Cbl-b inhibitors

Abstract

The present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof. The compounds of formula (I) possess utility as inhibitors of Cb1-b. The compounds are useful as medicaments in the treatment of diseases or conditions wherein inhibition of Cb1-b is desired, such as cancer.

Description

[0001] CBL-B INHIBITORS

[0002] This application claims the benefit of Indian provisional application number 202411056975, filed on 26thJuly 2024; the specification of which is hereby incorporated by reference in it’s entirety.

[0003] TECHNICAL FIELD

[0004] The present invention relates to therapeutically active compounds useful in the inhibition of E3 ligase Casitas B -lineage lymphoma b enzyme also known as Cbl-b, and to pharmaceutical compositions containing such compounds. The compounds are useful, for example, for modulating immune system in the treatment of various diseases and disorders, such as cancer.

[0005] BACKGROUND

[0006] Maintenance of immunological tolerance and induction of T-cell anergy is critical for prevention of autoimmunity. However, in the case of malignancies, tumor- induced T-cell anergy leads to cancer-associated immune paralysis, resulting in uncontrolled tumor growth and metastasis. Proteins that negatively regulate the amplitude and duration of TCR signalling would play critical roles in determining the induction of T cell anergy. Cbl-b family of E3 ubiquitin ligases, which includes Cbl-b and c-Cbl, have emerged as key proteins that modulate several signalling pathways in T cells, NK cells, and B cells by ubiquitination of several activating tyrosine kinases (Bachmaier, K. et al., Nature, 403, 6766, 211-216, 2000).

[0007] Ubiquitination is an important post-transcriptional mechanism that regulates cellular function by proteasomal degradation of proteins involved in several signalling pathways. Ubiquitination of target proteins occurs stepwise with three enzymes. Ubiquitination is initiated by catalyses of ubiquitin activation by first enzyme (El). The activated ubiquitin is then transferred from El to Ubiquitin conjugating enzymes (E2). Finally, the third enzyme (E3 ligases) confers substrate specificity and catalyse the transfer of ubiquitin from E2 into the target protein substrate. Addition of poly-ubiquitin chains to protein marks it for degradation by the proteasomal degradation machinery (Staub, O. et al., Physiological Reviews, 86, 2, 669-707, 2006).

[0008] Ubiquitination regulates multiple biological functions including cell division, DNA repair and cellular signalling. Molecules that can modulate components of the ubiquitin proteosome system can be used as therapeutic agents for a wide range of conditions, including cancer and autoimmune diseases.

[0009] E3 ubiquitin ligases confer specificity and their role in fine tuning of immunological responses have been described recently. Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) stands out as one of the most important gate keepers of immune activation due to its function as a non-redundant negative regulator of immune activation (Chiang, Y. et al., Nature, 403, 6766, 16-220, 2000).

[0010] Cbl-b family of E3 ligases selectively regulate activated PTKs by recognizing specific phospho tyrosine containing motifs. Cbl-b also downregulates signalling from antigen and cytokine receptors through ubiquitination of receptor chains and associated cytosolic tyrosine kinases, leading to inactivation and / or proteasomal degradation of target proteins (Schmidt. M. H. et al., Nat Rev Mol Cell Biol, 2005, 6(12):907-918).

[0011] Cbl-b is preferentially expressed in peripheral lymphoid organs and acts as a major regulator of immune cell activation and maintains peripheral tolerance. Cbl-b deficient immune cells display lower activation thresholds and Cbl-b knockout mice rejects tumor mediated by cytotoxic T cells and NK cells (Loeser, S. et al., Journal of Experimental Medicine, 204, 4, 879-891, 2007).

[0012] Cbl-b proteins not only regulate adaptive immune cell functions but are also critically involved in the regulation of innate lymphocyte populations, such as NK cells, dendritic cells and myeloid cells. Thus, targeting Cbl-b provides opportunities to enhance anti-cancer immunity.

[0013] Compounds with Cbl-b inhibition activity have been disclosed, for example, in W02019 / 148005, W02020 / 210508, WO2020 / 236654, WO2020 / 264398, WO2022 / 169997, WO2022 / 217276, WO2022 / 272248, CN1 19868356A,

[0014] WO2025067468, WO2025076299, CN119823121 A, and CN119930582A.

[0015] SUMMARY

[0016] It has been found that compounds of formula (I) are potent inhibitors of E3 ligase Casitas B-lineage lymphoma b enzyme (Cbl-b) and exhibit good safety and good Cbl-b selectivity over binding to c-Cbl. The compounds are therefore useful for the treatment of conditions and diseases where inhibition of Cbl-b is desired. Such conditions and diseases include, but are not limited to, cancer.

[0017] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein

[0018] Ri is hydrogen, halogen, C1.7 alkyl, C3-7 cycloalkyl, hydroxy, C1.7 alkoxy, halogen C1.7 alkyl or cyano;

[0019] R2 is hydrogen, C2-7 alkoxy, halogen C1.7 alkoxy, cyano C1.7 alkoxy, C1.7 alkoxy

[0020] C1.7 alkoxy, hydroxy C1.7 alkyl, hydroxy C1.7 alkoxy or -NHR9;

[0021] R9 is C1.7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1.7 alkyl, halogen C1.7 alkyl, C1.7 alkoxy C1.7 alkyl, cyano C1.7 alkyl or cyano C1.7 alkyl C3-7 cycloalkyl, hydroxy C1.7 alkyl or oxetanyl;

[0022] R3 is any of the following groups Zi, Z2, and Z3 are independently CH, CX, C-CF3 or N;

[0023] X is halogen;

[0024] Y is 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring atoms independently selected from O, S and N;

[0025] R4 is hydrogen or halogen;

[0026] Rio and R14 are, independently, -C1.7 alkyl-NR2iR22, -SO2-NR21R22 or a group

[0027] L is a bond, -CH2-, -CH-, -CH(CH3)-, -C(CH2)- or -C(O)-;

[0028] R11 is hydrogen, C1.7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1.7 alkyl, halogen, C1.7 alkoxy or halogen C1.7 alkyl;

[0029] A is any of the following groups:

[0030] R5 and Rs are, independently, hydrogen or C1.7 alkyl;

[0031] B 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;

[0032] R15 is absent, hydrogen, C1.7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1.7 alkyl, halogen, C1.7 alkoxy or halogen C1.7 alkyl;

[0033] Ri8, R19 and R20 are, independently, absent, hydrogen, C1.7 alkyl, C1.7 alkoxy, halogen, cyano, halogen C1.7 alkyl, hydroxy, hydroxy C1.7 alkyl or oxo;

[0034] R21 and R22 are, independently, hydrogen, C1.7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1.7 alkyl, C1.7 alkyl C3-7 cycloalkyl, (C3-7 cycloalkyl)2 C1.7 alkyl, C1.7 alkyl C3-7 cycloalkyl C1.7 alkyl, C3-7 cycloalkyl halogen C1.7 alkyl, halogen C1.7 alkyl C3-7 cycloalkyl C1.7 alkyl, halogen C1.7 alkyl, halogen C3-7 cycloalkyl, halogen C3-7 cycloalkyl C1.7 alkyl, hydroxy C1.7 alkyl, hydroxy C1.7 alkyl C3-7 cycloalkyl C1.7 alkyl, hydroxy C3-7 cycloalkyl, C1.7 alkoxy C3-7 cycloalkyl, cyano C3-7 cycloalkyl C1.7 alkyl, (hydroxy)(C3-7 cycloalkyl) C1.7 alkyl, C1.7 alkoxy C3-7 cycloalkyl C1.7 alkyl, C1.7 alkoxy C1.7 alkyl, aminohydroxy C1.7 alkyl, C1.7 alkyl amide C1.7 alkyl, -SO2-C1.7 alkyl, -S(O)-Ci-7 alkyl, -SO2-C3-7 cycloalkyl, -SCh-hydroxy C1.7 alkyl, -C1.7 alkyl-(O-Ci-7 alkyl) 1.3-NH2, -C1.7 alkyl (C3-7 cycloalkyl)(OH), C1.7 alkoxy carbonyl C1.7 alkyl, -C1.7 alkyl-NH-C(O)-C2-7 alkenyl, or a group

[0035] L’ is a bond, C1.7 alkyl or C2-7 alkenyl;

[0036] A’ is an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms independently selected from O, S and N; with the proviso that when R2 is hydrogen and A is (2”), then R21 is -SO2-C2-7 alkyl, -SO2-C3-7 cycloalkyl, -SCh-hydroxy C1.7 alkyl, C1.7 alkyl C3-4 cycloalkyl C1.7 alkyl, (C1.7 alkyl)2 C3-7 cycloalkyl C1.7 alkyl, dihalogen C1.7 alkyl, -CH(C3-7 cycloalkyl)(dihalogen C1.7 alkyl), adamantane C1.7 alkyl, bicyclopentane C1.7 alkyl, -CH2-CH3, -CH(CI-7 alkyl)(hydroxy C3-7 cycloalkyl), -CH2-CH(CH2OH)- CH2-CH3, -CH(CH2OH)-CH2-CH2-CH3, -CH(CH2OH)-CH2-CH2-CH2-CH3, -CH(CH2- CH2OH)-CH-(CH3)2, -CH(CH(CH3)2)-C(OH(CH3)2), -C(CH3)2-C3-7 cycloalkyl, -CH2- CH-(CI-7 alkyl)(C2-7 alkyl), methoxy C3-7 alkyl, -CH(R7)CH2-ORs, -C1.7 alkyl-NH-C(O)- C2-7 alkenyl or C1.7 alkoxy carbonyl C1.7 alkyl; wherein R7 is C3-7 cycloalkyl, and Rs is hydrogen or C1.7 alkyl; or Zi is CX and Rn is -CF3; or B is oxazolidin-2-one; or Rio is -SO2-NR21R22; or Rn is cyclopropyl; or Zi and Z2 is N, and Rio is -CH(CH3)-NR2iR22; wherein optional substitution, in each occurrence, is 1-2 substituents independently selected from C1.7 alkyl, C3-7 cycloalkyl, halogen, hydroxy, C1.7 alkoxy, halogen C1.7 alkyl and cyano.

[0037] According to one embodiment, the invention provides a method for the treatment of a disease or condition wherein 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 wherein A, Ri, R2, R3 andR4 are as defined above.

[0038] According to one embodiment, the disease or condition wherein inhibition of Cbl-b is desired is cancer, for example, 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.

[0039] According to one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

[0040] BRIEF DESCRIPTION OF THE DRAWINGS

[0041] FIG. 1 illustrates the impact of Compound 8 on percent body weight change in CT26 syngeneic mouse model.

[0042] FIG. 2 illustrates the anti-tumor efficacy of Compound 8 in CT26 syngeneic mouse model.

[0043] FIG. 3 illustrates the survival analysis of animals bearing CT26 tumor following treatment with Compound 8.

[0044] DETAILED DESCRIPTION

[0045] The present application provides compounds of formula (I) or pharmaceutically acceptable salts thereof which are useful as Cbl-b inhibitors. One of the embodiments of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof wherein

[0046] Ri is hydrogen, halogen, C1.7 alkyl, C3-7 cycloalkyl, hydroxy, C1.7 alkoxy, halogen C1.7 alkyl or cyano;

[0047] R2 is hydrogen, C2-7 alkoxy, halogen C1.7 alkoxy, cyano C1.7 alkoxy, C1.7 alkoxy C1.7 alkoxy, hydroxy C1.7 alkyl, hydroxy C1.7 alkoxy or -NHR9;

[0048] R9 is C1.7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1.7 alkyl, halogen C1.7 alkyl, C1.7 alkoxy C1.7 alkyl, cyano C1.7 alkyl or cyano C1.7 alkyl C3-7 cycloalkyl, hydroxy C1.7 alkyl or oxetanyl;

[0049] R3 is any of the following groups

[0050] Zi, Z2, and Z3 are, independently, CH, CX, C-CF3 or N;

[0051] X is halogen;

[0052] Y is 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring atoms independently selected from O, S and N;

[0053] R4 is hydrogen or halogen;

[0054] Rio and R14 are, independently, -C1.7 alkyl-NR2iR22, -SO2-NR21R22 or a group

[0055] L is a bond, -CH2-, -CH-, -CH(CH3)-, -C(CH2)- or -C(O)-;

[0056] Rn is hydrogen, C1.7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1.7 alkyl, halogen, C1.7 alkoxy or halogen C1.7 alkyl;

[0057] A is any of the following groups:

[0058] R5 and Rs are, independently, hydrogen or C1.7 alkyl;

[0059] B 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;

[0060] R15 is absent, hydrogen, C1.7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1.7 alkyl, halogen, C1.7 alkoxy or halogen C1.7 alkyl;

[0061] Ri8, R19 and R2o are, independently, absent, hydrogen, C1.7 alkyl, C1.7 alkoxy, halogen, cyano, halogen C1.7 alkyl, hydroxy, hydroxy C1.7 alkyl or oxo;

[0062] R2I and R22are, independently, hydrogen, C1.7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1.7 alkyl, C1.7 alkyl C3-7 cycloalkyl, (C3-7 cycloalkyl)2C1.7 alkyl, C1.7 alkyl C3-7 cycloalkyl C1.7 alkyl, C3-7 cycloalkyl halogen C1.7 alkyl, halogen C1.7 alkyl C3-7 cycloalkyl C1.7 alkyl, halogen C1.7 alkyl, halogen C3-7 cycloalkyl, halogen C3-7 cycloalkyl C1.7 alkyl, hydroxy C1.7 alkyl, hydroxy C1.7 alkyl C3-7 cycloalkyl C1.7 alkyl, hydroxy C3-7 cycloalkyl, C1.7 alkoxy C3-7 cycloalkyl, cyano C3-7 cycloalkyl C1.7 alkyl, (hydroxy)(C3-7 cycloalkyl) C1.7 alkyl, C1.7 alkoxy C3-7 cycloalkyl C1.7 alkyl, C1.7 alkoxy C1.7 alkyl, aminohydroxy C1.7 alkyl, C1.7 alkyl amide C1.7 alkyl, -SO2-Ci-7 alkyl, -S(O)-Ci-7 alkyl, -SO2-C3-7 cycloalkyl, -SO2-hydroxy C1.7 alkyl, -C1.7 alkyl-(O-Ci-7 alkyl) 1.3-NH2, -C1.7 alkyl (C3-7 cycloalkyl)(OH), C1.7 alkoxy carbonyl C1.7 alkyl, -C1.7 alkyl-NH-C(O)-C2-7 alkenyl, or a group

[0063] L’ is a bond, C1.7 alkyl or C2-7 alkenyl;

[0064] A’ is an optionally substituted 3-6 membered heterocyclic ring having 1-3 heteroatoms as ring atoms independently selected from O, S and N; with the proviso that when R2 is hydrogen and A is (2”), then R21 is -SO2-C2-7 alkyl, -SO2-C3-7 cycloalkyl, -SCh-hydroxy C1.7 alkyl, C1.7 alkyl C3-4 cycloalkyl C1.7 alkyl, (C1.7 alkyl)2 C3-7 cycloalkyl C1.7 alkyl, dihalogen C1.7 alkyl, -CH (C3-7 cycloalkyl)(dihalogen C1.7 alkyl), adamantane C1.7 alkyl, bicyclopentane C1.7 alkyl, -CH2-CH3, -CH(CI-7 alkyl)(hydroxy C3-7 cycloalkyl), -CH2-CH(CH2OH)- CH2-CH3, -CH(CH2OH)-CH2-CH2-CH3, -CH(CH2OH)-CH2-CH2-CH2-CH3, -CH(CH2- CH2OH)-CH-(CH3)2, -CH(CH(CH3)2)-C(OH(CH3)2), -C(CH3)2-C3-7 cycloalkyl, -CH2- CH-(CI-7 alkyl)(C2-7 alkyl), methoxy C3-7 alkyl, -CH(R7)CH2-ORs, -C1.7 alkyl-NH-C(O)- C2-7 alkenyl or C1.7 alkoxy carbonyl C1.7 alkyl, wherein R7 is C3-7 cycloalkyl, and Rs is hydrogen or C1.7 alkyl; or Zi is CX and Rn is -CF3; or B is oxazolidin-2-one; or Rio is -SO2-NR21R22; or Rn is cyclopropyl; or Zi and Z2 is N, and Rio is -CH(CH3)-NR2iR22; wherein the optional substitution, in each occurrence is 1-2 substituents independently selected from C1.7 alkyl, C3-7 cycloalkyl, halogen, hydroxy, C1.7 alkoxy, halogen C1.7 alkyl and cyano.

[0065] According to one embodiment, specifically provided are compounds according to formula (I) wherein Ri is hydrogen, halogen, C1.7 alkyl or C3-7 cycloalkyl.

[0066] According to one embodiment, specifically provided are compounds according to formula (I) wherein Ri is hydrogen or halogen.

[0067] According to one embodiment, specifically provided are compounds according to formula (I) wherein Ri is halogen. According to one embodiment, specifically provided are compounds according to formula (I) wherein R2 is C2-7 alkoxy, halogen C1.7 alkoxy, cyano C1.7 alkoxy, C1.7 alkoxy C1.7 alkoxy, hydroxy C1.7 alkyl, hydroxy C1.7 alkoxy or -NHR9 and A is (1 ’ ’).

[0068] According to one embodiment, specifically provided are compounds according to formula (I) wherein R2 is hydrogen, or -NHR9.

[0069] According to one embodiment, specifically provided are compounds according to formula (I) wherein R2 is hydrogen.

[0070] According to one embodiment, specifically provided are compounds according to formula (I) wherein R2 is C2-7 alkoxy, halogen C1.7 alkoxy, cyano C1.7 alkoxy, C1.7 alkoxy C1.7 alkoxy, or hydroxy C1.7 alkoxy.

[0071] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein R2 is -NHR9. In a subgroup of the preceding embodiment are compounds wherein R9 is C1.7 alkyl.

[0072] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein R2 is C2-7 alkoxy. According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein R9 is C1.7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1.7 alkyl.

[0073] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein R9 is halogen C1.7 alkyl, C1.7 alkoxy C1.7 alkyl, cyano C1.7 alkyl or cyano C1.7 alkyl C3-7 cycloalkyl, hydroxy C1.7 alkyl or oxetanyl.

[0074] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein A is (1”). According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein R5 is methyl.

[0075] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments, wherein R21 is -CH(R7)CH2-ORs. According to yet another embodiment, specifically provided are compounds wherein R21 is -CH2-CH-(Ci.7alkyl)(C2-7 alkyl).

[0076] According to yet another embodiment, specifically provided are compounds wherein R21 is -CH(CH2OH)-CH2-CH2-CH3 or -CH(CH2OH)-CH2-CH2-CH2-CH3.

[0077] According to yet another embodiment, specifically provided are compounds wherein R21 is dihalogen C1.7 alkyl. According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein R3 is any of the following groups:

[0078] In a subgroup of the preceding embodiment are compounds wherein R3 is group (lb’).

[0079] According to one embodiment, R3 is the following group: diment, R3 is the following group:

[0080] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein Rn is C1.7 alkyl, C3-7 cycloalkyl or halogen C1.7 alkyl.

[0081] In a subgroup of the preceding embodiment are compounds wherein Rn is methyl or -CF3.

[0082] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein, with the proviso that when R2 is hydrogen and A is (2”), then R21 is -SO2-C2-7 alkyl, -SO2-C3-7 cycloalkyl, -SCh-hydroxy C1.7 alkyl, C1.7 alkyl C3-4 cycloalkyl C1.7 alkyl, (C1.7 alkyl)2 C3-7 cycloalkyl C1.7 alkyl, dihalogen C1.7 alkyl, -CH (C3-7 cycloalkyl)( dihalogen C1.7 alkyl), adamantane C1.7 alkyl, bicyclopentane C1.7 alkyl, -CH2-CH3, -CH(CI-7 alkyl)(hydroxy C3-7 cycloalkyl, -CH2-CH-(CI-7 alkyl)(C2-7 alkyl), methoxy C3-7 alkyl, -CH(R?)CH2-OR8, -C1.7 alkyl-NH-C(O)-C2-7 alkenyl or C1.7 alkoxy carbonyl C1.7 alkyl, wherein R7 is C3-7 cycloalkyl, and Rs is hydrogen or C1.7 alkyl; or Zi is CX and Rn is -CF3; or B is oxazolidin-2-one; or Rio is -SO2-NR21R22; or Rn is cyclopropyl; or Zi and Z2 is N, and Rio is -CH(CH3)-NR2iR22; wherein the optional substitution, in each occurrence is 1-2 substituents independently selected from C1.7 alkyl, C3-7 cycloalkyl, halogen, hydroxy, C1.7 alkoxy, halogen C1.7 alkyl and cyano.

