JP4792126B2

Pyrazole compounds and their use as raf inhibitors

Abstract

This record has no abstract on file.

Term

Projected expiry 21 July 2028.

3 claims: 1 independent, 2 dependent

1
下記に示される化合物または薬学的に許容できるその塩。
2
請求項1に記載の化合物または薬学的に許容できるその塩および薬学的に許容できる担体または希釈剤を含む、医薬組成物。
3
異常な細胞増殖を治療するための、請求項2に記載の医薬組成物。

Independent claims3

146 paragraphs, as filed

This application is incorporated herein by reference in its entirety. US Patent Provisional Application Nos. 60 / 953,235 filed on August 1, 2007 and US Patent Provisional Application No. 61 / filed on July 11, 2008. Claim the interests of No. 080,054.

The present invention is directed to compounds, their synthesis and their use as regulators or inhibitors of Raf enzymes. The compounds of the present invention are useful for regulating (eg, inhibiting) Raf activity and for treating Raf-mediated diseases or conditions, such as disease states associated with abnormal cell proliferation such as cancer. It is useful for.

The "Erk pathway" is an intracellular signaling pathway used by almost all types of human cells to translate extracellular signals into cell decisions involving proliferation, differentiation, aging or apoptosis (Wellbrock et al., Nat). .Rev.Mol.Cell Biol.11: 875 ~ 885 (2004)). One of the invariant components of this pathway is the Ras GTPase, which receives a signal from a membrane receptor and activates Raf protein kinase, which activates Mek protein kinase, which in turn is Erk protein kinase. To activate. Activated Erk kinase phosphorylates several nuclear and cytoplasmic targets to initiate various cell decisions. The biological importance of Raf in the Erk pathway is highlighted by the discovery that mutant forms of Raf are associated with certain human malignant lesions (eg, Monia et al., Nature Medicine 2: 668 ~. 675 (1996), Davies et al., Nature See 417: 949-954 (2002)). Three distinct genes encoding the Raf protein have been identified in mammals (a-Raf, b-Raf and c-Raf (also known as Raf-1)) and result from mRNA differentiation splicing. Isoform variants are known (Chong et al., EMBO J. 20: 3716-3727 (2001)). The Erk pathway is mutatedly activated in some human cancers, most often by mutations in the Ras or b-Raf genes. Mutations in the Ras and b-Raf genes generally occur in the same tumor type, including colon, lung and pancreatic cancers and melanomas, but are usually mutually exclusive. This suggests that activation of either Ras or Raf is sufficient for pathway activation and cancer progression.

Tumor cells often become dependent on or "addicted" to one or two key signaling pathways for their survival (eg, Jonkers et al., Cancer Cell. 6: 535-538 (eg, Jonkers et al., Cancer Cell. 6: 535-538). (See 2004)), the Erk pathway represents a very attractive target for drug interventions to treat cancer. Protein kinases are generally considered the preferred target for drug therapy, as evidenced by recent success in targeting growth factor receptors and intracellular tyrosine kinases. Although Mek inhibitors have been promising in clinical trials, there is ample evidence of Mek-independent Raf signaling, which can also contribute to cancer progression. (Wellbrock et al., Nat.Rev.Mol.Cell Biol. 11: 875-885 (2004)). Therefore, targeting Raf kinase promises another complementary approach for treating tumors with mutated Ras or Raf genes.

In one embodiment, the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof.<chemistry num="1"><img file="JP4792126B2_D0001.tif" /></chemistry>[During the ceremony, X is N or CR7And R1Is H, C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl or C2~ C9Heteroaryl, where C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl is one or more Rs, respectively8May be replaced with R2Is C2~ C9Cycloheteroalkyl or C5~ C14Heteroaryl, where C2~ C9Cycloheteroalkyl and C5~ C14Heteroaryl is one or more Rs, respectively8May be replaced with R3Is H or -NR9R10And R4, R5, R6, R7Are independent, H, -NR9R10, -CN, -C (O) R9, -C (O) OR9, -NO2, -SR9, -OR9, C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl or C2~ C9Heteroaryl, where C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl or C2~ C9Heteroaryl is one or more Rs, respectively8May be replaced with R8Independently, -OH, Fluorine, Chlorine, Bromine, Cyano, -NR9R10, -C (O) N (R)9R10), -C (O) R9, -C (O) OR9, -NO2, C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl, C2~ C9Heteroaryl or-(CH2)nC (O) R9And here, the above C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl is one or more Rs, respectively11May be replaced with R9And R10Are independently H and C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl or C2~ C9Heteroaryl, where C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl and C2~ C9Each heteroaryl has at least one R11May be replaced with, or R9And R10Along with the nitrogen they are bound to, one or more R11Form a 4- to 7-membered ring that may be replaced by R11Independently, fluorine, chlorine, bromine, -OH, cyano, C1~ C6Alkyl, C1~ C11Heteroalkyl, C3~ C8Cycloalkyl, -O- (C3~ C8Cycloalkyl), -S- (C3~ C8Cycloalkyl), C6~ C14Aryl, -O- (C6~ C14Aryl), -S- (C6~ C14Aryl), C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl, where C3~ C8Cycloalkyl, -O- (C3~ C8Cycloalkyl), -S- (C3~ C8Cycloalkyl), C6~ C14Aryl, -O- (C6~ C14Aryl), -S- (C6~ C14Aryl), C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryls are fluorine, chlorine, bromine, -OH, cyano and C, respectively.1~ C6It may be substituted with one or more groups selected from alkyl. n is 0, 1, 2, 3 or 4]. In one aspect of this embodiment, X is N. In another aspect of this embodiment, X is CR7Is. In a further aspect, R4Is H. In a further aspect of this embodiment, R5Is H. In a further aspect of this embodiment, R6Is H. In a further aspect of this embodiment, R4, R5And R6Is H. In a further aspect of this embodiment, R1Is one or more R8May be replaced with C1~ C6It is alkyl. In a further aspect of this embodiment, R1Is at least one R8C replaced by1~ C6It is alkyl. In a further aspect of this embodiment, R1Is selected from methyl, isopropyl, (3-methyloxetane-3-yl) methyl, 2,2-difluoroethyl and acetonitrile. In another aspect of this embodiment, R3Is -NR9R10Is. In another aspect of this embodiment, R2Is<chemistry num="2-1"><img file="JP4792126B2_D0002.tif" /></chemistry><chemistry num="2-2"><img file="JP4792126B2_D0003.tif" /></chemistry>Selected from the group consisting of. In a further embodiment, the invention is a compound of formula (Ia) having the following structure or a pharmaceutically acceptable salt thereof:<chemistry num="3"><img file="JP4792126B2_D0004.tif" /></chemistry>[During the ceremony, R1Is one or more R8May be replaced with C1~ C6Alkyl R2Is C2~ C9Cycloheteroalkyl or C5~ C14Heteroaryl, where C3~ C12Cycloheteroalkyl and C2~ C9Heteroaryl is one or more Rs, respectively8May be replaced with R3Is H or -NR9R10And R8Independently, -OH, Fluorine, Chlorine, Bromine, Cyano, -NR9R10, -C (O) N (R)9R10), C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl, C2~ C9Heteroaryl or-(CH2)nC (O) R9And here, the above C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl is one or more Rs, respectively11May be replaced with R9And R10Are independently H and C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C3~ C9Cycloheteroalkyl or C5~ C9Heteroaryl, where C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl and C2~ C9Each heteroaryl has at least one R11May be replaced with, or R9And R10Along with the nitrogen they are bound to, one or more R11Form a 4- to 7-membered ring that may be replaced by R11Independently, fluorine, chlorine, bromine, -OH, cyano, C1~ C6Alkyl, C1~ C11Heteroalkyl, C3~ C8Cycloalkyl, -O- (C3~ C8Cycloalkyl), -S- (C3~ C8Cycloalkyl), C6~ C14Aryl, -O- (C6~ C14Aryl), -S- (C6~ C14Aryl), C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl, where C3~ C8Cycloalkyl, -O- (C3~ C8Cycloalkyl), -S- (C3~ C8Cycloalkyl), C6~ C14Aryl, -O- (C6~ C14Aryl), -S- (C6~ C14Aryl), C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryls are fluorine, chlorine, bromine, -OH, cyano and C, respectively.1~ C6It may be substituted with one or more groups selected from alkyl]. In one aspect of this embodiment, R1Is selected from methyl, isopropyl, (3-methyloxetane-3-yl) methyl, 2,2-difluoroethyl and acetonitrile. In another aspect of this embodiment, R3Is -NR9R10Is. In another aspect of this embodiment, R2Is<chemistry num="4"><img file="JP4792126B2_D0005.tif" /></chemistry>Selected from the group consisting of. In other embodiments, the invention is a compound of formula (II) or a pharmaceutically acceptable salt thereof.<chemistry num="5"><img file="JP4792126B2_D0006.tif" /></chemistry>[During the ceremony, X is N or CR7And R1Is H, C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl or C2~ C9Heteroaryl, where C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl is one or more Rs, respectively8May be replaced with R2Is C2~ C9Cycloheteroalkyl or C2~ C9Heteroaryl, where C2~ C9Cycloheteroalkyl and C5~ C14Heteroaryl is one or more Rs, respectively8May be replaced with, or in some cases R2Is C2~ C9If heteroaryl, the hydrogen atoms on any two adjacent ring atoms can be one or more R together.85- to 7-membered cycloalkyl, which may be substituted with, one or more Rs85- to 7-membered cycloheteroalkyl or one or more Rs that may be substituted with8It may form a 5- to 7-membered heteroaryl which may be substituted with. R3Is H or -NR9R10Or X is CR7If, then R3Is R7With one or more R85- to 7-membered heteroaryl, which may be substituted with, one or more Rs85- to 7-membered cycloheteroalkyl, one or more Rs that may be substituted with8Phenyl or one or more Rs which may be substituted with8It may form a 5- to 7-membered cycloalkyl which may be substituted with. R4, R5, R6, R7Are independent, H, -NR11R12, -CN, -C (O) R11, -C (O) OR11, -NO2, -SR11, -S (O)2R11, -OR11, C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl or C2~ C9Heteroaryl, where C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl or C2~ C9Heteroaryl is one or more Rs, respectively8May be replaced with R8Are independent, -OR11, Fluorine, chlorine, bromine, oxo, cyano, -NR13R14, -C (O) N (R)13R14), -C (O) R13, -C (O) OR13, -NO2, C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl, C2~ C9Heteroaryl or-(CH2)nC (O) R11And here, the above C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl is one or more Rs, respectively11May be replaced with R9And R10Are independently H, -C (O) N (R)13R14), -C (O) R13, -C (O) OR13, C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl or C2~ C9Heteroaryl, where C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl and C2~ C9Each heteroaryl has at least one R11May be replaced with, or R9And R10Along with the nitrogen they are bound to, one or more R11Form a 4- to 7-membered cycloheteroalkyl ring that may be substituted with R11And R12Independently, fluorine, chlorine, bromine, -OH, -C (O) R13, -C (O) OR13, -SR13, -S (O)2R13, -OR13, -NR13R14, -C (O) N (R)13R14), Cyano, C1~ C6Alkyl, C1~ C11Heteroalkyl, C3~ C8Cycloalkyl, -O- (C3~ C8Cycloalkyl), -S- (C3~ C8Cycloalkyl), C6~ C14Aryl, -O- (C6~ C14Aryl), -S- (C6~ C14Aryl), C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl, where C3~ C8Cycloalkyl, -O- (C3~ C8Cycloalkyl), -S- (C3~ C8Cycloalkyl), C6~ C14Aryl, -O- (C6~ C14Aryl), -S- (C6~ C14Aryl), C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl is one or more Rs, respectively13May be replaced with R13And R14Are independently H, oxo, and C1~ C6Alkyl, C1~ C11Heteroalkyl, C3~ C8Cycloalkyl, -O- (C3~ C8Cycloalkyl), -S- (C3~ C8Cycloalkyl), C6~ C14Aryl, -O- (C6~ C14Aryl), -S- (C6~ C14Aryl), C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl, where C3~ C8Cycloalkyl, -O- (C3~ C8Cycloalkyl), -S- (C3~ C8Cycloalkyl), C6~ C14Aryl, -O- (C6~ C14Aryl), -S- (C6~ C14Aryl), C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryls are fluorine, chlorine, bromine, -OH, cyano and C, respectively.1~ C6It may be substituted with one or more groups selected from alkyl. n is 0, 1, 2, 3 or 4]. In one aspect of this embodiment, X is N or a pharmaceutically acceptable salt thereof. In another aspect of this embodiment, X is CR7Or the salt that is pharmaceutically acceptable. In a further aspect, R4Is H or its pharmaceutically acceptable salt. In a further aspect of this embodiment, R5Is H or its pharmaceutically acceptable salt. In a further aspect of this embodiment, R6Is H or its pharmaceutically acceptable salt. In a further aspect of this embodiment, R4, R5And R6Is H or its pharmaceutically acceptable salt. In a further aspect of this embodiment, R1Is one or more R8May be replaced with C1~ C6Alkyl or its pharmaceutically acceptable salt. In a further aspect of this embodiment, R1Is at least one R8C replaced by1~ C6Alkyl or its pharmaceutically acceptable salt. In one aspect of this embodiment, R1Methyl, ethyl, isopropyl, cyclopropyl, 2,2-difluoroethyl, cyanomethyl, difluorocyclobutanyl, (3-methyloxetane-3-yl) methyl, 1,1-dimethyl-2-hydroxyethyl, 1- Methyl-1-cyanoethyl, difluoromethyl, tert-butyl, 3-hydroxypropan-2-yl, piperidinyl, N-acetyl-piperidinyl, H, tetrahydro-2H-pyranyl, tetrahydrofuranyl, 4-cyanophenyl, cis-fluorocyclo It is selected from butanyl, trans-fluorocyclobutanyl, oxetanyl and N-methyl-piperidinyl or its pharmaceutically acceptable salts. In a further aspect of this embodiment, R1Is selected from methyl, isopropyl, (3-methyloxetane-3-yl) methyl, 2,2-difluoroethyl and acetonitrile or its pharmaceutically acceptable salts. In another aspect of this embodiment, R3Is -NR9R10Or the salt that is pharmaceutically acceptable. In another aspect of this embodiment, R2Is<chemistry num="6-1"><img file="JP4792126B2_D0007.tif" /></chemistry><chemistry num="6-2"><img file="JP4792126B2_D0008.tif" /></chemistry>Alternatively, it is selected from the group consisting of the pharmaceutically acceptable salt. In another aspect of this embodiment, R3Is -NR9R10Is. In another aspect of this embodiment, R3Is NH2, H,<chemistry num="7"><img file="JP4792126B2_D0009.tif" /></chemistry>Or the salt that is pharmaceutically acceptable. In a further embodiment, the invention is a compound of formula (IIa) having the following structure or a pharmaceutically acceptable salt thereof:<chemistry num="8"><img file="JP4792126B2_D0010.tif" /></chemistry>[During the ceremony, R1Is one or more R8May be replaced with C1~ C6Alkyl R2Is C2~ C9Cycloheteroalkyl or C5~ C14Heteroaryl, where C3~ C12Cycloheteroalkyl and C2~ C9Heteroaryl is one or more Rs, respectively8May be replaced with R3Is H or -NR9R10And R8Are independent, -OR11, Fluorine, chlorine, bromine, oxo, cyano, -NR13R14, -C (O) N (R)13R14), -C (O) R13, -C (O) OR13, -NO2, C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl, C2~ C9Heteroaryl or-(CH2)nC (O) R9And here, the above C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl is one or more Rs, respectively11May be replaced with R9And R10Are independently H, -C (O) N (R)13R14), -C (O) R13, -C (O) OR13, C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl or C2~ C9Heteroaryl, where C1~ C6Alkyl, C2~ C8Alkenyl, C2~ C8Alkyne, C3~ C8Cycloalkyl, C6~ C14Aryl, C2~ C9Cycloheteroalkyl and C2~ C9Each heteroaryl has at least one R11May be replaced with, or R9And R10Along with the nitrogen they are bound to, one or more R11Form a 4- to 7-membered cycloheteroalkyl ring that may be substituted with R11And R12Independently, fluorine, chlorine, bromine, -OH, -C (O) R13, -C (O) OR13, -SR13, -S (O)2R13, -OR13, -NR13R14, -C (O) N (R)13R14), Cyano, C1~ C6Alkyl, C1~ C11Heteroalkyl, C3~ C8Cycloalkyl, -O- (C3~ C8Cycloalkyl), -S- (C3~ C8Cycloalkyl), C6~ C14Aryl, -O- (C6~ C14Aryl), -S- (C6~ C14Aryl), C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl, where C3~ C8Cycloalkyl, -O- (C3~ C8Cycloalkyl), -S- (C3~ C8Cycloalkyl), C6~ C14Aryl, -O- (C6~ C14Aryl), -S- (C6~ C14Aryl), C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl is one or more Rs, respectively13May be replaced with R13And R14Are independently H, oxo, and C1~ C6Alkyl, C1~ C11Heteroalkyl, C3~ C8Cycloalkyl, -O- (C3~ C8Cycloalkyl), -S- (C3~ C8Cycloalkyl), C6~ C14Aryl, -O- (C6~ C14Aryl), -S- (C6~ C14Aryl), C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryl, where C3~ C8Cycloalkyl, -O- (C3~ C8Cycloalkyl), -S- (C3~ C8Cycloalkyl), C6~ C14Aryl, -O- (C6~ C14Aryl), -S- (C6~ C14Aryl), C2~ C9Cycloheteroalkyl and C2~ C9Heteroaryls are fluorine, chlorine, bromine, -OH, cyano and C, respectively.1~ C6It may be substituted with one or more groups selected from alkyl]. In one aspect of this embodiment, R1Methyl, ethyl, isopropyl, cyclopropyl, 2,2-difluoroethyl, cyanomethyl, difluorocyclobutanyl, (3-methyloxetane-3-yl) methyl, 1,1-dimethyl-2-hydroxyethyl, 1- Methyl-1-cyanoethyl, difluoromethyl, tert-butyl, 3-hydroxypropan-2-yl, piperidinyl, N-acetyl-piperidinyl, H, tetrahydro-2H-pyranyl, tetrahydrofuranyl, 4-cyanophenyl, cis-fluorocyclo It is selected from butanyl, trans-fluorocyclobutanyl, oxetanyl and N-methyl-piperidinyl or its pharmaceutically acceptable salts. In another aspect of this embodiment, R2Is<chemistry num="9-1"><img file="JP4792126B2_D0011.tif" /></chemistry><chemistry num="9-2"><img file="JP4792126B2_D0012.tif" /></chemistry>Alternatively, it is selected from the group consisting of the pharmaceutically acceptable salt. In another aspect of this embodiment, R3Is -NR9R10Is. In another aspect of this embodiment, R3Is NH2, H,<chemistry num="10"><img file="JP4792126B2_D0013.tif" /></chemistry>Or the salt that is pharmaceutically acceptable. In a further embodiment, the present invention relates to (2S) -1- (4- (1-isopropyl-3- (3-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole). -4-yl) Pyrimidine-2-ylamino) Propan-2-ol, (2S) -1- (4- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridine-5-yl)) -1-Isopropyl-1H-pyrazole-4-yl) pyrimidin-2-ylamino) propan-2-ol, (2S) -1- (4- (3- (2,3-dimethyl-1H-pyrrolo] 3-b] Pyridine-5-yl) -1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2-ol, (2S) -1- (4- (1-isopropyl-3) -(3-Methyl-1H-pyrazolo [3,4-b] pyridin-5-yl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol, 4- [1-isopropyl- 3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl] -N- [2- (1H-pyrazol-1-yl) ethyl] pyrimidine-2-amine , (2S) -1- (4- (1-Isopropyl-3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) propane -2-ol, N- (2-fluoroethyl) -4- [1-isopropyl-3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl] pyrimidine -2-amine, (2S) -1- (4- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-methyl-1H-pyrazol-4-yl) ) Pyrimidine-2-ylamino) Propan-2-ol, 2-({4- [1-isopropyl-3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4- Il] pyrimidine-2-yl} amino) ethanol, 4- [1-isopropyl-3- (1H-pyrrolo [2,,3-b] Pyridine-5-yl) -1H-pyrazol-4-yl] -N- [2- (1H-pyrazol-4-yl) ethyl] pyrimidin-2-amine, (2S) -1- (4) -(3- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2- All, [4- [2-((S) -2-hydroxy-propylamino) -pyrimidine-4-yl] -3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -pyrazole- 1-Il] -acetominate, 1- [2-({4- [1-isopropyl-3-(1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl] pyrimidin -2-yl} amino) ethyl] Pyridine-2 (1H) -one, (2R) -2-({4- [1-Isopropyl-3- (1H-pyrrolo [2,3-b] Pyridine-5-) Il) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propan-1-ol, N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -4- [1-isopropyl -3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl] pyrimidin-2-amine, N-[(2,5-dimethyl-1,3-oxazole) -4-yl) methyl] -4- [1-isopropyl-3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl] pyrimidin-2-amine, 4 -[1-Isopropyl-3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl] -N- (tetrahydrofuran-3-ylmethyl) pyrimidin-2-amine, 4- (1-Isopropyl-3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl) -N- (pyridin-2-ylmethyl) pyrimidin-2-amine , (2S) -1- (4- (1-Isopropyl-3- (1H-pyrazolo [3,,4-b] pyridine-5-yl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol, 4- [1-isopropyl-3-(1H-pyrrolo [2,3-b] ] Pyridin-5-yl) -1H-pyrazol-4-yl] -N- (2-methoxyethyl) pyrimidine-2-amine, 1-ethyl-4-[({4- [1-isopropyl-3-({4-] 1-isopropyl-3-( 1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidine-2-yl} amino) methyl] pyrrolidine-2-one, (2S) -1- (4- (4-) (1-Isopropyl-3- (5-methyl-6- (methylamino) pyridine-3-yl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) Propan-2-ol, (2S) -1 -(4- (1-Isopropyl-3- (2-methyl-1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) Propane-2 -All, (2S) -1- (4- (1-isopropyl-3- (5-methyl-5H-pyrrolo [2,3-b] pyrazine-3-yl) -1H-pyrazol-4-yl) pyrimidine -2-Ilamino) Propan-2-ol, (2S) -1-(4- (1-Methyl-3- (1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4 -Il) Pyrimidine-2-ylamino) Propan-2-ol, (2S) -1- (4- (1-Isopropyl-3- (2-methylimidazo [1,2-a] pyrimidin-6-yl)- 1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol, (2S) -1- (4- (1-isopropyl-3-(6- (methylamino) pyridine-3-yl)-)- 1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol, (2S) -1- (4- (3- (2,3-dimethylimidazo] [1,2-a] Pyrimidine-6-yl) -1-isopropyl-1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol, (2S) -1- (4- (1- (2,,,) 2-Difluoroethyl) -3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol, (2S)- 1-(4- (3- (3-Chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) pyrimidine -2-Ilamino) Propan-2-ol, (2S) -1-(4-(3- (3-Chloro-2-methyl-1H-pyrrolo [2,3-b] Pyridine-5-yl) -1) -Isopropyl-1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol, (2S) -1-(4-(1-((3-methyloxetane-3-yl) methyl) -3) -(1H-Pyrrolo [2,3-b] Pyridine-5-yl) -1H-Pyrazole-4-yl) Pyrimidine-2-ylamino) Propan-2-ol, 5- (4- (2-((SS) ) -2-Hydroxypropylamino) Pyrimidine-4-yl) -1-Isopropyl-1H-pyrazol-3-yl) -3,3-dimethyl-1H-pyrrolo [2,3-b] Pyridine-2 (3H) -On, (2S) -1- (4- (3- (3,3-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-methyl-1H -Pyrazole-4-yl) Pyrimidine-2-ylamino) Propan-2-ol and (2S) -1- (4- (3- (3-Chloro-1H-pyrrolo [2,3-b] Pyridine-5-) Il)-1-((3-methyloxetane-3-yl) methyl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) Propane-2-ol A compound selected from the group consisting of or pharmaceutically That salt is acceptable.3-b] Pyridine-5-yl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol, (2S) -1- (4- (3- (3-chloro-1H-) Pyrrolo [2,3-b] Pyridine-5-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) Pyrimidine-2-ylamino) Propan-2-ol, (2S)- 1-(4- (3- (3-Chloro-2-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-isopropyl-1H-pyrazol-4-yl) pyrimidine-2- Ilamino) Propan-2-ol, (2S) -1- (4- (1-((3-Methyloxetane-3-yl) methyl) -3- (1H-pyrrolo [2,3-b] Pyridine-5) -Il) -1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol, 5-(4-(2-((S) -2-hydroxypropylamino) pyrimidin-4-yl)- 1-Isopropyl-1H-pyrazole-3-yl) -3,3-dimethyl-1H-pyrrolo [2,3-b] Pyridine-2 (3H) -one, (2S) -1- (4- (3- (3- (3-) (3,3-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-methyl-1H-pyrazol-4-yl) pyrimidine-2-ylamino) Propane- 2-ol and (2S) -1- (4- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-((3-methyloxetane-3-yl) A compound selected from the group consisting of) methyl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol or a pharmaceutically acceptable salt thereof.3-b] Pyridine-5-yl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol, (2S) -1- (4- (3- (3-chloro-1H-) Pyrrolo [2,3-b] Pyridine-5-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) Pyrimidine-2-ylamino) Propan-2-ol, (2S)- 1-(4- (3- (3-Chloro-2-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-isopropyl-1H-pyrazol-4-yl) pyrimidine-2- Ilamino) Propan-2-ol, (2S) -1- (4- (1-((3-Methyloxetane-3-yl) methyl) -3- (1H-pyrrolo [2,3-b] Pyridine-5) -Il) -1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol, 5-(4-(2-((S) -2-hydroxypropylamino) pyrimidin-4-yl)- 1-Isopropyl-1H-pyrazole-3-yl) -3,3-dimethyl-1H-pyrrolo [2,3-b] Pyridine-2 (3H) -one, (2S) -1- (4- (3- (3- (3-) (3,3-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-methyl-1H-pyrazol-4-yl) pyrimidine-2-ylamino) Propane- 2-ol and (2S) -1- (4- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-((3-methyloxetane-3-yl) A compound selected from the group consisting of) methyl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol or a pharmaceutically acceptable salt thereof.3-b] Pyridine-5-yl) -1-Isopropyl-1H-pyrazol-4-yl) Pyrimidine-2-ylamino) Propan-2-ol, (2S) -1- (4- (1-((3) -Methyloxetane-3-yl) methyl) -3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol , 5- (4- (2-((S) -2-Hydroxypropylamino) pyrimidine-4-yl) -1-isopropyl-1H-pyrazol-3-yl) -3,3-dimethyl-1H-pyrrolo [ 2,3-b] Pyridine-2 (3H) -one, (2S) -1- (4- (3- (3,3-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b]] Pyridine-5-yl) -1-methyl-1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol and (2S) -1- (4- (3- (3-chloro-1H-) Pyrrolo [2,3-b] Pyridine-5-yl) -1-((3-Methyloxetane-3-yl) Methyl) -1H-Pyrazole-4-yl) Pyrimidine-2-ylamino) Propan-2-ol A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.3-b] Pyridine-5-yl) -1-Isopropyl-1H-pyrazol-4-yl) Pyrimidine-2-ylamino) Propan-2-ol, (2S) -1- (4- (1-((3) -Methyloxetane-3-yl) methyl) -3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol , 5- (4- (2-((S) -2-Hydroxypropylamino) pyrimidine-4-yl) -1-isopropyl-1H-pyrazol-3-yl) -3,3-dimethyl-1H-pyrrolo [ 2,3-b] Pyridine-2 (3H) -one, (2S) -1- (4- (3- (3,3-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b]] Pyridine-5-yl) -1-methyl-1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol and (2S) -1- (4- (3- (3-chloro-1H-) Pyrrolo [2,3-b] Pyridine-5-yl) -1-((3-Methyloxetane-3-yl) Methyl) -1H-Pyrazole-4-yl) Pyrimidine-2-ylamino) Propan-2-ol A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.3-b] Pyridine-5-yl) -1-methyl-1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol and (2S) -1- (4- (3- (3- (3- (3- (3- (3-)3-) Chloro-1H-pyrrolo [2,3-b] Pyridine-5-yl) -1-((3-Methyloxetane-3-yl) methyl) -1H-pyrazole-4-yl) Pyrimidine-2-ylamino) Propane A compound selected from the group consisting of -2-ol or a pharmaceutically acceptable salt thereof.3-b] Pyridine-5-yl) -1-methyl-1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol and (2S) -1- (4- (3- (3- (3- (3- (3- (3-)3-) Chloro-1H-pyrrolo [2,3-b] Pyridine-5-yl) -1-((3-Methyloxetane-3-yl) methyl) -1H-pyrazole-4-yl) Pyrimidine-2-ylamino) Propane A compound selected from the group consisting of -2-ol or a pharmaceutically acceptable salt thereof. In a further embodiment, the present invention comprises (2S) -1- (4- (1-isopropyl-3- (3-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole). -4-yl) Pyrimidine-2-ylamino) Propan-2-ol, (2S) -1- (4- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridine-5-yl)) -1-Isopropyl-1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol, (2S) -1- (4- (3- (2,3-dimethyl-1H-pyrrolo] 3-b] Pyridine-5-yl) -1-Isopropyl-1H-pyrazol-4-yl) Pyrimidine-2-ylamino) Propan-2-ol, (2S) -1- (4- (3- (3- (3- (3- (3- (3-)3-) Chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol and (2S) -1- (4- (1-Isopropyl-3- (3-methyl-1H-pyrazolo [3,4-b] pyridin-5-yl) -1H-pyrazol-4-yl) pyrimidine-2- A compound selected from the group consisting of (ylamino) propan-2-ol or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S) -1- (4- (1-isopropyl-3- (3-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole- 4-Il) Pyrimidine-2-ylamino) Propan-2-ol or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S) -1- (4- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-isopropyl-1H-pyrazole- 4-Il) Pyrimidine-2-ylamino) Propan-2-ol or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S) -1- (4- (3- (2,3-dimethyl-1H-pyrrolo [2,, 3-b] Pyridine-5-yl) -1-Isopropyl-1H-pyrazole-4-yl) Pyrimidine-2-ylamino) Propan-2-ol or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S) -1- (4- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (2,2-difluoro) Ethyl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2-ol or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is 4- [3- (6-amino-5-methoxypyridin-3-yl) -1-isopropyl-1H-pyrazol-4-yl] -N-cyclopropylpyrimidine-2-amine. , (2S) -1-({4- [3- (3-Chloro-1H-pyrrolo [2,3-b] pyridine-5-yl) -1- (3,3-difluorocyclobutyl) -1H- Pyrazole-4-yl] pyrimidin-2-yl} amino) propan-2-ol, (2S) -1-({4- [3- (6-amino-5-methylpyridine-3-yl) -1-] (2,2-difluoroethyl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propan-2-ol, 3-({4- [3- (3-fluoro-1H-pyrrolo [2) , 3-b] pyridine-5-yl) -1-isopropyl-1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-({4- [3- (2,3-dihydro) -1H-pyrrolo [2,3-b] pyridine-5-yl) -1-isopropyl-1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-({4- [1-]1-yl) (2,2-difluoroethyl) -3- (3-fluoro-1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propane Nitrile, 3-({4- [3- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-5-yl) -1- (2-hydroxy-1,1-dimethylethyl)- 1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-({4- [1- (2-hydroxy-1,1-dimethylethyl) -3- (3-methyl-1H-) Pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-({4- [3- (3-fluoro-1H-) Pyrrolo [2,3-b] pyridine-5-yl) -1- (2-hydroxy-1,1-Dimethylethyl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-({4- [1- (2-hydroxy-1,1-dimethylethyl) -3- ( 1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, N- {5- [4- {2-[(2) -Cyanoethyl) amino] pyrimidin-4-yl} -1- (2,2-difluoroethyl) -1H-pyrazol-3-yl] -4-methylpyridine-2-yl} acetamide, N- [1- (cyclo) Propyl-sulfonyl) piperidin-4-yl] -4- [1- (2,2-difluoroethyl) -3- (1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4 -Il] pyrimidin-2-amine, 3-({4- [1- (2,2-difluoroethyl) -3- (6-methylpyridine-3-yl) -1H-pyrazol-4-yl] pyrimidin- 2-Il} amino) propanenitrile, (2S) -1-({4- [1- (2,2-difluoroethyl) -3- (1H-pyrrolo [2,3-b] pyridine-4-yl)) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propan-2-ol, 3-({4- [3- (5-amino-6-methoxypyrazine-2-yl) -1-tert -Butyl-1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-({4- [3- (5-amino-6-methoxypyrazine-2-yl) -1-isopropyl- 1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-({4- [3- (5-amino-6-methoxypyrazine-2-yl) -1- (2,2-yl) Difluoroethyl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-({4- [3- (5-amino-6-methoxypyrazine-2-yl) -1- ( 2,2-Difluoroethyl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 2- [3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl] ) -4- (2-{[(2S) -2-Hydroxypropyl] amino} pyrimidin-4-yl) -1H-pyrazol-1-yl] -2-methylpropanenitrile, (2S) -1-({ 4- [1- (2,2-difluoroethyl) -3- (1-methyl-1H-pyrrolo [3,2-b] pyridin-6-yl) -1H-pyrazol-4-yl] pyrimidin-2- Il} amino) propan-2-ol, 3-({4- [1- (2,2-difluoroethyl) -3- (1H-pyrrolo [3,2-b] pyridin-6-yl) -1H- Pyrazole-4-yl] pyrimidin-2-yl} amino) propanenitrile, and 3-({4- [1- (2-hydroxy-1,1-dimethylethyl) -3- (1-methyl-1H-pyrrolo) [3,2-b] Pyridine-6-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) Propanenitrile, or a pharmaceutically acceptable salt thereof.2-b] Pyridine-6-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) Propionitrile, or its pharmaceutically acceptable salt.2-b] Pyridine-6-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) Propionitrile, or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is 3-({4- [1- (2-hydroxy-1,1-dimethylethyl) -3- (1-methyl-1H-pyrrolo [3,2-b] pyridine-6). -Il) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, (2S) -1-[(4- {3- [6-amino-5- (difluoromethoxy) -pyridine- 3-yl] -1-isopropyl-1H-pyrazol-4-yl} pyrimidin-2-yl) amino] propan-2-ol, 4- [1- (difluoromethyl) -3- (3-methyl-1H-) Pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidin-2-amine, (2S) -1-({4- [3- (6-amino-5-methoxy) Pyridin-3-yl) -1- (difluoromethyl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propan-2-ol, (2S) -1-({4- [3- ({4- [3- ( 2-Aminopyrimidine-5-yl) -1-isopropyl-1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propan-2-ol, 4- [3- (3-chloro-1H-pyrrolo [ 2,3-b] Pylin-5-yl) -1- (difluoromethyl) -1H-pyrazol-4-yl] pyrimidin-2-amine, 3-({4- [1- (difluoromethyl) -3-) (3-Methyl-1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) -propanenitrile, 2-amino-5- [4 -(2-{[(2S) -2-Hydroxypropyl] -amino} pyrimidin-4-yl) -1-isopropyl-1H-pyrazol-3-yl] pyridine-3-ol, 3-({4- [ 1- (2,2-difluoroethyl) -3- (5-methoxypyridine-3-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-({4- [ 3- (6-Amino-5-Methylpyridine-3-yl) -1- (2-Hydroxy-1,1-Dimethylethyl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) -propanenitrile, 2- [4- {2-[(2,2-difluoroethyl) amino] pyrimidin-4-yl } -3- (1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-1-yl] -2-methylpropan-1-ol, 3-({4- [1- ({4- [1- ( 2-Hydroxy-1,1-dimethylethyl) -3- (5-methoxypyridine-3-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-({4-) [1-Isopropyl-3- (1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) -propanenitrile, 3-({4) -[1-Isopropyl-3- (3-methyl-1H-pyrazolo [3,4-b] pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3 -({4- [3- (5-Acetyl-6-aminopyridine-3-yl) -1-isopropyl-1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-{[ 4- (1-Isopropyl-3-pyridine-3-yl-1H-pyrazol-4-yl) pyrimidin-2-yl] amino} -propanenitrile, 4- [3- (6-amino-5-methoxypyridine-) 3-yl) -1-tert-butyl-1H-pyrazol-4-yl] -N- (2,2-difluoroethyl) pyrimidin-2-amine, (2R) -2- [4- (2-aminopyrimidine) -4-yl) -3- (3-chloro-1H-pyrrolo [2,3-b] Pyridine-5-yl) -1H-pyrazol-1-yl] Propan-1-ol, 4- [3- (6-amino-5-methoxypyridin-3-yl) -1-cyclopropyl- 1H-pyrazol-4-yl] pyrimidin-2-amine, 3-({4- [3- (6-amino-5-methoxypyridin-3-yl) -1-cyclopropyl-1H-pyrazol-4-yl) ] Pyrimidin-2-yl} amino) -propanenitrile, 2- [4- (2-aminopyrimidin-4-yl) -3- (3-methyl-1H-pyrrolo [2,3-b] pyridine-5- Il) -1H-pyrazol-1-yl] -2-methylpropan-1-ol, 4- [3- (6-amino-5-methoxypyridin-3-yl) -1-cyclopropyl-1H-pyrazol- 4-yl] -N- (2,2-difluoroethyl) pyrimidin-2-amine, and 4- [3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1 -Isopropyl-1H-pyrazol-4-yl] Pyrimidin-2-amine, or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S) -1-({4- [3- (3-chloro-1H-pyrrolo [2,3-b] pyridine-5-yl) -1-ethyl-1H-pyrazole). -4-yl] pyrimidin-2-yl} amino) propan-2-ol, 4- [1-isopropyl-3- (3-methyl-1H-pyrrolo [2,3-b] pyridine-5-yl)- 1H-pyrazol-4-yl] pyrimidin-2-amine, 4- [3- (3-chloro-1H-pyrrolo [2,3-b] pyridine-5-yl) -1-piperidin-4-yl-1H -Pyrazole-4-yl] pyrimidin-2-amine, 3-chloro-5- (1-piperidin-4-yl-4-pyrimidine-4-yl-1H-pyrazol-3-yl) -1H-pyrrolo [2 , 3-b] pyridine, 4- [1-tert-butyl-3- (3-chloro-1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidin- 2-amine, (2S) -1-({4- [1-tert-butyl-3- (3-methyl-1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4) -Il] pyrimidin-2-yl} amino) propan-2-ol, 4- [1- (1-acetylpiperidin-4-yl) -3- (3-chloro-1H-pyrrolo [2,3-b]] Pylin-5-yl) -1H-pyrazol-4-yl] -N- (2,2-difluoroethyl) -pyrimidine-2-amine, 4- [3- (6-amino-5-methoxypyridine-3-) Il) -1H-pyrazol-4-yl] -N- (2,2-difluoroethyl) -pyrimidine-2-amine, 3-({4- [3- (6-amino-5-methoxypyridine-3-) Il) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 4- [3- (6-amino-5-methoxypyridine) -3-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl] -N- (2,2-Difluoroethyl) -pyrimidine-2-amine, 3-({4- [1-tert-butyl-3- (3-methyl-1H-pyrazolo [3,4-b] pyridine-5-yl) -1H) -Pyrazole-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-({4- [1-tert-butyl-3- (2,3-dihydro-1H-pyrrolo [2,3-b]] Pylin-5-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-[(4- {3- (5-methoxypyridin-3-yl) -1-[( 3R)-tetrahydrofuran-3-yl] -1H-pyrazol-4-yl} pyrimidin-2-yl) amino] propanenitrile, 3-({4- [1-tert-butyl-3- (1H-pyrrolo [2H-pyrrolo [2) , 3-b] Pylin-5-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) -propanenitrile, 3-[(4- {3- (1H-pyrrolo [2,3-pyrrolo [2,3-) b] Pylin-5-yl) -1-[(3R)-tetrahydrofuran-3-yl] -1H-pyrazol-4-yl} pyrimidin-2-yl) amino] propanenitrile, (2S) -1-({ 4- [3- (3-Chloro-1H-pyrrolo [2,3-b] pyridine-5-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl] pyrimidine -2-yl} amino) propan-2-ol, 4- [3- (3-chloro-1H-pyrrolo [2,3-b] pyridine-5-yl) -1-piperidin-4-yl-1H- Pyrazole-4-yl] -N- (2,2-difluoroethyl) pyrimidin-2-amine, 3- (4- (3- (5-acetyl-6-aminopyridine-3-yl) -1- (2) , 2-Difluoroethyl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) -propanenitrile, 3-({4- [3- (5-amino-6-methoxypyrazine-2-yl) -1) -(2,2-Difluoroethyl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propanenitrile, 4- [3- (6-amino-5-methoxypyridin-3-yl) -4- {2- [(2-Hydroxyethyl) -amino] pyrimidin-4-yl} -1H-pyrazol-1-yl] -benzonitrile, 4- [1- (2,2-difluoroethyl) -3- (1H-pyrrolo [ 2,3-b] Pyridine-5-yl) -1H-pyrazol-4-yl] -N- (6-methoxypyridin-3-yl) pyrimidin-2-amine, 3- (4- (3- (6) -Amino-5-methoxypyridin-3-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) propanenitrile, 3- (4- (3- (3- (3-) 6-Amino-5-methoxypyridin-3-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) -propanenitrile, (S) -1-( 4- (3- (3-Chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-((1s, 3s) -3-fluorocyclobutyl) -1H-pyrazol-4-yl ) Pyrimidine-2-ylamino) Propan-2-ol, (S) -1- (4- (3- (6-amino-5-methoxypyridin-3-yl) -1-((1r, 3r) -3) -Fluorocyclobutyl) -1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol, (S) -1- (4- (3- (3-chloro-1H-pyrrolo [2,3) -b] Pyridine-5-yl) -1-((1r, 3r) -3-fluorocyclobutyl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2-ol, (2S)- 1-(4- (1- (2,2-difluoroethyl) -3- (3-methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole) -4-yl) pyrimidine-2-ylamino) propan-2-ol, 3- (4- (1- (2,2-difluoroethyl) -3- (2,,)3-Dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propanenitrile, and 1- (4- (1- (2,,,) 2-Difluoroethyl) -3- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazole-4-yl) pyrimidine-2-ylamino) -2-methyl It is selected from propan-2-ol, or its pharmaceutically acceptable salt. In a further embodiment, the compound is N- (2,2-difluoroethyl) -4-(1- (2,2-difluoroethyl) -3- (2,3-dihydro-1H-pyrrolo] [2,3- b] Pyridine-5-yl) -1H-pyrazol-4-yl) pyrimidin-2-amine, 3- (4- (1- (2,2-difluoroethyl) -3- (3-methyl-1H-pyrazolo) [3,4-b] Pyridine-5-yl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) propanenitrile, (S) -1- (4- (1- (2,2-difluoroethyl) ) -3-((R) -3-Methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) Propane-2-ol, 3- (4- (1- (2,2-difluoroethyl) -3- (3-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol -4-yl) pyrimidine-2-ylamino) propanenitrile, 3-(4- (1- (1-hydroxy-2-methylpropan-2-yl) -3- (3-methyl-1H-pyrazolo] [3, 4-b] Pyridine-5-yl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) propanenitrile, 3-(4- (1- (2,2-difluoroethyl) -3- (2-) Oxo-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl) -pyrimidine-2-ylamino) propanenitrile, (2S) -1-( {4- [3- (3-Chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl] pyrimidin-2 -Il} amino) propan-2-ol, (2S) -1-({4- [3- (3-chloro-2-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl)- 1-Isopropyl-1H-pyrazole-4-yl] pyrimidin-2-yl} amino) propan-2-ol, (2S) -1-[(4- {3- (3-chloro-1H-pyrrolo [2,,)3-b] Pyridine-5-yl) -1-[(3-Methyloxetane-3-yl) methyl] -1H-pyrazol-4-yl} pyrimidin-2-yl) amino] propan-2-ol, ( 2S) -1-({4- [3- (3-Chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-oxetane-3-yl-1H-pyrazol-4-yl] Pyrimidine-2-yl} amino) propan-2-ol, (2S) -1-({4- [1- (2,2-difluoroethyl) -3- (3-methyl-1H-pyrrolo [2,3] -b] Pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidine-2-yl} amino) propan-2-ol, (2S) -1-({4- [1- (2,2-) Difluoroethyl) -3- (3-fluoro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl] pyrimidine-2-yl} amino) propan-2-ol, (2S) -1-({4- [1- (2,2-difluoroethyl) -3- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H- Pyrazole-4-yl] pyrimidin-2-yl} amino) propan-2-ol, 5- [1- (2,2-difluoroethyl) -4- (2-{[(2S) -2-hydroxypropyl]] Amino} pyrimidin-4-yl) -1H-pyrazol-3-yl] -1H-pyrrolo [2,3-b] pyridin-3-carbonitrile, (2S) -1-({4- [3- (6) -Amino-5-methoxypyridin-3-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propan-2-ol, 2-({{ 4- [1- (2,2-difluoroethyl) -3- (3-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl] pyrimidine-2- Il} amino) ethanol, 2-({4- [3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (2,2-Difluoroethyl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) ethanol, 4- [3- (3-chloro-1H-pyrrolo [2,3-b] pyridine-5-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl] pyrimidin-2-amine, 4- [1- (2,2-difluoroethyl) -3- (3-methyl-1H-pyrrolo [2,3-b] Pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidin-2-amine, (2S) -1-({4- [3- (3-chloro-1H-pyrrolo [ 2,3-b] Pyridine-5-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propan-2-ol, (2S ) -1- ({4- [3- (3-Chloro-1H-pyrrolo [2,3-b] pyridine-5-yl) -1- (3-methoxypropyl) -1H-pyrazol-4-yl] Pyrimidin-2-yl} amino) propan-2-ol, (2S) -1-({4- [3- (6-amino-5-methoxypyridin-3-yl) -1-isopropyl-1H-pyrazol- 4-yl] pyrimidin-2-yl} amino) propan-2-ol, (2S) -1-({4- [3- (3-chloro-1H-pyrrolo [2,3-b] pyridine-5- Il) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propan-2-ol, N- (2,2-difluoroethyl) -4 -[1- (1-Methylpiperidin-4-yl) -3- (3-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl] pyrimidin-2 -Amine, 4- [3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl ] -N- (2,2-Difluoroethyl) pyrimidin-2-amine, 4- [3- (6-amino-5-methoxypyridin-3-yl) -1H-pyrazol-4-yl] pyrimidin-2-amine, 3- (4-) (1- (2,2-difluoroethyl) -3- (1-cyanoethyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) Propanenitrile, 3-({4- [3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (2-hydroxy-1,1-dimethylethyl) -1H -Pyrazole-4-yl] pyrimidin-2-yl} amino) -propanenitrile, 2- [4- (2-amino-pyrimidin-4-yl) -3- (3-chloro-1H-pyrrolo [2,3] -b] Pyridine-5-yl) -1H-pyrazol-1-yl] -2-methylpropan-1-ol, 3-chloro-5- (1-isopropyl-4-pyrimidine-4-yl-1H-pyrazole) -3-yl) -1H-pyrrolo [2,3-b] pyridine, 3-chloro-5- [1- (1-methylpiperidin-4-yl) -4-pyrimidine-4-yl-1H-pyrazol- 3-yl] -1H-pyrrolo [2,3-b] pyridine, 5- (1-tert-butyl-4-pyrimidine-4-yl-1H-pyrazol-3-yl) -3-methoxypyridine-2- Amine, (2S) -1- (4- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (tetra-3-yl) -1H-pyrazol- 4-yl) pyrimidin-2-ylamino) propan-2-ol, 3-({4- [3- (6-amino-5-methoxypyridin-3-yl) -1-methyl-1H-pyrazole-4- Il] pyrimidine-2-yl} amino) propanenitrile, N- (2,2-difluoroethyl) -4- [1- (2,2-difluoroethyl) -3- (3-methyl-1H-pyrazolo [3] , 4-b] Pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidin-2-amine, 4- [1- (2,,2-Difluoroethyl) -3- (3-Methyl-1H-pyrazolo [3,4-b] Pyridine-5-yl) -1H-pyrazol-4-yl] -N- (tetra-3-yl) pyrimidin- 2-amine, 2- [3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -4- {2-[(2-hydroxyethyl) amino] pyrimidin-4-yl } -1H-pyrazol-1-yl] -2-methylpropanenitrile, 2- [4- (2-aminopyrimidin-4-yl) -3- (3-chloro-1H-pyrrolo [2,3-b]] Pyridine-5-yl) -1H-pyrazol-1-yl] -2-methylpropanenitrile, 3- (4- (3- (6-amino-5-methylpyridin-3-yl) -1- (2,, 2-Difluoroethyl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) -propanenitrile, 4- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-Isopropyl-1H-pyrazol-4-yl) Pyridine-2-amine, 4- (1-Isopropyl-3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol- 4-yl) Pyridine-2-amine, 4- (1-isopropyl-3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazol-4-yl) -1H-pyrrolo [ 2,3-b] Pyridine, 3-Chloro-5- (1-Isopropyl-4- (1H-pyrrolo [2,3-b] Pyridine-4-yl) -1H-pyrazol-3-yl) -1H- Pyrrolo [2,3-b] Pyridine, (2S) -1-({4- [3- (5-amino-6-methoxypyrazine-2-yl) -1- (2,2-difluoroethyl) -1H -Pyrazole-4-yl] pyrimidin-2-yl} amino) propan-2-ol, (2S) -1-({4- [3- (7-chloro-5H-pyrrolo [2,3-b] pyrazine -2-yl) -1-Isopropyl-1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propan-2-ol, or a pharmaceutically acceptable salt thereof.It is selected from 3-b] pyrazine-2-yl) -1-isopropyl-1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propan-2-ol, or its pharmaceutically acceptable salt. In a further embodiment, the compound is 3-({4- [1- (2-hydroxy-1,1-dimethylethyl) -3- (5-methoxypyrimidine-3-yl) -1H-pyrazol-4-yl). ] Pyrimidine-2-yl} amino) Propanenitrile, 3-({4- [1- (2,2-difluoroethyl) -3- (1H-pyrrolo [2,3-b] pyridine-5-yl)- 1H-pyrazole-4-yl] pyrimidine-2-yl} amino) propanenitrile, 3-({4- [3- (5-amino-6-methoxypyrazine-2-yl) -1- (2,2-yl) Difluoroethyl) -1H-pyrazol-4-yl] pyrimidine-2-yl} amino) propanenitrile, (2S) -1- (4- (1-isopropyl-3- (3-methyl-1H-pyrazolo] [3,, 4-b] Pyridin-5-yl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol and 3- (4- (3- (5-acetyl-6-aminopyridine-3) -Il) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) -Propanenitrile, or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is 3-({4- [1- (2-hydroxy-1,1-dimethylethyl) -3- (5-methoxypyridin-3-yl) -1H-pyrazol-4-yl). ] Pyrimidine-2-yl} amino) Propanenitrile, 3-({4- [1- (2,2-difluoroethyl) -3- (1H-pyrolo [2,3-b] pyridine-5-yl)- 1H-pyrazole-4-yl] pyrimidin-2-yl} amino) propanenitrile, 3-({4- [3- (5-amino-6-methoxypyrazine-2-yl) -1- (2,2-yl) Difluoroethyl) -1H-pyrazol-4-yl] pyrimidine-2-yl} amino) propanenitrile, and 3- (4- (3- (5-acetyl-6-aminopyridine-3-yl) -1- ( It is selected from 2,2-difluoroethyl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) -propanenitrile, or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S) -1- (4- (1-isopropyl-3- (3-methyl-1H-pyrazolo [3,4-b] pyridin-5-yl) -1H-pyrazole- 4-Il) Pyrimidine-2-ylamino) Propan-2-ol or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S) -1- (4- (1-isopropyl-3- (3-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole- 4-Il) Pyrimidine-2-ylamino) Propan-2-ol or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S) -1- (4- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-isopropyl-1H-pyrazole- 4-Il) Pyrimidine-2-ylamino) Propan-2-ol or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S) -1-(4-(3- (2,3-dimethyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-isopropyl-1H- Pyrazole-4-yl) pyrimidin-2-ylamino) propan-2-ol or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S) -1- (4- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (2,2-difluoro) Ethyl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2-ol or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is 3-({4- [1- (2-hydroxy-1,1-dimethylethyl) -3- (5-methoxypyridin-3-yl) -1H-pyrazol-4-yl). ] Pyrimidine-2-yl} amino) Propionitrile or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is 3-({4- [1- (2,2-difluoroethyl) -3- (1H-pyrrolo [2,, 3-b] Pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidine-2-yl} amino) Propionitrile or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is 3-({4- [3- (5-amino-6-methoxypyrazine-2-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl). ] Pyrimidine-2-yl} amino) Propionitrile or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is 3- (4- (3- (5-acetyl-6-aminopyridine-3-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl). Pyrimidine-2-ylamino) -Propionitrile or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is selected from any group consisting of the 10 compounds shown in Table 1 or their pharmaceutically acceptable salts. A further embodiment is any of the above embodiments in combination with any of the other embodiments that are consistent with each other. The present invention also relates to pharmaceutical compositions comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. The present invention also relates to a method of treating abnormal cell proliferation or any Raf-mediated disease or condition in a mammal in need thereof, which is described herein in a therapeutically effective amount for said mammal. It comprises the step of administering at least one compound or a pharmaceutically acceptable salt thereof. For example, in one embodiment, the abnormal cell proliferation is cancerous. In a further embodiment, the abnormal cell proliferation is non-cancerous. The present invention further relates to a method of inhibiting Raf enzyme activity, which comprises contacting the Raf enzyme with a Raf inhibitory amount of at least one compound described herein or a pharmaceutically acceptable salt thereof. .. The present invention further relates to the use of any of the compounds described herein or salts or solvates thereof in the manufacture of pharmaceuticals for treating abnormal cell growth in mammals. The present invention is further set forth in specific examples herein, as well as in the general synthetic methods A, B, C, D, E, F, G, H and I described herein. The method relates to a method of producing the compounds described herein. The present invention further relates to any of the above compounds or salts or solvates thereof for use as pharmaceuticals. The present invention further relates to the use of any of the above compounds or salts or solvates thereof for producing pharmaceuticals for treating abnormal cell growth.

