Novel compounds as GCN2 inhibitors, pharmaceutical compositions and uses thereof

Abstract

# imgabs0 # provided herein are novel compounds that are inhibitors of GCN2, such as those of formula (I). Also provided herein are pharmaceutical compositions comprising one or more of the novel compounds and pharmaceutical uses thereof. The compounds provided herein can generally inhibit the activity of GCN2, and thus can be used to treat or prevent diseases associated therewith.

Description

Invention Field

[0001] This invention relates to novel compounds as GCN2 inhibitors, pharmaceutical compositions comprising the same, and their pharmaceutical uses, which inhibit the activity of GCN2 and can thus be valuable for the prevention or treatment of related diseases. Background of the Invention

[0003] Despite the existence of various drugs as therapeutic tools for cancer, it is generally believed that more options are needed to address the unmet needs in cancer patient treatment. Several studies suggest that modulating essential components of the tumor microenvironment may be a promising therapeutic option for cancer treatment. Cancer cells are typically deprived of several nutrients, such as glucose, oxygen, and amino acids, within the tumor microenvironment. Integrated stress response (ISR) is a pathway by which tumor cells adapt to nutrient deprivation. Generalized regulatory repressor protein kinase 2 (GCN2) (encoded by EIF2AK4 in humans) is one of the cytoplasmic serine / threonine protein kinases that mediates the nutrient stress pathway in the tumor microenvironment. In response to amino acid deprivation, GCN2 phosphorylates eukaryotic initiation factor 2α (eIF2a) to activate ISR, thereby initiating a transcriptional program through activation of transcription factor-4 (ATF4). ATF4 functions as a key ISR transcription factor, promoting stress repair by inducing the expression of a subset of important genes related to amino acid input and metabolism. GCN2 is a key component in the ATF4-mediated ISR pathway, responding to recovery from nutrient deprivation. Furthermore, elevated GCN2 expression levels have been observed in various human tumors compared to normal tissues. GCN2 is highly expressed at both the protein and mRNA levels in a variety of cancers, including thyroid cancer, melanoma, testicular cancer, endometrial cancer, lung cancer, head and neck cancer, pancreatic cancer, glioma, gastric cancer, urothelial carcinoma, skin cancer, breast cancer, colorectal cancer, and kidney cancer. Additionally, GCN2 function is closely associated with inducing T cell anergy under tryptophan depletion conditions induced by indoleamine 2,3-dioxygenase (IDO). Inhibition of GCN2 has been reported as a therapeutic approach for cancer (see, for example, Wei, C. et al., Mol. Biol. Cell. 2015, 26(6), 1044). Therefore, inhibiting GCN2 activity could provide a beneficial therapeutic option for cancer patients. Furthermore, several GCN2 inhibitors that lead to eIF2a phosphorylation and downregulation of ATF expression have shown potential for treating neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia, as well as doxorubicin-induced cardiotoxicity (Nakagawa, T. et al., Int. J. Mol. Sci. 2019, 20, 2761). Recent studies have suggested that GCN2 inhibitors may be potential drugs for inflammatory diseases (Wang, P. et al., J. Allergy Clin. Immunol. 2019, 144, p. 1091) and hepatic steatosis (Yuan, J. et al., Redox Biology 2022, 49, 102224). Invention Overview

[0005] The object of this invention is to provide novel compounds, their stereoisomers, pharmaceutically acceptable salts thereof, or solvates thereof that exhibit general regulatory activity against GCN2 (GCN2) inhibitory activity.

[0006] The object of this invention is to provide a method for preparing the compounds of this invention, their stereoisomers, their pharmaceutically acceptable salts, or their solvates.

[0007] The purpose of this invention is to provide a pharmaceutical composition for treating or preventing diseases related to GCN2 activation, comprising the compounds of this invention, their stereoisomers, their pharmaceutically acceptable salts, or their solvates as active ingredients.

[0008] The object of this invention is to provide a method for preventing or treating GCN2 activation-related diseases, comprising administering to an individual a therapeutically effective amount of the compound of the invention, its stereoisomer, its pharmaceutically acceptable salt, or its solvation.

[0009] The object of this invention is to provide the use of the compounds of this invention, their stereoisomers, their pharmaceutically acceptable salts or solvates thereof in the preparation of medicaments for the prevention or treatment of diseases related to GCN2 activation.

[0010] The purpose of this invention is to provide the use of the compounds of this invention, their stereoisomers, their pharmaceutically acceptable salts or solvates thereof for the prevention or treatment of diseases related to GCN2 activation.

[0011] The object of this invention is to provide a method for inhibiting GCN2 activity, comprising administering to an individual a therapeutically effective amount of the compound of the invention, its stereoisomer, its pharmaceutically acceptable salt, or its solvation. Invention Details

[0013] GCN2 inhibitor compounds

[0014] This invention provides compounds represented by formula (I), their stereoisomers, pharmaceutically acceptable salts thereof, or solvates thereof:

[0015] [Formula (I)]

[0016]

[0017] in,

[0018] L 1 and L 2 Each independently represents H; optionally substituted with 4 to 6-membered heterocyclic alkyl groups (C 1-5 )alkyl; or L 1 and L 2 The connection forms a 5- to 6-membered ring.

[0019] M represents H; halogen; (C)1-5 )alkyl; (C 3-7 )cycloalkyl; or (C 1-5 )alkoxy,

[0020] G represents H; halogen; (C) 1-5 )alkyl; (C 1-5 )alkoxy; or -NH2, wherein at least one H of -NH2 is optionally replaced by (C 1-5 )alkyl substitution,

[0021] Y 1 Indicates H; or (C) 1-5 )alkyl,

[0022] Z represents -C (=O)-; or optionally is defined by one or more (C 1-5 )alkyl-substituted -CH2-; or Z with Y 1 The connection forms a 5- to 6-membered ring.

[0023] Y 3 It represents a 4- to 6-membered heterocyclic alkyl group, wherein at least one H is optionally and independently formed by W. 1 or W 2 Replace; or in Z and Y 1 When the connection forms a 5- to 6-member ring, Y 3 The aryl or heteroaryl group formed by Y3 and Z is optionally and independently substituted with W3.

[0024] W1 and W2 each independently represent H; halogen; -OH; (C) optionally substituted with -OH, -NH2, or -CN. 1-5 )alkyl; optionally coated with (C 1-5 )alkyl-substituted 5- to 7-membered heterocyclic alkyl groups; optionally substituted with (C 1-5 )alkyl-substituted heteroaryl groups; -COR 1 ;-OR 2 ; or -NH2, wherein at least one H of -NH2 is optionally and independently substituted with a heteroaryl group.

[0025] R 1 Indicates (C) 1-5 )alkoxy group; -OH group; optionally coated with (C 1-5 ) alkyl-substituted 5-7 membered heterocyclic alkyl groups; or -NH2, wherein at least one H of -NH2 is optionally and independently replaced by (C 3-7 )cycloalkyl substitution,

[0026] R 2 Indicates (C) that is optionally substituted with a heteroaryl group. 1-5)alkyl; aryl; or heteroaryl, wherein at least one H of said aryl or heteroaryl is optionally and independently constituting one or more R 2a replace,

[0027] One or more R 2a Each independently represents a halogen; (C) optionally substituted with an aryl group 1-5 )alkyl, or by (C 1-5 )alkyl-substituted 5- to 7-membered heterocyclic alkyl groups; optionally substituted with (C 1-5 )alkyl-substituted (C 5-6 )cycloalkenyl; optionally coated with (C 1-5 )alkyl or -OH substituted 5- to 7-membered heterocyclic alkyl groups; -CF3; optionally substituted with aryl groups (C 1-5 )alkoxy; aryl, wherein at least one H of the aryl group is optionally and independently substituted with a halogen; optionally substituted with (C 1-5 )alkyl-substituted heteroaryl groups; thio(C 1-5 alkyl; -COR 1a ; or NR 3 R 4 ,

[0028] R 1a Indicates (C) 1-5 )alkoxy group; -OH group; optionally coated with (C 1-5 ) alkyl-substituted 5-7 membered heterocyclic alkyl groups; or -NH2, wherein at least one H of -NH2 is optionally and independently replaced by (C 1-5 )alkyl or (C 3-7 )cycloalkyl substitution,

[0029] R 3 and R 4 Each independently represents H; halogen; optionally halogenated, -CF3, -OH, (C 1-5 )alkoxy, -N-[(C 1-5 )alkyl][(C 1-5 [alkyl], aryl or (C 3-7 )cycloalkyl-substituted (C 1-5 )alkyl; (C 3-7 )cycloalkyl; (C 1-5 )alkoxy; aryl; or -C (=O)(C 1-5 )alkyl, and

[0030] One or more W3s independently represent H, halogens; (C 1-5 )alkyl; (C 1-5 )alkoxy group; -OH; -NO2; -NR 5 R 6 -CH=CR 7 R8 ;-C≡CR 9 ;(C 5-6 )cycloalkenyl; optionally coated with (C 1-5 )alkyl, -C(=O)O(C 1-5 )alkyl, -S(=O)2(C 1-5 )alkyl, -C(=O)(C 1-5 5- to 7-membered heterocyclic alkyl groups substituted with alkyl or -C(=O)(NH2); aryl; or heteroaryl, wherein at least one H of the aryl or heteroaryl group is optionally replaced by one or more R groups. 10 replace,

[0031] R 5 and R 6 Each represents H independently; optionally by (C) 3-7 )cycloalkyl or aryl substituted (C 1-5 )alkyl; optionally coated with (C 1-5 Alkyl-substituted 5- to 7-membered heterocyclic alkyl groups; aryl; -C(=O)R 11 ;or-S(=O)2R 12 ,

[0032] R 7 (C) indicates that it is optionally substituted with -OH. 1-5 )alkyl; optionally halogenated aryl; or -C(=O)R 13 ,

[0033] R 8 Indicates H; or (C) 1-5 )alkyl,

[0034] R 9 This indicates an aryl group that is optionally substituted with -NH2.

[0035] One or more R 10 Each independently represents H; halogen; -CN; -CF3; -OH; -OCF3; optionally, it is replaced by (C 3-7 )cycloalkyl, 5- to 7-membered heterocyclic alkyl or -OH substituted (C 1-5 )alkyl; (C 1-5 )alkoxy; optionally surrounded by one or more (C 1-5 )alkyl or -C(=O)O(C 1-5 )alkyl-substituted -NH2; optionally (C 1-5 Alkyl-substituted 5- to 7-membered heterocyclic alkyl groups; -C(=O)R 14 ;-S(=O)2-(5 to 7-membered heterocyclic alkyl); or aryl, wherein R 10 They can be arbitrarily connected to form 5 to 6-membered rings.

[0036] R11 (C) indicates that it is optionally substituted with -N(CH3)2, aryl or hydroxyaryl. 1-5 )alkyl; optionally containing C (=O) (C 3-7 )cycloalkyl; optionally coated with (C 1-5 )alkyl-substituted (C 3-7 )cycloalkyl; fused with aryl (C 3-7 )cycloalkyl; optionally coated with (C 1-5 )alkyl-substituted (C 5-6 )cycloalkenyl; optionally coated with (C 1-5 )alkyl or -NH2-substituted 5- to 7-membered heterocyclic alkyl groups; aryl; or optionally substituted with (C 1-5 )alkyl or -OH substituted heteroaryl groups,

[0037] R 12 Indicates (C) 1-5 )alkyl; or aryl, wherein at least one H of the aryl group is optionally and independently (C 1-5 Alkyl or halogen substitution,

[0038] R 13 Indicates (C) 1-5 )alkyl; (C 1-5 )alkoxy group; -OH group; -NH2 group, wherein at least one H group of -NH2 is optionally and independently controlled by (C 1-5 )alkyl or OH-substituted (C 1-5 )alkyl substitution; (C 3-7 )cycloalkyl; hydroxyl (C 1-5 )alkyl; (C 1-5 )alkoxy (C 1-5 )alkyl; -NH2,

[0039] R 14 It represents a 5- to 7-membered heterocyclic alkyl group; -NH2; or -OH.

[0040] According to another specific embodiment of the present invention, it can be provided that,

[0041] Y 3 This indicates a nitrogen-containing heterocyclic butyl group; pyrrolidinyl group; piperidinyl group; tetrahydropyridinyl group; or oxopyrrolidinyl group, optionally marked with W. 1 and W 2 replace,

[0042] W1 and W2 each independently represent H; halogen; -OH; (C) optionally substituted with -OH or -CN. 1-5 )alkyl; methylpiperazinyl; morpholinyl; pyridyl; methylpyrazolyl; -COR 1 ;-OR 2-NH2; -NH (pyridinyl) or -NH (pyrimidinyl),

[0043] R 1 Indicates (C) 1-5 )alkoxy group; -OH; -NH2; -NH-(C 3-7 )cycloalkyl; oxopiperazinyl; morpholinyl; thiomorpholinyl; methylpiperazinyl; or tetrahydropyridyl,

[0044] R 2 (C) indicates that it is optionally substituted with a pyridyl group. 1-5Alkyl; Halogenated phenyl; Dihalogenated phenyl; (amino)halogenated phenyl; (methylpiperazinyl)(methyl)phenyl; (dimethylamino)phenyl; Aminophenyl; Diethylaminophenyl; Biphenyl; (phenylpropyl)phenyl; (cyclopropylamino)pyrimidinyl; (trifluoroethylamino)pyrimidinyl; Pyridinyl; Pyrimidinyl; (cyclopropyl)(isoxazole)formamide; (dimethyl)pyrimidinyl; Pyrazinyl; Aminopyridinyl; Halogenated pyrimidinyl; Aminopyrazinyl; Halogenated pyrimidinyl; (methyl)halogenated pyrimidinyl; (amino)(methyl)pyrimidinyl; (amino)halogenated pyrimidinyl; Dihalogenated pyrimidinyl; Amino(dihalogenated phenyl)pyrimidinyl; (amino)(trifluoromethyl)pyrimidinyl; Pentylpyrimidinyl; Methylpyrazolyl; (benzothiophene)formate; (thiophene)formic acid Methyl ester; (thiophene)carboxylic acid; (thiophene)formamide; methyl (thiophene)formamide; cyclopropyl (thiophene)formamide; methyl isoxazolyl; benzo[a]isoxazolyl; isothiazolyl; methylthiophenyl; pyrazolyl; (methyl)(trifluoromethyl)pyrazolyl; isoxazolyl; aminopyrazolyl; methyl (pyrrole)formate; ethyl (isoxazol)formate; (isoxazol)formamide; methyl (isoxazol)formamide; dimethyl (isoxazol)formamide; cyclopropyl (oxazol)formamide; (pyrimidine)carboxylic acid; (pyrimidine)formamide; methyl (pyrimidine)formamide; dimethyl (pyrimidine)formamide; (pyrazine)formamide; methyl (pyrazine)formamide; aminotriazinyl; (methylamino)triazinyl; (dimethylamino) Triazine; (cyclopropylamino)triazine; diaminotriazine; (amino)(pyrrolyl)triazine; aminopyrimidinyl; (methylamino)pyrimidinyl; (ethylamino)pyrimidinyl; (propylamino)pyrimidinyl; (butylamino)pyrimidinyl; (hydroxyethylamino)pyrimidinyl; (hydroxypropylamino)pyrimidinyl; (methoxyethylamino)pyrimidinyl; (((dimethylamino)propyl)amino)pyrimidinyl; (benzylamino)pyrimidinyl; (phenethylamino)pyrimidinyl; (cyclohexylamino)pyrimidinyl; (dimethylamino)pyrimidinyl; (ethylmethylamino)pyrimidinyl; (diethylamino)pyrimidinyl; (ethylpropylamino)pyrimidinyl; (butylethylamino)pyrimidinyl; pyrrolylpyrimidinyl; (hydroxypyrrolyl)pyrimidinyl; piperidinylpyrimidinyl Pyridyl; (hydroxypiperidinyl)pyrimidinyl; morpholinopyrimidinyl; (methylpiperazinyl)pyrimidinyl; (amino)(methylamino)pyrimidinyl; (amino)(pyrrolyl)pyrimidinyl; (methylamino)halopyrimidinyl; (ethylamino)halopyrimidinyl; (cyclopropylamino)halopyrimidinyl; (cyclohexylamino)halopyrimidinyl; (dimethylamino)halopyrimidinyl; (ethylmethylamino)halopyrimidinyl; (diethylamino)halopyrimidinyl; (methylphenylamino)halopyrimidinyl; (benzylmethylamino)halopyrimidinyl; (pyrrolyl)halopyrimidinyl; (piperidinyl)halopyrimidinyl; (morpholino)halopyrimidinyl; (thiomorpholino)halopyrimidinyl; (methylpiperazinyl)halopyrimidinyl; (cyclopropylamino)methylpyrimidinyl;(amino)pyrimidinyl; (methylthio)pyrimidinyl; (methoxy)pyrimidinyl; (benzyloxy)pyrimidinyl; acetamylpyrimidinyl; (difluoropropylamino)pyrimidinyl; (difluoroethylamino)pyrimidinyl; (trifluoropropylamino)pyrimidinyl; (fluoroethylamino)pyrimidinyl; (cyclobutylamino)pyrimidinyl; (cyclopentylamino)pyrimidinyl; (isopropylamino)pyrimidinyl; (sec-butylamino)pyrimidinyl; ((cyclopropylmethyl)amino)pyrimidinyl; (((dimethylamino)ethyl)amino)pyrimidinyl; (((dimethylamino)propyl)amino)pyrimidinyl; (methoxyamino)pyrimidinyl; (benzylmethylamino)pyrimidinyl ; (cyclohexylamino)halopyrimidinyl; (cyclopropylmethylamino)halopyrimidinyl; (benzylamino)halopyrimidinyl; (cyclopropylamino)halopyrimidinyl; (cyclopropylamino)methylpyrimidinyl; (cyclopropylamino)(trifluoromethyl)pyrimidinyl; (cyclopropylamino)(methoxy)pyrimidinyl; (cyclopropylamino)pyrazinyl; (ethylamino)pyrazinyl; (propylamino)pyrazinyl; (hydroxyethylamino)pyrazinyl; (((dimethylamino)ethyl)amino)pyrazinyl; phenylpyrimidinyl; (methylpyrazolyl)pyrimidinyl; (dimethylcyclohexenyl)pyrimidinyl; dihydropyranylpyrimidinyl; or pyridylpyrimidinyl.

[0045] According to another specific embodiment of the present invention, the compound represented by formula (I) above can be provided as the compound represented by formula (Ib):

[0046] [Equation (Ib)]

[0047]

[0048] In equation (Ib),

[0049] X represents -CH2-; or -C(=O)-,

[0050] V 1 V 2 V 3 and V 4 Each can be represented independently as CH or N, where in all V 1 V 2 V 3 and V 4 When neither of them is N, V 1 V 2 V 3 and V 4 One or more H in the equation are optionally and independently controlled by W. 3 replace,

[0051] One or more W 3 Each independently represents H and halogen; (C 1-5 )alkyl; (C 1-5)alkoxy group; -OH; -NO2; -NR 5 R 6 -CH=CR 7 R 8 ;-C≡CR 9 ;(C 5-6 )cycloalkenyl; optionally coated with (C 1-5 )alkyl, -C(=O)O(C 1-5 )alkyl, -S(=O)2(C 1-5 )alkyl, -C(=O)(C 1-5 5- to 7-membered heterocyclic alkyl groups substituted with alkyl or -C(=O)(NH2); aryl; or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one or more R 10 replace,

[0052] R 5 and R 6 Each represents H independently; optionally by (C) 3-7 )cycloalkyl or aryl substituted (C 1-5 )alkyl; optionally coated with (C 1-5 Alkyl-substituted 5- to 7-membered heterocyclic alkyl groups; aryl; -C(=O)R 11 ;or-S(=O)2R 12 ,

[0053] R 7 (C) indicates that it is optionally substituted with -OH. 1-5 )alkyl; optionally halogenated aryl; or -C(=O)R 13 ,

[0054] R 8 Represents H; or (C) 1-5 )alkyl,

[0055] R 9 This indicates an aryl group that is optionally substituted with -NH2.

[0056] One or more R 10 Each independently represents H; halogen; -CN; -CF3; -OH; -OCF3; optionally with (C 3-7 )cycloalkyl, 5- to 7-membered heterocyclic alkyl or -OH substituted (C 1-5 )alkyl; (C 1-5 )alkoxy; optionally surrounded by one or more (C 1-5 )alkyl or -C(=O)O(C 1-5 )alkyl-substituted -NH2; optionally (C 1-5 Alkyl-substituted 5- to 7-membered heterocyclic alkyl groups; -C(=O)R 14;-S(=O)2-(5 to 7-membered heterocyclic alkyl); or aryl, wherein R 10 They can be arbitrarily connected to form 5 to 6-membered rings.

[0057] R 11 (C) indicates that it is optionally substituted with -N(CH3)2, aryl or hydroxyaryl. 1-5 )alkyl; optionally containing C (=O) (C 3-7 )cycloalkyl; optionally coated with (C 1-5 )alkyl-substituted (C 3-7 )cycloalkyl; fused with aryl (C 3-7 )cycloalkyl; optionally coated with (C 1-5 )alkyl-substituted (C 5-6 )cycloalkenyl; optionally coated with (C 1-5 )alkyl or -NH2-substituted 5- to 7-membered heterocyclic alkyl groups; aryl; or optionally substituted with (C 1-5 )alkyl or -OH substituted heteroaryl groups,

[0058] R 12 Indicates (C) 1-5 )alkyl; or aryl, wherein at least one H of the aryl group is optionally and independently (C 1-5 Alkyl or halogen substitution,

[0059] R 13 Indicates (C) 1-5 )alkyl; (C 1-5 )alkoxy; -OH; -NH2, wherein at least one H of -NH2 is optionally replaced by (C 1-5 )alkyl or OH-substituted (C 1-5 )alkyl substitution; (C 3-7 )cycloalkyl; hydroxyl (C 1-5 )alkyl; (C 1-5 )alkoxy (C 1-5 )alkyl; -NH2,

[0060] R 14 Indicates a 5- to 7-membered heterocyclic alkyl group; -NH2; or -OH.

[0061] L 1 L 2 M and G are as defined in equation (I).

[0062] According to another specific embodiment of the present invention, the following can be provided:

[0063] W 3 Independently represent H; halogen; (C) 1-5 )alkyl; (C 1-5 )alkoxy group; -OH; -NO2; -NR 5R 6 -CH=CR 7 R 8 ;-C≡CR 9 ;(C 5-6 Cycloalkenyl; Morpholinyl; Tetrahydropyridyl; Dihydropyranyl; Tert-butyl (tetrahydropyridyl)carboxylate; Tert-butyl (dihydropyridyl)carboxylate; Dihydrothiopyranyl; Methyltetrahydropyridyl; (Methylsulfonyl)tetrahydropyridyl; Acetyltetrahydropyridyl; (tetrahydropyridyl)formamide; 1,1-dioxide-dihydrothiopyranyl; Phenyl; (trifluoromethoxy)phenyl; Aminophenyl; Tert-butyl (phenyl)carboxylate; (pyrrolidinylsulfonyl)phenyl; Oxypiperidine (carbonyl)phenyl; Methylpiperazinyl; (Methylpiperazinyl)phenyl; Isoindolyl; Cyanophenyl; Cyanohalophenyl; (trifluoromethyl)phenyl; (dimethylamino)phenyl; Hydroxybenzyl; Methoxyphenyl; Biphenyl; Methylphenyl; Hydroxyphenyl; Dihydroindene; Benzoic acid; Methyl benzoate; Pyridyl Pyridyl; pyrazolyl; methylpyrazolyl; furanyl; aminopyridyl; halopyridyl; hydroxypyridyl; (methoxy)halopyridyl; methoxypyridyl; (methyl)halopyridyl; piperazinylpyridyl; pyrrolopyridyl; (dimethylamino)pyrimidinyl; (cyclopropylmethyl)pyrazolyl; (morpholinoethyl)pyrazolyl; pyrimidinyl; aminopyrimidinyl; (methylpiperazinyl)pyridyl; piperazinylpyrimidinyl; morpholinopyridyl; dihalopyridyl; methylpyridyl; pyrroleyl; (pyrrole) tert-butyl formate; dimethylisooxazolyl; isoquinolinyl; methylindazole; methylthiophenyl; indazole; thiophenyl; cyanopyridyl; (hydroxymethyl)pyridyl; pyridinamide; (dimethylamino)pyridyl; dimethylpyridyl; or (methylamino)pyridyl

[0064] R 5 and R 6 Each represents H independently; optionally by (C) 3-7 )cycloalkyl or phenyl substituted (C 1-5 )alkyl; optionally coated with (C 1-5 Alkyl-substituted morpholino or piperazine; phenyl; -C(=O)R 11 ;or-S(=O)2R 12 ,

[0065] R 7 This indicates a methyl group optionally substituted with -OH; a phenyl group optionally substituted with a halogen; or -C(=O)R 13 ,

[0066] R 9 This indicates a phenyl group that is optionally substituted with -NH2.

[0067] R 11 (C) indicates that it is optionally substituted with -N(CH3)2, phenyl, or hydroxyphenyl.1-5 )alkyl; optionally containing C (=O) (C 3-7 )cycloalkyl; by (C 1-5 )alkyl-substituted (C 3-7 )cycloalkyl; fused with phenyl (C 3-7 )cycloalkyl; optionally coated with (C 1-5 )alkyl-substituted (C 5-6 Cycloalkenyl; morpholinyl; methylpiperidinyl; oxopyrrolyl; oximidazolyl; pyrrolyl; piperidinyl; tetrahydrofuranyl; tetrahydropyranyl; methyltetrahydropyranyl; aminopyrrolyl; methylpyrrolyl; phenyl; pyridinyl; oxazolyl; pyridazinyl; methylisooxazolyl; methyloxazolyl; isoxazolyl; methylpyridinyl; furanyl; or hydroxypyrimidinyl.

[0068] R 12 Indicates (C) 1-5 alkyl; phenyl; methylphenyl; or (methyl)halophenyl,

[0069] R 14 It represents an oxopiperidinyl group; -NH2; or -OH.

[0070] Throughout this specification, when defining compounds of formulas (I) and (Ib), the concepts defined below are used. Unless otherwise specified, the following definitions also apply to terms used alone throughout this specification or as part of a larger group.

[0071] The term "alkyl" refers to a straight-chain, branched, or cyclic hydrocarbon group, in which each carbon atom may be substituted by at least one of the following, but is not limited to: cyano, hydroxyl, alkoxy, oxo, halogen, carbonyl, sulfonyl, cyano.

[0072] The term "cycloalkyl" refers to a saturated monocyclic hydrocarbon ring that can be fused with an aryl group in any way. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., but are not limited to these.

[0073] The term "cycloalkenyl" refers to an unsaturated carbocyclic moiety, such as cyclopentenyl, cyclohexenyl, and cycloheptenyl. A cycloalkenyl moiety can contain a double bond between the two carbon atoms forming the ring. The cycloalkenyl moiety can be linked in a spirocyclic manner, such as spiropropyl.

[0074] The term "alkoxy" refers to -O-alkyl, where the alkyl group is as defined above. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, n-pentoxy, tert-butoxy, etc.

[0075] The term "n-membered ring" refers to an n-membered saturated or unsaturated carbon ring in which one or more carbon atoms may optionally be replaced by heteroatoms (such as N, O, S); the n-membered saturated or unsaturated carbon ring may optionally contain one or more C (= O) (n can be 4 to 6). Examples include pyrrolidine, 1H-pyrrole-2,5-dione, 1,5-dihydro-2H-pyrrole-2-one, etc., but are not limited thereto.

[0076] The term "heterocyclic alkyl" refers to a form containing 1 to 4 heteroatoms selected from N, O, and S; "heterocyclic alkyl" is saturated or partially saturated (partially unsaturated) or aromatic; "heterocyclic alkyl" may optionally contain one or more -C (=O-) or -S (=O)2-. Suitable heterocyclic alkyl groups may include, for example, azirrocyclic butyl; pyrrolidinyl; piperidinyl; tetrahydropyridinyl; oxopyrrolidinyl; oxopipetainyl; morpholinyl; thiomorpholinyl; pipeazinyl; dihydropyranyl; dihydrothiopyranyl; 1,1-dihydrothiaran-1,1-dioxide; isoindolyl; pyridinyl; pyrazolyl; pyrimidinyl; pyrroleyl; isoquinolinyl; indazoleyl; thiophenyl; oxoimidazoalkyl; tetrahydrofuranyl; tetrahydropyranyl; oxazolyl; pyridazinyl; isoxazolyl; oxopipetainyl, etc., but are not limited thereto.

[0077] The term "halogenated" refers to a substituent selected from fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0078] The term "aryl" refers to aromatic groups including, but not limited to, phenyl, naphthyl, etc., and is optionally fused with cycloalkyl groups, such as dihydroindenyl, etc.

[0079] The term "heteroaryl" refers to a 5- to 7-membered aromatic monocyclic ring containing at least one heteroatom, such as 1 to 4, or in some exemplary embodiments 1 to 3 heteroatoms selected from N, O, and S, wherein the remaining ring atoms are carbon; an 8- to 12-membered bicyclic ring containing at least one heteroatom, such as 1 to 4, or in some exemplary embodiments 1 to 3 heteroatoms selected from N, O, and S, wherein the remaining ring atoms are carbon, and at least one ring is aromatic; examples of heteroaryl groups. Including, but not limited to, pyridinyl, pyridazinyl, pyrazinyl, triazinyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thiophene, benzothiophene, furanyl, benzofuranyl, benzimidazolyl, indolyl, indololinyl, pyrroleyl, thiophene, pyridazinyl, triazolyl, quinolinyl, pyrazolyl, pyrrolopyridyl, pyrazolopyridyl, benzoxazolyl, benzothiazolyl, indazole, and 5,6,7,8-tetrahydroisoquinoline.

[0080] As used in this article, the term "amino" refers to the group -NH2.

[0081] Unless otherwise defined, other terms and abbreviations used in this specification shall have their original meanings.

[0082] In this invention, representative examples of the compounds represented by Formula 1 above are as follows.

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105] Methods for preparing GCN2 inhibitor compounds

[0106] In the following description, for a better understanding of the invention, methods for preparing compounds represented by formula (I) or formula (Ib) are described based on exemplary reaction formulas. However, those skilled in the art will understand that compounds of formula (I) or formula (Ib) can be prepared by various methods based on the structures of formulas (I) and (Ib), and all such methods are included within the scope of the invention. In other words, it should be understood that compounds according to the invention can be prepared by any combination of various synthetic methods described herein or disclosed in the prior art, which is within the scope of the invention. In the following reaction formulas, unless otherwise stated, all substituents are the same as defined above.

