or halogen C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkoxy C 3-7 cycloalkyl or hydroxy C 3-7 cycloalkyl.

35. The compound of claim 1 having the structure (Ib) wherein R 25 and R 26 independently are hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen or cyano; R 11 is hydrogen, C1-7alkyl or halogen; R 22 is C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl, (C 3-7 cycloalkyl)2C 1-7 alkyl, C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, C 3-7 cycloalkyl halogen C 1-7 alkyl, halogen C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, halogen C 1-7 alkyl, halogen C 3-7 cycloalkyl, halogen C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 1-7 alkyl, hydroxy C 1-7 alkyl C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 3-7 cycloalkyl, C 1-7 alkoxy C 3-7 cycloalkyl, cyano C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkoxy C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkoxy C 1-7 alkyl, amino hydroxy C 1-7 alkyl, C 1-7 alkyl amide C 1-7 alkyl, -SO2-C 1-7 alkyl, -S(O)-C 1-7 alkyl, -C 1-7 alkyl-(O-C 1-7 alkyl) 1-3 -NH2, -C 1-7 alkyl(C 3-7 cycloalkyl)(OH), or a group ； L' is a bond, C 1-7 alkyl or C 2-7 alkenyl; A' is an optionally substituted 3-6 membered heterocycle having 1-3 heteroatoms as ring atoms, independently selected from O, S, and N, wherein the optional substituents are 1-2 substituents independently selected from C 1-7 alkyl, C 3-7 cycloalkyl, halogen, hydroxy, C 1-7 alkoxy, halogen C 1-7 alkyl and cyano.

36. The compound of claim 35, wherein, R 22 is C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, halogen C 1-7 alkyl, halogen C 3-7 cycloalkyl, halogen C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkoxy C 3-7 cycloalkyl, hydroxy C 3-7 cycloalkyl or the group ； L' is a bond or C 1-7 alkyl; A' is an optionally substituted 3-6 membered heterocycle having 1-3 heteroatoms as ring atoms, independently selected from O, S, and N, wherein the optional substituents are 1-2 substituents independently selected from C 1-7 alkyl, C 3-7 cycloalkyl, halogen, hydroxy, C 1-7 alkoxy, halogen C 1-7 alkyl and cyano.

