Aminopyrazine compounds as HPK1 inhibitors and their uses

Abstract

Disclosed herein is an aminopyrazine compound having formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the aminopyrazine compound having formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also disclosed is a method for treating HPK1-related disorders or diseases by using the compounds disclosed herein. #imgabs0#

Description

Technical Field

[0001] The present application provides aminopyrazine compounds and compositions and methods of use thereof. The compounds disclosed herein modulate (eg, inhibit) the activity of hematopoietic progenitor kinase 1 (HPK1) and can be used to treat a variety of diseases including cancer. Background Art

[0002] HPK1 regulates multiple functions of various immune cells, and its kinase activity has been demonstrated in T cell receptor (TCR) [Liou J. et al., Immunity, 2000. 12(4): 399-408], B cell receptor (BCR) [Liou J. et al., Immunity, 2000. 12(4): 399-408], transforming growth factor receptor (TGF-βR) [Wang, W. et al., J Biol Chem, 1997. 272(36): 22771-5; Zhou, G. et al., J Biol Chem, 1999. 274(19): 13133-8], and Gs-coupled PGE2 receptors (EP2 and EP4) [Ikegami, R. et al., J Biol Chem, 1998. 12(4): 399-40 ... [Journal of Immunology, 2001. 166(7): 4689-96]. Overexpression of HPK1 inhibits TCR-induced activation of AP-1-dependent gene transcription in a kinase-dependent manner, suggesting that HPK1 is required for inhibition of the Erk MAPK pathway [Liou J. et al., Immunity, 2000. 12(4): 399-408], and this blockade is considered to be a mechanism of inhibition that negatively regulates TCR-induced IL-2 gene transcription [S. Sawasdikosol. et al., Immunol Res, 2012. 54: 262-265].

[0003] In vitro, HPK1- / - T cells have a lower TCR activation threshold, can proliferate robustly, and produce increased amounts of Th1 cytokines. HPK1- / - mice experience increasingly severe autoimmune symptoms [S. Sawasdikosol. et al., Immunol Res, 2012. 54: pp. 262-265]. In humans, HPK1 is downregulated in peripheral blood mononuclear cells from patients with psoriatic arthritis or in T cells from patients with systemic lupus erythematosus (SLE) [Batliwalla FM et al., Mol Med, 2005. 11(1-12): pp. 21-9], indicating that reduced HPK1 activity may contribute to autoimmunity in patients. In addition, HPK1 can also control anti-tumor immunity via T cell-dependent mechanisms. In a Lewis lung cancer tumor model that produces PGE2, tumors in HPK1 knockout mice develop more slowly compared to wild-type mice [U.S. Patent Application No. 2007 / 0087988]. HPK1-deficient T cells are more effective than wild-type T cells in controlling tumor growth and metastasis [Alzabin, S. et al., Cancer Immunol Immunother, 2010. 59(3): 419-29]. Similarly, BMDCs from HPK1-knockout mice are more effective than wild-type BMDCs in enhancing T cell responses to eradicate Lewis lung carcinoma [Alzabin, S. et al., J Immunol, 2009. 182(10): 6187-94]. In summary, HPK1 may be a good target for enhancing anti-tumor immunity.

[0004] As HPK1 modulators, WO 2016205942 discloses benzimidazoles, WO 2018049152 A1 discloses pyrazolopyrimidines, WO 2018049191 A1 discloses pyrazolopyridones, and WO 2008124849, WO 2018049200 A1, and WO 2018049214 A1 disclose pyrazolopyridines.

[0005] However, there is a need to provide new HPK1 kinase inhibitors that are useful in treating cancer. Summary of the Invention

[0006] In a first aspect, disclosed herein are aminopyrazine compounds having formula (I) and methods of use thereof. The first embodiment comprises the following aspects:

[0007] Aspect 1: A compound of formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0010] in

[0011] Cy 1 is a cycloalkyl group, an aryl group, a monocyclic heterocyclic group, a monocyclic heteroaryl group, a bicyclic fused heteroaryl group, or a bicyclic fused heterocyclic group;

[0012] L 1 Selected from single bond, alkylene (preferably -CR a R b -), -O-, -NR a -、-S-、-S(O)-、-S(O)2-、-cycloalkylene、* 1 -O-Alkylene-** 1 (Preferred* 1 -O-CR a R b -** 1 ),* 1 -alkylene-O-** 1 (Preferred* 1 -CR a R b -O-** 1 ),* 1 -NR c -alkylene-** 1 (Preferred* 1 -NR c -CR a R b -** 1 ),* 1 -alkylene-NR c -** 1 (Preferred* 1 -CR a R b -NR c -** 1 ),* 1 -NR c C(O)-** 1 、* 1 -C(O)NR c -** 1 , alkenylene, or alkynylene; wherein * 1 Refers to the attachment to Cy 1 Part of the location, and ** 1 refers to the position of attachment to the aminopyrazine moiety;

[0013] R 1 、R 2 or R 4 is independently hydrogen, halogen, -C1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR a 、-SO2R a 、-COR a 、-CO2R a 、-CONR a R b 、-C(=NR a )NR b R c 、-NR a R b 、-NR a COR b 、-NR a CONR b R c 、-NR a CO2R b 、-NR a SONR b R c 、-NR a SO2NR b R c , or -NR a SO2R b , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted by at least one R d replace;

[0014] R 3 It is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted by at least one R d replace;

[0015] R a 、R b , and R c are independently hydrogen, deuterium, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; the -C 1-8Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R e ;or

[0016] (R a and R b )、(R b and R c ), or (R c and R a ) together with the one or more atoms to which they are attached form a 3- to 12-membered ring containing 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring optionally substituted with at least one substituent R e replace;

[0017] R d and R e are each independently halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR f 、-SO2R f 、-SO2NR f R g 、-COR f 、-CO2R f 、-CONR f R g 、-C(=NR f )NR g R h 、-NR f R g 、-NR f COR g 、-NR f CONR g R h 、-NR f CO2R f 、-NR f SONR f R g 、-NR f SO2NR g R h , or -NR f SO2R g , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR i 、-NR i R j 、-CO-NR i R j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents;

[0018] R f 、R g 、R h 、R i and R j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0019] m, n and t are each independently 0, 1, 2, 3 or 4; and

[0020] p and s are each independently 0, 1, 2, 3 or 4.

[0021] Aspect 2: The compound according to aspect 1, wherein L 1 Is a single bond, -CR a R b -、-O-、-NR a 、* 1 -CR a R b -NR c -** 1 、* 1 -O-CR a R b -** 1 、* 1 -CR a R b -O-** 1 、* 1 -C(O)NH-** 1 、* 1 -NHC(O)-** 1 , or -S-; R a 、R b and R c are independently hydrogen, deuterium, halogen, -C 1-8 Alkyl or C 3-8 Cycloalkyl, such -C 1-8 Alkyl or C 3-8Each of the cycloalkyl groups is optionally replaced by OR f Replacement; R f are each independently hydrogen or -C 1-8 Alkyl; or R a and R b Together with the carbon atoms to which they are attached, they form a 3- to 5-membered ring.

[0022] Aspect 3: The compound according to Aspect 2, wherein R a 、R b and R c and each is independently hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, butyl, pentyl, or hexyl, each of which is optionally substituted with OH.

[0023] Aspect 4: A compound according to any one of aspects 1 to 3, wherein L 1 Selected from single bond, -O-, * 1 -CH2-O-** 1 、* 1 -NHC(O)-** 1 、* 1 -CHCH3-O-** 1 、* 1 -CH2-NH-** 1 、* 1 -CH2-N(CH3)-** 1 、* 1 -C(CH3)2-O-** 1 ,or* 1 -CF2-O-** 1 .

[0024] Aspect 5: The compound according to any one of aspects 1 to 4, wherein m=1; R 1 Selected from hydrogen, -C 1-8 Alkyl (preferably methyl), OR a 、-NR a R b , or halogen, the -C 1-8 The alkyl group is optionally substituted with at least one halogen; R a and R b are each independently hydrogen or -C 1-8 alkyl.

[0025] Aspect 6: The compound according to any one of aspects 1-5, wherein p=1, and s=1; or p=0, and s=2.

[0026] Aspect 7: The compound according to any one of aspects 1-6, wherein n=0.

[0027] Aspect 8: A compound according to any one of aspects 1 to 7, wherein R 3 Selected from -C 1-8 Alkyl (preferably methyl, ethyl, propyl, 2-methylpropyl, butyl, pentyl or hexyl) or C 4-8 Heterocyclic group (preferably piperidinyl), the -C 1-8 Alkyl core C 4-8 The heterocyclic group (preferably piperidinyl) is optionally replaced by R d Replacement, R d Selected from -C 1-8 Alkyl (preferably methyl), -NR f R g or -CONR f R g , R f and R g are each independently hydrogen or -C 1-8 Alkyl (preferably methyl or butyl).

[0028] Aspect 9: The compound according to Aspect 1, wherein Formula (I) is Formula (Ia) or Formula (Ib)

[0029]

[0030] R 1 、R 4 、R 3 ,t,Cy 1 、L 1 As defined in formula (I).

[0031] Aspect 10: The compound according to Aspect 9, wherein R 1 and R 3 Each is independently selected from hydrogen, -CH3, OCH3, halogen (such as F or Cl), -NHCH3, -NHCH2CH3, CHF2, -CF3 or

[0032] Aspect 11: The compound according to Aspect 9, wherein the formula (I) is the formula (Ic) or (Id)

[0033]

[0034]

[0035] Aspect 12: The compound according to Aspect 11, wherein formula (Ic) is selected from

[0036]

[0037]

[0038]

[0039] where R 4 ,t,Cy 1 is as defined in formula (I); and R c is hydrogen or -C 1-8 Alkyl (preferably methyl).

[0040] Aspect 13: A compound according to any one of aspects 1 to 12, wherein Cy 1 is selected from 3- to 8-membered monocyclic heterocyclic groups containing one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, wherein Cy 1 Optionally, -(R 4 ) t replace.

[0041] Aspect 14: The compound according to Aspect 13, wherein Cy 1 Selected from oxiranyl, aziridinyl, thiirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), imidazolidinyl (imidazolidin-2-yl, imidazolidin-4-yl), pyrazolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azocanyl, azetidine alkyl, dihydropyridinyl, tetrahydropyridinyl, pyranyl, homopiperidinyl, homopiperazinyl, azepanyl, oxepinyl, thiepanyl, oxathianyl, 1,4-oxathianyl, 1,4-dioxepinyl, 1,4-oxathianyl, 1,4-oxazepanyl, 1,4-dithianyl, 1,4-thiazepanyl, 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepanyl, Base, diazepine thiazolinone 1-H-pyranyl, 2-H-pyranyl, 3-H-pyranyl, 1-pyrrolinyl, 2-H-pyranyl, 3-H-pyrrolinyl, 1-indolinyl, 2-H-pyranyl, 4-H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinyl, or 1,1-dioxo-thiomorpholinyl, wherein Cy 1 Optionally defined as -(R 4 ) treplace.

[0042] Aspect 15: The compound according to Aspect 14, wherein Cy 1 is selected from piperidinyl, dihydropyridinyl or pyrrolidinyl (pyrrolidin-1-yl, pyrrolidin-2-yl, or pyrrolidin-3-yl); T=0 or 1, each R 4 Selected from hydrogen, oxo, or -C 1-8 Alkyl (preferably methyl).

[0043] Aspect 16: The compound according to Aspect 15, wherein Selected from

[0044] Aspect 17: A compound according to any one of aspects 1 to 12, wherein Cy 1 is optionally defined as -(R 4 ) t Substituted monocyclic or bicyclic aryl groups.

[0045] Aspect 18: The compound according to Aspect 17, wherein Cy 1 is naphthyl or phenyl; t=0, 1, 2 or 3; each R 4 are independently selected from hydrogen, halogen, optionally substituted with halogen or -OR f Substituted -C 1-8 Alkyl, -CN, -COOR a 、-OR a 、-CONR a R b , or -NR a R b , where R a 、R b and R f are independently hydrogen, -C 1-8 Alkyl, -C 3-6 Cycloalkyl, or -C 3-6 Heterocyclic group, or R a and R b Together with the nitrogen atom to which they are attached, they form a 3- to 12-membered ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; preferably, each R 4 It is hydrogen, chlorine, fluorine, methoxy, -COOH, -CON(CH3)2, -CF3, -CH2-OCH3, -CN, pyrrolidin-1-ylcarbonyl, morpholinocarbonyl, or N-cyclopropylaminocarbonyl.

[0046] Aspect 19: The compound according to Aspect 18, wherein Selected from

[0047]

[0048] Aspect 20: A compound according to any one of aspects 1-12, wherein Cy 1 is optionally defined as -(R 4 ) t substituted 5-membered or 6-membered heteroaryl.

[0049] Aspect 21: The compound according to Aspect 20, wherein Cy 1 is selected from pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazolyl, thiazolyl ... oxazinyl, benzothiophenyl, furyl (furyl / furanyl), benzofuranyl, benzimidazolyl, indolyl, isoindolyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl), wherein Cy 1 Optionally defined as -(R 4 ) t replace.

[0050] Aspect 22: The compound according to Aspect 21, wherein Cy 1 Selected from Among them, Cy 1 Optionally defined as -(R 4 ) t Substitution; preferably, t = 0, 1, 2 or 3, provided that the valence theory is satisfied; more preferably, t = 1 or 2; each R 4 are independently selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkynyl (preferably ethynyl), cycloalkyl, heterocyclyl, oxo, -CN, -OR a 、-CONR a R b 、-NR a COR b , or -NR a R b , the -C 1-8 Alkyl, -C 2-8Each of the alkynyl, cycloalkyl or heterocyclyl groups is optionally substituted by at least one R d More preferably, each R 4 is -C optionally substituted by at least one halogen such as fluorine or cyano 1-8 Alkyl; or each R 4 is optionally substituted with cyano, -C 1-8 Alkyl or hydroxy substituted cycloalkyl; or each R 4 is optionally replaced by halogen or -C 1-8 an alkyl-substituted heterocyclic group; or each R 4 is optionally replaced by at least one R d Substituted -C 2-8 Alkynyl (e.g., ethynyl), where R d Independently -C 1-8 Alkyl, cycloalkyl (preferably cyclopropyl or cyclohexyl), aryl, heteroaryl (preferably pyridyl (e.g. pyridin-3-yl or pyridin-4-yl), pyrazolyl (e.g. 1H-pyrazol-3-yl or 1H-pyrazol-5-yl), or thiazolyl), -SO2R f or -CONR f R g , the -C 1-8 Each of the alkyl, cycloalkyl, aryl, or heteroaryl groups is optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR i , or -NR i R j substituted by a substituent; and wherein R f 、R g 、R i and R j are each independently hydrogen or -C 1-8 Alkyl; or each R 4 Yes-OR a 、-CONR a R b , or -NR a R b , where R a and R b Each is hydrogen, -C 1-8 Alkyl, cycloalkyl, aryl or heterocyclic group, wherein the -C 1-8 The alkyl group is optionally replaced by an R selected from a cycloalkyl group, an aryl group or a heterocyclic group. e Substituted, each cycloalkyl, aryl or heterocyclyl is optionally replaced by at least one -CO-NR i R j Substituted, where R i and R j are each independently hydrogen or -C 1-8 Alkyl; or R a and Rb Together with the nitrogen atom to which they are attached, they form a 3- to 12-membered ring containing 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring optionally substituted by at least one substituent R e replace.

[0051] Aspect 23: The compound according to Aspect 22, wherein Selected from

[0052]

[0053]

[0054] Aspect 24: A compound according to any one of aspects 1-12, wherein Cy 1 is selected from 7- to 12-membered bicyclic fused heteroaryl or heterocyclyl groups containing one or two or three heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, wherein Cy 1 Optionally -(R 4 ) t As defined in formula (I).

[0055] Aspect 25: The compound according to Aspect 24, wherein Cy 1 is selected from indazole, benzimidazole, quinoline, pyridoxazine, pyrrolopyridine, isoquinoline, benzoxazine, quinoxaline, isochromene, pyranopyrazole, pyranopyridine, benzodioxole, quinazoline, benzoxazole, indole, pyrrolopyrazine, pyrrolopyrimidine, imidazopyrimidine, or thienopyridine, wherein one or two carbon-carbon double bonds or carbon-nitrogen double bonds are optionally hydrogenated, and wherein Cy 1 Optionally defined as -(R 4 ) t substituted; preferably t is 0, 1, or 2; each R 4 Is halogen, -C 1-8 Alkyl, oxo, or -OR a , the -C 1-8 The alkyl group is optionally substituted with halogen, hydroxy or alkoxy, and wherein R a is hydrogen or -C 1-8 alkyl.

[0056] Aspect 26: The compound according to Aspect 24, wherein Cy 1 Selected from Among them, Cy 1 Optionally defined as -(R 4 ) t replace.

[0057] Aspect 27: The compound according to Aspect 26, wherein Selected from

[0058] Aspect 28: The compound is selected from

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0083] In a second aspect, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0084] In a third aspect, disclosed herein is a method of inhibiting HPK1 activity, comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof, including a compound of formula (I) or a specific compound exemplified herein.

[0085] In a fourth aspect, disclosed herein is a method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, as an HPK1 kinase inhibitor, wherein the compound disclosed herein includes a compound of Formula (I) or a specific compound exemplified herein. In some embodiments, the disease or disorder is associated with inhibition of an HPK1 interaction. Preferably, the disease or disorder is cancer. DETAILED DESCRIPTION

[0086] The following terms have the indicated meanings throughout this specification:

[0087] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0088] The following terms have the indicated meanings throughout this specification:

[0089] As used herein, including the appended claims, singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0090] Unless the context clearly indicates otherwise, the term "or" means and is used interchangeably with the term "and / or."

[0091] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing from 1 to 18 (e.g., from 1 to 12, further such as from 1 to 10, further such as from 1 to 8, or from 1 to 6, or from 1 to 4) carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2- pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl groups.

[0092] The term "propyl" refers to 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0093] The term "butyl" refers to 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu").

[0094] The term "pentyl" refers to 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl.

[0095] The term "hexyl" refers to 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0096] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0097] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine and iodine). Examples of haloalkyl groups include halo C 1-8 Alkyl, halogenated C 1-6 Alkyl or halogenated C 1-4Alkyl groups include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CHCl2, -CF3, etc.

[0098] The term "alkenyl" refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C=C double bond and from 2 to 18 (e.g., from 2 to 8, further e.g., from 2 to 6) carbon atoms. 2-6 Examples of (enyl) groups include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, butane-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0099] The term "alkynyl" refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C≡C triple bond and from 2 to 18 (e.g., from 2 to 8, further e.g., 2 to 6) carbon atoms. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0100] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups.

[0101] For example, cycloalkyl group can comprise from 3 to 12, for example from 3 to 10, further for example 3 to 8, further for example 3 to 6, 3 to 5 or 3 to 4 carbon atoms.Even further for example, cycloalkyl group can be selected from and comprise from 3 to 12, for example from 3 to 10, further for example 3 to 8, 3 to 6 carbon atom monocyclic group.The example of monocyclic cycloalkyl group comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl group.Especially, saturated monocyclic cycloalkyl group (for example C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, cycloalkyl groups are monocyclic rings (abbreviated as C 3-6Examples of bicyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms, having fused bicyclic ring arrangements (selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems), or having bridged bicyclic ring arrangements (selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane). Additional examples of bicyclic cycloalkyl groups include those having bicyclic ring arrangements (selected from [5,6] and [6,6] ring systems).

[0102] The term "fused cycloalkyl" refers to a bicyclic cycloalkyl group as defined herein that is saturated and formed by two or more rings which share two adjacent atoms.

[0103] The term "bridged cycloalkyl" refers to a ring structure containing carbon atoms and formed by two rings, wherein at least two atoms are shared by the rings. The term "7- to 10-membered bridged cycloalkyl" refers to a ring structure containing 7 to 12 carbon atoms and formed by two rings, wherein the two rings share two atoms are not adjacent to each other.

[0104] The term "cycloalkenyl" refers to a non-aromatic cycloalkyl group of from 3 to 10 carbon atoms having a monocyclic or multiple rings and at least one double bond and preferably from 1 to 2 double bonds. In one embodiment, the cycloalkenyl is a cyclopentenyl or cyclohexenyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, preferably cyclohexenyl.

[0105] The term "fused cycloalkenyl" refers to a bicyclic cycloalkyl group as defined herein containing at least one double bond and formed by two or more rings which share two adjacent atoms.

[0106] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group of from 5 to 10 carbon atoms having a single ring or multiple rings and having at least one triple bond.

[0107] The term "fused cycloalkynyl" refers to a bicyclic cycloalkyl group as defined herein containing at least one triple bond and formed by two or more rings which share two adjacent atoms.

[0108] The term "benzo-fused cycloalkyl" is a bicyclic fused cycloalkyl group in which a 4- to 8-membered monocyclic cycloalkyl ring is fused to a benzene ring. For example, a benzo-fused cycloalkyl group is The wavy lines indicate the attachment points.

[0109] The term "benzo-fused cycloalkenyl" is a bicyclic fused cycloalkenyl wherein a 4- to 8-membered monocyclic cycloalkenyl ring is fused to a benzene ring.

[0110] The term "benzo-fused cycloalkynyl" is a bicyclic fused cycloalkynyl group wherein a 4- to 8-membered monocyclic cycloalkynyl ring is fused to a benzene ring.

[0111] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl groups include, but are not limited to, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo[3- to 8-membered cycloalkyl, benzo[C] 4-6 Cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc. A preferred embodiment is an 8- to 9-membered fused ring, which refers to a cyclic structure containing 8 to 9 ring atoms in the above examples.

[0112] The term "aryl" used alone or in combination with other terms refers to a group selected from:

[0113] a) 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0114] b) bicyclic ring systems (e.g. 7- to 12-membered bicyclic ring systems) in which at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl; and,

[0115] c) tricyclic ring systems (eg 10- to 15-membered tricyclic ring systems) in which at least one ring is carbocyclic and aromatic, such as fluorenyl.

[0116] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring carbon atoms (i.e., C 5-10 Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0117] In particular, the term "bicyclic fused aryl" refers to a bicyclic aryl ring as defined herein. A typical bicyclic fused aryl is naphthalene.

[0118] The term "heteroaryl" refers to a group selected from:

[0119] a) a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, in some embodiments, from 1 to 2 heteroatoms) selected from nitrogen (N), sulfur (S), and oxygen (O), wherein the remaining ring atoms are carbon;

[0120] b) a 7- to 12-membered bicyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) selected from N, O, and S, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0121] c) an 11- to 14-membered tricyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) selected from N, O, and S, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.

[0122] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. The nitrogen atoms in one or more rings of the heteroaryl group can be oxidized to form N-oxides.

[0123] In particular, the term "bicyclic fused heteroaryl" refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused bicyclic heteroaryl ring as defined herein. Typically, the bicyclic fused heteroaryl is a 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic ring. The group can be attached to the rest of the molecule through either ring.

[0124] Representative examples of bicyclic fused heteroaryl groups include, but are not limited to, the following: benzisoxazolyl, benzodiazolyl, benzofuranyl, benzofurazanyl, benzofuranyl, benzimidazolyl, benzisothiazolyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, fluoropyridyl, furopyrrolyl, imidazopyridyl, imidazopyridyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolinyl (i pyridinyl, pyrazinopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrazolotriazinyl, pyridazinopyridinyl, pyrrolopyridinyl, quinazolinyl, quinolinyl (quinolinyl / quinolyl), quinoxalinyl, thiazolopyridinyl, thienopyrazinyl, thienopyrazolyl, thienopyridinyl, thienopyrrolyl, thienothiphenyl, or triazolopyridinyl.

[0125] The term "benzo-fused heteroaryl" is a bicyclic fused heteroaryl group wherein a 5- to 7-membered (preferably 5- or 6-membered) monocyclic heteroaryl ring as defined herein is fused to a benzene ring.

[0126] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout the disclosure herein. In certain embodiments, monocyclic or bicyclic aromatic heterocycles have 5, 6, 7, 8, 9 or 10 ring members, wherein 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulphur (S) and oxygen (O), and the remaining ring members are carbon. In certain embodiments, monocyclic or bicyclic aromatic heterocycles are monocyclic or bicyclic rings comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulphur (S) and oxygen (O). In certain embodiments, monocyclic or bicyclic aromatic heterocycles are 5 to 6 yuan heteroaryl rings, which are monocyclic and have 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulphur (S) and oxygen (O). In certain embodiments, monocyclic or bicyclic aromatic heterocycles are 8 to 10 yuan heteroaryl rings, which are bicyclic and have 1 or 2 heteroatom ring members independently selected from nitrogen, sulphur and oxygen.

[0127] Examples of heteroaryl groups, or monocyclic or bicyclic aromatic heterocycles, include, but are not limited to, (numbering starting from the attachment position designated as priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl), quinolyl, isoquinolyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4 -oxadiazole, 1-thia-2,3-oxadiazole, 1-thia-2,4-oxadiazole, 1-thia-2,5-oxadiazole, 1-thia-3,4-oxadiazole, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, fluoropyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), and indazolyl (e.g., 1H-indazol-5-yl).

[0128] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclyl groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, wherein the remaining ring members are carbon, including monocyclic fused rings, i.e., monocyclic heterocyclyl and fused heterocyclic groups.

[0129] As used herein, the term "optionally oxidized sulfur" refers to S, SO or SO2.

[0130] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member (e.g., 1-3 heteroatoms, 1 or 2 heteroatoms) is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

[0131] Exemplary monocyclic 4- to 9-membered heterocyclyl groups include, but are not limited to, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidinon-2-yl, imidazolidinon-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, azetidin-4-yl, azetidin-5-yl, thiirane, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, azetidin-4-yl, azetidin-5-yl, thiirane, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, azetidin-4-yl, azetidin-5-yl, thiirane heterocyclobutan-3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxetanyl, thietanyl, 1,4-oxathianyl, 1,4-dioxetanyl, 1,4-oxathianyl, 1,4-oxazepanyl, 1,4-dithianyl, 1,4-thiazepanyl, and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxath ... Base, diazepine thiazolinone 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone,

[0132] The term "fused heterocyclic radical" refers to a 5- to 20-membered polycyclic heterocyclic radical group (wherein each ring in the system shares adjacent pairs of atoms (carbon and carbon atoms, or carbon and nitrogen atoms) with another ring), comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulphur as ring members, and the remaining ring members are carbon. One or more rings of the fused heterocyclic radical may contain one or more double bonds, but the fused heterocyclic radical does not have a completely conjugated π electron system. Preferably, the fused heterocyclic radical is 6 to 14 yuan and more preferably 7 to 12 yuan or 7 to 10 yuan. Depending on the number of member rings, the fused heterocyclic radical is divided into two rings, three rings, four rings or polycyclic fused heterocyclic radicals. The group can be attached to the rest of the molecule through any ring.

[0133] In particular, the term "bicyclic fused heterocyclyl" refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused heterocyclyl as defined herein, comprising two fused rings and comprising 1 to 4 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members. Typically, the bicyclic fused heterocyclyl is a 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic fused heterocyclyl. Representative examples of (bicyclic) fused heterocycles include, but are not limited to, the following: octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolyl, octahydro-benzo[b][1,4]dioxin, dihydroindolyl, isoindolyl, benzopyranyl, dihydrothiazolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl (or tetrahydroisoquinolinyl), dihydrobenzofuranyl, dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, benzodioxolyl (benzod dihydrobenzoxazine), dihydrobenzodioxepinyl, dihydrothienodioxynyl, dihydrobenzoxazepine, dihydrobenzoxazine ... Tetrahydrobenzoxazepine Benzazepine, dihydrobenzazepine Tetrahydrobenzazepine 1,5-a]pyrimidin-3-yl.

[0134] The term "benzo-fused heterocyclyl" is a bicyclic fused heterocyclyl wherein a monocyclic 4- to 9-membered heterocyclyl (preferably 5- or 6-membered) as defined herein is fused to a benzene ring.

[0135] The term "bridged heterocyclic group" refers to a 5 to 14-membered polycyclic heterocycloalkyl group (wherein every two rings in the system share two discontinuous atoms), comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, wherein the remaining ring members are carbon. One or more rings of the bridged heterocyclic group may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the bridged heterocyclic group is 6 to 14 members and more preferably 7 to 10 members. Depending on the number of member rings, the bridged heterocyclic group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, and more preferably a bicyclic or tricyclic bridged heterocyclic group. Representative examples of bridged heterocyclic groups include, but are not limited to, the following: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0136] The term "at least one substituent" disclosed herein includes, for example, from 1 to 4, such as from 1 to 3, further such as 1 or 2 substituents, provided that the valence theory is satisfied. For example, the term "at least one substituent R" disclosed herein includes, for example, from 1 to 4, such as from 1 to 3, further such as 1 or 2 substituents, provided that the valence theory is satisfied. d " includes from 1 to 4, such as from 1 to 3, further such as 1 or 2 substituents selected from R as disclosed herein d .

[0137] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more chiral centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader category of stereoisomers. It is intended to include all possible stereoisomers, such as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. It is intended to include stereoisomers of all compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically stated, a reference to an isomer applies to any possible isomer. Whenever the composition of the isomers is not specified, all possible isomers are included.

[0138] The compounds disclosed herein also include deuterated compounds. The term "deuterated compound" refers to a compound in which one or more carbon-bonded hydrogens are replaced by one or more deuteriums. Similarly, the term "deuterated" is used herein to modify a chemical structure or organic group (group or radical) in which one or more carbon-bonded hydrogens are replaced by one or more deuteriums, such as "deuterated alkyl," "deuterated cycloalkyl," "deuterated heterocycloalkyl," "deuterated aryl," "deuterated morpholinyl," and the like. For example, the term "deuterated alkyl" as defined above refers to an alkyl group as defined herein in which at least one carbon-bonded hydrogen atom is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to deuterium; and a carbon atom may be bonded to at most one deuterium; and more than one carbon atom in an alkyl group may also be bonded to deuterium.

[0139] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight, such as no more than 30%, further such as no more than 25%, and even further such as no more than 20% of any one or more other stereoisomers. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight, such as no more than 5%, such as no more than 1% of any one or more other stereoisomers.

[0140] When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are intended to include both E and Z geometric isomers.

[0141] When the compounds disclosed herein contain a disubstituted ring system, the substituents found on such ring systems can be in both cis and trans forms. Cis formation means that both substituents are located on the upper side of the carbon 2 substituent positions, while trans formation means that they are located on opposite sides. For example, the disubstituted ring system can be a cyclohexyl ring or a cyclobutyl ring.

[0142] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter referred to as separation) to the desired uniformity by common techniques in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, for example: reverse phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small-scale analysis; simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques. Those skilled in the art will apply the technology most likely to achieve the desired separation.

[0143] "Diastereoisomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of each other. Diastereoisomer mixtures can be separated into their single diastereoisomers according to their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated as follows: by reacting an enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acidchlorid), converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereoisomers, and converting (e.g., hydrolyzing) the individual diastereoisomers into the corresponding pure enantiomers. Enantiomers can also be separated using chiral HPLC columns.

[0144] Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolution of the racemic mixture using an optically active resolving agent to form the diastereomers (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3) (1975): 283-302). Racemic mixtures of the chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods; (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers and conversion to pure stereoisomers; and (3) separation of substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., ed., Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0145] The term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base group with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0146] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt (e.g., a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0147] As defined herein, "pharmaceutically acceptable salts thereof" include salts of at least one compound of formula (I), and salts of stereoisomers of compounds of formula (I), such as enantiomeric salts and / or diastereomeric salts.

[0148] As used herein, the terms "administration" and "treating" refer to the contacting of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells encompasses contacting an agent with a cell and contacting an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment of a cell, such as by an agent, diagnostic agent, binding compound, or another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0149] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (e.g., a compound) that, when administered to a subject to treat a disease, or at least one clinical symptom of a disease or disorder, is sufficient to affect the treatment of such disease, disorder, or symptom. A "therapeutically effective amount" may vary with the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case will be apparent to those skilled in the art or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, as defined herein, that is effective to treat the disease or disorder of the subject. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination subject used to effectively treat the disease, disorder, or condition.

[0150] The pharmaceutical compositions comprising the compounds disclosed herein can be administered orally, by inhalation, rectally, parenterally, or topically to a subject in need thereof. For oral administration, the pharmaceutical composition can be a conventional solid formulation, such as a tablet, powder, granule, capsule, etc.; a liquid formulation, such as an aqueous or oily suspension; or other liquid formulations, such as a syrup, solution, suspension, etc.; for parenteral administration, the pharmaceutical composition can be a solution, an aqueous solution, an oily suspension concentrate, a lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition can be a single unit administration with a precise dosage. In addition, the pharmaceutical composition may further comprise other active ingredients.