[0107] The method for synthesizing the compound of formula (I) according to the present invention can be exemplified by the following reaction formula 1:

[0108] [Reaction Formula 1]

[0109]

[0110] Wherein, G, M, L1, L2, Y1, Z, Y3, W1 and R2 are as defined in formula (I); LG represents -Cl or -OH.

[0111] In reaction formula 1 above, intermediate compound Y3 can be synthesized by the following reaction formulas 1-1, 1-2, or 1-3:

[0112] [Reaction Formula 1-1]

[0113]

[0114] [Reaction 1-2]

[0115]

[0116] [Reaction Formula 1-3]

[0117]

[0118] Wherein, Nu represents -NH- or -O-;

[0119] A represents a nitrogen-containing heterocyclic butyl, pyrrolidinyl, piperidinyl, or oxopyrrolidinyl;

[0120] A' represents tetrahydropyridyl;

[0121] "A" indicates piperidinyl;

[0122] B represents pyridyl or methylpyrazolyl;

[0123] B' represents methylpiperazinyl or morpholinyl.

[0124] The method for synthesizing the compound of formula (Ib) according to the present invention can be exemplified by the following reaction formula 2:

[0125] [Reaction 2]

[0126]

[0127] G, M, L1, L2, V1, V2, V3, V4, W3, and X are defined as in equation (Ib).

[0128] In reaction formula 2 above, the intermediate compound It can be It can be synthesized using the following reaction formulas 2-1 or 2-2:

[0129] [Reaction 2-1]

[0130]

[0131] [Reaction 2-2]

[0132]

[0133] Where W3' represents -NR 5' R 6' -CH=CR 7' R 8' ;-C≡CR 9' ;(C 5-6 )cycloalkenyl, (C 1-5 )alkyl, -C(=O)O(C 1-5 )alkyl, -S(=O)2(C 1-5 )alkyl, -C(=O)(C 1-5 )alkyl or -C(=O)(NH2); aryl; or heteroaryl, wherein the aryl or heteroaryl is optionally surrounded by one or more R 10 'replace,

[0134] "W3" indicates -C(=O)R 11' ;or-S(=O)2R 12' ,

[0135] R 5' and R 6' Each represents H independently; optionally by (C) 3-7 )cycloalkyl or aryl substituted (C 1-5 )alkyl; optionally coated with (C 1-5 )alkyl or aryl-substituted 5- to 7-membered heterocyclic alkyl groups,

[0136] R 7' (C) indicates that it is optionally substituted with -OH. 1-5)alkyl; optionally halogenated aryl; or -C(=O)R 13' ,

[0137] R 8' Indicates H; or (C) 1-5 )alkyl,

[0138] R 9' This indicates an aryl group that is optionally substituted with -NH2.

[0139] One or more R 10' Each independently represents H; halogen; -CN; -CF3; -OH; -OCF3; optionally, it is replaced by (C 3-7 )cycloalkyl, 5- to 7-membered heterocyclic alkyl or -OH substituted (C 1-5 )alkyl; (C 1-5 )alkoxy; optionally surrounded by one or more (C 1-5 )alkyl or -C(=O)O(C 1-5 )alkyl-substituted -NH2; optionally (C 1-5 Alkyl-substituted 5- to 7-membered heterocyclic alkyl groups; -C(=O)R 14 ;-S(=O)2-(5 to 7-membered heterocyclic alkyl); or aryl, wherein R 10 They can be arbitrarily connected to form 5 to 6-membered rings.

[0140] R 11' (C) indicates that it is optionally substituted with -N(CH3)2, aryl or hydroxyaryl. 1-5 )alkyl; optionally containing C (=O) (C 3-7 )cycloalkyl; optionally coated with (C 1-5 )alkyl-substituted (C 3-7 )cycloalkyl; fused with aryl (C 3-7 )cycloalkyl; optionally coated with (C 1-5 )alkyl-substituted (C 5-6 )cycloalkenyl; optionally coated with (C 1-5 )alkyl or -NH2-substituted 5- to 7-membered heterocyclic alkyl groups; aryl; or optionally substituted with (C 1-5 )alkyl or -OH substituted heteroaryl groups,

[0141] R 12' Indicates (C) 1-5 )alkyl; or optionally coated with (C 1-5 )alkyl and / or halogen-substituted aryl groups,

[0142] R 13' Indicates (C) 1-5 )alkyl; (C 1-5 )alkoxy; -OH; -NH2, wherein at least one H of -NH2 is optionally replaced by (C1-5 )alkyl or OH-substituted (C 1-5 )alkyl substitution; (C 3-7 )cycloalkyl; hydroxyl (C 1-5 )alkyl; (C 1-5 )alkoxy (C 1-5 )alkyl; -NH2,

[0143] R 14' It represents a 5- to 7-membered heterocyclic alkyl group; -NH2; or -OH.

[0144] The compounds of formulas (I) and (Ib) according to the present invention can be separated or purified from the products of the above-described reactions 1 and 2 by several methods such as crystallization, silica gel column chromatography, etc. Thus, the compounds according to the present invention, as well as the initiators, intermediates, etc. used to prepare the compounds, can be synthesized by a variety of methods, and it should be understood that such methods are included within the scope of the present invention concerning the preparation of compounds of formulas (I) and (Ib).

[0145] Compositions containing GCN2 inhibitor compounds and their uses

[0146] This invention provides pharmaceutical compositions and their use in treating or preventing GCN2 activation-related diseases, said compositions comprising, as an active ingredient, a compound represented by formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:

[0147] [Formula (I)]

[0148]

[0149] Equation (I) is the same as that defined above.

[0150] The compound represented by formula (I) above can also be a compound represented by formula (Ib):

[0151] [Equation (Ib)]

[0152]

[0153] Equation (Ib) is the same as that defined above.

[0154] Compounds of formula (I) or (Ib), their stereoisomers, pharmaceutically acceptable salts, or solvates thereof exhibit significant effects in the prevention or treatment of GCN2 activation-related diseases by demonstrating GCN2 inhibitory activity. Therefore, significant effects in the prevention or treatment of GCN2 activation-related diseases have been achieved.

[0155] In this invention, the term "GCN2 activation-related diseases" refers to diseases associated with enhanced GCN2 activity, including cancer, neurodegenerative diseases, chronic infections, and metabolic diseases such as hepatic steatosis. Specifically, cancers include thyroid cancer, melanoma, prostate cancer, endometrial cancer, lung cancer, head and neck cancer, pancreatic cancer, glioma, gastric cancer, urothelial carcinoma, skin cancer, breast cancer, colorectal cancer, kidney cancer, fibrosarcoma, osteosarcoma, connective tissue sarcoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, adenocarcinoma, hepatocellular carcinoma, multiple myeloma, and myeloproliferative disorders. Symptoms related to birth abnormalities, myeloproliferative neoplasms, malignant gliomas, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia, small cell lung cancer, pediatric neuroblastoma, or related conditions.

[0156] In this invention, pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, such as those derived from 1-hydroxy-2-naphtholic acid, 2,2-dichloroacetic acid, 2-hydroxyethylsulfonic acid, 2-ketoglutaric acid, 4-acetaminobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosic acid, and methyl methacrylate. Acidic salts prepared from cholic acid, D-glucoheponic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutamate, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, L-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, thiocyanate, toluenesulfonic acid, undecenoic acid, or other compounds that can be used as acids.

[0157] For administration, the pharmaceutical compositions of the present invention may contain at least one type of pharmaceutically acceptable carrier, in addition to the compounds represented by formula (I) or (Ib), their stereoisomers, their pharmaceutically acceptable salts or solvates thereof, and may be used with other conventional additives such as antioxidants, buffer solutions, antibacterial agents, etc., if desired. Furthermore, such pharmaceutical compositions may be formulated by additionally adding diluents, dispersants, surfactants, binders and lubricants.

[0158] The compositions of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or locally) according to the intended method, wherein the dosage varies within a range depending on the patient's weight, age, sex, health condition and diet, timing of administration, method of administration, excretion rate, severity of disease, etc. The daily dose of the compounds represented by formula (I) or (Ib) is from about 0.001 to 1000 mg / kg and can be administered once daily or divided into several doses.

[0159] In addition to compounds represented by formula (I) or (Ib), their stereoisomers, pharmaceutically acceptable salts thereof, or solvates thereof, the pharmaceutical compositions of the present invention may further comprise at least one therapeutic agent as an active ingredient, said therapeutic agent exhibiting the same or similar pharmaceutical effects. The therapeutic agent may be selected from chemotherapeutic agents, radiotherapy agents, immunotherapy agents, and tumor microenvironment modulators.

[0160] According to the present invention, the compounds represented by formula (I) or (Ib), their stereoisomers, their pharmaceutically acceptable salts or their solvates exhibit GCN2 inhibitory activity, thereby achieving significant effects in preventing or treating diseases related to GCN2 activation.

[0161] According to one specific embodiment of the present invention, the present invention provides a method for preventing or treating GCN2 activation-related diseases, comprising administering to an individual a therapeutically effective amount of a compound represented by formula (I) or (Ib), its stereoisomer, its pharmaceutically acceptable salt, or a solvation thereof. The method for preventing or treating GCN2 activation-related diseases according to the present invention includes not only treating the cancer itself before its symptoms are expressed, but also inhibiting or avoiding such symptoms by administering a compound represented by formula (I) or (Ib), its stereoisomer, its pharmaceutically acceptable salt, or a solvation thereof.

[0162] According to one specific embodiment of the present invention, the present invention provides the use of compounds represented by formula (I) or (Ib), their stereoisomers, pharmaceutically acceptable salts thereof, or solvates thereof in the preparation of medicaments for treating GCN2 activation-related diseases. For the preparation of the medicament, compounds represented by formula (I) or (Ib), their stereoisomers, their pharmaceutically acceptable salts thereof, or solvates thereof may be combined with acceptable adjuvants, diluents, carriers, etc., and may be prepared into complex formulations with other active agents (therapeutic agents), thereby exhibiting a synergistic effect of the active components.

[0163] According to one specific embodiment of the present invention, the present invention also provides a method for inhibiting GCN2 activity, wherein the method comprises administering to an individual a therapeutically effective dose of formula (I) or (Ib), its stereoisomer, its pharmaceutically acceptable salt, or a solvation thereof.

[0164] As used in this article, “individual” means mammal, including humans, and “administered” means the provision of the intended material to a patient by any appropriate means.

[0165] As used herein, the term “therapeutic effective amount” refers to the amount of a compound of formula (I) or (Ib), its stereoisomer, its pharmaceutically acceptable salt or its solvation that is effective in the prevention or treatment of GCN2 activation-related diseases.

[0166] (1) The present invention provides compounds represented by formula (I), their stereoisomers, pharmaceutically acceptable salts thereof, or solvates thereof:

[0167] [Formula (I)]

[0168]

[0169] in,

[0170] L 1 and L 2 Each independently represents H; optionally substituted with 4 to 6-membered heterocyclic alkyl groups (C 1-5 )alkyl; or L 1 and L 2 The connection forms a 5- to 6-membered ring.

[0171] M represents H; halogen; (C) 1-5 )alkyl; (C 3-7 )cycloalkyl; or (C 1-5 )alkoxy,

[0172] G represents H; halogen; (C) 1-5 )alkyl; (C 1-5 )alkoxy; or -NH2, wherein at least one H of -NH2 is optionally replaced by (C 1-5 )alkyl substitution,

[0173] Y 1 Represents H; or (C) 1-5 )alkyl,

[0174] Z represents -C (=O)-; or optionally is defined by one or more (C 1-5 )alkyl-substituted -CH2-; or Z with Y 1 The connection forms a 5- to 6-membered ring.

[0175] Y 3 It represents a 4- to 6-membered heterocyclic alkyl group, wherein at least one H is optionally and independently formed by W. 1 or W 2 Replace; or in Z and Y 1 When the connection forms a 5- to 6-membered ring, Y 3The aryl or heteroaryl group formed by Y3 and Z is optionally and independently substituted with W3.

[0176] W1 and W2 each independently represent H; halogen; -OH; (C) optionally substituted with -OH, -NH2, or -CN. 1-5 )alkyl; optionally coated with (C 1-5 )alkyl-substituted 5- to 7-membered heterocyclic alkyl groups; optionally substituted with (C 1-5 )alkyl-substituted heteroaryl groups; -COR 1 ;-OR 2 ; or -NH2, wherein at least one H of -NH2 is optionally and independently substituted with a heteroaryl group.

[0177] R 1 Indicates (C) 1-5 )alkoxy group; -OH group; optionally coated with (C 1-5 ) alkyl-substituted 5-7 membered heterocyclic alkyl groups; or -NH2, wherein at least one H of -NH2 is optionally and independently replaced by (C 3-7 )cycloalkyl substitution,

[0178] R 2 Indicates (C) that is optionally substituted with a heteroaryl group. 1-5 )alkyl; aryl; or heteroaryl, wherein at least one H of said aryl or heteroaryl is optionally and independently constituting one or more R 2a replace,

[0179] One or more R 2a Each independently represents a halogen; (C) optionally substituted with an aryl group 1-5 )alkyl, or by (C 1-5 )alkyl-substituted 5- to 7-membered heterocyclic alkyl groups; optionally substituted with (C 1-5 )alkyl-substituted (C 5-6 )cycloalkenyl; optionally coated with (C 1-5 )alkyl or -OH substituted 5- to 7-membered heterocyclic alkyl groups; -CF3; optionally substituted with aryl groups (C 1-5 )alkoxy; aryl, wherein at least one H of the aryl group is optionally and independently substituted with a halogen; optionally substituted with (C 1-5 )alkyl-substituted heteroaryl groups; thio(C 1-5 alkyl; -COR 1a ; or NR 3 R 4 ,

[0180] R 1a Indicates (C) 1-5 )alkoxy group; -OH group; optionally coated with (C 1-5) alkyl-substituted 5-7 membered heterocyclic alkyl groups; or -NH2, wherein at least one H of -NH2 is optionally and independently replaced by (C 1-5 )alkyl or (C 3-7 )cycloalkyl substitution,

[0181] R 3 and R 4 Each independently represents H; halogen; optionally halogenated, -CF3, -OH, (C 1-5 )alkoxy, -N-[(C 1-5 )alkyl][(C 1-5 [alkyl], aryl or (C 3-7 )cycloalkyl-substituted (C 1-5 )alkyl; (C 3-7 )cycloalkyl; (C 1-5 )alkoxy; aryl; or -C (=O)(C 1-5 )alkyl, and

[0182] One or more W3s independently represent H, halogens; (C 1-5 )alkyl; (C 1-5 )alkoxy group; -OH; -NO2; -NR 5 R 6 -CH=CR 7 R 8 ;-C≡CR 9 ;(C 5-6 )cycloalkenyl; optionally coated with (C 1-5 )alkyl, -C(=O)O(C 1-5 )alkyl, -S(=O)2(C 1-5 )alkyl, -C(=O)(C 1-5 5- to 7-membered heterocyclic alkyl groups substituted with alkyl or -C(=O)(NH2); aryl; or heteroaryl, wherein at least one H of the aryl or heteroaryl group is optionally replaced by one or more R groups. 10 replace,

[0183] R 5 and R 6 Each represents H independently; optionally by (C) 3-7 )cycloalkyl or aryl substituted (C 1-5 )alkyl; optionally coated with (C 1-5 Alkyl-substituted 5- to 7-membered heterocyclic alkyl groups; aryl; -C(=O)R 11 ;or-S(=O)2R 12 ,

[0184] R 7 (C) indicates that it is optionally substituted with -OH. 1-5)alkyl; optionally halogenated aryl; or -C(=O)R 13 ,

[0185] R 8 Indicates H; or (C) 1-5 )alkyl,

[0186] R 9 This indicates an aryl group that is optionally substituted with -NH2.

[0187] One or more R 10 Each independently represents H; halogen; -CN; -CF3; -OH; -OCF3; optionally, it is replaced by (C 3-7 )cycloalkyl, 5- to 7-membered heterocyclic alkyl or -OH substituted (C 1-5 )alkyl; (C 1-5 )alkoxy; optionally surrounded by one or more (C 1-5 )alkyl or -C(=O)O(C 1-5 )alkyl-substituted -NH2; optionally (C 1-5 Alkyl-substituted 5- to 7-membered heterocyclic alkyl groups; -C(=O)R 14 ;-S(=O)2-(5 to 7-membered heterocyclic alkyl); or aryl, wherein R 10 They can be arbitrarily connected to form 5 to 6-membered rings.

[0188] R 11 (C) indicates that it is optionally substituted with -N(CH3)2, aryl or hydroxyaryl. 1-5 )alkyl; optionally containing C (=O) (C 3-7 )cycloalkyl; optionally coated with (C 1-5 )alkyl-substituted (C 3-7 )cycloalkyl; fused with aryl (C 3-7 )cycloalkyl; optionally coated with (C 1-5 )alkyl-substituted (C 5-6 )cycloalkenyl; optionally coated with (C 1-5 )alkyl or -NH2-substituted 5- to 7-membered heterocyclic alkyl groups; aryl; or optionally substituted with (C 1-5 )alkyl or -OH substituted heteroaryl groups,

[0189] R 12 Indicates (C) 1-5 )alkyl; or aryl, wherein at least one H of the aryl group is optionally and independently (C 1-5 Alkyl or halogen substitution,

[0190] R 13 Indicates (C) 1-5 )alkyl; (C 1-5)alkoxy group; -OH group; -NH2 group, wherein at least one H group of -NH2 is optionally and independently controlled by (C 1-5 )alkyl or OH-substituted (C 1-5 )alkyl substitution; (C 3-7 )cycloalkyl; hydroxyl (C 1-5 )alkyl; (C 1-5 )alkoxy (C 1-5 )alkyl; -NH2,

[0191] R 14 It represents a 5- to 7-membered heterocyclic alkyl group; -NH2; or -OH.

[0192] (2) The compound, its stereoisomer, its pharmaceutically acceptable salt or its solvate, according to (1), wherein:

[0193] Y 3 This indicates a nitrogen-containing heterocyclic butyl group; pyrrolidinyl group; piperidinyl group; tetrahydropyridinyl group; or oxopyrrolidinyl group, optionally marked with W. 1 and W 2 replace,

[0194] W1 and W2 each independently represent H; halogen; -OH; (C) optionally substituted with -OH or -CN. 1-5 )alkyl; methylpiperazinyl; morpholinyl; pyridyl; methylpyrazolyl; -COR 1 ;-OR 2 -NH2; -NH (pyridinyl) or -NH (pyrimidinyl),

[0195] R 1 Indicates (C) 1-5 )alkoxy group; -OH; -NH2; -NH-(C 3-7 )cycloalkyl; oxopiperazinyl; morpholinyl; thiomorpholinyl; methylpiperazinyl; or tetrahydropyridyl,

[0196] R 2 (C) indicates that it is optionally substituted with a pyridyl group. 1-5Alkyl; Halogenated phenyl; Dihalogenated phenyl; (amino)halogenated phenyl; (methylpiperazinyl)(methyl)phenyl; (dimethylamino)phenyl; Aminophenyl; Diethylaminophenyl; Biphenyl; (phenylpropyl)phenyl; (cyclopropylamino)pyrimidinyl; (trifluoroethylamino)pyrimidinyl; Pyridinyl; Pyrimidinyl; (cyclopropyl)(isoxazole)formamide; (dimethyl)pyrimidinyl; Pyrazinyl; Aminopyridinyl; Halogenated pyrimidinyl; Aminopyrazinyl; Halogenated pyrimidinyl; (methyl)halogenated pyrimidinyl; (amino)(methyl)pyrimidinyl; (amino)halogenated pyrimidinyl; Dihalogenated pyrimidinyl; Amino(dihalogenated phenyl)pyrimidinyl; (amino)(trifluoromethyl)pyrimidinyl; Pentylpyrimidinyl; Methylpyrazolyl; (benzothiophene)formate; (thiophene)formic acid Methyl ester; (thiophene)carboxylic acid; (thiophene)formamide; methyl(thiophene)formamide; cyclopropyl(thiophene)formamide; methylisoxazolyl; benzo[a]isoxazolyl; isothiazolyl; methylthiophene; pyrazolyl; (methyl)(trifluoromethyl)pyrazolyl; isoxazolyl; aminopyrazolyl; methyl (pyrrole)carboxylic acid; ethyl (isoxazol)carboxylic acid; (isoxazol)formamide; methyl(isoxazol)formamide; dimethyl(isoxazol)formamide; cyclopropyl(oxazol)formamide; (pyrimidine)carboxylic acid; (pyrimidine)formamide; methyl(pyrimidine)formamide; dimethyl(pyrimidine)formamide; (pyrazine)formamide; methyl(pyrazine)formamide; aminotriazinyl; (methylamino)triazinyl; (dimethylamino)triazinyl; (cyclopropylamino)triazinyl; diamino Triazine; (amino)(pyrrolyl)triazine; aminopyrimidinyl; (methylamino)pyrimidinyl; (ethylamino)pyrimidinyl; (propylamino)pyrimidinyl; (butylamino)pyrimidinyl; (hydroxyethylamino)pyrimidinyl; (hydroxypropylamino)pyrimidinyl; (methoxyethylamino)pyrimidinyl; (((dimethylamino)propyl)amino)pyrimidinyl; (benzylamino)pyrimidinyl; (phenethylamino)pyrimidinyl; (cyclohexylamino)pyrimidinyl; (dimethylamino)pyrimidinyl; (ethylmethylamino)pyrimidinyl; (diethylamino)pyrimidinyl; (ethylpropylamino)pyrimidinyl; (butylethylamino)pyrimidinyl; pyrrolylpyrimidinyl; (hydroxypyrrolyl)pyrimidinyl; piperidinylpyrimidinyl; (hydroxypiperidinyl)pyrimidinyl; morpholinopyrimidinyl Pyridyl; (methylpiperazinyl)pyrimidinyl; (amino)(methylamino)pyrimidinyl; (amino)(pyrrolyl)pyrimidinyl; (methylamino)halopyrimidinyl; (ethylamino)halopyrimidinyl; (cyclopropylamino)halopyrimidinyl; (cyclohexylamino)halopyrimidinyl; (dimethylamino)halopyrimidinyl; (ethylmethylamino)halopyrimidinyl; (diethylamino)halopyrimidinyl; (methylphenylamino)halopyrimidinyl; (benzylmethylamino)halopyrimidinyl; (pyrrolyl)halopyrimidinyl; (piperidinyl)halopyrimidinyl; (morpholino)halopyrimidinyl; (thiomorpholino)halopyrimidinyl; (methylpiperazinyl)halopyrimidinyl; (cyclopropylamino)methylpyrimidinyl; (amino)pyrimidinyl; (methylthio)pyrimidinyl;(Methoxy)pyrimidinyl; (benzyloxy)pyrimidinyl; acetamoxypyrimidinyl; (difluoropropylamino)pyrimidinyl; (difluoroethylamino)pyrimidinyl; (trifluoropropylamino)pyrimidinyl; (fluoroethylamino)pyrimidinyl; (cyclobutylamino)pyrimidinyl; (cyclopentylamino)pyrimidinyl; (isopropylamino)pyrimidinyl; (sec-butylamino)pyrimidinyl; ((cyclopropylmethyl)amino)pyrimidinyl; (((dimethylamino)ethyl)amino)pyrimidinyl; (((dimethylamino)propyl)amino)pyrimidinyl; (methoxyamino)pyrimidinyl; (benzylmethylamino)pyrimidinyl; (cyclohexylamino) Halogenated pyrimidinyl; (cyclopropylmethylamino)halogenated pyrimidinyl; (benzylamino)halogenated pyrimidinyl; (cyclopropylamino)halogenated pyrimidinyl; (cyclopropylamino)methylpyrimidinyl; (cyclopropylamino)(trifluoromethyl)pyrimidinyl; (cyclopropylamino)(methoxy)pyrimidinyl; (cyclopropylamino)pyrazinyl; (ethylamino)pyrazinyl; (propylamino)pyrazinyl; (hydroxyethylamino)pyrazinyl; (((dimethylamino)ethyl)amino)pyrazinyl; phenylpyrimidinyl; (methylpyrazolyl)pyrimidinyl; (dimethylcyclohexenyl)pyrimidinyl; dihydropyranylpyrimidinyl; or pyridylpyrimidinyl.

[0197] (3) The compound according to (1) or (2), its stereoisomer, its pharmaceutically acceptable salt or its solvate, wherein the compound represented by formula (I) above is the compound represented by formula (Ib):

[0198] [Equation (Ib)]

[0199]

[0200] In equation (Ib),

[0201] X represents -CH2-; or -C(=O)-,

[0202] V 1 V 2 V 3 and V 4 Each can be represented independently as CH or N, where in all V 1 V 2 V 3 and V 4 When neither of them is N, V 1 V 2 V 3 and V 4 One or more H in the equation are optionally and independently controlled by W. 3 replace,

[0203] One or more W 3 Each independently represents H and halogen; (C 1-5 )alkyl; (C 1-5)alkoxy group; -OH; -NO2; -NR 5 R 6 -CH=CR 7 R 8 ;-C≡CR 9 ;(C 5-6 )cycloalkenyl; optionally coated with (C 1-5 )alkyl, -C(=O)O(C 1-5 )alkyl, -S(=O)2(C 1-5 )alkyl, -C(=O)(C 1-5 5- to 7-membered heterocyclic alkyl groups substituted with alkyl or -C(=O)(NH2); aryl; or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one or more R 10 replace,

[0204] R 5 and R 6 Each represents H independently; optionally by (C) 3-7 )cycloalkyl or aryl substituted (C 1-5 )alkyl; optionally coated with (C 1-5 Alkyl-substituted 5- to 7-membered heterocyclic alkyl groups; aryl; -C(=O)R 11 ;or-S(=O)2R 12 ,

[0205] R 7 (C) indicates that it is optionally substituted with -OH. 1-5 )alkyl; optionally halogenated aryl; or -C(=O)R 13 ,

[0206] R 8 Indicates H; or (C) 1-5 )alkyl,

[0207] R 9 This indicates an aryl group that is optionally substituted with -NH2.

[0208] One or more R 10 Each independently represents H; halogen; -CN; -CF3; -OH; -OCF3; optionally, it is replaced by (C 3-7 )cycloalkyl, 5- to 7-membered heterocyclic alkyl or -OH substituted (C 1-5 )alkyl; (C 1-5 )alkoxy; optionally surrounded by one or more (C 1-5 )alkyl or -C(=O)O(C 1-5 )alkyl-substituted -NH2; optionally (C 1-5 Alkyl-substituted 5- to 7-membered heterocyclic alkyl groups; -C(=O)R 14;-S(=O)2-(5 to 7-membered heterocyclic alkyl); or aryl, wherein R 10 They can be arbitrarily connected to form 5 to 6-membered rings.

[0209] R 11 (C) indicates that it is optionally substituted with -N(CH3)2, aryl or hydroxyaryl. 1-5 )alkyl; optionally containing C (=O) (C 3-7 )cycloalkyl; optionally coated with (C 1-5 )alkyl-substituted (C 3-7 )cycloalkyl; fused with aryl (C 3-7 )cycloalkyl; optionally coated with (C 1-5 )alkyl-substituted (C 5-6 )cycloalkenyl; optionally coated with (C 1-5 )alkyl or -NH2-substituted 5- to 7-membered heterocyclic alkyl groups; aryl; or optionally substituted with (C 1-5 )alkyl or -OH substituted heteroaryl groups,

[0210] R 12 Indicates (C) 1-5 )alkyl; or aryl, wherein at least one H of the aryl group is optionally and independently (C 1-5 Alkyl or halogen substitution,

[0211] R 13 Indicates (C) 1-5 )alkyl; (C 1-5 )alkoxy; -OH; -NH2, wherein at least one H of -NH2 is optionally replaced by (C 1-5 )alkyl or OH-substituted (C 1-5 )alkyl substitution; (C 3-7 )cycloalkyl; hydroxyl (C 1-5 )alkyl; (C 1-5 )alkoxy (C 1-5 )alkyl; -NH2,

[0212] R 14 Indicates a 5- to 7-membered heterocyclic alkyl group; -NH2; or -OH.

[0213] L 1 L 2 M and G are as defined in (1) or (2).

[0214] (4) The compound, its stereoisomer, its pharmaceutically acceptable salt or its solvate, according to (1), (2) or (3).

[0215] W 3 Independently represent H; halogen; (C) 1-5 )alkyl; (C 1-5)alkoxy group; -OH; -NO2; -NR 5 R 6 -CH=CR 7 R 8 ;-C≡CR 9 ;(C 5-6 Cycloalkenyl; Morpholinyl; Tetrahydropyridyl; Dihydropyranyl; Tert-butyl (tetrahydropyridyl)carboxylate; Tert-butyl (dihydropyridyl)carboxylate; Dihydrothiopyranyl; Methyltetrahydropyridyl; (Methylsulfonyl)tetrahydropyridyl; Acetyltetrahydropyridyl; (tetrahydropyridyl)formamide; 1,1-dioxide-dihydrothiopyranyl; Phenyl; (trifluoromethoxy)phenyl; Aminophenyl; Tert-butyl (phenyl)carboxylate; (pyrrolidinylsulfonyl)phenyl; Oxypiperidine (carbonyl)phenyl; Methylpiperazinyl; (Methylpiperazinyl)phenyl; Isoindolyl; Cyanophenyl; Cyanohalophenyl; (trifluoromethyl)phenyl; (dimethylamino)phenyl; Hydroxybenzyl; Methoxyphenyl; Biphenyl; Methylphenyl; Hydroxyphenyl; Dihydroindene; Benzoic acid; Methyl benzoate; Pyridyl Pyridyl; pyrazolyl; methylpyrazolyl; furanyl; aminopyridyl; halopyridyl; hydroxypyridyl; (methoxy)halopyridyl; methoxypyridyl; (methyl)halopyridyl; piperazinylpyridyl; pyrrolopyridyl; (dimethylamino)pyrimidinyl; (cyclopropylmethyl)pyrazolyl; (morpholinoethyl)pyrazolyl; pyrimidinyl; aminopyrimidinyl; (methylpiperazinyl)pyridyl; piperazinylpyrimidinyl; morpholinopyridyl; dihalopyridyl; methylpyridyl; pyrroleyl; (pyrrole) tert-butyl formate; dimethylisooxazolyl; isoquinolinyl; methylindazole; methylthiophenyl; indazole; thiophenyl; cyanopyridyl; (hydroxymethyl)pyridyl; pyridinamide; (dimethylamino)pyridyl; dimethylpyridyl; or (methylamino)pyridyl

[0216] R 5 and R 6 Each represents H independently; optionally by (C) 3-7 )cycloalkyl or phenyl substituted (C 1-5 )alkyl; optionally coated with (C 1-5 Alkyl-substituted morpholino or piperazine; phenyl; -C(=O)R 11 ;or-S(=O)2R 12 ,

[0217] R 7 This indicates a methyl group optionally substituted with -OH; a phenyl group optionally substituted with a halogen; or -C(=O)R 13 ,

[0218] R 9 This indicates a phenyl group that is optionally substituted with -NH2.

