Novel compounds as GCN2 inhibitors, pharmaceutical compositions thereof, and uses

Abstract

Provided herein is a novel compound, for example, a compound of formula (I), as a GCN2 inhibitor. Also provided are pharmaceutical compositions comprising one or more of the novel compounds, and the use of such pharmaceuticals. The compounds provided herein can typically inhibit GCN2 activity and thus can be used to treat or prevent diseases associated therewith. TIFF2025521366000691.tif92170

Description

Technical Field

[0001] The present invention relates to novel compounds as GCN2 inhibitors, pharmaceutical compositions containing the same, and their pharmaceutical uses, which inhibit the activity of GCN2 and can thus be usefully used in the prevention or treatment of diseases associated therewith.

Background Art

[0002] A variety of agents currently exist as treatment tools for cancer, but it is widely accepted that more options still need to be invented to address unmet needs in the treatment of cancer patients. Some studies have shown that the regulation of essential components in the tumor microenvironment may be a promising treatment option for cancer therapy. Cancer cells are generally in a tumor microenvironment lacking some nutrients, such as glucose, oxygen, and amino acids. The integrated stress response (ISR) is one pathway by which tumor cells adapt to nutrient deprivation. General control non-derepressible kinase 2 (GCN2), which is encoded by EIF2AK4 in humans, is one of the cytoplasmic serine / threonine protein kinases that mediate the nutrient stress pathway in the tumor microenvironment. In response to amino acid deprivation, GCN2 phosphorylates eukaryotic translation initiation factor 2α (eIF2a), which activates the integrated stress response (ISR), leading to the initiation of a transcriptional program by activating transcription factor-4 (ATF4). ATF4 functions as an important ISR transcription factor that promotes stress resolution by inducing the expression of a substantial portion of genes related to amino acid transport and metabolism. Under the ATF4-mediated ISR pathway, GCN2 acts as a crucial component in the response to recovery from nutrient depletion. Furthermore, in various human tumors, an increase in the expression level of GCN2 has been observed compared to normal tissues. GCN2 is highly expressed in various cancers (thyroid cancer, melanoma, testicular cancer, endometrial cancer, lung cancer, head and neck cancer, pancreatic cancer, glioma, gastric cancer, urothelial cancer, skin cancer, breast cancer, colorectal cancer or rectal cancer, etc.) at the protein and mRNA levels. In addition, the function of GCN2 is closely related to the induction of T cell anergy under tryptophan depletion caused by indoleamine-2,3-dioxygenase (IDO). Inhibition of GCN2 has been reported as a therapeutic approach for cancer treatment (see, for example, Wei, C. et al. in Mol. Biol. Cell. 2015, 26(6), 1044). Therefore, inhibition of GCN2 activity may provide a beneficial treatment option for cancer patients.Furthermore, some GCN2 inhibitors that result in the downregulation of eIF2a phosphorylation and ATF expression show potential for treating neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and spinocerebellar degeneration, as well as doxorubicin-induced cardiotoxicity (Nakagawa, T. et al. Int. J. Mol. Sci. 2019, 20, 2761). Recent studies have shown that GCN2 inhibitors may have potential as drugs for inflammatory diseases (Wang, P. et al. in J. Allergy Clin. Immunol. 2019, 144, p. 1091) and fatty liver (Yuan, J. et al. in Redox Biology 2022, 49, 102224). SUMMARY OF THE INVENTION

[0003] An object of the present invention is to provide a novel compound showing general control non-repressible kinase 2 (GCN2) inhibitory activity, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0004] An object of the present invention is to provide a method for preparing the compound of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0005] An object of the present invention is to provide a pharmaceutical composition for treating or preventing GCN2 activation-related diseases, comprising the compound of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

[0006] An object of the present invention is to provide a method for treating or preventing GCN2 activation-related diseases, comprising administering a therapeutically effective amount of the compound of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject.

[0007] An object of the present invention is to provide the use of the compound of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof in the formulation of a medicament for treating or preventing GCN2 activation-related diseases.

[0008] An object of the present invention is to provide the use of a compound of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof for the treatment or prevention of GCN2 activation-related diseases.

[0009] An object of the present invention is to provide a method for inhibiting GCN2 activity, which comprises administering to a subject a therapeutically effective amount of a compound of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

BRIEF DESCRIPTION OF THE INVENTION

[0010] GCN2 inhibitor compound The present invention relates to the following formula (I):

[0011]

Chemical formula

[0012] A compound represented by the formula, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein in the formula (I), L 1 and L 2 are each independently H; (C 1~5 ) alkyl which may be substituted by a 4- to 6-membered heterocycloalkyl; or L 1 and L 2 are connected to form a 5- to 6-membered ring, M is H; halogen; (C 1~5 ) alkyl; (C 3~7 ) cycloalkyl; or (C 1~5 ) alkoxy, G is H; halogen; (C 1~5 ) alkyl; (C 1~5 ) alkoxy; or -NH2, and at least one H of -NH2 may be substituted by (C 1~5 ) alkyl, Y 1 is H; or (C 1~5 ) alkyl, Z is -C(=O)-; or -CH2- which may be substituted by one or more (C 1~5 )alkyl; or Z is Y 1 connected to form a 5- to 6-membered ring, Y 3 is a 4- to 6-membered heterocycloalkyl in which at least one H is each independently substituted by W 1 or W 2 ; or when Z is connected to Y 1 to form a 5- to 6-membered ring, Y 3 is connected to Z to form an aryl or heteroaryl, and at least one H of the aryl and heteroaryl formed by Y3 and Z may be independently substituted by W3, W1 and W2 are each independently H; halogen; -OH; (C 1~5 )alkyl which may be substituted by -OH, -NH2 or -CN; 5- to 7-membered heterocycloalkyl which may be substituted by (C 1~5 )alkyl; heteroaryl which may be substituted by (C 1~5 )alkyl; -COR 1 ; -OR 2 ; or -NH2, and at least one H of -NH2 may be independently substituted by heteroaryl, R 1 is (C 1~5 )alkoxy; -OH; 5- to 7-membered heterocycloalkyl which may be substituted by (C 1~5 )alkyl; or -NH2, and at least one H of -NH2 may be independently substituted by (C 3~7 )cycloalkyl, R 2 is (C 1~5 )alkyl which may be substituted by heteroaryl; aryl; or heteroaryl, and at least one H of the aryl or heteroaryl may be independently substituted by one or more R 2a ; One or more R 2ais, independently of each other, halogen; (C 1~5 )alkyl which may be substituted by aryl, or 5- to 7-membered heterocycloalkyl which may be substituted by (C 1~5 )alkyl; (C 1~5 )cycloalkenyl which may be substituted by (C 5~6 )alkyl; 5- to 7-membered heterocycloalkyl which may be substituted by (C 1~5 )alkyl or -OH; -CF3; (C 1~5 )alkoxy which may be substituted by aryl; aryl, wherein at least one H of said aryl may be independently substituted by halogen; heteroaryl which may be substituted by (C 1~5 )alkyl; thio(C 1~5 )alkyl; -COR 1a ; or NR 3 R 4 , and R 1a is (C 1~5 )alkoxy; -OH; 5- to 7-membered heterocycloalkyl which may be substituted by (C 1~5 )alkyl; or -NH2, and at least one H of -NH2 may be independently substituted by (C 1~5 )alkyl or (C 3~7 )cycloalkyl,

[0013] R 3 and R 4 are each independently H; halogen; (C 1~5 )alkyl which may be substituted by halogen, -CF3, -OH, (C 1~5 )alkoxy, -N-[(C 1~5 )alkyl][(C 1~5 )alkyl], aryl or (C3-7)cycloalkyl; (C 3~7 )cycloalkyl; (C 1~5 )alkoxy; aryl; or -C(=O)(C 1~5 )alkyl, and one or more W3 are each independently H; halogen; (C 1~5) Alkyl; (C 1~5 ) Alkoxy; -OH; -NO2; -NR 5 R 6 ; -CH=CR 7 R 8 ; -C≡C-R 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)-substituted 5- to 7-membered heterocycloalkyl; aryl; or heteroaryl, wherein at least one H of the aryl or the heteroaryl may be substituted by one or more R 10 ; and R 5 and R 6 are each independently H; (C 3~7 ) Cycloalkyl- or aryl-substituted (C 1~5 ) alkyl; (C 1~5 ) 5- to 7-membered heterocycloalkyl optionally substituted by (C 11 ) alkyl; aryl; -C(=O)R 12 ; or -S(=O)2R R 7 is (C 1~5 ) alkyl optionally substituted by -OH; aryl optionally substituted by halogen; or -C(=O)R 13 ; and R 8 is H; or (C 1~5 ) alkyl, R 9 is aryl optionally substituted by -NH2, one or more R 10 are each independently H; halogen; -CN; -CF3; -OH; -OCF3; (C 3~7 ) cycloalkyl, 5- to 7-membered heterocycloalkyl, or (C 1~5 ) alkyl optionally substituted by -OH; (C 1~5 ) alkoxy; one or more (C1~5 ) -NH₂ optionally substituted by alkyl or -C(=O)O(alkyl); (C 1~5 ) 5- to 7-membered heterocycloalkyl optionally substituted by alkyl; -C(=O)R 1~5 ) -S(=O)₂-(5- to 7-membered heterocycloalkyl); or aryl, where R 14 may be connected to each other to form a 5- to 6-membered ring, 10 and R is (C 11 ) alkyl optionally substituted by -N(CH₃)₂, aryl, or hydroxyaryl; (C 1~5 ) cycloalkyl which may contain C(=O); (C 3~7 ) cycloalkyl optionally substituted by alkyl; (C 1~5 ) cycloalkyl fused to aryl; (C 3~7 ) cycloalkyl optionally substituted by alkyl; (C 3~7 ) cycloalkenyl optionally substituted by alkyl; (C 1~5 ) 5- to 7-membered heterocycloalkyl optionally substituted by alkyl or -NH₂; aryl; or (C 5~6 ) heteroaryl optionally substituted by alkyl or -OH, 1~5 and R 1~5 is aryl which is (C ) alkyl or aryl, and at least one H of said aryl is each independently aryl optionally substituted by (C 12 ) alkyl or halogen, 1~5 and R 1~5 is (C ) alkyl; (C 13 ) alkoxy; -OH; -NH₂, where at least one H of -NH₂ is each independently (C 1~5 ) alkyl optionally substituted by alkyl or OH; -NH₂ optionally substituted by (C 1~5 ) alkyl; (C 1~5 ) cycloalkyl; hydroxy(C 1~5 ) alkyl; (C 3~7 ) alkoxy(C 1~5 ) alkyl, 1~5 ) alkoxy(C 1~5) is alkyl; -NH2, R 14 is 5- to 7-membered heterocycloalkyl; -NH2; or -OH, and provides a compound, its stereoisomer, its pharmaceutically acceptable salt, or its solvate.

[0014] According to another specific embodiment of the present invention, Y 3 is azetidinyl; pyrrolidinyl; piperidinyl; tetrahydropyridinyl; or oxopyrrolidinyl, and may be substituted by W 1 and W 2 and may be substituted, W1 and W2 are each independently H; halogen; -OH; (C 1~5 ) alkyl optionally substituted by -OH or -CN; methylpiperazinyl; morpholinyl; pyridinyl; methylpyrazolyl; -COR 1 ; -OR 2 ; -NH2; -NH(pyridinyl) or -NH(pyrimidinyl), R 1 is (C 1~5 ) alkoxy; -OH; -NH2; -NH-(C 3~7 ) cycloalkyl; oxopiperazinyl; morpholinyl; thiomorpholinyl; methylpiperazinyl; or tetrahydropyridinyl, R 2is pyridinyl; 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; methyl (thiophene)carboxylate; (thiophene)carboxylic acid; (thiophene)carboxamide; methyl (thiophene)carboxamide; cyclopropyl (thiophene)carboxamide; methylisoxazolyl; benzisoxazolyl; isothiazolyl; methylthiophenyl; 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; diaminotriazinyl; (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; (methylpiperazinyl)pyrimidinyl; (amino)(methylamino)pyrimidinyl; (amino)(pyrrolidinyl)pyrimidinyl; (methylamino)halopyrimidinyl; (ethylamino)halopyrimidinyl; (cyclopropylamino)halopyrimidinyl; (cyclohexylamino)halopyrimidinyl; (dimethylamino)halopyrimidinyl; (ethylmethylamino)halopyrimidinyl; (diethylamino)halopyrimidinyl; (methylphenylamino)halopyrimidinyl; (benzylmethylamino)halopyrimidinyl; (pyrrolidinyl)halopyrimidinyl; (piperidinyl)halopyrimidinyl; (morpholino)halopyrimidinyl; (thiomorpholino)halopyrimidinyl; (methylpiperazinyl)halopyrimidinyl; (cyclopropylamino)methylpyrimidinyl; (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; dihydropyranyl pyrimidinyl; or pyridinylpyrimidinyl, which may be substituted by C; 1~5 is alkyl, which may be provided.

[0015] According to another specific embodiment of the present invention, the compound represented by the above formula (I) is the following formula ( Ib):

[0016]

Chemical formula

[0017] In formula (Ib), X is -CH2-; or -C(=O)-, V 1 、V 2 、V 3 and V 4 are each independently CH or N, and when not all of V 1 、V 2 、V 3 and V 4 are N, one or more H of V 1 、V 2 、V 3 and V 4 may each independently be substituted by W 3 , one or more W 3 are each independently H; halogen; (C 1~5 )alkyl; (C 1~5 )alkoxy; -OH; -NO2; -NR5 R 6 ;-CH=CR 7 R 8 ;-C≡C-R 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)-substituted 5- to 7-membered heterocycloalkyl; aryl; or heteroaryl, wherein said aryl or said heteroaryl may be substituted by one or more R 10 and R 5 and R 6 are each independently H; (C 3~7 ) cycloalkyl- or aryl-substituted (C 1~5 ) alkyl; 5- to 7-membered heterocycloalkyl substituted by (C 1~5 ) alkyl; aryl; -C(=O)R 11 ; or -S(=O)2R 12 and R 7 is (C 1~5 ) alkyl optionally substituted by -OH; aryl optionally substituted by halogen; or -C(=O)R 13 and R 8 is H; or (C 1~5 ) alkyl and R 9 is aryl optionally substituted by -NH2 and one or more R 10 are each independently H; halogen; -CN; -CF3; -OH; -OCF3; (C 3~7 ) cycloalkyl, 5- to 7-membered heterocycloalkyl, or (C 1~5 ) alkyl optionally substituted by -OH; (C 1~5 ) alkoxy; one or more (C 1~5 ) alkyl or -C(=O)O(C 1~5) -NH2 optionally substituted by alkyl; (C 1~5 ) 5- to 7-membered heterocycloalkyl optionally substituted by alkyl; -C(=O)R 14 ; -S(=O)2-(5- to 7-membered heterocycloalkyl); or aryl, and R 10 may be connected to each other to form a 5- to 6-membered ring, R 11 is optionally substituted by -N(CH3)2, aryl, or hydroxyaryl, (C 1~5 ) alkyl; cycloalkyl optionally containing C(=O); (C 3~7 ) cycloalkyl optionally substituted by alkyl; cycloalkyl fused to aryl; (C 1~5 ) cycloalkenyl optionally substituted by alkyl; 5- to 7-membered heterocycloalkyl optionally substituted by alkyl or -NH2; aryl; or (C 3~7 ) heteroaryl optionally substituted by alkyl or -OH, 3~7 (C 1~5 ) cycloalkyl; (C 5~6 ) cycloalkenyl; (C 1~5 ) 5- to 7-membered heterocycloalkyl optionally substituted by alkyl or -NH2; aryl; or (C 1~5 ) heteroaryl optionally substituted by alkyl or -OH, R 12 is (C 1~5 ) alkyl or aryl, wherein at least one H of said aryl is each independently aryl optionally substituted by (C 1~5 ) alkyl or halogen, R 13 is (C 1~5 ) alkyl; (C 1~5 ) alkoxy; -OH; -NH2, wherein at least one H of -NH2 is optionally substituted by (C 1~5 ) alkyl substituted by alkyl or OH; (C 1~5 ) cycloalkyl; hydroxy(C 3~7 ) alkyl; (C 1~5 ) alkoxy(C 1~5 ) alkyl; -NH2, 1~5 and R R 14is a 5- to 7-membered heterocycloalkyl; -NH2; or -OH, L 1 , L 2 , M, and G are as defined in formula (I).

[0018] According to another specific embodiment of the present invention, W 3 is independently H; halogen; (C 1~5 )alkyl; (C 1~5 )alkoxy; -OH; -NO2; -NR 5 R 6 ; -CH=CR 7 R 8 ; -C≡C-R 9 ; (C 5~6Cycloalkenyl; morpholinyl; tetrahydropyridinyl; dihydropyranyl; (tetrahydropyridine)carboxylic acid tert-butyl; (dihydropyridine)carboxylic acid tert-butyl; dihydrothiopyranyl; methyltetrahydropyridinyl; (methylsulfonyl)tetrahydropyridinyl; acetyltetrahydropyridinyl; (tetrahydropyridine)carboxamide; 1,1-dioxide-dihydrothiopyranyl; phenyl; (trifluoromethoxy)phenyl; aminophenyl; tert-butyl(phenyl)carbamate; (pyrrolidinylsulfonyl)phenyl; oxopiperidine(carbonyl)phenyl; methylpiperazinyl; (methylpiperazinyl)phenyl; isoindolyl; cyanophenyl; cyanohalophenyl; (trifluoromethyl)phenyl; (dimethylamino)phenyl; hydroxybenzyl; methoxyphenyl; biphenyl; methylphenyl; hydroxyphenyl; dihydroindenyl; benzoic acid; methyl benzoate; 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; (pyrrole)carboxylic acid tert-butyl; dimethylisoxazolyl; isoquinolinyl; methylindazolyl; methylthiophenyl; indazolyl; thiophenyl; cyanopyridinyl; (hydroxymethyl)pyridinyl; picolinamide; (dimethylamino)pyridinyl; dimethylpyridinyl; or (methylamino)pyridinyl, and R 5 and R 6 each independently is H; (C 3~7 )alkyl optionally substituted by cycloalkyl or phenyl; (C 1~5 )alkyl; (C 1~5Morpholinyl or piperazinyl, which may be substituted by alkyl; phenyl; -C(=O)R 11 ; or -S(=O)2R 12 wherein R 7 is methyl which may be substituted by -OH; phenyl which may be substituted by halogen; or -C(=O)R 13 wherein R 9 is phenyl which may be substituted by -NH2, R 11 is (C 1~5 )alkyl which may be substituted by -N(CH3)2, phenyl, or hydroxyphenyl; (C 3~7 )cycloalkyl which may contain C(=O); (C )cycloalkyl which may be substituted by (C 1~5 )alkyl; (C 3~7 )cycloalkyl which is condensed with phenyl; (C 3~7 )cycloalkenyl which may be substituted by (C 1~5 )alkyl; morpholinyl; methylpiperidinyl; oxopyrrolidinyl; oxoimidazolidinyl; pyrrolidinyl; piperidinyl; tetrahydrofuranyl; tetrahydropyranyl; methyltetrahydropyranyl; aminopyrrolidinyl; methylpyrrolidinyl; phenyl; pyridinyl; oxazolyl; pyridazinyl; methylisoxazolyl; methyloxazolyl; isoxazolyl; methylpyridinyl; furanyl; or hydroxypyrimidinyl, and R 12 is (C 1~5 )alkyl; phenyl; methylphenyl; or (methyl)halophenyl, and 14 R is oxopiperidinyl; -NH2; or -OH,

[0019] Throughout this specification, when defining compounds of formula (I) and formula (Ib), the concepts defined below are used. Unless otherwise indicated, the following definitions also apply to the terms used either individually or as part of a larger group throughout this specification.

[0020] The term "alkyl" means a straight-chain, branched-chain, or cyclic hydrocarbon radical, each carbon atom of which may optionally be substituted by at least one of, but not limited to, cyano, hydroxy, alkoxy, oxo, halogen, carbonyl, sulfonyl, cyanilyl, and the like.

[0021] The term "cycloalkyl" means a saturated monocyclic hydrocarbon ring, which may optionally be fused to an aryl. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclohexyl, and the like.

[0022] The term "cycloalkenyl" means an unsaturated carbocyclic moiety such as cyclopentenyl, cyclohexenyl, cycloheptenyl, and others. Cycloalkenyl may contain one double bond of two carbons forming the ring. The cycloalkenyl moiety may be attached spirocyclically, such as spirocyclopropyl.

[0023] The term "alkoxy" represents -O-alkyl where alkyl is as defined above. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, 2-butoxy, n-pentoxy, t-butoxy, and the like.

[0024] The term "n-membered ring" means an n-membered saturated or unsaturated carbon ring, where one or more carbon atoms may optionally be substituted by heteroatoms (N, O, S, etc.), and this n-membered saturated or unsaturated carbon ring may contain one or more C(=O) (n can be 4 to 6). Examples include, but are not limited to, pyrrolidine, 1H-pyrrole-2,5-dione, 1,5-dihydro-2H-pyrrol-2-one, and the like.

[0025] The term "heterocycloalkyl" means a form containing 1 to 4 heteroatoms selected from N, O, and S; "heterocycloalkyl" is saturated or partially saturated (partially unsaturated) or aromatic; "heterocycloalkyl" may optionally contain one or more -C(=O- or -S(=O)2-. Suitable heterocycloalkyls include, for example, azetidinyl; pyrrolidinyl; piperidinyl; tetrahydropyridinyl; oxopyrrolidinyl; oxopiperazinyl; morpholinyl; thiomorpholinyl; piperazinyl; dihydropyranyl; dihydrothiopyranyl; 1,1-dihydrothiopyran-1,1-dioxide; isoindolyl; pyridinyl; pyrazolyl; pyrimidinyl; pyrrolyl; isoquinolin yl; indazolyl; thiophenyl; oxoimidazolidinyl; tetrahydrofuranyl; tetrahydropyranyl; oxazolyl; pyridazinyl; isoxazolyl; oxopiperidinyl and the like, but are not limited thereto.

[0026] The term "halo(ogen)" means a substituent selected from fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0027] The term "aryl" means an aromatic group including, but not limited to, phenyl, naphthyl, and others; it is optionally condensed with cycloalkyl such as dihydroindenyl and others.

[0028] The term "heteroaryl" refers to a 5- to 7-membered aromatic monocyclic ring containing at least one heteroatom, for example, 1 to 4 heteroatoms, or in some exemplary embodiments, 1 to 3 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; an 8- to 12-membered bicyclic ring containing at least one heteroatom, for example, 1 to 4 heteroatoms or in some exemplary embodiments, 1 to 3 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and at least one ring being aromatic; examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzimidazolyl, indolyl, indolinyl, pyrrolyl, thiophenyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, pyrrolopyridinyl, pyrazolopyridinyl, benzoxazolyl, benzothiazolyl, indazolyl, and 5,6,7,8-tetrahydroisoquinoline, and the like.

[0029] As used herein, the term "amino" represents the group -NH2.

[0030] Other terms and abbreviations used herein have their original meanings unless otherwise defined.

[0031] In the present invention, representative examples of the compounds represented by the above formula 1 are as follows.

[0032]

Table 1-1

[0033]

Table 1-2

[0034]

Table 1-3

[0035]

Table 1-4

[0036]

Table 1-5

[0037]

Table 1-6

[0038]

Table 1-7

[0039]

Table 1-8

[0040]

Table 1-9

[0041]

Table 1-10

[0042]

Table 1-11

[0043]

Table 1-12

[0044]

Table 1-13

[0045]

Table 1-14

[0046]

Table 1-15

[0047]

Table 1-16

[0048]

Table 1-17

[0049]

Table 1-18

[0050]

Table 1-19

[0051]

Table 1-20

[0052]

Table 1-21

[0053]

Table 1-22

[0054]

Table 1-23

[0055]

Table 1-24

[0056]

Table 1-25

[0057]

Table 1-26

[0058]

Table 1-27

[0059]

Table 1-28

[0060]

Table 1-29

[0061]

Table 1-30

[0062]

Table 1-31

[0063]

Table 1-32

[0064]

Table 1-33

[0065]

Table 1-34

[0066]

Table 1-35

[0067]

Table 1-36

[0068]

Table 1-37

[0069]

Table 1-38

[0070]

Table 1-39

[0071]

Table 1-40

[0072]

Table 1-41

[0073]

Table 1-42

[0074]

Table 1-43

[0075]

Table 1-44

[0076]

Table 1-45

[0077]

Table 1-46

[0078]

Table 1-47

[0079] Method for preparing GCN2 inhibitor compounds Hereinafter, the method for preparing the compound represented by formula (I) or formula (Ib) will be described based on exemplary reaction schemes for better understanding of the present invention. However, the compound represented by formula (I) or formula (Ib) may be prepared by various methods based on the structures of formula (I) and formula (Ib), and all such methods should be interpreted by those skilled in the art to which the present invention pertains as being included within the scope of the present invention. In other words, the compounds according to the present invention may be prepared by arbitrarily combining various synthetic methods described herein or disclosed in the prior art, which should be understood to be within the scope of the present invention. In the following reaction schemes, all substituents are the same as the above definitions unless otherwise indicated.

[0080] The synthetic method for the compound of formula (I) according to the present invention can be shown as an example such as the following Reaction Scheme 1:

[0081]

Chemical formula

[0082] Wherein, G, M, L1, L2, Y1, Z, Y3, W1 and R2 are as defined in formula (I); LG is -Cl or -OH.

[0083] In the above Reaction Scheme 1, the intermediate compound Y3 may be synthesized by the methods of the following Reaction Schemes 1-1, 1-2, or 1-3:

[0084]

Chemical formula

[0085]

Chemical formula

[0086]

Chemical formula

[0087] In the formula, Nu is -NH- or -O-; A is azetidinyl, pyrrolidinyl, piperidinyl or oxopyrrolidinyl; A' is tetrahydropyridinyl; A'' is piperidinyl; B is pyridinyl or methylpyrazolyl; B' is methylpiperazinyl or morpholinyl.

[0088] The synthesis method for the compound of the above formula (Ib) according to the present invention can be shown as examples such as the following Reaction Scheme 2:

[0089]

Chemical formula

[0090] In the formula, G, M, L1, L2, V1, V2, V3, V4, W3 and X are as defined in formula (Ib).

[0091] In the above Reaction Scheme 2, the intermediate compound

Chemical formula

[0092]

Chem.

[0093] It may be and may be synthesized by the method of the following Reaction Formula 2-1 or 2-2:

[0094]

Chem.

Chem.

[0095] In the formula, W3’ is -NR5’R6’; -CH=CR7’R8’; -C≡C-R9’; (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, and the aryl or heteroaryl may be substituted by one or more R 10 ’, W 3 ’’ is -C(=O)R 11 ’; or -S(=O)2R 12 ’, R 5 ’ and R 6 ’ are each independently H; (C 3~7 ) cycloalkyl or aryl -substituted (C 1~5 ) alkyl; 5- to 7-membered heterocycloalkyl optionally substituted by (C 1~5 ) alkyl or aryl, R 7 ’ is (C 1~5 ) alkyl optionally substituted by -OH; aryl optionally substituted by halogen; or -C(=O)R13 is " R 8 ' is H; or (C 1~5 )alkyl, R 9 ' is aryl which may be substituted by -NH2, One or more R 10 ' are each independently H; halogen; -CN; -CF3; -OH; -OCF3; (C 3~7 )cycloalkyl, 5- to 7-membered heterocycloalkyl, or (C 1~5 )alkyl which may be substituted by -OH; (C 1~5 )alkoxy; -NH2 which may be substituted by one or more (C 1~5 )alkyl or -C(=O)O(C 1-5 )alkyl; 5- to 7-membered heterocycloalkyl which may be substituted by (C 1~5 )alkyl; -C(=O)R 14 ; -S(=O)2-(5- to 7-membered heterocycloalkyl); or aryl, and R 10 may be connected to each other to form a 5- to 6-membered ring, R 11 ' is (C 1~5 )alkyl which may be substituted by -N(CH3)2, aryl, or hydroxyaryl; (C 3~7 )cycloalkyl which may contain C(=O); (C 1~5 )cycloalkyl which may be substituted by (C 3~7 )alkyl; (C 3~7 )cycloalkyl fused to aryl; (C 1~5 )cycloalkenyl which may be substituted by (C 5~6 )alkyl; 5- to 7-membered heterocycloalkyl which may be substituted by (C 1~5 )alkyl or -NH2; aryl; or (C 1~5 )heteroaryl which may be substituted by (C R 12 ' is (C 1~5 )alkyl; or (C 1~5aryl optionally substituted by alkyl and / or halogen, R 13 ’ is (C 1~5 )alkyl; (C 1~5 )alkoxy; -OH; -NH2 in which at least one H is substituted by (C 1~5 )alkyl or OH-substituted (C 1~5 )alkyl-substituted -NH2; (C 3~7 )cycloalkyl; hydroxy(C 1~5 )alkyl; (C 1~5 )alkoxy(C 1~5 )alkyl; -NH2, R 14’ is 5- to 7-membered heterocycloalkyl; -NH2; or -OH.

