N- (PHENYL) -2- (PHENYL) PYRIMIDIN-4-CARBOXAMIDE DERIVATIVES AND COMPOUNDS RELATED TO HPK1 INHIBITOR

专利摘要:
the present invention relates to n- (phenyl) -2- (phenyl) -pyrimidine-4-carboxamide derivatives and related compounds of formula i as inhibitors of hpk1 (hematopoietic progenitor kinase 1) to treat cancer, such as example, breast cancer, colorectal cancer, lung cancer, ovarian cancer and pancreatic cancer. preferred compounds are, for example, n- (5-fluoro-2- (2pyridin-2-yl) pyrrolidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide and n - (5-fluoro-2- (hexahydropyrrolo [3,4-b] pyrrol-1 (2h) -yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide. (i)
公开号:BR112020016927A2
申请号:R112020016927-7
申请日:2019-02-19
公开日:2020-12-15
发明作者:Oleg Vechorkin；Jun Pan；Alexander Sokolsky；Evan Styduhar；Qinda Ye；Wenqing Yao
申请人:Incyte Corporation；
IPC主号:

专利说明:

[001] [001] The present invention relates to compounds, as well as their compositions and methods of use. The compounds modulate the activity of the hematopoietic parent kinase 1 (HPK1) and are useful in the treatment of various diseases, including cancer. BACKGROUND
[002] [002] Hematopoietic progenitor kinase 1 (HPK1) originally cloned from hematopoietic progenitor cells is a member of the MAP kinase kinase kinase kinase (MAP4Ks) family, which includes MAP4K1 / HPK1, MAP4K2 / GCK, MAP4K3 / GLK , MAP4K4 / HGK, MAP4K5 / KHS, and MAP4K6 / MINK (Hu, MC, et al., Genes Dev, 1996. 10 (18): p. 2251-64). HPK1 is of particular interest because it is predominantly expressed in hematopoietic cells, such as T cells, B cells, macrophages, dendritic cells, neutrophils and mast cells (Hu, MC, et al., Genes Dev, 1996. 10 (18) : p. 2251-64; Kiefer, F., et al., EMBO J, 1996. 15 (24): p. 7013-25). HPK1 kinase activity has been shown to be induced after activation of T cell receptors (TCR) (Liou, J., et al., Immunity, 2000. 12 (4): p. 399-408), B cell receptors (BCR) (Liou, J., et al., Immunity, 2000. 12 (4): p. 399-408), transforming growth factor receptor (TGF-βR) (Wang, W., et al ., J Biol Chem, 1997. 272 (36): p. 22771-5; Zhou, G., et al., J Biol Chem,
[003] [003] HPK1 is important in regulating the functions of several immune cells and has been implicated in autoimmune diseases and antitumor immunity (Shui, JW, et al., Nat Immunol, 2007. 8 (1): p. 84-91 ; Wang, X., et al., J Biol Chem, 2012. 287 (14): p. 11037-48). HPK1 knockout mice were more susceptible to induction of experimental autoimmune encephalomyelitis (EAE) (Shui, J.W., et al., Nat Immunol,
[004] [004] The present invention provides, inter alia, a compound of Formula (I '): I' or a pharmaceutically acceptable salt thereof, wherein the constituent variables are defined herein.
[005] [005] The present invention further provides a pharmaceutical composition comprising a compound of the description, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
[006] [006] The present invention further provides methods of inhibiting HPK1 activity, which comprises administering to a subject a compound of the description, or a pharmaceutically acceptable salt thereof. The present invention also provides uses of the compounds described herein in the manufacture of a medicament for use in therapy. The present invention also provides the compounds described herein for use in therapy.
[007] [007] The present invention further provides methods for treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of a compound of the description, a pharmaceutically acceptable salt thereof.
[008] [008] The present invention provides a compound of Formula (I '):
[009] [009] The present invention provides a compound of Formula (I ') or a pharmaceutically acceptable salt thereof, wherein: CyA is C3-12 cycloalkyl or 4-12 membered heterocycloalkyl; wherein the 4-12 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; where N and S are optionally oxidized; wherein a 4-12 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein C3-12 cycloalkyl and 4-12 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from RA; A is N or CR16;
[0010] [0010] The present invention provides a compound of Formula (I ') or a pharmaceutically acceptable salt thereof, wherein: CyA is 4-12 membered heterocycloalkyl; wherein the 4-12 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming hetero atoms independently selected from N, O and S; wherein a 4-12 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 4-12 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from RA;
[0011] [0011] The present invention provides a compound of Formula (I): (R 4) n A N CyA
[0012] [0012] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided here, wherein: CyA is C3-12 cycloalkyl or 4-12 membered heterocycloalkyl; wherein the 4-12 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; where N and S are optionally oxidized; wherein a 4-12 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein C3-12 cycloalkyl and 4-12 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected substituents from RA; A is N or CF; R1 is selected from H, D, halo, CN, C1-6 alkyl, ORa15 and NRc15Rd15; wherein the C1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from Rg; R2 is selected from H, D, Cy2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
[0013] [0013] In some modalities, a compound of
[0014] [0014] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided here, wherein: CyA is C3-12 cycloalkyl or 4-12 membered heterocycloalkyl; wherein the 4-12 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; where N and S are optionally oxidized; wherein a 4-12 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein C3-12 cycloalkyl and 4-12 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected substituents from RA; A is N or CR16; R16 is selected from H, D, C1-6 alkyl, halo, CN and ORa16; R1 is selected from H, D, halo, CN, C1-6 alkyl and ORa15; wherein C1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from Rg; R2 is selected from H, D, Cy2, C1-6 alkyl, C1-6 haloalkyl, halo, CN and S (O) 2Rb; wherein said C 1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10; Cy2 is selected from C3-10 cycloalkyl, heterocycloalkyl of 4-10 members, C6-10 aryl and heteroaryl of 5-10 members; wherein the 4-10 membered heterocycloalkyl and the 5-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein a 5-10 membered heteroaryl and 4-10 membered heteroarylalkyl carbon atom is optionally substituted by oxo to form a carbonyl group; and where C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10; R3 is selected from H, D, Cy3, halo and CN; Cy3 is 6-10 membered heteroaryl; wherein the 6-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; each R4 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, halo, D, CN and ORa8; each R5 is independently selected from halo, D and CN; RA is selected from H, D, Cy1, C1-6 alkyl, C1-6 haloalkyl, halo, CN, ORa11, C (O) NRc11Rd11, and NRc11Rd11; wherein said C 1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from R7; Cy1 is selected from C3-10 cycloalkyl and 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein a 5- to 10-membered heteroryl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 5-10 membered C3-10 cycloalkyl and heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7; each R7 is independently selected from C1-6 alkyl, halo, D, CN, ORa12 and NRc12Rd12; each R10 is independently selected from C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, ORa1,
[0015] [0015] In some embodiments, CyA is 4-12 membered heterocycloalkyl; wherein 4-12 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming hetero atoms independently selected from N, O and S; wherein a 4-12 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 4-12 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from RA.
[0016] [0016] In some modalities, CyA is selected from 2,5-diaza-bicycles [2.2.1] heptan-2-ila; 3-aminopyrrolidin-1-yl; 2- (aminomethyl) pyrrolidin-1-yl; 2- (hydroxymethyl) pyrrolidin-1-yl; 2- (methoxymethyl) pyrrolidin-1-yl; 4-amino-2- (hydroxymethyl) pyrrolidin-1-yl; 4-hydroxy-2-methylpyrrolidin-1-yl; 2- (pyridin-2-yl) pyrrolidin-1-yl; hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -yl; 2-methylpiperazin-1-yl; 2- (hydroxymethyl) piperazin-1-yl; 3- (hydroxymethyl) morpholine; 5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl; (2-hydroxyethyl) -2,5-diazabicle [2.2.1] heptan-2-yl); 5- (propylcarbamoyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl; 4-hydroxy-2- (hydroxymethyl) pyrrolidin-1-yl; 2- (hydroxymethyl) -5-methylpiperazin-1-yl; 6- (hydroxymethyl) -4,7-diazaspiro [2.5] octan-7-yl; 4-amino-2- (1-hydroxycyclopropyl) pyrrolidin-1-yl; 4-amino-2- (2-hydroxypropan-2-yl) pyrrolidin-1-yl; 4-amino-2- (hydroxymethyl-d2) pyrrolidin-1-yl; 3- (hydroxymethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl; 4-amino-2-methylpiperidin-1-yl; piperidin-4-yl; 4- (dimethylamino) -2- (hydroxymethyl) pyrrolidin-1-yl; 2- (hydroxymethyl) -4- (isopropylamino) pyrrolidin-1-yl; 4- (hydroxymethyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl; 2- (hydroxymethyl) morpholino; 2- (2 - ((dimethylamino) methyl) morpholino; 2- (cyanomethyl) morpholino; 3-oxotetrahydro-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl; 3- ( hydroxymethyl) piperazin-1-yl; 3- (methoxymethyl) azetidin-1-yl; 2- (hydroxymethyl) azetidin-1-yl; 2 - ((dimethyl-methyl) azetidin-1-yl; 4-methylpiperazin- 1-yl; and 4- (2-hydroxyethyl) piperazin-1-yl.
[0017] [0017] In some modalities, CyA is selected from 2,5-diaza-bicycles [2.2.1] heptan-2-ila; 3-aminopyrrolidin-1-yl; 2- (aminomethyl) pyrrolidin-1-yl; 2- (hydroxymethyl) pyrrolidin-1-yl; 2- (methoxymethyl) pyrrolidin-1-yl; 4-amino-2- (hydroxymethyl) pyrrolidin-1-yl; 4-hydroxy-2-methylpyrrolidin-1-yl; 2- (pyridin-2-yl) pyrrolidin-1-yl; hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -yl; 2-methylpiperazin-1-yl; 2- (hydroxymethyl) piperazin-1-yl; 3- (hydroxymethyl) morpholine; 5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl; (2-hydroxyethyl) -2,5-diazabicle [2.2.1] heptan-2-yl); 5- (propylcarbamoyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl; 4-hydroxy-2- (hydroxymethyl) pyrrolidin-1-yl; 2- (hydroxymethyl) -5-methylpiperazin-1-yl; 6- (hydroxymethyl) -4,7-diazaspiro [2.5] octan-7-yl; 4-amino-2- (1-hydroxycyclopropyl) pyrrolidin-1-yl; 4-amino-2- (2-hydroxypropan-2-yl) pyrrolidin-1-yl; 4-amino-2- (hydroxymethyl-d2) pyrrolidin-1-yl; 3- (hydroxymethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl; and 4-amino-2-methylpiperidin-1-yl.
[0018] [0018] In some modalities, CyA is selected from 2,5-diaza-bicycles [2.2.1] heptan-2-ila; 3-aminopyrrolidin-1-yl; 2- (aminomethyl) pyrrolidin-1-yl; 2- (hydroxymethyl) pyrrolidin-1-yl; 2- (methoxymethyl) pyrrolidin-1-yl; 4-amino-2- (hydroxymethyl) pyrrolidin-1-yl; 4-hydroxy-2-methylpyrrolidin-1-yl; 2- (pyridin-2-yl) pyrrolidin-1-yl; hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -yl; 2-methylpiperazin-1-yl; 2- (hydroxymethyl) piperazin-1-yl; 3- (hydroxymethyl) morpholine; 5-ethyl-2,5-diazabicycl [2.2.1] heptan-2-yl; (2-hydroxyethyl) -2,5-diazabicle [2.2.1] heptan-2-yl); and 5- (propylcarbamoyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl.
[0019] [0019] In some embodiments, CyA is selected from 4-hydroxy-2- (hydroxymethyl) pyrrolidin-1-yl; 2- (hydroxymethyl) -5-methylpiperazin-1-yl; 6- (hydroxymethyl) -4,7-diazaspiro [2.5] octan-7-yl; 4-amino-2- (1-hydroxycyclopropyl) pyrrolidin-1-yl; 4-amino-2- (2-hydroxypropan-2-yl) pyrrolidin-1-yl; 4-amino-2- (hydroxymethyl-d2) pyrrolidin-1-yl; 3- (hydroxymethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl; and 4-amino-2-methylpiperidin-1-yl.
[0020] [0020] In some embodiments, CyA is 4-amino-2- (hydroxymethyl) pyrrolidin-1-yl.
[0021] [0021] In some modalities, CyA is 5-membered heterocycloalkyl.
[0022] [0022] In some embodiments, CyA is selected from 2,5-diazabicle [2.2.1] heptanyl, pyrrolidinyl, hexahydropyrrolo [3,4-b] pyrrol-1 (2H) - ila, and piperazinyl, each one of which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from RA.
[0023] [0023] In some embodiments, CyA is C3-10 cycloalkyl, where C3-10 cycloalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from RA. In some embodiments, CyA is selected from cyclopentyl and cyclohexyl, where cyclopentyl and cyclohexyl are optionally substituted by NH2.
[0024] [0024] In some modalities, A is N.
[0025] [0025] In some modalities, A is CF.
[0026] [0026] In some modalities, A is CR16.
[0027] [0027] In some modalities, R16 is H, CN, or ORa16.
[0028] [0028] In some embodiments, Ra16 is independently selected from H and C1-6 alkyl. In some embodiments, Ra16 is methyl.
[0029] [0029] In some embodiments, R1 is selected from H, D, halo, CN, C1-6 alkyl and ORa15; wherein the C1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from Rg.
[0030] [0030] In some modalities, R1 is selected from H, D, F, CN, methyl, hydroxymethyl and methoxy.
[0031] [0031] In some modalities, R1 is H or D. In some modalities, R1 is H. In some modalities, R1 is D.
[0032] [0032] In some modalities, R1 is halo.
[0033] [0033] In some modalities, R1 is F.
[0034] [0034] In some modalities, R1 is ORa15.
[0035] [0035] In some modalities, R1 is methoxy.
[0036] [0036] In some embodiments, R1 is C1-6 alkyl; wherein the C1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from Rg.
[0037] [0037] In some embodiments, R1 is hydroxymethyl. <
[0038] [0038] In some modalities, R1 is CN.
[0039] [0039] In some modalities, R1 is methyl.
[0040] [0040] In some embodiments, R2 is selected from H, D, Cy2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa, SRa, C (O ) Rb, C (O) NRcRd, C (O) ORa, NRcRd, NRcC (O) Rb, NRcC (O) ORa, and S (O) 2Rb; wherein said Ca C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10.
[0041] [0041] In some embodiments, R2 is selected from H, D, Cy2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa, SRa, C (O ) Rb, C (O) NRcRd, C (O) ORa, NRcRd, NRcC (O) Rb, and NRcC (O) ORa; wherein said Ca C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10.
[0042] [0042] In some embodiments, R2 is selected from H, D, Cy2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, and ORa; wherein said Ca C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10.
[0043] [0043] In some embodiments, R2 is selected from H, D, Cy2, C1-6 alkyl, C1-6 haloalkyl, halo, CN; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10.
[0044] [0044] In some modalities, R2 is selected from H, D, Cy2, C1-
[0045] [0045] In some embodiments, R2 is selected from H, D, Cy2, C1-6 alkyl and halo; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10.
[0046] [0046] In some modalities, R2 is H or D. In some modalities, R2 is H. In some modalities, R2 is D.
[0047] [0047] In some embodiments, R2 is C1-6 alkyl; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10.
[0048] [0048] In some modalities, R2 is selected from isopropyl, F, Cl, Br, and S (O) 2CH3.
[0049] [0049] In some embodiments, R2 is isopropyl.
[0050] [0050] In some modalities, R2 is halo.
[0051] [0051] In some modalities, R2 is selected from Br, Cl and F.
[0052] [0052] In some modalities, R2 is Br.
[0053] [0053] In some embodiments, R2 is S (O) 2CH3.
[0054] [0054] In some modalities, R2 is Cy2.
[0055] [0055] In some embodiments, Cy2 is selected from 4-10 membered heterocycloalkyl, C6-10 membered and 5-10 membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and the 5-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 independently ring-forming heteroatoms, O and S; wherein N and S are optionally oxidized; wherein a 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 4-10 membered heterocycloalkyl, C6-10 member and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10.
[0056] [0056] In some embodiments, Cy2 is selected from 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S ; wherein a 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 4-10 membered heterocycloalkyl and the 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10;
[0057] [0057] In some modalities, Cy2 is C6-10 aryl optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10.
[0058] [0058] Cy2 is selected 1-methyl-1H-pyrazol-4-yl; 6- (hydroxymethyl) pyridin-3-yl; 6- (methylcarbamoyl) pyridin-3-yl; 1-methyl-6-oxo-1,6-dihydropyridin-3-yl; 2-methylpyridin-3-yl; 4-methoxypyridin-3-yl; 4-cyanopyridin-3-yl; 1,3,5-trimethyl-1H-pyrazol-4-yl; morpholino; azetidin-1-yl; 2- (methoxymethyl) azetidin-1-yl); 3-cyanopyridin-4-yl; 3-methoxypyridin-4-yl; 2-cyano-6-fluorophenyl; 3-cyanopyridin-2-yl; 4-cyano-1-methyl-1H-pyrazol-5-yl; tetrahydro-2H-pyran-4-yl; 5-cyano-2- (pyrrolidin-1-yl) pyridin-4-yl; and 1-cyanocyclopropyl. In some embodiments, Cy2 is selected from 1-methyl-1H-pyrazol-4-yl; 6- (hydroxymethyl) pyridin-3-yl; 6- (methylcarbamoyl) pyridin-3-yl; 1-methyl-6-oxo-1,6-dihydropyridin-3-yl; 2-methylpyridin-3-yl; 4-methoxypyridin-3-yl; 4-cyanopyridin-3-yl; 1,3,5-trimethyl-1H-pyrazol-4-yl; morpholino; azetinin-1-yl; 2- (methoxymethyl) azetidin-1-yl); 3-cyanopyridin-4-yl; 3-methoxypyridin-4-yl; 2-cyano-6-fluorophenyl; 3-cyanopyridin-2-yl; and 4-cyano-1-methyl-1H-pyrazol-5-yl.
[0059] [0059] In some embodiments, Cy2 is selected from 1-methyl-1H-pyrazol-4-yl; 6- (hydroxymethyl) pyridin-3-yl; 6- (methylcarbamoyl) pyridin-3-yl; 1-methyl-6-oxo-1,6-dihydropyridin-3-yl; 2-methylpyridin-3-yl; 4-methoxypyridin-3-yl; 4-cyanopyridin-3-yl; 1,3,5-trimethyl-1H-pyrazol-4-yl; morpholino; and azetidin-1-yl.
[0060] [0060] In some embodiments, Cy2 is selected from 2- (methoxymethyl) azetidin-1-yl); 3-cyanopyridin-4-yl; 3-methoxypyridin-4-yl; 2-cyano-6-fluorophenyl; 3-cyanopyridin-2-yl; and 4-cyano-1-methyl-1H-pyrazol-5-yl.
[0061] [0061] In some embodiments, Cy2 is selected from 3-cyanopyridin-4-yl; 4-cyanopyridin-3-yl; and 3-cyanopyridin-2-yl. In some modalities, Cy2 is 4-cyanopyridin-3-yl.
[0062] [0062] In some modalities, Z is N.
[0063] [0063] In some modalities, Z is CR3.
[0064] [0064] In some embodiments, R3 is selected from H, D, Cy3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa4, SRa4, C (O ) Rb4, C (O) NRc4Rd4, C (O) ORa4, OC (O) Rb4, OC (O) NRc4Rd4, NRc4Rd4, NRc4C (O) Rb4, NRc4C (O) ORa4, NRc4C (O) NRc4Rd4, NRc4S (O ) Rb4, NRc4S (O) 2Rb4, NRc4S (O) 2NRc4Rd4, S (O) Rb4, S (O) NRc4Rd4, S (O) 2Rb4, S (O) 2NRc4Rd4 and BRh4Ri4; wherein said Ca C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R13.
[0065] [0065] In some embodiments, R3 is selected from H, D, Cy3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa4, SRa4, C (O ) Rb4, NRc4Rd4, and NRc4C (O) Rb4; wherein said Ca C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R13.
[0066] [0066] In some modalities, R3 is selected from H, D, Cy3, halo and CN. In some modalities, R3 is selected from H, D, F, Br and CN.
[0067] [0067] In some modalities, R3 is H or D. In some modalities, R3 is H. In some modalities, R3 is D.
[0068] [0068] In some modalities, R3 is halo.
[0069] [0069] In some modalities, R3 is Br.
[0070] [0070] In some modalities, R3 is F.
[0071] [0071] In some modalities, R3 is CN.
[0072] [0072] In some modalities, R3 is Cy3.
[0073] [0073] In some modalities, Cy3 is a 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein a 5-10 membered heteroaryl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and where the 5-10 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R13.
[0074] [0074] In some modalities, Cy3 is a 6-10 membered heteroaryl; wherein the 6-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; where a 6-10 membered heteroaryl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group, and where the 6-10 membered heteroaryl is optionally substituted by 1, 2 , 3 or 4 substituents independently selected from R13.
[0075] [0075] In some embodiments, Cy3 is selected from pyridin-3-yl and 1-methyl-1H-pyrazol-4-yl.
[0076] [0076] In some embodiments, R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl , C3-10 cycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 membered heteroaryl-C1-3 alkylene, halo, D, CN, NO2, ORa8, SRa8, C (O ) Rb8, C (O) NRc8Rd8, C (O) ORa8, OC (O) Rb8, OC (O) NRc8Rd8, NRc8Rd8, NRc8C (O) Rb8, NRc8C (O) ORa8, NRc8C (O) NRc8Rd8, C (= NRe8) Rb8, C (= NORa8) Rb8, C (= NRe8) NRc8Rd8, NRc8C (= NRe8) NRc8Rd8, NRc8S (O) Rb8, NRc8S (O) 2Rb8, NRc8S (O) 2NRc8Rd8, S (O) Rb8 (O) NRc8Rd8, S (O) 2Rb8, S (O) 2NRc8Rd8 and BRh8Ri8; wherein said Ca is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-3 alkylene, C6 -10 aryl-C1-3 alkylene and 5-10 membered heteroaryl-C1-3 alkylene are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R5.
[0077] [0077] In some embodiments, R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, D, CN, NO2, ORa8, SRa8, C (O) Rb8, C (O) NRc8Rd8, C (O) ORa8, NRc8Rd8, NRc8C (O) Rb8, NRc8C (O) ORa8, S (O) Rb8, S (O) NRc8Rd8, S (O) 2Rb8, and S (O ) 2NRc8Rd8; wherein said Ca C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1 or 2 substituents independently selected from R5.
[0078] [0078] In some embodiments, R4 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, halo, D, CN and ORa8; wherein said C 1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R5.
[0079] [0079] In some embodiments, each R4 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, D, CN and ORa8; wherein said C 1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R5.
[0080] [0080] In some embodiments, each R4 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, D, CN, and ORa8.
[0081] [0081] In some embodiments, each R4 is independently selected from D, methyl, F, Cl, CN, methoxy, methoxy-d3, ethoxy, difluoro-methoxy and cyclopropyl.
[0082] [0082] In some modalities, each R4 is independently selected from halo and ORa8.
[0083] [0083] In some modalities, each R4 is independently selected from F and methoxy.
[0084] [0084] In some modalities, each R4 is independently selected from halo.
[0085] [0085] In some modalities, each R4 is independently selected from F and Cl.
[001] [001] In some modalities, each R4 is independently selected from F and methyl.
[0086] [0086] In some modalities, each R4 is F.
[0087] [0087] In some embodiments, R4 is not substituted or substituted 4-morpholinyl, unsubstituted or substituted 4-thiomorpholinyl, unsubstituted or substituted 1-oxide-4-thiomorpholinyl, or 1,1-dioxide-4-thiomorpholinyl not replaced or replaced.
[0088] [0088] In some embodiments, each R5 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, D, CN, ORa9 and NRc9Rd9.
[0089] [0089] In some modalities, each R5 is independently selected from F and D.
[0090] [0090] In some embodiments, each RA is selected from H, D, Cy1, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa11, SRa11, C ( O) Rb11, C (O) NRc11Rd11, C (O) ORa11, and NRc11Rd11; wherein said Ca C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7.
[0091] [0091] In some embodiments, RA is selected from H, D, Cy1, C1-6 alkyl, C1-6 haloalkyl, halo, CN, ORa11, C (O) NRc11Rd11, and
[0092] [0092] In some modalities, RA is selected from Cy1, C1-6 alkyl, ORa11, C (O) NRc11Rd11, and NRc11Rd11; wherein said Ca C1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7.
[0093] [0093] In some embodiments, RA is C1-6 alkyl; wherein said Ca C1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7.
[0094] [0094] In some modalities, RA is selected from methyl and ethyl; wherein said methyl and ethyl are each optionally substituted by 1, 2 or 3 substituents independently selected from R7.
[0095] [0095] In some modalities, RA is Cy1.
[0096] [0096] In some embodiments, RA is selected from OH, NH2, aminomethyl, hydroxymethyl, methoxymethyl, OH, pyridinyl, ethyl, hydroxyethyl and propylcarbamoyl.
[0097] [0097] In some embodiments, Cy1 is selected from C3-10 cycloalkyl and 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; where N and S are optionally oxidized; wherein a 5-10 membered heteroaryl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and in which C3-10 cycloalkyl and heteroaryl of 5-10 members are each optionally substituted by 1, 2, 3 or 4 substitutes independently selected from R7.
[0098] [0098] In some modalities, Cy1 is heteroaryl of 5-10 members; wherein the 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; and in which the 5-10 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7.
[0099] [0099] In some modalities, Cy1 is selected from C3-10 cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7.
[00100] [00100] In some modalities, Cy1 is pyridinyl. In some modalities, Cy1 is cyclopropyl.
[00101] [00101] In some embodiments, each R7 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, D, CN, NO2, ORa12, SRa12, C (O) Rb12 , C (O) NRc12Rd12, C (O) ORa12, OC (O) Rb12, and NRc12Rd12; wherein said Ca C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R8.
[00102] [00102] In some embodiments, each R7 is independently selected from C1-6 alkyl, halo, D, CN, ORa12 and NRc12Rd12.
[00103] [00103] In some modalities, each R7 is independently selected from CN, ORa12, NRc12Rd12, and D.
[00104] [00104] In some modalities, each R7 is independently selected from ORa12, D, and NRc12Rd12.
[00105] [00105] In some modalities, each R7 is independently selected from D, CN, NH2, and methoxy.
[00106] [00106] In some embodiments, each R7 is independently selected from OH, D, NH2, and methoxy.
[00107] [00107] In some embodiments, each R10 is independently selected from C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, ORa1, C (O) NRc1Rd1 and NRc1Rd1; wherein said C1-6 alkyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R11.
[00108] [00108] In some embodiments, each R10 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, NO2, ORa1, SRa1, C (O) Rb1, C (O) NRc1Rd1, C (O) ORa1, OC (O) Rb1, OC (O) NRc1Rd1, NRc1Rd1, NRc1C (O) Rb1, NRc1C (O) ORa1, and NRc1C (O ) NRc1Rd1; wherein said Ca C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R11.
[00109] [00109] In some embodiments, each R10 is independently selected from C1-6 alkyl, 4-10 membered heterocycloalkyl, CN, OH, ORa1, C (O) NRc1Rd1 and NRc1Rd1; wherein said Ca C1-6 alkyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R11.
[00110] [00110] In some embodiments, each R10 is independently selected from C1-6 alkyl, 4-10 membered heterocycloalkyl, halo, CN, OH, ORa1, C (O) NRc1Rd1 and NRc1Rd1; wherein said Ca C1-6 alkyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R11.
[00111] [00111] In some embodiments, each R10 is independently selected from OH, CN, methyl, hydroxymethyl, methylcarbamoyl, methoxy, morpholino and cyclobutylamino.
[00112] [00112] In some modalities, each R10 is independently selected from OH, F, CN, methyl, hydroxymethyl, methylcarbamoyl, methoxy, morpholino and cyclobutylamino.
[00113] [00113] In some embodiments, each R11 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, D, CN and ORa2.
[00114] [00114] In some modalities, each R11 is ORa2. In some embodiments, each R11 is OH.
[00115] [00115] In some embodiments, each R13 is independently selected from C1-6 alkyl and C1-6 haloalkyl.
[00116] [00116] In some embodiments, each R13 is independently C1-6 alkyl.
[00117] [00117] In some modalities, R13 is methyl.
[00118] [00118] In some modalities, each Ra1, Rc1 and Rd1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl and C3-10 cycloalkyl; wherein said Ca C1-6 alkyl and C3-10 cycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R11.
[00119] [00119] In some modalities, each Ra1, Rc1 and Rd1 is independently selected from H, C1-6 alkyl, and C3-10 cycloalkyl; wherein said Ca C1-6 alkyl and C3-10 cycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R11.
[00120] [00120] In some modalities, each Ra2, Rc2 and Rd2 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl. In some modalities, each Ra2, Rc2 and Rd2 is independently H.
[00121] [00121] In some modalities, each Ra8, Rc8 and Rd8 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, each Ra8, Rc8 and Rd8 is independently selected from H and C1-6 alkyl.
[00122] [00122] In some modalities, each Ra9, Rc9 and Rd9 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, each Ra9, Rc9 and Rd9 is independently selected from H and C1-6 alkyl.
[00123] [00123] In some modalities, each Ra11, Rc11 and Rd11 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl; where the
[00124] [00124] In some modalities, each Ra12, Rc12 and Rd12 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl.
[00125] [00125] In some modalities, Ra12 is H.
[00126] [00126] In some modalities, Rc12 and Rd12 are each H.
[00127] [00127] In some modalities, each Ra15, Rc15 and Rd15 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl; wherein said C 1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from Rg. In some modalities, each Ra15, Rc15 and Rd15 is independently selected from H and C1-6 alkyl; wherein said C 1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from Rg.
[00128] [00128] In some embodiments, each Rg is independently selected from OH, CN, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylthio, C1-6 alkylsulfonyl . In some modes, each Rg is OH.
[00129] [00129] In some modalities, n is 0, 1, 2, 3 or 4. In some modalities, n is 0, 1, 2 or 3. In some modalities, n is 0. In some modalities, n is 1. In some modalities, n is 2. In some modalities, n is 3. In some modalities, n is 4.
[00130] [00130] In some modalities, a compound with Formula IA is provided here:
[00131] [00131] In some embodiments, a compound of Formula IB: IB is provided here, or a pharmaceutically acceptable salt thereof.
[00132] [00132] In some embodiments, a compound of Formula IC: IC is provided here, or a pharmaceutically acceptable salt thereof.
[00133] [00133] In some modalities, a compound with Formula IIA is provided here:
[00134] [00134] In some embodiments, a compound of Formula IIB: IIB, or a pharmaceutically acceptable salt thereof, is provided here.
[00135] [00135] In some embodiments, a compound of Formula IIC: IIC is provided here, or a pharmaceutically acceptable salt thereof.
[00136] [00136] In some embodiments, a compound with Formula IID is provided here:
[00137] [00137] In some embodiments, a compound of Formula III: III, or a pharmaceutically acceptable salt thereof, is provided here.
[00138] [00138] In some embodiments, a compound of Formula IV: IV, or a pharmaceutically acceptable salt thereof, is provided here.
[00139] [00139] In some modalities, a compound with Formula V is provided here:
[00140] [00140] In some embodiments, a compound of Formula VI: VI is provided here, or a pharmaceutically acceptable salt thereof.
[00141] [00141] In some embodiments, a compound is selected here from: N- (2 - ((1R, 4R) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; (S) -N- (2- (3-aminopyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; (R) -N- (2- (2- (aminomethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; (R) -N- (5-fluoro-2- (2- (hydroxymethyl) pyrrolidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; (R) -N- (5-fluoro-2- (2- (methoxymethyl) pyrrolidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide;
[00142] [00142] It is further understood that certain features of the invention, which are, for clarity, described in the context of separate modalities, can also be provided in combination in a single modality (although it is provided that the modalities are combined as if written in multiple dependent ways ). On the other hand, several characteristics of the invention that are briefly described in the context of a single modality, can also be provided separately or in any subcombination. Thus, it is contemplated that features described as modalities of the compounds of Formula (I) and (I ') can be combined in any suitable combination.
[00143] [00143] In several places in this specification, certain characteristics of the compounds are disclosed in groups or in bands. It is specifically intended that the description includes each and every individual subcombination of the members of these groups and bands. For example, the term "C1-6 alkyl" is specifically intended to individually disclose (without limitation) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.
[00144] [00144] The term "n-members", where n is an integer, typically describes the number of ring-forming atoms in a fraction where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered 1,2,3,4-tetrahydroaryl ring -
[00145] [00145] In several places in this specification, variables that define divalent linking groups can be described. It is specifically intended that each bonding substituent includes both forward and backward forms of the bonding substituent. For example, -NR (CR'R '') n- includes both -NR (CR'R '') n- and - (CR'R '') nNR- and is intended to disclose each of the forms individually. Where the structure requires a link group, the Markush variables listed for that group are understood to be link groups. For example, if the structure requires a bonding group and the definition of the Markush group for that variable to list "alkyl" or "aryl" then it is understood that the "alkyl" or "aryl" represents an alkylene bonding group or group arylene, respectively.
[00146] [00146] The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted", unless otherwise stated, refers to any level of substitution, for example, mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted. The substituents are selected independently and the substitution can be in any chemically accessible position. It is to be understood that the substitution on a given atom is limited by valence. It should be understood that the substitution on a given atom results in a chemically stable molecule. The phrase "optionally replaced" means not replaced or replaced. The term "substituted" means that a hydrogen atom is removed and replaced with a substitute. A single divalent substituent, for example, oxo, can replace two hydrogen atoms.
[00147] [00147] The term "Cn-m" indicates a range that includes the end points, where n and m are integers and indicate the number of carbons. Examples include C1-4, C1-6 and the like.
[00148] [00148] The term "alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group that can be straight or branched chain. The term "Cn-m here", refers to a group alkyl with nam carbon atoms.An alkyl group formally corresponds to an alkane with a CH bond substituted by the point of attachment of the alkyl group to the rest of the compound.In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms Examples of alkyl fractions include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl , n-butyl, tert-butyl, isobutyl, sec-butyl; superior counterparts such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl and the like tees.
[00149] [00149] The term "alkenyl”, used alone or in combination with other terms, refers to a straight or branched chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. formally corresponds to an alkene with a CH bond substituted by the point of attachment of the alkenyl group to the rest of the compound. The term "Cn-m alkenyl" refers to an alkenyl group with nam carbons. In some embodiments, the alkenyl fraction contains 2 to 6, 2 to 4 or 2 to 3 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethylene, n-propenyl, isopropenyl, n-butenyl, sec-butenyl and the like.
[00150] [00150] The term "alkynyl”, used alone or in combination with other terms, refers to a straight or branched chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. formally corresponds to an alkyl with a CH bond substituted by the point of attachment of the alkyl group to the rest of the compound. The term "Cn-m alkynyl"
[00151] [00151] The term "alkylene", used alone or in combination with other terms, refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane with two C-H bonds substituted by points of attachment of the alkylene group to the rest of the compound. The term "Cn-m alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethan-1,2-diyl, ethan-1,1-diyl, propan-1,3-diyl, propan-1, 2-diyl, propan-1,1-diyl, butan-1,4-diyl, bu-tan-1,3-diyl, butan-1,2-diyl, 2- methyl-propan-1,3-diyl and the like.
[00152] [00152] The term "alkoxy", used alone or in combination with other terms, refers to a group of the formula -O-alkyl, where the alkyl group is as defined above. The term "Cn-m alkoxy" refers to refers to an alkoxy group, the alkyl group of which has carbons. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4 or 1 to 3 carbon atoms. The term "C nm di-alkoxy" refers to a bonding group of the formula -O- (Cn-m alkyl) -O-, the alkyl group of which has carbons. Example dialkoxy groups include -OCH2CH2O- and OCH2CH2CH2O- In some embodiments, the two O atoms of a C nm dialkoxy group may be linked to the same B atom to form a 5- or 6-membered heterocycloalkyl group.
[00153] [00153] The term "amino" refers to a group of formula -NH2.
[00154] [00154] The term "carbonyl", used alone or in combination with other terms, refers to a group -C (= O) -, which can also be written as C (O).
[00155] [00155] The term "cyan" or "nitrile" refers to a group of formula -C≡N, which can also be written as -CN.
[00156] [00156] The terms "halo" or "halogen", used alone or in combination with other terms, refer to fluorine, chlorine, bromine and iodine. In some embodiments, "halo" refers to a halogen atom selected from F, Cl or Br. In some embodiments, the halo groups are F.