[0219] R 11(C) indicates that it is optionally substituted with -N(CH3)2, phenyl, or hydroxyphenyl. 1-5 )alkyl; optionally containing C (=O) (C 3-7 )cycloalkyl; by (C 1-5 )alkyl-substituted (C 3-7 )cycloalkyl; fused with phenyl (C 3-7 )cycloalkyl; optionally coated with (C 1-5 )alkyl-substituted (C 5-6 Cycloalkenyl; morpholinyl; methylpiperidinyl; oxopyrrolyl; oximidazolyl; pyrrolyl; piperidinyl; tetrahydrofuranyl; tetrahydropyranyl; methyltetrahydropyranyl; aminopyrrolyl; methylpyrrolyl; phenyl; pyridinyl; oxazolyl; pyridazinyl; methylisooxazolyl; methyloxazolyl; isoxazolyl; methylpyridinyl; furanyl; or hydroxypyrimidinyl.

[0220] R 12 Indicates (C) 1-5 alkyl; phenyl; methylphenyl; or (methyl)halophenyl,

[0221] R 14 It represents an oxopiperidinyl group; -NH2; or -OH, and the halogen and halogen are independently F, Cl, Br, or I.

[0222] (5) The compound, its stereoisomer, its pharmaceutically acceptable salt or its solvate according to (1), (2), (3) or (4), wherein the compound is selected from one of the following compounds.

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244] (5a) The present invention provides the above-described compounds, their stereoisomers, their pharmaceutically acceptable salts or solvates thereof.

[0245] (6) The present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound according to (1), (2), (3), (4), (5) or (5a), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

[0246] (7) The pharmaceutical composition according to (6) is used for the prevention or treatment of GCN2 activation-related diseases.

[0247] (8) The pharmaceutical composition according to (6) further comprises one or more therapeutic agents selected from chemotherapeutic agents, radiotherapy agents, immunotherapy agents and tumor microenvironment modulators.

[0248] (9) The present invention provides a method for preventing or treating GCN2 activation-related diseases, comprising administering to an individual a therapeutically effective amount of a compound according to (1), (2), (3), (4), (5) or (5a), its stereoisomer, its pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition according to (6), (7) or (8).

[0249] (10) According to the method of (9), the GCN2 activation-related diseases include cancer, neurodegenerative diseases, chronic infections and metabolic diseases.

[0250] (11) According to the method of (10), wherein the cancer is selected from thyroid cancer, melanoma, prostate cancer, endometrial cancer, lung cancer, head and neck cancer, pancreatic cancer, glioma, gastric cancer, urothelial carcinoma, skin cancer, breast cancer, colorectal cancer, kidney cancer, fibrosarcoma, osteosarcoma, connective tissue sarcoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, adenocarcinoma, hepatocellular carcinoma, multiple myeloma, myelodysplastic syndrome, myeloproliferative neoplasm, malignant glioma, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia, small cell lung cancer, and pediatric neuroblastoma.

[0251] (12) The present invention provides a method for inhibiting GCN2 activity, comprising administering to an individual a therapeutically effective amount of a compound according to (1), (2), (3), (4), (5) or (5a), its tautomer, its stereoisomer, its pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition according to (6), (7) or (8).

[0252] (13) The present invention provides the use of the compounds according to (1), (2), (3), (4), (5) or (5a), their stereoisomers, their pharmaceutically acceptable salts or solvates thereof for the prevention or treatment of diseases related to GCN2 activation.

[0253] (14) The present invention provides the use of the compounds according to (1), (2), (3), (4), (5) or (5a), their stereoisomers, their pharmaceutically acceptable salts or solvates thereof in the preparation of medicaments for the prevention or treatment of diseases related to GCN2 activation.

[0254] The matters mentioned in the uses, compositions and treatments of this invention shall apply equally if they do not contradict each other.

[0255] Invention Embodiments

[0256] In the following sections, preferred embodiments will be presented to better understand the invention. However, these embodiments are provided for illustrative purposes only and are not intended to limit the invention.

[0257] All chemical reagents are commercially available. Unless otherwise specified, rapid column chromatography refers to silica gel chromatography performed on a Teledyne Combiflash-RF200 system. 1H NMR spectra (δ, ppm) were recorded on an instrument at 400 MHz or 600 MHz. Mass spectrometry data (ESI, m / z) using the positive ionization method were measured by an Agilent Technologies single quadrupole G6120B equipped with an Agilent Technologies 1260 Infinity system. Preparative HPLC (Prep HPLC) was performed on an Agilent Technologies G1361A.

[0258] In the following text, those skilled in the art can appropriately change and modify the following embodiments within the scope of the present invention.

[0259] Preparation Examples: Synthesis of 3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-amine and 2-chloro-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0260] [General Method A]

[0261]

[0262] [Step a] Preparation of 7-nitro-1-toluenesulfonyl-1H-indole. In a dried 3L round-bottom flask containing a magnetic stir bar, a mixture of 7-nitro-1H-indole (CAS No.: 6960-42-5, 81 g, 500 mmol) and p-toluenesulfonyl chloride (TsCl, 114 g, 600 mmol) in DCM (660 mL) was cooled to 0 °C with stirring. A solution of NaOH (200 g, 5,000 mmol) in water (330 mL) was slowly added to the mixture. The reaction mixture was heated to room temperature and stirred for 2 h. The reaction mixture was poured into 1 L of water, extracted with DCM (3 × 2 L), washed with 10% K₂CO₃ aqueous solution (400 mL) and 1N HCl aqueous solution (400 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was then ground with MeOH (300 mL), filtered, and vacuum dried to obtain the target product as a white solid (yield 95%).

[0263] MS(ESI, m / z): 317.0 [M+H] + .

[0264] 1H NMR (400MHz, DMSO) δ8.05 (d, J=3.7Hz, 1H), 7.97 (dd, J=7.8, 0.9Hz, 1H), 7.83 (dt, J=7.9, 1.9Hz, 1H), 7.80–7.76(m,2H),7.48(d,J=7.8Hz,1H),7.44(d,J=8.3Hz,2H),7.08(d,J=3.7Hz,1H),2.37(s,3H).

[0265] [Step b] Preparation of 3-bromo-7-nitro-1-toluenesulfonyl-1H-indole. In a dried 5L round-bottom flask containing a magnetic stir bar, a DMF solution of N-bromosuccinimide (NBS, 98.0 g) in 300 mL was slowly added to a mixture of 7-nitro-1-toluenesulfonyl-1H-indole (145.5 g, 460 mmol) in 500 mL of DMF. The reaction mixture was heated to 60 °C for 3 h. After cooling to room temperature, the reaction mixture was poured into 3 L of water with stirring to give a yellow precipitate. The precipitate was filtered and redissolved in DCM (10 L), washed with 1N NaOH aqueous solution (4 L) and water (2 L). The product was then dried over anhydrous Na2SO4, concentrated under reduced pressure, ground with MeOH (250 mL), filtered, and dried under vacuum to give the target product as a white solid (yield 91%).

[0266] MS(ESI, m / z): 394.9 [M+H] + .

[0267] 1 H NMR (400MHz, dmso) δ8.47(s,1H),7.97(dd,J=7.9,0.9Hz,1H),7.89–7.84(m,3H),7.59(t,J=7.9Hz,1H),7.48(dd,J=8.6,0.6Hz,2H),2.40(s,3H).

[0268] [Step c] Preparation of 7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-1-toluenesulfonyl-1H-indole. In a dried 5L round-bottom flask containing a magnetic stir bar, under N2 atmosphere, a mixture of 3-bromo-7-nitro-1-toluenesulfonyl-1H-indole (130 g, 330 mmol), pinacol diboronate (B2pin2, 117 g, 462 mmol), Pd(dppf)Cl2 / CH2Cl2 (27 g, 33 mmol), and KOAc (65 g, 660 mmol) in dimethoxyethane (DME, 2 L) was heated to 85 °C for 12 h. After cooling to room temperature, the mixture was... The reaction mixture was filtered and concentrated under reduced pressure. The residue was then ground with MeOH (3 × 400 mL), filtered, and dried under vacuum to give the target product as a light gray solid (yield 68%).

[0269] MS(ESI, m / z): 443.1 [M+H] + .

[0270] 1 H NMR(400MHz,dmso)δ8.32(s,1H),8.18(dd,J=7.9,1.1Hz,1H),8.01–7.96(m,2H),7.86(dd ,J=7.9,1.0Hz,1H),7.54(d,J=7.9Hz,1H),7.52–7.47(m,2H),2.42(s,3H),1.34(s,12H).

[0271] [Step d] Preparation of 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1-toluenesulfonyl-1H-indole. In a dried 2L round-bottom flask with a magnetic stirrer, a mixture of 7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-toluenesulfonyl-1H-indole (63 g, 142 mmol), Pd(PPh3)4 (16 g, 14 mmol), 2,4-dichloro-5-methylpyrimidinyl (30 g, 185 mmol) and K2CO3 (39 g, 284 mmol) in 1,4-dioxane (700 mL) and water (260 mL) was heated to 80 °C for 12 h. After cooling to room temperature, the reaction mixture was poured into water (500 mL), extracted with DCM (3 × 1.5 L), washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was then ground with MeOH (250 mL), filtered, and dried under vacuum to give the target product as a white solid (yield 91%).

[0272] MS(ESI, m / z): 443.0 [M+H] + .

[0273] 1 H NMR(400MHz,dmso)δ8.78(t,J=6.7Hz,1H),8.63(s,1H),8.39(dt,J=19.8,9.9Hz,1H),7.97(dd,J=7.9,0. 9Hz, 1H), 7.92 (dd, J=8.7, 2.0Hz, 2H), 7.61 (t, J=8.0Hz, 1H), 7.52–7.46 (m, 2H), 2.44 (s, 3H), 2.40 (s, 3H).

[0274] [Step e] Preparation of 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1H-indole. K₂CO₃ (30 g, 214 mmol) was added to a MeOH (1 L) solution of 47 g (107 mmol) of 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1-toluenesulfonyl-1H-indole. The reaction mixture was heated to 50 °C for 6 h and then cooled to room temperature. The reaction mixture was then poured into water (400 mL) with stirring to obtain a precipitate. The precipitate was filtered, washed with MeOH, and dried under vacuum to give the target product as a brown solid (yield 98%).

[0275] MS(ESI, m / z): 289.0 [M+H] + .

[0276] 1 H NMR(400MHz,dmso)δ12.65(s,1H),8.89(dd,J=8.0,1.0Hz,1H),8.62(d,J=0.7Hz,1H),8.24 (dd, J = 8.1, 1.0 Hz, 1H), 8.19 (d, J = 3.9 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 2.51 (t, J = 0.9 Hz, 3H).

[0277] [Step f] Preparation of N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-methyl-4-(7-nitro-1H-indole-3-yl)pyrimidin-2-amine. A mixture of 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1H-indole (5.80 g, 20 mmol), 1,5-dimethyl-1H-pyrazol-3-amine (2.80 g, 25 mmol), and concentrated HCl (1.67 mL, 20 mmol) in 2-methoxyethanol (40 mL) was heated to 130 °C for 72 h. After cooling to room temperature, the reaction mixture was mixed with 10 mL of isopropanol (IPA) to give a precipitate. The precipitate was filtered, washed with IPA (100 mL), and dried under vacuum to give the target product as a pale yellow solid (yield 83%).

[0278] MS(ESI, m / z): 364.1 [M+H] + .

[0279] 1H NMR(400MHz,dmso)δ12.83(s,1H),11.21(s,1H),9.27(d,J=7.8Hz,1H),8.37(s,1H),8.34(d,J=3.1H z,1H),8.28–8.24(m,1H),7.46(t,J=8.0Hz,1H),6.12(s,1H),3.77(s,3H),2.50(s,3H),2.29(s,3H).

[0280] [Step g] Synthesis of 3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-amine (intermediate 001). A mixture of N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-methyl-4-(7-nitro-1H-indole-3-yl)pyrimidin-2-amine (15 g, 40 mmol), Fe (powder form, 11 g, 200 mmol), and NH4Cl (21 g, 400 mmol) in THF (560 mL) and water (260 mL) was heated under reflux for 8 h. After cooling to room temperature, the reaction mixture was filtered to remove the black slurry. The filtrate was then concentrated under reduced pressure and cured with a mixed solvent of MeOH (250 mL) and DCM (750 mL). The precipitate was filtered, washed with MeOH (100 mL), and dried under vacuum to obtain the target product as a white solid (yield 93%).

[0281] MS(ESI, m / z): 334.1 [M+H] + .

[0282] 1 H NMR(400MHz,dmso)δ11.25(s,1H),9.10(s,1H),8.17(s,1H),7.88(d,J=2.6Hz,1H),7.79(d,J=8.2Hz,1H),6. 81(t,J=7.7Hz,1H),6.46(s,1H),6.41(d,J=7.3Hz,1H),5.11(s,2H),3.62(s,3H),2.33(s,3H),2.19(s,3H).

[0283] [Step h] Preparation of 2-chloro-N-(3-(2-(((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide (intermediate 002). A mixture of 3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-amine (10 g, 30 mmol) in THF (300 mL) was heated to 60 °C for 2 h until completely dissolved. The mixture was cooled to room temperature and 2-chloroacetyl chloride (7.6 mL, 100 mmol) was added dropwise. The reaction mixture was heated under reflux for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove the solvent and ground with MeOH (100 mL) to obtain a precipitate. The precipitate was filtered, washed with MeOH (100 mL), and dried under vacuum to obtain the target product as a light green solid (yield 70%).

[0284] MS(ESI, m / z): 410.1 [M+H] + .

[0285] 1 H NMR(600MHz,cd3od)δ8.70(s,1H),8.30(s,1H),8.18(s,1H),7.35–7.16(m,2H),5.99(s,1H),4.35(s,2H),3.80(s,3H),2.53(s,3H),2.32(s,3H).

[0286] Example 1: Synthesis of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-fluoro-1H-indole-7-yl)acetamide

[0287]

[0288] [General Method B]

[0289]

[0290] [Step a'] A solution of 2-chloro-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-fluoro-1H-indol-7-yl)acetamide (intermediate 002'; 345 mg, 0.8 mmol) and (R)-pyrrolidine-3-ol (104 mg, 1.2 mmol) in DMF (3 mL) was treated with triethylamine (0.22 mL, 1.6 mmol) and stirred at 50 °C for 2 h. The mixture was concentrated under vacuum and purified by column chromatography (0–30% MeOH / DCM) to give (R)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-fluoro-1H-indol-7-yl)-2-(3-hydroxypyrrolidine-1-yl)acetamide (280 mg, 72%). MS (ESI, m / z): 479.2 [M+H] + .

[0291] [Step b'] A solution of (R)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-fluoro-1H-indol-7-yl)-2-(3-hydroxypyrrolidine-1-yl)acetamide (191 mg, 0.4 mmol), 2-chloropyrimidin-4-ol (65 mg, 0.5 mmol) and triphenylphosphine (157 mg, 0.6 mmol) in THF (3 mL) was treated with diisopropyl azodicarbonate (0.157 mL, 0.8 mmol) and stirred for 2 h. The mixture was concentrated under vacuum and purified by column chromatography (0–30% MeOH / DCM) to give (S)-2-(3-(((2-chloropyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-fluoro-1H-indol-7-yl)acetamide (170 mg, 71%). MS (ESI, m / z): 591.2 [M+H] + .

[0292] [Step c'] A solution of (S)-2-(3-(((2-chloropyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-fluoro-1H-indol-7-yl)acetamide (118 mg, 0.2 mmol) in DMF (1 mL) and cyclopropylamine (20 μL, 0.3 mmol) was treated with triethylamine (70 μL, 0.5 mmol) and stirred at 50 °C for 2 h. The mixture was then separated from the solution on a UCT SPE CUBCX column and purified by preparative HPLC to give the corresponding product (60 mg, 49%) as a white solid. MS (ESI, m / z): 612.3 [M+H] + .

[0293] 2-chloro-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-fluoro-1H-indole-7-yl)acetamide (which is prepared by general method A in steps b, c, d, f, g, and h using N-(6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-yl)-4-methylbenzenesulfonamide instead of 7-nitro-1-toluenesulfonyl-1H-indole) is given by means of N-(6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-yl)-4-methylbenzenesulfonamide instead of 7-nitro-1-toluenesulfonyl-1H-indole)

[0294] Example 2: Synthesis of (S)-N-(5-amino-3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0295]

[0296] The title product was obtained using (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide (prepared by conventional method B using intermediate 002').

[0297] Step a”: At 0°C, a solution of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide (297 mg, 0.5 mmol) in c-H2SO4 (3 mL) was treated with HNO3 (0.1 mL). Stir for 8 hours. Dilute the mixture with water (10 mL), alkalize with sodium bicarbonate (9 g), and filter to obtain (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-5-nitro-1H-indole-7-yl)acetamide (35 mg, 10%).

[0298] Step b”: Under H2 gas, a solution of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-5-nitro-1H-indole-7-yl)acetamide (33 mg, 0.05 mmol) and 10% Pd / C (10 mg) in MeOH (1 mL) was stirred for 1 h. The mixture was then separated from the solution on a UCT SPE CUBCX column and purified by preparative HPLC to give the corresponding product as a white solid (16 mg, 52%). MS (ESI, m / z): 609.3 [M+H] + .

[0299] Example 3: Synthesis of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-(dimethylamino)-1H-indole-7-yl)acetamide

[0300]

[0301] The title product was obtained by conventional method B using 2-chloro-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-(dimethylamino)-1H-indole-7-yl)acetamide instead of 2-chloro-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-fluoro-1H-indole-7-yl)acetamide (which was prepared by conventional method A using N,N-dimethyl-7-nitro-1H-indole-6-amine instead of 7-nitro-1H-indole). MS (ESI, m / z): 637.3 [M+H] + .

[0302] Example 4: Synthesis of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-methoxy-1H-indole-7-yl)acetamide

[0303]

[0304] The title product was obtained by using a procedure similar to that described for the synthesis of Example 3, but instead of 7-nitro-1H-indole, 6-methoxy-7-nitro-1H-indole. MS (ESI, m / z): 624.3 [M+H] + .

[0305] Example 5: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-(dimethylamino)-1H-inden-7-yl)-2-(3-((2-((2,2,2-trifluoroethyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0306]

[0307] The title product was obtained by using a procedure similar to that described for the synthesis of Example 3, but with 2,2,2-trifluoroethyl-1-amine instead of cyclopropylamine. MS (ESI, m / z): 678.3 [M+H] + .

[0308] Example 6: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-methoxy-1H-indol-7-yl)-2-(3-((2-((2,2,2-trifluoroethyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0309]

[0310] The title product was obtained by using a procedure similar to that described for the synthesis of Example 4, but instead of cyclopropylamine, 2,2,2-trifluoroethyl-1-amine. MS (ESI, m / z): 666.3 [M+H] + .

[0311] Example 7: Synthesis of (S)-2-(3-((6-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0312]

[0313] The title product was obtained by a procedure similar to that described for the synthesis of Example 3, using 7-nitro-1H-indole instead of N,N-dimethyl-7-nitro-1H-indole-6-amine, 2,4-dichloropyrimidine instead of 2,4-dichloro-5-methylpyrimidine, and 6-chloropyrimidine-4-ol instead of 2-chloropyrimidine-4-ol. MS (ESI, m / z): 580.3 [M+H] + .

[0314] Example 8: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-fluoropyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyridin-4-yloxy)pyrrolidine-1-yl)acetamide

[0315]

[0316] The title product was obtained by a procedure similar to that described for the synthesis of Example 7, using 2,4-dichloro-5-fluoropyrimidine instead of 2,4-dichloropyrimidine and pyridin-4-ol instead of 6-chloropyrimidin-4-ol. MS (ESI, m / z): 542.2 [M+H] + .

[0317] Example 9: Synthesis of (S)-N-(3-(5-chloro-2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyridin-4-yloxy)pyrrolidine-1-yl)acetamide

[0318]

[0319] The title product was obtained by using a procedure similar to that described for the synthesis of Example 8, but with 2,4-dichloro-5-chloropyrimidine instead of 2,4-dichloro-5-fluoropyrimidine. MS (ESI, m / z): 558.2 [M+H] + .

[0320] Example 10: Synthesis of (S)-N-(3-(5-chloro-2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0321]

[0322] The title product was obtained by a procedure similar to that described for the synthesis of Example 7, using 2,4,5-trichloropyrimidine instead of 2,4-dichloropyrimidine and 2-chloropyrimidine instead of 6-chloropyrimidin-4-ol. MS (ESI, m / z): 614.2 [M+H] + .

[0323] Example 11: Synthesis of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-ethylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0324]

[0325] The title product was obtained by using a procedure similar to that described for the synthesis of Example 10, but with 2,4-dichloro-5-ethylpyrimidine instead of 2,4,5-trichloropyrimidine. MS (ESI, m / z): 608.3 [M+H] + .

[0326] Example 12: Synthesis of (S)-N-(3-(5-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0327]

[0328] The title product was obtained by using a procedure similar to that described for the synthesis of Example 10, but with 2,4-dichloro-5-cyclopropylpyrimidine instead of 2,4,5-trichloropyrimidine. MS (ESI, m / z): 620.3 [M+H] + .

[0329] Example 13: Synthesis of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methoxypyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0330]

[0331] The title product was obtained by using a procedure similar to that described for the synthesis of Example 10, but with 2,4-dichloro-5-methoxypyrimidine instead of 2,4,5-trichloropyrimidine. MS (ESI, m / z): 610.3 [M+H] + .

[0332] Example 14: Synthesis of (S)-2-(3-((3-(cyclopropylamino)-1,2,4-triazin-5-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methoxypyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0333]

[0334] The title product was obtained by using a procedure similar to that described for the synthesis of Example 13, but with 3-chloro-1,2,4-triazine-5-ol instead of 2-chloropyrimidin-4-ol. MS (ESI, m / z): 611.3 [M+H] + .

[0335] Example 15: Synthesis of (S)-N-(3-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyrimidin-4-yloxy)pyrrolidine-1-yl)acetamide

[0336]

[0337] The title product was obtained by conventional method A, using 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-amine instead of 1,5-dimethyl-1H-pyrazole-3-amine, and by conventional method B, using pyrimidin-4-ol instead of 2-chloropyrimidin-4-ol. MS (ESI, m / z): 551.3 [M+H] + .

[0338] Example 16: Synthesis of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0339]

[0340] The title product was obtained by conventional method A, using 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-amine instead of 1,5-dimethyl-1H-pyrazole-3-amine, and conventional method B. MS (ESI, m / z): 606.3 [M+H] + .

[0341] Example 17: Synthesis of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(5-methyl-2-((5-methyl-1-(2-morpholinoethyl)-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0342]

[0343] The title product was obtained by using a procedure similar to that described for the synthesis of Example 16, but instead of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-amine. MS (ESI, m / z): 693.4 [M+H] + .

[0344] [General Method C]

[0345]

[0346] [Step a”] A THF (5 mL) solution of (R)-3-hydroxypyrrolidine-1-carboxylate (187 mg, 1 mmol), 2-chloropyrimidin-4-ol (156 mg, 1.2 mmol) (or pyrimidin-4-ol (114 mg, 1.2 mmol)) and triphenylphosphine (367 mg, 1.4 mmol) was treated with diisopropyl azodicarbonate (0.354 mL, 1.8 mmol) and stirred for 2 h. The mixture was concentrated under vacuum and purified by column chromatography (0–40% EA / Hx) to give (S)-3-((2-chloropyrimidin-4-yl)oxy)pyrrolidine-1-carboxylate (220 mg, 73%). MS (ESI, m / z): 300.1 [M+H] +(Or (S)-3-(pyridin-4-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 75%). MS (ESI, m / z): 265.2 [M+H] + ).

[0347] [Step b”] A DMF (2 mL) solution of (S)-3-((2-chloropyrimidin-4-yl)oxy)pyrrolidine-1-carboxylate (450 mg, 1.5 mmol) and cyclopropylamine (200 μL, 3 mmol) was treated with triethylamine (420 μL, 3 mmol) and stirred at 50 °C for 2 h. The mixture was then concentrated under vacuum and purified by column chromatography (0–50% EA / Hx) to give tert-butyl (S)-3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-carboxylate (300 mg, 62%). MS (ESI, m / z): 321.2 [M+H] + .

[0348] [Step c”] Dissolve (S)-3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (160 mg, 0.5 mmol) (or (S)-3-(pyridin-4-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (132 mg, 0.5 mmol)) in MeOH (2 mL) containing 1 N HCl. Stir the mixture for 2 h, separate it from a UCT SPE CUBCX column, and quantify the product by preparative HPLC. MS (ESI, m / z): 221.1 [M+H] + (Or MS(ESI, m / z): 165.1 [M+H]) + ).

[0349] Example 18: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-oxo-2-(3-(pyridin-4-yloxy)pyrrolidine-1-yl)acetamide

[0350]

[0351] To a stirred mixture of 2-((3-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoacetic acid (20 mg, 0.05 mmol), HATU (23 mg, 0.06 mmol), and Et3N (14 μL, 0.10 mmol) in 0.5 mL DMF, (S)-4-(pyrrolidine-3-yloxy)pyridine (10 mg, 0.06 mmol) was added. The reaction mixture was heated to 50 °C for 3 h. The mixture was then separated from a UCT SPE CUBCX column and purified by preparative HPLC to give the corresponding product as a white solid (yield 40%).

[0352] MS(ESI, m / z): 552.2 [M+H] + .

[0353] Example 19: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-oxo-2-(3-(pyridin-2-yloxy)pyrrolidine-1-yl)acetamide

[0354]

[0355] The title product was obtained by using a procedure similar to that described for the synthesis of Example 18, but with 2-(pyrrolidine-3-yloxy)pyridine instead of (S)-4-(pyrrolidine-3-yloxy)pyridine. MS (ESI, m / z): 552.2 [M+H] + .

[0356] Example 20: Synthesis of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-oxoacetamide

[0357]

[0358] The title product was obtained by using a procedure similar to that described for the synthesis of Example 18, but with (S)-N-cyclopropyl-4-(pyrrolidine-3-yloxy)pyrimidine-2-amine instead of (S)-4-(pyrrolidine-3-yloxy)pyridine. MS (ESI, m / z): 608.3 [M+H] + .

[0359] Example 21: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-N-methyl-2-(3-(pyrimidin-4-yloxy)pyrrolidine-1-yl)acetamide

[0360]

[0361] The title compound was obtained by general method A, using N-(1H-indol-7-yl)-N,4-dimethylbenzenesulfonamide instead of 7-nitro-1H-indol, and by general method B, using pyrimidin-4-ol instead of 2-chloropyrimidin-4-ol. MS (ESI, m / z): 553.3 [M+H] + .

[0362] Example 22: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(pyrrolidine-1-yl)propionamide

[0363]

[0364] The title compound was obtained by conventional method A, which used 2-chloropropionyl chloride instead of 2-chloroacetyl chloride, and by conventional method B, which used pyrrolidine instead of (R)-pyrrolidine-3-ol. MS (ESI, m / z): 459.3 [M+H] + .

[0365] Example 23: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-((S)-3-(pyridin-4-yloxy)pyrrolidine-1-yl)propionamide

[0366]

[0367] The title product was obtained by using a procedure similar to that described for the synthesis of Example 22, but with (S)-4-(pyrrolidine-3-yloxy)pyridine instead of pyrrolidine. MS (ESI, m / z): 551.3 [M+H] + .

[0368] Example 24: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-methyl-2-(pyrrolidine-1-yl)propionamide

[0369]

[0370] The title product was obtained by using a procedure similar to that described for the synthesis of Example 22, but instead of 2-chloropropionyl chloride. MS (ESI, m / z): 473.3 [M+H] + .

[0371] Example 25: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-methyl-2-(3-(pyridin-4-yloxy)pyrrolidine-1-yl)propionamide

[0372]

[0373] The title product was obtained by using a procedure similar to that described for the synthesis of Example 23, but instead of 2-chloropropionyl chloride. MS (ESI, m / z): 566.3 [M+H] + .

[0374] Example 26: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-hydroxyazacyclobutane-1-yl)acetamide

[0375]

[0376] The title product was obtained by using a procedure similar to step a' of general method B, replacing (R)-pyrrolidine-3-ol from intermediate 002 prepared by method A with azircyclobutane-3-ol. MS (ESI, m / z): 447.2 [M+H] + .

[0377] Example 27: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyridin-4-ylmethoxy)azacyclobutane-1-yl)acetamide

[0378]

[0379] A DMF (2 mL) solution of Example 26 (223 mg, 0.5 mmol) and cesium carbonate (325 mg, 1 mmol) was treated with 4-(bromomethyl)pyridine (120 mg, 0.7 mmol). The mixture was then separated from the DMF on a UCT SPE CUBCX column and purified by preparative HPLC to give the corresponding product (100 mg, 37%). MS (ESI, m / z): 538.3 [M+H] + .

[0380] Example 28: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyridin-4-yloxy)azacyclobutane-1-yl)acetamide

[0381]

[0382] The title product was obtained by using a procedure similar to that described for the synthesis of Example 26, but instead of aziridine-3-ol, 4-(aziridine-3-yloxy)pyridine. 4-(aziridine-3-yloxy)pyridine was prepared by a procedure similar to that described in general method C, but instead of (R)-3-hydroxypyrrolidine-1-carboxylate tert-butyl ester. MS (ESI, m / z): 524.2 [M+H] + .

[0383] Example 29: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyrimidin-4-yloxy)azacyclobutane-1-yl)acetamide

[0384]

[0385] The title product was obtained by using a procedure similar to that described for the synthesis of Example 28, but instead of 4-(azacyclobutane-3-yloxy)pyridine. MS (ESI, m / z): 525.2 [M+H] + .

[0386] Example 30: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyridin-3-yloxy)azacyclobutane-1-yl)acetamide

[0387]

[0388] The title product was obtained by using a procedure similar to that described for the synthesis of Example 28, but with 3-(azacyclobutane-3-yloxy)pyridine instead of 4-(azacyclobutane-3-yloxy)pyridine. MS (ESI, m / z): 524.2 [M+H] + .