37. The compound of claim 1, wherein, the compound is (S)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)isoindolin-1-one (Compound 1); (S)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((3- methylpiperidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-1-one (Compound 2); (S)-2-(3-fluoro-5-((3-methylpiperidin-1-yl)methyl)phenyl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 3); (S)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-methyl-5- ((3-methylpiperidin-1-yl)methyl)phenyl)isoindolin-1-one (Compound 4); (S)-2-(3-methoxy-5-((3-methylpiperidin-1-yl)methyl)phenyl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 5); (S)-2-(3-chloro-5-((3-methylpiperidin-1-yl)methyl)phenyl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 6); (S)-2-(3-cyclopropyl-5-((3-methylpiperidin-1-yl)methyl)phenyl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 7); (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)isoindolin-l-one (Compound 13); (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)isoindolin-l-one (Compound 13); (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)isoindolin-l-one (Compound 13); (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)isoindolin-l-one (Compound 13); (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)isoindolin-l-one (Compound 13); (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)isoindolin-l-one (Compound 13); (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)isoindolin-l-one (Compound 13); (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)isoindolin-l-one (Compound 13); (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)isoindolin-l-one (Compound 13); (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3- methylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)isoindolin-l-one (Compound 13); 2-(3-(((cyclopropylmethyl)amino)methyl)-5-methylphenyl)-6-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 18); 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-methyl-5-(((3,3,3- trifluoropropyl)amino)methyl)phenyl)isoindolin-1-one (Compound 19); 2-(3-((((2,2-difluorocyclopropyl)methyl)amino)methyl)-5-methylphenyl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 20); (S)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-((3-methylpiperidin-1- yl)methyl)-5-(pyrrolidin-1-yl)phenyl)isoindolin-1-one (Compound 21); 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(3-methyl-5-(((2,2,2- trifluoroethyl)amino)methyl)phenyl)isoindolin-1-one (Compound 22); (S)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(2-methyl-6-((3- methylpiperidin-1-yl)methyl)pyridin-4-yl)isoindolin-1-one (Compound 23); (S)-2-(3-(azetidin-1-yl)-5-((3-methylpiperidin-1-yl)methyl)phenyl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 24); 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(6-(trifluoromethyl)-4-(((3,3,3- trifluoropropyl)amino)methyl)pyridin-2-yl)isoindolin-1-one (Compound 25); (S)-2-(6-methyl-4-((3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 26); (S)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(6-(trifluoromethyl)-4- ((3-(trifluoromethyl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-1-one (Compound 27); 2-(4-((4,4-difluoro-3-methylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 28); 1-((2-(6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-l-oxoisoindolin-2-yl)-6- (trifluoromethyl)pyridin-4-yl)methyl)piperidine-3-carbonitrile (Compound 29); (S)-2-(4-((3-hydroxypiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 30); 2-(4-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 31); 2-(4-((l-Oxa-8-azaspiro[4.5]dec-8-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 32); 2-(4-((3-fluoropiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 33); (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((3-methylpyrrolidin-l- yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-l-one (Compound 34); 2-(4-((Hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 35); (S)-2-(4-(3-hydroxypyrrolidine-l-carbonyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 36); 2-(4-((3-(hydroxymethyl)piperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 37); 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(6-(trifluoromethyl)- 4-((4-(trifluoromethyl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-1-one (Compound 38); 2-(4-(((3S,5R)-3,5-dimethylpiperidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6- (3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 39); (S)-2-(6-chloro-4-((3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 40); (R)-2-(4-((hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)-6-(trifluoromethyl)pyridin- 2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 41); 2-(4-(((3S,5S)-3,5-dimethylpiperidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6- (3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 42); 2-(4-((4-hydroxypiperidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 43); 2-(4-((6-azaspiro[2.5]octan-6-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 44); 6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((2-methylpiperidin-1-yl) methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-1-one (Compound 45); (R)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((2-methylmorpholino) methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-1-one (Compound 46); 2-(4-((3,3-difluoropiperidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 47); 2-(4-((4,4-difluoropiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 48); (S)-2-(3-(cyclopropylmethyl)-5-((3-methylpiperidin-l-yl)methyl)phenyl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 49); 2-(4-((l-oxa-7-azaspiro[4.4]nonan-7-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 50); 2-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 51); 2-(6-chloro-4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 52); (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(2-methyl-6-((3- methylpiperidin-l-yl)methyl)pyrimidin-4-yl)isoindolin-l-one (Compound 53); 2-(4-((2-methyl-lH-imidazol-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 54); 2-(4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 55); 2-(3-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-5-methylphenyl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 56); 2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 57); 2-(6-chloro-4-(((3S,5S)-3,5-dimethylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 60); 2-(3-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 65); 2-(6-chloro-4-(((3S,5S)-3,5-dimethylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 60); (S)-2-(4-((3-fluoropyrrolidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 