[00157] [00157] The term "haloalkyl", as used in this document, refers to an alkyl group in which one or more of the hydrogen atoms have been replaced by a halogen atom. The term "Cn-m haloalkyl” refers to a Cn-m alkyl group with nam carbon atoms and at least one to {2 (nam) +1} halogen atoms, which can be the same or different. In some embodiments, halogen atoms are fluorine atoms. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5 and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.
[00158] [00158] The term "haloalkoxy", used alone or in combination with other terms, refers to a group of the formula -O-haloalkyl, where the haloalkyl group is as defined above. The term "Cn-m haloalkoxy "refers to a haloalkoxy group, whose haloalkyl group has carbons. Examples of haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkyl group has 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
[00159] [00159] The term "oxo" refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an N-oxide group. In some embodiments, the heterocyclic groups can be optionally substituted by 1 or 2 oxo substitutes (= O).
[00160] [00160] The term "sulfoxide" refers to a sulfur atom as a divalent substituent, forming a thiocarbonyl group (C = S) when attached to carbon.
[00161] [00161] The term "oxidized" in reference to a ring-forming N atom refers to a ring-forming N-oxide.
[00162] [00162] The term "oxidized" in reference to a ring-forming S atom refers to a ring-forming sulfonyl or ring-forming sulfinyl.
[00163] [00163] The term "aromatic" refers to a carbocycle or heterocycle having one or more polyunsaturated rings having an aromatic character (i.e., having delocalized (4n + 2) electrons π (pi) where n is an integer.
[00164] [00164] The term "aryl", used alone or in combination with other terms, refers to a group of aromatic hydrocarbons, which can be monocyclic or polycyclic (for example, having 2 fused rings). "Cn-m aryl" refers to an aryl group having ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl and the like. In some embodiments, aryl groups have 6 to about 10 carbon atoms. In some modalities, the aryl groups have 6 carbon atoms. In some embodiments, aryl groups have 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some modalities, the aryl group is naphthyl.
[00165] [00165] The term "heteroaryl" or "heteroaromatic", used alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one member of the heteroaromatic ring selected from sulfur, oxygen and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3 or 4 members of the heteroatom ring independently selected from nitrogen, sulfur and oxygen.In some embodiments, any ring-forming N in a heteroaryl fraction can be an N-oxide. some modalities
[00166] [00166] A five-membered heteroaryl ring is a heteroaryl group having five ring atoms in which one or more (for example, 1, 2 or 3) ring atoms are independently selected from N, O and S. five exemplary members include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
[00167] [00167] A six-membered heteroaryl ring is a heteroaryl group having six ring atoms in which one or more (for example, 1, 2 or 3)
[00168] [00168] The term "cycloalkyl," used alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups. The term "Cn-m cycloalkyl" refers to a cycloalkyl having n carbon atoms of the ring member. Cycloalkyl groups can include mono- or polycyclic groups (for example, having 2, 3 or 4 fused rings) and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C3-7). In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some modalities, the cycloalkyl group is monocyclic. In some modalities, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can optionally be oxidized to form an oxo or sulfoxide group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are fractions having one or more fused aromatic rings (i.e., having a bond in common with) the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane and the like. A cycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornila, norpinila, norcarnyl, bicycle [1.1.1] pentanyl, bicycle [2.1.1] hexanyl and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
[00169] [00169] The term "heterocycloalkyl”, used alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur oxygen and phosphorus, and that has 4-10 ring members, 4-7 ring members or 4-6 ring members. Included within the term "heterocycloalkyl ”Are the monocyclic heterocycloalkyl groups with 4, 5, 6 and 7 members. Heterocycloalkyl groups can include mono- or bicyclic (for example, with two fused or bridged rings) or spirocyclic ring systems. In some modalities, the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. The carbon atoms and ring-forming hetero atoms of a heterocycloalkyl group can optionally be oxidized to form an oxo or sulfoxide group or other oxidized bond (for example, C (O), S (O), C (S) or S ( O) 2, N-oxide etc.) or a nitrogen atom can be quantized. The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are fractions that have one or more fused aromatic rings (ie, having a bond in common with) the heterocycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine , etc. A heterocycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of heterocycloalkyl groups include 2,5-diazobicyclo [2.2.1] heptanyl; pyrrolidinyl; hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -yl; 1,6-dihydropyridinyl; morpholinyl; azetidinyl; piperazinyl; and 4,7-diazaspiro [2.5] octan-7-yl.
[00170] [00170] In certain locations, definitions or modalities refer to specific rings (for example, an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any member of the ring as long as the valence of the atom is not exceeded. For example, an azetidine ring can be attached at any position on the ring, while an azetidine-3-yl ring is attached at position 3.
[00171] [00171] The compounds described here can be asymmetric (for example, with one or more stereocenters). All stereoisomers, such as diastereomers and enantiomers, are targeted, unless otherwise indicated. The compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms of optically inactive starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C = N double bonds, and the like can also be present in the compounds described herein, and all of these stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms.
[00172] [00172] The resolution of racemic mixtures of compounds can be performed by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid which is an optically active organic salt-forming acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as forms D and L of tartaric acid, diacetyl tartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylphedrine, cyclohexylethylamine , 1,2-diaminocyclohexane and the like.
[00173] [00173] The resolution of racemic mixtures can also be carried out by eluting on a column packed with an optically active resolving agent (for example, dinitrobenzoylphenylglycine). A suitable eluting solvent composition can be determined by one skilled in the art.
[00174] [00174] In some embodiments, the compounds of the invention have the (R) -configuration. In other embodiments, the compounds have the (S) -configuration. In compounds with more than one chiral center, each of the chiral centers in the compound can be independent (R) or (S), except where indicated.
[00175] [00175] The compounds of the invention also include tautomeric forms. Tautomeric forms result from exchanging a single bond for an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers that are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs and annular forms in which a proton can occupy two or more positions in a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically blocked in an appropriate substitution form.
[00176] [00176] The compounds of the invention can also include all the isotopes of atoms that occur in the intermediate or final compounds. Isotopes include those atoms having the same atomic number, but different mass numbers. For example, hydrogen isotopes include tritium and deuterium. One or more atoms constituting the compounds of the invention can be substituted or replaced by isotopes of the atoms in natural or unnatural abundance. In some modalities, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present invention can be substituted or replaced with deuterium. In some modes, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes in organic compounds are known in the art (Deuterium Labing in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atz-rodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labeling by James R. Hanson, Royal Society of Chemistry, 2011). isotopically labeled compounds can be used in several studies, such as NMR spectroscopy, metabolism experiments and / or assays.
[00177] [00177] Substitution by heavier isotopes, such as deuterium, may provide certain therapeutic advantages resulting from greater metabolic stability, for example, greater in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. (A. Kerekes et.al. J. Med. Chem. 2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015, 58, 308-312).
[00178] [00178] The term "compound", as used in this document, is intended to include all stereoisomers, geometric isomers, tautomers, and the isotopes of represented structures. The term also intends to refer to compounds of the invention, regardless of how they are prepared, for example, synthetically, through a biological process (for example, metabolism or enzymatic conversion), or a combination of these.
[00179] [00179] All compounds, and their pharmaceutically acceptable salts, can be found together with other substances, such as water and solvents (for example, hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein and their salts can occur in various forms and can, for example, take the form of solvates, including hydrates. The compounds can be in any solid state, such as a polymorph or solvate, unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood to encompass any form of solid state of the compound.
[00180] [00180] In some embodiments, the compounds of the invention, the salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95% at least about 97%, or at least about 99% by weight of the compounds of the invention, or a salt thereof.
[00181] [00181] The term "pharmaceutically acceptable" is used in this document to refer to those compounds, materials, compositions and / or pharmaceutical forms that are, in the context of medical judgment, suitable for use in contact with the tissues of beings humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, assessed according to a reasonable risk / benefit ratio.
[00182] [00182] The expressions "room temperature" and "natural temperature", as used here, are understood in the art, and refer generally to a temperature, for example, a reaction temperature, which is about the temperature of the environment in which the reaction is carried out, for example, a temperature between about 20ºC and about 30ºC.
[00183] [00183] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acid or base portion to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acid residues, such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, for example, from non-toxic organic or inorganic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, alcohols (for example, methanol,
[00184] [00184] The compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of the numerous possible synthetic pathways, such as those in the Schemes below.
[00185] [00185] The reactions to prepare compounds of the invention can be carried out in suitable solvents that can be readily selected by one skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with starting materials (reagents), intermediates, or products at temperatures at which reactions are carried out, for example, temperatures that may be in the freezing temperature range of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in a solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled technician.
[00186] [00186] The preparation of the compounds of the invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of suitable protection groups can be easily determined by persons skilled in the art. The chemistry of protection groups is described, for example, in Koscenski, Protecting Groups, (Thieme, 2007); Robertson, Protecting
[00187] [00187] The reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (for example, 1H or 13 C), infrared spectroscopy, spectrophotometry (for example, visible UV) or mass spectrometry; or by chromatographic methods, such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
[00188] [00188] The Schemes below provide general guidance regarding the preparation of the compounds of the invention. One skilled in the art will understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention.
[00189] [00189] The compounds of Formula (I) and (I ') can be prepared, for example, using a process as illustrated in the schemes below.
[00190] [00190] The compounds of Formula (I) and (I ') can be prepared using a process as illustrated in Scheme 1. In the process shown in Scheme 1, the halo substituent of Formula 1-1 compounds can be used to install a CyA substituent by a number of methods, for example, by nucleophilic displacement with an appropriate amine nucleophile with a suitable base (for example, triethylamine or DIPEA) in a suitable solvent (for example, DMF, DMSO, dioxane) , or by an appropriate cross-coupling reaction, to give compounds of Formula 1-2. Suitable cross-coupling reactions include, but are not limited to, a Buchwald coupling (for example, in the presence of a paladacycle pre-catalyst, such as RuPhod Pd G2), and a Negishi or Suzuki coupling (for example, in presence of a paladacycle pre-catalyst, such as Xphos Pd G2). Examples of different cross coupling procedures include Stille (ACS Catalysis 2015, 5, 3040-3053), Suzuki (Tetrahedron 2002, 58, 9633-9695), Sonogashira (Chem. Soc. Rev. 2011, 40, 5084-5121 ), Negishi (ACS Catalysis 2016, 6, 1540-1552), Buchwald-Hartwig amination (Chem. Sci. 2011, 2, 27-50) and Cu-catalyzed amination (Org. React. 2014, 85, 1- 688), among others.
[00191] [00191] The reduction of the nitro group with an appropriate reducing agent (for example, iron in the presence of ammonium chloride or hydrogen gas in the presence of Pd / C catalyst) provides compounds of Formula 1-3. The formation of the amide bond with Formula 1-5 acids (for example, using HATU and a base such as Hunig's base) provides compounds of the desired Formula (I) or (I '). Scheme 1 SnAr or amide coupling reduction coupling
[00192] [00192] Formula 1-5 acids can be prepared from Formula 1-4 compounds using a cross-coupling, such as Suzuki (for example, in the presence of a paladacycle pre-catalyst, such as Xphos Pd G2) or Stille (for example, in the presence of a palladium catalyst such as (PPh3) 2PdCl2 and base such as triethylamine). Scheme 2 HPK1 Kinase
[00193] [00193] Studies have established that HPK1 is a negative regulator of T and B cell activation (Hu, MC, et al., Genes Dev, 1996. 10 (18): p. 2251-64; Kiefer, F., et al ., EMBO J, 1996. 15 (24): p. 7013-25). HPK1-deficient mouse T cells showed dramatically increased activation of proximal TCR signaling, increased IL-2 production and in vitro hyperproliferation after anti-CD3 stimulation (Shui, JW, et al., Nat Immunol, 2007. 8 (1): p. 84-91). Similar to T cells, HPK1 knockout B cells produced much higher levels of IgM and IgG isoforms after KLH immunization and potentially exhibited hyperproliferation as a result of increased BCR signaling. Wang, X., et al., J Biol Chem, 2012. 287 (14): p. 11037-48. Mechanically, during TCR or BCR signaling, HPK1 is activated by LCK / ZAP70 (T cells) or by SYK / LYN-mediated Tyr379 phosphorylation (B cells) and its subsequent binding to the SLP-76 adapter protein (T cells ) or BLNK (B cells) (Wang, X., et al., J Biol Chem, 2012. 287 (14): p. 11037-48). HPK1 activated phosphoryl SLP-76 in Ser376 or BLNK in Thr152, leading to recruitment of the signaling molecule 14-3-3 and degradation mediated by final ubiquitination of SLP-76 or BLNK (Liou, J., et al., Immunity, 2000 12 (4): pp. 399-408; Di Bartolo, V.,
[00194] [00194] Bone marrow-derived dendritic cells (BDMCs) from HPK1 knockout mice showed greater expression of co-stimulatory molecules (eg CD80 / CD86) and enhanced production of pro-inflammatory cytokines (IL-12, TNF-  etc), and demonstrated a superior ability to stimulate proliferation of T cells in vitro and in vivo compared to wild-type DCs (Alzabin, S., et al., J Immunol, 2009. 182 (10): p. 6187- 94). These data suggest that HPK1 is also an important negative regulator of dermal cell activation (Alzabin, S., et al., J Immunol, 2009. 182 (10): p. 6187-94). However, the signaling mechanisms underlying HPK-1-mediated negative regulation of DC activation have yet to be elucidated.
[00195] [00195] In contrast, HPK1 appears to be a positive regulator of suppressive functions of regulatory T cells (Treg) (Sawasdikosol, S. et al., The journal of immunology, 2012. 188 (supplement 1): p. 163). Foxp3 + HPK1-deficient mouse tregs were defective in suppressing TCR-induced effector T cell proliferation and, paradoxically, gained the ability to produce IL-2 after TCR involvement (Sawasdikosol, S. et al., The Journal of Immunology,
[00196] [00196] HPK1 was also involved in inhibition mediated by
[00197] [00197] The present invention provides methods of modulating (e.g., inhibiting) HPK1 activity by contacting HPK1 with a compound of the invention, or a pharmaceutically acceptable salt thereof. In some embodiments, contact may be to administer to a patient a compound provided herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are useful for therapeutic administration to increase, stimulate and / or increase immunity in cancer. For example, a method of treating a disease or disorder associated with inhibiting HPK1 interaction may include administering to a patient in need a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. The compounds of the present invention can be used alone, in combination with other agents or therapies or as an adjuvant or neoadjuvant for the treatment of diseases or disorders, including cancers. For the uses described herein, any of the compounds of the description, including any of its modalities, can be used.
[00198] [00198] Examples of cancers that are treatable using the compounds of the present invention include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, endometrial cancer cervical carcinoma, cervical carcinoma vagina, carcinoma of the vulva, Hodgkin's disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, soft tissue sarcoma, cancer of the urethra, cancer of the penis, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid childhood tumors, lymphocytic lymphoma , bladder cancer, kidney or urethra cancer, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, pituitary syndrome Kaposi sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos and combinations of said cancers.
[00199] [00199] In some embodiments, cancers treatable with the compounds of the present invention include melanoma (eg, metastatic malignant melanoma), kidney cancer (eg, clear cell carcinoma), prostate cancer (eg, adenocarcinoma of the refractory hormone prostate), breast cancer, triple negative breast cancer, colon cancer and lung cancer (for example, non-small cell lung cancer and small cell lung cancer). In addition, the description includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the description.
[00200] [00200] In some embodiments, cancers that are treatable using the compounds of the present invention include, but are not limited to, solid tumors (eg, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, cancer bladder, etc.), hematological cancer (for example, lymphoma, leukemia, such as acute lymphoblastic leukemia (ALL), acute myelogenic leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML) , DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including recurrent or refractory and recurrent follicular NHL), Hodgkin's lymphoma or multiple myeloma) and combinations of these cancers.
[00201] [00201] In some embodiments, diseases and indications that are treatable using the compounds of the present invention include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, cancers of the genitourinary tract, liver cancer , bone cancers, cancers of the nervous system, gynecological cancers and skin cancers.
[00202] [00202] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse lymphoma large B cells (DLBCL), mantle cell lymphoma, Non-Hodgkin's lymphoma (including relapsing or refractory and recurrent follicular NHL), Hodgkin's lymphoma, myeloproliferative diseases (for example, primary myelofibrosis (PMF) , polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), acute T-cell lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma,
[00203] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdoarcoma, fibroma, lipoma, harmatoma and teratoma.
[00204] [00204] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cells, small undifferentiated cells, large undifferentiated cells, adenocarcinoma), alveolar carcinoma ( bronchiolar), bronchial adenoma, chondromatous hamartoma and mesothelioma.
[00205] [00205] Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leomyo-sarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagon, gastrinoma, glucagon, tuminoma, glucagon carcinoids, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adeno-carcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma and leiomyoma colorectal cancer.
[00206] [00206] Exemplary cancers of the genitourinary tract include kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma) and testis (seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibro-adenoma, adenomatoid tumors, lipoma).
[00207] [00207] Exemplary liver cancers include hepatoma (cardiac
[00208] [00208] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, cell tumor chordoma malignant giants, exotic chondrosarcoma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors
[00209] [00209] Exemplary nervous system cancers include cranial cancers (osteoma, hemangioma, granuloma, xanthoma, deforming osteitis), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma, germ- piniomatoma), gliomablasma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.
[00210] [00210] Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cell carcinoma) , granulosa-cell tumors-thecol, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryoma ) and fallopian tubes (carcinoma).
[00211] [00211] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, soft dysplastic nevi,
[00212] [00212] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas, adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancer, thyroid and parathyroid cancer.
[00213] [00213] In some embodiments, HPK1 inhibitors can be used to treat tumors that produce PGE2 (eg, tumors with overexpression of Cox-2) and / or adenosine (tumors with overexpression of CD73 and CD39). Overexpression of Cox-2 has been detected in several tumors, such as colorectal, breast, pancreatic and lung cancer, where it correlates with a poor prognosis. Overexpression of COX-2 has been reported in hematological cancer models, such as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia), as well as in patient blast cells. CD73 is overloaded in several human carcinomas, including those of the colon, lung, pancreas and ovary. It is important to note that higher levels of CD73 expression are associated with tumor neovascularization, invasiveness and metastasis and with shorter patient survival time in breast cancer.
[00214] [00214] As used in this document, the term "contact" refers to the assembly of the fractions indicated in an in vitro system or an in vivo system so that they are in sufficient physical proximity to interact.
[00215] [00215] The terms "individual" or "patient", used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates and more preferably humans.
[00216] [00216] The phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that causes the biological or medicinal response in a tissue, system, animal, individual or human being investigated by an investigator, veterinarian, doctor or another clinician.
[00217] [00217] As used in this document, the term "treating" or "treatment" refers to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or symptomatology of the disease, condition or disorder (ie, stopping the further development of the pathology and / or symptomatology); and (2) improve the disease; for example, improving a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or symptomatology of the disease, condition or disorder (ie, reversing the pathology and / or symptomatology), such as decreasing the severity of disease.
[00218] [00218] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; for example, preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder, but does not yet experience or exhibit the pathology or symptoms of the disease. Combination Therapies I. Immune Checkpoint Therapies
[00219] [00219] In some embodiments, the HPK1 inhibitors provided in this document can be used in combination with one or more immune checkpoint inhibitors for the treatment of cancer, as described in this document. The compounds of the present invention can be used in combination with one or more immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules, such as CD20, CD28, CD39, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM , arginase, CD137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1 and PD-L2 . In some embodiments, the immune checkpoint molecule is an immune checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory immune checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD- 1, TIM3, TIGIT and VISTA. In some embodiments, the compounds of the description provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
[00220] [00220] In some embodiments, the compounds provided here may be used in combination with one or more agonists of immune checkpoint molecules, for example, OX40, CD27, GITR and CD137 (also known as 4-1BB ).
[00221] [00221] In some embodiments, the inhibitor of an immune checkpoint molecule is anti-PD1 antibody, anti-PD-L1 antibody or anti-CTLA-4 antibody.
[00222] [00222] In some embodiments, the inhibitor of an immune checkpoint molecule is a PD-1 inhibitor, for example, an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®), pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122 or AMP-224 . In some modalities, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Other anticancer agents include antibody therapy such as 4-1BB (eg, urelumab, utomilumab).
[00223] [00223] In some embodiments, the inhibitor of an immune checkpoint molecule is a PD-L1 inhibitor, for example, an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446) or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.
[00224] [00224] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, for example, an anti-PD-1 / PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 / PD-L1 is MCLA-136.
[00225] [00225] In some embodiments, the inhibitor is MCLA-145.
[00226] [00226] In some embodiments, the inhibitor of an immune checkpoint molecule is a CTLA-4 inhibitor, for example, an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884 or CP-675,206.
[00227] [00227] In some embodiments, the inhibitor of an immune checkpoint molecule is a CSF1R inhibitor, for example, an anti-CSF1R antibody. In some embodiments, the anti-CSF1R antibody is IMC-CS4 or RG7155.
[00228] [00228] In some embodiments, the inhibitor of an immune checkpoint molecule is an LAG3 inhibitor, for example, an anti-LAG3 monoclonal antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, IMP321, GSK2831781 or IN-CAGN2385.
[00229] [00229] In some embodiments, the inhibitor of an immune checkpoint molecule is a TIM3 inhibitor, for example, an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is IN-CAGN2390, MBG453 or TSR-022.
[00230] [00230] In some embodiments, the inhibitor of an immune checkpoint molecule is a GITR inhibitor, for example, an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323 or MEDI1873.
[00231] [00231] In some embodiments, the inhibitor of an immune checkpoint molecule is an OX40 agonist, for example, an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is INCAGN01949, MEDI0562, MEDI6469, MOXR-0916, PF-04518600, GSK3174998 or BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383.
[00232] [00232] In some embodiments, the inhibitor of an immune checkpoint molecule is a CD20 inhibitor, for example, an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.
[00233] [00233] The compounds of the present invention can be used in combination with bispecific antibodies. In some embodiments, one of the bispecific antibody domains targets the PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGFβ receptor.
[00234] [00234] In some embodiments, the compounds of the description may be used in combination with one or more inhibitors of metabolic enzymes. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196. An example of an arginase inhibitor is CB-1158.
[00235] [00235] As provided, compounds, inhibitors, agents, etc. Additional dosages can be combined with the present compound in a single or continuous dosage form, or can be administered simultaneously or sequentially as separate dosage forms. II. Cancer Therapies
[00236] [00236] The growth and survival of cancer cells can be affected by multiple signaling pathways. Thus, it is useful to combine different enzymatic / protein / receptor inhibitors, displaying different preferences in the targets in which they modulate activities, to treat such conditions. Examples of agents that can be combined with compounds of the present invention include PI3K-AKT-mTOR pathway inhibitors, Raf-MAPK pathway inhibitors, JAK-STAT pathway inhibitors, beta catenin pathway inhibitors, notch pathway inhibitors, the hedgehog pathway, Pim kinase inhibitors and protein capsule inhibitors and cell cycle progression. Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) can reduce the likelihood of drug resistance arising in a cell population and / or reduce treatment toxicity .
[00237] [00237] The compounds of the present invention can be used in combination with one or more other enzyme / protein / receptor inhibitors for the treatment of diseases, such as cancer. Examples of cancers include solid tumors and liquid tumors, such as blood cancers. For example, the compounds of the present invention can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf.
[00238] [00238] The compounds of the present invention can be used in combination with one or more agents for the treatment of diseases, such as cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of an alkylating agent include bendamustine, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes, uracil mustard, chlormetin, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chloram-bucyl, pipobromone, melamine, triethylene thiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine and themezolomide. In some embodiments, the proteasome inhibitor is carfilzomib. In some modalities, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulating agent is linalidomide (LEN) or pomalidomide (POM).
[00239] [00239] The compounds of the present invention can also be used in combination with other methods of treating cancer, for example, by chemotherapy, irradiation therapy, tumor-directed therapy, adjuvant therapy, immunotherapy or surgery. Examples of immunotherapy include treatment with cytokines (eg interferons, GM-CSF, G-CSF, IL-2), immunotherapy with CRS-207, vaccine against cancer, monoclonal antibody, transfer of adoptive T cells, treatment with T cells CAR (chimeric antigen receptor) as a booster for T cell activation, oncolytic virotherapy and small immunomodulatory molecules, including thalidomide or JAK1 / 2 inhibitor and the like.
[00240] [00240] Other anti-cancer agent (s) include therapeutic antibody agents, such as trastuzumab (Herceptin), antibodies to co-stimulatory molecules with CTLA-4 (eg, ipilimumab or tremelimumab), 4-1BB, antibodies to PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.). Examples of antibodies to PD-1 and / or PD-L1 that can be combined with compounds of the present invention for the treatment of cancer or infections, such as viral, bacterial, fungal and parasitic infections include, but are not limited to nivolumab, pembrolizumab , MPDL3280A, MEDI-4736 and SHR-1210.
[00241] [00241] Other anticancer agents include inhibitors of cell proliferative disorder associated with kinases. These kinases include, but are not limited to Aurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3, JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk and SGK.
[00242] [00242] Other anticancer agents also include those that block the migration of immune cells, such as chemokine receptor antagonists, including CCR2 and CCR4.
[00243] [00243] The compounds of the present invention can also be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants or therapeutic antibodies. Steroids include, but are not limited to, 17 alpha-ethinyl estradiol, diethylstilbes-
[00244] [00244] The compounds of the present invention can also be used in combination with telafarnib (SCH6636), tipifarnib (R115777), L778123, BMS 214662, tezacitabine (MDL 101731), Sml1, triapine, didox, trimidox and amidox.
[00245] [00245] The compounds of Formula (I) or (I ') or any of the formulas as described herein, a compound, as recited in any one of the claims and described herein, or salts thereof can be combined with another immunogenic agent, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides and carbohydrate molecules), cells and cells transfected with genes that encode immunostimulatory cytokines. Non-limiting examples of tumor vaccines that can be used include peptides from melanoma antigens, such as gp100 peptides, MAGE, Trp-2, MARTI and / or tyrosinase antigens, or transfected tumor cells to express the cytokine GM- CSF.
[00246] [00246] The compounds of Formula (I) or (I ') or any of the formulas as described herein, a compound as recited in any one of the claims and described herein, or salts thereof can be used in combination with a vaccination protocol for cancer treatment. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses implicated in human cancers, such as human papilloma virus (HPV), hepatitis virus (HBV and HCV) and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, the compounds of the present invention can be used in combination with tumor specific antigen, such as heat shock proteins isolated from the tumor tissue itself.
[00247] [00247] The compounds of the present invention can be used in combination with bispecific macrocyclic peptides that target effector cells expressing the Fe-alpha or Fe-Fe receptor. The compounds of the present invention can also be combined with acrocyclic peptides that activate the host's immune response.
[00248] [00248] The compounds of the present invention can be used in combination with bone marrow transplantation for the treatment of a variety of tumors of hematopoietic origin.
[00249] Suitable antiviral agents contemplated for use in combination with the compounds of the present invention may comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNR-TIs), protease inhibitors and other antiviral drugs.
[00250] [00250] Examples of suitable NRTIs include zidovudine (AZT); di-damagesin (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis (POM) -PMEA]; lobucavir (BMS-180194); BCH-10652; emissricitabine [(-) - FTC]; beta-L-FD4 (also called beta-L-D4C and called beta-L-2 ', 3'-dichleoxy-5-fluoro-cytidene); DAPD, ((-) - beta-D-2,6, -diamino-purine dioxolane); and lodnosine (FddA). Suitable typical NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1- (ethoxy-methyl) -5- (1-methylethyl) -6- (phenylmethyl) - (2.4 (1H, 3H) -pyrimidinedione); and (+) - calanolide A (NSC -675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-
[00251] [00251] When more than one pharmaceutical agent is administered to a patient, it can be administered simultaneously, separately, sequentially or in combination (for example, for more than two agents).
[00252] [00252] In some embodiments, the compounds of the description can be used in combination with INCB086550. Formulation, Dosage Forms and Administration
[00253] [00253] When used as pharmaceuticals, the compounds of the present invention can be administered in the form of pharmaceutical compositions. Thus, the present invention provides a composition comprising a compound of Formula (I), (I '), or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt pharmaceutically acceptable carrier, or any of its modalities, and at least a pharmaceutically acceptable carrier or excipient. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is indicated and the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic and mucous membranes including intrascal, vaginal and rectal application), pulmonary (for example, by inhalation or insufflation of powders or aerosols, including by nebuliser; intratracheal or intranasal ), oral or parenteral. Parenteral administration includes intramuscular, intraperitoneal, subcutaneous, intra-arterial or intravenous injection or infusion; or intracranial, for example, intrathecal or intraventricular. Parenteral administration can be in the form of a single bolus dose or it can be, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional carriers, aqueous, powdered or oily bases, thickeners and the like may be necessary or desirable.
[00254] [00254] This invention also includes pharmaceutical compositions that contain, as an active ingredient the compound of the present invention or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the composition is suitable for topical administration. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or confined within such a carrier in the form of, for example, a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, capsule-shaped tablets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing , for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
[00255] [00255] By preparing a formulation, the active compound can be milled to provide the appropriate particle size before combining with the other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size less than 200 mesh. If the active compound is substantially soluble in water, the particle size can be adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.
[00256] [00256] The compounds of the invention can be ground using known milling procedures, such as wet milling to obtain an appropriate particle size for tabletting and for other types of formulation. Finely divided (non-particulate) preparations of the compounds of the invention can be prepared by processes known in the art, for example, WO 2002/000196.
[00257] [00257] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. The formulations may additionally include: lubricating agents, such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservation agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide rapid, prolonged or delayed release of the active ingredient after administration to the patient using procedures known in the art.
[00258] [00258] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w / w.
[00259] [00259] In some embodiments, the composition is an extended release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropylmethylcellulose and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate and hydroxypropylmethylcellulose. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, microcrystalline cellulose is Avicel PH102 ™. In some embodiments, the lactose monohydrate is Fast-flo 316 ™. In some embodiments, hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (for example, Methocel K4 M Premier ™) and / or hydroxypropyl methylcellulose 2208 K100LV (for example, Methocel K00LV ™). In some embodiments, polyethylene oxide is polyethylene oxide WSR 1105 (for example, Polyox WSR 1105 ™).
[00260] [00260] In some modalities, a wet granulation process is used to produce the composition. In some embodiments, a dry granulation process is used to produce the composition.
[00261] [00261] The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g) more normally about 100 mg to about 500 mg, of the active ingredient. In some embodiments, each dosage contains about 10 mg of the active ingredient. In some embodiments, each dosage contains about 50 mg of the active ingredient. In some modalities, each dosage contains about 25 mg of the active ingredient. The term "unit dosage forms" refers to physically distinct units suitable as unit dosages for humans and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
[00262] [00262] The components used to formulate the pharmaceutical compositions are of high purity and are substantially free of potentially harmful contaminants (for example, at least, National Food grade, generally at least analytical grade, and more typically at least pharmaceutical grade) . Particularly for human consumption, the composition is preferably manufactured or formulated under the Good Manufacturing Practices standards defined in the applicable regulations of the U.S. Food and Drug Administration. For example, suitable formulations can be sterile and / or substantially isotonic and / or in full compliance with all Good Food Practice regulations of the U.S. Food and Drug Administration.
[00263] [00263] The active compound can be effective over a wide dosage scale and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will normally be determined by a doctor, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight and the response of the individual patient, the severity of the patient's symptoms and the like.
[00264] [00264] The therapeutic dosage of a compound of the present invention may vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending on a number of factors including dosage, chemical characteristics (e.g., hydrophobicity) and the route of administration. For example, the compounds of the invention can be supplied in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are from about 1 µg / kg to about 1 g / kg of body weight per day. In some modalities, the dose range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage is likely to depend on such variables as type and the extent of progression of the disease or disorder, the general health situation of the particular patient, the relative efficacy of the compound of the selected compound, the formulation of the excipient and its route of administration. Effective dosages can be extrapolated from these dosage response curves derived from animal model or in vitro test systems.
[00265] [00265] To prepare solid compositions, such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. With reference to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly in the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. The solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.
[00266] [00266] The tablets or pills of the present invention can be coated or otherwise formulated to provide a dosage form providing the advantage of prolonged action. For example, the tablet or pill may comprise an internal and external dosage component, the second being in the form of an envelope over the first. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allows the internal component to pass intact through the duodenum, or until it is released in a delayed manner. A variety of materials can be used for such enteric layers or coatings, such materials, including a number of polymeric acids and mixtures of polymeric acids, with such materials as shellac, cetyl alcohol and cellulose acetate.
[00267] [00267] The liquid forms in which the compounds and pharmaceutical compositions of the present invention can be incorporated for oral or injection administration include, aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
[00268] [00268] Compositions for inhalation and insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof and powders. Liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. In some modalities, the compositions are administered via the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by using inert gases. Nebulized solutions can be breathed directly from the nebulizer device or the nebulizer device can be attached to a face mask chamber, or intermittent positive pressure breathing machine. Compositions in solution, suspension or powder can be administered orally or nasally from devices that apply the formulation appropriately.
[00269] [00269] Topical formulations may contain one or more conventional carriers. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petroleum jelly and the like. Carrier compositions of creams may be water-based in combination with glycerol and one or more other components, for example, glycerinammonostearate, PEG-glycerinammonostearate and cetilstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose and the like. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of the compound of the invention. Topical formulations can be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the selected indication, for example, psoriasis or other skin condition.
[00270] [00270] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration, such as prophylaxis or therapy, the condition of the patient, the manner of administration and the like. In therapeutic applications, the compositions can be administered to a patient who is already suffering from a disease in an amount sufficient to cure or at least partially cure the symptoms of the disease and its complications. Effective doses will depend on the condition of the disease being treated as well as on the judgment of the attending physician depending on factors such as the severity of the disease, age, weight and general condition of the patient and the like.
[00271] [00271] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or can be filtered until sterilized. Aqueous solutions can be packaged for use as is or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of compound preparations will typically be between 3 and 11, more preferably 5 to 9 and most preferably 7 to 8. It will be understood that the use of certain excipients, carriers or prior stabilizers will result in the formation of salts pharmacists.
[00272] [00272] The therapeutic dosage of a compound of the present invention can vary according to, for example, the particular use for which the treatment is made, the way of administration of the compound, the health and condition of the patient and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending on a number of factors including dosage, chemical characteristics (e.g., hydrophobicity) and the route of administration. For example, the compounds of the invention can be supplied in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are from about 1 µg / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. It is likely that the dosage depends on such variables as type and the extent of progression of the disease or disorder, the general health situation of the particular patient, the efficacy re-
[00273] [00273] Another aspect of the present invention relates to labeled compounds of the description (radiolabeled, fluorescently labeled, etc.) that would be useful not only in imaging techniques, but also in assays, both in vitro and in vivo, to locate and quantifying the HPK1 protein in tissue samples, including humans, and to identify HPK1 ligands by inhibiting the binding of a labeled compound. The substitution of one or more of the atoms of the compounds of the present invention can also be useful in the generation of differentiated ADME (Adsorption, Distribution, Metabolism and Excretion). Accordingly, the present invention includes HPK1 binding assays that contain such labeled or substituted compounds.
[00274] [00274] The present invention further includes isotope-labeled compounds of the description. An "isotopically" or "radiomarked" compound is a compound of the description in which one or more atoms are replaced or replaced by an atom with an atomic mass or mass number other than the atomic mass or mass number normally found in nature (ie naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present invention include, but are not limited to, 2H (also written as D for deuterium), 3H (also written as T for tritium), 11 13 14 13 15 15 17 18 18 35 36 82 75 76 77 C, C, C, N, N, O, O, O, F, S, Cl, Br, Br, Br, Br, 123 124 125 131 I, I, I and I. For example, one or more hydrogen atoms in a compound of the present invention can be replaced by deuterium atoms (for example, one or more hydrogen atoms of a C1-6 alkyl group of Formula (I) or (I ') can be optionally subs - replaced by deuterium atoms, such as –CD3 being replaced by - CH3). In some embodiments, the alkyl groups in Formula (I) or (I ') may be substituted.
[00275] [00275] One or more constituent atoms of the compounds presented here can be substituted or replaced by isotopes of the atoms in natural or unnatural abundance. In some embodiments, the compound includes at least one deuterium atom. In some modes, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1-2, 1-3, 1-4, 1-5 or 1-6 deuterium atoms. In some embodiments, all the hydrogen atoms in a compound can be replaced or replaced with deuterium atoms.
[00276] [00276] Synthetic methods for including isotopes in organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labeling by James R. Hanson, Royal Society of Chemistry, 2011). The isotopically labeled compounds can be used in several studies, such as NMR spectroscopy, metabolism experiments and / or assays.