[0389] Example 31: Synthesis of methyl 1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)azacyclobutane-3-carboxylate

[0390]

[0391] The title product was obtained by using a procedure similar to that described for the synthesis of Example 26, but instead of methyl aziridine-3-carboxylate. MS (ESI, m / z): 489.2 [M+H] + .

[0392] Example 32: Synthesis of 1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)azacyclobutane-3-carboxylic acid

[0393]

[0394] The title product was obtained by using a procedure similar to that described for the synthesis of Example 26, but instead of aziridine-3-carboxylic acid. MS (ESI, m / z): 475.2 [M+H] + .

[0395] Example 33: Synthesis of N-cyclopropyl-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)azacyclobutane-3-yl)oxy)isoxazole-5-carboxamide

[0396]

[0397] A THF (3 mL) solution of Example 26 (446 mg, 1 mmol), methyl 3-hydroxyisoxazole-5-carboxylate (143 mg, 1 mmol), and triphenylphosphine (314 mg, 1.2 mmol) was treated with diisopropyl azodicarbonate (0.314 mL, 1.6 mmol) and stirred for 2 h. The mixture was concentrated under vacuum and purified by column chromatography (0–30% MeOH / DCM) to give methyl 3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)azacyclobutane-3-yl)oxy)isoxazole-5-carboxylate (480 mg, 84%).

[0398] A solution of methyl 3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)azacyclobutane-3-yl)oxy)isoxazole-5-carboxylic acid (400 mg, 0.7 mmol) in MeOH (1 mL) was treated with 1N NaOH / MeOH (0.5 mL) and stirred for 1 h. The mixture was concentrated under vacuum and neutralized with 1N HCl to quantitatively obtain 3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)azacyclobutane-3-yl)oxy)isoxazole-5-carboxylic acid.

[0399] A solution of 3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)azacyclobutane-3-yl)oxy)isoxazol-5-carboxylic acid (278 mg, 0.5 mmol), cyclopropylamine (60 μL, 0.9 mmol), and HATU (460 mg, 1.2 mmol) in DMF (2 mL) was treated with triethylamine (210 μL, 1.5 mmol) and stirred for 2 h. The mixture was then separated from the solution on a UCT SPE CUBCX column and purified by preparative HPLC to give the product (200 mg, 67%). MS (ESI, m / z): 597.3 [M+H] + .

[0400] Example 34: Synthesis of 2-(5,6-dihydro-[4,4'-bipyridine]-1(2H)-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0401]

[0402] A DMF (3 mL) solution of intermediate 002 (818 mg, 2 mmol) prepared by method A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,6-tetrahydropyridine (501 mg, 2.4 mmol) was treated with triethylamine (0.55 mL, 4 mmol) and stirred at 50 °C for 2 h. The mixture was concentrated under vacuum and purified by column chromatography (0-30% MeOH / DCM) to give N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridin-1(2H)-yl)acetamide (720 mg, 62%). MS (ESI, m / z): 583.3 [M+H] +

[0403] A solution of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridin-1(2H)-yl)acetamide (291 mg, 0.5 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), 4-bromopyridine (126 mg, 0.8 mmol), and K2CO3 (207 mg, 1.5 mmol) in 1,4-dioxane (0.9 mL) and water (0.3 mL) was heated to 80 °C for 12 h. The mixture was then separated from the solution on a UCT SPE CUBCX column and purified by preparative HPLC to give the product (170 mg, 64%). MS(ESI, m / z): 534.3 [M+H] + .

[0404] Example 35: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-(1-methyl-1H-pyrazol-4-yl)-5,6-dihydropyridine-1(2H)-yl)acetamide

[0405]

[0406] The title product was obtained by using a procedure similar to that described for the synthesis of Example 34, but instead of 4-bromopyridine. MS (ESI, m / z): 537.3 [M+H] + .

[0407] Example 36: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)acetamide

[0408]

[0409] A DMF (3 mL) solution of intermediate 002 (818 mg, 2 mmol) prepared by method A and piperidine-4-ol (303 mg, 3 mmol) was treated with triethylamine (0.55 mL, 4 mmol) and stirred at 50 °C for 2 h. The mixture was concentrated under vacuum and purified by column chromatography (0–20% MeOH / DCM) to give N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-hydroxypiperidin-1-yl)acetamide (820 mg, 86%). MS (ESI, m / z): 475.2 [M+H] + .

[0410] A solution of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-hydroxypiperidin-1-yl)acetamide (711 mg, 1.5 mmol) and methanesulfonyl chloride (193 μL, 2.5 mmol) was treated with triethylamine (0.7 mL, 5 mmol) and stirred at 0 °C for 3 h. The mixture was concentrated under vacuum and purified by column chromatography (0-20% MeOH / DCM) to give 1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)piperidin-4-yl methanesulfonate (620 mg, 75%). MS (ESI, m / z): 553.2 [M+H] + .

[0411] A DMF (3 mL) solution of 1-(2-((3-(2-(((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)piperidin-4-yl methanesulfonate (552 mg, 1 mmol) and 1-methylpiperazine (200 mg, 2 mmol) was treated with triethylamine (0.42 mL, 3 mmol) and stirred at 50 °C for 2 h. The mixture was then separated from the DMF on a UCT SPE CUBCX column and purified by preparative HPLC to give the product (310 mg, 55%). MS (ESI, m / z): 557.3 [M+H] + .

[0412] Example 37: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-morpholinopiperidin-1-yl)acetamide

[0413]

[0414] The title product was obtained by using a procedure similar to that described for the synthesis of Example 36, but with morpholine instead of 1-methylpiperazine. MS (ESI, m / z): 544.3 [M+H] + .

[0415] Example 38: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-(pyridin-3-yloxy)piperidin-1-yl)acetamide

[0416]

[0417] The title product was obtained by using a procedure similar to that described for the synthesis of Example 36, but with pyridine-3-ol instead of 1-methylpiperazine. MS (ESI, m / z): 552.3 [M+H] + .

[0418] Example 39: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-(pyridin-2-yloxy)piperidin-1-yl)acetamide

[0419]

[0420] The title product was obtained by using a procedure similar to that described for the synthesis of Example 36, but with pyridine-2-ol instead of 1-methylpiperazine. MS (ESI, m / z): 552.3 [M+H] + .

[0421] Example 40: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-(pyridin-4-yloxy)piperidin-1-yl)acetamide

[0422]

[0423] The title product was obtained by using a procedure similar to that described for the synthesis of Example 36, but with pyridine-4-ol instead of 1-methylpiperazine. MS (ESI, m / z): 552.3 [M+H] + .

[0424] Example 41: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-(pyrimidin-2-yloxy)piperidin-1-yl)acetamide

[0425]

[0426] The title product was obtained by using a procedure similar to that described for the synthesis of Example 36, but with pyrimidin-2-ol instead of 1-methylpiperazine. MS (ESI, m / z): 553.3 [M+H] + .

[0427] Example 42: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-((4,6-dimethylpyrimidin-2-yl)oxy)piperidin-1-yl)acetamide

[0428]

[0429] The title product was obtained by using a procedure similar to that described for the synthesis of Example 36, but instead of 1-methylpiperazine. MS (ESI, m / z): 581.3 [M+H] + .

[0430] Example 43: Synthesis of N-cyclopropyl-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)piperidin-4-yl)oxy)isoxazole-5-carboxamide

[0431]

[0432] The title product was obtained by using a procedure similar to that described for the synthesis of Example 33, but instead of aziridine-4-ol. MS (ESI, m / z): 625.3 [M+H] + .

[0433] Example 44: Synthesis of N-cyclopropyl-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)piperidin-3-yl)oxy)isoxazole-5-carboxamide

[0434]

[0435] The title product was obtained by using a procedure similar to that described for the synthesis of Example 33, but instead of aziridine-3-ol, piperidine-3-ol was used. MS (ESI, m / z): 625.3 [M+H] + .

[0436] Example 45: Synthesis of 2-(3-(cyanomethyl)pyrrolidone-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0437]

[0438] The title product was obtained by using a procedure similar to that described for the synthesis of Example 26, but instead of aziridine-3-ol, 2-(pyrrolidone-3-yl)acetonitrile. MS (ESI, m / z): 484.3 [M+H] + .

[0439] Example 46: Synthesis of (R)-2-(3-(cyanomethyl)pyrrolidone-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0440]

[0441] The title product was obtained by using a procedure similar to that described for the synthesis of Example 26, but instead of azacyclic butane-3-ol, (R)-2-(pyrrolidone-3-yl)acetonitrile. MS (ESI, m / z): 484.3 [M+H] + .

[0442] Example 47: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyrimidin-4-ylamino)pyrrolidine-1-yl)acetamide

[0443]

[0444] A DMF (3 mL) solution of intermediate 002 (410 mg, 1 mmol) prepared by method A and (S)-pyrrolidine-3-ylcarbamate tert-butyl ester (223 mg, 1.2 mmol) was treated with triethylamine (0.29 mL, 2 mmol) and stirred at 50 °C for 2 h. The mixture was concentrated under vacuum and purified by column chromatography (0–20% MeOH / DCM) to give (S)-(1-(2-((3-(2-((1,5-dimethyl-1H-pyrazole-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)carbamate tert-butyl ester (520 mg, 93%). MS (ESI, m / z): 560.3 [M+H] + .

[0445] (S)-(1-(2-((3-(2-((1,5-dimethyl-1H-pyrazole-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)carbamate tert-butyl (280 mg, 0.5 mmol) was dissolved in 1N HCl / MeOH (2 mL). The mixture was concentrated under vacuum and purified by column chromatography (0-40% MeOH / DCM) to quantitatively give (S)-2-(3-aminopyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazole-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide. MS (ESI, m / z): 460.2 [M+H] + .

[0446] A DMF (2 mL) solution of (S)-2-(3-aminopyrrolidone-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazole-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide (230 mg, 0.5 mmol) and 4-chloropyrimidine (80 mg, 0.7 mmol) was treated with triethylamine (0.29 mL, 2 mmol) and stirred at 50 °C for 2 h. The mixture was stirred for 2 h, separated from a UCTSPE CUBCX column, and purified by preparative HPLC to give (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazole-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyrimidin-4-ylamino)pyrrolidone-1-yl)acetamide (200 mg, 74%). MS(ESI, m / z): 538.3 [M+H] + .

[0447] Example 48: Synthesis of (R)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyrimidin-4-ylamino)pyrrolidine-1-yl)acetamide

[0448]

[0449] The title product was obtained by using a procedure similar to that described for the synthesis of Example 47, but instead of (S)-pyrrolidine-3-ylcarbamate tert-butyl ester. MS (ESI, m / z): 538.3 [M+H] + .

[0450] Example 49: Synthesis of (R)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyridin-4-ylamino)pyrrolidine-1-yl)acetamide

[0451]

[0452] The title product was obtained by using a procedure similar to that described for the synthesis of Example 48, but with 4-chloropyridine instead of 4-chloropyrimidine. MS (ESI, m / z): 537.3 [M+H] + .

[0453] Example 50: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-((3R,4S)-3-fluoro-4-hydroxypyrrolidine-1-yl)acetamide

[0454]

[0455] The title product was obtained by using a procedure similar to step a' of general method B, replacing (R)-pyrrolidine-3-ol with (3R,4S)-4-fluoropyrrolidine-3-ol. MS (ESI, m / z): 479.2 [M+H] + .

[0456] Example 51: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-((3R,4R)-3-fluoro-4-(pyridin-4-yloxy)pyrrolidine-1-yl)acetamide

[0457]

[0458] The title product was obtained by following a procedure similar to steps a' and b' of general method B, using (3S,4R)-4-fluoropyrrolidine-3-ol and pyridin-4-ol instead of (R)-pyrrolidine-3-ol and 2-chloropyrimidin-4-ol. MS (ESI, m / z): 556.3 [M+H] + .

[0459] Example 52: Synthesis of 2-((3R,4S)-3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)-4-fluoropyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0460]

[0461] The title product was obtained by using a procedure similar to that of general method B, with (3S,4S)-4-fluoropyrrolidine-3-ol instead of (R)-pyrrolidine-3-ol. MS (ESI, m / z): 612.3 [M+H] + .

[0462] Example 53: Synthesis of 2-((3R,4R)-3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)-4-fluoropyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0463]

[0464] The title product was obtained by using a procedure similar to that of general method B, with (3S,4R)-4-fluoropyrrolidine-3-ol instead of (R)-pyrrolidine-3-ol. MS (ESI, m / z): 612.3 [M+H] + .

[0465] Example 54: Synthesis of 2-((3S,4R)-3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)-4-fluoropyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0466]

[0467] The title product was obtained by using a procedure similar to that of general method B, with (3R,4R)-4-fluoropyrrolidine-3-ol instead of (R)-pyrrolidine-3-ol. MS (ESI, m / z): 612.3 [M+H]+ .

[0468] Example 55: Synthesis of methyl (2S,4S)-4-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)-1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-2-carboxylate

[0469]

[0470] The title product was obtained using a procedure similar to that of general method B, with methyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate instead of (R)-pyrrolidine-3-ol. MS (ESI, m / z): 652.3 [M+H] + .

[0471] Example 56: Synthesis of (2S,4S)-4-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)-1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-2-carboxylic acid

[0472]

[0473] Example 55 (195 mg, 0.3 mmol) was dissolved in 1 N LiOH / MeOH (2 mL). The mixture was stirred for 2 h, separated from a UCT SPE CUBCX column, and purified quantitatively by preparative HPLC. MS (ESI, m / z): 638.3 [M+H] + .

[0474] Example 57: Synthesis of 2-((2S,4S)-4-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)-2-(hydroxymethyl)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0475]

[0476] At 0 °C, a THF (1 mL) solution of Example 55 (326 mg, 0.5 mmol) was treated with LAH (1 N in THF, 1 mL) and stirred for 4 h. The mixture was diluted with EA (5 mL), washed with water (5 mL × 2), and concentrated under vacuum. The crude product was separated from a UCT SPECUBCX column and purified by preparative HPLC to give the corresponding product (120 mg, 38%). MS (ESI, m / z): 624.3 [M + H] + .

[0477] Example 58: Synthesis of (2S,4S)-4-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)-1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-2-carboxamide

[0478]

[0479] A DMF (2 mL) solution of Example 56 (320 mg, 0.5 mmol), HATU (304 mg, 0.8 mmol), and NH4OH (30% solution, 30 μL) was treated with triethylamine (280 μL, 2 mmol) and stirred for 1 h. The mixture was separated from the product by preparative HPLC on a UCT SPE CUBCX column to give the product (95 mg, 29%). MS (ESI, m / z): 637.3 [M+H] + .

[0480] Example 59: Synthesis of 2-((2S,4S)-2-(aminomethyl)-4-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0481]

[0482] At 0 °C, a THF (1 mL) solution (63 mg, 0.1 mmol) from Example 58 was treated with LAH (1 N in THF, 1 mL) and stirred for 4 h. The mixture was diluted with EA (3 mL), washed with water (3 mL × 2), and concentrated under vacuum. The crude product was separated from a UCT SPECUBCX column and purified by preparative HPLC to give the corresponding product (23 mg, 37%). MS (ESI, m / z): 623.3 [M + H] + .

[0483] Example 60: Synthesis of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)-2-oxopyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0484]

[0485] The title product was obtained by using a procedure similar to that of general method B, with (S)-3-hydroxypyrrolidone instead of (R)-pyrrolidone-3-ol. MS (ESI, m / z): 608.3 [M+H] + .

[0486] Example 61: Synthesis of (S)-2-(4-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)-2-oxopyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0487]

[0488] The title product was obtained by using a procedure similar to that of general method B, with (S)-4-hydroxypyrrolidone-2-one instead of (R)-pyrrolidone-3-ol. MS (ESI, m / z): 608.3 [M+H] + .

[0489] Example 62: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(3-oxoperazin-1-carbonyl)pyrrolidine-1-yl)acetamide

[0490]

[0491] A DMF (20 mL) solution of intermediate 002 (4090 mg, 10 mmol) prepared by method A and methyl (S)-pyrrolidine-3-carboxylate (1548 mg, 12 mmol) was treated with triethylamine (2.8 mL, 20 mmol) and stirred at 50 °C for 4 h. The mixture was concentrated under vacuum and purified by column chromatography (0–20% MeOH / DCM) to give methyl (S)-1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-carboxylate (4600 mg, 91%). MS (ESI, m / z): 503.2 [M+H]+ .

[0492] (S)-1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-carboxylic acid (4518 mg, 9 mmol) was dissolved in 1N LiOH / MeOH (20 mL). The mixture was concentrated under vacuum and purified by column chromatography (0-50% MeOH / DCM) to quantitatively obtain (S)-1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-carboxylic acid. MS (ESI, m / z): 489.2 [M+H] + .

[0493] A DMF (2 mL) solution of (S)-1-(2-((3-(2-(((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-carboxylic acid (244 mg, 0.5 mmol), HATU (304 mg, 0.8 mmol), and piperazine-2-one (70 mg, 0.7 mmol) was treated with triethylamine (280 μL, 2 mmol) and stirred for 3 h. The mixture was separated from the product by preparative HPLC on a UCT SPE CUBCX column to give the product (160 mg, 56%). MS (ESI, m / z): 571.3 [M+H] + .

[0494] Example 63: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(morpholin-4-carbonyl)pyrrolidine-1-yl)acetamide

[0495]

[0496] The title product was obtained by using a procedure similar to that described for the synthesis of Example 62, but instead of piperazine-2-one. MS (ESI, m / z): 558.3 ​​[M+H] + .

[0497] Example 64: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(thiomorpholine-4-carbonyl)pyrrolidine-1-yl)acetamide

[0498]

[0499] The title product was obtained by using a procedure similar to that described for the synthesis of Example 62, but with thiomorpholine instead of piperazine-2-one. MS (ESI, m / z): 574.3 [M+H] + .

[0500] Example 65: Synthesis of (R)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(4-methylpiperazin-1-carbonyl)pyrrolidine-1-yl)acetamide

[0501]

[0502] The title product was obtained by using a procedure similar to that described for the synthesis of Example 62, but with (R)-pyrrolidine-3-carboxylate and 1-methylpiperazine instead of (S)-pyrrolidine-3-carboxylate and piperazine-2-one. MS (ESI, m / z): 571.3 [M+H] + .

[0503] Example 66: Synthesis of (R)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(3-oxoperazin-1-carbonyl)pyrrolidine-1-yl)acetamide

[0504]

[0505] The title product was obtained by using a procedure similar to that described for the synthesis of Example 65, but with piperazine-2-one instead of 1-methylpiperazine. MS (ESI, m / z): 571.3 [M+H] + .

[0506] Example 67: Synthesis of (R)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(morpholin-4-carbonyl)pyrrolidine-1-yl)acetamide

[0507]

[0508] The title product was obtained by using a procedure similar to that described for the synthesis of Example 65, but with morpholine instead of 1-methylpiperazine. MS (ESI, m / z): 558.3 ​​[M+H] + .

[0509] Example 68: Synthesis of (R)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(thiomorpholin-4-carbonyl)pyrrolidine-1-yl)acetamide

[0510]

[0511] The title product was obtained by using a procedure similar to that described for the synthesis of Example 65, but instead of 1-methylpiperazine. MS (ESI, m / z): 574.3 [M+H] + .

[0512] Example 69: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(1,2,3,6-tetrahydropyridine-1-carbonyl)pyrrolidine-1-yl)acetamide

[0513]

[0514] The title product was obtained by using a procedure similar to that described for the synthesis of Example 62, but with 1,2,3,6-tetrahydropyridine instead of piperazine-2-one. MS (ESI, m / z): 554.3 [M+H] + .

[0515] Example 70: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-hydroxypyrrolidine-1-yl)acetamide

[0516]

[0517] The title product was obtained by using a procedure similar to step a' of general method B, replacing (R)-pyrrolidine-3-ol from intermediate 002 prepared by method A. MS (ESI, m / z): 461.2 [M+H] + .

[0518] Example 71: Synthesis of (R)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-hydroxypyrrolidine-1-yl)acetamide

[0519]

[0520] The title product was obtained from intermediate 002 prepared by method A using a procedure similar to step a' of general method B. MS (ESI, m / z): 461.2 [M+H] + .

[0521] Example 72: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-hydroxypyrrolidine-1-yl)acetamide

[0522]

[0523] The title product is obtained by using a procedure similar to step a' of general method B, replacing (R)-pyrrolidine-3-ol from intermediate 002 with (S)-pyrrolidine-3-ol.

[0524] MS(ESI, m / z): 461.2 [M+H] + .

[0525] Example 73: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyridin-2-yloxy)pyrrolidine-1-yl)acetamide

[0526]

[0527] The title product was obtained by using a procedure similar to that described for the synthesis of Example 39, but with (R)-pyrrolidine-3-ol instead of piperidine-4-ol. MS (ESI, m / z): 538.3 [M+H] + .

[0528] Example 74: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyridin-4-yloxy)pyrrolidine-1-yl)acetamide

[0529]

[0530] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with pyridine-4-ol instead of pyridine-2-ol. MS (ESI, m / z): 538.3 [M+H] + .

[0531] Example 75: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyridin-3-yloxy)pyrrolidine-1-yl)acetamide

[0532]

[0533] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with pyridine-3-ol instead of pyridine-2-ol. MS (ESI, m / z): 538.3 [M+H] + .

[0534] Example 76: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyridin-4-yloxy)pyrrolidine-1-yl)acetamide

[0535]

[0536] The title product was obtained by using a procedure similar to that described for the synthesis of Example 74, but instead of (R)-pyrrolidine-3-ol. MS (ESI, m / z): 538.3 [M+H] + .

[0537] Example 77: Synthesis of (R)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyridin-4-yloxy)pyrrolidine-1-yl)acetamide

[0538]

[0539] The title product was obtained by using a procedure similar to that described for the synthesis of Example 74, but with (S)-pyrrolidine-3-ol instead of (R)-pyrrolidine-3-ol. MS (ESI, m / z): 538.3 [M+H] + .

[0540] Example 78: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyrimidin-4-yloxy)pyrrolidine-1-yl)acetamide

[0541]

[0542] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with pyrimidin-4-ol instead of pyridin-2-ol. MS (ESI, m / z): 539.3 [M+H] + .

[0543] Example 79: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyrazin-2-yloxy)pyrrolidine-1-yl)acetamide

[0544]

[0545] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with pyrazin-2-ol instead of pyridine-2-ol. MS (ESI, m / z): 539.3 [M+H] + .

[0546] Example 80: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(4-fluorophenoxy)pyrrolidine-1-yl)acetamide

[0547]

[0548] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 4-fluorophenol instead of pyridine-2-ol. MS (ESI, m / z): 555.3 [M+H] + .

[0549] Example 81: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(3-fluorophenoxy)pyrrolidine-1-yl)acetamide

[0550]

[0551] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 3-fluorophenol instead of pyridine-2-ol. MS (ESI, m / z): 555.3 [M+H] + .

[0552] Example 82: Synthesis of (S)-2-(3-(4-chlorophenoxy)pyrrolidone-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0553]

[0554] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 4-chlorophenol instead of pyridine-2-ol. MS (ESI, m / z): 571.2 [M+H] + .

[0555] Example 83: Synthesis of (S)-2-(3-(2,4-difluorophenoxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0556]

[0557] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 2,4-difluorophenol instead of pyridine-2-ol. MS (ESI, m / z): 573.3 [M+H] + .

[0558] Example 84: Synthesis of (S)-2-(3-(3,4-difluorophenoxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0559]

[0560] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 3,4-difluorophenol instead of pyridine-2-ol. MS (ESI, m / z): 573.3 [M+H] + .

[0561] Example 85: Synthesis of (S)-2-(3-(2-chloro-4-fluorophenoxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0562]

[0563] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 2-chloro-4-fluorophenol instead of pyridine-2-ol. MS (ESI, m / z): 589.2 [M+H] + .

[0564] Example 86: Synthesis of (S)-2-(3-(3,5-difluorophenoxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0565]

[0566] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 3,5-difluorophenol instead of pyridine-2-ol. MS (ESI, m / z): 573.3 [M+H] + .

[0567] Example 87: Synthesis of (S)-2-(3-(3-amino-4-fluorophenoxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0568]

[0569] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 3-amino-4-fluorophenol instead of pyridine-2-ol. MS (ESI, m / z): 570.3 [M+H] + .

[0570] Example 88: Synthesis of (S)-2-(3-(3-(diethylamino)phenoxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0571]

[0572] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 3-(diethylamino)phenol instead of pyridine-2-ol. MS (ESI, m / z): 608.3 [M+H] + .

[0573] Example 89: Synthesis of (S)-2-(3-(3-aminophenoxy)pyrrolidone-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0574]

[0575] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 3-aminophenol instead of pyridine-2-ol. MS (ESI, m / z): 552.3 [M+H] + .

[0576] Example 90: Synthesis of (S)-2-(3-((2-aminopyridin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0577]

[0578] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 2-aminopyridine-4-ol instead of pyridine-2-ol. MS (ESI, m / z): 553.3 [M+H] + .

[0579] Example 91: Synthesis of (S)-2-(3-(((2-chloropyridin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0580]

[0581] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 2-chloropyridin-4-ol instead of pyridin-2-ol. MS (ESI, m / z): 572.2 [M+H] + .

[0582] Example 92: Synthesis of (S)-2-(3-((6-aminopyrazin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0583]

[0584] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 6-aminopyrazin-2-ol instead of pyridine-2-ol. MS (ESI, m / z): 554.3 [M+H] + .

[0585] Example 93: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-fluoropyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0586]

[0587] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 5-fluoropyrimidin-2-ol instead of pyridine-2-ol. MS (ESI, m / z): 557.3 [M+H] + .

[0588] Example 94: Synthesis of (S)-2-(3-((6-chloro-5-methylpyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0589]

[0590] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but instead of pyridine-2-ol. MS (ESI, m / z): 587.2 [M+H] + .

[0591] Example 95: Synthesis of (S)-2-(3-((2-amino-6-methylpyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0592]

[0593] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but instead of pyridine-2-ol. MS (ESI, m / z): 568.3 [M+H] + .

[0594] Example 96: Synthesis of (S)-2-(3-((5-amino-2-chloropyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0595]

[0596] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but instead of pyridine-2-ol. MS (ESI, m / z): 588.2 [M+H] + .

[0597] Example 97: Synthesis of (S)-2-(3-((5-bromo-2-methylpyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0598]

[0599] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but instead of pyridine-2-ol. MS (ESI, m / z): 631.2 [M+H] + .

[0600] Example 98: Synthesis of (S)-2-(3-((2-amino-6-(5-chloro-2-fluorophenyl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0601]

[0602] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 2-amino-6-(5-chloro-2-fluorophenyl)-2-methylpyrimidin-4-ol instead of pyridine-2-ol. MS (ESI, m / z): 682.3 [M+H] + .

[0603] Example 99: Synthesis of (S)-2-(3-((2-amino-6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0604]

[0605] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 2-amino-6-(trifluoromethyl)pyrimidin-4-ol instead of pyridine-2-ol. MS (ESI, m / z): 622.3 [M+H]+ .

[0606] Example 100: Synthesis of (S)-2-(3-([1,1'-biphenyl]-4-yloxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0607]

[0608] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with [1,1'-biphenyl]-4-ol instead of pyridine-2-ol. MS (ESI, m / z): 613.3 [M+H] + .

[0609] Example 101: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(4-(2-phenylprop-2-yl)phenoxy)pyrrolidine-1-yl)acetamide

[0610]

[0611] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 4-(2-phenylprop-2-yl)phenol instead of pyridin-2-ol. MS (ESI, m / z): 655.3 [M+H] + .

[0612] Example 102: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-pentylpyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0613]

[0614] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 5-pentylpyrimidin-2-ol instead of pyridine-2-ol. MS (ESI, m / z): 609.3 [M+H] + .

[0615] Example 103: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)pyrrolidine-1-yl)acetamide

[0616]

[0617] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but instead of pyridin-2-ol, 4-((4-methylpiperazin-1-yl)methyl)phenol. MS (ESI, m / z): 649.4 [M+H] + .

[0618] Example 104: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((1-methyl-1H-pyrazol-5-yl)oxy)pyrrolidine-1-yl)acetamide

[0619]

[0620] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but instead of pyridine-2-ol. MS (ESI, m / z): 541.3 [M+H] + .

[0621] Example 105: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((1-methyl-1H-pyrazol-3-yl)oxy)pyrrolidine-1-yl)acetamide

[0622]

[0623] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 1-methyl-1H-pyrazole-3-ol instead of pyridine-2-ol. MS (ESI, m / z): 541.3 [M+H] + .

[0624] Example 106: Synthesis of (S)-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)benzo[b]thiophene-2-carboxylic acid methyl ester

[0625]

[0626] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but instead of pyridine-2-ol, methyl 3-hydroxybenzo[b]thiophene-2-carboxylate. MS (ESI, m / z): 651.2 [M+H] + .

[0627] Example 107: Synthesis of methyl (S)-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)thiophene-2-carboxylate

[0628]

[0629] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but instead of pyridine-2-ol, methyl 3-hydroxythiophene-2-carboxylate. MS (ESI, m / z): 601.2 [M+H] + .

[0630] Example 108: Synthesis of (S)-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)thiophene-2-carboxylic acid

[0631]

[0632] The title product was obtained using Example 107 through a procedure similar to that described for the synthesis of Example 56 from Example 55. MS(ESI, m / z): 587.2 [M+H] + .

[0633] Example 109: Synthesis of (S)-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)thiophene-2-carboxamide

[0634]

[0635] The title product was obtained using Example 107 through a procedure similar to that described for synthesizing Example 58 from Example 55. MS(ESI, m / z): 586.2 [M+H] + .

[0636] Example 110: Synthesis of (S)-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)-N-methylthiophene-2-carboxamide

[0637]

[0638] The title product was obtained by using a procedure similar to that described for the synthesis of Example 109, but with methylamine instead of ammonium hydroxide. MS (ESI, m / z): 600.2 [M+H] + .

[0639] Example 111: Synthesis of (S)-N-cyclopropyl-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)thiophene-2-carboxamide

[0640]

[0641] The title product was obtained using a procedure similar to that described for the synthesis of Example 109, but with cyclopropylamine instead of ammonium hydroxide. MS (ESI, m / z): 626.3 [M+H] + .

[0642] Example 112: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-methylisoxazol-3-yl)oxy)pyrrolidine-1-yl)acetamide

[0643]

[0644] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 5-methylisoxazol-3-ol instead of pyridine-2-ol. MS (ESI, m / z): 542.3 [M+H] + .

[0645] Example 113: Synthesis of (S)-2-(3-(benzo[d]isoxazol-3-yloxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0646]

[0647] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but instead of pyridine-2-ol. MS (ESI, m / z): 578.3 [M+H] + .