61); 2-(4-((5-azaspiro[2.4]heptan-5-yl)methyl)-6-chloropyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 62); 2-(4-((4-methyl-3-oxopiperazin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 63); 2-(6-chloro-4-(piperidin-l-ylmethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3- yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 64); 2-(3-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(3-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 65); 2-(6-chloro-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 66); (S)-2-(6-chloro-4-((3-methylpyrrolidin-l-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 67); (R)-2-(6-chloro-4-((3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 68); 2-(4-((5-methyl-1 H-imidazol-1 -yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 69); 2-(4-((4-methyl-1 H-imidazol-1 -yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 70); 2-(4-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 71 ); 2-(4-(((2R,6S)-2,6-dimethylmorpholino)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3- ((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 72); (S)-2-(6-cyclopropyl-4-((3-methylpiperidin-1 -yl)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 73); 2-(4-(((3,3-difluorocyclobutyl)amino)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 74); 2-(3-(2-(ethylamino)ethyl)-5-(trifluoromethyl)phenyl)-6-(3-((4-methyl-4H-1,2,4-triazol- 3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 75); 2-(1 -(2-(dimethylamino)ethyl)-4-methyl-1 H-indazol-6-yl)-6-(3-((4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 76); 2-(2-ethyl-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 77); 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-((S)-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 87); 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-((S)-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 87); 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-((S)-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 87); 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-((S)-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 87); 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-((S)-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 87); 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-((S)-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 87); 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-((S)-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 87); 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-((S)-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 87); 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-((S)-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 87); 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-((S)-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 87); 6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-(((l- methylcyclobutyl)amino)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-l- one (Compound 88); (S)-2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(l-((4- methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)isoindolin-l-one (Compound 89); 2-(6-chloro-4-(((S)-3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-((R)-l-(4- methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 90); 2-(6-chloro-4-(((S)-3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-((S)-l-(4- methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)isoindolin-l-one (Compound 91); 2-(4-((l-methyl-l,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methyl)-6- (trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan- 3-yl)isoindolin-l-one (Compound 92); 2-(4-((2,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3- ((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 93); (S)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((3- methylpiperidin-l-yl)methyl)benzofuran-6-yl)isoindolin-l-one (Compound 94); 2-(4-(lH-pyrazol-4-yl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 95); (R)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)-2-(4-((3- methylpiperazin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)isoindolin-l-one (Compound 96); (R)-2-(4-((3,4-dimethylpiperazin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)- 6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 97); 2-(4-(((3R,5S)-3,5-dimethylpiperazin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 98); 2-(4-(13-amino-5,8,11-trioxa-2-azatridecyl)-6-chloropyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 99); 2-(3-(l-hydroxy-2-(isopropylamino)ethyl)-5-(trifluoromethyl)phenyl)-6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 100); 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 101); 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 102); 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(l-((cyclopropylmethyl)amino)ethyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 103); 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(l-(cyclopentylamino)ethyl)pyridin-2-yl)isoindolin-l-one, enantiomer 1 (Compound 104); 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(l-(cyclopentylamino)ethyl)pyridin-2-yl)isoindolin-l-one, enantiomer 2 (Compound 105); 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((cyclopentylamino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 106); 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(l-((cyclobutylmethyl)amino)ethyl)pyridin-2-yl)isoindolin-l-one (Compound 107); 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(((l-cyclopropylethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 1] (Compound 108); 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(((l- cyclopropylethyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 109); 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(l-((cyclopropylmethyl)amino)ethyl)pyridin-2-yl)isoindolin-l-one [enantiomer 1] (Compound 110); 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(l-((cyclopropylmethyl)amino)ethyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 111); (S)-4-(2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-3-oxoisoindolin-5-yl)-3-(4-methyl-4H-l,2,4-triazol-3-yl)benzonitrile (Compound 112); (S)-6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((3- methylpiperidin-l-yl)methyl)pyridin-2-yl)isoindolin-l-one (Compound 113); (S)-2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(l-methyl-4-(4- methyl-4H-l,2,4-triazol-3-yl)-lH-pyrazol-5-yl)isoindolin-l-one (Compound 114); (S)-2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(2-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)phenyl)isoindolin-l-one (Compound 115); 