[0151] All formulations of the pharmaceutical composition disclosed herein can be produced by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients and then made into the desired formulation. "Pharmaceutically acceptable excipient" refers to conventional pharmaceutical carriers suitable for desired pharmaceutical formulations, such as: diluents, vehicles (such as water, various organic solvents, etc.), fillers (such as starch, sucrose, etc.), adhesives (such as cellulose derivatives, alginates, gelatin and polyvinyl pyrrolidone (PVP)); Wetting agents, such as glycerol; Disintegrants, such as agar, calcium carbonate and sodium bicarbonate; Absorption enhancers, such as quaternary ammonium compounds; Surfactants, such as hexadecanol; Absorption carriers, such as kaolin and bentonite; Lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition also includes other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, aromatic compounds, sweeteners and dyes.

[0152] The term "disease" refers to any illness, ailment, disease, symptom, or indication and is interchangeable with the terms "disorder" or "condition."

[0153] Throughout this specification and the appended claims, unless the context requires otherwise, the term "comprise" and variations such as "comprises and comprising" are intended to specify the presence of the following features, but do not preclude the presence or addition of one or more other features. When used herein, the term "comprise" may be replaced with the terms "contain" or "include", or sometimes "have".

[0154] Throughout the specification and the appended claims, the term “C n-m " indicates a range including endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 、C 1-6 wait.

[0155] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0156] Universal synthesis

[0157] The compounds disclosed herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0158] The reaction for preparing the compound disclosed herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with starting materials, intermediates or products at a temperature (e.g., a temperature ranging from the boiling temperature of the solvent) at which the reaction is carried out. A given reaction can be carried out in a solvent or a mixture of multiple solvents.

[0159] The selection of appropriate protecting groups can be readily determined by one skilled in the art.

[0160] The reaction can be monitored according to any suitable method known in the art (e.g., NMR, UV, HPLC, LC-MS, and TLC).The compound can be purified by a variety of methods including HPLC and normal phase silica gel chromatography.

[0161] Chiral analytical HPLC was used for retention time analysis of different chiral examples, and the conditions were divided into the following methods based on the column, mobile phase, and solvent ratio used.

[0162] Plan I

[0163]

[0164] For example, compounds of formula (I) can be formed as shown in Scheme 1. Compound (i) can be deprotonated and reacted with 2-amino-3,5-dihalopyrazine to give compound (ii); compound (ii) can be coupled with compound (iii) using a transition metal catalyzed reaction to give compound (iv) [i.e., formula (I)].

[0165] Option II

[0166]

[0167] For example, compounds of formula (I) can be formed as shown in Scheme II. Compound (vi) can be selectively coupled with 2-amino-3,5-dihalopyrazine to give compound (ii); compound (ii) can be linked with compound (iii) to give compound (iv) [i.e., formula (I)].

[0168] Option III

[0169]

[0170] For example, a compound of formula (Ia) can be formed as shown in Scheme III. Compound (i) can be protected to give compound (ii); compound (ii) can be cyclized with formaldehyde to give compound (iii); compound (iii) can be deprotected to give compound (iv); compound (iv) can be alkylated to give compound (v); compound (v) can be borylated to give compound (vi). Compound (vii) can be deprotonated and reacted with 2-amino-3,5-dihalopyrazine to give compound (viii). Finally, compound (vi) and compound (viii) can be coupled using a transition metal catalyzed reaction to give compound (ix) [i.e., formula (Ia)].

[0171] Option IV

[0172]

[0173] For example, a compound of formula (Ia) can be formed as shown in Scheme IV. Compound (i) can be deprotected to give compound (ii); compound (ii) can be cyclized with formaldehyde to give compound (iii); compound (iii) can be deprotected to give compound (iv); compound (iv) can be alkylated to give compound (v); compound (v) can be borylated to give compound (vi); compound (vi) can be selectively coupled with 2-amino-3,5-dihalopyrazine to give compound (vii); compound (vii) can be linked to compound (viii) to give compound (ix) [i.e., formula (Ia)].

[0174] Plan V

[0175]

[0176] For example, a compound of formula (Ib) can be formed as shown in Scheme V. Compound (i) can be derivatized with O-pivaloylhydroxylamine to give compound (ii); compound (ii) can be cyclized with ethylene using a transition metal catalyzed reaction to give compound (iii); compound (iii) can be reduced to give compound (iv); compound (iv) can be alkylated to give compound (v); compound (v) can be borylated to give compound (vi). Compound (vii) can be deprotonated and reacted with 2-amino-3,5-dihalopyrazine to give compound (viii). Finally, compound (vi) and compound (viii) can be coupled using a transition metal catalyzed reaction to give compound (ix) [i.e., formula (Ib)].

[0177] Plan VI

[0178]

[0179] For example, a compound of formula (Ib) can be formed as shown in Scheme VI. Compound (i) can be derivatized with O-pivaloylhydroxylamine to give compound (ii); compound (ii) can be cyclized with ethylene using a transition metal catalyzed reaction to give compound (iii); compound (iii) can be reduced to give compound (iv); compound (iv) can be alkylated to give compound (v); compound (v) can be borylated to give compound (vi); compound (vi) can be selectively coupled with 2-amino-3,5-dihalopyrazine to give compound (vii); compound (vii) can be linked with compound (viii) to give compound (ix) [i.e., formula (Ib)].

[0180] abbreviation

[0181] Boc tert-butyloxycarbonyl

[0182] Me methyl

[0183] TEA triethylamine

[0184] TFAA trifluoroacetic anhydride

[0185] LC-MS liquid chromatography-mass spectrometry

[0186] NMR Nuclear Magnetic Resonance

[0187] DCM dichloromethane

[0188] Et ethyl

[0189] Ac acetyl

[0190] BPD Bis(pinacol)diboron

[0191] dppf 1,1'-bis(diphenylphosphino)ferrocene

[0192] THF Tetrahydrofuran

[0193] HPLC high-performance liquid chromatography

[0194] DMSO dimethyl sulfoxide

[0195] PE petroleum ether

[0196] DMF N,N-dimethylformamide

[0197] Butyl

[0198] Ph Phenyl

[0199] TLC thin layer chromatography

[0200] UV

[0201] dba dibenzylideneacetone

[0202] Tf trifluorosulfonyl

[0203] MTBE Methyl tert-butyl ether

[0204] DIPEA N,N-Diisopropylethylamine

[0205] SEM 2-(trimethylsilyl)ethoxymethyl

[0206] LDA lithium diisopropylamide

[0207] pTSA p-Toluenesulfonic acid

[0208] HATU 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0209] DMAP 4-dimethylaminopyridine

[0210] Examples

[0211] Example 1: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(pyridin-4-ylmethoxy)pyrazine- 2-Amine

[0212]

[0213] Step 1: 2-(4-Bromo-2-methylphenyl)ethanamine hydrochloride

[0214]

[0215] To a solution of 2-(4-bromo-2-methylphenyl)acetonitrile (30.0 g, 0.143 mol) in MeOH (200 mL) was added NiCl2·6H2O (3.39 g, 0.0143 mol) and Boc2O (62.3 g, 0.286 mol) at 0°C. NaBH4 (64.8 g, 1.71 mol) was then added portionwise over 15 min. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with ice water. The resulting solution was extracted with ethyl acetate (1000 mL x 3). The organic phases were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. To the residue was added HCl (7N, 50 mL, 0.350 mol) in MeOH at room temperature, and the solution was stirred at room temperature for 16 h. The solvent was concentrated under reduced pressure to give the title compound (35.0 g, crude product). LC-MS (M+H) + =214.0.

[0216] Step 2: N-[2-(4-bromo-2-methylphenyl)ethyl]-2,2,2-trifluoroacetamide

[0217]

[0218] To a solution of 2-(4-bromo-2-methylphenyl)ethylamine hydrochloride (350 mg, crude product) in DCM (15 mL) was added TEA (345 mg, 3.42 mmol) and TFAA (356 mg, 1.70 mmol) at 0 ° C. under a nitrogen atmosphere with stirring. After 15 h, the reaction was quenched by adding water (20 mL). The resulting solution was extracted with DCM (35 mL x 3). The organic phases were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound (271 mg, 61% for 2 steps). LC-MS (M+H) + =310.0.

[0219] Step 3: 1-(7-Bromo-5-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone

[0220]

[0221] To a solution of N-[2-(4-bromo-2-methylphenyl)ethyl]-2,2,2-trifluoroacetamide (271 mg, 0.874 mmol) in AcOH (3 mL) was added H2SO4 (2 mL) and paraformaldehyde (176 mg, 1.95 mmol) at room temperature with stirring. After 16 h, the reaction was diluted by adding water (30 mL). The resulting solution was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by C18 column chromatography (eluted with MeCN (40% to 70%) in water) to give the title compound (100 mg, 36%). LC-MS (M+H) + =322.2.

[0222] Step 4: 7-Bromo-5-methyl-1,2,3,4-tetrahydroisoquinoline

[0223]

[0224] To a solution of 1-(7-bromo-5-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (100 mg, 0.270 mmol) in EtOH (5 mL) and water (1 mL) was added K2CO3 (147 mg, 1.06 mmol) at room temperature with stirring. The resulting mixture was warmed to 80°C. After 2 h, the reaction was cooled and diluted with water (10 mL). The resulting mixture was extracted with DCM (30 mL x 3). The organic phases were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound (49 mg, 81%). LC-MS (M+H) + =226.1.

[0225] Step 5: 7-Bromo-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline

[0226]

[0227] To a stirred solution of 7-bromo-5-methyl-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.398 mmol) and formalin (40%, 45 mg, 0.597 mmol) in MeOH (5 mL) was added portionwise NaBH3CN (39 mg, 0.60 mmol) at room temperature under a nitrogen atmosphere. After 3 h, the resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with DCM / MeOH (10:1)) to give the title compound (102 mg, 99%). LC-MS (M+H) + =240.0.

[0228] Step 6: 2,5-Dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline

[0229]

[0230] Under nitrogen, 7-bromo-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline (2.5 g, 10.4 mmol), BPD (3.96 g, 15.6 mmol), Pd(dppf)Cl2 (457 mg, 0.62 mmol) and AcOK (2.0 g, 20.8 mmol) were added to dioxane (50 mL). The reaction mixture was heated to reflux overnight and then cooled to room temperature. EtOAc (50 mL) was added and the mixture was washed with brine (30 mL x 2). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with MeOH / DCM (1:15)) to give the title compound (2.11 g, 71%). LC-MS (M+H) + =288.1.

[0231] Step 7: 5-Bromo-3-(pyridin-4-ylmethoxy)pyrazin-2-amine

[0232]

[0233] At room temperature, NaH (60%, 90 mg, 2.25 mmol) was added to a solution of 4-pyridinemethanol (246 mg, 2.25 mmol) in THF (15 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h. At room temperature, 3,5-dibromopyrazine-2-amine (475 mg, 1.88 mmol) was added to the above mixture in batches over 10 min. The resulting mixture was stirred at 70 ° C under a reflux condenser for another 2 h. The reaction mixture was cooled to room temperature and quenched by adding ice water (20 mL). The resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with ethyl acetate (0% to 80% gradient) in DCM) to give the title compound (76 mg, 56%). LC-MS (M+H) + =281.2.

[0234] Step 8: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(pyridin-4-ylmethoxy)pyrazin-2-amine

[0235]

[0236] 5-Bromo-3-(pyridin-4-ylmethoxy)pyrazin-2-amine (50 mg, 0.174 mmol), 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline (60 mg, 0.209 mmol), Pd(dppf)Cl2·DCM (15 mg, 0.017 mmol), and K2CO3 (49 mg, 0.348 mmol) were added to dioxane (4.0 mL) and water (1.0 mL) at room temperature. The resulting mixture was stirred at 100°C under nitrogen for 2 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by basic Al2O3 gel column chromatography (eluting with DCM / MeOH (1:1)) to yield a preliminarily purified substance. The material was purified by preparative HPLC to give Example 1 (37 mg, 58%). 1 H NMR(400MHz,DMSO-d6)δ8.61-8.55(m,2H),8.08(s,1H),7.60-7.54(m,2H),7.48(s,1H),7.36 (s,1H),6.51(s,2H),5.55(s,2H),3.48(s,2H),2.71-2.58(m,4H),2.34(s,3H),2.21(s,3H). LC-MS(M+H) + =362.2.

[0237] Example 2: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-methylpiperidin-4-yl)methoxy 1-Methyl-2-pyrazin-2-amine

[0238]

[0239] Step 1: 5-Bromo-3-((1-methylpiperidin-4-yl)methoxy)pyrazin-2-amine

[0240]

[0241] The title compound (149 mg, 57%) was prepared in a similar manner to Example 1, Step 7, from (1-methylpiperidin-4-yl)methanol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =301.1.

[0242] Step 2: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-methylpiperidin-4-yl)methoxy)pyrazin-2-amine

[0243]

[0244] Example 2 (23 mg, 13%) was prepared in a manner analogous to Example 1, Step 8 from 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline and 5-bromo-3-((1-methylpiperidin-4-yl)methoxy)pyrazin-2-amine. 1 H NMR (400MHz, DMSO-d6) δ8.02(s,1H),7.52(s,1H),7.40(s,1H),6.29(s,2H),4.24(d,J=6.0Hz,2H),3.50(s,2H),2.8 2(d,J=11.2Hz,2H),2.70-2.60(m,4H),2.34(s,3H),2.22(s,3H),2.18(s,3H),1.95-1.76(m,5H),1.42-1.28(m,2H). LC-MS(M+H) + =382.2.

[0245] Example 3: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(pyrimidin-4-ylmethoxy)pyrazine- 2-Amine

[0246]

[0247] Step 1: 5-Bromo-3-(pyrimidin-4-ylmethoxy)pyrazin-2-amine

[0248]

[0249] The title compound (185 mg, 31%) was prepared in a similar manner to Example 1, Step 7, from 3,5-dibromopyrazin-2-amine and pyrimidin-4-ylmethanol. LC-MS (M+H) + =282.0.

[0250] Step 2: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(pyrimidin-4-ylmethoxy)pyrazin-2-amine

[0251]

[0252] Example 3 (39 mg, 12%) was prepared in a manner analogous to Example 1, Step 8 from 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline and 5-bromo-3-(pyrimidin-4-ylmethoxy)pyrazin-2-amine. 1 H NMR (400MHz, DMSO-d6) δ9.19(s,1H),8.83(d,J=5.2Hz,1H),8.09(s,1H),7.81(d,J=5.2,1H),7.40(s, 1H),7.29(s,1H),6.59(s,2H),5.56(s,2H),3.47(s,2H),2.69-2.59(m,4H),2.35(s,3H),2.19(s,3H). LC-MS(M+H) + =363.2

[0253] Example 4: (1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H- Indazol-5-yl)methanol

[0254]

[0255] Step 1: (1-(3-amino-6-bromopyrazin-2-yl)-1H-indazol-5-yl)methanol

[0256]

[0257] The title compound (357 mg, 35%) was prepared in a similar manner to Example 1, Step 7 from 3,5-dibromopyrazin-2-amine and (1H-indazol-5-yl)methanol. LC-MS (M+H) + =320.2.

[0258] Step 2: (1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-indazol-5-yl)methanol

[0259]

[0260] Example 4 (8 mg, 6%) was prepared in a manner analogous to Example 1, Step 8 from 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline and (1-(3-amino-6-bromopyrazin-2-yl)-1H-indazol-5-yl)methanol. 1 H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.50-8.41(m,2H),7.86(s,1H),7.63(s,1H),7.58(d,J=8 .8Hz,1H),7.50(s,1H),4.65(s,2H),3.54(s,2H),2.72-2.56(m,4H),2.34(s,3H),2.24(s,3H). LC-MS(M+H) + =401.2.

[0261] Example 5: (2-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-2H- Indazol-5-yl)methanol

[0262]

[0263] Step 1: (2-(3-amino-6-bromopyrazin-2-yl)-2H-indazol-5-yl)methanol

[0264]

[0265] The title compound (260 mg, 26%) was another product isolated from Example 4, Step 1. LC-MS (M+H) + =320.2.

[0266] Step 2: (2-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-2H-indazol-5-yl)methanol

[0267]

[0268] Example 5 (14 mg, 10%) was prepared in a manner analogous to Example 1, Step 8 from 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline and (2-(3-amino-6-bromopyrazin-2-yl)-2H-indazol-5-yl)methanol. 1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.67(s,1H),7.76-7.69(m,3H),7.63(s,1H),7.34(d, J=8.9,1.6Hz,1H),4.56(s,2H),3.57(s,2H),2.74-2.63(m,4H),2.36(s,3H),2.26(s,3H). LC-MS(M+H) + =401.2.

[0269] Example 6: 3-(1H-pyrazol-4-yloxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrrolidone Oxazine-2-amine

[0270]

[0271] Step 1: 3-(1H-pyrazol-4-yloxy)-5-bromopyrazin-2-amine

[0272]

[0273] To a solution of 1H-pyrazol-4-ol (285 mg, 3.39 mmol) in DMSO (5 mL) was added 3,5-dibromopyrazin-2-amine (814 mg, 3.39 mmol) and K2CO3 (946 mg, 6.78 mmol) at room temperature. The resulting mixture was stirred at 75 ° C. overnight under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was loaded onto a C18 gel column (eluted with MeOH (10% to 95%) in water) to give the title compound (87 mg, 10%). LC-MS (M+H) + =256.0.

[0274] Step 2: 3-(1H-pyrazol-4-yloxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0275]

[0276] Example 6 (12 mg, 17%) was prepared in a manner analogous to Example 1, Step 8 from 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline and 3-(1H-pyrazol-4-yloxy)-5-bromopyrazin-2-amine. 1H NMR(400MHz,DMSO-d6)δ12.76(br s,1H),8.16(s,1H),7.83(br s,2H),7.45(s,1H),7.32(s,1H),6.62(s,2H),3.47(s,2H),2.70-2.57(m,4H),2.33(s,3H),2.20(s,3H). LC-MS(M+H) + =337.2.

[0277] Example 7: 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H- Pyrazole-4-ol

[0278]

[0279] Step 1: 1-(3-amino-6-bromopyrazin-2-yl)-1H-pyrazol-4-ol

[0280]

[0281] The title compound (70 mg, 21%) was another product isolated from Example 6, Step 1. LC-MS (M+H) + =256.0.

[0282]

[0283] Step 2: 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazol-4-ol

[0284]

[0285] Example 7 (13 mg, 9%) was prepared in a manner analogous to Example 1, Step 8 from 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline and 1-(3-amino-6-bromopyrazin-2-yl)-1H-pyrazol-4-ol. 1 H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.47(s,1H),8.26(s,1H),7.66(s,1H),7.5 4(s,2H),7.46(s,2H),3.53(s,2H),2.75-2.59(m,4H),2.35(s,3H),2.25(s,3H). LC-MS(M+H) + =337.1.

[0286] Example 8: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-fluoropyridin-4-yl)methoxy 1-Methyl-2-pyrazin-2-amine

[0287]

[0288] Step 1: 5-Bromo-3-((3-fluoropyridin-4-yl)methoxy)pyrazin-2-amine

[0289]

[0290] The title compound (648 mg, 64%) was prepared in a similar manner to Example 1, Step 7 from (3-fluoropyridin-4-yl)methanol and 5-bromo-3-chloropyrazin-2-amine. LC-MS (M+H) + =298.9.

[0291] Step 2: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-fluoropyridin-4-yl)methoxy)pyrazin-2-amine

[0292]

[0293] Example 8 (42 mg, 11%) was prepared in a manner similar to Example 1, Step 8 from 5-bromo-3-((3-fluoropyridin-4-yl)methoxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.46(d,J=4.9Hz,1H),8.10(s,1H),7.78-7.71(m,1H),7.49(s,1H) ,7.37(s,1H),6.54(s,2H),5.62(s,2H),3.55-3.51(m,2H),2.71-2.67(m,4H),2.38(s,3H),2.22(s,3H). LC-MS(M+H) + =380.3.

[0294] Example 9: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-methylpyridin-4-yl)methoxy 1-Methyl-2-pyrazin-2-amine

[0295]

[0296] Step 1: 5-Bromo-3-((3-methylpyridin-4-yl)methoxy)pyrazin-2-amine

[0297]

[0298] The title compound (360 mg, 63%) was prepared in a similar manner to Example 1, Step 7 from (3-methylpyridin-4-yl)methanol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =295.1.

[0299] Step 2: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-methylpyridin-4-yl)methoxy)pyrazin-2-amine

[0300]

[0301] Example 9 (23 mg, 15%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-((3-methylpyridin-4-yl)methoxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR (400MHz, DMSO-d6) δ8.44-8.37(m,2H),8.06(s,1H),7.53(d,J=5.0Hz,1H),7.47(s,1H),7.36(s,1 H),6.49(s,2H),5.53(s,2H),3.48(s,2H),2.69-2.58(m,4H),2.39(s,3H),2.34(s,3H),2.20(s,3H). LC-MS(M+H) + =376.2.

[0302] Example 10: 3-((2-aminopyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin- 7-aminobenzoic acid)pyrazin-2-amine

[0303]

[0304] Step 1: 3-((2-aminopyridin-4-yl)methoxy)-5-bromopyrazin-2-amine

[0305]

[0306] The title compound (721 mg, 66%) was prepared in a similar manner to Example 1, Step 7 from (2-aminopyridin-4-yl)methanol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =296.1.

[0307] Step 2: 3-((2-aminopyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0308]

[0309] Example 10 (18 mg, 9%) was prepared in a manner analogous to Example 1, Step 8, from 3-((2-aminopyridin-4-yl)methoxy)-5-bromopyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.89(d,J=5.2Hz,1H),7.49(s,1H),7.36(s,1H),6.63(d,J=5.3Hz,1H),6 .54(s,1H),6.43(s,2H),5.90(s,2H),5.38(s,2H),3.49(s,2H),2.71-2.58(m,4H),2.35(s,3H),2.21(s,3H). LC-MS(M+H) + =376.2.

[0310] Example 11: 3-((2-(cyclopropylethynyl)pyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetramethyl (2-Hydroisoquinolin-7-yl)pyrazin-2-amine

[0311]

[0312] Step 1: (2-(cyclopropylethynyl)pyridin-4-yl)methanol

[0313]

[0314] To an 8 mL sealed tube was added ethynylcyclopropane (112 mg, 1.60 mmol), (2-bromopyridin-4-yl)methanol (200 mg, 1.04 mmol), CuI (40 mg, 0.198 mmol), Pd(dppf)Cl2 (152 mg, 0.198 mmol), Et3N (3.80 mL, 27 mmol) and THF (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 20 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (1:1)) to give the title compound (163 mg, 91%). LC-MS (M+H) + =174.1.

[0315] Step 2: 5-Bromo-3-((2-(cyclopropylethynyl)pyridin-4-yl)methoxy)pyrazin-2-amine

[0316]

[0317] The title compound (48 mg, 12%) was prepared in a manner similar to that in Example 1, Step 7, from (2-(cyclopropylethynyl)pyridin-4-yl)methanol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =344.9.

[0318] Step 3: 3-((2-(cyclopropylethynyl)pyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0319]

[0320] Example 11 (10 mg, 16%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-((2-(cyclopropylethynyl)pyridin-4-yl)methoxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR (400MHz, DMSO-d6) δ8.48(d,J=5.1Hz,1H),8.07(s,1H),7.62(s,1H),7.51-7.44(m,2H),7.34(s,1H),6.54(s,2H),5.50 (s,2H),3.49(s,2H),2.69-2.59(m,4H),2.35(s,3H),2.21(s,3H),1.64-1.53(m,1H),0.98-0.87(m,2H),0.82-0.74(m,2H). LC-MS(M+H) + =426.3.

[0321] Example 12: 3-((2-chloro-5-isopropoxypyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetramethyl (2-Hydroisoquinolin-7-yl)pyrazin-2-amine

[0322]

[0323] Step 1: 5-Bromo-3-((2-chloro-5-fluoropyridin-4-yl)methoxy)pyrazin-2-amine

[0324]

[0325] The title compound (341 mg, 86%) was prepared in a similar manner to Example 1, Step 7, from (2-chloro-5-fluoropyridin-4-yl)methanol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =332.8.

[0326] Step 2: 3-((2-chloro-5-fluoropyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0327]

[0328] The title compound (32 mg, 17%) was prepared in a manner analogous to that described in Example 1, Step 8, from 5-bromo-3-((2-chloro-5-fluoropyridin-4-yl)methoxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H),8.11(s,1H),7.98(d,J=5.1Hz,1H),7.49(s,1H),7.37( s,1H),6.62(s,2H),5.59(s,2H),3.49(s,2H),2.71-2.58(m,4H),2.34(s,3H),2.21(s,3H). LC-MS(M+H) + =414.1.

[0329] Step 3: 3-((2-chloro-5-isopropoxypyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0330]

[0331] To a solution of 3-((2-chloro-5-fluoropyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (78 mg, 0.188 mmol) in DMF (5 mL) was added CsCO (117 mg, 0.377 mmol) and isopropanol (11 mg, 0.189 mmol) at room temperature. The resulting mixture was stirred at 100 ° C for 1.5 h. The reaction mixture was cooled to room temperature and the solvent was concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 12 (24 mg, 27%). 1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.11(s,1H),7.74(s,1H),7.52(s,1H),7.39(s,1H),6.63(s,2H),5.51(d,J =1.0Hz,2H),4.88-4.77(m,1H),3.56(s,2H),2.73-2.68(m,4H),2.40(s,3H),2.22(s,3H),1.34(d,J=6.0Hz,6H). LC-MS(M+H) + =455.0.

[0332] Example 13: 3-(6,7-dihydro-5H-cyclopenta[c]pyridin-5-yloxy)-5-(2,5-dimethyl-1,2,3,4-tetrakis (2-Hydroisoquinolin-7-yl)pyrazin-2-amine

[0333]

[0334] Step 1: 5-Bromo-3-(6,7-dihydro-5H-cyclopenta[c]pyridin-5-yloxy)pyrazin-2-amine

[0335]

[0336] To a solution of 5H,6H,7H-cyclopenta[c]pyridin-5-ol (120 mg, 0.890 mmol) in THF (8 mL) was added NaH (60%, 36 mg, 0.890 mmol) at 0 ° C. The resulting mixture was stirred at 0 ° C for 20 min. To the above mixture was added 3,5-dibromopyrazin-2-amine (150 mg, 0.593 mmol). The resulting mixture was stirred at 70 ° C for 16 h. The reaction mixture was cooled to room temperature and quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH / DCM (0% to 10% gradient)) to give the title compound (152 mg, 88%). LC-MS (M+H) + =307.0.

[0337] Step 2: 3-(6,7-dihydro-5H-cyclopenta[c]pyridin-5-yloxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0338]

[0339] Example 13 (24 mg, 12%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-(6,7-dihydro-5H-cyclopenta[c]pyridin-5-yloxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.42(d,J=5.0Hz,1H),8.11(s,1H),7.60(s,1H),7.51-7.44(m,2H),6.67-6.59(m,1H),6. 33(s,2H),3.34(s,2H),3.24-3.12(m,1H),3.00(m,1H),2.79-2.66(m,3H),2.66-2.59(m,2H),2.34(s,3H),2.30-2.13(m,4H). LC-MS(M+H) + =388.2.

[0340] Example 14: 4-(4-(((3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazine-2-yl)pyrazine (2-Methyl)but-3-yn-2-ol)

[0341]

[0342] Step 1: (2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid

[0343]

[0344] To a solution of 7-bromo-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline (20.0 g, 83.3 mmol) in THF (200 mL) was added n-BuLi (1.6 M, 78 mL, 125 mmol) dropwise at -78 ° C. After addition, the mixture was stirred at -78 ° C for 30 min. Triisopropyl borate (23.5 g, 125 mmol) was added dropwise to the mixture at -78 ° C. The mixture was stirred at -78 ° C for 1 h and at 0 ° C for 30 min. The mixture was quenched with water (200 mL), basified to pH = 14 with aqueous NaOH solution (2 M), and washed with EtOAc (50 mL). The aqueous layer was acidified to pH = 9 with aqueous HCl solution (1 M). The precipitate was collected by filtration and dried under vacuum to give the title compound (15.0 g, 87%). LC-MS (M+H) + =206.0.

[0345] Step 2: 4-(4-(Hydroxymethyl)pyridin-2-yl)-2-methylbut-3-yn-2-ol

[0346]

[0347] To a solution of (2-bromopyridin-4-yl)methanol (1.0 g, 5.3 mmol) and 2-methylbut-3-yn-2-ol (0.5 g, 5.9 mmol) in THF (20 mL) was added CuI (30 mg, 0.16 mmol), PPh3 (70 mg, 0.27 mmol), Pd(PPh3)2Cl2 (75 mg, 0.11 mmol) and Et3N (6 mL). The mixture was stirred at 70 ° C under N2 overnight. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (1: 1)) to give the title compound (800 mg, 79%). LC-MS (M+H) + =192.0.

[0348] Step 3: 4-(4-(((3-amino-6-bromopyrazin-2-yl)oxy)methyl)pyridin-2-yl)-2-methylbut-3-yn-2-ol

[0349]

[0350] To a solution of 4-(4-(hydroxymethyl)pyridin-2-yl)-2-methylbut-3-yn-2-ol (100 mg, 0.52 mmol) in DMF (5 mL) was added NaH (60%, 65 mg, 1.63 mmol) at 0°C. The mixture was stirred at 0°C for 10 min. 3,5-dibromopyrazin-2-amine (130 mg, 0.52 mmol) was added to the mixture. The mixture was stirred at 0°C for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (30 mL), brine (30 mL) and dried over Na2SO4. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (1:1)) to give the title compound (150 mg, 79%). LC-MS (M+H) + =362.9,364.9.

[0351] Step 4: 4-(4-(((3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)oxy)methyl)pyridin-2-yl)-2-methylbut-3-yn-2-ol

[0352]

[0353] To a mixture of 4-(4-(((3-amino-6-bromopyrazin-2-yl)oxy)methyl)pyridin-2-yl)-2-methylbut-3-yn-2-ol (150 mg, 0.41 mmol) and (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid (90 mg, 0.47 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was added Pd(dppf)Cl (20 mg, 0.02 mmol) and KCO (120 mg, 0.87 mmol). The mixture was stirred at 80 ° C under N for 15 hours. The mixture was cooled to room temperature and diluted with water (10 mL), then extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over NaSO, filtered and concentrated. The residue was purified by preparative TLC (DCM / MeOH=10:1) to give Example 14 (30 mg, 16%). 1 HNMR (400MHz, DMSO-d6) δ8.53(d,J=4.7Hz,1H),8.07(s,1H),7.62(s,1H),7.54(d,J=5.0Hz,1H),7.46(s,1H),7.35(s ,1H),6.53(s,2H),5.57(s,1H),5.53(s,2H),3.48(s,2H),2.72-2.57(m,4H),2.35(s,3H),2.21(s,3H),1.47(s,6H). LC-MS(M+H) + =444.5.

[0354] Example 15: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(pyridin-3-ylmethoxy)pyrrolidone Oxazine-2-amine

[0355]

[0356] Step 1: 5-Bromo-3-(pyridin-3-ylmethoxy)pyrazin-2-amine

[0357]

[0358] At 0 ° C, NaH (60%, 240 mg, 6.0 mmol) was added in batches to a solution of pyridin-3-ylmethanol (654 mg, 6.0 mmol) in THF (20 mL). The mixture was stirred for 30 min, and then 3,5-dibromopyrazin-2-amine (1.0 g, 4.0 mmol) was added. The mixture was stirred at 70 ° C for 2 h. After cooling to room temperature, the reaction mixture was concentrated, diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (800 mg, 71%). LC-MS (M+H) + =281.0,283.0.

[0359] Step 2: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(pyridin-3-ylmethoxy)pyrazin-2-amine

[0360]

[0361] Under N2, 5-bromo-3-(pyridin-3-ylmethoxy)pyrazin-2-amine (300 mg, 1.1 mmol), (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid (328 mg, 1.6 mmol), Pd(dppf)Cl2 (87.3 mg, 0.11 mmol) and K2CO3 (368 mg, 2.7 mmol) were added to dioxane (10 mL) and H2O (2.5 mL). The mixture was warmed to 80°C and stirred overnight. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried, filtered and concentrated. The residue was purified by preparative HPLC to give Example 15 (24 mg, 6%). 1 H NMR (400MHz, DMSO-d6) δ8.79(s,1H),8.53(d,J=4.0Hz,1H),8.07(s,1H),7.98(d,J=8.0Hz,1H),7.56(s ,1H),7.41-7.44(m,2H),6.44(s,2H),5.54(s,2H),3.61(s,2H),2.67(s,4H),2.33(s,3H),1.91(s,3H). LC-MS(M+H) + =362.4.