[0096] The compounds of formula (I) and formula (Ib) according to the present invention may be separated or purified from the products of Schemes 1 and 2 above by several methods such as crystallization, silica gel column chromatography, and others. In this method, the compounds according to the present invention for preparing this, as well as starting materials, intermediates, and others, may be synthesized by various methods, and such methods should be understood to be included within the scope of the present invention with respect to the preparation of the compounds of formula (I) and formula (Ib).

[0097] Compositions containing GCN2 inhibitor compounds, and their use The present invention provides a pharmaceutical composition and use for the treatment or prevention of GCN2 activation-related diseases, a composition containing a compound represented by the following formula (I), its stereoisomers, its pharmaceutically acceptable salts or its solvates as an active ingredient.

[0098]

Chemical formula

[0099] Said formula (I) is the same as the above definition.

[0100] The compound represented by the above formula (I) may be a compound represented by the following formula (Ib).

[0101]

Chemical formula

[0102] Formula (Ib) is the same as the above definition.

[0103] The compound of formula (I) or formula (Ib), its stereoisomer, its pharmaceutically acceptable salt or its solvate exhibits GCN2 inhibitory activity and thus has a remarkable effect on the prevention or treatment of GCN2 activation-related diseases. Therefore, a remarkable effect on the prevention or treatment of GCN2 activation-related diseases is achieved.

[0104] In the present invention, the GCN2 activation-related disease means a disease related to enhanced activity of GCN2, including metabolic diseases such as cancer, neurodegenerative diseases, chronic infections, and fatty liver, and cancer includes thyroid cancer, melanoma, prostate cancer, endometrial cancer, lung cancer, head and neck cancer, pancreatic cancer, glioma, gastric cancer, urothelial cancer, skin cancer, breast cancer, colorectal cancer, rectal cancer, fibrosarcoma, osteosarcoma, connective tissue sarcoma, giant cell cancer, squamous cell cancer, leukemia, skin cancer, soft tissue cancer, liver cancer, adenocarcinoma, hepatocellular carcinoma, multiple myeloma, myelodysplastic syndrome, myeloproliferative tumor, malignant glioma, non-Hodgkin lymphoma, Hodgkin lymphoma, Burkitt lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocyte leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia, small cell lung cancer and pediatric neuroblastoma or symptoms related thereto.

[0105] In the present invention, pharmaceutically acceptable salts mean salts conventionally used in the pharmaceutical industry, for example, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, 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, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid or other compounds that can be used as acids, and the like.

[0106] For its administration, the pharmaceutical composition of the present invention may further contain at least one type of the compound represented by formula (I) or formula (Ib), its stereoisomers, its pharmaceutically acceptable salts or its solvates, and may be used together with the addition of other conventional additives such as antioxidants, buffer solutions, bacteriostatic agents, and the like, if necessary. Further, such a pharmaceutical composition may be formulated in a manner such as additionally adding a diluent, a dispersant, a surfactant, a binder, and a lubricant thereto.

[0107] The composition of the present invention may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically applied) according to the intended method, and the dosage thereof varies within a range depending on the patient's weight, age, gender, health status and diet, number of administrations, administration method, excretion rate, severity of the disease and the like. The daily dosage of the compound represented by formula (I) or formula (Ib) is about 0.001 to 1000 mg / kg, and it may be administered once a day or divided into multiple times a day.

[0108] In addition to the compound represented by formula (I) or formula (Ib), its stereoisomers, its pharmaceutically acceptable salts or its solvates, the pharmaceutical composition of the present invention may further contain at least one therapeutic agent as an active ingredient showing the same or similar medicinal effects. The therapeutic agent may be selected from the group consisting of chemotherapeutic agents, radiotherapeutic agents, immunotherapeutic agents and tumor microenvironment regulating agents.

[0109] According to the present invention, the compound represented by formula (I) or formula (Ib), its stereoisomers, its pharmaceutically acceptable salts or its solvates exhibit GCN2 inhibitory activity, and thus achieve a remarkable effect in the prevention or treatment of GCN2 activation-related diseases.

[0110] According to one specific embodiment of the present invention, the present invention provides a method for preventing or treating a GCN2 activation-related disease, which comprises administering to a subject a therapeutically effective amount of the compound represented by formula (I) or formula (Ib), its stereoisomers, its pharmaceutically acceptable salts or its solvates. The method for preventing or treating a GCN2 activation-related disease according to the present invention not only addresses cancer itself before the onset of these symptoms, but also includes inhibiting or avoiding such symptoms by administering the compound represented by formula (I) or formula (Ib), its stereoisomers, its pharmaceutically acceptable salts or its solvates.

[0111] According to one particular embodiment of the present invention, the present invention provides the use of a compound represented by formula (I) or formula (Ib), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof in the preparation of a medicament for the treatment of GCN2 activation-related diseases. For the preparation of a medicament, the compound represented by formula (I) or formula (Ib), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof may be formulated with acceptable adjuvants, diluents, carriers and the like, and may be formulated into a combined preparation together with other active drugs (therapeutic agents), and thus has a synergistic effect of the active ingredients.

[0112] According to one particular embodiment of the present invention, the present invention also provides a method for inhibiting GCN2 activity, said method comprising administering to a subject a therapeutically effective amount of the compound represented by formula (I) or formula (Ib), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

[0113] As used herein, "subject" means a mammal including a human, and "administering" means providing a predetermined substance to a patient by any suitable method.

[0114] As used herein, the term "therapeutically effective amount" refers to an amount of a compound represented by formula (I) or formula (Ib), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof that is effective in the prevention or treatment of GCN2 activation-related diseases.

[0115] (1) The present invention provides a compound represented by the following formula (I):

[0116]

Chemical formula

[0117] a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein in the above formula (I), L 1 and L 2 are each independently H; (C optionally substituted by a 4- to 6-membered heterocycloalkyl1~5 ) is alkyl; or L 1 and L 2 are connected to form a 5- to 6-membered ring, M is H; halogen; (C 1~5 )alkyl; (C 3~7 )cycloalkyl; or (C 1~5 )alkoxy, G is H; halogen; (C 1~5 )alkyl; (C 1~5 )alkoxy; or -NH2, and at least one H of -NH2 may be substituted by (C 1~5 )alkyl, Y 1 is H; or (C 1~5 )alkyl, Z is -C(=O)-; or -CH2- which may be substituted by one or more (C 1~5 )alkyl; or Z is connected to Y 1 to form a 5- to 6-membered ring, Y 3 is a 4- to 6-membered heterocycloalkyl in which at least one H is each independently substituted by W 1 or W 2 ; or when Z is connected to Y 1 to form a 5- to 6-membered ring, Y 3 is connected to Z to form aryl or heteroaryl, and at least one H of the aryl and heteroaryl formed by Y3 and Z may be independently substituted by W3, W1 and W2 are each independently H; halogen; -OH; (C 1~5 )alkyl which may be substituted by -OH, -NH2 or -CN; 5- to 7-membered heterocycloalkyl which may be substituted by (C 1~5 )alkyl; heteroaryl which may be substituted by (C 1~5 )alkyl; -COR 1 ;-OR 2 ; or -NH2, and at least one H of -NH2 may be independently substituted by heteroaryl, R 1 is (C 1~5 ) alkoxy; -OH; 5- to 7-membered heterocycloalkyl optionally substituted by (C 1~5 ) alkyl; or -NH2, and at least one H of -NH2 is each independently optionally substituted by (C 3~7 ) cycloalkyl, R 2 is alkyl optionally substituted by heteroaryl; aryl; or heteroaryl, and at least one H of the aryl or heteroaryl is each independently optionally substituted by one or more R 1~5 , 2a one or more R are each independently halogen; alkyl optionally substituted by aryl, or 5- to 7-membered heterocycloalkyl optionally substituted by (C 2a ) alkyl; (C 1~5 ) cycloalkenyl optionally substituted by (C 1~5 ) alkyl; 5- to 7-membered heterocycloalkyl optionally substituted by (C 1~5 ) alkyl or -OH; -CF3; alkoxy optionally substituted by aryl; aryl wherein at least one H of the aryl is each independently optionally substituted by halogen; heteroaryl optionally substituted by (C 5~6 ) alkyl; thio (C 1~5 ) alkyl; -COR 1~5 ; or NR 1~5 R 1~5 1a 3 ; or NR 3 R 4 1a R 1a is (C 1~5 ) alkoxy; -OH; 5- to 7-membered heterocycloalkyl optionally substituted by (C 1~5 ) alkyl; or -NH2, and at least one H of -NH2 is each independently optionally substituted by (C 1~5 ) alkyl or (C 3~7 ) cycloalkyl,

[0118] R 3 and R 4 each independently is H; halogen; halogen, -CF3, -OH, (C 1~5 )alkoxy, -N-[(C 1~5 )alkyl][(C 1~5 )alkyl], aryl or (C3-7)cycloalkyl optionally 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 is H; halogen; (C 1~5 )alkyl; (C 1~5 )alkoxy; -OH; -NO2; -NR 5 R 6 ; -CH=CR 7 R 8 ; -C≡C-R 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) optionally substituted 5- to 7-membered heterocycloalkyl ; aryl; or heteroaryl, at least one H of said aryl or said heteroaryl may be substituted by one or more R 10 , R 5 and R 6 each independently is H; (C 3~7 )cycloalkyl or aryl optionally substituted (C 1~5 )alkyl; 5- to 7-membered heterocycloalkyl optionally substituted by (C 1~5 )alkyl; aryl; -C(=O)R 11 ; or -S(=O)2R 12 , R 7 is (C optionally substituted by -OH1~5 ) alkyl; aryl optionally substituted by halogen; or -C(=O)R 13 wherein R 8 is H; or (C 1~5 ) alkyl, R 9 is aryl optionally substituted by -NH2, one or more Rs 10 are each independently H; halogen; -CN; -CF3; -OH; -OCF3; (C 3~7 ) cycloalkyl, 5- to 7-membered heterocycloalkyl, or (C 1~5 ) alkyl optionally substituted by -OH; (C 1~5 ) alkoxy; -NH2 optionally substituted by one or more (C 1~5 ) alkyl or -C(=O)O(C 1-5 ) alkyl; 5- to 7-membered heterocycloalkyl optionally substituted by (C 1~5 ) alkyl; -C(=O)R 14 ; -S(=O)2-(5- to 7-membered heterocycloalkyl); or aryl, and Rs 10 may be connected to each other to form a 5- to 6-membered ring, R 11 is (C 1~5 ) alkyl optionally substituted by -N(CH3)2, aryl, or hydroxyaryl; (C 3~7 ) cycloalkyl optionally containing C(=O); (C 1~5 ) cycloalkyl optionally substituted by (C 3~7 ) alkyl; (C 3~7 ) cycloalkyl fused to aryl; (C 1~5 ) cycloalkenyl optionally substituted by (C 5~6 ) alkyl; 5- to 7-membered heterocycloalkyl optionally substituted by (C 1~5 ) alkyl or -NH2; aryl; or (C 1~5 ) heteroaryl optionally substituted by (C R 12 is (C 1~5Alkyl or aryl, wherein at least one H of said aryl is each independently (C 1~5 ) aryl which may be substituted by alkyl or halogen, R 13 is (C 1~5 ) alkyl; (C 1~5 ) alkoxy; -OH; -NH2, wherein at least one H of -NH2 is each independently (C 1~5 ) alkyl substituted by alkyl or OH (C 1~5 ) -NH2 which may be substituted by alkyl; (C 3~7 ) cycloalkyl; hydroxy (C 1~5 ) alkyl; (C 1~5 ) alkoxy (C 1~5 ) alkyl; -NH2, R 14 is 5- to 7-membered heterocycloalkyl; -NH2; or -OH, There is provided a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

[0119] (2) The compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof according to (1), wherein in the formula (I): Y 3 is azetidinyl; pyrrolidinyl; piperidinyl; tetrahydropyridinyl; or oxopyrrolidinyl, and may be substituted by W 1 and W 2 ; W1 and W2 are each independently H; halogen; -OH; (C 1~5 ) alkyl which may be substituted by -OH or -CN; methylpiperazinyl; morpholinyl; pyridinyl; methylpyrazolyl; -COR 1 ; -OR 2 ; -NH2; -NH(pyridinyl) or -NH(pyrimidinyl), R 1 is (C 1~5 ) alkoxy; -OH; -NH2; -NH-(C 3~7) is cycloalkyl; oxopiperazinyl; morpholinyl; thiomorpholinyl; methylpiperazinyl; or tetrahydropyridinyl, R 2is pyridinyl; 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; methyl (thiophene)carboxylate; (thiophene)carboxylic acid; (thiophene)carboxamide; methyl (thiophene)carboxamide; cyclopropyl (thiophene)carboxamide; methylisoxazolyl; benzisoxazolyl; isothiazolyl; methylthiophenyl; 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; diaminotriazinyl; (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; (methylpiperazinyl)pyrimidinyl; (amino)(methylamino)pyrimidinyl; (amino)(pyrrolidinyl)pyrimidinyl; (methylamino)halopyrimidinyl; (ethylamino)halopyrimidinyl; (cyclopropylamino)halopyrimidinyl; (cyclohexylamino)halopyrimidinyl; (dimethylamino)halopyrimidinyl; (ethylmethylamino)halopyrimidinyl; (diethylamino)halopyrimidinyl; (methylphenylamino)halopyrimidinyl; (benzylmethylamino)halopyrimidinyl; (pyrrolidinyl)halopyrimidinyl; (piperidinyl)halopyrimidinyl; (morpholino)halopyrimidinyl; (thiomorpholino)halopyrimidinyl; (methylpiperazinyl)halopyrimidinyl; (cyclopropylamino)methylpyrimidinyl; (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; dihydropyranyl pyrimidinyl; or pyridinylpyrimidinyl, which may be substituted by C; 1~5 is an alkyl compound, its stereoisomers, its pharmaceutically acceptable salts, or its solvates.

[0120] (3) The compound represented by the above formula (I) is the following formula (Ib):

[0121]

Chemical formula

[0122] In formula (Ib), X is -CH2-; or -C(=O)-, V 1 V 2 V 3 and V 4 are each independently CH or N, and when not all of V 1 V 2 V 3 and V 4 are N, one or more H of V 1 V 2 V 3 and V 4 may each independently be substituted by W 3 and one or more W 3 are each independently H; halogen; (C 1~5) alkyl; (C 1~5 ) alkoxy; -OH; -NO2; -NR 5 R 6 ; -CH=CR 7 R 8 ; -C≡C-R 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)-substituted 5- to 7-membered heterocycloalkyl; aryl; or heteroaryl, wherein the aryl or the heteroaryl may be substituted by one or more R 10 ; provided that R 5 and R 6 are each independently H; (C 3~7 ) cycloalkyl- or aryl-substituted (C 1~5 ) alkyl; (C 1~5 ) 5- to 7-membered heterocycloalkyl optionally substituted by (C 11 ) alkyl; aryl; -C(=O)R 12 ; or -S(=O)2R R 7 is (C 1~5 ) alkyl optionally substituted by -OH; aryl optionally substituted by halogen; or -C(=O)R 13 ; provided that R 8 is H; or (C 1~5 ) alkyl, provided that R 9 is aryl optionally substituted by -NH2, provided that one or more R 10 are each independently H; halogen; -CN; -CF3; -OH; -OC F3; (C 3~7 ) cycloalkyl, 5- to 7-membered heterocycloalkyl, or (C 1~5 ) alkyl optionally substituted by -OH; (C 1~5)alkoxy; one or more (C 1~5 )alkyl or -C(=O)O(C 1-5 )alkyl which may be substituted with -NH2; (C 1~5 )5- to 7-membered heterocycloalkyl which may be substituted with (C 14 )alkyl; -C(=O)R 10 ; -S(=O)2-(5- to 7-membered heterocycloalkyl); or aryl, and R R 11 may be (C 1~5 )alkyl which may be substituted with -N(CH3)2, aryl, or hydroxyaryl; (C 3~7 )cycloalkyl which may contain C(=O); (C 1~5 )cycloalkyl which may be substituted with (C 3~7 )alkyl; (C 3~7 )cycloalkyl which is fused to aryl; (C 1~5 )cycloalkyl which may be substituted with (C 5~6 )alkyl; (C 1~5 )5- to 7-membered heterocycloalkyl which may be substituted with (C 1~5 )alkyl or -NH2; aryl; or (C R 12 is (C 1~5 )alkyl or aryl, wherein at least one H of said aryl is each independently (C 1~5 )aryl which may be substituted with alkyl or halogen, R 13 is (C 1~5 )alkyl; (C 1~5 )alkoxy; -OH; -NH2, wherein at least one H of which is (C 1~5 )alkyl which may be substituted with alkyl or OH; (C 1~5 )alkyl which may be substituted with -NH2; (C 3~7 )cycloalkyl; hydroxy(C 1~5 )alkyl; (C 1~5 )alkoxy(C 1~5) is alkyl; -NH2, R 14 is 5- to 7-membered heterocycloalkyl; -NH2; or -OH, L 1 L 2 M, and G are as defined in (1) or (2).

[0123] (4) A compound according to (1), (2) or (3), its stereoisomers, its pharmaceutically acceptable salts, or its solvates: W 3 is independently H; halogen; (C 1-5 )alkyl; (C 1-5 )alkoxy; -OH; -NO2; -NR 5 R 6 ; -CH=CR 7 R 8 ; -C≡C-R 9 ; (C 5-6Cycloalkenyl; morpholinyl; tetrahydropyridinyl; dihydropyranyl; (tetrahydropyridine)carboxylic acid tert-butyl; (dihydropyridine)carboxylic acid tert-butyl; dihydrothiopyranyl; methyltetrahydropyridinyl; (methylsulfonyl)tetrahydropyridinyl; acetyltetrahydropyridinyl; (tetrahydropyridine)carboxamide; 1,1-dioxide-dihydrothiopyranyl; phenyl; (trifluoromethoxy)phenyl; aminophenyl; tert-butyl(phenyl)carbamate; (pyrrolidinylsulfonyl)phenyl; oxopiperidine(carbonyl)phenyl; methylpiperazinyl; (methylpiperazinyl)phenyl; isoindolyl; cyanophenyl; cyanohalophenyl; (trifluoromethyl)phenyl; (dimethylamino)phenyl; hydroxybenzyl; methoxyphenyl; biphenyl; methylphenyl; hydroxyphenyl; dihydroindenyl; benzoic acid; methyl benzoate; 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; (pyrrole)carboxylic acid tert-butyl; dimethylisoxazolyl; isoquinolinyl; methylindazolyl; methylthiophenyl; indazolyl; thiophenyl; cyanopyridinyl; (hydroxymethyl)pyridinyl; picolinamide; (dimethylamino)pyridinyl; dimethylpyridinyl; or (methylamino)pyridinyl, R 5 and R 6 each independently is H; (C 3~7 )alkyl which may be substituted by cycloalkyl or phenyl; (C 1~5 )alkyl; (C 1~5Morpholinyl or piperazinyl optionally substituted by alkyl; phenyl; -C(=O)R 11 ; or -S(=O)2R 12 wherein, R 7 is methyl optionally substituted by -OH; phenyl optionally substituted by halogen; or -C(=O)R 13 wherein, R 9 is phenyl optionally substituted by -NH2, R 11 is (C 1~5 )alkyl optionally substituted by -N(CH3)2, phenyl, or hydroxyphenyl; (C 3~7 )cycloalkyl optionally containing C(=O); (C 1~5 )cycloalkyl optionally substituted by (C 3~7 )alkyl; (C 3~7 )cycloalkyl fused to phenyl; (C 1~5 )cycloalkenyl optionally substituted by (C 5-6 )alkyl; morpholinyl; methylpiperidinyl; oxopyrrolidinyl; oxoimidazolidinyl; pyrrolidinyl; piperidinyl; tetrahydrofuranyl; tetrahydropyranyl; methyltetrahydropyranyl; aminopyrrolidinyl; methylpyrrolidinyl; phenyl; pyridinyl; oxazolyl; pyridazinyl; methylisoxazolyl; methyloxazolyl; isoxazolyl; methylpyridinyl; furanyl; or hydroxypyrimidinyl, R 12 is (C 1~5 )alkyl; phenyl; methylphenyl; or (methyl)halophenyl, R 14 is oxopiperidinyl; -NH2; or -OH, and halo and halogen are each independently F, Cl, Br or I.

[0124] (5) The compound is one selected from the group consisting of the compounds described in (1), (2), (3) or (4), its stereoisomers, its pharmaceutically acceptable salts, or its solvates.

[0125]

Table 2-1

[0126]

Table 2-2

[0127]

Table 2-3

[0128]

Table 2-4

[0129]

Table 2-5

[0130]

Table 2-6

[0131]

Table 2-7

[0132]

Table 2-8

[0133]

Table 2-9

[0134]

Table 2-10

[0135]

Table 2-11

[0136]

Table 2-12

[0137]

Table 2-13

[0138]

Table 2-14

[0139]

Table 2-15

[0140]

Table 2-16

[0141]

Table 2-17

[0142]

Table 2-18

[0143]

Table 2-19

[0144]

Table 2-20

[0145]

Table 2-21

[0146]

Table 2-22

[0147]

Table 2-23

[0148]

Table 2-24

[0149]

Table 2-25

[0150]

Table 2-26

[0151]

Table 2-27

[0152]

Table 2-28

[0153]

Table 2-29

[0154]

Table 2-30

[0155]

Table 2-31

[0156]

Table 2-32

[0157]

Table 2-33

[0158]

Table 2-34

[0159]

Table 2-35

[0160]

Table 2-36

[0161]

Table 2-37

[0162]

Table 2-38

[0163]

Table 2-39

[0164]

Table 2-40

[0165]

Table 2-41

[0166]

Table 2-42

[0167]

Table 2-43

[0168]

Table 2-44

[0169]

Table 2-45

[0170]

Table 2-46

[0171]

Table 2-47

[0172]

Table 2-48

[0173]

Table 2-49

[0174]

Table 2-50

[0175]

Table 2-51

[0176] (5a) The present invention provides the above compound, its stereoisomer, its pharmaceutically acceptable salt or its solvate.

[0177] (6) The present invention provides a pharmaceutical composition comprising, as an active ingredient, the compound, its stereoisomer, its pharmaceutically acceptable salt, or its solvate described in (1), (2), (3), (4), (5) or (5a).

[0178] (7) Use the pharmaceutical composition described in (6) for the prevention or treatment of GCN2 activation-related diseases.

[0179] (8) The pharmaceutical composition described in (6) further comprises one or more therapeutic agents selected from the group consisting of chemotherapeutic agents, radiation therapy agents, immunotherapy agents and tumor microenvironment regulating agents.

[0180] (9) The present invention provides a method for preventing or treating a GCN2 activation-related disease, the method comprising administering to a subject a therapeutically effective amount of the compound, its stereoisomer, its pharmaceutically acceptable salt, or its solvate described in (1), (2), (3), (4), (5) or (5a); or the pharmaceutical composition described in (6), (7) or (8).

[0181] (10) The GCN2 activation-related diseases include cancer, neurodegenerative diseases, chronic infectious diseases and metabolic diseases, according to the method described in (9).

[0182] (11) The cancer is one or more 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 cancer, skin cancer, breast cancer, colorectal cancer, rectal cancer, fibrosarcoma, osteosarcoma, connective tissue sarcoma, giant cell cancer, squamous cell cancer, leukemia, skin cancer, soft tissue cancer, liver cancer, adenocarcinoma, hepatocellular cancer, multiple myeloma, myelodysplastic syndrome, myeloproliferative tumor, malignant glioma, non-Hodgkin lymphoma, Hodgkin lymphoma, Burkitt 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 lymphocyte leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia, small cell lung cancer and pediatric neuroblastoma, the method according to (10).

[0183] (12) The present invention is a method for preventing or treating a GCN2 activation-related disease, the method comprising administering to a subject a therapeutically effective amount of the compound according to (1), (2), (3), (4), (5) or (5a), its stereoisomer, its pharmaceutically acceptable salt, or its solvate; or the pharmaceutical composition according to (6), (7) or (8).

[0184] (13) The present invention provides the use of the compound according to (1), (2), (3), (4), (5) or (5a), its stereoisomer, its pharmaceutically acceptable salt, or its solvate for the prevention or treatment of a GCN2 activation-related disease.

[0185] (14) The present invention provides the use of the compound according to (1), (2), (3), (4), (5) or (5a), its stereoisomer, its pharmaceutically acceptable salt, or its solvate in the manufacture of a medicament for the prevention or treatment of a GCN2 activation-related disease.

[0186] The description matters in use, the compositions and treatment methods of the present invention are equally applicable as long as they do not conflict with each other.

Examples

[0187] Hereinafter, preferred embodiments are proposed for a better understanding of the present invention. However, the following embodiments are provided only for the purpose of illustrating the present invention, and thus the present invention is not limited thereto.

[0188] All chemical reagents are commercially available. Flash column chromatography means silica gel chromatography unless otherwise specified, and was performed on a Teledyne Combiflash-RF200 system. 1H NMR spectra (δ, ppm) were recorded on a 400 MHz or 600 MHz instrument. Mass spectrometry data (ESI, m / z) for the cationization method was measured from an Agilent technologies single quadrupole G6120B equipped with an Agilent technologies 1260 Infinity system. Preparative HPLC was performed on an Agilent technologies G1361A.

[0189] Hereinafter, the following embodiments may be appropriately changed and modified by those skilled in the art within the scope of the present invention.

[0190] Preparation of Examples: 3-(2-((1,5-Dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine and 2-chloro-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide Synthesis

[0191]

Chemical formula

[0192] [Process a] Preparation of 7-nitro-1-tosyl-1H-indole. In an oven-dried 3 L round-bottom flask containing a magnetic stirrer bar, a mixture of 7-nitro-1H-indole (CAS number: 6960-42-5, 81 g, 500 mmol) and tosyl chloride (TsCl, 114 g, 600 mmol) in DCM (660 mL) was stirred while cooled to 0 °C. A solution of NaOH (200 g, 5,000 mmol) in water (330 mL) was slowly added to this mixture. The reaction was left to warm to room temperature and stirred for 2 hours. The reaction mixture was poured into 1 L of water, extracted with DCM (3 × 2 L), washed with 10% aqueous K2CO3 solution (400 mL) and 1 N aqueous HCl solution (400 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was then triturated with MeOH (300 mL), filtered and dried in vacuo to give the desired product as a white solid (95% yield). MS (ESI, m / z): 317.0 [M+H] + 1 1H NMR (400 MHz, DMSO) δ 8.05 (d, J = 3.7 Hz, 1H), 7.97 (dd, J = 7.8, 0.9 Hz, 1H), 7.83 (dt, J = 7.9, 1.9 Hz, 1H), 7.80 - 7.76 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 3.7 Hz, 1H), 2.37 (s, 3H).