[00277] [00277] Substitution by heavier isotopes, such as deuterium, may provide certain therapeutic advantages resulting from greater metabolic stability, for example, greater in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. (see, for example, A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more sites of metabolism may provide one or more of the therapeutic advantages.
[00278] [00278] The radionuclide that is incorporated into the present radiolabeled compounds will depend on the specific application of that radiolabeled compound. For example, for in vitro adenosine receptor labeling and competition assays, compounds that incorporate 3H, 14 C, 82 Br, 125 I, 131 I or 35 S may be useful. For radio imaging applications C, 18F, 125I, 123I, 124I, 131I, 75Br, 76Br or 77Br may be useful.
[00279] [00279] It is understood that a "radiolabeled" or "labeled compound" is a compound that has incorporated at least one radionuclide. In some modalities, the radionuclide is selected from the group consisting of 3H, 14C, 125I, 35S and 82Br.
[00280] [00280] The present invention can further include synthetic methods for incorporating radioisotopes in compounds of the description. Synthetic methods for incorporating radioisotopes in organic compounds are well known in the art, and one skilled in the art will readily recognize the methods applicable to the compounds of the description.
[00281] [00281] A labeled compound of the invention can be used in a screening assay to identify and / or evaluate compounds. For example, a newly synthesized or identified compound (ie test compound) that is labeled can be evaluated for its ability to bind to an HPK1 protein by monitoring its concentration variation when it comes in contact with HPK1, through mark tracking. For example, a test compound (labeled) can be evaluated for its ability to reduce the binding of another compound that is known to bind to an HPK1 protein (i.e., standard compound). Therefore, the ability of a test compound to compete with the standard compound for binding to the HPK1 protein directly correlates with its binding affinity. On the other hand, in some other screening assays, the standard compound is labeled and the test compounds are not labeled. Consequently, the concentration of the labeled standard compound is monitored in order to assess the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained. Kits
[00282] [00282] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of diseases or disorders associated with HPK1 activity, such as cancer or infections, which include one or more containers containing a pharmaceutical composition comprising an amount therapeutically effective use of a compound of Formula (I), (I '), or any of the modalities thereof. Such kits may further include one or more of several conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. . Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, may also be included in the kit.
[00283] [00283] The invention will be described in more detail by way of specific examples. The following examples are offered for purposes of illustration and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to yield essentially the same results. The compounds of the Examples have been found to inhibit HPK1 activity according to at least one assay described herein. EXAMPLES:
[00284] [00284] Experimental procedures for compounds of the invention are provided below. Preparatory purifications by LC-MS of high
[00285] [00285] The separated compounds were typically subjected to analytical liquid chromatography (LCMS) mass spectrometry to check for purity under the following conditions: Instrument; Agile 1100 series, LC / MSD, Column: Waters SunfireTM C18 particle size of 5 µm, 2.1 x 5.0 mm, Buffers: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient of 2% to 80% B in 3 minutes with a flow rate of 2.0 mL / minute.
[00286] [00286] Some of the prepared compounds were also separated on a preparative scale by reverse phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the Examples. The typical conditions of the reverse phase preparative high performance liquid chromatography column (RP-HPLC) are as follows:
[00287] [00287] pH = 2 purifications: Waters SunfireTM C18 5 µm particle size, 19 x 100 mm column, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile ; the flow rate was 30 mL / minute, the separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol, as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization" , K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used with the 30 x 100 mm column was 60 ml / minute.
[00288] [00288] pH = 10 purifications: Waters XBridge C18 particle size 5 µm, 19 x 100 mm column, eluting with mobile phase A: 0.15% NH4OH in water and mobile phase B: acetonitrile; the flow rate was 30 mL / minute, the separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol, as described in the literature [see "Preparative LCMS Purification: Impact Compound Specific Method Optimization" , K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used with the 30 x 100 mm column was 60 ml / minute.
[00289] [00289] The following abbreviations can be used here: AcOH (acetic acid); Ac2O (acetic anhydride); aq. (aqueous); atm. (atmosphere (s)); Boc (t-butoxycarbonyl); BOP ((benzotriazol-1-yloxy) tris (dimethylamine) phosphonium hexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc. (calculated); d (doublet); dd (doublet of doublets); DBU (1,8-diazabicyclo [5.4.0] undec-7-ene); DCM (dichloromethane); DIAD (diisopropyl N, N'-azidodicarboxylate); DIEA (N, N-diisopropylethylamine); DIPEA (N, N-diisopropylethylamine); DIBAL (diisobutylaluminum hydride); DMF (N, N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); FCC (flash column chromatography); g (gram (s)); h (hour (s)); HATU (N, N, N ', N'-tetramethyl-O- (7-azabenzotriazol-1-yl) uranium hexafluorophosphate); HCl (hydrochloric acid); HPLC (high performance liquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquid chromatography -
[00290] [00290] A mixture of 2-chloropyrimidine-4-carboxylic acid (9.0 g, 56.8 mmol), boronic acid (2-fluoro-6-methoxyphenyl) (11.58 g, 68.1 mmol), XPhosPd Tribasic G2 (1.340 g, 1.703 mmol) and potassium phosphate (24.10 g, 114 mmol) were combined with 1,4-dioxane (100 mL) and water (20.00 mL). The reaction flask was evacuated, filled back with nitrogen and then heated to 80 ˚C for 2 h. The reaction mixture was then cooled to room temperature, treated with water and diluted with ethyl acetate. The aqueous phase was separated and acidified with HCl1 N. The resulting solid was collected by filtration and washed with water. After air drying, it was used in Step 4 without further purification. LCMS calculated for C12H10FN2O3 (M + H) +: m / z = 249.2; found 249.2. Step 2. (1R, 4R) -tert-Butyl Boc 5- (4-fluoro-2-nitrophenyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate N
[00291] [00291] A solution of 1,4-difluoro-2-nitrobenzene (257 mg, 1.6 mmol) and tert-butyl (1R, 4R) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate ( 320 mg, 1.6 mmol) in DMSO (2.5 mL) was treated with triethylamine (338 µl, 2.4 mmol). The reaction mixture was heated to 80 ˚C for 3 h. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and washed with brine. The separated organic layer was dried over sodium sulfate and concentrated. The crude product was used in the next step, without further purification. LCMS calculated for C12H13FN3O4 (M + H-C4H8) +: m / z = 282.1; found 282.1. Step 3. (1R, 4R) -tert-Butyl Boc 5- (2-amino-4-fluorophenyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate N
[00292] [00292] A mixture of tert-butyl (1R, 4R) -5- (4-fluoro-2-nitrophenyl) -2,5-diazabi- cycle [2.2.1] heptane-2-carboxylate (545 mg, 1 , 6 mmol), iron (451 mg, 8.1 mmol) and ammonium chloride (518 mg, 9.7 mmol) in THF (2 mL), water (2 mL) and methanol (2 mL) were stirred at 60 ˚C for 3 h. After cooling to room temperature, the reaction mixture was filtered through a plug of Celite and diluted with dichloromethane. The organic phase was separated, washed with brine, dried over sodium sulfate and the solvents were evaporated in vacuo. The crude product was used in the next step, without further purification. LCMS calculated for C16H23FN3O2 (M + H) +: m / z = 308.2; Found: 308.2. Step 4. N- (2 - ((1R, 4R) 2,5-Diazabicyclo [2.2.1] heptan-2-yl) -5-fluorophenyl) - 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4 -carboxamide
[00293] [00293] HATU (178 mg, 0.468 mmol) was added to a solution of (1R, 4R) -5- (2-amino-4-fluorophenyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate tert-butyl (96 mg, 0.312 mmol), 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxylic acid (from Step 1; 78 mg, 0.312 mmol) and DI-PEA (109 µl, 0.625 mmol) in DMF (2mL). The reaction mixture was stirred at room temperature for 30 min and then treated with water. The precipitated product was collected by filtration, washed with water and air dried. The solid residue was then redissolved in TFA and the solution was stirred at room temperature for 10 min. The mixture was then diluted with acetonitrile and purified with prep LCMS (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 mL / min) to isolate the compound of the title as the TFA salt. LCMS calculated for C23H22F2N5O2 (M + H) +: m / z = 438.2; Found: 438.2. Example 2. (S) -N- (2- (3-Aminopyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00294] [00294] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using (S) -pyrrolidin-3-amine instead of (1R, 4R) -2,5-diazabicyclo [2.2. 1] tert-butyl heptane-2-carboxylate as starting material. LCMS calculated for C22H22F2N5O2 (M + H) +: m / z = 426.2; Found: 426.3. Example 3. (R) -N- (2- (2- (Aminomethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00295] [00295] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using (R) -tert-butyl pyrrolidin-2-ylmethylcarbamate instead of tert-butyl (1R, 4R) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate as starting material. LCMS calculated for C23H24F2N5O2 (M + H) +: m / z = 440.2; Found: 440.1. Example 4. (R) -N- (5-Fluoro-2- (2- (hydroxymethyl) pyrrolidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide F O OH N N N H N O F
[00296] [00296] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using (R) -pyrrolidin-2-ylmethanol instead of tert-butyl (1R, 4R) -2,5-diazabicycles [2.2.1] heptane-2-carboxylate as starting material. LCMS calculated for C23H23F2N4O3 (M + H) +: m / z = 441.2; Found: 441.1. Example 5. (R) -N- (5-Fluoro-2- (2- (methoxymethyl) pyrrolidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00297] [00297] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using (R) -2- (methoxymethyl) pyrrolidine instead of tert-butyl (1R, 4R) -2, 5-diazabicyclo [2.2.1] hepta-2-carboxylate as starting material. LCMS calculated for C24H25F2N4O3 (M + H) +: m / z = 455.2; Found: 455.3. Example 6. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4 -carboxamide H 2N F O OH N N N H N O F
[00298] [00298] The free base and TFA salt of the title compound were prepared according to the procedures described in Example 1, (and detailed below) using tert-butyl (3S, 5S) -5- (hydroxymethyl) - pyrrolidin-3-ylcarbamate instead of tert-butyl (1R, 4R) -2,5-diazabicyclo [2.2.1] heptatan-2-carboxylate as starting material.
[00299] [00299] A solution of 1,4-difluoro-2-nitrobenzene (68.2 µL, 0.629 mmol) and tert-butyl ((3S, 5S) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate (136 mg, 0.629 mmol) in DMSO (2.5 mL) was treated with triethylamine (131 µL, 0.943 mmol) and the reaction mixture was heated to 80 ˚C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with DCM, washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The crude product obtained was used in the next step, without further purification. LCMS calculated for C12H15FN3O5 (M + H-C4H8) +: m / z = 300.1; found 300.1. Step 2. tert-Butyl carbamate ((3S, 5S) -1- (2-amino-4-fluorophenyl) -5- (hydroxymethyl) pyrrolidin-3-yl)
[00300] [00300] A mixture of tert-butyl ((3S, 5S) -1- (4-fluoro-2-nitrophenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate (100 mg, 0.281 mmol) , iron (79 mg, 1.407 mmol) and ammonium chloride (90 mg, 1.7 mmol) in THF (2 mL), water (2 mL) and methanol (2 mL) was stirred at 60 ˚C for 3 hours. After cooling to room temperature, the mixture was filtered through a plug of Celite and diluted with DCM. The organic phase was separated, washed with brine, dried over sodium sulfate and the solvents were evaporated in vacuo. The crude product obtained was used in the next step, without further purification. LCMS calculated for C16H25FN3O3 (M + H) +: m / z = 326.2; Found: 326.2. Step 3. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine -4-carboxamide
[00301] [00301] HATU (175 mg, 0.461 mmol) was added to a solution of tert-butyl acid ((3S, 5S) -1- (2-amino-4-fluorophenyl) -5- (hydroxymethyl) pyrrolidin-3 -yl) carbamate (100 mg, 0.307 mmol), 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxylic (the product of Example 1, step 1, 76 mg, 0.307 mmol) and DIPEA (107 µL, 0.615 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 30 minutes, then water was added and the precipitated product was collected by filtration, washed with water and air dried. The solid was dissolved in TFA and the resulting solution was stirred at room temperature for 10 minutes. The solution was then diluted with acetonitrile and purified with prep LCMS. LCMS calculated for C23H24F2N5O3 (M + H) +: m / z = 456.2; Found: 456.3. LCMS Prep (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% NH4OH, at a flow rate of 60 mL / min). Free base: 1H NMR (600 MHz, DMSO-d6) δ 9.34 - 9.18 (m, 1H), 8.25 - 8.19 (m, 1H), 8.18 - 8.14 (m, 1H), 7.60 - 7.49 (q, J = 7.7 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.08 - 7.02 (d, J = 8, 4 Hz, 1H), 7.02 - 6.94 (m, 2H), 3.78 - 3.71 (s, 3H), 3.38 - 3.30 (t, J = 6.4 Hz, 1H ), 3.30 - 3.23 (m, 1H), 3.23 - 3.17 (m, 1H), 3.17 - 3.10 (dd, J = 11.1, 6.1 Hz, 1H ), 2.95 - 2.88 (t, J = 7.4 Hz, 1H), 2.88 - 2.80 (m, 1H), 2.35 - 2.25 (dt, J = 14.1 , 8.0 Hz, 1H), 1.25 - 1.12 (m, 1H) ppm. LCMS Prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, flow rate 60 mL / min) TFA salt: 1H NMR (600 MHz, DMSO-d6) δ 10, 78 - 10.58 (s, 1H), 9.32 - 9.20 (d, J = 5.0 Hz, 1H), 8.24 - 8.08 (m, 2H), 7.93 - 7, 77 (br, J = 5.7 Hz, 2H), 7.62 - 7.53 (td, J = 8.4, 6.8 Hz, 1H), 7.53 - 7.46 (dd, J = 8.8, 5.7 Hz, 1H), 7.10 - 7.02 (m, 2H), 7.02 - 6.93 (t, J = 8.8 Hz, 1H), 3.82 - 3 , 73 (s, 3H), 3.75 - 3.67 (m, 1H),
[00302] [00302] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using (3S, 5S) -5-methylpyrrolidin-3-ol tert-butyl (1R, 4R) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate as starting material. LCMS calculated for C23H23F2N4O3 (M + H) +: m / z = 441.2; Found: 441.3. Example 8. N - (5-Fluoro-2- (2- (pyridin-2-yl) pyrrolidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; F O N N N N H N O F
[00303] [00303] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using 2- (pyrrolidin-2-yl) pyridine instead of (1R, 4R) -2,5-diazabicyclo [2.2 .1] tert-butyl heptane-2-carboxylate as starting material. LCMS calculated for C27H24F2N5O2 (M + H) +: m / z = 488.2; Found: 488.1. Example 9. N- (5-Fluoro-2- (hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine- 4-carboxamide; F O NH N N N H N O F
[00304] [00304] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using tert-butyl-hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carboxylate instead of tert -butyl (1R, 4R) - 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate as starting material. LCMS calculated for C24H24F2N5O2 (M + H) +: m / z = 452.2; Found: 452.2. Example 10. (R) -N- (5-Fluoro-2- (2-methylpiperazin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N H N O F
[00305] [00305] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using (R) -tert-butyl 3-methylpiperazine-1-carboxylate instead of tert-butyl (1R, 4R) - 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate as starting material. LCMS calculated for C23H24F2N5O2 (M + H) +: m / z = 440.2; Found: 440.2. Example 11. (R) -N- (5-Fluoro-2- (2- (hydroxymethyl) piperazin-1-yl) phenyl) - 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; H N F O OH N N N H N O F
[00306] [00306] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using (R) -tert-butyl 3- (hydroxymethyl)-1-carboxylate instead of (1R, 4R) tert-Butyl -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate as starting material. LCMS calculated for C23H24F2N5O3 (M + H) +: m / z = 456.2; Found: 456.2. Example 12. N- (5-Fluoro-2- (3- (hydroxymethyl) morpholino) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; O F O OH N N N H N O F
[00307] [00307] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using morpholin-3-ylmethanol instead of tert-butyl (1R, 4R) -2,5-diazabicyclo [2.2 .1] heptane-2-carboxylate as a starting material. LCMS calculated for C23H23F2N4O4 (M + H) +: m / z = 457.2; Found: 457.2. Example 13. N- (2 - ((1R, 4R) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -3-bromo-5-fluorophenyl) -2- (2-fluoro-6- methoxyphenyl) pyrimidine-4-carbo-xamide H N F O N N N
[00308] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using 1-bromo-2,5-difluoro-3-nitrobenzene instead of 1,4-difluoro-2-nitrobenzene as starting material. LCMS calculated for C23H21BrF2N5O2 (M + H) +: m / z = 516.1; Found: 516.1. Example 14. N- (2 - ((1R, 4R) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -3-cyanophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N H N CN O
[00309] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using 2-fluoro-3-nitro-benzonitrile instead of 1,4-difluoro-2-nitrobenzene as starting material. LCMS calculated for C24H22FN6O2 (M + H) +: m / z = 445.2; Found: 445.2. Example 15. N- (2 - ((1R, 4R) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-3- (pyridin-3-yl) phenyl) - 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N N H N O F
[00310] [00310] A mixture of (1R, 4R) -5- (2-bromo-4-fluoro-6- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -2,5- diazabicyclo [2.2.1] tert-butyl heptane-2-carboxylate (from Example 13; 10 mg, 0.016 mmol), pyridin-3-ylboronic acid (4 mg, 0.032 mmol), XPhosPd G2 (1.3 mg , 1.6 µmol) and potassium phosphate, tribasic (6.7 mg, 0.032 mmol) was combined with 1,4-dioxane (1 ml) and water (0.1 ml). The reaction flask was evacuated, again filled with nitrogen and the mixture was stirred at 80 ° C for 1 h. The reaction mixture was cooled to room temperature and the solvents were evaporated in vacuo. The residue was combined with TFA (1 ml) and stirred at room temperature for 10 min. The reaction mixture was diluted with CH3CN and water and purified with LCMS prep (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA, at a flow rate of 60 mL / min) to provide the TFA salt of the title compound. LCMS calculated for C28H25F2N6O2 (M + H) +: m / z = 515.2; Found: 515.3. Example 16. N- (2 - ((1R, 4R) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-3- (1-methyl-1H-pyrazole-4 -yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N N H N N O F
[00311] [00311] The TFA salt of the title compound was prepared according to the procedures described in Example 15, using 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -il) -1H-pyrazole instead of pyridin-3-ylboronic acid as starting material. LCMS calculated for C27H26F2N7O2 (M + H) +: m / z = 518.2; Found: 518.3. Example 17. N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4- (hydroxymethyl) phenyl) -2- (2 -fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N H N O F OH
[00312] [00312] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using (2,5-difluoro-4-nitrophenyl) methanol instead of 1,4-difluoro-2-nitrobenzene and ( Tert-butyl 1S, 4S) -2,5-diazabicyclo [2.2.1] tert-butyl heptane-2-carboxylate instead of tert (1R, 4R) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate -butyl as starting material. LCMS calculated for C24H24F2N5O3 (M + H) +: m / z = 468.2; Found: 468.2. 1H NMR (600 MHz, DMSO-d6) δ 10.81 - 10.70 (s, 1H), 9.33 - 9.25 (d, J = 5.0 Hz, 1H), 8.19 - 8, 12 (d, J = 5.0 Hz, 1H), 8.12 - 8.04 (d, J = 11.4 Hz, 1H), 7.63 - 7.52 (q, J = 7.9 Hz , 1H), 7.38 - 7.28 (d, J = 7.2 Hz, 1H), 7.13 - 7.06 (d, J = 8.5 Hz, 1H), 7.05 - 6, 95 (t, J = 8.8 Hz, 1H), 5.28 - 5.16 (s, 1H), 4.57 - 4.42 (s, 2H), 3.82 - 3.71 (s, 3H), 3.70 - 3.60 (s, 1H), 3.54 - 3.46 (s, 1H), 3.26 - 3.17 (d, J = 9.0 Hz, 1H), 3 , 12 - 3.04 (d, J = 9.0 Hz, 1H), 2.92 - 2.86 (d, J = 10.0 Hz, 1H), 2.67 - 2.59 (d, J = 9.7 Hz, 1H), 1.65 - 1.59 (d, J = 9.3 Hz, 1H), 1.54 - 1.38 (d, J = 9.1 Hz, 1H) ppm. Example 18. N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -4-bromo-5-fluorophenyl) -2- (2-fluoro-6- methoxyphenyl) pyrimidine-4-carbo-xamide H N F O N N N H N
[00313] [00313] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using 1-bromo-2,5-difluoro-4-nitrobenzene instead of 1,4-difluoro-2-nitrobenzene and Tert-butyl (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane-2-carboxolate instead of (1R, 4R) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate tert-butyl as a starting material. LCMS calculated for C23H21BrF2N5O2 (M + H) +: m / z = 516.1; Found: 516.1.
[00314] [00314] A mixture of (1S, 4S) -5- (5-bromo-4-fluoro-2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -2,5- diazabicyclo [2.2.1] tert-butyl heptane-2-carboxylate (from Example 18; 10 mg, 0.016 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) -1Hpi- razol (6.8 mg, 0.032 mmol), XPhosPd G2 (1.3 mg, 1.6 µmol) and potassium phosphate, tribasic (6.7 mg, 0.032 mmol) it was combined with 1,4-dioxane (1mL) and water (0.1 ml). The reaction flask was evacuated, again filled with nitrogen and then stirred at 80 ° C for 1 h. The reaction mixture was cooled to room temperature, the solvents were evaporated in vacuo, and TFA (1 ml) was added. The reaction mixture was stirred at room temperature for 10 min, then diluted with CH3CN and water and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 ml / min) to provide the TFA salt of the title compound. LCMS calculated for C 27H26F2N7O2 (M + H) +: m / z = 518.2; Found: 518.3. 1H NMR (600 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.30 (d, J = 4.9 Hz, 1H), 8.94 (br, 2H), 8.20 - 8 , 15 (m, 2H), 8.14 (s, 1H), 7.94 (s, 1H), 7.67 - 7.53 (m, 2H), 7.09 (d, J = 8.5 Hz, 1H), 7.02 (t, J = 8.7 Hz, 1H), 4.41 (s, 1H), 4.04 (s, 1H), 3.91 (s, 3H), 3, 78 (s, 3H), 3.51 (d, J = 11.0 Hz, 1H), 3.42 (d, J = 11.2 Hz, 1H), 3.34 - 3.20 (m, 1H ), 3.03 (s, 1H), 1.91 (d, J = 10.6 Hz, 1H), 1.77 (d, J = 10.7 Hz, 1H) ppm.
[00315] [00315] The TFA salt of the title compound was prepared according to the procedures described in Example 19, using (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- il) pyridin-2-yl) methanol instead of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole as starting material. LCMS calculated for C29H27F2N6O3 (M + H) +: m / z = 545.2; Found: 545.3. Example 21. N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4- (6- (methylcarbamoyl) pyridin-3- il) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N H N O
[00316] [00316] The TFA salt of the title compound was prepared according to the procedures described in Example 19, using N-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl) picolinamide instead of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole as starting material. LCMS calculated for C30H28F2N7O3 (M + H) +: m / z = 572.2; Found: 572.3.
[00317] [00317] The TFA salt of the title compound was prepared according to the procedures described in Example 19, using 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl) pyridin-2 (1H) -one instead of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole as match. LCMS calculated for C29H27F2N6O3 (M + H) +: m / z = 545.2; Found: 545.3. Example 23. N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4- (2-methylpyridin-3-yl) phenyl ) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N H N O N F
[00318] [00318] The TFA salt of the title compound was prepared according to the procedures described in Example 19, using 2-methyl-pyridin-3-ylboronic acid instead of 1-methyl-4- (4,4,5, 5-tetramethyl-1,3,2-dioxoborolan-2-yl) -1H-pyrazole as starting material. LCMS calculated for C29H27F2N6O2 (M + H) +: m / z = 529.2; Found: 529.3. Example 24. N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -4- (2-
[00319] [00319] This compound was prepared according to the procedures described in Example 18, using 4-bromo-2-fluoro-1-nitrobenzene instead of 1-bromo-2,5-difluoro-4-nitrobenzene as material of match. LCMS calculated for C28H30BrFN5O4 (M + H) +: m / z = 598.2; Found: 598.2. Step 2. N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -4- (2-methylpyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00320] [00320] A mixture of (1S, 4S) -5- (5-bromo-2- (2- (2-fluoro-6-methoxy-phenyl) pyrimidine-4-carboxamido) phenyl) -2,5-diazabicycles [ 2.2.1] tert-butyl heptane-2-carboxylate (10 mg, 0.017 mmol), boronic acid (2-methylpyridin-3-yl) (4.6 mg, 0.033 mmol), XPhosPd G2 (1.3 mg, 1.6 µmol) and tribasic potassium phosphate (6.7 mg, 0.032 mmol) was combined with 1,4-dioxane (1 ml) and water (0.1 ml). The reaction flask was evacuated, again filled with nitrogen, and then stirred at 80 ° C for 1 h. The reaction mixture was cooled to room temperature, the solvents were evaporated in vacuo and TFA (1 ml) was added. The reaction mixture was stirred at room temperature for 10 min, then diluted with CH3CN and water and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate 60 mL / min) to provide the TFA salt of the title compound. LCMS calculated for C29H28FN6O2 (M + H) +: m / z = 511.2; Found: 511.2. 1H NMR (600 MHz, DMSO-d6) δ 10.54 - 10.46 (s, 1H), 9.33 - 9.18 (d, J = 5.0 Hz, 1H), 9.06 - 8, 91 (s, 1H), 8.80 - 8.74 (s, 1H), 8.67 - 8.63 (dd, J = 5.2, 1.8 Hz, 1H), 8.20 - 8, 14 (d, J = 5.0 Hz, 1H), 8.14 - 8.09 (d, J = 8.2 Hz, 1H), 8.09 - 7.98 (d, J = 8.1 Hz , 1H), 7.70 - 7.61 (m, 1H), 7.61 - 7.55 (td, J = 8.4, 6.8 Hz, 1H), 7.31 - 7.27 (d , J = 1.9 Hz, 1H), 7.21 - 7.15 (dd, J = 8.2, 1.8 Hz, 1H), 7.12 - 7.06 (d, J = 8.5 Hz, 1H), 7.06 - 6.96 (t, J = 8.8 Hz, 1H), 4.39 - 4.30 (s, 1H)), 4.28 - 4.17 (s, 1H ), 3.84 - 3.71 (s, 3H), 3.62 - 3.52 (m, 1H), 3.39 - 3.34 (d, J = 11.2 Hz, 1H), 3, 34 - 3.28 (m, 1H), 3.15 - 3.04 (m, 1H), 2.63 - 2.58 (s, 3H), 1.97 - 1.90 (dd, J = 10 , 8, 2.5 Hz, 1H), 1.84 - 1.67 (m, 1H). Example 25. N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -4- (4-methoxypyridin-3-yl) phenyl) -2- (2 -fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N H N O
[00321] [00321] The TFA salt of the title compound was prepared according to the procedures described in Example 24, using 4-methoxypyridin-3-ylboronic acid instead of boronic (2-methylpyridin-3-yl) acid as material of departure. LCMS calculated for C29H28FN6O3 (M + H) +: m / z = 527.2; Found: 527.2.
[00322] [00322] The TFA salt of the title compound was prepared according to the procedures described in Example 24, (and detailed below) using 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) isonicotinonitrile instead of (2-methylpyridin-3-yl) boronic acid as starting material. Step 1. tert-Butyl (1S, 4S) -5- (5-bromo-2-nitrophenyl) -2,5-diazabicyclo [2.2.1] hepato-2-carboxylate
[00323] [00323] To a solution of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.3 mmol) and (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate tert-butyl (451 mg, 2.3 mmol) in DMSO (8 mL) triethylamine (475 µl, 3.41 mmol) was added and the reaction mixture was heated at 80 ° C for 2 h. After cooling to room temperature, water was added and the precipitated product was collected by filtration, washed with water and air dried. It was used in the next step, without further purification. LCMS calculated for C16H21BrN3O4 (M + H) +: m / z = 398.1 / 400.1; found 398.1 / 400.1.
[00324] [00324] A mixture of tert-butyl (1S, 4S) -5- (5-bromo-2-nitrophenyl) -2,5-diazabi- [2.2.1] heptane-2-carboxylate (914 mg, 2.295 mmol), iron (684 mg, 12.25 mmol) and ammonium chloride (786 mg, 14.70 mmol) in THF (5 mL), water (5 mL) and methanol (5 mL) were stirred at 60 ˚C for 3 hours. After cooling to room temperature, it was filtered through a plug of Celite and diluted with DCM. The organic phase was separated, washed with brine, dried over sodium sulfate and the solvents were evaporated in vacuo. The crude product obtained was used in the next step, without further purification. LCMS calculated for C16H23BrN3O2 (M + H) +: m / z = 368.1 / 370.1; Found: 368.1 / 370.1. Step 3. (1S, 4S) -5- (5-bromo-2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -2,5-diazabicyclo [2.2.1] heptane Tert-butyl -2-carboxylate
[00325] [00325] A solution of tert-butyl (1S, 4S) -5- (2-amino-5-bromophenyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (845 mg, 2.294 mmol), 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxylic (the product of Example 1, Step 1, 570 mg, 2.3 mmol) and DIPEA (800 µl, 4.6 mmol) in DMF (5 ml) was treated with HATU (1.3 g, 3.4 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then water was added and the precipitated product was collected by filtration, washed with water and dried in air. The crude product was used in the next step, without further purification. LCMS calculated for C28H30BrFN5O4 (M + H) +: m / z = 598.2 / 600.2; Found: 598.2 / 600.2. Step 4. N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00326] [00326] A mixture of (1S, 4S) -5- (5-bromo-2- (2- (2-fluoro-6-methoxy-phenyl) pyrimidine-4-carboxamido) phenyl) -2,5-diazabicycles [ 2.2.1] tert-butyl heptane-2-carboxylate (10 mg, 0.017 mmol), 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isonicotinonitrile (9, 8 mg, 0.043 mmol), Xphos Pd G2 (1.3 mg, 1.6 µmol) and potassium phosphate, tribasic (6.7 mg, 0.032 mmol) in 1,4-dioxane (1 mL) and water (0 , 1 mL) were degassed by evacuation and back filling with nitrogen. The reaction mixture was stirred at 80 ° C for 1 hour, cooled to room temperature and the solvents were evaporated in vacuo. TFA (1 mL) was added to the residue and the reaction mixture was stirred at room temperature for 10 min, then diluted with CH3CN and water and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0, 1% TFA, at a flow rate of 60 mL / min). LCMS calculated for C29H25FN7O2 (M + H) +: m / z = 522.2; Found: 522.3. 1H NMR (600 MHz, DMSO-d6) δ 10.60 - 10.51 (s, 1H), 9.33 - 9.22 (d, J = 4.9 Hz, 1H), 9.08 - 9, 00 (m, 1H), 9.01 - 8.95 (s, 1H), 8.88 - 8.80 (d, J = 4.9 Hz, 1H), 8.81 - 8.70 (m, 1H), 8.21 - 8.15 (d, J = 4.9 Hz, 1H), 8.15 - 8.10 (d, J = 8.2 Hz, 1H), 8.06 - 8.00 (d, J = 5.0 Hz, 1H), 7.60 - 7.53 (q, J = 7.9 Hz, 1H), 7.53 - 7.49 (s, 1H), 7.40 - 7.32 (d, J = 8.1 Hz, 1H), 7.13 - 7.07 (d, J = 8.5 Hz, 1H), 7.05 - 6.95 (t, J = 8, 8 Hz, 1H), 4.42 - 4.35 (s, 1H), 4.32 - 4.24 (s, 1H), 3.84 - 3.76 (s, 3H), 3.67 - 3 , 58 (d, J = 11.0 Hz, 1H), 3.46 - 3.35 (d, J = 10.9 Hz, 2H), 3.15 - 3.04 (dd, J = 11.6 , 8.2 Hz, 1H), 1.99 - 1.92 (d, J = 10.8 Hz, 1H), 1.89 - 1.75 (d, J = 10.7 Hz, 1H).
[00327] [00327] The TFA salt of the title compound was prepared according to the procedures described in Example 24, using 1,3,5-trimethyl-4- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) -1H-pyrazole instead of (2-methylpyridin-3-yl) boronic acid as starting material. LCMS calculated for C29H31FN7O2 (M + H) +: m / z = 528.2; Found: 528.2. Example 28. N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4-morpholinophenyl) -2- (2-fluoro- 6-methoxyphenyl) pyrimidine-4-carbo-xamide H N F O N N N H N O N F O
[00328] [00328] A mixture of (1S, 4S) -5- (5-bromo-4-fluoro-2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -2,5- diazabicyclo [2.2.1] tert-butyl heptane-2-carboxylate (from Example 18, 10 mg, 0.016 mmol), morpholine (1.4 mg, 0.016 mmol), RuPhosPd G2 (1.2 mg, 1, 6 µmol) and cesium carbonate (10.6 mg, 0.032 mmol) was combined with 1,4-dioxane (1 ml). The reaction flask was evacuated, again filled with nitrogen and stirred at 100 ° C for 3 h. The reaction mixture was cooled to room temperature, the solvents were evaporated in vacuo, and TFA (1 ml) was added. The reaction mixture was stirred at room temperature for 10 min, then diluted with CH3CN and water and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a rate flow rate of 60 mL / min) to provide the TFA salt of the title compound. LCMS calculated for C27H29F2N6O3 (M + H) +: m / z = 523.2; Found: 523.2. Example 29. N- (4- (Azetidin-1-yl) -2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluorophenyl) -2 - (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N H N O N F
[00329] [00329] The TFA salt of the title compound was prepared according to the procedures described in Example 28, using azetidine instead of morpholine as a starting material. LCMS calculated for C26H27F2N6O2 (M + H) +: m / z = 493.2; Found: 493.2. Example 30. N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4- (morpholinomethyl) phenyl) -2- (2 -fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N H N O The N F
[00330] [00330] Dess-Martin periodinane (269 mg, 0.634 mmol) was added to a solution of (1S, 4S) -5-4-fluoro-2- (2- (2-fluoro-6-methoxyphenyl) ) pyrimidine-4-carboxamido) -5- (hydroxymethyl) phenyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (Example 17, 300 mg, 0.529 mmol) and pyridine (51, 0 µl, 0.63 mmol) in dichloromethane (5 mL). After stirring at room temperature for 1 h, the solvent was evaporated in vacuo and the crude product was purified by BiotageIsolera ™. LCMS calculated for C29H30F2N5O5 (M + H) + m / z = 566.2; found 566.3. Step 2. N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4- (morpholinomethyl) phenyl) -2- (2-fluoro -6-methoxyphenyl) pyrimidine-4-carboxamide
[00331] [00331] Sodium triacetoxyborohydride (7.5 mg, 0.035 mmol) was added to a solution of morpholine (1.5 mg, 0.018 mmol), acetic acid (2 µl, 0.035 mmol) and (1S, 4S ) -5- (4-fluoro-2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) -5-formylphenyl) -2,5-diazabicyclo [2.2.1] heptane-2 - carboxylate (10 mg, 0.018 mmol) in dichloroethane (1 ml). The reaction mixture was stirred at room temperature for 2 h and then treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The crude residue was taken up in TFA (1 ml) and the reaction was stirred at room temperature for 30 min. The reaction mixture was diluted with acetonitrile and purified with LCMS prep (XBridge C18 column, eluting with a gradient of acetonitrile /
[00332] [00332] The TFA salt of the title compound was prepared according to the procedures described in Example 30, using cyclobutanamine instead of morpholine as the starting material. LCMS calculated for C28H31F2N6O2 (M + H) +: m / z = 521.2; Found: 521.2. Example 32. N- (2 - ((1R, 4R) -5-Ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) - 5-fluorophenyl) -2- (2-fluoro-6- methoxyphenyl) pyrimidine-4-carboxamide N F O N N N H N O F
[00333] [00333] Sodium triacetoxyborohydride (10 mg, 0.046 mmol) was added to a solution of acetaldehyde (1 mg, 0.023 mmol), acetic acid (2 µl, 0.035 mmol) and N- (2- ( (1R, 4R) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide (from Example 1; 10 mg, 0.023 mmol) in dichloroethane (1 ml). After the reaction mixture was stirred at room temperature for 2 h, it was diluted with acetonitrile and purified with LCMS prep (XBridge column
[00334] [00334] Sodium triacetoxyborohydride (10 mg, 0.046 mmol) was added to a solution of 2 - ((dimethylsilyl) oxy) acetaldehyde (3.98 mg, 0.023 mmol), acetic acid (2 µl, 0.035 mmol ) and N- (2 - ((1R, 4R) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pirimi - dine-4-carboxamide (from Example 1; 10 mg, 0.023 mmol) in dichloroethane (1 ml). After the reaction mixture was stirred at room temperature for 2 h, the solvent was evaporated in vacuo and a solution of 4 M HCl in dioxane (1 ml) was added to the residue. After additional stirring at room temperature for 1 h, the reaction mixture was diluted with acetonitrile and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 ml / min) to provide the TFA salt of the title compound. LCMS calculated for C25H26F2N5O3 (M + H) +: m / z = 482.2; Found: 482.2. Example 34. (1R, 4R) -5- (4-Fluoro-2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -N-propyl-2,5-diazabicycles [2.2.1] heptane-2-carboxamide H The N N F O N N N H N O F
[00335] [00335] Triphosgene (4.1 mg, 0.014 mmol) was added to a solution of N- (2 - ((1R, 4R) -2,5-diazabicyclo [2.2.1] heptan-2-yl) - 5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide (from Example 1, 6 mg, 0.014 mmol) and triethylamine (4 µl, 0.027 mmol) in THF (1 ml). After the reaction mixture was stirred at room temperature for 30 min, propan-1-amine (1.2 mg, 0.021 mmol) was added and the mixture was stirred at room temperature for another 30 min. The reaction mixture was diluted with acetonitrile and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 mL / min) to provide the TFA salt of the title compound. LCMS calculated for C27H29F2N6O3 (M + H) +: m / z = 523.2; Found: 523.3. Example 35. N- (2 - ((1R, 4R) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -5-me-toxiphenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N H N
[00336] [00336] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using 1-fluoro-4-methoxy-2-nitrobenzene instead of 1,4-difluoro-2-nitrobenzene as starting material. LCMS calculated for C24H25FN5O3 (M + H) +: m / z = 450.2; Found: 450.3.