As used herein, the terms "include" and "include" are used in their open, non-limiting sense.

The terms "halo" and / or "halogen" refer to fluorine, chlorine, bromine or iodine.

As used herein, the term "oxo" is covalently attached to a carbon atom on an alkyl, cycloalkyl or cycloheteroalkyl by a double bond, the carbon of which is sp.2Refers to oxygen that is in a hybridization state and the resulting functional group becomes a ketone.

"C1~ C6The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups consisting of 1 to 6 carbon atoms. (C1From C6) Examples of alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and the like.

As used herein, "C2~ C8The term "alkenyl" means an alkyl moiety containing 2 to 8 carbons with at least one carbon-carbon double bond. The carbon-carbon double bond in such a group can be at any position along the 2 to 8 carbon chains as long as it provides a stable compound. Such groups include both the E and Z isomers of the alkenyl moiety. Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, allyl and pentenyl. As used herein, the term "allyl" is -CH.2CH = CH2Means a group. As used herein, the term "C (R) = C (R)" refers to a carbon-carbon double bond in which each carbon is substituted with an R group.

As used herein, "C2~ C8The term "alkynyl" means an alkyl moiety containing 2 to 8 carbon atoms and having at least one carbon-carbon triple bond. The carbon-carbon triple bond in such a group can be at any position along the 2 to 8 carbon chains as long as it provides a stable compound. Examples of such groups include, but are not limited to, ethyne, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne and 3-hexyne. To.

As used herein, "C1~ C6The term "alkoxy" means an O-alkyl group in which the alkyl group contains 1 to 6 carbon atoms and is linear, branched or cyclic. Alternatively, "C1~ C6"Alkoxy" means "-OC"1~ C6Alkylation is used interchangeably herein. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy, iso-butoxy, tert-butoxy, cyclopentyloxy and cyclohexyloxy. To.

"C1~ C11The term "heteroalkyl" includes 1 to 11 carbon atoms and has a total of 2 to 12 atoms in the chain, one or more of which are selected from S, O and N. A heteroatom to be produced, said chain refers to a straight or branched chain alkyl group that cannot contain two adjacent O atoms and two adjacent S atoms. The S atom in the chain can also be oxidized by one or two oxygen atoms to give sulfides and sulfones, respectively. Furthermore, C in the compounds of the present invention1~ C11Heteroalkyl groups can contain an oxo group at any carbon or heteroatom, which is expected to result in a stable compound. C1~ C11Examples of heteroalkyl groups include, but are not limited to, alcohols, alkyl ethers, primary, secondary and tertiary alkylamines, amides, ketones, esters, sulfides and sulfones.

As used herein, "C6~ C14The term "aryl" means, for example, a group derived from an aromatic hydrocarbon containing 6 to 14 carbon atoms, which may be monocyclic, bicyclic or tricyclic. Examples of such groups include, but are not limited to, phenyl or naphthyl. As used herein, the terms "Ph" and "phenyl" are -C.6H5Means a group. As used herein, the term "benzyl" is -CH.2C6H5Means a group.

As used herein, "C6~ C14The term "aryloxy" means an O-aryl group, wherein the aryl group contains 6 to 14 carbon atoms, which may be, for example, monocyclic, bicyclic or tricyclic. It is a group derived from aromatic hydrocarbons. Alternatively, "C6~ C14"Aryloxy" is referred to herein as "-OC".6~ C14Used interchangeably with "aryl". Examples of such groups include, but are not limited to, phenolyl or naphtholyl.

As used herein, "-SC"6~ C14The term "aryl" means an S-aryl group, wherein the aryl group contains 6 to 14 carbon atoms, which may be, for example, monocyclic, bicyclic or tricyclic. It is a group derived from aromatic hydrocarbons.

As used herein, "C2~ C9A "heteroaryl" has a total of 5 to 10 atoms in its ring and contains 2 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from O, S and N respectively. However, the ring of the group does not contain two adjacent O atoms or two adjacent S atoms. Heterocyclic groups include benzo-condensed ring systems. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, frill, thienyl, isooxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl. , Indazolyl, indolidinyl, phthalazinyl, pyridazinyl, triazinyl, isoindyl, pteridinyl, prynyl, oxadiazolyl, thiadiazolyl, frazayl, benzofrazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyldinyl, 1H-pyrrolo b] pyridinyl, 1H-pyrazolo [3,4-b] pyridinyl, 3H-imidazole [4,5-b] pyridinyl, imidazole [1,2-a] pyrimidinyl and flopyridinyl. C4From C9Heteroaryl groups can be C- or N-bonds where possible. For example, the group derived from pyrrole may be pyrrole-1-yl (N-bond) or pyrrole-3-yl (C-bond). Furthermore, the group derived from imidazole may be imidazol-1-yl (N-bond) or imidazol-3-yl (C-bond).

As used herein, "C2~ C9"Cycloheteroalkyl" has a total of 4 to 13 atoms in its ring system, 2 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from O, S and N, respectively. Containing non-aromatic, monocyclic, bicyclic, tricyclic, spirocyclic or tetracyclic groups, where the ring of the group is two adjacent O atoms or two. Does not contain adjacent S atoms. In addition, such C2From C9The cycloheteroalkyl group may contain an oxo substituent at any available atom as long as it results in a stable compound. For example, such groups may contain oxo atoms in the available carbon or nitrogen atoms. Such groups may contain more than one oxo substituent, if chemically possible. In addition, such C2From C9It should be understood that if the cycloheteroalkyl group contains a sulfur atom, the sulfur atom may be oxidized with one or two oxygen atoms to yield a sulfoxide or sulfone. An example of a 4-membered cycloheteroalkyl group is azetidine (derived from azetidine). An example of a 5-membered cycloheteroalkyl group is pyrrolidinyl. An example of a 6-membered cycloheteroalkyl group is piperidinyl. An example of a 9-membered cycloheteroalkyl group is indolinyl. An example of a 10-membered cycloheteroalkyl group is 4H-quinolidinyl. C like this2From C9Other examples of cycloheteroalkyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, tioxanyl, Piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indrinyyl, 2H-pyranyl, 4H-pyranyl , Dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] Heptanyl, 3H-indrillinoridinyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, 1-oxo-2,8, diazaspiro [4.5] des-8-yl, 1H- Pyrrolo [2,3-b] Pyridine-2 (3H) -one, 2,3-dihydro-1H-pyrrolo [2,3-b] pyridinyl and 6,7-dihydro-5H-pyrrolo [3,4-d ] Pyrimidinyl is included.

"C3~ C8The term "cycloalkyl group" means a saturated, monocyclic, condensed, spirocyclic or polycyclic ring structure having a total of 3 to 8 carbocyclic atoms. Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl and adamantyl.

The term "cyano" refers to the -CN group.

The term "substituted" means that the identified group or moiety has one or more substituents. The term "unsubstituted" means that the identified group does not have a substituent. The term "may be substituted" means that the identified group is unsubstituted or substituted with one or more substituents. In the compounds of the invention, if the group is stated to be "unsubstituted" or "substituted" with less than satisfying the valence of all atoms in the compound, the rest of such groups It should be understood that the valence is filled with hydrogen. For example, C, also referred to herein as "phenyl".6If the aryl group is substituted with one additional substituent, such groups will be C6You will understand that it leaves four vacant positions on the carbon atom of the aryl ring (the initial position is six, and the rest of the compounds of the invention are subtracted and added one attached. If you subtract one with the substituent, four remain). In such a case, each of the remaining four carbon atoms is bonded to one hydrogen atom to satisfy its valence. Similarly, C in the compounds of the invention6If the aryl group is stated to be "disubstituted", this would be C6You will understand that aryl means that it leaves behind three carbon atoms that are unsubstituted. Each of these three unsubstituted carbon atoms is bonded to one hydrogen atom to satisfy its valence.

The term "solvate" is used to describe a molecular complex between a compound of the invention and a solvent molecule. Examples of solvates include, but are not limited to, combinations of the compounds of the invention with water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine or mixtures thereof. Will be done. The term "hydrate" can be used when the solvent is water. It is particularly contemplated in the present invention that one solvent molecule, such as a hydrate, can bind to one molecule of a compound of the invention. Furthermore, it is particularly contemplated in the present invention that more than one solvent molecule, such as dihydrate, can bind to one molecule of the compounds of the present invention. In addition, it is particularly contemplated in the present invention that less than one solvent molecule, such as a hemihydrate, may bind to one molecule of the compounds of the present invention. Furthermore, the solvate of the present invention is contemplated as a solvate of the compound of the present invention, which retains the biological effectiveness of the non-hydrated form of the compound.

As used herein, the term "pharmaceutically acceptable salt" retains the biological effectiveness of the free acids and bases of a particular derivative and has other biological meanings. It also means a salt of the compound of the present invention, which is not undesirable.

As used herein, the term "pharmaceutically acceptable formulation" is compatible with a compound of the invention or a salt or solvate thereof and a compound of the invention to its recipients. Means a combination with a non-hazardous carrier, diluent and / or excipient. The pharmaceutical formulation can be prepared by a procedure known to those skilled in the art. For example, the compounds of the present invention can be formulated with common excipients, diluents or carriers and molded into tablets, capsules and the like. Examples of excipients, diluents and carriers suitable for such formulations include: fillers and bulking agents such as starch, sugar, mannitol and silicic acid derivatives; carboxymethyl cellulose and others. Cellulose derivatives, excipients such as alginate, gelatin and polyvinylpyrrolidone; wetting agents such as glycerin; disintegrants such as povidone, sodium starch glycolate, sodium carboxymethyl cellulose, agar, calcium carbonate and sodium bicarbonate; dissolution of paraffin etc. Delayers; Absorption enhancers such as quaternary ammonium compounds; Surfactants such as cetyl alcohol, glycerin monostearate; Adsorption carriers such as kaolin and bentonite; and lubricants such as talc, calcium stearate and magnesium and solid polyethylene glycol. The final pharmaceutical form may be pills, tablets, powders, lozenges, sachets, cashiers or sterile packaging powders, depending on the type of excipient used. In addition, it is particularly contemplated that the pharmaceutically acceptable formulations of the present invention may contain more than one active ingredient. For example, such formulations can contain more than one compound according to the invention. Alternatively, such formulations may contain one or more compounds of the invention and one or more additional agents that reduce abnormal cell growth.

As used herein, the term "Raf inhibitory amount" refers to a compound of the invention or a salt thereof, which is necessary to inhibit the enzymatic activity of Raf in vivo, such as in mammals, or in vitro. Refers to the amount of solvate. The amount of such a compound required to result in such inhibition can be determined without undue experimentation using the methods described herein and those commonly known to those of skill in the art. Can be decided.

As used herein, the term "inhibiting Raf enzyme activity" is used in vitro or in vivo, such as in mammals such as humans, by contacting the enzyme with a compound of the invention. , Means to reduce the activity or function of the Raf enzyme.

As used herein, the term "Raf" means a-Raf, b-Raf, c-Raf or variants thereof or any known Raf isoform splice variant. ..

As used herein, the term "therapeutically effective amount" is sufficient to provide the treatment as defined herein when administered to a mammal in need of such treatment. It means the amount of a compound of the present invention or a salt or solvate thereof. Thus, a therapeutically effective amount of a compound of the invention or a salt or solvate thereof is sufficient to regulate or inhibit the activity of the Raf enzyme and reduce or alleviate the disease state mediated by the activity of the Raf enzyme. Is.

The terms "treat," "treat," and "treatment" associated with abnormal cell proliferation or any Raf-mediated disease or condition in mammals, especially humans, include (i) treatment as a pathological condition. To prevent the development of a disease or condition in a subject susceptible to the condition so as to constitute prophylactic treatment for; (ii) to regulate or inhibit the disease or condition, i.e. to stop its progression. (Iii) Relieving a disease or condition, i.e. regressing a disease or condition; or (iv) Relieving and / or alleviating a disease or condition or symptoms resulting from a disease or condition, eg, an underlying disease Alternatively, reducing the inflammatory response without coping with the condition is included. With respect to abnormal cell growth such as cancer, these terms simply mean extending the expected lifespan of an individual suffering from abnormal cell growth or alleviating one or more symptoms of the disease. There is.

Unless otherwise indicated, all references herein to compounds of the invention are salts, solvates and their salts, including polymorphs, stereoisomers, tautomers and their isotope-labeled versions. Includes references to the complex. For example, the compounds of the invention may be pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates.

As used herein, "abnormal cell proliferation" refers to cell proliferation that is independent of normal regulatory mechanisms (eg, loss of contact inhibition), unless otherwise indicated, normal cell abnormalities. Includes proliferative and abnormal cell proliferation. This includes, but is not limited to, tumor cells (tumors) that proliferate due to expression of mutant tyrosine kinase or overexpression of receptor tyrosine kinase; benign and malignant of other proliferative disorders that result in abnormal tyrosine kinase activity. Cells; Any tumor that grows with receptor tyrosine kinase; Any tumor that grows with abnormal serine / threonine kinase activity; Benign and malignant cells of other proliferative disorders that produce abnormal serine / threonine kinase activity; Activated Ras Both benign and malignant tumors that express cancer genes; both benign and malignant tumor cells in which Ras proteins are activated as a result of cancer gene mutations in other genes; other tumors that result in abnormal Ras activation Includes benign and abnormal proliferation of malignant cells in proliferative disorders. Examples of such benign proliferative disorders are psoriasis, benign prostatic hyperplasia, human papillomavirus (HPV) and restenosis. "Abnormal cell proliferation" also refers to and includes both benign and malignant abnormal cell proliferation resulting from the activity of the enzyme farnesyl protein transferase.

The terms "abnormal cell proliferation" and "hyperproliferative disorder" are used interchangeably in this application.

The term "three isomers" refers to compounds that have the same chemical structure but differ in terms of their atomic or group arrangement in space. In particular, the term "enantiomer" refers to two stereoisomers of a compound, which are mirror images that cannot be superimposed on each other. As used herein, the term "racemic" or "racemic mixture" refers to a 1: 1 mixture of enantiomers of a particular compound. On the other hand, the term "diastereoisomer" refers to the relationship of stereoisomer pairs that contain two or more asymmetric centers and are not mirror images of each other.

The compounds of the present invention are useful for regulating or inhibiting Raf activity. Therefore, these compounds are useful for preventing and / or treating disease states associated with abnormal cell growth, such as cancer, alone or in combination with other anti-cancer agents.

According to the rules used in the art, the symbol:

<chemistry num="11"><img file="JP4792126B2_D0014.tif" /></chemistry>Is used in the structural formulas herein to indicate a bond that is the point of attachment of a moiety or substituent to a nuclear or backbone structure. According to other rules, in some structural formulas herein, carbon atoms and their bonded hydrogen atoms are not specified, eg, for example.

<chemistry num="12"><img file="JP4792126B2_D0015.tif" /></chemistry>Represents an ethyl group

<chemistry num="13"><img file="JP4792126B2_D0016.tif" /></chemistry>Represents a cyclopentyl group, and so on.

The compounds of the present invention may have an asymmetric carbon atom. The carbon-carbon bonds of the compounds of the invention are shown herein by solid line:

<chemistry num="14"><img file="JP4792126B2_D0017.tif" /></chemistry>Solid wedge:

<chemistry num="15"><img file="JP4792126B2_D0018.tif" /></chemistry>Or dashed wedge:

<chemistry num="16"><img file="JP4792126B2_D0019.tif" /></chemistry>May be indicated using. The use of solid lines to indicate a bond to an asymmetric carbon atom indicates that all possible stereoisomers at that carbon atom (eg, individual enantiomers, racemic mixtures, etc.) are included. To do. The use of a solid or dashed wedge to indicate a bond to an asymmetric carbon atom shall indicate that it means that only the shown stereoisomers are included. The compound of the present invention can also contain more than one asymmetric carbon atom. In these compounds, the use of a solid line to indicate a bond to an asymmetric carbon atom shall indicate that all possible stereoisomers are included. For example, unless otherwise stated, it is intended that the compounds of the invention may exist as enantiomers and diastereoisomers, or as racemic compounds and mixtures thereof. Use of a solid line to indicate a bond to one or more asymmetric carbon atoms in a compound of the invention and use of a solid or broken wedge to indicate a bond to another asymmetric carbon atom in the same compound. Indicates the presence of a mixture of diastereoisomers.

Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or racemates using, for example, chiral high performance liquid chromatography (HPLC). Is included. Alternatively, the racemate (or racemic precursor) may be a suitable optically active compound, such as tartaric acid or 1-phenylethylamine if the compound contains an acidic or basic moiety, such as alcohol. It can also be reacted with an acid or base. The resulting mixture of diastereoisomers is separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers are corresponding pure enantiomers by means well known to those skilled in the art. Can be converted to. Chromatography, typically HPLC, on asymmetric resins, hydrocarbons, typically isopropanol 0-50%, typically 2-20% and alkylamines 0-5%, typically diethylamine It can also be used with a mobile phase consisting of heptane or hexane containing 0.1% to obtain the chiral compounds of the invention (and their chiral precursors) in enantiomerically enriched form. Concentrating the eluate gives a concentrated mixture. The stereoisomer complex can be separated by conventional techniques known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds" (Wiley, New York, 1994) by EL Eliel, the entire disclosure of which is incorporated herein by reference.

Geometric cis / trans (or Z / E) isomers are possible if the compounds of the invention contain alkenyl or alkenylene groups. Tautomerism can occur if the compound contains, for example, a keto or oxime group or an aromatic moiety. Examples of tautomers include keto and enol tautomers. A single compound may exhibit more than one type of isomerism. All stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one isomer and one or more mixtures thereof, are included within the scope of the invention. .. The cis / trans isomers can be separated by conventional techniques well known to those of skill in the art, such as chromatography and fractional crystallization.

The compounds of the present invention can be administered as prodrugs. For example, certain derivatives of compounds of formula (I) that may or may not have little pharmacological activity on their own are desired when administered to mammals, eg, by hydrolysis by hydrolysis. Can be converted to a compound of formula (I) having the activity of. Such derivatives are referred to as "prodrugs". For example, a prodrug can be made by substituting the appropriate functional groups present in the compound of formula (I) with certain moieties known to those of skill in the art. For example, "Pro-drugs as Novel Delivery Systems", Vol.14, ACS Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design", the entire disclosure of which is incorporated herein by reference. Pergamon Press, 1987 (EBRoche ed., American Pharmaceutical See Association). Some examples of such prodrugs include ester moieties instead of carboxylic acid functional groups, ether or amide moieties instead of alcohol functional groups and amide moieties instead of primary or secondary amino functional groups. Is included. Further examples of substituents are known to those of skill in the art. See, for example, "Design of Prodrugs" (Elsevier, 1985) by H Bundgaard, the entire disclosure of which is incorporated herein by reference. It is also possible that certain compounds of formula (I) can act as prodrugs of other compounds of formula (I) by themselves.

The salts of the present invention can be prepared according to methods known to those skilled in the art. Examples of salts include, but are not limited to, acetates, acrylates, benzenesulfonates, benzoates (chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates and methoxy). (Salvate, etc.), hydrogen carbonate, hydrogen sulfate, hydrogen sulfite, hydrogen tartrate, borate, bromide, butin-1,4-dioate, calcium edetate, cansilate, carbonic acid Salts, chlorides, capronates, caprilates, clavulanates, citrates, decanoates, dihydrochlorides, dihydrogen phosphates, edetates, edicylates, estolates , Esilate, ethyl succinate, formate, fumarate, glucate, gluconate, glutamate, glycolate, glycolyl alsanylate, heptaneate, hexin-1,

The compounds of the invention, which are inherently basic, can form a wide variety of salts with a variety of inorganic and organic acids. Such salts must be pharmaceutically acceptable for administration to animals, but in practice the compounds of the invention are initially isolated from the reaction mixture as pharmaceutically unacceptable salts, and then this. Is often converted back to a free base compound by treatment with an alkaline reagent, followed by conversion of this free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of the invention can be obtained by treating the base compounds with substantially equivalent amounts of the selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Can be prepared. Evaporation of the solvent gives the desired solid salt. The desired acid salt can also be precipitated from a solution of free bases in an organic solvent by adding a suitable inorganic or organic acid to the solution.