[0083] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein Rio and R14 is -C1.7 alkyl-NR2iR22.

[0084] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein Rio and R14 are independently -C1.7 alkyl-NR2iR22.

[0085] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein R21 is C1.7 alkyl, C3-7 cycloalkyl Ci- 7 alkyl, hydroxy C1.7 alkyl, C1.7 alkoxy C3-7 cycloalkyl C1.7 alkyl, halogen C1.7 alkyl, (hydroxy)(C3-7 cycloalkyl) C1.7 alkyl or C1.7 alkyl C3-7 cycloalkyl C1.7 alkyl.

[0086] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein R22 is hydrogen.

[0087] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein Rw and R14 is a group wherein -L- is -CH2- or -CH(CH3)-.

[0088] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein Rw is a group — xR18t-L-b B -R19

[0089] - ^R20

[0090] (1’) wherein -L- is -CH2- or -CH(CHa)-. According to yet another embodiment, specifically provided are compounds according to any of the above embodiments wherein B is any of the following groups: According to yet another embodiment, specifically provided are compounds according to any of the above embodiments, wherein B is group (2j’).

[0091] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments where compounds are represented by formula (la) wherein

[0092] R-2 is C2-7 alkoxy, halogen C1.7 alkoxy, cyano C1.7 alkoxy, C1.7 alkoxy C1.7 alkoxy or -

[0093] NHR9 and Rio is -C1.7 alkyl-NHRii.

[0094] According to yet another embodiment, specifically provided are compounds according to any of the above embodiments where compounds are represented by formula (lb) wherein R.2 is hydrogen, C2-7 alkoxy, halogen C1.7 alkoxy, cyano C1.7 alkoxy, C1.7 alkoxy C1.7 alkoxy or -NHR9 and Rio is -C1.7 alkyl-NHRii.

[0095] According to one embodiment, specifically provided are the following compounds:

[0096] or a pharmaceutically acceptable salt thereof.

[0097] According to one embodiment, specifically provided are the following compounds: or a pharmaceutically acceptable salt thereof. According to yet another embodiment, the present invention provides a method for the treatment of a disease or condition wherein 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.

[0098] According to yet another embodiment, the present invention provides a method for the treatment of a disease or condition wherein inhibition of Cbl-b is desired, such as cancer, comprising 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.

[0099] In some embodiments, the disease or condition wherein inhibition of Cbl-b is desired is cancer.

[0100] In some embodiments, the disease or condition wherein inhibition of Cbl-b is desired is cancer, wherein the cancer is 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.

[0101] In some embodiments, the disease or condition mediated by Cbl-b is colon cancer.

[0102] In some embodiments, the disease or condition mediated by Cbl-b is nonHodgkin’s lymphoma.

[0103] In some embodiments, the disease or condition mediated by Cbl-b is solid tumor.

[0104] In some embodiments, the disclosure provides a method 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.

[0105] In some embodiments, the present disclosure provides a method further comprising administering an additional anti-cancer agent.

[0106] In some embodiments, the present disclosure provides a method wherein the additional anti-cancer agent is a chemotherapeutic agent or an immune checkpoint inhibitor. In some embodiments, the present disclosure provides a method wherein the additional anti-cancer agent is an immune checkpoint inhibitor.

[0107] In some embodiments, the present disclosure provides a method wherein the immune checkpoint inhibitor is PD-1, PD-L1 or CTLA-4 antagonist.

[0108] In some embodiments, the present disclosure provides a method wherein the immune checkpoint inhibitor is PD-1 or PD-L1 antagonist.

[0109] In some embodiments, the present disclosure provides a method wherein the PD- 1 antagonist is an anti -PD-1 antibody and the PD-L1 antagonist is an anti-PD-Ll antibody.

[0110] In some embodiments, the present disclosure provides a method wherein a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and the anti-cancer agent are administered simultaneously or sequentially.

[0111] According to one embodiment, the invention 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.

[0112] In some embodiments, the present application provides a compound selected from the group consisting of:

[0113] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-((((l- methylcyclopropyl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 1);

[0114] ((R)-6-(4-Fluoro-2-(4-methyl-4H- 1,2, 4-triazol-3-yl)phenyl)-2-(4-(((l -meth oxy- 3-methylbutan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 2);

[0115] 2-(4-((((3,3-Dimethylcyclobutyl)methyl)amino)methyl)-6-methylpyridin-2-yl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 3);

[0116] (R)-6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((l -hydroxy-4- methylpentan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 4);

[0117] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-((((l- methylcyclobutyl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 5); (R)-2-(4-(((l-Cyclopropyl-2-hydroxyethyl)amino)methyl)-6-methylpyridin-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 6);

[0118] (R)-6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((2-hydroxy- 2,4-dimethylpentan-3-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 7);

[0119] 2-(4-(((3,3-Difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 8);

[0120] (R)-6-(4-Fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)-2-(4-(((l -(1 - hydroxy cyclopropyl)-2-methylpropyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin- 1-one (Compound 9);

[0121] 6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((l -hydroxy-4- methylpentan-3-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound

[0122] 10);

[0123] (R)-6-(4-Fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)-2-(4-(((l - hydroxyhexan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound

[0124] 11);

[0125] 2-(4-(((Bicyclo[l.l.l]pentan-l-ylmethyl)amino)methyl)-6-methylpyri din-2 -yl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 12);

[0126] (R)-6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((l -hydroxy- pentan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 13);

[0127] 2-(4-(((((3r,5r,7r)-Adamantan-l-yl)methyl)amino)methyl)-6-methylpyri din-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 14);

[0128] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(((2- methylbutyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 15);

[0129] Methyl 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)butanoate (Compound 16);

[0130] 2-(4-(((l-Cyclopropyl-2-methoxyethyl)amino)methyl)-6-methylpyridin-2-yl)-6- (4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 17);

[0131] 2-(4-(((4,4-Difluorobutyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 18); 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((2-methoxy-2- methylpropyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 19);

[0132] 2-(4-(((2-Cyclopropylpropan-2-yl)amino)methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 20);

[0133] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((2-

[0134] (hydroxymethyl)butyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 21);

[0135] 2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4Z / -l,2,4-triazol-3-yl) phenyl)-4-propoxyisoindolin-l-one (Compound 22);

[0136] 2-(4-((Ethylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 23);

[0137] 2-(6-Cyclopropyl-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 24);

[0138] 2-(5-(((Cyclopropylmethyl)amino)methyl)-2-fluoro-3-(trifluoromethyl)phenyl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 25);

[0139] 2-(4-(((Cyclopropylmethyl)amino)methyl-d2)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 26);

[0140] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6,7-dihydro-5H-cyclopenta[b]- pyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 27);

[0141] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(methylamino)isoindolin-l-one (Compound 28);

[0142] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-(ethyl- amino)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 29);

[0143] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(isobutylamino)isoindolin-l-one (Compound 30);

[0144] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-ethoxy-6-(4- fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 31);

[0145] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-isobutoxyisoindolin-l-one (Compound 32); 4-((2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)- 1 -oxoisoindolin-4-yl)oxy)- butanenitrile (Compound 33);

[0146] 4-(Butylamino)-2-(4-(((cy cl opropylmethyl)amino)methyl)-6-methylpyri din-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 34);

[0147] (7?)-3-((2-(6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-l -oxoisoindo- lin-2-yl)-6-methylpyridin-4-yl)methyl)-4-propyloxazolidin-2-one (Compound 35);

[0148] 2-(4-(Aminomethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- 1,2,4- triazol-3-yl)phenyl)isoindolin-l-one (Compound 36);

[0149] N-((2-(6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin- 2-yl)-6-methylpyridin-4-yl)methyl)propane-2-sulfonamide (Compound 37);

[0150] 2-(6-(l-((Cyclopropylmethyl)amino)ethyl)-2-methylpyrimidin-4-yl)-6-(4-fluoro- 2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 38);

[0151] 2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (5-methyl-lZ / -l,2,3-triazol-4-yl) phenyl) isoindolin-l-one (Compound 39);

[0152] (2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(5-methyl-lH- l,2,3-triazol-4-yl)phenyl)isoindolin-l-one (Compound 40);

[0153] 2-(4-(((3,3-Difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (5-methyl- 1H- 1,2,3 -triazol-4-yl)phenyl)isoindolin- 1 -one (Compound 41);

[0154] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(propylamino)isoindolin-l-one (Compound 42);

[0155] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-((3,3,3-trifluoropropyl)amino)isoindolin-l- one (Compound 43);

[0156] 4-((2-Cyclopropylethyl)amino)-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 44);

[0157] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-4-((2 -methoxy ethyl)amino)isoindolin-l-one (Compound 45); 2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-4-(ethylamino)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 46);

[0158] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-4-(2-methoxy ethoxy )isoindolin-l -one (Compound 47);

[0159] 4-((2-(4-((Butylamino)methyl)-6-methylpyri din-2 -yl)-6-(4-fluoro-2-(4-methyl- 4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin-4-yl)oxy)butanenitrile (Compound 48);

[0160] 4-Butoxy-2-(4-(((cy cl opropylmethyl)amino)methyl)-6-methylpyri din-2 -yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 49);

[0161] 2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-4-ethoxy-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 50);

[0162] 2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- l,2,4-triazol-3-yl)phenyl)-4-propoxyisoindolin-l-one (Compound 51);

[0163] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(oxetan-3-ylamino)isoindolin-l-one (Compound 52);

[0164] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-((2,2- difluoroethyl)amino)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-

[0165] 1-one (Compound 53);

[0166] 2-Chloro-N-(cyclopropylmethyl)-6-(6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3- yl)phenyl)-l-oxoisoindolin-2-yl)pyridine-4-sulfonamide (Compound 54);

[0167] 2-Chloro-6-(6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoiso- indolin-2-yl)-N-(2-hydroxy-2-methylpropyl)pyridine-4-sulfonamide (Compound 55);

[0168] 2-(4-(((3,3-difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-4-(ethylamino)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one(compound 56);

[0169] 2-(4-(((3,3-difluoropropyl)amino)methyl)-6-methylpyri din-2 -yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-propoxyisoindolin-l-one(compound 57);

[0170] 2-(4-(((3,3-difluoropropyl)amino)methyl)-6-methylpyri din-2 -yl)-4-ethoxy-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one(compound 58);

[0171] 4-((2-(4-(((3,3-difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-

[0172] 2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin-4-yl)oxy)butanenitrile (compound 59); N-((2-(6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin-2- yl)-6-methylpyridin-4-yl)methyl)- 1 -hydroxymethanesulfonamide(compound 60);

[0173] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(2-hydroxypropan-2-yl)isoindolin-l- one(compound 61);

[0174] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(l-hydroxyethyl)isoindolin-l-one(compound 62);

[0175] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-(2,2- difluoroethoxy)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l- one(compound 63);

[0176] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-(3,3- difluoropropoxy)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l- one(compound 64);

[0177] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(2-hydroxyethoxy)isoindolin-l- one(compound 65); and

[0178] 2-(4-(((l-Cyclopropyl-3,3-difluoropropyl)amino)methyl)-6-methyl-pyridin-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one(compound 66); or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0180] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament.

[0181] In some embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutical acceptable salt or a stereoisomer thereof, for use in the treatment of a disease or condition wherein inhibition of Cbl-b is desired.

[0182] According to one embodiment, a compound for use according to any of the above embodiments, wherein the disease is cancer. According to one embodiment, a compound for use according to any of the above embodiments, wherein the cancer is 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.

[0183] According to one embodiment, a compound for use according to any of the above embodiments, 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.

[0184] According to one embodiment, the disease is cancer.

[0185] According to one embodiment, the cancer is 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.

[0186] According to one embodiment, the disclosure provides a pharmaceutical composition comprising a compound according to any of the above embodiments together with a pharmaceutically acceptable carrier.

[0187] The compounds of the invention can be prepared by a variety of synthetic routes analogously to the methods known in the literature using suitable starting materials. The compounds according to formula (I) can be prepared e.g. analogously or according to the following reaction Schemes. Some compounds included in the formula (I) can be obtained by converting the functional groups of the other compounds of formula (I) obtained in accordance with the following Schemes, by well known reaction steps such as oxidation, reduction, hydrolysis, acylation, alkylation, amidation, amination, sulfonation and others. It should be noted that any appropriate leaving groups, e.g. N- protecting groups, such as a t-butoxycarbonyl (t-BOC) group or a phenyl sulfonyl group, can be used in well-known manner during the syntheses in order to improve the selectivity of the reaction steps. Compounds of formula (I) can be prepared, for example, according to Scheme 1, wherein A, Ri, R2, R3 and R4 are as defined above and X is a halogen, for example chloro, bromo or iodo. In the method of Scheme 1, the compound of formula [la] is reacted with a halogen compound of formula [lb] in a suitable solvent, such as 1,4- dioxane or DMF, in the presence of a base such as cesium carbonate, and a suitable catalyst system such as a combination Pd2dba3 and 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos), or copper(I) iodide and potassium iodide, to produce a compound of formula (I).

[0188] Compounds of formula (I), wherein R3 is group of formula (la) can also be prepared, for example, according to Scheme 2, wherein A, Ri, R2, R4, R11, R21, Zi and Z2 are as defined above and X is a halogen, for example chloro, bromo or iodo. In the method of Scheme 2, the compound of formula [2a] is reacted with an amine compound of formula [2b] in a suitable solvent, such as acetonitrile, in the presence of a base such as potassium carbonate, to produce a compound of formula [2c],

[0189] Alternatively, the compounds of formula (1), wherein R3 is group of formula (la), can be prepared according to Scheme 3, wherein A, Ri, R2, R4, Ru, R21, Zi and Z2 are as defined above and X is a halogen, for example chloro, bromo or iodo. In the method of Scheme 3, the compound of formula [3a] is reacted with a halogen compound of formula [3b] in a suitable solvent, such as THF, in the presence of a suitable base such as triethylamine and a suitable catalyst such as 4-dimethylamino- pyridine (DMAP), to produce a compound of formula [2c],

[0190] Intermediate compounds can be prepared according to the methods disclosed in the literature or as disclosed in the present disclosure.

[0191] For example, intermediate compounds of formula [la] can be prepared, for example, according to Scheme 4, wherein Ri, R2, and R4 are as defined above and X is a halogen, for example chloro or bromo. In the method of Scheme 4, the compound of formula [4a] is reacted with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxa- borolan-2-yl)-l,3,2-dioxaborolane in a suitable solvent such as 1,4-dioxane in the presence of potassium acetate and [l,l'-bis(diphenylphosphino)ferrocene]dichloro- palladium(II) complex to produce a compound of formula [4b], The obtained compound of formula [4b] is then coupled with the halogen compound of formula [4c] in a suitable solvent, such as dioxane / water mixture, in the presence of a suitable base such as K2CO3 and a suitable catalyst such as Pd(amphos)C12 to produce the intermediate compound of formula [la].

[0192] Alternatively, the compounds of formula (I) can be prepared as disclosed in the specific Examples of the present disclosure.

[0193] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention.

[0194] The term “subject”, as employed herein, refers to humans and animals.

[0195] The term “halo” or “halogen”, as employed herein as such or as part of another group, refers to chlorine, bromine, fluorine or iodine. Preferred halogens are chlorine and bromine and fluorine.

[0196] The term “C1.7 alkyl”, as employed herein as such or as part of another group, refers to a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, 6 or 7 carbon atom(s). Representative examples of C1.7 alkyl include, but are not limited to, methyl, ethyl, / / -propyl, Ao-propyl, / / -butyl, Ao-butyl, .scc-butyl, Zc / 7-butyl, / / -pentyl, Ao-pentyl and / / -hexyl. One preferred embodiment of “C1.7 alkyl” is C1.3 alkyl. The term “C1.3 alkyl” refers to an embodiment of “C1.7 alkyl” having 1, 2 or 3 carbon atoms. Examples of “C1.3 alkyl” include, but are not limited to, methyl, ethyl, / / -propyl and Ao-propyl. One preferred “C1.7 alkyl” is methyl group.

[0197] The term “C2-7 alkenyl”, as employed herein as such or as part of another group, refers to an aliphatic hydrocarbon group having 2, 3, 4, 5, 6 or 7 carbon atoms and containing one or several double bonds. Representative examples include, but are not limited to, ethenyl, propenyl and hexenyl. One preferred embodiment of “C2-7 alkenyl” is C2-4 alkenyl. The term “C2-4 alkenyl” refers to an embodiment of “C2-7 alkenyl” having 2, 3 or 4 carbon atoms. Representative examples include, but are not limited to, ethenyl, propenyl and butenyl. One preferred “C2-7 alkenyl” is -CH=CH2 group.

[0198] The term “5-6 membered carbocyclic ring”, as employed herein, refers to a saturated, partially saturated or aromatic ring with 5 or 6 ring atoms consisting of carbon atoms only. Representative examples of a 5-6 membered carbocyclic ring include, but are not limited to, phenyl, cyclohexyl, cyclohexenyl, cyclopentyl, and cyclopentenyl rings.

[0199] The term “C3-7 cycloalkyl”, as employed herein as such or as part of another group, refers to a saturated monocyclic or bicyclic (fused, bridged or in spiro configuration) hydrocarbon ring containing 3, 4, 5, 6 or 7 ring atoms consisting of carbon atoms only. Representative examples of C3-7 cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and spiro(3,3)heptane. One preferred C3-7 cycloalkyl group is a saturated monocyclic hydrocarbon ring containing 3, 4, 5, 6 or 7 ring atoms consisting of carbon atoms only, for example cyclopropyl group.

[0200] The term “C3-6 cycloalkyl C1.7 alkyl”, as employed herein as such or as part of another group, refers to a C3-6 cycloalkyl group as defined herein, appended to the parent molecular moiety through a C1.7 alkyl group, as defined herein.

[0201] The term “C1.7 alkyl C3-7 cycloalkyl” as employed herein as such or as part of another group, refers to a C1.7 alkyl group as defined herein, appended to the parent molecular moiety through a C3-7 cycloalkyl group, as defined herein.

[0202] The term “halogen C3-7 cycloalkyl” as employed herein as such or as part of another group, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a C3-7 cycloalkyl group, as defined herein.

[0203] The term “halogen C3-7 cycloalkyl C1.7 alkyl” as employed herein as such or as part of another group, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a C3-7 cycloalkyl C1.7 alkyl group, as defined herein.

[0204] The term “hydroxy”, as employed herein as such or as part of another group, refers to an -OH group. The term “cyano”, as employed herein as such or as part of another group, refers to a -CN group.

[0205] The term “carboxy”, as employed herein as such or as part of another group, refers to -COOH group.

[0206] The term “carbonyl”, as employed herein as such or as part of another group, refers to a carbon atom double-bonded to an oxygen atom (C=O).

[0207] The term “oxo”, as employed herein as such or as part of another group, refers to oxygen atom linked to another atom by a double bond (=0).

[0208] The term “C1.7 alkoxy”, as employed herein as such or as part of another group, refers to C1.7 alkyl, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of C1.7 alkoxy include, but are not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, .scc-butoxy and Zc / V-butoxy. One preferred embodiment of “C1.7 alkoxy” is C1.3 alkoxy. The term “C1.3 alkoxy” refers to an embodiment of “C1.7 alkoxy” having 1, 2 or 3 carbon atoms. Representative examples of C1.3 alkoxy include, but are not limited to methoxy, ethoxy, propoxy. One preferred “C1.7 alkoxy” group is methoxy.

[0209] The term “hydroxy C1.7 alkyl”, as employed herein, refers to at least one hydroxy group, as defined herein, appended to the parent molecular moiety through a C1.7 alkyl group, as defined herein. Representative examples of hydroxy C1.7 alkyl include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1 -hydroxy ethyl, 3 -hydroxypropyl, 1 -hydroxypropyl, 1 -methyl- 1 -hydroxy ethyl and 1 -methyl- 1-hydroxypropyl.

[0210] The term “halogen C1.7 alkyl”, as employed herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a C1.7 alkyl group, as defined herein. Representative examples of halogen C1.7 alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl and 3 -bromopropyl. Preferred “halogen C1.7 alkyl” groups are trifluoromethyl, trifluoroethyl and tri fluoropropyl.