[0362] Example 16: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-methylpyridin-4-yl)methane (2-Methyl-2-oxy)pyrazin-2-amine

[0363]

[0364] Step 1: 5-Bromo-3-((2-methylpyridin-4-yl)methoxy)pyrazin-2-amine

[0365]

[0366] At 0 ° C, NaH (60%, 195 mg, 4.9 mmol) was added portionwise to a solution of (2-methylpyridin-4-yl)methanol (500 mg, 4.0 mmol) in THF (10 mL). The reaction mixture was stirred for 30 min, and then 3,5-dibromopyrazine-2-amine (1.1 g, 4.5 mmol) was added. The mixture was stirred at 70 ° C for 2 h. After cooling to room temperature, the reaction mixture was concentrated, diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried, filtered, and concentrated. The residue was purified by silica gel chromatography to give the title compound (1.0 g, 83%). LC-MS (M+H) + =295.0,297.0.

[0367] Step 2: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-methylpyridin-4-yl)methoxy)pyrazin-2-amine

[0368]

[0369] Under N2, 5-bromo-3-((2-methylpyridin-4-yl)methoxy)pyrazin-2-amine (200 mg, 0.7 mmol), (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid (209 mg, 1.0 mmol), Pd(dppf)Cl2 (44 mg, 0.05 mmol) and K2CO3 (235 mg, 1.7 mmol) were added to dioxane (7.5 mL) and H2O (2.5 mL). The mixture was warmed to 80°C and stirred overnight. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried, filtered and concentrated. The residue was purified by preparative HPLC to give Example 16 (45 mg, 17%). 1 H NMR(400MHz, DMSO-d6)δ8.43(d,J=4.0Hz,1H),8.07(s,1H),7.52-7.42(m,2H),7.34-7.37(m,2H), 6.50(s,2H),5.50(s,2H),3.49(s,2H),2.70-2.60(m,4H),2.50(s,3H),2.35(s,3H),2.21(s,3H). LC-MS(M+H) +=376.4.

[0370] Example 17: 3-((2,6-dichlorobenzyl)oxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) Pyrazin-2-amine

[0371]

[0372] Step 1: 5-Bromo-3-((2,6-dichlorobenzyl)oxy)pyrazin-2-amine

[0373]

[0374] NaH (60%, 40 mg, 1.0 mmol) was added to a solution of 3,5-dibromopyrazin-2-amine (200 mg, 0.80 mmol) and (2,6-dichlorophenyl)methanol (140 mg, 0.80 mmol) in THF (15 mL). The reaction mixture was heated to reflux overnight. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by preparative TLC (PE / EtOAc=5:1) to give the title compound (53 mg, 19%). LC-MS (M+H) + =347.9,349.9.

[0375] Step 2: 3-((2,6-dichlorobenzyl)oxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0376]

[0377] Under nitrogen, 5-bromo-3-((2,6-dichlorobenzyl)oxy)pyrazin-2-amine (53 mg, 0.15 mmol), 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (52 mg, 0.18 mmol), Pd(dppf)Cl2 (11 mg, 0.02 mmol), and K2CO3 (42 mg, 0.30 mmol) were added to a mixture of dioxane (10 mL) and water (2 mL). The reaction mixture was heated to reflux overnight. The mixture was cooled to room temperature and diluted with water (20 mL), then extracted with EtOAC (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by preparative TLC (DCM / MeOH=10:1) to give Example 17 (3 mg, 5%). 1HNMR(400MHz,DMSO-d6)δ8.15(s,1H),7.75(s,1H),7.65-7.53(m,3H),7.48(s,1H),6.3 6(s,2H),5.66(s,2H),4.30(s,2H),3.37(s,2H),2.94(s,2H),2.85(s,3H),2.29(s,3H). LC-MS(M+H) + =429.1.

[0378] Example 18: 3-(Benzyloxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0379]

[0380] Step 1: 3-(Benzyloxy)-5-bromopyrazin-2-amine

[0381]

[0382] Under nitrogen, NaH (60%, 52 mg, 1.3 mmol) was added to a solution of 3,5-dibromopyrazine-2-amine (253 mg, 1.0 mmol) and benzyl alcohol (108 mg, 1.0 mmol) in THF (10 mL). The solution was heated to reflux for 4 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc (20 mL), washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC (PE / EA=5:1) to give the title compound (170 mg, 61%). LC-MS (M+H) + =280.0,282.0.

[0383] Step 2: 3-(Benzyloxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0384]

[0385] Example 18 (25 mg, 11%) was prepared in a manner analogous to Example 17, Step 2, from (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid and 3-(benzyloxy)-5-bromopyrazin-2-amine. 1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.59-7.49(m,3H),7.44-7.36(m,3H),7.32(t,J=7.1H z,1H),6.37(s,2H),5.51(s,2H),3.51(s,2H),2.70-2.55(m,4H),2.35(s,3H),2.22(s,3H). LC-MS(M+H) + =361.2.

[0386] Example 19: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-(pyridin-3-ylethynyl) (4-pyridinyl)methoxy)pyrazin-2-amine

[0387]

[0388] Step 1: (2-(Pyridin-3-ylethynyl)pyridin-4-yl)methanol

[0389]

[0390] Under nitrogen, (2-bromopyridin-4-yl)methanol (548 mg, 2.9 mmol), 3-ethynylpyridine (300 mg, 2.9 mmol), Pd(PPh 3 )Cl 2 (90 mg, 0.2 mmol), CuI (28 mg, 0.15 mmol) and Et 3 N (2.0 mL, 14.6 mmol) were added to THF (20 mL). The reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL), washed with brine (20 mL) and dried over Na 2 SO 4 . The crude product was purified by preparative TLC (DCM / MeOH = 20: 1) to give the title compound (380 mg, 62%). LC-MS (M + H) + =211.0.

[0391] Step 2: 5-Bromo-3-((2-(pyridin-3-ylethynyl)pyridin-4-yl)methoxy)pyrazin-2-amine

[0392]

[0393] 3,5-Dibromopyrazin-2-amine (458 mg, 1.8 mmol), (2-(pyridin-3-ylethynyl)pyridin-4-yl)methanol (380 mg, 1.8 mmol) and NaH (60%, 217 mg, 5.4 mmol) were sequentially added to THF (20 mL). The reaction mixture was stirred at room temperature overnight, then diluted with EtOAc (20 mL), washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by preparative TLC (PE / EtOAc=5:1) to give the title compound (200 mg, 29%). LC-MS (M+H) + =382.0.

[0394] Step 3: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-(pyridin-3-ylethynyl)pyridin-4-yl)methoxy)pyrazin-2-amine

[0395]

[0396] Example 19 (20 mg, 8%) was prepared in a manner analogous to Example 17, Step 2, from (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid and 5-bromo-3-((2-(pyridin-3-ylethynyl)pyridin-4-yl)methoxy)pyrazin-2-amine. 1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.67-8.61(m,2H),8.09(s,1H),8.05(d,J=7.9Hz,1H),7.93(s,1H),7.62(d,J=4.8Hz,1 H),7.54-7.46(m,2H),7.35(s,1H),6.57(s,2H),5.57(s,2H),3.50(s,2H),2.64(d,J=7.6Hz,4H),2.31(s,3H),2.21(s,3H). LC-MS(M+H) + =463.2.

[0397] Example 20: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-((4-fluorophenyl)acetylene 4-(2-Yl)pyridin-4-yl)methoxy)pyrazin-2-amine

[0398]

[0399] Step 1: (2-((4-Fluorophenyl)ethynyl)pyridin-4-yl)methanol

[0400]

[0401] The title compound (430 mg, 76%) was prepared in a similar manner to Example 19, Step 1, from (2-bromopyridin-4-yl)methanol and 1-ethynyl-4-fluorobenzene. LC-MS (M+H) + =227.1.

[0402] Step 2: 5-Bromo-3-((2-((4-fluorophenyl)ethynyl)pyridin-4-yl)methoxy)pyrazin-2-amine

[0403]

[0404] The title compound (140 mg, 19%) was prepared in a similar manner to Example 19, step 2 from 3,5-dibromopyrazin-2-amine and (2-((4-fluorophenyl)ethynyl)pyridin-4-yl)methanol. LC-MS (M+H) + =399.0.

[0405] Step 3: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-((4-fluorophenyl)ethynyl)pyridin-4-yl)methoxy)pyrazin-2-amine

[0406]

[0407] Example 20 (20 mg, 12%) was prepared in a manner analogous to Example 17, Step 2, from (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid and 5-bromo-3-((2-((4-fluorophenyl)ethynyl)pyridin-4-yl)methoxy)pyrazin-2-amine. 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=4.8Hz,1H),8.08(s,1H),7.88(s,1H),7.72-7.66(m,2H),7.59(d,J=4.9Hz,1H),7.48(s,1H),7 .38-7.28(m,3H),6.56(s,2H),5.56(s,2H),3.49(s,2H),2.65(d,J=4.5Hz,2H),2.61(d,J=4.2Hz,2H),2.30(s,3H),2.21(s,3H). LC-MS(M+H) + =480.2.

[0408] Example 21: 3-((3-chloropyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1-Methyl-2-pyrazin-2-amine

[0409]

[0410] Step 1: 5-Bromo-3-((3-chloropyridin-4-yl)methoxy)pyrazin-2-amine

[0411]

[0412] The title compound (80 mg, 18%) was prepared in a similar manner to Example 17, step 1, from 3,5-dibromopyrazin-2-amine and (3-chloropyridin-4-yl)methanol. LC-MS (M+H) + =314.9,316.9.

[0413] Step 2: 3-((3-chloropyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0414]

[0415] Example 21 (20 mg, 12%) was prepared in a manner analogous to Example 17, Step 2, from (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid and 5-bromo-3-((3-chloropyridin-4-yl)methoxy)pyrazin-2-amine. 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.53(d,J=4.9Hz,1H),8.09(s,1H),7.73(d,J=4.8Hz,1H),7.45(s ,1H),7.33(s,1H),6.57(s,2H),5.61(s,2H),3.47(s,2H),2.72-2.60(m,2H),2.34(s,3H),2.19(s,3H). LC-MS(M+H) + =396.1.

[0416] Example 22: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(quinolin-4-ylmethoxy)pyrrolidone Oxazine-2-amine

[0417]

[0418] Step 1: Quinolin-4-ylmethanol

[0419]

[0420] At 0 ° C, NaBH4 (582 mg, 15.4 mmol) was added to a solution of quinoline-4-carboxaldehyde (2.0 g, 12.8 mmol) in MeOH (25 mL). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. Water (10 mL) was added and the mixture was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. The residue was purified by silica gel chromatography to give the title compound (1.9 g, 94%). LC-MS (M+H) + =160.0.

[0421] Step 2: 5-Bromo-3-(quinolin-4-ylmethoxy)pyrazin-2-amine

[0422]

[0423] At 0 ° C, NaH (60%, 119 mg, 2.97 mmol) was added to a solution of quinolin-4-ylmethanol (313 mg, 1.98 mmol) and 3,5-dibromopyrazin-2-amine (500 mg, 1.98 mmol) in anhydrous THF (20 mL). The reaction mixture was heated to 50 ° C and stirred overnight. After cooling to 0 ° C, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. The residue was purified by silica gel chromatography to give the title compound (261 mg, 40%). LC-MS (M+H) + =331.0.

[0424] Step 3: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(quinolin-4-ylmethoxy)pyrazin-2-amine

[0425]

[0426] 5-Bromo-3-(quinolin-4-ylmethoxy)pyrazin-2-amine (261 mg, 0.79 mmol), (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid (242 mg, 1.82 mmol), K2CO3 (218 mg, 1.58 mmol) and Pd(dppf)Cl2 (29 mg, 0.04 mmol) were dissolved in a mixture of 1,4-dioxane (20 mL) and water (4 mL). Under N2, the mixture was heated to 90°C overnight. After cooling to room temperature, the solvent was removed in vacuo. Brine (15 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. The residue was purified by preparative HPLC to give Example 22 (93 mg, 29%). 1 H NMR (400MHz, DMSO-d6) δ8.90(d,J=3.6Hz,1H),8.31(d,J=8.1Hz,1H),8.09(d,J=7.1Hz,2H),7.82(t,J=7.2Hz,1H),7.79-7 .63(m,2H),7.45(s,1H),7.29(s,1H),6.56(s,2H),6.04(s,2H),3.56(s,2H),2.69-2.77(m,4H),2.44(s,3H),2.15(s,3H). LC-MS(M+H) + =412.0.

[0427] Example 23: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-(pyridin-4-ylethynyl) (4-pyridinyl)methoxy)pyrazin-2-amine

[0428]

[0429] Step 1: (2-(pyridin-4-ylethynyl)pyridin-4-yl)methanol

[0430]

[0431] The title compound (335 mg, 82%) was prepared in a similar manner to Example 19, Step 1 from 4-ethynylpyridine and (2-bromopyridin-4-yl)methanol. LC-MS (M+H) + =211.0.

[0432] Step 2: 5-Bromo-3-((2-(pyridin-4-ylethynyl)pyridin-4-yl)methoxy)pyrazin-2-amine

[0433]

[0434] The title compound (330 mg, 54%) was prepared in a similar manner to Example 19, Step 2 from 3,5-dibromopyrazin-2-amine and (2-(pyridin-4-ylethynyl)pyridin-4-yl)methanol. LC-MS (M+H) + =382.0.

[0435] Step 3: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-(pyridin-4-ylethynyl)pyridin-4-yl)methoxy)pyrazin-2-amine

[0436]

[0437] Example 23 (89 mg, 22%) was prepared in a manner analogous to Example 17, Step 2, from (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid and 5-bromo-3-((2-(pyridin-4-ylethynyl)pyridin-4-yl)methoxy)pyrazin-2-amine. 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=4.7Hz,2H),8.64(d,J=5.0Hz,1H),8.09(s,1H),7.96(s,1H),7.65(d,J=4.7Hz,1H),7.59(d ,J=4.6Hz,2H),7.48(s,1H),7.35(s,1H),6.58(s,2H),5.57(s,2H),3.48(s,2H),2.60-2.65(m,4H),2.29(s,3H),2.20(s,3H). LC-MS(M+H) + =463.0.

[0438] Example 24: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-(3,3-dimethylbutane-1- (alkyn-1-yl)pyridin-4-yl)methoxy)pyrazin-2-amine

[0439]

[0440] Step 1: (2-(3,3-Dimethylbut-1-yn-1-yl)pyridin-4-yl)methanol

[0441]

[0442] The title compound (240 mg, 79%) was prepared in a similar manner to Example 14, step 2, from (2-bromopyridin-4-yl)methanol and 3,3-dimethylbut-1-yne. LC-MS (M+H) + =190.1.

[0443] Step 2: 5-Bromo-3-((2-(3,3-dimethylbut-1-yn-1-yl)pyridin-4-yl)methoxy)pyrazin-2-amine

[0444]

[0445] The title compound (250 mg, 53%) was prepared in a similar manner to Example 14, step 3, from (2-(3,3-dimethylbut-1-yn-1-yl)pyridin-4-yl)methanol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =360.9,362.9.

[0446] Step 3: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-(3,3-dimethylbut-1-yn-1-yl)pyridin-4-yl)methoxy)pyrazin-2-amine

[0447]

[0448] Example 24 (100 mg, 32%) was prepared in a manner analogous to Example 14, Step 4, from 5-bromo-3-((2-(3,3-dimethylbut-1-yn-1-yl)pyridin-4-yl)methoxy)pyrazin-2-amine and (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 H NMR (400MHz, DMSO-d6) δ8.50(d,J=5.0Hz,1H),8.07(s,1H),7.60(s,1H),7.51(d,J=5.0Hz,1H),7.46(s,1H),7.35(s,1H ),6.54(s,2H),5.51(s,2H),3.48(s,2H),2.70-2.64(m,2H),2.64-2.58(m,2H),2.34(s,3H),2.21(s,3H),1.30(s,9H). LC-MS(M+H) + =442.5.

[0449] Example 25: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-(prop-1-ynyl)pyridine- 4-amino)methoxy)pyrazin-2-amine

[0450]

[0451] Step 1: (2-(Propan-1-ynyl)pyridin-4-yl)methanol

[0452]

[0453] The title compound (270 mg, 90%) was prepared in a similar manner to Example 11, Step 1, from (2-bromopyridin-4-yl)methanol and prop-1-yne. LC-MS (M+H) + =147.9.

[0454] Step 2: 5-Bromo-3-((2-(prop-1-ynyl)pyridin-4-yl)methoxy)pyrazin-2-amine

[0455]

[0456] The title compound (120 mg, 45%) was prepared in a manner similar to that in Example 1, Step 7, from (2-(prop-1-ynyl)pyridin-4-yl)methanol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =319.0.

[0457] Step 3: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-(prop-1-ynyl)pyridin-4-yl)methoxy)pyrazin-2-amine

[0458]

[0459] Example 25 (15 mg, 11%) was prepared in a manner analogous to Example 1, Step 8 from 5-bromo-3-((2-(prop-1-ynyl)pyridin-4-yl)methoxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=5.1Hz,1H),8.08(s,1H),7.65(s,1H),7.53-7.45(m,2H),7.35(s,1 H),6.53(s,2H),5.52(s,2H),3.50(s,2H),2.71-2.59(m,4H),2.36(s,3H),2.22(s,3H),2.08(s,3H). LC-MS(M+H) + =400.2.

[0460] Example 26: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(5,6,7,8-tetrahydroisoquinolin- 5-aminobenzoic acid)pyrazin-2-amine

[0461]

[0462] Step 1: 3-Chloro-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0463]

[0464] The title compound (720 mg, 79%) was prepared in a manner similar to that in Example 1, Step 8, from 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline and 5-bromo-3-chloropyrazin-2-amine. LC-MS (M+H) + =289.2.

[0465] Step 2: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(5,6,7,8-tetrahydroisoquinolin-5-yloxy)pyrazin-2-amine

[0466]

[0467] Example 26 (26 mg, 21%) was prepared in a manner analogous to Example 1, Step 7, from 5,6,7,8-tetrahydroisoquinolin-5-ol and 3-chloro-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine. 1H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.35(d,J=5.1Hz,1H),8.09(s,1H),7.56(s,1H),7.44(s,1H),7.34(d,J=5.1Hz,1H),6.43(t,J=5.5Hz,1H),6 .30(s,2H),3.50(s,2H),2.94-2.73(m,2H),2.71-2.59(m,4H),2.34(s,3 H),2.23(s,3H),2.23-2.15(m,1H),2.10-1.98(m,1H),1.94-1.86(m,1H). LC-MS(M+H) + =402.2.

[0468] Example 27: 3-((5-chloropyridin-3-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1-Methyl-2-pyrazin-2-amine

[0469]

[0470] Step 1: 5-Bromo-3-((5-chloropyridin-3-yl)methoxy)pyrazin-2-amine

[0471]

[0472] The title compound (387 mg, 90%) was prepared in a similar manner to Example 1, Step 7 from (5-chloropyridin-3-yl)methanol and 5-bromo-3-chloropyrazin-2-amine. LC-MS (M+H) +=316.9.

[0473] Step 2: 3-((5-chloropyridin-3-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0474]

[0475] Example 27 (32 mg, 14%) was prepared in a manner analogous to Example 1, Step 8 from 5-bromo-3-((5-chloropyridin-3-yl)methoxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.60(s,1H),8.22(s,1H),8.09(s,1H),7.55(s,1H),7.4 3(s,1H),6.50(s,2H),5.56(s,2H),3.52(s,2H),2.73-2.61(m,4H),2.36(s,3H),2.24(s,3H). LC-MS(M+H) + =396.0.

[0476] Example 28: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-methoxypyridin-4-yl) (methoxy)pyrazin-2-amine

[0477]

[0478] Step 1: (3-Methoxypyridin-4-yl)methanol

[0479]

[0480] BH3 (1.0 M, 26.2 mL, 26.2 mmol) in THF was added to a solution of 3-methoxyisonicotinic acid (2.0 g, 13.1 mmol) in anhydrous THF (10 mL). The mixture was stirred at room temperature overnight and then cooled to 0°C before the addition of MeOH (20 mL). HCl (4.0 M, 10 mL) in dioxane was added and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (492 mg, 26%). LC-MS (M+H) + =140.0.

[0481] Step 2: 5-Bromo-3-((3-methoxypyridin-4-yl)methoxy)pyrazin-2-amine

[0482]

[0483] The title compound (335 mg, 55%) was prepared in a similar manner to Example 17, step 1, from 3,5-dibromopyrazin-2-amine and (3-methoxypyridin-4-yl)methanol. LC-MS (M+H) + =311.0.

[0484] Step 3: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-methoxypyridin-4-yl)methane (2-Methyl-2-oxy)pyrazin-2-amine

[0485]

[0486] Example 28 (200 mg, 48%) was prepared in a manner analogous to Example 17, Step 2, from (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid and 5-bromo-3-((3-methoxypyridin-4-yl)methoxy)pyrazin-2-amine. 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),8.23(d,J=4.6Hz,1H),8.06(s,1H),7.57(d,J=4.5Hz,1H),7.45(s,1H),7 .33(s,1H),6.51(s,2H),5.51(s,2H),3.99(s,3H),3.47(s,2H),2.61-2.66(m,4H),2.34(s,3H),2.20(s,3H). LC-MS(M+H) + =392.0.

[0487] Example 29: 3-((2-amino-3-methylpyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydro (Isoquinolin-7-yl)pyrazin-2-amine

[0488]

[0489] Step 1: Methyl 2-amino-3-methylisonicotinate

[0490]

[0491] To methyl 2-chloro-3-methyl isonicotinate (2.52g, 13.6mmol), benzophenone imine (2.76g, 15.0mmol), Pd(dba) 2 (705mg, 1.36mmol), Xantphos (1.62g, 2.72mmol) and Cs cO 3 (6.2g, 15.5mmol) in dioxane (30mL) and toluene (30mL) stir overnight at 100 ℃ under nitrogen atmosphere. The reaction mixture is cooled to 0 ℃, then the methanol solution of HCl (1M, 50mL) is added in the reaction solution, and the mixture is stirred at room temperature for 3 hours. The solvent is concentrated under reduced pressure. Residue is alkalized to pH=8-9 with NaHCO 3, and extracted with EtOAc (30mL x 3). The organic layer merged is washed with salt water (30mL), through Na 2 SO 4 drying, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1 to 2:1) to give the title compound (1.3 g, 57%). LC-MS (M+H) + =167.0.

[0492] Step 2: (2-amino-3-methylpyridin-4-yl)methanol

[0493]

[0494] At 0 ° C, a solution of methyl 2-amino-3-methyl isonicotinate (1.3 g, 7.8 mmol) in THF (2 mL) was added dropwise to a suspension of LiAlH4 (593 mg, 15.6 mmol) in THF (8 mL). After stirring for 2 h, the reaction mixture was cooled to 0 ° C, and water (0.6 mL) was slowly added, followed by a 3.0 M NaOH solution (0.6 mL) and another portion of water (1.8 mL). The mixture was stirred at room temperature for 10 minutes and then filtered. The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (1.0 g, 93%). LC-MS (M+H) + =139.1.

[0495] Step 3: 3-((2-amino-3-methylpyridin-4-yl)methoxy)-5-bromopyrazin-2-amine

[0496]

[0497] NaH (60%, 145 mg, 3.62 mmol) was added to a solution of (2-amino-3-methylpyridin-4-yl)methanol (500 mg, 3.62 mmol) and 3,5-dibromopyrazin-2-amine (700 mg, 2.79 mmol) in THF (20 mL). The reaction mixture was stirred at reflux for 5 h. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (5: 1 to 1: 1)) to give the title compound (600 mg, 54%). LC-MS (M+H) + =309.9,311.9.

[0498] Step 4: 3-((2-amino-3-methylpyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0499]

[0500] Example 29 (110 mg, 28%) was prepared in a manner analogous to Example 17, Step 2, from 3-((2-amino-3-methylpyridin-4-yl)methoxy)-5-bromopyrazin-2-amine and ((2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 HNMR(400MHz,DMSO-d6)δ8.04(s,1H),7.77(d,J=4.6Hz,1H),7.50(s,1H),7.38(s,1H),6.71(d,J=4.8Hz,1H), 6.40(s,2H),5.71(s,2H),5.43(s,2H),3.48(s,2H),2.74-2.59(m,4H),2.34(s,3H),2.21(s,3H),2.10(s,3H). LC-MS(M+H) + =391.4.

[0501] Example 30: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-isopropoxypyridine-4- (methyl)methoxy)pyrazin-2-amine

[0502]

[0503] Step 1: Methyl 3-isopropoxyisonicotinate

[0504]

[0505] To a solution of methyl 3-hydroxyisonicotinate (500 mg, 3.27 mmol) and 2-iodopropane (558 mg, 3.27 mmol) in anhydrous DMF (10 mL) was added K CO (677 mg, 4.91 mmol), and the mixture was stirred at 60 ° C overnight. The mixture was cooled to room temperature and diluted with EtOAc (30 mL). The mixture was washed with water (20 mL), and the aqueous layer was extracted with EtOAc (20 mL x3), dried over Na SO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (5: 1)) to give the title compound (380 mg, 60%). LC-MS (M+H) + =196.2.

[0506] Step 2: (3-Isopropoxypyridin-4-yl)methanol

[0507]

[0508] To a 0°C solution of methyl 3-isopropoxyisonicotinate (380 mg, 1.95 mmol) in anhydrous THF (10 mL) was added LiAlH4 (156 mg, 3.90 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (10 mL) and the mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (277 mg, 85%). LC-MS (M+H) + =168.2.

[0509] Step 3: 5-Bromo-3-((3-isopropoxypyridin-4-yl)methoxy)pyrazin-2-amine

[0510]

[0511] The title compound (300 mg, 53%) was prepared in a similar manner to Example 17, step 1, from 3,5-dibromopyrazin-2-amine and (3-isopropoxypyridin-4-yl)methanol. LC-MS (M+H) + =339.1,341.1.

[0512] Step 4: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-isopropoxypyridin-4-yl)methoxy)pyrazin-2-amine

[0513]

[0514] Example 30 (121 mg, 33%) was prepared in a manner analogous to Example 17, Step 2, from (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid and 5-bromo-3-((3-isopropoxypyridin-4-yl)methoxy)pyrazin-2-amine. 1 HNMR(400MHz,DMSO-d6)δ8.41(s,1H),8.18(d,J=4.6Hz,1H),8.07(s,1H),7.54(d,J=4.4Hz,1H),7.47(s,1H),7.34(s,1H),6 .51(s,2H),5.54(s,2H),4.89-4.73(m,1H),3.45(s,2H),2.71-2.55(m,4H),2.33(s,3H),2.19(s,3H),1.33(d,J=6.0Hz,6H). LC-MS(M+H) + =420.5.

[0515] Example 31: 3-((2-aminopyridin-4-yl)methoxy)-5-(2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin- 6-aminobenzoyl)pyrazin-2-amine

[0516]

[0517] Step 1: tert-Butyl (pivaloyloxy) carbamate

[0518]

[0519] At 0 ℃, pivalic anhydride (23.1g, 123.9mmol) is added into the solution of hydroxy tert-butyl carbamate (15.0g, 112.7mmol) in acetonitrile (300mL).Mixture is heated to reflux and spends the night, and solvent is removed in a vacuum.Crude product is dissolved in ethyl acetate (300mL) and is cooled to 0 ℃, then adds saturated NaHCO (200mL).Organic layer is separated and with saturated NaHCO (200mL x 2) and salt solution (50mL) washing, then through Na SO Drying.Solvent is evaporated under reduced pressure to provide title compound (24.8g, 100%). 1 H NMR (400MHz, CDCl3) δ7.81(s,1H),1.49(s,9H),1.31(s,9H).

[0520] Step 2: O-pivaloylhydroxylamine trifluoromethanesulfonate

[0521]

[0522] TfOH (18.9 g, 125.7 mmol) was added to a solution of tert-butyl (pivaloyloxy) carbamate (24.8 g, 114.3 mmol) in MTBE (230 mL) at 0°C and stirred at room temperature for 4 h. The volume of the solution was reduced to approximately 100 mL under reduced pressure, and the precipitate was collected by filtration. The solid was dried under vacuum to give the title compound (26.0 g, 85%). LC-MS (M+H) + =118.0.

[0523] Step 3: 4-Bromo-2-methyl-N-(pivaloyloxy)benzamide

[0524]

[0525] At 0 ° C, DIPEA (15.7 g, 121.6 mmol) was added to a solution of 4-bromo-2-methylbenzoic acid (8.82 g, 40.52 mmol) in THF (150 mL), followed by T3P (25.8 g, 81.1 mmol) and O-pivaloylhydroxylamine trifluoromethanesulfonate (26.0 g, 97.3 mmol). The reaction was stirred at room temperature overnight. Brine (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (7.5 g, 59%). LC-MS (M+H) + =314.0.

[0526] Step 4: 6-Bromo-8-methyl-3,4-dihydroisoquinolin-1(2H)-one

[0527]

[0528] KOAc (5.16 g, 52.5 mmol) and dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (737.7 mg, 1.19 mmol) were added to a solution of 4-bromo-2-methyl-N-(pivaloyloxy)benzamide (7.5 g, 23.9 mmol) in acetonitrile (150 mL). The solution was stirred at room temperature overnight under an ethylene atmosphere (3 bar). The solvent was removed in vacuo, and the residue was partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (4.67 g, 82%). LC-MS (M+H) + =240.0.

[0529] Step 5: 6-Bromo-8-methyl-1,2,3,4-tetrahydroisoquinoline

[0530]

[0531] 6-Bromo-8-methyl-3,4-dihydroisoquinolin-1(2H)-one (4.67 g, 19.5 mmol) was dissolved in BH3 (1.0 M, 77.8 mL, 77.8 mmol) in THF, and the reaction mixture was refluxed overnight. The mixture was cooled to 0°C, and MeOH (5 mL) was added, followed by HCl (2M, 25 mL). The solution was heated to 80°C for 3 h. The mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in DCM (50 mL), and the solution was washed successively with saturated NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (3.79 g, 86%). LC-MS (M+H) + =226.0.

[0532] Step 6: 6-Bromo-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline

[0533]

[0534] Formalin (37%, 3.48 g, 42.90 mmol) was added to a solution of 6-bromo-8-methyl-1,2,3,4-tetrahydroisoquinoline (1.94 g, 8.58 mmol) in DCM (30 mL). After 5 min, NaBH(OAc)3 (3.64 g, 17.2 mmol) was added, and the mixture was stirred at room temperature overnight. Saturated NaHCO3 (20 mL) was added, and the mixture was extracted with DCM (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.85 g, 90%). LC-MS (M+H) + =240.0.

[0535] Step 7: 2,8-Dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline

[0536]

[0537] 6-Bromo-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline (1.85 g, 7.71 mmol), BPD (3.92 g, 15.4 mmol), Pd(dppf)Cl2 (282 mg, 0.385 mmol) and KOAc (2.27 g, 23.1 mmol) were added to 1,4-dioxane (25 mL), and the mixture was heated to 95 ° C. overnight under N2. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (1.77 g, 80%). LC-MS (M+H) + =288.0.

[0538] Step 8: 3-((2-aminopyridin-4-yl)methoxy)-5-(2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-amine

[0539]

[0540] Example 31 (20 mg, 3.1%) was prepared in a manner analogous to Example 17, Step 2, from 3-((2-aminopyridin-4-yl)methoxy)-5-bromopyrazin-2-amine and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR (400MHz, DMSO-d6) δ8.06(s,1H),7.88(d,J=5.1Hz,1H),7.45(s,1H),7.42(s,1H),6.62(d,J=4.8Hz,1H),6.52(s,1H ),6.42(s,2H),5.88(s,2H),5.37(s,2H),3.39(s,2H),2.86-2.80(m,2H),2.50-2.58(m,2H),2.38(s,3H),2.18(s,3H). LC-MS(M+H) + =377.4

[0541] Example 32: 3-((2-amino-5-methylpyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydro (Isoquinolin-7-yl)pyrazin-2-amine

[0542]

[0543] Step 1: Methyl 2-amino-5-methylisonicotinate

[0544]

[0545] Solid methyl 2-amino-5-bromoisonicotinate (2.31 g, 10 mmol), Pd(OAc)2 (225 mg, 1 mmol), S-Phos (821 mg, 2 mmol) and K3PO4 (4.24 g, 20 mmol) were placed in a flask and flushed with N2. DMSO (50 ml) was added at room temperature, followed by trimethylborane (3.5 M, 11 mL, 40 mmol) in THF. The mixture was heated to 80°C overnight. After cooling to room temperature, the mixture was diluted with EtOAc (250 mL) and washed with H2O (50 mL x 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (5: 1 to 2: 1)) to give the title compound (1.3 g, 78%). LCMS (M+H) + =167.0.