[0193] [Step b] Preparation of 3-bromo-7-nitro-1-tosyl-1H-indole. In an oven-dried 5 L round-bottom flask containing a magnetic stirrer bar, a solution of N-bromosuccinimide (NBS, 98.0 g) in DMF (300 mL) was slowly added to a mixture of 7-nitro-1-tosyl-1H-indole (145.5 g, 460 mmol) in DMF (500 mL). 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 obtain a yellow precipitate. The precipitate was filtered, redissolved in DCM (10 L), and washed with 1 N aqueous NaOH solution (4 L) and water (2 L). The product was then dried over anhydrous Na2SO4, concentrated under reduced pressure, triturated with MeOH (250 mL), filtered, and dried in vacuo to give the desired product (yield 91%) as a white solid. MS (ESI, m / z): 394.9 [M+H] + 1 1H NMR (400 MHz, dmso) δ 8.47 (s, 1H), 7.97 (dd, J = 7.9, 0.9 Hz, 1H), 7.89~7.84 (m, 3H), 7.59 (t, J = 7.9 Hz, 1H), 7.48 (dd, J = 8.6, 0.6 Hz, 2H), 2.40 (s, 3H).

[0194] [Step c] Preparation of 7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole. Under an N2 atmosphere, in an oven-dried 5 L round-bottom flask containing a magnetic stirrer bar, a mixture of 3-bromo-7-nitro-1-tosyl-1H-indole (130 g, 330 mmol), bis(pinacolato)diboron (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 reaction mixture was filtered through Celite® and concentrated under reduced pressure. The residue was then triturated with MeOH (3 × 400 mL), filtered, and dried in vacuo to give the desired product (yield 68%) as a light gray solid. MS (ESI, m / z): 443.1 [M+H] + 1 H NMR (400 MHz, dmso) δ 8.32 (s, 1H), 8.18 (dd, J = 7.9, 1.1 Hz, 1H), 8.01~7.96 (m, 2H), 7.86 (dd, J = 7.9, 1.0 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.52~7.47 (m, 2H), 2.42 (s, 3H), 1.34 (s, 12H).

[0195] [Step d] Preparation of 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1-tosyl-1H-indole. In an oven-dried 2 L round-bottom flask containing a magnetic stirrer bar, a mixture of 7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (63 g, 142 mmol), Pd(PPh 3)4 (16 g, 14 mmol), 2,4-dichloro-5-methylpyrimidine (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 triturated with MeOH (250 mL), filtered, and dried in vacuo to afford the desired product as a white solid (yield 91%). MS (ESI, m / z): 443.0 [M+H] + 1 H NMR (400 MHz, dmso) δ 8.78 (t, J = 6.7 Hz, 1H), 8.63 (s, 1H), 8.39 (dt, J = 19.8, 9.9 Hz, 1H), 7.97 (dd, J = 7.9, 0.9 Hz, 1H), 7.92 (dd, J = 8.7, 2.0 Hz, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.52~7.46 (m, 2H), 2.44 (s, 3H), 2.40 (s, 3H).

[0196] [Process e] Preparation of 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1H-indole. To a solution of 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1-tosyl-1H-indole (47 g, 107 mmol) in MeOH (1 L) was added K2CO3 (30 g, 214 mmol). The reaction mixture was heated to 50 °C for 6 hours 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 in vacuo to give the desired product (98% yield) as a brown solid. MS(ESI,m / z):289.0[M+H] + 1 H NMR(400MHz,dmso) δ 12.65(s,1H),8.89(dd,J=8.0,1.0Hz,1H),8.62(d,J=0.7Hz,1H),8.24(dd,J=8.1,1.0Hz,1H),8.19(d,J=3.9Hz,1H),7.46(t,J=8.0Hz,1H),2.51(t,J=0.9Hz,3H).

[0197] [Process f] Preparation of N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-methyl-4-(7-nitro-1H-indol-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 hours. After cooling to room temperature, the reaction mixture was mixed with isopropyl alcohol (IPA) (10 mL) to obtain a precipitate. The precipitate was filtered, washed with IPA (100 mL), and dried in vacuo to give the desired product (83% yield) as a yellowish solid. MS(ESI,m / z):364.1[M+H] + 11H NMR (400 MHz, dmso) δ 12.83 (s, 1H), 11.21 (s, 1H), 9.27 (d, J = 7.8 Hz, 1H), 8.37 (s, 1H), 8.34 (d, J = 3.1 Hz, 1H), 8.28 - 8.24 (m, 1H), 7.46 (t, J = 8.0 Hz, 1H), 6.12 (s, 1H), 3.77 (s, 3H), 2.50 (s, 3H), 2.29 (s, 3H).

[0198] [Step g] Synthesis of 3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine (Intermediate 001). A mixture of N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-methyl-4-(7-nitro-1H-indol-3-yl)pyrimidin-2-amine (15 g, 40 mmol), Fe (powder, 11 g, 200 mmol), and NH4Cl (21 g, 400 mmol) in THF (560 mL) and water (260 mL) was heated to reflux for 8 h. After cooling to room temperature, the reaction mixture was filtered to remove the black slurry. Then, the filtrate was concentrated under reduced pressure and solidified from a mixed solvent of MeOH (250 mL) and DCM (750 mL). The precipitate was filtered, washed with MeOH (100 mL), and dried in vacuo to give the desired product (yield 93%) as a white solid. MS (ESI, m / z): 334.1 [M + H] + 1 1H NMR (400 MHz, dmso) δ 11.25 (s, 1H), 9.10 (s, 1H), 8.17 (s, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 6.81 (t, J = 7.7 Hz, 1H), 6.46 (s, 1H), 6.41 (d, J = 7.3 Hz, 1H), 5.11 (s, 2H), 3.62 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H).

[0199] [Process h] Preparation of 2-chloro-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide (Intermediate 002). A mixture of 3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine (10 g, 30 mmol) in THF (300 mL) was heated to 60 °C for 2 hours until it dissolved transparently. The mixture was cooled to room temperature, and 2-chloroacetyl chloride (7.6 mL, 100 mmol) was added dropwise. The reaction mixture was heated to reflux for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then triturated with MeOH (100 mL) to obtain a precipitate. The precipitate was filtered, washed with MeOH (100 mL), and dried under vacuum to obtain the desired product (yield 70%) as a bright green solid. MS(ESI,m / z):410.1[M+H] + 1 H NMR(600MHz,cd3od) δ 8.70(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).

[0200] Example 1: Synthesis of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-fluoro-1H-indol-7-yl)acetamide

[0201]

Chemical formula

[0202]

Chemical formula

[0203] [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)-pyrrolidin-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 in vacuo and purified by column chromatography (0 - 30% MeOH in 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-hydroxypyrrolidin-1-yl)acetamide (280 mg, 72%). MS (ESI, m / z): 479.2 [M + H] +

[0204] [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-hydroxypyrrolidin-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 azodicarboxylate (0.157 mL, 0.8 mmol) and stirred for 2 h. The mixture was concentrated in vacuo and purified by column chromatography (0 - 30% MeOH in DCM) to give (S)-2-(3-((2-chloropyrimidin-4-yl)oxy)pyrrolidin-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] +

[0205] [Process c'] A solution of (S)-2-(3-((2-chloropyrimidin-4-yl)oxy)pyrrolidin-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) and cyclopropylamine (20 μL, 0.3 mmol) in DMF (1 mL) was treated with triethylamine (70 μL, 0.5 mmol) and stirred at 50 °C for 2 h. The mixture was then separated from a UCT SPE CUBCX cartridge 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] +

[0206] 2-Chloro-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-fluoro-1H-indol-7-yl)acetamide prepared by steps b, c, d, f, g and h of General Method A using N-(6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)-4-methylbenzenesulfonamide instead of 7-nitro-1-tosyl-1H-indole was used to obtain 2-chloro-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-fluoro-1H-indol-7-yl)acetamide.

[0207] 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)pyrrolidin-1-yl)acetamide

[0208] [Chemical formula]

[0209] The title product was obtained using (S)-2-(3-((2-(cyclopropylamino)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 prepared by general method B using intermediate 002'.

[0210] Step a''. At 0 °C, a solution of (S)-2-(3-((2-(cyclopropylamino)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 (297 mg, 0.5 mmol) in c-H2SO4 (3 mL) was treated with HNO3 (0.1 mL) and stirred for 8 hours. The mixture was diluted with water (10 mL), basified with sodium bicarbonate (9 g), filtered to obtain (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-5-nitro-1H-indol-7-yl)acetamide (35 mg, 10%).

[0211] Step b''. A solution of (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-5-nitro-1H-indol-7-yl)acetamide (33 mg, 0.05 mmol) and 10% Pd / C (10 mg) in MeOH (1 mL) was stirred for 1 hour under H2 gas. The mixture was then separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to obtain the corresponding product as a white solid (16 mg, 52%). MS (ESI, m / z): 609.3 [M+H] +

[0212] Example 3: Synthesis of (S)-2-(3-((2-(Cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-(dimethylamino)-1H-indol-7-yl)acetamide

[0213]

Chemical formula

[0214] The title compound was obtained by General Method B using 2-chloro-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-(dimethylamino)-1H-indol-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-indol-7-yl)acetamide prepared by General Method A using N,N-dimethyl-7-nitro-1H-indol-6-amine instead of 7-nitro-1H-indole. MS(ESI,m / z):637.3[M+H] +

[0215] Example 4: Synthesis of (S)-2-(3-((2-(Cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-6-methoxy-1H-indol-7-yl)acetamide

[0216]

Chemical formula

[0217] Using 6-methoxy-7-nitro-1H-indole instead of 7-nitro-1H-indole, the title product was obtained by the same procedure as described for the synthesis of Example 3. MS(ESI, m / z): 624.3 [M+H] +

[0218] 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)pyrrolidin-1-yl)acetamide

[0219]

Chemical Structure

[0220] Using 2,2,2-trifluoroethan-1-amine instead of cyclopropylamine, the title product was obtained by the same procedure as described for the synthesis of Example 3. MS(ESI, m / z): 678.3 [M+H] +

[0221] 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)pyrrolidin-1-yl)acetamide

[0222]

Chemical Structure

[0223] Using 2,2,2-trifluoroethan-1-amine instead of cyclopropylamine, the title product was obtained by the same procedure as described for the synthesis of Example 4. MS(ESI, m / z): 666.3 [M+H]+

[0224] Example 7: Synthesis of (S)-2-(3-((6-(Cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0225]

Chemical formula

[0226] The title product was obtained by the same procedure as 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-chloropyrimidin-4-ol instead of 2-chloropyrimidin-4-ol. MS(ESI, m / z): 580.3 [M+H] +

[0227] 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)pyrrolidin-1-yl)acetamide

[0228]

Chemical formula

[0229] The title product was obtained by the same procedure as 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] +

[0230] 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)pyrrolidin-1-yl)acetamide

[0231]

Chemical formula

[0232] The title product was obtained by the same procedure described for the synthesis of Example 8 using 2,4-dichloro-5-chloropyrimidine instead of 2,4-dichloro-5-fluoropyrimidine. MS(ESI, m / z): 558.2 [M+H] +

[0233] 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)pyrrolidin-1-yl)acetamide

[0234]

Chemical formula

[0235] The title product was obtained by the same procedure 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] +

[0236] Example 11: (S)-2-(3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-ethylpyrimidin-4-yl)-1H-ind 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)pyrrolidin-1-yl)acetamide

[0237]

Chemical Structure

[0238] The title product was obtained by the same procedure as described for the synthesis of Example 10, using 2,4-dichloro-5-ethylpyrimidine instead of 2,4,5-trichloropyrimidine. MS(ESI, m / z): 608.3 [M+H] +

[0239] 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)pyrrolidin-1-yl)acetamide

[0240]

Chemical Structure

[0241] The title product was obtained by the same procedure as described for the synthesis of Example 10, using 2,4-dichloro-5-cyclopropylpyrimidine instead of 2,4,5-trichloropyrimidine. MS(ESI, m / z): 620.3 [M+H] +

[0242] Example 13: Synthesis of (S)-2-(3-((2-(Cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methoxypyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0243]

Chemical Structure

[0244] The title product was obtained by the same procedure described for the synthesis of Example 10 using 2,4-dichloro-5-methoxypyrimidine instead of 2,4,5-trichloropyrimidine. MS(ESI, m / z): 610.3 [M+H] +

[0245] Example 14: Synthesis of (S)-2-(3-((3-(Cyclopropylamino)-1,2,4-triazin-5-yl)oxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methoxypyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0246]

Chemical Structure

[0247] The title product was obtained by the same procedure described for the synthesis of Example 13 using 3-chloro-1,2,4-triazin-5-ol instead of 2-chloropyrimidin-4-ol. MS(ESI, m / z): 611.3 [M+H] +

[0248] Example 15: Synthesis of (S)-N-(3-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(pyrimidin-4-yloxy)pyrrolidin-1-yl)acetamide

[0249]

Chemical Structure

[0250] The title product was obtained by General Method A using 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-amine instead of 1,5-dimethyl-1H-pyrazol-3-amine and General Method B using pyrimidin-4-ol instead of 2-chloropyrimidin-4-ol. MS(ESI, m / z): 551.3 [M+H] +

[0251] Example 16: Synthesis of (S)-2-(3-((2-(Cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-N-(3-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0252]

Chemical Structure

[0253] The title product was obtained by General Method A and General Method B using 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-amine instead of 1,5-dimethyl-1H-pyrazol-3-amine. MS(ESI, m / z): 606.3 [M+H] +

[0254] Example 17: Synthesis of (S)-2-(3-((2-(Cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-N-(3-(5-methyl-2-((5-methyl-1-(2-morpholinoethyl)-1H-pyrazol-3-yl)amino)pyrimidin- 4-yl)-1H-indol-7-yl)acetamide

[0255]

Chemical Structure

[0256] The title product was obtained by the same procedure described for the synthesis of Example 16 using 5-methyl-1-(2-morpholinoethyl)-1H-pyrazole-3-amine instead of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-amine. MS(ESI,m / z):693.4[M+H] +

[0257]

Chemical formula

[0258] [Step a''] A solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (187 mg, 1 mmol), 2-chloropyrimidin-4-ol (156 mg, 1.2 mmol) (or pyridin-4-ol (114 mg, 1.2 mmol)) and triphenylphosphine (367 mg, 1.4 mmol) in THF (5 mL) was treated with diisopropyl azodicarboxylate (0.354 mL, 1.8 mmol) and stirred for 2 hours. The mixture was concentrated in vacuo and purified by column chromatography (0 - 40% EA in Hx) to give tert-butyl (S)-3-((2-chloropyrimidin-4-yl)oxy)pyrrolidine -1-carboxylate (220 mg, 73%). MS(ESI,m / z):300.1[M+H] + (or tert-butyl (S)-3-(pyridin-4-yloxy)pyrrolidine-1-carboxylate (200 mg, 75%). MS(ESI,m / z):265.2[M+H] + )

[0259] [Step b''] A solution of (S)-3-((2-chloropyrimidin-4-yl)oxy)pyrrolidine-1-carboxylate (450 mg, 1.5 mmol) and cyclopropylamine (200 μL, 3 mmol) in DMF (2 mL) was treated with triethylamine (420 μL, 3 mmol) and stirred at 50 °C for 2 h. The mixture was then concentrated in vacuo and purified by column chromatography (0 - 50% EA in Hx) to afford tert-butyl (S)-3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-carboxylate (300 mg, 62%). MS (ESI, m / z): 321.2 [M+H] +

[0260] [Step c''] tert-Butyl (S)-3-((2-(cyclopropylamino)pyrimidin-4-yl)oxy)pyrrolidine-1-carboxylate (160 mg, 0.5 mmol) (or tert-butyl (S)-3-(pyridin-4-yloxy)pyrrolidine-1-carboxylate (132 mg, 0.5 mmol)) was dissolved in 1N HCl in MeOH (2 mL). The mixture was stirred for 2 h, separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to afford the corresponding product quantitatively. MS (ESI, m / z): 221.1 [M+H] + (or MS (ESI, m / z): 165.1 [M+H] + )

[0261] 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)pyrrolidin-1-yl)acetamide

[0262] [Chemical formula]

[0263] 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 DMF 0.5 mL was added (S)-4-(pyrrolidin-3-yloxy)pyridine (10 mg, 0.06 mmol). The reaction mixture was heated at 50 °C for 3 hours. The mixture was then separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to afford the corresponding product as a white solid (yield 40%). MS(ESI,m / z):552.2[M+H] +

[0264] 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)pyrrolidin-1-yl)acetamide

[0265]

Chemical formula

[0266] The title product was obtained by the same procedure as described for the synthesis of Example 18 using 2-(pyrrolidin-3-yloxy)pyridine instead of (S)-4-(pyrrolidin-3-yloxy)pyridine. MS(ESI,m / z):552.2[M+H] +

[0267] Example 20: Synthesis of (S)-2-(3-((2-(cyclopropylamino)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)-2-oxoacetamide

[0268]

Chemical formula

[0269] (S)-N-Cyclopropyl-4-(pyrrolidin-3-yloxy)pyrimidin-2-amine was used instead of (S)-4-(pyrrolidin-3-yloxy)pyridine and the title product was obtained by the same procedure as described for the synthesis of Example 18. MS(ESI,m / z):608.3[M+H] +

[0270] Example 21: (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)pyrrolidin-1-yl)acetamide Synthesis

[0271]

Chemical Structure

[0272] The title compound was obtained by General Method A using N-(1H-indol-7-yl)-N,4-dimethylbenzenesulfonamide instead of 7-nitro-1H-indole and General Method B using pyrimidin-4-ol instead of 2-chloropyrimidin-4-ol. MS(ESI,m / z):553.3[M+H] +

[0273] Example 22: Synthesis of N-(3-(2-((1,5-Dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(pyrrolidin-1-yl)propenamide

[0274]

Chemical Structure

[0275] The title compound was obtained by the general method A using 2-chloropropanoyl chloride instead of 2-chloroacetyl chloride and by the general method B using pyrrolidine instead of (R)-pyrrolidin-3-ol. MS(ESI, m / z): 459.3 [M+H] +

[0276] 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)pyrrolidin-1-yl)propenamide

[0277]

Chemical Structure

[0278] The title product was obtained by the same procedure as described for the synthesis of Example 22 using (S)-4-(pyrrolidin-3-yloxy)pyridine instead of pyrrolidine. MS(ESI, m / z): 551.3 [M+H] +

[0279] 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-(pyrrolidin-1-yl)propenamide

[0280]

Chemical Structure

[0281] The title product was obtained by the same procedure as described for the synthesis of Example 22 using 2-chloro-2-methylpropanoyl chloride instead of 2-chloropropanoyl chloride. MS(ESI, m / z): 473.3 [M+H] +

[0282] 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)pyrrolidin-1-yl)propenamide

[0283]

Chemical formula

[0284] The title product was obtained by the same procedure as described for the synthesis of Example 23 using 2-chloro-2-methylpropanoyl chloride instead of 2-chloropropanoyl chloride. MS(ESI, m / z): 566.3 [M+H] +

[0285] 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-hydroxyazetidin-1-yl)acetamide

[0286]

Chemical formula

[0287] The title product was obtained by the same procedure as step a' of General Method B using azetidin-3-ol instead of (R)-pyrrolidin-3-ol from Intermediate 002 prepared by Method A. MS(ESI, m / z): 447.2 [M+H] +

[0288] 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)azetidin-1-yl)acetamide

[0289]

Chemical formula

[0290] A solution of Example 26 (223 mg, 0.5 mmol) and cesium carbonate (325 mg, 1 mmol) in DMF (2 mL) was treated with 4-(bromomethyl)pyridine (120 mg, 0.7 mmol). The mixture was then separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to give the corresponding product (100 mg, 37%). MS (ESI, m / z): 538.3 [M+H] +

[0291] 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)azetidin-1-yl)acetamide

[0292]

Chemical formula

[0293] The title product was obtained by the same procedure as described for the synthesis of Example 26 using 4-(azetidin-3-yloxy)pyridine instead of azetidin-3-ol. 4-(Azetidin-3-yloxy)pyridine was prepared by a procedure similar to General Method C using tert-butyl 3-hydroxyazetidine-1-carboxylate instead of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate. MS (ESI, m / z): 524.2 [M+H] +

[0294] 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)azetidin-1-yl)acetamide

[0295]

Chemical formula

[0296] The title product was obtained by the same procedure as described for the synthesis of Example 28 using 4-(azetidin-3-yloxy)pyrimidine instead of 4-(azetidin-3-yloxy)pyridine. MS(ESI, m / z): 525.2 [M+H] +

[0297] 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)azetidin-1-yl)acetamide

[0298]

Chemical formula

[0299] The title product was obtained by the same procedure as described for the synthesis of Example 28 using 3-(azetidin-3-yloxy)pyridine instead of 4-(azetidin-3-yloxy)pyridine. MS(ESI, m / z): 524.2 [M+H] +

[0300] Example 31: Synthesis of methyl 1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)azetidine-3-carboxylate

[0301]

Chemical formula

[0302] The title product was obtained by the same procedure as described for the synthesis of Example 26 using methyl azetidine-3-carboxylate instead of azetidin-3-ol. MS(ESI, m / z): 489.2 [M+H] +

[0303] Example 32: Synthesis of 1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)azetidine-3-carboxylic acid

[0304]

Chem.

[0305] The title product was obtained by the same procedure described for the synthesis of Example 26 using azetidine-3-carboxylic acid instead of azetidine-3-ol. MS(ESI, m / z): 475.2 [M+H] +

[0306] Example 33: Synthesis of 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)azetidin-3-yl)oxy)isoxazole-5-carboxamide

[0307]

Chem.

[0308] A solution of Example 26 (446 mg, 1 mmol), methyl 3-hydroxyisoxazole-5-carboxylate (143 mg, 1 mmol) and triphenylphosphine (314 mg, 1.2 mmol) in THF (3 mL) was treated with diisopropyl azodicarboxylate (0.314 mL, 1.6 mmol) and stirred for 2 hours. The mixture was concentrated in vacuo and purified by column chromatography (0 - 30% MeOH in DCM) to give methyl 3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)azetidin-3-yl)oxy)isoxazole-5-carboxylate (480 mg, 84%).

[0309] A solution of methyl 3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)azetidin-3-yl)oxy)isoxazole-5-carboxylate (400 mg, 0.7 mmol) in MeOH (1 mL) was treated with 1 N NaOH in MeOH (0.5 mL) and stirred for 1 hour. The mixture was concentrated in vacuo and neutralized with 1 N HCl to give 3-((1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)azetidin-3-yl)oxy)isoxazole-5-carboxylic acid quantitatively.

[0310] 3-((1-(2-((3-(2-((1,5-Dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)azetidin-3-yl)oxy)isoxazole-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) were treated with triethylamine (210 μL, 1.5 mmol) and stirred for 2 hours. The mixture was then separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to give the corresponding product (200 mg, 67%). MS (ESI, m / z): 597.3 [M+H] +

[0311] Example 34: Synthesis of 2-(5,6-Dihydro-[4,4’-bipyridin]-1(2H)-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0312]

Chemical Structure

[0313] A solution of Intermediate 002 (818 mg, 2 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (501 mg, 2.4 mmol) prepared by Method A in DMF (3 mL) was treated with triethylamine (0.55 mL, 4 mmol) and stirred at 50 °C for 2 h. The mixture was concentrated in vacuo and purified by column chromatography (0 - 30% MeOH in 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-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)acetamide (720 mg, 62%). MS (ESI, m / z): 583.3 [M+H] +

[0314] 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-dioxaborolan-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 at 80 °C for 12 h. The mixture was then separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to give the corresponding product (170 mg, 64%). MS (ESI, m / z): 534.3 [M+H] +

[0315] 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-dihydropyridin-1(2H)-yl)acetamide

[0316]

Chem.

[0317] The title product was obtained by the same procedure as described for the synthesis of Example 34 using 4-bromo-1-methyl-1H-pyrazole instead of 4-bromopyridine. MS(ESI, m / z): 537.3 [M+H] +

[0318] 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

[0319]

Chem.

[0320] A solution of intermediate 002 (818 mg, 2 mmol) prepared by Method A in DMF (3 mL) and piperidin-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 in vacuo and purified by column chromatography (0 - 20% MeOH in 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] +

[0321] 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 hours. The mixture was concentrated in vacuo and purified by column chromatography on silica gel (0 - 20% MeOH in 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] +

[0322] A 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) in DMF (3 mL) was treated with triethylamine (0.42 mL, 3 mmol) and stirred at 50 °C for 2 hours. The mixture was then separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to give the corresponding product (310 mg, 55%). MS(ESI,m / z):557.3[M+H] +

[0323] 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

[0324]

Chemical Structure

[0325] The title product was obtained by the same procedure as described for the synthesis of Example 36 using morpholine instead of 1-methylpiperazine. MS(ESI, m / z): 544.3 [M+H] +

[0326] 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

[0327]

Chemical formula

[0328] The title product was obtained by the same procedure as described for the synthesis of Example 36 using pyridin-3-ol instead of 1-methylpiperazine. MS(ESI, m / z): 552.3 [M+H] +

[0329] 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

[0330]

Chemical formula

[0331] The title product was obtained by the same procedure as described for the synthesis of Example 36 using pyridin-2-ol instead of 1-methylpiperazine. MS(ESI, m / z): 552.3 [M+H] +

[0332] 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

[0333]

Chem.

[0334] The title product was obtained by the same procedure as described for the synthesis of Example 36 using pyridin-4-ol instead of 1-methylpiperazine. MS(ESI,m / z):552.3[M+H] +

[0335] 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

[0336]

Chem.

[0337] The title product was obtained by the same procedure as described for the synthesis of Example 36 using pyrimidin-2-ol instead of 1-methylpiperazine. MS(ESI,m / z):553.3[M+H] +

[0338] 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

[0339]

Chem.

[0340] The title product was obtained by the same procedure as described for the synthesis of Example 36 using 4,6-dimethylpyrimidin-2-ol instead of 1-methylpiperazine. MS(ESI, m / z): 581.3 [M+H] +

[0341] Example 43: Synthesis of 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)piperidin-4-yl)oxy)isoxazole-5-carboxamide

[0342] [Chemical formula]

[0343] The title product was obtained by the same procedure as described for the synthesis of Example 33 using piperidin-4-ol instead of azetidin-3-ol. MS(ESI, m / z): 625.3 [M+H] +

[0344] Example 44: Synthesis of 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)piperidin-3-yl)oxy)isoxazole-5-carboxamide

[0345] [Chemical formula]

[0346] The title product was obtained by the same procedure as described for the synthesis of Example 33 using piperidin-3-ol instead of azetidin-3-ol. MS(ESI, m / z): 625.3 [M+H] +

[0347] Example 45: Synthesis of 2-(3-(Cyanomethyl)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0348]

Chemical Structure

[0349] The title product was obtained by the same procedure described for the synthesis of Example 26, using 2-(Pyrrolidin-3-yl)acetonitrile instead of azetidin-3-ol. MS(ESI,m / z):484.3[M+H] +

[0350] Example 46: Synthesis of (R)-2-(3-(Cyanomethyl)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0351]

Chemical Structure

[0352] The title product was obtained by the same procedure described for the synthesis of Example 26, using (R)-2-(Pyrrolidin-3-yl)acetonitrile instead of azetidin-3-ol. MS(ESI,m / z):484.3[M+H] +

[0353] 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)pyrrolidin-1-yl)acetamide

[0354]

Chemical Structure

[0355] Intermediate 002 (410 mg, 1 mmol) prepared by Method A in DMF (3 mL) and tert-butyl (S)-pyrrolidin-3-ylcarbamate (223 mg, 1.2 mmol) were treated with triethylamine (0.29 mL, 2 mmol) and stirred at 50 °C for 2 h. The mixture was concentrated in vacuo and purified by column chromatography (0 - 20% MeOH in DCM) to give tert-butyl (S)-(1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidin-3-yl)carbamate (520 mg, 93%). MS (ESI, m / z): 560.3 [M+H] +

[0356] tert-butyl (S)-(1-(2-((3-(2-((1,5-dimethyl-1H- tert-butyl (S)-(1-(2-((3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-2-oxoethyl)pyrrolidin-3-yl)carbamate (280 mg, 0.5 mmol) was dissolved in 1N HCl in MeOH (2 mL). The mixture was concentrated in vacuo and purified by column chromatography (0 - 40% MeOH in DCM) to give (S)-2-(3-aminopyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide quantitatively. MS (ESI, m / z): 460.2 [M+H] + 。

[0357] A solution of (S)-2-(3-aminopyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-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) in DMF (2 mL) 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 UCT SPE CUBCX cartridge, and purified by preparative HPLC to give (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)pyrrolidin-1-yl)acetamide (200 mg, 74%). MS (ESI, m / z): 538.3 [M+H] + 。

[0358] 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)pyrrolidin-1-yl)acetamide

[0359]

Chemical Structure

[0360] The title product was obtained in the same procedure as described for the synthesis of Example 47 using tert-butyl (R)-pyrrolidin-3-ylcarbamate instead of tert-butyl (S)-pyrrolidin-3-ylcarbamate. MS (ESI, m / z): 538.3 [M+H] +

[0361] 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)pyrrolidin-1-yl)acetamide

[0362]

Chem.