2-(6-chloro-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-6-(2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 116); 2-(4-(((3S,5R)-3,5-dimethylpiperidin-l-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 117); (S)-2-(6-chloro-4-((3-methylpiperidin-l-yl)methyl)pyridin-2-yl)-6-(2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 118); 6-(4-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(3-chloro-5-(((cyclopropylmethyl)amino)methyl)phenyl)isoindolin-l-one (Compound 119); 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-methyl-3-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 120); 6-(4-Chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((((tetrahydrofuran- 2-yl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 124); 6-(4-Chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((((tetrahydrofuran- 2-yl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 124); 6-(4-Chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((((tetrahydrofuran- 2-yl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 124); 6-(4-Chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((((tetrahydrofuran- 2-yl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 124); 6-(4-Chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-((((tetrahydrofuran- 2-yl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one [enantiomer 2] (Compound 124); 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl- 4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 127); 2-(6-Chloro-4-(((l-cyclopropylethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-l,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 131); 6-(4-Chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((cyclopropylmethyl)amino)methyl)- 6-(trifluoromethyl)pyridin-2-yl)isoindolin-l-one (Compound 132); 2-(6-(((cyclopropylmethyl)amino)methyl)-2-methylpyrimidin-4-yl)-6-(4-fluoro-2-(4-methyl- 4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 133); ​ 2-(4-(((cyclobutylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindoline-1-one (compound 134); 2-(6-chloro-4-(((cyclobutylmethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetane-3-yl)isoindoline-1-one (compound 144); 2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)isoindoline-1-one (compound 145); 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetane-3-yl)isoindoline-1-one (compound 147); 2-(6-chloro-4-((3-ethylpiperidin-1-yl)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetane-3-yl)isoindoline-1-one (compound 148); 2-(6-chloro-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-6-(1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)isoindoline-1-one (compound 151); (S)-2-(6-chloro-4-((3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-6-(3,3-difluoro-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)isoindoline-1-one (compound 152); 3-(2-(6-chloro-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-3-oxoisoindoline-5-yl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1-carboxylonitrile (compound 158); 2-(6-chloro-4-(((cyclopentylmethyl)amino)methyl)pyridin-2-yl)-6-(3-(((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetane-3-yl)isoindoline-1-one (compound 159); (S)-2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(1-(4-methyl-4H-1,2,4-triazol-3-yl)propane-2-yl)isoindoline-1-one (compound 160); (R)-2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(1-(4-methyl-4H-1,2,4-triazol-3-yl)propane-2-yl)isoindoline-1-one (compound 161); 2-(4-(((cyclobutylmethyl)amino)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 162); (S)-2-(6-chloro-4-(((3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-6-(1-(4-methyl- 4H-1,2,4-triazol-3-yl)propan-2-yl)isoindolin-1 -one (Compound 163); (R)-2-(6-chloro-4-(1-((cyclopropylmethyl)amino)ethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 166); (S)-2-(6-chloro-4-(1-((cyclopropylmethyl)amino)ethyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 167); 3-(2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-3-oxoisoindolin-5-yl)- 3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutan-1 -carbonitrile (Compound 168); 2-(6-chloro-4-((((3,3-difluorocyclobutyl)methyl)amino)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 169); (R)-2-(6-chloro-4-(((cyclobutylmethyl)amino)methyl)pyridin-2-yl)-6-(1-(4-methyl- 4H-1,2,4-triazol-3-yl)propan-2-yl)isoindolin-1 -one (Compound 170); (S)-2-(6-chloro-4-(((cyclobutylmethyl)amino)methyl)pyridin-2-yl)-6-(1-(4-methyl- 4H-1,2,4-triazol-3-yl)propan-2-yl)isoindolin-1 -one (Compound 171); 2-(6-chloro-4-((((1-methylcyclobutyl)methyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 172); 2-(6-chloro-4-((((2,2-difluorocyclopropyl)methyl)amino)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 175); (1S,3r)-3-(2-(6-chloro-4-(((S)-3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-3- oxoisoindolin-5-yl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1- carbonitrile (Compound 179); 2-(6-chloro-4-(((S)-3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-6-((S)-1,1,1- trifluoro-3-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)isoindolin-1-one (Compound 181); 3-(2-(6-chloro-4-(((cyclobutylmethyl)amino)methyl)pyridin-2-yl)-3-oxoisoindolin-5- yl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1-carbonitrile (Compound 182); 2-(6-chloro-4-((((tetrahydrofuran-2-yl)methyl)amino)methyl)pyridin-2-yl)-6-(3- ((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 188); 2-(6-chloro-4-(((2-hydroxycyclopentyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 193); (S)-2-(6-chloro-4-((((tetrahydrofuran-2-yl)methyl)amino)methyl)pyridin-2-yl)-6-(3- ((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 196); 2-(6-chloro-4-(1-(((2,2-difluorocyclopropyl)methyl)amino)ethyl)pyridin-2-yl)-6-(3- ((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 199); 2-(6-chloro-4-((cyclopentylamino)methyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 201); 2-(6-chloro-4-(((3,3,3-trifluoro-2-methylpropyl)amino)methyl)pyridin-2-yl)-6-(3- ((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 202); 2-(6-chloro-4-(1-(((2,2-difluorocyclopropyl)methyl)amino)ethyl)pyridin-2-yl)-6-(3- ((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1-one (Compound 206); 2-(6-chloro-4-(((2-hydroxycyclopentyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 209); 2-(6-chloro-4-(l-((cyclobutylmethyl)amino)ethyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 213); 2-(6-chloro-4-((R)-l-((((S)-tetrahydrofuran-2-yl)methyl)amino)ethyl)pyridin-2-yl)- 6-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 219); (S)-2-(6-chloro-4-(l-(((3,3-difluorocyclobutyl)methyl)amino)ethyl)pyridin-2-yl)-6- (3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 