The compounds of the invention, which are inherently acidic, can form a variety of pharmacologically acceptable cations and base salts. Examples of such salts include alkali metal or alkaline earth metal salts, especially sodium and potassium salts. All of these salts are prepared by conventional techniques. The chemical base used as a reagent for preparing a pharmaceutically acceptable base salt of the present invention forms a non-toxic base salt with the acidic compound of the present invention. Such non-toxic base salts include those derived from pharmaceutically acceptable cations such as sodium, potassium, calcium and magnesium. These salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution under reduced pressure until dry. it can. Alternatively, they can also be prepared by mixing a lower alkanol solution of the acidic compound and the desired alkali metal alkoxide together and then evaporating the resulting solution in the same manner as described above until dry. In either case, theoretical amounts of reagents are preferably used to ensure completion of the reaction and maximum yield of the desired final product.

When the compounds of the invention are bases, any suitable method available in the art, for example, free bases with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitrate, phosphoric acid, or acetic acid, Pyranosidilic acids such as maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvate, oxalic acid, glycolic acid, salicylic acid, glucuronic acid or galacturonic acid, alpha-hydroxy acids such as citric acid or tartaric acid, aspartic acid or A desired salt can be prepared by treatment with an amino acid such as glutamic acid, an aromatic acid such as benzoic acid or silicic acid, or an organic acid such as sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid.

When the compound of the present invention is an acid, by any suitable method, for example, the free acid can be an amine (primary, secondary or tertiary), alkali metal hydroxide or alkaline earth metal hydroxide. The desired salt can be prepared by treating with an inorganic or organic base such as a substance. Examples of suitable salts include amino acids such as glycine and arginine, organic salts derived from ammonia, primary, secondary and tertiary amines and cyclic amines such as piperidine, morpholine and piperazine and sodium, calcium, Included are inorganic salts derived from potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

If the agent is solid, the compounds, agents and salts of the invention may be present in various crystalline or polymorphic forms, all of which are intended to be within the formulas of the present invention and specified. What has been done will be understood by those skilled in the art.

The present invention also presents isotope labeling in which one or more atoms have the same atomic number but are replaced by atoms having an atomic mass or mass number that is different from the atomic mass or mass number normally found in nature. Includes the compound of the present invention. Examples of isotopes suitable for inclusion in the compounds of the present invention include2H and3Hydrogen such as H,11C,13C and14Carbon such as C,36Chlorine such as Cl,18Fluorine such as F,123I and125Iodine, such as I13N and15Nitrogen such as N,15O,17O and18Oxygen such as O,32Phosphorus such as P and35Sulfur isotopes such as S are included. Certain isotope-labeled compounds of the invention, such as those containing radioisotopes, are useful in drug and / or substrate tissue distribution studies. Radioisotope tritium,3H and carbon-14,14C is particularly useful for this purpose in that it is easy to introduce and a quick means of detection. Juuterium,2Substitution with a heavy isotope such as H may be preferable in some cases as it can provide certain therapeutic benefits resulting from greater metabolic stability, eg, higher in vivo half-life or lower dose requirements.11C,18F,15O and13Substitution with positron emitting isotopes such as N may be useful in positron emission tomography (PET) studies to determine substrate receptor occupancy.

Isotopically labeled by conventional techniques known to those of skill in the art, or by a process similar to the process described herein using the appropriate isotope labeling reagent in place of the unlabeled reagent used elsewhere. The compounds of the present invention can usually be prepared.

The compounds of the present invention can be formulated in the following pharmaceutical compositions in any pharmaceutical form that can be recognized by those skilled in the art as appropriate. The pharmaceutical composition of the invention comprises a therapeutically effective amount of at least one compound of the invention and an inert pharmaceutically acceptable carrier or diluent.

At least one compound of the invention (activity) of a therapeutically effective amount (ie, a Raf-modulated, regulated or inhibitory amount effective to achieve a therapeutic effect) to treat or prevent a Raf-mediated disease or condition. As an ingredient) is prepared by combining with one or more pharmaceutically suitable carriers which can be selected from, for example, diluents, excipients and auxiliaries, which facilitate the processing of the active compound into the final pharmaceutical formulation. The pharmaceutical composition of the present invention is administered with an appropriate formulation.

The pharmaceutical carrier used may be solid or liquid. Examples of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the compositions of the present invention include time-delayed or sustained-release substances known in the art such as glyceryl monostearate or glyceryl distearate alone, or wax, ethyl cellulose, hydroxypropyl methyl cellulose, methyl methacrylate and the like. May be included with. Other additives or excipients can also be added to achieve the desired formulation properties. For example, bioavailability enhancers such as Labrasol and Gelucire or compounding agents such as CMC (carboxymethyl cellulose), PG (propylene glycol) or PEG (polyethylene glycol) can be added. Gelucire®, a semi-solid medium that protects the active ingredient from light, moisture and oxidation, can be added, for example, when preparing capsule formulations.

When using a solid carrier, the formulation can be tableted, placed in hard gelatin capsules in powder or pellet form, or molded into lozenges or lozenges. The amount of solid support can vary, but is typically from about 25 mg to about 1 g. When using liquid carriers, the formulation may be in the form of sterile injections or suspensions or non-aqueous liquid suspensions in syrups, emulsions, soft gelatin capsules, ampoules or vials. When using a semi-solid carrier, the formulation may be in the form of hard and soft gelatin capsule formulations. The compositions of the present invention are prepared in a dosage form, eg, a unit dosage form suitable for parenteral or oral administration.

In order to obtain a stable water-soluble dosage form, salts of the compounds of the present invention can be dissolved in aqueous solutions of organic or inorganic acids such as 0.3 M solution of succinic acid or citric acid. If soluble salt forms are not available, the drug can be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable co-solvents include alcohols, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like at concentrations in the range 0-60% of the total volume. In an exemplary embodiment, the compounds of the invention are dissolved in DMSO and diluted with water. The composition may also be in the form of a suitable aqueous medium solution or dextrose solution, such as water in the salt form of the active ingredient or isotonic saline.

The proper formulation depends on the route of administration chosen. For injection, the agents of the compounds of the invention can preferably be formulated in aqueous solution in a physiologically compatible buffer, such as Hanks solution, Ringer solution or saline buffer. For transmucosal administration, a penetrant suitable for the permeation barrier is used in the formulation. Such penetrants are commonly known in the art.

For oral administration, the compound can be formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers allow the compounds of the invention to be formulated as tablets, pills, sugar-coated pills, capsules, solutions, gels, syrups, slurries, suspensions and the like for oral ingestion by the patient being treated. Using a solid excipient to be mixed with the active ingredient (drug), the resulting mixture may be ground, and if desired, the granule mixture may be processed into tablets or sugar-coated pills after adding the appropriate auxiliaries. By obtaining the core of (dragee), a pharmaceutical preparation for oral use can be obtained. Suitable excipients are: fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; and cellulose preparations such as malt starch, wheat starch, rice starch, potato starch, gelatin, rubber, methylcellulose, hydroxypropyl. Included are methyl-cellulose, sodium carboxymethyl cellulose or polyvinylpyrrolidone (PVP). If desired, a disintegrant such as crosslinked polyvinylpyrrolidone, agar or a salt thereof such as alginic acid or sodium alginate can also be added.

The core of sugar-coated pills has an appropriate coating. For this purpose, concentrated sugar solutions may also contain gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments can also be added to tablets or sugar-coated round coatings to identify or characterize different combinations of activators.

Pharmaceutical formulations that can be used orally include push-fit capsules made of gelatin, as well as soft sealed capsules consisting of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in the form of a filler such as lactose, a binder such as starch and / or a lubricant such as talc or magnesium stearate and optionally a stabilizer. In soft capsules, the activator can be dissolved or suspended in a suitable liquid such as aliphatic oil, liquid petrolatum or liquid polyethylene glycol. In addition, stabilizers can be added. All formulations for oral administration should be at doses suitable for such administration. For buccal administration, the composition can take the form of tablets or lozenges formulated in a conventional manner.

For intranasal or inhalation administration, the compound for use in accordance with the present invention is added with a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can be conveniently delivered in the form of an aerosol spray presentation from a pressure pack or nebulizer. In the case of pressurized aerosols, the unit of dosing can be determined by equipping a valve for delivering the measured amount. Gelatin capsules and cartridges for use in inhalers or injectors and the like can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

The compounds can also be formulated for parenteral administration by injection, eg, bolus injection or continuous infusion. Formulations for injection can be provided in unit dosage forms with preservatives added, eg, in ampoules or in multi-dose containers. The composition can take the form of suspensions, solutions or emulsions in oily or aqueous media and can contain prescription agents such as suspending agents, stabilizers and / or dispersants. ..

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In addition, active agent suspensions can be prepared as suitable oily injection suspensions. Suitable hydrophobic solvents or vehicles include aliphatic oils such as sesame oil or synthetic fatty acid esters or liposomes such as ethyl oleate or triglycerides . Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. In some cases, the suspending agent may also contain suitable stabilizers or agents that increase the solubility of the compound so that high concentration solutions can be prepared.

Alternatively, the active ingredient may be in powder form to be composed of a suitable medium, eg, sterile pyrogen-free water, prior to use.

In addition to the formulation described above, the compounds of the invention can also be formulated as depot formulations. Such long-acting formulations can be administered by transplantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymers or hydrophobic substances (eg, as emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives, such as sparingly soluble salts. .. Pharmaceutical carriers for hydrophobic compounds are co-solvent systems containing benzyl alcohol, non-polar surfactants, water-miscible organic polymers and an aqueous phase. The co-solvent system may be a VPD co-solvent system. VPD is a solution consisting of 3% w / v benzyl alcohol, 8% w / v non-polar surfactant polysorbate 80 and 65% w / v polyethylene glycol 300, replenished to volume in absolute ethanol. There is. The VPD co-solvent system (VPD: 5W) contains VPD diluted 1: 1 with 5% aqueous dextrose. This co-solvent system dissolves hydrophobic compounds well and, by itself, results in low toxicity upon systemic administration. The proportion of co-solvent system can be appropriately varied without compromising its solubility and toxic properties. In addition, the identity of the co-solvent component can be varied. For example, other low-toxic non-polar surfactants can be used in place of the polysorbate 80, the fraction size of polyethylene glycol can be varied, and other biocompatible polymers such as polyvinylpyrrolidone can be used with polyethylene glycol. Can be used as a substitute for dextrose, and other sugars or polysaccharides can be used as a substitute for dextrose.

Alternatively, other delivery systems can be used for hydrophobic pharmaceutical compounds. Liposomes and emulsions are known examples of delivery media or carriers for hydrophobic drugs. Certain organic solvents, such as dimethyl sulfoxide, can also be used, although usually at the expense of higher toxicity due to the toxicity of DMSO. In addition, the compounds can be delivered using a sustained release system such as a semipermeable matrix of solid hydrophobic polymers containing therapeutic agents. Various sustained release substances have been established and are known to those of skill in the art. Sustained release capsules release compounds for weeks to over 100 days, depending on their chemistry. Additional measures for protein stabilization can also be used, depending on the chemistry and biological stability of the therapeutic agent.

The pharmaceutical composition may also contain a suitable solid or gel phase carrier or excipient. These carriers and excipients can provide significant improvements in the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include polymers such as calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin and polyethylene glycol. In addition, Gelucire®, Capryol®, Labrafil®, Labrasol®, Lauroglycol®, Pllurol®, Peceol®, Transcutol®, etc. Additives or excipients can be used.

In addition, the pharmaceutical composition can be introduced into a skin patch for delivering the drug directly onto the skin.

It is understood that the actual dose of the agents of the invention will vary depending on the particular agent used, the particular composition formulated, the mode of administration and the particular site being treated, the recipient and the disease. Will. Using conventional dose determination tests, taking into account experimental data for a given compound, one of ordinary skill in the art can ascertain the optimal dose for a given set of conditions. For oral administration, the exemplary daily dose commonly used is from about 0.001 to about 1000 mg / kg body weight over a course of treatment repeated at appropriate intervals.

In addition, the pharmaceutically acceptable formulations of the invention are compounds of the invention or salts or solvates thereof, from about 10 mg to about 2000 mg, or about 10 mg to about 1500 mg, or about 10 mg to about 1000 mg, or about 10 mg. It can be contained in an amount of about 750 mg, or about 10 mg to about 500 mg, or about 25 mg to about 500 mg, or about 50 mg to about 500 mg, or about 100 mg to about 500 mg.

In addition, the pharmaceutically acceptable formulations of the invention are compounds of the invention or salts or solvates thereof, from about 0.5 w / w% to about 95 w / w%, or from about 1 w / w% to about 95 w /. w%, or about 1w / w% to about 75w / w%, or about 5w / w% to about 75w / w%, or about 10w / w% to about 75w / w%, or about 10w / w% to about It can be contained in an amount of 50 w / w%.

The compounds of the invention or salts or solvates thereof may be used alone or as part of a pharmaceutically acceptable formulation in mammals such as humans suffering from abnormal cell proliferation, once daily, 2 daily. It can be administered at a frequency of 3 times a day, 4 times a day or more.

With respect to the compounds of the present invention, the specific pharmaceutical formulation, dose and prescribed number of doses per day to mammals in need of such treatment are all choices within the knowledge of ordinary skill in the art and are excessive. Those skilled in the art will understand that the determination can be made without the experimentation of.

The present invention also relates to a method of treating abnormal cell growth in mammals, including humans, wherein the method is an amount defined above that is effective in treating the abnormal cell growth in the mammal. Includes administration of the compound of (I) or a salt or solvate thereof.

In one embodiment of this method, abnormal cell proliferation is not limited to these, but mesencephalic tumors, hepatobiliary tracts (hepatic and biliary tracts), primary or secondary CNS tumors, primary or secondary brain tumors, lung cancer. (NSCLC and SCLC), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, gastric cancer, gastrointestinal (gastric, colonic rectal) And duodenum), breast cancer, uterine cancer, oviduct cancer, endometrial cancer, cervical cancer, vaginal cancer, genital cancer, Hodgkin's disease, esophageal cancer, small intestinal cancer, endocrine cancer, Cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urinary tract, cancer of the penis, cancer of the prostate, cancer of the testis, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic leukemia, cancer of the bladder , Kidney or urinary tract cancer, renal cell cancer, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, non-hodgkin lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, adrenal cortex Cancer, biliary sac cancer, multiple myeloma, biliary tract cancer, fibrosarcoma, neuroblast type, retinal blast type or cancer including one or more combinations of the above-mentioned cancers.

In one embodiment of the invention, the cancer is lung cancer (NSCLC and SCLC), head or neck cancer, ovarian cancer, colon cancer, rectal cancer, anal region cancer, gastric cancer, breast cancer, kidney or urinary tract cancer. It is selected from one or more combinations of kidney cell cancer, renal pelvis cancer, central nervous system (CNS) neoplasia, primary CNS lymphoma, non-Hodgkin's lymphoma, spinal axis tumor or the cancers described above.

In another embodiment of the invention, the cancer is selected from lung cancer (NSCLC and SCLC), ovarian cancer, colon cancer, rectal cancer, cancer in the anal region or a combination of one or more of the above cancers.

In other embodiments of the invention, the cancer is selected from lung cancer (NSCLC and SCLC), ovarian cancer, colon cancer, rectal cancer or a combination of one or more of the above cancers.

In other embodiments of the method, the abnormal cell proliferation is a benign proliferative disorder including, but not limited to, psoriasis, benign prostatic hyperplasia or restenosis.

The present invention also relates to a method of treating abnormal cell growth in a mammal, which comprises an effective amount of the compound of the invention or a salt or solvent thereof for treating the abnormal cell growth in the mammal. Mitosis inhibitors, alkylating agents, antimetabolites, intercalation antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response regulators, antibodies, cytotoxicities, Includes administration in combination with an antitumor agent selected from the group consisting of antihormones and antiandrogens.

In one embodiment of the invention, the antitumor agent used in combination with the compounds and pharmaceutical compositions of the invention described herein is an antitumorogenic agent, a kinase inhibitor, a pan kinase inhibitor or a growth factor inhibitor. It is an agent. Preferred pan kinase inhibitors include Sutent (sunitinib) described in US Pat. No. 6,573,293 (Pfizer, Inc, NY, USA). Antiangiogenic agents include, but are not limited to, EGF inhibitors, EGFR inhibitors, VEGF inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGF1R inhibitors, COX-II (cyclooxygenase II) inhibitors, MMP- Drugs such as 2 (matrix-metalloproteinase 2) inhibitors and MMP-9 (matrix-metalloproteinase 9) inhibitors are included.

Preferred VEGF inhibitors include, for example, Avastin (bevacizumab) from Genentech, Inc. (South San Francisco, California), anti-VEGF monoclonal antibodies. Additional VEGF inhibitors include CP-547632 (Pfizer Inc., NY, USA), AG13736 (Pfizer Inc.), ZD-6474 (AstraZeneca), AEE788 (Novartis), AZD-2171), VEGF Trap (Regeneron / Aventis), Bataranib (PTK-787, also known as ZK-222584; Novartis & Schering AG), McGen (Pegaptanib Octasodium, NX-1838, EYE-001, Pfizer Inc./Gilead/Eyetech), IM862 (Cytran) Includes synthetic ribozymes from Inc., Kirkland, Washington, USA) and angiozymes, ribozymes (Boulder, Colorado) and Kiron (Chiron, Emeryville, California) and combinations thereof.

VEGF inhibitors useful in practicing the present invention are described in US Pat. Nos. 6,534,524 and 6235764, both of which are incorporated in their entirety for any purpose. Additional VEGF inhibitors are, for example, WO99 / 24440, WO95 / 21613, WO99 / 61422, US Pat. No. 5834504, WO98 / 50356, US Pat. No. 5883113, US Pat. No. 5886020, US Pat. No. 5792783, US Pat. No. 6653308, WO99 / 10349, WO97 / 32856, WO97 / 22596, WO98 / 54093, WO98 / 02438, WO99 / 16755 and WO98 / 02437, all of which are hereby incorporated by reference in their entirety. It will be used.

Other anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, apridin, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Includes levrimide, squalamine, ucline, vitaxin and combinations thereof.

Other antiproliferative agents that can be used in combination with the compounds of the present invention include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, which includes the following US Pat. , U.S. Patent No. 6194438, U.S. Patent No. 6258824, U.S. Patent No. 6586447, U.S. Patent No. 6071935, U.S. Patent No. 6495564 and U.S. Patent No. 6150377, U.S. Patent No. 6596735, U.S. Patent No. 6479513, WO01 / 40217, US Pat. No. 2003-0166675, includes the compounds disclosed and claimed. Each of the above patents and patent applications is incorporated herein by reference in their entirety.

PDGRr inhibitors include, but are not limited to, those disclosed in WO 01/40217 and WO 2004/020431, the entire contents of which are incorporated for all purposes. Preferred PDGFRr inhibitors include Pfizer CP-673451 and CP-868596 and salts thereof.

Preferred GARF inhibitors include Pfizer AG-2037 (pelitrexol and salts thereof). GARF inhibitors useful in practicing the present invention are disclosed in US Pat. No. 5,560,082, which is incorporated in its entirety for all purposes.

Examples of useful COX-II inhibitors that can be used in combination with the compounds of formula (I) and pharmaceutical compositions disclosed herein include CELEBREX (celecoxib), palecoxib, delacoxib, and others. ABT-963, MK-663 (etricoxib), COX-189 (Lumiracoxib), BMS347070, RS57067, NS-398, Bextra (Valdecoxib), Paracoxib, Vioxx (Rofecoxib), SD-8381, 4-Methyl-2- (3) , 4-Dimethylphenyl) -1- (4-Sulfamoyl-phenyl) -1H-pyrrole, 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) -1H-pyrrole, T -614, JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (etricoxib) are included. In addition, COX-II inhibitors are disclosed in US Patent Application Nos. 2005-0148627 and 2005-0148777, the contents of which are incorporated in their entirety for all purposes.

In a particular embodiment, the antitumor agents are celecoxib (US Pat. No. 5,466,823), valdecoxib (US Pat. No. 5,633,272), parecoxib (US Pat. No. 5,932,598), delacoxib (US Pat. No. 5,521,207) SD-8381 ( US Pat. No. 6034256, Example 175), ABT-963 (WO2002 / 24719), Rofecoxib (CAS No.162011-90-7), MK-663 (or etricoxib) disclosed in WO1998 / 03484, WO1999 / COX-189 (Lumiracoxib), BMS-347070 (US Pat. No. 6,180,651), NS-398 (CAS123653-11-2), RS 57067 (CAS 17932-91-3), 4-Methyl-, disclosed in 11605. 2- (3,4-dimethylphenyl) -1- (4-sulfamoyl-phenyl) -1H-pyrrole, 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) -1H -Pyrol or meloxicam.

Other inhibitors useful as anti-tumor agents used in combination with the compounds and pharmaceutical compositions of the invention disclosed herein include inhibition of prostaglandin-producing enzymes (cyclooxygenases I and II). And include aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) that result in low levels of prostaglandin, including, but not limited to, Salsalate (Amigesic), Diflunisal (Dolobid), Ibuprofen. (Motrin), Ketoprofen (Orudis), Nabumetone (Relafen), Piroxicam (Feldene), Naproxen (Aleve, Naprosyn), Diclofenac (Voltaren), Indomethacin (Indocin), Sulindac (Clinoril), Tolmetin (Tolectin), Etodolac , Ketorolac (Toradol), Oxaprozin (Daypro) and combinations thereof.

Preferred COX-I inhibitors include ibuprofen (Motrin), nuprin, naproxen (Aleve), indomethacin (Indocin), nabumetone (Relafen) and combinations thereof.

Target agents used in combination with the compounds and pharmaceutical compositions of the invention disclosed herein include Iressa (gefitinib, AstraZeneca), Tarceva (erlotinib or OSI-774, OSI Pharmaceuticals Inc.), Erbitux ( Cetuximab, Imclone Pharmaceuticals, Inc., EMD-7200 (Merck AG), ABX-EGF (Amgen Inc. and Abgenix Inc.), HR3 (Cuban Government), IgA antibody (Erlangen-Nuremberg University), TP-38 (IVAX) ), EGFR fusion proteins, EGF-vacuants, anti-EGFr immunolipolips (Hermes Biosciencs Inc.) and EGFr inhibitors such as combinations thereof. Preferred EGFr inhibitors include Iressa, Erbitux, Tarceva and combinations thereof.

Other antitumor agents include CP-724714 (Pfizer Inc.), CI-1033 (canertinib, Pfizer Inc.), Herceptin (trastuzumab, Genentech Inc.), Omitarg (2C4, pertuzumab, Genentech Inc.) , TAK-165 (Takeda), GW-572016 (Ionafarnib, GlaxoSmithKline), GW-282974 (GlaxoSmithKline), EKB-569 (Wyeth), PKI-166 (Novartis), dHER2 (HER2 vaccine, Corixa and GlaxoSmithKline), APC8024 HER2 vaccine, Dendreon), anti-HER2 / neu bispecific antibody (Decof Cancer Center), B7.her2.IgG3 (Agensys), AS HER2 (Research Institute for Rad Biology & Medicine), trifunctional bispecific antibody (Munich) University) and mAB AR-209 (Aronex) Included are those selected from pan erb receptor inhibitors or ErbB 2 receptor inhibitors such as Pharmaceuticals Inc) and mAB 2B-1 (Chiron) and combinations thereof.

Preferred erb-selective antitumor agents include Herceptin, TAK-165, CP-724714, ABX-EGF, HER3 and combinations thereof. Preferred pan erbb receptor inhibitors include GW572016, CI-1033, EKB-569 and Omitarg and combinations thereof.

Additional erbB2 inhibitors include those disclosed in WO98 / 02434, WO99 / 35146, WO99 / 35132, WO98 / 02437, WO97 / 13760, WO95 / 19970, U.S. Pat. No. 5,587,458 and U.S. Pat. No. 5,877,305. Inclusive, each of these is incorporated herein by reference in its entirety. ErbB2 receptor inhibitors useful in the present invention are also disclosed in US Pat. Nos. 6465449 and 6284764 and WO 2001/98277, each of which is incorporated herein by reference in its entirety.

In addition, other antitumor agents can be selected from the following agents: BAY-43-9006 (Onyx Pharmaceuticals Inc.), Genasense (augmerosen, Genta), Panitumumab (Abgenix / Amgen), Zevalin (Schering), Bexxar (Corixa / GlaxoSmithKline), Abarelix, Alimta, EPO906 (Novartis), Disco del Morido (XAA-296), ABT-510 (Abbott), Neovastat (Aeterna), Eli Lilly, Combrestatin A4P (Oxigene), ZD-6126 (AstraZeneca), Flavopyridor (Aventis), CYC-202 (Cyclacel), AVE-8062 (Aventis), DMXAA (Roche / Antisoma), Thymitaq (Eximias), Temodar (Temozolomide, Schering) Plough) and Revilimd (Celegene) and combinations thereof.

Other antitumor agents can be selected from the following agents: CyPat (cyproterone acetate), Histrelin (histrelin acetate), Plenaixis (Avalerix Depot), Atrasentan (ABT-627), Satraplatin (JM-216), Talomide (thalidomide), Theratope, Temilifene (DPPE), ABI-007 (paclitaxel), Evista (raloxifene), Atamestane (Biomed-777), Xyotax (polyglutamate paclitaxel), Targetin (bexarotine) and these combination.

In addition, other antitumor agents can be selected from the following agents: Trizaone (tyrapazamin), Aposyn (exisulind), Nevastat (AE-941), Ceplene (histamine dihydrochloride), Orathecin (rubitecan) ), Virulizin, Gastrimmune (G17DT), DX-8951f (exatecan mesylate), Onconase (ranpirnase), BEC2 (mitumoab), Xcytrin (motexafin gadolinium) and combinations thereof.

Additional antitumor agents can be selected from the following agents: CeaVac (CEA), NeuTrexin (trimetresate glucuronate) and combinations thereof. Additional antitumor agents can be selected from the following agents: OvaRex (olegobomab), Osidem (IDM-1) and combinations thereof. Additional antitumor agents can also be selected from the following agents: Advexin (ING201), Tirazone (tyrapazamin) and combinations thereof. Additional antitumor agents can be selected from the following agents: RSR13 (efaproxiral), Cotara (131lchTNT1 / b), NBI-3001 (IL-4) and combinations thereof. Additional antitumor agents can be selected from the following agents: Canvaxin, GMK vaccine, PEG Interon A, Taxoprexin (DHA / paclitaxel) and combinations thereof.

Other antitumor agents include Pfizer's MEK1 / 2 inhibitor PD325901, Array Biopharm's MEK inhibitor ARRY-142886, Bristol Myer's CDK2 inhibitor BMS-387032, Pfizer's CDK inhibitor PD0332991 and AstraZeneca's AXD-5438 and These combinations are included.

In addition, mTOR inhibitors such as CCI-779 (Wyeth) and rapamycin derivatives RAD001 (Novartis) and AP-23573 (Ariad), HDAC inhibitors, SAHA (Merck Inc./Aton Pharmaceuticals) and combinations thereof are also utilized. can do. Additional antitumor agents include the Aurora 2 inhibitor VX-680 (Vertex) and the Chk1 / 2 inhibitor XL844 (Exilixis).

One selected from the group consisting of the following cytotoxic agents, such as epirubicin (Ellence), docetaxel (Taxotere), paclitaxel, Zinecard (dexrazoxane), rituximab (Rituxan), imatinib mesylate (Gleevec) and combinations thereof. A plurality may be used in combination with the compounds and pharmaceutical compositions of the present invention disclosed herein.

The invention is also limited to, but not limited to, exemestane (Aromasin, Pfizer Inc.), leuprorelin (Lupron or Leuplin, TAP / Abbott / Takeda), anastrosol (Arimidex, Astrazeneca), gosrelin (Zoladex, AstraZeneca). , Doxel calciferol, fadrosole, formestane, tamoxifen citrate (tamoxifen, Nolvadex, AstraZeneca), Casodex (AstraZeneca), Abarelix (Praecis), Trelstar and hormonal therapy including combinations thereof. Is intended.

The present invention also includes, but is not limited to, fulvestrant, toremifene, raloxifene, lasofoxyphene, anti-estrogens including letrozole (Femara, Novartis), bicalutamide, flutamide, mifepriston, niltamide, Casodex ( Hormones such as anti-androgen such as (trademark) (4'-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methyl-3'-(trifluoromethyl) propionanilide, bicalutamide) and combinations thereof. Concerning the use of the compounds of the invention with therapeutic agents.

In addition, the invention presents the compounds of the invention alone or in one or more supportive care products such as Filgrastim (Neupogen), Ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend or these. Provided in combination with a product selected from the group consisting of combinations.

Particularly preferred cytotoxic agents include Camptosar, Erbitux, Iressa, Gefitinib, Taxotere and combinations thereof.

The following topoisomerase I inhibitors are also available as antitumor agents: camptothecin, irinotecan HCl (Camptosar), edtecalin, oratecin (Supergen), exatecan (Daiichi), BN-80915 (Roche) and combinations thereof. Particularly preferred topoisomerase II inhibitors include epirubicin (Ellence).

Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosphamide, merphalan, busulfan, mitobronitol, carboplatin, thiotepa, lanimustin, nimustin, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamstin, carboplatin, estramustin, fotemstin, gluphosphamide, ifosfamide, KW-2170, maphosphamide and mitractol are included; Includes, but is not limited to, cisplatin, Paraplatin, eptaplatin, donaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi) or satrplatin and combinations thereof. Particularly preferred alkylating agents include Eloxatin.

Antimetabolites include, but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone, or leucovorin, tegaflu, UFT, doxiflulysin, carmofur. , Cytarabine, cytarabine ocphosphate, enocitabine, S-1, Alimta (premetrexed disodium, LY231514, MTA), Gemzar (gemcitabine, Eli) Lilly), fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornitine, ethynylcitidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, noratrexed, octofostate, disodium premethrexed , Pentostatin, peritrexol, lartitrexed, triapine, trimetrexate, vidarabine, vincristine, vinorelbine; or, for example, N- (5- [N- (3,4-dihydro-2-methyl-4-oxoquinazoline-) One of the preferred antimetabolites disclosed in European Patent Application No. 239362, such as 6-ylmethyl) -N-methylamino] -2-tenoyl) -L-glutamic acid, and a combination thereof. Included in.

Antibiotics include, but are not limited to, intercalation antibiotics: acralubicin, actinomycin D, amurubicin, anamycin, adriamycin, bleomycin, daunorubicin, doxorubicin, elsamitorcin, epirubicin, garalubicin, idarubicin, mitomycin C , Nemorphicin, neocardinostatin, pepromycin, pirarubicin, rebeccamycin, stimalamar, streptozocin, valrubicin, dinostatin and combinations thereof.

Plant-derived antitumor substances include, for example, mitotic inhibitors such as vinblastine, docetaxel, paclitaxel and those selected from combinations thereof.

Cytotoxic topoisomerase inhibitors include acralubicin, amonafide, verotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diphlomotecan, irinotecan HCl (Camptosar), edtecalin, epirubicin (Ellence), etoposide, epirubicin. Includes one or more agents selected from the group consisting of gimatecan), lultotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobzoxane, SN-38, tafluposide, topotecan and combinations thereof.

Preferred cytotoxic topoisomerase inhibitors are selected from the group consisting of camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan HCl (Camptosar), edtecalin, epirubicin (Ellence), etoposide, SN-38, topotecan and combinations thereof. One or more drugs to be used are included.

Immunological enhancers include interferon and a number of other immunopotentiators. Interferon includes interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1a, interferon gamma-1b (Actimmune) or interferon gamma-n1 and combinations thereof. Other drugs include filgrastim, lentinan, sizophyllan, TheraCys, juvenimex, WF-10, aldesroykin, alemtuzumab, BAM-002, dacarbazine, dacrizumab, deniroykin, gemtuzumab, ozogamicin, ibritsumomab, imikimod, lenograstim, lentinan. Tumor vaccine (Corixa), morgramostim, OncoVAX-CL, salgramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitsumomab, olegobomab, pemmu venge (Y) ) And combinations thereof.

Biological response modifiers are agents that regulate the defense mechanisms or biological responses of living organisms such as survival, proliferation or differentiation of histiocytes so that they have antitumor activity. Such agents include Krestin, Lentinan, Schizophyllan, Picibanil, Juvenimex and combinations thereof.

Other anti-cancer agents that can be used in combination with the compounds of the invention include alitretinoin, ampligen, atlascentan, bexarotene, bortezomib, Bosentan, calcitriol, exislind, finasteride, fotemustine, ibandronic acid, miltefosine, mitoxantrone, I-aspartinase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, Telcyta (TLK-286, Telik Inc.), Velcade (bortemazib, Millenium), tretinoin and combinations thereof Included.

Platinum coordination compounds include, but are not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin and combinations thereof.

Camptothecin derivatives include, but are not limited to, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edtecalin, topotecan and combinations thereof. Other antitumor agents include mitoxantrone, I-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin and combinations thereof.

Can block anti-tumor agents such as CTLA4 (cytotoxic lymphocyte antigen 4) antibody that can enhance anti-tumor immune response and CTLA4 such as MDX-010 (Medarex) and CTLA4 compounds disclosed in US Pat. No. 6,682,736. Other agents; as well as other anti-proliferative agents such as farnesyl protein transferase inhibitors, such as farnesyl protein transferase inhibitors, can also be used. In addition, specific CTLA4 antibodies that can be used in combination with the compounds of the invention include those disclosed in US Pat. No. 6,682,736 and US Pat. No. 6,682,736, both of which are disclosed. , All of which is incorporated herein by reference.

Specific IGF1R antibodies that can be used in combination with the methods of the invention include those disclosed in WO 2002/053596, which is incorporated herein by reference in its entirety.

Specific CD40 antibodies that can be used in the present invention include those disclosed in WO 2003/040170, which is incorporated herein by reference in its entirety. Gene therapy agents such as TNFerade (GeneVec), which express TNFalpha in response to radiation therapy, can also be used as antitumor agents.

In one embodiment of the invention, statins can be used with the compounds of the invention and their pharmaceutical compositions. Statin (HMG-CoA reductase inhibitor) is Atorvastatin (Lipitor Pfizer Inc.), Provastatin (Pravachol , Bristol-Myers Squibb), Lovastatin (Mevacor , Merck Inc.), Simvastatin (Zocor). , Merck Inc., Fluvastatin (Lescol , Novartis), Cerivastatin (Baycol , Bayer), Rosuvastatin (Crestor , AstraZeneca), Lovastatin and Niacin (Advicor , Kos Pharmaceuticals) ), These derivatives and combinations thereof can be selected.

In a preferred embodiment, the statin is selected from the group consisting of Atovorstatin and Lovastatin, derivatives and combinations thereof. Other agents useful as antitumor agents include Caduet.

Preparation method The compounds of the invention can be prepared using the following reaction pathways and synthetic schemes and techniques available in the art using readily available starting materials. Those skilled in the art will appreciate that a variety of different reagents and protecting groups can be used to make the compounds of the invention according to the following general schemes. Therefore, if terms such as "appropriate base", "appropriate catalyst", "appropriate oxidizer" are used in the general schemes below, various alternatives that can be used by those skilled in the art. You will be able to understand things.

The preparation of certain embodiments of the invention will be detailed in Examples according to the general scheme outlined herein. Those skilled in the art will appreciate that the described preparations can be readily adapted to prepare other embodiments of the invention. For example, the synthesis of compounds not exemplified by the present invention can be transformed into other suitable reagents known in the art by modifications apparent to those skilled in the art, eg, by adequately protecting interfering groups. This can be done by or by routine changes in reaction conditions. Alternatively, it will be appreciated that other reactions referred to herein or known in the art have adaptability for preparing other compounds of the invention.

In a general synthetic method, reactive intermediate compounds of general structure represented by A and B are prepared according to Method A.

<chemistry num="17"><img file="JP4792126B2_D0020.tif" /></chemistry> The thiol (1) is reacted with a methylating agent in the presence of a suitable base to give the thio-methyl ether of formula 2. 2 is treated with oxalyl chloride to form the aldehyde represented by formula 3. By treating with hydroxylamine, the aldehyde 3 can be further converted to the isooxazole represented by the formula 4. Isoxazole 4 can be decomposed into aldehyde 5 by treatment with an appropriate base. By reacting with hydrazine, isooxazole 5 can be further converted to the type of pyrazole of formula 6. Pyrazole 6, NaNO2Can be converted to A by a two-step sequence involving the reaction with and subsequently with iodide. Finally, A can be converted to B by reacting the amine with dihydropyran.

In other common synthetic processes, compounds of general structure represented by 11 are prepared according to Method B.