[0648] Example 114: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(isothiazolyl-3-yloxy)pyrrolidine-1-yl)acetamide

[0649]

[0650] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with isothiazol-3-ol instead of pyridine-2-ol. MS (ESI, m / z): 544.2 [M+H] + .

[0651] Example 115: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-methylthiophen-3-yl)oxy)pyrrolidine-1-yl)acetamide

[0652]

[0653] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 2-methylthiophene-3-ol instead of pyridin-2-ol. MS (ESI, m / z): 557.2 [M+H] + .

[0654] Example 116: Synthesis of (S)-2-(3-((1H-pyrazol-3-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0655]

[0656] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 1H-pyrazole-3-ol instead of pyridine-2-ol. MS (ESI, m / z): 527.3 [M+H] + .

[0657] Example 117: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)pyrrolidine-1-yl)acetamide

[0658]

[0659] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-ol instead of pyridine-2-ol. MS (ESI, m / z): 609.3 [M+H] + .

[0660] Example 118: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(isoxazo-3-yloxy)pyrrolidine-1-yl)acetamide

[0661]

[0662] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with isoxazol-3-ol instead of pyridine-2-ol. MS (ESI, m / z): 528.2 [M+H] + .

[0663] Example 119: Synthesis of (S)-2-(3-((5-amino-1H-pyrazol-3-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0664]

[0665] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 5-amino-1H-pyrazole-3-ol instead of pyridine-2-ol. MS (ESI, m / z): 542.3 [M+H] + .

[0666] Example 120: Synthesis of methyl (S)-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)-1H-pyrrole-2-carboxylic acid

[0667]

[0668] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but instead of pyridine-2-ol, methyl 3-hydroxy-1H-pyrrole-2-carboxylate. MS (ESI, m / z): 584.3 [M+H] + .

[0669] Example 121: Synthesis of (S)-5-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)isoxazole-4-carboxylic acid ethyl ester

[0670]

[0671] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but instead of pyridine-2-ol, ethyl 5-hydroxyisoxazole-4-carboxylate. MS (ESI, m / z): 600.3 [M+H] + .

[0672] Example 122: Synthesis of (S)-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)isoxazole-5-carboxamide

[0673]

[0674] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but instead of pyridine-2-ol. MS (ESI, m / z): 571.3 [M+H] + .

[0675] Example 123: Synthesis of (S)-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)-N-methylisoxazol-5-carboxamide

[0676]

[0677] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 3-hydroxy-N-methylisoxazole-5-carboxamide instead of pyridine-2-ol. MS (ESI, m / z): 585.3 [M+H]+ .

[0678] Example 124: Synthesis of (S)-N-cyclopropyl-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)isoxazole-5-carboxamide

[0679]

[0680] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with N-cyclopropyl-3-hydroxyisoxazole-5-carboxamide instead of pyridine-2-ol. MS (ESI, m / z): 611.3 [M+H] + .

[0681] Example 125: Synthesis of (S)-3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)-N,N-dimethylisoxazol-5-carboxamide

[0682]

[0683] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 3-hydroxy-N,N-dimethylisoxazole-5-carboxamide instead of pyridine-2-ol. MS (ESI, m / z): 599.3 [M+H] + .

[0684] Example 126: Synthesis of (S)-N-cyclopropyl-2-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)oxazol-5-carboxamide

[0685]

[0686] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with N-cyclopropyl-2-hydroxyoxazol-5-carboxamide instead of pyridine-2-ol. MS (ESI, m / z): 611.3 [M+H] + .

[0687] Example 127: Synthesis of (S)-N-cyclopropyl-2-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)oxazol-4-carboxamide

[0688]

[0689] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with N-cyclopropyl-2-hydroxyoxazol-4-carboxamide instead of pyridine-2-ol. MS (ESI, m / z): 611.3 [M+H] + .

[0690] Example 128: Synthesis of (S)-2-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)pyrimidin-4-carboxylic acid

[0691]

[0692] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 2-hydroxypyrimidine-4-carboxylic acid instead of pyridine-2-ol. MS (ESI, m / z): 583.3 [M+H] + .

[0693] Example 129: Synthesis of (S)-2-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)pyrimidin-4-carboxamide

[0694]

[0695] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 2-hydroxypyrimidine-4-carboxamide instead of pyridine-2-ol. MS (ESI, m / z): 582.3 [M+H] + .

[0696] Example 130: Synthesis of (S)-2-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)-N-methylpyrimidin-4-carboxamide

[0697]

[0698] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 2-hydroxy-N-methylpyrimidine-4-carboxamide instead of pyridine-2-ol. MS (ESI, m / z): 596.3 [M+H] + .

[0699] Example 131: Synthesis of (S)-2-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)-N,N-dimethylpyrimidin-4-carboxamide

[0700]

[0701] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 2-hydroxy-N,N-dimethylpyrimidine-4-carboxamide instead of pyridine-2-ol. MS (ESI, m / z): 610.3 [M+H] + .

[0702] Example 132: Synthesis of (S)-6-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)pyrazine-2-carboxamide

[0703]

[0704] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 6-hydroxypyrazin-2-carboxamide instead of pyridine-2-ol. MS (ESI, m / z): 582.3 [M+H] + .

[0705] Example 133: Synthesis of (S)-6-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)amino)-2-oxoethyl)pyrrolidine-3-yl)oxy)-N-methylpyrazine-2-carboxamide

[0706]

[0707] The title product was obtained by using a procedure similar to that described for the synthesis of Example 73, but with 6-hydroxy-N-methylpyrazine-2-carboxamide instead of pyridine-2-ol. MS (ESI, m / z): 596.3 [M+H] + .

[0708] Example 134: Synthesis of (S)-2-(3-((4-amino-1,3,5-triazin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0709]

[0710] The title product was obtained using a procedure similar to that of general method B, but with 4-chloro-1,3,5-triazin-2-ol and ammonium hydroxide instead of 2-chloropyrimidin-4-ol and cyclopropylamine. MS (ESI, m / z): 555.3 [M+H] + .

[0711] Example 135: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((4-(methylamino)-1,3,5-triazin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0712]

[0713] The title product was obtained by using a procedure similar to that described for the synthesis of Example 134, but with methylamine instead of ammonium hydroxide. MS (ESI, m / z): 569.3 [M+H] + .

[0714] Example 136: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((4-(dimethylamino)-1,3,5-triazin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0715]

[0716] The title product was obtained using a procedure similar to that described for the synthesis of Example 134, but with dimethylamine instead of ammonium hydroxide. MS (ESI, m / z): 583.3 [M+H] + .

[0717] Example 137: Synthesis of (S)-2-(3-((4-(cyclopropylamino)-1,3,5-triazin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0718]

[0719] The title product was obtained using a procedure similar to that described for the synthesis of Example 134, but with cyclopropylamine instead of ammonium hydroxide. MS (ESI, m / z): 595.3 [M+H] + .

[0720] Example 138: Synthesis of (S)-2-(3-((4,6-diamino-1,3,5-triazin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0721]

[0722] The title product was obtained by using a procedure similar to that described for the synthesis of Example 134, but instead of 4-chloro-1,3,5-triazine-2-ol. MS (ESI, m / z): 570.3 [M+H] + .

[0723] Example 139: Synthesis of (S)-2-(3-((4-amino-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)oxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0724]

[0725] The title product was obtained by using a procedure similar to that described for the synthesis of Example 138, but with pyrrolidine instead of ammonium hydroxide. MS (ESI, m / z): 624.3 [M+H] + .

[0726] Example 140: Synthesis of (S)-2-(3-((6-aminopyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0727]

[0728] The title product was obtained by using a procedure similar to that described for the synthesis of Example 134, but with 6-chloropyrimidin-4-ol instead of 4-chloro-1,3,5-triazine-2-ol. MS (ESI, m / z): 554.3 [M+H] + .

[0729] Example 141: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(methylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0730]

[0731] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with methylamine instead of ammonium hydroxide. MS (ESI, m / z): 568.3 [M+H] + .

[0732] Example 142: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(ethylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0733]

[0734] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with ethylamine instead of ammonium hydroxide. MS (ESI, m / z): 582.3 [M+H] + .

[0735] Example 143: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(propylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0736]

[0737] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with n-propylamine instead of ammonium hydroxide. MS (ESI, m / z): 596.3 [M+H] + .

[0738] Example 144: Synthesis of (S)-2-(3-((6-(butylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0739]

[0740] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but instead of ammonium hydroxide, n-butylamine. MS (ESI, m / z): 610.3 [M+H] + .

[0741] Example 145: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-((2-hydroxyethyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0742]

[0743] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with 2-aminoethanol instead of ammonium hydroxide. MS (ESI, m / z): 598.3 [M+H] + .

[0744] Example 146: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-((3-hydroxypropyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0745]

[0746] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with 3-aminoprop-1-ol instead of ammonium hydroxide. MS (ESI, m / z): 612.3 [M+H] + .

[0747] Example 147: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-((2-methoxyethyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0748]

[0749] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with 2-methoxyethyl-1-amine instead of ammonium hydroxide. MS (ESI, m / z): 612.3 [M+H] + .

[0750] Example 148: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-((3-(dimethylamino)propyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0751]

[0752] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with N1,N1-dimethylpropane-1,3-diamine instead of ammonium hydroxide. MS (ESI, m / z): 639.4 [M+H] + .

[0753] Example 149: Synthesis of (S)-2-(3-((6-(benzylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0754]

[0755] The title product was obtained using a procedure similar to that described for the synthesis of Example 140, but with benzylamine instead of ammonium hydroxide. MS (ESI, m / z): 644.3 [M+H] + .

[0756] Example 150: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(phenylethylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0757]

[0758] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with 2-phenylethyl-1-amine instead of ammonium hydroxide. MS (ESI, m / z): 658.3 [M+H] + .

[0759] Example 151: Synthesis of (S)-2-(3-((6-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0760]

[0761] The title product was obtained using a procedure similar to that described for the synthesis of Example 140, but with cyclopropylamine instead of ammonium hydroxide. MS (ESI, m / z): 594.3 [M+H] + .

[0762] Example 152: Synthesis of (S)-2-(3-((6-(cyclohexylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0763]

[0764] The title product was obtained using a procedure similar to that described for the synthesis of Example 140, but with cyclohexylamine instead of ammonium hydroxide. MS (ESI, m / z): 636.3 [M+H] + .

[0765] Example 153: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(dimethylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0766]

[0767] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with dimethylamine instead of ammonium hydroxide. MS (ESI, m / z): 582.3 [M+H] + .

[0768] Example 154: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(ethyl(methyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0769]

[0770] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with N-methylethylamine instead of ammonium hydroxide. MS (ESI, m / z): 596.3 [M+H] + .

[0771] Example 155: Synthesis of (S)-2-(3-((6-(diethylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0772]

[0773] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with diethylamine instead of ammonium hydroxide. MS (ESI, m / z): 610.3 [M+H] + .

[0774] Example 156: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(ethyl(propyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0775]

[0776] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with N-ethylpropyl-1-amine instead of ammonium hydroxide. MS (ESI, m / z): 624.3 [M+H] + .

[0777] Example 157: Synthesis of (S)-2-(3-((6-(butyl(ethyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0778]

[0779] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with N-ethylbut-1-amine instead of ammonium hydroxide. MS (ESI, m / z): 638.4 [M+H] + .

[0780] Example 158: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(pyrrolidine-1-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0781]

[0782] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with pyrrolidine instead of ammonium hydroxide. MS (ESI, m / z): 608.3 [M+H] + .

[0783] Example 159: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-((3S)-3-((6-(3-hydroxypyrrolidine-1-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0784]

[0785] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with pyrrolidine-3-ol instead of ammonium hydroxide. MS (ESI, m / z): 624.3 [M+H] + .

[0786] Example 160: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-((S)-3-((6-(((R)-3-hydroxypyrrolidine-1-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0787]

[0788] The title product was obtained by a procedure similar to that described for the synthesis of Example 140, using (R)-pyrrolidine-3-ol instead of ammonium hydroxide. MS (ESI, m / z): 624.3 [M+H] + .

[0789] Example 161: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-((S)-3-((6-((S)-3-hydroxypyrrolidine-1-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0790]

[0791] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with (S)-pyrrolidine-3-ol instead of ammonium hydroxide. MS (ESI, m / z): 624.3 [M+H] + .

[0792] Example 162: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(piperidin-1-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0793]

[0794] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with piperidine instead of ammonium hydroxide. MS (ESI, m / z): 622.3 [M+H] + .

[0795] Example 163: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(4-hydroxypiperidin-1-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0796]

[0797] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but instead of ammonium hydroxide. MS (ESI, m / z): 638.3 [M+H] + .

[0798] Example 164: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0799]

[0800] The title product was obtained using a procedure similar to that described for the synthesis of Example 140, but with morpholine instead of ammonium hydroxide. MS (ESI, m / z): 624.3 [M+H] + .

[0801] Example 165: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0802]

[0803] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with 1-methylpiperazine instead of ammonium hydroxide. MS (ESI, m / z): 637.3 [M+H] + .

[0804] Example 166: Synthesis of (S)-2-(3-((2-amino-6-(methylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0805]

[0806] The title product was obtained by using a procedure similar to that described for the synthesis of Example 141, but with 2-amino-6-chloropyrimidin-4-ol instead of 6-chloropyrimidin-4-ol. MS (ESI, m / z): 583.3 [M+H] + .

[0807] Example 167: Synthesis of (S)-2-(3-((2-amino-6-(pyrrolidin-1-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0808]

[0809] The title product was obtained by using a procedure similar to that described for the synthesis of Example 166, but with pyrrolidine instead of methylamine. MS (ESI, m / z): 623.3 [M+H] + .

[0810] Example 168: Synthesis of (S)-2-(3-(((4-aminopyrimidin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0811]

[0812] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with 4-chloropyrimidin-2-ol instead of 6-chloropyrimidin-4-ol. MS (ESI, m / z): 554.3 [M+H] + .

[0813] Example 169: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((4-(methylamino)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0814]

[0815] The title product was obtained by using a procedure similar to that described for the synthesis of Example 168, but with methylamine instead of ammonium hydroxide. MS (ESI, m / z): 568.3 [M+H] + .

[0816] Example 170: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((4-(dimethylamino)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0817]

[0818] The title product was obtained using a procedure similar to that described for the synthesis of Example 168, but with dimethylamine instead of ammonium hydroxide. MS (ESI, m / z): 582.3 [M+H] + .

[0819] Example 171: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((4-(ethyl(methyl)amino)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0820]

[0821] The title product was obtained by using a procedure similar to that described for the synthesis of Example 168, but with N-methylethylamine instead of ammonium hydroxide. MS (ESI, m / z): 596.3 [M+H] + .

[0822] Example 172: Synthesis of (S)-2-(3-((4-(diethylamino)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0823]

[0824] The title product was obtained by using a procedure similar to that described for the synthesis of Example 168, but with diethylamine instead of ammonium hydroxide. MS (ESI, m / z): 610.3 [M+H] + .

[0825] Example 173: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((4-(pyrrolidine-1-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0826]

[0827] The title product was obtained by using a procedure similar to that described for the synthesis of Example 168, but with pyrrolidine instead of ammonium hydroxide. MS (ESI, m / z): 608.3 [M+H] + .

[0828] Example 174: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((4-(piperidin-1-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0829]

[0830] The title product was obtained using a procedure similar to that described for the synthesis of Example 168, but with piperidine instead of ammonium hydroxide. MS (ESI, m / z): 622.3 [M+H] + .

[0831] Example 175: Synthesis of (S)-2-(3-((4-(cyclopropylamino)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0832]

[0833] The title product was obtained using a procedure similar to that described for the synthesis of Example 168, but with cyclopropylamine instead of ammonium hydroxide. MS (ESI, m / z): 594.3 [M+H] + .

[0834] Example 176: Synthesis of (S)-2-(3-((4-amino-5-fluoropyrimidin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0835]

[0836] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with 4-chloro-5-fluoropyrimidin-2-ol instead of 6-chloropyrimidin-4-ol. MS (ESI, m / z): 572.3 [M+H] + .

[0837] Example 177: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-fluoro-4-(methylamino)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0838]

[0839] The title product was obtained by using a procedure similar to that described for the synthesis of Example 176, but with methylamine instead of ammonium hydroxide. MS (ESI, m / z): 586.3 [M+H] + .

[0840] Example 178: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((4-(ethylamino)-5-fluoropyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0841]

[0842] The title product was obtained by using a procedure similar to that described for the synthesis of Example 176, but with ethylamine instead of ammonium hydroxide. MS (ESI, m / z): 600.3 [M+H] + .

[0843] Example 179: Synthesis of (S)-2-(3-((4-(cyclopropylamino)-5-fluoropyrimidin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0844]

[0845] The title product was obtained using a procedure similar to that described for the synthesis of Example 176, but with cyclopropylamine instead of ammonium hydroxide. MS (ESI, m / z): 612.3 [M+H] + .

[0846] Example 180: Synthesis of (S)-2-(3-((4-(cyclohexylamino)-5-fluoropyrimidin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0847]

[0848] The title product was obtained using a procedure similar to that described for the synthesis of Example 176, but with cyclohexylamine instead of ammonium hydroxide. MS (ESI, m / z): 654.3 [M+H] + .

[0849] Example 181: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((4-(dimethylamino)-5-fluoropyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0850]

[0851] The title product was obtained using a procedure similar to that described for the synthesis of Example 176, but with dimethylamine instead of ammonium hydroxide. MS (ESI, m / z): 600.3 [M+H] + .

[0852] Example 182: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((4-(ethyl(methyl)amino)-5-fluoropyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0853]

[0854] The title product was obtained by using a procedure similar to that described for the synthesis of Example 176, but with N-methylethylamine instead of ammonium hydroxide. MS (ESI, m / z): 614.3 [M+H] + .

[0855] Example 183: Synthesis of (S)-2-(3-((4-(diethylamino)-5-fluoropyrimidin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0856]

[0857] The title product was obtained using a procedure similar to that described for the synthesis of Example 176, but with diethylamine instead of ammonium hydroxide. MS (ESI, m / z): 628.3 [M+H] + .

[0858] Example 184: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-fluoro-4-(methyl(phenyl)amino)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0859]

[0860] The title product was obtained by using a procedure similar to that described for the synthesis of Example 176, but with N-methylaniline instead of ammonium hydroxide. MS (ESI, m / z): 662.3 [M+H] + .

[0861] Example 185: Synthesis of (S)-2-(3-((4-(benzyl(methyl)amino)-5-fluoropyrimidin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0862]

[0863] The title product was obtained by using a procedure similar to that described for the synthesis of Example 176, but with N-methylbenzylamine instead of ammonium hydroxide. MS (ESI, m / z): 676.3 [M+H] + .

[0864] Example 186: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-fluoro-4-(pyrrolidine-1-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0865]

[0866] The title product was obtained by using a procedure similar to that described for the synthesis of Example 176, but with pyrrolidine instead of ammonium hydroxide. MS (ESI, m / z): 626.3 [M+H] + .

[0867] Example 187: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-fluoro-4-(piperidin-1-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0868]

[0869] The title product was obtained using a procedure similar to that described for the synthesis of Example 176, but with piperidine instead of ammonium hydroxide. MS (ESI, m / z): 640.3 [M+H] + .

[0870] Example 188: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-fluoro-4-morpholinopyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0871]

[0872] The title product was obtained by using a procedure similar to that described for the synthesis of Example 176, but with morpholine instead of ammonium hydroxide. MS (ESI, m / z): 642.3 [M+H] + .

[0873] Example 189: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-fluoro-4-thiomorpholinopyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0874]

[0875] The title product was obtained using a procedure similar to that described for the synthesis of Example 176, but with thiomorpholine instead of ammonium hydroxide. MS (ESI, m / z): 658.3 [M+H] + .

[0876] Example 190: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-fluoro-4-(4-methylpiperazin-1-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[0877]

[0878] The title product was obtained by using a procedure similar to that described for the synthesis of Example 176, but with 1-methylpiperazine instead of ammonium hydroxide. MS (ESI, m / z): 655.3 [M+H] + .

[0879] Example 191: Synthesis of (S)-2-(3-((4-(cyclopropylamino)-5-methylpyrimidin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0880]

[0881] The title product was obtained by using a procedure similar to that described for the synthesis of Example 179, but instead of 4-chloro-5-fluoropyrimidin-2-ol. MS (ESI, m / z): 608.3 [M+H] + .

[0882] Example 192: Synthesis of (S)-2-(3-((2-aminopyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0883]

[0884] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but instead of 6-chloropyrimidin-4-ol. MS (ESI, m / z): 554.3 [M+H] + .

[0885] Example 193: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(methylthio)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0886]

[0887] The title product was obtained using a procedure similar to that described for the synthesis of Example 192, but with sodium methanethiol instead of ammonium hydroxide. MS (ESI, m / z): 585.2 [M+H] + .

[0888] Example 194: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-methoxypyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0889]

[0890] The title product was obtained using a procedure similar to that described for the synthesis of Example 192, but with sodium methoxide instead of ammonium hydroxide. MS (ESI, m / z): 569.3 [M+H] + .

[0891] Example 195: Synthesis of (S)-2-(3-((2-(benzyloxy)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0892]

[0893] The title product was obtained using a procedure similar to that described for the synthesis of Example 192, but with sodium benzyl oxide instead of ammonium hydroxide. MS (ESI, m / z): 645.3 [M+H] + .

[0894] Example 196: Synthesis of (S)-2-(3-((2-acetamidopyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0895]

[0896] The MeOH (1 mL) solution of Example 192 (110 mg, 0.2 mmol) was treated with acetyl chloride (10 μL) and stirred for 1 h. The crude product was separated from the product by preparative HPLC on a UCT SPE CUBCX column to obtain the corresponding product (74 mg, 62%). MS (ESI, m / z): 596.3 [M+H] + .

[0897] Example 197: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(methylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0898]

[0899] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with methylamine instead of ammonium hydroxide. MS (ESI, m / z): 568.3 [M+H] + .

[0900] Example 198: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-((2,2,2-trifluoroethyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0901]

[0902] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with 2,2,2-trifluoroethyl-1-amine instead of ammonium hydroxide. MS (ESI, m / z): 636.3 [M+H] + .

[0903] Example 199: Synthesis of (S)-2-(3-((2-((2,2-difluoropropyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0904]

[0905] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with 2,2-difluoropropane-1-amine instead of ammonium hydroxide. MS (ESI, m / z): 632.3 [M+H] + .

[0906] Example 200: Synthesis of (S)-2-(3-((2-((2,2-difluoroethyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0907]

[0908] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but instead of ammonium hydroxide, 2,2-difluoroethyl-1-amine. MS (ESI, m / z): 618.3 [M+H] + .

[0909] Example 201: Synthesis of N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-((3S)-3-((2-((1,1,1-trifluoroprop-2-yl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0910]

[0911] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with 1,1,1-trifluoropropane-2-amine instead of ammonium hydroxide. MS (ESI, m / z): 650.3 [M+H] + .

[0912] Example 202: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-((2-fluoroethyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0913]

[0914] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with 2-fluoroethyl-1-amine instead of ammonium hydroxide. MS (ESI, m / z): 600.3 [M+H] + .

[0915] Example 203: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(ethylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0916]

[0917] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with ethylamine instead of ammonium hydroxide. MS (ESI, m / z): 582.3 [M+H] + .

[0918] Example 204: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(propylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0919]

[0920] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with n-propylamine instead of ammonium hydroxide. MS (ESI, m / z): 596.3 [M+H] + .

[0921] Example 205: Synthesis of (S)-2-(3-((2-(butylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0922]

[0923] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but instead of ammonium hydroxide, n-butylamine. MS (ESI, m / z): 610.3 [M+H] + .

[0924] Example 206: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-((3-hydroxypropyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0925]

[0926] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with 3-aminoprop-1-ol instead of ammonium hydroxide. MS (ESI, m / z): 612.3 [M+H] + .

[0927] Example 207: Synthesis of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0928]

[0929] The title product was obtained using a procedure similar to that described for the synthesis of Example 192, but with cyclopropylamine instead of ammonium hydroxide. MS (ESI, m / z): 594.3 [M+H] + .

[0930] Example 208: Synthesis of (S)-2-(3-((2-(cyclobutylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0931]

[0932] The title product was obtained using a procedure similar to that described for the synthesis of Example 192, but with cyclobutane instead of ammonium hydroxide. MS (ESI, m / z): 608.3 [M+H] + .

[0933] Example 209: Synthesis of (S)-2-(3-((2-(cyclopentylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0934]

[0935] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with cyclopentylamine instead of ammonium hydroxide. MS (ESI, m / z): 622.3 [M+H] + .

[0936] Example 210: Synthesis of (S)-2-(3-((2-(cyclohexylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0937]

[0938] The title product was obtained using a procedure similar to that described for the synthesis of Example 192, but with cyclohexylamine instead of ammonium hydroxide. MS (ESI, m / z): 606.3 [M+H] + .

[0939] Example 211: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(isopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0940]

[0941] The title product was obtained using a procedure similar to that described for the synthesis of Example 192, but with isopropylamine instead of ammonium hydroxide. MS (ESI, m / z): 596.3 [M+H] + .

[0942] Example 212: Synthesis of 2-((3S)-3-((2-(sec-butylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0943]

[0944] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but instead of ammonium hydroxide. MS (ESI, m / z): 610.3 [M+H] + .

[0945] Example 213: Synthesis of (S)-2-(3-((2-((cyclopropylmethyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0946]

[0947] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with cyclopropylmethylamine instead of ammonium hydroxide. MS (ESI, m / z): 608.3 [M+H] + .

[0948] Example 214: Synthesis of (S)-2-(3-((2-(benzylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0949]

[0950] The title product was obtained using a procedure similar to that described for the synthesis of Example 192, but with benzylamine instead of ammonium hydroxide. MS (ESI, m / z): 644.3 [M+H] + .

[0951] Example 215: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-((2-hydroxyethyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0952]

[0953] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with ethanolamine instead of ammonium hydroxide. MS (ESI, m / z): 598.3 [M+H] + .

[0954] Example 216: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-((2-methoxyethyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0955]

[0956] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with 2-methoxyethyl-1-amine instead of ammonium hydroxide. MS (ESI, m / z): 612.3 [M+H] + .

[0957] Example 217: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-((2-(dimethylamino)ethyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0958]

[0959] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with N1,N1-dimethylethane-1,2-diamine instead of ammonium hydroxide. MS (ESI, m / z): 625.3 [M+H] + .

[0960] Example 218: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-((3-(dimethylamino)propyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0961]

[0962] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with N1,N1-dimethylpropane-1,3-diamine instead of ammonium hydroxide. MS (ESI, m / z): 639.4 [M+H] + .

[0963] Example 219: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(methoxyamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0964]

[0965] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with O-methylhydroxylamine instead of ammonium hydroxide. MS (ESI, m / z): 584.3 [M+H] + .

[0966] Example 220: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(dimethylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0967]

[0968] The title product was obtained using a procedure similar to that described for the synthesis of Example 192, but with dimethylamine instead of ammonium hydroxide. MS (ESI, m / z): 582.3 [M+H] + .

[0969] Example 221: Synthesis of (S)-2-(3-((2-(benzyl(methyl)amino)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0970]

[0971] The title product was obtained using a procedure similar to that described for the synthesis of Example 192, but with methylbenzylamine instead of ammonium hydroxide. MS (ESI, m / z): 658.3 [M+H] + .

[0972] Example 222: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(pyrrolidine-1-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0973]

[0974] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with pyrrolidine instead of ammonium hydroxide. MS (ESI, m / z): 608.3 [M+H] + .

[0975] Example 223: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(piperidin-1-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0976]

[0977] The title product was obtained using a procedure similar to that described for the synthesis of Example 192, but with piperidine instead of ammonium hydroxide. MS (ESI, m / z): 622.3 [M+H] + .

[0978] Example 224: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-morpholinopyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0979]

[0980] The title product was obtained using a procedure similar to that described for the synthesis of Example 192, but with morpholine instead of ammonium hydroxide. MS (ESI, m / z): 624.3 [M+H] + .

[0981] Example 225: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[0982]

[0983] The title product was obtained by using a procedure similar to that described for the synthesis of Example 192, but with 1-methylpiperazine instead of ammonium hydroxide. MS (ESI, m / z): 637.3 [M+H] + .

[0984] Example 226: Synthesis of (S)-2-(3-((2-amino-5-fluoropyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0985]

[0986] The title product was obtained by using a procedure similar to that described for the synthesis of Example 140, but with 2-chloro-5-fluoropyrimidin-4-ol instead of 6-chloropyrimidin-4-ol. MS (ESI, m / z): 572.3 [M+H] + .

[0987] Example 227: Synthesis of (S)-2-(3-((2-(cyclopropylamino)-5-fluoropyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0988]

[0989] The title product was obtained using a procedure similar to that described for the synthesis of Example 226, but with cyclopropylamine instead of ammonium hydroxide. MS (ESI, m / z): 612.3 [M+H] + .

[0990] Example 228: Synthesis of (S)-2-(3-((2-(cyclohexylamino)-5-fluoropyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0991]

[0992] The title product was obtained using a procedure similar to that described for the synthesis of Example 226, but with cyclohexylamine instead of ammonium hydroxide. MS (ESI, m / z): 654.3 [M+H] + .

[0993] Example 229: Synthesis of (S)-2-(3-((2-((cyclopropylmethyl)amino)-5-fluoropyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0994]

[0995] The title product was obtained by using a procedure similar to that described for the synthesis of Example 226, but with cyclopropylmethylamine instead of ammonium hydroxide. MS (ESI, m / z): 626.3 [M+H] + .

[0996] Example 230: Synthesis of (S)-2-(3-((2-(benzylamino)-5-fluoropyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[0997]

[0998] The title product was obtained using a procedure similar to that described for the synthesis of Example 226, but with benzylamine instead of ammonium hydroxide. MS (ESI, m / z): 662.3 [M+H] + .

[0999] Example 231: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(dimethylamino)-5-fluoropyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[1000]

[1001] The title product was obtained using a procedure similar to that described for the synthesis of Example 226, but with dimethylamine instead of ammonium hydroxide. MS (ESI, m / z): 600.3 [M+H] + .

[1002] Example 232: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-fluoro-2-morpholinopyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[1003]

[1004] The title product was obtained by using a procedure similar to that described for the synthesis of Example 226, but with morpholine instead of ammonium hydroxide. MS (ESI, m / z): 642.3 [M+H] + .

[1005] Example 233: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[1006]

[1007] The title product was obtained by using a procedure similar to that described for the synthesis of Example 226, but with 1-methylpiperazine instead of ammonium hydroxide. MS (ESI, m / z): 655.3 [M+H] + .