[0546] Step 2: (2-amino-5-methylpyridin-4-yl)methanol

[0547]

[0548] A solution of methyl 2-amino-5-methyl isonicotinate (1.3 g, 7.8 mmol) in THF (2 mL) was added dropwise to a suspension of LiAlH 4 (593 mg, 15.6 mmol) in THF (8 mL) at 0° C., and the mixture was stirred at room temperature for 2 h. The solution was cooled to 0° C., and H 2 O (0.6 mL) was slowly added, followed by a 3.0 M NaOH solution (0.6 mL) and another portion of water (1.8 mL). The mixture was stirred at room temperature for 10 minutes and then filtered. The organic phase was dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (1.0 g, 93%). LC-MS (M+H) + =139.1.

[0549] Step 3: 3-((2-amino-5-methylpyridin-4-yl)methoxy)-5-bromopyrazin-2-amine

[0550]

[0551] At 0 ° C, NaH (60%, 310 mg, 7.8 mmol) was added to a solution of (2-amino-5-methylpyridin-4-yl)methanol (700 mg, 5.07 mmol), 3,5-dibromopyrazin-2-amine (980 mg, 3.9 mmol) in THF (20 mL). The reaction was stirred at reflux for 5 h. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (5: 1 to 1: 1)) to give the title compound (600 mg, 50%). LC-MS (M+H) + =309.9,311.9.

[0552] Step 4: 3-((2-amino-5-methylpyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0553]

[0554] Example 32 (158 mg, 41%) was prepared in a manner analogous to Example 17, Step 2, from 3-((2-amino-5-methylpyridin-4-yl)methoxy)-5-bromopyrazin-2-amine and ((2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 HNMR(400MHz,DMSO-d6)δ8.05(s,1H),7.73(s,1H),7.47(s,1H),7.34(s,1H),6.55(s,1H),6.41(s,2 H),5.62(s,2H),5.37(s,2H),3.47(s,2H),2.70-2.57(m,4H),2.33(s,3H),2.20(s,3H),2.17(s,3H). LC-MS(M+H) + =391.4.

[0555] Example 33: 3-((3-(Benzyloxy)pyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolone (Methyl-7-pyrazin-2-amine)

[0556]

[0557] Step 1: Methyl 3-(benzyloxy)isonicotinate

[0558]

[0559] The title compound (200 mg, 25%) was prepared in a similar manner to Example 30, Step 1, from methyl 3-hydroxyisonicotinate and benzyl bromide. LC-MS (M+H) + =244.2.

[0560] Step 2: (3-(Benzyloxy)pyridin-4-yl)methanol

[0561]

[0562] The title compound (157 mg, 89%) was prepared from methyl 3-(benzyloxy)isonicotinate in a manner similar to that in Example 30, Step 2. LC-MS (M+H) + =216.2.

[0563] Step 3: 3-((3-(Benzyloxy)pyridin-4-yl)methoxy)-5-bromopyrazin-2-amine

[0564]

[0565] The title compound (211 mg, 75%) was prepared in a manner similar to that in Example 17, Step 1, from 3,5-dibromopyrazin-2-amine and (3-(benzyloxy)pyridin-4-yl)methanol. LC-MS (M+H) + =387.2.

[0566] Step 4: 3-((3-(Benzyloxy)pyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0567]

[0568] Example 33 (45 mg, 18%) was prepared in a manner analogous to Example 17, Step 2, from 3-((3-(benzyloxy)pyridin-4-yl)methoxy)-5-bromopyrazin-2-amine and ((2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 HNMR (400MHz, DMSO-d6) δ8.48(s,1H),8.24(d,J=4.7Hz,1H),8.08(s,1H),7.67(d,J=4.7Hz,1H),7.57-7.50(m,2H),7.47(s ,1H),7.43-7.29(m,4H),6.54(s,2H),5.59(s,2H),5.35(s,2H),3.41(s,2H),2.69-2.55(m,4H),2.32(s,3H),2.17(s,3H). LC-MS(M+H) + =468.5.

[0569] Example 34: 3-((1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetramethyl (2-Hydroisoquinolin-7-yl)pyrazin-2-amine

[0570]

[0571] Step 1: 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

[0572]

[0573] To a solution of 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (2.0 g, 14.0 mmol) in THF (40 mL) was added NaH (60%, 672 mg, 16.8 mmol) at 0 ° C. After 15 min, SEMCl (3.02 g, 18.2 mmol) was added. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was poured into water (100 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (10: 1)) to give the title compound (3.0 g, 78%). LC-MS (M+H) + =274.0.

[0574] Step 2: 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid

[0575]

[0576] To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (3.0 g, 10.9 mmol) in EtOH (40 mL) and H2O (40 mL) was added NaOH (4.36 g, 109 mmol). The resulting solution was stirred at 80 ° C for 16 h. After cooling to room temperature, EtOH was removed under vacuum. The mixture was diluted with water (100 mL) and then washed with EtOAc (100 mL). The aqueous layer was acidified with HCl (1 M) until pH = 3. The precipitate was collected by filtration and dried under vacuum to give the title compound (2.0 g, 62%). LC-MS (M+H) + =293.0.

[0577] Step 3: (1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol

[0578]

[0579] To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (2.0 g, 6.85 mmol) in THF (40 mL) was added LiAlH4 (672 mg, 10.3 mmol) at 0°C. The reaction mixture was stirred at room temperature for 4 h, then NaOH solution (2 M, 0.50 mL) was carefully added. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (10:1)) to give the title compound (550 mg, 29%). LC-MS (M+H) + =279.0.

[0580] Step 4: 5-Bromo-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)pyrazin-2-amine

[0581]

[0582] To a solution of (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (550 mg, 1.98 mmol) in DMF (15 mL) was added NaH (60%, 103 mg, 2.57 mmol) at 0°C. After 15 min, 3,5-dibromopyrazin-2-amine (495 mg, 1.98 mmol) was added. The resulting solution was stirred at room temperature for 4 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (1:1)) to give the title compound (400 mg, 45%). LC-MS (M+H) + =449.9.

[0583] Step 5: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)pyrazin-2-amine

[0584]

[0585] To a solution of 5-bromo-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)pyrazin-2-amine (300 mg, 0.67 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid (137 mg, 0.67 mmol), KCO (276 mg, 2.00 mmol), and Pd(dppf)Cl (57 mg, 0.07 mmol). The resulting solution was stirred at 90° C. under nitrogen for 16 h. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with DCM / MeOH (20:1)) to give the title compound (300 mg, 84%). LC-MS (M+H) + =531.0.

[0586] Step 6: 3-((1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0587]

[0588] To a solution of 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)pyrazin-2-amine (300 mg, 0.57 mmol) in DCM (10 mL) was added TFA (3 mL). The solution was stirred at room temperature for 3 h and concentrated under vacuum, then MeOH (5 mL) and NH4OH (25%, 5 mL) were added. The mixture was stirred at room temperature for 3 h and concentrated under vacuum. The crude product was purified by preparative HPLC to give Example 34 (20 mg, 9%). 1H NMR(400MHz, DMSO-d6)δ11.70(s,1H),8.20(d,J=4.9Hz,1H),8.02(s,1H),7.51-7.45(m,1H),7.41(s,1H),7.27(s,2H), 7.22(d,J=4.7Hz,1H),6.71(s,1H),6.47(s,2H),5.80(s,2H),3.42(s,2H),2.65-2.56(m,4H),2.34(s,3H),2.17(s,3H). LC-MS(M+H) + =401.4.

[0589] Example 35: 3-((2-amino-3-methoxypyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetramethyl (2-Hydroisoquinolin-7-yl)pyrazin-2-amine

[0590]

[0591] Step 1: 2-Chloro-3-methoxyisonicotinic acid

[0592]

[0593] At -78 ° C, to a solution of 2-chloro-3-methoxypyridine (1.5 g, 10 mmol) in THF (20 mL), LDA (2.0 M, 10 mL, 20 mmol) in THF / hexane was added dropwise, and the mixture was stirred at -78 ° C for 2 h. Pulverized dry ice (10 g) was carefully added to the mixture, and the mixture was stirred at -78 ° C for 1 h. The mixture was warmed to room temperature, and water (50 mL) was carefully added. The mixture was washed with EtOAc (30 mL), and the aqueous layer was collected. The aqueous layer was acidified to pH = 4 with HCl (2 M), then extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (600 mg, 31%). LC-MS (M+H) + =187.9.

[0594] Step 2: Ethyl 2-chloro-3-methoxyisonicotinate

[0595]

[0596] To a solution of 2-chloro-3-methoxyisonicotinic acid (600 mg, 3.2 mmol) in EtOH (20 mL) was added H2SO4 (0.50 mL). The mixture was stirred at 70 ° C overnight. After cooling to room temperature, most of the EtOH was evaporated under vacuum. The residue was neutralized with saturated NaHCO3 (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (10: 1)) to give the title compound (500 mg, 71%). LC-MS (M+H) + =215.9.

[0597] Step 3: Ethyl 2-amino-3-methoxyisonicotinate

[0598]

[0599] To a mixture of ethyl 2-chloro-3-methoxyisonicotinate (500 mg, 2.3 mmol) and benzophenone imine (500 mg, 2.7 mmol) in dioxane (20 mL) was added Pd(dba)2 (130 mg, 0.20 mmol), Xantphos (260 mg, 0.40 mmol) and Cs2CO3 (1.5 g, 4.6 mmol). The mixture was stirred at 100 ° C under a nitrogen atmosphere overnight. The mixture was cooled and filtered. HCl (6 M, 2 mL) was added to the filtrate. The mixture was stirred for 1 h. The mixture was neutralized with NaHCO3 solution (50 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (2: 1)) to give the title compound (300 mg, 65%). LC-MS (M+H) + =197.1.

[0600] Step 4: (2-amino-3-methoxypyridin-4-yl)methanol

[0601]

[0602] To a solution of ethyl 2-amino-3-methoxyisonicotinate (300 mg, 1.5 mmol) in THF (10 mL) was added LiAlH4 (170 mg, 4.5 mmol) at 0 ° C. The mixture was stirred at room temperature for 1 h. Water (170 mg) and NaOH solution (15%, w / w, 400 mg) were sequentially added to the mixture, stirred for 15 min, and diluted with EtOAc (30 mL). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (3: 1 to 1: 1)) to give the title compound (150 mg, 66%). LC-MS (M+H) + =155.1.

[0603] Step 5: 3-((2-amino-3-methoxypyridin-4-yl)methoxy)-5-bromopyrazin-2-amine

[0604]

[0605] To a mixture of (2-amino-3-methoxypyridin-4-yl)methanol (150 mg, 1.0 mmol) in THF (10 mL) was added NaH (60%, 120 mg, 3.0 mmol). The mixture was stirred at room temperature for 10 min. 3,5-dibromopyrazin-2-amine (250 mg, 1.0 mmol) was added to the mixture. After stirring the mixture at 60 ° C for 3 h, it was cooled to room temperature and diluted with water (30 mL). The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (1: 1)) to give the title compound (100 mg, 30%). LC-MS (M+H) + =326.0.

[0606] Step 6: 3-((2-amino-3-methoxypyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0607]

[0608] Example 35 (40 mg, 32%) was prepared in a manner analogous to Example 17, Step 2, from 3-((2-amino-3-methoxypyridin-4-yl)methoxy)-5-bromopyrazin-2-amine and (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1HNMR(400MHz,DMSO-d6)δ8.05(s,1H),7.66(d,J=5.1Hz,1H),7.48(s,1H),7.35(s,1H),6.66(d,J=5.1Hz,1H),6.43(s,2 H),5.90(s,2H),5.49(s,2H),3.75(s,3H),3.47(s,2H),2.70-2.64(m,2H),2.64-2.58(m,2H),2.33(s,3H),2.20(s,3H). LC-MS(M+H) + =407.5.

[0609] Example 36: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1H-pyrazol-4-yl)pyrazine-2-yl amine

[0610]

[0611] To a solution of 1H-pyrazol-4-ylboronic acid (116 mg, 1.04 mmol) in dioxane (8 mL) was added 3-chloro-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (200 mg, 0.69 mmol), water (2 mL), bis(tricyclohexylphosphine)dichloropalladium (51 mg, 0.069 mmol) and K2CO3 (191 mg, 1.38 mmol). The mixture was stirred at 120°C under a nitrogen atmosphere for 2 h and then cooled to room temperature. The mixture was diluted with water (30 mL) and then extracted with EtOAc (30 mL x 3). The organic phases were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 36 (23 mg, 10%). 1 H NMR(400MHz,DMSO-d6)δ13.18(s,1H),8.53-8.05(m,3H),7.67(s,1H),7.55(s ,1H),6.15(s,2H),3.53(s,2H),2.79-2.59(m,4H),2.35(s,3H),2.25(s,3H). LC-MS(M+H) + =321.0.

[0612] Example 37: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-((tetrahydro-2H-pyran-4- 4-(2-Yl)methoxy)pyridin-4-yl)methoxy)pyrazin-2-amine

[0613]

[0614] Step 1: Methyl 3-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinate

[0615]

[0616] The title compound (480 mg, 59%) was prepared in a similar manner to Example 30, Step 1, from methyl 3-hydroxyisonicotinate and 4-(bromomethyl)tetrahydro-2H-pyran. LC-MS (M+H) + =252.3.

[0617] Step 2: (3-((Tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methanol

[0618]

[0619] The title compound (355 mg, 83%) was prepared in a similar manner to Example 30, Step 2, from methyl 3-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinate. LC-MS (M+H) + =224.3.

[0620] Step 3: 5-Bromo-3-((3-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methoxy)pyrazin-2-amine

[0621]

[0622] The title compound (210 mg, 33%) was prepared in a manner similar to that in Example 17, step 1, from 3,5-dibromopyrazin-2-amine and (3-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methanol. LC-MS (M+H) + =395.2,397.2.

[0623] Step 4: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methoxy)pyrazin-2-amine

[0624]

[0625] Example 37 (75 mg, 30%) was prepared in a manner analogous to Example 17, Step 2, from 5-bromo-3-((3-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methoxy)pyrazin-2-amine and ((2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1H NMR(400MHz, DMSO-d6)δ8.38(s,1H),8.23(d,J=4.3Hz,1H),8.09(s,1H),7.64(d, J=4.3Hz,1H),7.48(s,1H),7.36(s,1H),6.52(s,2H),5.54(s,2H),4.05(d,J=5.9 Hz,2H),3.96-3.80(m,2H),3.47(s,2H),3.39-3.24(m,2H),2.75-2.57(m,4H),2. 34(s,3H),2.20(s,3H),2.12-1.98(m,1H),1.76-1.64(m,2H),1.48-1.31(m,2H). LC-MS (M+H) + =476.5.

[0626] Example 38: 3-((2-((cyclopropylmethyl)amino)pyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3, 4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0627]

[0628] Step 1: (2-((cyclopropylmethyl)amino)pyridin-4-yl)methanol

[0629]

[0630] At 0 ° C, AcOH (483 mg, 8.06 mmol) was added to a solution of (2-aminopyridin-4-yl)methanol (1.0 g, 8.06 mmol) and cyclopropylcarboxaldehyde (672 mg, 9.6 mmol) in THF (30 mL). Sodium triacetoxyborohydride (3.4 g, 16.1 mmol) was added in batches. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (800 mg, 60%). LC-MS (M+H) + =179.0.

[0631] Step 2: 5-Bromo-3-((2-((cyclopropylmethyl)amino)pyridin-4-yl)methoxy)pyrazin-2-amine

[0632]

[0633] At 0 ° C, NaH (60%, 216 mg, 5.4 mmol) was added to a solution of (2-((cyclopropylmethyl)amino)pyridin-4-yl)methanol (800 mg, 4.5 mmol) in THF (20 mL). The mixture was stirred at 0 ° C for 30 min, and then 3,5-dibromopyrazin-2-amine (1.35 g, 5.4 mmol) was added portionwise. The mixture was warmed to 70 ° C and stirred under N2 for 2 h, then cooled to room temperature. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (900 mg, 60%). LC-MS (M+H) + =350.0,352.0.

[0634] Step 3: 3-((2-((cyclopropylmethyl)amino)pyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0635]

[0636] Example 38 (75 mg, 20%) was prepared in a manner analogous to Example 17, Step 2, from 5-bromo-3-((2-((cyclopropylmethyl)amino)pyridin-4-yl)methoxy)pyrazin-2-amine and (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 H NMR (400MHz, DMSO-d6) δ8.05(s,1H),7.92(d,J=4.0Hz,1H),7.48(s,1H),7.36(s,1H),6.58(m,2H),6.53(t,J=8.0Hz,1H),6.42(s,2H),5.37(s,2H) ,3.47(s,2H),3.10(t,J=8.0Hz,2H),2.61-2.66(m,4H),2.33(s,3H),2.2 0(s,3H),0.97-1.06(m,1H),0.40(d,J=8.0Hz,2H),0.17(d,J=8.0Hz,2H). LC-MS(M+H) + =431.5.

[0637] Example 39: N-(4-(((3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazine-2-yl)pyrazine (2-(4-(2-methyl)pyridin-2-yl)acetamide)

[0638]

[0639] Step 1: Methyl (2-acetamidopyridin-4-yl)acetate

[0640]

[0641] Ac2O (4.92 g, 48.3 mmol) was added to a solution of (2-aminopyridin-4-yl)methanol (2.0 g, 16.1 mmol) in pyridine (18 mL, 224 mmol) at 0°C. The mixture was stirred at room temperature overnight. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (3.5 g, crude). The material was used in step 2 without further purification. LC-MS (M+H) + =209.0.

[0642] Step 2: N-(4-(Hydroxymethyl)pyridin-2-yl)acetamide

[0643]

[0644] Ammonium hydroxide solution (28%, 10 mL) was added to a solution of crude (2-acetamidopyridin-4-yl)acetic acid methyl ester (3.5 g) in MeOH (30 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (2.5 g, 90% over 2 steps). LC-MS (M+H) + =167.0.

[0645] Step 3: N-(4-(((3-amino-6-bromopyrazin-2-yl)oxy)methyl)pyridin-2-yl)acetamide

[0646]

[0647] The title compound (100 mg, 10%) was prepared in a manner similar to that in Example 38, Step 2, from N-(4-(hydroxymethyl)pyridin-2-yl)acetamide and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =338.0,340.0.

[0648] Step 4: N-(4-(((3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)oxy)methyl)pyridin-2-yl)acetamide

[0649]

[0650] Example 39 (20 mg, 16%) was prepared in a manner analogous to Example 17, Step 2, from N-(4-(((3-amino-6-bromopyrazin-2-yl)oxy)methyl)pyridin-2-yl)acetamide and (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.28(s,1H),8.21(s,1H),8.05(s,1H),7.44(s,1H),7.30(s,1H),7.2 3(s,1H),6.45(s,2H),5.51(s,2H),3.45(s,2H),2.61-2.66(m,4H),2.30(s,3H),2.19(s,3H),2.09(s,3H). LC-MS(M+H) + =419.5.

[0651] Example 40: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-(ethylamino)pyridine-4- (methyl)methoxy)pyrazin-2-amine

[0652]

[0653] Step 1: (2-(Ethylamino)pyridin-4-yl)methanol

[0654]

[0655] LiAlH4 (228 mg, 6.0 mmol) was added portionwise to N-(4-(hydroxymethyl)pyridin-2-yl)acetamide (500 mg, 3.0 mmol) in THF (10 mL) at 0 ° C. The mixture was warmed to 60 ° C and stirred for 4 h. After cooling to room temperature, water (0.3 mL) was added and the mixture was filtered. The filtrate was concentrated to give the title compound (150 mg) as a crude product. The material was used in step 2 without further purification. LC-MS (M+H) + =153.0.

[0656] Step 2: 5-Bromo-3-((2-(ethylamino)pyridin-4-yl)methoxy)pyrazin-2-amine

[0657]

[0658] This compound (75 mg, 8% over 2 steps) was prepared in a manner similar to Example 38, Step 2, from (2-(ethylamino)pyridin-4-yl)methanol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =324.0,326.0.

[0659] Step 3: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((2-(ethylamino)pyridin-4-yl)methoxy)pyrazin-2-amine

[0660]

[0661] Example 40 (33 mg, 35%) was prepared in a manner analogous to Example 38, Step 3, from 5-bromo-3-((2-(ethylamino)pyridin-4-yl)methoxy)pyrazin-2-amine and (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 HNMR(400MHz,DMSO-d6)δ8.05(1H),7.93(d,J=4.0Hz,1H),7.48(s,1H),7.35(s,1H),6.59(d,J=4.0Hz,1H),6.53(s,1H),6. 42(s,3H),5.37(s,2H),3.47(s,2H),3.19-3.26(m,2H),2.61-2.66(m,4H),2.34(s,3H),2.20(s,3H),1.10(t,J=8.0Hz,3H). LC-MS(M+H) + =405.5.

[0662] Example 41: 3-((2-amino-3-ethoxypyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetramethyl (2-Hydroisoquinolin-7-yl)pyrazin-2-amine

[0663]

[0664] Step 1: 2-Chloro-3-ethoxypyridine

[0665]

[0666] To a solution of 2-chloropyridin-3-ol (2.6 g, 20 mmol) in DMSO (30 mL) was added KOH (1.1 g, 20 mmol). The mixture was stirred at room temperature for 1 h. EtI (3.1 g, 20 mmol) was added to the mixture. The mixture was stirred at room temperature for 3 h, diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (5:1)) to give the title compound (2.7 g, 85%). LC-MS (M+H) + =158.0.

[0667] Step 2: 2-Chloro-3-ethoxyisonicotinic acid

[0668]

[0669] The title compound (250 mg, 12%) was prepared from 2-chloro-3-ethoxypyridine in a similar manner to Example 35, step 1. LC-MS (M+H) + =202.0.

[0670] Step 3: Ethyl 2-chloro-3-ethoxyisonicotinate

[0671]

[0672] The title compound (200 mg, 72%) was prepared in a similar manner to Example 35, Step 2, from 2-chloro-3-ethoxyisonicotinic acid and ethanol. LC-MS (M+H) + =230.1.

[0673] Step 4: Ethyl 2-amino-3-ethoxyisonicotinate

[0674]

[0675] The title compound (100 mg, 77%) was prepared in a similar manner to Example 35, Step 3, from ethyl 2-chloro-3-ethoxyisonicotinate and diphenylformimine. LC-MS (M+H) + =211.1.

[0676] Step 5: (2-Amino-3-ethoxypyridin-4-yl)methanol

[0677]

[0678] The title compound (60 mg, 80%) was prepared from ethyl 2-amino-3-ethoxyisonicotinate in a similar manner to Example 35, Step 4. LC-MS (M+H) + =168.1.

[0679] Step 6: 3-((2-amino-3-ethoxypyridin-4-yl)methoxy)-5-bromopyrazin-2-amine

[0680]

[0681] The title compound (60 mg, 50%) was prepared in a similar manner to Example 35, Step 5, from (2-amino-3-ethoxypyridin-4-yl)methanol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =340.0.

[0682] Step 7: 3-((2-amino-3-ethoxypyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0683]

[0684] Example 41 (20 mg, 23%) was prepared in a manner analogous to Example 17, Step 2, from 3-((2-amino-3-ethoxypyridin-4-yl)methoxy)-5-bromopyrazin-2-amine and (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 HNMR(400MHz, DMSO-d6)δ8.06(s,1H),7.66(d,J=5.1Hz,1H),7.50(s,1H),7.38(s,1H),6.71(d,J=5.0Hz,1H),6.44(s,2H),5.81(s,2H), 5.51(s,2H),3.94(q,J=7.0Hz,2H),3.47(s,2H),2.70-2.64(m,2H),2.64-2.58(m,2H),2.33(s,3H),2.20(s,3H),1.37(t,J=7.0Hz,3H). LC-MS(M+H) + =421.5.

[0685] Example 42: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-phenoxypyridin-4-yl) (methoxy)pyrazin-2-amine

[0686]

[0687] Step 1: Methyl 3-phenoxyisonicotinate

[0688]

[0689] At room temperature, diphenyliodonium trifluoromethanesulfonate (2.0 g, 4.6 mmol), methyl 3-hydroxyisonicotinate (700 mg, 4.6 mmol) and t-BuOK (564 mg, 5.0 mmol) were added to THF (30 mL), and the mixture was stirred overnight. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA (4:1)) to give the title compound (650 mg, 62%). LC-MS (M+H) + =230.0.

[0690] Step 2: (3-Phenoxypyridin-4-yl)methanol

[0691]

[0692] The title compound (355 mg, 83%) was prepared from methyl 3-phenoxyisonicotinate in a similar manner to Example 30, Step 2. LC-MS (M+H) + =202.0.

[0693] Step 3: 5-Bromo-3-((3-phenoxypyridin-4-yl)methoxy)pyrazin-2-amine

[0694]

[0695] The title compound (90 mg, 44%) was prepared in a similar manner to Example 17, step 1, from 3,5-dibromopyrazin-2-amine and (3-phenoxypyridin-4-yl)methanol. LC-MS (M+H) + =373.0 375.0.

[0696] Step 4: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-phenoxypyridin-4-yl)methoxy)pyrazin-2-amine

[0697]

[0698] Example 42 (40 mg, 37%) was prepared in a manner analogous to Example 17, Step 2, from 5-bromo-3-((3-phenoxypyridin-4-yl)methoxy)pyrazin-2-amine and ((2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 HNMR (400MHz, DMSO) δ8.44(d,J=4.8Hz,1H),8.26(s,1H),8.06(s,1H),7.77(d,J=4.6Hz,1H),7.44-7.34(m,3H),7.28(s,1H),7.16(t,J=7.3H z,1H),7.06(d,J=7.8Hz,2H),6.49(s,2H),5.54(s,2H),3.42(s,2H),2.65(d,J=4.4Hz,2H),2.61(d,J=4.7Hz,2H),2.33(s,3H),2.17(s,3H). LC-MS(M+H) + =454.2.

[0699] Example 43: 3-((1H-pyrazol-3-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1-Methyl-2-pyrazin-2-amine

[0700]

[0701] Step 1: (1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol

[0702]

[0703] At 0 ° C, NaH (60%, 291 mg, 7.26 mmol) was added to a solution of 1H-pyrazol-3-ylmethanol (475 mg, 4.84 mmol) in DMF (10 mL). The mixture was stirred at 0 ° C for 10 min, and then SEMCl (847 mg, 5.08 mmol) was added dropwise over 10 min. The mixture was stirred for another 3 h at room temperature under a nitrogen atmosphere. The reaction was then quenched by adding ice water (30 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM / MeOH (1: 0 to 4: 1)) to give the title compound (250 mg, 22%). LC-MS (M+H) + =229.0.

[0704] Step 2: 5-Bromo-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methoxy)pyrazin-2-amine

[0705]

[0706] The title compound (311 mg, 97%) was prepared in a manner similar to that in Example 1, Step 7, from (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol and 5-bromo-3-chloropyrazin-2-amine. LC-MS (M+H) + =402.0.

[0707] Step 3: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methoxy)pyrazin-2-amine

[0708]

[0709] The title compound (150 mg, 40%) was prepared in a manner similar to that described in Example 1, Step 8, from 5-bromo-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methoxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. LC-MS (M+H)+ =481.0.

[0710] Step 4: 3-((1H-pyrazol-3-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0711]

[0712] To a solution of 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methoxy)pyrazin-2-amine (146 mg, 0.304 mmol) in DCM (6 mL) was added TFA (346 mg, 3.04 mmol) at 0°C. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to give Example 43 (23 mg, 21%). 1 H NMR(400MHz,DMSO-d6)δ12.81(s,1H),8.07(s,1H),7.72-7.55(m,2H),7.47(s,1H),6.44-6.3 9(m,1H),6.31(s,2H),5.49(s,2H),3.52(s,2H),2.73-2.60(m,4H),2.35(s,3H),2.24(s,3H). LC-MS(M+H) + =351.0.

[0713] Example 44: 3-((3H-imidazo[4,5-b]pyridin-7-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetramethyl Hydroisoquinolin-7-yl)pyrazin-2-amine and 3-((1H-imidazo[4,5-b]pyridin-7-yl)methoxy)-5-(2,5-dimethyl- 1,2,3,4-Tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0714]

[0715] Step 1: 7-Methyl-3H-imidazo[4,5-b]pyridine

[0716]

[0717] To a solution of 4-methylpyridine-2,3-diamine (2.0 g, 16.3 mmol) in CH(OMe) 3 (30 mL) was added pTSA (279 mg, 1.63 mmol). The mixture was stirred at 100 ° C for 16 h, cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH (20: 1)) to give the title compound (1.7 mg, 78%). LC-MS (M+H) + =134.0.

[0718] Step 2: 3H-imidazo[4,5-b]pyridine-7-carboxylic acid

[0719]

[0720] To a mixture of 7-methyl-3H-imidazo[4,5-b]pyridine (1.7 g, 12.8 mmol) and Na2CO3 in water (60 mL) was added KMnO4 (5.05 g, 31.9 mmol) at 100°C. The mixture was stirred at 100°C for 1 h and cooled to 60°C. MnO2 was filtered off and the solid was washed with warm water (60°C, 20 mL x 2). The filtrate was concentrated in vacuo to a volume of 50 mL and then acidified with 10% HCl solution until pH = 3. The solid was collected by filtration, washed with water (10 mL x 2) and dried under vacuum to give the title compound (750 mg, 36%). LC-MS (M+H) + =164.0.

[0721] Step 3: Methyl 3H-imidazo[4,5-b]pyridine-7-carboxylate

[0722]

[0723] To a solution of 3H-imidazo[4,5-b]pyridine-7-carboxylic acid (750 mg, 4.6 mmol) in MeOH (20 mL) was added H2SO4 (2 mL). The reaction mixture was stirred at 60 ° C for 16 h, cooled to room temperature, and then concentrated under vacuum until the volume was about 10 mL. The solution was cooled to 0 ° C and then neutralized with ammonia until pH = 9. The solid was collected by filtration, washed with water (10 mL x 2) and then dried under vacuum to give the title compound (510 mg, 63%). LC-MS (M+H) + =178.0.

[0724] Step 4: Methyl 3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate

[0725]

[0726] At 0 ° C, to a solution of methyl 3H-imidazo [4,5-b] pyridine-7-carboxylate (510 mg, 2.88 mmol) in DMF (20 mL) was added NaH (60%, 138 mg, 3.46 mmol) and the mixture was stirred for 15 min, and then SEMCl (622 mg, 3.74 mmol) was added. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with PE: EA (1: 1)) to give the title compound (376 mg, 43%). LC-MS (M+H) + =308.0.

[0727] Step 5: (3-((2-(Trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)methanol

[0728]

[0729] To a solution of methyl 3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate (376 mg, 1.22 mmol) in THF (15 mL) was added LiAlH4 (70 mg, 1.84 mmol) at 0°C. The mixture was stirred at room temperature for 4 h. The reaction mixture was poured into NaOH (2 M, 0.5 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH (20:1)) to give the title compound (76 mg, 22%). LC-MS (M+H) + =280.0.

[0730] Step 6: 5-Bromo-3-((3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)methoxy)pyrazin-2-amine

[0731]

[0732] To a solution of (3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)methanol (76 mg, 0.27 mmol) in THF (8 mL) was added NaH (60%, 22 mg, 0.54 mmol) at 0°C and stirred for 15 min, followed by the addition of 3,5-dibromopyrazin-2-amine (103 mg, 0.41 mmol). The mixture was stirred at 50°C for 4 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH (20:1)) to give the title compound (85 mg, 70%). LC-MS (M+H) + =450.9.

[0733] Step 7: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)methoxy)pyrazin-2-amine

[0734]

[0735] To a solution of 5-bromo-3-((3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)methoxy)pyrazin-2-amine (85 mg, 0.19 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid (39 mg, 0.19 mmol), KCO (78 mg, 0.57 mmol), and Pd(dppf)Cl (15 mg, 0.02 mmol). The resulting solution was stirred at 90° C. under nitrogen for 16 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH (10:1)) to give the title compound (80 mg, 80%). LC-MS (M+H) + =532.1.

[0736] Step 8: 3-((3H-imidazo[4,5-b]pyridin-7-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine and 3-((1H-imidazo[4,5-b]pyridin-7-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0737]

[0738] To a solution of 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)methoxy)pyrazin-2-amine (80 mg, 0.15 mmol) in DCM (5 mL) was added TFA (2 mL). The resulting solution was stirred at room temperature for 3 h and concentrated under vacuum, then MeOH (3 mL) and ammonium hydroxide (25%, 3 mL) were added. The mixture was stirred at room temperature for 3 h and concentrated under vacuum. The residue was purified by preparative HPLC to give Example 44 (4.3 mg, 7%) as a mixture of two tautomers. 1 H NMR (400MHz, DMSO-d6) δ13.33-12.92(m,1H),8.64-8.43(m,1H),8.43-8.26(m,1H),8.13-7.98(m,1H),7.50-7.38(m,2H),7.38- 7.20(m,1H),6.59-6.41(m,2H),6.03-5.72(m,2H),3.53-3.38(m,2H),2.72-2.61(m,4H),2.38-2.31(m,3H),2.22-2.12(m,3H). LC-MS(M+H) + =402.4.