<chemistry num="18"><img file="JP4792126B2_D0021.tif" /></chemistry> Method A can be used to prepare reactive intermediate A. Reactive drug (eg R1-I, R1-Br, R1-Cl, R1-OMs, R1-R to 7 by alkylating A under conditions suitable for coupling (such as OTs)1Can be achieved. Sulfur in 7 can be oxidized to sulfone 8 with a suitable oxidizing agent such as oxone. Achieving the introduction of amines on the pyrimidine ring by replacing sulfur with amines gives 9. Suzuki coupling of 9 with a suitable boronic acid (or boronic acid ester) in the presence of a suitable catalyst, such as a palladium catalyst, yields Intermediate 10. Finally, if compound 10 requires deprotection of any residual protecting group, such deprotection can be achieved in a variety of ways to yield compound 11. These methods are known to those of skill in the art (see, eg, T. Greene and P. Wuts, "Protective Groups in Organic Synthesis", 3rd Edition, 1999, John Wiley & Sons).

In other common synthetic processes, compounds of general structure represented by 10 and 11 can also be prepared according to Method C.

<chemistry num="19"><img file="JP4792126B2_D0022.tif" /></chemistry> Reactive intermediate B can be prepared using Method A. Suzuki coupling of B with a suitable boronic acid (or boronic acid ester) in the presence of a suitable catalyst, such as a palladium catalyst, yields Intermediate 12. Exposure of THP-protected amines by deprotection using a variety of methods can result in amine 13. Methods of removing THP from amines are known to those of skill in the art (see, eg, T. Greene and P. Wuts, "Protective Groups in Organic Synthesis", 3rd Edition, 1999, John Wiley & Sons). Reactive drug (eg R1-I, R1-Br, R1-Cl, R1-OMs, R1-R to 14 by alkylating 13 under conditions suitable for coupling (such as OTs)1Can be achieved. Sulfur in 14 can be oxidized to 15a and / or 15b by treatment with a suitable oxidizing agent such as ozone. Achieving the introduction of amines on the pyrimidine ring by replacing sulfur with amines gives 10. Finally, if compound 10 requires deprotection of any residual protecting group, such deprotection can be achieved in a variety of ways to yield compound 11.

In other common synthetic processes, compounds of general structure represented by 20 and 22 are prepared according to Method D.

<chemistry num="20"><img file="JP4792126B2_D0023.tif" /></chemistry> Reactive intermediate A can be prepared using method A. Reactive drug (eg R1-I, R1-Br, R1-Cl, R1-OMs, R1-R to 7 by alkylating A under conditions suitable for coupling (such as OTs)1Can be achieved. Suzuki coupling of 7 with a suitable boronic acid (or boronic acid ester) in the presence of a suitable catalyst, such as a palladium catalyst, yields Intermediate 16. Sulfur in 16 can be oxidized to 17a and / or 17b by treatment with a suitable oxidizing agent such as ozone. Achieving the introduction of amines on the pyrimidine ring by replacing sulfur with amines gives 10. Finally, if compound 10 requires deprotection of any residual protecting group, such deprotection can be achieved in a variety of ways to yield compound 11.

In other common synthetic processes, the compound represented by 20 is prepared according to Method E.

<chemistry num="21"><img file="JP4792126B2_D0024.tif" /></chemistry> Reactive intermediate A can be prepared using method A. Reactive drug (eg R1-I, R1-Br, R1-Cl, R1-OMs, R1-R to 7 by alkylating A under conditions suitable for coupling (such as OTs)1Can be achieved. Sulfur in 7 can be oxidized to sulfone 8 with a suitable oxidizing agent such as oxone. Achieving the introduction of amines on the pyrimidine ring by replacing sulfur with amines gives 9. Suzuki coupling 9 with a suitable boronic acid or boronic acid ester (where R is hydrogen or a suitable nitrogen protecting group) in the presence of a suitable catalyst, such as a palladium catalyst, will result in an intermediate 18 Occurs. If compound 18 requires deprotection of any residual protecting group, such deprotection can be achieved in a variety of ways to yield compound 19. Finally, compound 19 can be obtained by chlorinating compound 19 under appropriate chlorinating conditions.

In other common synthetic processes, the compound represented by 29 can be prepared according to Method F.

<chemistry num="22"><img file="JP4792126B2_D0025.tif" /></chemistry> Preparation of isooxazole 22 is accomplished via a Vilsmeier reaction with 4-methylpyrimidine or picoline followed by condensation with hydroxylamine. Isoxazole is ring-opened with a suitable base such as aqueous sodium hydroxide solution and subsequently condensed with hydrazine to give aminopyrazole 24. The sandmeyer reaction converts the amino group to iodopyrazole (25) and pyrazole NH is preferred R prior to the Suzuki coupling reaction.3Alkylate with a group or protect with a protecting group to give 26. Suzuki coupling reaction of 26 with the appropriate boronic acid or boronic acid ester completes the synthesis of the compound represented by 27. Achieving deprotection and / or chlorination, as described above, if required, can result in 28 or 29, respectively.

In other common synthetic processes, the compound represented by 40 can be prepared according to Method G.

<chemistry num="23"><img file="JP4792126B2_D0026.tif" /></chemistry> Compound 31 reacts with 5-bromo-1H-pyrrolo [2,3-b] pyridine 30 from carbon monoxide in the presence of a suitable catalyst, followed by protection of pyrrole nitrogen, if necessary. Can be prepared by. Condensation of compound 31 with 2-methyl-6- (methylthio) pyridine by reaction in the presence of a suitable base such as LIHMDS gives 32. 33 can be obtained by introducing an imine in compound 33 by reacting 32 with DMF-DMA. By reacting with hydrazine, compound 33 can be cyclized to form pyrazole 34. Pyrazole NH, preferred R1Alkylate with a group or protect with a protecting group to give 35. If the 1-position on the 1H-pyrrolo [2,3-b] pyridine group is H, protection with a suitable protecting group such as vesylate is achieved by known means to give 36. Oxonication of the methylthio group yields 37. By heating, SO2Replacing the Me group with the appropriate amine gives 38. Achieving deprotection and / or chlorination, as described above, if required, can result in 39 or 40, respectively.

In other common synthetic processes, the compound represented by 51 can be prepared according to Method H.

<chemistry num="24"><img file="JP4792126B2_D0027.tif" /></chemistry> Compound 42 can be obtained by protecting compound 41 with pyrrole nitrogen, if necessary. Coupling reactions in the presence of suitable tin reagents and suitable catalysts can yield 43 types of compounds. Compound 43 can then be converted to ketone 44 by heating with a suitable acid and subsequently condensed with DMF-DMA to form the enone 45. Pyrazole 46 can be formed by cyclizing compound 45 by reacting with hydrazine. Pyrazole NH is preferred R1Alkylate with a group or protect with a protecting group to give 47. Suzuki coupling reaction of 49 with the appropriate boronic acid or boronic acid ester to complete the synthesis of the compound represented by 50. If desired, deprotection and / or chlorination is achieved, as described above, to obtain 51 types of compounds.

In other common synthetic processes, the compound represented by 56 can be prepared according to Method I.

<chemistry num="25"><img file="JP4792126B2_D0028.tif" /></chemistry> Reaction of 52 types of halides with anhydride 53 can form compound 54. Coupling of compound 54 to the appropriate intermediate 55 via Stille coupling can yield 56 types of products. Intermediate 55 can be prepared by reacting 9 types of compounds with the appropriate tin reagents.