[0363] The title product was obtained by the same procedure described for the synthesis of Example 48 using 4-chloropyridine instead of 4-chloropyrimidine. MS(ESI, m / z): 537.3 [M+H] +

[0364] 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-hydroxypyrrolidin-1-yl)acetamide

[0365]

Chem.

[0366] (3S,4R)-4-Fluoropyrrolidin-3-ol was used instead of (R)-pyrrolidin-3-ol, and the title product was obtained by the same procedure as Step a' of General Method B. MS(ESI, m / z): 479.2 [M+H] +

[0367] 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)pyrrolidin-1-yl)acetamide

[0368]

Chem.

[0369] (3S,4R)-4-Fluoropyrrolidin-3-ol and pyridin-4-ol were used instead of (R)-pyrrolidin-3-ol and 2-chloropyrimidin-4-ol, and the title product was obtained by the same procedure as steps a’ and b’ of General Method B. MS(ESI, m / z): 556.3 [M+H] +

[0370] Example 52: Synthesis of 2-((3R,4S)-3-((2-(Cyclopropylamino)pyrimidin-4-yl)oxy)-4-fluoropyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0371]

Chemical Structure

[0372] (3S,4S)-4-Fluoropyrrolidin-3-ol was used instead of (R)-pyrrolidin-3-ol, and the title product was obtained by the same procedure as General Method B. MS(ESI, m / z): 612.3 [M+H] +

[0373] Example 53: Synthesis of 2-((3R,4R)-3-((2-(Cyclopropylamino)pyrimidin-4-yl)oxy)-4-fluoropyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0374]

Chemical Structure

[0375] (3S,4R)-4-Fluoropyrrolidin-3-ol was used instead of (R)-pyrrolidin-3-ol, and the title product was obtained by the same procedure as General Method B. MS(ESI, m / z): 612.3 [M+H]+

[0376] Example 54: Synthesis of 2-((3S,4R)-3-((2-(Cyclopropylamino)pyrimidin-4-yl)oxy)-4-fluoropyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0377]

Chem.

[0378] (3R,4R)-4-Fluoropyrrolidin-3-ol was used instead of (R)-pyrrolidin-3-ol, and the title product was obtained by the same procedure as General Method B. MS(ESI, m / z): 612.3 [M+H] +

[0379] 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

[0380]

Chem.

[0381] (2S,4S)-4-Hydroxypyrrolidine-2-carboxylic acid methyl ester was used instead of (R)-pyrrolidin-3-ol, and the title product was obtained by the same procedure as General Method B. MS(ESI, m / z): 652.3 [M+H] +

[0382] 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

[0383]

Chem.

[0384] Example 55 (195 mg, 0.3 mmol) was dissolved in 1N LiOH in MeOH (2 mL). The mixture was stirred for 2 hours, separated from a UCT SPE CUBCX cartridge, and purified by preparative HPLC to obtain the corresponding product quantitatively. MS (ESI, m / z): 638.3 [M+H] +

[0385] Example 57: 2-((2S,4S)-4-((2-(Cyclopropylamino)pyrimidin-4-yl)oxy)-2-(hydroxymethyl)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyr idine-4-yl)-1H-indol-7-yl)acetamide synthesis

[0386]

Chem.

[0387] A solution of Example 55 (326 mg, 0.5 mmol) in THF (1 mL) was treated with LAH (1N THF solution, 1 mL) at 0 °C. The mixture was diluted with EA (5 mL), washed with water (5 mL×2), and concentrated in vacuo. The crude product was separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to obtain the corresponding product (120 mg, 38%). MS (ESI, m / z): 624.3 [M+H] +

[0388] 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

[0389]

Chemical formula

[0390] A solution of Example 56 (320 mg, 0.5 mmol), HATU (304 mg, 0.8 mmol) and NH4OH (30% solution, 30 μL) in DMF (2 mL) was treated with triethylamine (280 μL, 2 mmol) and stirred for 1 hour. The mixture was separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to give the corresponding product (95 mg, 29%). MS (ESI, m / z): 637.3 [M+H] +

[0391] Example 59: Synthesis of 2-((2S,4S)-2-(Aminomethyl)-4-((2-(cyclopropylamino)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

[0392]

Chemical formula

[0393] A solution of Example 58 (63 mg, 0.1 mmol) in THF (1 mL) was treated with LAH (1 N THF solution, 1 mL) at 0 °C and stirred for 4 h. The mixture was diluted with EA (3 mL), washed with water (3 mL × 2), and concentrated in vacuo. The crude product was separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to give the corresponding product (23 mg, 37%). MS (ESI, m / z): 623.3 [M+H] +

[0394] Example 60: Synthesis of (S)-2-(3-((2-(Cyclopropylamino)pyrimidin-4-yl)oxy)-2-oxopyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0395]

Chem.

[0396] (S)-3-Hydroxypyrrolidin-2-one was used instead of (R)-pyrrolidin-3-ol, and the title product was obtained in the same procedure as General Method B. MS (ESI, m / z): 608.3 [M+H] +

[0397] Example 61: Synthesis of (S)-2-(4-((2-(Cyclopropylamino)pyrimidin-4-yl)oxy)-2-oxopyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0398]

Chem.

[0399] The title product was obtained by a procedure similar to general method B, using (S)-4-hydroxypyrrolidin-2-one instead of (R)-pyrrolidin-3-ol. MS (ESI, m / z): 608.3 [M+H] +

[0400] 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-oxopiperazine-1-carbonyl)pyrrolidin-1-yl)acetamide

[0401] [ka]

[0402] Intermediate 002 (4090 mg, 10 mmol) prepared by Method A and (S)-methyl pyrrolidine-3-carboxylate (1548 mg, 12 mmol) in DMF (20 mL) A 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-carboxylate (4600 mg, 91%) was treated with triethylamine (2.8 mL, 20 mmol) and stirred at 50° C. for 4 h. The mixture was concentrated in vacuo and purified by column chromatography (0-20% MeOH in 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] +

[0403] (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 (4518 mg, 9 mmol) was dissolved in 1N LiOH in MeOH (20 mL). The mixture was concentrated in vacuo and purified by column chromatography (0 - 50% MeOH in DCM) to give (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 quantitatively. MS (ESI, m / z): 489.2 [M+H] +

[0404] A 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 piperazin-2-one (70 mg, 0.7 mmol) in DMF (2 mL) was treated with triethylamine (280 μL, 2 mmol) and stirred for 3 h. The mixture was separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to give the corresponding product (160 mg, 56%). MS (ESI, m / z): 571.3 [M+H] +

[0405] 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-(morpholine-4-carbonyl)pyrrolidin-1-yl)acetamide

[0406]

Chemical formula

[0407] The title product was obtained by the same procedure described for the synthesis of Example 62 using morpholine instead of piperazin-2-one. MS(ESI, m / z): 558.3 [M+H] +

[0408] Example 64: (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)pyrrolidin-1-yl)acetamide Synthesis

[0409]

Chemical Structure

[0410] The title product was obtained by the same procedure described for the synthesis of Example 62 using thiomorpholine instead of piperazin-2-one. MS(ESI, m / z): 574.3 [M+H] +

[0411] Example 65: (R)-N-(3-(2-((1,5-Dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(3-(4-methylpiperazine-1-carbonyl)pyrrolidin-1-yl)acetamide Synthesis

[0412]

Chemical Structure

[0413] (R)-Methyl pyrrolidine-3-carboxylate and 1-methylpiperazine were used instead of (S)-methyl pyrrolidine-3-carboxylate and piperazin-2-one, and the title product was obtained by the same procedure described for the synthesis of Example 62. MS(ESI, m / z): 571.3 [M+H] +

[0414] 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-oxopiperazine-1-carbonyl)pyrrolidin-1-yl)acetamide

[0415]

Chemical Structure

[0416] The title product was obtained by the same procedure as described for the synthesis of Example 65 using piperazin-2-one instead of 1-methylpiperazine. MS(ESI, m / z): 571.3 [M+H] +

[0417] 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-(morpholine-4-carbonyl)pyrrolidin-1-yl)acetamide

[0418]

Chemical Structure

[0419] The title product was obtained by the same procedure as described for the synthesis of Example 65 using morpholine instead of 1-methylpiperazine. MS(ESI, m / z): 558.3 [M+H] +

[0420] 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-(thiomorpholine-4-carbonyl)pyrrolidin-1-yl)acetamide

[0421]

Chemical Structure

[0422] The title product was obtained by the same procedure described for the synthesis of Example 65 using thiomorpholine instead of 1-methylpiperazine. MS(ESI, m / z): 574.3 [M+H] +

[0423] 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)pyrrolidin-1-yl)acetamide

[0424]

Chemical formula

[0425] The title product was obtained by the same procedure described for the synthesis of Example 62 using 1,2,3,6-tetrahydropyridine instead of piperazin-2-one. MS(ESI, m / z): 554.3 [M+H] +

[0426] 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-hydroxypyrrolidin-1-yl)acetamide

[0427]

Chemical formula

[0428] The title product was obtained by the same procedure as step a' of General Method B using pyrrolidin-3-ol instead of (R)-pyrrolidin-3-ol from Intermediate 002 prepared by Method A. MS(ESI, m / z): 461.2 [M+H] +

[0429] 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-hydroxypyrrolidin-1-yl)acetamide

[0430]

Chemical formula

[0431] The title product was obtained from Intermediate 002 prepared by Method A by the same procedure as Step a' of General Method B. MS(ESI, m / z): 461.2[M+H] +

[0432] 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-hydroxypyrrolidin-1-yl)acetamide

[0433]

Chemical formula

[0434] The title product was obtained from Intermediate 002 by the same procedure as Step a' of General Method B using (S)-pyrrolidin-3-ol instead of (R)-pyrrolidin-3-ol. MS(ESI, m / z): 461.2[M+H] +

[0435] 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)pyrrolidin-1-yl)acetamide

[0436]

Chemical formula

[0437] The title product was obtained by the same procedure as described for the synthesis of Example 39 using (R)-pyrrolidin-3-ol instead of piperidin-4-ol. MS(ESI, m / z): 538.3 [M+H] +

[0438] 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)pyrrolidin-1-yl)acetamide

[0439]

Chemical formula

[0440] The title product was obtained by the same procedure as described for the synthesis of Example 73 using pyridin-4-ol instead of pyridin-2-ol. MS(ESI, m / z): 538.3 [M+H] +

[0441] 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)pyrrolidin-1-yl)acetamide

[0442]

Chemical formula

[0443] The title product was obtained by the same procedure as described for the synthesis of Example 73 using pyridin-3-ol instead of pyridin-2-ol. MS(ESI, m / z): 538.3 [M+H] +

[0444] 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)pyrrolidin-1-yl)acetamide

[0445]

Chemical formula

[0446] The title product was obtained by the same procedure as described for the synthesis of Example 74 using pyrrolidin-3-ol instead of (R)-pyrrolidin-3-ol. MS(ESI, m / z): 538.3 [M+H] +

[0447] 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)pyrrolidin-1-yl)acetamide

[0448]

Chemical formula

[0449] The title product was obtained by the same procedure as described for the synthesis of Example 74 using (S)-pyrrolidin-3-ol instead of (R)-pyrrolidin-3-ol. MS(ESI, m / z): 538.3 [M+H] +

[0450] 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)pyrrolidin-1-yl)acetamide

[0451]

Chemical formula

[0452] The title product was obtained by the same procedure described for the synthesis of Example 73 using pyrimidin-4-ol instead of pyridin-2-ol. MS(ESI, m / z): 539.3 [M+H] +

[0453] 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)pyrrolidin-1-yl)acetamide

[0454]

Chemical Structure

[0455] The title product was obtained by the same procedure described for the synthesis of Example 73 using pyrazin-2-ol instead of pyridin-2-ol. MS(ESI, m / z): 539.3 [M+H] +

[0456] 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)pyrrolidin-1-yl)acetamide

[0457]

Chemical Structure

[0458] The title product was obtained by the same procedure described for the synthesis of Example 73 using 4-fluorophenol instead of pyridin-2-ol. MS(ESI, m / z): 555.3 [M+H] +

[0459] 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)pyrrolidin-1-yl)acetamide

[0460]

Chemical Structure

[0461] The title product was obtained by the same procedure as described for the synthesis of Example 73, using 3-fluorophenol instead of pyridin-2-ol. MS(ESI, m / z): 555.3 [M+H] +

[0462] Example 82: Synthesis of (S)-2-(3-(4-chlorophenoxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0463]

Chemical Structure

[0464] The title product was obtained by the same procedure as described for the synthesis of Example 73, using 4-chlorophenol instead of pyridin-2-ol. MS(ESI, m / z): 571.2 [M+H] +

[0465] Example 83: Synthesis of (S)-2-(3-(2,4-difluorophenoxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0466]

Chemical Structure

[0467] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 2,4-difluorophenol instead of pyridin-2-ol. MS(ESI, m / z): 573.3 [M+H] +

[0468] Example 84: Synthesis of (S)-2-(3-(3,4-difluorophenoxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0469] [Chemical formula]

[0470] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 3,4-difluorophenol instead of pyridin-2-ol. MS(ESI, m / z): 573.3 [M+H] +

[0471] Example 85: Synthesis of (S)-2-(3-(2-chloro-4-fluorophenoxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0472] [Chemical formula]

[0473] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 2-chloro-4-fluorophenol instead of pyridin-2-ol. MS(ESI, m / z): 589.2 [M+H] +

[0474] Example 86: Synthesis of (S)-2-(3-(3,5-Difluorophenoxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0475]

Chem.

[0476] The title product was obtained by the same procedure as described for the synthesis of Example 73, using 3,5-difluorophenol instead of pyridin-2-ol. MS(ESI, m / z): 573.3 [M+H] +

[0477] Example 87: Synthesis of (S)-2-(3-(3-Amino-4-fluorophenoxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0478]

Chem.

[0479] The title product was obtained by the same procedure as described for the synthesis of Example 73, using 3-amino-4-fluorophenol instead of pyridin-2-ol. MS(ESI, m / z): 570.3 [M+H] +

[0480] Example 88: Synthesis of (S)-2-(3-(3-(Diethylamino)phenoxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0481]

Chem.

[0482] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 3-(diethylamino)phenol instead of pyridin-2-ol. MS(ESI, m / z): 608.3 [M+H] +

[0483] Example 89: Synthesis of (S)-2-(3-(3-aminophenoxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0484]

Chemical formula

[0485] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 3-aminophenol instead of pyridin-2-ol. MS(ESI, m / z): 552.3 [M+H] +

[0486] Example 90: Synthesis of (S)-2-(3-((2-aminopyridin-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

[0487]

Chemical formula

[0488] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 2-aminopyridin-4-ol instead of pyridin-2-ol. MS(ESI, m / z): 553.3 [M+H] +

[0489] Example 91: Synthesis of (S)-2-(3-((2-Chloropyridin-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

[0490]

Chemical formula

[0491] The title product was obtained by the same procedure as described for the synthesis of Example 73, using 2-chloropyridin-4-ol instead of pyridin-2-ol. MS(ESI, m / z): 572.2 [M+H] +

[0492] Example 92: Synthesis of (S)-2-(3-((6-Aminopyrazin-2-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

[0493]

Chemical formula

[0494] The title product was obtained by the same procedure as described for the synthesis of Example 73, using 6-aminopyrazin-2-ol instead of pyridin-2-ol. MS(ESI, m / z): 554.3 [M+H] +

[0495] 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)pyrrolidin-1-yl)acetamide

[0496] [Chemistry]

[0497] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 5-fluoropyrimidin-2-ol instead of pyridin-2-ol. MS(ESI, m / z): 557.3 [M+H] +

[0498] Example 94: Synthesis of (S)-2-(3-((6-chloro-5-methylpyrimidin-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

[0499] [Chemistry]

[0500] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 6-chloro-5-methylpyrimidin-4-ol instead of pyridin-2-ol. MS(ESI, m / z): 587.2 [M+H] +

[0501] Example 95: Synthesis of (S)-2-(3-((2-amino-6-methylpyrimidin-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

[0502] [Chemistry]

[0503] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 2-amino-6-methylpyrimidin-4-ol instead of pyridin-2-ol. MS(ESI,m / z):568.3[M+H] +

[0504] Example 96: Synthesis of (S)-2-(3-((5-amino-2-chloropyrimidin-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

[0505]

Chemical Structure

[0506] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 5-amino-2-chloropyrimidin-4-ol instead of pyridin-2-ol. MS(ESI,m / z):588.2[M+H] +

[0507] Example 97: Synthesis of (S)-2-(3-((5-bromo-2-methylpyrimidin-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

[0508]

Chemical Structure

[0509] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 5-bromo-2-methylpyrimidin-4-ol instead of pyridin-2-ol. MS(ESI,m / z):631.2[M+H] +

[0510] Example 98: Synthesis of (S)-2-(3-((2-amino-6-(5-chloro-2-fluorophenyl)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

[0511]

Chem.

[0512] The title product was obtained in the same procedure as described for the synthesis of Example 73, using 2-amino-6-(5-chloro-2-fluorophenyl)-2-methylpyrimidin-4-ol instead of pyridin-2-ol. MS(ESI, m / z): 682.3 [M+H] +

[0513] Example 99: Synthesis of (S)-2-(3-((2-amino-6-(trifluoromethyl)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

[0514]

Chem.

[0515] The title product was obtained in the same procedure as described for the synthesis of Example 73, using 2-amino-6-(trifluoromethyl)pyrimidin-4-ol instead of pyridin-2-ol. MS(ESI, m / z): 622.3 [M+H] +

[0516] Example 100: Synthesis of (S)-2-(3-([1,1'-Biphenyl]-4-yloxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0517]

Chemical formula

[0518] The title product was obtained by the same procedure as described for the synthesis of Example 73 using [1,1'-biphenyl]-4-ol instead of pyridin-2-ol. MS(ESI, m / z): 613.3 [M+H] +

[0519] 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-phenylpropan-2-yl)phenoxy)pyrrolidin-1-yl)acetamide

[0520]

Chemical formula

[0521] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 4-(2-phenylpropan-2-yl)phenol instead of pyridin-2-ol. MS(ESI, m / z): 655.3 [M+H] +

[0522] 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)pyrrolidin-1-yl)acetamide

[0523]

Chem.

[0524] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 5-pentylpyrimidin-2-ol instead of pyridin-2-ol. MS(ESI, m / z): 609.3 [M+H] +

[0525] 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)pyrrolidin-1-yl)acetamide

[0526]

Chem.

[0527] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 4-((4-methylpiperazin-1-yl)methyl)phenol instead of pyridin-2-ol. MS(ESI, m / z): 649.4 [M+H] +

[0528] 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)pyrrolidin-1-yl)acetamide

[0529]

Chem.

[0530] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 1-methyl-1H-pyrazol-5-ol instead of pyridin-2-ol. MS(ESI, m / z): 541.3 [M+H] +

[0531] 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)pyrrolidin-1-yl)acetamide

[0532]

Chemical formula

[0533] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 1-methyl-1H-pyrazol-3-ol instead of pyridin-2-ol. MS(ESI, m / z): 541.3 [M+H] +

[0534] Example 106: 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)pyrrolidin-3-yl)oxy)benzo[b]thiophene-2-carboxylate

[0535]

Chemical formula

[0536] The title product was obtained by the same procedure as described for the synthesis of Example 73 using methyl 3-hydroxybenzo[b]thiophene-2-carboxylate instead of pyridin-2-ol. MS(ESI, m / z): 651.2 [M+H] +

[0537] 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)pyrrolidin-3-yl)oxy)thiophene-2-carboxylate

[0538]

Chemical Structure

[0539] The title product was obtained by the same procedure described for the synthesis of Example 73 using methyl 3-hydroxy thiophene-2-carboxylate instead of 2-pyridinol. MS(ESI, m / z): 601.2 [M+H] +

[0540] 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)pyrrolidin-3-yl)oxy)thiophene-2-carboxylic acid

[0541]

Chemical Structure

[0542] The title product was obtained using Example 107 by the same procedure described for the synthesis from Example 55 to Example 56. MS(ESI, m / z): 587.2 [M+H] +

[0543] 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)pyrrolidin-3-yl)oxy)thiophene-2-carboxamide

[0544] [Chemistry]

[0545] The title product was obtained using Example 107 by the same procedure as described for the synthesis of Examples 55 to 58. MS (ESI, m / z): 586.2 [M+H] +

[0546] Example 110: 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)pyrrolidin-3-yl)oxy)-N-methylthiophene-2-carboxamide

[0547] The title product was obtained using methylamine instead of ammonium hydroxide by the same procedure as described for the synthesis of Example 109. MS (ESI, m / z): 600.2 [M+H]

[0548] The title product was obtained using methylamine instead of ammonium hydroxide by the same procedure as described for the synthesis of Example 109. MS (ESI, m / z): 600.2 [M+H] +

[0549] 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)pyrrolidin-3-yl)oxy)thiophene-2-carboxamide

[0550] The title product was obtained using cyclopropylamine instead of ammonium hydroxide by the same procedure as described for the synthesis of Example 109. MS (ESI, m / z): 626.3 [M+H]

[0551] The title product was obtained using cyclopropylamine instead of ammonium hydroxide by the same procedure as described for the synthesis of Example 109. MS (ESI, m / z): 626.3 [M+H] +

[0552] 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)pyrrolidin-1-yl)acetamide

[0553]

Chemical formula

[0554] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 5-methylisoxazol-3-ol instead of pyridin-2-ol. MS(ESI, m / z): 542.3 [M+H] +

[0555] Example 113: Synthesis of (S)-2-(3-(benzo[d]isoxazol-3-yloxy)pyrrolidin-1-yl)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)acetamide

[0556]

Chemical formula

[0557] The title product was obtained by the same procedure as described for the synthesis of Example 73 using benzo[d]isoxazol-3-ol instead of pyridin-2-ol. MS(ESI, m / z): 578.3 [M+H] +

[0558] 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-(isothiazol-3-yloxy)pyrrolidin-1-yl)acetamide

[0559]

Chem.

[0560] The title product was obtained by the same procedure as described for the synthesis of Example 73 using isothiazol-3-ol instead of pyridin-2-ol. MS(ESI, m / z): 544.2 [M+H] +

[0561] Example 115: (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)pyrrolidin-1-yl ) Synthesis of acetamide

[0562]

Chem.

[0563] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 2-methylthiophen-3-ol instead of pyridin-2-ol. MS(ESI, m / z): 557.2 [M+H] +

[0564] Example 116: Synthesis of (S)-2-(3-((1H-pyrazol-3-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

[0565]

Chem.

[0566] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 1H-pyrazol-3-ol instead of pyridin-2-ol. MS(ESI,m / z):527.3[M+H] +

[0567] 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)pyrrolidin-1-yl)acetamide

[0568]

Chemical formula

[0569] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ol instead of pyridin-2-ol. MS(ESI,m / z):609.3[M+H] +

[0570] 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-(isoxazol-3-yloxy)pyrrolidin-1-yl)acetamide

[0571]

Chemical formula

[0572] The title product was obtained by the same procedure as described for the synthesis of Example 73 using isoxazol-3-ol instead of pyridin-2-ol. MS(ESI,m / z):528.2[M+H] +

[0573] Example 119: Synthesis of (S)-2-(3-((5-amino-1H-pyrazol-3-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

[0574]

Chemical formula

[0575] The title product was obtained by the same procedure as described for the synthesis of Example 73, using 5-amino-1H-pyrazol-3-ol instead of pyridin-2-ol. MS(ESI, m / z): 542.3 [M+H] +

[0576] 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)pyrrolidin-3-yl)oxy)-1H-pyrrole-2-carboxylate

[0577]

Chemical formula

[0578] The title product was obtained by the same procedure as described for the synthesis of Example 73, using methyl 3-hydroxy-1H-pyrrole-2-carboxylate instead of pyridin-2-ol. MS(ESI, m / z): 584.3 [M+H] +

[0579] Example 121: Synthesis of ethyl (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)pyrrolidin-3-yl)oxy)isoxazole-4-carboxylate

[0580]

Chem.

[0581] The title product was obtained by the same procedure as described for the synthesis of Example 73 using ethyl 5-hydroxyisoxazole-4-carboxylate instead of pyridin-2-ol. MS(ESI, m / z): 600.3 [M+H] +

[0582] Example 122: 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)pyrrolidin-3-yl)oxy)isoxazole-5-carboxamide

[0583]

Chem.

[0584] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 3-hydroxyisoxazole-5-carboxamide instead of pyridin-2-ol. MS(ESI, m / z): 571.3 [M+H] +

[0585] Example 123: 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)pyrrolidin-3-yl)oxy)-N-methylisoxazole-5-carboxamide

[0586]

Chem.

[0587] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 3-hydroxy-N-methylisoxazole-5-carboxamide instead of pyridin-2-ol. MS(ESI, m / z): 585.3 [M+H] +

[0588] 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-indol-7-yl)amino)-2-oxoethyl)pyrrolidin-3-yl)oxy)isoxazole-5-carboxamide

[0589]

Chemical Structure

[0590] The title product was obtained by the same procedure as described for the synthesis of Example 73 using N-cyclopropyl-3-hydroxyisoxazole-5-carboxamide instead of pyridin-2-ol. MS(ESI, m / z): 611.3 [M+H] +

[0591] Example 125: 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)pyrrolidin-3-yl)oxy)-N,N-dimethylisoxazole-5-carboxamide

[0592]

Chemical Structure

[0593] The title product was obtained by the same procedure described for the synthesis of Example 73 using 3-hydroxy-N,N-dimethylisoxazole-5-carboxamide instead of pyridin-2-ol. MS(ESI,m / z):599.3[M+H] +

[0594] 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-indol-7-yl)amino)-2-oxoethyl)pyrrolidin-3-yl)oxy)oxazole-5-carboxamide

[0595]

Chemical formula

[0596] The title product was obtained by the same procedure described for the synthesis of Example 73 using N-cyclopropyl-2-hydroxyoxazole-5-carboxamide instead of pyridin-2-ol. MS(ESI,m / z):611.3[M+H] +

[0597] 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-indol-7-yl)amino)-2-oxoethyl)pyrrolidin-3-yl)oxy)oxazole-4-carboxamide

[0598]

Chemical formula

[0599] The title product was obtained by the same procedure described for the synthesis of Example 73 using N-cyclopropyl-2-hydroxyoxazole-4-carboxamide instead of pyridin-2-ol. MS(ESI,m / z):611.3[M+H]+

[0600] 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)pyrrolidin-3-yl)oxy)pyrimidine-4-carboxylic acid

[0601]

Chem.

[0602] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 2-hydroxypyrimidine-4-carboxylic acid instead of pyridin-2-ol. MS(ESI, m / z): 583.3 [M+H] +

[0603] 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)pyrrolidin-3-yl)oxy)pyrimidine-4-carboxamide

[0604]

Chem.

[0605] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 2-hydroxypyrimidine-4-carboxamide instead of pyridin-2-ol. MS(ESI, m / z): 582.3 [M+H] +

[0606] Example 130: 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)pyrrolidin-3-yl)oxy)-N-methylpyrimidine-4-carboxamide

[0607]

Chem.

[0608] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 2-hydroxy-N-methylpyrimidine-4-carboxamide instead of pyridin-2-ol. MS(ESI, m / z): 596.3 [M+H] +

[0609] Example 131: 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)pyrrolidin-3-yl)oxy)-N,N-dimethylpyrimidine-4-carboxamide

[0610]

Chem.