[1008] Example 234: Synthesis of (S)-2-(3-((2-(cyclopropylamino)-6-fluoropyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[1009]

[1010] The title product was obtained by using a procedure similar to that described for the synthesis of Example 227, but instead of 2-chloro-5-fluoropyrimidin-4-ol. MS (ESI, m / z): 612.3 [M+H] + .

[1011] Example 235: Synthesis of (S)-2-(3-((2-(cyclopropylamino)-5-methylpyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[1012]

[1013] The title product was obtained by using a procedure similar to that described for the synthesis of Example 227, but instead of 2-chloro-5-methylpyrimidin-4-ol. MS (ESI, m / z): 608.3 [M+H] + .

[1014] Example 236: Synthesis of (S)-2-(3-((2-(cyclopropylamino)-6-methylpyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[1015]

[1016] The title product was obtained by using a procedure similar to that described for the synthesis of Example 227, but instead of 2-chloro-5-fluoropyrimidin-4-ol. MS (ESI, m / z): 608.3 [M+H] + .

[1017] Example 237: Synthesis of (S)-2-(3-((2-(cyclopropylamino)-6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[1018]

[1019] The title product was obtained by using a procedure similar to that described for the synthesis of Example 227, but instead of 2-chloro-5-fluoropyrimidin-4-ol. MS (ESI, m / z): 662.3 [M+H] + .

[1020] Example 238: Synthesis of (S)-2-(3-((2-(cyclopropylamino)-6-methoxypyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[1021]

[1022] The title product was obtained by using a procedure similar to that described for the synthesis of Example 227, but instead of 2-chloro-5-fluoropyrimidin-4-ol. MS (ESI, m / z): 624.3 [M+H] + .

[1023] Example 239: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-((2-(dimethylamino)ethyl)amino)pyrimidin-5-yl)oxy)pyrrolidine-1-yl)acetamide

[1024]

[1025] The title product was obtained by using a procedure similar to that described for the synthesis of Example 217, but instead of 2-chloropyrimidin-4-ol. MS (ESI, m / z): 625.3 [M+H] + .

[1026] Example 240: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(dimethylamino)pyrimidin-5-yl)oxy)pyrrolidine-1-yl)acetamide

[1027]

[1028] The title product was obtained by using a procedure similar to that described for the synthesis of Example 239, but with dimethylamine instead of N1,N1-dimethylethane-1,2-diamine. MS (ESI, m / z): 582.3 [M+H] + .

[1029] Example 241: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-morpholinopyrimidin-5-yl)oxy)pyrrolidine-1-yl)acetamide

[1030]

[1031] The title product was obtained by using a procedure similar to that described for the synthesis of Example 239, but with morpholine instead of N1,N1-dimethylethane-1,2-diamine. MS (ESI, m / z): 624.3 [M+H] + .

[1032] Example 242: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyrrolidine-1-yl)acetamide

[1033]

[1034] The title product was obtained by using a procedure similar to that described for the synthesis of Example 239, but with 1-methylpiperazine instead of N1,N1-dimethylethane-1,2-diamine. MS (ESI, m / z): 637.3 [M+H] + .

[1035] Example 243: Synthesis of (S)-2-(3-((6-(cyclopropylamino)pyrazin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[1036]

[1037] The title product was obtained by using a procedure similar to that described for the synthesis of Example 227, but with 6-chloropyrazine-2-ol instead of 2-chloro-5-fluoropyrimidin-4-ol. MS (ESI, m / z): 594.3 [M+H] + .

[1038] Example 244: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(ethylamino)pyrazin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[1039]

[1040] The title product was obtained by using a procedure similar to that described for the synthesis of Example 243, but with ethylamine instead of cyclopropylamine. MS (ESI, m / z): 582.3 [M+H] + .

[1041] Example 245: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(propylamino)pyrazin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[1042]

[1043] The title product was obtained by using a procedure similar to that described for the synthesis of Example 243, but with n-propylamine instead of cyclopropylamine. MS (ESI, m / z): 596.3 [M+H] + .

[1044] Example 246: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-((2-hydroxyethyl)amino)pyrazin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[1045]

[1046] The title product was obtained by using a procedure similar to that described for the synthesis of Example 243, but with ethanolamine instead of cyclopropylamine. MS (ESI, m / z): 598.3 [M+H] + .

[1047] Example 247: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-((2-(dimethylamino)ethyl)amino)pyrazin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[1048]

[1049] The title product was obtained by using a procedure similar to that described for the synthesis of Example 243, but with N1,N1-dimethylethane-1,2-diamine instead of cyclopropylamine. MS (ESI, m / z): 625.3 [M+H] + .

[1050] Example 248: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-phenylpyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[1051]

[1052] (S)-2-(3-((6-chloropyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide is an intermediate in the synthesis of Example 140.

[1053] A solution of (S)-2-(3-(((6-chloropyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide (286 mg, 0.5 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), phenylboronic acid (97 mg, 0.8 mmol), and K2CO3 (207 mg, 1.5 mmol) in 1,4-dioxane (0.9 mL) and water (0.3 mL) was heated to 80 °C for 4 h. The mixture was then separated from the solution on a UCT SPE CUBCX column and purified by preparative HPLC to give the product (180 mg, 58%). MS (ESI, m / z): 615.3 [M+H] + .

[1054] Example 249: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[1055]

[1056] The title product was obtained by using a procedure similar to that described for the synthesis of Example 248, but instead of phenylboronic acid, (1-methyl-1H-pyrazol-4-yl)boronic acid. MS (ESI, m / z): 619.3 [M+H] + .

[1057] Example 250: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((6-(4,4-dimethylcyclohexyl-1-en-1-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)acetamide

[1058]

[1059] The title product was obtained by using a procedure similar to that described for the synthesis of Example 248, but with (4,4-dimethylcyclohexyl-1-en-1-yl)boronic acid instead of phenylboronic acid. MS (ESI, m / z): 647.3 [M+H] + .

[1060] Example 251: Synthesis of (S)-2-(3-((6-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-4-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[1061]

[1062] The title product was obtained by using a procedure similar to that described for the synthesis of Example 248, but instead of phenylboronic acid, (3,6-dihydro-2H-pyran-4-yl)boronic acid. MS (ESI, m / z): 621.3 [M+H] + .

[1063] Example 252: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((4-(4,4-dimethylcyclohexyl-1-en-1-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[1064]

[1065] The title product was obtained by using a procedure similar to that described for the synthesis of Example 250, but with 4-chloropyrimidin-2-ol instead of 6-chloropyrimidin-4-ol. MS (ESI, m / z): 647.4 [M+H] +.

[1066] Example 253: Synthesis of (S)-2-(3-((4-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)acetamide

[1067]

[1068] The title product was obtained by using a procedure similar to that described for the synthesis of Example 251, but with 4-chloropyrimidin-2-ol instead of 6-chloropyrimidin-4-ol. MS (ESI, m / z): 621.3 [M+H] + .

[1069] Example 254: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((4-phenylpyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[1070]

[1071] The title product was obtained by using a procedure similar to that described for the synthesis of Example 248, but with 4-chloropyrimidin-2-ol instead of 6-chloropyrimidin-4-ol. MS (ESI, m / z): 614.3 [M+H] + .

[1072] Example 255: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-(pyridin-3-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[1073]

[1074] The title product was obtained by a procedure similar to that described for the synthesis of Example 248, using 5-chloropyrimidin-2-ol and pyridin-3-ylboronic acid instead of 6-chloropyrimidin-4-ol and phenylboronic acid. MS (ESI, m / z): 616.3 [M+H] + .

[1075] Example 256: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((5-(pyridin-4-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-yl)acetamide

[1076]

[1077] The title product was obtained by using a procedure similar to that described for the synthesis of Example 255, but instead of pyridine-3-ylboronic acid. MS (ESI, m / z): 616.3 [M+H] + .

[1078] Example 257: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-phenylpyrimidin-5-yl)oxy)pyrrolidine-1-yl)acetamide

[1079]

[1080] The title product was obtained by using a procedure similar to that described for the synthesis of Example 248, but with 2-chloropyrimidin-5-ol instead of 6-chloropyrimidin-4-ol. MS (ESI, m / z): 615.3 [M+H] + .

[1081] Example 258: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(pyridin-3-yl)pyrimidin-5-yl)oxy)pyrrolidine-1-yl)acetamide

[1082]

[1083] The title product was obtained by using a procedure similar to that described for the synthesis of Example 257, but instead of phenylboronic acid, pyridin-3-ylboronic acid. MS (ESI, m / z): 616.3 [M+H] + .

[1084] Example 259: Synthesis of (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-((2-(pyridin-4-yl)pyrimidin-5-yl)oxy)pyrrolidine-1-yl)acetamide

[1085]

[1086] The title product was obtained by using a procedure similar to that described for the synthesis of Example 257, but instead of phenylboronic acid, pyridin-4-ylboronic acid. MS (ESI, m / z): 616.3 [M+H] + .

[1087] Example 260: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolline-1,3-dione

[1088]

[1089] [General Method D]

[1090]

[1091] A mixture of 3-[2-[(1,5-dimethylpyrazol-3-yl)amino]-5-methyl-pyrimidin-4-yl]-1H-indole-7-amine (1.00 eq, 15 mg, 0.0450 mmol) and isobenzofuran-1,3-dione (2.00 eq, 13 mg, 0.0900 mmol) in 1,4-dioxane (0.5000 mL) was stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was separated by preparative HPLC and dried under vacuum to give the target product as a white solid (yield 50%).

[1092] 1 H NMR(600MHz,cd3od)δ8.94(s,1H),8.35(s,1H),8.16(s,1H),8.09–8.00(m,2H),7.99–7.86(m,2H) ,7.42(t,J=7.8Hz,1H),7.33(d,J=7.4Hz,1H),5.97(s,1H),3.82(s,3H),2.53(s,3H),2.34(s,3H). MS(ESI,m / z):464.1[M+H] + .

[1093] Example 261: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-fluoroisoindolline-1,3-dione

[1094]

[1095] The title product was obtained using 4-fluoroisobenzofuran-1,3-dione, as described in General Method D for Example 260. MS (ESI, m / z): 482.1 [M+H] + .

[1096] Example 262: Synthesis of 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolline-1,3-dione

[1097]

[1098] The title product was obtained using 4-bromoisobenzofuran-1,3-dione, as described in General Method D for Example 260. MS (ESI, m / z): 542.1 [M+H] + .

[1099] Example 263: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-hydroxyisoindolline-1,3-dione

[1100]

[1101] The title product was obtained using 4-hydroxyisobenzofuran-1,3-dione, as described in General Method D with respect to Example 260. MS (ESI, m / z): 480.1 [M+H] + .

[1102] Example 264: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-5-nitroisoindololin-1,3-dione

[1103]

[1104] The title product was obtained using 5-nitroisobenzofuran-1,3-dione, as described in General Method D for Example 260. MS (ESI, m / z): 509.1 [M+H] + .

[1105] Example 265: Synthesis of 6-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[1106]

[1107] The title product was obtained using furano[3,4-b]pyridine-5,7-dione, as described in General Method D for Example 260. MS (ESI, m / z): 465.1 [M+H] + .

[1108] Example 266: Synthesis of 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1109]

[1110] [General Method E]

[1111]

[1112] Under N2, a suspension of methyl 3-bromo-2-methylbenzoate (1.15 g, 5.000 mmol) in CCl4 (17 mL) was treated with NBS (1.07 g, 6.000 mmol) and ABIN (410.5 mg, 2.500 mmol). The resulting mixture was heated overnight at 80 °C. The reaction mixture was cooled to room temperature and then extracted from water (20 mL) into DCM (2 × 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then purified by rapid column chromatography, eluting with 30% EtOAc / n-hexane. The target fraction was concentrated and dried under vacuum to give the brominated intermediate methyl 3-bromo-2-(bromomethyl)benzoate as a colorless liquid. A suspension of methyl 3-bromo-2-(bromomethyl)benzoate (44.7 mg, 0.10 mmol) in DMF (1 mL) was treated with 3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-amine (33.3 mg, 0.10 mmol). The resulting mixture was heated overnight at 120 °C. The reaction mixture was cooled to room temperature, purified by preparative HPLC, and dried under vacuum to give the target product as a white solid (45% yield in two steps). 1H NMR(600MHz,cd3od)δ8.86(brs,1H),8.34(s,1H),8.17(brs,1H),7.93(d,J=7.8Hz,2H).7.89(d,J=7.8Hz,1H ),7.57(t,J=7.8Hz,1H),7.39-7.44(m,2H),5.96(s,1H),4.99(s,2H),3.80(s,3H),2.53(s,3H),2.33(s,3H). MS(ESI,m / z):528.1[M+H] + .

[1113] Example 267: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1114]

[1115] The title product was obtained using methyl 2-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 450.2 [M+H] + .

[1116] Example 268: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-6-nitroisoindololin-1-one

[1117]

[1118] The title product was obtained using methyl 2-methyl-5-nitrobenzene as described in General Method E with respect to Example 266. MS (ESI, m / z): 495.1 [M+H] + .

[1119] Example 269: Synthesis of 6-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1120]

[1121] The title product was obtained using methyl 5-amino-2-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 465.2 [M+H] + .

[1122] Example 270: Synthesis of 5-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1123]

[1124] The title product was obtained using methyl 4-bromo-2-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 528.1 [M+H] + .

[1125] Example 271: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-nitroisoindololin-1-one

[1126]

[1127] The title product was obtained using methyl 2-methyl-3-nitrobenzene as described in General Method E with respect to Example 266. MS (ESI, m / z): 495.2 [M+H] + .

[1128] Example 272: Synthesis of 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1129]

[1130] The title product was obtained using methyl 3-amino-2-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 465.2 [M+H] + .

[1131] Example 273: Synthesis of 7-chloro-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1132]

[1133] The title product was obtained using methyl 2-chloro-6-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 484.1 [M+H] + .

[1134] Example 274: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-nitroisoindololin-1-one

[1135]

[1136] The title product was obtained using methyl 2-methyl-6-nitrobenzene as described in General Method E with respect to Example 266. MS (ESI, m / z): 495.1 [M+H] + .

[1137] Example 275: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-iodoisoindololin-1-one

[1138]

[1139] The title product was obtained using methyl 2-iodo-6-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 576.1 [M+H] + .

[1140] Example 276: Synthesis of 7-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1141]

[1142] The title product was obtained using methyl 2-amino-6-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 465.2 [M+H] + .

[1143] Example 277: Synthesis of 7-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1144]

[1145] The title product was obtained using methyl 2-bromo-6-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 528.1 [M+H] + .

[1146] Example 278: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-iodoisoindololin-1-one

[1147]

[1148] The title product was obtained using methyl 3-iodo-2-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 576.1 [M+H] + .

[1149] Example 279: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-6-methoxyisoindololin-1-one

[1150]

[1151] The title product was obtained using methyl 5-methoxy-2-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 480.2 [M+H] + .

[1152] Example 280: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4,6-dimethoxyisoindololin-1-one

[1153]

[1154] The title product was obtained using methyl 3,5-dimethoxy-2-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 510.2 [M+H] + .

[1155] Example 281: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-hydroxyisoindololin-1-one

[1156]

[1157] The title product was obtained using methyl 3-hydroxy-2-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 466.2 [M+H] + .

[1158] Example 282: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoroisoindololin-1-one

[1159]

[1160] The title product was obtained using methyl 2-fluoro-6-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 468.2 [M+H] + .

[1161] Example 283: Synthesis of 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoroisoindololin-1-one

[1162]

[1163] The title product was obtained using methyl 3-bromo-6-fluoro-2-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 546.1 [M+H] + .

[1164] Example 284: Synthesis of 6-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1165]

[1166] The title product was obtained using methyl 5-bromo-2-methylbenzoate as described in General Method E with respect to Example 266. MS (ESI, m / z): 528.1 [M+H] + .

[1167] Example 285: Synthesis of 3-bromo-6-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[1168]

[1169] The title product was obtained using methyl 5-bromo-3-methylpyridinecarboxylate, as described in General Method E with respect to Example 266. MS (ESI, m / z): 529.1 [M+H] + .

[1170] Example 286: Synthesis of 4-bromo-6-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[1171]

[1172] The title product was obtained using methyl 4-bromo-3-methylpyridinecarboxylate, as described in General Method E with respect to Example 266. MS (ESI, m / z): 529.1 [M+H] + .

[1173] Example 287: Synthesis of 6-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-3-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[1174]

[1175] The title product was obtained using methyl 3,5-dimethylpyridinecarboxylate as described in General Method E with respect to Example 266. MS (ESI, m / z): 465.2 [M+H] + .

[1176] Example 288: Synthesis of 6-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[1177]

[1178] The title product was obtained using methyl 3-methylpyridinecarboxylate as described in General Method E with respect to Example 266. MS (ESI, m / z): 451.2 [M+H] + .

[1179] Example 289: Synthesis of 7-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

[1180]

[1181] The title product was obtained using methyl 5-bromo-4-methylnicotinate as described in General Method E with respect to Example 266. MS (ESI, m / z): 529.1 [M+H] + .

[1182] Example 290: Synthesis of 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[1183]

[1184] The title product was obtained using methyl 2-bromo-3-methylisonicotinic acid as described in General Method E with respect to Example 266. MS (ESI, m / z): 529.1 [M+H] + .

[1185] Example 291: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-3-oxoisoindololin-5-yl)cyclopropaneformamide

[1186]

[1187] [General Method F]

[1188]

[1189] Cyclopropylformic acid (9 mg, 0.11 mmol) was added to a stirred solution of 6-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one (46 mg, 0.10 mmol), HATU (39 mg, 0.10 mmol), and Et3N (28 μL, 0.20 mmol) in DMF (0.5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was then separated from the reaction mixture on a UCT SPE CUBCX column and purified by preparative HPLC to give the corresponding product as a white solid (60% yield). MS (ESI, m / z): 533.2 [M+H] + .

[1190] Example 292: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-3-oxoisoindololin-4-yl)cyclohexaneformamide

[1191]

[1192] The title product was obtained using 7-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and cyclohexanecarboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 575.2 [M+H] + .

[1193] Example 293: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-3-oxoisoindololin-4-yl)benzamide

[1194]

[1195] The title product was obtained using 7-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and benzoic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 569.2 [M+H] + .

[1196] Example 294: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)benzamide

[1197]

[1198] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and benzoic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 569.2 [M+H] + .

[1199] Example 295: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)cyclohexaneformamide

[1200]

[1201] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and cyclohexanecarboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 575.2 [M+H] + .

[1202] Example 296: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)morpholine-4-carboxamide

[1203]

[1204] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and morpholin-4-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 578.2 [M+H] + .

[1205] Example 297: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)pyridine amide

[1206]

[1207] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and pyridinecarboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 570.2 [M+H] + .

[1208] Example 298: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)nicotinamide

[1209]

[1210] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and nicotinic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 570.2 [M+H] + .

[1211] Example 299: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)oxazol-4-carboxamide

[1212]

[1213] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and oxazol-4-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 560.2 [M+H] + .

[1214] Example 300: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)cyclopropaneformamide

[1215]

[1216] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and cyclopropanecarboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 533.2 [M+H] + .

[1217] Example 301: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)isonicotinamide

[1218]

[1219] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and isonicotinic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 570.2 [M+H] + .

[1220] Example 302: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)pyridazine-4-carboxamide

[1221]

[1222] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and pyridazin-4-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 571.2 [M+H] + .

[1223] Example 303: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-4-methylcyclohexane-1-carboxamide

[1224]

[1225] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 4-methylcyclohexane-1-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 589.3 [M+H] + .

[1226] Example 304: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-2-(3-hydroxyphenyl)acetamide

[1227]

[1228] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 2-(3-hydroxyphenyl)acetic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 599.2 [M+H] + .

[1229] Example 305: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-2-phenylacetamide

[1230]

[1231] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 2-phenylacetic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 583.2 [M+H] + .

[1232] Example 306: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-1-methylpiperidine-4-carboxamide

[1233]

[1234] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 1-methylpiperidin-4-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 590.3 [M+H] + .

[1235] Example 307: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-1-methylpiperidine-3-carboxamide

[1236]

[1237] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 1-methylpiperidin-3-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 590.3 [M+H] + .

[1238] Example 308: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-5-oxopyrrolidine-2-carboxamide

[1239]

[1240] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 5-oxopyrrolidine-2-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 576.2 [M+H] + .

[1241] Example 309: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)cyclohex-3-ene-1-carboxamide

[1242]

[1243] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and cyclohexyl-3-en-1-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 573.2 [M+H] + .

[1244] Example 310: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)cyclopent-3-ene-1-carboxamide

[1245]

[1246] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and cyclopent-3-en-1-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 559.2 [M+H] + .

[1247] Example 311: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-1-methylcyclopent-3-ene-1-carboxamide

[1248]

[1249] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 1-methylcyclopent-3-en-1-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 573.2 [M+H] + .

[1250] Example 312: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)cycloheptaneformamide

[1251]

[1252] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and cycloheptanecarboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 589.3 [M+H] + .

[1253] Example 313: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-2-oxoimidazolidine-1-carboxamide

[1254]

[1255] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 2-oxoimidazolidine-1-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 577.2 [M+H] + .

[1256] Example 314: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-2,3-dihydro-1H-indene-2-carboxamide

[1257]

[1258] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 2,3-dihydro-1H-indene-2-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 609.2 [M+H] + .

[1259] Example 315: Synthesis of (R)-N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)pyrrolidine-3-carboxamide

[1260]

[1261] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and (R)-pyrrolidine-3-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 562.2 [M+H] + .

[1262] Example 316: Synthesis of (S)-N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)pyrrolidine-3-carboxamide

[1263]

[1264] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and (S)-pyrrolidine-3-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 562.2 [M+H] + .

[1265] Example 317: Synthesis of (S)-N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-5-oxopyrrolidine-2-carboxamide

[1266]

[1267] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and (S)-5-oxopyrrolidine-2-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 576.2 [M+H] + .

[1268] Example 318: Synthesis of (R)-N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-5-oxopyrrolidine-2-carboxamide

[1269]

[1270] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and (R)-5-oxopyrrolidine-2-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 576.2 [M+H] + .

[1271] Example 319: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)piperidine-3-carboxamide

[1272]

[1273] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and piperidine-3-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 576.2 [M+H] + .

[1274] Example 320: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-4-oxocyclohexane-1-carboxamide

[1275]

[1276] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 4-oxocyclohexane-1-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 589.2 [M+H] + .

[1277] Example 321: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-5-methylisoxazole-4-carboxamide

[1278]

[1279] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 5-methylisoxazole-4-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 574.2 [M+H] + .

[1280] Example 322: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-2-methyloxazol-4-carboxamide

[1281]

[1282] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 2-methyloxazol-4-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 574.2 [M+H] + .

[1283] Example 323: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)oxazol-5-carboxamide

[1284]

[1285] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and oxazol-5-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 560.2 [M+H] + .

[1286] Example 324: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)isoxazole-3-carboxamide

[1287]

[1288] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and isoxazol-3-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 560.2 [M+H] + .

[1289] Example 325: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-5-methylisoxazole-3-carboxamide

[1290]

[1291] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 5-methylisoxazole-3-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 574.2 [M+H] + .

[1292] Example 326: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)tetrahydrofuran-3-carboxamide

[1293]

[1294] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and tetrahydrofuran-3-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 563.2 [M+H] + .

[1295] Example 327: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)tetrahydro-2H-pyran-3-carboxamide

[1296]

[1297] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and tetrahydro-2H-pyran-3-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 577.2 [M+H] + .

[1298] Example 328: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-4-methyltetrahydro-2H-pyran-4-carboxamide

[1299]

[1300] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 4-methyltetrahydro-2H-pyran-4-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 591.2 [M+H] + .

[1301] Example 329: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-3-methylcyclohexane-1-carboxamide

[1302]

[1303] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 3-methylcyclohexane-1-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 589.3 [M+H] + .

[1304] Example 330: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-4-methylcyclohex-3-ene-1-carboxamide

[1305]

[1306] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 4-methylcyclohexane-3-en-1-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 587.2 [M+H] + .

[1307] Example 331: Synthesis of (2R,4S)-4-amino-N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)-1-oxoisoindoline-4-yl)pyrrolidine-2-carboxamide

[1308]

[1309] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and (2R,4S)-4-aminopyrrolidine-2-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 577.2 [M+H] + .

[1310] Example 332: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-3-methylpiperidine-3-carboxamide

[1311]

[1312] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 3-methylpiperidin-3-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 590.3 [M+H] + .

[1313] Example 333: Synthesis of (R)-N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-1-methylpyrrolidine-3-carboxamide

[1314]

[1315] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and (R)-1-methylpyrrolidine-3-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 576.2 [M+H] + .

[1316] Example 334: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-5-methylnicotinamide

[1317]

[1318] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 5-methylnicotinic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 584.2 [M+H] + .

[1319] Example 335: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-2-(dimethylamino)acetamide

[1320]

[1321] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and dimethylglycine, as described in General Method F with respect to Example 291. MS (ESI, m / z): 550.2 [M+H] + .

[1322] Example 336: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)cyclopentaneformamide

[1323]

[1324] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and cyclopentanecarboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 561.2 [M+H] + .

[1325] Example 337: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)tetrahydro-2H-pyran-4-carboxamide

[1326]

[1327] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and tetrahydro-2H-pyran-4-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 577.2 [M+H] + .

[1328] Example 338: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)furan-3-carboxamide

[1329]

[1330] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and furan-3-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 559.2 [M+H] + .

[1331] Example 339: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-6-hydroxypyrimidin-4-carboxamide

[1332]

[1333] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 6-hydroxypyrimidin-4-carboxylic acid, as described in General Method F with respect to Example 291. MS (ESI, m / z): 587.2 [M+H] + .

[1334] Example 340: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-3-oxoisoindololin-4-yl)benzenesulfonamide

[1335]

[1336] A mixture of 7-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one (46 mg, 0.10 mmol) and benzenesulfonyl chloride (19 mg, 0.11 mmol) in pyridine (0.5 mL) was heated under reflux for 12 h. After cooling to room temperature, the reaction mixture was separated from a UCT SPE CUBCX column and purified by preparative HPLC to give the corresponding product as a white solid (yield 55%).

[1337] 1 H NMR(600MHz,cd3od)δ8.99(s,1H),8.38(s,1H),8.18(s,1H),8.19–8.00(m,5H),7.99–7.86( m,3H),7.42–7.33(m,2H),5.99(s,1H),4.77(s,2H),3.85(s,3H),2.59(s,3H),2.35(s,3H). MS(ESI,m / z):605.2[M+H] + .

[1338] Example 341: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)benzenesulfonamide

[1339]

[1340] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and benzenesulfonyl chloride, as described in General Method G with respect to Example 340. MS (ESI, m / z): 605.2 [M+H] + .

[1341] Example 342: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)methanesulfonamide

[1342]

[1343] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and methanesulfonyl chloride, as described in General Method G with respect to Example 340. MS (ESI, m / z): 543.1 [M+H] + .

[1344] Example 343: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-4-methylbenzenesulfonamide

[1345]

[1346] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 4-methylbenzenesulfonyl chloride, as described in General Method G with respect to Example 340. MS (ESI, m / z): 619.2 [M+H] + .

[1347] Example 344: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)prop-2-sulfonamide

[1348]

[1349] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and propane-2-sulfonyl chloride, as described in General Method G with respect to Example 340. MS (ESI, m / z): 571.2 [M+H] + .

[1350] Example 345: Synthesis of N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-4-fluoro-3-methylbenzenesulfonamide

[1351]

[1352] The title product was obtained using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 4-fluoro-3-methylbenzenesulfonyl chloride, as described in General Method G with respect to Example 340. MS (ESI, m / z): 637.2 [M+H] + .

[1353] Example 346: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-(phenylamino)isoindololin-1-one

[1354]

[1355] [General Method G]

[1356]

[1357] [General Method H]

[1358]

[1359] A mixture of 7-chloro-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one (prepared according to Example 273, 48 mg, 0.10 mmol), aniline (10 mg, 0.11 mmol), Pd(dba)2 (5.8 mg, 0.01 mmol), BINAP (12 mg, 0.02 mmol), and NaOtBu (29 mg, 0.300 mmol) was heated to 100 °C for 12 h. After cooling to room temperature, the reaction mixture was separated from a UCT SPE CUBCX column and purified by preparative HPLC to give the corresponding product as a white solid (yield 35%).

[1360] 1 H NMR(600MHz,cd3od)δ8.82(s,1H),8.36(s,1H),8.19(s,1H),7.48–7.28(m,8H),7.08( m,1H),6.98(m,1H),5.96(s,1H),5.01(s,2H),3.80(s,3H),2.56(s,3H),2.33(s,3H). MS(ESI,m / z):541.2[M+H] + .

[1361] Example 347: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-morpholinoisoindololin-1-one

[1362]

[1363] The title product was obtained using 7-chloro-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and morpholine, as described in General Method H with respect to Example 346. MS (ESI, m / z): 535.2 [M+H] + .

[1364] Example 348: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-(4-methylpiperazin-1-yl)isoindololin-1-one

[1365]

[1366] The title product was obtained using 7-chloro-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 1-methylpiperazine, as described in General Method H with respect to Example 346. MS (ESI, m / z): 548.2 [M+H] + .

[1367] Example 349: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-(dimethylamino)isoindololin-1-one

[1368]

[1369] The title product was obtained using 7-chloro-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and dimethylamine hydrochloride, as described in General Method H with respect to Example 346. MS (ESI, m / z): 493.2 [M+H] + .

[1370] Example 350: Synthesis of 7-(benzylamino)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1371]

[1372] The title product was obtained using 7-chloro-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and benzylamine, as described in General Method H with respect to Example 346. MS (ESI, m / z): 555.2 [M+H] + .

[1373] Example 351: Synthesis of 7-((cyclopropylmethyl)amino)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1374]

[1375] The title product was obtained using 7-chloro-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and cyclopropylmethylamine, as described in General Method H with respect to Example 346. MS (ESI, m / z): 519.2 [M+H] + .

[1376] Example 352: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-morpholinoisoindololin-1-one

[1377]

[1378] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and morpholine, as described in General Method H with respect to Example 346. MS (ESI, m / z): 535.2 [M+H] + .

[1379] Example 353: Synthesis of 4-((cyclopropylmethyl)amino)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1380]

[1381] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and cyclopropylmethylamine, as described in General Method H with respect to Example 346. MS (ESI, m / z): 519.2 [M+H] + .

[1382] Example 354: Synthesis of 4-(benzylamino)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1383]

[1384] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and benzylamine, as described in General Method H with respect to Example 346. MS (ESI, m / z): 555.2 [M+H] + .