The compounds of the present invention and methods of preparing such compounds are further described and illustrated by the examples and preparations shown below. Examples B-1 to I-1 present detailed synthetic steps for preparing several specific compounds of the invention. Table 1 shows analytical data for compounds prepared using the methods described herein. Tables 2 and 3 show biochemical and cellular data for the compounds of Examples B-1 to I-2. It should be understood that the scope of the invention is not limited by the scope of the following examples and preparations. In the following examples, the molecule with a single chiral center exists as a racemic mixture unless otherwise specified or indicated by its structural formula or chemical name. Molecules with two or more chiral centers exist as a racemic mixture of diastereoisomers unless otherwise specified or indicated by structural formula or chemical name. A single enantiomer / diastereoisomer can be obtained by methods known to those of skill in the art. Various starting materials and other reagents were purchased from market suppliers such as Aldrich Chemical Company and used without further purification unless otherwise indicated.1The H-NMR spectrum was recorded on a Bruker instrument operating at 300MHz or 400MHz and13C-NMR spectra were manipulated and recorded at 75 MHz. The NMR spectrum is CDCl3Chloroform (7.25 ppm and 77.00 ppm) or DMSO-D as a solution (reported in ppm) as a reference standard6(2.50ppm and 39.51ppm) or CD3Obtained using OD (3.4 ppm and 4.8 ppm and 49.3 ppm) or, where appropriate, internal tetramethylsilane (0.00 ppm). Other NMR solvents were used if required. If peak multiplicity is reported, use the following abbreviations: s (singlet), d (doublet), t (triplet), m (multiplet), br (broad), dd (two). Doublet doublet), dt (doublet triplet). If present, the coupling constant is reported in Hertz (Hz). The following abbreviations may be used herein: Et.2O (diethyl ether), DMF (N, N-dimethylformamide), THF (tetrahydrofuran), DHP (dihydropyran), DCM (dimethane), DMA (dimethylacetal), DBU (1,8-diazabicyclo [5.4.0]] Undeca-7-ene); LiHMDS or LHMDS (lithium hexamethyldisilazide), TBME (tert-butylmethyl ether), LDA (lithium diisopropylamide), DMSO (dimethylsulfoxide), MeOH (methanol), EtOH (ethanol) , EtOAc (ethyl acetate), THF (tetrahydrofuran), Ac (acetyl), Me (methyl), Et (ethyl) and Ph (phenyl). Boronic acid and boronic acid ester intermediates: All boronic acids and esters are commercially available, known in the literature, or can be prepared according to the following methods. For those skilled in the art, the following are only described as exemplary boronic acid and boronic acid ester intermediates, and these exemplary intermediates are modified according to known methods to the extent claimed. It will be readily appreciated that a wide variety of possible boronic acids and boronic acid esters can be obtained that can be used to prepare the compounds within. Preparation of 1- (tert-Butyloxycarbonyl) -3-methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-5-ylboronic acid (64)<chemistry num="26"><img file="JP4792126B2_D0029.tif" /></chemistry> step 1<chemistry num="27"><img file="JP4792126B2_D0030.tif" /></chemistry> CCl of compound 57 (74 g, 0.80 mol) being agitated4NBS (296 g, 1.68 mol) was added to the (2 L) suspension in small portions at 20 ° C. After the addition, the mixture was stirred at room temperature for 24 hours. TLC (EtOAc / Hexanes 1: 4) showed that the material was completely consumed. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give compound 58 (170 g, 83.7%) as a brown solid. Step 2:<chemistry num="28"><img file="JP4792126B2_D0031.tif" /></chemistry> The mixture of compound 58 (172 g, 0.688 mol) and benzenesulfonyl chloride (182.2 g, 1.032 mol) in pyridine (1000 mL) was heated to 85 ° C for 72 hours with stirring. TLC (EtOAc / Hexanes 1: 4) showed that most of the material was consumed. Pyridine was removed in vacuo. The residue was suspended in EtOAc and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (EtOAc / petroleum ether, 1:40 to 1: 4) to give compound 59 (65 g, 24.2%) as a yellow solid. Step 3:<chemistry num="29"><img file="JP4792126B2_D0032.tif" /></chemistry> Mixture of compound 3 (45 g, 0.115 mol), 3-bromopropene (45.7 g, 0.38 mol) and K2CO3 (63.5 g, 0.46 mol) in anhydrous DMF (900 mL) under N2 atmosphere to 110? 16 Heated for hours. The mixture was cooled to room temperature, poured into water (1.5 L) and extracted 3 times with EtOAc (1 L). The combined organic solvents were washed 3 times with water (1 L) with brine (1 L), dried over Na2SO4 and concentrated in vacuo. Washing the residue with petroleum ether gave compound 60 (39 g, 78.9%) as a yellow solid. Step 4:<chemistry num="30"><img file="JP4792126B2_D0033.tif" /></chemistry> N a mixture of compound 60 (47.4 g, 0.11 mol), tris (trimethylsilyl) silane (54.7 g, 0.22 mol) and azobisisobutyronitrile (AIBN, 18 g, 0.11 mol) in anhydrous toluene (1000 mL).2Heated down to 80-83 ° C for 3 hours. TLC (EtOAc / Hexanes 1: 4) showed that the material was completely consumed. The mixture was concentrated in vacuo. The residue was purified by column chromatography (EtOAc / petroleum ether, 1: 100 to 1:30) to give the product (10 g, 25.8%) as a white solid. Step 5:<chemistry num="31"><img file="JP4792126B2_D0034.tif" /></chemistry> 2.0 mL (127 mg, 2.26 mmol) of an aqueous sodium hydroxide solution was added dropwise to a solution of the stirred compound 61 (800 mg, 2.26 mmol) in 10 mL of boiling ethanol. The reaction was sealed, then heated in an oil bath at 100 ° C. and monitored by LCMS. The reaction remained homogeneous and after 5 hours LCMS indicated that the reaction was complete. The reaction was concentrated under high vacuum until dry. The resulting residue was stirred in 100 mL of DCM overnight and then filtered. LCMS showed that the solid did not contain the desired substance, so concentration of the filtrate gave compound 62 (458 mg, 94.9%) as an off-white solid. Step 6:<chemistry num="32"><img file="JP4792126B2_D0035.tif" /></chemistry> A mixture of compound 62 (458 mg, 2.15 mmol), Boc anhydride (563 mg, 2.58 mmol) and 1,1-diisopropylethylamine (305 mg, 2.37 mmol) in 50 mL anhydrous THF was refluxed under nitrogen for 2 hours. TLC showed the reaction was complete. The reaction was concentrated under reduced pressure until dry. The residue was partitioned between EtOAc (100 mL) and brine (50 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and then loaded onto a 150 g silica gel column. Elution with 0-5% EtOAc in DCM gave compound 63 (460 mg, 68.4%) as an off-white solid. Step 7:<chemistry num="33"><img file="JP4792126B2_D0036.tif" /></chemistry> Add a solution of butyllithium (2.5 M, 1.47 mL, 3.67 mmol in hexane) to a 25 mL solution of anhydrous THF of compound 63 (460 mg, 1.47 mmol) and triisopropyl borate (691 mg, 3.67 mmol) being stirred at -78 ° C. It was added dropwise under nitrogen. The reaction was stirred at -78 ° C and monitored by LCMS. After 2 hours, LCMS showed the reaction was complete. The reaction was quenched with 25 mL of water and concentrated under reduced pressure to a total volume of about 15 mL. The residue was washed with ether (2 x 10 mL) and the aqueous layer was placed in an ice-water bath. With stirring, a 10 N aqueous HCl solution was carefully added dropwise until pH = 7. Filtration and washing with ice-water (3 x 5 mL) gave compound 64 (208 mg, 51%) as a white solid. Preparation of 3-Fluoro-1H-pyrrolo [2,3-b] Pyridine-5-ylboronic Acid (67)<chemistry num="34"><img file="JP4792126B2_D0037.tif" /></chemistry> Select-Fluorine (10 g, 30 mmol) was added to a solution of compound 65 (4 g, 20 mmol) in MeCN (500 mL) and AcOH (100 mL), and the resulting mixture was heated at 80 ° C. overnight. TLC (petroleum ether / EtOAc 5: 1) showed complete consumption of compound 1. The reaction mixture was concentrated in vacuo and the residue was purified via silica gel flash chromatography (petroleum ether / EtOAc 10: 1) to give 66 (0.64 g, 13%) as an off-white solid. 1H NMR: (400 MHz, CDCl3): δ 9.434 (brs, 1H), 8.311-8.280 (m, 1H), 8.056-8.023 (m, 1H), 7.191 (s, 1H), 7.086-7.053 (m, 1H). A solution of butyllithium (2.5 M, 1.16 mL, 2.91 mmol in hexanes) at -78 ° C in an anhydrous THF 3 mL solution of agitated compound 66 (250 mg, 1.16 mmol) and triisopropyl borate (547 mg, 2.91 mmol). It was added dropwise under nitrogen. The reaction was stirred at -78 ° C and monitored by LCMS. After 2 hours, LCMS showed a 1: 1: 1 SM: desbromo-SM: desired product. An additional 1.16 mL of n-butyllithium was added. The reaction was stirred under nitrogen at 78 ° C. for another hour, quenched with 3 mL of water and concentrated under reduced pressure to a total volume of about 3 mL. The residue was washed with ether (2 x 10 mL) and the aqueous layer was placed in an ice-water bath. A 10N aqueous HCl solution was carefully added dropwise to pH = 7 with stirring. A milky white suspension was produced and filtration did not result in a significant amount of solids. Concentration of the mixture in high vacuum gave compound 67 (200 mg, 95%) as an off-white solid. Preparation of 2-oxo-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-ylboronic acid (69)<chemistry num="35"><img file="JP4792126B2_D0038.tif" /></chemistry> Compound 68 (1.0 g, 4.7 mmol), bis (pinacolato) diboron (1.79 g, 7.04 mmol), potassium acetate (1.38 g, 14.1 mmol) and catalyst PdCl2The mixture in 20 ml of DMF (dppf) (68.7 mg, 0.094 mmol) was heated in a microwave reactor at 100 ° C. for 60 minutes. LCMS showed that the reaction was 20% complete. When the reaction was heated overnight in an oil bath at 100 ° C., LCMS indicated that the reaction was complete. The reaction was concentrated to dryness under high vacuum. The residue was then partitioned between EtOAc (50 mL) and brine (30 mL). The aqueous layer was extracted with EtOAc (3 x 25 mL)). The combined organic layers were dried over sodium sulphate and then concentrated to residue. Silica gel flash chromatography gave an off-white powder as the desired product (803 mg, 66%) with 2-5% MeOH in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 1.35 (s, 12 H) 3.56 (s, 2 H) 7.85 (s, 1 H) 8.54 (s, 1 H). 71 preparation<chemistry num="36"><img file="JP4792126B2_D0039.tif" /></chemistry> Compound 70 (40 g, 99.2 mmol) cooled to -60 ° C and (iPrO)3To a solution of B (59.2 mL, 258 mmol) in 2-methyl-tetrahydrofuran (496 mL) (496 mL) was added n-BuLi (108 mL, 267 mmol). The reaction mixture was stirred at -60 ° C for 2 hours. TLC (petroleum ether: EtOAc = 2: 1) showed that the reaction was complete. The reaction mixture was quenched by the addition of water (500 mL) and concentrated under reduced pressure. The aqueous solution was acidified with concentrated HCl to pH = 5. The precipitate was filtered and the filter cake was washed with ice water to give the product (60 g, yield: 82.19%) as a white solid. Preparation of 6-acetamide-4-methylpyridine-3-ylboronic acid (73)<chemistry num="37"><img file="JP4792126B2_D0040.tif" /></chemistry> In a THF solution of stirred 2-acetylamino-5-bromo-4-methylpyridine (1.858 g, 8.11 mmol) and boron isopropoxide (7.5 ml, 32.4 mmol) cooled to -78 ° C. n-Butyllithium (4.1 ml, 41 mmol of 10 M solution in hexane) was added. After 1 hour at -78 ° C, the reaction was quenched with water and warmed to room temperature. THF was removed under reduced pressure. 2N HCl was added until a precipitate formed. It was filtered, washed with a minimum amount of water and dried under vacuum. 1H NMR (400 MHz, DMSO-d6) d ppm 2.07 (s, 3 H) 2.39 (s, 3 H) 7.84 (s, 1 H) 8.09 (s, 2 H) 8.33 (s, 1 H) 10.36 (s, 1 H). Preparation of 3-Methyl-5- (4,4,5,5-Tetramethyl- [1,3,2] Dioxaborolan-2-yl) -1H-Pyrazolo [3,4-b] Pyridine (79)<chemistry num="38"><img file="JP4792126B2_D0041.tif" /></chemistry> step 1<chemistry num="39"><img file="JP4792126B2_D0042.tif" /></chemistry> N-BuLi (200 mL, 0.5 mol) in anhydrous THF (1000 mL) solution of agitated diisopropyl-amine (50 g, 0.5 mol) at -78 ° C.2Dropped in the atmosphere. After the addition, the resulting mixture was warmed to 0 ° C, maintained for 10 minutes and cooled again to -78 ° C. Mixture of compound 74 (80 g, 0.455 mol) in THF (1000 mL) into LDA solution N at -78 ° C2Dropped in the atmosphere. After the addition, the reaction mixture was stirred at -78 ° C for 30 minutes. Ethyl formate ester (50 g, 0.68 mol) was then added to the mixture in small portions at -78 ° C. After 2 minutes, the resulting mixture was quenched with 10% citric acid solution in THF (400 mL) at -78 ° C. Warm the mixture to room temperature, H2It was poured into O (500 mL) and extracted with EtOAc (500 mL x 3). Wash the combined organic layers with brine (500 mL) and Na2SO4Drying on top and vacuum concentration gave compound 75 (92 g, 99%) as a yellow solid. Step 2:<chemistry num="40"><img file="JP4792126B2_D0043.tif" /></chemistry> Add MeMgBr (230 mL, 0.69 mol) in small portions to a solution of compound 75 (92 g, 0.455 mol) in THF (2 L) at -78 ° C.2Added to the atmosphere. After the addition, the reaction mixture was warmed to room temperature and stirred at room temperature overnight. TLC (petroleum ether / EtOAc 10: 1) showed complete consumption of compound 2. Saturate the reaction mixture NH4It was quenched with Cl (300 mL) and extracted with EtOAc (1 L × 3). Wash the combined organic layer with brine (1L) and Na2SO4Drying on top and vacuum concentration gives crude compound 76, which is purified by column chromatography (silica gel, petroleum ether / EtOAc 10: 1) to give pure compound 76 (85 g, 85%) yellow. Obtained as oil. Step 3:<chemistry num="41"><img file="JP4792126B2_D0044.tif" /></chemistry> PDC (365g, 0.97mol) and CH2Cl2Compound 76 (85 g, 0.39 mol) was added to the mixture (2000 mL) at 0 ° C. After the addition, the reaction mixture was warmed to room temperature and stirred overnight. TLC (petroleum ether / EtOAc 10: 1) showed that the reaction was complete. The resulting mixture was filtered and the filtrate was vacuum concentrated to give crude compound 77, which was purified by column chromatography (silica gel, petroleum ether / EtOAc 50: 1) to pure compound 77 (56 g, 63). %) Was obtained as a yellow solid. Step 4:<chemistry num="42"><img file="JP4792126B2_D0045.tif" /></chemistry> In a solution of compound 77 (40 g, 0.184 mol) in ethanol (300 mL), NH2NH2(27.6 g, 0.553 mol) was added at room temperature. After the addition, the reaction mixture was refluxed overnight. TLC (petroleum ether / EtOAc 3: 1) showed complete consumption of compound 77. The reaction mixture was cooled to room temperature and concentrated in vacuum to give a crude product, which was purified by column chromatography (silica gel, petroleum ether / EtOAc, from 10: 1 to 3: 1) to 78 (30 g). , 76%) was obtained as a white solid. Step 5:<chemistry num="43"><img file="JP4792126B2_D0046.tif" /></chemistry> 5-Bromo-3-methyl-1H-pyrazolo [3,4-b] pyridine (1.04 g, 40.987 mmol), bis (pinacolato) diboron (1.93 g, 7.45 mmol, 1.5 eq), potassium acetate (1.66 g, 16.9) A 10 mL suspension of anhydrous DMSO of mmol, 3.04 eq) and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1: 1) (0.109 g, 0.149 mmol, 0.03 eq). , Degassed for 20 minutes by introducing air bubbles through the needle. The reaction was then heated in a microwave reactor at 150 ° C. for 2 hours (high absorption). After this time, the reaction is cooled to room temperature and then H2It was poured into O (200 mL) and EtOAc (200 mL). The bilayer mixture is filtered through compressed Celite and the filtrate is Na2SO4Dry on top, vacuum concentrated in dark oil and this by a biotage column (Si40 + M) filled with hexane; EtOAc / Hexanes (0-30%: 900 mL, 30-30%: 900 mL, 30- Elution with 50%; 900 mL, 27 mL fraction) gave the product as a white solid (1.19 g, 93.6%). 1H NMR (300 MHz, chloroform-d) δ ppm 8.88 (d, J = 1.51 Hz, 1 H) 8.51 (d, J = 1.51 Hz, 1 H) 2.60 (s, 3 H) 1.30 (s, 6 H) 1.25 (s, 6 H); NH was not found during NMR. Preparation of compound 85<chemistry num="44"><img file="JP4792126B2_D0047.tif" /></chemistry> step 1:<chemistry num="45"><img file="JP4792126B2_D0048.tif" /></chemistry> Dioxane (450 mL) and H of compound 80 (28 g, 0.2 mol) and NaOH (40 g, 1 mol)2CF in solution in O (150 mL) at 70 ° C2It was whipped through HCl gas for 20 minutes and stirred at the same temperature overnight. TLC (petroleum ether / EtOAc 2: 1) showed that the reaction took place. Et the reaction mixture2Extraction with O (3 x 300 mL) and vacuum concentration of the combined organic layers yields a crude product, which is purified via column chromatography (petroleum ether / EtOAc 30: 1 to 3: 1). Then, compound 81 (20 g, 52.6%) was obtained as a yellow liquid. Step 2:<chemistry num="46"><img file="JP4792126B2_D0049.tif" /></chemistry> EtOH / H of compound 81 (10 g, 0.0526 mol)2Iron powder (15 g, 0.268 mol) was added to the O (2: 1, 450 mL) solution, followed by NH.4Cl (7.5 g, 0.14 mol) was added in one dose. After the addition, the mixture was refluxed overnight. TLC (petroleum ether / EtOAc 2: 1) showed that the reaction was complete. EtOH is removed under reduced pressure to saturate the residue.3It was partitioned into aqueous solution (500 mL) and EtOAc (400 mL). The aqueous layer was extracted with EtOAc (2 x 300 mL), the combined organic layers were washed with brine (2 x 300 mL) and anhydrous Na.2SO4Drying on top and vacuum concentration gave compound 82 (8.0 g, 95%) as a yellow solid. Step 3:<chemistry num="47"><img file="JP4792126B2_D0050.tif" /></chemistry> Bromine (8.0 g, 0.05 mol) was added dropwise to a solution of compound 82 (8.0 g, 0.05 mol) in AcOH (100 mL) at room temperature. The mixture was stirred at ambient temperature for 2 hours. TLC (petroleum ether / EtOAc 2: 1) showed that the reaction was complete. AcOH is removed under reduced pressure to saturate the residue.3It was partitioned into aqueous solution (200 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (200 mL) and the combined organic layers were washed with brine (2 x 300 mL) and anhydrous Na.2SO4Drying on top and vacuum concentration gives a crude product, which is purified via column chromatography (petroleum ether / EtOAc 8: 1-4: 1) to produce 83 (10.9 g, 91.2%) product. ) Was obtained as a yellow solid. Step 4:<chemistry num="48"><img file="JP4792126B2_D0051.tif" /></chemistry> Di-tert-butyl dicarbonate (15.65 g, 71.71 mmol), 4- (dimethylamino) pyridine (571 mg, 4.67 mmol) and triethylamine (16.5 mL) in an acetonitrile (250 mL) solution of compound 83 (5.61 g, 23.5 mmol). , 118 mmol) was added. The mixture was stirred at room temperature for 1.5 hours, then concentrated to dryness and purified by silica gel chromatography (eluting with a gradient of 10-25% ethyl acetate in hexanes) to whiten compound 84 (9.53 g, 92.4%). Obtained as a solid of. Step 5:<chemistry num="49"><img file="JP4792126B2_D0052.tif" /></chemistry> A solution of bromide 84 (3.30 g, 7.51 mmol) and triisopropyl borate (4.4 mL, 19 mmol) in 2-methyl-tetrahydrofuran (38 mL) was cooled to -65 ° C (bath temperature) in a dry ice / isopropanol bath. A 2.5 M solution of n-butyllithium (7.5 mL, 19 mmol) in hexane was added dropwise over 3 minutes. After stirring at -65 ° C for 3 hours, deionized water (10 mL) was added, the cooling bath was removed, and the solution was warmed to room temperature. The volatiles were removed in vacuo and the aqueous residue was extracted with diethyl ether (2 x 20 mL). These extracts were discarded. The aqueous layer was cooled to 0 ° C., acidified to pH 3 with 6N HCl and extracted with diethyl ether (20 mL) followed by ethyl acetate (20 mL). The combined organic extracts were dried over magnesium sulphate, filtered and concentrated to give crude boronic acid 85 as yellow foam (2.27 g, purity about 60%, uncorrected yield 75%). This crude boronic acid was used in the Suzuki reaction without further purification.(Example A-1) Preparation of Reactive Intermediates A and B According to Method A Preparation of 4-methyl-2- (methylthio) pyrimidine (2)<chemistry num="50"><img file="JP4792126B2_D0053.tif" /></chemistry> Compounds 4-Methylpyrimidine-2-thiol (500g, 3.05mol), iodomethane (611g, 4.27mol) and K2CO3The mixture in THF (4 L) (915 g, 6.71 mol) was stirred at room temperature for 18 hours. The suspension was filtered and the solid was washed with ether (500 mL x 2). The filtrate was concentrated and dried in vacuo to give compound 2 (380 g, 89.2%) as a yellow oil. Preparation of (E) -3-Hydroxy-2- (2- (Methylthio) Pyrimidine-4-yl) Acrolein Aldehyde (3)<chemistry num="51"><img file="JP4792126B2_D0054.tif" /></chemistry> DMF (114.9g, 1.57mol) CHCl3Oxalyl chloride (190.3 g, 1.50 mol) was added dropwise to the (800 mL) solution at 0 ° C. After the addition, the resulting mixture was warmed at 30 ° C and stirred for 1 hour. The mixture was cooled to 0 ° C. and 4-methyl-2- (methylthio) pyrimidine (2) (100 g, 0.714 mol) was added to the mixture. The resulting mixture was warmed to 40 ° C and stirred for 16 hours. The reaction mixture was cooled to room temperature and filtered. CHCl the cake3When washed with (150 mL x 3) and dried in vacuum, (E) -3-hydroxy-2- (2- (methylthio) pyrimidin-4-yl) acrolein aldehyde (3) (342.0 g, 100%) Was obtained as a yellow solid. Preparation of 4- (isoxazole-4-yl) -2- (methylthio) pyrimidine (4)<chemistry num="52"><img file="JP4792126B2_D0055.tif" /></chemistry> (E) -3-Hydroxy-2- (2- (methylthio) pyrimidine-4-yl) acrolein aldehyde (3) (342 g, 0.714 mol) in a solution of hydroxylamine hydrochloride (60.0 g, 0.86 mol) in water (2 L). ) Was added little by little. After the addition, the mixture was heated at 60 ° C and stirred for 2 hours. The reaction mixture is cooled to room temperature and the solution is 10% LVDS.3The pH was adjusted to about 4 by adding an aqueous solution. The resulting precipitate was filtered, washed with water (200 mL x 2) and vacuum dried to give 4- (isoxazole-4-yl) -2- (methylthio) pyrimidine (4) (112 g, 81.2%). Obtained as a yellow solid. Preparation of 2- (2- (methylthio) pyrimidine-4-yl) -3-oxopropanenitrile (5)<chemistry num="53"><img file="JP4792126B2_D0056.tif" /></chemistry> Mixture of 4- (isoxazole-4-yl) -2- (methylthio) pyrimidine (4) (112.0 g, 0.58 mol) and NaOH (23.2 g) in water / MeOH (350 mL / 350 mL) at 70 ° C. Stirred for 6 hours. The reaction mixture was cooled to room temperature and adjusted to pH 3.5 with citric acid. The resulting precipitate was filtered and washed with water (500 mL x 3) and ethyl ether (500 mL x 3). The precipitate was then vacuum dried to give 2- (2- (methylthio) pyrimidine-4-yl) -3-oxopropanenitrile (5) (100 g, 89.3%) as a yellow solid. Preparation of 4- (2- (Methylthio) Pyrimidine-4-yl) -1H-Pyrazole-5-amine (6)<chemistry num="54"><img file="JP4792126B2_D0057.tif" /></chemistry> 2- (2- (Methylthio) pyrimidine-4-yl) -3-oxopropanenitrile (5) (100 g, 0.52 mol), NH2NH2 H2An ethanol (1 L) suspension of O (85%, 31.2 g, 0.62 mol) and concentrated HCl (60 mL) was stirred at reflux for 5 hours. After cooling to room temperature, the mixture is concentrated in vacuo, the residue is washed with ether (200 mL x 3) and H2Suspended in O (200 mL). Saturated Na2CO3The mixture was basicized to pH 9 using aqueous solution and the precipitate was collected. Solid H2Washed with O (100 mL x 3) and ether (200 mL x 3) and then vacuum dried, 4-(2- (methylthio) pyrimidin-4-yl) -1H-pyrazole-5-amine (6) ( 56.8 g, 51.8%) was obtained as a yellow solid.11 H NMR (400 MHz, CD3CN): δ 8.295 (d, 1H), 7.826 (s, 1H), 7.101 (d, 2H), 5.800 (d, 1H), 2.586 (s, 3H). Preparation of 4- (5-iodo-1H-pyrazole-4-yl) -2- (methylthio) pyrimidine (A)<chemistry num="55"><img file="JP4792126B2_D0058.tif" /></chemistry> NaNO2A solution of (20.0 g, 0.29 mol) in water (150 mL) to 4- (2- (methylthio) pyrimidin-4-yl) -1H-pyrazole-5-amine 6 (50.0 g, 0.24 mol) glacial acetic acid (400 mL) And poured into a solution in a mixture of water (100 mL) at -3 ° C. The temperature was raised to -1 ° C. Dark H2SO4In addition to the resulting solution (10 mL), potassium iodide (120.0 g, 1.2 mol.) And I2A solution of (123.0 g, 10.48 mol) in water (200 mL) was added dropwise. The resulting solution was heated to 50 ° C. for 2 hours and the mixture was neutralized with aqueous ammonia. Excess iodine Na2S2O3Processed in. The precipitate was filtered and the filtrate was extracted with ethyl acetate. The organic layer was evaporated and the residue was purified by chromatography (THF: EtOAc = 4: 1) and 4- (5-iodo-1H-pyrazol-4-yl) -2- (methylthio) pyrimidine (A) (42.2). g, 54.6%) was obtained as a yellow solid.11 H NMR (400 MHz, DMSO): δ 8.55 (d, 1H), 8.35 (s, 1H), 7.55 (d, 1H), 2.55 (s, 3H).(Example A-2) Procedure for preparing 4- (5-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) -2- (methylthio) pyrimidine (B)<chemistry num="56"><img file="JP4792126B2_D0059.tif" /></chemistry> Compound A (75.0 g, 0.235 mmol), DHP (39.6 g, 0.471 mmol) and TsOH · H2The mixture of O (7.5 g) was stirred at 60 ° C. for 6 hours. The mixture was cooled to room temperature and concentrated. When the residue was purified by chromatography (EtOAc: petroleum ether = 1: 15), 4- (5-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) -2- (Methylthio) pyrimidine (B) (57.6 g, 60.8%) was obtained. 1H NMR (400 MHz, CDCl3): δ 8.495 (d, 1H), 8.400 (s, 1H), 7.638 (d, 1H), 5.398 (m, 1H), 4.070 (m, 1H), 3.732 (m, 1H), 2.796 (s, 3H), 2.110 (m, 3H), 1.900 (m, 3H).(Example B-1) (2S) -1- (4- (1-Isopropyl-3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole-4-yl) pyrimidine-2-ylamino) propane- Preparation of 2-ol (B-1)<chemistry num="57"><img file="JP4792126B2_D0060.tif" /></chemistry> Preparation of 4- (3-iodo-1-isopropyl-1H-pyrazole-4-yl) -2-methylthio) pyrimidine (B-1-1)<chemistry num="58"><img file="JP4792126B2_D0061.tif" /></chemistry> 4- (5-Iodine-1H-pyrazol-4-yl) -2- (methylthio) pyrimidine (A) (31.8 g, 0.1 mol), 2-iodine-propane (85 g, 50 mL, 0.5 mol) and K2CO3The mixture in (16.5 g, 0.12 mol) DMF (500 mL) was heated overnight at 40-50 ° C. When TLC (hexane: EtOAc = 15: 1) indicated that the reaction was complete, the DMF was evaporated under reduced pressure. The residue was mixed with EtOAc (400 mL). The mixture was washed with saturated aqueous NaCl solution and Na2SO4Drying on and concentrating gives a crude product, which is purified via preparative HPLC to be pure 4- (3-iodo-1-isopropyl-1H-pyrazole-4-yl)-. 2- (Methylthio) pyrimidin B-1-1 (17 g, 47.2%) was obtained as a yellow oil. Preparation of 4- (3-iodo-1-isopropyl-1H-pyrazole-4-yl) -2- (methylsulfonyl) pyrimidine (B-1-2)<chemistry num="59"><img file="JP4792126B2_D0062.tif" /></chemistry> Solution of 4- (3-iodo-1-isopropyl-1H-pyrazol-4-yl) -2- (methylthio) pyrimidine B-1-1 (15.5 g, 43 mmol) in THF (350 mL) and water (350 mL) Oxone (39.6 g, 64.6 mmol) was added at 0-5 ° C. After the addition, the mixture was stirred at room temperature overnight. When TLC (Hexane: EtOAc = 5: 1) indicated that the reaction was complete, EtOAc (500 mL) was added. The organic layer is separated, washed with saturated aqueous NaCl solution, and Na2SO4Drying on and concentrating gave 4- (3-iodo-1-isopropyl-1H-pyrazole-4-yl) -2- (methylsulfonyl) pyrimidine B-1-2 (16 g, 94.9%). .. Preparation of (2S) -1- (4- (3-iodo-1-isopropyl-1H-pyrazole-4-yl) pyrimidin-2-ylamino) propan-2-ol (B-1-3)<chemistry num="60"><img file="JP4792126B2_D0063.tif" /></chemistry> 4- (3-Iodo-1-isopropyl-1H-pyrazol-4-yl) -2- (methylsulfonyl) pyrimidine B-1-2 (16 g, 40 mmol) and (s) -1-amino-propane-2- The mixture in all (9 g, 122 mmol) THF (160 mL) was reflux heated overnight. When TLC (Hexane: EtOAc = 2: 1) indicated that the reaction was complete, EtOAc (80 mL) and saturated aqueous NaCl solution (80 mL) were added to the mixture and the layers were separated. The organic layer is separated, washed with saturated aqueous NaCl solution (30 mL), and Na.2SO4When dried on and concentrated, (2S) -1- (4- (3-iodo-1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2-ol (B-1-) 3) (15 g, 96.9%) was obtained as brown oil. (2S) -1- (4- (1-Isopropyl-3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole-4-yl) pyrimidine-2-ylamino) propane- Preparation of 2-ol (B-1)<chemistry num="61"><img file="JP4792126B2_D0064.tif" /></chemistry> (2S) -1- (4- (3-iodo-1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2-ol B-1-3 (0.312 g, 0.8 mmol) 1H-pyrrolo [2,3-b] pyridin-5-ylboronic acid (0.40 g, 1.6 mmol) and 2N Na in solution in toluene (15 mL) and EtOH (5 mL)2CO3Add aqueous solution (1.24 mL) and add N to the resulting mixture.2Degassed down for 2 minutes. Then Pd (PPh)3)4(0.23 g, 0.2 mmol) was added and the mixture was degassed again. The resulting mixture was reflux heated and stirred overnight. The organic layer was separated, concentrated and the residue was purified via preparative HPLC to result in (2S) -1- (4- (1-isopropyl-3- (1H-pyrrolo [2,3-b] pyridine-5). -Il) -1H-pyrazole-4-yl) pyrimidin-2-ylamino) propan-2-ol (B-1) (0.260 g, 66.19%) was obtained as a yellow solid.(Example B-2) (2S) -1- (4- (1-isopropyl-3- (6- (methylamino) pyridin-3-yl) -1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol ( Preparation of B-2)<chemistry num="62"><img file="JP4792126B2_D0065.tif" /></chemistry> Preparation of N-Methyl-5- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine-2-amine B-2-3<chemistry num="63"><img file="JP4792126B2_D0066.tif" /></chemistry> KOAc (1.58 g, 16.1 mmol) and bis (pinacolato) diboron (2 g, 8.06 mmol) in a DMF (30 mL) solution of 5-bromo-N-methylpyridine-2-amine B-2-2 (1 g, 5.37 mmol). ) Was added. N the resulting mixture2Degassed down for 2 minutes. Then Pd (PPh)3)2Cl2(0.5 g, 0.53 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90 ° C and stirred overnight. DMF was removed under reduced pressure. Dissolve the residue in EtOAc (40 mL), wash with saturated aqueous NaCl solution, Na2SO4Dry on top and concentrate to crude N-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine B-2-3 (2.3g) was obtained, which was used as is in the next step. (2S) -1- (4- (1-isopropyl-3- (6- (methylamino) pyridin-3-yl) -1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol ( Preparation of B-2)<chemistry num="64"><img file="JP4792126B2_D0067.tif" /></chemistry> (2S) -1- (4- (3-iodo-1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2-ol (9) (0.65 g, 1.68 mmol) toluene ( In solution in 20 mL) and EtOH (7 mL), N-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine 12 (1.44) g, in theory 3.36 mmol) and 2N Na2CO3Aqueous solution (2.5 mL) was added. N the resulting mixture2Degassed down for 2 minutes. Then Pd (PPh)3)4(0.2 g, 0.168 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90 ° C and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. When the residue was purified by preparative HPLC, (2S) -1- (4- (1-isopropyl-3- (6- (methylamino) pyridin-3-yl) -1H-pyrazole-4-yl) pyrimidin-2 -Ilamino) Propan-2-ol (B-2) (0.020 g, 3.2%) was obtained as a pale yellow solid.(Example B-3) (2S) -1- (4- (3- (6-amino-5-methylpyridine-3-yl) -1-isopropyl-1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol Preparation of (B-3)<chemistry num="65"><img file="JP4792126B2_D0068.tif" /></chemistry> Preparation of 3-Methyl-5- (4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-yl) Pyridine-2-amine (B-3-2)<chemistry num="66"><img file="JP4792126B2_D0069.tif" /></chemistry> KOAc (3.2 g, 33 mmol) and bis (pinacolato) diboron (4.1 g, 16 mmol) in a solution of 5-bromo-3-methylpyridine-2-amine B-3-1 (2 g, 11 mmol) in DMF (70 mL). added. N the resulting mixture2Degassed down for 2 minutes. Then Pd (PPh)3)2Cl2(1 g, 1.1 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90 ° C and stirred overnight. The mixture was poured into water (100 mL). The mixture is extracted with EtOAc (50 mL x 3), the organic layer is washed with saturated aqueous NaCl solution and Na2SO4Dry above and concentrated to crude 3-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine (B-3-) 2) (3.5 g) was obtained, which was used as is in the next step. (2S) -1- (4- (3- (6-amino-5-methylpyridine-3-yl) -1-isopropyl-1H-pyrazole-4-yl) pyrimidine-2-ylamino) propan-2-ol Preparation of (B-3)<chemistry num="67"><img file="JP4792126B2_D0070.tif" /></chemistry> (2S) -1- (4- (3-iodo-1-isopropyl-1H-pyrazole-4-yl) pyrimidin-2-ylamino) propan-2-ol (B-1-3) (0.52 g, 1.34 mmol) ) Intoluene (21 mL) and EtOH (7 mL) in 3-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-. Amine (B-3-2) (1 g, 2.68 mmol in theory) and 2N Na2CO3Aqueous solution (2 mL) was added. N the resulting mixture2Degassed down for 2 minutes. Then Pd (PPh)3)4(0.15 g, 0.134 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90 ° C and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. When the residue was purified by preparative HPLC, (2S) -1- (4- (3- (6-amino-5-methylpyridine-3-yl) -1-isopropyl-1H-pyrazole-4-yl) pyrimidin- 2-Ilamino) Propan-2-ol (B-3) (0.057 g, 11.6%) was obtained as a pale yellow solid.(Example B-4) (2S) -1- (4- (1-Isopropyl-3- (5-methyl-6- (methylamino) pyridin-3-yl) -1H-pyrazole-4-yl) pyrimidin-2-ylamino) propane- Preparation of 2-ol (B-4)<chemistry num="68"><img file="JP4792126B2_D0071.tif" /></chemistry> Preparation of 5-bromo-N, 3-dimethylpyridin-2-amine (B-4-2)<chemistry num="69"><img file="JP4792126B2_D0072.tif" /></chemistry> To a solution of 5-bromo-3-methylpyridine-2-amine (B-4-1) (3.7 g, 0.02 mol) in THF (50 mL), add NaH (0.8 g, 0.02 mol) little by little at 0 ° C. It was. After the addition, the mixture was stirred at room temperature for about 0.5 hours and cooled again to 0 ° C. Iodomethane (2.8 g, 0.02 mol) was added gradually. The resulting mixture was raised to room temperature and stirred for 1 hour. TLC (EtOAc: petroleum ether = 1: 4) showed that the reaction was complete. Saturated aqueous NaCl solution (10 mL) and EtOAc (10 mL) were added. The organic layer is concentrated and the residue is eluted via a silica gel column with EtOAc / petroleum ether (1: 8) for purification and purified by 5-bromo-N, 3-dimethylpyridin-2-amine (B-4-2). ) (2.3 g, 57.8%) was obtained as a white solid. Preparation of N,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine (B-4-3)<chemistry num="70"><img file="JP4792126B2_D0073.tif" /></chemistry> In a solution of 5-bromo-N, 3-dimethylpyridin-2-amine (B-4-2) (2.3 g, 11.4 mmol) in DMF (70 mL), KOAc (3.35 g, 34.2 mmol) and bis ( Pinacolato) diboron (4.34 g, 17.1 mmol) was added. N the resulting mixture2Degassed down for 2 minutes. Then Pd (PPh)3)2Cl2(1 g, 1.1 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90 ° C and stirred overnight. The mixture was poured into saturated aqueous NaCl solution (80 mL). The mixture was extracted with EtOAc (50 mL x 3). Wash the organic layer with saturated aqueous NaCl solution and Na2SO4Dry above and concentrated to crude N,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine (B-) 4-3) (3.5 g) was obtained, which was used as is in the next step without purification. (2S) -1- (4- (1-Isopropyl-3- (5-methyl-6- (methylamino) pyridin-3-yl) -1H-pyrazole-4-yl) pyrimidin-2-ylamino) propane- Preparation of 2-ol (B-4)<chemistry num="71"><img file="JP4792126B2_D0074.tif" /></chemistry> (2S) -1- (4- (3-iodo-1-isopropyl-1H-pyrazole-4-yl) pyrimidin-2-ylamino) propan-2-ol (B-1-3) (1 g, 2.58 mmol) In solution in toluene (30 mL) and EtOH (10 mL), N,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 -Amine (B-4-3) (2 g, 6.3 mmol in theory) and 2N Na2CO3Aqueous solution (4 mL) was added. N the resulting mixture2Degassed down for 2 minutes. Then Pd (PPh)3)4(0.3 g, 0.26 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90 ° C and stirred overnight. MS indicated that the reaction was complete and the mixture was cooled. The organic layer was separated and concentrated. When the residue is purified by preparative HPLC, (2S) -1- (4- (1-isopropyl-3- (5-methyl-6- (methylamino) pyridin-3-yl) -1H-pyrazol-4-yl) ) Pyrimidine-2-ylamino) Propan-2-ol (B-4) (0.167 g, 16.98%) was obtained as a pale yellow solid.(Example B-5) (2S) -1- (4- (1-Isopropyl-3- (3-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole-4-yl) pyrimidine-2- Preparation of Ilamino) Propane-2-ol (B-5)<chemistry num="72"><img file="JP4792126B2_D0075.tif" /></chemistry> Preparation of 5-bromo-3-iodopyridin-2-amine (B-5-2)<chemistry num="73"><img file="JP4792126B2_D0076.tif" /></chemistry> 5-Bromopyridine-2-amine (B-5-1) (50 g, 0.29 mol), I2(59g, 0.233mol) and NaIO4The mixture in (24.8 g, 0.116 mol) DMF 600 mL) was stirred at 80-90 ° C overnight. TLC (EtOAc: petroleum ether = 1: 5) showed that the reaction was complete. The mixture was concentrated under reduced pressure to remove the solvent. Dissolve the residue in EtOAc (500 mL), wash with water (100 mL) and saturated aqueous NaCl solution (100 mL), Na2SO4Drying on and concentrating gives crude compound B-5-2, which is eluted with EtOAc / petroleum ether (12: 1) via a silica gel column and purified to pure 5-bromo. -3-Iodopyridine-2-amine (B-5-2) (35 g, 40.5%) was obtained as an orange solid. Preparation of 5-bromo-3-methyl-2- (trimethylsilyl) -1H-pyrrolo [2,3-b] pyridine (B-5-3)<chemistry num="74"><img file="JP4792126B2_D0077.tif" /></chemistry> KOAc (29.4 g, 0.3 mol) and LiCl (4.25 g, 0.1 mol) in a solution of 5-bromo-3-iodopyridine-2-amine (B-5-2) (30 g, 0.1 mol) in DMF (600 mL). Was added. Mixture N2After degassing 3 times down, Pd (OAc)2(2.24 g, 0.01 mol) was added and the mixture was degassed again. Then trimethyl-prop-1-ynyl-silane (56 g, 0.5 mol) was added. The resulting mixture was heated to 80-100 ° C for 2 days. TLC (EtOAc: petroleum ether = 1: 5) showed that the reaction was complete. Excess DMF was removed under reduced pressure. Dissolve the residue in EtOAc (500 mL), wash with saturated aqueous NaCl solution, Na2SO4Drying and concentrating on top gives a crude product, which is purified via silica gel column chromatography (100-200) (petroleum ether, then EtOAc: petroleum ether = 10: 10), 5 -Bromo-3-methyl-2- (trimethylsilyl) -1H-pyrrolo [2,3-b] pyridine (B-5-3) (impure, 5 g, 17.7%) was obtained as a brown oil. Preparation of 5-bromo-3-methyl-1H-pyrrolo [2,3-b] pyridine (B-5-4)<chemistry num="75"><img file="JP4792126B2_D0078.tif" /></chemistry> 5-Bromo-3-methyl-2- (trimethylsilyl) -1H-pyrrolo [2,3-b] Pyridine (B-5-3) (5 g, 17.8 mmol) in THF (50 mL) solution with 2N HCl ( 20 mL) was added. The mixture was stirred at reflux overnight. HPLC showed that the reaction was complete. After concentrating the mixture under reduced pressure, the residue is LVDS3It was dissolved in aqueous solution (20 mL) and extracted with EtOAc (10 mL x 3). Wash the organic layer with saturated aqueous NaCl solution and Na2SO4Drying on and concentrating gives a crude product, which is purified via preparative HPLC to give 5-bromo-3-methyl-1H-pyrrolo [2,3-b] pyridine (B-). 5-4) (2 g, 53.2%) was obtained as a pale solid. 3-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] Pyridine (B-5-5) Preparation<chemistry num="76"><img file="JP4792126B2_D0079.tif" /></chemistry> In a solution of 5-bromo-3-methyl-1H-pyrrolo [2,3-b] pyridine (B-5-4) (0.5 g, 2.37 mmol) in DMF (150 mL), KOAc (0.7 g, 7.11 mmol) and Bis (Pinacolato) diboron (0.72 g, 2.84 mmol) was added. N the resulting mixture2Degassed down for 2 minutes. Then Pd (PPh)3)2Cl2(0.2 g, 0.237 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90 ° C and stirred overnight. The mixture was poured into water (30 mL) and extracted with EtOAc (15 mL x 3). Wash the organic layer with saturated aqueous NaCl solution and Na2SO4Dry above and concentrated to crude 3-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] Pyridine (B-5-5) (0.7 g) was obtained, which was used as is in the next step. (2S) -1- (4- (1-Isopropyl-3- (3-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole-4-yl) pyrimidine-2- Preparation of Ilamino) Propane-2-ol (B-5)<chemistry num="77"><img file="JP4792126B2_D0080.tif" /></chemistry> (2S) -1- (4- (3-iodo-1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2-ol (9) (0.65 g, 1.7 mmol) toluene ( In solution in 21 mL) and EtOH (7 mL), 3-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3 -b] Pyridine 21 (0.7 g, 2.37 mmol in theory) and 2N Na2CO3Aqueous solution (2.5 mL) was added. N the resulting mixture2Degassed down for 2 minutes. Then Pd (PPh)3)4(0.19 g, 0.17 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90 ° C and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. When the residue was purified by preparative HPLC, (2S) -1- (4- (1-isopropyl-3- (3-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole) -4-yl) Pyrimidine-2-ylamino) Propan-2-ol (B-5) (0.150 mg, 16.2%) was obtained as a white solid.(Example B-6) (2S) -1- (4- (3- (2,3-dimethyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-isopropyl-1H-pyrazole-4-yl) pyrimidine- Preparation of 2-ylamino) propane-2-ol (B-6)<chemistry num="78"><img file="JP4792126B2_D0081.tif" /></chemistry> Preparation of 5-bromo-3-methyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (B-6-2)<chemistry num="79"><img file="JP4792126B2_D0082.tif" /></chemistry> Add NaH (0.34 g, 8.5 mmol) to a solution of 5-bromo-3-methyl-1H-pyrrolo [2,3-b] pyridine (B-6-1) (1.2 g, 5.68 mmol) in THF (30 mL). N2It was added below at 0 ° C. and after 30 minutes, 4-bromophenylsulfonyl chloride (1.2 g, 6.8 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. TLC (petroleum ether: EtOAc = 5: 1) showed that the reaction was complete. When saturated aqueous NaCl solution (10 mL) was added and the mixture was filtered, 5-bromo-3-methyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (B-6-2) (0.8 g). ) Was obtained as a white solid. The organic layer was separated from the filtrate, concentrated to 8 mL and then filtered to 5-bromo-1- (4-bromophenylsulfonyl) -3-methyl-1H-pyrrolo [2,3-b] pyridine (0.5 g). )was gotten. When the two batches are combined, 5-bromo-3-methyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (B-6-2) (1.3 g, 65.2%) is white. Obtained as a solid. Preparation of 5-bromo-2,3-dimethyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (B-6-3)<chemistry num="80"><img file="JP4792126B2_D0083.tif" /></chemistry> THF (20 mL) suspension of 5-bromo-1- (4-bromophenylsulfonyl) -3-methyl-1H-pyrrolo [2,3-b] pyridine (B-6-2) (0.9 g, 2.56 mmol) LDA (15 mL, 0.2 M in THF) was added dropwise to the solution at -40 ° C. The mixture was stirred at -10 to -20 ° C for 0.5 hours. Methyl iodide (0.55 g, 3.84 mmol) was added dropwise at -40 to -30 ° C. The reaction was stirred at room temperature overnight. LC-MS showed that the reaction was complete. Aqueous saturated NaCl solution (10 mL) and EtOAc (10 mL) were added to the mixture. The organic layer is separated and anhydrous Na2SO4When dried and concentrated on, 5-bromo-2,3-dimethyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (B-6-3) (0.9 g, 96.3%), (Contains some starting material (B-6-2)) was obtained as a pale yellow solid. Preparation of 5-bromo-2,3-dimethyl-1H-pyrrolo [2,3-b] pyridine (B-6-4)<chemistry num="81"><img file="JP4792126B2_D0084.tif" /></chemistry> 5-Bromo-2,3-dimethyl-1- (Phenylsulfonyl) -1H-pyrrolo [2,3-b] Pyridine (B-6-3) (0.9 g, 2.5 mmol) in THF (30 mL) and MeOH ( Aqueous NaOH solution (20%, 19 mL) was added to the suspension in 30 mL) at room temperature. The mixture was reflux heated overnight. TLC (petroleum ether: EtOAc = 5: 1) showed that the reaction was complete. After removing the solvent under reduced pressure, water (20 mL) and CH2Cl2(20 mL) was added to the mixture. The organic layer is separated and anhydrous Na2SO4Dry on top. Concentration of the mixture gives a crude mixture, which is purified via preparative HPLC to give 5-bromo-2,3-dimethyl-1H-pyrrolo [2,3-b] pyridine (B-6-). 4) (0.4 g, 72.4%) was obtained as a white solid. 2,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (B-6-5) ) Preparation<chemistry num="82"><img file="JP4792126B2_D0085.tif" /></chemistry> KOAc (0.52 g, 5.3 mmol) in a solution of 5-bromo-2,3-dimethyl-1H-pyrrolo [2,3-b] pyridine (B-6-4) (0.4 g, 1.77 mmol) in DMF (30 mL). ) And bis (Pinacolato) diboron (0.68 g, 2.65 mmol) and add N to the resulting mixture.2Degassed down for 2 minutes. Then Pd (dppf)2Cl2(40 mg, 0.049 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90 ° C and stirred overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (40 mL x 3). Wash the organic layer with saturated aqueous NaCl solution and Na2SO4Dry on top and concentrate to crude 2,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3 -b] Pyridine (B-6-5) (0.7 g) was obtained, which was used as is in the next step without purification. (2S) -1- (4- (3- (2,3-dimethyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-isopropyl-1H-pyrazole-4-yl) pyrimidine- Preparation of 2-ylamino) propane-2-ol (B-6)<chemistry num="83"><img file="JP4792126B2_D0086.tif" /></chemistry> (2S) -1- (4- (3-iodo-1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2-ol (B-1-3) (0.34 g, 0.885 mmol) ) Intoluene (30 mL) and EtOH (10 mL) solution, 2,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrolo [2,3-b] Pyridine (B-6-5) (0.7 g, 1.77 mmol in theory) and 2N Na2CO3Aqueous solution (1.3 mL) was added. N the resulting mixture2Degassed down for 2 minutes. Then Pd (PPh)3)4(68 mg, 0.058 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90 ° C and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. When the residue was purified by preparative HPLC, (2S) -1-(4-(3- (2,3-dimethyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-isopropyl-1H -Pyrazole-4-yl) Pyrimidine-2-ylamino) Propan-2-ol (B-6) (0.170 mg, 23.6%) was obtained as a pale yellow solid.(Example B-7) (2S) -1- (4- (1-Isopropyl-3- (2-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole-4-yl) pyrimidine-2- Preparation of Ilamino) Propane-2-ol (B-7)<chemistry num="84"><img file="JP4792126B2_D0087.tif" /></chemistry> Preparation of 5-bromo-3- (2- (trimethylsilyl) ethynyl) pyridin-2-amine (B-7-2)<chemistry num="85"><img file="JP4792126B2_D0088.tif" /></chemistry> Et of 5-bromo-3-iodopyridin-2-amine (B-7-1) (20 g, 66.9 mmol)3CuI (1.27 g, 6.69 mmol) was added to the N (200 mL) solution, and the resulting mixture was N.2Degassed down for 2 minutes. Then Pd (PPh)3)2Cl2(1.4 g, 20.1 mmol) was added and the mixture was degassed again. Ethynyl-trimethyl-silane (7.2 g, 73.6 mmol) was then added dropwise to the mixture at 0 ° C. The mixture was stirred at room temperature for 4 hours. TLC (petroleum ether: EtOAc = 5: 1) showed that the reaction was complete. Evaporation of the mixture under reduced pressure gives a crude mixture, which is eluted with petroleum ether / EtOAc (20: 1) via a silica gel column for purification and 5-bromo-3- (2-). (Trimethylsilyl) ethynyl) Pyridine-2-amine (B-7-2) (10 g, 55.6%) was obtained as a white solid. Preparation of 5-bromo-1H-pyrrolo [2,3-b] pyridine (B-7-3)<chemistry num="86"><img file="JP4792126B2_D0089.tif" /></chemistry> 5-Bromo-3- (2- (trimethylsilyl) ethynyl) Pyridine-2-amine (B-7-2) (9.5 g, 35.3 mmol) in a t-BuOH (100 mL) solution, t-BuOK (10.5 g, 141.3 mmol) was added. The mixture was stirred at 80 ° C. for 20 hours. TLC (petroleum ether: EtOAc = 5: 1) showed that the reaction was complete. The mixture was then cooled to room temperature. Concentrated hydrochloric acid (50 mL) was added to the mixture. The mixture was then reflux heated for 8 hours. TLC (petroleum ether: EtOAc = 5: 1) showed that the reaction was complete. The mixture was cooled to room temperature and poured into water (100 mL). The mixture was filtered through a Celite bed. The filtrate was diluted with water (100 mL) and made basic by adding 50% sodium hydroxide. The mixture was extracted with EtOAc (150 mL x 3). The organic layer was washed with water (100 mL) and saturated sodium chloride (100 mL), dried over sodium sulfate and concentrated under reduced pressure to give 5-bromo-1H-pyrrolo [2,3-b] pyridine (B-7). -3) (6.2 g, 88.6%) was obtained as a pale yellow solid. Preparation of 5-Bromo-1- (Phenylsulfonyl) -1H-Pyrrolo [2,3-b] Pyridine (B-7-4)<chemistry num="87"><img file="JP4792126B2_D0090.tif" /></chemistry> NaH (1.51 g, 0.037 mol) was added to a suspension of 5-bromo-1H-pyrrolo [2,3-b] pyridine (B-7-3) (6.2 g, 0.031 mol) in THF (100 mL).2Added below. BsCl (3.58 g, 0.035 mol) was added after 30 minutes. The mixture was stirred at room temperature overnight. TLC (petroleum ether: EtOAc = 5: 1) showed that the reaction was complete. Water (200 mL) and EtOAc (50 mL x 3) were added to the mixture. When the organic layer was separated and concentrated, 5-bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (B-7-4) (10 g, 94.3%) became a pale yellow solid. Obtained.1HNMR (400 MHz, CDCl3): δ 8.465 (s, 1H), 8.141-8.114 (d, 2H), 7.905 (s, 1H), 7.679-7.669 (d, 1H), 7.586-7.529 (m, 1H), 7.430-7.351 (2, 1H), 6.458-6.475 (d, 1H). Preparation of 5-bromo-1- (4-bromophenylsulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridine (B-7-5)<chemistry num="88"><img file="JP4792126B2_D0091.tif" /></chemistry> LDA (200 mL, THF) in THF (50 mL) suspension of 5-bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (B-7-4) (10 g, 0.03 mol) Medium 0.21 M) was added dropwise at -78 ° C. The mixture was stirred at -78 ° C for 1 hour. MeI (5.2 g, 0.038 mol) was then added dropwise at -78 ° C. The reaction was stirred at 70 ° C. for 3 hours and then at room temperature overnight. LC-MS showed that the reaction was complete. Water (200 mL) and EtOAc (100 mL x 3) were added to the mixture. The organic layer is separated and anhydrous Na2SO4When dried above and concentrated, 5-bromo-1- (4-bromophenylsulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridine (B-7-5) (6g, 57.7%) Was obtained as a pale yellow solid.1HNMR (400 MHz, CDCl3): δ 8.390-8.385 (d, 1H), 8.176-8.145 (d, 2H), 7.828-7.823 (d, 1H), 7.613-7.576 (t, 1H), 7.517-7.479 (t, 2H), 6.254 (s, 1H), 2.748 (s, 3H). Preparation of 5-bromo-2-methyl-1H-pyrrolo [2,3-b] pyridine (B-7-6)<chemistry num="89"><img file="JP4792126B2_D0092.tif" /></chemistry> THF (20 mL) suspension of 5-bromo-1- (4-bromophenylsulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridine (B-7-5) (4 g, 11.4 mmol) To the mixture was an aqueous NaOH solution (20 mL) at room temperature. The mixture was reflux heated overnight. LC-MS showed that the reaction was complete. Water (100 mL) and EtOAc (50 mL x 3) were added to the mixture. The organic layer is separated and anhydrous Na2SO4Drying on and concentrating gives a crude mixture, which is purified via preparative HPLC to 5-bromo-2-methyl-1H-pyrrolo [2,3-b] pyridine (B-7). -6) (1.2 g, 50.2%) was obtained as a white solid. 