[0611] The title product was obtained by the same procedure as described for the synthesis of Example 73 using 2-hydroxy-N,N-dimethylpyrimidine-4-carboxamide instead of pyridin-2-ol. MS(ESI, m / z): 610.3 [M+H] +

[0612] 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)pyrrolidin-3-yl)oxy)pyrazine-2-carboxamide

[0613]

Chemical formula

[0614] The title product was obtained by the same procedure as described for the synthesis of Example 73, using 6-hydroxypyrazine-2-carboxamide instead of pyridin-2-ol. MS(ESI, m / z): 582.3 [M+H] +

[0615] Example 133: 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)pyrrolidin-3-yl)oxy)-N-methylpyrazine-2-carboxamide

[0616]

Chemical formula

[0617] The title product was obtained by the same procedure as described for the synthesis of Example 73, using 6-hydroxy-N-methylpyrazine-2-carboxamide instead of pyridin-2-ol. MS(ESI, m / z): 596.3 [M+H] +

[0618] Example 134: Synthesis of (S)-2-(3-((4-amino-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-indol-7-yl)acetamide

[0619]

Chem.

[0620] The title product was obtained by a procedure similar to General Method B using 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] +

[0621] 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)pyrrolidin-1-yl)acetamide

[0622]

Chem.

[0623] The title product was obtained by a procedure similar to that described for the synthesis of Example 134 using methylamine instead of ammonium hydroxide. MS(ESI, m / z): 569.3 [M+H] +

[0624] 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)pyrrolidin-1-yl)acetamide

[0625]

Chem.

[0626] The title product was obtained by the same procedure as described for the synthesis of Example 134 using dimethylamine instead of ammonium hydroxide. MS(ESI, m / z): 583.3 [M+H] +

[0627] Example 137: Synthesis of (S)-2-(3-((4-(Cyclopropylamino)-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-indol-7-yl)acetamide

[0628]

Chemical Structure

[0629] The title product was obtained by the same procedure as described for the synthesis of Example 134 using cyclopropylamine instead of ammonium hydroxide. MS(ESI, m / z): 595.3 [M+H] +

[0630] Example 138: Synthesis of (S)-2-(3-((4,6-Diamino-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-indol-7-yl)acetamide

[0631]

Chemical Structure

[0632] The title product was obtained by the same procedure as described for the synthesis of Example 134 using 4-amino-6-chloro-1,3,5-triazin-2-ol instead of 4-chloro-1,3,5-triazin-2-ol. MS(ESI, m / z): 570.3 [M+H] +

[0633] Synthesis of Example 139: (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-indol-7-yl)acetamide

[0634] [Chemical Formula]

[0635] The title product was obtained by the same procedure as described for the synthesis of Example 138 using pyrrolidine instead of ammonium hydroxide. MS(ESI, m / z): 624.3 [M+H] +

[0636] Synthesis of Example 140: (S)-2-(3-((6-Aminopyrimidin-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

[0637] [Chemical Formula]

[0638] The title product was obtained by the same procedure as described for the synthesis of Example 134 using 6-chloropyrimidin-4-ol instead of 4-chloro-1,3,5-triazin-2-ol. MS(ESI, m / z): 554.3 [M+H] +

[0639] Synthesis of Example 141: (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)pyrrolidin-1-yl)acetamide

[0640] [Chemistry]

[0641] The title product was obtained by the same procedure described for the synthesis of Example 140 using methylamine instead of ammonium hydroxide. MS(ESI, m / z): 568.3 [M+H] +

[0642] 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)pyrrolidin-1-yl)acetamide

[0643] [Chemistry]

[0644] The title product was obtained by the same procedure described for the synthesis of Example 140 using ethylamine instead of ammonium hydroxide. MS(ESI, m / z): 582.3 [M+H] +

[0645] 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)pyrrolidin-1-yl)acetamide

[0646] [Chemistry]

[0647] The title product was obtained by the same procedure described for the synthesis of Example 140 using n-propylamine instead of ammonium hydroxide. MS(ESI, m / z): 596.3 [M+H]+

[0648] Example 144: Synthesis of (S)-2-(3-((6-(butylamino)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

[0649]

Chemical Structure

[0650] The title product was obtained by the same procedure as described for the synthesis of Example 140, using n-butylamine instead of ammonium hydroxide. MS(ESI, m / z): 610.3 [M+H] +

[0651] 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)pyrrolidin-1-yl)acetamide

[0652]

Chemical Structure

[0653] The title product was obtained by the same procedure as described for the synthesis of Example 140, using 2-aminoethanol instead of ammonium hydroxide. MS(ESI, m / z): 598.3 [M+H] +

[0654] 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)pyrrolidin-1-yl)acetamide

[0655]

Chemical formula

[0656] The title product was obtained by the same procedure as described for the synthesis of Example 140 using 3-aminopropan-1-ol instead of ammonium hydroxide. MS(ESI, m / z): 612.3 [M+H] +

[0657] 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)pyrrolidin-1-yl)acetamide

[0658]

Chemical formula

[0659] The title product was obtained by the same procedure as described for the synthesis of Example 140 using 2-methoxyethan-1-amine instead of ammonium hydroxide. MS(ESI, m / z): 612.3 [M+H] +

[0660] 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)pyrrolidin-1-yl)acetamide

[0661]

Chem.

[0662] The title product was obtained by the same procedure as described for the synthesis of Example 140 using N1,N1-dimethylpropane-1,3-diamine instead of ammonium hydroxide. MS(ESI, m / z): 639.4 [M+H] +

[0663] Example 149: Synthesis of (S)-2-(3-((6-(benzylamino)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

[0664]

Chem.

[0665] The title product was obtained by the same procedure as described for the synthesis of Example 140 using benzylamine instead of ammonium hydroxide. MS(ESI, m / z): 644.3 [M+H] +

[0666] 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-(phenethylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)acetamide

[0667]

Chem.

[0668] The title product was obtained by the same procedure as described for the synthesis of Example 140 using 2-phenylethane-1-amine instead of ammonium hydroxide. MS(ESI, m / z): 658.3 [M+H] +

[0669] Example 151: Synthesis of (S)-2-(3-((6-(Cyclopropylamino)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

[0670]

Chemical Structure

[0671] The title product was obtained by the same procedure as described for the synthesis of Example 140 using cyclopropylamine instead of ammonium hydroxide. MS(ESI, m / z): 594.3 [M+H] +

[0672] Example 152: Synthesis of (S)-2-(3-((6-(Cyclohexylamino)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

[0673]

Chemical Structure

[0674] The title product was obtained by the same procedure as described for the synthesis of Example 140 using cyclohexylamine instead of ammonium hydroxide. MS(ESI, m / z): 636.3 [M+H] +

[0675] 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)pyrrolidin-1-yl)acetamide

[0676]

Chemical formula

[0677] The title product was obtained by the same procedure as described for the synthesis of Example 140 using dimethylamine instead of ammonium hydroxide. MS(ESI, m / z): 582.3 [M+H] +

[0678] 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)pyrrolidin-1-yl)acetamide

[0679]

Chemical formula

[0680] The title product was obtained by the same procedure as described for the synthesis of Example 140 using N-methylethanamine instead of ammonium hydroxide. MS(ESI, m / z): 596.3 [M+H] +

[0681] Example 155: Synthesis of (S)-2-(3-((6-(diethylamino)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

[0682] [Chemical formula]

[0683] The title product was obtained by the same procedure described for the synthesis of Example 140 using diethylamine instead of ammonium hydroxide. MS(ESI, m / z): 610.3 [M+H] +

[0684] 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)pyrrolidin-1-yl)acetamide

[0685] [Chemical formula]

[0686] The title product was obtained by the same procedure described for the synthesis of Example 140 using N-ethylpropan-1-amine instead of ammonium hydroxide. MS(ESI, m / z): 624.3 [M+H] +

[0687] Example 157: Synthesis of (S)-2-(3-((6-(butyl(ethyl)amino)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

[0688] [Chemical formula]

[0689] The title product was obtained by the same procedure described for the synthesis of Example 140 using N-ethylbutan-1-amine instead of ammonium hydroxide. MS(ESI, m / z): 638.4 [M+H] +

[0690] 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-(pyrrolidin-1-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)acetamide

[0691]

Chemical Structure

[0692] The title product was obtained by the same procedure described for the synthesis of Example 140 using pyrrolidine instead of ammonium hydroxide. MS(ESI, m / z): 608.3 [M+H] +

[0693] 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-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)acetamide

[0694]

Chemical Structure

[0695] The title product was obtained by the same procedure described for the synthesis of Example 140 using pyrrolidin-3-ol instead of ammonium hydroxide. MS(ESI, m / z): 624.3 [M+H] +

[0696] Synthesis of Example 160: 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-Hydroxypyrrolidin-1-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)acetamide

[0697]

Chem.

[0698] The title product was obtained by the same procedure as described for the synthesis of Example 140 using (R)-pyrrolidin-3-ol instead of ammonium hydroxide. MS(ESI, m / z): 624.3 [M+H] +

[0699] Synthesis of Example 161: 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-Hydroxypyrrolidin-1-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)acetamide

[0700]

Chem.

[0701] The title product was obtained by the same procedure as described for the synthesis of Example 140 using (S)-pyrrolidin-3-ol instead of ammonium hydroxide. MS(ESI, m / z): 624.3 [M+H] +

[0702] Synthesis of Example 162: (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)pyrrolidin-1-yl)acetamide

[0703]

Chem.

[0704] The title product was obtained by the same procedure as described for the synthesis of Example 140 using piperidine instead of ammonium hydroxide. MS(ESI, m / z): 622.3 [M+H] +

[0705] 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)pyrrolidin-1-yl)acetamide

[0706]

Chem.

[0707] The title product was obtained by the same procedure as described for the synthesis of Example 140 using piperidin-4-ol instead of ammonium hydroxide. MS(ESI, m / z): 638.3 [M+H] +

[0708] 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)pyrrolidin-1-yl)acetamide

[0709]

Chem.

[0710] The title product was obtained by the same procedure described for the synthesis of Example 140 using morpholine instead of ammonium hydroxide. MS(ESI, m / z): 624.3 [M+H] +

[0711] 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)pyrrolidin-1-yl)acetamide

[0712]

Chemical Structure

[0713] The title product was obtained by the same procedure described for the synthesis of Example 140 using 1-methylpiperazine instead of ammonium hydroxide. MS(ESI, m / z): 637.3 [M+H] +

[0714] Example 166: Synthesis of (S)-2-(3-((2-amino-6-(methylamino)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

[0715]

Chemical Structure

[0716] The title product was obtained by the same procedure described for the synthesis of Example 141 using 2-amino-6-chloropyrimidin-4-ol instead of 6-chloropyrimidin-4-ol. MS(ESI, m / z): 583.3 [M+H] +

[0717] 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

[0718]

Chemical formula

[0719] The title product was obtained by the same procedure as described for the synthesis of Example 166 using pyrrolidine instead of methylamine. MS(ESI,m / z):623.3[M+H] +

[0720] Example 168: Synthesis of (S)-2-(3-((4-Aminopyrimidin-2-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

[0721]

Chemical formula

[0722] The title product was obtained by the same procedure as described for the synthesis of Example 140 using 4-chloropyrimidin-2-ol instead of 6-chloropyrimidin-4-ol. MS(ESI,m / z):554.3[M+H] +

[0723] 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)pyrrolidin-1-yl)acetamide

[0724] [Chem.]

[0725] The title product was obtained by the same procedure as described for the synthesis of Example 168 using methylamine instead of ammonium hydroxide. MS(ESI, m / z): 568.3 [M+H] +

[0726] 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)pyrrolidin-1-yl)acetamide

[0727] [Chem.]

[0728] The title product was obtained by the same procedure as described for the synthesis of Example 168 using dimethylamine instead of ammonium hydroxide. MS(ESI, m / z): 582.3 [M+H] +

[0729] 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)pyrrolidin-1-yl)acetamide

[0730] [Chem.]

[0731] The title product was obtained by the same procedure as described for the synthesis of Example 168 using N-methylethanamine instead of ammonium hydroxide. MS(ESI, m / z): 596.3 [M+H]+

[0732] Example 172: Synthesis of (S)-2-(3-((4-(diethylamino)pyrimidin-2-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

[0733]

Chemical Structure

[0734] The title product was obtained by the same procedure as described for the synthesis of Example 168 using diethylamine instead of ammonium hydroxide. MS(ESI, m / z): 610.3 [M+H] +

[0735] 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-(pyrrolidin-1-yl)pyrimidin-2-yl)oxy)pyrrolidin-1-yl)acetamide

[0736]

Chemical Structure

[0737] The title product was obtained by the same procedure as described for the synthesis of Example 168 using pyrrolidine instead of ammonium hydroxide. MS(ESI, m / z): 608.3 [M+H] +

[0738] 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)pyrrolidin-1-yl)acetamide

[0739]

Chem.

[0740] The title product was obtained by the same procedure as described for the synthesis of Example 168 using piperidine instead of ammonium hydroxide. MS(ESI, m / z): 622.3 [M+H] +

[0741] Example 175: Synthesis of (S)-2-(3-((4-(Cyclopropylamino)pyrimidin-2-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

[0742]

Chem.

[0743] The title product was obtained by the same procedure as described for the synthesis of Example 168 using cyclopropylamine instead of ammonium hydroxide. MS(ESI, m / z): 594.3 [M+H] +

[0744] Example 176: Synthesis of (S)-2-(3-((4-Amino-5-fluoropyrimidin-2-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

[0745]

Chem.

[0746] The title product was obtained by the same procedure as described for the synthesis of Example 140 using 4-chloro-5-fluoropyrimidin-2-ol instead of 6-chloropyrimidin-4-ol. MS(ESI, m / z): 572.3 [M+H] +

[0747] 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)pyrrolidin-1-yl)acetamide

[0748]

Chemical Structure

[0749] The title product was obtained by the same procedure as described for the synthesis of Example 176 using methylamine instead of ammonium hydroxide. MS(ESI, m / z): 586.3 [M+H] +

[0750] 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)pyrrolidin-1-yl)acetamide

[0751]

Chemical Structure

[0752] The title product was obtained by the same procedure as described for the synthesis of Example 176 using ethylamine instead of ammonium hydroxide. MS(ESI, m / z): 600.3 [M+H] +

[0753] Example 179: Synthesis of (S)-2-(3-((4-(Cyclopropylamino)-5-fluoropyrimidin-2-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

[0754]

Chemical Structure

[0755] The title product was obtained by the same procedure as described for the synthesis of Example 176, using cyclopropylamine instead of ammonium hydroxide. MS(ESI, m / z): 612.3 [M+H] +

[0756] Example 180: Synthesis of (S)-2-(3-((4-(Cyclohexylamino)-5-fluoropyrimidin-2-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

[0757]

Chemical Structure

[0758] The title product was obtained by the same procedure as described for the synthesis of Example 176, using cyclohexylamine instead of ammonium hydroxide. MS(ESI, m / z): 654.3 [M+H] +

[0759] 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)pyrrolidin-1-yl)acetamide

[0760]

Chem.

[0761] The title product was obtained by the same procedure described for the synthesis of Example 176 using dimethylamine instead of ammonium hydroxide. MS(ESI, m / z): 600.3 [M+H] +

[0762] 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)pyrrolidin-1-yl)acetamide

[0763]

Chem.

[0764] The title product was obtained by the same procedure described for the synthesis of Example 176 using N-methylethanamine instead of ammonium hydroxide. MS(ESI, m / z): 614.3 [M+H] +

[0765] Example 183: Synthesis of (S)-2-(3-((4-(diethylamino)-5-fluoropyrimidin-2-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

[0766]

Chem.

[0767] The title product was obtained by the same procedure as described for the synthesis of Example 176 using diethylamine instead of ammonium hydroxide. MS(ESI, m / z): 628.3 [M+H] +

[0768] 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)pyrrolidin-1-yl)acetamide

[0769]

Chemical formula

[0770] The title product was obtained by the same procedure as described for the synthesis of Example 176 using N-methylaniline instead of ammonium hydroxide. MS(ESI, m / z): 662.3 [M+H] +

[0771] Example 185: Synthesis of (S)-2-(3-((4-(benzyl(methyl)amino)-5-fluoropyrimidin-2-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

[0772]

Chemical formula

[0773] The title product was obtained by the same procedure as described for the synthesis of Example 176 using N-methylbenzylamine instead of ammonium hydroxide. MS(ESI, m / z): 676.3 [M+H] +

[0774] 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-(pyrrolidin-1-yl)pyrimidin-2-yl)oxy)pyrrolidin-1-yl)acetamide

[0775]

Chem.

[0776] The title product was obtained by the same procedure as described for the synthesis of Example 176 using pyrrolidine instead of ammonium hydroxide. MS (ESI, m / z): 626.3 [M+H] +

[0777] 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)pyrrolidin-1-yl)acetamide

[0778]

Chem.

[0779] The title product was obtained by the same procedure as described for the synthesis of Example 176 using piperidine instead of ammonium hydroxide. MS (ESI, m / z): 640.3 [M+H] +

[0780] 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)pyrrolidin-1-yl)acetamide

[0781] [Chemical formula]

[0782] The title product was obtained by the same procedure described for the synthesis of Example 176 using morpholine instead of ammonium hydroxide. MS (ESI, m / z): 642.3 [M+H] +

[0783] 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)pyrrolidin-1-yl)acetamide

[0784] [Chemical formula]

[0785] The title product was obtained by the same procedure described for the synthesis of Example 176 using thiomorpholine instead of ammonium hydroxide. MS (ESI, m / z): 658.3 [M+H] +

[0786] 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)pyrrolidin-1-yl)acetamide

[0787] [Chemical formula]

[0788] The title product was obtained by the same procedure described for the synthesis of Example 176 using 1-methylpiperazine instead of ammonium hydroxide. MS(ESI,m / z): 655.3[M+H] +

[0789] Example 191: Synthesis of (S)-2-(3-((4-(Cyclopropylamino)-5-methylpyrimidin-2-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

[0790]

Chemical Structure

[0791] The title product was obtained by the same procedure described for the synthesis of Example 179 using 4-chloro-5-methylpyrimidin-2-ol instead of 4-chloro-5-fluoropyrimidin-2-ol. MS(ESI,m / z): 608.3[M+H] +

[0792] Example 192: Synthesis of (S)-2-(3-((2-Aminopyrimidin-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

[0793]

Chemical Structure

[0794] The title product was obtained by the same procedure described for the synthesis of Example 140 using 2-chloropyrimidin-4-ol instead of 6-chloropyrimidin-4-ol. MS(ESI,m / z): 554.3[M+H] +

[0795] 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)pyrrolidin-1-yl)acetamide

[0796]

Chem.

[0797] The title product was obtained by the same procedure as described for the synthesis of Example 192 using sodium thiomethoxide instead of ammonium hydroxide. MS(ESI, m / z): 585.2 [M+H] +

[0798] 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)pyrrolidin-1-yl)acetamide

[0799]

Chem.

[0800] The title product was obtained by the same procedure as described for the synthesis of Example 192 using sodium methoxide instead of ammonium hydroxide. MS(ESI, m / z): 569.3 [M+H] +

[0801] Example 195: Synthesis of (S)-2-(3-((2-(benzyloxy)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

[0802]

Chem.

[0803] The title product was obtained by the same procedure as described for the synthesis of Example 192 using sodium benzyloxide instead of ammonium hydroxide. MS(ESI, m / z): 645.3 [M+H] +

[0804] Example 196: Synthesis of (S)-2-(3-((2-Acetamidopyrimidin-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

[0805]

Chem.

[0806] A solution of Example 192 (110 mg, 0.2 mmol) in MeOH (1 mL) was treated with acetyl chloride (10 μL) and stirred for 1 h. The crude product was separated on a UCT SPE CUBCX cartridge and purified by preparative HPLC to give the corresponding product (74 mg, 62%). MS(ESI, m / z): 596.3 [M+H] +

[0807] 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)pyrrolidin-1-yl)acetamide

[0808]

Chem.

[0809] The title product was obtained by the same procedure as described for the synthesis of Example 192 using methylamine instead of ammonium hydroxide. MS(ESI, m / z): 568.3[M+H] +

[0810] 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)pyrrolidin-1-yl)acetamide

[0811]

Chemical formula

[0812] The title product was obtained by the same procedure as described for the synthesis of Example 192 using 2,2,2-trifluoroethan-1-amine instead of ammonium hydroxide. MS(ESI, m / z): 636.3[M+H] +

[0813] Example 199: Synthesis of (S)-2-(3-((2-((2,2-Difluoropropyl)amino)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

[0814]

Chemical formula

[0815] The title product was obtained by the same procedure as described for the synthesis of Example 192 using 2,2-difluoropropan-1-amine instead of ammonium hydroxide. MS(ESI, m / z): 632.3[M+H] +

[0816] Example 200: Synthesis of (S)-2-(3-((2-((2,2-difluoroethyl)amino)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

[0817]

Chemical Structure

[0818] The title product was obtained by the same procedure as described for the synthesis of Example 192 using 2,2-difluoroethan-1-amine instead of ammonium hydroxide. MS (ESI, m / z): 618.3 [M+H] +

[0819] 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-trifluoropropan-2-yl)amino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)acetamide

[0820]

Chemical Structure

[0821] The title product was obtained by the same procedure as described for the synthesis of Example 192 using 1,1,1-trifluoropropan-2-amine instead of ammonium hydroxide. MS (ESI, m / z): 650.3 [M+H] +

[0822] 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)pyrrolidin-1-yl)acetamide

[0823]

Chemical formula

[0824] The title product was obtained by the same procedure as described for the synthesis of Example 192, using 2-fluoroethan-1-amine instead of ammonium hydroxide. MS(ESI, m / z): 600.3 [M+H] +

[0825] 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)pyrrolidin-1-yl)acetamide

[0826]

Chemical formula

[0827] The title product was obtained by the same procedure as described for the synthesis of Example 192, using ethylamine instead of ammonium hydroxide. MS(ESI, m / z): 582.3 [M+H] +

[0828] 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)pyrrolidin-1-yl)acetamide

[0829] [Chemical formula]

[0830] The title product was obtained by the same procedure described for the synthesis of Example 192 using n-propylamine instead of ammonium hydroxide. MS(ESI, m / z): 596.3 [M+H] +

[0831] Example 205: Synthesis of (S)-2-(3-((2-(butylamino)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

[0832] [Chemical formula]

[0833] The title product was obtained by the same procedure described for the synthesis of Example 192 using n-butylamine instead of ammonium hydroxide. MS(ESI, m / z): 610.3 [M+H] +

[0834] 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)pyrrolidin-1-yl)acetamide

[0835] [Chemical formula]

[0836] The title product was obtained by the same procedure as described for the synthesis of Example 192 using 3-aminopropan-1-ol instead of ammonium hydroxide. MS(ESI, m / z): 612.3 [M+H] +

[0837] Example 207: Synthesis of (S)-2-(3-((2-(Cyclopropylamino)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

[0838]

Chem.

[0839] The title product was obtained by the same procedure as described for the synthesis of Example 192 using cyclopropylamine instead of ammonium hydroxide. MS(ESI, m / z): 594.3 [M+H] +

[0840] Example 208: Synthesis of (S)-2-(3-((2-(Cyclobutylamino)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

[0841]

Chem.

[0842] The title product was obtained by the same procedure as described for the synthesis of Example 192 using cyclobutylamine instead of ammonium hydroxide. MS(ESI, m / z): 608.3 [M+H] +

[0843] Example 209: Synthesis of (S)-2-(3-((2-(Cyclopentylamino)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

[0844] [Chemical formula]

[0845] The title product was obtained by the same procedure as described for the synthesis of Example 192 using cyclopentylamine instead of ammonium hydroxide. MS(ESI,m / z):622.3[M+H] +

[0846] Example 210: Synthesis of (S)-2-(3-((2-(Cyclohexylamino)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

[0847] [Chemical formula]

[0848] The title product was obtained by the same procedure as described for the synthesis of Example 192 using cyclohexylamine instead of ammonium hydroxide. MS(ESI,m / z):606.3[M+H] +

[0849] 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)pyrrolidin-1-yl)acetamide

[0850] [Chemical formula]

[0851] The title product was obtained by the same procedure as described for the synthesis of Example 192 using isopropylamine instead of ammonium hydroxide. MS(ESI, m / z): 596.3 [M+H] +

[0852] Example 212: Synthesis of 2-((3S)-3-((2-(sec-butylamino)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

[0853] [Chemical formula]

[0854] The title product was obtained by the same procedure as described for the synthesis of Example 192 using sec-butylamine instead of ammonium hydroxide. MS(ESI, m / z): 610.3 [M+H] +

[0855] Example 213: Synthesis of (S)-2-(3-((2-((cyclopropylmethyl)amino)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

[0856] [Chemical formula]

[0857] The title product was obtained by the same procedure described for the synthesis of Example 192 using cyclopropylmethylamine instead of ammonium hydroxide. MS(ESI, m / z): 608.3[M+H] +

[0858] Example 214: Synthesis of (S)-2-(3-((2-(benzylamino)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

[0859]

Chemical formula

[0860] The title product was obtained by the same procedure described for the synthesis of Example 192 using benzylamine instead of ammonium hydroxide. MS(ESI, m / z): 644.3[M+H] +

[0861] 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)pyrrolidin-1-yl)acetamide

[0862]

Chemical formula

[0863] The title product was obtained by the same procedure described for the synthesis of Example 192 using ethanolamine instead of ammonium hydroxide. MS(ESI, m / z): 598.3[M+H] +

[0864] 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)pyrrolidin-1-yl)acetamide

[0865]

Chem.

[0866] The title product was obtained by the same procedure described for the synthesis of Example 192 using 2-methoxyethan-1-amine instead of ammonium hydroxide. MS (ESI, m / z): 612.3 [M+H] +

[0867] 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)pyrrolidin-1-yl)acetamide

[0868]

Chem.

[0869] The title product was obtained by the same procedure described for the synthesis of Example 192 using N1,N1-dimethylethane-1,2-diamine instead of ammonium hydroxide. MS (ESI, m / z): 625.3 [M+H] +

[0870] 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)pyrrolidin-1-yl)acetamide

[0871]

Chem.

[0872] The title product was obtained by the same procedure as described for the synthesis of Example 192 using N1,N1-dimethylpropane-1,3-diamine instead of ammonium hydroxide. MS(ESI,m / z):639.4[M+H] +

[0873] 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)pyrrolidin-1-yl)acetamide

[0874]

Chem.

[0875] The title product was obtained by the same procedure as described for the synthesis of Example 192 using O-methylhydroxylamine instead of ammonium hydroxide. MS(ESI,m / z):584.3[M+H] +

[0876] 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)pyrrolidin-1-yl)acetamide

[0877]

Chem.