[1385] Example 355: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-6-(phenylethynyl)isoindololin-1-one

[1386]

[1387] [General Method I]

[1388]

[1389] A stirred mixture of 6-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one (prepared according to Example 284, 53 mg, 0.10 mmol), PdCl2(PPh3)2 (70 mg, 0.10 mmol), CuI (19 mg, 0.10 mmol), Et3N (42 μL, 0.03 mmol), and acetylenebenzene (11 mg, 0.11 mmol) in THF (1 mL) was heated under reflux for 12 h. After cooling to room temperature, the reaction mixture was separated from a UCT SPE CUBCX column and purified by preparative HPLC to give the corresponding product as a white solid (yield 70%).

[1390] 1H NMR(600MHz,cd3od)δ8.84(s,1H),8.31(s,1H),8.14(s,1H),7.91(d,J=7.8Hz,1H),7.84(d,J=7.8Hz,1H),7.65(t,J =7.4Hz,1H),7.58–7.54(m,2H),7.43–7.37(m,5H),5.94(s,1H),5.15(s,2H),3.79(s,3H),2.52(s,3H),2.32(s,3H). MS(ESI,m / z):550.2[M+H] + .

[1391] Example 356: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(phenylethynyl)isoindololin-1-one

[1392]

[1393] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and acetylene, as described in General Method I with respect to Example 355. MS (ESI, m / z): 550.2 [M+H] + .

[1394] Example 357: Synthesis of 4-((4-aminophenyl)ethynyl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1395]

[1396] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and 4-ethynylaniline, as described in General Method I with respect to Example 355. MS (ESI, m / z): 565.2 [M+H] + .

[1397] Example 358: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)acrylamide

[1398]

[1399] [General Method J]

[1400]

[1401] A mixture of 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one (prepared according to Example 266, 53 mg, 0.10 mmol), Pd(OAc)2 (2 mg, 0.010 mmol), (o-MePh)3P (6 mg, 0.020 mmol), Et3N (42 μL, 0.030 mmol), and acrylamide (8 mg, 0.11 mmol) in DMF (1 mL) was heated to 130 °C for 12 h. After cooling to room temperature, the reaction mixture was separated from a UCT SPE CUBCX column and purified by preparative HPLC to give the corresponding product as a white solid (yield 75%).

[1402] 1 H NMR(400MHz,cd3od)δ8.88(m,2H),8.39(s,1H),8.23(s,1H),8.03–7.90(m,1H),7.71(m,2H),7.47(m,2 H), 6.78 (d, J = 15.9Hz, 1H), 5.98 (d, J = 0.6Hz, 1H), 5.26 (s, 2H), 3.83 (s, 3H), 2.58 (s, 3H), 2.35 (s, 3H). MS(ESI,m / z):519.2[M+H] + .

[1403] Example 359: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoro-1-oxoisoindololin-4-yl)-N,N-dimethylacrylamide

[1404]

[1405] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoroisoindololin-1-one and N,N-dimethylacrylamide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 565.2 [M+H] + .

[1406] Example 360: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-N,N-dimethylacrylamide

[1407]

[1408] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and N,N-dimethylacrylamide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 547.2 [M+H] + .

[1409] Example 361: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-2-methylacrylamide

[1410]

[1411] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and methacrylamide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 533.2 [M+H] + .

[1412] Example 362: Synthesis of (E)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(3-oxobut-1-en-1-yl)isoindololin-1-one

[1413]

[1414] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and but-3-en-2-one, as described in General Method J with respect to Example 358. MS (ESI, m / z): 518.2 [M+H] + .

[1415] Example 363: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-N-methylacrylamide

[1416]

[1417] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and N-methacrylamide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 533.2 [M+H] + .

[1418] Example 364: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-N-ethylacrylamide

[1419]

[1420] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and N-ethylacrylamide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 547.2 [M+H] + .

[1421] Example 365: Synthesis of (E)-N-cyclopropyl-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)acrylamide

[1422]

[1423] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and N-cyclopropylacrylamide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 559.2 [M+H] + .

[1424] Example 366: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)acrylhydrazide

[1425]

[1426] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and acrylhydrazide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 534.2 [M+H] + .

[1427] Example 367: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)acrylic acid

[1428]

[1429] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and acrylic acid, as described in General Method J with respect to Example 358. MS (ESI, m / z): 520.2 [M+H] + .

[1430] Example 368: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-N,N-diethylacrylamide

[1431]

[1432] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and N,N-diethylacrylamide, as described in General Method J for Example 358. MS (ESI, m / z): 575.2 [M+H] + .

[1433] Example 369: Synthesis of (E)-N,N-dibutyl-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)acrylamide

[1434]

[1435] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and N,N-dibutylacrylamide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 631.3 [M+H] + .

[1436] Example 370: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-N-isopropylacrylamide

[1437]

[1438] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and N-isopropylacrylamide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 577.3 [M+H] + .

[1439] Example 371: Synthesis of (E)-N-(tert-butyl)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)-1-oxoisoindoline-4-yl)acrylamide

[1440]

[1441] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and N-(tert-butyl)acrylamide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 575.2 [M+H] + .

[1442] Example 372: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-N-(2-hydroxyethyl)acrylamide

[1443]

[1444] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and N-(2-hydroxyethyl)acrylamide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 563.2 [M+H] + .

[1445] Example 373: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-N-propylacrylamide

[1446]

[1447] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and N-propylacrylamide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 561.2 [M+H] + .

[1448] Example 374: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-N-(2-methoxyethyl)acrylamide

[1449]

[1450] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and N-(2-methoxyethyl)acrylamide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 577.2 [M+H] + .

[1451] Example 375: Synthesis of (E)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(3-hydroxypropyl-1-en-1-yl)isoindololin-1-one

[1452]

[1453] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and propen-2-en-1-ol, as described in General Method J with respect to Example 358. MS (ESI, m / z): 506.2 [M+H] + .

[1454] Example 376: Synthesis of (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-N-ethyl-2-methylacrylamide

[1455]

[1456] The title product was obtained using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one and N-ethylmethacrylamide, as described in General Method J with respect to Example 358. MS (ESI, m / z): 561.2 [M+H] + .

[1457] Example 377: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-phenylisoindololin-1-one

[1458]

[1459] [General Method K]

[1460]

[1461] [Step a”'] Preparation of methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzoate. A suspension of methyl 3-bromo-2-methylbenzoate (1.150 g, 5.0 mmol) in 1,4-dioxane (18 mL) was treated with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhexacyclopentanane) (1.90 g, 7.50 mmol), Pd(dppf)Cl2 (182.9 mg, 0.250 mmol), and potassium acetate (1.47 g, 15.0 mmol). The resulting mixture was heated at 110 °C overnight. After cooling to room temperature, the reaction mixture was... Filter. Then, concentrate and dry the filtrate under vacuum, and purify it by rapid column chromatography, eluting with 30% EtOAc / n-hexane. Concentrate and dry the target fraction under vacuum to give the corresponding product as a colorless oil (yield 85%). 1 H NMR (600MHz, CDCl3) δ7.55-7.81(m,2H),7.19(t,1H),3.86(s,3H),2.72(s,3H),1.34(s,12H). MS(ESI,m / z):277.1[M+H] + .

[1462] [Step b”'] Preparation of methyl 2-(bromomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzoate. Under N2, a suspension of methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzoate (1.18 g, 4.27 mmol) in MeCN (15 mL) was treated with NBS (912.9 mg, 5.12 mmol) and ABIN (350.9 mg, 2.13 mmol). The resulting mixture was heated at 90 °C for 3 h. The reaction mixture was cooled to room temperature and extracted from water (50 mL) into DCM (3 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then purified by rapid column chromatography with 30% EtOAc / n-hexane elution. The target fraction was concentrated and dried under vacuum to give the corresponding product as a colorless oil (yield 84%). 1 H NMR (600MHz, CDCl3) δ7.84-7.86(m,2H)7.24(t,1H),5.33(s,2H),3.84(s,3H),1.28(s,12H). MS(ESI,m / z):355.0[M+H] + .

[1463] [Step c”'] A suspension of 3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-amine (prepared according to intermediate 001, 166.5 mg, 0.50 mmol) in DMF (2 mL) was treated with methyl 2-(bromomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzoate (212.4 mg, 0.60 mmol). The resulting mixture was heated at 100 °C for 1 h. The reaction mixture was cooled to room temperature and extracted from water (50 mL) into DCM (3 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum. The resulting mixture was dried under vacuum and used without further purification. MS (ESI, m / z): 576.2 [M+H] + .

[1464] Bromobenzene (11 mg, 0.070 mmol) was added to a mixture of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)isoindolin-1-one (48 mg, 0.084 mmol), Pd(PPh3)4 (8 mg, 0.007 mmol), and potassium carbonate (19 mg, 0.140 mmol) in 1,4-dioxane (0.7 mL) and H2O (0.3 mL). The reaction mixture was heated to 100 °C for 12 h. After cooling to room temperature, the reaction mixture was separated from a UCT SPE CUBCX column and purified by preparative HPLC to give the corresponding product as a white solid (yield 50%).

[1465] 1 H NMR(600MHz,cd3od)δ8.88(brs,1H),8.81(s,1H),8.39(s,1H),8.22(brs,1H),8.12(d,J=7.8Hz,1H),8.07(d,J=7.8Hz,1H),8 .00(d,J=7.8Hz,1H),7.85–7.75(m,3H),7.41–7.47(m,3H),5.97(s,1H),5.33(s,2H),3.82(s,3H),2.57(s,3H),2.34(s,3H). MS(ESI,m / z):526.2[M+H] + .

[1466] Example 378: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-5-phenylisoindololin-1-one

[1467]

[1468] The title product was obtained using methyl 4-bromo-2-methylbenzoate and bromobenzene as described in General Method K with respect to Example 377. MS (ESI, m / z): 526.2 [M+H] + .

[1469] Example 379: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-6-phenylisoindololin-1-one

[1470]

[1471] The title product was obtained using methyl 5-bromo-2-methylbenzoate and bromobenzene, as described in General Method K with respect to Example 377. MS (ESI, m / z): 526.2 [M+H] + .

[1472] Example 380: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-6-(pyridin-4-yl)isoindololin-1-one

[1473]

[1474] The title product was obtained using methyl 5-bromo-2-methylbenzoate and 4-bromopyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 527.2 [M+H] + .

[1475] Example 381: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)isoindololin-1-one

[1476]

[1477] The title product was obtained using methyl 5-bromo-2-methylbenzoate and tert-butyl 4-bromo-3,6-dihydropyridine-1(2H)-carboxylate, as described in General Method K for Example 377 (the Boc group of the product was deprotected during the reaction). MS (ESI, m / z): 531.2 [M+H] + .

[1478] Example 382: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-phenylisoindololin-1-one

[1479]

[1480] The title product was obtained using methyl 2-bromo-6-methylbenzoate and bromobenzene as described in General Method K with respect to Example 377. MS (ESI, m / z): 526.2 [M+H] + .

[1481] Example 383: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-(pyridin-4-yl)isoindololin-1-one

[1482]

[1483] The title product was obtained using methyl 2-bromo-6-methylbenzoate and 4-bromopyridine as described in General Method K with respect to Example 377. MS (ESI, m / z): 527.2 [M+H] + .

[1484] Example 384: Synthesis of 7-(cyclohex-1-en-1-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1485]

[1486] The title product was obtained using methyl 2-bromo-6-methylbenzoate and 1-bromocyclohexyl-1-ene, as described in General Method K with respect to Example 377. MS (ESI, m / z): 530.2 [M+H] + .

[1487] Example 385: Synthesis of 7-(3,6-dihydro-2H-pyran-4-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1488]

[1489] The title product was obtained using methyl 2-bromo-6-methylbenzoate and 4-bromo-3,6-dihydro-2H-pyran, as described in General Method K with respect to Example 377. MS (ESI, m / z): 532.2 [M+H] + .

[1490] Example 386: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-(1H-pyrazol-4-yl)isoindololin-1-one

[1491]

[1492] The title product was obtained using methyl 2-bromo-6-methylbenzoate and 4-bromo-1H-pyrazole, as described in General Method K with respect to Example 377. MS (ESI, m / z): 516.2 [M+H] + .

[1493] Example 387: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(pyridin-4-yl)isoindololin-1-one

[1494]

[1495] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromopyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 527.2 [M+H] + .

[1496] Example 388: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(pyridin-3-yl)isoindololin-1-one

[1497]

[1498] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 3-chloropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 527.2 [M+H] + .

[1499] Example 389: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(1-methyl-1H-pyrazol-4-yl)isoindololin-1-one

[1500]

[1501] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-1-methyl-1H-pyrazole, as described in General Method K with respect to Example 377. MS (ESI, m / z): 530.2 [M+H] + .

[1502] Example 390: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(1H-pyrazol-4-yl)isoindololin-1-one

[1503]

[1504] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-1H-pyrazole, as described in General Method K with respect to Example 377. MS (ESI, m / z): 516.2 [M+H] + .

[1505] Example 391: Synthesis of 4-(cyclohexyl-1-en-1-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1506]

[1507] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 1-bromocyclohexyl-1-ene, as described in General Method K with respect to Example 377. MS (ESI, m / z): 530.2 [M+H] + .

[1508] Example 392: Synthesis of 4-(3,6-dihydro-2H-pyran-4-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1509]

[1510] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-3,6-dihydro-2H-pyran, as described in General Method K with respect to Example 377. MS (ESI, m / z): 532.2 [M+H] + .

[1511] Example 393: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(furan-3-yl)isoindololin-1-one

[1512]

[1513] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 3-bromofuran, as described in General Method K with respect to Example 377. MS (ESI, m / z): 516.2 [M+H] + .

[1514] Example 394: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)isoindololin-1-one

[1515]

[1516] The title product was obtained using methyl 3-bromo-2-methylbenzoate and tert-butyl 4-bromo-3,6-dihydropyridine-1(2H)-carboxylate, as described in General Method K for Example 377 (the Boc group of the product was deprotected during the reaction). MS (ESI, m / z): 531.2 [M+H] + .

[1517] Example 395: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(4-(trifluoromethoxy)phenyl)isoindololin-1-one

[1518]

[1519] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 1-bromo-4-(trifluoromethoxy)benzene, as described in General Method K with respect to Example 377. MS (ESI, m / z): 610.2 [M+H] + .

[1520] Example 396: Synthesis of 4-(4-aminophenyl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1521]

[1522] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromoaniline as described in General Method K with respect to Example 377. MS (ESI, m / z): 541.2 [M+H] + .

[1523] Example 397: Synthesis of tert-butyl 4-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid

[1524]

[1525] The title product was obtained using methyl 3-bromo-2-methylbenzoate and tert-butyl 4-bromo-3,6-dihydropyridine-1(2H)-carboxylate, as described in General Method K with respect to Example 377. MS (ESI, m / z): 631.3 [M+H] + .

[1526] Example 398: Synthesis of tert-butyl (4-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indole-7-yl)-1-oxoisoindoline-4-yl)phenyl)carbamate

[1527]

[1528] The title product was obtained using methyl 3-bromo-2-methylbenzoate and tert-butyl (4-bromophenyl)carbamate, as described in General Method K with respect to Example 377. MS (ESI, m / z): 641.3 [M+H] + .

[1529] Example 399: Synthesis of 4-(2-aminopyridin-4-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1530]

[1531] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromopyridin-2-amine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 542.2 [M+H] + .

[1532] Example 400: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(3-fluoropyridin-4-yl)isoindololin-1-one

[1533]

[1534] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-3-fluoropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 545.2 [M+H] + .

[1535] Example 401: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(6-hydroxypyridin-3-yl)isoindololin-1-one

[1536]

[1537] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromopyridin-2-ol, as described in General Method K with respect to Example 377. MS (ESI, m / z): 543.2 [M+H] + .

[1538] Example 402: Synthesis of 4-(2-chloropyridin-4-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1539]

[1540] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-2-chloropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 561.2 [M+H] + .

[1541] Example 403: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(5-fluoro-2-methoxypyridin-4-yl)isoindololin-1-one

[1542]

[1543] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-5-fluoro-2-methoxypyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 575.2 [M+H] + .

[1544] Example 404: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-fluoropyridin-4-yl)isoindololin-1-one

[1545]

[1546] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-2-fluoropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 545.2 [M+H] + .

[1547] Example 405: Synthesis of 4-(6-chloropyridin-3-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1548]

[1549] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromo-2-chloropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 561.2 [M+H] + .

[1550] Example 406: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(6-methoxypyridin-3-yl)isoindololin-1-one

[1551]

[1552] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromo-2-methoxypyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 557.2 [M+H] + .

[1553] Example 407: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(6-fluoro-5-methylpyridin-3-yl)isoindololin-1-one

[1554]

[1555] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromo-2-fluoro-3-methylpyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 559.2 [M+H] + .

[1556] Example 408: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-(piperazin-1-yl)pyridin-4-yl)isoindololin-1-one

[1557]

[1558] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 1-(4-bromopyridin-2-yl)piperazine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 611.3 [M+H] + .

[1559] Example 409: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(4-(pyrrolidine-1-ylsulfonyl)phenyl)isoindololin-1-one

[1560]

[1561] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 1-((4-bromophenyl)sulfonyl)pyrrolidine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 659.2 [M+H] + .

[1562] Example 410: Synthesis of (E)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(3-fluorostyryl)isoindololin-1-one

[1563]

[1564] The title product was obtained using methyl 3-bromo-2-methylbenzoate and (E)-1-(2-bromovinyl)-3-fluorobenzene, as described in General Method K with respect to Example 377. MS (ESI, m / z): 570.2 [M+H] + .

[1565] Example 411: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)isoindololin-1-one

[1566]

[1567] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-1H-pyrrolo[2,3-b]pyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 566.2 [M+H] + .

[1568] Example 412: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(4-(4-oxopiperidin-1-carbonyl)phenyl)isoindololin-1-one

[1569]

[1570] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 1-(4-bromobenzoyl)piperidin-4-one, as described in General Method K with respect to Example 377. MS (ESI, m / z): 651.2 [M+H] + .

[1571] Example 413: Synthesis of 4-(3,6-dihydro-2H-thiaran-4-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1572]

[1573] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-3,6-dihydro-2H-thiaran, as described in General Method K with respect to Example 377. MS (ESI, m / z): 548.2 [M+H] + .

[1574] Example 414: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-(dimethylamino)pyrimidin-5-yl)isoindololin-1-one

[1575]

[1576] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromo-N,N-dimethylpyrimidin-2-amine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 571.2 [M+H] + .

[1577] Example 415: Synthesis of 4-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1578]

[1579] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-1-(cyclopropylmethyl)-1H-pyrazole, as described in General Method K with respect to Example 377. MS (ESI, m / z): 570.2 [M+H] + .

[1580] Example 416: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)isoindololin-1-one

[1581]

[1582] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)morpholine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 629.3 [M+H] + .

[1583] Example 417: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(pyrimidin-5-yl)isoindololin-1-one

[1584]

[1585] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromopyrimidine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 528.2 [M+H] + .

[1586] Example 418: Synthesis of 4-(2-aminopyrimidin-5-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1587]

[1588] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromopyrimidine-2-amine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 543.2 [M+H] + .

[1589] Example 419: Synthesis of 4-(5-aminopyridin-3-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1590]

[1591] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromopyridin-3-amine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 542.2 [M+H] + .

[1592] Example 420: Synthesis of 4-(6-aminopyridin-3-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1593]

[1594] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromopyridin-2-amine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 542.2 [M+H] + .

[1595] Example 421: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(pyrimidin-4-yl)isoindololin-1-one

[1596]

[1597] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromopyrimidine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 528.2 [M+H] + .

[1598] Example 422: Synthesis of 4-(2-aminopyrimidin-4-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1599]

[1600] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromopyrimidine-2-amine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 543.2 [M+H] + .

[1601] Example 423: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(4-(4-methylpiperazin-1-yl)pyridin-2-yl)isoindololin-1-one

[1602]

[1603] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 1-(2-bromopyridin-4-yl)-4-methylpiperazine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 625.3 [M+H] + .

[1604] Example 424: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-(piperazin-1-yl)pyrimidin-5-yl)isoindololin-1-one

[1605]

[1606] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromo-2-(piperazin-1-yl)pyrimidine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 612.3 [M+H] + .

[1607] Example 425: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(6-morpholinopyridin-3-yl)isoindololin-1-one

[1608]

[1609] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-(5-bromopyridin-2-yl)morpholine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 612.2 [M+H] + .

[1610] Example 426: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(4-(4-methylpiperazin-1-yl)phenyl)isoindololin-1-one

[1611]

[1612] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 1-(4-bromophenyl)-4-methylpiperazine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 624.3 [M+H] + .

[1613] Example 427: Synthesis of 4-(2,6-difluoropyridin-4-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1614]

[1615] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-2,6-difluoropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 563.2 [M+H] + .

[1616] Example 428: Synthesis of 4-(3,5-difluoropyridin-4-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1617]

[1618] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-3,5-difluoropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 563.2 [M+H] + .

[1619] Example 429: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-methylpyridin-4-yl)isoindololin-1-one

[1620]

[1621] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-2-methylpyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 541.2 [M+H] + .

[1622] Example 430: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-[4,5'-diisoindololin]-1-one

[1623]

[1624] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromoisoindoline, as described in General Method K with respect to Example 377. MS (ESI, m / z): 567.2 [M+H] + .

[1625] Example 431: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-fluoropyridin-3-yl)isoindololin-1-one

[1626]

[1627] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 3-bromo-2-fluoropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 545.2 [M+H] + .

[1628] Example 432: Synthesis of 4-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)benzonitrile

[1629]

[1630] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromobenzonitrile as described in General Method K with respect to Example 377. MS (ESI, m / z): 551.2 [M+H] + .

[1631] Example 433: Synthesis of 4-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-3-fluorobenzonitrile

[1632]

[1633] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-3-fluorobenzonitrile as described in General Method K with respect to Example 377. MS (ESI, m / z): 569.2 [M+H] + .

[1634] Example 434: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-(trifluoromethyl)phenyl)isoindololin-1-one

[1635]

[1636] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 1-bromo-2-(trifluoromethyl)benzene, as described in General Method K with respect to Example 377. MS (ESI, m / z): 594.2 [M+H] + .

[1637] Example 435: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-methoxypyridin-3-yl)isoindololin-1-one

[1638]

[1639] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 3-bromo-2-methoxypyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 557.2 [M+H] + .

[1640] Example 436: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(4-(dimethylamino)phenyl)isoindololin-1-one

[1641]

[1642] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-N,N-dimethylaniline as described in General Method K with respect to Example 377. MS (ESI, m / z): 569.2 [M+H] + .

[1643] Example 437: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-(hydroxymethyl)phenyl)isoindololin-1-one

[1644]

[1645] The title product was obtained using methyl 3-bromo-2-methylbenzoate and (2-bromophenyl)methanol, as described in General Method K with respect to Example 377. MS (ESI, m / z): 556.2 [M+H] + .

[1646] Example 438: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-methoxyphenyl)isoindololin-1-one

[1647]

[1648] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 1-bromo-2-methoxybenzene as described in General Method K with respect to Example 377. MS (ESI, m / z): 556.2 [M+H] + .

[1649] Example 439: Synthesis of 4-([1,1'-biphenyl]-2-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1650]

[1651] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 2-bromo-1,1'-biphenyl, as described in General Method K with respect to Example 377. MS (ESI, m / z): 602.2 [M+H] + .

[1652] Example 440: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(o-tolyl)isoindololin-1-one

[1653]

[1654] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 1-bromo-2-methylbenzene as described in General Method K with respect to Example 377. MS (ESI, m / z): 540.2 [M+H] + .

[1655] Example 441: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-hydroxyphenyl)isoindololin-1-one

[1656]

[1657] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 2-bromophenol as described in General Method K with respect to Example 377. MS (ESI, m / z): 542.2 [M+H] + .

[1658] Example 442: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(1H-pyrrolo-2-yl)isoindololin-1-one

[1659]

[1660] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 2-bromo-1H-pyrrole, as described in General Method K with respect to Example 377. MS (ESI, m / z): 515.2 [M+H] + .

[1661] Example 443: Synthesis of tert-butyl 2-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-1H-pyrrole-1-carboxylic acid

[1662]

[1663] The title product was obtained using methyl 3-bromo-2-methylbenzoate and tert-butyl 2-bromo-1H-pyrrole-1-carboxylate as described in General Method K with respect to Example 377. MS (ESI, m / z): 615.2 [M+H] + .

[1664] Example 444: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(3,5-dimethylisoxazol-4-yl)isoindololin-1-one

[1665]

[1666] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-3,5-dimethylisoxazole, as described in General Method K with respect to Example 377. MS (ESI, m / z): 545.2 [M+H] + .

[1667] Example 445: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-methoxypyridin-4-yl)isoindololin-1-one

[1668]

[1669] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-2-methoxypyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 557.2 [M+H] + .

[1670] Example 446: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-hydroxypyridin-4-yl)isoindololin-1-one

[1671]

[1672] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromopyridin-2-ol, as described in General Method K with respect to Example 377. MS (ESI, m / z): 543.2 [M+H] + .

[1673] Example 447: Synthesis of 4-(3-aminopyridin-4-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1674]

[1675] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromopyridin-3-amine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 542.2 [M+H] + .

[1676] Example 448: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(isoquinolin-7-yl)isoindololin-1-one

[1677]

[1678] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 7-bromoisoquinoline, as described in General Method K with respect to Example 377. MS (ESI, m / z): 577.2 [M+H] + .

[1679] Example 449: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(1-methyl-1H-indol-5-yl)isoindololin-1-one

[1680]

[1681] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromo-1-methyl-1H-indazole, as described in General Method K with respect to Example 377. MS (ESI, m / z): 580.2 [M+H] + .

[1682] Example 450: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(1-methyl-1H-indol-6-yl)isoindololin-1-one

[1683]

[1684] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 6-bromo-1-methyl-1H-indazole, as described in General Method K with respect to Example 377. MS (ESI, m / z): 580.2 [M+H] + .

[1685] Example 451: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(5-methylthiophen-2-yl)isoindololin-1-one

[1686]

[1687] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 2-bromo-5-methylthiophene, as described in General Method K with respect to Example 377. MS (ESI, m / z): 546.2 [M+H] + .

[1688] Example 452: Synthesis of 4-(2,3-dihydro-1H-inden-5-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1689]

[1690] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromo-2,3-dihydro-1H-indene, as described in General Method K with respect to Example 377. MS (ESI, m / z): 566.2 [M+H] + .

[1691] Example 453: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(4-methylthiophen-3-yl)isoindololin-1-one

[1692]

[1693] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 3-bromo-4-methylthiophene, as described in General Method K with respect to Example 377. MS (ESI, m / z): 546.2 [M+H] + .

[1694] Example 454: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoro-4-(2-methylpyridin-4-yl)isoindololin-1-one

[1695]

[1696] The title product was obtained using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromo-2-methylpyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 559.2 [M+H] + .

[1697] Example 455: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(3-methylpyridin-4-yl)isoindololin-1-one

[1698]

[1699] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-3-methylpyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 541.2 [M+H] + .

[1700] Example 456: Synthesis of 4-(6-aminopyrimidin-4-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1701]

[1702] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 6-bromopyrimidine-4-amine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 543.2 [M+H] + .

[1703] Example 457: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(1H-indol-4-yl)isoindololin-1-one

[1704]

[1705] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-1H-indazole, as described in General Method K with respect to Example 377. MS (ESI, m / z): 566.2 [M+H] + .

[1706] Example 458: Synthesis of 2-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)benzoic acid

[1707]

[1708] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 2-bromobenzoic acid, as described in General Method K with respect to Example 377. MS (ESI, m / z): 570.2 [M+H] + .

[1709] Example 460: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(4-(hydroxymethyl)phenyl)isoindololin-1-one

[1710]

[1711] The title product was obtained using methyl 3-bromo-2-methylbenzoate and (4-bromophenyl)methanol, as described in General Method K with respect to Example 377. MS (ESI, m / z): 556.2 [M+H] + .

[1712] Example 461: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(thiophen-3-yl)isoindololin-1-one

[1713]

[1714] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 3-bromothiophene, as described in General Method K with respect to Example 377. MS (ESI, m / z): 532.1 [M+H] + .

[1715] Example 462: Synthesis of 4-(2-aminophenyl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1716]

[1717] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 2-bromoaniline as described in General Method K with respect to Example 377. MS (ESI, m / z): 541.2 [M+H] + .

[1718] Example 463: Synthesis of methyl 2-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)benzoate

[1719]

[1720] The title product was obtained using methyl 3-bromo-2-methylbenzoate and methyl 2-bromobenzoate as described in General Method K with respect to Example 377. MS (ESI, m / z): 584.2 [M+H] + .

[1721] Example 464: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)isoindololin-1-one

[1722]

[1723] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-1-methyl-1,2,3,6-tetrahydropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 545.2 [M+H] + .

[1724] Example 465: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(1-(methanesulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)isoindololin-1-one

[1725]

[1726] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-1-(methanesulfonyl)-1,2,3,6-tetrahydropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 609.2 [M+H] + .

[1727] Example 466: Synthesis of 4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindololin-1-one

[1728]

[1729] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 1-(4-bromo-3,6-dihydropyridin-1(2H)-yl)ethyl-1-one, as described in General Method K with respect to Example 377. MS (ESI, m / z): 573.2 [M+H] + .

[1730] Example 467: Synthesis of 4-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)-5,6-dihydropyridine-1(2H)-formamide

[1731]

[1732] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-3,6-dihydropyridine-1(2H)-formamide, as described in General Method K with respect to Example 377. MS (ESI, m / z): 574.2 [M+H] + .

[1733] Example 468: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(1,1-dioxy-3,6-dihydro-2H-thiaran-4-yl)isoindololin-1-one

[1734]

[1735] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 1,1-dioxide of 4-bromo-3,6-dihydro-2H-thiaran, as described in General Method K with respect to Example 377. MS (ESI, m / z): 580.2 [M+H] + .

[1736] Example 469: Synthesis of 4-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)pyridinecarboxynitrile

[1737]

[1738] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromopyridinecarboxylate, as described in General Method K with respect to Example 377. MS (ESI, m / z): 552.2 [M+H] + .

[1739] Example 470: Synthesis of 5-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)pyridinecarboxynitrile

[1740]

[1741] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromopyridinecarboxylate, as described in General Method K with respect to Example 377. MS (ESI, m / z): 552.2 [M+H] + .

[1742] Example 471: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(3-(hydroxymethyl)pyridin-4-yl)isoindololin-1-one

[1743]

[1744] The title product was obtained using methyl 3-bromo-2-methylbenzoate and (4-bromopyridin-3-yl)methanol, as described in General Method K with respect to Example 377. MS (ESI, m / z): 557.2 [M+H] + .