2-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] Pyridine (B-7-7) Preparation<chemistry num="90"><img file="JP4792126B2_D0093.tif" /></chemistry> 5-Bromo-2-methyl-1H-pyrrolo [2,3-b] Pyridine (B-7-6) (0.5 g, 2.4 mmol), Bis (Pinacolato) diboron (1.2 g, 4.7 mmol) and KOAc (0.7 mmol) Pd (dppf) to the mixture in DMF (50 mL) of g, 7.1 mmol)2Cl2(0.05 g, 0.06 mmol) was added. Mixture N2Degassed down for 2 minutes. The mixture was then stirred at 80 ° C. overnight. TLC (CH)2Cl2: MeOH = 20: 1) indicated that the reaction was complete. Water (50 mL) and EtOAc (50 mL x 3) were added to the mixture. The organic layer is separated and anhydrous Na2SO4Dry on top and concentrate to crude 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] Pyridine (B-7-7) (1.8 g) was obtained as a brown solid. (2S) -1- (4- (1-Isopropyl-3- (2-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole-4-yl) pyrimidine-2- Preparation of Ilamino) Propane-2-ol (B-7)<chemistry num="91"><img file="JP4792126B2_D0094.tif" /></chemistry> 2-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (B-7-7) ( 1.8 g, theoretically 2.3 mmol) and (2S) -1- (4- (3-iodo-1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2-ol (B-1) -3) In a suspension of (0.45 g, 1.2 mmol) in toluene / EtOH (3: 1, 50 mL), Na2CO3Aqueous solution (1.7 mL, 2 M) was added. Mixture N2Degas down for 2 minutes, Pd (PPh)3)4(0.05 g, 0.042 mmol) was added to the mixture and degassed again. The mixture was stirred at 80 ° C. for 30 hours. TLC (CH)2Cl2: MeOH = 20: 1) indicated that the reaction was complete. Water (50 mL) and EtOAc (50 mL x 3) were added to the mixture. The organic layer is separated and anhydrous Na2SO4Drying on and concentrating gives a crude product, which is purified via preparative HPLC to (2S) -1- (4- (1-isopropyl-3- (2-methyl-1H)). -Pyrolo [2,3-b] Pyridine-5-yl) -1H-Pyrazole-4-yl) Pyrimidine-2-ylamino) Propane-2-ol (B-7) (0.169g, 18.6%) is white Obtained as a solid.(Example B-8) (2S) -1- (4- (1-Isopropyl-3- (2-methylimidazole [1,2-a] pyrimidin-6-yl) -1H-pyrazole-4-yl) pyrimidin-2-ylamino) propane -2-Preparation of all (B-8)<chemistry num="92"><img file="JP4792126B2_D0095.tif" /></chemistry> Preparation of 6-Bromo-2-methylimidazole [1,2-a] pyrimidine (B-8-2)<chemistry num="93"><img file="JP4792126B2_D0096.tif" /></chemistry> To a solution of 5-bromopyrimidine-2-amine (170.0 g, 0.98 mol) in i-PrOH (2 L) and DMF (500 mL) is added 1-chloropropane-2-one (606 g, 6.53 mol), followed by The mixture was stirred at 100 ° C for 16 hours. TLC (petroleum ether: ethyl acetate = 1: 2) showed that the reaction was complete. The reaction mixture is Na2CO3Quenched with and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to give compound B-8-2 (10.0 g, 4.8%) as a yellow solid. Preparation of 2-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) imidazole [1,2-a] pyrimidine (B-8-3)<chemistry num="94"><img file="JP4792126B2_D0097.tif" /></chemistry> Bis (pinacolato) diboron (3.95 g, 15.5 mmol) and KOAc (4.58 g, 42.4 mmol) were added to a solution of compound B-8-3 (3.0 g, 14.1 mmol) in DMF (60 mL). N the resulting mixture2Degassed down for 2 minutes. Then Pd (PPh)3)2Cl2(0.20 g, 0.23 mmol) was added and the mixture was degassed again. The resulting mixture was heated to 90 ° C and stirred overnight. TLC (petroleum ether: ethyl acetate = 1: 2) showed that the reaction was complete. The mixture was then cooled and filtered. Concentration of the filtrate gave crude compound B-8-3 (2.5 g) as a brown solid, which was used in the next step without purification. (2S) -1- (4- (1-Isopropyl-3- (2-methylimidazole [1,2-a] pyrimidin-6-yl) -1H-pyrazole-4-yl) pyrimidin-2-ylamino) propane -2-Preparation of all (B-8)<chemistry num="95"><img file="JP4792126B2_D0098.tif" /></chemistry> In a solution of compound B-1-3 (2.0 g, 5.16 mmol) in toluene (48 mL) and EtOH (16 mL), crude compound B-8-3 (2.5 g, 9.26 mmol) and 2N Na2CO3Aqueous solution (7.5 mL) was added. N the resulting mixture2Degassed down for 2 minutes. Then Pd (PPh)3)4(0.41 g, 0.36 mmol) was added and the mixture was degassed again. The resulting mixture was heated to 80 ° C and stirred overnight. TLC (CH)2CL2: MeOH = 20: 1) indicated that the reaction was complete and the mixture was cooled. The organic layer was separated, concentrated and the residue was purified by preparative HPLC to give compound (B-8) (60 mg, 1.6%) as a yellow solid.(Example B-9) (2S) -1- (4- (3- (2,3-dimethylimidazole [1,2-a] pyrimidin-6-yl) -1-isopropyl-1H-pyrazole-4-yl) pyrimidin-2-ylamino ) Preparation of Propan-2-ol PF-04597926 (B-9) Preparation of 3-Bromobutane-2-one (B-9-2)<chemistry num="96"><img file="JP4792126B2_D0099.tif" /></chemistry> Butane-2-one (600 g, 8.3 mol) AcOH (500 mL) and H2Bromine (360 g, 8.5 mol) was added dropwise to the solution in O (2 L) at 70 ° C for 3 hours, then the resulting mixture was stirred at room temperature for 14 hours. TLC (petroleum ether: ethyl acetate = 5: 1) showed that the reaction was complete. Water (1 L) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (400 mL x 3). The combined organic layer is Na2SO4It was dried on top and concentrated. Distillation of the residue gave compound B-9-2 (400 g, 70%) as a yellow oil. Preparation of 6-Bromo-2,3-Dimethylimidazole [1,2-a] pyrimidine (B-9-4)<chemistry num="97"><img file="JP4792126B2_D0100.tif" /></chemistry> Compound B-9-2 (400 g, 2.6 mol) was added to a solution of 5-bromopyrimidine-2-amine (400 g, 2.2 mol) in i-PrOH (2 L) and DMF (500 mL) to give the resulting mixture. The mixture was stirred at 100 ° C for 20 hours. TLC (petroleum ether: ethyl acetate = 1: 1) indicates that the reaction is complete and the reaction mixture is Na2CO3Quenched by adding aqueous solution and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give compound B-9-4 (12.0 g, 2.4%) as a yellow solid. Preparation of 2,3-dimethyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) imidazole [1,2-a] pyrimidine (B-9-5)<chemistry num="98"><img file="JP4792126B2_D0101.tif" /></chemistry> Bis (pinacolato) diboron (2.79 g, 11 mmol) and KOAc (2.74 g, 30 mmol) were added to a solution of compound B-9-4 (2.0 g, 8.92 mmol) in DMF (60 mL), and the resulting mixture was N.2Degassed down for 2 minutes. Then Pd (PPh)3)2Cl2(0.20 g, 0.23 mmol) was added and the mixture was degassed again. The resulting mixture was heated to 90 ° C and stirred overnight. The mixture was cooled, filtered and the filtrate concentrated to give crude compound B-9-5 (2.4 g) as a brown solid, which was used in the next step without purification. (2S) -1- (4- (3- (2,3-dimethylimidazole [1,2-a] pyrimidin-6-yl) -1-isopropyl-1H-pyrazole-4-yl) pyrimidin-2-ylamino ) Preparation of propane-2-ol (B-9)<chemistry num="99"><img file="JP4792126B2_D0102.tif" /></chemistry> Compound B-9-5 (2.4 g) and 2N Na in a solution of compound B-1-3 (2.0 g, 5.16 mmol) in toluene (48 mL) and EtOH (16 mL).2CO3Add aqueous solution (7.5 mL) and add N to the resulting mixture.2Degassed down for 2 minutes. Then Pd (PPh)3)4(0.41 g, 0.36 mmol) was added and the mixture was degassed again. The resulting mixture was heated to 80 ° C and stirred overnight. After cooling the mixture, the organic layer was separated and concentrated. Purification of the residue by preparative HPLC gave compound B-9 (220 mg, 1.6%) as a yellow solid.(Example B-10) (2S) -1- (4- (1-Isopropyl-3- (5-methyl-5H-pyrrolo [3,2-b] pyrazine-2-yl) -1H-pyrazole-4-yl) pyrimidin-2- Preparation of Ilamino) Propane-2-ol (B-10)<chemistry num="100"><img file="JP4792126B2_D0103.tif" /></chemistry> Preparation of 6-chloropyrazine-2-amine (B-10-2)<chemistry num="101"><img file="JP4792126B2_D0104.tif" /></chemistry> 2,6-dichloropyrazine (300g, 2mol) and 28% NH3The mixture of aqueous solution (8 L) was stirred at 140 ° C. in a closed system for 14 hours. TLC (petroleum ether / EtOAc 3: 1) showed complete consumption of starting material. The reaction mixture was extracted with EtOAc (3L × 3). Wash the combined organic layer with saturated aqueous NaCl solution (3L) and Na2SO4Drying on top and vacuum concentration gives crude compound B-10-2, which is purified by column chromatography (silica gel, petroleum ether / EtOAc 2: 1) to pure compound B-10-2. (410 g, yield: 59.7%) was obtained as a white solid. Preparation of 3-Bromo-6-chloropyrazine-2-amine (B-10-3)<chemistry num="102"><img file="JP4792126B2_D0105.tif" /></chemistry> CHCl of compound B-10-2 (110 g, 0.85 mol)3N-Bromosuccinimide (151.3 g, 0.85 mol) in solution (1.5 L) at 0 ° C.2It was added little by little under the atmosphere. After the addition, the reaction mixture was warmed to room temperature and stirred overnight. TLC (petroleum ether / EtOAc 3: 1) showed that most of compound B-10-2 was consumed. Saturate the reaction mixture Na2CO3(1L x 3), H2Continuously wash with O (1L x 3) and saturated aqueous NaCl solution (1L) and Na2SO4It was dried on top and concentrated in vacuo. Purification of the residue via column chromatography (silica gel, EtOAc / Hexanes 1:20) reveals that pure B-10-3b (35 g) and pure compound B-10-3 (45 g, 28%) are yellow solids. Obtained as. Preparation of 6-chloro-3- (2- (trimethylsilyl) ethynyl) pyrazine-2-amine (B-10-4)<chemistry num="103"><img file="JP4792126B2_D0106.tif" /></chemistry> Compounds B-10-3 (70 g, 0.336 mol), CuI (6.3 g, 0.0336 mol) and Pd (PPh)3)2Cl2(7g) Et3Add ethynyl-trimethyl-silane (35.6 g, 0.352 mol) to the mixture in N (1 L) at 0 ° C.2Dropped in the atmosphere. After the addition, the reaction mixture was warmed to room temperature and stirred for 1.5 hours. TLC (petroleum ether / EtOAc 5: 1) showed complete consumption of starting material. Vacuum concentration of the mixture gives crude compound B-10-4, which is purified by column chromatography (silica gel, petroleum ether / EtOAc 20: 1) to give pure compound B-10-4 (36.5 g). , Yield 42%) was obtained as a yellow solid. Preparation of 3-chloro-5H-pyrrolo [2,3-b] pyrazine (B-10-5)<chemistry num="104"><img file="JP4792126B2_D0107.tif" /></chemistry> A solution of compound B-10-4 (32 g, 0.14 mol) and t-BuOK (63.5 g, 0.57 mol) in t-BuOH (1 L) was stirred at 80 ° C overnight. TLC (petroleum ether / EtOAc 5: 1) showed complete consumption of starting material. The reaction mixture was cooled to room temperature. Concentrated HCl (200 mL) was then added to the mixture. The resulting mixture was heated to 80 ° C and refluxed overnight. TLC (petroleum ether / EtOAc 5: 1) showed that the reaction was complete. The reaction mixture was cooled to room temperature, poured into water (1 L) and extracted with EtOAc (1 L × 3). Combined organic layer 50% Na2CO3(300mL), H2Continuously wash with O (500 mL) and saturated aqueous NaCl solution (1 L) and Na2SO4Drying on top and vacuum concentration gives crude B-10-5, which is purified by column chromatography (silica gel, petroleum ether / EtOAc 10: 1) to give pure B-10-5 (15 g). , Yield: 63%) was obtained as a yellow solid. Preparation of 3-chloro-5-methyl-5H-pyrrolo [2,3-b] pyrazine (B-10-6)<chemistry num="105"><img file="JP4792126B2_D0108.tif" /></chemistry> The solution was prepared from Compound B-10-5 310 mg (1.95 mmol) in 3 ml anhydrous DMF. This mixture was added to a solution of 125 mg (3.05 mmol) of NaH dispersion in mineral oil in 3 ml anhydrous DMF. In addition, 6 ml of DMF was used to rinse the container. The reaction mixture was stirred at room temperature for 15 minutes. Further, 150 μl (2.40 mmol) of MeI was added. Stir for 2 hours. LCMS shows one peak M + H = 168 in the Cl isotope pattern. Saturate the reaction mixture NH4Gradually poured into Cl solution (100 ml) and then extracted with EtOAc (3 x 50 ml). Combine the organic layers and EDTA4It was dried on and filtered. Silica gel chromatography gave compound B-10-6 257 mg (76% yield) as a yellow solid using EtOAc / Hexanes. Preparation of 5-methyl-5H-pyrrolo [2,3-b] pyrazine-3-ylboronic acid (B-10-7)<chemistry num="106"><img file="JP4792126B2_D0109.tif" /></chemistry> In flask, tricyclohexylphosphine 36 mg (0.128 mmol) and Pd2(dba)348 mg (0.052 mmol) was dissolved in 5 ml of anhydrous dioxane. It was whipped with argon for 10 minutes and stirred at room temperature for an additional 20 minutes. To this was added bis (pinacolato) diboron 429 mg (1.69 mmol). Finally, a 5 ml suspension of compound B-10-6 257 mg (1.53 mmol) and KOAc 226 mg (2.30 mmol) dioxane was added. The reaction flask was equipped with an air-cooled condenser and heated to 80 ° C overnight. After 24 hours, the reaction mixture was poured into saturated aqueous NaCl solution, extracted with EtOAc (3 x 75 ml) and washed with water. Combine the organic layers and EDTA4It was dried on top, filtered and the solvent was evacuated. Gradient column at Biotage, CHCl3From CHCl3Medium 15% (5% NH in EtOH)4When flushed with OH), compound B-10-7 was isolated as a brown solid (73 mg, 27% yield). (2S) -1- (4- (1-Isopropyl-3- (5-methyl-5H-pyrrolo [3,2-b] pyrazine-2-yl) -1H-pyrazole-4-yl) pyrimidin-2- Preparation of Ilamino) Propane-2-ol (B-10)<chemistry num="107"><img file="JP4792126B2_D0110.tif" /></chemistry> In a flask, compound B-1-3 155 mg (0.40 mmol) and boronic acid B-10-7 73 mg (0.41 mmol) were dissolved in 6 ml anhydrous DMF. 2.0M Na in this mixture2CO3600 μl of the solution was added. Argon gas was bubbled into the reaction mixture for 10 minutes. Finally, Pd (dppf)2CH2Cl217 mg (0.052 mmol) of catalyst was added and the reaction was heated to 80 ° C. overnight. After 20 hours, the reaction mixture was poured into 40 ml of saturated aqueous NaCl solution and extracted with EtOAc (3 x 50 ml). The organic extracts were combined, dried over magnesium sulphate, filtered and the solvent evacuated. Compound (B-10) was isolated by HPLC as a glassy solid in a yield of 20% (34 mg).(Example B-12) (2S) -1- (4- (3- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-isopropyl-1H-pyrazole-4-yl) pyrimidine- Preparation of 2-ylamino) propane-2-ol (B-12)<chemistry num="108"><img file="JP4792126B2_D0111.tif" /></chemistry> Preparation of tert-butyl 5-bromo-2,3-dihydropyrrolo [2,3-b] pyridine-1-carboxylate (B-12-2)<chemistry num="109"><img file="JP4792126B2_D0112.tif" /></chemistry> Diisopropylethylamine (357 mg) in a 10 mL solution of agitated 5-bromo-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine (500 mg, 2.51 mmol) and Boc anhydride (658 mg, 3.01 mmol) in DMF. , 2.76 mmol) was added. The mixture was refluxed under nitrogen for 1 hour. TLC showed the reaction was complete. The reaction was concentrated to dryness (under high vacuum). The residue was partitioned between EtOAc and saturated aqueous NaCl solution. The organic layer was washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a 15 g prepacked silica gel cartridge. When eluted with 0-5% EtOAc in DCM, tert-butyl 5-bromo-2,3-dihydropyrrolo [2,3-b] pyridine-1-carboxylate (B-12-2) is off-white in color. Obtained as a solid (725 mg).11 H NMR (400 MHz, chloroform-d) δ ppm 1.56 (s, 9 H) 3.05 (t, J = 8.59 Hz, 2 H) 4.03 (t, 2 H) 7.50 (d, J = 2.02 Hz, 1 H) 8.26 (d, J = 2.02 Hz, 1 H). Preparation of 1- (tert-Butyloxycarbonyl) -2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-ylboronic acid (B-12-3)<chemistry num="110"><img file="JP4792126B2_D0113.tif" /></chemistry> tert-butyl 5-bromo-2,3-dihydropyrrolo [2,3-b] pyridin-1-carboxylate (B-12-2) (725 mg, 2.42 mmol) and bis (pinacolato) diboron (894 mg, 3.52 mmol) ) In a mixture in 20 ml of DMF, potassium acetate (691 mg, 7.04 mmol) and [1,1-bis (diphenylphosphino) -ferrocene] dichloropalladium (II) dichloromethane (1: 1) complex (34.3 mg, 0.0469 mmol). ) Was added. The mixture was heated in a microwave reactor at 100 ° C for 60 minutes. LCMS showed that the reaction was complete. The reaction was filtered and the filtrate was concentrated under high vacuum until dry. The residue was partitioned between EtOAc and saturated aqueous NaCl solution. The aqueous layer was extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed in a 25 g silica gel cartridge with 1-4% MeOH in DCM as solvent. The crude product was used in the next step. (2S) -1- (4- (3- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-isopropyl-1H-pyrazole-4-yl) pyrimidine- Preparation of 2-ylamino) propane-2-ol (B-12)<chemistry num="111"><img file="JP4792126B2_D0114.tif" /></chemistry> 1- (tert-butoxycarbonyl) -2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-5-ylboronic acid (B-12-3) (546 mg, 2.07 mmol) and (2S) -1 -(4- (3-Iodo-1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2-ol (400 mg, 1.03 mmol) in a 10 mL solution of [1,1-bis ( Diphenylphosphino) -ferrocene] dichloropalladium (II) dichloromethane (1: 1) complex (22.7 mg, 0.031 mmol) and 2N aqueous sodium carbonate solution (1.55 mL, 3.10 mmol) were added. The mixture was swept with nitrogen for 5 minutes and then heated in microwaves at 100 ° C. for 1 hour. LCMS showed the reaction was complete. The reaction was filtered and the filtrate was concentrated under high vacuum to residue. The residue was partitioned between EtOAc and water. The organic layer was washed once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated to residue. The residue was then loaded onto a 25 g silica gel cartridge. Elution with 50% EtOAc in DCM first and then 2-5% MeOH in 1: 3 MTBE: DCM gave the Boc-protected product as a white solid. This was treated in DCM with 4N HCl in dioxane at room temperature under nitrogen overnight and then the solvent was removed to give a brownish residue. The residue was dissolved in DCM, washed with saturated sodium bicarbonate, dried over sodium sulfate, concentrated and then loaded onto a 15 g silica gel cartridge. When eluted with 2-5% MeOH in DCM, (2S) -1-(4-(3- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- Isopropyl-1H-pyrazole-4-yl) pyrimidin-2-ylamino) propan-2-ol (B-12) was obtained as white foam (125 mg).(Example B-33) 3-({4- [1- (2,2-difluoroethyl) -3- (1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidin-2- Preparation of yl} amino) propanenitrile Preparation of 4- (1- (2,2-difluoroethyl) -3-iodo-1H-pyrazole-4-yl) -2- (methylthio) pyrimidine (B-33-1)<chemistry num="112"><img file="JP4792126B2_D0115.tif" /></chemistry> Intermediate A (83 g, 0.26 mol) in DMF (600 mL) solution, K2CO3(58 g, 0.417 mol) and 1,1-difluoro-2-iodo-ethane (60 g, 0.313 mol) were added. The mixture was then stirred at room temperature overnight. TLC (CH)2Cl2: MeOH = 20: 1) indicated that the reaction was complete. Concentrate the mixture and CH the solid2Cl2Diluted with (500 mL). The slurry was filtered and the filtrate concentrated to give a crude product, which was purified via preparative SFC to give compound B-33-1 (41.1 g, 41.3%) as a white solid. It was. 4- (1- (2,2-difluoroethyl) -3-iodo-1H-pyrazole-4-yl) -2- (methylsulfonyl) pyrimidine and / or 4- (1- (2,2-difluoroethyl)) Preparation of -3-iodo-1H-pyrazol-4-yl) -2- (methylsulfinyl) pyrimidine<chemistry num="113"><img file="JP4792126B2_D0116.tif" /></chemistry> Compound B-33-1 (41.1 g, 0.107 mol) in THF (360 mL) solution with oxone (81.2 g, 0.132 mol) in H2O (200 mL) solution was added. The mixture was then stirred at room temperature overnight. TLC (CH)2Cl2: MeOH = 10: 1) indicated that the reaction was complete. The mixture was concentrated to about 1/2. CH the mixture2Cl2Extracted with (600 mL). The organic layer was washed with water (100 mL x 2), dried over Na2SO4 and concentrated to give a mixture of sulfone and sulfoxide (7: 3 as determined by HPLC) (38.6 g, 88.2%) as a yellow solid. It was. Preparation of 3- (4- (1- (2,2-difluoroethyl) -3-iodo-1H-pyrazol-4-yl) pyrimidine-2-ylamino) propanenitrile (B-33-3)<chemistry num="114"><img file="JP4792126B2_D0117.tif" /></chemistry> To a mixture of sulfone and sulfoxide (16 g, 0.039 mol) in THF (250 mL) was added 3-amino-propionitrile (16 g, 0.23 mol). The mixture was then stirred at 80 ° C for 2 days. TLC (CH)2Cl2: MeOH = 10: 1) showed that the reaction was not complete. The mixture was stirred at this temperature for an additional day. The mixture was concentrated to dryness. Silica gel chromatography (CH) of the residue2Cl2Purification with: MeOH = 80: 1) gave B-33-3 (9.8 g, 61.5%) as a white solid. 3-({4- [1- (2,2-difluoroethyl) -3- (1H-pyrrolo [2,3-b] pyridine-5-yl) -1H-pyrazol-4-yl] pyrimidin-2- Preparation of Il} Amino) Propionitrile (B-33)<chemistry num="115"><img file="JP4792126B2_D0118.tif" /></chemistry> 5- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-) prepared according to literature methods known from 5-bromo-1H-pyrrolo [2,3-b] pyridine Il) -1H-pyrolo [2,3-b] Pyridine B-33-4 (145 mg, 0.594 mmol), 3-({4- [1- (2,2-difluoroethyl) -3-iodo-1H- Pyrazole-4-yl] pyrimidin-2-yl} amino) A mixture of propanenitrile (200 mg, 0.495 mmol) and cesium fluoride (1.48 mL of 1 M aqueous solution) in 3 mL of DME was deoxidized with nitrogen bubbles for 5 minutes. Then, a 1: 1 complex (41 mg, 0.05 mmol) of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) with dichloromethane was added. The mixture was then heated in a microwave reactor at 80 ° C. for 2.5 hours. The reaction was degassed and a new catalyst (20 mg) was added. The mixture was heated in microwaves at 80 ° C. for an additional 4 hours. The resulting dark mixture was partitioned between ethyl acetate and brine. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulphate to reduce the amount to a minimum. Purification of the residue on silica gel using a gradient of 0-8% methanol (containing 10% ammonium hydroxide) in a mixture of tert-butyl methyl ether and dichloromethane (1: 1) yields the desired product. Obtained as a pale orange solid. When this substance is ground twice with tert-butyl methyl ether, it is analyzed to be pure 3-({4- [1- (2,2-difluoroethyl) -3- (1H-pyrolo [2,3-b]. ] Pyridine-5-yl) -1H-pyrazol-4-yl] Pyrimidine-2-yl} Amino) Propionitrile 82 mg (42%) was obtained as an off-white solid. 1H NMR (400 MHz, acetonitrile-d3) δ ppm 9.73 (br. S., 1 H), 8.37 (d, J = 2.02 Hz, 1 H), 8.22 (s, 1 H), 8.10 (d, J = 5.31 Hz, 1 H), 8.08 (d, J = 1.52 Hz, 1 H), 7.35 --7.46 (m, 1 H), 6.54 (d, J = 3.79 Hz, 1 H), 6.51 (dd, J = 3.54, 2.02 Hz, 1 H), 6.30 (tt, J = 55.04, 3.82) Hz, 1 H), 5.91 (br. T, J = 6.82 Hz, 1 H), 4.62 (td, J = 14.65, 3.79 Hz, 2 H), 3.39 (br. S., 2 H), 2.40 (br. S., 2 H).(Example B-49) 3- (4- (1- (1-Hydroxy-2-methylpropan-2-yl) -3- (5-methoxypyridin-3-yl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) Preparation of propanenitrile<chemistry num="116"><img file="JP4792126B2_D0119.tif" /></chemistry> Preparation of Methyl 2- (3-Iodo-4- (2- (Methylthio) Pyrimidine-4-yl) -1H-Pyrazole-1-yl) -2-Methylpropanoate (B-49-1)<chemistry num="117"><img file="JP4792126B2_D0120.tif" /></chemistry> A mixture of compound A (60 g, 0.19 mol) and methyl 2-bromo-2-methylpropanoate (102 g, 0.57 mol) in DMF (400 mL) was supplemented with freshly ground potassium carbonate (65 g, 0.47 mol). Added once. The reaction mixture was stirred at 80 ° C. for 18 hours. LC-MS showed that the reaction was complete. The reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (1200 mL) and brine (300 mL). The aqueous layer was extracted with EtOAc (2 x 500 mL). The combined organic layers are washed with brine and anhydrous Na2SO4It was dried on top and concentrated. Purification of the residue by silica gel chromatography using 5-30% EtOAc in petroleum ether as eluent gives compound B-49-1 (62 g, 78%) as a syrup, which solidifies when left to stand. did. Preparation of 2- (3-iodo-4- (2- (methylthio) pyrimidin-4-yl) -1H-pyrazol-1-yl) -2-methylpropan-1-ol (B-49-2)<chemistry num="118"><img file="JP4792126B2_D0121.tif" /></chemistry> Anhydrous CH of compound B-49-1 (48 g, 0.11 mol)2Cl2DIBAL solution (256 mL, 1 M) was added dropwise to the (1800 mL) solution at -78 ° C via a syringe. The mixture was stirred at -78 ° C to 0 ° C for 1 hour. The reaction mixture was quenched by adding MeOH (80 mL), then the mixture was saturated with aqueous Rochelle salt solution and CH.2Cl2Diluted with. The resulting suspension was vigorously stirred until the layers separated. The aqueous layer was extracted with dichloromethane (2 x 500 mL). The combined organic layers were dried over sodium sulfate and concentrated to 70 g of yellow oil. Purification of the oil by silica gel chromatography using 0-40% ether in DCM as an eluent gave compound B-49-2 (20 g, 45%) as a white solid. Preparation of 2- (3-iodo-4- (2- (methylsulfonyl) pyrimidin-4-yl) -1H-pyrazol-1-yl) -2-methylpropan-1-ol (B-49-3)<chemistry num="119"><img file="JP4792126B2_D0122.tif" /></chemistry> A mixture of compound B-49-3 (20 g, 51 mmol) and oxone (61.5 g, 0.10 mol) in THF (300 mL) and water (300 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc (2 L) and brine (600 mL). The aqueous layer was extracted with EtOAc (1 L × 2). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by short column chromatography using 0-50% ether / DCM as an eluent to give product B-49-3 (15 g, 74%) as a white solid. 3- (4- (1- (1-Hydroxy-2-methylpropan-2-yl) -3-iodo-1H-pyrazol-4-yl) pyrimidine-2-ylamino) propanenitrile (B-49-4) Preparation<chemistry num="120"><img file="JP4792126B2_D0123.tif" /></chemistry> In a microwave reactor, sulfone B-49-3 (6 g, 14.3 mmol, in 5 batches), 3-aminopropanenitrile (3.0 g, 42.9 mmol) and CsF (2.39 g, 15.7 mmol) in DMSO (60 mL). I charged it with. The resulting solution was exposed to microwave irradiation at 120 ° C for 30 minutes. The reaction mixture was cooled to room temperature. The mixture was partitioned between EtOAc (600 mL) and brine (100 mL x 3). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic phase is anhydrous Na2SO4It was dried on top, filtered and concentrated in vacuo. The residue was purified by short column chromatography using 0-50% EtOAc in petroleum ether as an eluent and further purified by preparative HPLC to produce product B-49-4 (3.055 g, 55%). Was obtained as a brown foamy solid. 3- (4- (1- (1-Hydroxy-2-methylpropan-2-yl) -3- (5-methoxypyridin-3-yl) -1H-pyrazol-4-yl) pyrimidin-2-ylamino) Preparation of propanenitrile (B-49)<chemistry num="121"><img file="JP4792126B2_D0124.tif" /></chemistry> A solution of iodide B-49-4 (156.2 mg, 0.374 mmol) and 5-methoxypyridin-3-boronic acid (122.1 mg, 0.798 mmol) dissolved in DME (3.7 mL) was removed by exhaust until the solvent began to boil. Gas was followed by argon purging (3 cycles). 1.5 mL of 2.0 M aqueous sodium carbonate solution and 25.5 mg (0.035 mmol) of [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex were added and degassed in 3 cycles. It was heated in an oil bath at 80 ° C for 3.5 hours and then cooled to room temperature overnight. The reaction mixture was partitioned between 25 mL of ethyl acetate and 10 mL of deionized water. The aqueous layer was back extracted with 15 mL of ethyl acetate. The combined organic extracts were dried over magnesium sulphate, filtered, concentrated and purified by silica gel chromatography eluting with 0-20% [ethanol + 5% concentrated ammonium hydroxide] in ethyl acetate. The product was lyophilized to give B-49 (128.4 mg, 84%) as a pale pink solid. 3- (4- (3- (5-Acetyl-6-aminopyridine-3-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propanenitrile Preparation of (B-78)<chemistry num="122"><img file="JP4792126B2_D0125.tif" /></chemistry> Preparation of 5-bromo-3- (prop-1-en-2-yl) pyridin-2-amine (B-78-2)<chemistry num="123"><img file="JP4792126B2_D0126.tif" /></chemistry> 2-Amino-5-bromo-3-iodopyridine B-78-1 (4.75 g, 15.9 mmol), isopropenylboronic acid pinacol ester (3.28 mL, 2.94 g, 17.5 mmol) and [1,1'-bis (1,1'-bis). A solution of diphenylphosphino) ferrocene] -palladium (II) dichloride dichloromethane complex (1: 1) (295 mg, 0.403 mmol) in dimethylformamide (48 mL) was treated with 24 mL of 2.0 M aqueous sodium carbonate solution. The resulting two-phase mixture was stirred under argon in an oil bath at 65 ° C. for 6 hours. After cooling to room temperature, the mixture was diluted with 200 mL of ethyl acetate and 75 mL of deionized water and then suction filtered to remove some insoluble black precipitate. After separation, the aqueous layer was back extracted with 100 mL of ethyl acetate. The combined organic extracts were dried over magnesium sulphate, filtered and concentrated to 5.87 g of brown oil. The crude product was purified by silica gel chromatography (eluting with a gradient of 10-50% ethyl acetate in hexanes) to give B-78-2 (2.5501 g, 75.3%) as a yellowish brown solid. Preparation of B-78-3<chemistry num="124"><img file="JP4792126B2_D0127.tif" /></chemistry> Compound B-78-2 (2.50 g, 11.7 mmol), di-tert-butyl dicarbonate (7.75 g, 35.5 mmol), triethylamine (8.3 mL, 60 mmol) and 4- (dimethylamino) pyridine (391 mg, 3.1 mmol) The acetonitrile (59 mL) solution of the above was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was then partitioned between 100 mL of ethyl acetate and 25 mL of saturated aqueous sodium bicarbonate solution. The aqueous layer was back-extracted with 30 mL of ethyl acetate and the combined organic extracts were dried over magnesium sulphate, filtered and concentrated to give 5.38 g of an orange gel. The crude product was purified by silica gel chromatography (eluting with a gradient of 0-40% ethyl acetate in hexanes) to give compound B-78-3 (4.22 g, 87%) as a colorless oil. Preparation of B-78-4<chemistry num="125"><img file="JP4792126B2_D0128.tif" /></chemistry> A solution of B-78-3 (4.15 g, 10.0 mmol) and triisopropyl borate (5.8 mL, 4.8 g, 25 mmol) in 2-methyltetrahydrofuran (67 mL) was cooled to -70 ° C (internal temperature). To this, 16 mL (25.6 mmol) of a 1.6 M n-butyllithium solution in hexane was added dropwise over 4 minutes. After stirring at -70 ° C for 30 minutes, 25 mL of deionized water was added and the mixture was warmed to room temperature. The volatiles were removed in vacuo and the aqueous residue was extracted with diethyl ether (2 x 30 mL). These extracts were discarded. The aqueous layer was acidified to pH 2 with 6N HCl and stirred overnight at room temperature to form a granular white precipitate. The precipitate was collected by suction filtration and dried in a vacuum oven at 50 ° C. for 6 hours to give boronic acid B-78-4 (2.9348 g, 62.2%) as a white powder. 3- (4- (3- (6-Amino-5- (prop-1-en-2-yl) pyridine-3-yl) -1- (2,2-difluoroethyl) -1H-pyrazole-4- Preparation of yl) pyrimidin-2-ylamino) propanenitrile (B-78-5)<chemistry num="126"><img file="JP4792126B2_D0129.tif" /></chemistry> Boronic acid B-78-4 (721.4 mg, 1.88 mmol), iodide B-33-3 (576.0 mg, 1.425 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride-dichloromethane A solution of the complex (66.5 mg, 0.091 mmol) in DME (14.2 mL) was treated with 2.0 M aqueous sodium carbonate solution (2.4 mL) and the resulting two-phase mixture was heated in an oil bath at 80 ° C. for 15 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate (50 mL) and deionized water (25 mL). The aqueous layer was back extracted with 25 mL of ethyl acetate. The combined organic extracts were dried over magnesium sulphate, filtered and concentrated to dryness. The residue was dissolved in dichloromethane (27 mL), trifluoroacetic acid (3 mL) was added and the mixture was stirred at room temperature for 6.5 hours. The solvent was then evaporated and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic layer was dried over magnesium sulphate, filtered and concentrated to brown tar. When the crude product is purified by silica gel chromatography, eluting with 0 to 20% [ethanol + 5% concentrated ammonium hydroxide] in ethyl acetate, B-78-5 (325.7 mg, 56%) is light brown. Obtained as foam. 3- (4- (3- (5-Acetyl-6-aminopyridine-3-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) pyrimidine-2-ylamino) propanenitrile Preparation of (B-78)<chemistry num="127"><img file="JP4792126B2_D0130.tif" /></chemistry> A solution of alkene 6 (227.8 mg, 0.555 mmol) in dichloromethane (28 mL) was cooled to -70 ° C and treated with ozone for 30 seconds, sufficient time for the solution to change color from brown to bright yellow. The solution was purged with nitrogen for 2 minutes and then quenched with dimethyl sulfide (0.50 ml, 6.8 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 3 hours. The solution was concentrated to dryness and purified by silica gel chromatography, eluting with 0-20% [EtOH + 5% NH4OH] in ethyl acetate. Ketone B-78 (63.4 mg, 28%) was obtained as a yellow solid. 1H NMR 1H NMR (400 MHz, chloroform-d) δ ppm 2.57 (s, 3 H) 2.60 --2.71 (m, 2 H) 3.56 --3.74 (m, 2 H) 4.55 (td, J = 13.45, 4.17 Hz, 2 H) 5.54 (t, J = 5.05 Hz, 1 H) 6.21 (tt, J = 55.29, 4.20 Hz, 1 H) 6.61 (d, J = 5.31 Hz, 1 H) 8.03 (s, 1 H) 8.21 (d, 1 H) J = 5.05 Hz, 1 H) 8.23 (d, J = 2.02 Hz, 1 H) 8.45 (d, J = 2.27 Hz, 1 H).(Example B-79) 3- {4- [3- (5-Amino-6-methoxy-pyrazin-2-yl) -1- (2,2-difluoro-ethyl) -1H-pyrazol-4-yl] -pyrimidine-2-ylamino }-Preparation of propionitrile<chemistry num="128"><img file="JP4792126B2_D0131.tif" /></chemistry> Preparation of B-79-2:<chemistry num="129"><img file="JP4792126B2_D0132.tif" /></chemistry> Di-tert-butyl dicarbonate (10.4 g, 10.4 g, di-tert-butyl dicarbonate (10.4 g,) in a solution of 5-bromo-3-methoxypyrazines-2-amine (4.50 g, 19.8 mmol) and 4- (dimethylamino) pyridine (1.24 g, 10.1 mmol) in 70 ml of THF. 47.6 mmol) was added and the reaction mixture was stirred at room temperature for 5.5 hours. The solvent was removed under reduced pressure and the residue was run on a silica gel flash column eluting with 3: 1 hexane / EtOAc to give B-79-2 as a white solid (5.403 g, 67%). Di-tert-butyl [3-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazine-2-yl] imide dicarbonate (B-79- 3) Preparation:<chemistry num="130"><img file="JP4792126B2_D0133.tif" /></chemistry> Bis (Pinacolato) diboron (1.12 g, 4.4 mmol), di-tert-butyl (5-bromo-3-methoxypyrazin-2-yl) imide dicarbonate B-79-2 (1.62 g, 4 mmol) and potassium acetate (1.62 g, 4 mmol) The mixture in 1.2 g, 12 mmol) of toluene (40 mL) was deoxidized with a nitrogen bubbler for a few minutes, after which the 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichromethane complex (78 mg, 0.096 mmol) was added. The mixture was then heated in an oil bath at 50 ° C. for 4 days. LCMS showed that the reaction was complete. The mixture was filtered to reduce the filtrate to a minimum amount. Residue B-79-3 was carried over to the next step without purification, assuming quantification. 3- {4- [3- (5-Amino-6-methoxy-pyrazin-2-yl) -1- (2,2-difluoro-ethyl) -1H-pyrazol-4-yl] -pyrimidine-2-ylamino }-Preparation of propionitrile (B-79)<chemistry num="131"><img file="JP4792126B2_D0134.tif" /></chemistry> Crude di-tert-butyl [3-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazine-2-yl] imide dicarbonate B-79 In a solution of -3 (0.6 mmol) in dimethoxyethane (2.5 mL), 3-{4- [1- (2,2-difluoro-ethyl) -3-iodo-1H-pyrazol-4-yl] -pyrimidine-2 -Ilamino} -propionitrile B-33-3 (150 mg, 0.37 mmol) and cesium fluoride (1 M aqueous solution 1.1 mL, 1.1 mmol) were added. The resulting mixture was deoxidized with a nitrogen bubbler for 5 minutes, then 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (15 mg, 0.019 mmol) was added. The mixture was then heated in an oil bath at 80 ° C. for 20 hours. LCMS showed that iodide was completely consumed. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate to reduce the amount to a minimum. The residue was placed in dimethoxyethane (3 mL) and then heated in microwaves at 170 ° C. for 25 minutes to thermally decompose the tert-butoxycarbonyl group. The resulting dark mixture was filtered through a 0.45 μ filter to reduce the amount of filtrate to a minimum. The residue was purified by HPLC to give B-79 59 mg (37%) as a fluffy white solid after lyophilization of the desired fraction. 1H NMR (400 MHz, acetonitrile-d3) δ ppm 8.17 (s, 1 H), 8.15 (d, J = 5.05 Hz, 1 H), 7.83 (s, 1 H), 6.72 (d, J = 5.31 Hz, 1 H), 6.27 (tt, J = 54.98, 3.76 Hz, 1 H), 5.91 (br.t, J = 5.18 Hz, 1 H), 5.34 (br. S., 2 H), 4.59 (td, J = 14.65, 3.79 Hz, 2 H), 3.76 (s, 3 H), 3.55 (q, J = 6.23 Hz, 2 H), 2.64 (t, J = 6.44 Hz, 2 H)(Example C-1) [4- [2-((S) -2-Hydroxy-propylamino) -pyrimidine-4-yl] -3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -pyrazole-1- Il]-Preparation of acetonitrile 5- [4- (2-Methylsulfanyl-pyrimidine-4-yl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -1H-pyrrolo [2,3-b] pyridine Preparation of (C-1-1)<chemistry num="132"><img file="JP4792126B2_D0135.tif" /></chemistry> 4- [3-Iodo-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-4-yl] -2-methylsulfanyl-pyrimidine B (1.33 g, 3.3 mmol) and 5- (4,4, 5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrolo [2,3-b] pyridine (1 g, 4.1 mmol) in DMF (30 mL) solution in 2M sodium carbonate The solution (2 mL) was added. Upon addition, sodium carbonate appeared to come out of the solution. The mixture was deoxidized with a nitrogen bubbler for a few minutes. Palladium catalyst was added and nitrogen bubble introduction was continued for several minutes, after which the bubbler was removed. The mixture was heated at 85 ° C for 18 hours. LCMS shows the complete conversion to the product. The mixture was added dropwise to saturated aqueous NaCl solution, the resulting solid was collected by filtration and rinsed with water. Dissolve the solid in methanol / dichloromethane (1: 9) and deli4It was dried on top and reduced to a minimum amount. Purification of the residue on a short column of silica gel using a gradient of 0-50% ethyl acetate in dichloromethane as an eluent 5- [4- (2-methylsulfanyl-pyrimidine-4-yl) -1- ( Tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -1H-pyrrolo [2,3-b] Pyridine (C-1-1) (0.89 g, 69%) was obtained as a yellow solid. It was.11 H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (br. S., 1 H), 8.69 (s, 1 H), 8.43 (d, J = 5.31 Hz, 1 H), 8.29 (d, J = 2.02 Hz, 1 H), 8.07 (d, J = 2.02 Hz, 1 H), 7.51 (t, J = 3.03 Hz, 1 H), 7.11 (d, J = 5.31 Hz, 1 H), 6.48 (dd, J = 3.28, 1.77 Hz, 1 H), 5.53 (dd, J = 9.85, 2.27 Hz, 1 H), 4.00 (br. D, J = 13.39 Hz, 1 H), 3.61 --3.76 (br. M, 1 H), 2.10- 2.24 (br. M, 4 H), 1.91 --2.06 (br. M, 2 H), 1.65 --1.80 (br. M, 1 H), 1.50- 1.63 (br. M, 2 H). 1-Benzenesulfonyl-5- [4- (2-methylsulfanyl-pyrimidine-4-yl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -1H-pyrrolo [2, 3-b] Preparation of pyridine (C-1-2)<chemistry num="133"><img file="JP4792126B2_D0136.tif" /></chemistry> 5- [4- (2-Methylsulfanyl-pyrimidine-4-yl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -1H-pyrrolo [2,3-b] pyridine Sodium hydride (60% dispersion in oil, 133 mg, 3.32 mmol) was added to a solution of (C-1-1) (870 mg, 2.22 mmol) in DMF (10 mL) at 25 ° C. The resulting suspension was stirred at ambient temperature for several minutes until gas generation stopped. Addition of benzenesulfonyl chloride (0.4 mL, 3.13 mmol) made the mixture cloudy. After stirring at ambient temperature for 15 minutes, LCMS showed complete conversion to the desired product. The mixture was added slowly to 150 ml of saturated aqueous NaCl solution. The resulting precipitate was filtered, washed with water and air dried. Dissolve the solid in dichloromethane and EDTA4It was dried on top and reduced to a minimum amount. Purification of the residue on a short column of silica gel using a gradient of 0-20% ethyl acetate in dichloromethane as an eluent 1-benzenesulfonyl-5- [4- (2-methylsulfanyl-pyrimidine-4-yl) )-1- (Tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -1H-pyrrolo [2,3-b] Pyridine (C-1-2) (0.83g, 70%) is yellow Obtained as foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.77 (s, 1 H), 8.47 (d, J = 5.31 Hz, 1 H), 8.43 (d, J = 2.02 Hz, 1 H), 8.16 (d, J = 2.02 Hz, 1 H), 8.09 --8.15 (m, 2 H), 7.95 (d, J = 4.04 Hz, 1 H), 7.68 --7.77 (m, 1 H), 7.57 --7.67 (m, 2 H), 7.29 (d, J = 5.05 Hz, 1 H), 6.86 (d, J = 4.04 Hz, 1 H), 5.52 (dd, J = 9.85, 2.27 Hz, 1 H), 3.98 (br. D, J = 11.87 Hz, 1 H), 3.62 --3.74 (m, 1 H), 2.07 --2.23 (br. M, 1 H), 1.90 --2.05 (br. M, 2 H), 1.66 --- 1.77 (br. m, 1 H), 1.65 (s, 3 H), 1.50 --1.61 (br. M, 2 H). 5- {4- [2- (Methylthio) pyrimidin-4-yl] -1H-pyrazole-3-yl} -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (C-1-) 3) Preparation<chemistry num="134"><img file="JP4792126B2_D0137.tif" /></chemistry> 1-Benzenesulfonyl-5- [4- (2-methylsulfanyl-pyrimidine-4-yl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -1H-pyrrolo [2, 3-b] A dioxane solution of HCl (approximately 4N, 0.1 mL) was added to a solution of pyridine (C-1-2) (750 mg, 1.41 mmol) in MeOH (1 mL). After stirring at ambient temperature for 45 minutes, the solution was added dropwise to phosphate buffer (pH 7, 15 mL). The resulting precipitate is collected by filtration, rinsed with water and air dried to give 5- {4- [2- (methylthio) pyrimidin-4-yl] -1H-pyrazol-3-yl} -1- (phenylsulfonyl). ) -1H-pyrrolo [2,3-b] pyridine (C-1-3) (622 mg, 98%) was obtained, which was carried over without further purification.11 H NMR (400 MHz, acetonitrile-d3) δ ppm 11.51 (br. S., 1 H), 8.47 (d, J = 2.02 Hz, 1 H), 8.34 (d, J = 5.05 Hz, 1 H), 8.23 (br. S., 1 H), 8.14 (d, J = 7.58 Hz, 2 H), 8.10 (d, J = 1.77 Hz, 1 H), 7.84 (d, J = 2.78 Hz, 1 H), 7.68 (t, J = 7.45 Hz, 1 H), 7.57 (t, J = 7.71 Hz, 2 H), 7.07 (d, J = 4.80 Hz, 1 H), 6.75 (d, J = 3.79 Hz, 1 H), 1.81 (s, 3 H). [3- (1-Benzenesulfonyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -4- (2-methylsulfanyl-pyrimidine-4-yl) -pyrazole-1-yl] -acetonitrile ( Preparation of C-1-4)<chemistry num="135"><img file="JP4792126B2_D0138.tif" /></chemistry> 5- {4- [2- (Methylthio) pyrimidin-4-yl] -1H-pyrazole-3-yl} -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (C-1-) 3) Freshly ground potassium carbonate (254 mg, 1.84 mmol) was added to a DMF solution of (638 mg, 1.42 mmol) and bromoacetonitrile (0.5 mL, 7 mmol). The resulting suspension was stirred at 75 ° C for 18 hours. LCMS showed complete consumption of starting material. The mixture was partitioned between ethyl acetate and saturated aqueous NaCl solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with water with saturated aqueous NaCl solution and deli4It was dried on top and reduced to a minimum amount. Purification of the residue on silica gel using a gradient of 25 to 100% methyl tert-butyl in hexanes as an eluent [3- (1-benzenesulfonyl-1H-pyrrolo [2,3-b] pyridine-5). -Il) -4- (2-methylsulfanyl-pyrimidine-4-yl) -pyrazole-1-yl] -acetoethane (C-1-4) (440 mg, 63%) was obtained as a crispy foam.11 H NMR (400 MHz, acetonitrile-d3) δ ppm 8.46 (d, J = 2.02 Hz, 1 H), 8.36 (d, J = 5.31 Hz, 1 H), 8.31 (s, 1 H), 8.11 --8.16 (m, 2 H), 8.09 (d, J = 2.02 Hz, 1 H), 7.83 (d, J = 4.04 Hz, 1 H), 7.64 --7.71 (m, 1 H), 7.57 (t, J = 7.71 Hz, 2 H), 7.01 (d, J = 5.31 Hz, 1 H), 6.75 (d, J = 4.04 Hz, 1 H), 5.26 (s, 2 H), 1.88 (s, 3 H). [3- (1-Benzenesulfonyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -4- (2-methanesulfonyl-pyrimidine-4-yl) -pyrazole-1-yl] -acetonitrile ( Preparation of C-1-5)<chemistry num="136"><img file="JP4792126B2_D0139.tif" /></chemistry> [3- (1-Benzenesulfonyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -4- (2-methylsulfanyl-pyrimidine-4-yl) -pyrazole-1-yl] -acetonitrile (C -1-4) (175 mg, 0.36 mmol) THF (2 mL) and H2The solution in O (2 mL) was cooled to 0 ° C. and oxone (330 mg, 0.54 mmol, 1.5 eq) was added in one dose. The resulting yellow slurry was stirred at 0 ° C. for 10 minutes and then at ambient temperature overnight. The resulting mixture was filtered and the solid was rinsed with ethyl acetate and water. The filtrate was partitioned between ethyl acetate and water. The aqueous layer is extracted with ethyl acetate, and the combined organic layer is EDTA.4It was dried on top and reduced to a minimum amount. The residue was ground with methyl tert-butyl ether and the solid was collected by filtration to give [3- (1-benzenesulfonyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -4- (2-methane). Sulfonyl-pyrimidine-4-yl) -pyrazole-1-yl] -acetonitrile (C-1-5) (158 mg, 85%) was obtained, which was carried over without further purification.11 H NMR (400 MHz, acetonitrile-d3) δ ppm 8.74 (d, J = 5.56 Hz, 1 H), 8.53 (d, J = 2.02 Hz, 1 H), 8.45 (s, 1 H), 8.18 (d, J = 2.27 Hz, 1 H), 8.12- 8.17 (m, 2 H), 7.84 (d, J = 4.04 Hz, 1 H), 7.63 --7.73 (m, 1 H), 7.55 --7.62 (m, 2 H), 7.53 (d, J = 5.31 Hz, 1 H), 6.75 (d, J = 4.04 Hz, 1 H), 5.29 (s, 2 H), 2.78 (s, 3 H). {3- (1-Benzenesulfonyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -4- [2-((S) -2-hydroxy-propylamino) -pyrimidine-4-yl] -Preparation of pyrazole-1-yl} -acetonitrile (C-1-6)<chemistry num="137"><img file="JP4792126B2_D0140.tif" /></chemistry> [3- (1-Benzenesulfonyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -4- (2-methanesulfonyl-pyrimidine-4-yl) -pyrazole-1-yl] -acetohydrate ( A mixture of C-1-5) (310 mg, 0.6 mmol) and (S)-(+)-1-amino-2-propanol (134 mg, 1.8 mmol) in THF (5 mL) is heated at 80 ° C for 18 hours. did. The mixture is concentrated on silica gel and then purified on silica gel using a methanol gradient of 0-6% in a mixture of dichloromethane and ethyl acetate (1: 1) as an eluent to create {3- (1-benzenesulfonyl). -1H-pyrrolo [2,3-b] pyridine-5-yl) -4- [2-((S) -2-hydroxy-propylamino) -pyrimidine-4-yl] -pyrazole-1-yl}- 220 mg (72%) of acetonitrile (C-1-6) was obtained as foam from methyl tert-butyl ether.11 H NMR (400 MHz, acetonitrile-d3) δ ppm 8.52 (d, J = 2.02 Hz, 1 H), 8.20 (s, 1 H), 8.07 --8.17 (m, 4 H), 7.81 (d, J = 4.04 Hz, 1 H), 7.63 --7.73 (m, 1 H), 7.52 --7.60 (m, 2 H), 6.75 (d, J = 4.04 Hz, 1 H), 6.53 (br. S., 1 H), 5.67 (br. T, J = 4.93 Hz, 1 H), 5.24 (s, 2 H), 3.56 (br. S., 1 H), 2.64 --3.28 (br. M, 3 H), 0.74 (br. S., 3 H). [4- [2-((S) -2-Hydroxy-propylamino) -pyrimidine-4-yl] -3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -pyrazole-1- Il] -Preparation of acetonitrile (C-1)<chemistry num="138"><img file="JP4792126B2_D0141.tif" /></chemistry> {3- (1-Benzenesulfonyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -4- [2-((S) -2-hydroxy-propylamino) -pyrimidine-4-yl] -Pyrazole-1-yl} -A solution of acetonitrile (C-1-6) (145 mg, 0.28 mmol) in THF (5 mL) at -40 ° C, sodium hydroxide (10 mg / mL solution in MeOH 1.1 mL, 0.28) mmol) was added. The mixture was gradually warmed to 0 ° C. After 2 hours, the mixture was diluted with 10 mL of THF and stirring was continued at 0 ° C for 2 hours. The mixture was partitioned between pH 7 phosphate buffer and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers are washed with saturated aqueous NaCl solution and deli4It was dried on top and reduced to a minimum amount. When the residue was purified by HPLC, [4- [2-((S) -2-hydroxy-propylamino) -pyrimidine-4-yl] -3- (1H-pyrrolo [2,3-b] pyridine-5- Ill) -pyrazole-1-yl] -acetonitrile (C-1) was obtained in a yield of 23%.11 H NMR (400 MHz, acetonitrile-d3) δ ppm 9.78 (br. S., 1H), 8.42 (d, J = 2.02 Hz, 1 H), 8.22 (s, 1 H), 8.05-8.14 (m, 2 H), 7.38 --7.75 (m, 1 H), 6.42 --6.56 (m, 2 H), 5.74 (br. S., 1 H), 5.25 (s, 2 H), 3.72 (br. S., 1 H), 3.19 (br. S., 1 H), 3.04 (br. S., 1 H), 0.95 (br. S., 3 H).(Example D-1) (2S) -1- (4- (1-isopropyl-3- (1H-pyrazolo [3,4-b] pyridin-5-yl) -1H-pyrazole-4-yl) pyrimidine-2-ylamino) propane- 2-Ol preparation<chemistry num="139"><img file="JP4792126B2_D0142.tif" /></chemistry> Preparation of 5-bromo-2-fluoronicotinaldehyde (D-1-2)<chemistry num="140"><img file="JP4792126B2_D0143.tif" /></chemistry> 2.5 M n-BuLi (68 mL, 0.17 mol) in hexane in anhydrous THF (200 mL) solution of diisopropylamine (17 mL, 0.17 mol) at 0 ° C.2Dropped in the atmosphere. After the addition, the resulting mixture was cooled to -65 ° C. Then, a solution of 5-bromo-2-fluoropyridine (25 g, 0.14 mol) in anhydrous THF (100 mL) was added dropwise. The resulting mixture was stirred at -65 ° C for 90 minutes. Ethyl formate (15.6 g, 0.21 mol) was then added dropwise to the mixture. After stirring for 10 minutes, the reaction mixture was quenched with 10% citric acid solution in THF (100 mL) at -65 ° C. The resulting mixture was warmed to room temperature, poured into water (100 mL) and extracted with EtOAc (200 mL). The organic layer is separated, washed with saturated aqueous NaCl solution (100 mL x 2), and Na.2SO4Drying on top and vacuum concentration gave compound D-1-2 (25 g, 85%) as a yellow solid. Preparation of 5-Bromo-1H-Pyrazolo [3,4-b] Pyridine (D-1-3)<chemistry num="141"><img file="JP4792126B2_D0144.tif" /></chemistry> An ethanol solution of compound D-1-2 (20 g, 0.1 mol) and anhydrous hydrazine (18 g, 0.56 mol) was refluxed and heated overnight. TLC (petroleum ether / EtOAc 2: 1) showed complete consumption of starting material. The reaction mixture was concentrated in vacuo to a volume of about 50 mL, poured into water (500 mL) and the resulting mixture filtered. The cake was washed with water (50 mL x 3) and ether (20 mL x 3) and then vacuum dried to give compound D-1-3 (9.0 g, 46%) as a yellow solid. Preparation of 1- (4-methoxybenzyl) -5-bromo-1H-pyrazolo [3,4-b] pyridine (D-1-4)<chemistry num="142"><img file="JP4792126B2_D0145.tif" /></chemistry> To a solution of compound D-1-3 (3.47 g, 17.5 mmol) in anhydrous DMF (50 mL) was added NaH (77 mg, 19.25 mmol) in small portions at 0 ° C. After the addition, the resulting mixture was stirred at 0 ° C for 30 minutes. PMBCl (3.29 g, 21 mmol) was then added dropwise at 0 ° C. The resulting mixture was stirred at room temperature overnight. TLC (petroleum ether / EtOAc 1: 1) showed complete consumption of starting material. H the reaction mixture2It was poured into O (100 mL) and extracted with EtOAc (100 mL × 3). Combined organic layer H2Wash with O (100 mL x 2) and saturated aqueous NaCl solution (100 mL) and Na2SO4It was dried on top and concentrated in vacuo. Purification of the crude product by column chromatography (silica gel, petroleum ether / EtOAc, 50: 1 to 4: 1) reveals that pure compound D-1-4 (4.3 g, yield: 77.2%) is yellow. Obtained as a solid. 1- (4-Methoxybenzyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazolo [3,4-b] pyridine (D- Preparation of 1-5)<chemistry num="143"><img file="JP4792126B2_D0146.tif" /></chemistry> 4,4,5,5,4', 4', 5', 5'-octamethyl- [2] in anhydrous DMF (80 mL) solution of compound D-1-4 (4.3 g, 13.5 mmol) being stirred. , 2'] bi [[1,3,2] dioxaborolanyl] (6.9 g, 27 mmol), KOAc (3.9 g, 40.5 mmol) and Pd (PPh)3)2Cl2(0.43g, 0.5 mmol) N2Added to the atmosphere. The resulting mixture was heated at 80-90 ° C overnight. TLC (petroleum ether / EtOAc 4: 1) showed complete consumption of compound 39. H the reaction mixture2It was poured into O (300 mL) and extracted with EtOAc (300 mL × 3). Combined organic layer H2Wash with O (300 mL x 2) and saturated aqueous NaCl solution (300 mL) and Na2SO4Drying above and vacuum concentrating gave crude D-1-5 (8 g, yield: 100%) as a black oil, which was used as is for the next step without any purification. 1- (4-methoxybenzyl) -5- (1-isopropyl-4-(2- (methylthio) pyrimidin-4-yl) -1H-pyrazole-3-yl) -1H-pyrazolo [3,4-b] Preparation of pyridine (D-1-6)<chemistry num="144"><img file="JP4792126B2_D0147.tif" /></chemistry> A crude mixture of compound D-1-5 (8 g, 13.5 mmol), 2N in a solution of compound B-1-1 (1.8 g, 5 mmol) in toluene (60 mL) and EtOH (20 mL) being stirred. Na2CO3Aqueous solution (7.5 mL) and Pd (PPh)3)4(0.18 g, 0.11 mmol) N2Added to the atmosphere. The resulting mixture was reflux heated overnight. TLC (petroleum ether / EtOAc 2: 1) showed complete consumption of compound 7. H the reaction mixture2Wash with O (50 mL) and saturated aqueous NaCl solution (100 mL) and Na2SO4It was dried on top and concentrated in vacuo. Purification of the residue via column chromatography (silica gel, petroleum ether / EtOAc 2: 1) yields crude compound D-1-6, which is purified via preparative HPLC to pure compound D-. 