[0211] The term “dihalogen C1.7 alkyl”, as employed herein, refers to two halogen atoms, as defined herein, appended to the parent molecular moiety through a C1.7 alkyl group, as defined herein. Representative examples of dihalogen C1.7 alkyl group include, but are not limited to, 1,1 -difluoropropyl, 1,1 -difluoropropyl, 1,1 -di chloropropyl, 1,1- difluoroethyl.

[0212] The term “halogen C1.7 alkoxy”, as employed herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a C1.7 alkoxy group, as defined herein.

[0213] The term “C1.7 alkoxy C1.7 alkyl”, as employed herein as such or as part of another group, refers to at least one C1.7 alkoxy group, as defined herein, appended to the parent molecular moiety through a C1.7 alkyl group, as defined herein.

[0214] The term “3-6 membered heterocyclic ring” as employed herein, refers to saturated, partially saturated or aromatic ring with 3-6 ring atoms, of which 1-3 atoms are heteroatoms selected from a group consisting of N, O and S. Representative examples of a 3-6 membered heterocyclic ring include, but are not limited to, oxetanyl, azetidinyl, oxiranyl, pyrazolyl, pyrimidinyl, pyridinyl, piperidinyl, piperazinyl, furanyl, l,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.

[0215] The term “5-6 membered heterocyclic ring” as employed herein, refers to saturated, partially saturated or aromatic ring with 5-6 ring atoms, of which 1-4 atoms are heteroatoms selected from a group consisting of N, O and S. Representative examples of a 5-6 membered heterocyclic ring 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, pyridinyl, piperidinyl, piperazinyl, furanyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, thiazolyl, isoxazolyl, pyrazinyl, tetrahydropyranyl, oxazolyl and imidazolyl rings.

[0216] The term “5-10 membered monocyclic, bicyclic or spiro bicyclic heterocyclic ring”, as employed herein, refers to a saturated, partially saturated or aromatic monocyclic or bicyclic (fused, bridged or in spiro configuration) ring system with 5 to 10 ring atoms, of which 1-4 atoms are heteroatoms selected from a group consisting of N, O and S. Representative examples of a “5-10 membered monocyclic, bicyclic or spiro bicyclic heterocyclic ring” 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]decan-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. l]heptan-2-yl, l,5,6,7-tetrahydro-4H- pyrazolo[4,3-b]pyridin-4-yl,l,2,4-triazol-l-yl, 1,2, 3 -triazol- 1-yl, pyrimidinyl, pyridinyl, tetrazolyl, furanyl, tetrahydrofuranyl, thiazolyl, isoxazolyl, pyrazinyl, tetrahydropyranyl, 1,2,4-oxadiazolyl, oxazolyl, indolyl and 4,5-dihydroimidazolyl rings.

[0217] The term “spiro bicyclic ring”, as employed herein, refers to a ring system where the two rings have one common carbon atom.

[0218] The term “bicyclic ring”, as employed herein, refers to a saturated, partially saturated or aromatic ring system where the two rings are fused (have two common ring atoms) or bridged (share three or more common ring atoms).

[0219] The term "substituted" as used herein in connection with various residues refers to, if not otherwise defined, to halogen substituents, such as fluorine, chlorine, bromine, iodine, or C1.7 alkyl, C3-7 cycloalkyl, hydroxy, amino, nitro, cyano, thiol C1.7 alkyl, methylsulfonyl, C1.7 alkoxy, halo C1.7 alkyl, hydroxy C1.7 alkyl or amino C1.7 alkyl substituents. Preferred are halogen, C1.7 alkyl, hydroxy, amino, halo C1.7 alkyl, C1.7 alkoxy and methyl sulfonyl substituents. In one group of preferred substituents are 1-2 substituents selected from C1.7 alkyl or halogen substituents, particularly C1.3 alkyl or halogen substituents, particularly methyl, ethyl, chloro, fluoro or bromo substituents.

[0220] The "substituted" groups may contain 1 to 3, preferably 1 or 2, of the above mentioned substituents, if not otherwise defined.

[0221] Optically active enantiomers or diastereomers of compounds of formula (I) can be prepared e.g. by resolution of the racemic end 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 a racemic starting material thereof can be carried out, for example, by converting the racemic compound into its diastereomeric salt mixture by reaction with an optically active acid and subsequent separation of the diastereomers by crystallization. Representative examples of said optically active acids include, but are not limited to, D-tartaric acid and dibenzoyl-D-tartaric acid. Alternatively, preparative chiral chromatography may be used for resolution of the racemic mixture. Pharmaceutically acceptable salts are well known in the field of pharmaceuticals. Non-limiting examples of suitable salts include metal salts, ammonium salts, salts with an organic base, salts with an inorganic acid, salts with organic acid, and salts with basic or acidic amino acid. Non-limiting examples of metal salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, and magnesium salt. Non-limiting examples of salts with inorganic or organic acids include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates, acetates, oxalates, fumarates, hemifumarates, and succinates. Pharmaceutically acceptable esters, when applicable, may be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals and that retain the pharmacological properties of the free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl esters. Phosphate esters and carbonate esters, are also within the scope of the invention.

[0222] The definition of formula (I) above is inclusive of all the possible isotopes and isomers, such as stereoisomers, of the compounds, including geometric isomers, for example Z and E isomers (cis and trans isomers), and optical isomers, e.g. diastereomers and enantiomers, and prodrug esters, e.g. phosphate esters and carbonate esters. The term, “isotope as used herein refers to the compound of formula (I) wherein one or more atoms of compound of formula (I) are substituted by their respective isotopes. For example, isotopes of hydrogen include2H (deuterium or D) and3H (tritium).

[0223] It will be appreciated by those skilled in the art that the present compounds may contain at least one chiral center. Accordingly, the compounds may exist in optically active or racemic forms. It is to be understood that the formula (I) includes any racemic or optically active form, or mixtures thereof. In one embodiment, the compounds are the pure (R)-isomers. In another embodiment, the compounds are the pure (S)-isomers. In another embodiment, the compounds are a mixture of the (R) and the (S) isomers. In another embodiment, the compounds are a racemic mixture comprising an equal amount of the (R) and the (S) isomers. The compounds may contain two chiral centres. In such case, according to one embodiment, the compounds are a mixture of diastereomers. According to another embodiment, the compounds of the invention are a mixture of enantiomers. According to still another embodiment, the compounds are pure enantiomers. The individual isomers may be obtained using the corresponding isomeric forms of the starting material or they may be separated after the preparation of the end compound according to conventional separation methods. For the separation of optical isomers, e.g. enantiomers or diastereomers, from the mixture thereof the conventional resolution methods, e.g. fractional crystallisation, may be used.

[0224] The present compounds may also exist as tautomers or equilibrium mixtures thereof wherein a proton of a compound shifts from one atom to another. Examples of tautomerism include, but are not limited to, amido-imido, keto-enol, phenol-keto, oxime-nitroso, nitro-aci, imine-enamine, annular tautomerism of heterocyclic rings such as pyrozole ring, and the like. Tautomeric forms are intended to be encompassed by compounds of formula (I), even though only one tautomeric form may be depicted.

[0225] Examples of preferred compounds of the invention include:

[0226] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-((((l- methylcyclopropyl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 1);

[0227] ((R)-6-(4-Fluoro-2-(4-methyl-4H- 1,2, 4-triazol-3-yl)phenyl)-2-(4-(((l -meth oxy- 3-methylbutan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 2);

[0228] 2-(4-((((3,3-Dimethylcyclobutyl)methyl)amino)methyl)-6-methylpyridin-2-yl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 3);

[0229] (R)-6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((l -hydroxy-4- methylpentan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 4);

[0230] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-((((l- methylcyclobutyl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 5);

[0231] (R)-2-(4-(((l-Cyclopropyl-2-hydroxyethyl)amino)methyl)-6-methylpyridin-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 6);

[0232] (R)-6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((2 -hydroxy- 2,4-dimethylpentan-3-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 7); 2-(4-(((3,3-Difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 8);

[0233] (R)-6-(4-Fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)-2-(4-(((l -(1 - hydroxy cyclopropyl)-2-methylpropyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin- 1-one (Compound 9);

[0234] 6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((l -hydroxy-4- methylpentan-3-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound

[0235] 10);

[0236] (R)-6-(4-Fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)-2-(4-(((l - hydroxyhexan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound

[0237] 11);

[0238] 2-(4-(((Bicyclo[l.l.l]pentan-l-ylmethyl)amino)methyl)-6-methylpyri din-2 -yl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 12);

[0239] (R)-6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((l -hydroxy- pentan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 13);

[0240] 2-(4-(((((3r,5r,7r)-Adamantan-l-yl)methyl)amino)methyl)-6-methylpyri din-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 14);

[0241] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(((2- methylbutyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 15);

[0242] Methyl 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)butanoate (Compound 16);

[0243] 2-(4-(((l-Cyclopropyl-2-methoxyethyl)amino)methyl)-6-methylpyridin-2-yl)-6- (4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 17);

[0244] 2-(4-(((4,4-Difluorobutyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 18);

[0245] 6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((2-m ethoxy-2- methylpropyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 19);

[0246] 2-(4-(((2-Cyclopropylpropan-2-yl)amino)methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 20);

[0247] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((2-(hydroxy- methyl)butyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 21); 2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4Z / -l,2,4-triazol-3-yl) phenyl)-4-propoxyisoindolin-l-one (Compound 22);

[0248] 2-(4-((Ethylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 23);

[0249] 2-(6-Cyclopropyl-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 24);

[0250] 2-(5-(((Cyclopropylmethyl)amino)methyl)-2-fluoro-3-(trifluoromethyl)phenyl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 25);

[0251] 2-(4-(((Cyclopropylmethyl)amino)methyl-d2)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 26);

[0252] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6,7-dihydro-5H-cyclopenta[b]- pyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 27);

[0253] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(methylamino)isoindolin-l-one (Compound 28);

[0254] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-(ethyl- amino)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 29);

[0255] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(isobutylamino)isoindolin-l-one (Compound 30);

[0256] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-ethoxy-6-(4- fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 31);

[0257] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-isobutoxyisoindolin-l-one (Compound 32);

[0258] 4-((2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)- 1 -oxoisoindolin-4-yl)oxy)butane- nitrile (Compound 33);

[0259] 4-(Butylamino)-2-(4-(((cy cl opropylmethyl)amino)methyl)-6-methylpyri din-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound (7?)-3-((2-(6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindo- lin-2-yl)-6-methylpyridin-4-yl)methyl)-4-propyloxazolidin-2-one (Compound 35);

[0260] 2-(4-(Aminomethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- 1,2,4- triazol-3-yl)phenyl)isoindolin-l-one (Compound 36);

[0261] N-((2-(6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin- 2-yl)-6-methylpyridin-4-yl)methyl)propane-2-sulfonamide (Compound 37);

[0262] 2-(6-(l-((Cyclopropylmethyl)amino)ethyl)-2-methylpyrimidin-4-yl)-6-(4-fluoro- 2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 38);

[0263] 2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (5-methyl-lZ / -l,2,3-triazol-4-yl) phenyl) isoindolin-l-one (Compound 39);

[0264] (2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(5-methyl-lH- l,2,3-triazol-4-yl)phenyl)isoindolin-l-one (Compound 40);

[0265] 2-(4-(((3,3-Difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (5-methyl- 1H- 1,2,3 -triazol-4-yl)phenyl)isoindolin- 1 -one (Compound 41);

[0266] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(propylamino)isoindolin-l-one (Compound 42);

[0267] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-((3,3,3-trifluoropropyl)amino)isoindolin-l- one (Compound 43);

[0268] 4-((2-Cyclopropylethyl)amino)-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 44);

[0269] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-4-((2 -methoxy ethyl)amino)isoindolin-l-one (Compound 45);

[0270] 2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-4-(ethylamino)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 46);

[0271] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-4-(2-methoxy ethoxy )isoindolin-l -one (Compound 47);

[0272] 4-((2-(4-((Butylamino)methyl)-6-methylpyri din-2 -yl)-6-(4-fluoro-2-(4-methyl- 4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin-4-yl)oxy)butanenitrile (Compound 48); 4-Butoxy-2-(4-(((cy cl opropylmethyl)amino)methyl)-6-methylpyri din-2 -yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 49);

[0273] 2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-4-ethoxy-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 50);

[0274] 2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- l,2,4-triazol-3-yl)phenyl)-4-propoxyisoindolin-l-one (Compound 51);

[0275] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(oxetan-3-ylamino)isoindolin-l-one (Compound 52);

[0276] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-((2,2-di- fluoroethyl)amino)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l- one (Compound 53);

[0277] 2-Chloro-N-(cyclopropylmethyl)-6-(6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3- yl)phenyl)-l-oxoisoindolin-2-yl)pyridine-4-sulfonamide (Compound 54);

[0278] 2-Chloro-6-(6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoiso- indolin-2-yl)-N-(2-hydroxy-2-methylpropyl)pyridine-4-sulfonamide (Compound 55); or a tautomer or a pharmaceutically acceptable salt thereof.

[0279] Examples of compounds of the invention include:

[0280] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-((((l- methylcyclopropyl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 1);

[0281] ((R)-6-(4-Fluoro-2-(4-methyl-4H- 1,2, 4-triazol-3-yl)phenyl)-2-(4-(((l -meth oxy- 3-methylbutan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 2);

[0282] 2-(4-((((3,3-Dimethylcyclobutyl)methyl)amino)methyl)-6-methylpyridin-2-yl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 3);

[0283] (R)-6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((l -hydroxy-4- methylpentan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 4);

[0284] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-((((l- methylcyclobutyl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 5);

[0285] (R)-2-(4-(((l-Cyclopropyl-2-hydroxyethyl)amino)methyl)-6-methylpyridin-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 6); (R)-6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((2-hydroxy- 2,4-dimethylpentan-3-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 7);

[0286] 2-(4-(((3,3-Difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 8);

[0287] (R)-6-(4-Fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)-2-(4-(((l -(1 - hydroxy cyclopropyl)-2-methylpropyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin- 1-one (Compound 9);

[0288] 6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((l -hydroxy-4- methylpentan-3-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound

[0289] 10);

[0290] (R)-6-(4-Fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)-2-(4-(((l - hydroxyhexan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound

[0291] 11);

[0292] 2-(4-(((Bicyclo[l.l.l]pentan-l-ylmethyl)amino)methyl)-6-methylpyri din-2 -yl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 12);

[0293] (R)-6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((l -hydroxy- pentan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 13);

[0294] 2-(4-(((((3r,5r,7r)-Adamantan-l-yl)methyl)amino)methyl)-6-methylpyri din-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 14);

[0295] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(((2- methylbutyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 15);

[0296] Methyl 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)butanoate (Compound 16);

[0297] 2-(4-(((l-Cyclopropyl-2-methoxyethyl)amino)methyl)-6-methylpyridin-2-yl)-6- (4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 17);

[0298] 2-(4-(((4,4-Difluorobutyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 18);

[0299] 6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((2-m ethoxy-2- methylpropyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 19);

[0300] 2-(4-(((2-Cyclopropylpropan-2-yl)amino)methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 20); 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((2-(hydroxy- methyl)butyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 21);

[0301] 2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4Z / -l,2,4-triazol-3-yl) phenyl)-4-propoxyisoindolin-l-one (Compound 22);

[0302] 2-(4-((Ethylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 23);

[0303] 2-(6-Cyclopropyl-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 24);

[0304] 2-(5-(((Cyclopropylmethyl)amino)methyl)-2-fluoro-3-(trifluoromethyl)phenyl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 25);

[0305] 2-(4-(((Cyclopropylmethyl)amino)methyl-d2)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 26);

[0306] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6,7-dihydro-5H-cyclopenta[b]- pyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 27);

[0307] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(methylamino)isoindolin-l-one (Compound 28);

[0308] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-(ethyl- amino)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 29);

[0309] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(isobutylamino)isoindolin-l-one (Compound 30);

[0310] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-ethoxy-6-(4- fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 31);

[0311] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-isobutoxyisoindolin-l-one (Compound 32);

[0312] 4-((2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)- 1 -oxoisoindolin-4-yl)oxy)butane- nitrile (Compound 33); 4-(Butylamino)-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 34);

[0313] (7?)-3-((2-(6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-l -oxoisoindo- lin-2-yl)-6-methylpyridin-4-yl)methyl)-4-propyloxazolidin-2-one (Compound 35);

[0314] 2-(4-(Aminomethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- 1,2,4- triazol-3-yl)phenyl)isoindolin-l-one (Compound 36);

[0315] N-((2-(6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin- 2-yl)-6-methylpyridin-4-yl)methyl)propane-2-sulfonamide (Compound 37);

[0316] 2-(6-(l-((Cyclopropylmethyl)amino)ethyl)-2-methylpyrimidin-4-yl)-6-(4-fluoro- 2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 38);

[0317] 2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (5-methyl-lZ / -l,2,3-triazol-4-yl) phenyl) isoindolin-l-one (Compound 39);

[0318] (2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(5-methyl-lH- l,2,3-triazol-4-yl)phenyl)isoindolin-l-one (Compound 40);

[0319] 2-(4-(((3,3-Difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (5-methyl- 1H- 1,2,3 -triazol-4-yl)phenyl)isoindolin- 1 -one (Compound 41);

[0320] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(propylamino)isoindolin-l-one (Compound 42);

[0321] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-((3,3,3-trifluoropropyl)amino)isoindolin-l- one (Compound 43);

[0322] 4-((2-Cyclopropylethyl)amino)-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 44);

[0323] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-4-((2 -methoxy ethyl)amino)isoindolin-l-one (Compound 45);

[0324] 2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-4-(ethylamino)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 46); 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-4-(2-methoxy ethoxy )isoindolin-l -one (Compound 47);

[0325] 4-((2-(4-((Butylamino)methyl)-6-methylpyri din-2 -yl)-6-(4-fluoro-2-(4-methyl- 4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin-4-yl)oxy)butanenitrile (Compound 48);

[0326] 4-Butoxy-2-(4-(((cy cl opropylmethyl)amino)methyl)-6-methylpyri din-2 -yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 49);

[0327] 2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-4-ethoxy-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 50);

[0328] 2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- l,2,4-triazol-3-yl)phenyl)-4-propoxyisoindolin-l-one (Compound 51);

[0329] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(oxetan-3-ylamino)isoindolin-l-one (Compound 52);

[0330] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-((2,2-di- fluoroethyl)amino)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l- one (Compound 53);

[0331] 2-Chloro-N-(cyclopropylmethyl)-6-(6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3- yl)phenyl)-l-oxoisoindolin-2-yl)pyridine-4-sulfonamide (Compound 54);

[0332] 2-Chloro-6-(6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoiso- indolin-2-yl)-N-(2-hydroxy-2-methylpropyl)pyridine-4-sulfonamide (Compound 55);

[0333] 2-(4-(((3,3-difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-4-(ethylamino)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one(compound 56);

[0334] 2-(4-(((3,3-difluoropropyl)amino)methyl)-6-methylpyri din-2 -yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-propoxyisoindolin-l-one(compound 57);

[0335] 2-(4-(((3,3-difluoropropyl)amino)methyl)-6-methylpyri din-2 -yl)-4-ethoxy-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one(compound 58);

[0336] 4-((2-(4-(((3,3-difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro- 2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin-4-yl)oxy)butanenitrile (compound 59);

[0337] N-((2-(6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin-2- yl)-6-methylpyridin-4-yl)methyl)- 1 -hydroxymethanesulfonamide(compound 60); 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(2-hydroxypropan-2-yl)isoindolin-l- one(compound 61);

[0338] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(l-hydroxyethyl)isoindolin-l-one(compound 62);

[0339] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-(2,2- difluoroethoxy)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l- one(compound 63);

[0340] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-(3,3- difluoropropoxy)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l- one(compound 64);

[0341] 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(2-hydroxyethoxy)isoindolin-l- one(compound 65); or

[0342] 2-(4-(((l-Cyclopropyl-3,3-difluoropropyl)amino)methyl)-6-methyl-pyridin-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (compound 66); or a tautomer or a pharmaceutically acceptable salt thereof.