222); (R)-2-(6-chloro-4-(((l-cyclopropylethyl)amino)methyl)pyridin-2-yl)-6-(3-((4-methyl- 4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 223); 3-(2-(6-chloro-4-(l-((cyclopropylmethyl)amino)ethyl)pyridin-2-yl)-3-oxoisoindolin- 5-yl)-3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutane-l-carbonitrile (Compound 225); 3-(2-(6-chloro-4-((((3,3-difluorocyclobutyl)methyl)amino)methyl)pyridin-2-yl)-3- oxoisoindolin-5-yl)-3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutane-l- carbonitrile (Compound 227); 3-(2-(6-chloro-4-((((2,2-difluorocyclopropyl)methyl)amino)methyl)pyridin-2-yl)-3- oxoisoindolin-5-yl)-3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutane-l- carbonitrile (Compound 230); (R)-2-(6-chloro-4-(l-(cyclopentylamino)ethyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 231); (S)-2-(6-chloro-4-(l-(cyclopentylamino)ethyl)pyridin-2-yl)-6-(3-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-l-one (Compound 232); (1r,3r)-3-(2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-3- oxoisoindolin-5-yl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1 - carbonitrile (Compound 233); (1s,3s)-3-(2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-3- oxoisoindolin-5-yl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1 - carbonitrile (Compound 234); 2-(6-chloro-4-((R)-1 -(((S)-1 -cyclopropylethyl)amino)ethyl)pyridin-2-yl)-6-(3- ((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 239); (1r,3r)-3-(2-(6-chloro-4-(((cyclobutylmethyl)amino)methyl)pyridin-2-yl)-3- oxoisoindolin-5-yl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1 - carbonitrile (Compound 244); 2-(6-chloro-4-(1 -((2-cyclopropylpropan-2-yl)amino)ethyl)pyridin-2-yl)-6-(3- ((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 247); 2-(6-chloro-4-(1 -(cyclopentylamino)propyl)pyridin-2-yl)-6-(3-((4-methyl-4H-1,2,4- triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 251 ); 2-(6-chloro-4-(((2-methoxycyclopentyl)amino)methyl)pyridin-2-yl)-6-(3-((4- methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)isoindolin-1 -one (Compound 253); 2-(6-chloro-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(2-((4-methyl-4H- 1,2,4-triazol-3-yl)methyl)spiro[3.3]heptan-2-yl)isoindolin-1 -one (Compound 255); 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-1,2,4-triazol-3-yl)phenyl)-4-(trifluoromethyl)isoindolin-1 -one (Compound 256); 2-(4-((((3,3-difluorocyclobutyl)methyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 260); 2-(4-(((cyclopropylmethyl)amino)methyl)-5-fluoro-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 261 ); 6-(5-chloro-3-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-1 -one (Compound 263); 2-(4-(((cyclopropylmethyl)amino)methyl)-6-(trifluoromethyl)pyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 265); 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-methoxy-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 273); 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(((cyclobutylmethyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-1 -one (Compound 274); 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(6-chloro-4-(2-((cyclopropylmethyl)amino)propan-2-yl)pyridin-2-yl)isoindolin-1 -one (Compound 275); 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 277); 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(1 -((cyclobutylmethyl)amino)ethyl)-6-methylpyridin-2-yl)isoindolin-1 -one (Compound 278); 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-((((3,3-difluorocyclobutyl)methyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-1 -one (Compound 279); 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(3-(((cyclopropylmethyl)amino)methyl)-5-methylphenyl)isoindolin-1 -one (Compound 280); 6-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(1 -(((3,3-difluorocyclobutyl)methyl)amino)ethyl)-6-methylpyridin-2-yl)isoindolin-1 -one (Compound 281 ); 2-(4-(1-((cyclopropylmethyl)amino)ethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 282); 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methylisoxazol-3-yl)phenyl)isoindolin-1 -one (Compound 289); 2-(4-(2-((cyclopropylmethyl)amino)propan-2-yl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 293); 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(2-(4-ethyl-4H-1,2,4- triazol-3-yl)-4-fluorophenyl)isoindolin-1 -one (Compound 294); 2-(4-((sec-butylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-1,2,4- triazol-3-yl)phenyl)isoindolin-1 -one (Compound 295); 2-(4-(((dicyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 298); 6-(4-Fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-((isopentylamino)methyl)-6- methylpyridin-2-yl)isoindolin-1 -one (Compound 300); 6-(4-Fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(((2-methoxyethyl)amino)methyl)- 6-methylpyridin-2-yl)isoindolin-1 -one (Compound 302); 6-(4-Fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-((neopentylamino)methyl) pyridin-2-yl)isoindolin-1 -one (Compound 303); 2-(4-(((2-cyclopropylethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl- 4H-1,2,4-triazol-3-yl)phenyl)isoindolin-1 -one (Compound 307); 6-(4-Fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(4-(((2-hydroxy-2-methylpropyl) amino)methyl)-6-methylpyridin-2-yl)isoindolin-1 -one (Compound 309); 2-(4-(((cyclopentylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 329); 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-((((l- hydroxycyclopentyl)methyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 319); 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-((((l- hydroxycyclopentyl)methyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 319); 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-((((l- hydroxycyclopentyl)methyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 319); 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-((((l- hydroxycyclopentyl)methyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 319); 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-((((l- hydroxycyclopentyl)methyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 319); 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-((((l- hydroxycyclopentyl)methyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 319); 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-((((l- hydroxycyclopentyl)methyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 319); 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-((((l- hydroxycyclopentyl)methyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 319); 2-(4-(((cyclopentylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 329); 2-(4-(((cyclopentylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 329); or a tautomer or a pharmaceutically acceptable salt thereof.