[0739] Example 45: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-ethyl-1H-pyrazol-4-yl)- (2-Methyl-2-oxy)pyrazin-2-amine

[0740]

[0741] Step 1: 5-Bromo-3-(1-ethyl-1H-pyrazol-4-yloxy)pyrazin-2-amine

[0742]

[0743] The title compound (190 mg, 31%) was prepared in a similar manner to Example 1, Step 7, from 1-ethyl-1H-pyrazol-4-ol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) +=284.0.

[0744] Step 2: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-ethyl-1H-pyrazol-4-yloxy)pyrazin-2-amine

[0745]

[0746] Example 45 (28 mg, 14%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-(1-ethyl-1H-pyrazol-4-yloxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.19(s,1H),8.05(s,1H),7.59(s,1H),7.48(s,1H),7.35(s,1H),6.62(s,2H) ,4.22-4.12(m,2H),3.49(s,2H),2.70-2.61(m,4H),2.35(s,3H),2.21(s,3H),1.42(t,J=7.3Hz,3H). LC-MS(M+H) + =365.2.

[0747] Example 46: 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N, N-Dimethyl-1H-pyrazole-4-carboxamide

[0748]

[0749] Step 1: Ethyl 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylate

[0750]

[0751] The title compound (176 mg, 52%) was prepared in a similar manner to Example 6, Step 1, from 3-chloro-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine and ethyl 1H-pyrazole-4-carboxylate. LC-MS (M+H) + =393.0.

[0752] Step 2: 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid

[0753]

[0754] To a solution of ethyl 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylate (200 mg, 0.510 mmol) in THF (10 mL) was added LiOH (1 M, 5 mL, 5.0 mmol) in H2O at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with hexane / EtOAc (1:0 to 3:2)) to give the title compound (96 mg, 51%). LC-MS (M+H) + =365.1.

[0755] Step 3: 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

[0756]

[0757] Under N2, HATU (157 mg, 0.41 mmol) was added to a solution of 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid (96 mg, 0.26 mmol) and DIPEA (102 mg, 0.79 mmol) in DMF (3 mL) at 0°C. To the above mixture was added dimethylamine hydrochloride (27 mg, 0.33 mmol), and the mixture was stirred at room temperature for another 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 46 (9 mg, 9%). 1 H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.64(s,1H),8.14(s,1H),7.71(s,1H),7.60(s,1H),7.49-7 .37(m,2H),3.54(s,2H),3.21(s,3H),3.01(s,3H),2.75-2.58(m,4H),2.35(s,3H),2.26(s,3H). LC-MS(M+H) + =392.3.

[0758] Example 47A / 47B: (R)-3-(1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrrolidone (S)-3-(1-(3-amino-6-(2,5-dimethyl- (1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)ethyl)-2,4-dichloro-N-cyclopropylbenzamide

[0759]

[0760] Step 1: tert-Butyl 2,4-dichlorobenzoate

[0761]

[0762] To a solution of 2,4-dichlorobenzoic acid (10.00 g, 52.35 mmol) in THF (100 mL) was added Boc2O (12.34 g, 56.54 mmol) and DMAP (640 mg, 5.235 mmol) at room temperature. The mixture was stirred at 40 ° C under a nitrogen atmosphere for 12 h and then cooled to room temperature. Water (200 mL) was added and the mixture was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with hexane / EtOAc (1: 0 to 9: 1)) to give the title compound (10.0 g, 77%). LC-MS (M+H) + =247.0.

[0763] Step 2: tert-Butyl 2,4-dichloro-3-formylbenzoate

[0764]

[0765] At -78 ° C, to a solution of tert-butyl 2,4-dichlorobenzoate (10.00 g, 40.5 mmol) in THF (100 mL), LDA (1.6 M, 30 mL, 48 mmol) was added. The mixture was stirred at -78 ° C under a nitrogen atmosphere for 90 min, and then DMF (8.87 g, 121 mmol) was added. The mixture was stirred at -78 ° C under a nitrogen atmosphere for 110 min. The reaction mixture was poured into HCl (6 M, 50 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with hexane / EtOAc (1: 0 to 9: 1)) to give the title compound (10.0 g, 89%). 1 H NMR (300MHz, DMSO-d6) δ10.34(s,1H),7.86(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),1.56(s,9H).

[0766] Step 3: tert-Butyl 2,4-dichloro-3-(1-hydroxyethyl)benzoate

[0767]

[0768] At -78 ° C, under a nitrogen atmosphere, to a solution of 2,4-dichloro-3-formylbenzoate (10.0 g, 36.3 mmol) in THF (150 mL) was added MeMgBr (1 M, 43 mL, 43.0 mmol) in THF. The mixture was stirred at room temperature for 1 h. Then an aqueous HCl solution (1 M, 200 mL) was carefully added. The mixture was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with hexane / EtOAc (1: 0 to 4: 1)) to give the title compound (9.30 g, 88%). LC-MS (M+H) + =291.0.

[0769] Step 4: tert-Butyl 3-(1-(3-amino-6-bromopyrazin-2-yloxy)ethyl)-2,4-dichlorobenzoate

[0770]

[0771] The title compound (1.42 g, 18%) was prepared in a similar manner to Example 1, Step 7, from tert-butyl 2,4-dichloro-3-(1-hydroxyethyl)benzoate and 5-bromo-3-chloropyrazin-2-amine. LC-MS (M+H) + =462.0.

[0772] Step 5: tert-Butyl 3-(1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)ethyl)-2,4-dichlorobenzoate

[0773]

[0774] The title compound (1.30 g, 74%) was prepared in a manner similar to that in Example 1, Step 8, from tert-butyl 3-(1-(3-amino-6-bromopyrazin-2-yloxy)ethyl)-2,4-dichlorobenzoate and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. LC-MS (M+H) + =543.2.

[0775] Step 6: 3-(1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)ethyl)-2,4-dichlorobenzoic acid

[0776]

[0777] The title compound (990 mg, 92%) was prepared in a manner similar to that in Example 43, Step 4, from tert-butyl 3-(1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)ethyl)-2,4-dichlorobenzoate. LC-MS (M+H) + =487.1.

[0778] Step 7: (R)-3-(1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)ethyl)-2,4-dichloro-N-cyclopropylbenzamide and (S)-3-(1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)ethyl)-2,4-dichloro-N-cyclopropylbenzamide

[0779]

[0780] Example 47A / 47B was prepared in a manner analogous to Example 46, Step 3, from 3-(1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)ethyl)-2,4-dichlorobenzoic acid and cyclopropylamine. The enantiomers were separated by chiral HPLC to give (R)-3-(1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)ethyl)-2,4-dichloro-N-cyclopropylbenzamide (Example 47A) and (S)-3-(1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)ethyl)-2,4-dichloro-N-cyclopropylbenzamide (Example 47B).

[0781] Analytical chiral HPLC conditions: CHIRALPAK IG-3, 0.46 x 5 cm, 3.0 μm. Mobile phase: 0.2% isopropylamine in (hexane: DCM = 3:1): EtOH, 1 mL / min over 6 min.

[0782] Example 47A: (36 mg, 36%) 1H NMR (400MHz, DMSO-d6) δ8.50(d,J=4.4Hz,1H),8.01(s,1H),7.55-7.42(m,2H),7.31(s,1H),7.26(d,J=8.2Hz,1H),6.72-6.66(m,1H),6.32(s, 2H),3.49(s,2H),2.83-2.74(m,1H),2.69-2.61(m,4H),2.37(s,3H),2. 19(s,3H),1.78(d,J=6.9Hz,3H),0.72-0.63(m,2H),0.54-0.45(m,2H). LC-MS(M+H) + =526.2. Chiral HPLC: tR=3.99 min.

[0783] Example 47B: (23 mg, 23%) 1 H NMR (400MHz, DMSO-d6) δ8.50(d,J=4.4Hz,1H),8.01(s,1H),7.55-7.42(m,2H),7.31(s,1H),7.26(d,J=8.2Hz,1H),6.72-6.66(m,1H),6.32(s, 2H),3.49(s,2H),2.83-2.74(m,1H),2.69-2.61(m,4H),2.37(s,3H),2. 19(s,3H),1.78(d,J=6.9Hz,3H),0.72-0.63(m,2H),0.54-0.45(m,2H). LC-MS(M+H) + =526.2. Chiral HPLC: tR=4.86 min.

[0784] Example 116: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-methyl-1H-pyrazole-4- 2-Methyl)oxy)pyrazin-2-amine

[0785]

[0786] Step 1: 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0787]

[0788] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (1.0 g, 5.15 mmol) and MeI (1.1 g, 7.73 mmol) in THF (50 mL) was added NaH (60%, 412 mg, 10.3 mmol) at 0°C. The mixture was stirred at 60°C under N2 for 8 h. The mixture was cooled to room temperature, quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (680 mg, 63%). LC-MS (M+H) + =209.2.

[0789] Step 2: 1-Methyl-1H-pyrazol-4-ol

[0790]

[0791] To a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (680mg, 3.27mmol) and the NaOH aqueous solution (3M, 2.2mL, 6.54mmol) in THF (20mL) was added H o (741mg, 6.54mmol). The mixture was stirred at room temperature for 3 hours. The pH of the mixture was adjusted to 7 with the HCl aqueous solution (3M), and the mixture was then extracted with EtOAc (50mL x 3). The combined organic layer was dried over Na sO , filtered and concentrated to give the title compound (330mg, 99%).

[0792] Step 3: 5-Bromo-3-((1-methyl-1H-pyrazol-4-yl)oxy)pyrazin-2-amine

[0793]

[0794] To a solution of 1-methyl-1H-pyrazol-4-ol (330 mg, 3.27 mmol) and 3,5-dibromopyrazin-2-amine (852 mg, 3.37 mmol) in DMSO (20 mL) was added K2CO3 (1.4 g, 10.1 mmol). The mixture was stirred at 75 ° C under N2 for 6 h and then cooled to room temperature. Water (40 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with MeOH / DCM (1: 100)) to give the title compound (420 mg, 48%). LC-MS (M+H) + =270.1,272.1.

[0795] Step 4: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-methyl-1H-pyrazol-4-yl) (2-Methyl-2-oxy)pyrazin-2-amine

[0796]

[0797] To a solution of 5-bromo-3-((1-methyl-1H-pyrazol-4-yl)oxy)pyrazin-2-amine (420 mg, 1.56 mmol), (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid (336 mg, 1.64 mmol), and Pd(dppf)Cl2·DCM (64 mg, 0.078 mmol) in 1,4-dioxane (15 mL) and water (15 mL) was added K2CO3 (646 mg, 4.68 mmol). The mixture was stirred at 90°C under N2 for 12 h and then cooled to room temperature. Water (20 mL) was added, and the mixture was extracted sequentially with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH / DCM (1:20) and then by preparative TLC eluting with MeOH / DCM (1:10) to give Example 116 (246 mg, 45%). 1 H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.98(s,1H),7.59(s,1H),7.47(s,1H),7.33(s,1H ),6.65(s,2H),3.87(s,3H),3.48(s,2H),2.71-2.57(m,4H),2.34(s,3H),2.21(s,3H). LC-MS(M+H) + =351.2.

[0798] Example 141: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(thieno[2,3-c]pyridine- 3-aminobenzoyloxy)pyrazin-2-amine

[0799]

[0800] Step 1: 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[2,3-c]pyridine

[0801]

[0802] The title compound (300 mg, 52%) was prepared from 3-bromothieno[2,3-c]pyridine in a similar manner to Example 1, Step 6. LC-MS (M-pin) + =180.1.

[0803] Step 2: Thieno[2,3-c]pyridin-3-ol

[0804]

[0805] The title compound (230 mg, 89%) was prepared from 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[2,3-c]pyridine in a similar manner to Example 116, Step 2. LC-MS (M+H) + =152.1.

[0806] Step 3: 5-Bromo-3-(thieno[2,3-c]pyridin-3-yloxy)pyrazin-2-amine

[0807]

[0808] The title compound (250 mg, 58%) was prepared in a similar manner to Example 116, Step 3, from thieno[2,3-c]pyridin-3-ol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =323.0.

[0809] Step 4: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(thieno[2,3-c]pyridin-3-yloxy)pyrazin-2-amine

[0810] Example 141 (45 mg, 36%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-(thieno[2,3-c]pyridin-3-yloxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR (400MHz, DMSO-d6) δ9.30(s,1H),8.51(d,J=5.5Hz,1H),8.28(s,1H),8.21(s,1H),7.91(d,J=5.5Hz ,1H),7.32(s,1H),7.21(s,1H),6.87(s,2H),3.41(s,2H),2.66-2.55(m,4H),2.32(s,3H),2.13(s,3H). LC-MS(M+H) + =404.3.

[0811] Example 149: 3-((3-cyclopropyloxypyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoxazole Quinolin-7-yl)pyrazin-2-amine

[0812]

[0813] Step 1: Methyl 3-cyclopropyloxyisonicotinate

[0814]

[0815] NaH (60%, 503 mg, 12.6 mmol) was added to a solution of methyl 3-fluoroisonicotinate (1.0 g, 6.45 mmol) and cyclopropanol (749 mg, 12.9 mmol) in anhydrous THF (30 mL) at 0°C, and the mixture was stirred at room temperature overnight. Brine (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (850 mg, 68%). LC-MS (M+H) + =194.0.

[0816] Step 2: (3-cyclopropyloxypyridin-4-yl)methanol

[0817]

[0818] The title compound (850 mg, 86%) was prepared from methyl 3-cyclopropyloxyisonicotinate in a similar manner to Example 30, Step 2. LC-MS (M+H) + =166.0.

[0819] Step 3: 5-Bromo-3-((3-cyclopropyloxypyridin-4-yl)methoxy)pyrazin-2-amine

[0820]

[0821] The title compound (560 mg, 70%) was prepared in a similar manner to Example 17, step 1, from 3,5-dibromopyrazin-2-amine and (3-cyclopropyloxypyridin-4-yl)methanol. LC-MS (M+H) + =337.0.

[0822] Step 4: 3-((3-cyclopropyloxypyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0823]

[0824] Example 149 (135 mg, 20%) was prepared in a manner analogous to Example 17, Step 2, from (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid and 5-bromo-3-((3-cyclopropyloxypyridin-4-yl)methoxy)pyrazin-2-amine. 1HNMR(400MHz,DMSO-d6)δ8.65(s,1H),8.24(d,J=4.6Hz,1H),8.06(s,1H),7.54(d,J=4.3Hz,1H),7.44(s,1H),7.32(s,1H), 6.51(s,2H),5.46(s,2H),4.16-4.08(s,1H),3.47(s,2H),2.70-2.57(m,4H),2.33(s,3H),2.20(s,3H),0.90-0.72(m,4H). LC-MS(M+H) + =418.0.

[0825] Example 150: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-((tetrahydro-2H-pyran- 4-yl)oxy)pyridin-4-yl)methoxy)pyrazin-2-amine

[0826]

[0827] Step 1: Methyl 3-((tetrahydro-2H-pyran-4-yl)oxy)isonicotinate

[0828]

[0829] The title compound (192 mg, 24%) was prepared in a similar manner to Example 30, Step 1, from methyl 3-hydroxyisonicotinate and 4-bromotetrahydro-2H-pyran. LC-MS (M+H) + =238.2.

[0830] Step 2: (3-((Tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)methanol

[0831]

[0832] The title compound (178 mg, quantitative) was prepared in a similar manner to Example 30, Step 2, from methyl 3-((tetrahydro-2H-pyran-4-yl)oxy)isonicotinate. LC-MS (M+H) + =210.1.

[0833] Step 3: 5-Bromo-3-((3-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)methoxy)pyrazin-2-amine

[0834]

[0835] The title compound (114 mg, 35%) was prepared in a manner similar to that in Example 17, step 1, from 3,5-dibromopyrazin-2-amine and (3-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)methanol. LC-MS (M+H) +=381.1,383.1.

[0836] Step 4: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)methoxy)pyrazin-2-amine

[0837]

[0838] Example 150 (18 mg, 13%) was prepared in a manner analogous to Example 17, Step 2, from 5-bromo-3-((3-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)methoxy)pyrazin-2-amine and ((2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 H NMR (400MHz, DMSO-d6) δ8.47 (s, 1H), 8.21 (d, J = 4.6Hz, 1H), 8.09 (s, 1H), 7. 62(d,J=4.4Hz,1H),7.48(s,1H),7.36(s,1H),6.54(s,2H),5.58(s,2H),4. 91-4.78(m,1H),3.91-3.78(m,2H),3.60-3.49(m,2H),3.46(s,2H),2.72-2 .56(m,4H),2.33(s,3H),2.19(s,3H),2.08-1.97(m,2H),1.76-1.62(m,2H). LC-MS(M+H) + =462.5.

[0839] Example 152: 3-((2-amino-3-chloropyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoxazole Quinolin-7-yl)pyrazin-2-amine

[0840]

[0841] Step 1: Ethyl 2,3-dichloroisonicotinate

[0842]

[0843] 2,3-Dichloroisonicotinic acid (2.0 g, 10.4 mmol) and H2SO4 (1.0 mL) were carefully added to EtOH (20 mL), and the mixture was stirred at 78 ° C overnight. The solvent was concentrated under reduced pressure. The residue was basified to pH = 8-9 with NaHCO3 and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.2 g, 96%). LC-MS (M+H) + =220.0.

[0844] Step 2: Ethyl 2-amino-3-chloroisonicotinate

[0845]

[0846] The title compound (0.80 g, 40%) was prepared from ethyl 2,3-dichloroisonicotinate in a similar manner to Example 29, Step 1. LC-MS (M+H) + =201.0.

[0847] Step 3: (2-Amino-3-chloropyridin-4-yl)methanol

[0848]

[0849] The title compound (590 mg, 93%) was prepared from ethyl 2-amino-3-chloroisonicotinate in a similar manner to Example 29, Step 2. LC-MS (M+H) + =159.0.

[0850] Step 4: 3-((2-amino-3-chloropyridin-4-yl)methoxy)-5-bromopyrazin-2-amine

[0851]

[0852] The title compound (400 mg, 63%) was prepared in a similar manner to Example 29, Step 3, from (2-amino-3-chloropyridin-4-yl)methanol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =330.0,332.0.

[0853] Step 5: 3-((2-amino-3-chloropyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0854]

[0855] Example 152 (80 mg, 40%) was prepared in a manner analogous to Example 17, Step 2, from 3-((2-amino-3-chloropyridin-4-yl)methoxy)-5-bromopyrazin-2-amine and ((2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1HNMR(400MHz,DMSO-d6)δ8.07(s,1H),7.87(d,J=5.0Hz,1H),7.46(s,1H),7.34(s,1H),6.79(d,J=5.0Hz ,1H),6.50(s,2H),6.33(s,2H),5.51(s,2H),3.47(s,2H),2.70-2.58(m,4H),2.34(s,3H),2.20(s,3H). LC-MS(M+H) + =411.4.

[0856] Example 161: 3-((2-amino-5-cyclopropyloxypyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4- Tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0857]

[0858] Step 1: 2-Bromo-5-cyclopropyloxyisonicotinic acid

[0859]

[0860] The title compound (963 mg, 41%) was prepared in a similar manner to Example 149, Step 1, from 2-bromo-5-fluoroisonicotinic acid and cyclopropanol. LC-MS (M+H) + =258.0.

[0861] Step 2: Methyl 2-bromo-5-cyclopropyloxyisonicotinate

[0862]

[0863] The title compound (816 mg, 77%) was prepared from 2-bromo-5-cyclopropyloxyisonicotinic acid in a similar manner to Example 44, Step 3. LC-MS (M+H) + =272.0.

[0864] Step 3: Methyl 2-(tert-butoxycarbonylamino)-5-cyclopropyloxyisonicotinate

[0865]

[0866] To a stirred solution of methyl 2-bromo-5-cyclopropyloxypyridine-4-carboxylate (800 mg, 2.94 mmol) and BocNH2 (413 mg, 3.53 mmol) in dioxane (20 mL) was added X-Phos (280 mg, 0.59 mmol), Cs2CO3 (1.92 g, 5.88 mmol) and Pd2(dba)3 (269 mg, 0.294 mmol). The mixture was stirred at 100 ° C under nitrogen for 2 h. The mixture was cooled to room temperature and then diluted with water (30 mL). The mixture was extracted with EtOAc (10 mL x 3) in sequence. The combined organic layer was washed with water (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE (1:3)) to give the title compound (369 mg, 41%). LC-MS (M+H) + =309.2.

[0867] Step 4: tert-Butyl 5-cyclopropyloxy-4-(hydroxymethyl)pyridin-2-ylcarbamate

[0868]

[0869] To a solution of methyl 2-(tert-butoxycarbonylamino)-5-cyclopropyloxyisonicotinate (350 mg, 1.14 mmol) in THF (10 mL) was added LiBH4 (124 mg, 5.68 mmol) and MeOH (2 mL) at 0 ° C. The mixture was stirred at 70 ° C under nitrogen for 2 h. The mixture was cooled to room temperature and then quenched with water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (eluted with EtOAc / PE (0% to 35% gradient) to give the title compound (287 mg, 90%). LC-MS (M+H) + =281.2.

[0870] Step 5: tert-Butyl 4-((3-amino-6-bromopyrazin-2-yloxy)methyl)-5-cyclopropyloxypyridin-2-ylcarbamate

[0871]

[0872] The title compound (254 mg, 63%) was prepared in a similar manner to Example 1, Step 7, from tert-butyl 5-cyclopropyloxy-4-(hydroxymethyl)pyridin-2-ylcarbamate and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) +=452.1.

[0873] Step 6: tert-Butyl 4-((3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)methyl)-5-cyclopropyloxypyridin-2-ylcarbamate

[0874]

[0875] The title compound (222 mg, 75%) was prepared in a manner similar to that in Example 1, Step 8, from tert-butyl 4-((3-amino-6-bromopyrazin-2-yloxy)methyl)-5-cyclopropyloxypyridin-2-ylcarbamate and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. LC-MS (MH) + =533.4.

[0876] Step 7: 3-((2-amino-5-cyclopropyloxypyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0877] Example 161 (36 mg, 22%) was prepared in a manner analogous to Example 34, Step 6 from tert-butyl 4-((3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)methyl)-5-cyclopropyloxypyridin-2-ylcarbamate. 1 H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.92(s,1H),7.44(s,1H),7.32(s,1H),6.54(s,1H),6.40(s,2H),5.46(s,2 H),5.36(s,2H),3.94-3.85(m,1H),3.48(s,2H),2.71-2.58(m,4H),2.34(s,3H),2.20(s,3H),0.79-0.64(m,4H). LC-MS(M+H) + =433.2.

[0878] Example 179: 3-((2-aminopyridin-4-yl)methoxy)-5-(5-methoxy-2-methyl-1,2,3,4-tetrahydroisoxazole Quinolin-7-yl)pyrazin-2-amine

[0879]

[0880] Step 1: N-(3-bromo-5-methoxybenzyl)-2,2-dimethoxyethylamine

[0881]

[0882] To a solution of 2,2-dimethoxyethylamine (1.09 g, 10.4 mmol) in toluene (15 mL) was added 3-bromo-5-methoxybenzaldehyde (2.04 g, 9.50 mmol) at room temperature. The resulting mixture was stirred at 120 ° C under a nitrogen atmosphere for 15 h and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure and then redissolved in MeOH (15 mL). The mixture was cooled in an ice bath and NaBH4 (4.18 mg, 110 mmol) was added thereto in batches over 10 min. The resulting mixture was warmed to room temperature. After 5 h, the reaction was quenched with ice water (20 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was concentrated under reduced pressure to give the title compound (2.80 g, crude product). LCMS (M+H) + =304.4.

[0883] Step 2: 7-Bromo-5-methoxy-1,2,3,4-tetrahydroisoquinolin-4-ol

[0884]

[0885] A mixture of N-(3-bromo-5-methoxybenzyl)-2,2-dimethoxyethanamine (2.80 g, from step 4) in HCl (6 M, 6.0 mL) was stirred at 40 ° C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (108 mg, 5% over 2 steps). LCMS (M+H) + =258.1.

[0886] Step 3: 7-Bromo-5-methoxy-1,2,3,4-tetrahydroisoquinoline

[0887]

[0888] To a stirred mixture of 7-bromo-5-methoxy-1,2,3,4-tetrahydroisoquinolin-4-ol (100 mg, 0.38 mmol) and triethylsilane (1.00 mL, 8.6 mmol) in DCM (5 mL) was added TFA (0.50 mL, 4.4 mmol) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 40°C for 48 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was partitioned between EtOAc (30 mL) and saturated NaHCO₃ (30 mL). The combined organic layers were separated, dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by C₁₈ chromatography (eluting with MeCN (45% to 70%) in 0.05% aqueous NH₄HCO₃) to give the title compound (75 mg, 81%). 1 H NMR (400MHz, DMSO-d6) δ6.92 (d, J = 1.9 Hz, 1H), 6.84 (d, J = 1.9 Hz, 1H), 3.82-3.74 (m, 5H), 2.90 (t, J = 6.0 Hz, 2H), 2.77 (s, 1H), 2.43 (t, J = 6.0 Hz, 2H). LCMS(M+H) + =242.1.

[0889] Step 4: 7-Bromo-5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

[0890]

[0891] The title compound (600 mg, 99%) was prepared from 7-bromo-5-methoxy-1,2,3,4-tetrahydroisoquinoline in a similar manner to Example 1, Step 5. LC-MS (M+H) + =256.0.

[0892] Step 5: 5-Methoxy-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline

[0893]

[0894] The title compound (705 mg, 99%) was prepared from 7-bromo-5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline in a similar manner to Example 1, Step 6. LC-MS (M+H) + =304.2.

[0895] Step 6: 3-((2-aminopyridin-4-yl)methoxy)-5-(5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0896]

[0897] Example 179 (23 mg, 14%) was prepared in a manner analogous to Example 17, Step 2, from 3-((2-aminopyridin-4-yl)methoxy)-5-bromopyrazin-2-amine and 5-methoxy-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR (400MHz, DMSO-d6) δ8.11 (s, 1H), 7.87 (d, J = 5.2Hz, 1H), 7.22-7.14 (m, 2H), 6.65-6.59 (m, 1H), 6. 56-6.45(m,3H),5.89(s,2H),5.38(s,2H),3.81(s,3H),3.47(s,2H),2.70-2.55(m,2H),2.34(s,3H). LC-MS(M+H) + =393.3.

[0898] Example 180: 5-(5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((3-methoxypyridine- 4-amino)methoxy)pyrazin-2-amine

[0899]

[0900] Example 180 (11 mg, 7%) was prepared in a manner analogous to Example 17, Step 2, from 5-bromo-3-((3-methoxypyridin-4-yl)methoxy)pyrazin-2-amine and 5-methoxy-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR (400MHz, DMSO-d6) δ8.40(s,1H),8.23(d,J=4.8Hz,1H),8.13(s,1H),7.54(d,J=4.8Hz,1H),7.21-7.12 (m,2H),6.55(s,2H),5.53(s,2H),3.98(s,3H),3.79(s,3H),3.46(s,2H),2.67-2.55(m,2H),2.33(s,3H). LC-MS(M+H) + =408.2.

[0901] Example 188: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((5-methoxy-1H-pyrrolo- [2,3-b]pyridin-4-yl)methoxy)pyrazin-2-amine

[0902]

[0903] Step 1: 4-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine

[0904]

[0905] To a solution of 4-chloro-5-methoxy-1H-pyrrolo[2,3-b]pyridine (950 mg, 5.20 mmol) in MeCN (35 mL) was added NaI (3.90 g, 26.0 mmol) and acetyl chloride (782 mg, 9.96 mmol) at room temperature. The mixture was stirred at 80 ° C for 2 h. The mixture was cooled to room temperature and concentrated under vacuum. K2CO3 (10%, 80 mL) and NaHSO4 (10%, 80 mL) aqueous solutions were added, and the mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in THF (30 mL) and NaOH (1 M, 30 mL) aqueous solution, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated NH4Cl (100 mL). The mixture was extracted with EtOAc (100 mL x2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.07 g, 74%). LC-MS (M+H) + =275.0.

[0906] Step 2: 4-iodo-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

[0907]

[0908] The title compound (502 mg, 74%) was prepared from 4-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine in a similar manner to Example 34, Step 1. LC-MS (M+H) + =405.1.

[0909] Step 3: (5-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol

[0910]

[0911] The title compound (211 mg, 60%) was prepared in a manner similar to that in Example 222, Step 2, from 4-iodo-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine and (tributylstannyl)methanol. LC-MS (M+H) + =309.1.

[0912] Step 4: 5-Bromo-3-((5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)pyrazin-2-amine

[0913] The title compound (55 mg, 20%) was prepared in a manner similar to that in Example 34, Step 4, from (5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =480.2.

[0914] Step 5: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)pyrazin-2-amine

[0915]

[0916] The title compound (52 mg, 82%) was prepared in a manner analogous to Example 34, Step 5, from 5-bromo-3-((5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. LC-MS (M+H) + =561.5.

[0917] Step 6: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((5-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)pyrazin-2-amine

[0918] Example 188 (5 mg, 11%) was prepared in a manner analogous to Example 34, Step 6 from 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)pyrazin-2-amine. 1 H NMR(400MHz,DMSO-d6)δ11.46(s,1H),8.15(s,1H),8.01(s,1H),7.48(s,1H),7.44-7.34(m,2H),6.63-6.5 7(m,1H),6.39(s,2H),5.81(s,2H),3.97(s,3H),3.66(s,2H),2.85-2.68(m,4H),2.46(s,3H),2.21(s,3H). LC-MS(M+H) + =431.2.

[0919] Example 193: 3-((2-amino-3-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methoxy)-5- (2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0920]

[0921] Step 1: tert-Butyl (2-chloropyridin-3-yl) carbonate

[0922]

[0923] To a solution of 2-chloropyridin-3-ol (19.5 g, 150 mmol) in dichloromethane (300 mL) was added (Boc)2O (36.5 g, 167 mmol) and DMAP (500 mg, 4.1 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give the title compound (37.7 g, crude). The material was used in step 2 without further purification. LC-MS (M+H) + =230.1.

[0924] Step 2: tert-Butyl 2-chloro-3-hydroxyisonicotinate

[0925]

[0926] To a solution of tert-butyl (2-chloropyridinyl-3-yl) carbonate (37.7 g, crude product) in THF (300 mL) was added LDA (2.0 M, 150 mL, 300 mmol) at -78 ° C. The mixture was stirred at -78 ° C for 3 h and then quenched with water (200 mL). The pH of the mixture was neutralized to 6 with HCl (6 M). The mixture was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE (1: 10)) to give the title compound (10.0 g, 29% over 2 steps). LC-MS (M+H) + =230.1.

[0927] Step 3: tert-Butyl 2-chloro-3-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinate

[0928]

[0929] To a solution of tert-butyl 2-chloro-3-hydroxyisonicotinate (1.0 g, 4.4 mmol) in DMSO (10 mL) was added KOH (250 mg, 4.4 mmol). After 1 h, 4-(bromomethyl)tetrahydro-2H-pyran (790 mg, 4.4 mmol) was added. The mixture was stirred at room temperature for 15 h and then at 70 ° C for 6 h. The mixture was cooled and diluted with water (30 mL) and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE (1:10)) to give the title compound (600 mg, 42%). LC-MS (M+H) + =328.1.

[0930] Step 4: tert-Butyl 2-amino-3-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinate

[0931]

[0932] The title compound (300 mg, 54%) was prepared in a similar manner to Example 35, Step 3 from tert-butyl 2-chloro-3-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinate. LC-MS (M+H) + =309.2.

[0933] Step 5: (2-amino-3-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methanol

[0934]

[0935] The title compound (180 mg, 75%) was prepared in a similar manner to Example 35, Step 4 from tert-butyl 2-amino-3-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinate. LC-MS (M+H) + =239.1.

[0936] Step 6: 3-((2-amino-3-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methoxy)-5-bromopyrazin-2-amine

[0937]

[0938] The title compound (120 mg, 39%) was prepared in a manner similar to that in Example 35, Step 5, from (2-amino-3-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methanol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =410.1.