[00337] [00337] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using (4-fluoro-3-nitrophenyl) methanol instead of 1,4-difluoro-2-nitrobenzene as material of departure. LCMS calculated for C24H25FN5O3 (M + H) +: m / z = 450.2; Found: 450.3. Example 37. N- (2 - ((1R, 4R) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -5-cyanophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N H N O CN
[00338] [00338] The TFA salt of the title compound was prepared according to the procedures described in Example 1, using 4-fluoro-3-nitro-benzonitrile instead of 1,4-difluoro-2-nitrobenzene as starting material. LCMS calculated for C24H22FN6O2 (M + H) +: m / z = 445.2; Found: 445.1. Example 38. N- (4- (Azetidin-1-yl) -2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) -2- (2 -fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N H N O N
[00339] [00339] This compound was prepared according to the procedures described in Example 28 and 29, using N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2- il) -4-bromophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide instead of N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan - 2-yl) -4-bromo-5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carbamide as starting material. LCMS calculated for C26H28FN6O2 (M + H) +: m / z = 475.2; Found: 475.2. 1H NMR (500 MHz, DMSO-d6) δ 10.17 - 10.04 (s, 1H), 9.27 - 9.16 (d, J = 5.0 Hz, 1H), 8.15 - 8, 04 (d, J = 5.1 Hz, 1H), 7.83 - 7.71 (d, J = 8.3 Hz, 1H), 7.59 - 7.48 (td, J = 8.4, 6.6 Hz, 1H), 7.10 - 7.02 (d, J = 8.5 Hz, 1H), 7.02 - 6.96 (t, J = 8.8 Hz, 1H), 6, 07 - 5.95 (m, 2H), 3.89 - 3.83 (s, 1H), 3.81 - 3.72 (m, 7H), 3.49 - 3.44 (s, 1H), 3.38 - 3.25 (m, 1H), 3.00 - 2.89 (m, 2H), 2.71 - 2.63 (d, J = 9.7 Hz, 1H), 2.34 - 2.23 (q, J = 7.1 Hz, 2H), 1.64 - 1.57 (d, J = 9.1 Hz, 1H), 1.52 - 1.38 (d, J = 9, 0 Hz, 1H) ppm. Example 39. N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -4 - ((S) - 2- (methoxymethyl) azetidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O N N N
[00340] [00340] This compound was prepared according to the procedures described in Example 38, using (S) -2- (methoxymethyl) azetidine instead of azetidine as starting material. LCMS calculated for
[00341] [00341] This compound was prepared according to the procedures described in Example 18, using 1-bromo-2,3-difluoro-4-nitrobenzene instead of 1-bromo-2,5-difluoro-4- nitrobenzene as starting material. LCMS calculated for C28H29BrF2N5O4 (M + H) +: m / z = 616.1; Found: 616.1. Step 2. N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -4- (3-cyanopyridin-4-yl) -3-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00342] [00342] A mixture of (1S, 4S) -5- (3-bromo-2-fluoro-6- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -2,5- diazabici-clo [2.2.1] tert-butyl heptane-2-carboxylate (10 mg, 0.016 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) nicotinonitrile (10 mg, 0.043 mmol), Xphos Pd G2 (1.3 mg, 1.6 µmol) and potassium phosphate, tribasic (6.7 mg, 0.032 mmol) was combined with 1,4-dioxane (1 ml) and water (0.1 ml). The reaction mixture was degassed under vacuum, again filled with nitrogen and then stirred at 80 ° C for 1 h. The reaction mixture was cooled to room temperature, the solvents were concentrated and TFA (1 ml) was added. The reaction mixture was stirred at room temperature for 10 min, then diluted with CH3CN and water and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate 60 mL / min). LCMS calculated for C 29H24F2N7O2 (M + H) +: m / z = 540.2; Found: 540.1. 1H NMR (500 MHz, DMSO-d6) δ 10.94 - 10.84 (s, 1H), 9.37 - 9.27 (d, J = 5.0 Hz, 1H), 9.20 - 9, 11 (s, 1H), 9.07 - 8.99 (br, 1H), 8.98 - 8.94 (d, J = 5.2 Hz, 1H), 8.81 - 8.72 (br, 1H), 8.44 - 8.37 (d, J = 8.6 Hz, 1H), 8.27 - 8.16 (d, J = 5.0 Hz, 1H), 7.79 - 7.75 (d, J = 5.2 Hz, 1H), 7.62 - 7.56 (td, J = 8.5, 6.9 Hz, 1H), 7.56 - 7.51 (t, J = 8 , 1 Hz, 1H), 7.12 - 7.06 (d, J = 8.5 Hz, 1H), 7.05 - 6.97 (m, 1H), 4.46 - 4.34 (m, 1H), 4.15 - 4.08 (s, 1H), 3.82 - 3.74 (s, 3H), 3.62 - 3.54 (d, J = 10.7 Hz, 1H), 3 , 49 - 3.41 (m, 1H), 3.41 - 3.33 (n, 1H), 3.17 - 3.07 (m, 1H), 1.95 - 1.88 (d, J = 10.6 Hz, 1H), 1.68 - 1.58 (m, 1H) ppm. Example 41. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4-
[00343] [00343] This compound was prepared according to the procedures described in Example 22 and 1, using (3S, 5S) -5- (hydroxymethyl) pyrrolidin-3-ylcarbamate instead of (1S, 4S) - 2 , 5-diazabicyclo [2.2.1] heptane-2-carboxylate as starting material. LCMS calculated for C28H32BrFN5O5 (M + H) +: m / z = 616.2; Found: 616.2. Step 2. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (3-cyano-pyridin-4-yl) phenyl) -2- ( 2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00344] [00344] A mixture of ((3S, 5S) -1- (5-bromo-2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate (10 mg, 0.016 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) nicotinonitrile (9.8 mg, 0.043 mmol), Xphos Pd G2 (1.3 mg, 1.6 µmol) and tribasic potassium phosphate (6.7 mg, 0.032 mmol) were combined with 1,4-dioxane (1 ml) and water (0.1 ml). The reaction mixture was degassed under vacuum, again filled with nitrogen and then stirred at 80 ° C for 1 h. The mixture was cooled to room temperature, the solvents were concentrated and TFA (1 ml) was added. The reaction mixture was stirred at room temperature for 10 min, then diluted with CH3CN and water and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate 60 mL / min). LCMS calculated for C29H27FN7O3 (M + H) +: m / z = 540.2; Found: 540.1. 1 H NMR (600 MHz, DMSO-d6) δ 10.69 - 10.61 (s, 1H), 9.32 - 9.25 (d, J = 5.0 Hz, 1H), 9.14 - 9 , 04 (s, 1H), 8.94 - 8.86 (d, J = 5.3 Hz, 1H), 8.35 - 8.28 (d, J = 8.4 Hz, 1H), 8, 22 - 8.13 (d, J = 5.0 Hz, 1H), 7.97 - 7.85 (d, J = 5.5 Hz, 2H), 7.81 - 7.75 (d, J = 5.4 Hz, 1H), 7.73 - 7.68 (d, J = 2.1 Hz, 1H), 7.60 - 7.53 (td, J = 8.4, 6.8 Hz, 1H ), 7.53 - 7.47 (dd, J = 8.4, 2.0 Hz, 1H), 7.11 - 7.05 (d, J = 8.5 Hz, 1H), 7.04 - 6.96 (t, J = 8.8 Hz, 1H), 3.89 - 3.81 (m, 1H), 3.79 - 3.76 (s, 3H), 3.76 - 3.68 ( m, 1H), 3.44 - 3.29 (m, 3H), 3.27 - 3.22 (dd, J = 11.1, 2.6 Hz, 1H), 2.43 - 2.33 ( m, 1H), 1.90 - 1.80 (m, 1H) ppm. Example 42. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2- fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H2N F O OH N N N H N CN O N
[00345] [00345] This compound (free base and TFA salt) was prepared according to the procedures described in Example 41 (and detailed below), using 3- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) isonicoti- nonitrile instead of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) nicotinitrile as a starting material. Step 1. ((3S, 5S) -1- (5-bromo-2-nitrophenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate
[00346] [00346] A solution of 4-bromo-2-fluoro-1-nitrobenzene (532 mg, 2.42 mmol) and ((3S, 5S) -5-hydroxymethyl) pyrrolidin-3-yl) carbamate (523 mg, 2 , 42 mmol) in DMSO (8 mL) was treated with triethylamine (506 µL, 3.63 mmol) and the reaction mixture was heated at 80 ° C for 2 h. After cooling to room temperature, water was added and the precipitated product was collected by filtration, washed with water and air dried. It was used in the next step, without further purification. LCMS calculated for C12H15BrN3O5 (M + H-C4H8) +: m / z = 360.0 / 362.0; found 360.0 / 362.0. Step 2. ((3S, 5S) -1- (2-amino-5-bromophenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate
[00347] [00347] A mixture of ((3S, 5S) -1- (5-bromo-2-nitrophenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate (1 g, 2.45 mmol), iron (684 mg, 12.25 mmol) and ammonium chloride (786 mg, 14.70 mmol) in THF (5 mL), water (5 mL) and methanol (5 mL) was stirred at 60 ˚C for 3 hours. After cooling to room temperature, it was filtered through a plug of Celite and diluted with DCM. The organic phase was separated, washed with saturated aqueous sodium chloride, dried over sodium sulfate and the solvents were evaporated in vacuo. The crude product obtained was used in the next step, without further purification. LCMS calculated for C16H25BrN3O3 (M + H) +: m / z = 386.1 / 388.1; Found: 386.1 / 388.1. Step 3. (((3S, 5S) -1- (5-bromo-2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-
[00348] [00348] HATU (1196 mg, 3.15 mmol) was added to a solution of ((3S, 5S) -1- (2-amino-5-bromophenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) car - bamate (810 mg, 2.097 mmol), 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxylic (the product of Example 1, step 1, 520 mg, 2.097 mmol) and DIPEA (732 µl, 4, 19 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 30 minutes, then water was added and the precipitated product was collected by filtration, washed with water and dried in air. The solid was used in the next step, without further purification. LCMS calculated for C28H32BrFN5O5 (M + H) +: m / z = 616.2 / 618.2; Found: 616.2 / 618.2. Step 4. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyano-pyridin-3-yl) phenyl) -2- ( 2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00349] [00349] A mixture of ((3S, 5S) -1- (5-bromo-2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) tert-butyl carbamate (10 mg, 0.016 mmol), 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isonicotinonitrile (9, 8 mg, 0.043 mmol), Xphos Pd G2 (1.3 mg, 1.6 µmol) and potassium phosphate, tribasic (6.7 mg, 0.032 mmol) was combined with 1,4-dioxane (1 mL) and water (0.1 mL) and the reaction flask was evacuated, filled back with nitrogen, then stirred at 80 ° C for 1 hour. The reaction mixture was cooled to room temperature, the solvents were evaporated in vacuo and TFA (1 ml) was added. The reaction mixture was stirred at room temperature for 10 min, then diluted with CH3CN and water and purified with LCMS prep. LCMS calculated for C29H27FN7O3 (M + H) +: m / z = 540.2; Found: 540.1. LCMS Prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% NH4OH, at a flow rate of 60 mL / min). Free base: 1H NMR (500 MHz, DMSO-d6) δ 9.33 - 9.25 (d, J = 5.0 Hz, 1H), 8.98 - 8.93 (s, 1H), 8.84 - 8.78 (d, J = 5.0 Hz, 1H), 8.46 - 8.39 (d, J = 8.4 Hz, 1H), 8.22 - 8.18 (d, J = 5 , 0 Hz, 1H), 8.00 - 7.92 (dd, J = 5.1, 0.7 Hz, 1H), 7.67 - 7.64 (m, 1H), 7.59 - 7, 52 (td, J = 8.4, 6.8 Hz, 1H), 7.48 - 7.43 (dd, J = 8.3, 2.1 Hz, 1H), 7.11 - 7.04 ( d, J = 8.5 Hz, 1H), 7.03 - 6.90 (t, J = 8.8 Hz, 1H), 3.85 - 3.73 (s, 3H), 3.68 - 3 , 56 (m, 1H), 3.39 - 3.29 (m, 3H), 3.28 - 3.22 (d, J = 4.8 Hz, 1H), 3.06 - 2.97 (d , J = 5.4 Hz, 1H), 2.31 - 2.18 (dt, J = 12.6, 7.5 Hz, 1H), 1.40 - 1.29 (dt, J = 12.7 , 6.2 Hz, 1H) ppm. LCMS Prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 mL / min). TFA salt: 1H NMR (500 MHz, DMSO-d6) δ10.66 - 10.59 (s, 1H), 9.31 - 9.24 (d, J = 5.0 Hz, 1H), 9.03 - 8.94 (d, J = 0.8 Hz, 1H), 8.88 - 8.78 (d, J = 5.0 Hz, 1H), 8.34 - 8.24 (d, J = 8 , 4 Hz, 1H), 8.24 - 8.17 (d, J = 5.0 Hz, 1H), 8.04 - 7.95 (dd, J = 5.1, 0.8 Hz, 1H) , 7.92 - 7.82 (br, J = 5.5 Hz, 2H), 7.73 - 7.65 (d, J = 2.0 Hz, 1H), 7.61 - 7.54 (td , J = 8.5, 6.9 Hz, 1H), 7.50 - 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 7.11 - 7.05 (d, J = 8.5 Hz, 1H), 7.05 - 6.98 (t, J = 8.8 Hz, 1H), 3.89 - 3.82 (m, 1H), 3.81 - 3.77 ( s, 3H), 3.76 - 3.69 (m, 1H), 3.42 - 3.21 (m, 4H), 2.43 - 2.31 (m, 1H), 1.90 - 1, 77 (dt, J = 13.2, 5.3 Hz, 1H) ppm. Example 43. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (2-methylpyridin-3-yl) phenyl) -2- (2- fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H2N F O OH N N N H N O N
[00350] [00350] This compound was prepared according to the procedures described in Example 41, using (2-methylpyridin-3-yl) boronic acid instead of 4- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) nicotinonitrile as starting material. LCMS calculated for C29H30FN6O3 (M + H) +: m / z = 529.2; Found: 529.2. 1H NMR (500 MHz, DMSO-d6) δ 10.69 - 10.55 (s, 1H), 9.33 - 9.17 (d, J = 5.0 Hz, 1H), 8.72 - 8, 62 (dd, J = 5.4, 1.7 Hz, 1H), 8.31 - 8.20 (d, J = 8.3 Hz, 1H), 8.23 - 8.15 (d, J = 5.0 Hz, 1H), 8.14 - 8.05 (d, J = 7.6 Hz, 1H), 8.05 - 7.86 (br, J = 5.4 Hz, 2H), 7, 75 - 7.64 (dd, J = 7.7, 5.4 Hz, 1H), 7.62 - 7.52 (td, J = 8.4, 6.8 Hz, 1H), 7.47 - 7.41 (d, J = 2.0 Hz, 1H), 7.31 - 7.23 (dd, J = 8.3, 1.9 Hz, 1H), 7.11 - 7.05 (d, J = 8.5 Hz, 1H), 7.05 - 6.95 (t, J = 8.8 Hz, 1H), 3.87 - 3.76 (m, 4H), 3.76 - 3.66 (m, 1H), 3.42 - 3.20 (m, 4H), 2.65 - 2.57 (s, 3H), 2.43 - 2.32 (dt, J = 13.2, 7, 9 Hz, 1H), 1.91 - 1.65 (dt, J = 13.3, 5.5 Hz, 1H) ppm. Example 44. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (3-methoxypyridin-4-yl) phenyl) -2- (2- fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H2N F O OH N N N H
[00351] [00351] This compound was prepared according to the procedures described in Example 41, using (3-methoxypyridin-4-yl) boronic acid instead of 4- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) nicotinonitrile as starting material. LCMS calculated for C29H30FN6O4 (M + H) +: m / z = 545.2; Found: 545.3. 1H NMR (500 MHz, DMSO-d6) δ 10.66 - 10.59 (s, 1H), 9.30 - 9.25 (d, J = 5.0 Hz, 1H), 8.55 - 8, 48 (s, 1H), 8.39 - 8.33 (d, J = 5.0 Hz, 1H), 8.28 - 8.21 (d, J = 8.4 Hz, 1H), 8.21 - 8.16 (d, J = 5.0 Hz, 1H), 7.92 - 7.81 (br, 2H), 7.63 - 7.59 (m, 1H), 7.59 - 7.55 (m, 1H), 7.55 - 7.51 (m, 1H), 7.48 - 7.44 (dd, J = 8.4, 1.9 Hz, 1H), 7.14 - 7.11 (s, 1H), 7.09 - 7.05 (d, J = 8.5 Hz, 1H), 7.01 - 6.96 (d, J = 8.8 Hz, 1H), 3.99 - 3.90 (s, 3H), 3.83 - 3.73 (m, 4H), 3.73 - 3.67 (m, 1H), 3.40 - 3.19
[00352] [00352] This compound was prepared according to the procedures described in Example 41, using 3-fluoro-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzonitrile instead of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) nicotinonitrile as a starting material. LCMS calculated for C30H27F2N6O3 (M + H) +: m / z = 557.2; Found: 557.1. Example 46. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (3-cyanopyridin-2-yl) phenyl) -2- (2- fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H2N F O OH N N N H N CN O
[00353] [00353] 1,4-Dioxane (10 ml) was added to a mixture of 4,4,5,5,4 ', 4', 5 ', 5'-octamethyl- [2,2'] bi [[1 , 3.2] dioxaborolanil] (412 mg, 1.6 mmol), potassium acetate (159 mg, 1.6 mmol), complexed [1,1'-bis (diphenylphosphine) ferrocene] dichloropalladium (II) with dichloromethane (1: 1) (66.2 mg, 0.081 mmol) and ((3S, 5S) -1- (5-bromo-2- (2- (2-fluoro-6-methoxy-phenyl) pyrimidine-4 -carboxamido) phenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) tert-butyl carbamate (500 mg, 0.811 mmol). The reaction mixture was degassed under vacuum, again filled with nitrogen and stirred at 100 ° C overnight. The reaction mixture was then cooled to room temperature, filtered through a plug of Celite and the solvent concentrated in vacuo. The crude material was purified by Biotage Isolera to give a yellow solid (300 mg, 56%). LCMS calculated for C34H44BFN5O7 (M + H) +: m / z = 664.3; Found: 664.3. Step 2. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (3-cyano-pyridin-2-yl) phenyl) -2- ( 2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00354] [00354] A mixture of ((3S, 5S) -1- (2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) -5- (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) tert-butyl carbamate (10 mg, 0.015 mmol), 2-bromonicotinonitrile (5.52 mg, 0.030 mmol), Xphos Pd G2 (1.3 mg, 1.6 µmol) and potassium phosphate, tribasic (6.7 mg, 0.032 mmol) was combined with 1,4-dioxane (1 ml) and water ( 0.1 ml). The reaction mixture was degassed under vacuum, again filled with nitrogen and then stirred at 80 ° C for 1 h. The reaction mixture was cooled to room temperature, the solvents were concentrated and TFA (1 ml) was added. The reaction mixture was stirred at room temperature for 10 min, then diluted with CH3CN and water and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at flow rate of 60 mL / min). LCMS calculated for C29H27FN7O3 (M + H) +: m / z = 540.2; Found: 540.1. 1 H NMR (500 MHz, DMSO-d6) δ 10.71 - 10.58 (s, 1H), 9.35 - 9.21 (d, J = 5.0 Hz, 1H), 8.97 - 8 , 91 (dd, J = 4.8, 1.7 Hz, 1H), 8.49 - 8.40 (dd, J = 7.9, 1.7 Hz, 1H), 8.39 - 8.30 (d, J = 8.4 Hz, 1H), 8.26 - 8.16 (d, J = 5.0 Hz, 1H), 7.96 - 7.82 (m, 3H), 7.75 - 7.70 (dd, J = 8.4, 2.0 Hz, 1H), 7.66 - 7.60 (dd, J = 7.9, 4.9 Hz, 1H), 7.60 - 7, 52 (td, J = 8.4, 6.8 Hz, 1H), 7.11 - 7.05 (d, J = 8.5 Hz, 1H), 7.04 - 6.97 (t, J = 8.8 Hz, 1H), 3.87 - 3.76 (m, 4H), 3.75 - 3.69 (m, 1H), 3.46 - 3.15 (m, 4H), 2.44 - 2.33 (m, 1H), 1.91 - 1.76 (m, 1H) ppm. Example 47. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyano-1-methyl-1H-pyrazol-5-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H2N F O OH N N N H N The N N NC
[00355] [00355] This compound was prepared according to the procedures described in Example 46, using 5-bromo-1-methyl-1H-pyrazol-4-carbonitrile instead of 2-bromonicotinonitrile as the starting material. LCMS calculated for C28H28FN8O3 (M + H) +: m / z = 543.2; Found: 543.2. Example 48. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4-isopropylenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4 -carboxamide
[00356] [00356] This compound was prepared according to the procedures described in Example 41, using 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl) -1,3,2- dioxaborolane instead of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaboro-lan-2-yl) nicotinonitrile as starting material. LCMS calculated for C31H37FN5O5 (M + H) +: m / z = 578.3; Found: 578.3. Step 2. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4-isopropylphenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine -4-carboxamide
[00357] [00357] Palladium on carbon (10% by weight, 18.42 mg, 0.017 mmol) was added to a solution of ((3S, 5S) -1- (2- (2- (2-fluoro-6-me- toxifenyl) pyrimidine-4-carboxamido) -5- (prop-1-en-2-yl) phenyl) -5 - (hydroxymethyl) pyrrolidin-3-yl) carbamate (100 mg, 0.173 mmol) in methanol ( 6 ml). The reaction mixture was stirred at room temperature for 5 h under an atmosphere of hydrogen. The catalyst was removed by filtration, the solvent was concentrated and TFA (1 ml) was added. The reaction mixture was stirred at room temperature for 10 min, then diluted with CH3CN and water and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA,
[00358] [00358] This compound was prepared according to the procedures described in Example 41, using (3S, 5S) -5- (hydroxymethyl) pyrrolidin-3-ol instead of (3S, 5S) -5- (hydroxymethyl) pyrrolidin-3-ylcarbamate as a starting material. LCMS calculated for C29H26FN6O4 (M + H) +: m / z = 541.2; Found: 541.2. Intermediate 1. 3- (3-Fluoro-4-nitrophenyl) isonicotinonitrile
[00359] [00359] A mixture of 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isonicotinonitrile (1 g, 4.34 mmol), 4-bromo-2-fluoro- 1-nitrobenzene (637 mg, 2.90 mmol), XPhos Pd G2 (228 mg, 0.29 mmol) and potassium phosphate, tribasic (1.23 g, 5.79 mmol) was combined with dioxane (88 mL) and water (8.8 ml). The reaction mixture was degassed under vacuum, again filled with nitrogen and then stirred at 80 ˚C for 16 h. After cooling to room temperature, the mixture was filtered through Celite and washed with ethyl acetate, followed by concentration under vacuum. The residue was then purified by Biotage Isolera to give 3- (3-fluoro-4-nitrophenyl) isonicotinonitrile as a brownish-yellow solid (550 mg, 78% yield). LCMS calculated for C12H7FN3O2 (M + H) +: m / z = 244.0; found 244.0. Example 50. N- (4- (4-Cyanopyridin-3-yl) -2 - ((2S, 5R) -2- (hydroxymethyl) -5-methylpiperazin-1-yl) phenyl) -2- (2-fluoro -6-methoxyphenyl) pyrimidine-4-carboxamide
[00360] [00360] A solution of 3- (3-fluoro-4-nitrophenyl) isonicotinonitrile (Intermediate 1, 52.8 mg, 0.22 mmol) and (2R, 5S) - 5- (hydroxymethyl) -2-methyl - (2R, 5S) -tert-butyl perazine-1-carboxylate (50 mg, 0.22 mmol; prepared by an adaptation of the procedure described in: Chessari, G. et al. J. Med. Chem. 2015 , 58, 6574–6588) in DMSO (724 µL) was treated with triethylamine (45.4 µL, 0.33 mmol) and the reaction mixture was heated at 100 ° C for 16 h. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was used for the next reaction without purification. LCMS calculated for C23H28N5O5 (M + H) +: m / z = 454.2; found 454.2. Step 2. (2R, 5S) -tert-butyl 4- (2-amino-5- (4-cyanopyridin-3-yl) phenyl) -5- (hydroxymethyl) -2-methyl-piperazine-1-carboxylate Boc Me N OH
[00361] [00361] A mixture of 4- (5- (4-cyanopyridin-3-yl) -2-nitrophenyl) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate of (2R, 5S) -tert- butyl (98 mg, 0.22 mmol), iron (60 mg, 1.08 mmol) and ammonium chloride (69 mg, 1.30 mmol) in THF (2 mL), water (2 mL) and methanol (2 ml) was stirred at 60 ° C for 1 h. After cooling to room temperature, the reaction mixture was filtered through a plug of Celite and diluted with CH2Cl2. The organic phase was separated, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was used in the next step, without further purification. LCMS calculated for C23H30N5O3 (M + H) +: m / z = 424.2; Found: 424.2. Step 3. N- (4- (4-cyanopyridin-3-yl) -2 - ((2S, 5R) -2- (hydroxymethyl) -5-methylpiperazin-1-yl) phenyl) -2- (2 -fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00362] [00362] HATU (124 mg, 0.326 mmol) was added to a solution of (2R, 5S) - 4- (2-amino-5- (4-cyanopyridin-3-yl) phenyl) -5- (hydroxymethyl) - 2-methylpiperazine-1-carboxylate (92 mg, 0.22 mmol), 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxylic acid (54 mg, 0.22 mmol) and DIPEA (76 µL, 0 , 43 mmol) in DMF (510 µL). The reaction mixture was stirred at 60 ˚C for 30 min and then treated with water. The precipitated product was collected by filtration, washed with water and air dried. It was then redissolved in TFA and the solution was stirred at 60 ˚C for 10 min. After cooling, the solvent was concentrated in vacuo and the crude residue was dissolved in THF (1 ml), MeOH (1 ml) and aq. (1 mL). The reaction mixture was stirred at 60 ˚C for 30 min in a sealed container. The mixture was cooled, the solvent concentrated in vacuo and the resulting residue was diluted with acetonitrile and purified with prep-LCMS (column XBridge C18, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 ml / min) C 30H29FN7O3 (M + H) +: m / z = 554.2; found 554.3. Example 51. N- (4- (4-Cyanopyridin-3-yl) -2 - ((2S, 5S) -2- (hydroxymethyl) -5-methylpiperazin-1-yl) phenyl) -2- (2-fluoro -6-methoxyphenyl) pyrimidine-4-carboxamide
[00363] [00363] This compound was prepared according to the procedures described in Example 50, using (2S, 5S) -tert-butyl 5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate instead of (2R, 5S ) - 5- (hydroxymethyl) - 2-methylpiperazine-1-carboxylate of (2R, 5S) -tert-butyl as starting material. LCMS calculated for C30H29FN7O3 (M + H) +: m / z = 554.2; Found: 554.1. Example 52. (S) -N- (4- (4-Cyanopyridin-3-yl) -2- (6- (hydroxymethyl) -4,7-diazaspiro [2.5] octan-7-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H N F O OH N N N H N O N NC
[00364] [00364] This compound was prepared according to the procedures described in Example 50, using (S) -tert-butyl 6- (hydroxymethyl) -4,7-diazaspiro [2.5] octane-4-carboxylate instead of 5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (2R, 5S) -tert-butyl as starting material. LCMS calculated for C31H29FN7O3 (M + H) +: m / z = 566.2; Found: 566.2. Example 53. N- (2 - ((2S, 4S) -4-Amino-2- (1-hydroxycyclopropyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2 - (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H 2N F OMe OH N N N H N O N
[00365] [00365] A solution of 4- (tert-butoxycarbonylamino) pyrrolidine-2-carboxylate (2S, $ s) -methyl (250 mg, 1.02 mmol) and DIPEA (536 µL, 3.07 mmol) in CH2Cl2 ( 6.4 mL) at 0 ° C was treated with benzyl chloroformate (175 µL, 1.23 mmol) and the reaction mixture was allowed to stir for 1 h. The reaction mixture was treated with sat. NaHCO3. aq. and diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was used for the next reaction without purification. LCMS calculated for C19H27N2O6 (M + H) +: m / z = 379.2; found 379.1. Step 2. 4- (tert-butoxycarbonylamino) -2- (1-hydroxycyclopropyl) pyrrolidine-1-carboxylate (2S, 4S) -Benzyl BocHN OH
[00366] [00366] A solution of (2S, 4S) -1-benzyl 2-methyl 4- (tert-butoxycarbonylamino) pyrrolidine-1,2-dicarboxylate (100 mg, 0.26 mmol) and titanium isopropoxide ( 16 µL, 0.053 mmol) in THF (755 µL) at 0 ° C was treated with ethylmagnesium bromide (1 M in THF, 1.06 mL, 1.06 mmol) and the reaction mixture was stirred at room temperature for 1 H. The reaction mixture was then treated with sat. NH4Cl. aq. and diluted with EtOAc. The separated organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was used in the next reaction without purification. LCMS calculated for C20H29N2O5 (M + H) +: m / z = 377.2; found 377.1. Step 3. tert-butyl BocHN (3S, 5S) -5- (1-hydroxycyclopropyl) pyrrolidin-3-ylcarbamate OH N H
[00367] [00367] A Parr reaction vessel was loaded with 4- (tert-butoxycarbonylamino) -2- (1-hydroxycyclopropyl) pyrrolidine-1-carboxylate (2S, 4S) -Benzyl (99 mg, 0.26 mmol), Pd / C (10% wet, Degussa type, 28 mg) followed by MeOH (10.5 ml). The reaction mixture was evacuated and filled 3x with nitrogen gas, followed by another evacuation cycle and then pressurized with hydrogen gas at 25 psi. The reaction vessel was stirred overnight. The reaction mixture was then filtered over Celite and the solvent concentrated in vacuo. The crude product was used for the next reaction without purification. LCMS calculated for C12H23N2O3 (M + H) +: m / z = 243.2; found 243.3. Step 4. -Butyl (3S, 5S) -1- (5- (4-cyanopyridin-3-yl) -2-nitrophenyl) -5- (1-hydroxycyclopropyl) pyrrolidine-3-ylcarbamate OH
[00368] [00368] A solution of 3- (3-fluoro-4-nitrophenyl) isonicotinonitrile (Intermediate 1, 64 mg, 0.26 mmol) and (3S, 5S) -5- (1-hydroxycyclopropyl) pyrrolidin- Tert-butyl 3-ylcarbamate (64 mg, 0.26 mmol) in DMSO (880 µL) was treated with triethylamine (55 µL, 0.40 mmol) and the reaction mixture was heated at 100 ˚C for 16 h. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered and the solvent concentrated in vacuo. The crude product was used for the next reaction without purification. LCMS calculated for C24H28N5O5 (M + H) +: m / z = 466.2; found 466.3. Step 5. tert-Butyl tert-butyl (3S, 5S) -1- (2-amino-5- (4-cyanopyridin-3-yl) phenyl) -5- (1-hydroxycyclopropyl) pyrrolidine-3-ylcarbamate OH
[00369] [00369] A mixture of tert-butyl (3S, 5S) -5- (1-hydroxycyclopropyl) pyrrolidin-3-ylcarbamate (123 mg, 0.26 mmol), iron (74 mg, 1.32 mmol) and chloride of ammonium (85 mg, 1.58 mmol) in THF (2 mL), water (2 mL) and methanol (2 mL) was stirred at 60 ° C for 1 h. After cooling to room temperature, the mixture was filtered through a plug of Celite and diluted with CH2Cl2. The organic phase was separated, washed with brine, dried over MgSO4, filtered and the solvents concentrated in vacuo. The crude product was used in the next step, without further purification. LCMS calculated for C24H30N5O3 (M + H) +: m / z = 436.1; Found: 436.2. Step 6. N- (2 - ((2S, 4S) -4-amino-2- (1-hydroxycyclopropyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- ( 2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00370] [00370] HATU (151 mg, 0.40 mmol) was added to a solution of (3S, 5S) -1- (2-amino-5- (4-cyanopyridin-3-yl) phenyl) -5- (1 tert-butyl-hydroxycyclopropyl) pyrrolidin-3-ylcarbamate (115 mg, 0.26 mmol), 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxylic acid (65 mg, 0.26 mmol) and DI-PEA (92 µL, 0.53 mmol) in DMF (620 µL). The reaction mixture was stirred at 60 ˚C for 30 min and then treated with water. The precipitated product was collected by filtration, washed with water and air dried. It was redissolved in TFA and the solution was stirred at 60 ˚C for 10 min. After cooling, the solvent was concentrated and the crude product was then diluted with CH3CN and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 ml / min). LCMS calculated for C31H29FN7O3 (M + H) +: m / z = 566.2; Found: 566.3. Example 54. N- (2 - ((2S, 4S) -4-Amino-2- (2-hydroxypropan-2-yl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H2N F OMe OH
[00371] [00371] A solution of 4- (tert-butoxycarbonylamino) pyrrolidine-2-carboxylate (2S, 4S) -methyl (100 mg, 0.41 mmol) in THF (4.1 mL) at 0 ˚C was treated with methylmagnesium bromide (3M in THF, 546 µL, 1.64 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was treated with sat. NH4Cl. aq. and diluted with EtOAc. The separated organic phase, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was used for the next reaction without purification. LCMS calculated for C12H25N2O3 (M + H) +: m / z = 245.2; found 245.2. Step 2. tert- (3S, 5S) -1- (5- (4-cyanopyridin-3-yl) -2-nitrophenyl) -5- (2-hydroxypro-pan-2-yl) pyrrolidin-3-ylcarbamate butyl BocHN OH
[00372] [00372] A solution of 3- (3-fluoro-4-nitrophenyl) isonicotinonitrile (Intermediate 1, 50 mg, 0.20 mmol) and (3S, 5S) -5- (2-hydroxypropan-2-yl) tert-butyl pyrrolidin-3-ylcarbamate (50 mg, 0.20 mmol) in DMSO (680 µL) was treated with triethylamine (43 µL, 0.31 mmol) and the reaction mixture was heated to 100˚C for 16 h. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was used for the next reaction without purification. LCMS calculated for C24H30N5O5 (M + H) +: m / z = 468.2; found 468.1.