[1745] Example 472: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-(hydroxymethyl)pyridin-4-yl)isoindololin-1-one

[1746]

[1747] The title product was obtained using methyl 3-bromo-2-methylbenzoate and (4-bromopyridin-2-yl)methanol, as described in General Method K with respect to Example 377. MS (ESI, m / z): 557.2 [M+H] + .

[1748] Example 473: Synthesis of 4-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)pyridine amide

[1749]

[1750] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromopyridine amide, as described in General Method K with respect to Example 377. MS (ESI, m / z): 570.2 [M+H] + .

[1751] Example 474: Synthesis of 5-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindololin-4-yl)pyridine amide

[1752]

[1753] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 5-bromopyridine amide, as described in General Method K with respect to Example 377. MS (ESI, m / z): 570.2 [M+H] + .

[1754] Example 475: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-(dimethylamino)pyridin-4-yl)isoindololin-1-one

[1755]

[1756] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-N,N-dimethylpyridin-2-amine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 570.2 [M+H] + .

[1757] Example 476: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-(methylamino)pyridin-4-yl)isoindololin-1-one

[1758]

[1759] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-N-methylpyridin-2-amine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 556.2 [M+H] + .

[1760] Example 477: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(5-methylpyridin-3-yl)isoindololin-1-one

[1761]

[1762] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 3-bromo-5-methylpyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 541.2 [M+H] + .

[1763] Example 478: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(5-fluoropyridin-3-yl)isoindololin-1-one

[1764]

[1765] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 3-bromo-5-fluoropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 545.2 [M+H] + .

[1766] Example 479: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2,6-dimethylpyridin-4-yl)isoindololin-1-one

[1767]

[1768] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-2,6-dimethylpyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 555.2 [M+H] + .

[1769] Example 480: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoro-4-(pyridin-4-yl)isoindololin-1-one

[1770]

[1771] The title product was obtained using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromopyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 545.2 [M+H] + .

[1772] Example 481: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoro-4-(2-methoxypyridin-4-yl)isoindololin-1-one

[1773]

[1774] The title product was obtained using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromo-2-methoxypyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 575.2 [M+H] + .

[1775] Example 482: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoro-4-(2-(methylamino)pyridin-4-yl)isoindololin-1-one

[1776]

[1777] The title product was obtained using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromo-N-methylpyridin-2-amine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 574.2 [M+H] + .

[1778] Example 483: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-(dimethylamino)pyridin-4-yl)-7-fluoroisoindololin-1-one

[1779]

[1780] The title product was obtained using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromo-N,N-dimethylpyridin-2-amine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 588.2 [M+H] + .

[1781] Example 484: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoro-4-(5-fluoropyridin-3-yl)isoindololin-1-one

[1782]

[1783] The title product was obtained using methyl 3-bromo-6-fluoro-2-methylbenzoate and 3-bromo-5-fluoropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 563.2 [M+H] + .

[1784] Example 485: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoro-4-(2-fluoropyridin-4-yl)isoindololin-1-one

[1785]

[1786] The title product was obtained using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromo-2-fluoropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 563.2 [M+H] + .

[1787] Example 486: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoro-4-(5-methylpyridin-3-yl)isoindololin-1-one

[1788]

[1789] The title product was obtained using methyl 3-bromo-6-fluoro-2-methylbenzoate and 3-bromo-5-methylpyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 559.2 [M+H] + .

[1790] Example 487: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoro-4-(3-methylpyridin-4-yl)isoindololin-1-one

[1791]

[1792] The title product was obtained using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromo-3-methylpyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 559.2 [M+H] + .

[1793] Example 488: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2,6-dimethylpyridin-4-yl)-7-fluoroisoindololin-1-one

[1794]

[1795] The title product was obtained using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromo-2,6-dimethylpyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 573.2 [M+H] + .

[1796] Example 489: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-nitro-4-(pyridin-4-yl)isoindololin-1-one

[1797]

[1798] The title product was obtained using methyl 3-bromo-2-methyl-6-nitrobenzoate and 4-bromopyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 572.2 [M+H] + .

[1799] Example 490: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-(dimethylamino)-4-(pyridin-4-yl)isoindololin-1-one

[1800]

[1801] The title product was obtained using methyl 3-bromo-6-(dimethylamino)-2-methylbenzoate and 4-bromopyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 570.2 [M+H] + .

[1802] Example 491: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-(methylamino)-4-(pyridin-4-yl)isoindololin-1-one

[1803]

[1804] The title product was obtained using methyl 3-bromo-2-methyl-6-(methylamino)benzoate and 4-bromopyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 556.2 [M+H] + .

[1805] Example 492: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-iodo-4-phenylisoindololin-1-one

[1806]

[1807] The title product was obtained using methyl 3-bromo-6-iodo-2-methylbenzoate and bromobenzene, as described in General Method K with respect to Example 377. MS (ESI, m / z): 652.1 [M+H] + .

[1808] Example 493: Synthesis of 6-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-phenyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[1809]

[1810] The title product was obtained using methyl 4-bromo-3-methylpyridinecarboxylate and bromobenzene, as described in General Method K with respect to Example 377. MS (ESI, m / z): 527.2 [M+H] + .

[1811] Example 494: Synthesis of 6-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[1812]

[1813] The title product was obtained using methyl 4-bromo-3-methylpyridinecarboxylate and 4-bromopyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 528.2 [M+H] + .

[1814] Example 495: Synthesis of 6-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[1815]

[1816] The title product was obtained using methyl 4-bromo-3-methylpyridinecarboxylate and 3-bromopyridine as described in General Method K with respect to Example 377. MS (ESI, m / z): 528.2 [M+H] + .

[1817] Example 496: Synthesis of 6-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[1818]

[1819] The title product was obtained using methyl 4-bromo-3-methylpyridinecarboxylate and tert-butyl 4-bromo-3,6-dihydropyridine-1(2H)-carboxylate, as described in General Method K for Example 377 (with deprotection of the Boc group during the reaction). MS (ESI, m / z): 532.2 [M+H] + .

[1820] Example 497: Synthesis of 6-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-3-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[1821]

[1822] The title product was obtained using methyl 5-bromo-3-methylpyridinecarboxylate and 4-bromopyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 528.2 [M+H] + .

[1823] Example 498: Synthesis of 6-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[1824]

[1825] The title product was obtained using methyl 5-bromo-3-methylpyridinecarboxylate and tert-butyl 4-bromo-3,6-dihydropyridine-1(2H)-carboxylate, as described in General Method K for Example 377 (with deprotection of the Boc group during the reaction). MS (ESI, m / z): 532.2 [M+H] + .

[1826] Example 499: 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

[1827]

[1828] The title product was obtained using methyl 5-bromo-4-methylnicotinate and tert-butyl 4-bromo-3,6-dihydropyridine-1(2H)-carboxylate, as described in General Method K for Example 377 (with deprotection of the Boc group during the reaction). MS (ESI, m / z): 532.2 [M+H] + .

[1829] Example 500: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-(pyridin-4-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

[1830]

[1831] The title product was obtained using methyl 5-bromo-4-methylnicotinate and 4-bromopyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 528.2 [M+H] + .

[1832] Example 501: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[1833]

[1834] The title product was obtained using methyl 2-bromo-3-methylisonicotinic acid and 4-bromopyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 528.2 [M+H] + .

[1835] Example 502: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-methylpyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[1836]

[1837] The title product was obtained using methyl 2-bromo-3-methylisonicotinate and 4-bromo-2-methylpyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 542.2 [M+H] + .

[1838] Example 503: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(5-fluoropyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[1839]

[1840] The title product was obtained using methyl 2-bromo-3-methylisonicotinic acid and 3-bromo-5-fluoropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 546.2 [M+H] + .

[1841] Example 504: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[1842]

[1843] The title product was obtained using methyl 2-bromo-3-methylisonicotinic acid and 4-bromo-2-fluoropyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 546.2 [M+H] + .

[1844] Example 505: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(5-methylpyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[1845]

[1846] The title product was obtained using methyl 2-bromo-3-methylisonicotinate and 3-bromo-5-methylpyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 542.2 [M+H] +.

[1847] Example 506: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(3-methylpyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[1848]

[1849] The title product was obtained using methyl 2-bromo-3-methylisonicotinate and 4-bromo-3-methylpyridine, as described in General Method K with respect to Example 377. MS (ESI, m / z): 542.2 [M+H] + .

[1850] Experimental Example ...

Claims

1. A compound represented by the following formula (I), its stereoisomer, its pharmaceutically acceptable salt or its solvate: [Formula (I)] in, L 1 and L 2 Each independently represents H; (C 1-5 ) alkyl; or L 1 and L 2 Connected to form a 5- to 6-membered ring, M represents H; halogen; (C 1-5 ) alkyl; (C 3-7 )cycloalkyl; or (C 1-5 ) alkoxy, G represents H; halogen; (C 1-5 ) alkyl; (C 1-5 ) alkoxy; or -NH2, wherein at least one H of -NH2 is optionally replaced by (C 1-5 ) alkyl substituted, Y 1 represents H; or (C 1-5 )alkyl, Z represents -C(=O)-; or optionally one or more (C 1-5 ) alkyl-substituted -CH2-; or Z and Y 1 Connected to form a 5- to 6-membered ring, Y 3 represents a 4- to 6-membered heterocycloalkyl group, wherein at least one H is optionally and independently replaced by W 1 or W 2 Replace; or in Z and Y 1 When the 5- to 6-membered ring is formed, Y 3 is connected with Z to form an aryl or heteroaryl group, at least one H of the aryl and heteroaryl group formed by Y3 and Z is optionally and independently substituted by W3, W1 and W2 each independently represent H; halogen; -OH; (C 1-5 ) alkyl; optionally substituted by (C 1-5 ) alkyl-substituted 5- to 7-membered heterocycloalkyl; optionally substituted by (C 1-5 ) alkyl-substituted heteroaryl; -COR 1 ;-OR 2 ; or -NH2, wherein at least one H of -NH2 is optionally and independently substituted by heteroaryl, R 1 Indicates (C 1-5 ) alkoxy; -OH; optionally (C 1-5 ) alkyl-substituted 5-7 membered heterocycloalkyl; or -NH2, wherein at least one H of -NH2 is optionally and independently replaced by (C 3-7 ) cycloalkyl substituted, R 2 represents (C 1-5 ) alkyl; aryl; or heteroaryl, wherein at least one H of the aryl or heteroaryl is optionally and independently replaced by one or more R 2a replace, One or more R 2a Each independently represents halogen; optionally substituted by aryl (C 1-5 ) alkyl, or (C 1-5 ) alkyl-substituted 5- to 7-membered heterocycloalkyl; optionally substituted by (C 1-5 ) alkyl substituted (C 5-6 )cycloalkenyl; optionally substituted by (C 1-5 )alkyl or -OH substituted 5 to 7 membered heterocycloalkyl; -CF3; (C 1-5 )alkoxy; aryl, wherein at least one H of the aryl is optionally and independently substituted by halogen; optionally (C 1-5 ) alkyl-substituted heteroaryl; thio (C 1-5 )alkyl; -COR 1a ; or NR 3 R 4 , R 1a Indicates (C 1-5 ) alkoxy; -OH; optionally (C 1-5 ) alkyl-substituted 5-7 membered heterocycloalkyl; or -NH2, wherein at least one H of -NH2 is optionally and independently replaced by (C 1-5 ) alkyl or (C 3-7 ) cycloalkyl substituted, R 3 and R 4 Each independently represents H; halogen; optionally halogen, -CF3, -OH, (C 1-5 )alkoxy, -N-[(C 1-5 )alkyl][(C 1-5 )alkyl], aryl or (C 3-7 ) cycloalkyl substituted (C 1-5 ) alkyl; (C 3-7 )cycloalkyl; (C 1-5 )alkoxy; aryl; or -C(=O)(C 1-5 )alkyl, and One or more W3 each independently represents H, halogen; (C 1-5 ) alkyl; (C 1-5 )alkoxy; -OH; -NO2; -NR 5 R 6 ; -CH=CR 7 R 8 ; -C≡CR 9 ;(C 5-6 )cycloalkenyl; optionally substituted by (C 1-5 )alkyl, -C(=O)O(C 1-5 )alkyl, -S(=O)2(C 1-5 )alkyl, -C(=O)(C 1-5 )alkyl or -C(=O)(NH2)-substituted 5- to 7-membered heterocycloalkyl; aryl; or heteroaryl, wherein at least one H of the aryl or heteroaryl is optionally replaced by one or more R 10 replace, R 5 and R 6 Each independently represents H; optionally (C 3-7 ) cycloalkyl or aryl substituted (C 1-5 ) alkyl; optionally substituted by (C 1-5 )alkyl-substituted 5- to 7-membered heterocycloalkyl; aryl; -C(=O)R 11 ;or-S(=O)2R 12 , R 7 represents (C 1-5 )alkyl; aryl optionally substituted by halogen; or -C(=O)R 13 , R 8 represents H; or (C 1-5 )alkyl, R 9 represents an aryl group optionally substituted by -NH2, One or more R 10 Each independently represents H; halogen; -CN; -CF3; -OH; -OCF3; optionally (C 3-7 )cycloalkyl, 5- to 7-membered heterocycloalkyl or -OH substituted (C 1-5 ) alkyl; (C 1-5 ) alkoxy; optionally substituted by one or more (C 1-5 )alkyl or -C(=O)O(C 1-5 ) alkyl-substituted -NH2; optionally substituted by (C 1-5 ) alkyl-substituted 5- to 7-membered heterocycloalkyl; -C(=O)R 14 ; -S(=O)2-(5- to 7-membered heterocycloalkyl); or aryl, wherein R 10 are optionally linked to each other to form a 5- to 6-membered ring, R 11 represents (C 1-5 ) alkyl; optionally containing C(=O) (C 3-7 )cycloalkyl; optionally substituted by (C 1-5 ) alkyl substituted (C 3-7 ) cycloalkyl; fused with aryl (C 3-7 )cycloalkyl; optionally substituted by (C 1-5 ) alkyl substituted (C 5-6 )cycloalkenyl; optionally substituted by (C 1-5 )alkyl or -NH2-substituted 5 to 7 membered heterocycloalkyl; aryl; or optionally (C 1-5 ) alkyl or -OH substituted heteroaryl, R 12 Indicates (C 1-5 ) alkyl; or aryl, wherein at least one H of the aryl is optionally and independently replaced by (C 1-5 ) alkyl or halogen substituted, R 13 Indicates (C 1-5 ) alkyl; (C 1-5 ) alkoxy; -OH; -NH2, wherein at least one H of -NH2 is optionally and independently replaced by (C 1-5 ) alkyl or substituted by OH (C 1-5 ) alkyl substituted; (C 3-7 )cycloalkyl; hydroxyl (C 1-5 ) alkyl; (C 1-5 ) alkoxy (C 1-5 ) alkyl; -NH2, R 14 represents a 5- to 7-membered heterocycloalkyl group; -NH2; or -OH.

2. The compound according to claim 1, its stereoisomer, its pharmaceutically acceptable salt or solvate thereof, wherein: Y 3 represents azetidinyl; pyrrolidinyl; piperidinyl; tetrahydropyridinyl; or oxopyrrolidinyl, which is optionally replaced by W 1 and W 2 replace, W1 and W2 each independently represent H; halogen; -OH; (C 1-5 )alkyl; methylpiperazinyl; morpholinyl; pyridinyl; methylpyrazolyl; -COR 1 ;-OR 2 ; -NH2; -NH(pyridyl) or -NH(pyrimidinyl), R 1 Indicates (C 1-5 )alkoxy; -OH; -NH2; -NH-(C 3-7 )cycloalkyl; oxopiperazinyl; morpholinyl; thiomorpholinyl; methylpiperazinyl; or tetrahydropyridinyl, R 2 represents (C 1-5 )alkyl; halophenyl; dihalophenyl; (amino)halophenyl; (methylpiperazinyl)(methyl)phenyl; (dimethylamino)phenyl; aminophenyl; diethylaminophenyl; biphenyl; (phenylpropyl)phenyl; (cyclopropylamino)pyrimidinyl; (trifluoroethylamino)pyrimidinyl; pyridinyl; pyrimidinyl; (cyclopropyl)(isoxazole)carboxamide; (dimethyl)pyrimidinyl; pyrazinyl; aminopyridinyl; halopyridinyl; aminopyrazinyl; halopyrimidinyl; (methyl)halopyrimidinyl; (amino)(methyl)pyrimidinyl; (amino)halopyrimidinyl; dihalopyrimidinyl; amino(dihalophenyl)pyrimidinyl; (amino)(trifluoromethyl)pyrimidinyl; pentylpyrimidinyl; methylpyrazolyl; methyl(benzothiophene)carboxylate; (thiophene)carboxylic acid Methyl ester; (thiophene) carboxylic acid; (thiophene) carboxamide; methyl (thiophene) carboxamide; cyclopropyl (thiophene) carboxamide; methyl isoxazolyl; benzisoxazolyl; isothiazolyl; methylthienyl; pyrazolyl; (methyl) (trifluoromethyl) pyrazolyl; isoxazolyl; aminopyrazolyl; methyl (pyrrole) carboxylate; ethyl (isoxazole) carboxylate; (isoxazole) carboxamide; methyl (isoxazole) carboxamide; dimethyl (isoxazole) carboxamide; cyclopropyl (oxazole) carboxamide; (pyrimidine) carboxylic acid; (pyrimidine) carboxamide; methyl (pyrimidine) carboxamide; dimethyl (pyrimidine) carboxamide; (pyrazine) carboxamide; methyl (pyrazine) carboxamide; aminotriazinyl; (methylamino) triazinyl; (dimethylamino) triazinyl; (cyclopropylamino) triazinyl; diamino triazinyl; (amino)(pyrrolidinyl)triazinyl; aminopyrimidinyl; (methylamino)pyrimidinyl; (ethylamino)pyrimidinyl; (propylamino)pyrimidinyl; (butylamino)pyrimidinyl; (hydroxyethylamino)pyrimidinyl; (hydroxypropylamino)pyrimidinyl; (methoxyethylamino)pyrimidinyl; (((dimethylamino)propyl)amino)pyrimidinyl; (benzylamino)pyrimidinyl; (phenethylamino)pyrimidinyl; (cyclohexylamino)pyrimidinyl; (dimethylamino)pyrimidinyl; (ethylmethylamino)pyrimidinyl; (diethylamino)pyrimidinyl; (ethylpropylamino)pyrimidinyl; (butylethylamino)pyrimidinyl; pyrrolidinylpyrimidinyl; (hydroxypyrrolidinyl)pyrimidinyl; piperidinylpyrimidinyl; (hydroxypiperidinyl)pyrimidinyl; morpholinopyrimidinyl pyrimidinyl; (methylpiperazinyl) pyrimidinyl; (amino)(methylamino) pyrimidinyl; (amino)(pyrrolidinyl) pyrimidinyl; (methylamino) halogenated pyrimidinyl; (ethylamino) halogenated pyrimidinyl; (cyclopropylamino) halogenated pyrimidinyl; (cyclohexylamino) halogenated pyrimidinyl; (dimethylamino) halogenated pyrimidinyl; (ethylmethylamino) halogenated pyrimidinyl; (diethylamino) halogenated pyrimidinyl; (methylphenylamino) halogenated pyrimidinyl; (benzylmethylamino) halogenated pyrimidinyl; (pyrrolidinyl) halogenated pyrimidinyl; (piperidinyl) halogenated pyrimidinyl; (morpholino) halogenated pyrimidinyl; (thiomorpholino) halogenated pyrimidinyl; (methylpiperazinyl) halogenated pyrimidinyl; (cyclopropylamino) methyl pyrimidinyl; (amino) pyrimidinyl; (methylthio) pyrimidinyl;(Methoxy)pyrimidinyl; (Benzyloxy)pyrimidinyl; Acetamidopyrimidinyl; (Difluoropropylamino)pyrimidinyl; (Difluoroethylamino)pyrimidinyl; (Trifluoropropylamino)pyrimidinyl; (Fluoroethylamino)pyrimidinyl; (Cyclobutylamino)pyrimidinyl; (Cyclopentylamino)pyrimidinyl; (Isopropylamino)pyrimidinyl; (Sec-butylamino)pyrimidinyl; ((Cyclopropylmethyl)amino)pyrimidinyl; (((Dimethylamino)ethyl)amino)pyrimidinyl; (((Dimethylamino)propyl)amino)pyrimidinyl; (Methoxyamino)pyrimidinyl; (Benzylmethylamino)pyrimidinyl; (Cyclohexylamino) Halopyrimidinyl; (cyclopropylmethylamino)halopyrimidinyl; (benzylamino)halopyrimidinyl; (cyclopropylamino)halopyrimidinyl; (cyclopropylamino)methylpyrimidinyl; (cyclopropylamino)(trifluoromethyl)pyrimidinyl; (cyclopropylamino)(methoxy)pyrimidinyl; (cyclopropylamino)pyrazinyl; (ethylamino)pyrazinyl; (propylamino)pyrazinyl; (hydroxyethylamino)pyrazinyl; (((dimethylamino)ethyl)amino)pyrazinyl; phenylpyrimidinyl; (methylpyrazolyl)pyrimidinyl; (dimethylcyclohexenyl)pyrimidinyl; dihydropyranylpyrimidinyl; or pyridylpyrimidinyl. ; 3. The compound according to claim 1, its stereoisomer, its pharmaceutically acceptable salt or solvate thereof, wherein the compound represented by the above formula (I) is a compound represented by the following formula (Ib): [Formula (Ib)] X represents -CH2-; or -C(=O)-, V 1 、V 2 、V 3 and V 4 Each independently represents CH or N, wherein in all V 1 、V 2 、V 3 and V 4 If both are not N, V 1 、V 2 、V 3 and V 4 One or more H in is optionally and independently replaced by W 3 replace, One or more W 3 Each independently represents H, halogen; (C 1-5 ) alkyl; (C 1-5 )alkoxy; -OH; -NO2; -NR 5 R 6 ; -CH=CR 7 R 8 ; -C≡CR 9 ;(C 5-6 )cycloalkenyl; optionally substituted by (C 1-5 )alkyl, -C(=O)O(C 1-5 )alkyl, -S(=O)2(C 1-5 )alkyl, -C(=O)(C 1-5 )alkyl or -C(=O)(NH2)-substituted 5- to 7-membered heterocycloalkyl; aryl; or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted with one or more R 10 replace, R 5 and R 6 Each independently represents H; optionally (C 3-7 ) cycloalkyl or aryl substituted (C 1-5 ) alkyl; optionally substituted by (C 1-5 )alkyl-substituted 5- to 7-membered heterocycloalkyl; aryl; -C(=O)R 11 ;or-S(=O)2R 12 , R 7 represents (C 1-5 )alkyl; aryl optionally substituted by halogen; or -C(=O)R 13 , R 8 represents H; or (C 1-5 )alkyl, R 9 represents an aryl group optionally substituted by -NH2, One or more R 10 Each independently represents H; halogen; -CN; -CF3; -OH; -OCF3; optionally (C 3-7 )cycloalkyl, 5- to 7-membered heterocycloalkyl or -OH substituted (C 1-5 ) alkyl; (C 1-5 ) alkoxy; optionally substituted by one or more (C 1-5 )alkyl or -C(=O)O(C 1-5 ) alkyl-substituted -NH2; optionally substituted by (C 1-5 ) alkyl-substituted 5- to 7-membered heterocycloalkyl; -C(=O)R 14 ; -S(=O)2-(5- to 7-membered heterocycloalkyl); or aryl, wherein R 10 are optionally linked to each other to form a 5- to 6-membered ring, R 11 represents (C 1-5 ) alkyl; optionally containing C(=O) (C 3-7 )cycloalkyl; optionally substituted by (C 1-5 ) alkyl substituted (C 3-7 ) cycloalkyl; fused with aryl (C 3-7 )cycloalkyl; optionally substituted by (C 1-5 ) alkyl substituted (C 5-6 )cycloalkenyl; optionally substituted by (C 1-5 )alkyl or -NH2-substituted 5 to 7 membered heterocycloalkyl; aryl; or optionally (C 1-5 ) alkyl or -OH substituted heteroaryl, R 12 Indicates (C 1-5 ) alkyl; or aryl, wherein at least one H of the aryl is optionally and independently replaced by (C 1-5 ) alkyl or halogen substituted, R 13 Indicates (C 1-5 ) alkyl; (C 1-5 ) alkoxy; -OH; -NH2, wherein at least one H of -NH2 is optionally replaced by (C 1-5 ) alkyl or substituted by OH (C 1-5 ) alkyl substituted; (C 3-7 )cycloalkyl; hydroxyl (C 1-5 ) alkyl; (C 1-5 ) alkoxy (C 1-5 ) alkyl; -NH2, R 14 represents a 5- to 7-membered heterocycloalkyl group; -NH2; or -OH, L 1 , L 2 , M and G are as defined in claim 1.

4. The compound according to claim 3, its stereoisomer, its pharmaceutically acceptable salt or solvate thereof, wherein: W 3 independently represents H; halogen; (C 1-5 ) alkyl; (C 1-5 )alkoxy; -OH; -NO2; -NR 5 R 6 ; -CH=CR 7 R 8 ; -C≡CR 9 ;(C 5-6 )cycloalkenyl; morpholinyl; tetrahydropyridinyl; dihydropyranyl; (tetrahydropyridine)carboxylic acid tert-butyl ester; (dihydropyridine)carboxylic acid tert-butyl ester; dihydrothiopyranyl; methyltetrahydropyridinyl; (methylsulfonyl)tetrahydropyridinyl; acetyltetrahydropyridinyl; (tetrahydropyridine)carboxamide; 1,1-dioxide-dihydrothiopyranyl; phenyl; (trifluoromethoxy)phenyl; aminophenyl; (phenyl)carbamic acid tert-butyl ester; (pyrrolidinylsulfonyl)phenyl; oxopiperidinyl (carbonyl)phenyl; methylpiperazinyl; (methylpiperazinyl)phenyl; isoindolyl; cyanophenyl; cyanohalophenyl; (trifluoromethyl)phenyl; (dimethylamino)phenyl; hydroxybenzyl; methoxyphenyl; biphenyl; methylphenyl; hydroxyphenyl; dihydroindanyl; benzoic acid; methyl benzoate; pyrrolidinylsulfonyl pyridinyl; pyrazolyl; methylpyrazolyl; furanyl; aminopyridinyl; halopyridinyl; hydroxypyridinyl; (methoxy)halopyridinyl; methoxypyridinyl; (methyl)halopyridinyl; piperazinylpyridinyl; pyrrolopyridinyl; (dimethylamino)pyrimidinyl; (cyclopropylmethyl)pyrazolyl; (morpholinoethyl)pyrazolyl; pyrimidinyl; aminopyrimidinyl; (methylpiperazinyl)pyridinyl; piperazinylpyrimidinyl; morpholinopyridinyl; dihalopyridinyl; methylpyridinyl; pyrrolyl; tert-butyl (pyrrole)carboxylate; dimethylisoxazolyl; isoquinolinyl; methylindazolyl; methylthienyl; indazolyl; thienyl; cyanopyridinyl; (hydroxymethyl)pyridinyl; pyridineamide; (dimethylamino)pyridinyl; dimethylpyridinyl; or (methylamino)pyridinyl, R 5 and R 6 Each independently represents H; optionally (C 3-7 ) cycloalkyl or phenyl substituted (C 1-5 ) alkyl; optionally substituted by (C 1-5 ) alkyl-substituted morpholinyl or piperazinyl; phenyl; -C(=O)R 11 ;or-S(=O)2R 12 , R 7 represents methyl optionally substituted by -OH; phenyl optionally substituted by halogen; or -C(=O)R 13 , R 9 represents a phenyl group optionally substituted by -NH2, R 11 represents (C 1-5 ) alkyl; optionally containing C(=O) (C 3-7 ) cycloalkyl; 1-5 ) alkyl substituted (C 3-7 )cycloalkyl; phenyl fused (C 3-7 )cycloalkyl; optionally substituted by (C 1-5 ) alkyl substituted (C 5-6 )cycloalkenyl; morpholinyl; methylpiperidinyl; oxopyrrolidinyl; oxoimidazolidinyl; pyrrolidinyl; piperidinyl; tetrahydrofuranyl; tetrahydropyranyl; methyltetrahydropyranyl; aminopyrrolidinyl; methylpyrrolidinyl; phenyl; pyridinyl; oxazolyl; pyridazinyl; methylisoxazolyl; methyloxazolyl; isoxazolyl; methylpyridinyl; furanyl; or hydroxypyrimidinyl, R 12 Indicates (C 1-5 )alkyl; phenyl; methylphenyl; or (methyl)halophenyl, R 14 represents oxopiperidinyl; -NH2; or -OH.

5. A compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is selected from one of the following compounds:

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, its stereoisomer, its pharmaceutically acceptable salt or solvate thereof as an active ingredient.

7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is used to prevent or treat GCN2 activation-related diseases.

8. The pharmaceutical composition according to claim 6, wherein the composition further comprises one or more therapeutic agents selected from chemotherapeutic agents, radiotherapeutic agents, immunotherapeutic agents and tumor microenvironment modulators.

9. A method for preventing or treating a disease associated with GCN2 activation, comprising administering to an individual a therapeutically effective amount of a compound according to any one of claims 1 to 5, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

10. The method of claim 9, wherein the GCN2 activation-related diseases include cancer, neurodegenerative diseases, chronic infections, and metabolic diseases.

11. The method of claim 10, wherein the cancer is selected from the group consisting of thyroid cancer, melanoma, prostate cancer, endometrial cancer, lung cancer, head and neck cancer, pancreatic cancer, glioma, gastric cancer, urothelial carcinoma, skin cancer, breast cancer, colorectal cancer, kidney cancer, fibrosarcoma, osteosarcoma, connective tissue sarcoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, adenocarcinoma, hepatocellular carcinoma, multiple myeloma, myelodysplastic syndrome, myeloproliferative neoplasms, malignant gliomas. one or more of: non-Hodgkin's lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia, small cell lung cancer, and pediatric neuroblastoma.

12. A method for inhibiting GCN2 activity, comprising administering to an individual a therapeutically effective amount of a compound according to any one of claims 1 to 5, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

13. Use of the compound according to any one of claims 1 to 5, its stereoisomer, its pharmaceutically acceptable salt or its solvate for preventing or treating GCN2 activation-related diseases.

14. Use of the compound according to any one of claims 1 to 5, its stereoisomer, its pharmaceutically acceptable salt or its solvate in the preparation of a medicament for preventing or treating a disease related to GCN2 activation.

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