[0343] Examples of particularly preferred compounds of the invention include

[0344] (R)-6-(4-Fluoro-2-(4-methyl-4El-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((l -hydroxy-4- methylpentan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 4);

[0345] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-((((l- methylcyclobutyl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 5);

[0346] (R)-2-(4-(((l-Cyclopropyl-2-hydroxyethyl)amino)methyl)-6-methylpyridin-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 6);

[0347] 2-(4-(((3,3-Difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 8);

[0348] (R)-6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((l -hydroxy- hexan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 11); 2-(4-(((Bicyclo[ 1.1.1 ]pentan-l-ylmethyl)amino)methyl)-6-methylpyri din-2 -yl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 12);

[0349] (R)-6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((l-hydroxy- pentan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 13);

[0350] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(((2- methylbutyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 15);

[0351] 2-(4-(((l-Cyclopropyl-2-methoxyethyl)amino)methyl)-6-methylpyridin-2-yl)-6- (4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 17);

[0352] 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((2-(hydroxy- methyl)butyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 21);

[0353] 2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4Z / -l,2,4-triazol-3-yl) phenyl)-4-propoxyisoindolin-l-one (Compound 22);

[0354] 2-(4-(((Cyclopropylmethyl)amino)methyl-d2)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 26);

[0355] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6,7-dihydro-5H-cyclopenta[b]- pyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 27);

[0356] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-(ethyl- amino)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 29);

[0357] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-ethoxy-6-(4- fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 31);

[0358] 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-isobutoxyisoindolin-l-one (Compound 32);

[0359] 4-((2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)- 1 -oxoisoindolin-4-yl)oxy)- butanenitrile (Compound 33);

[0360] 2-(6-(l-((Cyclopropylmethyl)amino)ethyl)-2-methylpyrimidin-4-yl)-6-(4-fluoro- 2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 38);

[0361] 2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (5-methyl-lZ / -l,2,3-triazol-4-yl) phenyl) isoindolin-l-one (Compound 39);

[0362] (2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(5-methyl-lH- l,2,3-triazol-4-yl)phenyl)isoindolin-l-one (Compound 40); 2-(4-(((3,3-Difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (5-methyl- 1H- 1,2,3 -triazol-4-yl)phenyl)isoindolin- 1 -one (Compound 41);

[0363] 4-Butoxy-2-(4-(((cy cl opropylmethyl)amino)methyl)-6-methylpyri din-2 -yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 49);

[0364] 2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-4-ethoxy-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 50);

[0365] 2-Chloro-6-(6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoiso- indolin-2-yl)-N-(2-hydroxy-2-methylpropyl)pyridine-4-sulfonamide (Compound 55); or a tautomer or a pharmaceutically acceptable salt thereof.

[0366] Compounds of the invention may be administered to a patient in therapeutically effective amounts which range usually from about 0.5 to about 2000 mg, more typically form about 1 to about 500 mg, for example from about 2 to about 100 mg, daily depending on the age, sex, weight, condition of the patient, condition to be treated, administration route and the active ingredient used. The compounds of the invention can be formulated into dosage forms using the principles known in the art. The compound can be given to a patient as such or in combination with suitable pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, emulsions, suspensions or solutions. Suitable carriers, solvents, gel forming ingredients, dispersion forming ingredients, antioxidants, colours, sweeteners, wetting compounds and other ingredients normally used in this field of technology may also be used. The compositions containing the active compound can be given enterally or parenterally, the oral route being the preferred way. The contents of the active compound in the composition is from about 0.5 to 100 %, typically from about 0.5 to about 20 %, per weight of the total composition.

[0367] The compounds of the invention can be given to the subject as the sole active ingredient or in combination with one of more other active ingredients for treatment of a particular disease.

[0368] In the treatment of diseases and conditions wherein inhibition of Cbl-b is desired, such as various cancers, a combination of therapeutic agents and / or other treatments (e.g., radiation therapy) is often advantageous. The second (or third) agent to be administered may have the same or different mechanism of action than the primary therapeutic agent. Accordingly, a compound of the invention may be administered in combination with other anti-cancer treatments useful in the treatment of cancers. For example, a compound of the invention can be packaged together with instructions that the compound is to be used in combination with other anti-cancer agents and treatments for the treatment of cancer. The present invention further comprises combinations of a compound of the invention and one or more additional agents in kit form, for example, where they are packaged together or placed in separate packages to be sold together as a kit, or where they are packaged to be formulated together. According to one embodiment of the invention, the therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is co-administered with one or more anti-cancer agents or pain reliever agents.

[0369] The optional other anti-cancer agents which can be administered in addition to a compound of formula (I) or a pharmaceutically acceptable salt thereof include, but are not limited to, chemotherapeutic agents (e.g. docetaxel and paclitaxel),

[0370] - tyrosine kinase inhibitors including EGFR inhibitors (e.g. gefitinib and osimertinib), VEGFR inhibitors (e.g. bevacizumab) and FGFR inhibitors (e.g. erdafitinib); immune checkpoint inhibitors (e.g. PD-1, PD-L1 or CTLA-4 antagonists such as nivolumab and pembrolizumab), epigenetic modulators (e.g. BET inhibitors and HD AC inhibitors), mTOR inhibitors (e.g. everolimus);

[0371] AKT inhibitors (e.g. ipatasertib); radiopharmaceuticals (e.g. alpharadin);

[0372] GnRH / LHRH analogues (such as leuprorelin);

[0373] - PI3K inhibitors (e.g. idelalisib); and

[0374] CDK4 / 6 inhibitors (e.g. ribocyclib) steroidogenesis inhibitors (e.g. CYP17A1 inhibitors such as abiraterone acetate and seviteronel); and a non-steroidal androgen receptor antagonist (e.g. enzalutamide, apalutamide and darolutamide). The above other therapeutic agents, when employed in combination with a compound of the invention can be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

[0375] In some embodiments, the present disclosure provides compounds for use in a method of treating a disease or disorder in a subject that comprises administering to the subject the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more anti-cancer agents or pain reliever agents.

[0376] In some embodiments, the present disclosure provides compounds for use in a method of treating a disease or disorder in a subject that comprises administering to the subject the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more anti-cancer agents.

[0377] The compounds of the invention can be prepared by a variety of synthetic routes analogously to the methods known in the literature using suitable starting materials. The present invention will be explained in more detail by the following experiments and examples. The experiments and examples are meant only for illustrating purposes and do not limit the scope of the invention defined in claims.

[0378] EXPERIMENTAL

[0379] Intermediate 1. 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)iso- indolin-l-one a) 2-Bromo-5-fluorobenzohydrazide (lb)

[0380] To a solution of methyl 2-bromo-5-fluorobenzoate (4.0 g, 17.164 mmol) in

[0381] EtOH (40.0 ml) was added hydrazine hydrate (6.874 g, 137.31 mmol) drop wise at 0 °C followed by stirring at RT for 12 h. The reaction mixture was quenched with water. The mixture was filtered and the precipitate dried. The solid was triturated with pentane under reduced pressure to obtain the title compound as off white solid (3.8 g). LCMS: 234.9 [M+2+H]+b) 2-(2-Bromo-5-fhiorobenzoyl)-N-m ethylhydrazine- 1 -carbothioamide ( 1 c)

[0382] To a solution of 2-bromo-5-fluorobenzohydrazide (3.8 g, 16.306 mmol) in THF (40.0 ml) was added methyl isothiocyanate (2.384 g, 32.610 mmol) followed by stirring at RT for 12 h. The precipitated solid was filtered, washed with cold THF, and dried. Then the solid was triturated with pentane and dried under reduced pressure to afford the title compound as an off-white solid (3.7 g). LCMS: 306.0 [M+H]+c) 5-(2-Bromo-5-fhiorophenyl)-4-methyl-4H-l,2,4-triazole-3-thiol (Id)

[0383] 2-(2-Bromo-5-fluorobenzoyl)-N-methylhydrazine- 1 -carbothioamide (3.7 g, 12.86 mmol) in 2 N NaOH (40 ml) was stirred at 60 °C for 4 h. The reaction mixture was quenched with ice water and pH was adjusted to ~ 4 with 1 N HC1. The precipitate was filtered and dried under vacuum to afford the title compound as off-white solid (3.7 g). LCMS: 288.0 [M+H]+. d) 3-(2-Bromo-5-fluorophenyl)-4-methyl-4H-l,2,4-triazole (le)

[0384] To a solution of 5-(2-bromo-5-fluorophenyl)-4-methyl-4H-l,2,4-triazole-3-thiol (3.7 g, 12.84 mmol) and acetic acid (7.4 ml) in dichloromethane (40 ml) was added hydrogen peroxide (4 ml) dropwise at 0 °C. The mixture was stirred at RT for 12 h. The mixture was concentrated and co-evaporated with toluene. The obtained off-white solid was triturated with methanol, filtered, and dried under reduced pressure to afford the title compound as an off-white solid (3.2 g), LCMS: 255.9 [M+H]+e) 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Intermediate 1)

[0385] To a degassed solution of 3-(2-bromo-5-fluorophenyl)-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- 1-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)C12 (0.065 g, 0.09 mmol) followed by stirring at 100 °C for 4 h. The mixture was filtered through a celite pad and washed with ethyl acetate. The filtrate was concentrated and 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: 309.1 [M+H]+

[0386] Intermediate 2. 4-(Ethylamino)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3- yl)phenyl)isoindolin- 1 -one a) Methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (2b)

[0387] To a solution of methyl 5-bromo-3-fluoro-2-methylbenzoate (19.0 g, 76.90 mmol) in CCh (200.0 ml) was added A-bromosuccinimide (NBS) (20.53 g, 115.35 mmol)) and azobisisobutyronitrile (AIBN) (1.89 g, 11.53 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 layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the title compound (26.0 g) as crude which was used in next step as such.1HNMR (400 MHz, CDCh): 8 7.95 (d, 1H), 7.47 (dd, 1H), 4.95 (s, 2H), 3.99 (s, 3H). b) 6-Bromo-4-fluoroisoindolin-l-one (2c)

[0388] To a solution of methyl 5 -bromo-2-(bromomethyl)-3 -fluorobenzoate (34.0 g, 104.30 mmol) in MeOH (30.0 ml) was added 7 M methanol-ammonia solution (50.0 ml) at 0 °C. The mixture was warmed to RT and stirred for 3h. The mixture was concentrated, diluted with water to obtain a precipitate, which was filtered, washed with pentane and dried under reduced pressure to afford the title product (19.6 g, 81.69 %). LCMS: 232.0 [M+2+H]+. c) 6-Bromo-4-(ethyl amino) isoindolin-l-one (2d)

[0389] To a solution of 6-bromo-4-fluoroisoindolin-l-one (2.0 g, 8.69 mmol) and DIPEA (16.85 g, 130.4 mmol) in DMSO (20.0 ml) was added ethanamine (7.84 g, 17.88 mmol) followed by stirring at 130 °C for 12 h. The mixture was cooled to RT, quenched with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford the crude compound. The crude compound was purified by silica-gel flash column chromatography using 5-10 % MeOH in DCM as eluent to afford the title compound (0.95 g). LCMS: 257.0 [M+2+H]+. d) 4-(Ethyl amino)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) isoindolin-l- one (2e)

[0390] To a degassed solution of 6-bromo-4-(ethyl amino)isoindolin-l-one (0.75 g, 2.94 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxa- borolane (0.97 g, 3.82 mmol) and potassium acetate (0.43 g, 4.41 mmol) in 1,4 dioxane (20 ml) was added Pd(dppf)C12.DCM (0.12 g, 0.14 mmol) followed by stirring at 80 °C for 2 h The mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated and triturated with pentane to afford the title compound (1.2 g) as crude which was used in next step as such. LCMS: 303.0 [M+H]+. e) 4-(Ethyl amino)-6-(4-fluoro-2-(4-methyl-4J / -l,2,4-triazol-3-yl) phenyl) isoindolin-l-one (Intermediate 2)

[0391] To a degassed solution of 3-(2-bromo-5-fluorophenyl)-4-methyl-4H-l,2,4- triazole (0.60 g, 2.33 mmol), 4-(ethyl amino)-6-(4,4,5,5- tetramethyl- 1,3, 2-dioxa- borolan-2-yl)isoindolin-l-one (1.33 g, 3.75 mmol), and K2CO3 (0.97 g, 7.02 mmol) in dioxane (20.0 ml) and water (8.0 ml) was added Pd(dppf)C12.DCM (0.095 g, 0.18 mmol) followed by stirring at 80 °C for 12 h. The mixture was cooled to RT, quenched with water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford the crude compound. The crude compound was purified by silica-gel flash column chromatography using 5- 10 % MeOH in DCM as eluent to afford the title compound (0.38 g). LCMS: 352.2 [M+H]+.

[0392] The following intermediates were prepared according to the procedure described for Intermediate-2 from the starting materials indicated in the Table with appropriate variations in reactants, quantities of reagents, coupling methods and solvents. The characterization data of the compounds are also summarized in Table-1.

[0393] Table-1: Intermediate 6. 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4- propoxyi soindolin- 1 -one a) Methyl 5-bromo-2-methyl-3-propoxybenzoate (6b)

[0394] To a solution of methyl 5-bromo-3-hydroxy-2-methylbenzoate (2.5 g, 10.20 mmol) and 2-iodopropane (3.46 g, 20.40 mmol) in MeCN (25.0 ml) was added K2CO3 (3.52 g, 25.50 mmol) followed by stirring at 65 °C for 6 h. The mixture was cooled to RT, quenched with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford the title compound (2.8 g) as crude which was used in next step as such. 'H-NMR (400 MHz, CDCh): 8 7.55 (d, 1H), 7.09 (d, 1H), 3.93 (t, 2H), 3.90 (s, 3H), 2.40 (s, 3H), 1.95 - 1.85 (m, 2H), 1.08 (t, 3H). b) Methyl 5-bromo-2-(bromomethyl)-3-propoxybenzoate (6c)

[0395] To a solution of methyl 5-bromo-2-methyl-3-propoxybenzoate (2.8 g, 9.75 mmol) in CCI4 (30.0 ml) was added 7V-bromosuccinimide (NBS) (1.73 g, 9.75 mmol), benzoyl peroxide (BPO) (0.47 g, 1.95 mmol) followed by stirring at 65 °C for 2 h. The mixture was cooled to RT, quenched with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford the title compound (4.0 g crude) which was used in next step as such. 'H-NMR (400 MHz, DMSO-t / 6): 5 7.56 (d, 1H), 7.51 (d, 1H), 4.90 (s, 2H), 4.13 (t, 2H), 3.90 (s, 3H), 1.84 - 1.74 (m, 2H), 1.05 (t, 3H). c) 6-Bromo-4-propoxyisoindolin-l-one (6d) To a solution of methyl 5-bromo-2-(bromomethyl)-3-propoxybenzoate (4.0 g, 10.92 mmol) in DCM (15.0 ml) and methanol (3.0 ml) was added 7 M methanol - ammonia solution (20.0 ml) at 0 °C. The mixture was warmed to RT and stirred for 3 h. The solid was filtered and triturated with water and pentane to afford the title compound (1.7 g). LCMS: 272.0 [M+2+H]+. d) 4-Propoxy-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) isoindolin-l-one (6e)

[0396] To a degassed solution of 6-bromo-4-propoxyisoindolin-l-one (1.7 g, 6.29 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl- 1, 3, 2-dioxaborolan-2-yl)- 1,3, 2- dioxaborolane (2.07 g, 8.18 mmol) and potassium acetate (0.92 g, 9.44mmol) in 1,4 dioxane (25ml) was added Pd(dppf)C12.DCM (0.25 g, 0.31 mmol) followed by stirring at 80 °C for 2 h. The mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated and triturated with pentane to afford title compound (1.80 g). LCMS: 318.2 [M+H]+. e) 6-(4-Fluoro-2-(4-methyl-4J / -l,2,4-triazol-3-yl) phenyl)-4-propoxyisoindolin- 1-one (Intermediate 6)

[0397] To a degassed solution of 3-(2-bromo-5-fluorophenyl)-4-methyl-4H-l,2,4- triazole (0.250 g, 0.976 mmol), 4-propoxy-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)isoindolin-l-one (0.52 g, 1.65 mmol) and K2CO3 (0.337 g, 2.44 mmol) in dioxane (3.0 ml) and water (1.0 ml) was added Pd(dppf)C12.DCM (0.04 g, 0.04 mmol) followed by stirring at 80 °C for 12 h. The mixture was cooled to RT, quenched with water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to obtain the crude compound. The crude was purified by silica-gel flash column chromatography using 5-10 % MeOH in DCM as eluent to afford the title compound (0.230 g). LCMS: 367.2 [M+H]+.

[0398] The following intermediates were prepared according to the procedure described for Intermediate-6 from the starting materials indicated in the Table-2 with appropriate variations in reactants, quantities of reagents, coupling methods and solvents. The characterization data of the compounds are also summarized in Table-2. Table-2:

[0399] Intermediate 10. 2-(4-(Chloromethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Intermediate 10) a) (2-Bromo-6-methylpyridin-4-yl)methanol (10b) To a solution of methyl 2-bromo-6-methylisonicotinate (25 g, 108.67 mmol) in THF (250 ml) was added LiBLL (108.7 ml, 2 M in THF) dropwise at -78 °C. Then the mixture was slowly warmed to RT and stirred for 4 h. The mixture was cooled to 0 °C, quenched with ammonium chloride solution and water, and extracted with ethyl acetate. Then combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated to afford the title compound (22.0 g). LCMS: 202.20 [M+H]+. b) 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(hydroxymethyl)- 6-methylpyridin-2-yl)i soindolin- 1 -one (10c)

[0400] To a degassed solution of 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)- phenyl)i soindolin- 1 -one (15.00 g, 48.651 mmol), (2-bromo-6-methylpyridin-4-yl)- methanol (11.79 g, 58.381 mmol), and CS2CO3 (47.55 g, 145.950 mmol) in dioxane (200 ml) was added XantPhos PdG3 (4.61 g, 4.860 mmol) followed by stirring at 70 °C for 6 h. The mixture was cooled to RT, passed through celite and washed with 10 % methanol in DCM. The combined organic layer was concentrated and purified by silica- gel flash column chromatography using 0 to 10 % MeOH in DCM to afford the title compound (13.0 g, 62.00 %). LCMS: 430.0 [M+H]+. c) 2-(4-(Chloromethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- 1,2,4- triazol-3-yl)phenyl)isoindolin-l-one (Intermediate 10)

[0401] 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 (13.0 g, 30.271 mmol) in 1,2- di chloroethane (40.0 ml) was added thionyl chloride (8.80 ml, 121.08 mmol) at 5 °C. The mixture was warmed to RT and stirred at 60 °C for 1 h. The mixture was cooled to RT and concentrated. The residue was quenched with ice water and saturated sodium bicarbonate solution and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The residue was triturated with isopropyl alcohol. The precipitated solid was filtered and dried under vacuum to afford the title compound (12.00 g). LCMS: 448.1 [M+H]+.

[0402] Intermediate 11. 7V-((2-Bromo-6-methylpyridin-4-yl)methyl)butan-l -amine

[0403] 11a Intermediate 11

[0404] To a solution of 2-bromo-6-methylisonicotinaldehyde (0.5 g, 2.5 mmol) and butan-l-amine (0.274 g, 3.75 mmol) in DCM (5 ml) was added catalytic amount of acetic acid at RT followed by stirring for 1 h. Sodium triacetoxyborohydride (STAB) (1.06 g, 5.00 mmol) was added into the mixture at 0 °C followed by stirring at RT for

[0405] 16 h. The mixture was quenched with water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulphate, filtered, concentrated, and purified by silica-gel flash column chromatography using 5-10 % MeOH in DCM as eluent to afford the title compound (0.288 g). LCMS: 259.1 [M+2+H]+. The following intermediates were prepared according to the procedure described for Intermediate- 11 from the starting materials indicated in the Table-3 with appropriate variations in reactants, quantities of reagents, coupling methods and solvents. The characterization data of the compounds are also summarized in Table-3.