[00373] [00373] A mixture of (3S, 5S) -1- (5- (4-cyanopyridin-3-yl) -2-nitrophenyl) -5- (2-hydroxypropan-2-yl) pyrrolidin-3-ylcarbamate tert-butyl (96 mg, 0.20 mmol), iron (57 mg, 1.03 mmol) and ammonium chloride (66 mg, 1.23 mmol) in THF (2 mL), water (2 mL) and methanol (2 ml) was stirred at 60 ° C for 1 h. After cooling to room temperature, the mixture was filtered through a plug of Celite and diluted with CH 2Cl2. The organic phase was separated, washed with brine, dried over MgSO4, filtered and the solvents were concentrated in vacuo. The crude product was used in the next step, without further purification. LCMS calculated for C24H32N5O3 (M + H) +: m / z = 438.2; Found: 438.1. Step 4. N- (2 - ((2S, 4S) -4-Amino-2- (2-hydroxypropan-2-yl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00374] [00374] HATU (117 mg, 0.31 mmol) was added to a solution of tert-butyl (3S, 5S) -1- (2-amino-5- (4-cyanopyridin-3-yl) phenyl) -5 - (2-hydroxypro-pano-2-yl) pyrrolidin-3-ylcarbamate (90 mg, 0.21 mmol), 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxylic acid (51 mg, 0, 21 mmol) and DIPEA (72 µL, 0.41 mmol) in DMF (480 µL). The reaction mixture was stirred at 60 ˚C for 30 min and then treated with water. The precipitated product was collected by filtration, washed with water and air dried. The solid was dissolved in TFA and the resulting solution was stirred at 60 ˚C for 10 min. The solution was cooled, concentrated and the crude product was diluted with CH3CN and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 mL / min ). LCMS calculated for C31H31FN7O3 (M + H) +: m / z = 568.2; Found: 568.3 Example 55. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl-d2) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl ) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H 2N F OMe OH N N N H D D N O N
[00375] [00375] A solution of 4- (tert-butoxycarbonylamino) pyrrolidine-2-carboxylate (2S, 4S) -methyl (100 mg, 0.41 mmol) in THF (4.1 mL) at 0 ° C was treated with deuteride aluminum and lithium (17 mg, 0.41 mmol) and the reaction mixture was stirred for 1 h, then warmed to room temperature and stirred for another 30 min. The reaction mixture was diluted with Et2O, water and 15% aq. The separated organic phase was dried over MgSO4, filtered and the solvent concentrated in vacuo. The crude product was used for the next reaction without purification. LCMS calculated for C10H19D2N2O3 (M + H) +: m / z = 219.2; found 219.1. Step 2. tert-Butyl (3S, 5S) -1- (5- (4-cyanopyridin-3-yl) -2-nitrophenyl) -5- (hydroxymethyl-d2) pyrrolidin-3-ylcarbamate
[00376] [00376] A solution of 3- (3-fluoro-4-nitrophenyl) isonicotinonitrile (Intermediate 1, 99 mg, 0.41 mmol) and (3S, 5S) -5- (hydroxymethyl-d2) pyrrolidin- 3- tert-butyl ilcarbamate (89 mg, 0.41 mmol) in DMSO (1.36 mL) was treated with triethylamine (85 µL, 0.61 mmol) and the reaction mixture was heated at 100 ° C for 16 hours. After cooling to room temperature, the reaction mixture was diluted CH2Cl2, washed with brine, dried over MgSO4, filtered and the solvent was concentrated. The crude product was used for the next reaction without purification. LCMS calculated for C22H24D2N5O5 (M + H) +: m / z = 442.2; found 442.1. Step 3. tert -butyl (3S, 5S) -1- (2-amino-5- (4-cyanopyridin-3-yl) phenyl) -5- (hydroxybius-deuteromethyl) pyrrolidin-3-ylcarbamate OH
[00377] [00377] A mixture of tert-butyl (3S, 5S) -1- (5- (4-cyanopyridin-3-yl) -2-nitrophenyl) -5- (hydroxymethyl-d2) pyrrolidin-3-ylcarbamate (180 mg, 2.04 mmol), iron (114 mg, 1.03 mmol) and ammonium chloride (131 mg, 2.45 mmol) in THF (2 mL), water (2 mL) and methanol (2 mL) ) was stirred at 60 ˚C for 1 h. After cooling to room temperature, the mixture was filtered through a plug of Celite and diluted with CH2Cl2. The organic phase was separated, washed with brine, dried over MgSO4, filtered and the solvents concentrated. The crude product was used in the next step, without further purification. LCMS calculated for
[00378] [00378] HATU (233 mg, 0.61 mmol) was added to a solution of (3S, 5S) -1- (2-amino-5- (4-cyanopyridin-3-yl) phenyl) -5- (hydroxymethyl -d2) pyrrolidin-3-ylcarbamate (168 mg, 0.41 mmol), 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxylic acid (101 mg, 0.41 mmol) and DIPEA (143 µL, 0.82 mmol) in DMF (956 µL). The reaction mixture was stirred at 60 ˚C for 30 min and then treated with water. The precipitated product was collected by filtration, washed with water and air dried. The solid was then dissolved in TFA and the solution was stirred at 60 ° C for 10 min. After cooling, the solution was concentrated and the crude residue was dissolved in THF (1 ml), MeOH (1 ml) and aq. (1 mL). The mixture was stirred at 60 ˚C for 30 min in a sealed container. The mixture was cooled, concentrated in vacuo and the crude product was diluted with CH3CN and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 mL / min). LCMS calculated for C29H25D2FN7O3 (M + H) +: m / z = 542.2; Found: 542.4. 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.28 (d, J = 5.0 Hz, 1H), 8.97 (s, 1H), 8.82 (d , J = 5.0 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 5.0 Hz, 1H), 7.99 (d, J = 5.0 Hz, 1H), 7.96 - 7.84 (m, 3H), 7.67 (s, 1H), 7.56 (td, J = 8.4, 6.8 Hz, 1H) , 7.47 (dd, J = 8.4, 2.0 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 7.00 (t, J = 8.8 Hz, 1H), 4.96 (s, 1H), 3.83 (dd, J = 8.6, 5.3 Hz, 1H), 3.78 (s, 3H), 3.74 - 3.65 (m , 1H), 3.38 - 3.35 (m, 1H), 3.32 -3.29 (m, 1H), 2.38 (dt, J = 13.2, 7.8 Hz, 1H), 1.84 (dt, J = 13.3, 5.4 Hz, 1H) ppm. Example 56. N- (4- (4-Cyanopyridin-3-yl) -2 - ((1S, 3R, 4S) -3- (hydroxymethyl) -2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H
[00379] [00379] This compound was prepared according to the procedures described in Example 50, using 6- (hydroxymethyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (1S, 4S, 6R ) -tert-butyl (prepared by adapting the procedure described in: Balog, A. et al. Bioorg. Med. Chem. Lett. 2004, 14, 6107–6111) instead of (2R, 5S) -tert-butyil 5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate as starting material. LCMS calculated for C30H27FN7O3 (M + H) +: m / z = 552.2; Found: 552.2. Example 57. N- (4- (4-Cyanopyridin-3-yl) -2 - ((1S, 4S) -1- (hydroxymethyl) - 2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H
[00380] [00380] This compound was prepared according to the procedures described in Example 50, using 4- (hydroxymethyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (1S, 4S) - tert-butyl (prepared by adapting the procedure described in: Ivon, Y. et al. Synthesis 2015, 47, 1123–1130) instead of 5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (2R, 3S ) -tert-butyl as starting material. LCMS calculated for C30H27FN7O3 (M + H) +: m / z = 552.2; Found: 552.3.
[00381] [00381] A solution of (2S, 4R) - 4-hydroxy-2-methylpiperidine-1-carboxylate (2S, 4R) -tert-butyl (75 mg, 0.35 mmol), phthalimide (62 mg, 0.43 mmoL), and triphenylphosphine (111 mg, 0.43 mmol) in THF (1.7 mL) was treated with DIAD (83 µL, 0.43 mmol) and the mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with MeOH and EtOAc, washed with brine, dried over MgSO4, filtered and the solvent was concentrated. The crude product was then treated with HCl (4 M in dioxane, 1 ml) and stirred for 1 h at room temperature. The solvent was concentrated in vacuo and the crude product was used in the next reaction without purification. LCMS calculated for C14H17N2O2 (M + H) +: m / z = 245.1; found 245.1. Step 2. 3- (3 - ((2S, 4S) -4- (1,3-Dioxoisoindolin-2-yl) -2-methylpiperidin-1-yl) - 4-nitrophenyl) isonicotinonitrile
[00382] [00382] A solution of 3- (3-fluoro-4-nitrophenyl) isonicotinonitrile (Intermediate 1, 85 mg, 0.35 mmol) and 2 - ((2S, 4S) -2-methylpiperidin-4-yl) isoindoline-1,3-dione (85 mg, 0.35 mmol) in DMSO (1.2 mL) was treated with triethylamine (73 µL, 0.52 mmol) and the reaction mixture was heated to 100 ˚C for 16 h. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered and the solvent concentrated in vacuo. The crude product was used for the next reaction without purification. LCMS calculated for C26H22N5O4 (M + H) +: m / z = 468.2; found 468.1. Step 3. 3- (4-Amino-3 - ((2S, 4S) -4- (1,3-dioxoisoindolin-2-yl) -2-methylpipe-ridin-1-yl) phenyl) isonicotinonitrile
[00383] [00383] A mixture of 3- (3 - ((2S, 4S) -4- (1,3-dioxoisoindolin-2-yl) -2-methylpiperidin-1-yl) -4-nitrophenyl) isonicotinonitrile (163 mg, 0.35 mmol), iron (97 mg, 1.70 mmol) and ammonium chloride (112 mg, 2.10 mmol) in THF (2 mL), water (2 mL) and methanol (2 mL) were stirred at 60 ° C for 1 h. After cooling to room temperature, the mixture was filtered through a plug of Celite and diluted with CH2Cl2. The organic phase was separated, washed with brine, dried over MgSO 4, filtered and the solvents were concentrated. The crude product was used in the next step, without further purification. LCMS calculated for C26H24N5O2 (M + H) +: m / z = 438.2; Found: 438.1. Step 4. N- (2 - ((2S, 4S) -4-Amino-2- (methylpiperidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro- 6-methoxyphenyl) pyrimidine-4-carboxamide
[00384] [00384] HATU (99 mg, 0.26 mmol) was added to a solution of 3- (4-amino-3 - ((2S, 4S) -4- (1,3-dioxoisoindolin-2-yl) -2 -methylpiperidine-1-yl) phenyl) isonicotinonitrile (76 mg, 0.17 mmol), 2- (2-fluoro-6-methoxy-phenyl) pyrimidine-4-carboxylic acid (43 mg, 0.17 mmol) and DIPEA (61 µL, 0.35 mmol) in DMF (400 µL). The reaction mixture was stirred at 60 ˚C for 30 min and then treated with water. The precipitated product was collected by filtration, washed with water and air dried. The solid was then dissolved in EtOH (2 ml) and treated with hydrazine hydrate (aq. 50–60%, 1 ml). The solution was stirred at 60 ˚C for 16 h, cooled and concentrated. The residue was then diluted with acetonitrile and purified with prep LCMS (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 ml / min). LCMS calculated for C30H29FN7O2 (M + H) +: m / z = 538.2; Found: 538.4. Example 59. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -6- (2- fluoro-6-methoxyphenyl) picolinamide H2N F OMe OH N N H N O N
[00385] [00385] This compound was prepared according to the procedures described in Example 50, Step 2, using tert-butyl (3S, 5S) -5- (hydroxymethyl) pyrrolidin-3-ylcarbamate instead of (2R , 5S) - tert-butyl 5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate as starting material. LCMS calculated for C22H28N5O3 (M + H) +: m / z = 410.2; Found: 410.1. Step 2. tert-butyl Boc (3S, 5S) -1- (2- (6-chloropicolinamido) -5- (4-cyanopyridin-3-yl) phenyl) - 5- (hydroxymethyl) pyrrolidine-3-ylcarbamate Boc
[00386] [00386] HATU (320 mg, 0.843 mmol) was added to a solution of ((3S, 5S) -1- (2-amino-5- (4-cyanopyridin-3-yl) phenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate (230 mg, 0.562 mmol), 6-chloropicolinic acid (88 mg, 0.562 mmol) and DIPEA (0.196 ml, 1.113 mmol) in DMF (1 ml). After stirring at room temperature for 30 min, water (3 ml) was added. The desired product was collected by filtration, washed with water and dried overnight. LCMS calculated for C28H30ClN6O4 (M + H) +: m / z = 549.2; Found: 549.2. Step 3. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyano-nopiridin-3-yl) phenyl) -6- ( 2-fluoro-6-methoxyphenyl) picolinamide
[00387] [00387] A mixture of (3S, 5S) -1- (2- (6-chloropicolinamido) -5- (4-cyano-nopiridin-3-yl) phenyl) -5- (hydroxymethyl) pyrrolidin-3-ylcarbamate tert-butyl (20 mg, 0.036 mmol), boronic acid (2-fluoro-6-methoxyphenyl) (6.20 mg, 0.036 mmol), potassium phosphate, tribasic (15.49 mg, 0.073 mmol), XPhos Pd G2 (3.03 mg, 3.65 µmol) in p-dioxane (1 ml) and water (0.2 ml) was stirred at 70 ˚C for 2 h. The mixture was concentrated in vacuo and dissolved in DCM (1 ml) and TFA (1 ml). The resulting mixture was stirred at room temperature for 15 min. The solvent was concentrated in vacuo and the residue diluted with acetonitrile and purified with prep-LCMS (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 mL / min) LCMS calculated for C30H28FN6O3 (M + H) +: m / z = 539.2; found: 539.1. Example 60. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -5-cyano-6 - (2-fluoro-6-methoxyphenyl) picoline-mide H2N F OMe N OH N N H N O N NC
[00388] [00388] This compound was prepared according to the procedures described in Example 59, using 6-chloro-5-cyanopicolinic acid instead of 6-chloropicolinic acid as the starting material. LCMS calculated for C31H27FN7O3 (M + H) +: m / z = 564.2; Found: 564.2. Example 61. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -6- (2- fluoro-6-methoxyphenyl) -5-methoxypolycolamide
[00389] [00389] This compound was prepared according to the procedures described in Example 59, using 6-chloro-5-methoxypolyolinic acid instead of 6-chloropicolinic acid as the starting material. LCMS calculated for C31H30FN6O4 (M + H) +: m / z = 569.2; Found: 569.2. Example 62. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2, 6-difluorophenyl) pyrimidine-4-carboxamide H2N F F OH N N N H N O N
[00390] [00390] This compound was prepared according to the procedures described in Example 59, Step 2, using 2-chloropyrimidine-4-carboxylic acid instead of 6-chloropicolinic acid as the starting material. LCMS calculated for C27H29ClN7O4 (M + H) +: m / z = 550.2; Found: 550.1.
[00391] [00391] A mixture of (3S, 5S) -1- (2- (2-chloropyrimidine-4-carboxamide) -5- (4-cyanopyridin-3-yl) phenyl) -5- (hydroxymethyl) pyrrolidin- Tert-butyl 3-ylcarbamate (20 mg, 0.036 mmol), boronic acid (2,6-difluorophenyl) (5.75 mg, 0.036 mmol), potassium phosphate, tribasic (15.46 mg, 0.073 mmol), XPhos Pd G2 (3.02 mg, 3.64 µmol) in p-dioxane (1 ml) and water (0.2 ml) was stirred at 70 ˚C for 2 h. The mixture was concentrated in vacuo and dissolved in DCM (1 ml) and TFA (1 ml). The resulting mixture was stirred at room temperature for 15 min, and then the solvent was concentrated. The residue was diluted with acetonitrile and purified with prep LCMS (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 mL / min) LCMS calculated for C28H24F2N7O2 ( M + H) +: m / z = 528.2; Found: 528.4. Example 63. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2- fluoro-6-methylphenyl) pyrimidine-4-carboxamide H2N F OH N N N H N O N NC
[00392] [00392] This compound was prepared according to the procedures described in Example 62, using (2-fluoro-6-methylphenyl) boronic acid instead of (2,6-difluorophenyl) boronic acid as part material taken. LCMS calculated for C29H27FN7O2 (M + H) +: m / z = 524.2; Found: 524.1. Example 64. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4-
[00393] [00393] This compound was prepared according to the procedures described in Example 62, using (2-chloro-6-fluorophenyl) boronic acid instead of (2,6-difluorophenyl) boronic acid as part material taken. LCMS calculated for C28H24ClFN7O2 (M + H) +: m / z = 544.2; Found: 544.2. Example 65. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -6- (1,3,5-trimethyl-1H-pyrazol-4-yl) pyridin-3-yl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide H2N MeO F OH N N N H N N O N
[00394] [00394] This compound was prepared according to the procedures described in Examples 41 and 1, using 6-bromo-2-chloro-3-nitropyridine instead of 4-bromo-2-fluoro-1-nitrobenzene as starting material. LCMS calculated for C27H31BrFN6O5 (M + H) +: m / z = 617.2; Found: 617.2. Step 2. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -6- (1,3,5-trimethyl-1H-pyrazol-4-yl) pyridin-3-yl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide;
[00395] [00395] A mixture of ((3S, 5S) -1- (6-bromo-3- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) pyridin-2-yl) -5 - tert-butyl (hydroxymethyl) pyrrolidin-3-yl) carbamate (35 mg, 0.057 mmol), 1,3,5-trimethyl-4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) -1H-pyrazole (0.020 g, 0.085 mmol), Xphos Pd G2 (13 mg, 16 µmol) and potassium phosphate, tribasic (67 mg, 0.32 mmol) was combined with 1.4- dioxane (1 ml) and water (0.1 ml). The reaction flask was evacuated, again filled with nitrogen and then stirred at 80 ° C for 1 h. The reaction mixture was cooled to room temperature, the solvents were concentrated in vacuo and TFA (1 ml) was added. The reaction mixture was stirred at room temperature for 10 min, then diluted with CH3CN and water and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate 60 mL / min). LCMS calculated for C28H32FN8O3 (M + H) +: m / z = 547.3; Found: 547.3. Example 66. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2,6-difluorophenyl) pyrimidine-4-carboxamide
[00396] [00396] A solution of 1,4-difluoro-2-nitrobenzene (250 mg, 1.57 mmol) and tert-butyl ((3S, 5S) -5-pyrrolidin-3-yl) carbamate (340 mg, 1 , 57 mmol) in DMSO (5 mL) was treated with Hunig's base (274 µL, 1.57 mmol) and the reaction mixture was heated at 90 ° C for 1 hour. The reaction mixture was treated with water and the product was extracted with ethyl acetate. The organic phase was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was dissolved in a 1: 1: 1 THF / water / MeOH mixture (9 mL) and treated with iron (351 mg, 6.29 mmol) and ammonium chloride (504 mg, 9.43 mmol). The reaction mixture was heated at 60 ° C for 1 hour, then diluted with ethyl acetate and filtered through a plug of Celite. The filtrate was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by Biotage IsoleraTM (30-100% ethyl acetate in hexanes) to provide the desired product as a yellow solid (226 mg, 46%). LCMS calculated for C16H25FN3O3 (M + H) +: m / z = 326.2; Found: 326.2. Step 2. tert-Butyl ((3S, 5S) -1- (2- (2-chloropyrimidine-4-carboxamido) -4-fluorophenyl) - 5- (hydroxymethyl) pyrrolidin-3-yl) carbamate
[00397] [00397] A solution of 2-chloropyrimidine-4-carboxylic acid (87 mg, 0.550 mmol), HATU (230 mg, 0.605 mmol) and ((3S, 5S) -1- (2-amino-4-fluorophenyl) - Tert-Butyl 5- (hydroxymethyl) pyrrolidin-3-yl) carbamate (179 mg, 0.550 mmol) in DMF (1834 µl) was treated with Hunig's base (192 µl, 1,100 mmol) and the reaction mixture was stirred at room temperature for 30 minutes, then treated with water and the product was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by Biotage IsoleraTM (25-100% ethyl acetate in hexane) to provide the desired product (107 mg, 42%). LCMS calculated for C21H26ClFN5O4 (M + H) +: m / z = 466.2; Found: 466.2. Step 3. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluoro-phenyl) -2- (2,6-difluorophenyl) pyrimidine-4 -carboxamide
[00398] [00398] To a mixture of boronic acid (2,6-difluorophenyl) (15 mg, 0.097 mmol), XPhos Pd G2 (5.07 mg, 6.44 µmol), potassium phosphate (27.5 mg, 0.129 mmol) ) and tert-butyl ((3S, 5S) -1- (2- (2-chloropyrimidine-4-carboxamide) -4-fluorophenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate ( 30 mg, 0.064 mmol) 1,4-dioxane (530 µl) and water (100 µl) were added and the flask was evacuated, again filled with nitrogen, and then stirred at 90 ° C overnight. The reaction was diluted with DCM / water and the phases separated. The organic phase was concentrated and the residue was dissolved in TFA (1 ml) and left to stand at room temperature for 30 minutes, then diluted with MeOH and purified with LCMS prep (column XBridge C18, eluting with a gradient of acetonitrile / water containing 0.1% TFA, at a flow rate of 60 mL / min). LCMS calculated for C22H21F3N5O2 (M + H) +: m / z = 444.2; Found: 444.2. Example 67. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (3-cyano-2-fluoro-6-methoxyphenyl ) pyrimidine-4-carboxamide
[00399] [00399] This compound was prepared analogously to Example 66, step 3, using 2-fluoro-4-methoxy-3- (4,4,5,5-tetramethyl-1,3,2-dioxoboroolan-2 -yl) benzonitrile in place of boronic acid (2,6-difluorophenyl). LCMS calculated for C24H23F2N6O3 (M + H) +: m / z = 481.2; Found: 481.2. Example 68. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2,3-difluoro-6-methoxyphenyl) pyrimidine -4-carboxamide
[00400] This compound was prepared analogously to Example 66, step 3, using boronic acid (2,3-difluoro-6-methoxyphenyl) instead of boronic acid (2,6-difluorophenyl). LCMS calculated for C23H23F3N5O3 (M + H) +: m / z = 474.2; Found: 474.2. 1 H NMR (500 MHz, DMSO- d6) δ 10.69 (s, 1H), 9.30 (s, 1H), 8.21 (d, J = 5.0 Hz, 1H), 8.18 ( d, J = 3.0 Hz, 1H), 7.81 (s, 2H), 7.60 (q, J = 9.5 Hz, 1H), 7.53 (dd, J = 8.9, 5 , 8 Hz, 1H), 7.13 - 6.96 (m, 2H), 5.19 (s, 1H), 3.75 (s, 4H), 3.56 (dd, J = 8.2, 3.6 Hz, 1H), 3.26 - 3.17 (m, 4H), 2.46 - 2.35 (m, 1H), 1.77 (dt, J = 13.6, 4.1 Hz , 1H) ppm. Example 69. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6- (methoxy-d3) -3-methylphenyl) pyrimidine-4-carboxamide
[00401] [00401] A solution of 3-fluoro-4-methylphenol (1.0 g, 7.93 mmol) in DMF (26.4 ml) was treated with potassium carbonate (1.644 g, 11.89 mmol) and iodomethane- d3 (0.592 ml, 9.51 mmol) and the reaction mixture heated to 80 ° C for 1 hour. The reaction mixture was treated with water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step, without further purification. LCMS calculated for C8H7D3FO (M + H) +: m / z = 144.2; Found: 144.2. Step 2. 2- (2-Fluoro-6- (methoxy-d3) -3-methylphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
[00402] [00402] A solution of 2-fluoro-4- (methoxy-d3) -1-methylbenzene (1.0 g, 6.98 mmol) and HMPA (1.823 ml, 10.48 mmol) in THF (34.9 ml ) at - 78 ° C was treated with n-BuLi (2.5 M in hexanes, 3.35 ml, 8.38 mmol) dropwise and the reaction mixture stirred at this temperature for 1 h. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2,166 ml, 10.48 mmol) was then added and the reaction mixture was stirred at -78 ° C for 10 minutes and, then heated to room temperature by removing the cooling bath. The reaction was treated with aqueous 1N HCl and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step, without further purification. Step 3. Methyl 2- (2-fluoro-6- (methoxy-d3) -3-methylphenyl) pyrimidine-4-carboxylic acid
[00403] [00403] A solution of 2- (2-fluoro-6- (methoxy-d3) -3-methylphenyl) - 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.56 g, 5 , 79 mmol) and Hunig's base (1 ml, 5.79 mmol) in water (1333 µl) and 1,4-dioxane (12 ml) was treated with methyl 2-chloropyrimidine-4-carboxylate (500 mg, 2.90 mmol) and ((t-Bu) 3P) 2Pd (74.0 mg, 0.145 mmol). The reaction flask was evacuated, again filled with nitrogen and stirred at 80 ° C overnight. The reaction mixture was then diluted with DCM and filtered through a plug of Celite. The filtrate was concentrated and the residue purified by Biotage IsoleraTM (0-100% ethyl acetate in hexanes) to provide the desired intermediate. LCMS calculated for C14H11D3FN2O3 (M + H) +: m / z = 280.2; Found: 280.2. Step 4. 2- (2-fluoro-6- (methoxy-d3) -3-methylphenyl) pyrimidine-4-carboxylic acid
[00404] [00404] The product from the previous step was dissolved in a 1: 1 mixture of THF / water (4 mL). Lithium hydroxide (238 mg, 5.79 mmol) was added and the reaction mixture heated at 60 ° C for 1 h, then acidified to pH 1 with HCl 1 N and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product was used in the next step, without further purification. LCMS calculated for C13H9D3FN2O3 (M + H) +: m / z = 266.2; Found: 266.2. Step 5. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6- (methoxy- d3) -3-methylphenyl) pyrimidine-4-carboxamide
[00405] [00405] A solution of 2- (2-fluoro-6-methoxy-d3) -3-methylphenyl) pyrimidine-4-carboxylic acid (12.27 mg, 0.046 mmol), HATU (21.03 mg, 0.055 mmol) and ((3S, 5S) -1- (2-amino-4-fluorophenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate (Example 66, step 2; 15 mg, 0.046 mmol) in DMF (461 µl) was treated with Hunig's base (16.10 µl, 0.092 mmol) and the reaction mixture stirred at room temperature for 30 min. The reaction mixture was treated with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was dissolved in TFA (1 ml), kept at room temperature for 30 minutes, then diluted with MeOH and purified with prep LCMS (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1 % TFA, at a flow rate of 60 mL / min). LCMS calculated for C24H23D3F2N5O3 (M + H) +: m / z = 473.2; Found: 473.2. Example 70. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2- fluoro-6-methoxy-4-methylphenyl) pyrimidine-4-carboxamide
[00406] [00406] This compound was prepared analogously to Example 69, step 1-2 using 3-fluoro-5-methylphenol instead of 3-fluoro-4-methylphenol. Step 2. tert-butyl carbamate ((3S, 5S) -1- (2-amino-5-bromophenyl) -5- (hydroxymethyl) pyrrolidin-3-yl)
[00407] [00407] A solution of 4-bromo-2-fluoro-1-nitrobenzene (1.0 g, 4.55 mmol) and ((3S, 5S) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate (0.983 g, 4.55 mmol) in DMF (15.15 ml) was treated with Hunig's base (1.588 ml, 9.09 mmol) and the reaction mixture heated at 80 ° C for 1 hour. The reaction mixture was poured into water / ethyl acetate, the separated phases and the organic phase were washed with water and brine, dried over sodium sulfate and concentrated. The residue was dissolved in a 1: 1: 1 THF / MeOH / water mixture (15 mL) and treated with iron (1.015 g,
[00408] [00408] To a mixture of tert-butyl ((3S, 5S) -1- (2-amino-5-bromophenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate (200 mg, 0.518 mmol ), XPhos Pd G2 (20.37 mg, 0.026 mmol), 3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) isonicotinonitrile (155 mg, 0.673 mmol) and potassium phosphate (220 mg, 1.035 mmol), 1,4-dioxane (1438 µl) and water (288 µl) were added and the reaction flask was evacuated, refilled with nitrogen and then stirred at 90 ° C. ° C for 1 h. The mixture was diluted with ethyl acetate and filtered through a plug of Celite. The filtrate was concentrated and the residue was purified by Biotage IsoleraTM (30-100% ethyl acetate in hexanes, then 5-20% methanol in ethyl acetate) to provide the desired product as a brown solid ( 175 mg, 83%). LCMS calculated for C22H28N5O3 (M + H) +: m / z = 410.2; Found: 410.2 Step 4. (((3S, 5S) -1- (2- (2-chloropyrimidine-4-carboxamido) -5- (4-cyanopyridin-3-yl) phenyl) -5- (hydroxymethyl ) tert-butyl pyrrolidine-3-yl)
[00409] [00409] A solution of 2-chloropyrimidine-4-carboxylic acid (119 mg, 0.751 mmol), HATU (314 mg, 0.826 mmol) and ((3S, 5S) -1-2-amino- 5- (4-cyanopyridine -3-yl) phenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) tert-butyl carbamate (307 mg, 0.751 mmol) in DMF (3800 µl) was treated with Hunig's base (262 µl, 1.502 mmol) and left stirring at room temperature for 30 minutes. The reaction mixture was treated with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by Biotage IsoleraTM (40-100% ethyl acetate in hexanes) to provide the desired product as an orange solid (310 mg, 75%). LCMS calculated for C27H29ClN7O4 (M + H) +: m / z = 550.2; Found: 550.2 Step 5. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyano-nopiridin-3-yl ) phenyl) -2- (2-fluoro-6-methoxy-4-methylphenyl) pyrimidine-4-carbo-xamide
[00410] [00410] To a mixture of ((3S, 5S) -1- (2- (2-chloropyrimidine-4-carbo-xamido) -5- (4-cyanopyridin-3-yl) phenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) of tert-butyl (15 mg, 0.027 mmol), 2- (2-fluoro-6-methoxy-4-methylphenyl) -4,4,5,5-termethyl-1,3, 2-dioxaborolane (10.89 mg, 0.041 mmol), XPhos Pd G2 (2.145 mg, 2.73 µmol) and potassium phosphate (12 mg, 0.055 mmol) were added water (54.5 µl) and 1.4- dioxane (218 µl) and the reaction flask was evacuated, filled with nitrogen, then stirred at 90 ° C overnight. The mixture was partitioned between DCM / water and the concentrated organic phase. The residue was left in TFA (1 mL) for 30 min at room temperature, then diluted with MeOH and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, flow rate of 60 mL / min). LCMS calculated for C30H29F2N7O3 (M + H) +: m / z = 573.2; Found: 573.2. Example 71. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (3, 6-difluoro-2-methylphenyl) pyrimidine-4-carboxamide
[00411] [00411] This compound was prepared analogously to Example 70, step 5, using (3,6-difluoro-2-methylphenyl) boronic acid instead of 2- (2-fluoro-6-methoxy-4-methylphenyl) - 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS calculated for C29H26F2N7O2 (M + H) +: m / z = 542.2; Found: 542.2. Example 72. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2, 3-difluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00412] [00412] This compound was prepared analogously to Example 70, step 5, using (2,3-difluoro-6-methoxyphenyl) boronic acid instead of 2- (2-fluoro-6-methoxy-4-methylphenyl) - 4,4,5,5-tetramethyl-1,3,2-dioxaboro-
[00413] [00413] This compound was prepared analogously to Example 70, step 5, using (3,6-difluoro-2-methoxyphenyl) boronic acid instead of 2- (2-fluoro-6-methoxy-4-methylphenyl) - 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS calculated for C29H26F2N7O3 (M + H) +: m / z = 558.2; Found: 558.2. Example 74. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (3- cyano-2-fluoro-6- (methoxy-d3) phenyl) pyrimidine-4-carboxamide Step 1. Acid 2- (3-Cyano-2-fluoro-6-methoxy-d3) phenyl) pyrimidine-4-carbo - xylus
[00414] [00414] This compound was prepared analogously to Example 69, steps 1-4, starting with 3-fluoro-4-cyanophenol instead of 3-fluoro-4-methylphenol. LCMS calculated for C13H6D3FN3O3 (M + H) +: m / z = 277.2; Found: 277.2. Step 2. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyano-pyridin-3-yl) phenyl) -2- ( 3-cyano-2-fluoro-6- (methoxy-d3) phenyl) pyrimidine-4-carboxamide
[00415] [00415] A solution of 2- (3-cyano-2-fluoro-6- (methoxy-d3) phenyl) pyrimidine-4-carboxylic acid (9.72 mg, 0.037 mmol), HATU (16.71 mg , 0.044 mmol) and tert-butyl ((3S, 5S) -1- (2-amino-5- (4-cyanopyridin-3-yl) phenyl) - 5- (hydroxymethyl) pyrrolidin-3-yl) carbamate (Example 70, Step 4, 15 mg, 0.037 mmol) in DMF (366 µl) was treated with Hunig's base (12.80 µl, 0.073 mmol) and the reaction mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was treated with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was dissolved in TFA (1 mL) and left to stand at room temperature for 30 minutes, then diluted with MeOH and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1 % TFA, at a flow rate of 60 mL / min). LCMS calculated for C30H23D3FN8O3 (M + H) +: m / z = 568.2; Found: 568.2. Example 75. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (3, 6-difluoro-2- (methoxy-d3) phenyl) pyrimidine-4-carboxamide
[00416] [00416] This compound was prepared analogously to Example 69, steps 1-4, starting with 2,5-difluorophenol instead of 3-fluoro-4-methylphenol. LCMS calculated for C12H6D3F2N2O3 (M + H) +: m / z = 270.2; Found: 270.2. Step 2. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyano-pyridin-3-yl) phenyl) -2- ( 3,6-difluoro-2- (methoxy-d3) phenyl) pyrimidine-4-carbo-xamide
[00417] [00417] This compound was prepared analogously to Example 74, step 2, using 2- (3,6-difluoro-2- (methoxy-d3) phenyl) pyrimidine-4-carboxylic acid as the coupling partner. LCMS calculated for C29H23D3F2N7O3 (M + H) +: m / z = 561.2; Found: 561.2. Example 76. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2, 3-difluoro-6- (methoxy-d3) phenyl) pyrimidine-4-carboxamide
[00418] [00418] This compound was prepared analogously to Example 75, steps 1-2 using 4,5-difluorophenol as starting material. LCMS calculated for C29H23D3F2N7O3 (M + H) +: m / z = 561.2; Found: 561.2. Example 77. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2- fluoro-6- (methoxy-d3) phenyl-5-d) pyrimidine-4-carboxamide Step 1. 1-Bromo-4-fluoro-2- (methoxy-d3) benzene
[00419] [00419] A solution of 2-bromo-5-fluorophenol (1.0 g, 5.24 mmol) in DMF (17.45 ml) was treated with potassium carbonate (1.085 g, 7.85 mmol) and iodomethane- d3 (0.414 ml, 6.28 mmol). The reaction mixture was heated to 60 ° C overnight, then treated with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step, without further purification. LCMS calculated for C7H4D3BrFO (M + H) +: m / z = 208.0 / 210.0; Found: 208.0 / 210.0. Step 2. 2- (2-Fluoro-6- (methoxy-d3) phenyl-5-d) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
[00420] [00420] Magnesium (92 mg, 3.78 mmol) in THF (2 mL) was treated with iodine (23.97 mg, 0.094 mmol) followed by a solution of 1-bromo-4-fluoro-2- (methoxy- d3) benzene (393 mg, 1.889 mmol) in THF (8 mL) dropwise. The mixture was heated to 60 ° C for 1 hour, then the reaction mixture was cooled to room temperature and treated by the addition of methanol-d4 (382 µl, 9.45 mmol). After stirring at room temperature for 15 minutes, the mixture was further treated with 1N HCl to destroy the remaining magnesium. The mixture was then extracted with diethyl ether. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. To the crude intermediate, THF (10 mL) was added and the mixture cooled to -78 ° C. n-BuLi (1.6 M in hexanes, 907 µl, 2.267 mmol) was added dropwise and the reaction mixture was stirred at -78 ° C for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (586 µl, 2.83 mmol) was added. The mixture was stirred at -78 ° C for 10 minutes, then warmed up to room temperature. After 1 hour, the reaction was treated with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step, without further purification. Step 3. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyano-pyridin-3-yl) phenyl) -2- ( 2-fluoro-6- (methoxy-d3) phenyl-5-d) pyrimidine-4-carbo-xamide
[00421] [00421] This compound was prepared analogously to Example 70, step 5, using pinacol boronate prepared in Step 2 instead of 2- (2-fluoro-6-methoxy-4-methylphenyl) -4,4,5, 5-tetramethyl-1,3,2-dioxaborolane. LCMS calculated for C29H23D4FN7O3 (M + H) +: m / z = 544.2; Found: 544.2. 1H NMR (600 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.29 (d, J = 5.0 Hz, 1H), 8.98 (s, 1H), 8.83 (d , J = 5.0 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 5.0 Hz, 1H), 7.99 (d, J = 5.0 Hz, 1H), 7.93 (s, 2H), 7.68
[00422] [00422] To a mixture of terti- 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate butyl (230 mg, 0.743 mmol), 1-bromo-2-nitrobenzene (100 mg, 0.495 mmol), XPhos Pd G2 (38.9 mg, 0.050 mmol) and tribasic potassium phosphate (210 mg, 0.990 mmol) were added 1,4-dioxane (1320 µl) and water (330 µl) and the reaction mixture was evacuated, filled with nitrogen again, and then heated at 90 ° C for 1 hour. The mixture was diluted with DCM and filtered through a plug of Celite. The filtrate was concentrated and the residue purified by Biotage Isolera ™ (0-70% ethyl acetate in hexanes). To the purified product, MeOH (4 ml) was added followed by palladium hydroxide on carbon (20% w / w, 69.5 mg, 0.099 mmol). The reaction flask was evacuated, again filled with hydrogen gas from a flask and then heated to 60 ° C overnight. The mixture was then filtered through a plug of Celite and the filtrate concentrated. The crude product (130 mg, 95%) was used in the next step, without further purification. LCMS calculated for C16H25N2O2 (M + H) +: m / z = 277.2; Found: 277.2. Step 2. 2- (2-Fluoro-6-methoxyphenyl) -N- (2- (piperidin-4-yl) phenyl) pyrimidine-4-carboxamide;
[00423] [00423] A solution of 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxylic acid (93 mg, 0.376 mmol), HATU (215 mg, 0.564 mmol) and 4- (2-aminophenyl) piperidine-1 tert-butyl carboxylate (130 mg, 0.470 mmol) in DMF (2352 µl) was treated with Hunig's base (164 µl, 0.941 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was treated with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The residue was dissolved in TFA (1 mL) and left to stand for 30 minutes, then diluted with methanol and purified with LCMS prep (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA, at a flow rate of 60 mL / min). LCMS calculated for C23H24FN4O2 (M + H) +: m / z = 407.2; Found: 407.2. Example 79. N- (2- (cis) 4-Aminocyclohexyl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide and N- (2- (trans) 4-Aminocyclohexyl) phenyl ) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00424] [00424] These compounds were prepared in a manner analogous to Example 78, steps 1-2 beginning with (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) cyclohex-3- en-1-yl) tert-butyl carbamate. Purification by LCMS prep provided the cis and trans isomers. LCMS calculated for C24H26FN4O2 (M + H) +: m / z = 421.2; Found: 421.2.