1-6 (560 mg, yield: 23.8%) was obtained as yellow oil. 1- (4-Methoxybenzyl) -5- (1-isopropyl-4-(2- (methylsulfonyl) pyrimidin-4-yl) -1H-pyrazole-3-yl) -1H-pyrazolo [3,4-b ] Preparation of pyridine (D-1-7)<chemistry num="145"><img file="JP4792126B2_D0148.tif" /></chemistry> THF (10 mL) and H of compounds D-1-6 (560 mg, 1.19 mmol) and oxone (1.1 g, 1.79 mmol)2The mixture in O (10 mL) was stirred at room temperature for 2 hours. TLC (petroleum ether / EtOAc 2: 1) showed complete consumption of starting material. The reaction mixture was concentrated in vacuo. H2O (30 mL) was added to the residue and the mixture was extracted with EtOAc (50 mL x 3). Wash the combined organic layers with saturated aqueous NaCl solution (50 mL) and Na2SO4Drying on top and vacuum concentration gave compound D-1-7 (600 mg, yield: 100%) as a red oil. (2S) -1- (4- (3- (1- (4-methoxybenzyl) -1H-pyrazolo [3,4-b] pyridin-5-yl) -1-isopropyl-1H-pyrazole-4-yl) ) Preparation of pyrimidine-2-ylamino) propan-2-ol (D-1-8)<chemistry num="146"><img file="JP4792126B2_D0149.tif" /></chemistry> A mixture of compounds D-1-7 (600 mg, 1.2 mmol) and (S) -1-aminopropan-2-ol (528 mg, 7.15 mmol) in THF (30 mL) was reflux heated for 2 days. TLC (CH)2Cl2/ MeOH 15: 1) showed complete consumption of starting material. The mixture was vacuum concentrated and the residue was purified via column chromatography (silica gel, EtOAc) to give compound D-1-8 (460 mg, yield: 77.4%) as a yellowish oil. (2S) -1- (4- (1-Isopropyl-3- (1H-pyrazolo [3,4-b] pyridin-5-yl) -1H-pyrazole-4-yl) pyrimidine-2-ylamino) propane- Preparation of 2-ol (D-1)<chemistry num="147"><img file="JP4792126B2_D0150.tif" /></chemistry> A solution of compound D-1-8 (460 mg, 0.92 mmol) in TFA (20 mL) was stirred at room temperature for 3 days. TLC (CH)2Cl2/ MeOH 15: 1) showed that almost half of compound D-1-8 was consumed. The reaction mixture was concentrated in vacuo. Saturated LVDS3The residue was basicized to pH about 8 with (10 mL) and extracted with EtOAc (50 mL x 3). Wash the combined organic layers with saturated aqueous NaCl solution (100 mL) and Na2SO4It was dried on top and concentrated in vacuo. Purification of the residue via preparative HPLC gave D-1 (130 mg, yield: 21.5%) as a yellow solid.(Example D-2) (2S) -1- (4- (1-Isopropyl-3- (3-methyl-1H-pyrazolo [3,4-b] pyridin-5-yl) -1H-pyrazole-4-yl) pyrimidin-2- Preparation of Ilamino) Propane-2-ol<chemistry num="148"><img file="JP4792126B2_D0151.tif" /></chemistry> Preparation of 5-bromo-2-chloro-N-methoxy-N-methylnicotinamide (D-2-2)<chemistry num="149"><img file="JP4792126B2_D0152.tif" /></chemistry> Anhydrous CH of compound D-2-1 (23.5 g, 0.1 mol)2Cl2Add CDI (19.5 g, 0.12 mol) to a (400 mL) solution at room temperature.2It was added little by little under the atmosphere. After the addition, the mixture was stirred for 1 hour. Then, O, N-dimethyl-hydroxylamine (11.5 g, 0.12 mol) was added little by little at room temperature. After the addition, the resulting mixture was stirred at room temperature overnight. TLC (petroleum ether / EtOAc 8: 1) showed complete consumption of starting material. H2Add O (200 mL), separate the organic layer, 1N HCl (100 mL), 1N Na2CO3Wash continuously with (100 mL) and saturated aqueous NaCl solution (200 mL) and Na2SO4Drying on top and vacuum concentration gave compound D-2-2 (25 g, 90%) as a yellow solid. Preparation of 5-bromo-2-chloronicotine aldehyde (D-2-3)<chemistry num="150"><img file="JP4792126B2_D0153.tif" /></chemistry> LiAlH in anhydrous THF (200 mL) solution of agitated compound D-2-2 (25 g, 89.4 mmol)4(1.7g, 27 mmol) N at -10 ° C2Added to the atmosphere. After the addition, the reaction mixture was warmed to room temperature and stirred overnight. TLC (petroleum ether / EtOAc 5: 1) showed complete consumption of starting material. 1N KHSO in the reaction mixture4(200 mL) was added and extracted with EtOAc (300 mL x 3). Wash the combined organic layers with saturated aqueous NaCl solution (200 mL) and Na2SO4Drying on top and vacuum concentration gives crude compound D-2-3, which is purified by column chromatography (silica gel, petroleum ether / EtOAc 30: 1) to pure compound D-2-3. (8.0 g, 45%) was obtained as a white solid. Preparation of 1- (5-Bromo-2-chloropyridin-3-yl) ethanol (D-2-4)<chemistry num="151"><img file="JP4792126B2_D0154.tif" /></chemistry> 3M CH in THF in anhydrous THF (100 mL) solution of agitated compound D-2-3 (8.0 g, 36.3 mmol)3MgBr solution (18.14 mL, 54.4 mmol) N at -78 ° C2Dropped in the atmosphere. After the addition, the resulting mixture was warmed to room temperature and stirred overnight. TLC (petroleum ether / EtOAc 8: 1) showed that most of the compound D-2-3 was consumed. H2O (200 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (100 mL × 3). Wash the combined organic layers with saturated aqueous NaCl solution (200 mL) and Na2SO4Drying on top and vacuum concentration gives crude compound D-2-4, which is purified by column chromatography (silica gel, petroleum ether / EtOAc 50: 1) to pure compound D-2-4. (6.3 g, 73.6%) was obtained as yellow oil. Preparation of 1- (5-Bromo-2-chloropyridin-3-yl) etanone (D-2-5)<chemistry num="152"><img file="JP4792126B2_D0155.tif" /></chemistry> CH of pyridine (13 g, 0.165 mol) being agitated2Cl2CrO in (200 mL) solution3(8.25 g, 0.083 mol) and silica gel (20 mL) were added in small portions at 0 ° C. After the addition, the reaction mixture was stirred for 10 minutes. Compound D-2-4 (6.5 g, 27.5 mmol) was then added and the resulting mixture was stirred at room temperature overnight. TLC (petroleum ether / EtOAc 8: 1) showed that most of the compound D-2-4 was consumed. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give crude compound D-2-5, which was purified by column chromatography (silica gel petroleum ether / EtOAc 20: 1) to give pure compound D-2-. 5 (5 g, yield: 77%) was obtained as yellow oil. Preparation of 5-bromo-3-methyl-1H-pyrazolo [3,4-b] pyridine (D-2-6)<chemistry num="153"><img file="JP4792126B2_D0156.tif" /></chemistry> A mixture of compound D-2-5 (4 g, 16 mmol) and hydrazine (30 mL) in ethanol (300 mL) was stirred at room temperature overnight. TLC (petroleum ether / EtOAc 5: 1) showed complete consumption of starting material. The reaction mixture was vacuum concentrated and the residue was purified via column chromatography (silica gel, petroleum ether / EtOAc 15: 1) to give crude compound D-2-6, which was further purified by preparative HPLC. Then, pure compound D-2-6 (800 mg, yield: 20%) was obtained as a white solid. Preparation of 1- (4-Methoxybenzyl) -5-bromo-3-methyl-1H-pyrazolo [3,4-b] pyridine (D-2-7)<chemistry num="154"><img file="JP4792126B2_D0157.tif" /></chemistry> NaH (0.24 g, 6 mmol) in anhydrous DMF (50 mL) solution of agitated compound D-2-6 (0.6 g, 3 mmol) at 0 ° C.2It was added little by little under the atmosphere. The resulting mixture was stirred at room temperature for 1 hour. PMBCl (0.52 g, 3.3 mmol) was then added dropwise at 0 ° C. The resulting mixture was stirred at room temperature overnight. TLC (petroleum ether / EtOAc 3: 1) showed complete consumption of starting material. H the reaction mixture2It was quenched with O (50 mL) and extracted with EtOAc (50 mL x 3). Wash the combined organic layers with saturated aqueous NaCl solution (100 mL) and Na2SO4It was dried on top and concentrated in vacuo. Purification of the residue via column chromatography (silica gel, petroleum ether / EtOAc 8: 1 to 5: 1) yields compound D-2-7 (0.7 g, yield: 71%) as a white solid. It was. 1- (4-Methoxybenzyl) -3-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazolo [3,4-b] Preparation of pyridine (D-2-8)<chemistry num="155"><img file="JP4792126B2_D0158.tif" /></chemistry> Compound D-2-7 (0.7 g, 2.1 mmol), 4,4,5,5,4', 4', 5', 5'-octamethyl- [2,2'] bi [[1,3,2' ] Dioxaborolanyl] (1.05 g, 4.2 mmol), KOAc (0.63 g, 6.3 mmol) and catalytic amount of Pd (PPh)3)2Cl2Anhydrous DMF (80 mL) solution in N at 80-90 ° C2Stir overnight in the atmosphere. TLC (petroleum ether / EtOAc 3: 1) showed complete consumption of starting material. H2O (100 mL) was added and the reaction mixture was extracted with EtOAc (100 mL × 3). Wash the combined organic layers with saturated aqueous NaCl solution (100 mL) and Na2SO4Drying on top and vacuum concentration gave crude D-2-8 (0.8 g, yield: 100%) as a brown oil, which was used as is without any further purification. 1- (4-Methoxybenzyl) -5- (1-isopropyl-4-(2- (methylthio) pyrimidin-4-yl) -1H-pyrazole-3-yl) -3-methyl-1H-pyrazolo [3, 4-b] Preparation of pyridine (D-2-9)<chemistry num="156"><img file="JP4792126B2_D0159.tif" /></chemistry> In a solution of agitated compound B-1-1 (0.38 g, 1.05 mmol) in toluene (60 mL) and EtOH (20 mL), a crude material of compound D-2-8 (0.8 g, 2.1 mmol) and 2N. Na2CO3Aqueous solution (1.6 mL) N2Added to the atmosphere. After 10 minutes, the catalytic amount of Pd (PPh)3)4Was added. The resulting mixture was refluxed overnight. TLC (petroleum ether / EtOAc 2: 1) showed complete consumption of D-2-8. Water (30 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (100 mL × 3). Wash the combined organic layers with saturated aqueous NaCl solution (100 mL) and Na2SO4It was dried on top and concentrated in vacuo. The residue was purified via column chromatography (silica gel, petroleum ether / EtOAc 5: 1) to give compound D-2-9 (0.9 g, 30.1%) as a white solid. 1- (4-methoxybenzyl) -5- (1-isopropyl-4-(2- (methylsulfonyl) pyrimidin-4-yl) -1H-pyrazole-3-yl) -3-methyl-1H-pyrazolo [3 , 4-b] Preparation of pyridine (D-2-10)<chemistry num="157"><img file="JP4792126B2_D0160.tif" /></chemistry> THF (10 mL) and H of compounds D-2-9 (0.4 g, 0.82 mmol) and oxone (0.76 g, 1.2 mmol)2The mixture in O (10 mL) was stirred at room temperature for 2 hours. TLC (EtOAc) showed complete consumption of starting material. The reaction mixture was concentrated in vacuo. H2O (30 mL) was added to the residue and the mixture was extracted with EtOAc (50 mL x 3). Wash the combined organic layers with saturated aqueous NaCl solution (50 mL) and Na2SO4Drying on top and vacuum concentration gave compound D-2-10 (0.42 g, yield: 100%) as a yellow solid. (2S) -1- (4- (3- (1- (4-Methoxybenzyl) -3-methyl-1H-pyrazolo [3,4-b] pyridin-5-yl) -1-isopropyl-1H-pyrazole Preparation of -4-yl) pyrimidin-2-ylamino) propan-2-ol (D-2-11)<chemistry num="158"><img file="JP4792126B2_D0161.tif" /></chemistry> A mixture of compounds D-2-10 (0.42 g, 0.82 mmol) and (S) -1-aminopropan-2-ol (0.6 g, 8.2 mmol) in toluene (25 mL) was refluxed overnight. TLC (EtOAc) showed complete consumption of starting material. The mixture was concentrated in vacuo and the residue was purified via column chromatography (silica gel, EtOAc) to give compound D-2-11 (0.4 g, yield: 100%) as a yellow solid. (2S) -1- (4- (1-Isopropyl-3- (3-methyl-1H-pyrazolo [3,4-b] pyridin-5-yl) -1H-pyrazole-4-yl) pyrimidin-2- Preparation of Ilamino) Propane-2-ol (D-2)<chemistry num="159"><img file="JP4792126B2_D0162.tif" /></chemistry> A solution of compound D-2-11 (400 mg, 0.82 mmol) in TFA (5 mL) was stirred at room temperature for 48 hours. TLC (petroleum ether / EtOAc 1: 2) showed that approximately half of compound D-2-11 was consumed. Et3N (10 mL) was added to the mixture and the resulting mixture was concentrated in vacuo. Purification of the residue by column chromatography (silica gel, petroleum ether / EtOAc 1: 1) yields a crude product, which is further purified by preparative HPLC to pure D-2 (141.1 mg, yield: 1). 47%) was obtained as a white solid.(Example F-1) Preparation of 3-chloro-5- (1-isopropyl-4- (pyrimidine-4-yl) -1H-pyrazole-3-yl) -1H-pyrrolo [2,3-b] pyridine<chemistry num="160"><img file="JP4792126B2_D0163.tif" /></chemistry> Preparation of 4-isoxazole-4-ylpyrimidine (F-1-2)<chemistry num="161"><img file="JP4792126B2_D0164.tif" /></chemistry> Crystalline triphosgene (44.3 g, 0.447 mol, 2.1 eq) was started to be added to a solution of 4-methylpyrimidine (20.3 g, 0.213 mol) and dimethylformamide (32.7 g, 0.447 mol, 2.1 eq) at -10 ° C. This was accompanied by intense exotherm and densification of reactants. It was necessary to change the cooling mixture multiple times and add chloroform to the reaction mixture (60 mL total). After 3 hours, when the addition of triphosgene was complete, the cooling mixture was removed and the reaction mixture was heated to 35 ° C. When the reaction mixture began to cool, chloroform was evaporated and the red oily residue was triturated with ethyl acetate to give the crude compound F-1-1a (78 g yield). Compound F-1-1a with hydroxylamine hydrochloride (17.8 g, 0.258 mol, 1.2 eq) and LVDS3Carefully sprayed (17.9 g, 0.213 mol) in a solution of water (300 mL) at 10 ° C with stirring. In addition, LVDS3(36 g, 2 eq.) Was added to the resulting mixture (note foaming), which was accompanied by the formation of a light crystalline precipitate. The precipitate was extracted with ethyl acetate. The next day, the extraction was repeated. Evaporation of the combined extracts gave compound F-1-2 as a crystalline product (94% yield, 29.6 g, calculated with 4-methylpyrimidine). Preparation of 3-oxo-2-pyrimidine-4-ylpropanenitrile (F-1-3)<chemistry num="162"><img file="JP4792126B2_D0165.tif" /></chemistry> Compound F-1-2 was sprayed into a solution of NaOH (8.06 g, 0.201 mol) in a water / ethanol mixture (30 mL / 30 mL) with stirring. The mixture spontaneously generated heat at 70 ° C, forming a brownish-red solution and forming a light precipitate. After densification, water was added. After the spontaneous exotherm stopped, the mixture was stirred at room temperature for 1 hour. Ethanol was added and the solution was rotary evaporated. This operation was repeated twice and the residue was washed with ethyl acetate and ether on a filter to give compound F-1-3 as beige crystals (100% yield, 34 g). Preparation of 4-pyrimidine-4-yl-1H-pyrazole-3-amine (F-1-4)<chemistry num="163"><img file="JP4792126B2_D0166.tif" /></chemistry> Compound F-1-3 (30 g, 0.178 mol) was applied to a solution of hydrazine hydrate (20 mL) in glacial acetic acid (300 mL), which was accompanied by the formation of a dense orange precipitate. The resulting mixture was held at 70-80 ° C for 1 hour with stirring. The precipitate disappeared and the solution became a less dark color. The reactants were evaporated to half the volume and neutralized with excess aqueous ammonia to give compound F-1-4 as a light precipitate (yield 66%, 18.9 g). Preparation of 3- [5- (methoxycarbonyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-3-yl] benzoic acid (F-1-5)<chemistry num="164"><img file="JP4792126B2_D0167.tif" /></chemistry> NaNO2A mixture of compound F-1-4 (10.9 g, 0.068 mol) in glacial acetic acid (200 mL) and water (50 mL) in a dilute jet at -3 ° C with a solution of (4.7 g, 0.068 mol) in water (20 mL). Pour into the solution inside. The temperature increased to -1 ° C and the solution turned clear orange. Dark H2SO4Pour into the resulting solution (1.85 mL, 0.0338 mol), KI (33.7 g, 0.2 mol, 3 eq) and I2A solution (35 g, 138 mmol, 2 eq) was added. The resulting solution was heated to 55 ° C. for 1 hour and acetic acid was neutralized with a fairly excess aqueous ammonia solution. Na with excess iodine2S2O3Neutralized with to form a light precipitate (16.5 g). The precipitate was separated by filtration and the mother liquor was extracted with ethyl acetate. Ethyl acetate was evaporated and the residue was dissolved in THF. The solution was washed through silica gel with ethyl acetate, passed through, and evaporated to give compound F-1-5 (overall yield 93%, 17.1 g). Preparation of 4- (3-iodo-1-isopropyl-1H-pyrazole-4-yl) -pyrimidine (F-1-6)<chemistry num="165"><img file="JP4792126B2_D0168.tif" /></chemistry> Isopropyl iodide (5.51 ml, 55.1 mmol) was added to a DMF solution of pyrazole F-1-5 (3.0 g, 11 mmol) and K2CO3 (1.98 g, 14.3 mmol). The reaction mixture was heated at 55 ° C. After 25 hours, additional isopropyl iodide (1 ml 10 mmol) and K2CO3 (457 mg, 3.3 mmol) were added. The mixture was further stirred for 2 hours. Cooled. It was poured into 300 ml of saturated NaCl solution and extracted with TBME (2 ×). The combined organic layers were washed with saturated aqueous NaCl solution, dried over DDL4 and concentrated under reduced pressure to give a yellow / orange solid. Recrystallized from TBME. TLC analysis showed that the crystalline product was enriched with one isomer of the isopropyl product F-1-6. Grinding the solid with TBME (3x) yields 680 mg of yellow powder, which represents the pure isomer F-1-6. Preparation of 3-chloro-5- (1-isopropyl-4- (pyrimidine-4-yl) -1H-pyrazole-3-yl) -1H-pyrrolo [2,3-b] pyridine<chemistry num="166"><img file="JP4792126B2_D0169.tif" /></chemistry> 4- (3-Iodo-1-isopropyl-1H-pyrazol-4-yl) -pyrimidine (0.05 g, 0.2 mmol), 3-chloro-5- (4,4,5,5-tetramethyl- [1, 3,2] Dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (0.089 g, 0.318 mmol) and 2 M Na2CO3The mixture in aqueous solution (0.067 g, 0.636 mmol, 0.318 mL, 3.0 eq) in DMF (4 mL) was whipped with nitrogen for 15 minutes and DPPF PdCl.2(0.0140 g, 0.019 mmol, 0.06 eq) was added and then heated in a biotage microwave initiator at 100 ° C. under high absorption for 2 hours. The resulting black reactant was cooled to room temperature. The reaction was poured into H2O (100 mL) and extracted (EtOAC 3 x 50 mL). The combined organic layer is Na2SO4Dry above and vacuum concentrate to black oil, which is hexane-filled with a Biotage column (Si25 + M) to produce (5% MeOH / EtOAc) / hexane (0-50%: 700 mL, 50 Elution with ~ 100%: 700 mL, 100%; 700 mL, 27 mL fraction) gave product F-1 as an off-white solid (0.025, 50%).(Example G-1) (2S) -1- (4- (3- (3-Chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (tetrahydrofuran-3-yl) -1H-pyrazole-4- Preparation of pyrimidin-2-ylamino) propan-2-ol Preparation of Methyl 1H-Pyrrolo [2,3-b] Pyridine-5-carboxylate (G-1-1a)<chemistry num="167"><img file="JP4792126B2_D0170.tif" /></chemistry> Pd (OAc) in a mixture of 5-bromo-1H-pyrrolo [2,3-b] pyridine (90 g, 0.4 mol) and dppp (3 g, 0.072 mol) in DMSO (300 mL) and MeOH (300 mL).2(16.5 g, 0.072 mol) was added. N the resulting mixture2It was degassed down for 2 minutes and then heated to 100 ° C. under 2 MPa of CO gas for 2 days. TLC (petroleum ether: EtOAc = 4: 1) showed that the reaction was complete. The mixture was cooled, filtered and then concentrated. The resulting residue was poured into ice-water. The solids formed were collected and dried under vacuum to give crude compound 5 (86.1 g, crude), which was used as is for the next reaction without further purification. Preparation of Methyl 1- (Phenylsulfonyl) -1H-Pyrrolo [2,3-b] Pyridine-5-carboxylate (G-1-2)<chemistry num="168"><img file="JP4792126B2_D0171.tif" /></chemistry> NaH (20 g, 0.495 mol) was added little by little at 0-10 ° C to a solution of G-1-1a (58 g, 0.33 mol) in anhydrous THF (800 mL). The resulting mixture was stirred at 10 ° C for 1 hour. BsCl (70.1 g, 0.397 mol) was added dropwise. The resulting mixture was warmed to room temperature and stirred overnight. TLC (petroleum ether: EtOAc = 2: 1) showed that the reaction was complete. The reaction mixture was cooled and quenched with water. The mixture was extracted with EtOAc (400 mL x 3). Wash the combined organic layer with saturated aqueous NaCl solution and Na2SO4Drying, filtering and concentrating in, yields a crude product, which is purified by recrystallization with petroleum ether: EtOAc = 3: 1 to compound G-1-2 (60 g, 57.6%). Was obtained as a gray-yellow solid. 2- (2- (Methylthio) pyrimidine-4-yl) -1- (1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) etanone (G-1-3) Preparation<chemistry num="169"><img file="JP4792126B2_D0172.tif" /></chemistry> n-BuLi (2.5M, 93mL, 0.233mol) was added dropwise to a solution of i-Pr2NH (32.5mL, 0.233mol) in anhydrous THF (420mL) at -78 ° C, and the resulting solution was added dropwise at -78 ° C at 30. Stir for minutes. A solution of 4-methyl-2- (methylthio) pyrimidine (22.33 g, 0.16 mol) in anhydrous THF (110 mL) was then added dropwise and the resulting mixture was stirred at -78 ° C for an additional 30 minutes. An anhydrous THF (250 mL) solution of compound G-1-2 (50.0 g, 0.145 mol) was then added dropwise at -110 ° C. After the addition, the resulting mixture was stirred at -110 ° C for 10 minutes. TLC (Hexane: EtOAc 1: 1) showed that the reaction was complete. EtOAc (300 mL) and H2O (300 mL) was added to the reaction mixture to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (300 mL x 3). Wash the combined organic layers with saturated aqueous NaCl solution (500 mL) and Na2SO4It was dried on top and concentrated in vacuo. Column chromatography (CH) of the residue2Cl2), Compound 7 (36.0 g, 58.5%) was obtained as a yellow solid. (Z) -3- (dimethylamino) -2- (2- (methylthio) pyrimidine-4-yl) -1- (1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-5- Il) Preparation of prop-2-en-1-one (G-1-4)<chemistry num="170"><img file="JP4792126B2_D0173.tif" /></chemistry> A solution of compound G-1-3 (30 g, 70.7 mmol) in DMF-DMA (300 mL) was heated to 80 ° C. for 3.5 hours. TLC (CH)2Cl2: MeOH = 20: 1) indicated that the reaction was complete. Concentration of the solvent under reduced pressure gave crude compound G-1-4 (36 g) as a dark red oil, which was used as is for the next reaction without purification. 5- (4- (2- (Methylthio) pyrimidin-4-yl) -1H-pyrazole-5-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (G-1-) 5) Preparation<chemistry num="171"><img file="JP4792126B2_D0174.tif" /></chemistry> NH a solution of compound G-1-4 (36 g, crude) in EtOH (360 mL)2NH2.H2Added to O (30 mL). The mixture was stirred at room temperature for 5 hours. The product was deposited from the reaction mixture. The mixture was filtered and the solid washed with EtOH (50 mL x 3) to give the product (19.6 g, 62.1% in 2 steps) as an orange solid. 5- (4- (2- (Methylthio) pyrimidin-4-yl) -1- (tetrahydrofuran-3-yl) -1H-pyrazol-3-yl) -1H-pyrrolo [2,3-b] pyridine (G) Preparation of -1-6)<chemistry num="172"><img file="JP4792126B2_D0175.tif" /></chemistry> Compound G-1-5 (1.9 g, 4.24 mmol),<chemistry num="173"><img file="JP4792126B2_D0176.tif" /></chemistry>(1.02g, 5.088 mmol), Cs2CO3The mixture in DMSO (20 mL) (4.13 g, 12.72 mol) was heated to 80 ° C and stirred overnight. Cool the mixture to room temperature, water (100 mL) and CH2Cl2Diluted with (100 mL). The organic layer was separated and the aqueous layer was extracted 3 times with CH2Cl2. The combined organic layer was washed with saturated aqueous NaCl solution (300 mL x 3) and anhydrous Na.2SO4Drying on and evaporating yields a crude compound, which is purified by column chromatography and then via preparative HPLC to give compound G-1-6 (700 mg, 43.75%) a yellow color. Obtained as a solid. 5- (4- (2- (Methylthio) pyrimidin-4-yl) -1- (tetrahydrofuran-3-yl) -1H-pyrazol-3-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b] Preparation of pyridine (G-1-7)<chemistry num="174"><img file="JP4792126B2_D0177.tif" /></chemistry> NaH (47.0 mg, 1.176 mmol, 60% in oil) was added slowly to the mixture of cooled compound G-1-6 (370 mg, 0.98 mmol) in THF (30 mL). After the addition, the mixture is stirred for 1 hour, followed by the addition of BsCl (207.56 mg, 1.176 mmol) and TLC analysis (MeOH / CH).2Cl2The mixture was stirred at room temperature for 2 hours until it was shown that the starting material was consumed by = 1/10). The resulting mixture is then saturated NH4It was quenched with Cl aqueous solution and concentrated. The residue was extracted with EtOAc (50 m × 3). The combined organic layer was washed with saturated aqueous NaCl solution (300 mL x 3) and anhydrous Na.2SO4Drying on and evaporating gave crude compound G-1-7 (600 mg, 100%), which was used as is in the next step without further purification. 5- (4- (2- (Methylsulfonyl) pyrimidin-4-yl) -1- (tetrahydrofuran-3-yl) -1H-pyrazol-3-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2 , 3-b] Preparation of pyridine (G-1-8)<chemistry num="175"><img file="JP4792126B2_D0178.tif" /></chemistry> Crude compound G-1-7 (600 mg, 0.98 mmol) in THF / H2Mix with oxone (0.90 g, 1.47 mmol) in O (1/1, 15 mL) and at room temperature until TLC analysis (EtOAc / petroleum = 1/2) indicates that the starting material has been consumed 5 Stirred for hours. The resulting mixture was diluted with EtOAc (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted 3 times with EtOAc. Next, the combined organic layer is watered (100 mL x 1), saturated LVDS.3The cells were washed separately with an aqueous solution (100 mL × 2) and a saturated NaCl aqueous solution (100 mL). The resulting organic layer is anhydrous Na2SO4Drying on and evaporating gave compound G-1-8 (600 mg, 100%), which was used as is in the next step without further purification. (2S) -1- (4- (3- (1- (Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (tetrahydrofuran-3-yl) -1H-pyrazole Preparation of -4-yl) pyrimidin-2-ylamino) propan-2-ol (G-1-9)<chemistry num="176"><img file="JP4792126B2_D0179.tif" /></chemistry> A mixture of compound G-1-8 (600 mg, 0.98 mmol), S-1-aminopropan-2-ol (367.5 mg, 4.9 mmol) in THF (25 mL) was refluxed and heated for TLC analysis (MeOH / CH).2Cl21/10) stirs for 24 hours until it is shown that the starting material has been consumed. The resulting mixture is then concentrated to dryness and the residue CH2Cl2Dissolve in (200 mL), wash with water (100 mL x 2) and saturated aqueous NaCl solution (100 mL x 1), anhydrous Na2SO4Drying on top, followed by evaporation, gave compound G-1-9 (500 mg, 100%) as a yellow oil. (2S) -1- (4- (3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (tetrahydrofuran-3-yl) -1H-pyrazol-4-yl) pyrimidine- Preparation of 2-ylamino) propane-2-ol (G-1-10)<chemistry num="177"><img file="JP4792126B2_D0180.tif" /></chemistry> H of NaOH (78.4 mg, 1.96 mmol) in a solution of crude compound G-1-9 (500 mg, 0.98 mmol) in MeOH (15 mL).2O (3 mL) solution was added. The mixture was then gently heated and stirred overnight. TLC analysis (MeOH / CH2Cl2= 1/10) showed complete consumption of starting material and formation of new products. Therefore, the resulting mixture was diluted with EtOAc (250 mL), the organic layer was separated, washed with saturated aqueous NaCl solution (100 mL x 2), and anhydrous Na.2SO4Drying and evaporation on top gave the crude product G-1-10 (400 mg, 100%), which was used as is in the next step. (2S) -1- (4- (3- (3-Chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (tetrahydrofuran-3-yl) -1H-pyrazole-4- Preparation of pyrimidin-2-ylamino) propan-2-ol (G-1)<chemistry num="178"><img file="JP4792126B2_D0181.tif" /></chemistry> Crude azaindole G-1-10 (400 mg, 0.98 mmol) in DMF (50 mL), N-chlorosuccinimide (NCS, 130.83 mg, 0.98 mmol) N2The mixture was heated to 40 ° C. under an atmosphere and stirred overnight. LC-MS showed that the starting material was completely consumed. The resulting mixture was then diluted with EtOAc (500 mL). The organic layer is separated, washed multiple times with water and saturated aqueous NaCl solution, and anhydrous Na2SO4Drying on and evaporating gave a crude product (380 mg). Purification of the crude product by preparative HPLC gave product G-1 (170 mg, 39.53%) as a green solid. 1H NMR (400 MHz, CDCl3): δ 11.281 (s, 1H), 9.809 (s, 1H), 8.508 (s, 1H), 8.284 (s, 1H), 8.2166 (m, 1H), 7.811 (s, 1H), 7.353 (s, 1H), 7.194 (s, 1H), 6.604 (s, 1H), 5.044 (s, 1H), 4.190-4.122 (m, 2H), 4.061-4.022 (m, 1H), 3.966-3.908 (m, 1H), 2.940 (s, 2H), 2.583-2.510 (m, 1H), 2.490-2.364 (m, 1H), 0.917 (s, 3H).(Example H-1) 4- (3- (3-Chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-isopropyl-1H-pyrazole-4-yl) pyridin-2-amine Preparation of 5-Bromo-1- (Phenylsulfonyl) -1H-Pyrrolo [2,3-b] Pyridine (H-1-2)<chemistry num="179"><img file="JP4792126B2_D0182.tif" /></chemistry> In anhydrous THF (1 L) suspension of NaH (87 g, 2.18 mol, 60% in oil), 5-bromo-1H-pyrrolo [2,3-b] pyridine H-1-1 (120 g, 0.62 mol) It was added dropwise to an anhydrous THF (1 L) solution at 0 ° C. After addition, the mixture is N at 0 ° C.2Stir down for 0.5 hours. BsCl (219.5 g, 1.24 mol) was added dropwise to the mixture at 5 ° C. After the addition, the mixture was stirred at room temperature overnight. TLC (petroleum ether / EtOAc 5: 1) showed that the reaction was complete. Ice-cooled saturated NH for the reaction mixture4Gradually poured into Cl (500 mL). The mixture was extracted with EtOAc (600 mL x 2). Wash the combined organic layers with saturated aqueous NaCl solution (700 mL) and Na2SO4It was dried on top and concentrated in vacuo. The residue was washed with petroleum ether / EtOAc (15: 1, 1.5 L) to give compound H-1-2 (198 g, 94.8%) as an off-white solid. Preparation of 5- (1-ethoxyvinyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (H-1-3)<chemistry num="180"><img file="JP4792126B2_D0183.tif" /></chemistry> Pd (PPh) in a solution of compounds H-1-2 (110 g, 0.33 mol) and 2-ethoxyprop-1-ene (141.3 g, 0.39 mol) in toluene (2 L).3)2Cl2(11.4g, 16.3 mmol) N2Added below. The mixture was refluxed overnight. TLC (petroleum ether / EtOAc 5: 1) showed that the reaction was complete. The reaction mixture was used as is in the next step. Preparation of 1-(1- (Phenylsulfonyl) -1H-Pyrrolo [2,3-b] Pyridine-5-yl) Etanone (H-1-4)<chemistry num="181"><img file="JP4792126B2_D0184.tif" /></chemistry> HCl (3N, 440 mL, 1.32 mol) was added to the mixture of compound H-1-3 (216 g, 0.66 mol) in toluene (2 L). The mixture was stirred at room temperature for 2 hours. TLC (petroleum ether / EtOAc 3: 1) showed that the reaction was complete. The mixture was concentrated in vacuo. Purification of the residue via column chromatography (silica gel, petroleum ether / EtOAc 5: 1-3: 1) gave compound H-1-4 (188 g, 95.0%) as an off-white solid. (E) -3- (Dimethylamino) -1- (1- (Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) prop-2-en-1-one (H-1) -5) Preparation<chemistry num="182"><img file="JP4792126B2_D0185.tif" /></chemistry> N the mixture of compound H-1-4 (97.5 g, 0.325 mol) in DMF-DMA (500 mL)2Refluxed down overnight. TLC (petroleum ether / EtOAc 1: 1) showed that the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was washed with EtOAc to give compound H-1-5 (35 g, 30.3%) as a yellow solid and crude compound H-1-5 (90 g) as a brown oil. Preparation of 1- (Phenylsulfonyl) -5- (1H-Pyrazole-3-yl) -1H-Pyrrol [2,3-b] Pyridine (H-1-6)<chemistry num="183"><img file="JP4792126B2_D0186.tif" /></chemistry> Compound 5B (6.8 g, 0.21 mol) N in a mixture of compound H-1-5 (50 g, 0.14 mol) in EtOH (200 mL).2Added below. After the addition, the mixture was refluxed overnight. TLC (petroleum ether / EtOAc 1: 1) showed that the reaction was complete. Approximately half of the EtOH solvent was evacuated and the resulting mixture was filtered. Drying the cake in vacuo gave compound H-1-6 (34 g, 75%) as a gray solid. Preparation of 5- (1-isopropyl-1H-pyrazole-3-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (H-1-7)<chemistry num="184"><img file="JP4792126B2_D0187.tif" /></chemistry> Compound H-1-6 (20 g, 61.7 mmol) in a mixture of NaH (2.96 g, 74.1 mmol, 60% in oil) in DMF (200 mL) at 0 ° C.2Added little by little below. After stirring at 0 ° C for 0.5 hours, isopropyl iodide (31.5 g, 185.2 mmol) was added dropwise to the mixture at 0 ° C. The resulting mixture was stirred at 0 ° C for 0.5 hours. TLC (petroleum ether / EtOAc 1: 1) showed that most of the compound H-1-6 was consumed. Ice-cooled saturated NH for the reaction mixture4Pour into Cl (1000 mL). The mixture was extracted with EtOAc (400 mL). Aqueous layer K2CO3Was basified to pH about 8 with, saturated with NaCl and extracted with EtOAc (400 mL). Wash the combined organic layer with saturated aqueous NaCl solution (400 mL x 5) and Na2SO4It was dried on top and concentrated in vacuo. Purification of the residue via column chromatography (silica gel, petroleum ether / EtOAc 10: 1) results in compound H-1-7 (9 g, 38.1%) as a white solid, crude compound H-1-7 (3 g). ) Was obtained as brown oil. Preparation of 5- (4-bromo-1-isopropyl-1H-pyrazole-3-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (H-1-8)<chemistry num="185"><img file="JP4792126B2_D0188.tif" /></chemistry> CHCl of compound H-1-7 (5 g, 14 mmol)3NBS (2.8 g, 16 mmol) in (100 mL) solution2Added below. After the addition, the mixture was stirred at room temperature for 3 hours. TLC (petroleum ether / EtOAc 3: 1) showed that the reaction was complete. The reaction mixture was concentrated in vacuo. EtOAc (200 mL) was added to the residue. The mixture was washed with water (200 mL) and saturated aqueous NaCl solution (200 mL) and Na2SO4It was dried on top and concentrated in vacuo. Washing the residue with petroleum ether / EtOAc (3: 1, 15 mL) gave crude compound H-1-8 (4.5 g, 72%) as a yellow solid. CH crude solid2Cl2Recrystallization from petroleum ether (1:20, 50 mL) gave pure compound H-1-8 (4.35 g, 70%) as an off-white solid. Preparation of 5- (4-Bromo-1-isopropyl-1H-pyrazole-3-yl) -1H-pyrrolo [2,3-b] pyridine (H-1-9)<chemistry num="186"><img file="JP4792126B2_D0189.tif" /></chemistry> An 8 ml solution of KOH in water was added to a 50 ml suspension of Bs-protected azaindole (H-1-8) in EtOH. Stir overnight at room temperature. The reaction was concentrated by rotary evaporation. The concentrated reaction mixture was diluted with EtOAc and saturated aqueous NaCl solution and the layers were separated. The aqueous layer was re-extracted with EtOAc. The combined organic layers are washed with saturated aqueous NaCl solution and deli4Dry on top. The solution was filtered and concentrated under reduced pressure to give a yellow solid. Grinding with TBME (2 ×) gave 3.37 g of H-1-9 as a yellow solid. The product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (d, J = 6.82 Hz, 6 H) 4.36 --4.66 (m, 1 H) 6.53 (d, J = 2.53 Hz, 1 H) 7.40 --7.60 (m, 1) H) 8.15 (s, 1 H) 8.30 (d, J = 2.02 Hz, 1 H) 8.61 (d, J = 2.02 Hz, 1 H) 11.76 (br. s., 1 H). Preparation of 4- (1-isopropyl-3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole-4-yl) pyridin-2-amine (H-1-10)<chemistry num="187"><img file="JP4792126B2_D0190.tif" /></chemistry> Pyrazole H-1-9 (400 mg, 1.31 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine (375 mg, 1.70 mmol) And a mixture of 1N sodium carbonate (4 ml, 4 mmol) in 5 mL of DME was evacuated with nitrogen for 5 minutes. Then 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride (96 mg, 0.131 mmol) was added and the mixture was heated in an oil bath. Within 5 minutes the reaction turned dark. Heating at 80 ° C was continued for an additional 18 hours, at which point an additional 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine 150 mg And an additional 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride 25 mg was added. After degassing, the reaction was sealed and placed in microwaves at 80 ° C for 60 minutes. The mixture was filtered and the solid was rinsed with water and MeOH. The filtrate was partitioned between ethyl acetate and saturated aqueous NaCl solution. The aqueous layer was extracted with ethyl acetate (2x). The combined organic layer was washed with water and a saturated aqueous solution of NaCl, and deli was used.4Dry above and concentrated under vacuum to crude brown oil (570 mg), which was purified by reverse phase HPLC to give H-1-10 51 mg (12% yield) as a white solid. It was. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J = 6.57 Hz, 6 H) 4.45 --4.65 (s, 1 H) 5.79 (s, 2 H) 6.25 --6.38 (m, 2 H) 6.45 (dd, J = 3.41, 1.89 Hz, 1 H) 7.40 --7.55 (m, 1 H) 7.71 --7.76 (m, 1 H) 7.95 (d, J = 2.02 Hz, 1 H) 8.09 (s, 1 H) 8.22 (d, J = 1.77 Hz, 1 H) 11.68 (br. S., 1 H). 4- (3- (3-Chloro-1H-pyrrolo [2,3-b] pyridine-5-yl) -1-isopropyl-1H-pyrazole-4-yl) Pyridine-2-amine (H-1) Preparation<chemistry num="188"><img file="JP4792126B2_D0191.tif" /></chemistry> 4- (1-Isopropyl-3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazole-4-yl) Pyridine-2-amine (H-1-10) (40 mg, 0.13 mmol) and N-chlorosuccinimide (19.3 mg, 0.14 mmol) CH2Cl2The mixture in (2 ml) was stirred at room temperature for 18 hours. An additional portion of N-chlorosuccinimide (5 mg, 0.04 mmol) was added and stirring was continued at room temperature for an additional 4 hours. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase HPLC when 4-(3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-isopropyl-1H- Pyrazole-4-yl) Pyridine-2-amine (H-1) 14 mg (31% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J = 6.82 Hz, 6 H) 4.43 --4.69 (m, 1 H) 6.22 --6.63 (m, 4 H) 7.72 (d, J = 2.78 Hz, 1 H) 7.82 (d, J = 5.81 Hz, 1 H) 7.92 (d, J = 1.77 Hz, 1 H) 8.23 (s, 1 H) 8.30 (d, J = 2.02 Hz, 1 H) 12.08 (d, J = 1.77 Hz, 1 H).(Example I-1) (2S) -1-({4- [3- (5-amino-6-methoxypyrazine-2-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl] pyrimidin-2 -Preparation of yl} amino) propan-2-ol Preparation of I-1-1<chemistry num="189"><img file="JP4792126B2_D0192.tif" /></chemistry> DMAP (1.24 g, 10.1 mmol) followed by boc anhydride (10.4 g, 47.6 mmol) in a 70 mL solution of 5-bromo-3-methoxypyrazines-2-amine (4.05 g, 19.8 mmol) anhydrous THF. Add at room temperature in times. The resulting mixture was stirred at room temperature. When the starting material was exhausted by TLC, the reaction mixture was concentrated under reduced pressure to an amber oil. Slurry of the oil residue in 3: 1 hexane / EtOAc produced a precipitate, which was collected. The precipitate was dissolved in EtOAc and washed with saturated aqueous NaCl solution containing some 0.5N HCl to a pH of about 5. EDTA the organic layer4It was dried on top and concentrated. The crude product was purified by silica gel chromatography (eluting with 3: 1 hexane / EtOAc) to give 5.40 g of compound I-1-1 as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 18) H) 3.99 (s, 3 H) 8.37 (s, 1 H). (2S) -1-({4- [1- (2,2-difluoroethyl) -3- (trimethylstannyl) -1H-pyrazole-4-yl] pyrimidine-2-yl} amino) propan-2- Preparation of oars (I-1-2)<chemistry num="190"><img file="JP4792126B2_D0193.tif" /></chemistry> (2S) -1-({4- [1- (2,2-difluoroethyl) -3-iodo-1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propan-2-ol (2.0 g) , 4.9 mmol) and hexamethyldistin (1.9 g, 5.9 mmol) in toluene (15 mL) for 5 minutes with a nitrogen bubbler, followed by tetrakis (triphenylphosphine) palladium (0) (566 mg, 0.489 mmol). ) Was added. The resulting mixture was sealed in a 20 mL microwave reaction vial and heated in an oil bath at 90 ° C for 18 hours and then at 110 ° C for 2 hours. The mixture was removed from the oil bath and cooled to room temperature. The mixture was loaded directly onto silica gel and purified using a gradient of 0-35% ethyl acetate in dichloromethane as an eluent to give 1.26 g (58%) of I-1-3 as an oil. 1H NMR (400 MHz, chloroform-d) δ ppm 8.17 (d, J = 5.31 Hz, 1 H), 7.99 (s, 1 H), 6.68 (d, J = 5.31 Hz, 1 H), 6.15 (tt, J = 55.52, 4.55, 4.42 Hz, 1 H), 5.23 (br. T, J = 5.31 Hz, 1 H), 4.56 (td, J = 13.52, 4.29 Hz, 2 H), 3.91 --4.17 (m, 1 H), 3.51 --3.75 (m, 1 H), 3.28- 3.48 (m, 1 H), 1.25 (d, J = 6.32 Hz, 3 H), 0.36 (t, J = 28.55 Hz, 9 H) (2S) -1-({4- [3- (5-amino-6-methoxypyrazine-2-yl) -1- (2,2-difluoroethyl) -1H-pyrazol-4-yl] pyrimidin-2 -Preparation of yl} amino) propan-2-ol (I-1)<chemistry num="191"><img file="JP4792126B2_D0194.tif" /></chemistry> Di-tert-butyl (5-bromo-3-methoxypyrazine-2-yl) imide dicarbonate (517 mg, 1.28 mmol), (2S) -1-({4- [1- (2,2-difluoroethyl)) -3- (trimethylstannyl) -1H-pyrazol-4-yl] pyrimidine-2-yl} amino) propan-2-ol (570 mg, 1.28 mmol), copper iodide (5 mg, 0.026 mmol) DMF (13 mL) ) N the mixture in2It was deoxidized with a bubbler for a few minutes, after which tetrakis (triphenylphosphine) palladium (0) (74 mg, 0.064 mmol) was added. The mixture was sealed in a microwave vial and heated in an oil bath at 100 ° C. for 18 hours. The mixture was then heated in microwaves at 170 ° C. for 20 minutes to thermally decompose the tert-butoxycarbonyl group. The mixture was partitioned between ethyl acetate and saturated aqueous NaCl solution. Some dark insoluble solids did not enter either phase and were removed by filtration. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed once each with water and saturated aqueous NaCl solution and dried over magnesium sulphate to reduce the volume to a minimum. The residue was then purified on silica gel using a gradient of 0-8% methanol (containing 10% ammonium hydroxide) in a mixture of tert-butyl methyl ether and dichloromethane (1: 1) as an eluent. A small amount of product still containing the tert-butoxycarbonyl group was recovered from the column. The material was treated with 10% hydrochloric acid in methanol at 70 ° C. for 2 hours to complete deprotection. The mixture was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with water (1 ×) and saturated aqueous NaCl solution (1 ×), and DDL was used.4It was dried on top and reduced to a minimum volume. The residue was then purified on silica gel in a similar manner to give a second batch of product. The batches were combined, dissolved in a mixture of methanol and water, and then lyophilized to give (2S) -1-({4- [3- (5-amino-6-methoxypyrazine-2-yl) -1- ( 2,2-Difluoroethyl) -1H-pyrazol-4-yl] pyrimidin-2-yl} amino) propan-2-ol (I-1) 180 mg (33%) was obtained as a fluffy white solid. 1H NMR (400 MHz, acetonitrile-d3) δ ppm 8.05 --8.15 (m, 2 H), 7.83 (s, 1 H), 6.65 (d, J = 5.31 Hz, 1 H), 6.27 (tt, J = 54.95, 3.79 Hz, 1 H), 5.73 (br. T, J = 4.93 Hz, 1 H), 5.34 (br. S., 2) H), 4.58 (td, J = 14.72, 3.66 Hz, 2 H), 3.81 (br. S., 1 H), 3.76 (s, 3 H), 3.54 (br. S., 1 H), 3.27 --3.41 (br. M, 1 H), 3.06 --3.23 (br. M, 1 H), 1.08 (d, J = 6.32 Hz, 3 H). (2S) -1- (4- (1- (2,2-difluoroethyl) -3-iodo-1H-pyrazol-4-yl) pyrimidine-2-ylamino) propan-2-ol (I-1-2) ) Preparation step 1:<chemistry num="192"><img file="JP4792126B2_D0195.tif" /></chemistry> Compounds I-1-2a (22 g, 69.2 mmol), 1,1-difluoro-2-iodoethane (16 g, 83.3 mmol) and K2CO3The mixture in (19.2 g, 0.138 mol) DMF (80 mL) was stirred at 30 ° C overnight. When TLC (EtOAc / petroleum ether = 1: 4) indicated that the reaction was complete, the DMF was evaporated under reduced pressure. The residue was placed in EtOAc (500 mL). Rinse the mixture with brine and Na2SO4Drying on and concentrating gave a crude product, which was purified via SFC to give the product (12.1 g, 45.8%) as a yellow solid. Step 2:<chemistry num="193"><img file="JP4792126B2_D0196.tif" /></chemistry> Oxone (24 g, 39.1 mmol) was added to a solution of I-1-2b (10 g, 26.2 mmol) in THF (100 mL) and water (100 mL) at 0-5 ° C. After the addition, the mixture was stirred at room temperature overnight. TLC (EtOAc / petroleum ether = 1: 2) indicates that the reaction is complete, the mixture is concentrated to 1/2 volume, then EtOAc (200 mL) is added, the organic layer is separated and the brine is used. Wash and Na2SO4Drying on and concentrating gave I-1-2c (10.9 g, 100%) as a yellow solid. Step 3:<chemistry num="194"><img file="JP4792126B2_D0197.tif" /></chemistry> The mixture of I-1-2c (10.9 g, 26.3 mmol) and (S) -1-aminopropan-2-ol (7.9 g, 0.105 mol) in THF (100 mL) was reflux heated overnight. TLC (CH)2Cl2When: MeOH = 10: 1) indicated that the reaction was complete, EtOAc (300 mL) and brine (100 mL) were added to the mixture and the layers were separated. Wash the organic layer with brine (80 mL x 5) and Na2SO4After drying on, filtering and concentrating, product I-1-2 (10.1 g, 93.9%) was obtained as a pale solid.<tables num="1-1"><img file="JP4792126B2_D0198.tif" /></tables><tables num="1-2"><img file="JP4792126B2_D0199.tif" /></tables><tables num="1-3"><img file="JP4792126B2_D0200.tif" /></tables><tables num="1-4"><img file="JP4792126B2_D0201.tif" /></tables><tables num="1-5"><img file="JP4792126B2_D0202.tif" /></tables><tables num="1-6"><img file="JP4792126B2_D0203.tif" /></tables><tables num="1-7"><img file="JP4792126B2_D0204.tif" /></tables><tables num="1-8"><img file="JP4792126B2_D0205.tif" /></tables><tables num="1-9"><img file="JP4792126B2_D0206.tif" /></tables><tables num="1-10"><img file="JP4792126B2_D0207.tif" /></tables><tables num="1-11"><img file="JP4792126B2_D0208.tif" /></tables><tables num="1-12"><img file="JP4792126B2_D0209.tif" /></tables><tables num="1-13"><img file="JP4792126B2_D0210.tif" /></tables><tables num="1-14"><img file="JP4792126B2_D0211.tif" /></tables><tables num="1-15"><img file="JP4792126B2_D0212.tif" /></tables><tables num="1-16"><img file="JP4792126B2_D0213.tif" /></tables><tables num="1-17"><img file="JP4792126B2_D0214.tif" /></tables><tables num="1-18"><img file="JP4792126B2_D0215.tif" /></tables><tables num="1-19"><img file="JP4792126B2_D0216.tif" /></tables><tables num="1-20"><img file="JP4792126B2_D0217.tif" /></tables><tables num="1-21"><img file="JP4792126B2_D0218.tif" /></tables><tables num="1-22"><img file="JP4792126B2_D0219.tif" /></tables><tables num="1-23"><img file="JP4792126B2_D0220.tif" /></tables><tables num="1-24"><img file="JP4792126B2_D0221.tif" /></tables><tables num="1-25"><img file="JP4792126B2_D0222.tif" /></tables><tables num="1-26"><img file="JP4792126B2_D0223.tif" /></tables><tables num="1-27"><img file="JP4792126B2_D0224.tif" /></tables><tables num="1-28"><img file="JP4792126B2_D0225.tif" /></tables><tables num="1-29"><img file="JP4792126B2_D0226.tif" /></tables><tables num="1-30"><img file="JP4792126B2_D0227.tif" /></tables><tables num="1-31"><img file="JP4792126B2_D0228.tif" /></tables>(Example J) Raf biochemical assay The compounds of the invention were evaluated for efficacy against b-Raf using an in vitro kinase assay. Raf kinase activity is measured in vitro by determining the transfer of radiolabeled 32-P phosphate from ATP to the specific Raf substrate Mek1. Full-length wild-type b-Raf is expressed in recombinant form and purified from bacterial or insect cells. Recombinant Mek1 is purified from E. coli bacterial cells. In one assay format (referred to as G1), the full-length wild-type Mek1 is used as the b-Raf substrate. The second assay format (referred to as G2) uses the full-length K97R Mek1 mutant as the b-Raf substrate. In vitro kinase assay, 50 mM Hepes (pH 7.4), 5 nM b-Raf, 0.8 μM Mek1, 10 mM MgCl2, 25 μM ATP, 0.002% (v / v) Tween-20, 5 μg / mL. Leupeptin, 1.2 mM DTT, 2% (v / v) DMSO, 0.2-1.0 μCi [γ-32P] Perform in a solution containing ATP per well. The assay is performed in wells of a 96-well polypropylene round bottom plate, where each well contains 43.5 μL of assay mix and 1.5 μL of inhibitor compound or DMSO medium. Add 15 μL of b-Raf mix, shake the plate on a plate shaker and pre-incubate for 10 minutes at ambient temperature. Initiate the reaction by adding 15 μL of ATP mix and shaking. After 40 minutes, the reaction is stopped by adding 25 μL of 0.5 M EDTA (pH 7.4). Transfer 60 μL of the stopped reaction to the wells of a 96-well nylon 66 Biodyne A membrane Silent Screen filter plate (Nalge / Nunc: 256081). The wells are filtered and washed 5 times with 0.85% phosphoric acid. Place the filter in a tray with approximately 50 mL of 0.85% phosphoric acid and gently rotate on an orbital shaker for 10 minutes. Repeat the procedure once with fresh 0.85% phosphoric acid. Five samples of 0.5 μL of ATP mix are also spotted on the filter paper to calculate specific activity. Air dry the filter for 1 hour, sandwich between cellophane wraps on the Amersham Biosciences Storage Phosphor Screen and allow to deploy for at least overnight. Read the image using the Molecular Dynamics Storm 840 phosphoimager. The volume of the spot is calculated using ImageQuant 5.1. [32-P] Raf kinase activity is calculated from the specific activity of ATP, the introduction of 32-P into Mek1 and the b-Raf concentration.(Example K) Raf cell assay The compounds of the present invention were evaluated for efficacy against b-Raf using a cell assay as follows. Raf kinase activity in cells is determined by measuring the phosphorylation level of Mek1 / 2 at serine 217/221, the site phosphorylated by Raf kinase in vivo. Mek1 / 2 Ser phosphorylation is measured in ELISA format using anti-phospho-Mek1 / 2 antibody (Cell Signaling # 9121). Healthy developing human melanoma A2058 cells (encapsulating the b-Raf mutation) are used for the assay. A2058 cells are grown in 10% FBS DMEM medium. When the cells are close to 85% + confluence, rinse the cells once with PBS and trypsin with trypsin / EDTA for 3 minutes. Cells are resuspended in 10% FBS DMEM and centrifuged at 1000 rpm for 5 minutes. Cells are resuspended in 10% FBS DMEM and counted at the cell counter. Cells are seeded in 96-well flat-bottomed plates at 50,000 cells / well in a volume of 100 μL / well in 10% FBS DMEM. Negative control wells are given only 100 μL of 10% FBS DMEM medium without cells. Plate 5% CO in cell culture incubator2Incubate overnight at 37 ° C. On day 2, test compounds are prepared in 10% FBS DMEM medium and serially diluted 1: 3 for 11 test concentrations. Doubly test each concentration of compound. Add 25 μL / well of compound solution to the corresponding wells in the cell plate and 25 μL / well of vehicle (0.5% DMSO in 10% FBS DMEM) in negative control wells (cell-free) and positive control wells (cells without compound). ). Plate 5% CO in cell culture incubator2Incubate at 37 ° C for 1 hour. After 1 hour of incubation, remove the vehicle, add 100 μL / well of cell lysis buffer to the cell plate, and shake the plate at room temperature for 15 minutes. After 15 minutes, transfer the cell lysate to an ELISA plate (pre-coated with anti-Mek1 antibody, Cell Signaling # 2352) and incubate the plate for 2 hours at room temperature with gentle shaking. After 2 hours, the contents of the wells are aspirated and the wells are washed 4 times with wash buffer. Add 100 μL of phospho-Mek1 / 2 detection antibody (Cell Signaling # 9121) to each well and incubate for 1 hour at room temperature with gentle shaking of the plate. After 1 hour, the wells are aspirated and washed 4 times with wash buffer. Add 100 μL of anti-rabbit IgG HRP-binding antibody (Cell Signaling # 7074) to each well and incubate for 1 hour at room temperature with gentle shaking of the plate. After 1 hour, the contents of the wells are aspirated and the wells are washed 4 times with wash buffer. TMB Substrate Solution (Sigma # T0440) Add 100 μL to each well and incubate at room temperature for 10-20 minutes with gentle shaking of the plate. After color development, 100 μL of stop solution (1N hydrochloric acid) is added to each well to stop color development. Read the plate at 450 nm with an ELISA plate reader.<tables num="2"><img file="JP4792126B2_D0229.tif" /></tables><tables num="3-1"><img file="JP4792126B2_D0230.tif" /></tables><tables num="3-2"><img file="JP4792126B2_D0231.tif" /></tables>