[0406] Table-3:

[0407]

[0408] Intermediate 15. 7V-(3-Bromo-4-fluoro-5-(trifluoromethyl) benzyl)-l- cyclopropylmethanamine (Intermediate 15) a) Methyl 3-bromo-4-fluoro-5-(trifluoromethyl)benzoate (15b)

[0409] To a solution of methyl 4-fluoro-3-(trifluoromethyl) benzoate (5.0 g, 22.50 mmol) and H2SO4 (7.5 ml) in TFA (25.0 ml) was added NBS (6.0 g, 33.76 mmol) at 0 °C. The mixture was warmed to RT and stirred for 18 h. The mixture was quenched with ice water and extracted with hexane. The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the title compound (6.0 g) as crude which was used in next step as such.1HNMR (400 MHz, CDCh): 8 8.48 (dd, 1H), 8.29 (dd, 1H), 3.99 (s, 3H). b) (3-Bromo-4-fluoro-5-(trifluoromethyl)phenyl) methanol (15c)

[0410] To a solution of methyl 3 -bromo-4-fluoro-5 -(trifluoromethyl) benzoate (6.0 g, 19.93 mmol) in THF (60 ml) was added lithium borohydride (19.93 ml, 2.0 M in THF) dropwise at -78 °C. Then the mixture was slowly warmed to RT and stirred for 4 h. The mixture was cooled to 0 °C, quenched with aqueous NH4CI and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the title compound (4.30 g) as crude which was used in next step as such.1HNMR (400 MHz, DMSO- e): 5 7.91 (dd, 1H), 7.72 (dd, 1H), 5.54 (t, 1H), 4.55 (d, 2H). c) 3-Bromo-4-fluoro-5-(trifluoromethyl)benzaldehyde (15d)

[0411] To a solution (3-bromo-4-fluoro-5-(trifluoromethyl) phenyl) methanol (1.0 g, 3.66 mmol) in DCM (20.0 ml) was added Dess-Martin periodinane (DMP) (2.33 g, 5.49 mmol) portion wise at 0 °C. Then the mixture was slowly warmed to RT and stirred for 4 h. The mixture was cooled to 0 °C, quenched with aqueous sodium thiosulphate solution, aqueous sodium bicarbonate solution, and extracted with DCM. Then combined organic layer was, dried over sodium sulphate, filtered, and concentrated to afford the crude compound, which was purified by silica-gel flash column chromatography using 0-10 % ethyl acetate in hexane as eluent to afford the title compound (0.70 g).1HNMR (400 MHz, DMSO-t / 6): 8 10.02 (s, 1H), 8.52 (dd, 1H), 8.33 (dd, 1H). d) N-(3 -Bromo-4-fluoro-5-(trifluorom ethyl) benzyl)- 1 -cyclopropylmethanamine (Intermediate 15)

[0412] The compound was prepared according to the procedure described for Intermediate 11 with appropriate variations in reactants, quantities of reagents, and solvents. LCMS: 328.0 [M+2+H]+.

[0413] Intermediate 16. l-(2-Chloro-6-cyclopropylpyridin-4-yl)-N-(cyclopropyl- methyl)methanamine a) l-Cyclopropyl-N-((2,6-dichloropyridin-4-yl)methyl)methanamine (16b)

[0414] The compound was prepared according to the procedure described for Intermediate 11 with appropriate variations in reactants, quantities of reagents, and solvents. LCMS: 233.0 [M+2+H]+. b) l-(2-Chloro-6-cyclopropylpyridin-4-yl)-N-(cyclopropylmethyl)methanamine (Intermediate 16)

[0415] To a degassed solution of l-cyclopropyl-N-((2,6-dichloropyridin-4-yl)methyl)- methanamine (1.5 g, 6.49 mmol), cyclopropyl boronic acid (0.72 g, 8.43 mmol) and K2CO3 (2.69 g, 19.47 mmol) in dioxane (15.0 ml) and water (3.0 ml) was added Pd(amphos)C12 (0.46 g, 0.64 mmol) followed by stirring at 80°C for 12 h. The mixture was filtered and washed with ethyl acetate. The filtrate was concentrated and purified by silica-gel flash column chromatography using 10 % ethyl acetate in hexane as eluent to afford the title compound (0.75 g). LCMS: 237.1 [M+H]+.

[0416] Intermediate 17. l-(2-Bromo-6-methylpyridin-4-yl)-N-(cyclopropylmethyl)- methan-d2-amine a) (2-Bromo-6-methylpyridin-4-yl)methan-d2-ol (17b)

[0417] To a solution of methyl 2-bromo-6-methylisonicotinate (1.0 g, 4.34 mmol) in THF (10 ml) was added NaBD4 (0.363 g, 8.69 mmol) followed by heating to 45 °C for 8 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated to afford the title compound (0.8 g, 90.9 %) as crude product which was used in next step as such. LCMS: 203.9 [M+H]+. b) 2-Bromo-4-(chloromethyl-d2)-6-methylpyridine (17c)

[0418] (2-Bromo-6-methylpyridin-4-yl)methan-d2-ol (1.0 g, 4.90 mmol) was dissolved in thionyl chloride (2.915 g, 24.50 mmol) followed by stirring at 50 °C for 12 h. The mixture was cooled RT quenched with aqueous sodium bicarbonate solution and extracted with DCM. The combined organic layer was dried over sodium sulphate, filtered, and concentrated to afford the title compound (1.05 g) as crude product which was used in next step as such. LCMS: 221.9 [M+H]+. c) l-(2-Bromo-6-methylpyridin-4-yl)-N-(cyclopropylmethyl)methan-d2-amine (Intermediate 17) To a solution of 2-bromo-4-(chloromethyl-d2)-6-methylpyridine (0.40 g, 1.79 mmol) in acetonitrile (4.0 ml) was added cyclopropyl methanamine (0.192 g, 2.69 mmol) and potassium carbonate (0.745 g, 5.39 mmol) followed by stirring at RT for 12 h. The mixture was quenched with water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulphate, filtered, concentrated, and purified by silica-gel flash column chromatography using 5 % MeOH in DCM as eluent to afford the title compound (0.35 g), LCMS: 257.0 [M+H]+.

[0419] Intermediate 18. l-(2-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-N- (cyclopropylmethyl)methanamine a) Ethyl 3-cyano-2-hydroxy-6,7-dihydro-5H-cyclopenta [b] pyridine-4- carboxylate (18b)

[0420] To a solution of EtONa (32.05 g, 470.98 mmol, 21 % in EtOH) in EtOH (400 ml) was added diethyl oxalate (57.36 g, 392.48 mmol), and cyclopentanone (33.016 g, 392.48 mmol) followed by stirring at RT for 3 h. 2-Cyano acetamide (33.0 g, 392.48 mmol) was added to the mixture followed by stirring at 80 °C for 12 h. The mixture was concentrated, and the resulting solid was dissolved in water and heated to 100 °C for 1 h. The pH of aqueous layer was adjusted to ~1 with AcOH to obtain a precipitate. The precipitate was filtered and dried under vacuum to afford the title compound (45 g) as yellow solid. LCMS: 233.2 [M+H]+. b) 2-Hydroxy-6, 7-dihydro-5H-cyclopenta [b] pyridine-4-carboxylic acid (18c)

[0421] A solution of ethyl 3-cyano-2-hydroxy-6,7-dihydro-5H-cyclopenta [b] pyridine- 4-carboxylate (40 g, 172.23 mmol) in 400.0 ml HC1 (6 M) was stirred for 36 h at 115 °C. The mixture was poured into water to obtain a solid. The solid was filtered to afford the title compound. LCMS: 180.0 [M+H]+. c) Methyl 2-bromo-6,7-dihydro-5H-cyclopenta [b] pyridine-4-carboxylate (18d) To a solution of 2-hydroxy-6,7-dihydro-5H-cyclopenta [b] pyridine-4-carboxylic acid (8 g, 44.6 mmol) in toluene (180.0 ml) was added phosphoryl bromide (64.0 g, 223.2 mmol) followed by stirring for 20 h at 100 °C. The mixture was cooled to 0 °C, quenched with MeOH and concentrated. The residue was diluted with DCM and washed with aqueous ISfeCCh solution. Then combined organic layer was dried over sodium sulphate, filtered, and concentrated to afford the crude compound, which was purified by silica-gel flash column chromatography using 0-20 % ethyl acetate in hexane as eluent to afford the title compound (7 g) as a yellow solid. LCMS: 255.9 [M+H]+. d) (2-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methanol (18e)

[0422] The compound was prepared according to the procedure described for Intermediate 15c with appropriate variations in reactants, quantities of reagents, and solvents. LCMS: 228.0 [M+H]+. e) 2-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carbaldehyde (18f)

[0423] The compound was prepared according to the procedure described for Intermediate 15d with appropriate variations in reactants, quantities of reagents, and solvents. LCMS: 226.0 [M+H]+. f) l-(2-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-N-(cyclopropyl- methyl)methanamine (Intermediate 18)

[0424] The compound was prepared according to the procedure described for Intermediate 11 with appropriate variations in reactants, quantities of reagents, and solvents. LCMS: 281.0 [M+H]+.

[0425] Intermediate 19. (7?)-l-Methoxy-3-methylbutan-2-amine (Intermediate 19) 19 a) tert-Butyl (R)-(l -hydroxy-3 -methylbutan-2-yl)carbamate (19b)

[0426] To a solution of (A)-2-amino-3-methylbutan-l-ol (0.50 g, 4.846 mmol) in MeOH (10.0 ml) was added Boc anhydride (1.32 ml, 51.65 mmol) at 0 °C followed by stirring at RT for 12 h. The mixture was concentrated and purified by silica-gel flash column chromatography on silica gel using 30 % ethyl acetate in hexane as eluent to afford the title compound as a liquid (0.8 g, 81.00 %). LCMS: 148.10 [M-56+H]+b) tert-Butyl (R)-(l-methoxy-3-methylbutan-2-yl)carbamate (19c)

[0427] To a solution of tert-butyl (A)-(l-hydroxy-3-methylbutan-2-yl)carbamate (0.50 g, 2.46 mmol) in THF (10.0 ml) was added NaH (0.13 g, 3.190 mmol, 60 % by weight), and methyl iodide (0.30 ml, 4.92 mmol) at 0 °C. The mixture was warmed to RT and stirred for 4 h. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, concentrated, and purified by silica-gel flash column chromatography on silica gel using 5 - 10 % ethyl acetate in hexane as eluent to afford the title compound (0.50 g, 93.50 %). LCMS: 162.20 [M-56+H]+. c) ( / )-! -Methoxy-3-methylbutan-2-amine (Intermediate 19)

[0428] A solution of tert-butyl (A)-(l-methoxy-3-methylbutan-2-yl)carbamate (0.20 g, 0.92 mmol) in 4 M HC1 in dioxane (2.0 ml) was stirred at RT for 6 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 sulphate, filtered and concentrated to afford the title compound (0.10 g, 93 % ) as crude product which was used in next step as such. 'H-NMR (400 MHz, DMSO-t / 6): 5 8.87 (bs, 2H), 3.58 (d, 2H), 3.33 (s, 3H), 3.06 - 2.90 (m, 1H), 2.12 - 2.03 (m, 1H), 0.98 (d, 3H), 0.956 (d, 3H).

[0429] Intermediate 20. (A)-3-Amino-2,4-dimethylpentan-2-ol a) Ethyl (tert-butoxycarbonyl)-D-valinate (20b) To a solution of ethyl valinate (1.0 g, 6.88 mmol) and BOC2O (2.25 g, 10.33 mmol) in DCM (10.0 ml) was added triethylamine (TEA) (1.74 g, 17.21 mmol) followed by stirring for 12 h at RT. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford the title compound. (1.0 g). 'H-NMR (400 MHz, CDCh): 8 5.05 (d, 1H), 4.23 - 4.20 (m, 3H), 2.20 - 2.10 (m, 1H), 1.46 (s, 9H), 1.30 (t, 3H), 0.98 (d, 3H), 0.91 (d, 3H). b) tert-Butyl (A)-(2 -hydroxy-2, 4-dimethylpentan-3-yl)carbamate (20c)

[0430] To a solution of ethyl (tert-butoxycarbonyl)-D-valinate (0.5 g, 2.03 mmol) in THF (10 ml), was added methyl magnesium bromide (2.99 ml, 10.18 mmol, 3.4 M in 2- methyl THF) at 0 °C. The mixture was warmed to RT and stirred for 12 h. The mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica-gel flash column chromatography using 40-50 % ethyl acetate in hexane as eluent to afford the title compound (0.4 g). Tl-NMR (400 MHz, CDCh): 6 4.83 (d, 1H), 3.42 (dd, 1H), 2.14 - 2.09 (m, 1H), 1.49 (s, 9H), 1.29 (s, 3H), 1.26 (s, 3H), 1.04 (d, 3H), 0.99 (d, 3H). c) (A)-3-Amino-2,4-dimethylpentan-2-ol (Intermediate 20)

[0431] The compound was prepared according to the procedure described for step c) of Intermediate 19 with appropriate variations in reactants, quantities of reagents, and solvents. E-NMR (400 MHz, CDCh): 6 7.96 (brs, 2H), 5.32 (brs, 1H), 3.26 (brs, 1H), 2.10 - 1.97 (m, 1H), 1.46 (s, 3H), 1.41 (s, 3H), 1.25 - 1.18 (m, 6H).

[0432] Intermediate 21. (A)-l-(l-Amino-2-methylpropyl)cyclopropan-l-ol a) tert-Butyl (R)-(l-(l -hydroxy cyclopropyl)-2-methylpropyl)carbamate (21a)

[0433] To a solution of ethyl (tert-butoxycarbonyl)-D-valinate (2.0 g, 8.15 mmol) in diethyl ether (20.0 ml) was added titanium isopropoxide (2.31 g, 8.15 mmol) followed by ethyl magnesium bromide (13.59 ml, 40.76 mmol, 3 M in diethyl ether) dropwise at 0 °C. The mixture was wanned to RT and stirred for 12 h. The mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica-gel flash column chromatography using 20-50 % ethyl acetate in hexane as eluent to afford the title compound (0.50 g). 'H-NMR (400 MHz, DMSO-t / 6): 5 6.40 (d, 1H), 4.98 (s, 1H), 2.75 (dd, 1H), 2.00 - 1.91 (m, 1H), 1.39 (s, 9H), 0.96 (d, 3H),0.86 (d, 3H), 0.66 - 0.59 (m, 1H), 0.55 - 0.48 (m, 1H), 0.44 - 0.38 (m, 2H). b) (R)-l-(l-Amino-2-methylpropyl)cyclopropan-l-ol (Intermediate 21) The compound was prepared according to the procedure described for step c) of

[0434] Intermediate 19 with appropriate variations in reactants, quantities of reagents, and solvents. 'H-NMR (400 MHz, DMSO-t / 6): 5 8.26 (brs, 2H), 5.65 (s, 1H), 2.39 - 2.28 (m, 1H), 2.15 - 2.05 (m, 1H), 0.97 (d, 3H),0.85 (d, 3H), 0.85 - 0.78 (m, 1H), 0.75 - 0.68 (m, 1H), 0.66 - 0.54 (m, 2H). The following intermediates were prepared according to the procedure described for Intermediate 2 from the starting materials indicated in the Table with appropriate variations in reactants, quantities of reagents, coupling methods and solvents. The characterization data of the compounds are also summarized in Table-4.

[0435] Table-4:

[0436] The following intermediates were prepared according to the procedure described for Intermediate-6 from the starting materials indicated in the Table with appropriate variations in reactants, quantities of reagents, coupling methods and solvents. The characterization data of the compounds are also summarized in Table-5.

[0437] Table-5:

[0438]

[0439] Intermediate 30. 2,6-Dichloro-7V-(cyclopropylmethyl)pyridine-4-sulfonamide

[0440] Intermediate 30

[0441] To a solution of 2,6-dichloropyridine-4-sulfonyl chloride (0.5 g, 2.03 mmol) in acetonitrile (5.0 ml) was added cyclopropylmethanamine (0.288 g, 4.05 mmol) and cesium carbonate (1.98 g, 6.08 mmol) at RT followed by stirring for 12 h. Reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered, concentrated and purified by silica gel flash column chromatography using 20 - 30 % EtOAc in hexane as eluent to afford the title compound as off white solid (0.45 g, 78.92 %). LCMS: 278.9 [M-H]

[0442] Intermediate 31. 2,6-Dichloro-7V-(2-hydroxy-2-methylpropyl)pyridine-4- sulfonamide 30a

[0443] Intermediate 31

[0444] The compound was prepared according to the procedure described for Intermediate 30, from the starting materials indicated above with appropriate variations in reactants, quantities of reagents, coupling methods and solvents. LCMS: 298.95 [M+H]+

[0445] Intermediate 32. 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(2- hydroxyethoxy)isoindolin- 1 -one a) Methyl 5-bromo-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2 -methylbenzoate (32b)

[0446] A solution of methyl 5 -bromo-3 -hydroxy-2- methylbenzoate (2.00 g, 8.16 mmol), (2 -bromoethoxy )(tertbutyl)dimethyl silane (2.73 g, 11.43 mmol) and CS2CO3 (7.98 g, 24.48 mmol) in DMF (30.0 ml) was stirred at 600C for 4 h. The reaction mixture was cooled to RT, quenched with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered, concentrated, and purified by silica gel flash column chromatography using 4 - 5 % EtOAc in hexane as eluent to afford the title compound (2.50 g, 76 %). 'H-NMR (400 MHz, CDCh): 8 7.57 (d, 1H), 7.15 (d, 1H), 4.06 (t, 2H), 4.01 (t, 2H), 3.90 (s, 3H), 2.40 (s, 3H), 0.92 (s, 9H), 0.11 (s, 6H). b) Methyl 5-bromo-2-(bromomethyl)-3-(2 -hydroxyethoxy )benzoate (32c)

[0447] To a solution of methyl 5-bromo-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2- methylbenzoate (2.30 g, 5.70 mmol) in CCU (30.0 ml) was added 7V-bromosuccinimide (1.52 g, 8.55 mmol) and benzoyl peroxide (0.14 g, 0.57 mmol) at RT followed by stirring at 60 °C for 4 h. The reaction mixture was filtered and the filtrate was quenched with 10 % sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered, concentrated, and purified by silica gel flash column chromatography using 30 - 40 % EtOAc in hexane as eluent to afford the title compound (1.0 g, 48 %). E-NMR (400 MHz, CDCh): 8 7.72 (s, 1H), 7.21 (s, 1H), 5.01 (s, 2H), 4.23 (t, 2H), 4.05 (t, 2H), 3.93 (s, 3H). c) 6-Bromo-4-(2-hydroxyethoxy)isoindolin-l-one (32d)

[0448] To a solution of methyl 5-bromo-2-(bromomethyl)-3-(2-hydroxyethoxy)- benzoate (1.0 g, 2.72 mmol) in DCM (5.0 ml) was added 7 M methanol-ammonia solution (10 ml) at 0 °C followed by stirring at RT for 4 h. The reaction mixture was concentrated under vacuum. The crude product was suspended in water and then filtered. The solid was triturated with pentane to afford the title compound (0.55 g, 74 %). 'H-NMR (400 MHz, DMSO-t / 6): 6 7.72 (d, 1H), 7.22 (d, 1H), 5.02 (s, 2H), 4.22 (t, 1H), 4.05 (t, 2H), 3.96 (s, 3H). d) 4-(2 -Hydroxy ethoxy)-6-(4, 4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-iso- indolin-l-one (32e)

[0449] To a degassed solution of 6-bromo-4-(2-hydroxyethoxy)isoindolin-l-one (0.550 g, 2.02 mmol), bis(pinacolato)diboron (0.77 g, 3.303 mmol) and potassium acetate (0.60 g, 6.06 mmol) in dioxane (8.0 ml) was added Pd(dppf)C12-DCM (0.08 g, 0.10 mmol) followed by stirring at 80 °C for 3 h. The reaction mixture was filtered through celite pad and washed with dioxane. The filtrate was concentrated and purified by silica-gel flash column chromatography using 5 - 7 % MeOH in DCM as eluent to afford the title compound as brown solid (0.50 g, 78 %). LCMS: 320.2 [M+H]+. e) 6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-4-(2-hydroxy ethoxy)- isoindolin-l-one (Intermediate 32) To a degassed solution of 3-(2-bromo-5-fluorophenyl)-4- methyl-4H- 1,2,4- triazole (0.260 g, 1.01 mmol), 4-(2-hydroxyethoxy)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)isoindolin-l-one (0.49 g, 1.52 mmol) and potassium carbonate (0.421 g, 3.04 mmol) in water (1 ml) dioxane (4.0 ml) was added Pd(dppf)C12-DCM (0.07 g, 0.10 mmol) followed by stirring at 80 °C for 16 h. The reaction mixture was filtered through celite pad and washed with dioxane. The filtrate was concentrated and purified by silica-gel flash column chromatography using 5 - 7 % MeOH in DCM as eluent to afford the title compound as brown solid (0.13 g, 35 %). LCMS: 369.1 [M+H]+.