[0939] Step 7: 3-((2-amino-3-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[0940] Example 193 (25 mg, 34%) was prepared in a manner analogous to Example 17, Step 2, from 3-((2-amino-3-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methoxy)-5-bromopyrazin-2-amine and (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.69(d,J=5.1Hz,1H),7.51(s,1H),7.40(s,1H) ,6.79(d,J=5.0Hz,1H),6.45(s,2H),5.74(s,2H),5.49(s,2H),3.87-3.78(m,2H),3. 71(d,J=6.2Hz,2H),3.48(s,2H),3.32-3.24(m,2H),2.70-2.65(s,2H),2.64-2.58(m ,2H),2.34(s,3H),2.21(s,3H),2.10(brs,1H),1.77-1.68(m,2H),1.41-1.28(m,2H). LC-MS(M+H) + =491.5.

[0941] Example 204: 7-(5-amino-6-((2-aminopyridin-4-yl)methoxy)pyrazin-2-yl)-N,2-dimethyl-1, 2,3,4-Tetrahydroisoquinolin-5-amine

[0942]

[0943] Step 1: 5-Nitro-1,2,3,4-tetrahydroisoquinoline

[0944]

[0945] To a stirred mixture of 5-nitroisoquinoline (10.0 g, 54.6 mmol) in AcOH (272 mL) was added NaBH4 (7.60 g, 191 mmol) in portions at 0 ° C under N2. The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. Water (100 mL) was carefully added and the pH of the mixture was adjusted to 9 with NaOH solution. The resulting mixture was extracted with EtOAc (3x20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with MeOH / DCM (10: 1)) to give the title compound (7.0 g, 71%). LC-MS (M+H) + =179.1.

[0946] Step 2: 7-Bromo-5-nitro-1,2,3,4-tetrahydroisoquinoline

[0947]

[0948] To a solution of 5-nitro-1,2,3,4-tetrahydroisoquinoline (5.0 g, 28.0 mmol) in H2SO4 (50 mL) was carefully added potassium bromate (4.58 g, 28.0 mmol) in portions over 30 min at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was then quenched by carefully adding ice water (100 mL). The pH of the mixture was adjusted to 9 with NaOH solution. The mixture was extracted with DCM (300 mL x 3) in sequence. The combined organic phases were washed with brine (100 mL) and dried over Na2SO4. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH / DCM (0: 1 to 1: 9)) to give the title compound (1.43 mg, 20%). LC-MS (M+H) + =257.0.

[0949] Step 3: 7-Bromo-2-methyl-5-nitro-1,2,3,4-tetrahydroisoquinoline

[0950]

[0951] The title compound (1.46 g, 63%) was prepared in a similar manner to Example 1, Step 5, from 7-bromo-5-nitro-1,2,3,4-tetrahydroisoquinoline and formalin. LC-MS (M+H) + =271.0.

[0952] Step 4: 7-Bromo-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-amine

[0953]

[0954] A mixture of 7-bromo-2-methyl-5-nitro-3,4-dihydro-1H-isoquinoline (1.28 g, 4.70 mmol), iron powder (1.38 g, 23.5 mmol) and NH4Cl (1.06 g, 18.8 mmol) in ethanol (100 mL) and water (10 mL) was stirred at 70 ° C under N2 for 6 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was directly purified by silica gel column chromatography (eluted with MeOH / DCM (1:5)) to give the title compound (1.1 g, 89%). LC-MS (M+H) + =241.1.

[0955] Step 5: 7-Bromo-N,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-amine

[0956]

[0957] At room temperature under a nitrogen atmosphere, paraformaldehyde (71 mg, 2.36 mmol) and NaOMe (1.32 mL, 30 w %) were added dropwise to a solution of 7-bromo-2-methyl-3,4-dihydro-1H-isoquinolin-5-amine (285 mg, 1.18 mmol) in MeOH (12 mL). The resulting mixture was stirred at 60 ° C for another 16 h. The mixture was cooled to room temperature. NaBH4 (112 mg, 2.96 mmol) was added to the above mixture in batches. The resulting mixture was stirred at room temperature overnight. The reaction was then quenched by adding water (20 mL). The resulting solution was extracted with DCM (60 mL x 3). The organic phases were combined, washed with brine (50 mL), dried over Na2SO4 and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH / DCM (0: 1 to 1: 9)) to give the title compound (177 mg, 59%). LC-MS (M+H) + =255.0.

[0958] Step 6: N,2-Dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-5-amine

[0959]

[0960] The title compound (207 mg, 90%) was prepared in a similar manner to Example 1, Step 6 from methyl 7-bromo-N,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-amine and BPD. LC-MS (M+H) + =303.3.

[0961] Step 7: tert-Butyl 4-((3-amino-6-(2-methyl-5-(methylamino)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)methyl)pyridin-2-ylcarbamate

[0962]

[0963] The title compound (54 mg, 19%) was prepared in a manner similar to that in Example 1, Step 8, from N,2-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-5-amine and tert-butyl 4-((3-amino-6-bromopyrazin-2-yloxy)methyl)pyridin-2-ylcarbamate. LC-MS (M+H) + =492.4.

[0964] Step 8: 7-(5-amino-6-((2-aminopyridin-4-yl)methoxy)pyrazin-2-yl)-N,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-amine

[0965] Example 204 (6 mg, 16%) was prepared in a manner analogous to Example 34, Step 6 from tert-butyl 4-((3-amino-6-(2-methyl-5-(methylamino)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)methyl)pyridin-2-ylcarbamate. 1H NMR (400MHz, DMSO-d6) δ8.03(s,1H),7.87(d,J=5.2Hz,1H),6.83-6.75(m,2H),6.61(d,J=5.3Hz,1H),6.51(s,1H),6.37(s,2H), 5.87(s,2H),5.37(s,2H),5.01-4.96(m,1H),3.42(s,2H),2.79-2.83(m,3H),2.64-2.57(m,2H),2.49-2.42(m,2H),2.32(s,3H). LC-MS(M+H) + =392.2.

[0966] Example 205: 7-(5-amino-6-((3-methoxypyridin-4-yl)methoxy)pyrazin-2-yl)-N,2-dimethyl- 1,2,3,4-Tetrahydroisoquinolin-5-amine

[0967]

[0968] Example 205 (4.6 mg, 2%) was prepared in a manner analogous to Example 1, Step 8 from 5-bromo-3-((3-methoxypyridin-4-yl)methoxy)pyrazin-2-amine and N,2-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-5-amine. 1 H NMR (400MHz, DMSO-d6) δ8.40(s,1H),8.22(d,J=4.7Hz,1H),8.04(s,1H),7.52(d,J=4.7Hz,1H),6.79(s,1H),6.74(s,1H),6.46(s,2H) ,5.53(s,2H),5.03-4.97(m,1H),3.98(s,3H),3.40(s,2H),2.72(d,J=5.0Hz,3H),2.63-2.56(m,2H),2.49-2.41(m,2H),2.32(s,3H). LC-MS(M+H) + =407.2.

[0969] Example 222: 4-((3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy 2,6-diamine

[0970]

[0971] Step 1: Di-tert-butyl(4-bromopyridine-2,6-diyl)bis((tert-butoxycarbonyl)carbamate)

[0972]

[0973] To a stirred solution of 4-bromopyridine-2,6-diamine (500 mg, 2.53 mmol) and Boc2O (1.70 g, 7.40 mmol) in THF (15 mL) was added Et3N (806 mg, 7.81 mmol). The resulting mixture was stirred at 70 ° C under nitrogen overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM / PE (1: 1)) to give the title compound (640 mg, 43%). LC-MS (M + H) + =588.1.

[0974] Step 2: Di-tert-butyl(4-(hydroxymethyl)pyridine-2,6-diyl)bis((tert-butoxycarbonyl)carbamate)

[0975]

[0976] A solution of di-tert-butyl(4-bromopyridine-2,6-diyl)bis((tert-butoxycarbonyl)carbamate) (630 mg, 1.07 mmol), (tributylstannyl)methanol (693 mg, 2.12 mmol) and Pd(PPh3)4 (124 mg, 0.10 mmol) in toluene (15 mL) was stirred at 100°C under nitrogen overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (221 mg, 40%). LC-MS (M+H) + =540.3.

[0977] Step 3: Di-tert-butyl(4-(((3-amino-6-bromopyrazin-2-yl)oxy)methyl)pyridine-2,6-diyl)bis((tert-butoxycarbonyl)carbamate)

[0978]

[0979] The title compound (106 mg, 43%) was prepared in a manner similar to that in Example 1, Step 7, from di-tert-butyl(4-(hydroxymethyl)pyridine-2,6-diyl)bis((tert-butoxycarbonyl)carbamate) and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =711.5.

[0980] Step 4: 4-((3-amino-6-bromopyrazin-2-yloxy)methyl)pyridine-2,6-diamine

[0981]

[0982] The title compound (45 mg, 97%) was prepared in a manner similar to that in Example 34, Step 6, from di-tert-butyl(4-(((3-amino-6-bromopyrazin-2-yl)oxy)methyl)pyridine-2,6-diyl)bis((tert-butoxycarbonyl)carbamate). LC-MS (M+H) + =310.9.

[0983] Step 5: 4-((3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)methyl)pyridine-2,6-diamine

[0984]

[0985] Example 222 (11 mg, 19%) was prepared in a manner analogous to Example 1, Step 8, from 4-((3-amino-6-bromopyrazin-2-yloxy)methyl)pyridine-2,6-diamine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.50(s,1H),7.38(s,1H),6.34(s,2H),5.74(s,2H ),5.36(s,4H),5.23(s,2H),3.51(s,2H),2.71-2.61(m,4H),2.35(s,3H),2.22(s,3H). LC-MS(M+H) + =392.2.

[0986] Example 242: 5-(2,8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(1-isopropyl-1H-pyrazole-4-yl)- (2-Methyloxy)pyrazin-2-amine

[0987]

[0988] Step 1: 1-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0989]

[0990] The title compound (1.10 g, 45%) was prepared in a similar manner to Example 116, Step 1, from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 2-bromopropane. LC-MS (M+H) + =237.2.

[0991] Step 2: 1-Isopropyl-1H-pyrazol-4-ol

[0992]

[0993] The title compound (488 mg, 83%) was prepared from 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a similar manner to Example 116, Step 2. LC-MS (M+H) + =127.1.

[0994] Step 3: 5-Bromo-3-(1-isopropyl-1H-pyrazol-4-yloxy)pyrazin-2-amine

[0995]

[0996] The title compound (300 mg, 25%) was prepared in a similar manner to Example 116, step 3, from 1-isopropyl-1H-pyrazol-4-ol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =298.1.

[0997] Step 4: 5-(2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(1-isopropyl-1H-pyrazol-4-yloxy)pyrazin-2-amine

[0998] Example 242 (35 mg, 27%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-(1-isopropyl-1H-pyrazol-4-yloxy)pyrazin-2-amine and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.20(s,1H),8.10(s,1H),7.56(s,1H),7.48-7.40(m,2H),6.63(s,1H),4.57-4.4 6(m,1H),3.40(s,2H),2.872.79(m,2H),2.61-2.54(m,2H),2.38(s,3H),2.18(s,3H),1.50-1.44(m,6H). LC-MS(M+H) + =379.2.

[0999] Example 249: 3-((2-amino-3-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)methoxy)-5-(2, 5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[1000]

[1001] Step 1: 3-Hydroxy-2-nitroisonicotinic acid

[1002]

[1003] 3-Hydroxyisonicotinic acid (25.0 g, 180 mmol) was dissolved in concentrated H2SO4 (200 mL). Concentrated HNO3 (40 mL) was carefully added dropwise to the mixture. The mixture was stirred at room temperature overnight. The mixture was poured into ice water (500 mL). The precipitate was collected by filtration and then triturated with EtOH (50 mL). The precipitate was collected by filtration and then dried under vacuum to give the title compound (12.0 g, 36%). LC-MS (M+H) + =185.0.

[1004] Step 2: Methyl 3-hydroxy-2-nitroisonicotinate

[1005]

[1006] To a mixture of 3-hydroxy-2-nitroisonicotinic acid (200 mg, 1.1 mmol) in MeOH (20 mL) was added concentrated H2SO4 (0.5 mL). The mixture was stirred at 70 ° C overnight. The mixture was cooled to room temperature and neutralized with NaHCO3 solution (30 mL). The mixture was extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the title compound (200 mg, 90%). LC-MS (M+H) + =213.0.

[1007] Step 3: Methyl 2-nitro-3-((tetrahydro-2H-pyran-4-yl)oxy)isonicotinate

[1008]

[1009] To a solution of methyl 3-hydroxy-2-nitroisonicotinate (200 mg, 1.0 mmol) and 4-bromotetrahydro-2H-pyran (500 mg, 3.0 mmol) in DMF (10 mL) was added K2CO3 (420 mg, 3.0 mmol). The mixture was stirred at 100 ° C overnight. The mixture was cooled, diluted with water (30 mL), and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL) in sequence, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with EtOAc: PE (1: 3)) to give the title compound (200 mg, 70%). LC-MS (M+H) + =283.1.

[1010] Step 4: Methyl 2-amino-3-((tetrahydro-2H-pyran-4-yl)oxy)isonicotinate

[1011]

[1012] To a mixture of methyl 2-nitro-3-((tetrahydro-2H-pyran-4-yl)oxy)isonicotinate (200 mg, 0.7 mmol) in MeOH (20 mL) was added Pd / C (10%, 20 mg). The mixture was stirred under H2 (1 atm) for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (180 mg, 99%). LC-MS (M+H) + =253.1.

[1013] Step 5: (2-amino-3-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)methanol

[1014]

[1015] The title compound (160 mg, 99%) was prepared from methyl 2-amino-3-((tetrahydro-2H-pyran-4-yl)oxy)isonicotinate in a manner similar to that in Example 35, Step 4. LC-MS (M+H) + =225.1.

[1016] Step 6: 3-((2-amino-3-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)methoxy)-5-bromopyrazin-2-amine

[1017]

[1018] The title compound (100 mg, 36%) was prepared in a manner similar to that in Example 35, Step 5, from (2-amino-3-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)methanol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =396.1.

[1019] Step 7: 3-((2-amino-3-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[1020] Example 249 (15 mg, 24%) was prepared in a manner analogous to Example 17, Step 3, from 3-((2-amino-3-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)methoxy)-5-bromopyrazin-2-amine and (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 H NMR (400MHz, DMSO-d6) δ8.07 (s, 1H), 7.69 (d, J = 5.1Hz, 1H), 7.52 (s, 1H), 7.40 (s ,1H),6.80(d,J=5.1Hz,1H),6.45(s,2H),5.73(s,2H),5.51(s,2H),4.20-4.11( m,1H),3.91-3.84(m,2H),3.48(s,2H),3.30-3.26(m,2H),2.71-2.65(m,2H),2. 65-2.59(m,2H),2.34(s,3H),2.21(s,3H),1.99-1.91(m,2H),1.82-1.70(m,2H). LC-MS (M+H) + =477.5.

[1021] Example 266: 3-((2-aminopyridin-4-yl)methoxy-d2)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline (Methyl-7-pyrazin-2-amine)

[1022]

[1023] Step 1: (2-aminopyridin-4-yl)methan-d2-ol

[1024]

[1025] The title compound (410 mg, 100%) was prepared in a similar manner to Example 29, Step 2, from methyl 2-aminoisonicotinate and LiAlD4. LC-MS (M+H) + =127.0.

[1026] Step 2: 3-((2-aminopyridin-4-yl)methoxy-d2)-5-bromopyrazin-2-amine

[1027]

[1028] The title compound (700 mg, 71%) was prepared in a similar manner to Example 29, Step 3, from (2-aminopyridin-4-yl)methan-d2-ol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =298.0,300.0.

[1029] Step 3: 3-((2-aminopyridin-4-yl)methoxy-d2)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[1030] Example 266 (238 mg, 47%) was prepared in a manner analogous to Example 17, Step 2, from 3-((2-aminopyridin-4-yl)methoxy-d2)-5-bromopyrazin-2-amine and ((2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 HNMR(400MHz,DMSO-d6)δ8.06(s,1H),7.88(d,J=5.2Hz,1H),7.50(s,1H),7.37(s,1H),6.62(d,J=4.6Hz ,1H),6.53(s,1H),6.45(s,2H),5.91(s,2H),3.56(s,2H),2.74-2.64(m,4H),2.39(s,3H),2.21(s,3H). LC-MS(M+H) + =379.4.

[1031] Example 271: 3-((2-aminopyridin-4-yl)methoxy)-5-(2-methyl-5-(trifluoromethyl)-1,2,3,4-tetrafluoroethylene (2-Hydroisoquinolin-7-yl)pyrazin-2-amine

[1032]

[1033] Step 1: 2-(4-Bromo-2-(trifluoromethyl)phenyl)ethan-1-amine

[1034]

[1035] The title compound (5.0 g, 99%) was prepared in a manner similar to that described in Example 1, Step 1, from 2-(4-bromo-2-(trifluoromethyl)phenyl)acetonitrile. LC-MS (M+H) + =268.0,270.0.

[1036] Step 2: N-(4-bromo-2-(trifluoromethyl)phenethyl)-2,2,2-trifluoroacetamide

[1037]

[1038] The title compound (6.0 g, 88%) was prepared from 2-(4-bromo-2-(trifluoromethyl)phenyl)ethan-1-amine in a manner similar to that in Example 1, Step 2. LC-MS (M+H) + =364.0,366.0.

[1039] Step 3: 1-(7-Bromo-5-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one

[1040]

[1041] The title compound (5.0 g, 80%) was prepared from N-(4-bromo-2-(trifluoromethyl)phenethyl)-2,2,2-trifluoroacetamide in a manner similar to that in Example 1, Step 3. LC-MS (M+H) + =376.0,378.0.

[1042] Step 4: 7-Bromo-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline

[1043]

[1044] The title compound (3.5 g, 94%) was prepared from 1-(7-bromo-5-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one in a manner similar to that in Example 1, Step 4. LC-MS (M+H) + =280.0,282.0.

[1045] Step 5: 7-Bromo-2-methyl-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline

[1046]

[1047] The title compound (3.6 g, 98%) was prepared from 7-bromo-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline in a manner similar to that in Example 1, Step 5. LC-MS (M+H) + =294.0,296.0.

[1048] Step 6: (2-Methyl-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid

[1049]

[1050] The title compound (1.8 g, 62%) was prepared from 7-bromo-2-methyl-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline in a manner similar to that in Example 14, step 1. LC-MS (M+H) + =260.0.

[1051] Step 7: 3-((2-aminopyridin-4-yl)methoxy)-5-(2-methyl-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[1052] Example 271 (95 mg, 33%) was prepared in a manner analogous to Example 17, Step 2, from 3-((2-aminopyridin-4-yl)methoxy)-5-bromopyrazin-2-amine and (2-methyl-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 H NMR (400MHz, DMSO-d6) δ8.20(s,1H),7.96(s,1H),7.87(d,J=4.9Hz,1H),7.84(s,1H),6.66(s,2H),6.62(d,J=5. 1Hz,1H),6.50(s,1H),5.89(s,2H),5.37(s,2H),3.59(s,2H),2.96-2.88(m,2H),2.66-2.60(m,2H),2.36(s,3H). LCMS(M+H) + =431.4.

[1053] Example 272: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-isopropyl-1H-pyrazole-4-yl)- (2-Methyloxy)pyrazin-2-amine

[1054]

[1055] Example 272 (31 mg, 25%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-(1-isopropyl-1H-pyrazol-4-yloxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.19(s,1H),8.09(s,1H),7.57(s,1H),7.48(s,1H),7.36(s,1H),6.63(s,2 H),4.58-4.46(m,1H),3.47(s,2H),2.72-2.59(m,4H),2.34(s,3H),2.20(s,3H),1.52-1.42(m,6H). LC-MS(M+H) + =379.2.

[1056] Example 273: 3-((1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)-5-(2,5-dimethyl-1,2,3,4- Tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[1057]

[1058] Step 1: 1-(Cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Pyrazole

[1059]

[1060] At 0 ° C, NaH (60%, 463 mg, 11.6 mmol) was added to a solution of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1.5 g, 7.73 mmol) in anhydrous DMF (20 mL). After 5 min, (bromomethyl) cyclopropane (1.25 g, 9.28 mmol) was added at 0 ° C, and the mixture was stirred overnight. Water (20 mL) was added at 0 ° C, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and filtered. The residue was purified by silica gel chromatography to give the title compound (1.42 g, 74%). LC-MS (M+H) + =249.0.

[1061] Step 2: 1-(Cyclopropylmethyl)-1H-pyrazol-4-ol

[1062]

[1063] At 0 ° C, NaOH solution (2.0 M, 5.8 mL, 11.6 mmol) and H2O2 (30%, 11.6 mmol) were added to a solution of 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.42 g, 5.72 mmol) in THF (20 mL). The mixture was stirred at room temperature for 1 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated Na2S2O3 (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (790 mg, 99%). LC-MS (M+H) + =139.0.

[1064] Step 3: 5-Bromo-3-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine

[1065]

[1066] K2CO3 (1.18 g, 8.58 mmol) was added to a solution of 1-(cyclopropylmethyl)-1H-pyrazol-4-ol (780 mg, 5.72 mmol) and 3,5-dibromopyrazin-2-amine (1.74 g, 6.86 mmol) in DMSO (10 mL), and the mixture was heated to 80 ° C and stirred for 3 h. The mixture was cooled to room temperature and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x2). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The residue was purified by silica gel chromatography to give the title compound (1.40 g, 80%). LC-MS (M+H) + =310.0.

[1067] Step 4: 3-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)-5-(2,5-dimethyl-1,2,3,4-tetrakis (2-Hydroisoquinolin-7-yl)pyrazin-2-amine

[1068] 5-Bromo-3-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine (700 mg, 2.26 mmol), (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid (694 mg, 3.39 mmol), Pd(dppf)Cl2 (83 mg, 0.113 mmol) and K2CO3 (624 mg, 4.52 mmol) were added to 1,4-dioxane (20 mL) and water (4 mL), and the mixture was heated to 90°C under N2 for 3 h. The mixture was cooled to room temperature and then concentrated under reduced pressure. Water (20 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and filtered. The residue was purified by silica gel chromatography to give Example 273 (380 mg, 43%). 1 H NMR (400MHz, DMSO-d6) δ8.18(s,1H),8.10(s,1H),7.58(s,1H),7.48(s,1H),7.35(s,1H),6.66(s,2H),4.00(d,J=7.0Hz, 2H), 3.46 (s, 2H), 2.61-2.67 (m, 4H), 2.33 (s, 3H), 2.20 (s, 3H), 1.28 (s, 1H), 0.55 (d, J = 7.0Hz, 2H), 0.41 (d, J = 3.7Hz, 2H). LC-MS(M+H) + =391.0.

[1069] Example 274: 3-(1-Ethyl-1H-pyrazol-4-yloxy)-5-(5-methoxy-2-methyl-1,2,3,4-tetrahydroisothiazolin- Quinolin-7-yl)pyrazin-2-amine

[1070]

[1071] Example 274 (9 mg, 27%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-(1-ethyl-1H-pyrazol-4-yloxy)pyrazin-2-amine and 5-methoxy-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.22(s,1H),8.05(s,1H),7.57(s,1H),7.21(s,1H),7.13(s,1H),6.66(s,2H) ,4.19-4.06(m,2H),3.80(s,3H),3.45(s,2H),2.66-2.53(m,4H),2.32(s,3H),1.37(t,J=7.3Hz,3H). LC-MS(M+H) + =381.2.

[1072] Example 275: 7-(5-Amino-6-(1-ethyl-1H-pyrazol-4-yloxy)pyrazin-2-yl)-N,2-dimethyl-1, 2,3,4-Tetrahydroisoquinolin-5-amine

[1073]

[1074] Example 275 (32 mg, 34%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-(1-ethyl-1H-pyrazol-4-yloxy)pyrazin-2-amine and N,2-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-5-amine. 1 H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.03(s,1H),7.58(s,1H),6.80(s,2H),6.56(s,2H),5.08-4.97(m,1H),4.18-4.0 5(m,2H),3.42(s,2H),2.75(d,J=4.7Hz,3H),2.67-2.57(m,2H),2.48-2.40(m,2H),2.32(s,3H),1.37(t,J=7.2Hz,3H). LC-MS(M+H) + =380.2.

[1075] Example 276: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-(2-methoxyethyl)- 1H-pyrazol-4-yl)oxy)pyrazin-2-amine

[1076]

[1077] Step 1: 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1078]

[1079] The title compound (700 mg, 54%) was prepared in a similar manner to Example 116, Step 1, from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1-bromo-2-methoxyethane. LC-MS (M+H) + =253.2.

[1080] Step 2: 1-(2-methoxyethyl)-1H-pyrazol-4-ol

[1081]

[1082] The title compound (330 mg, 84%) was prepared from 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a similar manner to Example 116, Step 2. LC-MS (M+H) + =143.2.

[1083] Step 3: 5-Bromo-3-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine

[1084]

[1085] The title compound (250 mg, 34%) was prepared in a similar manner to Example 116, Step 3, from 1-(2-methoxyethyl)-1H-pyrazol-4-ol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =314.1,316.1.

[1086] Step 4: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine

[1087] Example 276 (79 mg, 25%) was prepared in a manner analogous to Example 116, Step 4, from 5-bromo-3-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine and (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.03(s,1H),7.61(s,1H),7.48(s,1H),7.34(s,1H),6.66(s,2H),4.3 1-4.23(m,2H),3.76-3.68(m,2H),3.49(s,2H),3.25(s,3H),2.71-2.58(m,4H),2.35(s,3H),2.21(s,3H). LC-MS(M+H) + =395.4.

[1088] Example 277: 3-(4-((3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazine-2-yl)pyrazine (1H-pyrazol-1-yl)propionitrile

[1089]

[1090] Step 1: 3-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propionitrile

[1091]

[1092] The title compound (500 mg, 39%) was prepared in a similar manner to Example 273, Step 1, from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 3-bromopropionitrile. LC-MS (M+H) + =248.0.

[1093] Step 2: 3-(4-Hydroxy-1H-pyrazol-1-yl)propionitrile

[1094]

[1095] The title compound (270 mg, 97%) was prepared from 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propionitrile in a manner similar to that in Example 273, Step 2. LC-MS (M+H) + =138.0.

[1096] Step 3: 3-(4-((3-amino-6-bromopyrazin-2-yl)oxy)-1H-pyrazol-1-yl)propionitrile

[1097]

[1098] The title compound (200 mg, 33%) was prepared in a similar manner to Example 273, Step 3, from 3-(4-hydroxy-1H-pyrazol-1-yl)propionitrile and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =309.0.

[1099] Step 4: 3-(4-((3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)oxy)-1H-pyrazol-1-yl)propionitrile

[1100] Example 277 (35 mg, 29%) was prepared in a manner analogous to Example 273, Step 4, from 3-(4-((3-amino-6-bromopyrazin-2-yl)oxy)-1H-pyrazol-1-yl)propionitrile and ((2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 H NMR (400MHz, DMSO-d6) δ8.21(s,1H),8.13(s,1H),7.70(s,1H),7.52(s,1H),7.38(s,1H),6.71(s,2H),4.42(t,J=6.3Hz,2H),3.70(br s,2H),3.11(t,J=6.3Hz,2H),2.91-2.79(m,2H),2.78-2.70(m,2H),2.46(s,3H),2.22(s,3H). LC-MS(M+H) + =390.3.

[1101] Example 278: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-(2-ethoxyethyl)- 1H-pyrazol-4-yl)oxy)pyrazin-2-amine

[1102]

[1103] Step 1: 1-(2-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1104]

[1105] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.15 mmol) in THF (20 mL) was added NaH (60%, 412 mg, 10.3 mmol) at 0 ° C., and the mixture was stirred for 30 min. 1-Bromo-2-ethoxyethane (1.18 g, 7.72 mmol) was added. The resulting solution was stirred at 65 ° C. for 6 h and cooled to room temperature. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE (1: 1)) to give the title compound (450 mg, 33%). LC-MS (M+H) + =267.2.

[1106] Step 2: 1-(2-ethoxyethyl)-1H-pyrazol-4-ol

[1107]

[1108] To a solution of 1-(2-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (450 mg, 1.69 mmol) in THF (10 mL) was added aqueous NaOH solution (2 M, 1.7 mL, 3.4 mmol) and H2O2 aqueous solution (0.39 mL, 3.38 mmol). The mixture was stirred at room temperature for 2 h. The pH of the mixture was acidified to 7 with HCl (1 M) and then extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give the title compound (450 mg, crude product). The material was used in step 3 without further purification. LC-MS (M+H) + =157.2.

[1109] Step 3: 5-Bromo-3-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine

[1110]

[1111] To a solution of 1-(2-ethoxyethyl)-1H-pyrazol-4-ol (450 mg, crude) in DMSO (8 mL) was added K2CO3 (1.20 g, 8.60 mmol) and 3,5-dibromopyrazine-2-amine (1.09 g, 4.29 mmol). The mixture was stirred at 70 ° C for 3 h and cooled to room temperature. The mixture was poured into water (80 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (80 mL x 2), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE (1: 1)) to give the title compound (170 mg, 31% over 2 steps). LC-MS (M+H) + =328.

[1112] Step 4: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine

[1113] To a solution of 5-bromo-3-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine (170 mg, 0.52 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid (117 mg, 0.57 mmol), KCO (215 mg, 1.56 mmol) and Pd(dppf)Cl (42 mg, 0.05 mmol). The mixture was stirred at 90° C. under nitrogen for 16 h. The reaction mixture was cooled to room temperature and poured into water (50 mL). The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to give Example 278 (85 mg, 40%). 1 HNMR(400MHz,DMSO-d6)δ8.18(s,1H),8.03(s,1H),7.62(s,1H),7.48(s,1H),7.34(s,1H),6.65(s,2H),4.27(t,J=5.3Hz,2H), 3.75(t,J=5.3Hz,2H),3.47(s,2H),3.43(q,J=7.0Hz,1H),2.74-2.57(m,4H),2.33(s,3H),2.21(s,3H),1.05(t,J=7.0Hz,3H). LC-MS(M+H) + =409.3.

[1114] Example 279: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- Methyl-N-(2-(methylamino)ethyl)-1H-pyrazole-4-carboxamide

[1115]

[1116] Step 1: 3-Chloro-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[1117]

[1118] To a solution of 5-bromo-3-chloropyrazin-2-amine (4.17 g, 20.0 mmol) and (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid (4.1 g, 20.0 mmol) in dioxane (100 mL) and water (20 mL) was added Pd(dppf)Cl2 (732 mg, 1.0 mmol) and K2CO3 (5.52 g, 40.0 mmol). The mixture was stirred at 60 ° C under nitrogen for 5 h. The mixture was cooled to room temperature and diluted with EtOAc (200 mL), washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with MeOH / DCM (1:40)) to give the title compound (2.50 g, 43%). LC-MS (M+H) + =289.0.

[1119] Step 2: Methyl 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylate

[1120]

[1121] To a solution of methyl 1H-pyrazole-4-carboxylate (984 mg, 7.81 mmol) in DMF (20 mL) was added NaH (60%, 312 mg, 7.81 mmol) at 0 ° C. The mixture was stirred at room temperature for 0.5 h, and then 3-chloro-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (1.5 g, 5.21 mmol) was added. After 5 h, at 0 ° C, the mixture was quenched with water (50 mL) and extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with MeOH / DCM (1:30)) to give the title compound (480 mg, 24%). LC-MS (M+H) + =378.9.

[1122] Step 3: 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid

[1123]

[1124] To a solution of methyl 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylate (480 mg, 1.27 mmol) in a mixture of MeOH (10 mL) and water (10 mL) was added LiOH (91 mg, 3.81 mmol). The reaction mixture was stirred at room temperature overnight, and then the methanol was evaporated under reduced pressure. The remaining solution was acidified to pH = 5-6 with HCl (1.0 M), and the precipitate was collected by filtration and then dried under vacuum to give the title compound (300 mg, 65%). LC-MS (M+H) + =365.2.

[1125] Step 4: 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N-methyl-N-(2-(methylamino)ethyl)-1H-pyrazole-4-carboxamide

[1126] To a solution of 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.41 mmol) in DMF (5 mL) was added HATU (235 mg, 0.62 mmol) and DIPEA (213 mg, 1.65 mmol). The mixture was stirred at 25 ° C for 30 min, and then N,N-dimethylethane-1,2-diamine (180 mg, 2.05 mmol) was added. The mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to give Example 279 (60 mg, 34%). 1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.66(s,1H),8.18(s,1H),7.72(s,1H),7.61(s,1H),7.44(s,2H),3.80-3.70(m,2H),3.69- 3.52(m,2H),3.26-3.20(m,2H),3.17-3.11(m,2H),2.81-2.65(m,4H),2.63-2.54(m,3H),2.44-2.36(m,4H),2.34-2.22(m,4H). LC-MS(M+H) + =435.4.