[00425] [00425] This compound was prepared analogously to Example 78, steps 1-2 beginning with (3- (4,4,5,5-tetramethyl-1,3,2-dioxaboro-lan-2-yl) cyclohex- Tert-butyl 2-en-1-yl) carbamate. LCMS calculated for C24H26FN4O2 (M + H) +: m / z = 421.2; Found: 421.2. Example 81. N- (2- (3-aminocyclopentyl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00426] [00426] This compound was prepared analogously to Example 78, steps 1-2 starting with (3- (4,4,5,5-tetramethyl-1,3,2-dioxaboro-lan-2-yl) cyclopent- Tert-butyl 3-en-1-yl) carbamate. LCMS calculated for C23H24FN4O2 (M + H) +: m / z = 407.2; Found: 407.2. Example 82. N- (2 - ((cis) -4-Aminocyclohexyl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide and N- (2- ((trans) -4-Aminocyclohexyl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00427] [00427] To a mixture of tert-butyl (4- (4,4,5,5-tetramethyl-1,3-dioxolan-2-yl) cyclohex-3-en-1-yl) carbamate (308 1,4-chloro-2-iodoaniline (200 mg, 0.789 mmol), DPPF-PdCl2 (64.4 mg, 0.079 mmol) and potassium carbonate (218 mg, 1.578 mmol) were added. dioxane (3156 µl) and water (789 µl). The reaction flask was evacuated, again filled with nitrogen and then stirred at 90 ° C for 2 hours. The mixture was diluted with DCM and filtered through a plug of Celite. The filtrate was concentrated and the residue purified by Biotage Isolera ™ (0-100% ethyl acetate in hexanes). The crude material was dissolved in EtOH (4 ml) and palladium hydroxide on carbon (20% w / w, 111 mg, 0.158 mmol) was added. The reaction flask was evacuated, refilled with hydrogen gas from a flask and then stirred at 60 ° C for 2 hours. The reaction mixture was then diluted with ethyl acetate and filtered through a plug of Celite. The filtrate was concentrated and the crude product used in the next step without further purification. LCMS calculated for C 17H27N2O3 (M + H) +: m / z = 307.2; Found: 307.2. Step 2. 3- (4 - (((tert-Butoxycarbonyl) amino) cyclohexyl) -4- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl trifluoromethanesulfonate
[00428] [00428] A solution of 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxylic acid (64.0 mg, 0.258 mmol), HATU (118 mg, 0.309 mmol) and (4- (2-amino- 5-hydroxyphenyl) cyclohexyl) carbamate (79 mg, 0.258 mmol) in DMF (1289 µl) was treated with Hunig's base (90 µl, 0.516 mmol) and the reaction mixture was stirred at room temperature for 30 minutes . The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by Bio-Isolage ™ (20-100% ethyl acetate in hexanes). The intermediate was dissolved in DCM (3 ml) and triethylamine (71.9 µl, 0.516 mmol) was added. The reaction mixture was cooled to 0 ° C and N-phenyltrifluoromethanesulfonimide (92 mg, 0.258 mmol) in DCM (0.5 ml) was added dropwise. The reaction mixture was then warmed to room temperature and stirred for 2 hours, and then treated with saturated sodium bicarbonate. The phases were separated and the organic phase dried over sodium sulfate and concentrated. The crude product was purified by Biotage Isolera ™ (20-100% ethyl acetate in hexanes) to provide the desired product as a white solid (68 mg, 40%). LCMS calculated for C30H33F4N4O7S (M + H) +: m / z = 669.2; Found: 669.2. Step 3. N- (2 - ((cis) -4-Aminocyclohexyl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide and N- (2 - ((trans) -4-aminocyclohexyl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00429] [00429] To a solution of 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isonicotinonitrile (35.1 mg, 0.153 mmol), DPPF-PdCl2 (8.30 mg, 10.17 µmol), cesium carbonate (66.3 mg, 0.203 mmol) and 3- (4 - ((tert-butoxycarbonyl) amino) cyclohexyl) -4- (2- (2-fluoro- 6-methoxyphenyl) pyrimidine-4-carboxamide) trifluoromethanesulfonate (68 mg, 0.102 mmol) was added 1,4-dioxane (915 µl) and water (102 µl) and the reaction flask was evacuated, again filled with nitrogen and then heated to 90 ° C overnight. The mixture was then diluted with water and DCM and the phases separated. The organic phase was concentrated. The residue was left to stand in TFA (1 mL) for 30 minutes at room temperature, then diluted with MeOH and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at flow rate of 60 mL / min). The two isomers were successfully separated by prep LCMS. LCMS calculated for C 30H28FN6O2 (M + H) +: m / z = 523.2; Found: 523.2. Example 83. N- (2 - ((cis) -4-Aminocyclohexyl) -4- (4-cyano-1-methyl-1H-pyrazol-5-yl) phenyl) -2- (2-fluoro-6 -methoxyphenyl) pyrimidine-4-carboxamide and N- (2 - ((trans) -4-aminocyclohexyl) -4- (4-cyano-1-methyl-1H-pyrazol-5-yl) phenyl ) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00430] [00430] This compound was prepared analogously to Example 82, step 2 using 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - 1H-pyrazole -4-carbonitrile as a coupling partner. LCMS calculated for C29H29FN7O2 (M + H) +: m / z = 526.2; Found: 526.2. Example 84. N- (2 - ((cis) -4-Aminocyclohexyl) -4- (1,3,5-trimethyl-1H-pyrazol-4-yl) phenyl) -2- (2-fluoro -6-methoxyphenyl) pyrimidine-4-carboxamide
[00431] [00431] This compound was prepared analogously to Example 82, step 2 using 1,3,5-trimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborol-2- il) -1H-pyrazole as a coupling partner. LCMS calculated for C30H34FN6O2 (M + H) +: m / z = 529.2; Found: 529.2. 1
[00432] [00432] A mixture of 2-fluoro-4- (methylsulfonyl) -1-nitrobenzene (100 mg, 0.456 mmol) and ((3S, 5S) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate (118 mg, 0.547 mmol) in DMSO (1521 µl) was treated with Hunig's base (159 µl, 0.912 mmol) and the reaction mixture stirred at 90 ° C for 1 hour, then treated with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The residue was dissolved in a 1: 1: 1 THF / water / MeOH mixture (3 mL) and treated with iron (102 mg, 1.825 mmol) and ammonium chloride (146 mg, 2.74 mmol). The reaction mixture was stirred at 60 ° C for 1 hour, then diluted with ethyl acetate and filtered through a plug of Celite. The filtrate was washed with water and brine, dried over sodium sulfate and concentrated. The crude solid was used in the next step, without further purification. LCMS calculated for C17H28N3O5S (M + H) +: m / z = 386.2; Found: 386.2. Step 2. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (methylsulfonyl) phenyl) -2- (2-fluoro-6- methoxyphenyl) pyrimidine-4-carboxamide
[00433] [00433] A solution of tert-butyl ((3S, 5S) -1- (2-amino-5- (methylsulfonyl) phenyl) - 5- (hydroxymethyl) pyrrolidin-3-yl) carbamate (55 mg, 0.143 mmol ) in DMF (476 µl) was treated with 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxylic acid (31.9 mg, 0.128 mmol), HATU (65.1 mg, 0.171 mmol) and Hunig's base (49.8 µl, 0.285 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then treated with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. To the crude residue was added 4N HCl in dioxane and MeOH (2 mL, 1: 1) and the reaction mixture heated at 60 ° C for 1 hour, then diluted with
[00434] [00434] A solution of tert-butyl 1-fluoro-2-nitrobenzene (30 µl, 0.283 mmol) and tert-butyl ((3S, 5S) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate (61.3 mg, 0.283 mmol) in DMSO (1.5 ml) was treated with triethylamine (59.3 µl, 0.425 mmol) and the reaction mixture was heated at 80 ° C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with DCM, washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The crude product obtained was used in the next step, without further purification. LCMS calculated for C12H16N3O5 (M + H-C4H8) +: m / z = 282.1; found 282.2. Step 2. ((3S, 5S) -1- (2-aminophenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) tert-butyl carbamate
[00435] [00435] A mixture of tert-butyl ((3S, 5S) -5- (hydroxymethyl) -1- (2-nitrophenyl) pyrrolidin-3-yl) carbamate (70 mg, 0.207 mmol), iron (57 , 9 mg, 1.037 mmol) and ammonium chloride (67 mg, 1.25 mmol) in THF (2 mL), water (2 mL) and methanol (2 mL) was stirred at 60 ° C for 3 hours. After cooling to room temperature, it was filtered through a plug of Celite and diluted with DCM. The organic phase was separated, washed with brine, dried over sodium sulfate and the solvents were evaporated in vacuo. The crude product obtained was used in the next step, without further purification. LCMS calculated for C16H26N3O3 (M + H) +: m / z = 308.2; Found: 308.2. Step 3. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00436] [00436] HATU (74.2 mg, 0.195 mmol) was added to a solution of tert-butyl ((3S, 5S) -1- (2-aminophenyl) -5- (hydroxymethyl) pyrrolidine-3-yl) car- bamate (40 mg, 0.130 mmol), 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxylic acid (the product of Example 1, step 1, 32.3 mg, 0.130 mmol) and DIPEA (45.5 µl, 0.260 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 30 minutes, then water was added and the precipitated product was collected by filtration, washed with water and dried in air. The solid was dissolved in TFA and the resulting solution was stirred at room temperature for 10 minutes. It was then diluted with acetonitrile and purified with prep-LCMS (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 mL / min). LCMS calculated for C23H25FN5O3 (M + H) +: m / z = 438.2; Found: 438.2. 1H NMR (500 MHz, DMSO-d6) δ 10.61 - 10.48 (s, 1H), 9.34 - 9.19 (d, J = 5.0 Hz, 1H), 8.21 - 8, 11 (m,
[00437] [00437] This compound was prepared according to the procedures described in Example 6, using 1-fluoro-4-methyl-2-nitrobenzene instead of 1,4-difluoro-2-nitrobenzene as starting material. LCMS calculated for C24H27FN5O3 (M + H) +: m / z = 452.2; Found: 452.2. Example 88. N- (2 - ((2S, 4S) -4- (Dimethylamino) -2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl ) pyrimidine-4-carbo-xamide
[00438] [00438] Sodium triacetoxyborohydride (9 mg, 0.044 mmol) was added to a solution of formaldehyde (1.4 mg, 0.044 mmol), acetic acid (2.51 µl, 0.044 mmol) and N- (2 - ((2S, 4S) -4-amino- 2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxy (Example 6, 10 mg, 0.022 mmol) in DCM (1 ml). After stirring at room temperature for 1 h, the solvent was evaporated, the reaction mixture was diluted with CH3CN and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a rate flow rate of 60 mL / min). LCMS calculated for C25H28F2N5O3 (M + H) +: m / z = 484.2; Found: 484.2. Example 89. N- (5-Fluoro-2 - ((2S, 4S) -2- (hydroxymethyl) -4- (isopropylamino) pyrrolidin-1-yl) phenyl) -2- (2-fluoro-6- methoxyphenyl) pyrimidine-4-carboxamide
[00439] [00439] This compound was prepared according to the procedures described in Example 88, using acetone instead of formaldehyde as the starting material. LCMS calculated for C26H30F2N5O3 (M + H) +: m / z = 498.2; Found: 498.1. Example 90. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (tetrahydro-2H-pyran-4-yl) phenyl) -2 - (2-fluoro-6-methoxyphenyl) pyrimidine- 4-carboxamide
[00440] [00440] This compound was prepared according to the procedures described in Example 49, using 2- (3,6-dihydro-2H-pyran-4-yl) - 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane instead of 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl) -1,3,2-dioxaborolane as starting material. LCMS calculated for C28H33FN5O4 (M + H) +: m / z = 522.2; Found: 522.2.
[00441] [00441] This compound was prepared according to the procedures described in Example 6, using 4-chloro-2-fluoro-1-nitrobenzene instead of 1,4-difluoro-2-nitrobenzene as starting material. LCMS calculated for C23H24ClFN5O3 (M + H) +: m / z = 472.2; Found: 472.3. Example 92. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4 -carboxamide
[00442] [00442] This compound was prepared according to the procedures described in Example 6, using 2,4-difluoro-1-nitrobenzene instead of 1,4-difluoro-2-nitrobenzene as starting material. LCMS calculated for C23H24F2N5O3 (M + H) +: m / z = 456.2; Found: 456.3. Example 93. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (5-cyano-2- (pyrrolidin-1-yl) pyridin-4 -yl) phenyl) -2- (2,6-difluorophenyl) pyrimidine-4-carboxamide
[00443] [00443] A solution of 4-bromo-6-chloronicotinonitrile (200 mg, 0.920 mmol) and pyrrolidine (327 mg, 4.60 mmol) in 2-propanol (2 mL) was stirred at 100 ° C for 12 h. Then, the solvent was evaporated in vacuo. The crude product obtained was used in the next step, without further purification. LCMS calculated for C10H11BrN3 (M + H) +: m / z = 252.0; Found: 252.0. Step 2. ((3S, 5S) -1- (2- (2- (2,6-difluorophenyl) pyrimidine-4-carboxamido) - 5- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) phenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) tert-butyl carbamate
[00444] [00444] This compound was prepared according to the procedures described in Examples 46 and 41 using (2,6-difluorophenyl) boronic acid instead of (2-fluoro-6-methoxyphenyl) boronic acid as starting material . LCMS calculated for C33H41BF2N5O6 (M + H) +: m / z = 652.3; Found: 652.2. Step 3. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (5-cyano-2- (pyrrolidin-1-yl) pyridin -4-yl) phenyl) -2- (2,6-difluorophenyl) pyrimidine-4-carboxamide
[00445] [00445] This compound was prepared according to the procedures described in Example 46, Step 2, using 4-bromo-6- (pyrrolidin-1-yl) nicotinonitrile instead of 2-bromonicotinonitrile and ((3S, 5S) -1- (2- (2- (2,6-difluorophenyl) pyrimidine-4-carboxamido) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) tert-butyl carbamate instead of ((3S, 5S) -1- (2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) tert-butyl carbamate as match. LCMS calculated for C32H31F2N8O2 (M + H) +: m / z = 597.3; Found: 597.2. Example 94. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (1-cyanocyclopropyl) phenyl) -2- (2,6-difluorophenyl) pyrimidine-4-carboxamide Step 1. (tert-butyl carbamate) (5- (cyanomethyl) -2-nitrophenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) carbamate
[00446] [00446] This compound was prepared according to the procedures described in Example 6, using 2- (3-fluoro-4-nitrophenyl) acetonitrile instead of 1,4-difluoro-2-nitrobenzene as starting material. LCMS calculated for C14H17N4O5 (M − C4H8 + H) +: m / z = 321.1; Found: 321.1.
[00447] [00447] tert-Butylchlorodimethylsilane (0.054 g, 0.359 mmol) was added to a solution of 1H-imidazole (0.024 g, 0.359 mmol) and ((3S, 5S) - 1- (5- (cyanomethyl) -2- nitrophenyl) -5- (hydroxymethyl) pyrrolidin-3-yl) tert-butyl carbamate (0.090 g, 0.239 mmol) in 1 ml of DCM. After the reaction mixture was stirred at room temperature for 2 h, water was added and the product was extracted with DCM. The combined organic phases were washed with water and brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The crude product obtained was used in the next step, without further purification. LCMS calculated for C20H31N4O5Si (M − C4H8 + H) +: m / z = 435.2; Found: 435.2. Step 3. tert (((3S, 5S) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) -1- (5- (1-cyanocyclopropyl) -2-nitrophenyl) pyrrolidin-3-yl) carbamate -butila
[00448] [00448] A solution of tert- ((3S, 5S) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) - 1- (5- (cyanomethyl) -2-nitrophenyl) pyrrolidin-3-yl) carbamate butyl (0.120 g, 0.245 mmol) in 1 mL of DMF was treated with 1,2-dibromethane (0.046 g, 0.245 mmol). The mixture was stirred at room temperature and then treated with sodium hydride (0.120 g, 5.00 mmol). The mixture was further stirred at room temperature overnight. In
[00449] [00449] This compound was prepared according to the procedures described in Example 1, using (2,6-difluorophenyl) boronic acid instead of (2-fluoro-6-methoxyphenyl) boronic acid and ((3S, 5S) -5 - (((tert-butyl-dimethylsilyl) oxy) methyl) -1- (5- (1-cyanocyclopropyl) -2-nitrophenyl) pyrrolidin-3-yl) tert-butyl carbamate instead of (1R, 4R ) - 5- (4-fluoro -2-nitrophenyl) - 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate as starting material. LCMS calculated for C26H25F2N6O2 (M + H) +: m / z = 491.2; Found: 491.1. Example 95. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2- difluoromethoxy-6-fluorophenyl) pyrimidine-4-carboxamide Step 1. 2-Bromo-1- (difluoromethoxy) -3-fluorobenzene
[00450] [00450] A mixture of 2-bromo-3-fluorophenol (0.865 g, 4.53 mmol), sodium chlorodifluoroacetate (4.14 g, 27.2 mmol) and cesium carbonate (4.43 g, 13.59 mmol) in DMF (10 mL) was stirred at 100 ˚C for 4 h. After cooling to room temperature, the mixture was concentrated in vacuo. The crude product obtained was purified by Biotage IsoleraTM to give the desired product. Step 2. 2- (2- (Difluoromethoxy) -6-fluorophenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
[00451] [00451] A solution of 2-bromo-1- (difluoromethoxy) -3-fluorobenzene (400 mg, 1.660 mmol) in THF (10 mL) was treated with 1.6 M nBuLi (1.72 mL, 4.32 mmol ) at -78 ˚C. After stirring for 1 h, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.02 ml, 4.98 mmol) was added and then the mixture was slowly heated to room temperature over 6 h. To the mixture, EtOAc (50 ml) and water (30 ml) were added. The organic phase was separated, washed with brine, dried over MgSO 4, filtered and the solvents were evaporated in vacuo. The crude product obtained was used in the next step, without further purification. Step 3. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyano-pyridin-3-yl) phenyl) -2- ( 2- (difluoromethoxy) -6-fluorophenyl) pyrimidine-4-carbo-xamide
[00452] [00452] This compound was prepared according to the procedures described in Example 63, using 2- (2- (difluoromethoxy) -6-fluorophenyl) - 4,4,5,5-tetramethyl-1,3,2- dioxaborolane instead of boronic acid (2,6-difluorophenyl) as a starting material. LCMS calculated for C29H25F3N7O3 (M + H) +: m / z = 576.2; Found: 576.3. Example 96. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2- fluoro-6- (methoxy-d3) phenyl) pyrimidine-4-carboxamide
[00453] [00453] This compound was prepared in a manner analogous to Example 69, starting with 3-fluorophenol instead of 3-fluoro-4-methylphenol. LCMS calculated for C13H16D3BFO3 (M + H) +: m / z = 256.2; Found: 256.2. Step 2. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyano-pyridin-3-yl) phenyl) -2- ( 2-fluoro-6-methoxy-d3) phenyl) pyrimidine-4-carboxamide
[00454] [00454] This compound was prepared according to the procedures described in Example 63, using 2- (2-fluoro-6- (methoxy-d3) phenyl) - 4,4,5,5-tetramethyl-1,3 , 2-dioxaborolane instead of boronic acid (2,6-difluorophenyl) as starting material. LCMS calculated for C29H24D3FN7O3 (M + H) +: m / z = 543.2; Found: 543.3. Example 97. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2- cyclopropyl-6-fluorophenyl) pyrimidine-4-carboxamide
[00455] [00455] This compound was prepared according to the procedures described in Example 63, using 2- (2-cyclopropyl-6-fluorophenyl) - 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in instead of boronic acid (2,6-difluorophenyl acid) as starting material. LCMS calculated for C31H29FN7O2 (M + H) +: m / z = 550.2; Found: 550.3. Example 98. N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2- ethoxy-6-fluorophenyl) pyrimidine-4-carboxamide
[00456] [00456] This compound was prepared according to the procedures described in Example 63, using (2-ethoxy-6-fluorophenyl) boronic acid instead of (2,6-difluorophenyl) boronic acid as part material taken. LCMS calculated for C30H29FN7O3 (M + H) +: m / z = 554.2; Found: 554.3. Example 99. N- (4- (4-Cyanopyridin-3-yl) -2 - ((1S, 4S) -4- (hydroxymethyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) -2- (2-fluoro-6-methoxy-phenyl) pyrimidine-4-carboxamide Step 1. (1S, 4S) -4- (hydroxymethyl) -2,5-diazabicyclo [2.2.1] heptane -2-tert-butyl carboxylate
[00457] [00457] A Parr reaction vessel was loaded with (1S, 4S) - 4- (hydroxymethyl) -5- (4-methoxybenzyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate ( prepared by an adaptation of the procedure described in Ivon, Y. et.al. Synthesis 2015, 47, 1123-1130) (25 mg, 0.072 mmol), Pd / C (10% wet, Degussa type, 7.7 mg) followed by MeOH (7.2 mL) and the reaction mixture was evacuated and filled 3 times with nitrogen gas, followed by another evacuation cycle and then pressurized with hydrogen gas at 25 psi. The vessel was stirred for 6 hours under pressure of hydrogen, after which time the solution was filtered over Celite and the solvent was evaporated in vacuo. The obtained crude product was used for the next reaction without purification. LCMS calculated for C11H21N2O3 (M + H) +: m / z = 229.2; found 229.2. Step 2. tert-Butyl (1S, 4S) -4- (hydroxymethyl) -5-methyl-2,5-diazabicyclo [2.2.1] hepato-2-carboxylate
[00458] [00458] A solution of tert-butyl (1S, 4S) -4- (hydroxymethyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (16.5 mg, 0.072 mmol) in CH3CN (200 µL) and H2O (50 µL) were treated with formaldehyde (37% by weight in H2O, 16.1 µL, 0.217 mmol) and sodium triacetoxyborohydride (31 mg, 0.145 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with CH2Cl2, washed with NaHCO3sat.aq., Dried over MgSO4, filtered and the solvent was evaporated in vacuo. The crude product obtained was used in the next reaction without purification. LCMS calculated for C12H23N2O3 (M + H) +: m / z = 243.2; found 243.2.
[00459] [00459] A mixture of tert-butyl (1S, 4S) -4- (hydroxymethyl) -5-methyl-2,5-diazabycle [2.2.1] heptane-2-carboxylate (17 mg, 0.070 mmol) and 4 M HCl / dioxane (1 ml) was stirred at room temperature for 1 hour before the solvent was evaporated in vacuo. The residue was then treated with 3- (3-fluoro-4-nitrophenyl) isonicotinonitrile (Intermediate 1 described between Example 49 and 50, 17.1 mg, 0.070 mmol), DMSO (300 µL), triethylamine (14, 7 µL, 0.943 mmol) and the reaction mixture was heated to 100 ˚C overnight. After cooling to room temperature, the reaction mixture was diluted with DCM, washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The crude product obtained was used in the next step, without further purification. LCMS calculated for C19H20N5O3 (M + H) +: m / z = 366.2; found 366.1. Step 4. 3- (4-Amino-3 - ((1S, 4S) -4- (Hydroxymethyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) isonicotinonitrile
[00460] [00460] A mixture of 3- (3 - ((1S, 4S) -4- (hydroxymethyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) -4-nitrophenyl) isonicotinonitrile (26 mg,
[00461] [00461] HATU (20.4 mg, 0.054 mmol) was added to a solution of 3- (4-amino-3 - ((1S, 4S) -4- (hydroxymethyl) -5-methyl-2,5-diazabici - clo [2.2.1] heptan-2-yl) phenyl) isonicotinonitrile (13 mg, 0.036 mmol), 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxylic acid (8.9 mg, 0.036 mmol) and DIPEA (12.5 µL, 0.072 mmol) in DMF (300 µL). The reaction mixture was stirred at 60 ˚C for 30 minutes, then water was added and the precipitated product was collected by filtration, washed with water and air dried. The solid was dissolved in TFA and the resulting solution was stirred at 60 ° C for 10 min before the solvent was evaporated in vacuo. The crude residue was then dissolved in THF (1 ml), MeOH (1 ml) and aq. NH4OH (1 ml), sealed and the solution was stirred at 60 ° C for 30 min before the solvent was evaporated in vacuo. The crude product obtained was then diluted with CH3CN and purified with LCMS Prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 ml / min). LCMS calculated for C31H29FN7O3 (M + H) +: m / z = 566.2; Found: 566.2. Example 100. (S) -N- (4- (4-Cyanopyridin-3-yl) -2- (2- (hydroxymethyl) morpholino) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine- 4-carboxamide
[00462] [00462] This compound was prepared according to the procedures described in Example 51, using (S) -morpholin-2-ylmethanol instead of (2R, 5S) - 5- (hydroxymethyl) -2-methylpiperazine-1- carboxylate as starting material. LCMS calculated for C29H26FN6O4 (M + H) +: m / z = 541.2; Found: 541.3. Example 101. (S) -N- (4- (4-Cyanopyridin-3-yl) -2- (2 - ((dimethylamino) methyl) morpholino) phenyl) -2- (2-fluoro-6-methoxyphenyl ) pyrimidine-4-carboxamide Step 1. (R) -N- (4- (4-Cyanopyridin-3-yl) -2- (2- (hydroxymethyl) morpholino) phenyl) - 2- (2-fluoro- 6-methoxyphenyl) pyrimidine-4-carboxamide
[00463] [00463] This compound was prepared in a similar way to Example
[00464] [00464] A solution of (R) -N- (4- (4-cyanopyridin-3-yl) -2- (2- (hydroxymethyl) morpholino) phenyl) -2- (2-fluoro-6-methoxyphenyl ) pyrimidine-4-carboxamide (100 mg, 0.185 mmol) in CH2Cl2 (740 µL) was treated with DMAP (2.3 mg, 0.018 mmol), triethylamine (77 µL, 0.555 mmol) and TsCl (42.3 mg, 0.222 mmol)) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with EtOAc, washed with 10% aq. Critical acid, NaHCO3sat. aq., dried over MgSO4, filtered and the solvent was evaporated in vacuo. The obtained crude product was used for the next reaction without purification. LCMS calculated for C36H32FN6O6S (M + H) +: m / z = 695.2; found 695.3. Step 3. (S) -N- (4- (4-Cyanopyridin-3-yl) -2- (2 - ((dimethylamino) methyl) morpholine) phenyl) -2- (2-fluoro-6-methoxyphenyl ) pyrimidine-4-carboxamide
[00465] [00465] A solution of (R) - (4- (5- (4-cyanopyridin-3-yl) -2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) morpholin- 2-yl) methyl 4-methyl-benzenesulfonate (20 mg, 0.029 mmol) in EtOH (480 µL) was treated with dimethylamine (461 µL, 0.921 mmol). The reaction mixture was stirred at 100 ˚C overnight. The solvent was evaporated in vacuo, and the resulting residue was diluted with acetonitrile and purified with LCMS prep (column XBridge C18, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate 60 mL / min) C 31H31FN7O3 (M + H) +: m / z = 568.2; found 568.3. Example 102. (R) -N- (2- (2- (Cyanomethyl) morpholino) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4- carboxamide
[00466] [00466] A solution of (R) - (4- (5- (4-cyanopyridin-3-yl) -2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) morpholin- 2-yl) methyl 4-methyl-benzenesulfonate (20 mg, 0.029 mmol) in EtOH (480 µL) was treated with potassium cyanide (5.6 mg, 0.086 mmol). The reaction mixture was stirred at 100 ˚C for 6 hours. The solvent was evaporated in vacuo, and the resulting residue was diluted with acetonitrile and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 ml / min) C30H25FN7O3 (M + H) +: m / z = 550.2; found 550.2. Example 103. (R) -N- (4- (4-cyanopyridin-3-yl) -2- (3-oxotetrahydro-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00467] [00467] This compound was prepared in a manner analogous to Example 51, steps 1-3, starting with tert-butyl (R) -2- (hydroxymethyl) piperazine-1-carboxylate instead of (2R, 5S) - -5- (hydroxymethyl) -2-methylpiperazin-1-carboxylate as a tert-butyl starting material. LCMS calculated for C34H35FN7O5 (M + H) +: m / z = 640.3; Found: 640.2. Step 2. (R) -4- (5- (4-cyanopyridin-3-yl) -2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -2- ( tert-butyl ((methylsulfonyl) oxy) methyl) piperazine-1-carboxylate
[00468] [00468] A solution of (R) -4- (5- (4-cyanopyridin-3-yl) -2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -2- tert-butyl (hydroxymethyl) piperazine-1-carboxylate (30 mg, 0.047 mmol) in CH2Cl2 (470 µL) was treated with triethylamine (13.1 µL, 0.094 mmol) and MsCl (5.5 µL, 0.070 mmol ) and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo. The obtained crude product was used for the next reaction without purification. LCMS calculated for
[00469] [00469] Potassium cyanide (9.2 mg, 0.142 mmol) was added to a solution of (R) -4- (5- (4-cyanopyridin-3-yl) -2- (2- (2-fluoro- Tert -butyl 6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -2 - (((methylsulfonyl) oxy) methyl) piperazine-1-carboxylate (34 mg, 0.047 mmol) in DMSO (475 µL) . The reaction mixture was stirred at 80 ˚C for 1 hour. After cooling to room temperature, the resulting solution was diluted with acetonitrile and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 mL / min ). C30H25FN7O4 (M + H) +: m / z = 566.2; found 566.3. Example 104. (S) -N- (5-Fluoro-2- (3- (hydroxymethyl) piperazin-1-yl) phenyl) - 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00470] [00470] This compound was prepared analogously to Example 6, starting with tert-butyl (S) -2- (hydroxymethyl) piperazine-1-carboxylate instead of ((3S, 5S) -5- (hydroxymethyl) pyrrolidine -3-yl) tert-butyl carbamate as starting material. LCMS calculated for C23H24F2N5O3 (M + H) +: m / z = 456.2; Found: 456.3. 1H NMR (400 MHz, DMSO) δ 11.03 - 10.69 (s, 1H), 9.48 - 9.26 (d, J = 5.0 Hz, 1H), 8.38 - 8.21 ( dd, J = 10.8, 3.0 Hz, 1H), 8.20 - 8.09 (d, J = 5.0 Hz, 1H), 7.68 - 7.51 (td, J = 8, 4, 6.9 Hz, 1H), 7.42 - 7.31 (dd, J = 8.8, 5.6 Hz, 1H), 7.13 - 6.96 (m, 3H), 3.83 - 3.71 (s, 3H), 3.59 - 3.18 (m, 6H), 3.15 - 2.79
[00471] [00471] This compound was prepared analogously to Example 51, starting with tert-butyl 3- (methoxymethyl) azetidine instead of tert-butyl (2R, 5S) - 5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate - departure rial. LCMS calculated for C29H26FN6O3 (M + H) +: m / z = 525.2; Found: 525.2. Example 106. (S) -N- (4- (4-Cyanopyridin-3-yl) -2- (2- (hydroxymethyl) azetin-din-1-yl) phenyl) -2- (2-fluoro-6- methoxyphenyl) pyrimidine-4-carboxamide
[00472] [00472] This compound was prepared analogously to Example 51, starting with (S) -azetidine-2-ylmethanol instead of 5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (2R, 5S) -de tert-butyl as starting material. LCMS calculated for C28H24FN6O3 (M + H) +: m / z = 511.2; Found: 511.2.