[0450] Example 1. 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl- 4-((((l-methylcyclopropyl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 1)

[0451] To a solution of 2-(4-(chloromethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (0.07 g, 0.15 mmol) in acetonitrile (1.0 ml) was added (l-methylcyclopropyl)methanamine (0.04 g, 0.46 mmol) and potassium carbonate (0.06 g, 0.46 mmol) at RT. Then the mixture was stirred at 60 °C for 6 h. The mixture was cooled to RT, diluted with water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to obtain the crude compound, which was purified by preparative TLC using 5.0 % methanol in DCM as eluent to afford the title compound (0.005 g, 6.45 %). LCMS: 497.2 [M+H]+. E-NMR (400 MHz, CH3OD): 5 8.40 (s, 1H), 8.32 (s, 1H), 7.79 - 7.70 (m, 2H), 7.62 (d, 1H), 7.57 - 7.51 (m, 1H), 7.49 - 7.44 (m, 2H), 7.07 (s, 1H), 5.16 (s, 2H), 3.84 (s, 2H), 3.20 (s, 3H), 2.53 (s, 3H), 2.48 (s, 2H), 1.18 (s, 3H), 0.44 - 0.38 (m, 2H), 0.37 - 0.31 (m, 2H).

[0452] The following intermediates were prepared according to the procedure described for Example 1 from the starting materials indicated in the Table with appropriate variations in reactants, quantities of reagents, coupling methods and solvents. The characterization data of the compounds are also summarized in Table-6.

[0453] Example 22. 2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)-

[0454] 6-(4-fluoro-2-(4-methyl-4J / -l,2,4-triazol-3-yl) phenyl)-4-propoxyi soindolin- 1 -one

[0455] (Compound 22)

[0456] To a degassed solution of 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)- 4-propoxyi soindolin- 1 -one (0.1 g, 0.273 mmol), l-(2-bromo-6-methylpyridin-4-yl)-N- (cyclopropylmethyl)methanamine (0.104 g, 0.41 mmol) and CS2CO3 (0.22 g, 0.680 mmol) in 1,4-dioxane (1.5 mL) was added XantPhos (0.008 g, 0.0010 mmol) and Pcbdbas (0.007 g, 0.0001 mmol) followed by stirring at 70 °C for 2 h. The mixture was cooled to RT, filtered through celite pad and washed with 10 % MeOH in DCM. The filtrate was washed with brine, dried over anhydrous sodium sulphate, concentrated, and purified by preparative TLC using 5 % MeOH in DCM as eluent to afford the title compound as an off-white solid (0.023 g, 15.58 %). LCMS: 541.3 [M+H]+. 'H-NMR (400 MHz, DMSO-t / 6): 5 8.47 (s, 1H), 8.29 (s, 1H), 7.78 (dd, 1H), 7.59 (dt, 1H), 7.52 (dd, 1H), 7.16 (d, 1H), 7.04 (s, 1H), 6.88 (d, 1H), 4.95 (s, 2H), 3.90 (t, 2H), 3.75 (s, 2H), 3.13 (s, 3H), 2.46 (s, 3H), 2.39 (d, 2H), 1.79 - 1.70 (m, 2H), 1.02 (t, 3H), 0.95 - 0.82 (m, 1H), 0.45 - 0.39 (m, 2H), 0.15 - 0.08 (m, 2H). The following intermediates were prepared according to the procedure described for Example 22 from the starting materials indicated in the Table with appropriate variations in reactants, quantities of reagents, coupling methods and solvents. The characterization data of the compounds are also summarized in Table-7.

[0457] Table-7:

[0458] Example 23. (7?)-3-((2-(6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)- l-oxoisoindolin-2-yl)-6-methylpyridin-4-yl)methyl)-4-propyloxazolidin-2-one (Compound 35)

[0459]

[0460] To a solution of (A)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4- (((l-hydroxypentan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (0.070 g, 0.140 mmol) in THF (2.0 ml) was added l,l'-carbonyldiimidazole (0.034 g, 0.210 mmol) followed by stirring at 60 °C for 16 h. The mixture was cooled to RT, quenched with ice water and extracted with DCM. The combined organic layer was dried over sodium sulphate, and concentrated. The obtained crude product was purified by silica- gel flash column chromatography using 3 - 4 % methanol in dichloromethane as eluent to afford the title compound as a white solid (0.029 g). LCMS: 541.10 [M+H]+;1H- NMR (400 MHz, DMSO-t / d): 5 8.45 (s, 1H), 8.28 (s, 1H), 7.73 (d, 1H), 7.65 (d, 1H), 7.58 (dt, 1H), 7.54 - 7.51 (m, 2H), 7.34 (dd, 1H), 6.99 (s, 1H), 5.09 (s,2H), 4.51 (d, 1H), 4.45 (dd, 1H), 4.30 (d, 1H), 4.04 (dd, 1H), 3.80 - 3.73 (m, 1H), 3.15 (s, 3H), 2.48 (s, 3H), 1.70 - 1.60 (m, 1H), 1.50 - 1.39 (m, 1H), 1.25 - 1.15 (m, 2H), 0.85 (t, 3H). Example 24. 2-(4-(Aminomethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 36) a) (E)-7V-((2-Bromo-6-methylpyridin-4-yl)methylene)-2-methylpropane-2- sulfinamide 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. The mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford the title compound as off white solid (0.54 g). LCMS: 303.0 [M+H]+b) 7V-((2-Bromo-6-methylpyridin-4-yl)methyl)-2-methylpropane-2-sulfinamide

[0461] To a solution of (E)-7V-((2-bromo-6-methylpyridin-4-yl)methylene)-2-methyl- propane-2-sulfmamide (0.4 g, 1.32 mmol) in MeOH (4.0 ml) was added sodium borohydride (0.1 g, 2.63 mmol) at 0 °C. The mixture was warmed to RT and stirred for 4 h. The reaction mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford the title compound as off white solid (0.54 g). LCMS: 305.0 [M+H]+c) 7V-((2-(6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-l -oxoisoindo- lin-2-yl)-6-methylpyridin-4-yl)methyl)-2-methylpropane-2-sulfmamide

[0462] To a degassed solution of 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)- phenyl)isoindolin-l-one (0.5 g, 1.62 mmol), 7V-((2-bromo-6-methylpyridin-4-yl)- methyl)-2-methylpropane-2-sulfinamide (0.59 g, 1.95 mmol), CS2CO3 (1.58 g, 4.86 mmol) and Xantphos (0.047 g, 0.08 mmol) in 1,4- dioxane (10.0 ml) was added Pd2dba3 (0.045 g, 0.04 mmol) followed by stirring at 70 °C for 4 h. The mixture was cooled to RT, filtered through celite pad and washed with 10 % MeOH in DCM. The filtrate was washed with brine, dried over anhydrous sodium sulphate, concentrated, and purified by silica-gel flash column chromatography using 5 % MeOH in DCM as eluent to afford the title compound as an off-white solid (0.3 g). LCMS: 533.3 [M+H]+d) 2-(4-(Aminomethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one

[0463] To a solution of 7V-((2-(6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l- oxoisoindolin-2-yl)-6-methylpyridin-4-yl)methyl)-2-methylpropane-2-sulfinamide (0.29 g, 0.54 mmol) in 1,4-dioxane was added 4 N HC1 in 1,4-dioxane (1.0 ml, 4.0 mmol) at 0 °C. The mixture was warmed to RT and stirred for 2 h. The mixture was concentrated and purified by preparative HPLC using 0.1 % TFA in water and MeCN as eluent, to obtain the title compound as white solid (0.060 g). LCMS: 429.2 [M+H]+e) 7V-((2-(6-(4-Fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)- 1 -oxoiso- indolin-2-yl)-6-methylpyridin-4-yl)methyl)cyclopropanesulfonamide (Compound 36)

[0464] To a solution of 2-(4-(aminomethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (0.100 g, 0.23 mmol), triethylamine (0.071 g, 0.69 mmol) and DMAP (0.003 g, 0.02 mmol) in THF was added cyclopropane sulfonyl chloride (0.039 g, 0.28 mmol) followed by stirring at RT for 12 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulphate, filtered, concentrated, and purified by silica-gel flash column chromatography using 5 % MeOH in DCM as eluent to afford the title compound (0.04 g). LCMS: 533.1 [M+H]+.1H- NMR (400 MHz, DMSO-t / 6): 5 8.45 (s, 1H), 8.37 (s, 1H), 7.83 (t, 1H), 7.73 (dd, 1H), 7.65 (d, 1H), 7.58 (dt, 1H), 7.54 - 7.51 (m, 2H), 7.39 (dd, 1H), 7.05 (s, 1H), 5.09 (s, 2H), 4.24 (d, 2H), 3.16 (s, 3H), 2.59 - 2.53 (m, 1H), 2.49 (s, 3H), 0.94 - 0.92 (m, 4H).

[0465] Example 25. N-((2-(6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l- oxoisoindolin-2-yl)-6-methylpyridin-4-yl)methyl)propane-2-sulfonamide (Compound 37)

[0466] The compound was prepared according to the procedure described for Compound 36 with appropriate variations in reactants, quantities of reagents, coupling methods and solvents. LCMS: 535.15 [M+H]+. 'H-NMR (400 MHz, DMSO-d6): 5 8.45 (s, 1H), 8.35 (s, 1H), 7.75 - 7.72 (m, 2H), 7.65 (d, 1H), 7.58 (dt, 1H), 7.54 - 7.51 (m, 2H), 7.39 (dd, 1H), 7.04 (s, 1H), 5.09 (s, 2H), 4.21 (d, 2H), 3.23 - 3.17 (m, 1H), 3.14 (s, 3H), 2.49 (s, 3H), 1.24 (d, 6H). Example 26. 2-(6-(l-((Cyclopropylmethyl)amino)ethyl)-2-methylpyrimidin-4- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 38) a) 4-Chloro-6-(l-ethoxyvinyl)-2-methylpyrimidine

[0467] To a degassed solution of 4,6-dichloro-2-methylpyrimidine (4.0 g, 24.540 mmol) in dioxane (240.0 ml) was added tributyl(l-ethoxyvinyl)stannane (13.294 g, 36.81 mmol), Tetrakis (triphenylphosphine)palladium(O) (2.84 g, 2.45 mmol) followed by stirring at 100 °C h for 4 h. The mixture was cooled to RT, filtered through celite pad and washed with ethyl acetate. The filtrate was concentrated and purified by silica-gel flash column chromatography using 3 - 4 % ethyl acetate in hexane as eluent to afford the title compound as a liquid (2.0 g). LCMS: 199.10 [M+H]+b) 2-(6-(l-Ethoxyvinyl)-2-methylpyrimidin-4-yl)-6-(4-fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one

[0468] To a degassed solution of 6-(4-fluoro-2-(4-methyl-4H-l,2,4- triazol-3-yl)- phenyl)isoindolin-l-one (0.50 g, 1.622 mmol), 4-chloro-6-(l-ethoxyvinyl)-2-methyl pyrimidine (0.387 g, 1.946 mmol), CS2CO3 (1.321 g, 4.050 mmol) in dioxane (10.0 ml) was added Xantphos PdG3 (0.31 g, 0.32 mmol) followed by stirring at 65 °C for 3 h. The mixture was cooled to RT, filtered through celite pad and washed with ethyl acetate. The filtrate was concentrated to afford the title compound as a crude material (0.58 g, crude) which was used in next step as such. LCMS: 471.10 [M + H]+. c) 2-(6-Acetyl-2-methylpyrimi din-4-yl)-6-(4-fluoro-2-(4-methyl-4H- 1,2,4- triazol-3 -yl)phenyl)i soindolin- 1 -one To a solution of 2-(6-(l-ethoxyvinyl)-2-methylpyrimidin-4-yl)-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (0.48 g, 1.02 mmol) in acetone (4.0 ml), was added 1 N HC1 (2.0 ml) and stirred at RT for 16 h. The mixture was poured into 10 % aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated. The obtained crude was purified by silica-gel flash column chromatography using 3 - 4 % methanol in dichloromethane as eluent to afford the title compound as a solid (0.30 g). LCMS: 443.10 [M+H]+d) 6-(4-Fluoro-2-(4-methyl-4H- 1,2, 4-triazol-3-yl)phenyl)-2-(6-(l -hydroxy ethyl)- 2-methylpyrimidin-4-yl)isoindolin-l-one

[0469] To a solution of 2-(6-acetyl-2-methylpyrimidin-4-yl)-6-(4-fluoro-2-(4-methyl- 4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (0.30 g, 0.678 mmol) in MeOH (9.0 ml) was added sodium borohydride (0.08 g, 2.03 mmol) at 0 °C. The mixture was warmed to RT and stirred for 16 h. The mixture was concentrated, diluted water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated. The obtained crude product was purified by silica- gel flash column chromatography using 6 - 7 % methanol in dichloromethane as eluent to afford the title compound (0.20 g). LCMS: 445.10 [M+H]+. e) 2-(6-(l-Chloroethyl)-2-methylpyrimidin-4-yl)-6-(4-fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one

[0470] To a solution of 6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-(l- hydroxyethyl)-2-methylpyrimidin-4-yl)isoindolin-l-one (0.150 g, 0.337 mmol) in DCM (8.0 ml) was added thionyl chloride (0.10 ml, 1.33 mmol) followed by stirring at 50 °C for 1 h. The mixture was cooled to RT, quenched with aqueous sodium bicarbonate solution and extracted with DCM. The combined organic layer was dried over sodium sulphate and concentrated to afford the title compound (0.16 g, crude) as crude product which was used in next step as such. LCMS: 463.1 [M+H]+. f) 2-(6-(l-((Cyclopropylmethyl)amino)ethyl)-2-methylpyrimidin-4-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 38)

[0471] The compound was prepared according to the procedure described for Compound 1 with appropriate variations in reactants, quantities of reagents, coupling methods and solvents. LCMS: 498.20 [M+H]+; 'H-NMR (400 MHz, DMSO-t / 6): 5 8.45 (s, 1H), 8.39 (s, 1H), 7.72 (dd, 1H), 7.66 (d, 1H), 7.59 (dt, 1H), 7.54 (s, 1H), 7.51 (d, 1H), 7.44 (dd, 1H), 5.08 (s, 2H), 3.85 - 3.75 (m, 1H), 3.15 (s, 3H), 2.58 (s, 3H), 2.46 - 2.36 (m, 1H), 2.19 - 2.28 (m, 1H), 1.29 (d, 3H), 0.92 - 0.82 (m, 1H), 0.43 - 0.39 (m, 2H), 0.11 - 0.06 (m, 2H).

[0472] Example 27. 2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)- 6-(4-fluoro-2-(5-methyl-lJ / -l,2,3-triazol-4-yl) phenyl) isoindolin-l-one (Compound 39) a) 4-(2-Bromo-5-fluorophenyl)-5-methyl-lJ / -l,2,3-triazole

[0473] To a solution of 2-bromo-5-fluorobenzaldehyde (5.0 g, 24.269 mmol), nitroethane (2.7 g, 36.94 mmol) and sodium azide (1.2 g, 19.7 mmol) in DMSO (15.0 ml) was added AlCh (0.19 g, 1.47 mmol) followed by stirring at 70 °C for 18 h. The mixture was cooled to RT, quenched with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to get the crude compound. The crude compound was purified by silica-gel flash column chromatography using 30-40 % ethyl acetate in hexane as eluent to afford the titled compound (0.9 g). LCMS: 257.95 [M+2+H]+. b) 4-(2-Bromo-5-fluorophenyl)-5-methyl-l-(tetrahydro-2J / -pyran-2-yl)-lJ / - 1,2, 3 -tri azole

[0474] To a solution of 4-(2-bromo-5-fluorophenyl)-5-methyl-lJ / -l,2,3-triazole (1.2 g, 4.686 mmol) in THF (20.0 ml) was added 3,4-dihydro-2H-pyran (0.59 g, 7.027 mmol) and / ?-toluenesulfonic acid (PTSA) (0.089 g, 0.460 mmol) followed by stirring at 65 °C for 12 h. The mixture was cooled to RT, quenched with water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to afford the title compound (0.9 g crude). LCMS: 256.20 [M-THP+H]+. c) 6-(4-Fluoro-2-(5-methyl- 1 -(tetrahydro-27 / -pyran-2-yl )- 1 H- 1 ,2,3-triazol-4-yl) phenyl) isoindolin-l-one

[0475] To a degassed solution of 4-(2-bromo-5-fluorophenyl)-5-methyl-l-(tetrahydro- 2J / -pyran-2-yl)-U / -l,2,3-triazole (1.0 g, 2.93 mmol), 6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl) isoindolin-l-one (0.99 g, 3.82 mmol), K2CO3 (1.01 g, 7.34 mmol) in dioxane (15.0 ml) and water (7.0 ml) was added Pd(amphos)C12 (0.104 g, 0.140 mmol) followed by stirring at 80 °C for 16 h. The mixture was cooled to RT, quenched with water, and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to afford the crude compound. The crude compound was purified by silica-gel flash column chromatography using 60-70 % ethyl acetate in hexane as eluent to afford the titled compound (1.0 g). 'H-NMR (400 MHz, Chloroform-tZ): 8 7.81 (s, 1H), 7.52 - 7.44 (m, 2H), 7.35 - 7.20 (m, 3H), 6.42 (s, 1H), 5.64 (dd, 1H), 4.45 (s, 2H), 4.05 - 3.98 (m, 1H), 3.78 - 3.70 (m, 1H), 2.41 - 2.31 (m, 2H),2.10 - 2.02 (m, 2H), 1.78 - 1.68 (m, 2H), 1.65 (s, 3H). d) 2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(5-methyl- 1 -(tetrahydro-27 / -pyran-2-yl )- 1H- 1 ,2,3 -triazol-4-yl) phenyl) isoindolin-l-one

[0476] To a degassed solution of 6-(4-fluoro-2-(5-methyl-l-(tetrahydro-2J7-pyran-2-yl)- U / -l,2,3-triazol-4-yl)phenyl)isoindolin-l-one (0.3 g, 0.764 mmol), l-(2-bromo-6- methylpyridin-4-yl)-7V-(cyclopropylmethyl)methanamine (0.23 g, 0.917 mmol), and CS2CO3 (0.74 g, 2.29 mmol) in 1,4- dioxane (10.0 ml) was added Xantphos (0.022 g, 0.03 mmol), Pd2dba3 (0.021 g, 0.02 mmol) followed by stirring at 70 °C for 8 h. The mixture was cooled to RT, filtered through celite pad, washed with 10 % MeOH in DCM. The filtrate was washed with brine, dried over anhydrous sodium sulphate, concentrated, and purified by silica-gel flash column chromatography using 10 % MeOH in DCM as eluent to afford the title compound as an off-white solid (0.25 g). LCMS: 567.5 [M+H]+. e) 2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(5-methyl-U / -l,2,3-triazol-4-yl) phenyl) isoindolin-l-one (Compound 39) To a solution of 2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2- yl)-6-(4-fluoro-2-(5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-l,2,3-triazol-4-yl)- phenyl)isoindolin-l-one (0.1 g, 0.176 mmol) in EtOH:water (2 ml : 2 ml) was added PTSA (0.05 g, 0.260 mmol) followed by stirring at RT for 12 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, extracted with 10 % MeOH in DCM. The organic layer was washed with brine, dried over anhydrous sodium sulphate, concentrated and purified by silica-gel flash column chromatography using 10 % MeOH in DCM as eluent to afford the title compound as an off-white solid (0.040 g). LCMS: 483.2 [M+H]+. E-NMR (400 MHz, DMSO-t / d): 5 8.32 (s, 1H), 7.63 - 7.59 (m, 2H), 7.47 (d, 1H), 7.43 (dt, 1H), 7.42 - 7.34 (m, 2H), 7.05 (s, 1H), 5.08 (s,

[0477] 2H), 3.78 (s, 2H), 2.46 (s, 3H), 2.42 (d, 2H), 1.72 (s, 3H), 0.98 - 0.82 (m, 1H), 0.45 - 0.40 (m, 2H), 0.16 - 0.10 (m, 2H).

[0478] The following compounds were prepared according to the procedure described for Compound 39 with appropriate variations in reactants, quantities of reagents, coupling methods and solvents. The characterization data of the compounds are also summarized in Table-8.

[0479] Table-8:

[0480] The following compounds were prepared according to the procedure described for Compound 22 from the starting materials indicated in the Table with appropriate variations in reactants, quantities of reagents, coupling methods and solvents. The characterization data of the compounds are also summarized in Table-9.