[1127] Example 280A / 280B: (R)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(1-methyl)- Pyrrolidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine and (S)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline (1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1128]

[1129] Step 1: 1-Methylpyrrolidin-3-yl 4-methylbenzenesulfonate

[1130]

[1131] At room temperature, to a solution of 1-methylpyrrolidin-3-ol (0.95g, 9.392mmol) in DCM (15mL), DMAP (327mg, 2.82mmol), TEA (1.92g, 18.8mmol) and p-toluenesulfonyl chloride (2.24g, 11.7mmol) are added. The mixture is stirred at room temperature under nitrogen for 16h and then concentrated under reduced pressure. Residue is purified by silica gel chromatography (eluting with MeOH / DCM (0% to 15% gradient)) to give title compound (750mg, 31%).

[1132] Step 2: 5-Bromo-3-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1133]

[1134] The title compound (105 mg, 36%) was prepared in a similar manner to Example 116, Step 1, from 1-methylpyrrolidin-3-yl 4-methylbenzenesulfonate and 3-(1H-pyrazol-4-yloxy)-5-bromopyrazin-2-amine. LC-MS (M+H) + =338.9.

[1135] Step 3: (R)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine and (S)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1136]

[1137] To a solution of 5-bromo-3-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine (90 mg, 0.265 mmol) in isopropanol (8 mL) was added 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline (152 mg, 0.531 mmol), Pd(Amphos)Cl2 (29 mg, 0.040 mmol), K3PO4 (57 mg, 0.265 mmol) and H2O (2 mL) at room temperature. The mixture was irradiated with microwaves at 80°C for 1 h. The mixture was cooled to room temperature and then diluted with water (30 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC and then by chiral prep-HPLC to give Example 280A and Example 280B.

[1138] Analytical chiral HPLC conditions: CHIRALPAK IG-3, 0.46 x 5 cm, 3.0 μm. Mobile phase: Hexane (10 mM NH 3 ) in (EtOH:DCM=1:1), 7:3 isocratic, 1 mL / min.

[1139] Example 280A: (10 mg, 17%) 1 H NMR (400MHz, CDCl3) δ8.15(s,1H),8.02(s,1H),7.69(s,1H),7.50(s,1H),7.37(s,1H),4.93(br s,3H),4.98-4.87(m,1H),3.63(s,2H),3.01-2.89(m,3H),2.88-2.71( m,4H),2.62-2.52(m,2H),2.49(s,3H),2.43(s,3H),2.32-2.20(m,4H). LC-MS(M+H) + =420.3. Chiral HPLC: tR=4.45 min.

[1140] Example 280B: (15 mg, 26%) 1 H NMR(400MHz, CDCl3)δ8.15(s,1H),8.01(s,1H),7.69(s,1H),7.50(s,1H),7.37(s,1H),5.00-4.89(m,3H),4.98-4.87(m, 1H),3.66(s,2H),3.00-2.89(m,3H),2.88-2.71(m,4H),2.62-2.52(m,2H),2.49(s,3H),2.43(s,3H),2.33-2.20(m,4H). LC-MS(M+H) + =420.3. Chiral HPLC: tR=4.96 min.

[1141] Example 281: (1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)- 1H-pyrazol-4-yl)(3,3-difluoropyrrolidin-1-yl)methanone

[1142]

[1143] Example 281 (26 mg, 21%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and 3,3-difluoropyrrolidine. 1 H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.66(s,1H),8.26(s,1H),7.71(s,1H),7.60(s,1H),7.38(s,2H),4.34-4.23(m,1H),4.10-4.02(m,1 H),3.98-3.87(m,1H),3.78-3.70(m,1H),3.55(s,2H),2.75-2.61(m,4H),2.61-2.52(m,1H),2.49-2.41(m,1H),2.36(s,3H),2.27(s,3H). LC-MS(M+H) + =454.3.

[1144] Example 282: (S)-3-((2-amino-3-((tetrahydrofuran-3-yl)oxy)pyridin-4-yl)methoxy)-5-(2, 5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[1145]

[1146] Step 1: Methyl (S)-2-chloro-3-((tetrahydrofuran-3-yl)oxy)isonicotinate

[1147]

[1148] NaH (60%, 858mg, 21.4mmol) is added to a solution of 2-chloro-3-fluoroisonicotinic acid (1.5g, 8.6mmol) and (S)-tetrahydrofuran-3-ol (754mg, 8.6mmol) in DMF (20mL), and the mixture is stirred at room temperature overnight. Water (60mL) is added and the mixture is extracted with EtOAc (50mL). The organic layer is washed with salt water (30mL), through Na SO Drying, filter and concentrate in a vacuum. Residue is dissolved in methanol (100mL), and concentrated H is added carefully SO (3.0mL). The reaction mixture is heated to reflux overnight. The solvent is removed in a vacuum, and residue is carefully diluted with ice water (70mL), then extracted with EtOAc (30mL). The organic layer is separated and washed with salt water (30mL), through Na SO Drying, filter and concentrate. The residue was purified by preparative TLC with PE / EtOAc (2:1) to give the title compound (1.1 g, 50%). LC-MS (M+H) + =258.0.

[1149] Step 2: Methyl (S)-2-amino-3-((tetrahydrofuran-3-yl)oxy)isonicotinate

[1150]

[1151] Under nitrogen, methyl (S) -2- chloro -3- ( (tetrahydrofuran -3- bases) oxy) isonicotinate (1.1 g, 4.3 mmol), diphenylmethane (852 mg, 4.7 mmol), Pd (dba) (123 mg, 0.21 mmol), Xantphos (247 mg, 0.43 mmol) and Cs CO (2.8 g, 8.6 mmol) are added to toluene (30 mL) and dioxane (30 mL). The mixture is heated to reflux overnight, then cooled to RT, filtered, and the solid is washed with DCM (20 mL). The filtrate is concentrated in a vacuum. The residue is redissolved in methanol (10 mL), and HCl (3.0 M, 10 mL) is added. The mixture is stirred for 30 min, then water (20 mL) is added. The mixture is extracted with EtOAc (30 mL), and the organic layer is concentrated in a vacuum. The residue was purified by preparative TLC with PE / EtOAc (2:1) to give the title compound (490 mg, 50%). LC-MS (M+H) + =239.1.

[1152] Step 3: (S)-(2-amino-3-((tetrahydrofuran-3-yl)oxy)pyridin-4-yl)methanol

[1153]

[1154] The title compound (400 mg, 93%) was prepared in a similar manner to Example 29, Step 2 from methyl (S)-2-amino-3-((tetrahydrofuran-3-yl)oxy)isonicotinate. LC-MS (M+H) + =211.1.

[1155] Step 4: (S)-3-((2-amino-3-((tetrahydrofuran-3-yl)oxy)pyridin-4-yl)methoxy)-5-bromopyrazin-2-amine

[1156]

[1157] The title compound (43 mg, 19%) was prepared in a manner similar to that in Example 29, Step 3, from (S)-(2-amino-3-((tetrahydrofuran-3-yl)oxy)pyridin-4-yl)methanol. LC-MS (M+H) + =382.0.

[1158] Step 5: (S)-3-((2-amino-3-((tetrahydrofuran-3-yl)oxy)pyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

[1159] Example 282 (401 mg, 16%) was prepared in a manner analogous to Example 17, Step 2, from (S)-3-((2-amino-3-((tetrahydrofuran-3-yl)oxy)pyridin-4-yl)methoxy)-5-bromopyrazin-2-amine and (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid. 1 H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.71(d,J=5.0Hz,1H),7.52(s,1H),7.40(s,1H ),6.78(d,J=4.9Hz,1H),6.47(s,2H),5.81(s,2H),5.54-5.44(m,2H),4.92(s,1H), 4.04(t,J=7.9Hz,1H),3.90(d,J=10.5Hz,1H),3.84-3.75(m,1H),3.62(d,J=10.3Hz ,1H),3.48(s,2H),2.70-2.58(m,4H),2.34(s,3H),2.21(s,3H),2.16-2.07(m,2H). LC-MS(M+H) + =463.4.

[1160] Example 283: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- (2-Methoxyethyl)-N-methyl-1H-pyrazole-4-carboxamide

[1161]

[1162] Step 1: 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N-(2-methoxyethyl)-N-methyl-1H-pyrazole-4-carboxamide

[1163] To a solution of 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.275 mmol) in DMF (10 mL) under nitrogen was added 2-methoxy-N-methylethan-1-amine (73 mg, 0.824 mmol), HATU (157 mg, 0.412 mmol) and DIPEA (177 mg, 1.37 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 283 (5 mg, 4%). 1 H NMR(400MHz,DMSO-d6)δ9.08-9.03(m,1H),8.64(s,1H),8.18-8.10(m,1H),7.71(s,1H),7.60(s,1H) ),7.45(s,2H),3.72-3.52(m,6H),3.31-2.98(m,6H),2.75-2.50(m,4H),2.38(s,3H),2.26(s,3H). LC-MS(M+H) + =436.4.

[1164] Example 284: (1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)- 1H-pyrazol-4-yl)(4-methylpiperazin-1-yl)methanone

[1165]

[1166] Example 284 (10 mg, 8%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and 1-methylpiperazine. 1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.64(s,1H),8.10(s,1H),7.71(s,1H),7.61(s,1H),7.41(s,2H),3.64( s,4H),3.54(s,2H),2.70(d,J=4.9Hz,2H),2.64(d,J=5.0Hz,2H),2.35(apps,7H),2.26(s,3H),2.21(s,3H). LC-MS(M+H) + =447.4.

[1167] Example 285: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- (2-(Pyrrolidin-1-yl)ethyl)-1H-pyrazole-4-carboxamide

[1168]

[1169] Example 285 (12 mg, 7%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and 2-(pyrrolidin-1-yl)ethanamine. 1 H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.64(s,1H),8.48-8.41(m,1H),8.24(s,1H),7.70(s,1H),7.58(s,1H),7.47-7.41(m,2H),3.5 5(s,2H),3.43-3.34(m,2H),2.75-2.56(m,6H),2.53-2.51(m,2H),2.50-2.46(m,2H),2.36(s,3H),2.28(s,3H),1.75-1.63(m,4H). LC-MS(M+H) + =461.3.

[1170] Example 286: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- (2-Chlorophenyl)-N-methyl-1H-pyrazole-4-carboxamide

[1171]

[1172] Example 286 (29 mg, 21%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and 2-chloro-N-methylaniline. 1HNMR(400MHz,DMSO-d6)δ8.58(s,1H),7.81-7.64(m,4H),7.62-7.49(m,3H),7.42-7 .32(m,3H),3.63(s,2H),3.30(s,3H),2.77-2.66(m,4H),2.42(s,3H),2.32(s,3H). LC-MS(M+H) + =488.1.

[1173] Example 287: 3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-(pyridin-4-yl)pyrrolidone Oxazine-2-carboxamide

[1174]

[1175] Step 1: 3-amino-6-bromo-N-(pyridin-4-yl)pyrazine-2-carboxamide

[1176]

[1177] The title compound (69 mg, 11%) was prepared in a similar manner to Example 279, Step 4, from 3-amino-6-bromopyrazine-2-carboxylic acid and pyridin-4-amine. LC-MS (M+H) + =294.0.

[1178] Step 2: 3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-(pyridin-4-yl)pyrazine-2-carboxamide

[1179] Example 287 (12 mg, 5%) was prepared in a manner analogous to Example 1, Step 8, from 3-amino-6-bromo-N-(4-chloro-3-methoxyphenyl)pyrazine-2-carboxamide and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.91(s,1H),8.55-8.49(m,2H),7.93-7.87(m,2H),7.8 5(s,1H),7.76(s,1H),7.64(s,2H),3.57(s,2H),2.77-2.61(m,4H),2.37(s,3H),2.29(s,3H). LC-MS(M+H) + =375.1.

[1180] Example 288: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(1-pyridin-3-yl)ethyl 1H-pyrazol-4-yloxy)pyrazin-2-amine

[1181]

[1182] Step 1: 3-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)pyridine

[1183]

[1184] The title compound (350 mg, 48%) was prepared in a similar manner to Example 116, Step 1, from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 3-(1-chloroethyl)pyridine. LC-MS (M+H) + =300.1.

[1185] Step 2: 1-(1-(Pyridin-3-yl)ethyl)-1H-pyrazol-4-ol

[1186]

[1187] The title compound (140 mg, 79%) was prepared in a manner similar to that in Example 116, step 2, from 3-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)pyridine. LC-MS (M+H) + =190.1.

[1188] Step 3: 5-Bromo-3-(1-(1-(pyridin-3-yl)ethyl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1189]

[1190] The title compound (90 mg, 60%) was prepared in a similar manner to Example 116, Step 3, from 1-(1-(pyridin-3-yl)ethyl)-1H-pyrazol-4-ol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =361.0.

[1191] Step 4: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(1-(pyridin-3-yl)ethyl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1192] Example 288 (17 mg, 18%) was prepared in a manner analogous to Example 116, Step 4, from 5-bromo-3-(1-(1-(pyridin-3-yl)ethyl)-1H-pyrazol-4-yloxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.54-8.47(m,2H),8.24(s,1H),8.19(s,1H),7.72-7.63(m,2H),7.45(s,1H),7.40-7.32(m,1H),7.32-7.27 (m,1H),6.66-6.61(m,2H),5.74(t,J=7.1Hz,1H),3.42(s,2H),2.70-2.57(m,4H),2.34(s,3H),2.17(s,3H),1.88(d,J=7.1Hz,3H). LC-MS(M+H) + =442.2.

[1193] Example 289: 1-(3-Amino-6-(2-methyl-5-(methylamino)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrrolidone Oxazine-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

[1194]

[1195] Step 1: Ethyl 1-(3-amino-6-bromopyrazin-2-yl)-1H-pyrazole-4-carboxylate

[1196]

[1197] To a stirred solution of ethyl 1H-pyrazole-4-carboxylate (5.0 g, 33.9 mmol) in DMF (100 mL) was added NaH (60%, 2.03 g, 50.8 mmol) at 0°C under nitrogen. The mixture was stirred at 0°C for 30 min, and then 3,5-dibromopyrazin-2-amine (9.0 g, 33.9 mmol) was added. The mixture was stirred at 70°C for 16 h. The mixture was cooled to room temperature and then poured into ice water (50 mL). The mixture was extracted with EtOAc (60 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with MeOH / DCM (1:9)) to give the title compound (3.9 g, 35%). LC-MS (M+H) + =312.0.

[1198] Step 2: 1-(3-amino-6-bromopyrazin-2-yl)-1H-pyrazole-4-carboxylic acid

[1199]

[1200] A mixture of ethyl 1-(3-amino-6-bromopyrazin-2-yl)pyrazole-4-carboxylate (1.0 g, 3.08 mmol) and NaOH (519 mg, 12.3 mmol) in EtOH (40 mL) and water (24 mL) was stirred at 80 ° C. under nitrogen for 1 h and then cooled to room temperature. The pH of the mixture was adjusted to 6 with aqueous HCl (1 M). The precipitate was collected by filtration and washed with water (10 mL x 2) and then dried under vacuum to give the title compound (610 mg, 69%). LC-MS (M+H) + =283.9.

[1201] Step 3: 1-(3-amino-6-bromopyrazin-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

[1202]

[1203] The title compound (565 mg, 90%) was prepared in a similar manner to Example 279, Step 4, from 1-(3-amino-6-bromopyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and dimethylamine. LC-MS (M+H) + =313.0.

[1204] Step 4: 1-(3-amino-6-(2-methyl-5-(methylamino)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

[1205] Example 289 (26 mg, 21%) was prepared in a manner analogous to Example 1, Step 8, from 1-(3-amino-6-bromopyrazin-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide and N,2-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-5-amine. 1 H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.62(s,1H),8.15(s,1H),7.39-7.33(m,2H),7.03(s,1H),6.95(s,1H),5.13-5.0 7(m,1H),3.48(s,2H),3.22(s,3H),3.04-2.99(m,2H),2.85-2.79(m,3H),2.67-2.59(m,2H),2.34(s,3H),2.08(s,3H). LC-MS(M+H) + =407.3.

[1206] Example 290: 1-(3-amino-6-(5-(cyclopropylamino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrrolidone Oxazine-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

[1207]

[1208] Step 1: 1-(3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

[1209]

[1210] The title compound (191 mg, 59%) was prepared from 1-(3-amino-6-bromopyrazin-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide in a manner similar to that in Example 1, Step 6. LC-MS (M-pin) + =277.0.

[1211] Step 2: 7-Bromo-N-(1-methoxycyclopropyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-amine

[1212]

[1213] To a solution of 7-bromo-2-methyl-3,4-dihydro-1H-isoquinolin-5-amine (185 mg, 0.77 mmol) in AcOH (4 mL) and MeOH (1 mL) was added (1-ethoxycyclopropyloxy)trimethylsilane (206 mg, 1.18 mmol) dropwise at 0°C. The mixture was stirred at 80°C under nitrogen for 1 h and then cooled to room temperature. The mixture was concentrated under reduced pressure to give the title compound (233 mg, 98%). LC-MS (M+H) + =311.0.

[1214] Step 3: 7-Bromo-N-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-amine

[1215]

[1216] To a suspension of NaBH4 (81 mg, 2.13 mmol) in THF (5 mL) was added BF3.Et2O (303 mg, 2.14 mmol) at 0°C. The mixture was stirred for 1 h, and then 7-bromo-N-(1-methoxycyclopropyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-amine (233 mg, 0.75 mmol) was added. The mixture was warmed to room temperature and stirred for 4 h. The mixture was poured into ice water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3) in sequence. The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (183 mg, 87%). LC-MS (M+H) + =281.1.

[1217] Step 4: 1-(3-amino-6-(5-(cyclopropylamino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

[1218]

[1219] Example 290 (19 mg, 19%) was prepared in a manner analogous to Example 1, Step 8, from 1-(3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide and 7-bromo-N-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-amine. 1 H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.58(s,1H),8.16(s,1H),7.44-7.34(m,3H),7.07(s,1H),5.41(s,1H),3.48(s,2H), 3.23(s,3H),3.04-2.99(m,4H),2.65-2.57(m,2H),2.50-2.44(m,2H),2.34(s,3H),0.81-0.72(m,2H),0.53-0.45(m,2H). LC-MS(M+H) + =433.3.

[1220] Example 291: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- Cyclopropyl-N-methyl-1H-pyrazole-4-carboxamide

[1221]

[1222] Example 291 (30 mg, 37%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and N-methylcyclopropylamine. 1 HNMR(400MHz,DMSO-d6)δ9.07(s,1H),8.63(s,1H),8.25(s,1H),7.68(s,1H),7.57(s,1H),7.41(d,J=5.0Hz,2H),3.53(s ,2H),3.24-3.15(m,1H),3.02(s,3H),2.77-2.59(m,4H),2.35(s,3H),2.25(s,3H),0.89-0.79(m,2H),0.71-0.62(m,2H). LC-MS(M+H) + =418.4.

[1223] Example 292: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- (2-Ethoxyethyl)-N-methyl-1H-pyrazole-4-carboxamide

[1224]

[1225] Example 292 (210 mg, 34%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and N-(2-ethoxyethyl)-N-methylamine hydrochloride. 1 H NMR(400MHz,DMSO-d6)δ9.11-8.98(m,1H),8.63(s,1H),8.20-8.09(m,1H),7.69(s,1H),7.58(s,1H),7.46-7.35( m,2H),3.66-3.44(m,8H),3.30-2.97(m,3H),2.75-2.60(m,4H),2.36(s,3H),2.25(s,3H),1.12(t,J=6.8Hz,3H). LC-MS(M+H) + =450.6.

[1226] Example 293: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-((tetrahydro-2H-pyran-4- (4-(2-(2-(2-(4-pyrazol-4-yloxy)methyl)pyrazin-2-amine))

[1227]

[1228] Step 1: 1-((Tetrahydro-2H-pyran-4-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1229]

[1230] The title compound (458 mg, 60%) was prepared in a similar manner to Example 116, Step 1, from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-(bromomethyl)-tetrahydro-2H-pyran. LC-MS (MH) + =293.1.

[1231] Step 2: 1-((Tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-ol

[1232]

[1233] The title compound (270 mg, 92%) was prepared from 1-((tetrahydro-2H-pyran-4-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a manner similar to that in Example 116, Step 2. LC-MS (MH) + =183.1.

[1234] Step 3: 5-Bromo-3-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1235]

[1236] The title compound (242 mg, 80%) was prepared in a similar manner to Example 116, Step 3, from 1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-ol and 5-bromo-3-chloropyrazin-2-amine. LC-MS (MH) + =354.0.

[1237] Step 4: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1238] Example 293 (19 mg, 9%) was prepared in a manner analogous to Example 1, Step 8 from 5-bromo-3-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yloxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1H NMR (400MHz, DMSO-d6) δ8.18(s,1H),8.02(d,J=0.8Hz,1H),7.57(s,1H),7.46(s,1H),7.32(s,1H),6.66(s,2H),4.03(d,J=7.1Hz,2H),3.88-3.7 9(m,2H),3.47(s,2H),3.32-3.22(m,2H),2.69-2.59(m,4H),2.34(s,3H ),2.20(s,3H),2.15-2.02(m,1H),1.49-1.40(m,2H),1.35-1.21(m,2H). LC-MS(M+H) + =435.3.

[1239] Example 294: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(4-ethoxy-1H-pyrazole-1- 1-Methyl-2-pyrazin-2-amine

[1240]

[1241] Step 1: 4-Ethoxy-1H-pyrazole

[1242]

[1243] To a stirred mixture of 1H-pyrazole-4-ol (800 mg, 9.04 mmol) and iodoethane (2.23 g, 13.6 mmol) in DMF (10 mL) was added CsCO (6.20 g, 18.1 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with MeOH / DCM (8:92)) to give the title compound (0.778 g, 77%). LC-MS (M+H) + =113.1.

[1244] Step 2: 5-Bromo-3-(4-ethoxy-1H-pyrazol-1-yl)pyrazin-2-amine

[1245]

[1246] The title compound (320 mg, 99%) was prepared in a similar manner to Example 279, Step 2, from 4-ethoxy-1H-pyrazole and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =284.0.

[1247] Step 3: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(4-ethoxy-1H-pyrazol-1-yl)pyrazin-2-amine

[1248] Example 294 (26 mg, 13%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-(4-ethoxy-1H-pyrazol-1-yl)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.55-8.48(m,2H),7.77-7.68(m,2H),7.59(s,1H),7.45(s,2H),4.16- 4.06(m,2H),3.55(s,2H),2.75-2.61(m,4H),2.36(s,3H),2.27(s,3H),1.36(t,J=7.0Hz,3H). LC-MS(M+H) + =365.2.

[1249] Example 295: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1250]

[1251] Step 1: tert-Butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

[1252]

[1253] The title compound (6.59 g, 73%) was prepared in a similar manner to Example 116, Step 1, from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and tert-butyl 3-bromoazetidine-1-carboxylate. LC-MS (M+H) + =350.2.

[1254] Step 2: 1-(azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1255]

[1256] The title compound (4.0 g, 71%) was prepared from tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate in a manner similar to that in Example 34, Step 6. LC-MS (M+H) + =250.2.

[1257] Step 3: 1-(1-(ethylsulfonyl)azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1258]

[1259] The title compound (578 mg, 42%) was prepared in a manner similar to Example 280A / 280B, Step 1, from 1-(azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and ethanesulfonyl chloride. LC-MS (M+H) + =342.2.

[1260] Step 4: 1-(1-(Ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-ol

[1261]

[1262] The title compound (277 mg, 74%) was prepared from 1-(1-(ethylsulfonyl)azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a manner similar to that in Example 116, Step 2. LC-MS (M+H) + =232.2.

[1263] Step 5: 5-Bromo-3-(1-(1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1264]

[1265] The title compound (145 mg, 33%) was prepared in a manner similar to that in Example 116, Step 3, from 1-(1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-ol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =403.0.

[1266] Step 6: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1267] Example 295 (16 mg, 13%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-(1-(1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.20(s,2H),7.79(s,1H),7.47(s,1H),7.34(s,1H),6.66(s,2H),5.39-5.28(m,1H),4.37 -4.25(m,4H),3.50(s,2H),3.28-3.18(m,2H),2.72-2.59(m,4H),2.35(s,3H),2.22(s,3H),1.27(t,J=7.4Hz,3H). LC-MS(M+H) + =484.2.

[1268] Example 296: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(1-phenylsulfonyl)azepine (cyclobutane-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1269]

[1270] Step 1: 1-(1-(phenylsulfonyl)azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1271]

[1272] The title compound (564 mg, 36%) was prepared in a similar manner to 280A / 280B, step 1, from 1-(azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and benzenesulfonyl chloride. LC-MS (M+H) + =390.1.

[1273] Step 2: 1-(1-(phenylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-ol

[1274]

[1275] The title compound (327 mg, 61%) was prepared from 1-(1-(phenylsulfonyl)azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a manner similar to that in Example 117, Step 2. LC-MS (M+H) + =280.1.

[1276] Step 3: 5-Bromo-3-(1-(1-(phenylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1277]

[1278] The title compound (290 mg, 60%) was prepared in a manner similar to that in Example 116, Step 3, from 1-(1-(phenylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-ol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =451.0.

[1279] Step 4: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(1-(phenylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1280] Example 296 (29 mg, 12%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-(1-(1-(phenylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.94-7.84(m,3H),7.82-7.73(m,1H),7.72-7.64(m,2H),7.61(s,1H),7.44(s,1H),7.31(s,1H ),6.62(s,2H),5.22-5.10(m,1H),4.27-4.18(m,2H),4.13-4.05(m,2H),3.50(s,2H),2.71-2.61(m,4H),2.37(s,3H),2.22(s,3H). LC-MS(M+H) + =532.3.

[1281] Example 297: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- (Cyclopropylmethyl)-1H-pyrazole-4-carboxamide

[1282]

[1283] Example 297 (26 mg, 28%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and cyclopropylmethylamine. 1 HNMR(400MHz,DMSO-d6)δ9.24(s,1H),8.64(s,1H),8.54(t,J=5.7Hz,1H),8.25(s,1H),7.71(s,1H),7.59(s,1H),7.45(s,2H),3.5 6(s,2H),3.21-3.14(m,2H),2.75-2.61(m,4H),2.36(s,3H),2.28(s,3H),1.08-0.98(m,1H),0.51-0.42(m,2H),0.29-0.21(m,2H). LC-MS(M+H) + =418.3.

[1284] Example 298: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- Cyclopropyl-1H-pyrazole-4-carboxamide

[1285]

[1286] Example 298 (27 mg, 35%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and cyclopropylamine. 1 H NMR(400MHz,DMSO-d6)δ9.20(s,1H),8.63(s,1H),8.44(s,1H),8.22(s,1H),7.70(s,1H),7.58(s,1H),7.44(s,2H), 3.55(s,2H),2.87-2.76(m,1H),2.76-2.60(m,4H),2.36(s,3H),2.27(s,3H),0.77-0.66(m,2H),0.61-0.53(m,2H). LC-MS(M+H) + =404.2.

[1287] Example 299: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- (2-Morpholinoethyl)-1H-pyrazole-4-carboxamide

[1288]

[1289] Example 299 (23 mg, 22%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and 2-morpholinoethylamine. 1 HNMR(400MHz,DMSO-d6)δ9.23(s,1H),8.64(s,1H),8.42(t,J=5.7Hz,1H),8.23(s,1H),7.71(s,1H),7.59(s,1H),7.45(s,2H ),3.62-3.53(m,6H),3.45-3.35(m,2H),2.74-2.68(m,2H),2.73-2.63(m,2H),2.51-2.40(m,6H),2.36(s,3H),2.28(s,3H). LC-MS(M+H) + =477.3.

[1290] Example 300: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- (2-Chloro-4-fluorobenzyl)-1H-pyrazole-4-carboxamide

[1291]

[1292] Example 300 (26 mg, 27%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and (2-chloro-4-fluorophenyl)methanamine. 1 H NMR(400MHz,DMSO-d6)δ9.30(s,1H),9.01(t,J=5.8Hz,1H),8.64(s,1H),8.30(s,1H),7.70(s,1H),7.58(s,1H),7 .54-7.41(m,4H),7.28-7.19(m,1H),4.56-4.50(m,2H),3.54(s,2H),2.74-2.61(m,4H),2.35(s,3H),2.27(s,3H). LC-MS(M+H) + =506.2.

[1293] Example 301: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- (1-(2-Chloro-4-ethoxyphenyl)ethyl)-1H-pyrazole-4-carboxamide

[1294]

[1295] Step 1: 1-(2-chloro-4-ethoxyphenyl)ethan-1-one

[1296]

[1297] The title compound (1.99 g, 90%) was prepared in a similar manner to Example 294, Step 1, from 1-(2-chloro-4-hydroxyphenyl)ethanone and iodoethane. LC-MS (M+H) + =199.0.

[1298] Step 2: N-(1-(2-chloro-4-ethoxyphenyl)ethyl)-2-methylpropane-2-sulfenamide

[1299]

[1300] To a solution of 1-(2-chloro-4-ethoxyphenyl)ethan-1-one (1.99 g, 10.0 mmol) in THF (50 mL) was added tert-butanesulfenamide (1.82 g, 15.0 mmol) and Ti(OEt)4 (3.43 g, 15.0 mmol) in portions at room temperature. The mixture was stirred at 70 ° C for 20 h. The reaction mixture was cooled to 0 ° C, and NaBH4 (1.33 g, 35.1 mmol) was added. The mixture was stirred at 0 ° C for 1 h and then quenched with saturated NaHCO3 (50 mL) under vigorous stirring. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.50 g, crude product). The material was used in step 3 without further purification. LC-MS (M+H) + =304.1.

[1301] Step 3: 1-(2-chloro-4-ethoxyphenyl)ethylamine

[1302]

[1303] To a solution of N-(1-(2-chloro-4-ethoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (2.50 g, crude product) in MeOH (30 mL) was added aqueous HCl (6 M, 5.0 mL, 30 mmol) dropwise at 0 ° C. The mixture was stirred at room temperature for 2 h, and then the solvent was evaporated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and saturated NaHCO 3 (50 mL). The organic layer was separated and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with MeOH / DCM (0% to 15% gradient)) to give the title compound (396 mg, 20% over 2 steps). LC-MS (M-NH 2) + =183.1.

[1304] Step 4: 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N-(1-(2-chloro-4-ethoxyphenyl)ethyl)-1H-pyrazole-4-carboxamide

[1305] Example 301 (30 mg, 33%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and 1-(2-chloro-4-ethoxyphenyl)ethanamine. 1 H NMR(400MHz, DMSO-d6)9.26(s,1H),8.80(d,J=7.5Hz,1H),8.64(s,1H),8.28( s,1H),7.70(s,1H),7.57(s,1H),7.48-7.41(m,3H),7.02-6.97(m,1H),6.97- 6.90(m,1H),5.44-5.33(m,1H),4.08-3.98(m,2H),3.55(s,2H),2.75-2.62(m ,4H),2.36(s,3H),2.28(s,3H),1.45(d,J=7.0Hz,3H),1.31(t,J=7.0Hz,3H). LC-MS(M+H) + =546.3.

[1306] Example 302: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- Methyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-4-carboxamide

[1307]

[1308] Example 302 (28 mg, 27%) was prepared in a manner similar to Example 12, last step, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and N-methyl-2-(pyrrolidin-1-yl)ethanamine. 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.63(s,1H),8.14(s,1H),7.70(s,1H),7.59(s,1H),7.42(s,2H),3.61-3.56(m,2 H),3.53(s,2H),3.29-2.96(m,3H),2.75-2.60(m,6H),2.45-2.41(m,4H),2.35(s,3H),2.26(s,3H),1.75-1.52(m,4H). LC-MS(M+H) + =475.3.

[1309] Example 303: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-(2,2,2-trifluoroethyl)- 1H-pyrazol-4-yl)oxy)pyrazin-2-amine

[1310]

[1311] Step 1: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole

[1312]

[1313] Cs2CO3 (1.84 g, 5.7 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.1 mmol) and 1,1,1-trifluoro-2-iodoethane (1.14 g, 5.4 mmol) in DMF (20 mL), and the mixture was heated to 80 ° C overnight. Water (60 mL) was added and the mixture was extracted with EtOAc (30 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (with EtOAc / PE (1: 1)) to give the title compound (290 mg, 21%). LC-MS (M+H) + =277.1.