38. A compound according to claim 1 for use as a medicament.

39. A compound for use according to claim 38 in the treatment of a disease or condition in which inhibition of Cbl-b is desired.

40. The compound for use according to claim 39, wherein, The disease is cancer.

41. The compound for use according to claim 40, wherein, The cancer is squamous cell carcinoma, bladder cancer, gastric cancer, liver cancer, lung and colon cancer, bone cancer, pancreatic cancer, melanoma, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, testicular cancer, uterine cancer, endometrial cancer, non-Hodgkin's lymphoma or leukemia.

42. The compound for use according to any one of claims 38-41, wherein, A therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in addition to one or more anti-cancer agents.

43. A method for treating a disease or condition in which inhibition of Cbl-b is desired, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1.

44. The method of claim 43, wherein, The disease is cancer.

45. The method of claim 44, wherein, The cancer is squamous cell carcinoma, bladder cancer, gastric cancer, liver cancer, lung and colon cancer, bone cancer, pancreatic cancer, melanoma, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, testicular cancer, uterine cancer, endometrial cancer, non-Hodgkin's lymphoma or leukemia.

46. The method of any one of claims 43-45, wherein, A therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in addition to one or more anti-cancer agents.

47. A pharmaceutical composition comprising a compound according to any one of claims 1 to 37 and a pharmaceutically acceptable carrier.

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