[0481] Table-9:

[0482] Example 28. 2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(l-hydroxyethyl)isoindolin-l- one (Compound 62) a) 6-Bromo-4-(l-ethoxyvinyl)isoindolin-l-one (33b) To a degassed solution of 6-bromo-4-iodoisoindolin-l-one (5.0 g, 14.09 mmol) and tributyl(l-ethoxyvinyl)stannane (8.02 g, 22.19 mmol) in dioxane (50.0 ml) was added Pd(PPh3)4 (1.71 g, 1.48 mmol) followed by stirring at 100 °C for 6 h. The reaction mixture was cooled to RT, filtered through celite pad and washed with dioxane. The filtrate was concentrated and triturated with diethyl ether to afford the title compound as pale yellow solid (3.5 g, 83 %). LCMS: 282.0 [M+H]+. b) 4-Acetyl-6-bromoisoindolin-l-one (33c)

[0483] To a solution of 6-bromo-4-(l-ethoxyvinyl)isoindolin-l-one (4.0 g, 14.77 mmol) in acetone (80.0 ml) was added 1 N HC1 (40.0 ml) followed by stirring at RT for 16 h. The reaction mixture was neutralised with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica-gel flash column chromatography using 0 - 5 % MeOH in DCM as eluent to afford the title compound as grey solid (0.8 g, 22 %). LCMS: 256.0 [M+2+H]+. c) 4-Acetyl-6-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl) isoindolin-1- one (33 d)

[0484] To a degassed solution of 4-acetyl-6-bromoisoindolin-l-one (0.80 g, 3.15 mmol), bis(pinacolato)diboron (1.04 g, 4.09 mmol) and potassium acetate (0.46 g, 4.72 mmol) in dioxane (16.0 ml) was added Pd(dppf)C12-DCM (0.26 g, 0.31 mmol) followed by stirring at 80 °C for 3 h. The reaction mixture was cooled to RT, filtered through celite pad and washed with dioxane. The filtrate was concentrated and purified by column chromatography by eluting 5 - 7 % MeOH in DCM to afford the title compound as brown solid (0.92 g, 97 %) LCMS: 302.1 [M+H]+. d) 4-Acetyl-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolinl- one (33 e)

[0485] To a degassed solution of 3-(2-bromo-5-fluorophenyl)-4- methyl-4H- 1,2,4- triazole (0.52 g, 2.31 mmol), 4-acetyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)isoindolin-l- one (0.88 g, 2.90 mmol) and potassium carbonate (0.84 g, 6.09 mmol) in water (8.0 ml) and dioxane (20.0 ml) was added Pd(dppf)C12-DCM (0.08 g, 0.10 mmol) followed by stirring at 80 ° C for 16 h. The reaction mixture was cooled to RT, filtered through celite pad and washed with dioxane. The filtrate was concentrated and purified by silica-gel flash column chromatography using 5 - 7 % MeOH in DCM as eluent to afford the title compound as brown solid (0.38 g, 53 %) LCMS: 351.8 [M+H] e) 4-Acetyl-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 (33f)

[0486] To a degassed solution of 4-acetyl-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- (cyclopropylmethyl)methanamine (0.13 g, 0.51 mmol) and CS2CO3 (0.45 g, 1.28 mmol) in dioxane (3.0 ml) was added xantphos (0.012 g, 0.02 mmol) and Pd2(dba)3 (0.02 g, 0.02 mmol) followed by stirring at 80°C for 5 h. The reaction mixture was cooled to RT, filtered through celite pad and washed with dioxane. The filtrate was concentrated and purified by silica-gel flash column chromatography using 5 - 7 % MeOH in DCM as eluent to afford the title compound as pale yellow solid (0.16 g, 71 %). LCMS: 525.02 [M+H]+. f) 2-(4-(((Cyclopropylmethyl) amino) methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl) phenyl)-4-(l -hydroxy ethyl) isoindolin-l-one (Example 61)

[0487] To a solution of 4-acetyl-2-(4-(((cyclopropylmethyl) amino) methyl)-6-methyl- pyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (0.5 g, 2.03 mmol) in methanol (5.0 ml) was added NaBHj (0.007 g, 0.19 mmol) portion wise at 00C followed by stirring at RT for 4 h. Reaction mixture was quenched with saturated ammonium chloride solution until pH ~ 7 and extracted with DCM. The combined organic layers was dried over sodium sulphate, filtered, concentrated and purified by preparative TLC by using 10 % MeOH in DCM as eluent to afford the title compound as off white solid (0.15 g, 30 %). LCMS: 527.2 [M+H]+; E-NMR (400 Hz, DMSO-t / 6): 5 8.44 (s, 1H), 8.32 (s, 1H), 7.74 (dd, 1H), 7.58 (dt, 1H), 7.52 (dd, 1H), 7.42 (d, 1H), 7.27 (d, 1H), 7.05 (s, 1H), 5.42 (d, 1H), 5.17 (s, 2H), 4.95 - 4.86 (m, 1H), 3.76 (s, 2H), 3.12 (s, 3H), 2.49 (s, 3H), 2.39 (d, 2H), 1.29 (d, 3H), 0.95 - 0.87 (m, 1H), 0.45 - 0.38 (m, 2H), 0.18 - 0.08 (m, 2H).

[0488] Example 29. 2-(4-(((l-Cyclopropyl-3,3-difluoropropyl)amino)methyl)-6- methyl-pyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l- one (Compound 66) a) (£)-7V-(Cyclopropylmethylene)-2-methylpropane-2-sulfinamide (34b)

[0489] To a solution of cyclopropane carbaldehyde (25 g, 356.68 mmol) in THF (250 mL) was added 2-methyl-2-propanesulfinamide (43.23 g, 356.68 mmol) followed by heating at 40°C for 14 h. The reaction mixture was quenched with brine solution and extracted by ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, concentrated and purified by silica-gel flash column chromatography using 5-10 % ethyl acetate in hexane as eluent to afford the title compound (11.5 g, 18.61%). LCMS: 174.1 [M+H]+. b) Ethyl 3-((tert-butylsulfinyl)amino)-3-cyclopropylpropanoate (34c)

[0490] To a stirred solution of zinc (52.86 g, 807.98 mmol) and cooper (I) chloride (7.99 g, 80.79 mmol) was added dry THF (150 mL) under nitrogen. The suspension was stirred at reflux 50 °C for 30 min, then cooled to 0 °C and ethyl 2-bromoacetate (13.49 g, 80.79 mmol) was added slowly followed by stirring for 15 min at RT, then 30 min at 50 °C. The mixture was cooled to 0 °C and (E)-7V-(cyclopropylmethylene)-2- methylpropane-2-sulfmamide (7.0 g, 40.39 mmol) in THF (45 mL) was added. The reaction was stirred at RT for 14 h. The mixture was filtered through celite pad and washed with ethyl acetate. The organic layer was washed with 0.25 M aqueous citric acid, followed by with 1 M aqueous sodium bicarbonate solution. The combined organic layer was dried over sodium sulphate, filtered, concentrated, and purified by silica-gel flash column chromatography using 0-50 % ethyl acetate in hexane as eluent to obtain the title compound (5 g, 47.35%). LC-MS: 262.2 [M+H]+. c) A-(l-Cyclopropyl-3-hydroxypropyl)-2-methylpropane-2-sulfinamide (34d)

[0491] To a solution of ethyl 3-((tert-butylsulfinyl)amino)-3-cyclopropylpropanoate (2.1 g, 8.03 mmol) in THF (15 mL) was added lithium borohydride (0.35 g, 16.06 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was quenched with ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, concentrated, and purified by silica-gel flash column chromatography using 10 % methanol in di chloromethane as eluent to afford the title compound (1.2 g, 68.10%); LCMS: 220.1 [M+H]+. d) 3-Amino-3-cyclopropylpropan-l-ol (34e)

[0492] To a solution of 7V-(l-cyclopropyl-3-hydroxypropyl)-2-methylpropane-2- sulfinamide (1.20 g, 5.47 mmol) in DCM (10 mL) was added 4 M HC1 in dioxane (12 mL) followed by stirring at RT for 16 h. The mixture was concentrated to afford the title compound (0.62 g, 98.40 %). LCMS: 116.10 [M+H]+. e) 2-(l-Cyclopropyl-3-hydroxypropyl)isoindoline-l, 3-dione (34f)

[0493] To a solution of pthalic anhydride (0.79 g, 5.36 mmol) and 3-amino-3-cyclo- propylpropan-l-ol (0.61 g, 5.36 mmol) in dioxane (10 mL) was added TEA (0.59 g, 5.90 mmol) followed by stirring at 100 °C for 14 h. The reaction mixture was cooled to RT, quenched with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, concentrated, and purified by silica- gel flash column chromatography using 5-10 % methanol in di chloromethane as eluent to afford the title compound (0.7 g, 53.18%); LCMS: 246.1 [M+H]+. f) 3-Cyclopropyl-3-(l,3-dioxoisoindolin-2-yl)propanal (34g)

[0494] To a solution of 2-(l-cyclopropyl-3-hydroxypropyl)isoindoline-l, 3-dione (0.7 g, 2.85 mmol) in DCM (15 mL) was added Dess-Martin periodinane (DMP) (2.42 g, 5.70 mmol) at 0 °C followed by stirring for 2 h at RT. The reaction mixture was quenched with bicarbonate solution and sodium thiosulfate solution and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulphate, filtered, concentrated, and purified by silica-gel flash column chromatography using 5 % methanol in di chloromethane as eluent to afford the title compound (0.5 g, 72.02 %); LCMS: 244.02 [M+H]+. g) 2-( 1 -Cy clopropyl-3 , 3 -difluoropropyl)i soindoline- 1 ,3 -di one (34h)

[0495] To a solution of 3-cyclopropyl-3-(l,3-dioxoisoindolin-2-yl)propanal (0.4 g, 1.64 mmol) in THF (5 mL) was added diethylaminosulfur trifluoride (DAST) (1.59 g, 9.86 mmol) at -78 °C followed by stirring for 12 h at RT. The reaction mixture was quenched with bicarbonate solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, concentrated, and purified by silica- gel flash column chromatography using 10-20 % ethyl acetate in hexane as eluent to afford the title compound (0.14 g, 32.10 %); Tf NMR (CDCh, 400 MHz): 5 7.89 - 7.85 (m, 2H), 7.78 - 7.73 (m, 2H), 5.90 (tt, 1H), 3.62 - 3.57 (m, 1H), 2.76 - 2.91 (m, 1H), 2.51 - 2.61 (m, 1H), 1.66 - 1.75 (m, 1H), 0.70 - 0.77 (m, 1H), 0.40 - 0.54 (m, 2H), 0.30 - 0.36 (M, 1H). h) l-Cyclopropyl-3,3-difluoropropan-l-amine hydrochloride (34i)

[0496] To a solution of 2-(l-cyclopropyl-3,3-difhioropropyl)isoindoline-l, 3-dione (0.14 g, 0.52 mmol) in ethanol (1.5 mL) was added hydrazine hydrate (0.04 g, 0.79 mmol) followed by stirring at 60 °C for 2 h. The reaction mixture was cooled to RT and filtered. The filtrate was acidified with 4 M HC1 in dioxane (3 mL) followed by stirring for 12 h at RT and concentrated to afford the title compound (0.45 g). 'H NMR (DMSO-t / 6, 400 MHz): 5 8.50 (bs, 3H), 6.38 (tt, 1H), 2.45 - 2.20 (m, 1H), 2.60 - 2.55 (m, 2H), 1.08 - 0.98 (m, 1H), 0.65 - 0.50 (m, 3H), 0.44 - 0.25 (m, 1H). i) / c / 7- Butyl (l-cyclopropyl-3,3-difluoropropyl)carbamate (34j)

[0497] To a solution of l-cyclopropyl-3,3-difluoropropan-l-amine hydrochloride (0.5 g, 2.91 mmol) in ethyl acetate (5 mL) was added triethylamine (0.88 g, 8.73 mmol) and (BOC)2O anhydride (0.95 g, 4.36 mmol) at 0 °C followed by stirring for 16 h at RT. The reaction mixture was quenched with brine solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate, filtered, concentrated, and purified by silica-gel flash column chromatography using 10-20 % ethyl acetate in hexane as eluent to afford the title compound (0.07 g, 10.21 %); 'H NMR (CDCh, 400 MHz): 5 5.98 (tt, 1H), 4.70 (d, 1H), 3.10 (s, 1H), 2.19 - 2.09 (m, 2H), 1.44 (s, 9H), 0.89 - 0.82 (m, 1H), 0.60 - 0.45 (m, 2H), 0.44 - 0.25 (m, 2H). j) l-Cyclopropyl-3,3-difluoropropan-l-amine hydrochloride (34k)

[0498] To a solution of tert-butyl (l-cyclopropyl-3,3-difluoropropyl)carbamate (0.07 g, 0.29 mmol) in DCM (1 mL) was added 4 M HC1 in dioxane (0.5 mL) at 0 °C. The reaction mixture was stirred for 6 h at RT. The reaction mixture was concentrated to afford the title compound (0.06 g). LCMS: 136.2 [M+H]+. k) 2-(4-(((l-Cyclopropyl-3,3-difhioropropyl)amino)methyl)-6-methylpyri din-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 62)

[0499] The compound was prepared according to the procedure described for Example 1 from the Int-10 and 34k with appropriate variations in reactants, quantities of reagents, coupling methods and solvents. LC-MS: 547.2 [M+H]+; 'H-NMR (DMSO-d6, 400 MHz): 5 8.45 (s, 1H), 8.34 (s, 1H), 7.73 (dd, 1H), 7.64 (d, 1H), 7.59 (dt, 1H), 7.54 - 7.50 (m, 2H), 7.38 (dd, 1H), 7.06 (s, 1H), 6.27 (tt, 1H), 5.08 (s, 2H), 3.94 (d, 1H), 3.82 (d, 1H), 3.15 (s, 3H), 2.46 (s, 3H), 2.15 - 1.98 (m, 2H), 1.98 - 1.85 (m, 1H), 0.80 - 0.74 (m, 1H), 0.56 - 0.52 (m, 1H), 0.45 - 0.35 (m, 1H), 0.35 - 0.25 (m, 1H).

[0500] Although the present application has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the present application encompasses the generic area as hereinbefore disclosed. For example, the compounds listed below in table- 10 which can be prepared by following a similar procedure as described in above Schemes / Examples with suitable modifications known to the one ordinary skilled in the art are also included in the scope of the present application:

[0501] Table-10:

[0502] ABBREVIATIONS:

[0503] DCM - Dichloromethane

[0504] DIPEA - N,N-diisopropylethylamine DMAP - 4-Dimethylaminopyridine

[0505] DMF - N,N-Dimethylformamide

[0506] DMSO - Dimethylsulfoxide

[0507] HATU - 2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate HPLC - High-performance liquid chromatography

[0508] LCMS - Liquid chromatography-mass spectrometry

[0509] Pd(amphos)C12 - Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloro- palladium(II)

[0510] Pd(dppf)C12 - [1,1 '-Bis(diphenylphosphino)ferrocene]palladium(II) di chloride Pd2(dba)3 - Tris(dibenzylideneacetone)dipalladium(0)

[0511] [Rh(COD)Cl]2 - Cyclooctadiene rhodium chloride dimer RT - Room temperature

[0512] STAB - Sodium triacetoxyborohydride

[0513] TFA - Trifluoroacetic acid

[0514] THF - Tetrahydrofuran

[0515] XantPhos - 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0516] BIOLOGY

[0517] Experiment 1. Biochemical assay for CBL-b inhibition

[0518] The inhibitory activity of the test compounds was assessed by Ligand displacement TR-FRET assay. The human recombinant CBL-b (human Biotin CBL-b recombinant protein a.a. 39 - 426; synthesised in-house) was diluted in enzyme assay buffer (20 mM HEPES, 150 mM NaCl, 0.01 % Triton X, 0.01 % BSA, 0.5 mM TCEP) in a 10 pl volume and plated in 384-well plates (Cat# 781075, Greiner) to a final concentration of 50 nM. The enzyme / compound mixture was incubated at RT for 60 min. The Bodipy FL-Probe described in WO 2020 / 210508 (synthesized in-house) diluted in enzyme assay buffer was added to the plate and incubated for 60 min RT, the final probe concentration was 0.3 pM. After 60 min incubation, 10 pl of detection mix (Terbium Streptavidin, (Cat# 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 2030 multilabel reader Victor5 (PerkinElmer). The IC50 (concentration for half maximal inhibition) and % maximum inhibition of the compounds were estimated by fitting the dose response data to a sigmoidal curve fitting equation using Graph pad Prism software V. 8.

[0519] The compounds of the invention were screened in the above mentioned assay and the IC50 values of the compounds are set forth in Table-11 below wherein “A” refers to a group of compounds having IC50 value of less than 0.03 pM, “B” refers to a group of compounds having IC50 value in range of 0.03 to 0.10 pM and “C” refers to a group of compounds having IC50 value greater than 0.10 pM.

[0520] Table-11.

[0521] Experiment 2: Jurkat NEAT reporter assay protocol

[0522] A human T lymphocyte Jurkat reporter cell line was further used to assess activation of the nuclear factor of activated T-cells (NF AT) signaling pathway by Cbl-b inhibitors. The reporter cell line is a genetically engineered Jurkat T cell line that expresses a luciferase reporter driven by an NFAT-response element (NF AT -RE). The Cbl-b inhibitor was incubated with 1 x 105Jurkat NF AT reporter cells per well for 30 minutes. Subsequently, cells were stimulated with soluble anti-human CD3 / CD28 antibody for 6 hours resulting in NFAT-RE-mediated luminescence. The bioluminescent signal is detected and quantified using Bio-Gio™ Luciferase Assay System. Readouts were reported as fold change over baseline. Here, baseline was the measurement obtained from Jurkat NF AT reporter cells stimulated with anti-CD3 antibody and anti-CD28 antibody, where the cells were not incubated with a Cbl-b inhibitor.

[0523] The compounds of the invention were screened in the above mentioned assay and the ECso values of the compounds are set forth in Table 12 below wherein “A” refers to a group of compounds having ECso value of less than 0.25 pM, “B” refers to a group of compounds having ECso value in range of 0.25 to 1.0 pM and “C” refers to a group of compounds having EC so value greater than 1.0 pM.

[0524] Table-12:

[0525] Experiment 3: Human PBMC Cytokine release assay Peripheral blood mononuclear cells (PBMC) were isolated from blood of healthy human donor using Histopaque (Sigma). The Cbl-b inhibitor was added to 1 x 105cells per well and the plate was incubated for 30 minutes at 37°C in 5% CO2 at different concentrations with a final DMSO concentration of <0.5 %. Following incubation with the Cbl-b inhibitor, human PBMCs were stimulated with Dynabeads™ Human T- Activator CD3 / CD28 (Thermo Fisher Scientific) for 48 hours. Cell free supernatant was collected after end of incubation and were analyzed for cytokine secretion, including IL- 2 by ELISA (R&D Systems). Readouts were reported as fold change over baseline. Here, baseline was 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.

[0526] The exemplary compounds were screened in the above mentioned assay and the ECso values of the compounds are set forth in Table 13 below wherein “A” refers to a group of compounds having EC 50 value of less than 0.25 pM, “B” refers to a group of compounds having EC 50 value in range of 0.25 to 0.5 pM and “C” refers to a group of compounds having EC so value greater than 0.5 pM.

[0527] Table-13.

[0528] Experiment 4: Human T Cytokine release assay

[0529] Peripheral blood mononuclear cells (PBMC) were isolated from blood of healthy human donor using Histopaque (Sigma). Subsequently T cells were purified from isolated PBMCs using EasySep™ Human T Cell Isolation Kit (Stem Cell technologies). Purified T-cells were seeded in 96-well plate (Coming) pre-coated with anti-human CD3 (Invitrogen) at a seeding density of 0.1 million / well. Multiple concentrations of compound were incubated with cells at 37°C for 30 min. Cells were further stimulated with anti -human CD28 (Invitrogen). The plate was incubated at 37°C for 48hrs. Cell free supernatant was collected after end of incubation and were analyzed for cytokine secretion, including IL-2 by ELISA (R&D Systems). Readouts were reported as fold change over baseline. Here, baseline was the measurement obtained from human T cells stimulated with anti-human CD3 / CD28, where the cells were not incubated with a Cbl-b inhibitor.

[0530] The EC50 (half maximal effective concentration) and % maximum IL-2 induction by the compounds were estimated by fitting the dose response data to a sigmoidal curve fitting equation using GraphPad Prism software V.8.

[0531] The compounds of the invention were screened in the above mentioned assay and the ECso values of the compounds are set forth in Table 14 below wherein “A” refers to a group of compounds having ECso value of less than 0.25 pM, “B” refers to a group of compounds having ECso value in range of 0.25 to 0.5 pM and “C” refers to a group of compounds having EC so value greater than 0.5 pM.

[0532] Table-14.