[00473] [00473] This compound was prepared analogously to Example 51, starting with (R) -azetidine-2-ylmethanol instead of (2R, 5S) - 5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate as starting material. LCMS calculated for C28H24FN6O3 (M + H) +: m / z = 511.2; Found: 511.2. Step 2. (R) - (1- (5- (4-cyanopyridin-3-yl) -2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) azetidin methanesulfonate -2-yl) methyl
[00474] [00474] A solution of (R) -N- (4- (4-cyanopyridin-3-yl) -2- (2- (hydroxymethyl) azetidin-1-yl) phenyl) -2- (2-fluoro -6-methoxyphenyl) pyrimidine-4-carboxamide (50 mg, 0.098 mmol) in CH2Cl2 (980 µL) was treated with triethylamine (27 µL, 0.196 mmol) and MsCl (11.4 µL, 0.147 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo. The crude product obtained was used in the next reaction without purification. LCMS calculated for C29H26FN6O5S (M + H) +: m / z = 589.2; found 589.3. Step 3. (R) -N- (4- (4-Cyanopyridin-3-yl) -2- (2 - ((dimethylamino) methyl) azetin-din-1-yl) phenyl) -2- (2-fluoro -6-methoxyphenyl) pyrimidine-4-carboxamide
[00475] [00475] A solution of (R) - (1- (5- (4-cyanopyridin-3-yl) -2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) azetidin- 2-yl) methyl methanesulfonate (20 mg, 0.034 mmol) in EtOH (570 µL) was treated with dimethylamine (544 µL, 1.09 mmol). The reaction mixture was stirred at 100 ˚C overnight. After cooling to room temperature, the solvent was evaporated in vacuo, and the resulting residue was diluted with acetonitrile and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA , at a flow rate of 60 mL / min) C30H29FN7O2 (M + H) +: m / z = 538.2; found 538.2. Example 108. N- (4- (4-Cyanopyridin-3-yl) -2- (4-methylpiperazin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide Step 1. N- (4- (4-cyanopyridin-3-yl) -2- (piperazin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00476] [00476] This compound was prepared analogously to Example 51, starting with tert-butyl piperazine-1-carboxylate instead of tert-butyl (2R, 5S) - 5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate butyl as a starting material. LCMS calculated for C28H25FN7O2 (M + H) +: m / z = 510.2; Found: 510.2. Step 2. N- (4- (4-Cyanopyridin-3-yl) -2- (4-methylpiperazin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide
[00477] [00477] A solution of N- (4- (4-cyanopyridin-3-yl) -2- (piperazin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4- carboxamide (15 mg, 0.029 mmol) in THF (980 µL) was treated with formaldehyde (37% by weight in H2O, 110 µL, 1.47 mmol), acetic acid (8.4 µL, 0.147 mmol) and triacetoxyboro -sodium hydride (12.5 mg, 0.059 mmol) and the reaction mixture was stirred at room temperature for 1 h. The solvent was then evaporated in vacuo, and the resulting residue was diluted with acetonitrile and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 mL / min). C29H27FN7O2 (M + H) +: m / z = 524.2; found 524.2. Example 109. N- (4- (4-Cyanopyridin-3-yl) -2- (4- (2-hydroxyethyl) piperazin-
[00478] [00478] A solution of N- (4- (4-cyanopyridin-3-yl) -2- (piperazin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4- carboxamide (15 mg, 0.029 mmol) in THF (980 µL) was treated with 2 - ((tert-butyldimethylsilyl) oxy) acetaldehyde (34 µL, 0.177 mmol), acetic acid (5.0 µL, 0.088 mmol) and sodium triacetoxyborohydride (12.5 mg, 0.059 mmol) and the reaction mixture was stirred at room temperature for 1 h. Upon completion, 4M HCl / dioxane (1 mL) was added and the reaction was allowed to stir for 30 min. The solvent was then evaporated in vacuo, and the resulting residue was diluted with acetonitrile and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at a flow rate of 60 mL / min). C30H29FN7O3 (M + H) +: m / z = 554.2; found 554.4. Example 110. (S) -N- (5-Fluoro-2- (3- (hydroxymethyl) piperazin-1-yl) -4-isopropylphenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide Step 1. (S) -4- (5-chloro-4-fluoro-2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -2- (hydroxymethyl) piperazine-1- tert-butyl carboxylate
[00479] [00479] This compound was prepared according to the procedures described in Example 41, using 1-chloro-2,5-difluoro-4-nitrobenzene instead of 3- (3-fluoro-4-nitrophenyl) isonicotinonitrila as starting material. LCMS calculated for C28H31ClF2N5O5 (M + H) +: m / z = 590.2; Found: 590.2. Step 2. (S) -4- (4-fluoro-2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carbo-xamido) -5- (prop-1-en-2-yl) tert-butyl phenyl) -2- (hydroxymethyl) piperazine-1-carboxylate
[00480] [00480] To a mixture of (S) -4- (5-chloro-4-fluoro-2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -2- (hydroxymethyl) tert-butyl piperazine-1-carboxylate (20 mg, 0.034 mmol), 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl) -1,3,2-dioxaborolane (9 , 6 µL, 0.051 mmol), Xphos Pd G2 (2.7 mg, 3.4 µmol) and potassium phosphate, tribasic (14.4 mg, 0.068 mmol) were added 1,4-dioxane (500 µL) and H2O (100 µL) and the reaction flask was evacuated, again filled with nitrogen and then stirred at 80 ° C for 1 hour. The reaction mixture was cooled to room temperature, the solvents were evaporated in vacuo and the crude product was purified by Biotage IsoleraTM (0-100% ethyl acetate in hexanes) to provide the desired product. LCMS calculated for C31H36F2N5O5 (M + H) +: m / z = 596.3; Found: 596.3. Step 3. (S) -N- (5-Fluoro-2- (3- (hydroxymethyl) piperazin-1-yl) -4-isopropylphenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4 -carboxamide
[00481] [00481] Palladium on carbon (10% wet, Degussa type, 3.6 mg) was added to a solution of (S) -4- (4-fluoro-2- (2- (2-fluoro-6-methoxy- teryl-butyl phenyl) pyrimidine-4-carboxamido) -5- (prop-1-en-2-yl) phenyl) -2- (hydroxymethyl) piperazine-1-carboxylate (20 mg, 0.034 mmol) - nol (1.1 ml). The reaction flask was connected to a hydrogen flask and the reaction mixture was stirred at room temperature for 2 hours. The catalyst was then removed by filtration, the solvent was evaporated in vacuo and TFA (2 ml) was added. The reaction mixture was stirred at room temperature for 15 min, then diluted with CH3CN and water and purified with LCMS prep (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.1% TFA, at flow rate of 60 mL / min). LCMS calculated for C26H30F2N5O3 (M + H) +: m / z = 498.2; Found: 498.3. Example A. HPK1 kinase binding assay
[00482] [00482] A 1 mM test compound stock solution was prepared in DMSO. The compound plate was prepared by serial dilutions of 3 times and 11 points. 0.1 L of the compound in DMSO was transferred from the compound plate to the 384-well white polystyrene plates. The assay buffer contained 50 mM HEPES, pH 7.5, 0.01% Tween-20, 5 mM MgCl2, 0.01% BSA, and 5 mM DTT. 5 µL of 4 nM of active HPK1 (SignalChem M23-11G) prepared in the buffer were added to the plate. The concentration of enzyme supplied was based on the stock concentration supplied reported by the seller. 5 µl of 18 nM of 222 tracker (ThermoFisher PV6121) and 4 nM of Lan- thaScreen Eu-Anti GST antibody (ThermoFisher PV5595) were added. After an hour of incubation at 25 ° C, the plates were read in a PHERAstar FS plate reader (BMG Labtech). The Ki values were determined.
[00483] [00483] One or more compounds of the invention can be tested using the p-SLP76S376 HTRF assay described below. Jurkat cells (cultured in RPMI1640 medium with 10% FBS) are collected and centrifuged, followed by resuspension in an appropriate medium at 3 x106 cells / mL. Jurkat cells (35 µL) are dispensed in each well in a 384-well plate. The test compounds are diluted with cell culture medium to a 40-fold dilution (addition of 39 µL of cell culture medium in 1 µL of compound). Jurkat cells in the well plate are treated with test compounds in various concentrations (adding 5 µl of compound diluted in 35 µL of Jurkat cells and starting from 3 µM with 1: 3 dilution) for 1 hour at 37 ° C , 5% CO2), followed by treatment with anti-CD3 (5 µg / mL, OKT3 clone) for 30 min. A 1:25 dilution of 100x blocking reagent (from the p-SLP76 ser376HTRF kit) with 4xLysis buffer (LB) is prepared and 15 µL of the 4xLB buffer with blocking reagent is added to each well and incubated at room temperature. 45 min with gentle agitation. Cell lysate (16 µL) is added to a white Greiner plate, treated with p-SLP76 ser376HTRF reagents (2 µL donor, 2ul acceptor) and incubated at 4 ° C overnight. Time-resolved homogeneous fluorescence (HTRF) is measured in a PHE-RAstar plate reader the next day. IC50 determination is performed by adapting the percent inhibition curve versus recording the inhibitor concentration using the GraphPad Prism 5.0 software. Example C. Isolation of CD4 + or CD8 + T cells and measurement of cytokines
[00484] [00484] Blood samples are collected from healthy donors.
[00485] [00485] One or more compounds can be tested using the regulatory T cell proliferation assay described below. Primary CD4 + / CD25- T cells and CD4 + / CD25 + regulatory T cells are isolated from human donated peripheral blood mononuclear cells using an isolated kit from Thermo Fisher Scientific (11363D). CD4 + / CD25- T cells are labeled with CFSE (Thermo Fisher Scientific, C34554) following the protocol provided by the supplier. CFSE-labeled T cells and CD4 + / CD25 + regulatory T cells are resuspended at a concentration of 1X 106 cells / mL in RPMI-
[00486] [00486] Several modifications of the invention, in addition to those shown in this document, will be evident to those skilled in the art from the description mentioned above.
Such modifications are intended to fall within the scope of the appended claims.
Each reference, including without limitation all patents, patent applications and publications, cited in this application is hereby incorporated by reference in its entirety.

权利要求:
Claims (93)
[1]
1. Compound, characterized by the fact that it has Formula (I '): I' or a pharmaceutically acceptable salt thereof, in which: CyA is C3-12 cycloalkyl or heterocycloalkyl of 4-12 members; wherein the 4-12 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; where N and S are optionally oxidized; wherein a 4-12 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein C3-12 cycloalkyl and 4-12 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected substituents from RA; A is N or CR16; R16 is selected from H, D, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa16, SRa16, C (O) Rb16, C (O) NRc16Rd16, C (O) ORa16, OC (O) Rb16, OC (O) NRc16Rd16, NRc16Rd16, NRc16C (O) Rb16, NRc16C (O) ORa16, NRc16C (O) NRc16Rd16, NRc16S (O) Rb16, NRc16S (O) 2Rb16, NRc16S (O) 2NRc16Rd16, S (O) Rb16, S (O) NRc16Rd16, S (O) 2Rb16, S (O) 2NRc16Rd16 and BRh16Ri16; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from Rg;
R1 is selected from H, D, halo, CN, C1-6 alkyl, ORa15 and NRc15Rd15; wherein C1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from Rg; R2 is selected from H, D, Cy2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa, SRa, C (O) Rb, C ( O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) ORa, NRcC (O) NRcRd, C (= NRe) Rb, C (= NORa) Rb, C (= NRe) NRcRd, NRcC (= NRe) NRcRd, NRcS (O) Rb, NRcS (O) 2Rb, NRcS (O) 2NRcRd, S (O) Rb, S (O) NRcRd, S (O) 2Rb, S (O) 2NRcRd and BRhRi; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10; Cy2 is selected from C3-10 cycloalkyl, heterocycloalkyl of 4-10 members, C6-10 aryl and heteroaryl of 5-10 members; wherein the 4-10 membered heterocycloalkyl and the 5-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein a 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10; Z is N or CR3; R3 is selected from H, D, Cy3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa4, SRa4, C (O) Rb4, C ( O) NRc4Rd4, C (O) ORa4, OC (O) Rb4, OC (O) NRc4Rd4, NRc4Rd4, NRc4C (O) Rb4, NRc4C (O) ORa4, NRc4C (O) NRc4Rd4, C (= NRe4) Rb4, C (= NORa4) Rb4, C (= NRe4) NRc4Rd4, NRc4C (= NRe4) NRc4Rd4,
NRc4S (O) Rb4, NRc4S (O) 2Rb4, NRc4S (O) 2NRc4Rd4, S (O) Rb4, S (O) NRc4Rd4, S (O) 2Rb4, S (O) 2NRc4Rd4 and BRh4Ri4; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R13; Cy3 is selected from C3-10 cycloalkyl, heterocycloalkyl of 4-10 members, C6-10 aryl and 5-10 membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and the 5-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein a 5-10 membered heteroaryl and 4-10 membered heteroarylalkyl carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R13; each R4 is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, NO2, ORa8, SRa8, C (O) Rb8, C (O) NRc8Rd8, C (O) ORa8, OC (O) Rb8, OC (O) NRc8Rd8, NRc8Rd8, NRc8C (O) Rb8, NRc8C ( O) ORa8, NRc8C (O) NRc8Rd8, C (= NRe8) Rb8, C (= NORa8) Rb8, C (= NRe8) NRc8Rd8, NRc8C (= NRe8) NRc8Rd8, NRc8S (O) Rb8, NRc8S (O) 2Rb8, NRc8S (O) 2NRc8Rd8, S (O) Rb8, S (O) NRc8Rd8, S (O) 2Rb8, S (O) 2NRc8Rd8 and BRh8Ri8; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocycloalkyl
4-10 members, C6-10 aryl, 5-10 members heteroaryl, C3-10 cycloalkyl-C1-3 alkylene, 4-10 members heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1- 3 5-10-membered C1-3 alkylene alkylene and heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R5; each R5 is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, ORa9, SRa9, C (O) Rb9, C (O) NRc9Rd9, C (O) ORa9, NRc9Rd9, NRc9C (O) Rb9, NRc9C (O) ORa9, NRc9S (O) Rb9, NRc9S (O) 2Rb9, NRc9S (O) 2NRc9Rd9, S (O) Rb9, S (O) NRc9Rd9, S (O) 2Rb9, S (O) 2NRc9Rd9 and BRh9Ri9; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene and 5-10 membered C1-3 alkylene heteroaryl are each optionally substituted by 1, 2, 3 or 4 substitutes independently selected from R6; each R6 is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo , D, CN, ORa10, SRa10, C (O) Rb10, C (O) NRc10Rd10, C (O) ORa10, NRc10Rd10, NRc10C (O) Rb10, NRc10C (O) ORa10, NRc10S (O) Rb10, NRc10S (O ) 2Rb10, NRc10S (O) 2NRc10Rd10, S (O) Rb10, S (O) NRc10Rd10, S (O) 2Rb10, and S (O) 2NRc10Rd10; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1 , 2, 3 or 4 substituents independently selected from Rg; each RA is selected H, D, Cy1, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa11, SRa11, C (O) Rb11, C (O) NRc11Rd11, C (O) ORa11, OC (O) Rb11, OC (O) NRc11Rd11, NRc11Rd11, NRc11C (O) Rb11, NRc11C (O) ORa11, NRc11C (O) NRc11Rd11, C (= NRe11) Rb11, C (= NORa11) Rb11, C (= NRe11) NRc11Rd11, NRc11C (= NRe11) NRc11Rd11, NRc11S (O) Rb11, NRc11S (O) 2Rb11, NRc11S (O) 2NRc11Rd11, S (O) Rb11, S (O) NRc11Rd O) 2Rb11, S (O) 2NRc11Rd11 and BRh11Ri11; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7; Cy1 is selected from C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 member and 5-10 membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and the 5-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein a 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7; each R7 is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, NO2, ORa12, SRa12, C (O) Rb12, C (O) NRc12Rd12, C (O) ORa12, OC (O) Rb12, OC (O) NRc12Rd12, NRc12Rd12, NRc12C (O) Rb12, NRc12C ( O) ORa12, NRc12C (O) NRc12Rd12, C (= NRe12) Rb12, C (= NORa12) Rb12, C (= NRe12) NRc12Rd12, NRc12C (= NRe12) NRc12Rd12, NRc12S (O) Rb12, NRc12S (O) 2Rb12, NRc12S (O) 2NRc12Rd12, S (O) Rb12, S (O) NRc12Rd12, S (O) 2Rb12, S (O) 2NRc12Rd12 and BRh12Ri12; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene and 5-10 membered heteroaryl-C1-3 alkylene are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R8; each R8 is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, ORa13, SRa13, C (O) Rb13, C (O) NRc13Rd13, C (O) ORa13, NRc13Rd13, NRc13C (O) Rb13, NRc13C (O) ORa13, NRc13S (O) Rb13, NRc13S (O) 2Rb13, NRc13S (O) 2NRc13Rd13, S (O) Rb13, S (O) NRc13Rd13, S (O) 2Rb13 S (O) 2NRc13Rd13 and BRh13Ri13; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-3 alkylene, 4 to 10 membered C1-3 alkylene heterocycloalkyl, C6-10 aryl-C1-3 alkylene and 5 to 10 membered C1-3 alkylene heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R9;
each R9 is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo , D, CN, ORa14, SRa14, C (O) Rb14, C (O) NRc14Rd14, C (O) ORa14, NRc14Rd14, NRc14C (O) Rb14, NRc14C (O) ORa14, NRc14S (O) Rb14, NRc14S (O ) 2Rb14, NRc14S (O) 2NRc14Rd14, S (O) Rb14, S (O) NRc14Rd14, S (O) 2Rb14 and S (O) 2NRc14Rd14; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from Rg; each R10 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, NO2, ORa1, SRa1, C (O) Rb1, C (O) NRc1Rd1, C (O) ORa1, OC (O) Rb1, OC (O) NRc1Rd1, NRc1Rd1, NRc1C (O) Rb1, NRc1C ( O) ORa1, NRc1C (O) NRc1Rd1, C (= NRe1) Rb1, C (= NORa1) Rb1, C (= NRe1) NRc1Rd1, NRc1C (= NRe1) NRc1Rd1, NRc1S (O) Rb1, NRc1S (O) 2Rb1, NRc1S (O) 2NRc1Rd1, S (O) Rb1, S (O) NRc1Rd1, S (O) 2Rb1, S (O) 2NRc1Rd1 and BRh1Ri1; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene and 5-10 membered C1-3 alkylene heteroaryl are each optionally substituted by 1, 2, 3 or 4 substitutes independently selected from R11; each R11 is independently selected from C1-6 alkyl, C2-6 alkyl
kenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-3 alkylene, heterocycloalkyl 4-10 members-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 members heteroaryl-C1-3 alkylene, halo, D, CN, ORa2, SRa2, C (O) Rb2, C ( O) NRc2Rd2, C (O) ORa2, NRc2Rd2, NRc2C (O) Rb2, NRc2C (O) ORa2, NRc2S (O) Rb2, NRc2S (O) 2Rb2, NRc2S (O) 2NRc2Rd2, S (O) Rb2, S (O) O) NRc2Rd2, S (O) 2Rb2 S (O) 2NRc2Rd2 and BRh2Ri2; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene and 5-10 membered heteroaryl-C1-3 alkylene are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R12; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl , halo, D, CN, ORa3, SRa3, C (O) Rb3, C (O) NRc3Rd3, C (O) ORa3, NRc3Rd3, NRc3C (O) Rb3, NRc3C (O) ORa3, NRc3S (O) Rb3, NRc3S (O) 2Rb3, NRc3S (O) 2NRc3Rd3, S (O) Rb3, S (O) NRc3Rd3, S (O) 2Rb3 and S (O) 2NRc3Rd3; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally subs substituted by 1, 2, 3 or 4 substituents independently selected from Rg; each R13 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, NO2, ORa5, SRa5, C (O) Rb5, C (O) NRc5Rd5, C (O) ORa5, OC (O) Rb5, OC (O) NRc5Rd5, NRc5Rd5, NRc5C (O) Rb5, NRc5C ( O) ORa5, NRc5C (O) NRc5Rd5, C (= NRe5) Rb5, C (= NORa5) Rb5, C (= NRe5) NRc5Rd5, NRc5C (= NRe5) NRc5Rd5, NRc5S (O) Rb5, NRc5S (O) 2Rb5, O NRc5S (O) 2NRc5Rd5, S (O) Rb5, S (O) NRc5Rd5, S (O) 2Rb5, S (O) 2NRc5Rd5 and BRh5Ri5; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene and 5-10 membered C1-3 alkylene heteroaryl are each optionally substituted by 1, 2, 3 or 4 substitutes independently selected from R14; each R14 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, ORa6, SRa6, C (O) Rb6, C (O) NRc6Rd6, C (O) ORa6, NRc6Rd6, NRc6C (O) Rb6, NRc6C (O) ORa6, NRc6S (O) Rb6, NRc6S (O) 2Rb6, NRc6S (O) 2NRc6Rd6, S (O) Rb6, S (O) NRc6Rd6, S (O) 2Rb6 S (O) 2NRc6Rd6 and BRh6Ri6; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene and 5-10 membered C1-3 alkylene heteroaryl are each optionally substituted by 1, 2, 3 or 4 substitutes independently selected from R15; each R15 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl , halo, D, CN,
ORa7, SRa7, C (O) Rb7, C (O) NRc7Rd7, C (O) ORa7, NRc7Rd7, NRc7C (O) Rb7, NRc7C (O) ORa7, NRc7S (O) Rb7, NRc7S (O) 2Rb7, NRc7S ( O) 2NRc7Rd7, S (O) Rb7, S (O) NRc7Rd7, S (O) 2Rb7 and S (O) 2NRc7Rd7; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from Rg; each Ra, Rc and Rd is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R10; or any Rc and Rd attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10; each Rb is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10; each Re is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1 -6 al-
kil) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh and Ri is independently selected from OH and C1-6 alkoxy; or any Rh and Ri attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, they form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra1, Rc1 and Rd1 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5-10 membered heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally subs substituted by 1, 2, 3 or 4 substituents independently selected from R11; or any Rc1 and Rd1 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R11; each Rb1 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R11; each Re1 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1-6 alkyl) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh1 and Ri1 is independently selected from OH and C1-6 alkoxy; or any Rh1 and Ri1 attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, they form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra2, Rc2 and Rd2 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5- 10 membered heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted substituted by 1, 2, 3 or 4 substituents independently selected from R12; or any Rc2 and Rd2 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R12; each Rb2 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R12; each Rh2 and Ri2 is independently selected from OH and C1-6 alkoxy; or any Rh2 and Ri2 attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, they form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra3, Rc3 and Rd3 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from Rg; each Rb3 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents selected from Rg; each Ra4, Rc4 and Rd4 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5-10 membered heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R13; or any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R13; each Rb4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally replaced by
1, 2, 3, or 4 substituents independently selected from R13; each Re4 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1-6 alkyl) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh4 and Ri4 is independently selected from OH and C1-6 alkoxy; or any Rh4 and Ri4 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra5, Rc5 and Rd5 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5-10 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and heteroaryl 5-10 members are each independently substituted by 1, 2, 3, or 4 substituents independently selected from R14; or any Rc5 and Rd5 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R14; each Rb5 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally replaced by
1, 2, 3 or 4 substituents independently selected from R14; each Re5 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1-6 alkyl) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh5 and Ri5 is independently selected from OH and C1-6 alkoxy; or any Rh5 and Ri5 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra6, Rc6 and Rd6 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5- 10 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and heteroaryl 5-10 members are each independently substituted by 1, 2, 3, or 4 substituents independently selected from R15; or any Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R15; each Rb6 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each independently substituted by 1, 2, 3, or 4 substituents independently selected from R15; each Rh6 and Ri6 is independently selected from OH and C1-6 alkoxy; or any Rh6 and Ri6 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra7, Rc7 and Rd7 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from Rg; each Rb7 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each independently substituted by 1, 2, 3, or 4 substituents independently selected from Rg; each Ra8, Rc8 and Rd8 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5-10 membered heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each independently substituted by 1, 2, 3, or 4 substituents independently selected from R5; or any Rc8 and Rd8 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R5;
each Rb8 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are, each independently substituted by 1, 2, 3 or 4 substituents independently selected from R5; each Re8 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1-6 alkyl) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh8 and Ri8 is independently selected from OH and C1-6 alkoxy; or any Rh8 and Ri8 attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, they form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra9, Rc9 and Rd9 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5-10 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and heteroaryl 5-10 members, are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R6; or any Rc9 and Rd9 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R6;
each Rb9 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are, each, optionally substituted by, 1, 2, 3 or 4 substituents independently selected from R6; each Rh9 and Ri9 is independently selected from OH and C1-6 alkoxy; or any Rh9 and Ri9 attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra10, Rc10 and Rd10 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by, 1, 2, 3 or 4 substituents independently selected from Rg; each Rb10 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by, 1, 2, 3 or 4 substituents independently selected from Rg; each Ra11, Rc11 and Rd11 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5- 10 members are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7; or any Rc11 and Rd11 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7; each Rb11 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are, each, optionally substituted by, 1, 2, 3 or 4 substituents independently selected from R7; each Re11 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1-6 alkyl) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh11 and Ri11 is independently selected from OH and C1-6 alkoxy; or any Rh11 and Ri11 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra12, Rc12 and Rd12 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5- 10 members are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R8; or any Rc12 and Rd12 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R8; each Rb12 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are, each, optionally substituted by, 1, 2, 3 or 4 substituents independently selected from R8; each Re12 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1-6 alkyl) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh12 and Ri12 is independently selected from OH and C1-6 alkoxy; or any Rh12 and Ri12 attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra13, Rc13 and Rd13 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl , are each optionally substituted by, 1, 2, 3 or 4 substituents independently selected from R9; or any Rc13 and Rd13 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R9; each Rb13 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are, each, optionally substituted by, 1, 2, 3 or 4 substituents independently selected from R9; each Rh13 and Ri13 is independently selected from OH and C1-6 alkoxy; or any Rh13 and Ri13 attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra14, Rc14 and Rd14 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by, 1, 2, 3 or 4 substituents independently selected from Rg; each Rb14 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by, 1, 2, 3 or 4 substituents independently selected from Rg; each Ra15, Rc15 and Rd15 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by, 1, 2, 3 or 4 substituents independently selected from Rg; each Ra16, Rc16 and Rd16 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by, 1, 2, 3 or 4 substituents independently selected from Rg; each Rb16 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl; wherein said C1-6 alkyl C2-6 alkenyl and C2-6 alkynyl a are each optionally substituted by, 1, 2, 3 or 4 substituents independently selected from Rg; each Rh16 and Ri16 is independently selected from OH and C1-6 alkoxy; or any Rh16 and Ri16 attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, they form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; and each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-2 alkylene, C1-6 alkoxy, C1-6 haloalkoxy, C1-3 alkoxy-C1-3 alkyl, C1-3 alkoxy-C1-3 alkoxy, HO-C1-3 alkoxy, HO-C1- 3 alkyl, cyano-C1- 3 alkyl, H2N-C1-3 alkyl, amino, C1-6 alkylmino, di (C1-6 alkyl) amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1-6 alkyl) carbamyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl-mino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di (C1-6 alkyl) di aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di (C1-6 alkyl) aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di (C1-6 alkyl) aminocarbonylamino; and n is 0, 1, 2, 3, 4;
[2]
2. Compound, characterized by the fact that it has Formula (I '): I' or a pharmaceutically acceptable salt thereof, in which: CyA is 4-12 membered heterocycloalkyl; wherein the 4-12 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming hetero atoms independently selected from N, O and S; wherein a 4-12 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 4-12 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from RA; A is N or CR16; R16 is selected from H, D, C1-6 alkyl, halo, CN and ORa16; R1 is selected from H, D, halo, CN, C1-6 alkyl and ORa15; where the
C1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from Rg; R2 is selected from H, D, Cy2, C1-6 alkyl, C1-6 haloalkyl, halo, CN; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10; Cy2 is selected from 4-10 membered heterocycloalkyl, C6-10 membered and 5-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N , O and S; wherein a 5-10 membered heteroaryl and 4-10 membered heteroarylalkyl carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 4-10 membered heterocycloalkyl and the 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected substituents from R10; Z is N or CR3; R3 is selected from H, D, Cy3, halo and CN; Cy3 is 6-10 membered heteroaryl; wherein the 6-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; each R4 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, D, CN and ORa8; RA is selected from H, D, Cy1, C1-6 alkyl, C1-6 haloalkyl, halo, CN, ORa11, C (O) NRc11Rd11, and NRc11Rd11; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7; Cy1 is selected from C3-10 cycloalkyl and 5-10 membered heteroaryl, where the 5-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3 or 4 heteroatoms forming ring independently selected from N, O and S; wherein a 5- to 10-membered heteroryl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 5-10 membered C3-10 cycloalkyl and heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7; each R7 is independently selected from C1-6 alkyl, halo, D, CN, ORa12 and NRc12Rd12; each R10 is independently selected from C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, ORa1, C (O) NRc1Rd1 and NRc1Rd1; wherein said C1-6 alkyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R11; each R11 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, D, CN and ORa2; each Ra1, Rc1 and Rd1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl and C3-10 cycloalkyl; wherein said C1-6 alkyl and C3-10 cycloalkyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R11; each Ra2, Rc2 and Rd2 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl; each Ra8, Rc8 and Rd8 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl; each Ra11, Rc11 and Rd11 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from R7; each Ra12, Rc12 and Rd12 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl;
each Ra15, Rc15 and Rd15 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from Rg; Ra16 is independently selected from H and C1-6 alkyl; each Rg is independently selected from OH, CN, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkyl, C1-6 alkylsulfonyl; and n is 0, 1, 2 or 3;
[3]
3. Compound, characterized by the fact that it presents Formula I: (R 4) n A N CyA
H N R3
The R2 R1
I or a pharmaceutically acceptable salt thereof, where: CyA is C3-12 cycloalkyl or 4-12 membered heterocycloalkyl; wherein the 4-12 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; where N and S are optionally oxidized; wherein a 4-12 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein C3-12 cycloalkyl and 4-12 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected substituents from RA; A is N or CF;
R1 is selected from H, D, halo, CN, C1-6 alkyl, ORa15 and NRc15Rd15; wherein the C1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from Rg; R2 is selected from H, D, Cy2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa, SRa, C (O) Rb, C ( O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) ORa, NRcC (O) NRcRd, C (= NRe) Rb, C (= NORa) Rb, C (= NRe) NRcRd, NRcC (= NRe) NRcRd, NRcS (O) Rb, NRcS (O) 2Rb, NRcS (O) 2NRcRd, S (O) Rb, S (O) NRcRd, S (O) 2Rb, S (O) 2NRcRd and BRhRi; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10; Cy2 is selected from C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and the 5-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein a 5-10 membered heteroaryl and 4-10 membered heteroarylalkyl carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10; R3 is selected from H, D, Cy3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa4, SRa4, C (O) Rb4, C ( O) NRc4Rd4, C (O) ORa4, OC (O) Rb4, OC (O) NRc4Rd4, NRc4Rd4, NRc4C (O) Rb4, NRc4C (O) ORa4, NRc4C (O) NRc4Rd4, C (= NRe4) Rb4, C (= NORa4) Rb4, C (= NRe4) NRc4Rd4, NRc4C (= NRe4) NRc4Rd4, NRc4S (O) Rb4, NRc4S (O) 2Rb4, NRc4S (O) 2NRc4Rd4, S (O) Rb4,
S (O) NRc4Rd4, S (O) 2Rb4, S (O) 2NRc4Rd4 and BRh4Ri4; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R13; Cy3 is selected from C3-10 cycloalkyl, heterocycloalkyl of 4-10 members, C6-10 aryl and heteroaryl of 5-10 members; wherein the 4-10 membered heterocycloalkyl and the 5-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein a 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R13; each R4 is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, NO2, ORa8, SRa8, C (O) Rb8, C (O) NRc8Rd8, C (O) ORa8, OC (O) Rb8, OC (O) NRc8Rd8, NRc8Rd8, NRc8C (O) Rb8, NRc8C ( O) ORa8, NRc8C (O) NRc8Rd8, C (= NRe8) Rb8, C (= NORa8) Rb8, C (= NRe8) NRc8Rd8, NRc8C (= NRe8) NRc8Rd8, NRc8S (O) Rb8, NRc8S (O) 2Rb8, NRc8S (O) 2NRc8Rd8, S (O) Rb8, S (O) NRc8Rd8, S (O) 2Rb8, S (O) 2NRc8Rd8 and BRh8Ri8; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl
alkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene and 5-10 membered heteroaryl-C1-3 alkylene are each optionally replaced by 1, 2, 3 or 4 substitutes independently selected from R5; each R5 is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, ORa9, SRa9, C (O) Rb9, C (O) NRc9Rd9, C (O) ORa9, NRc9Rd9, NRc9C (O) Rb9, NRc9C (O) ORa9, NRc9S (O) Rb9, NRc9S (O) 2Rb9, NRc9S (O) 2NRc9Rd9, S (O) Rb9, S (O) NRc9Rd9, S (O) 2Rb9, S (O) 2NRc9Rd9 and BRh9Ri9; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene and 5-10 membered C1-3 alkylene heteroaryl are each optionally substituted by 1, 2, 3 or 4 substitutes independently selected from R6; each R6 is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo , D, CN, ORa10, SRa10, C (O) Rb10, C (O) NRc10Rd10, C (O) ORa10, NRc10Rd10, NRc10C (O) Rb10, NRc10C (O) ORa10, NRc10S (O) Rb10, NRc10S (O ) 2Rb10, NRc10S (O) 2NRc10Rd10, S (O) Rb10, S (O) NRc10Rd10, S (O) 2Rb10, and S (O) 2NRc10Rd10; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1 , 2, 3 or 4 substituents independently selected from Rg;
RA is selected from H, D, Cy1, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, NO2, ORa11, SRa11, C (O) Rb11, C ( O) NRc11Rd11, C (O) ORa11, OC (O) Rb11, OC (O) NRc11Rd11, NRc11Rd11, NRc11C (O) Rb11, NRc11C (O) ORa11, NRc11C (O) NRc11Rd11, C (= NRe11) Rb11, C (= NORa11) Rb11, C (= NRe11) NRc11Rd11, NRc11C (= NRe11) NRc11Rd11, NRc11S (O) Rb11, NRc11S (O) 2Rb11, NRc11S (O) 2NRc11Rd11, S (O) Rb11, S (O) NRcR, S (O) 2Rb11, S (O) 2NRc11Rd11 and BRh11Ri11; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R7; Cy1 is selected from C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 member and 5-10 membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and the 5-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein a 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7; each R7 is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, NO2, ORa12, SRa12, C (O) Rb12, C (O) NRc12Rd12, C (O) ORa12, OC (O) Rb12, OC (O) NRc12Rd12,
NRc12Rd12, NRc12C (O) Rb12, NRc12C (O) ORa12, NRc12C (O) NRc12Rd12, C (= NRe12) Rb12, C (= NORa12) Rb12, C (= NRe12) NRc12Rd12, NRc12C (= NRe12) NRc12Rd, NRc12Rd O) Rb12, NRc12S (O) 2Rb12, NRc12S (O) 2NRc12Rd12, S (O) Rb12, S (O) NRc12Rd12, S (O) 2Rb12, S (O) 2NRc12Rd12 and BRh12Ri12; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene and 5-10 membered heteroaryl-C1-3 alkylene are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R8; each R8 is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, ORa13, SRa13, C (O) Rb13, C (O) NRc13Rd13, C (O) ORa13, NRc13Rd13, NRc13C (O) Rb13, NRc13C (O) ORa13, NRc13S (O) Rb13, NRc13S (O) 2Rb13, NRc13S (O) 2NRc13Rd13, S (O) Rb13, S (O) NRc13Rd13, S (O) 2Rb13 S (O) 2NRc13Rd13 and BRh13Ri13; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-3 alkylene, 4 to 10 membered C1-3 alkylene heterocycloalkyl, C6-10 aryl-C1-3 alkylene and 5 to 10 membered C1-3 alkylene heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R9; each R9 is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo , D, CN, ORa14, SRa14, C (O) Rb14, C (O) NRc14Rd14, C (O) ORa14, NRc14Rd14, NRc14C (O) Rb14, NRc14C (O) ORa14, NRc14S (O) Rb14, NRc14S (O ) 2Rb14, NRc14S (O) 2NRc14Rd14, S (O) Rb14, S (O) NRc14Rd14, S (O) 2Rb14 and S (O) 2NRc14Rd14; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from Rg; each R10 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, NO2, ORa1, SRa1, C (O) Rb1, C (O) NRc1Rd1, C (O) ORa1, OC (O) Rb1, OC (O) NRc1Rd1, NRc1Rd1, NRc1C (O) Rb1, NRc1C ( O) ORa1, NRc1C (O) NRc1Rd1, C (= NRe1) Rb1, C (= NORa1) Rb1, C (= NRe1) NRc1Rd1, NRc1C (= NRe1) NRc1Rd1, NRc1S (O) Rb1, NRc1S (O) 2Rb1, NRc1S (O) 2NRc1Rd1, S (O) Rb1, S (O) NRc1Rd1, S (O) 2Rb1, S (O) 2NRc1Rd1 and BRh1Ri1; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene and 5-10 membered C1-3 alkylene heteroaryl are each optionally substituted by 1, 2, 3 or 4 substitutes independently selected from R11; each R11 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, ORa2, SRa2, C (O) Rb2, C (O) NRc2Rd2, C (O) ORa2, NRc2Rd2, NRc2C (O) Rb2, NRc2C (O) ORa2, NRc2S (O) Rb2, NRc2S (O) 2Rb2, NRc2S (O) 2NRc2Rd2, S (O) Rb2, S (O) NRc2Rd2, S (O) 2Rb2 S (O) 2NRc2Rd2 and BRh2Ri2; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene and 5-10 membered C1-3 alkylene heteroaryl are each optionally substituted by 1, 2, 3 or 4 substitutes independently selected from R12; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl , halo, D, CN, ORa3, SRa3, C (O) Rb3, C (O) NRc3Rd3, C (O) ORa3, NRc3Rd3, NRc3C (O) Rb3, NRc3C (O) ORa3, NRc3S (O) Rb3, NRc3S (O) 2Rb3, NRc3S (O) 2NRc3Rd3, S (O) Rb3, S (O) NRc3Rd3, S (O) 2Rb3 and S (O) 2NRc3Rd3; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally subs substituted by 1, 2, 3 or 4 substituents independently selected from Rg; each R13 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, NO2, ORa5, SRa5, C (O) Rb5, C (O) NRc5Rd5, C (O) ORa5, OC (O) Rb5, OC (O) NRc5Rd5, NRc5Rd5, NRc5C (O) Rb5, NRc5C ( O) ORa5, NRc5C (O) NRc5Rd5, C (= NRe5) Rb5, C (= NORa5) Rb5,
C (= NRe5) NRc5Rd5, NRc5C (= NRe5) NRc5Rd5, NRc5S (O) Rb5, NRc5S (O) 2Rb5, NRc5S (O) 2NRc5Rd5, S (O) Rb5, S (O) NRc5Rd5, S (O) 2Rb, S (O) 2NRc5Rd5 and BRh5Ri5; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene and 5-10 membered heteroaryl-C1-3 alkylene are each optionally substituted by 1, 2, 3 or 4 substitutes independently selected from R14; each R14 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-heteroaryl -10 members, C3-10 cycloalkyl-C1-3 alkylene, 4-10 member heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 member heteroaryl-C1-3 alkylene, halo, D, CN, ORa6, SRa6, C (O) Rb6, C (O) NRc6Rd6, C (O) ORa6, NRc6Rd6, NRc6C (O) Rb6, NRc6C (O) ORa6, NRc6S (O) Rb6, NRc6S (O) 2Rb6, NRc6S (O) 2NRc6Rd6, S (O) Rb6, S (O) NRc6Rd6, S (O) 2Rb6 S (O) 2NRc6Rd6 and BRh6Ri6; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene and 5-10 membered C1-3 alkylene heteroaryl are each optionally substituted by 1, 2, 3 or 4 substitutes independently selected from R15; each R15 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl , halo, D, CN, ORa7, SRa7, C (O) Rb7, C (O) NRc7Rd7, C (O) ORa7, NRc7Rd7, NRc7C (O) Rb7, NRc7C (O) ORa7, NRc7S (O) Rb7, NRc7S (O) 2Rb7, NRc7S (O) 2NRc7Rd7, S (O) Rb7, S (O) NRc7Rd7, S (O) 2Rb7 and
S (O) 2NRc7Rd7; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from Rg; each Ra, Rc and Rd is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R10; or any Rc and Rd attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10; each Rb is independently selected from C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10; each Re is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1 -6 alkyl) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh and Ri is independently selected from OH and C1-6 alkoxy; or any Rh and Ri attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, they form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra1, Rc1 and Rd1 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5-10 membered heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally subs substituted by 1, 2, 3 or 4 substituents independently selected from R11; or any Rc1 and Rd1 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R11; each Rb1 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R11; each Re1 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1-6 alkyl) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh1 and Ri1 is independently selected from OH and C1-6 alkoxy; or any Rh1 and Ri1 attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, they form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra2, Rc2 and Rd2 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5-10 membered heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally subs substituted by 1, 2, 3 or 4 substituents independently selected from R12; or any Rc2 and Rd2 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R12; each Rb2 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R12; each Rh2 and Ri2 is independently selected from OH and C1-6 alkoxy; or any Rh2 and Ri2 attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, they form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra3, Rc3 and Rd3 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl; in which said
C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from Rg; each Rb3 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents selected from Rg; each Ra4, Rc4 and Rd4 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5-10 membered heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R13; or any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R13; each Rb4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R13; each Re4 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1-6 alkyl) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh4 and Ri4 is independently selected from OH and C1-6 alkoxy; or any Rh4 and Ri4 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra5, Rc5 and Rd5 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5-10 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and heteroaryl 5-10 members are each independently substituted by 1, 2, 3, or 4 substituents independently selected from R14; or any Rc5 and Rd5 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R14; each Rb5 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R14; each Re5 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1-6 alkyl) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh5 and Ri5 is independently selected from OH and C1-6 alkoxy; or any Rh5 and Ri5 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra6, Rc6 and Rd6 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5- 10 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and heteroaryl 5-10 members are each independently substituted by 1, 2, 3, or 4 substituents independently selected from R15; or any Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R15; each Rb6 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each independently substituted by 1, 2, 3, or 4 substituents independently selected from R15; each Rh6 and Ri6 is independently selected from OH and C1-6 alkoxy; or any Rh6 and Ri6 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra7, Rc7 and Rd7 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from Rg; each Rb7 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each independently substituted by 1, 2, 3, or 4 substituents independently selected from Rg; each Ra8, Rc8 and Rd8 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5-10 membered heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each independently substituted by 1, 2, 3, or 4 substituents independently selected from R5; or any Rc8 and Rd8 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R5; each Rb8 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are, each independently substituted by 1, 2, 3 or 4 substituents independently selected from R5; each Re8 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1-6 alkyl) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh8 and Ri8 is independently selected from OH and C1-6 alkoxy; or any Rh8 and Ri8 attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, they form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra9, Rc9 and Rd9 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- 10 aryl and 5-10 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and heteroaryl 5-10 members, are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R6; or any Rc9 and Rd9 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R6; each Rb9 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are, each, optionally substituted by, 1, 2, 3 or 4 substituents independently selected from R6; each Rh9 and Ri9 is independently selected from OH and C1-6 alkoxy; or any Rh9 and Ri9 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra10, Rc10 and Rd10 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by, 1, 2, 3 or 4 substituents independently selected from Rg; each Rb10 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted 1, 2, 3, or 4 substituents independently selected from Rg; each Ra11, Rc11 and Rd11 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5- 10 members are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7; or any Rc11 and Rd11 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7;
each Rb11 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R7; each Re11 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1-6 alkyl) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh11 and Ri11 is independently selected from OH and C1-6 alkoxy; or any Rh11 and Ri11 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra12, Rc12 and Rd12 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5- 10 members are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R8; or any Rc12 and Rd12 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2,
3 or 4 substituents independently selected from R8; each Rb12 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are, each, optionally substituted by, 1, 2, 3 or 4 substituents independently selected from R8; each Re12 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, di (C1-6 alkyl) carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di (C1-6 alkyl) aminosulfonyl; each Rh12 and Ri12 is independently selected from OH and C1-6 alkoxy; or any Rh12 and Ri12 attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra13, Rc13 and Rd13 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5- 10 members are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R9; or any Rc13 and Rd13 attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R9; each Rb13 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-heteroaryl -10 members, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are, each, optionally substituted by, 1, 2, 3 or 4 substituents independently selected from R9; each Rh13 and Ri13 is independently selected from OH and C1-6 alkoxy; or any Rh13 and Ri13 attached to the same atom B are C2-3 dialkoxy and together with the atom B to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl; each Ra14, Rc14 and Rd14 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by, 1, 2, 3 or 4 substituents independently selected from Rg; each Rb14 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by, 1, 2, 3 or 4 substituents independently selected from Rg; each Ra15, Rc15 and Rd15 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from Rg; each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-2 alkylene , C1-6 alkoxy, C1-6 haloalkoxy, C1-3 alkoxy-C1-3 alkyl, C1-3 alkoxy-C1-3 alkoxy, HO-C1-3 alkoxy, HO-C1- 3 alkyl, cyano-C1-3 alkyl, H2N-C1-3 alkyl, amino, C1-6 alkylmino, di (C1-6 alkyl) amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl , di (C1-6 alkyl) carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di (C1-6 alkyl) aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di (C1-6 alkyl) aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di (C1-6 alkyl) aminocarbonylamino; and n is 0, 1, 2, 3, or 4;
[4]
4. Compound, characterized by the fact that it presents Formula I: (R 4) n A N CyA
H N R3
The R2 R1
I or a pharmaceutically acceptable salt thereof, wherein: CyA is 4-12 membered heterocycloalkyl; wherein the 4-12 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming hetero atoms independently selected from N, O and S; wherein a 4-12 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 4-12 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from RA; A is N; R1 is selected from H, D, halo, CN, C1-6 alkyl and ORa15; wherein the C1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from Rg; R2 is selected from H, D, Cy2, C1-6 alkyl, C1-6 haloalkyl, halo, CN; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10; Cy2 is selected from 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and the 5-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming hetero atoms independently selected from N, O and S; wherein a carbon atom forming a 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the 4-10 membered heterocycloalkyl and the 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected substituents from R10; R3 is selected from H, D, Cy3, halo and CN; Cy3 is a 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein a 5-10 membered heteroaryl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 5-10 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R13; each R4 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, D, CN and ORa8; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R5; each R5 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, D, CN, ORa9 and NRc9Rd9; RA is selected from H, D, Cy1, C1-6 alkyl, C1-6 haloalkyl, halo, CN, ORa11, C (O) NRc11Rd11, and NRc11Rd11; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from R7; Cy1 is a 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein a 5-10 membered heteroaryl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substitutes independently selected from R7; each R7 is independently selected from C1-6 alkyl, halo, D, CN, ORa12 and NRc12Rd12; each R10 is independently selected from C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, ORa1, C (O) NRc1Rd1 and NRc1Rd1; wherein said C1-6 alkyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R11; each R11 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, D, CN and ORa2;
each R13 is independently selected from C1-6 alkyl and C1-6 haloalkyl; each Ra1, Rc1 and Rd1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl and C3-10 cycloalkyl; wherein said C1-6 alkyl and C3-10 cycloalkyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R11; each Ra2, Rc2 and Rd2 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl; each Ra8, Rc8 and Rd8 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl; each Ra9, Rc9 and Rd9 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl; each Ra11, Rc11 and Rd11 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from R7; each Ra12, Rc12 and Rd12 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl; each Ra15, Rc15 and Rd15 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from Rg; each Rg is independently selected from OH, CN, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkyl, C1-6 alkylsulfonyl; and n is 0, 1, 2 or 3;
[5]
A compound according to any one of claims 1 and 3, or a pharmaceutically acceptable salt thereof, characterized by the fact that CyA is 4-12 membered heterocycloalkyl; wherein the 4-12 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein a 4-12 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 4-12 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from RA.