[0878] The title product was obtained by the same procedure described for the synthesis of Example 192 using dimethylamine instead of ammonium hydroxide. MS(ESI, m / z): 582.3 [M+H] +

[0879] Example 221: Synthesis of (S)-2-(3-((2-(Benzyl(methyl)amino)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

[0880]

Chemical Structure

[0881] The title product was obtained by the same procedure described for the synthesis of Example 192 using methylbenzylamine instead of ammonium hydroxide. MS(ESI, m / z): 658.3 [M+H] +

[0882] 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-(pyrrolidin-1-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)acetamide

[0883]

Chemical Structure

[0884] The title product was obtained by the same procedure described for the synthesis of Example 192 using pyrrolidine instead of ammonium hydroxide. MS(ESI, m / z): 608.3 [M+H] +

[0885] 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)pyrrolidin-1-yl)acetamide

[0886]

Chemical Structure

[0887] The title product was obtained by the same procedure as described for the synthesis of Example 192, using piperidine instead of ammonium hydroxide. MS (ESI, m / z): 622.3 [M+H] +

[0888] 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)pyrrolidin-1-yl)acetamide

[0889]

Chemical Structure

[0890] The title product was obtained by the same procedure as described for the synthesis of Example 192, using morpholine instead of ammonium hydroxide. MS (ESI, m / z): 624.3 [M+H] +

[0891] 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)pyrrolidin-1-yl)acetamide

[0892] [Chemistry]

[0893] The title product was obtained by the same procedure as described for the synthesis of Example 192 using 1-methylpiperazine instead of ammonium hydroxide. MS(ESI, m / z): 637.3 [M+H] +

[0894] Example 226: Synthesis of (S)-2-(3-((2-Amino-5-fluoropyrimidin-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

[0895] [Chemistry]

[0896] The title product was obtained by the same procedure as described for the synthesis of Example 140 using 2-chloro-5-fluoropyrimidin-4-ol instead of 6-chloropyrimidin-4-ol. MS(ESI, m / z): 572.3 [M+H] +

[0897] Example 227: Synthesis of (S)-2-(3-((2-(Cyclopropylamino)-5-fluoropyrimidin-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

[0898] [Chemistry]

[0899] The title product was obtained by the same procedure as described for the synthesis of Example 226 using cyclopropylamine instead of ammonium hydroxide. MS(ESI, m / z): 612.3 [M+H] +

[0900] Example 228: Synthesis of (S)-2-(3-((2-(Cyclohexylamino)-5-fluoropyrimidin-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

[0901]

Chemical formula

[0902] The title product was obtained by the same procedure as described for the synthesis of Example 226 using cyclohexylamine instead of ammonium hydroxide. MS(ESI, m / z): 654.3 [M+H] +

[0903] Example 229: Synthesis of (S)-2-(3-((2-((Cyclopropylmethyl)amino)-5-fluoropyrimidin-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

[0904]

Chemical formula

[0905] The title product was obtained by the same procedure as described for the synthesis of Example 226 using cyclopropylmethylamine instead of ammonium hydroxide. MS(ESI, m / z): 626.3 [M+H] +

[0906] Example 230: Synthesis of (S)-2-(3-((2-(benzylamino)-5-fluoropyrimidin-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

[0907]

Chemical formula

[0908] The title product was obtained by the same procedure as described for the synthesis of Example 226 using benzylamine instead of ammonium hydroxide. MS(ESI, m / z): 662.3 [M+H] +

[0909] 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)pyrrolidin-1-yl)acetamide

[0910]

Chemical formula

[0911] The title product was obtained by the same procedure as described for the synthesis of Example 226 using dimethylamine instead of ammonium hydroxide. MS(ESI, m / z): 600.3 [M+H] +

[0912] 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)pyrrolidin-1-yl)acetamide

[0913] [Chemical formula]

[0914] The title product was obtained by the same procedure described for the synthesis of Example 226 using morpholine instead of ammonium hydroxide. MS(ESI, m / z): 642.3 [M+H] +

[0915] 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)pyrrolidin-1-yl)acetamide

[0916] [Chemical formula]

[0917] The title product was obtained by the same procedure described for the synthesis of Example 226 using 1-methylpiperazine instead of ammonium hydroxide. MS(ESI, m / z): 655.3 [M+H] +

[0918] Example 234: Synthesis of (S)-2-(3-((2-(cyclopropylamino)-6-fluoropyrimidin-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

[0919] [Chemical formula]

[0920] The title product was obtained by the same procedure as described for the synthesis of Example 227 using 2-chloro-6-fluoropyrimidin-4-ol instead of 2-chloro-5-fluoropyrimidin-4-ol. MS(ESI, m / z): 612.3 [M+H] +

[0921] Example 235: Synthesis of (S)-2-(3-((2-(Cyclopropylamino)-5-methylpyrimidin-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

[0922]

Chemical Structure

[0923] The title product was obtained by the same procedure as described for the synthesis of Example 227 using 2-chloro-5-methylpyrimidin-4-ol instead of 2-chloro-5-fluoropyrimidin-4-ol. MS(ESI, m / z): 608.3 [M+H] +

[0924] Example 236: Synthesis of (S)-2-(3-((2-(Cyclopropylamino)-6-methylpyrimidin-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

[0925]

Chemical Structure

[0926] The title product was obtained by the same procedure described for the synthesis of Example 227 using 2-chloro-6-methylpyrimidin-4-ol instead of 2-chloro-5-fluoropyrimidin-4-ol. MS(ESI, m / z): 608.3[M+H] +

[0927] Example 237: Synthesis of (S)-2-(3-((2-(Cyclopropylamino)-6-(trifluoromethyl)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

[0928]

Chemical Structure

[0929] The title product was obtained by the same procedure described for the synthesis of Example 227 using 2-chloro-6-(trifluoromethyl)pyrimidin-4-ol instead of 2-chloro-5-fluoropyrimidin-4-ol. MS(ESI, m / z): 662.3[M+H] +

[0930] Example 238: Synthesis of (S)-2-(3-((2-(Cyclopropylamino)-6-methoxypyrimidin-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

[0931]

Chemical Structure

[0932] The title product was obtained by the same procedure described for the synthesis of Example 227 using 2-chloro-6-methoxypyrimidin-4-ol instead of 2-chloro-5-fluoropyrimidin-4-ol. MS(ESI,m / z):624.3[M+H] +

[0933] 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)pyrrolidin-1-yl)acetamide

[0934]

Chemical formula

[0935] The title product was obtained by the same procedure described for the synthesis of Example 217 using 2-chloropyrimidin-5-ol instead of 2-chloropyrimidin-4-ol. MS(ESI,m / z):625.3[M+H] +

[0936] 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)pyrrolidin-1-yl)acetamide

[0937]

Chemical formula

[0938] The title product was obtained by the same procedure described for the synthesis of Example 239 using dimethylamine instead of N1,N1-dimethylethane-1,2-diamine. MS(ESI,m / z):582.3[M+H] +

[0939] 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)pyrrolidin-1-yl)acetamide

[0940]

Chemical Structure

[0941] The title product was obtained by the same procedure as described for the synthesis of Example 239 using morpholine instead of N1,N1-dimethylethane-1,2-diamine. MS(ESI, m / z): 624.3 [M+H] +

[0942] 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)pyrrolidin-1-yl)acetamide

[0943]

Chemical Structure

[0944] The title product was obtained by the same procedure as described for the synthesis of Example 239 using 1-methylpiperazine instead of N1,N1-dimethylethane-1,2-diamine. MS(ESI, m / z): 637.3 [M+H] +

[0945] Example 243: Synthesis of (S)-2-(3-((6-(cyclopropylamino)pyrazin-2-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

[0946]

Chem.

[0947] The title product was obtained by the same procedure as described for the synthesis of Example 227 using 6-chloropyrazin-2-ol instead of 2-chloro-5-fluoropyrimidin-4-ol. MS(ESI, m / z): 594.3 [M+H] +

[0948] 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)pyrrolidin-1-yl)acetamide

[0949]

Chem.

[0950] The title product was obtained by the same procedure as described for the synthesis of Example 243 using ethylamine instead of cyclopropylamine. MS(ESI, m / z): 582.3 [M+H] +

[0951] 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)pyrrolidin-1-yl)acetamide

[0952]

Chem.

[0953] The title product was obtained by the same procedure described for the synthesis of Example 243 using n-propylamine instead of cyclopropylamine. MS(ESI, m / z): 596.3[M+H] +

[0954] 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)pyrrolidin-1-yl)acetamide

[0955]

Chemical formula

[0956] The title product was obtained by the same procedure described for the synthesis of Example 243 using ethanolamine instead of cyclopropylamine. MS(ESI, m / z): 598.3[M+H] +

[0957] 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 yl)oxy)pyrrolidin-1-yl)acetamide

[0958]

Chemical formula

[0959] The title product was obtained by the same procedure described for the synthesis of Example 243 using N1,N1-dimethylethane-1,2-diamine instead of cyclopropylamine. MS(ESI, m / z): 625.3[M+H] +

[0960] 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)pyrrolidin-1-yl)acetamide

[0961] [Chemical Structure]

[0962] (S)-2-(3-((6-Chloropyrimidin-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 was an intermediate in the synthesis of Example 140.

[0963] A solution of (S)-2-(3-((6-Chloropyrimidin-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 (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 at 80 °C for 4 hours. The mixture was then separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to give the corresponding product (180 mg, 58%). MS (ESI, m / z): 615.3 [M+H] +

[0964] 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)pyrrolidin-1-yl)acetamide

[0965]

Chem.

[0966] The title product was obtained by the same procedure as described for the synthesis of Example 248 using (1-methyl-1H-pyrazol-4-yl)boronic acid instead of phenylboronic acid. MS(ESI, m / z): 619.3 [M+H] +

[0967] 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-dimethylcyclohex-1-en-1-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)acetamide

[0968]

Chem.

[0969] The title product was obtained by the same procedure as described for the synthesis of Example 248 using (4,4-dimethylcyclohex-1-en-1-yl)boronic acid instead of phenylboronic acid. MS(ESI, m / z): 647.3 [M+H] +

[0970] Example 251: Synthesis of (S)-2-(3-((6-(3,6-dihydro-2H-pyran-4-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

[0971]

Chem.

[0972] The title product was obtained by the same procedure described for the synthesis of Example 248 using (3,6-dihydro-2H-pyran-4-yl)boronic acid instead of phenylboronic acid. MS(ESI, m / z): 621.3 [M+H] +

[0973] 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-dimethylcyclohex-1-en-1-yl)pyrimidin-2-yl)oxy)pyrrolidin-1-yl)acetamide

[0974]

Chemical formula

[0975] The title product was obtained by the same procedure described for the synthesis of Example 250 using 4-chloropyrimidin-2-ol instead of 6-chloropyrimidin-4-ol. MS(ESI, m / z): 647.4 [M+H] +

[0976] Example 253: Synthesis of (S)-2-(3-((4-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-2-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

[0977]

Chemical formula

[0978] The title product was obtained by the same procedure described for the synthesis of Example 251 using 4-chloropyrimidin-2-ol instead of 6-chloropyrimidin-4-ol. MS(ESI, m / z): 621.3 [M+H] +

[0979] 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)pyrrolidin-1-yl)acetamide

[0980]

Chemical formula

[0981] The title product was obtained by the same procedure as described for the synthesis of Example 248 using 4-chloropyrimidin-2-ol instead of 6-chloropyrimidin-4-ol. MS(ESI, m / z): 614.3 [M+H] +

[0982] 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)pyrrolidin-1-yl)acetamide

[0983]

Chemical formula

[0984] The title product was obtained by the same procedure as 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] +

[0985] Example 256: (S)-N-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl )-Synthesis of -2-(3-((5-(pyridin-4-yl)pyrimidin-2-yl)oxy)pyrrolidin-1-yl)acetamide

[0986]

Chem.

[0987] The title product was obtained by the same procedure as described for the synthesis of Example 255 using pyridin-4-ylboronic acid instead of pyridin-3-ylboronic acid. MS(ESI, m / z): 616.3 [M+H] +

[0988] 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)pyrrolidin-1-yl)acetamide

[0989]

Chem.

[0990] The title product was obtained by the same procedure as described for the synthesis of Example 248 using 2-chloropyrimidin-5-ol instead of 6-chloropyrimidin-4-ol. MS(ESI, m / z): 615.3 [M+H] +

[0991] 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)pyrrolidin-1-yl)acetamide

[0992]

Chem.

[0993] The title product was obtained by the same procedure as described for the synthesis of Example 257 using pyridin-3-ylboronic acid instead of phenylboronic acid. MS(ESI, m / z): 616.3 [M+H] +

[0994] 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)pyrrolidin-1-yl)acetamide

[0995]

Chemical formula

[0996] The title product was obtained by the same procedure as described for the synthesis of Example 257 using pyridin-4-ylboronic acid instead of phenylboronic acid. MS(ESI, m / z): 616.3 [M+H] +

[0997] Example 260: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1,3-dione

[0998]

Chemical formula

[0999]

Chemical formula

[1000] A mixture of 3-[2-[(1,5-dimethylpyrazol-3-yl)amino]-5-methyl-pyrimidin-4-yl]-1H-indole-7-amine (1.00 equivalent, 15 mg, 0.0450 mmol) and isobenzofuran-1,3-dione (2.00 equivalents, 13 mg, 0.0900 mmol) in 1,4-dioxane (0.5000 mL) was stirred at 100 °C overnight. After cooling to room temperature, the reaction mixture was separated by preparative HPLC and dried in vacuo to afford the desired product as a white solid (50% yield). 1 1H NMR (600 MHz, CD3OD) δ 8.94 (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 = 7.8 Hz, 1H), 7.33 (d, J = 7.4 Hz, 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] +

[1001] Example 261: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-fluoroisoindoline-1,3-dione

[1002]

Chemical Structure

[1003] The title product was obtained as described for Example 260 in General Method D using 4-fluoroisobenzofuran-1,3-dione. MS (ESI, m / z): 482.1 [M + H] +

[1004] 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)isoindoline-1,3-dione

[1005] [Chemical formula]

[1006] Using 4-bromoisobenzofuran-1,3-dione, the title product was obtained as described for Example 260 in General Method D. MS(ESI, m / z): 542.1 [M+H] +

[1007] Example 263: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-hydroxyisoindoline-1,3-dione

[1008] [Chemical formula]

[1009] Using 4-hydroxyisobenzofuran-1,3-dione, the title product was obtained as described for Example 260 in General Method D. MS(ESI, m / z): 480.1 [M+H] +

[1010] Example 264: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-5-nitroisoindoline-1,3-dione

[1011] [Chemical formula]

[1012] Using 5-nitroisobenzofuran-1,3-dione, the title product was obtained as described for Example 260 in General Method D. MS(ESI, m / z): 509.1 [M+H] +

[1013] 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

[1014]

Chem.

[1015] Using pyrrolo[3,4-b]pyridine-5,7-dione, the title product was obtained as described for Example 260 in General Method D. MS(ESI, m / z): 465.1 [M+H] +

[1016] 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)isoindolin-1-one

[1017]

Chem.

[1018]

Chem.

[1019] 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) under N2. The resulting mixture was heated at 80 °C overnight. The reaction mixture was cooled to room temperature and then extracted from water (20 mL) with DCM (2 × 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was then purified by flash column chromatography eluting with 30% EtOAc in n-hexane. The desired fractions were concentrated to dryness in vacuo to afford the intermediate bromide, 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-indol-7-amine (33.3 mg, 0.10 mmol). The resulting mixture was heated at 120 °C overnight. The reaction mixture was cooled to room temperature, purified by preparative HPLC, and dried in vacuo to afford the desired product as a white solid (45% yield over two steps). 1 H NMR (600 MHz, cd3od) δ 8.86 (brs, 1H), 8.34 (s, 1H), 8.17 (brs, 1H), 7.93 (d, J = 7.8 Hz, 2H). 7.89 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.8 Hz, 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] +

[1020] Example 267: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one

[1021]

Chemical Structure

[1022] Using methyl 2-methylbenzoate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 450.2 [M+H] +

[1023] Example 268: Synthesis of 2-(3-(2-((1,5-Dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-6-nitroisoindolin-1-one

[1024]

Chemical Structure

[1025] Using methyl 2-methyl-5-nitrobenzoate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 495.1 [M+H] +

[1026] 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)isoindolin-1-one

[1027]

Chemical Structure

[1028] Using methyl 5-amino-2-methylbenzoate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 465.2 [M+H] +

[1029] 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)isoindolin-1-one

[1030]

Chem.

[1031] Using methyl 4-bromo-2-methylbenzoate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 528.1 [M+H] +

[1032] Example 271: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-nitroisoindolin-1-one

[1033]

Chem.

[1034] Using methyl 2-methyl-3-nitrobenzoate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 495.2 [M+H] +

[1035] 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)isoindolin-1-one

[1036]

Chem.

[1037] Using methyl 3-amino-2-methylbenzoate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 465.2 [M+H] +

[1038] 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)isoindolin-1-one

[1039]

Chemical Structure

[1040] Using methyl 2-chloro-6-methylbenzoate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 484.1 [M+H] +

[1041] Example 274: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-nitroisoindolin-1-one

[1042]

Chemical Structure

[1043] Using methyl 2-methyl-6-nitrobenzoate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 495.1 [M+H] +

[1044] Example 275: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-iodoisoindolin-1-one

[1045]

Chemical Structure

[1046] Methyl 2-iodo-6-methylbenzoate was used to obtain the title product as described for Example 266 in General Method E. MS(ESI, m / z): 576.1 [M+H] +

[1047] 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)isoindolin-1-one

[1048]

Chemical Structure

[1049] Methyl 2-amino-6-methylbenzoate was used to obtain the title product as described for Example 266 in General Method E. MS(ESI, m / z): 465.2 [M+H] +

[1050] 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)isoindolin-1-one

[1051]

Chemical Structure

[1052] Methyl 2-bromo-6-methylbenzoate was used to obtain the title product as described for Example 266 in General Method E. MS(ESI, m / z): 528.1 [M+H] +

[1053] Example 278: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-iodoisoindolin-1-one

[1054] [Chemical formula]

[1055] Using methyl 3-iodo-2-methylbenzoate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 576.1 [M+H] +

[1056] Example 279: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-6-methoxyisoindolin-1-one

[1057] [Chemical formula]

[1058] Using methyl 5-methoxy-2-methylbenzoate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 480.2 [M+H] +

[1059] 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-dimethoxyisoindolin-1-one

[1060] [Chemical formula]

[1061] Using methyl 3,5-dimethoxy-2-methylbenzoate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 510.2 [M+H] +

[1062] Example 281: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-hydroxyisoindolin-1-one

[1063]

Chemical formula

[1064] Using methyl 3-hydroxy-2-methylbenzoate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 466.2 [M+H] +

[1065] Example 282: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoroisoindolin-1-one

[1066]

Chemical formula

[1067] Using methyl 2-fluoro-6-methylbenzoate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 468.2 [M+H] +

[1068] 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-fluoroisoindolin-1-one

[1069]

Chemical formula

[1070] Methyl 3-bromo-6-fluoro-2-methylbenzoate was used to obtain the title product as described for Example 266 in General Method E. MS (ESI, m / z): 546.1 [M+H] +

[1071] 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)isoindolin-1-one

[1072]

Chem.

[1073] Methyl 5-bromo-2-methylbenzoate was used to obtain the title product as described for Example 266 in General Method E. MS (ESI, m / z): 528.1 [M+H] +

[1074] 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

[1075]

Chem.

[1076] Methyl 5-bromo-3-methylpicolinate was used to obtain the title product as described for Example 266 in General Method E. MS (ESI, m / z): 529.1 [M+H] +

[1077] 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

[1078]

Chemical Structure

[1079] Using methyl 4-bromo-3-methylpicolinate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 529.1 [M+H] +

[1080] 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

[1081]

Chemical Structure

[1082] Using methyl 3,5-dimethylpicolinate, the title product was obtained as described for Example 266 in General Method E. MS(ESI, m / z): 465.2 [M+H] +

[1083] 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

[1084]

Chemical Structure

[1085] Using methyl 3-methylpicolinate, the title product was obtained as described for Example 266 in General Method E. MS (ESI, m / z): 451.2 [M+H] +

[1086] 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

[1087]

Chemical Structure

[1088] Using methyl 5-bromo-4-methylnicotinate, the title product was obtained as described for Example 266 in General Method E. MS (ESI, m / z): 529.1 [M+H] +

[1089] 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

[1090]

Chemical Structure

[1091] Using methyl 2-bromo-3-methylnicotinate, the title product was obtained as described for Example 266 in General Method E. MS (ESI, m / z): 529.1 [M+H] +

[1092] 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-oxoisoindolin-5-yl)cyclopropanecarboxamide

[1093]

Chem.

[1094]

Chem.

[1095] 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)isoindolin-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) was added cyclopropanecarboxylic acid (9 mg, 0.11 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to afford the corresponding product (60% yield) as a white solid. MS (ESI, m / z): 533.2 [M+H] +

[1096] 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-oxoisoindolin-4-yl)cyclohexanecarboxamide

[1097]

Chem.

[1098] 7-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and cyclohexanecarboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI,m / z):575.2[M+H] +

[1099] 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-oxoisoindolin-4-yl)benzamide

[1100]

Chemical formula

[1101] 7-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and benzoic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI,m / z):569.2[M+H] +

[1102] 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-oxoisoindolin-4-yl)benzamide

[1103]

Chemical formula

[1104] Using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and benzoic acid, the title product was obtained as described for Example 291 in General Method F. MS(ESI, m / z): 569.2 [M+H] +

[1105] 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-oxoisoindolin-4-yl)cyclohexanecarboxamide

[1106]

Chemical Structure

[1107] Using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and cyclohexanecarboxylic acid, the title product was obtained as described for Example 291 in General Method F. MS(ESI, m / z): 575.2 [M+H] +

[1108] 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-oxoisoindolin-4-yl)morpholine-4-carboxamide

[1109]

Chemical Structure

[1110] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and morpholine-4-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 578.2 [M+H] +

[1111] 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-oxoisoindolin-4-yl)picolylamide

[1112]

Chemical formula

[1113] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and picolinic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 570.2 [M+H] +

[1114] 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-oxoisoindolin-4-yl)nicotinamide

[1115]

Chemical formula

[1116] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and nicotinic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 570.2 [M+H] +

[1117] 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-oxoisoindolin-4-yl)oxazole-4-carboxamide

[1118]

Chemical formula

[1119] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and oxazole-4-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z) : 560.2 [M+H] +

[1120] 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-oxoisoindolin-4-yl)cyclopropanecarboxamide

[1121]

Chemical formula

[1122] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and cyclopropanecarboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI,m / z):533.2[M+H] +

[1123] 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-oxoisoindolin-4-yl)isonicotinamide

[1124]

Chemical formula

[1125] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl) amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and isonicotinic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI,m / z):570.2[M+H] +

[1126] 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-oxoisoindolin-4-yl)pyridazine-4-carboxamide

[1127]

Chemical formula

[1128] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and pyridazine-4-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI,m / z):571.2[M+H] +

[1129] 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-oxoisoindolin-4-yl)-4-methylcyclohexane-1-carboxamide

[1130]

Chemical Structure

[1131] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and 4-methylcyclohexane-1-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI,m / z):589.3[M+H] +

[1132] 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-oxoisoindolin-4-yl)-2-(3-hydroxyphenyl)acetamide

[1133]

Chemical Structure

[1134] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and 2-(3-hydroxyphenyl)acetic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 599.2 [M+H] +

[1135] 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-oxoisoindolin-4-yl)-2-phenylacetamide

[1136]

Chemical formula

[1137] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and 2-phenylacetic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 583.2 [M+H] +

[1138] 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-oxoisoindolin-4-yl)-1-methylpiperidine-4-carboxamide

[1139]

Chemical formula

[1140] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and 1-methylpiperidine-4-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 590.3[M+H] +

[1141] 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-oxoisoindolin-4-yl)-1-methylpiperidine-3-carboxamide

[1142]

Chemical Structure

[1143] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and 1-methylpiperidine-3-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 590.3[M+H] +

[1144] 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-oxoisoindolin-4-yl)-5-oxopyrrolidine-2-carboxamide

[1145]

Chemical Structure

[1146] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and 5-oxopyrrolidine-2-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 576.2 [M+H] +

[1147] Example 309: N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl) -1-oxoisoindolin-4-yl)cyclohex-3-ene-1-carboxamide synthesis

[1148]

Chemical formula

[1149] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and cyclohex-3-ene-1-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 573.2 [M+H] +

[1150] Example 310: N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindolin-4-yl)cyclopent-3-ene-1-carboxamide synthesis

[1151]

Chemical formula

[1152] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and cyclopent-3-ene-1-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI , m / z): 559.2 [M+H] +

[1153] 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-oxoisoindolin-4-yl)-1-methylcyclopent-3-ene-1-carboxamide

[1154]

Chem.

[1155] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and 1-methylcyclopent-3-ene-1-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 573.2 [M+H] +

[1156] 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-oxoisoindolin-4-yl)cycloheptanecarboxamide

[1157]

Chem.

[1158] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and cycloheptanecarboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 589.3 [M+H] +

[1159] 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-oxoisoindolin-4-yl)-2-oxoimidazolidine-1-carboxamide

[1160]

Chemical formula

[1161] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and 2-oxoimidazolidine-1-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 577.2 [M+H] +

[1162] 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-oxoisoindolin-4-yl)-2,3-dihydro-1H-inden-2-carboxamide

[1163]

Chemical formula

[1164] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and 2,3-dihydro-1H-inden-2-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 609.2[M+H] +

[1165] 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-oxoisoindolin-4-yl)pyrrolidine-3-carboxamide

[1166]

Chem.

[1167] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and (R)-pyrrolidine-3-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 562.2[M+H] +

[1168] 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-oxoisoindolin-4-yl)pyrrolidine-3-carboxamide

[1169]

Chem.

[1170] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and (S)-pyrrolidine-3-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 562.2 [M+H] +

[1171] 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-oxoisoindolin-4-yl)-5-oxopyrrolidine-2-carboxamide

[1172]

Chemical formula

[1173] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and (S)-5-oxopyrrolidine-2-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 576.2 [M+H] +

[1174] 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-oxoisoindolin-4-yl)-5-oxopyrrolidine-2-carboxamide

[1175]

Chemical formula

[1176] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and (R)-5-oxopyrrolidine-2-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 576.2 [M+H] +

[1177] 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-oxoisoindolin-4-yl)piperidine-3-carboxamide

[1178]

Chemical Structure

[1179] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and piperidine-3-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F MS(ESI, m / z): 576.2 [M+H] +

[1180] 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-oxoisoindolin-4-yl)-4-oxocyclohexane-1-carboxamide

[1181]

Chemical Structure

[1182] Using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and 4-oxocyclohexane-1-carboxylic acid, the title product was obtained as described for Example 291 in General Method F. MS(ESI,m / z):589.2[M+H] +

[1183] 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-oxoisoindolin-4-yl)-5-methylisoxazole-4-carboxamide

[1184]

Chemical Structure

[1185] Using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and 5-methylisoxazole-4-carboxylic acid, the title product was obtained as described for Example 291 in General Method F. MS(ESI,m / z):574.2[M+H] +

[1186] 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-oxoisoindolin-4-yl)-2-methyloxazole-4-carboxamide

[1187]

Chemical Structure

[1188] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and 2-methyloxazole-4-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 574.2 [M+H] +

[1189] 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-oxoisoindolin-4-yl)oxazole-5-carboxamide

[1190]

Chemical Structure

[1191] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and oxazole-5-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 560.2 [M+H] +

[1192] 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-oxoisoindolin-4-yl)isoxazole-3-carboxamide

[1193]

Chemical Structure

[1194] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and isoxazole-3-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 560.2 [M+H] +

[1195] Example 325: N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl) -1-oxoisoindolin-4-yl)-5-methylisoxazole-3-carboxamide synthesis

[1196]

Chemical formula

[1197] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and 5-methylisoxazole-3-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 574.2 [M+H] +

[1198] Example 326: N-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindolin-4-yl)tetrahydrofuran-3-carboxamide synthesis

[1199]

Chemical formula

[1200] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and tetrahydrofuran-3-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI,m / z):563.2[M+H] +

[1201] 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-oxoisoindolin-4-yl)tetrahydro-2H-pyran-3-carboxamide

[1202]

Chem.

[1203] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and tetrahydro-2H-pyran-3-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI,m / z):577.2[M+H] +

[1204] 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-oxoisoindolin-4-yl)-4-methyltetrahydro-2H-pyran-4-carboxamide

[1205]

Chem.