Every citation, both waysCites: the store holds 12 of 13

Citations
Document	Relation	Office	Cited during
WO0075131A1	Cites	World Intellectual Property Organization (WIPO)	Examiner
JP2004521901A	Cites	Japan	Examiner
JP2004521915A	Cites	Japan	Examiner
JP2005517675A	Cites	Japan	Examiner
JP2006501183A	Cites	Japan	Examiner
JP2006507353A	Cites	Japan	Examiner
JP2004521901A	Cites	Japan	–
JP2006507353A	Cites	Japan	–
JP2004521915A	Cites	Japan	–
JP2006501183A	Cites	Japan	–
WO00075131A1	Cites	World Intellectual Property Organization (WIPO)	–
JP2005517675A	Cites	Japan	–
SAWYER, J. SCOTT,JOURNAL OF MEDICINAL CHEMISTRY,2003年 9月11日,V46 N19,P3953-3956	Non-patent	–	–

22 members in 18 offices

This recordMember, by publication datePriority claim8 more offices are in the list below

Priority claims11

Priority claims
Document	Office	Kind	Date
60953235	United States of America	–	2007-08-01
95323507	United States of America	P	2007-08-01
61080054	United States of America	–	2008-07-11
8005408	United States of America	P	2008-07-11
2008001952	International Bureau of the World Intellectual Property Organization (WIPO)	W	2008-07-21
2007953235	–	–	–
2008080054	–	–	–
2008001952	–	–	–
US20070953235P	–	–	–
US20080080054P	–	–	–
WO2008IB01952	–	–	–

Members22

Family members, oldest first
Document	Office	Kind
AU2008281543A1	Australia	A1	2009-02-05
CA2695114A1	Canada	A1	2009-02-05
WO2009016460A2	World Intellectual Property Organization (WIPO)	A2	2009-02-05
UY31260A1	Uruguay	A1	2009-03-02
TW200911243A	Taiwan Province of China	A	2009-03-16
WO2009016460A3	World Intellectual Property Organization (WIPO)	A3	2009-03-26
US2009221608A1	United States of America	A1	2009-09-03
WO2009016460A8	World Intellectual Property Organization (WIPO)	A8	2009-10-15
AR067759A1	Argentina	A1	2009-10-21
AP2010005167A0	African Regional Intellectual Property Organization (ARIPO)	A0	2010-02-28
KR20100038119A	Republic of Korea	A	2010-04-12
EP2183243A2	European Patent Office (EPO)	A2	2010-05-12
MA31574B1	Morocco	B1	2010-08-02
US7772246B2	United States of America	B2	2010-08-10
CN101815712A	China	A	2010-08-25
EA201000113A1	Eurasian Patent Organization (EAPO)	A1	2010-08-30
JP2010535189A	Japan	A	2010-11-18
CO6251265A2	Colombia	A2	2011-02-21
SV2010003472A	El Salvador	A	2011-03-23
TN2010000052A1	Tunisia	A1	2011-09-26
JP4792126B2This record	Japan	B2	2011-10-12
BRPI0815042A2	Brazil	A2	2015-02-10

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2011-07-28	First payment of annual fees (during grant procedure)JAPANESE INTERMEDIATE CODE: A61A61	A61
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2010-12-14	Notification of reasons for refusalJAPANESE INTERMEDIATE CODE: A131A131	A131