[6]
A compound according to any one of claims 1 and 3, or a pharmaceutically acceptable salt thereof, characterized by the fact that CyA is C3-10 cycloalkyl, wherein C3-10 cycloalkyl is optionally replaced by 1, 2 or 3 substituents independently selected from AR.
[7]
A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized by the fact that each RA is independently selected from Cy1, C1-6 alkyl, ORa11, C (O ) NRc11Rd11, and NRc11Rd11; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from R7.
[8]
A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized by the fact that each RA is independently C1-6 alkyl; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from R7.
[9]
A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized by the fact that each RA is independently selected from methyl and ethyl; wherein said methyl and ethyl are each optionally substituted by 1, 2 or 3 substituents independently selected from R7.
[10]
10. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized by the fact that each RA is independently selected from OH, NH2, aminomethyl, hydroxymethyl, methoxymethyl, pyridinyl, ethyl, hydroxyethyl and propylcarbamoyl.
[11]
A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized by the fact that each RA is independently Cy1.
[12]
A compound according to any one of claims 1 to 7 and 11, or a pharmaceutically acceptable salt thereof, characterized by the fact that Cy1 is selected from C3-10 cycloalkyl and 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein a 5-10 membered heteroaryl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein C3-10 cycloalkyl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7.
[13]
13. A compound according to any one of claims 1 to 7 and 11, or a pharmaceutically acceptable salt thereof, characterized by the fact that Cy1 is selected from C3-10 cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7.
[14]
A compound according to any one of claims 1 to 7 and 11, or a pharmaceutically acceptable salt thereof, characterized by the fact that Cy1 is 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; and wherein the 5-10 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R7.
[15]
A compound according to any one of claims 1 to 7 and 11, or a pharmaceutically acceptable salt thereof, characterized by the fact that Cy1 is pyridinyl.
[16]
16. A compound according to any one of claims 1 to 7 and 11, or a pharmaceutically acceptable salt thereof, characterized by the fact that Cy1 is cyclopropyl.
[17]
17. A compound according to any one of claims 1 to 9 and 11 to 14, or a pharmaceutically acceptable salt thereof, characterized in that R7 is independently selected from C1-6 alkyl, halo, D, CN, ORa12 and NRc12Rd12.
[18]
18. A compound according to any one of claims 1 to 9 and 11 to 14, or a pharmaceutically acceptable salt thereof, characterized by the fact that each R7 is independently selected from CN, ORa12, NRc12Rd12 and D.
[19]
19. A compound according to any one of claims 1 to 9 and 11 to 14, or a pharmaceutically acceptable salt thereof, characterized in that each R7 is independently selected from D, CN, OH, NH2, and methoxy.
[20]
20. A compound according to any one of claims 1 to 9, 11 to 14, 17 and 18, or a pharmaceutically acceptable salt thereof, characterized by the fact that Ra12 is H.
[21]
21. A compound according to any one of claims 1 to 9, 11 to 14, 17 and 18, or a pharmaceutically acceptable salt thereof, characterized in that Rc12 and Rd12 are each H.
[22]
22. A compound according to any one of the claims
sections 1 to 4, or a pharmaceutically acceptable salt thereof, characterized by the fact that CyA is selected from 2,5-diazabicyclo [2.2.1] heptan-2-ila; 3-aminopyrrolidin-1-yl; 2- (aminomethyl) pyrrolidin-1-yl; 2- (hydroxymethyl) pyrrolidin-1-yl; 2- (methoxymethyl) pyrrolidin-1-yl; 4-amino-2- (hydroxymethyl) pyrrolidin-1-yl; 4-hydroxy-2-methylpyrrolidin-1-yl; 2- (pyridin-2-yl) pyrrolidin-1-yl; hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -yl; 2-methylpiperazin-1-yl; 2- (hydroxymethyl) piperazin-1-yl; 3- (hydroxymethyl) morpholino; 5-ethyl-2,5-diaza-bicyclo [2.2.1] heptan-2-yl; (2-hydroxyethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl); 5- (propylcarbamoyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl; 4-hydroxy-2- (hydroxymethyl) pyrrolidin-1-yl; 2- (hydroxymethyl) -5-methylpiperazin-1-yl; 6- (hydroxymethyl) -4,7-diazaspiro [2.5] octan-7-yl; 4-amino-2- (1-hydroxycyclopropyl) pyrrolidin-1-yl; 4-amino-2- (2-hydroxypropan-2-yl) pyrrolidin-1-yl; 4-amino-2- (hydroxymethyl-d2) pyrrolidin-1-yl; 3- (hydroxymethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl; 4-amino-2-methylpiperidin-1-yl; piperidin-4-yl; 4- (dimethylamino) -2- (hydroxymethyl) pyrrolidin-1-yl; 2- (hydroxymethyl) -4- (isopropylamino) pyrrolidin-1-yl; 4- (hydroxymethyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl; 2- (hydroxymethyl) morpholino; 2- (2 - ((dimethylamino) methyl) morpholino; 2- (cyanomethyl) morpholino; 3-oxotetrahydro-3H-oxazolo [3,4- a] pyrazin-7 (1H) -yl; 3- ( hydroxymethyl) piperazin-1-yl; 3- (methoxymethyl) azetidin-1-yl; 2- (hydroxymethyl) azetidin-1-yl; 2 - ((dimethylamino) methyl) azetidin-1-yl; 4-methylpiperazin- 1-yl; and 4- (2-hydroxyethyl) piperazin-1-yl.
[23]
23. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized by the fact that CyA is selected from 2,5-diazabicyclo [2.2.1] hep- tan- 2-yl; 3-aminopyrrolidin-1-yl; 2- (aminomethyl) pyrrolidin-1-yl; 2- (hydroxymethyl) pyrrolidin-1-yl; 2- (methoxymethyl) pyrrolidin-1-yl; 4-amino-2- (hydroxymethyl) pyrrolidin-1-yl; 4-hydroxy-2-methylpyrrolidin-1-yl; 2- (pyridin-2-yl) pyrrolidin-1-yl; hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -yl; 2-methylpiperazin-1-yl; 2- (hydroxymethyl) piperazin-1-yl; 3- (hydroxymethyl) morpholino; 5-ethyl-2,5-diaza-bicycl [2.2.1] heptan-2-yl; (2-hydroxyethyl) -2,5-diazabicyclo [2.2.1] heptan-2-
il); and 5- (propylcarbamoyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl.
[24]
24. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized by the fact that CyA is 4-amino-2- (hydroxymethyl) pyrrolidin-1-yl.
[25]
25. A compound according to any one of claims 1 and 3, characterized by the fact that CyA is selected from cyclopentyl and cyclohexyl, wherein cyclopentyl and cyclohexyl are optionally substituted by NH2 .
[26]
26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, characterized in that R1 is selected from H, D, halo, CN, C1-6 alkyl and ORa15; wherein the C1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from Rg.
[27]
27. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, characterized in that R1 is selected from H, D, F, CN, methyl, hydroxymethyl and methoxy.
[28]
28. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, characterized by the fact that R1 is H.
[29]
29. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, characterized by the fact that R1 is F.
[30]
30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, characterized in that R2 is selected from H, D, Cy2, C1-6 alkyl, halo, and S (O) 2Rb; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10.
[31]
31. A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, characterized by the fact that R2 is selected from isopropyl, F, Cl, Br, and S (O) 2CH3 .
[32]
32. A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, characterized by the fact that R2 is Cy2.
[33]
33. A compound according to any one of claims 1 to 30 and 32, or a pharmaceutically acceptable salt thereof, characterized by the fact that Cy2 is selected from 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and the 5-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O, and S; wherein a 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R10.
[34]
34. A compound according to any one of claims 1 to 30 and 32, or a pharmaceutically acceptable salt thereof, characterized by the fact that Cy2 is C6-10 aryl optionally substituted by 1, 2, 3 or 4 independently selected substituents from R10.
[35]
35. A compound according to any one of claims 1 to 30 and 32 to 34, or a pharmaceutically acceptable salt thereof, characterized in that each R10 is independently selected from C1-6 alkyl, 4-10 heterocycloalkyl members, halo,
CN, OH, ORa1, C (O) NRc1Rd1 and NRc1Rd1; wherein said C1-6 alkyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R11.
[36]
36. A compound according to any one of claims 1 to 30 and 32 to 34, or a pharmaceutically acceptable salt thereof, characterized in that each R10 is independently selected from OH, F, CN, methyl, hydroxymethyl, methylcarbamoyl, methoxy, morpholino and cyclobutylamino.
[37]
37. A compound according to any one of claims 1 to 30 and 32 to 35, or a pharmaceutically acceptable salt thereof, characterized by the fact that Ra1, Rc1 and Rd1 is independently selected from H, C1-6 alkyl, and C3-10 cycloalkyl; wherein said C1-6 alkyl and C3-10 cycloalkyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R11.
[38]
38. A compound according to any one of claims 1 to 30, 32 to 35 and 37, or a pharmaceutically acceptable salt thereof, characterized in that R11 is ORa2.
[39]
39. A compound according to any one of claims 1 to 30, 32 to 35, 37 and 38, or a pharmaceutically acceptable salt thereof, characterized in that R11 is OH.
[40]
40. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, characterized by the fact that Cy2 is selected from 1-methyl-1H-pyrazol-4-yl; 6- (hydroxymethyl) pyridin-3-yl; 6- (methylcarbamoyl) pyridin-3-yl; 1-methyl-6-oxo-1,6-dihydropyridin-3-yl; 2-methylpyridin-3-yl; 4-methoxypyridin-3-yl; 4-cyanopiridin-3-yl; 1,3,5-trimethyl-1H-pyrazol-4-yl; morpholino; azetidin-1-yl; 2- (methoxymethyl) azetidin-1-yl); 3-cyanopyridin-4-yl; 3-methoxypyridin-4-yl; 2-cyano-6-fluorophenyl; 3-cyanopyridin-2-yl; 4-cyano-1-methyl-1H-pyrazol-5-yl;
tetrahydro-2H-pyran-4-yl; 5-cyano-2- (pyrrolidin-1-yl) pyridin-4-yl; and 1-cyano-cyclopropyl.
[41]
41. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, characterized by the fact that Cy2 is selected from 1-methyl-1H-pyrazol-4-yl; 6- (hydroxymethyl) pyridin-3-yl; 6- (methylcarbamoyl) pyridin-3-yl; 1-methyl-6-oxo-1,6-dihydropyridin-3-yl; 2-methylpyridin-3-yl; 4-methoxypyridin-3-yl; 4-cyanopiridin-3-yl; 1,3,5-trimethyl-1H-pyrazol-4-yl; morpholino; and azetidin-1-yl.
[42]
42. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, characterized by the fact that Cy2 is selected from 3-cyanopyridin-4-yl; 4-cyanopyridin-3-yl; and 3-cyanopyridin-2-yl.
[43]
43. A compound according to any one of claims 1 and 2, or a pharmaceutically acceptable salt thereof, characterized by the fact that Z is CR3.
[44]
44. A compound according to any one of claims 1 and 2, or a pharmaceutically acceptable salt thereof, characterized by the fact that Z is N.
[45]
45. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, characterized by the fact that R3 is selected from H, D, Cy3, halo and CN.
[46]
46. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, characterized by the fact that R3 is selected from H, D, F, Br, and CN.
[47]
47. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, characterized by the fact that R3 is H.
[48]
48. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, characterized by the fact that R3 is Cy3.
[49]
49. A compound according to any one of claims 1 to 43, 45 and 48, or a pharmaceutically acceptable salt thereof, characterized by the fact that Cy3 is 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O, and S; wherein a 5-10 membered heteroaryl ring-forming carbon atom is optionally substituted by oxo to form a carbonyl group; and wherein the 5-10 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R13.
[50]
50. A compound according to any one of claims 1 to 43, 45, 48 and 49, or a pharmaceutically acceptable salt thereof, characterized by the fact that each R13 is independently C1-6 alkyl.
[51]
51. A compound according to any one of claims 1 to 43, 45 and 49, or a pharmaceutically acceptable salt thereof, characterized by the fact that R13 is methyl.
[52]
52. A compound according to any one of claims 1 to 43 and 45, or a pharmaceutically acceptable salt thereof, characterized by the fact that Cy3 is selected from pyridin-3-yl and 1-methyl-1H-pyrazole- 4-ila.
[53]
53. A compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, characterized in that each R4 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3- 10 cycloalkyl, halo, D, CN, and ORa8; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R5.
[54]
54. A compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, characterized in that each R4 is independently selected from
C1-6 alkyl, C1-6 haloalkyl, halo, D, CN, and ORa8.
[55]
55. A compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, characterized by the fact that each R4 is independently selected from halo and ORa8.
[56]
56. A compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, characterized in that each R4 is independently selected from halo.
[57]
57. A compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, characterized by the fact that each R4 is independently selected from F and Cl.
[58]
58. A compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, characterized in that each R4 is independently selected from F and methoxy.
[59]
59. A compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, characterized in that each R4 is independently selected from F and methyl.
[60]
60. A compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, characterized by the fact that each R4 is F.
[61]
61. A compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, characterized in that each R5 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, D, CN, ORa9, and NRc9Rd9.
[62]
62. A compound according to any one of the claims
1 to 55, or a pharmaceutically acceptable salt thereof, characterized by the fact that each R5 is independently selected from D and F.
[63]
63. A compound according to any one of claims 1 to 30 and 32 to 38, or a pharmaceutically acceptable salt thereof, characterized by the fact that each Ra2, Rc2, and Rd2 is independently H.
[64]
64. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, characterized by the fact that each Ra8, Rc8, and Rd8 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl.
[65]
65. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, characterized by the fact that each Ra11, Rc11, and Rd11 is independently selected from H and C1-6 alkyl; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from R7.
[66]
66. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, characterized by the fact that each Ra15, Rc15 and Rd15 is independently selected from H and C1-6 alkyl ; wherein said C1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from Rg.
[67]
67. A compound according to any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, characterized in that each Rg is OH.
[68]
68. A compound according to any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, characterized in that n is 2.
[69]
69. A compound according to any one of claims 1 to 3 and 5 to 68, or a pharmaceutically acceptable salt thereof, characterized in that A is N.
[70]
70. A compound according to any one of claims 1, 2 and 5 to 68, or a pharmaceutically acceptable salt thereof, characterized in that A is CR16.
[71]
71. A compound according to any one of claims 1, 2, 5-a 68 and 70, or a pharmaceutically acceptable salt thereof, characterized by the fact that R16 is H, CN or ORa16.
[72]
72. A compound according to any one of claims 1, 2, 5 to 68, 70 and 71, or a pharmaceutically acceptable salt thereof, characterized by the fact that Ra16 is selected from H and C1-6 alkyl.
[73]
73. A compound according to any one of claims 1, 2, 5 to 68 and 70 to 72, or a pharmaceutically acceptable salt thereof, characterized in that Ra16 is methyl.
[74]
74. A compound according to any one of claims 1 to 4, characterized by the fact that it has Formula IA: IA, or a pharmaceutically acceptable salt thereof.
[75]
75. A compound according to any one of claims 1, 2 and 3, characterized by the fact that it presents Formula IB:
IB, or a pharmaceutically acceptable salt thereof.
[76]
76. A compound according to any one of claims 1 and 2, characterized by the fact that it has Formula IC: IC, or a pharmaceutically acceptable salt thereof.
[77]
77. A compound according to any one of claims 1 to 4, characterized by the fact that it has Formula IIA: IIA, or a pharmaceutically acceptable salt thereof.
[78]
78. A compound according to any one of claims 1 to 4, characterized by the fact that it presents Formula IIB:
IIB, or a pharmaceutically acceptable salt thereof.
[79]
79. A compound according to any one of claims 1 to 4, characterized by the fact that it has Formula IIC: IIC, or a pharmaceutically acceptable salt thereof.
[80]
80. A compound according to any one of claims 1 to 4, characterized by the fact that it has Formula IID: IID, or a pharmaceutically acceptable salt thereof.
[81]
81. A compound according to any one of claims 1 to 4, characterized by the fact that it presents Formula III:
III, or a pharmaceutically acceptable salt thereof.
[82]
82. A compound according to any one of claims 1 and 2, characterized by the fact that it has Formula IV: IV, or a pharmaceutically acceptable salt thereof.
[83]
83. A compound according to any one of claims 1 and 2, characterized by the fact that it has Formula V: V, or a pharmaceutically acceptable salt thereof.
[84]
84. A compound according to any one of claims 1 and 2, characterized by the fact that it presents Formula VI:
VI, or a pharmaceutically acceptable salt thereof.
[85]
85. Compound according to claim 1, characterized by the fact that it is selected from: N- (2 - ((1R, 4R) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; (S) -N- (2- (3-aminopyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; (R) -N- (2- (2- (aminomethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; (R) -N- (5-fluoro-2- (2- (hydroxymethyl) pyrrolidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; (R) -N- (5-fluoro-2- (2- (methoxymethyl) pyrrolidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (5-fluoro-2 - ((2S, 4S) -4-hydroxy-2-methylpyrrolidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (5-fluoro-2- (2- (pyridin-2-yl) pyrrolidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (5-fluoro-2- (hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; (R) -N- (5-fluoro-2- (2-methylpiperazin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; (R) -N- (5-fluoro-2- (2- (hydroxymethyl) piperazin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide;
N- (5-fluoro-2- (3- (hydroxymethyl) morpholino) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1R, 4R) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -3-bromo-5-fluorophenyl) - 2- (2-fluoro-6-methoxyphenyl) pyrimidine -4-carboxamide; N- (2 - ((1R, 4R) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -3-cyanophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4 -carboxamide; N- (2 - ((1R, 4R) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-3- (pyridin-3-yl) phenyl) -2- (2- fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1R, 4R) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4- (hydroxymethyl) phenyl) -2- (2-fluoro- 6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -4-bromo-5-fluorophenyl) - 2- (2-fluoro-6-methoxyphenyl) pyrimidine -4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4- (6- (hydroxymethyl) pyridin-3-yl) phenyl ) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4- (6- (methylcarbamoyl) pyridin-3-yl) phenyl ) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4- (1-methyl-6-oxo-1,6-di- hydropyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4- (2-methylpyridin-3-yl) phenyl) -2 - (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -4- (2-methylpyridin-3-yl) phenyl) -2- (2- fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -4- (4-methoxypyridin-3-
il) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro- 6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -4- (1,3,5-trimethyl-1H-pyrazol-4-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4-morpholinophenyl) -2- (2-fluoro-6-methoxyphenyl ) pyrimidine-4-carboxamide; N- (4- (azetidin-1-yl) -2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluorophenyl) -2- (2 -fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluoro-4- (morpholino-methyl) phenyl) -2- (2-fluoro- 6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -4 - ((cyclobutylamino) methyl) -5-fluorophenyl) -2- (2- fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1R, 4R) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine -4-carboxamide; N- (5-fluoro-2 - ((1R, 4R) -5- (2-hydroxyethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) -2- (2-fluoro- 6-methoxyphenyl) pyrimidine-4-carboxamide; (1R, 4R) -5- (4-fluoro-2- (2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamido) phenyl) -N-propyl-2,5-diazabicyclo [2.2. 1] heptane-2-carboxamide; N- (2 - ((1R, 4R) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-methoxyphenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4 -carboxamide; N- (2 - ((1R, 4R) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5- (hydroxymethyl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine- 4-carboxamide; and N- (2 - ((1R, 4R) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5-cyanophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine- 4-carboxamide; or a pharmaceutically acceptable salt thereof.
[86]
86. Compound according to claim 1, characterized by the fact that it is selected from: N- (4- (Azetidin-1-yl) -2 - ((1S, 4S) -2,5-diazabicycles [ 2.2.1] heptan-2-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide;
N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -4 - ((S) -2- (methoxymethyl) azetidin-1-yl) phenyl) - 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl) -4- (3-cyano-nopiridin-4-yl) -3-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carbo-xamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (3-cyanopyridin-4-yl) phenyl) -2- (2-fluoro -6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro -6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (2-methylpyridin-3-yl) phenyl) -2- (2-fluoro-6 -methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (3-methoxypyridin-4-yl) phenyl) -2- (2-fluoro-6 -methoxyphenyl) pyrimidine-4-carboxamide; N- (3 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -2'-cyano-6'-fluorobiphenyl-4-yl) -2- (2- fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (3-cyanopyridin-2-yl) phenyl) -2- (2-fluoro -6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyano-1-methyl-1H-pyrazol-5-yl) phenyl ) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4-isopropylenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4- carboxamide; N- (4- (3-Cyanopyridin-4-yl) -2 - ((2S, 4S) -4-hydroxy-2- (hydroxymethyl) pyrrolidin-1-yl) phenyl) -2- (2-fluoro -6-methoxyphenyl) pyrimidine-4-carboxamide;
N- (4- (4-Cyanopyridin-3-yl) -2 - ((2S, 5R) -2- (hydroxymethyl) -5-methyl-piperazin-1-yl) phenyl) -2- (2-fluoro- 6-methoxyphenyl) pyrimidine-4-carboxamide; N- (4- (4-Cyanopyridin-3-yl) -2 - ((2S, 5S) -2- (hydroxymethyl) -5-methyl-piperazin-1-yl) phenyl) -2- (2-fluoro- 6-methoxyphenyl) pyrimidine-4-carboxamide; (S) -N- (4- (4-Cyanopyridin-3-yl) -2- (6- (hydroxymethyl) -4,7-diazas-piro [2.5] octan-7-yl) phenyl) -2- ( 2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (1-hydroxycyclopropyl) pyrrolidin-1-yl) - 4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro -6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (2-hydroxypropan-2-yl) pyrrolidin-1-yl) - 4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carbo-xamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl-d2) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro -6-methoxyphenyl) pyrimidine-4-carboxamide; N- (4- (4-Cyanopyridin-3-yl) -2 - ((1S, 3R, 4S) -3- (hydroxymethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carbo-xamide; N- (4- (4-Cyanopyridin-3-yl) -2 - ((1S, 4S) -1- (hydroxymethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2-methyl) piperidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro- 6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -6- (2-fluoro -6-methoxyphenyl) picolinamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -5-cyano-6- (2-fluoro-6-methoxyphenyl) picolinamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -6- (2-fluoro -6-methoxyphenyl) -5-methoxypicolinamide;
N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2.6 -difluorophenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro -6-methylphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-chlorine -6-fluorophenyl) pyrimidine-4-carboxamide; and N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -6- (1,3,5-trimethyl-1H-pyrazol-4-yl) pyridin- 3-yl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carbo-xamide; or a pharmaceutically acceptable salt thereof.
[87]
87. A compound according to claim 1, characterized by the fact that it is selected from: N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) - 5-fluorophenyl) -2- (2,6-difluorophenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (3-cyano-2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2,3-difluoro-6-methoxyphenyl) pyrimidine- 4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6- (methoxy-d3) - 3-methylphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro -6-methoxy-4-methylphenyl) pyrimidine-4-carbo-xamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (3,6 -difluoro-2-methylphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2,3 -difluoro-6-methoxyphenyl) pyrimidine-4-carboxamide;
N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (3,6 -difluoro-2-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (3-cyano -2-fluoro-6- (methoxy-d3) phenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (3,6 -difluoro-2- (methoxy-d3) phenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2,3-difluoro -6- (methoxy-d3) phenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6 - (methoxy-d3) phenyl-5-d) pyrimidine-4-carboxamide; 2- (2-Fluoro-6-methoxyphenyl) -N- (2- (piperidin-4-yl) phenyl) pyrimidine-4-carboxamide; N- (2- (cis) 4-aminocyclohexyl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2- (trans) 4-Aminocyclohexyl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2- (3-Aminocyclohexyl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2- (3-aminocyclopentyl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((cis) -4-Aminocyclohexyl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((trans) -4-Aminocyclohexyl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((cis) -4-Aminocyclohexyl) -4- (4-cyano-1-methyl-1H-pyrazol-5-yl) phenyl) - 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide;
N- (2 - ((trans) -4-aminocyclohexyl) -4- (4-cyano-1-methyl-1H-pyrazol-5-yl) phenyl) -2- (2-fluoro-6- methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((cis) -4-aminocyclohexyl) -4- (1,3,5-trimethyl-1H-pyrazol-4-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (methylsulfonyl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine -4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -5-methylphenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4- (Dimethylamino) -2- (hydroxymethyl) pyrrolidin-1-yl) -5-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine- 4-carboxamide; N- (5-Fluoro-2 - ((2S, 4S) -2- (hydroxymethyl) -4- (isopropylamino) pyrrolidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4 -carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (tetrahydro-2H-pyran-4-yl) phenyl) -2- (2 -fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4-chlorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4-fluorophenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (5-cyano-2- (pyrrolidin-1-yl) pyridin-4- il) phenyl) -2- (2,6-difluorophenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (1-cyanocyclopropyl) phenyl) -2- (2,6-difluorophenyl) pyrimidine -4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-difluoromethoxy-6 fluorophenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6 - (methoxy-d3) phenyl) pyrimidine-4-carboxamide; N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-cyclopropyl-6 fluorophenyl) pyrimidine-4-carboxamide;
N- (2 - ((2S, 4S) -4-Amino-2- (hydroxymethyl) pyrrolidin-1-yl) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-ethoxy-6 fluorophenyl) pyrimidine-4-carboxamide; N- (4- (4-Cyanopyridin-3-yl) -2 - ((1S, 4S) -4- (hydroxymethyl) -5-methyl-2,5-diazabicle [2.2.1] heptan-2- il) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; (S) -N- (4- (4-Cyanopyridin-3-yl) -2- (2- (hydroxymethyl) morpholino) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide ; (S) -N- (4- (4-Cyanopyridin-3-yl) -2- (2 - ((dimethylamino) methyl) morpholino) phenyl) - 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4- carboxamide; (R) -N- (2- (2- (Cyanomethyl) morpholino) -4- (4-cyanopyridin-3-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide ; (R) -N- (4- (4-cyanopyridin-3-yl) -2- (3-oxotetrahydro-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) phenyl) - 2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; (S) -N- (5-Fluoro-2- (3- (hydroxymethyl) piperazin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (4- (4-Cyanopyridin-3-yl) -2- (3- (methoxymethyl) azetidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide ; (S) -N- (4- (4-Cyanopyridin-3-yl) -2- (2- (hydroxymethyl) azetidin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4 -carboxamide; (R) -N- (4- (4-Cyanopyridin-3-yl) -2- (2 - ((dimethylamino) methyl) azetidin-1-yl) phenyl) -2- (2-fluoro-6- methoxyphenyl) pyrimidine-4-carboxamide; N- (4- (4-Cyanopyridin-3-yl) -2- (4-methylpiperazin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; N- (4- (4-Cyanopyridin-3-yl) -2- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4 -carboxamide; and (S) -N- (5-Fluoro-2- (3- (hydroxymethyl) piperazin-1-yl) -4-isopropylphenyl) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.
[88]
88. Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
[89]
89. Method of inhibiting HPK1 activity, characterized in that it comprises contacting a compound as defined in any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof with HPK1.
[90]
90. Method according to claim 89, characterized in that the contact comprises administering the compound to a patient.
[91]
91. Method of treatment of a disease or disorder associated with inhibition of HPK1 interaction, characterized by the fact that it comprises administering to a patient in need of it a therapeutically effective amount of a compound as defined in any of the claims 1 to 87, or a pharmaceutically acceptable salt thereof.
[92]
92. Method for treating cancer in a patient, characterized by the fact that it comprises: administering to the patient a therapeutically effective amount of the compound as defined in any of claims 1 to 87, or a pharmaceutically acceptable salt thereof.
[93]
93. Method according to claim 92, characterized by the fact that the cancer is selected from breast cancer, colorectal cancer, lung cancer, ovarian cancer and pancreatic cancer.

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法律状态:
2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US62/750,371|2018-10-25|

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PCT/US2019/018608|WO2019164846A1|2018-02-20|2019-02-19|N--2-pyrimidine-4-carboxamide derivatives and related compounds as hpk1 inhibitors for treating cancer|

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