[1206] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and 4-methyltetrahydro-2H-pyran-4-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 591.2 [M+H] +

[1207] 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-oxoisoindolin-4-yl)-3-methylcyclohexane-1-carboxamide

[1208]

Chemical formula

[1209] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and 3-methylcyclohexane-1-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 589.3 [M+H] +

[1210] 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-oxoisoindolin-4-yl)-4-methylcyclohex-3-ene-1-carboxamide

[1211]

Chemical formula

[1212] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and 4-methylcyclohex-3-ene-1-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 587.2 [M+H] +

[1213] 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-indol-7-yl)-1-oxoisoindolin-4-yl)pyrrolidine-2-carboxamide

[1214]

Chemical formula

[1215] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and (2R,4S)-4-aminopyrrolidine-2-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 577.2 [M+H] +

[1216] 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-oxoisoindolin-4-yl)-3-methylpiperidine-3-carboxamide

[1217]

Chemical formula

[1218] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and 3-methylpiperidine-3-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI,m / z):590.3[M+H] +

[1219] 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-oxoisoindolin-4-yl)-1-methylpyrrolidine-3-carboxamide

[1220]

Chemical formula

[1221] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and (R)-1-methylpyrrolidine-3-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI,m / z):576.2[M+H] +

[1222] 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-oxoisoindolin-4-yl)-5-methylnicotinamide

[1223]

Chemical formula

[1224] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and 5-methylnicotinic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI,m / z):584.2[M+H] +

[1225] 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-oxoisoindolin-4-yl)-2-(dimethylamino)acetamide

[1226]

Chemical formula

[1227] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and dimethylglycine were used to obtain the title product as described for Example 291 in General Method F. MS(ESI,m / z):550.2[M+H] +

[1228] 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-oxoisoindolin-4-yl)cyclopentanecarboxamide

[1229]

Chemical formula

[1230] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and cyclopentanecarboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 561.2 [M+H] +

[1231] 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-oxoisoindolin-4-yl)tetrahydro-2H-pyran-4-carboxamide

[1232]

Chemical formula

[1233] 4-Amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and tetrahydro-2H-pyran-4-carboxylic acid were used to obtain the title product as described for Example 291 in General Method F. MS(ESI, m / z): 577.2 [M+H] +

[1234] 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-oxoisoindolin-4-yl)furan-3-carboxamide

[1235]

Chemical formula

[1236] Using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and furan-3-carboxylic acid, the title product was obtained as described for Example 291 in General Method F. MS(ESI, m / z): 559.2 [M+H] +

[1237] 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-oxoisoindolin-4-yl)-6-hydroxypyrimidine-4-carboxamide

[1238]

Chemical Structure

[1239] Using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and 6-hydroxypyrimidine-4-carboxylic acid, the title product was obtained as described for Example 291 in General Method F. MS(ESI, m / z): 587.2 [M+H] +

[1240] 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-oxoisoindolin-4-yl)benzenesulfonamide

[1241]

Chemical Structure

[1242] A mixture of 7-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one (46 mg, 0.10 mmol) and benzenesulfonyl chloride (19 mg, 0.11 mmol) in pyridine (0.5 mL) was heated to reflux for 12 h. After cooling to room temperature, the reaction mixture was separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to give the corresponding product as a white solid (55% yield). 1 1H NMR (600 MHz, CD3OD) δ 8.99 (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] +

[1243] 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-oxoisoindolin-4-yl)benzenesulfonamide

[1244]

Chemical Structure

[1245] The title product was obtained as described for Example 340 in General Method G using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and benzenesulfonyl chloride. MS (ESI, m / z): 605.2 [M+H] +

[1246] 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-oxoisoindolin-4-yl)methanesulfonamide

[1247]

Chem.

[1248] Using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and methanesulfonyl chloride, the title product was obtained as described for Example 340 in General Method G. MS(ESI, m / z): 543.1 [M+H] +

[1249] 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-oxoisoindolin-4-yl)-4-methylbenzenesulfonamide

[1250]

Chem.

[1251] Using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and 4-methylbenzenesulfonyl chloride, the title product was obtained as described for Example 340 in General Method G. MS(ESI, m / z): 619.2 [M+H] +

[1252] 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-oxoisoindolin-4-yl)propane-2-sulfonamide

[1253]

Chem.

[1254] Using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and propane-2-sulfonyl chloride, the title product was obtained as described for Example 340 in General Method G. MS(ESI, m / z): 571.2 [M+H] +

[1255] 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-oxoisoindolin-4-yl)-4-fluoro-3-methylbenzenesulfonamide

[1256]

Chem.

[1257] Using 4-amino-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and 4-fluoro-3-methylbenzenesulfonyl chloride, the title product was obtained as described for Example 340 in General Method G. MS(ESI, m / z): 637.2 [M+H] +

[1258] 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)isoindolin-1-one

[1259]

Chem.

[1260]

Chem.

[1261]

Chem.

[1262] A mixture of chloro-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one (prepared as 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 cartridge and purified by preparative HPLC to give the corresponding product as a white solid (yield 35%). 1 1H NMR (600 MHz, CD3OD) δ 8.82 (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] +

[1263] Example 347: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-morpholinoisoindolin-1-one

[1264]

Chemical formula

[1265] Using 7-chloro-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and morpholine, the title product was obtained as described for Example 346 in General Method H. MS(ESI, m / z): 535.2 [M+H] +

[1266] 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)isoindolin-1-one

[1267]

Chemical formula

[1268] Using 7-chloro-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and 1-methylpiperazine, the title product was obtained as described for Example 346 in General Method H. MS(ESI, m / z): 548.2 [M+H] +

[1269] Example 349: 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7- (Dimethylamino)isoindolin-1-one synthesis

[1270]

Chem.

[1271] Using 7-chloro-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and dimethylamine hydrochloride, the title product was obtained as described for Example 346 in General Method H. MS(ESI, m / z): 493.2[M + H] +

[1272] 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)isoindolin-1-one

[1273]

Chem.

[1274] Using 7-chloro-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and phenylmethanamine, the title product was obtained as described for Example 346 in General Method H. MS(ESI, m / z): 555.2[M + H] +

[1275] 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)isoindolin-1-one

[1276]

Chem.

[1277] Using 7-chloro-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and cyclopropylmethanamine, the title product was obtained as described for Example 346 in General Method H. MS(ESI, m / z): 519.2 [M+H] +

[1278] Example 352: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-morpholinoisoindolin-1-one

[1279]

Chemical formula

[1280] Using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and morpholine, the title product was obtained as described for Example 346 in General Method H. MS(ESI, m / z): 535.2 [M+H] +

[1281] 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)isoindolin-1-one

[1282]

Chemical formula

[1283] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and cyclopropylmethanamine were used to obtain the title product as described for Example 346 in General Method H. MS(ESI,m / z):519.2[M+H] +

[1284] 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)isoindolin-1-one

[1285]

Chemical Structure

[1286] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and phenylmethanamine were used to obtain the title product as described for Example 346 in General Method H. MS(ESI,m / z):555.2[M+H] +

[1287] 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)isoindolin-1-one

[1288]

Chemical Structure

[1289]

Chemical Structure

[1290] 6-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one (prepared as 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 a stirred mixture of ethynylbenzene (11 mg, 0.11 mmol) in THF (1 mL) were heated to reflux for 12 h. After cooling to room temperature, the reaction mixture was separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to give the corresponding product as a white solid (70% yield). 1 H NMR (600 MHz, cd3od) δ 8.84 (s, 1H), 8.31 (s, 1H), 8.14 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.4 Hz, 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] +

[1291] 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)isoindolin-1-one

[1292]

Chemical Structure

[1293] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and ethynylbenzene were used to obtain the title product as described for Example 355 in General Method I. MS(ESI,m / z):550.2[M+H] +

[1294] 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)isoindolin-1-one

[1295] [Chemical formula]

[1296] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and 4-ethynylaniline were used to obtain the title product as described for Example 355 in General Method I. MS(ESI,m / z):565.2[M+H] +

[1297] 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-oxoisoindolin-4-yl)acrylamide

[1298] [Chemical formula]

[1299] [Chemical formula]

[1300] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one (prepared as 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 a mixture of acrylamide (8 mg, 0.11 mmol) was heated to 130 °C for 12 h. After cooling to room temperature, the reaction mixture was separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to give the corresponding product as a white solid (yield 75%). 1 H NMR (400 MHz, cd3od) δ 8.88 (m, 2H), 8.39 (s, 1H), 8.23 (s, 1H), 8.03 - 7.90 (m, 1H), 7.71 (m, 2H), 7.47 (m, 2H), 6.78 (d, J = 15.9 Hz, 1H), 5.98 (d, J = 0.6 Hz, 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] +

[1301] 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-oxoisoindolin-4-yl)-N,N-dimethylacrylamide

[1302]

Chem.

[1303] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7-fluoroisoindolin-1-one and N,N-dimethylacrylamide were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 565.2 [M+H] +

[1304] 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-oxoisoindolin-4-yl)-N,N-dimethylacrylamide

[1305]

Chemical Structure

[1306] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and N,N-dimethylacrylamide were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 547.2 [M+H] +

[1307] 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-oxoisoindolin-4-yl)-2-methylacrylamide

[1308]

Chemical Structure

[1309] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and methacrylamide were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 533.2 [M+H] +

[1310] 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)isoindoline-1-one

[1311]

Chemical formula

[1312] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and but-3-en-2-one were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 518.2 [M+H] +

[1313] 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-oxoisoindolin-4-yl)-N-methylacrylamide

[1314]

Chemical formula

[1315] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and N-methylacrylamide were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 533.2 [M+H] +

[1316] 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-oxoisoindolin-4-yl)-N-ethylacrylamide

[1317]

Chemical formula

[1318] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and N-ethylacrylamide were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 547.2 [M+H] +

[1319] 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-oxoisoindolin-4-yl)acrylamide

[1320]

Chemical formula

[1321] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and N-cyclopropylacrylamide were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 559.2 [M+H] +

[1322] 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-oxoisoindolin-4-yl)acrylohydrazide

[1323]

Chemical formula

[1324] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and acrylohydrazide were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 534.2 [M+H] +

[1325] 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-oxoisoindolin-4-yl)acrylic acid

[1326]

Chemical formula

[1327] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and acrylic acid were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 520.2 [M+H] +

[1328] Example 368: (E)-3-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindolin-4-yl)-N,N-diethylacrylamide Synthesis

[1329]

Chemical Structure

[1330] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and N,N-diethylacrylamide were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 575.2 [M+H] +

[1331] 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-oxoisoindolin-4-yl)acrylamide

[1332]

Chemical Structure

[1333] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and N,N-dibutylacrylamide were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 631.3 [M+H] +

[1334] 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-oxoisoindolin-4-yl)-N-isopropylacrylamide

[1335]

Chemical Structure

[1336] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and N-isopropylacrylamide were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 577.3 [M+H] +

[1337] 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-indol-7-yl)-1-oxoisoindolin-4-yl)acrylamide

[1338]

Chemical Structure

[1339] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and N-(tert-butyl)acrylamide were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 575.2 [M+H] +

[1340] 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-oxoisoindolin-4-yl)-N-(2-hydroxyethyl)acrylamide

[1341]

Chemical formula

[1342] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one and N-(2-hydroxyethyl)acrylamide were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 563.2 [M+H] +

[1343] 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-oxoisoindolin-4-yl)-N-propylacrylamide

[1344]

Chemical formula

[1345] Using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and N-propylacrylamide, the title product was obtained as described for Example 358 in General Method J. MS(ESI, m / z): 561.2[M+H] +

[1346] 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-oxoisoindolin-4-yl)-N-(2-methoxyethyl)acrylamide

[1347]

Chemical formula

[1348] Using 4-bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and N-(2-methoxyethyl)acrylamide, the title product was obtained as described for Example 358 in General Method J. MS(ESI, m / z): 577.2[M+H] +

[1349] 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-hydroxyprop-1-en-1-yl)isoindolin-1-one

[1350]

Chemical formula

[1351] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl) amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and prop-2-en-1-ol were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 506.2 [M+H] +

[1352] 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-oxoisoindolin-4-yl)-N-ethyl-2-methylacrylamide

[1353]

Chemical Structure

[1354] 4-Bromo-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one and N-ethylmethacrylamide were used to obtain the title product as described for Example 358 in General Method J. MS(ESI, m / z): 561.2 [M+H] +

[1355] Example 377: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-phenylisoindolin-1-one

[1356]

Chemical Structure

[1357]

Chemical Structure

[1358] [Process a’’’] Preparation of methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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’-bi(1,3,2-dioxaborolane) (1.90 g, 7.50 mmol), Pd(dppf)Cl2 (1 82.9 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 filtered through Celite®. The filtrate was then concentrated to dryness in vacuo and purified by flash column chromatography eluting with 30% EtOAc in n-hexane. The desired fractions were concentrated to dryness in vacuo to afford the corresponding product as a colorless oil (85% yield). 1 1H NMR (600 MHz, CDCl3) δ 7.55 - 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] +

[1359] [Step b’’’] Preparation of methyl 2-(bromomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. A suspension of methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) under N2. 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) with DCM (3 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was then purified by flash column chromatography eluting with 30% EtOAc in n-hexane. The desired fractions were concentrated to dryness in vacuo to afford the corresponding product as a colorless oil (84% yield). 1 1H NMR (600 MHz, CDCl3) δ 7.84 - 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] +

[1360] [Step c’’’] A suspension of 3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine (prepared as 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-dioxaborolan-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) with DCM (3 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting mixture was dried in vacuo and used without further purification. MS (ESI, m / z): 576.2 [M+H] +

[1361] 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-dioxaborolan-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) was added with bromobenzene (11 mg, 0.070 mmol). The reaction mixture was heated at 100 °C for 12 h. After cooling to room temperature, the reaction mixture was separated from a UCT SPE CUBCX cartridge and purified by preparative HPLC to give the corresponding product (50% yield) as a white solid. 1 1H NMR (600 MHz, CD3OD) δ 8.88 (brs, 1H), 8.81 (s, 1H), 8.39 (s, 1H), 8.22 (brs, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 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] +

[1362] Example 378: 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl )amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-5-phenylisoindolin-1-one synthesis

[1363]

Chemical formula

[1364] Methyl 4-bromo-2-methylbenzoate and bromobenzene were used to obtain the title product as described for Example 377 in General Procedure K. MS (ESI, m / z): 526.2 [M+H] +

[1365] Example 379: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-6-phenylisoindolin-1-one

[1366]

Chem.

[1367] Methyl 5-bromo-2-methylbenzoate and bromobenzene were used to obtain the title product as described for Example 377 in General Procedure K. MS (ESI, m / z): 526.2 [M+H] +

[1368] Example 380: 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl )amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-6-(pyridin-4-yl)isoindolin-1-one synthesis

[1369]

Chem.

[1370] Methyl 5-bromo-2-methylbenzoate and 4-bromopyridine were used to obtain the title product as described for Example 377 in General Procedure K. MS (ESI, m / z): 527.2 [M+H] +

[1371] 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)isoindolin-1-one

[1372]

Chem.

[1373] Using methyl 5-bromo-2-methylbenzoate and tert-butyl 4-bromo-3,6-dihydropyridine-1(2H)-carboxylate, the title product was obtained as described for Example 377 in General Method K (the Boc group of the product was deprotected during the reaction). MS (ESI, m / z): 531.2 [M+H] +

[1374] Example 382: Synthesis of 2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-7- phenylisoindolin-1-one

[1375]

Chem.

[1376] Using methyl 2-bromo-6-methylbenzoate and bromobenzene, the title product was obtained as described for Example 377 in General Method K. MS (ESI, m / z): 526.2 [M+H] +

[1377] 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)isoindolin-1-one

[1378]

Chem.

[1379] The title product was obtained as described for Example 377 in General Method K using methyl 2-bromo-6-methylbenzoate and 4-bromopyridine. MS(ESI, m / z): 527.2 [M+H] +

[1380] 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)isoindolin-1-one

[1381]

Chemical formula

[1382] The title product was obtained as described for Example 377 in General Method K using methyl 2-bromo-6-methylbenzoate and 1-bromocyclohex-1-ene. MS(ESI, m / z): 530.2 [M+H] +

[1383] 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)isoindolin-1-one

[1384]

Chemical formula

[1385] The title product was obtained as described for Example 377 in General Method K using methyl 2-bromo-6-methylbenzoate and 4-bromo-3,6-dihydro-2H-pyran. MS(ESI, m / z): 532.2 [M+H] +

[1386] 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)isoindolin-1-one

[1387]

Chem.

[1388] Using methyl 2-bromo-6-methylbenzoate and 4-bromopyrazole, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 516.2 [M+H] +

[1389] 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)isoindolin-1-one

[1390]

Chem.

[1391] Using methyl 3-bromo-2-methylbenzoate and 4-bromopyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 527.2 [M+H] +

[1392] 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)isoindolin-1-one

[1393]

Chem.

[1394] The title product was obtained as described for Example 377 in General Method K using methyl 3-bromo-2-methylbenzoate and 3-chloropyridine. MS (ESI, m / z): 527.2 [M+H] +

[1395] 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)isoindolin-1-one

[1396]

Chem.

[1397] The title product was obtained as described for Example 377 in General Method K using methyl 3-bromo-2-methylbenzoate and 4-bromo-1-methyl-1H-pyrazole. MS (ESI, m / z): 530.2 [M+H] +

[1398] 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)isoindolin-1-one

[1399]

Chem.

[1400] The title product was obtained as described for Example 377 in General Method K using methyl 3-bromo-2-methylbenzoate and 4-bromo-1H-pyrazole. MS (ESI, m / z): 516.2 [M+H] +

[1401] Example 391: Synthesis of 4-(Cyclohex-1-en-1-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindoline-1-one

[1402]

Chemical formula

[1403] Using methyl 3-bromo-2-methylbenzoate and 1-bromocyclohex-1-ene, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 530.2 [M+H] +

[1404] 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)isoindoline-1-one

[1405]

Chemical formula

[1406] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-3,6-dihydro-2H-pyran, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 532.2 [M+H] +

[1407] 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)isoindoline-1-one

[1408]

Chemical formula

[1409] Using methyl 3-bromo-2-methylbenzoate and 3-bromofuran, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 516.2 [M+H] +

[1410] 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)isoindolin-1-one

[1411]

Chemical formula

[1412] Using methyl 3-bromo-2-methylbenzoate and tert-butyl 4-bromo-3,6-dihydropyridine-1(2H)-carboxylate, the title product was obtained as described for Example 377 in General Method K (the Boc group of the product was deprotected during the reaction). MS(ESI, m / z): 531.2 [M+H] +

[1413] 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)isoindolin-1-one

[1414]

Chemical formula

[1415] Methyl 3-bromo-2-methylbenzoate and 1-bromo-4-(trifluoromethoxy)benzene were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 610.2 [M+H] +

[1416] 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)isoindoline-1-one

[1417]

Chemical formula

[1418] Methyl 3-bromo-2-methylbenzoate and 4-bromoaniline were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 541.2 [M+H] +

[1419] 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-oxoisoindolin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

[1420]

Chemical formula

[1421] Methyl 3-bromo-2-methylbenzoate and tert-butyl 4-bromo-3,6-dihydropyridine-1(2H)-carboxylate were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 631.3 [M+H] +

[1422] Example 398: tert-Butyl (4-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindolin-4-yl)phenyl)carbamate

[1423]

Chemical formula

[1424] The title product was obtained as described for Example 377 in General Method K using methyl 3-bromo-2-methylbenzoate and tert-butyl (4-bromophenyl)carbamate. MS (ESI, m / z): 641.3 [M+H] +

[1425] 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)isoindolin-1-one

[1426]

Chemical formula

[1427] The title product was obtained as described for Example 377 in General Method K using methyl 3-bromo-2-methylbenzoate and 4-bromopyridin-2-amine. MS (ESI, m / z): 542.2 [M+H] +

[1428] 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)isoindolin-1-one

[1429]

Chemical formula

[1430] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-3-fluoropyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 545.2 [M+H] +

[1431] 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)isoindolin-1-one

[1432]

Chem.

[1433] Using methyl 3-bromo-2-methylbenzoate and 5-bromopyridin-2-ol, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 543.2 [M+H] +

[1434] 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)isoindolin-1-one

[1435]

Chem.

[1436] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-2-chloropyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 561.2 [M+H] +

[1437] 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)isoindoline-1-one

[1438]

Chemical formula

[1439] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-5-fluoro-2-methoxypyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 575.2 [M+H] +

[1440] 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)isoindoline-1-one

[1441]

Chemical formula

[1442] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-2-fluoropyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 545.2 [M+H] +

[1443] 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)isoindoline-1-one

[1444]

Chemical formula

[1445] Using methyl 3-bromo-2-methylbenzoate and 5-bromo-2-chloropyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 561.2 [M+H] +

[1446] 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)isoindolin-1-one

[1447] [Chemical formula]

[1448] Using methyl 3-bromo-2-methylbenzoate and 5-bromo-2-methoxypyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 557.2 [M+H] +

[1449] 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)isoindolin-1-one

[1450] [Chemical formula]

[1451] Using methyl 3-bromo-2-methylbenzoate and 5-bromo-2-fluoro-3-methylpyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 559.2 [M+H] +

[1452] 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)isoindolin-1-one

[1453]

Chemical formula

[1454] Using methyl 3-bromo-2-methylbenzoate and 1-(4-bromopyridin-2-yl)piperazine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 611.3 [M+H] +

[1455] 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)isoindolin-1-one

[1456]

Chemical formula

[1457] Using methyl 3-bromo-2-methylbenzoate and 1-((4-bromophenyl)sulfonyl)pyrrolidine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 659.2 [M+H] +

[1458] 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)isoindolin-1-one

[1459] [Chemical formula]

[1460] Using methyl 3-bromo-2-methylbenzoate and (E)-1-(2-bromovinyl)-3-fluorobenzene, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 570.2 [M+H] +

[1461] 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)isoindolin-1-one

[1462] [Chemical formula]

[1463] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-1H-pyrrolo[2,3-b]pyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 566.2 [M+H] +

[1464] 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-oxopiperidine-1-carbonyl)phenyl)isoindolin-1-one

[1465] [Chemical formula]

[1466] Methyl 3-bromo-2-methylbenzoate and 1-(4-bromobenzoyl)piperidin-4-one were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 651.2 [M+H] +

[1467] Example 413: Synthesis of 4-(3,6-dihydro-2H-thiopyran-4-yl)-2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)isoindolin-1-one

[1468]

Chemical formula

[1469] Methyl 3-bromo-2-methylbenzoate and 4-bromo-3,6-dihydro-2H-thiopyran were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 548.2 [M+H] +

[1470] 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)isoindolin-1-one

[1471]

Chemical formula

[1472] Methyl 3-bromo-2-methylbenzoate and 5-bromo-N,N-dimethylpyrimidin-2-amine were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 571.2 [M+H] +

[1473] 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)isoindolin-1-one

[1474]

Chem.

[1475] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-1-(cyclopropylmethyl)-1H-pyrazole, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 570.2 [M+H] +

[1476] 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)isoindolin-1-one

[1477]

Chem.

[1478] Using methyl 3-bromo-2-methylbenzoate and 4-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)morpholine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 629.3 [M+H] +

[1479] 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)isoindolin-1-one

[1480] [Chemical formula]

[1481] Using methyl 3-bromo-2-methylbenzoate and 5-bromopyrimidine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 528.2 [M+H] +

[1482] 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)isoindolin-1-one

[1483] [Chemical formula]

[1484] Using methyl 3-bromo-2-methylbenzoate and 5-bromopyrimidin-2-amine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 543.2 [M+H] +

[1485] 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)isoindolin-1-one

[1486] [Chemical formula]

[1487] Using methyl 3-bromo-2-methylbenzoate and 5-bromopyridin-3-amine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 542.2 [M+H] +

[1488] 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)isoindoline-1-one

[1489]

Chemical formula

[1490] Using methyl 3-bromo-2-methylbenzoate and 5-bromopyridin-2-amine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 542.2 [M+H] +

[1491] 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)isoindoline-1-one

[1492]

Chemical formula

[1493] Using methyl 3-bromo-2-methylbenzoate and 4-bromopyrimidine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 528.2 [M+H] +

[1494] 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)isoindoline-1-one

[1495]

Chemical formula

[1496] Using methyl 3-bromo-2-methylbenzoate and 4-bromopyrimidin-2-amine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 543.2 [M+H] +

[1497] 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)isoindolin-1-one

[1498]

Chemical formula

[1499] Using methyl 3-bromo-2-methylbenzoate and 1-(2-bromopyridin-4-yl)-4-methylpiperazine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 625.3 [M+H] +

[1500] 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)isoindolin-1-one

[1501]

Chemical formula

[1502] Methyl 3-bromo-2-methylbenzoate and 5-bromo-2-(piperazin-1-yl)pyrimidine were used to obtain the title product as described for Example 377 in General Method K. MS (ESI, m / z): 612.3 [M+H] +

[1503] 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)isoindolin-1-one

[1504]

Chem.

[1505] Methyl 3-bromo-2-methylbenzoate and 4-(5-bromopyridin-2-yl)morpholine were used to obtain the title product as described for Example 377 in General Method K. MS (ESI, m / z): 612.2 [M+H] +

[1506] 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)isoindolin-1-one

[1507]

Chem.

[1508] Methyl 3-bromo-2-methylbenzoate and 1-(4-bromophenyl)-4-methylpiperazine were used to obtain the title product as described for Example 377 in General Method K. MS (ESI, m / z): 624.3 [M+H] +

[1509] 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)isoindolin-1-one

[1510] [Chemical formula]

[1511] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-2,6-difluoropyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 563.2 [M+H] +

[1512] 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)isoindolin-1-one

[1513] [Chemical formula]

[1514] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-3,5-difluoropyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 563.2 [M+H] +

[1515] 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)isoindolin-1-one

[1516] [Chemical formula]

[1517] Methyl 3-bromo-2-methylbenzoate and 4-bromo-2-methylpyridine were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 541.2 [M+H] +

[1518] 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'-biisoindoline]-1-one

[1519] [Chemical formula]

[1520] Methyl 3-bromo-2-methylbenzoate and 5-bromoisoindoline were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 567.2 [M+H] +

[1521] 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)isoindoline-1-one

[1522] [Chemical formula]

[1523] Methyl 3-bromo-2-methylbenzoate and 3-bromo-2-fluoropyridine were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 545.2 [M+H] +

[1524] 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-oxoisoindolin-4-yl)benzonitrile

[1525]

Chemical formula

[1526] Using methyl 3-bromo-2-methylbenzoate and 4-bromobenzonitrile, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 551.2[M+H] +

[1527] 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-oxoisoindolin-4-yl)-3-fluorobenzonitrile

[1528]

Chemical formula

[1529] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-3-fluorobenzonitrile, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 569.2[M+H] +

[1530] 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)isoindolin-1-one

[1531]

Chemical formula

[1532] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 1-bromo-2-(trifluoromethyl)benzene as described for Example 377 in General Method K. MS(ESI, m / z): 594.2 [M+H] +

[1533] 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)isoindolin-1-one

[1534]

Chemical formula

[1535] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 3-bromo-2-methoxypyridine as described for Example 377 in General Method K. MS(ESI, m / z): 557.2 [M+H] +

[1536] 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)isoindolin-1-one

[1537]

Chemical formula

[1538] The title product was obtained using methyl 3-bromo-2-methylbenzoate and 4-bromo-N,N-dimethylaniline as described for Example 377 in General Method K. MS(ESI, m / z): 569.2 [M+H] +

[1539] 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)isoindolin-1-one

[1540]

Chem.

[1541] Using methyl 3-bromo-2-methylbenzoate and (2-bromophenyl)methanol, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 556.2 [M+H] +

[1542] 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)isoindolin-1-one

[1543]

Chem.

[1544] Using methyl 3-bromo-2-methylbenzoate and 1-bromo-2-methoxybenzene, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 556.2 [M+H] +

[1545] 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)isoindolin-1-one

[1546]

Chem.