[0533] Experiment 5: In-vivo anti-tumor efficacy of Compound 8 in CT26 syngeneic model

[0534] Protocols:

[0535] Unless mentioned otherwise, all procedures relating to animal care, handling, and treatment were approved by the Institutional Animal Ethics Committee (IAEC) of Aurigene Oncology Ltd, in line with the guidelines recommended by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA, Govt, of India).

[0536] Compound formulation preparation for in vivo studies:

[0537] Compound 8 was formulated fresh every day in 20 % v / v PEG 400, 30 % v / v of 1 % w / v Methyl cellulose in water, and 50 % v / v of 1 % w / v Tween 80 in water (QS). The pH was adjusted to 5.5 using IN HC1 if required. The final mixture included 50 parts of 1% w / v Tween 80 and 50 parts of 1% w / v methylcellulose in water to yield a clear solution.

[0538] CT26 Subcutaneous Tumor Generation, Dosing regimens, and Measurement of Anti-tumor Activity:

[0539] CT26 cell line was procured from American Type Culture Collection (ATCC) and grown in RPMI-1640 medium supplemented with 2.5 g / L glucose, ImM sodium pyruvate, 10% FBS and 1% penicillin streptomycin. To generate subcutaneous tumors, 0.1 mL of the inoculum containing 1 X 106cells / animal was inoculated subcutaneously on the right flank region of 7 to 8-week-old female Balb / C mice. Compound 8 treatment was initiated when the mean tumor volume (TV) reached approximately 30 to 60 mm3. Animals were selected based on TV and randomized into treatment groups of 8 animals per group. Compound 8 at a 30 mg / kg dose, alone and in combination with anti-mouse anti-PD-1 (200 pg / animal, thrice weekly) and anti -mouse anti-PD-Ll (200 pg / animal, thrice weekly) antibodies, was administered orally once daily at a dose volume of 10 mL / kg bodt weight starting from Day 1 and continued till Day 14. Treatment related changes in body weight as well as clinical signs were monitored daily, and tumor volumes were recorded at least biweekly using digital calipers. After the completion of 14 day treatment period, animals were monitored for survival without administering Compound 8. The Tumor volume (TV) in mm3was calculated according to the following formula:

[0540] TV = length x width2x 0.5 length: largest diameter of tumor (mm); width: diameter perpendicular to length (mm) Tumor growth inhibition (TGI %) was calculated as a measure of anti-tumor efficacy using the following formula

[0541] % TGI = 100 - ((AT / AC) X 100) where changes in tumor volume (A volumes) for each treated (T) and control (C) group was derived by subtracting the mean tumor volume on the first day of treatment (starting day) from the mean tumor volume on the specified observation day. Results:

[0542] In vivo anti-tumor efficacy of Compound 8 in CT26 syngeneic model: The in vivo anti-tumor efficacy of Compound 8 monotherapy and combination therapy with antimouse anti-PD-1 and anti -mouse anti-PD-Ll antibodies was evaluated in the CT26 syngeneic model. Compound 8 was administered once daily by oral gavage at a dose of 30 mg / kg for both monotherapy and combination therapy with anti-mouse anti-PD-1 and anti-mouse anti-PD-Ll antibodies for 14 days. Compound 8 monotherapy and combination therapy with anti -mouse anti-PD-1 and anti-mouse anti-PD-Ll antibodies were well tolerated without any treatment related body weight changes or clinical signs Figure 1.

[0543] Monotherapy with Compound 8 resulted in a tumor growth inhibition of 67%. Similar, combination therapy of Compound 8 with anti -mouse anti-PD-1 and anti -mouse anti- PD-Ll antibodies resulted in enhanced tumor growth inhibition of 154% and 99%, respectively Figure 2. Furthermore, the combination therapy resulted in 2 / 8 animals being tumor free with anti-PD-1, and 1 / 8 animals being tumor free with anti-PD-Ll. Compared to the control group, tumor growth inhibition observed with both Compound 8 monotherapy and combination therapy was statistically significant. Likewise, when compared to Compound 8 monotherapy, the combination therapies showed statistically significant improvements in tumor growth inhibition.

[0544] After the completion of 14-day treatment period, animals were monitored for survival without administering test Compound 8. Monotherapy with Compound 8 resulted in an increase in median survival compared to control arm. Similarly, Compound 8 combination therapy with anti -mouse anti-PD-1 and anti-mouse anti-PD-Ll antibodies significantly enhanced median survival compared to monotherapy arm Figure 3.

[0545] Incorporation by Reference

[0546] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. Equivalents

[0547] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

1. We Claim:

1. A compound of formula (I),or a pharmaceutically acceptable salt thereof whereinRi is hydrogen, halogen, C1.7 alkyl, C3-7 cycloalkyl, hydroxy, C1.7 alkoxy, halogen C1.7 alkyl or cyano;R2 is hydrogen, C2-7 alkoxy, halogen C1.7 alkoxy, cyano C1.7 alkoxy, C1.7 alkoxy C1.7 alkoxy, hydroxy C1.7 alkyl, hydroxy C1.7 alkoxy or -NHR9;R9 is C1.7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1.7 alkyl, halogen C1.7 alkyl, C1.7 alkoxy C1.7 alkyl, cyano C1.7 alkyl or cyano C1.7 alkyl C3-7 cycloalkyl, hydroxy C1.7 alkyl or oxetanyl;R3 is any of the following groupsZi, Z2, and Z3 are, independently, CH, CX, C-CF3 or N;X is halogen;Y is 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring having 1-4 heteroatoms as ring atoms independently selected from O, S and N;R4 is hydrogen or halogen;Rio and R14 are, independently, -C1.7 alkyl-NR2iR22, -SO2-NR21R22 or a groupL is a bond, -CH2-, -CH-, -CH(CH3)-, -C(CH2)- or -C(O)-;Rn is hydrogen, C1.7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1.7 alkyl, halogen, C1.7 alkoxy or halogen C1.7 alkyl;A is any of the following groups:R5 and Rs are independently hydrogen or C1.7 alkyl;B 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;R15 is absent, hydrogen, C1.7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1.7 alkyl, halogen, C1.7 alkoxy or halogen C1.7 alkyl;Ri8, R19 and R2o are independently absent, hydrogen, C1.7 alkyl, C1.7 alkoxy, halogen, cyano, halogen C1.7 alkyl, hydroxy, hydroxy C1.7 alkyl or oxo;R2I and R22are independently hydrogen, C1.7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1.7 alkyl, C1.7 alkyl C3-7 cycloalkyl, (C3-7 cycloalkyl)2C1.7 alkyl, C1.7 alkyl C3-7 cycloalkyl C1.7 alkyl, C3-7 cycloalkyl halogen C1.7 alkyl, halogen C1.7 alkyl C3-7 cycloalkyl C1.7 alkyl, halogen C1.7 alkyl, halogen C3-7 cycloalkyl, halogen C3-7 cycloalkyl C1.7 alkyl, hydroxy C1.7 alkyl, hydroxy C1.7 alkyl C3-7 cycloalkyl C1.7 alkyl, hydroxy C3-7 cycloalkyl, C1.7 alkoxy C3-7 cycloalkyl, cyano C3-7 cycloalkyl C1.7 alkyl, (hydroxy)(C3-7 cycloalkyl) C1.7 alkyl, C1.7 alkoxy C3-7 cycloalkyl C1.7 alkyl, C1.7 alkoxy C1.7 alkyl, aminohydroxy C1.7 alkyl, C1.7 alkyl amide C1.7 alkyl, -SO2-Ci-7 alkyl, -S(O)-Ci-7 alkyl, -SO2-C3-7 cycloalkyl, -SO2-hydroxy C1.7 alkyl, -C1.7 alkyl-(O-Ci-7 alkyl) 1.3-NH2, -C1.7 alkyl (C3-7 cycloalkyl)(OH), C1.7 alkoxy carbonyl C1.7 alkyl, -C1.7 alkyl-NH-C(O)-C2-7 alkenyl, or a group (la),L’ is a bond, C1.7 alkyl or C2-7 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; with the proviso that when R2 is hydrogen and A is (2”), then R21 is -SO2-C2-7 alkyl, -SO2-C3-7 cycloalkyl, -SCh-hydroxy C1.7 alkyl, C1.7 alkyl C3-4 cycloalkyl C1.7 alkyl, (C1.7 alkyl)2 C3-7 cycloalkyl C1.7 alkyl, dihalogen C1.7 alkyl, -CH (C3-7 cycloalkyl)(dihalogen C1.7 alkyl), adamantane C1.7 alkyl, bicyclopentane C1.7 alkyl, -CH2-CH3, -CH(CI-7 alkyl)(hydroxy C3-7 cycloalkyl), -CH2-CH(CH2OH)-CH2- CH3, -CH(CH2OH)-CH2-CH2-CH3, -CH(CH2OH)-CH2-CH2-CH2-CH3, -CH(CH2- CH2OH)-CH-(CH3)2, -CH(CH(CH3)2)-C(OH(CH3)2), -C(CH3)2-C3-7 cycloalkyl, -CH2- CH-(CI-7 alkyl)(C2-7 alkyl), methoxy C3-7 alkyl, -CH(R7)CH2-ORs, -C1.7 alkyl-NH-C(O)- C2-7 alkenyl, or C1.7 alkoxy carbonyl C1.7 alkyl, wherein R7 is C3-7 cycloalkyl, and Rs is hydrogen or C1.7 alkyl; or Zi is CX and Rn is -CF3; or B is oxazolidin-2-one; or Rio is -SO2-NR21R22; or Rn is cyclopropyl; or Zi and Z2 is N, and Rio is -CH(CH3)-NR2iR22; wherein optional substitution, in each occurrence, is 1-2 substituents independently selected from C1.7 alkyl, C3-7 cycloalkyl, halogen, hydroxy, C1.7 alkoxy, halogen C1.7 alkyl and cyano.

2. The compound according to claim 1, wherein R2 is C2-7 alkoxy, halogen C1.7 alkoxy, cyano C1.7 alkoxy, C1.7 alkoxy C1.7 alkoxy, hydroxy C1.7 alkyl, hydroxy C1.7 alkoxy or -NHR9 and A is (F ’).

3. The compound according to claim 2, wherein R2 is -NHR9.

4. The compound according to claim 3, wherein R9 is C1.7 alkyl.

5. The compound according to claim 2, wherein R2 is C2-7 alkoxy.

6. The compound according to claim 2, wherein A is (1”).

7. The compound according to claim 6, wherein Rs is methyl.

8. The compound according to any one of the preceding claims, wherein R21 is -CH(R7)CH2-OR8.

9. The compound according to any one of the preceding claims, wherein R21 is -CH2-CH-(CI-7alkyl)(C2-7 alkyl).

10. The compound according to any one of the preceding claims, wherein R21 is -CH(CH2OH)-CH2-CH2-CH3or -CH(CH2OH)-CH2-CH2-CH2-CH3.

11. The compound according to any one of the preceding claims, wherein R21 is dihalogen C1.7 alkyl.

12. The compound according to any one of the preceding claims, wherein R3is any of the following groups:

13. The compound according to claim 12, wherein R3is group (lb’).

14. The compound according to any one of the preceding claims, wherein Rn is C1.7 alkyl, C3-7 cycloalkyl or halogen C1.7 alkyl.

15. The compound according to claim 14, wherein Rn is methyl or -CF3.

16. The compound according to claim 1, wherein Rw and R14 are independently - Ci-7 alkyl-NR2iR22.

17. The compound according to claim 16, wherein R21 is C1.7 alkyl, C3.7cycloalkyl C1.7 alkyl, hydroxy C1.7 alkyl, C1.7 alkoxy C3.7cycloalkyl C1.7 alkyl, halogen C1.7 alkyl, (hydroxy)(C3-7 cycloalkyl) C1.7 alkyl or C1.7 alkyl C3.7cycloalkyl C1.7 alkyl.

18. The compound according to claim 1, wherein Rw is a groupwherein -L- is -CH2- or -CH(CH3)-.

19. The compound according to claim 18, wherein B is any of the following groups:

20. The compound according to claim 19, wherein B is group (2j’).

21. The compound according to any one of the preceding claims, wherein R22 is hydrogen.

22. The compound according to any one of the preceding claims, wherein R3 is the following group:

23. A compound selected from:6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-((((l- methylcyclopropyl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 1);((R)-6-(4-Fluoro-2-(4-methyl-4H- 1,2, 4-triazol-3-yl)phenyl)-2-(4-(((l -meth oxy- 3-methylbutan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 2);2-(4-((((3,3-Dimethylcyclobutyl)methyl)amino)methyl)-6-methylpyridin-2-yl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 3);6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-((((l- methylcyclobutyl)methyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 5);(R)-2-(4-(((l-Cyclopropyl-2-hydroxyethyl)amino)methyl)-6-methylpyridin-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 6);(R)-6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((2-hydroxy- 2,4-dimethylpentan-3-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 7);2-(4-(((3,3-Difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 8);(R)-6-(4-Fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)-2-(4-(((l -(1 - hydroxy cyclopropyl)-2-methylpropyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin- 1-one (Compound 9);6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((l -hydroxy-4- methylpentan-3-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound10);(R)-6-(4-Fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)-2-(4-(((l - hydroxyhexan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound11);2-(4-(((Bicyclo[l.l.l]pentan-l-ylmethyl)amino)methyl)-6-methylpyri din-2 -yl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 12);(R)-6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-2-(4-(((l -hydroxy- pentan-2-yl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 13);2-(4-(((((3r,5r,7r)-Adamantan-l-yl)methyl)amino)methyl)-6-methylpyri din-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 14);6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(6-methyl-4-(((2- methylbutyl)amino)methyl)pyridin-2-yl)isoindolin-l-one (Compound 15);Methyl 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)butanoate (Compound 16);2-(4-(((l-Cyclopropyl-2-methoxyethyl)amino)methyl)-6-methylpyridin-2-yl)-6- (4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 17);2-(4-(((4,4-Difluorobutyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 18);6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((2-methoxy-2- methylpropyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 19);2-(4-(((2-Cyclopropylpropan-2-yl)amino)methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 20);6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-2-(4-(((2-(hydroxymethyl)butyl)amino)methyl)-6-methylpyridin-2-yl)isoindolin-l-one (Compound 21);2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4Z / -l,2,4-triazol-3-yl) phenyl)-4-propoxyisoindolin-l-one (Compound 22);2-(4-((Ethylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 23);2-(6-Cyclopropyl-4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 24);2-(5-(((Cyclopropylmethyl)amino)methyl)-2-fluoro-3-(trifluoromethyl)phenyl)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 25);2-(4-(((Cyclopropylmethyl)amino)methyl-d2)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 26);2-(4-(((Cyclopropylmethyl)amino)methyl)-6,7-dihydro-5H-cyclopenta[b]- pyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 27);2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(methylamino)isoindolin-l-one (Compound 28);2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-(ethyl- amino)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 29);2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(isobutylamino)isoindolin-l-one (Compound 30);2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-ethoxy-6-(4- fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 31);2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-isobutoxyisoindolin-l-one (Compound 32);4-((2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)- 1 -oxoisoindolin-4-yl)oxy)- butanenitrile (Compound 33);4-(Butylamino)-2-(4-(((cy cl opropylmethyl)amino)methyl)-6-methylpyri din-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 34);(7?)-3-((2-(6-(4-Fluoro-2-(4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-l -oxoisoindo- lin-2-yl)-6-methylpyridin-4-yl)methyl)-4-propyloxazolidin-2-one (Compound 35);2-(4-(Aminomethyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- 1,2,4- triazol-3-yl)phenyl)isoindolin-l-one (Compound 36);N-((2-(6-(4-Fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin- 2-yl)-6-methylpyridin-4-yl)methyl)propane-2-sulfonamide (Compound 37);2-(6-(l-((Cyclopropylmethyl)amino)ethyl)-2-methylpyrimidin-4-yl)-6-(4-fluoro- 2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 38);2-(4-(((Cyclopropylmethyl)amino) methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (5-methyl-lZ / -l,2,3-triazol-4-yl) phenyl) isoindolin-l-one (Compound 39);(2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(5-methyl-lH- l,2,3-triazol-4-yl)phenyl)isoindolin-l-one (Compound 40);2-(4-(((3,3-Difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (5-methyl- 1H- 1,2,3 -triazol-4-yl)phenyl)isoindolin- 1 -one (Compound 41);2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(propylamino)isoindolin-l-one (Compound 42);2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-((3,3,3-trifluoropropyl)amino)isoindolin-l- one (Compound 43);4-((2-Cyclopropylethyl)amino)-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 44);2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-4-((2 -methoxy ethyl)amino)isoindolin-l-one (Compound 45);2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-4-(ethylamino)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 46);2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l, 2, 4-triazol-3-yl)phenyl)-4-(2-methoxy ethoxy )isoindolin-l -one (Compound 47);4-((2-(4-((Butylamino)methyl)-6-methylpyri din-2 -yl)-6-(4-fluoro-2-(4-methyl- 4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin-4-yl)oxy)butanenitrile (Compound 48);4-Butoxy-2-(4-(((cy cl opropylmethyl)amino)methyl)-6-methylpyri din-2 -yl)-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one (Compound 49);2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-4-ethoxy-6-(4-fluoro-2-(4- methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one (Compound 50);2-(4-((Butylamino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H- l,2,4-triazol-3-yl)phenyl)-4-propoxyisoindolin-l-one (Compound 51);2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(oxetan-3-ylamino)isoindolin-l-one (Compound 52);2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-((2,2- difluoroethyl)amino)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-1-one (Compound 53);2-Chloro-N-(cyclopropylmethyl)-6-(6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3- yl)phenyl)-l-oxoisoindolin-2-yl)pyridine-4-sulfonamide (Compound 54);2-Chloro-6-(6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoiso- indolin-2-yl)-N-(2-hydroxy-2-methylpropyl)pyridine-4-sulfonamide (Compound 55);2-(4-(((3,3-difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-4-(ethylamino)- 6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one(compound 56);2-(4-(((3,3-difluoropropyl)amino)methyl)-6-methylpyri din-2 -yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-propoxyisoindolin-l-one(compound 57);2-(4-(((3,3-difluoropropyl)amino)methyl)-6-methylpyri din-2 -yl)-4-ethoxy-6-(4- fluoro-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)isoindolin- 1 -one(compound 58);4-((2-(4-(((3,3-difluoropropyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin-4- yl)oxy)butanenitrile(compound 59);N-((2-(6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-l-oxoisoindolin-2- yl)-6-methylpyridin-4-yl)methyl)- 1 -hydroxymethanesulfonamide(compound 60);2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(2-hydroxypropan-2-yl)isoindolin-l- one(compound 61);2-(4-(((Cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(l-hydroxyethyl)isoindolin-l-one(compound 62);2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-(2,2- difluoroethoxy)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l- one(compound 63);2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-4-(3,3- difluoropropoxy)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l- one(compound 64);2-(4-(((cyclopropylmethyl)amino)methyl)-6-methylpyridin-2-yl)-6-(4-fluoro-2- (4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(2-hydroxyethoxy)isoindolin-l- one(compound 65); and2-(4-(((l-Cyclopropyl-3,3-difluoropropyl)amino)methyl)-6-methyl-pyridin-2- yl)-6-(4-fluoro-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)isoindolin-l-one(compound 66); or a pharmaceutically acceptable salt thereof or isotopes thereof.

24. A compound according to claim 1, for use as a medicament.

25. A compound according to any one of claims 1-23, for use in the treatment of a disease or condition wherein inhibition of Cbl-b is desired.

26. The compound for use according to claim 25, wherein the disease is cancer.

27. The compound for use according to claim 26, wherein the cancer is 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, nonHodgkin’s lymphoma or leukemia.

28. The compound for use according to any one of claims to 25-27, 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.

29. A method for the treatment of a disease or condition wherein inhibition of Cbl-b is desired, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

30. The method according to claim 29, wherein the disease is cancer.

31. The method according to claim 30, wherein the cancer is 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.

32. The method according to any one of claims 29 to 31, 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.

33. The method of claim 32, wherein the anti-cancer agent is a chemotherapeutic agent or an immune checkpoint inhibitor.

34. The method of claim 33, wherein the anti-cancer agent is an immune checkpoint inhibitor.

35. The method of claim 34, wherein the immune checkpoint inhibitor is PD- 1 or PD-Ll antagonist.

36. The method of claim 35, wherein the PD-1 antagonist is an anti-PD-1 antibody and the PD-L1 antagonist is an anti-PD-Ll antibody.

37. The method of any one of claims 32-36, wherein a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and the anti-cancer agent are administered simultaneously or sequentially.

38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

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