[1547] Using methyl 3-bromo-2-methylbenzoate and 2-bromobiphenyl, the title product was obtained as described for Example 377 in General Procedure K. MS (ESI, m / z): 602.2 [M+H] +

[1548] 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)isoindolin-1-one

[1549]

Chemical formula

[1550] Using methyl 3-bromo-2-methylbenzoate and 1-bromo-2-methylbenzene, the title product was obtained as described for Example 377 in General Procedure K. MS (ESI, m / z): 540.2 [M+H] +

[1551] 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)isoindolin-1-one

[1552]

Chemical formula

[1553] Using methyl 3-bromo-2-methylbenzoate and 2-bromophenol, the title product was obtained as described for Example 377 in General Procedure K. MS (ESI, m / z): 542.2 [M+H] +

[1554] 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-pyrrol-2-yl)isoindolin-1-one

[1555]

Chemical Structure

[1556] Using methyl 3-bromo-2-methylbenzoate and 2-bromo-1H-pyrrole, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 515.2 [M+H] +

[1557] Example 443: tert-Butyl 2-(2-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-1-oxoisoindolin-4-yl)-1H-pyrrole-1-carboxylate

[1558]

Chemical Structure

[1559] Using methyl 3-bromo-2-methylbenzoate and tert-butyl 2-bromo-1H-pyrrole-1-carboxylate, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 615.2 [M+H] +

[1560] 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)isoindolin-1-one

[1561]

Chemical Structure

[1562] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-3,5-dimethylisoxazole, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 545.2 [M+H] +

[1563] 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)isoindolin-1-one

[1564] [Chemical formula]

[1565] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-2-methoxypyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 557.2 [M+H] +

[1566] 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)isoindolin-1-one

[1567] [Chemical formula]

[1568] Using methyl 3-bromo-2-methylbenzoate and 4-bromopyridin-2-ol, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 543.2 [M+H] +

[1569] 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)isoindolin-1-one

[1570]

Chemical formula

[1571] The title product was obtained as described for Example 377 in General Method K using methyl 3-bromo-2-methylbenzoate and 4-bromopyridin-3-amine. MS(ESI, m / z): 542.2 [M+H] +

[1572] 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)isoindolin-1-one

[1573]

Chemical formula

[1574] The title product was obtained as described for Example 377 in General Method K using methyl 3-bromo-2-methylbenzoate and 7-bromoisoquinoline. MS(ESI, m / z): 577.2 [M+H] +

[1575] 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-indazol-5-yl)isoindolin-1-one

[1576]

Chemical formula

[1577] Using methyl 3-bromo-2-methylbenzoate and 5-bromo-1-methyl-1H-indazole, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 580.2 [M+H] +

[1578] 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-indazol-6-yl)isoindolin-1-one

[1579]

Chemical formula

[1580] Using methyl 3-bromo-2-methylbenzoate and 6-bromo-1-methyl-1H-indazole, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 580.2 [M+H] +

[1581] 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)isoindolin-1-one

[1582]

Chemical formula

[1583] Using methyl 3-bromo-2-methylbenzoate and 2-bromo-5-methylthiophene, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 546.2 [M+H] +

[1584] 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)isoindoline-1-one

[1585]

Chemical formula

[1586] Using methyl 3-bromo-2-methylbenzoate and 5-bromo-2,3-dihydro-1H-indene, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 566.2 [M+H] +

[1587] 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)isoindoline-1-one

[1588]

Chemical formula

[1589] Using methyl 3-bromo-2-methylbenzoate and 3-bromo-4-methylthiophene, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 546.2 [M+H] +

[1590] 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)isoindoline-1-one

[1591] [Chemistry]

[1592] The title product was obtained in the general method K using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromo-2-methylpyridine as described for Example 377. MS(ESI, m / z): 559.2 [M+H] +

[1593] 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)isoindolin-1-one

[1594] [Chemistry]

[1595] The title product was obtained in the general method K using methyl 3-bromo-2-methylbenzoate and 4-bromo-3-methylpyridine as described for Example 377. MS(ESI, m / z): 541.2 [M+H] +

[1596] 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)isoindolin-1-one

[1597] [Chemistry]

[1598] Methyl 3-bromo-2-methylbenzoate and 6-bromopyrimidin-4-amine were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 543.2 [M+H] +

[1599] 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-indazol-4-yl)isoindolin-1-one

[1600]

Chemical formula

[1601] Methyl 3-bromo-2-methylbenzoate and 4-bromo-1H-indazole were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 566.2 [M+H] +

[1602] 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-oxoisoindolin-4-yl)benzoic acid

[1603]

Chemical formula

[1604] Methyl 3-bromo-2-methylbenzoate and 2-bromobenzoic acid were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 570.2 [M+H] +

[1605] 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)isoindolin-1-one

[1606]

Chemical formula

[1607] Using methyl 3-bromo-2-methylbenzoate and (4-bromophenyl)methanol, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 556.2[M+H] +

[1608] 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)isoindolin-1-one

[1609]

Chemical formula

[1610] Using methyl 3-bromo-2-methylbenzoate and 3-bromothiophene, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 532.1[M+H] +

[1611] 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)isoindolin-1-one

[1612]

Chemical formula

[1613] Methyl 3-bromo-2-methylbenzoate and 2-bromoaniline were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 541.2 [M+H] +

[1614] 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-oxoisoindolin-4-yl)benzoate

[1615] [Chemical formula]

[1616] Methyl 3-bromo-2-methylbenzoate and methyl 2-bromobenzoate were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 584.2 [M+H] +

[1617] 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)isoindolin-1-one

[1618] [Chemical formula]

[1619] Methyl 3-bromo-2-methylbenzoate and 4-bromo-1-methyl-1,2,3,6-tetrahydropyridine were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 545.2 [M+H] +

[1620] 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-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one

[1621]

Chem.

[1622] The title product was obtained as described for Example 377 in General Method K using methyl 3-bromo-2-methylbenzoate and 4-bromo-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridine. MS(ESI, m / z): 609.2 [M+H] +

[1623] 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)isoindolin-1-one

[1624]

Chem.

[1625] The title product was obtained as described for Example 377 in General Method K using methyl 3-bromo-2-methylbenzoate and 1-(4-bromo-3,6-dihydropyridin-1(2H)-yl)ethan-1-one. MS(ESI, m / z): 573.2 [M+H] +

[1626] 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-oxoisoindolin-4-yl)-5,6-dihydropyridine-1(2H)-carboxamide

[1627]

Chemical formula

[1628] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-5,6-dihydropyridine-1(2H)-carboxamide, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 574.2 [M+H] +

[1629] 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-dioxide-3,6-dihydro-2H-thiopyran-4-yl)isoindolin-1-one

[1630]

Chemical formula

[1631] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-3,6-dihydro-2H-thiopyran 1,1-dioxide, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 580.2 [M+H] +

[1632] 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-oxoisoindolin-4-yl)picolyl nitrile

[1633] [Chem.]

[1634] The title product was obtained in General Method K as described for Example 377 using methyl 3-bromo-2-methylbenzoate and 4-bromopicolinonitrile. MS (ESI, m / z): 552.2 [M+H] +

[1635] 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-oxoisoindolin-4-yl)picolinonitrile

[1636] [Chem.]

[1637] The title product was obtained in General Method K as described for Example 377 using methyl 3-bromo-2-methylbenzoate and 5-bromopicolinonitrile. MS (ESI, m / z): 552.2 [M+H] +

[1638] 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)isoindolin-1-one

[1639] [Chem.]

[1640] Methyl 3-bromo-2-methylbenzoate and (4-bromopyridin-3-yl)methanol were used to obtain the title product as described for Example 377 in General Procedure K. MS (ESI, m / z): 557.2 [M+H] +

[1641] 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)isoindolin-1-one

[1642]

Chem.

[1643] Methyl 3-bromo-2-methylbenzoate and (4-bromopyridin-2-yl)methanol were used to obtain the title product as described for Example 377 in General Procedure K. MS (ESI, m / z): 557.2 [M+H] +

[1644] 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-oxoisoindolin-4-yl)picolinamide

[1645]

Chem.

[1646] Methyl 3-bromo-2-methylbenzoate and 4-bromopicolinamide were used to obtain the title product as described for Example 377 in General Procedure K. MS (ESI, m / z): 570.2 [M+H] +

[1647] 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-oxoisoindolin-4-yl)picolylamide

[1648]

Chemical formula

[1649] Using methyl 3-bromo-2-methylbenzoate and 5-bromopicolylamide, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 570.2 [M+H] +

[1650] 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)isoindolin-1-one

[1651]

Chemical formula

[1652] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-N,N-dimethylpyridin-2-amine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 570.2 [M+H] +

[1653] 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)isoindolin-1-one

[1654]

Chemical formula

[1655] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-N-methylpyridin-2-amine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 556.2 [M+H] +

[1656] 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)isoindolin-1-one

[1657]

Chemical formula

[1658] Using methyl 3-bromo-2-methylbenzoate and 3-bromo-5-methylpyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 541.2 [M+H] +

[1659] 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)isoindolin-1-one

[1660]

Chemical formula

[1661] Using methyl 3-bromo-2-methylbenzoate and 3-bromo-5-fluoropyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 545.2 [M+H] +

[1662] 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)isoindolin-1-one

[1663]

Chemical Structure

[1664] Using methyl 3-bromo-2-methylbenzoate and 4-bromo-2,6-dimethylpyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 555.2[M + H] +

[1665] 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)isoindolin-1-one

[1666]

Chemical Structure

[1667] Using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromopyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 545.2[M + H] +

[1668] 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)isoindolin-1-one

[1669]

Chemical Structure

[1670] Using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromo-2-methoxypyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 575.2 [M+H] +

[1671] 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)isoindolin-1-one

[1672]

Chemical formula

[1673] Using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromo-N-methylpyridin-2-amine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 574.2 [M+H] +

[1674] 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-fluoroisoindolin-1-one

[1675]

Chemical formula

[1676] Methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromo-N,N-dimethylpyridin-2-amine were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 588.2 [M+H] +

[1677] 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)isoindolin-1-one

[1678]

Chemical formula

[1679] Methyl 3-bromo-6-fluoro-2-methylbenzoate and 3-bromo-5-fluoropyridine were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 563.2 [M+H] +

[1680] 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)isoindolin-1-one

[1681]

Chemical formula

[1682] Methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromo-2-fluoropyridine were used to obtain the title product as described for Example 377 in General Method K. MS(ESI, m / z): 563.2 [M+H] +

[1683] 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)isoindolin-1-one

[1684]

Chemical formula

[1685] Using methyl 3-bromo-6-fluoro-2-methylbenzoate and 3-bromo-5-methylpyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 559.2 [M+H] +

[1686] 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)isoindolin-1-one

[1687]

Chemical formula

[1688] Using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromo-3-methylpyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 559.2 [M+H] +

[1689] 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-fluoroisoindolin-1-one

[1690]

Chemical formula

[1691] Using methyl 3-bromo-6-fluoro-2-methylbenzoate and 4-bromopyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 573.2 [M+H] +

[1692] 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)isoindolin-1-one

[1693]

Chem.

[1694] Using methyl 3-bromo-2-methyl-6-nitrobenzoate and 4-bromopyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 572.2 [M+H] +

[1695] 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)isoindolin-1-one

[1696]

Chem.

[1697] Using methyl 3-bromo-6-(dimethylamino)-2-methylbenzoate and 4-bromopyridine, the title product was obtained as described for Example 377 in General Method K. MS(ESI, m / z): 570.2 [M+H]+

[1698] 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)isoindolin-1-one

[1699]

Chemical formula

[1700] The title product was obtained as described for Example 377 in General Method K using methyl 3-bromo-2-methyl-6-(methylamino)benzoate and 4-bromopyridine. MS(ESI, m / z): 556.2 [M+H] +

[1701] 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-phenylisoindolin-1-one

[1702]

Chemical formula

[1703] The title product was obtained as described for Example 377 in General Method K using methyl 3-bromo-6-iodo-2-methylbenzoate and bromobenzene. MS(ESI, m / z): 652.1 [M+H] +

[1704] 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

[1705] [Chem.]

[1706] The title product was obtained using methyl 4-bromo-3-methylpicolinate and bromobenzene as described for Example 377 in General Method K. MS (ESI, m / z): 527.2 [M+H] +

[1707] Example 494: Synthesis of 6-(3-(2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-4-(pyrid...

Claims

1. A compound represented by the following formula (I): 【Chemical 1】 a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein in the formula (I), L １ and L ２ are each independently H; alkyl optionally substituted by a 4- to 6-membered heterocycloalkyl (C １～５ ); or L １ and L ２ are connected to form a 5- to 6-membered ring M is H; halogen; (C １～５ )alkyl; (C ３～７ )cycloalkyl; or (C １～５ )alkoxy, G is H; halogen; (C １～５ ) alkyl; (C １～５ ) alkoxy; or -NH ２ and at least one H of -NH ２ may be substituted by (C １～５ ) alkyl, Y １ is H; or (C １～５ )alkyl, and Z is -C(=O)-; or -CH which may be substituted by one or more (C １～５ ) alkyl; or Z is connected to Y ２ -; or Z forms a 5- to 6-membered ring by connecting with Y １ and Y ３ is a 4- to 6-membered heterocycloalkyl in which at least one H may each independently be replaced by W １ or W ２ ; or when Z connects with Y to form a 5- to 6-membered ring, Y １ connects with Z to form aryl or heteroaryl, and at least one H of the aryl and heteroaryl formed by Y ３ and Z may each independently be replaced by W ３ ; and ３ ​ W １ and W ２ each independently is H; halogen; -OH; -OH, -NH ２ optionally substituted by or -CN (C １～５ alkyl); 5- to 7-membered heterocycloalkyl optionally substituted by (C １～５ alkyl); heteroaryl optionally substituted by (C １～５ alkyl); -COR １ ; -OR ２ ; or -NH ２ and at least one H of -NH ２ may each independently be optionally substituted by heteroaryl, R １ is (C １～５ ) alkoxy; -OH; 5- to 7-membered heterocycloalkyl optionally substituted by (C １～５ ) alkyl; or -NH ２ wherein at least one H of -NH ２ is each independently optionally substituted by (C ３～７ ) cycloalkyl, R ２ is optionally substituted by a heteroaryl (C １～５ )alkyl; aryl ; or heteroaryl, and at least one H of the aryl or heteroaryl is each independently one or more R ２ａ may be substituted by, R of 1 or more ２ａ is, independently of one another, halogen; (C １～５ alkyl which may be substituted by aryl, or 5- to 7-membered heterocycloalkyl which may be substituted by (C １～５ alkyl; (C １～５ cycloalkenyl which may be substituted by (C ５～６ alkyl; 5- to 7-membered heterocycloalkyl which may be substituted by (C １～５ alkyl or -OH; -CF ３ ; (C １～５ alkoxy which may be substituted by aryl; aryl in which at least one H of said aryl may be independently substituted by halogen; (C １～５ heteroaryl which may be substituted by alkyl; thio(C １～５ alkyl; -COR １ａ ; or NR ３ R ４ and R １ａ is (C １～５ ) alkoxy; -OH; 5- to 7-membered heterocycloalkyl optionally substituted by (C １～５ ) alkyl; or -NH ２ , and at least one H of -NH ２ is each independently optionally substituted by (C １～５ ) alkyl or (C ３～７ ) cycloalkyl, R ３ and R ４ are each independently H; halogen; halogen, -CF ３ , -OH, (C １～５ ) alkoxy, -N-[(C １～５ ) alkyl][(C １～５ ) alkyl], aryl or (C ３～７ ) cycloalkyl which may be substituted by (C １～５ ) alkyl; (C ３～７ ) cycloalkyl; (C １～５ ) alkoxy; aryl; or -C(=O)(C １～５ ) alkyl, and W of 1 or more ３ each independently is H; halogen; (C １～５ alkyl; (C １～５ alkoxy; -OH; -NO ２ ; -NR ５ R ６ ; -CH=CR ７ R ８ ; -C≡C-R 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)(NH ２ )-substituted 5- to 7-membered heterocycloalkyl; aryl; or heteroaryl, and at least one H of the aryl or the heteroaryl may be substituted by 1 or more R １０ and R ５ and R ６ each independently is H; (C ３～７ ) cycloalkyl or aryl optionally substituted (C １～５ ) alkyl; 5- to 7-membered heterocycloalkyl optionally substituted by (C １～５ ) alkyl; aryl; -C(=O)R １１ ; or -S(=O) ２ R １２ and R ７ is (C １～５ )alkyl which may be substituted by -OH; aryl which may be substituted by halogen; or -C(=O)R １３ and R ８ is H; or (C １～５ )alkyl, and R ９ is an aryl which may be substituted by -NH ２ and R of 1 or more １０ is, independently of one another, H; halogen; -CN; -CF ３ ; -OH; -OCF ３ ; (C ３～７ ) cycloalkyl, 5- to 7-membered heterocycloalkyl, or (C １～５ ) alkyl which may be substituted by -OH; (C １～５ ) alkoxy; 1 or more (C １～５ ) alkyl or -C(=O)O(C １～５ ) alkyl-substituted -NH ２ ; 5- to 7-membered heterocycloalkyl which may be substituted by (C １～５ ) alkyl; -C(=O)R １４ ; -S(=O) ２ -(5- to 7-membered heterocycloalkyl); or aryl, and R １０ may be connected to each other to form a 5- to 6-membered ring, R １１ is -N(CH ３ ) ２ , aryl, or hydroxyaryl (C １～５ ) alkyl; may contain C(=O) (C ３～７ ) cycloalkyl; １～５ ) optionally substituted with alkyl (C ３～７ ) cycloalkyl; fused with aryl (C ３～７ ) cycloalkyl; １～５ ) optionally substituted with alkyl (C ５～６ ) cycloalkenyl; １～５ ) alkyl or -NH ２ 5- to 7-membered heterocycloalkyl, optionally substituted by aryl; or (C １～５ ) heteroaryl optionally substituted with alkyl or -OH; R １２ is (C １～５ ) alkyl or aryl, wherein at least one H of said aryl is each independently (C １～５ ) alkyl or aryl which may be substituted by halogen, R １３ is (C １～５ ) alkyl; (C １～５ ) alkoxy; -OH; -NH ２ wherein at least one H of -NH ２ is each independently substituted by (C １～５ ) alkyl or OH and may be substituted by (C １～５ ) alkyl-substituted -NH ２ ; (C ３～７ ) cycloalkyl; hydroxy(C １～５ ) alkyl; (C １～５ ) alkoxy(C １～５ ) alkyl; -NH ２ and R １４ is a 5- to 7-membered heterocycloalkyl; -NH ２ ; or -OH, a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

2. Y ３ is azetidinyl; pyrrolidinyl; piperidinyl; tetrahydropyridinyl; or oxopyrrolidinyl, and W １ and W ２ may be substituted by, W １ and W ２ each independently is H; halogen; -OH; alkyl which may be substituted by -OH or -CN １～５ ); methylpiperazinyl; morpholinyl; pyridinyl; methylpyrazolyl; -COR １ ; -OR ２ ; -NH ２ ; -NH(pyridinyl) or -NH(pyrimidinyl), and R １ is (C １～５ ) alkoxy; -OH; -NH ２ ; -NH-(C ３～７ ) cycloalkyl; oxopiperazinyl; morpholinyl; thiomorpholinyl; methylpiperazinyl; or tetrahydropyridinyl, and R ２ is pyridinyl; 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; methyl (thiophene)carboxylate; (thiophene)carboxylic acid; (thiophene)carboxamide; methyl (thiophene)carboxamide; cyclopropyl (thiophene)carboxamide; methylisoxazolyl; benzisoxazolyl; isothiazolyl; methylthiophenyl; 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; diaminotriazinyl; (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; (methylpiperazinyl)pyrimidinyl; (amino)(methylamino)pyrimidinyl; (amino)(pyrrolidinyl)pyrimidinyl; (methylamino)halopyrimidinyl; (ethylamino)halopyrimidinyl; (cyclopropylamino)halopyrimidinyl; (cyclohexylamino)halopyrimidinyl; (dimethylamino)halopyrimidinyl; (ethylmethylamino)halopyrimidinyl; (diethylamino)halopyrimidinyl; (methylphenylamino)halopyrimidinyl; (benzylmethylamino)halopyrimidinyl; (pyrrolidinyl)halopyrimidinyl; (piperidinyl)halopyrimidinyl; (morpholino)halopyrimidinyl; (thiomorpholino)halopyrimidinyl; (methylpiperazinyl)halopyrimidinyl; (cyclopropylamino)methylpyrimidinyl; (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; dihydropyranyl pyrimidinyl; or C optionally substituted by pyridinylpyrimidinyl; １～５ which is alkyl, The compound according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

3. The compound represented by the above formula (I) is a compound represented by the following formula (Ib): 【Chemical 2】 a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein in the formula (Ib), X is -CH ２ -; or -C(=O)-, and V １ , V ２ , V ３ and V ４ are each independently CH or N; V １ , V ２ , V ３ and V ４ If all of are not N, then V １ , V ２ , V ３ and V ４ One or more H's are each independently selected from the group consisting of W ３ and optionally substituted by W of 1 or more ３ each independently is H; halogen; (C １～５ alkyl; (C １～５ alkoxy; -OH; -NO ２ ; -NR ５ R ６ ; -CH=CR ７ R ８ ; -C≡C-R 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)(NH ２ )-substituted 5- to 7-membered heterocycloalkyl; aryl; or heteroaryl, and the aryl or the heteroaryl may be substituted by 1 or more R １０ and R ５ and R ６ are each independently H; (C ３～７ ) cycloalkyl or aryl optionally substituted (C １～５ ) alkyl; 5- to 7-membered heterocycloalkyl optionally substituted by (C １～５ ) alkyl; aryl; -C(=O)R １１ ; or -S(=O) ２ R １２ wherein R ７ is (C １～５ ) alkyl which may be substituted by -OH; aryl which may be substituted by halogen; or -C(=O)R １３ and R ８ is H; or (C １～５ )alkyl, and R ９ is an aryl which may be substituted by -NH ２ and R of 1 or more １０ is, independently of one another, H; halogen; -CN; -CF ３ ; -OH; -OCF ３ ; (C ３～７ ) cycloalkyl, 5- to 7-membered heterocycloalkyl, or (C １～５ ) alkyl which may be substituted by -OH; (C １～５ ) alkoxy; 1 or more (C １～５ ) alkyl or -C(=O)O(C １～５ ) alkyl-substituted -NH ２ ; 5- to 7-membered heterocycloalkyl which may be substituted by (C １～５ ) alkyl; -C(=O)R １４ ; -S(=O) ２ -(5- to 7-membered heterocycloalkyl); or aryl, and R １０ may be connected to each other to form a 5- to 6-membered ring 、 R １１ is -N(CH ３ ) ２ , aryl, or hydroxyaryl (C １～５ ) alkyl; may contain C(=O) (C ３～７ ) cycloalkyl; １～５ ) optionally substituted with alkyl (C ３～７ ) cycloalkyl; fused with aryl (C ３～７ ) cycloalkyl; １～５ ) optionally substituted with alkyl (C ５～６ ) cycloalkenyl; １～５ ) alkyl or -NH ２ 5- to 7-membered heterocycloalkyl, optionally substituted by aryl; or (C １～５ ) heteroaryl optionally substituted with alkyl or -OH; R １２ is (C １～５ ) alkyl or aryl, wherein at least one H of said aryl is each independently (C １～５ ) alkyl or aryl which may be substituted by halogen, R １３ is (C １～５ ) alkyl; (C １～５ ) alkoxy; -OH; -NH ２ where at least one H is substituted by (C １～５ ) alkyl or OH and may be substituted by (C １～５ ) alkyl-substituted -NH ２ ; (C ３～７ ) cycloalkyl; hydroxy(C １～５ ) alkyl; (C １～５ ) alkoxy(C １～５ ) alkyl; -NH ２ and R １４ is a 5- to 7-membered heterocycloalkyl; -NH ２ ; or -OH, L １ 、 L ２ , L, M, and G are as defined in claim 1 a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, which is the compound according to claim 1.

4. W ３ is independently H; halogen; (C １～５ )alkyl; (C １～５ )alkoxy; -OH; -NO ２ ; -NR ５ R ６ ; -CH=CR ７ R ８ ; -C≡C-R ９ ; (C ５～６ )cycloalkenyl; morpholinyl; tetrahydropyridinyl; dihydropyranyl; tert-butyl (tetrahydropyridine)carboxylate; tert-butyl (dihydropyridine)carboxylate; dihydrothiopyranyl; methyltetrahydropyridinyl; (methylsulfonyl)tetrahydropyridinyl; acetyltetrahydropyridinyl; (tetrahydropyridine)carboxamide; 1,1-dioxide-dihydrothiopyranyl; phenyl; (trifluoromethoxy)phenyl; aminophenyl; tert-butyl (phenyl)carbamate; (pyrrolidinylsulfonyl)phenyl; oxopiperidine(carbonyl)phenyl; methylpiperazinyl; (methylpiperazinyl)phenyl; isoindolyl; cyanophenyl; cyanohalophenyl; (trifluoromethyl)phenyl; (dimethylamino)phenyl; hydroxybenzyl; methoxyphenyl; biphenyl; methylphenyl; hydroxyphenyl; dihydroindenyl; benzoic acid; methyl benzoate; 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; methylthiophenyl; indazolyl; thiophenyl; cyanopyridinyl; (hydroxymethyl)pyridinyl; picolinamide; (dimethylamino)pyridinyl; dimethylpyridinyl; or (methylamino)pyridinyl, R ５ and R ６ each independently is H; (C ３～７ ) cycloalkyl or phenyl optionally substituted (C １～５ ) alkyl; morpholinyl or piperazinyl optionally substituted by (C １～５ ) alkyl; phenyl; -C(=O)R １１ ; or -S(=O) ２ R １２ and R ７ is methyl which may be substituted by -OH; phenyl which may be substituted by halogen; or -C(=O)R １３ wherein R ９ is phenyl which may be substituted by -NH ２ and R １１ is -N(CH ３ ) ２ , phenyl, or hydroxyphenyl (C １～５ ) alkyl; may contain C(=O) (C ３～７ ) cycloalkyl; １～５ ) optionally substituted with alkyl (C ３～７ ) cycloalkyl; fused to phenyl (C ３～７ ) cycloalkyl; １～５ ) optionally substituted with alkyl (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 is (C １～５ ) alkyl; phenyl; methylphenyl; or (methyl) halophenyl, and R １４ is oxopiperidinyl; -NH ２ ; or -OH, The compound according to claim 3, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

5. a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is one selected from the group consisting of the following compounds: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】 【Table 1-28】 【Table 1-29】 【Table 1-30】 【Table 1-31】 【Table 1-32】 【Table 1-33】 【Table 1-34】 【Table 1-35】 【Table 1-36】 【Table 1-37】 【Table 1-38】 【Table 1-39】 【Table 1-40】 【Table 1-41】 【Table 1-42】 【Table 1-43】 【Table 1-44】 【Table 1-45】 【Table 1-46】 【Table 1-47】 【Table 1-48】 【Table 1-49】 【Table 1-50】 【Table 1-51】 a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, which is one selected from the group consisting of.

6. A pharmaceutical composition comprising, as an active ingredient, the compound according to any one of claims 1 to 5, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

7. Use of the pharmaceutical composition for the prevention or treatment of GCN2 activation-related diseases.

8. The composition according to claim 6, further comprising one or more therapeutic agents selected from the group consisting of chemotherapeutic agents, radiotherapy agents, immunotherapy agents, and tumor microenvironment regulators.

9. A method for preventing or treating GCN2 activation-related diseases, the method comprising administering to a subject a therapeutically effective amount of the compound according to any one of claims 1 to 5, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

10. The GCN2 activation-related diseases according to claim 9, comprising cancer, neurodegenerative diseases, chronic infectious diseases, and metabolic diseases.

11. The cancer includes thyroid cancer, melanoma, prostate cancer, endometrial cancer, lung cancer, head and neck cancer, pancreatic cancer, glioma, gastric cancer, urothelial cancer, skin cancer, breast cancer, colorectal cancer, rectal cancer, fibrosarcoma, osteosarcoma, connective tissue sarcoma, giant cell cancer, squamous cell cancer, leukemia, skin cancer, soft tissue cancer, liver cancer, adenocarcinoma, hepatocellular cancer, multiple myeloma, myelodysplastic syndrome, bone The method according to claim 10, which is one or more selected from the group consisting of myeloproliferative tumors, malignant gliomas, non-Hodgkin lymphomas, Hodgkin lymphomas, Burkitt lymphomas, chronic lymphocytic leukemias, chronic myelogenous leukemias, hairy cell leukemias, plasmacytomas, lymphoplasmacytic lymphomas, acute lymphoblastic leukemias, acute myelogenous leukemias, chronic myelomonocytic leukemias, juvenile myelomonocytic leukemias, large granular lymphocyte leukemias, B-cell prolymphocytic leukemias, T-cell prolymphocytic leukemias, small cell lung cancers, and pediatric neuroblastomas.

12. A method for inhibiting GCN2 activation, the method comprising administering to a subject a therapeutically effective amount of the 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, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof for the prevention or treatment of a GCN2 activation-related disease.

14. Use of the compound according to any one of claims 1 to 5, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof in the manufacture of a medicament for the prevention or treatment of a GCN2 activation-related disease.

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