[1314] Step 2: 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-ol

[1315]

[1316] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (500 mg, 1.8 mmol) in THF (15 mL) was added aqueous NaOH solution (3 M, 1.2 mL, 3.6 mmol) and H2O2 (410 mg, 3.6 mmol) at 0°C. The mixture was stirred at room temperature for 3 h, then water (30 mL) was added, and the pH of the mixture was adjusted to 6 with HCl (1 M). The mixture was extracted with EtOAc (30 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (with EtOAc / PE (1:2)) to give the title compound (210 mg, 70%). LC-MS (M+H) + =167.1.

[1317] Step 3: 5-Bromo-3-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine

[1318]

[1319] The title compound (140 mg, 31%) was prepared in a similar manner to Example 273, Step 3, from 3,5-dibromopyrazin-2-amine and 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-ol. LC-MS (M+H) + =338.0.

[1320] Step 4: Compound 11: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine

[1321] Example 303 (15 mg, 9%) was prepared in a manner analogous to Example 273, Step 4, from (2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)boronic acid and 5-bromo-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrazin-2-amine. 1 HNMR(400MHz,DMSO-d6)δ8.20(d,J=8.1Hz,2H),7.73(s,1H),7.46(s,1H),7.34(s,1H),6.69(s,2H),5.1 8(q,J=9.2Hz,2H),3.46(s,2H),2.66(d,J=4.5Hz,2H),2.62(d,J=5.3Hz,2H),2.33(s,3H),2.19(s,3H). LC-MS(M+H) + =419.1.

[1322] Example 304: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- Methyl-N-((tetrahydrofuran-3-yl)methyl)-1H-pyrazole-4-carboxamide

[1323]

[1324] Example 304 (30 mg, 12%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and N-methyl-1-(tetrahydrofuran-3-yl)methanamine. 1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.63(s,1H),8.23-8.06(m,1H),7.71(s,1H),7.60(s,1H),7.42(s,2H),3.85-3.60(m,3H),3.53(s,3H), 3.50-3.40(m,2H),3.28-3.15(m,2H),3.08-2.92(m,1H),2.75-2.55(m ,5H),2.35(s,3H),2.26(s,3H),2.08-1.90(m,1H),1.68-1.45(m,1H). LC-MS(M+H) + =462.2.

[1325] Example 305: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- (Tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide

[1326]

[1327] Example 305 (40 mg, 17%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and tetrahydrofuran-3-amine. 1 HNMR(400MHz,DMSO-d6)δ9.26(s,1H),8.63(s,1H),8.53(d,J=6.6Hz,1H) ,8.26(s,1H),7.70(s,1H),7.57(s,1H),7.44(s,2H),4.46(s,1H),3.91-3 .83(m,2H),3.75-3.69(m,1H),3.63-3.60(m,1H),3.55(s,2H),2.75-2.5 8(m,4H),2.36(s,3H),2.27(s,3H),2.24-2.12(m,1H),1.97-1.86(m,1H). LC-MS(M+H) + =434.2.

[1328] Example 306: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N- Methyl-N-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide

[1329]

[1330] Example 306 (15 mg, 6%) was prepared in a manner analogous to Example 279, Step 4, from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid and N-methyltetrahydrofuran-3-amine.1 H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.64(s,1H),8.13(s,1H),7.71(s,1H),7.60(s,1H),3.99-3.97(m,1H),3.75-3.71(m,2H),3 .61-3.59(m,1H),3.53(s,2H),3.06(s,4H),2.70(s,2H),2.63(s,2H),2.35(s,3H),2.26(s,3H),2.24-2.16(m,1H),1.96(s,1H). LC-MS(M+H) + =448.3.

[1331] Example 307: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(1-methylpiperidin-4-yl)- 1H-pyrazol-4-yloxy)pyrazin-2-amine

[1332]

[1333] Step 1: tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[1334]

[1335] The title compound (528 mg, 29%) was prepared in a similar manner to Example 116, Step 1, from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate. LC-MS (M+H) + =378.2.

[1336] Step 2: tert-Butyl 4-(4-hydroxy-1H-pyrazol-1-yl)piperidine-1-carboxylate

[1337]

[1338] The title compound (282 mg, 75%) was prepared from tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate in a manner similar to that in Example 116, Step 2. LC-MS (M+H) + =268.2.

[1339] Step 3: 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-ol

[1340]

[1341] At 0 ° C, under nitrogen, to a solution of tert-butyl 4- (4-hydroxy -1H- pyrazol-1-yl) piperidine -1- carboxylate (235 mg, 0.88 mmol) in THF (3 mL) was added dropwise LiAlH4 (1.0 M, 1.3 mL, 1,30 mmol) in THF. The resulting mixture was stirred at 80 ° C under nitrogen for 1 h and then cooled to room temperature. The mixture was quenched by adding water (0.06 mL) and 20% NaOH (0.06 mL) and then water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (155 mg, 97%). LC-MS (M+H) + =182.1.

[1342] Step 4: 5-Bromo-3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1343]

[1344] The title compound (205 mg, 99%) was prepared in a similar manner to Example 116, Step 3, from 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-ol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =353.0.

[1345] Step 5: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1346] Example 307 (20 mg, 12%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.20(s,1H),8.14(s,1H),7.58(s,1H),7.48(s,1H),7.36(s,1H),6.64(s,2H),4.20-4.0 8(m,1H),3.47(s,2H),2.92-2.83(m,2H),2.70-2.58(m,4H),2.34(s,3H),2.24-2.18(m,6H),2.14-1.92(m,6H). LC-MS(M+H)+ =434.2.

[1347] Example 308: 3-(4-((3-amino-6-(2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazine-2-yl)pyrazine (1H-pyrazol-1-yl)propionitrile

[1348]

[1349] Example 308 (176 mg, 56%) was prepared in a manner analogous to Example 273, Step 4, from (2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)boronic acid and 3-(4-((3-amino-6-bromopyrazin-2-yl)oxy)-1H-pyrazol-1-yl)propionitrile. 1 H NMR(400MHz,DMSO-d6)δ8.21(s,1H),8.13(s,1H),7.69(s,1H),7.44(m,2H),6.68(s,2H),4.44-4.39(s,2 H),3.46-3.36(m,2H),3.22-3.01(m,2H),2.97-2.73(m,2H),2.62-2.53(m,2H),2.38(s,3H),2.18(s,3H). LCMS(M+H) + =390.4.

[1350] Example 309: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(tetrahydro-2H-pyran-4- 1H-pyrazol-4-yloxy)pyrazin-2-amine

[1351]

[1352] Step 1: 1-(Tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1353]

[1354] The title compound (618 mg, 22%) was prepared in a similar manner to Example 116, step 1, from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-bromo-tetrahydro-2H-pyran. LC-MS (M+H) + =279.2.

[1355] Step 2: 1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ol

[1356]

[1357] The title compound (297 mg, 82%) was prepared from 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a manner similar to that in Example 116, Step 2. LC-MS (M+H) + =169.1.

[1358] Step 3: 5-Bromo-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1359]

[1360] The title compound (105 mg, 21%) was prepared in a similar manner to Example 116, Step 3, from 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =340.0.

[1361] Step 4: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1362] Example 309 (7 mg, 5%) was prepared in a manner analogous to Example 1, Step 8 from 5-bromo-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.22-8.13(m,2H),7.61(s,1H),7.49(s,1H),7.36(s,1H),6.64(s,2H),4.50-4.38(m ,1H),4.03-3.93(m,2H),3.56-3.45(m,4H),2.70-2.61(m,4H),2.35(s,3H),2.21(s,3H),2.10-1.89(m,4H). LC-MS(M+H) + =421.2.

[1363] Example 310: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(1-ethylazetidine) (alkyl-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1364]

[1365] Step 1: 1-(1-ethylazetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1366]

[1367] The title compound (574 mg, 79%) was prepared in a similar manner to Example 38, Step 1, from 1-(azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and acetaldehyde. LC-MS (M+H) + =278.1.

[1368] Step 2: 1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-ol

[1369]

[1370] The title compound (300 mg, 83%) was prepared from 1-(1-ethylazetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a manner similar to that in Example 116, Step 2. LC-MS (M+H) + =168.1.

[1371] Step 3: 5-Bromo-3-(1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1372]

[1373] The title compound (291 mg, 48%) was prepared in a similar manner to Example 116, Step 3, from 1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-ol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =339.0.

[1374] Step 4: 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1375] Example 310 (37 mg, 12%) was prepared in a manner analogous to Example 1, Step 8, from 5-bromo-3-(1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-yloxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline.1 H NMR(400MHz,DMSO-d6)δ8.27(s,1H),8.21(s,1H),7.67(s,1H),7.51(s,1H),7.37(s,1H),6.69(s,2H),5.07-4.96(m,1H),3.81-3 .73(m,2H),3.57(s,2H),3.45-3.37(m,2H),2.72-2.68(m,4H),2.62-2.52(m,2H),2.39(s,3H),2.22(s,3H),0.94(t,=7.2Hz,3H). LC-MS(M+H) + =420.2.

[1376] Example 311: (1s,4s)-4-(4-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrrolidone (2-oxazin-2-yloxy)-1H-pyrazol-1-yl)-1-methylcyclohexanol

[1377]

[1378] Step 1: 1,4-Dioxaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate

[1379]

[1380] At 0 ° C, to a stirred mixture of 1,4-dioxaspiro [4.5] decane-8-ol (10.0 g, 60.0 mmol) and Et3N (19.2 g, 180 mmol) in DCM (150 mL) was added TsCl (13.9 g, 69.1 mmol). The mixture was warmed to room temperature and stirred for 12 h. The mixture was filtered, and the filter cake was rinsed with DCM (10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM / PE (8: 1)) to give the title compound (11.0 g, 53%). 1 H NMR(400MHz, DMSO-d6)δ7.83-7.78(m,2H),7.47(d,J=8.1Hz,2H),4.66-4.58( m,1H),3.88-3.76(m,4H),2.42(s,3H),1.75-1.56(m,6H),1.55-1.47(m,2H).

[1381] Step 2: 4-iodo-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole

[1382]

[1383] To a mixture of 1,4-dioxaspiro[4.5]decane-8-yl 4-methylbenzenesulfonate (9.35 g, 26.9 mmol) and Cs2CO3 (16.8 g, 49.0 mmol) in DMF (35 mL) was added 4-iodopyrazole (5.00 g, 24.5 mmol). The mixture was warmed to 100 ° C and stirred for 12 h. The mixture was cooled to room temperature, diluted with water (300 mL) and extracted with EtOAc (3x300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (7.5 g, 74%). LC-MS (M+H) + =335.1.

[1384] Step 3: 4-(4-iodo-1H-pyrazol-1-yl)cyclohexanone

[1385]

[1386] To a solution of 4-iodo-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole (6.09 g, 18.2 mmol) in MeCN (50 mL) and H2O (50 mL) was added pyridinium p-toluenesulfonate (9.16 g, 36.4 mmol) at room temperature. The mixture was stirred at 60 ° C for 15 h. The solution was cooled to room temperature and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (3.90 g, 74%). LC-MS (M+H) + =291.0.

[1387] Step 4: (1s,4s)-4-(4-iodo-1H-pyrazol-1-yl)-1-methylcyclohexanol

[1388]

[1389] To a stirred solution of 4-(4-iodopyrazol-1-yl)cyclohexan-1-one (2.43 g, 8.39 mmol) in DCM (100 mL) was added AlMe3 (26 mL, 2.0 M, 52 mmol) at 0 ° C. The mixture was stirred at room temperature for 2 h and then quenched with saturated NH4Cl (100 mL). The resulting mixture was extracted with DCM (150 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with EtOAc in PE (0% to 15% gradient)) to give the title compound (790 mg, 31%). LC-MS (M+H) + =307.0.

[1390] Step 5: (1s,4s)-1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclohexanol

[1391]

[1392] At 0 ° C, under a nitrogen atmosphere, to a solution of (1s, 4s) -4- (4-iodopyrazol-1-yl) -1-methylcyclohexan-1-ol (677 mg, 2.21 mmol) in THF (80 mL) was added i-PrMgCl (3.9 mL, 2.0 M, 7.80 mmol) in THF. After 1.5 h, at 0 ° C, under a nitrogen atmosphere, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.75 g, 11.1 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 4 h. The reaction was quenched with saturated NH4Cl (100 mL). The resulting solution was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was concentrated under reduced pressure to yield the title compound (400 mg, 59%). LC-MS (M+H) + =307.1.

[1393] Step 6: 1-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-1H-pyrazol-4-ol

[1394]

[1395] The title compound (140 mg, 61%) was prepared in a manner similar to that in Example 116, step 2, from (1s,4s)-1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclohexanol. LC-MS (M+H) + =197.2.

[1396] Step 7: (1s,4s)-4-(4-(3-amino-6-bromopyrazin-2-yloxy)-1H-pyrazol-1-yl)-1-methylcyclohexanol

[1397]

[1398] The title compound (39 mg, 20%) was prepared in a similar manner to Example 116, step 3, from 1-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-1H-pyrazol-4-ol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =367.9.

[1399] Step 8: (1s,4s)-4-(4-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)-1H-pyrazol-1-yl)-1-methylcyclohexanol

[1400] Example 311 (12 mg, 25%) was prepared in a manner analogous to Example 1, Step 8, from (1s,4s)-4-(4-(3-amino-6-bromopyrazin-2-yloxy)-1H-pyrazol-1-yl)-1-methylcyclohexanol and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.21(s,1H),8.12(s,1H),7.56(s,1H),7.50(d,J=1 .8Hz,1H),7.38(d,J=1.9Hz,1H),6.65(s,2H),4.24(s,1H),4.21-4.04(m,1 H),3.49(s,2H),2.71-2.58(m,4H),2.36(s,3H),2.21(s,3H),2.19-2.04(m ,2H),1.93-1.81(m,2H),1.74-1.64(m,2H),1.60-1.44(m,2H),1.17(s,3H). LC-MS(M+H) + =449.3.

[1401] Example 312: (1s,4s)-4-(4-(3-amino-6-(2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrrolidone (2-oxazin-2-yloxy)-1H-pyrazol-1-yl)-1-methylcyclohexanol

[1402]

[1403] Example 312 (22 mg, 23%) was prepared in a manner analogous to Example 1, Step 8 from (1s,4s)-4-(4-(3-amino-6-bromopyrazin-2-yloxy)-1H-pyrazol-1-yl)-1-methylcyclohexanol and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1H NMR(400MHz,DMSO-d6)δ8.20(s,1H),8.09(s,1H),7.55(s,1H),7.49-7.40( m,2H),6.63(s,2H),4.20(s,1H),4.17-4.05(m,1H),3.40(s,2H),2.83(t,J =5.7Hz,2H),2.58(t,J=5.8Hz,2H),2.39(s,3H),2.18(s,3H),2.16-2.05(m ,2H),1.90-1.81(m,2H),1.72-1.63(m,2H),1.57-1.44(m,2H),1.16(s,3H). LC-MS(M+H) + =449.3.

[1404] Example 313: 3-(4-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)-1H-pyrazol-1-yl)-3-methylbutanenitrile

[1405]

[1406] Step 1: 3-Methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butanenitrile

[1407]

[1408] The title compound (817 mg, 39%) was prepared in a similar manner to Example 273, Step 1, from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 3-methylbut-2-enenitrile. LC-MS (M+1) + =276.3.

[1409] Step 2: 3-(4-Hydroxy-1H-pyrazol-1-yl)-3-methylbutyronitrile

[1410]

[1411] The title compound (200 mg, 73%) was prepared from 3-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butanenitrile in a manner similar to that in Example 116, Step 2. LC-MS (M+H) + =166.1.

[1412] Step 3: 3-(4-(3-amino-6-bromopyrazin-2-yloxy)-1H-pyrazol-1-yl)-3-methylbutyronitrile

[1413]

[1414] The title compound (202 mg, 49%) was prepared in a similar manner to Example 116, Step 3, from 3-(4-hydroxy-1H-pyrazol-1-yl)-3-methylbutanenitrile and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =337.2.

[1415] Step 4: 3-(4-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)-1H-pyrazol-1-yl)-3-methylbutanenitrile

[1416] Example 313 (29 mg, 30%) was prepared in a manner analogous to Example 1, Step 8, from 3-(4-(3-amino-6-bromopyrazin-2-yloxy)-1H-pyrazol-1-yl)-3-methylbutanenitrile and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.21(s,1H),7.69(s,1H),7.50(s,1H),7.37(s,1H),6.6 5(s,2H),3.48(s,2H),3.27(s,2H),2.71-2.60(m,4H),2.34(s,3H),2.20(s,3H),1.69(s,6H). LC-MS(M+H) + =418.2.

[1417] Example 314: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-((4-fluoro-tetrahydro-2H-pyrrolidone)- (pyran-4-yl)methyl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1418]

[1419] Step 1: (4-Fluoro-tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate

[1420]

[1421] The title compound (300 mg, 46%) was prepared in a similar manner to Example 311, Step 1, from (4-fluorotetrahydro-2H-pyran-4-yl)methanol. LC-MS (M+H) + =289.0.

[1422] Step 2: 1-((4-Fluoro-tetrahydro-2H-pyran-4-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1423]

[1424] The title compound (167 mg, 52%) was prepared in a similar manner to Example 311, Step 5, from (4-fluoro-tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LC-MS (M+H) + =311.2.

[1425] Step 3: 1-((4-Fluoro-tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-ol

[1426]

[1427] The title compound (71 mg, 66%) was prepared from 1-((4-fluoro-tetrahydro-2H-pyran-4-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a similar manner to Example 116, Step 2. LC-MS (M+H) + =201.1.

[1428] Step 4: 5-Bromo-3-(1-((4-fluoro-tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1429]

[1430] The title compound (78 mg, 59%) was prepared in a similar manner to Example 116, step 3, from 1-((4-fluoro-tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-ol and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =372.1.

[1431] Step 5: 5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-((4-fluoro-tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yloxy)pyrazin-2-amine

[1432] Example 314 (28 mg, 29%) was prepared in a manner similar to that in Example 1, Step 8, from 5-bromo-3-(1-((4-fluoro-tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yloxy)pyrazin-2-amine and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.14-8.05(m,2H),7.72-7.60(m,2H),7.48(s,1H),4.54-4.33(m,2H),4.24(s,2H),3.88-3.77(m,2H ),3.76-3.63(m,2H),3.47-3.37(m,2H),3.08-2.98(m,2H),2.91(s,3H),2.32(s,3H),2.04-1.73(m,2H),1.72-1.58(m,2H). LC-MS (M+H)+=453.2.

[1433] Example 315: (1r,3r)-3-(4-((3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)oxy)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

[1434]

[1435] Step 1: 3-Hydroxycyclobutanecarbonitrile

[1436]

[1437] The title compound (428 mg, 55%) was prepared in a manner similar to that in Example 22, Step 1, from 3-oxocyclobutanecarbonitrile.

[1438] Step 2: 3-Cyanocyclobutyl 4-methylbenzenesulfonate

[1439]

[1440] The title compound (1097 mg, 99%) was prepared in a manner analogous to that in Example 311, Step 1, from 3-hydroxycyclobutanecarbonitrile.

[1441] Step 3: 3-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutanecarbonitrile

[1442]

[1443] The title compound (728 mg, 61%) was prepared in a similar manner to Example 311, Step 5, from 3-cyanocyclobutyl 4-methylbenzenesulfonate and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LC-MS (M+H) + =274.0.

[1444] Step 4: 3-(4-Hydroxy-1H-pyrazol-1-yl)cyclobutanecarbonitrile

[1445]

[1446] The title compound (240 mg, 58%) was prepared in a similar manner to Example 116, Step 2, from 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutanecarbonitrile. LC-MS (M+H) + =164.2.

[1447] Step 5: 3-(4-(3-amino-6-bromopyrazin-2-yloxy)-1H-pyrazol-1-yl)cyclobutanecarbonitrile

[1448]

[1449] The title compound (364 mg, 89%) was prepared in a similar manner to Example 116, Step 3, from 3-(4-hydroxy-1H-pyrazol-1-yl)cyclobutanecarbonitrile and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =335.1.

[1450] Step 6: (1r,3r)-3-(4-((3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)oxy)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

[1451] Example 315 (26 mg, 26%) was prepared in a manner analogous to Example 1, Step 8, from 3-(4-(3-amino-6-bromopyrazin-2-yloxy)-1H-pyrazol-1-yl)cyclobutanecarbonitrile and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1H NMR(300MHz,DMSO-d6)δ8.20-8.10(m,2H),7.69(s,1H),7.44(s,1H),7.31(s,1H),6.61(s,1H),5.2 7-5.10(m,1H),3.55-3.42(m,3H),3.01-2.73(m,4H),2.68-2.55(m,4H),2.32(s,3H),2.19(s,3H). LC-MS(M+H) + =416.3.

[1452] Example 316: (1r,3r)-3-(4-((3-amino-6-(2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)oxy)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

[1453]

[1454] Example 316 (23 mg, 46%) was prepared in a manner analogous to Example 1, Step 8, from 3-(4-(3-amino-6-bromopyrazin-2-yloxy)-1H-pyrazol-1-yl)cyclobutanecarbonitrile and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(300MHz,DMSO-d6)δ8.22-8.11(m,2H),7.68(s,1H),7.45-7.35(m,2H),6.61(s,1H),5.26-5.09(m ,1H),3.55-3.41(m,1H),3.38(s,2H),2.98-2.71(m,6H),2.61-2.51(m,3H),2.37(s,3H),2.16(s,3H). LC-MS(M+H) + =416.3.

[1455] Example 317: 2-(4-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)-1H-pyrazol-1-yl)-2-methylpropionitrile

[1456]

[1457] Step 1: 2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile

[1458]

[1459] The title compound (2467 mg, 43%) was prepared in a similar manner to Example 116, Step 1, from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 2-bromoacetonitrile. LC-MS (M+H) + =233.9.

[1460] Step 2: 2-Methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propionitrile

[1461]

[1462] To a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile (1542 mg, 6.6 mmol) in THF (50 mL) was added iodomethane (2822 mg, 19.9 mmol) at 0°C, followed by dropwise addition of NaHMDS (13.2 mL, 1.0 M in THF, 13.2 mmol). The mixture was stirred at room temperature for 1 h and then quenched with saturated NH4Cl (100 mL). The mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (848 mg, 49%). LC-MS (M+H) + =261.9.

[1463] Step 3: 2-(4-Hydroxy-1H-pyrazol-1-yl)-2-methylpropionitrile

[1464]

[1465] The title compound (380 mg, 77%) was prepared from 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propionitrile in a manner similar to that in Example 116, Step 2. LC-MS (M+H) + =152.1.

[1466] Step 4: 2-(4-(3-amino-6-bromopyrazin-2-yloxy)-1H-pyrazol-1-yl)-2-methylpropionitrile

[1467]

[1468] The title compound (350 mg, 59%) was prepared in a similar manner to Example 116, Step 3, from 2-(4-hydroxy-1H-pyrazol-1-yl)-2-methylpropionitrile and 5-bromo-3-chloropyrazin-2-amine. LC-MS (M+H) + =323.0.

[1469] Step 5: 2-(4-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yloxy)-1H-pyrazol-1-yl)-2-methylpropionitrile

[1470] Example 317 (50 mg, 21%) was prepared in a manner analogous to Example 1, Step 8, from 2-(4-(3-amino-6-bromopyrazin-2-yloxy)-1H-pyrazol-1-yl)-2-methylpropionitrile and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.20(s,1H),7.78(s,1H),7.47(s,1H),7.34(s,1H ),6.66(s,2H),3.46(s,2H),2.69-2.58(m,4H),2.32(s,3H),2.18(s,3H),2.01(s,6H). LC-MS(M+H) + =404.2.

[1471] Example 318: 3-(4-(3-amino-6-(2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yloxy)-1H-pyrazol-1-yl)-2,2-dimethylpropionitrile

[1472]

[1473] Step 1: 2,2-Dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propionitrile

[1474]

[1475] The title compound (973 mg, 52%) was prepared in a similar manner to Example 317, Step 2, from 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propionitrile and MeI. LC-MS (M+H) + =276.2.

[1476] Step 2: 3-(4-Hydroxy-1H-pyrazol-1-yl)-2,2-dimethylpropionitrile

[1477]

[1478] The title compound (584 mg, 75%) was prepared from 2,2-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propionitrile in a manner similar to that in Example 116, Step 2. LC-MS (M+H) + =166.2.

[1479] Step 3: 4-(4-(3-amino-6-bromopyrazin-2-yloxy)-1H-pyrazol-1-yl)-3-chlorobenzonitrile

[1480]

[1481] The title compound (477 mg, 36%) was prepared in a similar manner to Example 116, Step 3, from 3-(4-hydroxy-1H-pyrazol-1-yl)-2,2-dimethylpropionitrile and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =337.2.

[1482] Step 4: 3-(4-(3-amino-6-(2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yloxy)-1H-pyrazol-1-yl)-2,2-dimethylpropionitrile

[1483] Example 318 (26 mg, 12%) was prepared in a manner analogous to Example 1, Step 8, from 3-(4-(3-amino-6-bromopyrazin-2-yloxy)-1H-pyrazol-1-yl)-2,2-dimethylpropionitrile and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. 1 H NMR(400MHz,DMSO-d6)δ8.19(s,1H),8.08(s,1H),7.67(s,1H),7.45-7.36(m,2H),6.65(s,2H),4.3 6(s,2H),3.38(s,2H),2.86-2.78(m,2H),2.60-2.53(m,2H),2.38(s,3H),2.17(s,3H),1.36(s,6H). LC-MS(M+H) + =418.2.

[1484] Example 319: 1-(3-Amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N,N-dimethyl-3-(prop-1-ynyl)-1H-pyrazole-4-carboxamide

[1485]

[1486] Step 1: Ethyl 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate

[1487]

[1488] The title compound (5236 mg, 69%) was prepared in a similar manner to Example 34, Step 1 from ethyl 3-iodo-1H-pyrazole-4-carboxylate and SEM-Cl. LC-MS (M+H) + =397.2.

[1489] Step 2: Ethyl 3-(prop-1-ynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate

[1490]

[1491] The title compound (2691 mg, 67%) was prepared in a similar manner to Example 14, Step 2, from ethyl 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate and propyne. LC-MS (M+H) + =309.3.

[1492] Step 3: Ethyl 3-(prop-1-ynyl)-1H-pyrazole-4-carboxylate

[1493]

[1494] The title compound (469 mg, 58%) was prepared in a similar manner to Example 34, Step 6 from ethyl 3-(prop-1-ynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate. LC-MS (M+H) + =178.9.

[1495] Step 4: Ethyl 1-(3-amino-6-bromopyrazin-2-yl)-3-(prop-1-ynyl)-1H-pyrazole-4-carboxylate

[1496]

[1497] The title compound (211 mg, 36%) was prepared in a similar manner to Example 289, Step 1, from ethyl 3-(prop-1-ynyl)-1H-pyrazole-4-carboxylate and 3,5-dibromopyrazin-2-amine. LC-MS (M+H) + =351.9.

[1498] Step 5: Ethyl 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-3-(prop-1-ynyl)-1H-pyrazole-4-carboxylate

[1499]

[1500] The title compound (180 mg, 69%) was prepared in a manner similar to that in Example 1, Step 8, from ethyl 1-(3-amino-6-bromopyrazin-2-yl)-3-(prop-1-ynyl)-1H-pyrazole-4-carboxylate and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. LC-MS (M+H) + =431.1.

[1501] Step 6: 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-3-(prop-1-ynyl)-1H-pyrazole-4-carboxylic acid

[1502]

[1503] The title compound (108 mg, 64%) was prepared in a manner similar to that in Example 46, Step 2, from ethyl 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-3-(prop-1-ynyl)-1H-pyrazole-4-carboxylate. LC-MS (M+H) + =403.1.

[1504] Step 7: 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-N,N-dimethyl-3-(prop-1-ynyl)-1H-pyrazole-4-carboxamide

[1505] Example 319 (48 mg, 41%) was prepared from 1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)-3-(prop-1-ynyl)-1H-pyrazole-4-carboxylic acid and dimethylamine hydrochloride in a manner similar to Example 46, Step 3. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.65 (s, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.38 (s, 2H), 3.53 (s, 2H), 3.07-2.99 (m, 6H), 2.72-2.61 (m, 4H), 2.35 (s, 3H), 2.25 (s, 3H), 2.11 (s, 3H). LC-MS (M+H)+ = 430.2.

[1506] Biological activity

[1507] HPK kinase activity assay at 1 mM ATP

[1508] The compounds disclosed herein were tested for inhibition of HPK1 kinase (aa1-346, Life Technologies) activity in a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. The assay was performed in a 384-well small-volume black plate in a reaction mixture containing HPK1 kinase (40 nM), 1 mM ATP, 0.5 μM STK1 substrate, and 0-10 μM compound in a buffer containing 50 mM HEPES, 0.01% BSA, 0.1 mM orthovanadate, 10 mM MgCl2, 1 mM DTT (pH = 7.0), and 0.005% Tween-20. The kinase was incubated with the compounds disclosed herein or DMSO at room temperature for 60 minutes, and the reaction was initiated by adding ATP and STK1 substrate. After 120 minutes of reaction at room temperature, an equal volume of stop / detection solution was added according to the manufacturer's instructions (CisBio). The stop / detection solution contained STK antibody-cryptate and XL665-conjugated streptavidin in detection buffer. TR-FRET signal (the ratio of fluorescence emission at 665 nm to fluorescence emission at 620 nm after excitation at 337 nm) was recorded on a PHERAstar FS microplate reader (BMG Labtech). Phosphorylation of the STK1 substrate resulted in binding of the STK antibody-cryptate to the biotinylated STK1 substrate, which allowed the fluorescent donor (Eu 3+The cryptate (a cryptate) was placed in close proximity to the receptor (streptavidin-XL665), resulting in a high degree of fluorescence resonance energy transfer. The inhibition of HPK1 by the compound at increasing concentrations was calculated based on the fluorescence ratio at 665 nm to 620 nm. The data were fitted to a four-parameter logistic equation using Graphpad Prism software to derive the IC for each compound. 50 The compounds disclosed herein exhibited the enzymatic activity values ​​shown in Table 1.

[1509] Table 1. Enzyme activity IC of compounds disclosed herein 50 (nM)

[1510]

[1511]

[1512]

[1513] It will be appreciated that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.

[1514] The disclosures of all publications, patents, patent applications, and published patent applications mentioned herein by identifying citation are hereby incorporated by reference in their entirety.

[1515] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to one skilled in the art that certain minor modifications or alterations may be implemented. Therefore, the illustration and examples should not be construed as limiting the scope of the invention.

Claims

1. Compounds of formula (I): or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in Cy 1 is aryl, monocyclic heterocyclyl, monocyclic heteroaryl, bicyclic fused heteroaryl or bicyclic fused heterocyclyl; L 1 Selected from single bond, -O-, * 1 -Alkylene-O-** 1 ,* 1 -Alkylene-NR c -** 1 ,* 1 -NR c C(O)-** 1 ;in* 1 Refers to the attachment to Cy 1 The location of the part, and 1 refers to the position of attachment to the aminopyrazine moiety; R 1 For hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, oxo, -CN, -NO2, -OR a 、-SO2R a 、-COR a 、-CO2R a 、-CONR a R b 、-C(=NR a )NR b R c 、-NR a R b 、-NR a COR b 、-NR a CONR b R c 、-NR a CO2R b 、-NR a SONR b R c 、-NR a SO2NR b R c , or -NR a S02R b , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl groups is optionally substituted with at least one R d replace; R 2 It is H; R 4 For hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR a 、-SO2R a 、-COR a 、-CO2R a 、-CONR a R b 、-C(=NR a )NR b R c 、-NR a R b 、-NR a COR b 、-NR a CONR b R c 、-NR a CO2R b 、-NR a SONR b R c 、-NR a SO2NR b R c , or -NR a S02R b , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted by at least one R d replace; R 3 It is methyl; R a , R b , and R c are independently hydrogen, deuterium, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R e ;or R a and R b , R b and R c , or R c and R a Together with the one or more atoms to which they are attached, they form a 3- to 12-membered ring containing 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring optionally substituted by at least one substituent R e replace; R d and R e are independently halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR f 、-SO2R f 、-SO2NR f R g 、-COR f 、-CO2R f 、-CONR f R g 、-C(=NR f )NR g R h 、-NR f R g 、-NR f COR g 、-NR f CONR g R h 、-NR f CO2R f 、-NR f SONR f R g 、-NR f SO2NR g R h , or -NR f S02R g , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR i 、-NR i R j 、-CO-NR i R j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents; R f , R g , R h , R i and R j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; m, n and t are each independently 0, 1, 2, 3 or 4; P = 1, and s = 1; or p=0, and s=2.

2. The compound according to claim 1, wherein L 1 is a single bond, -O-, ** 1 -CR a R b -O-** 1 ,* 1 -CR a R b -NR c -** 1 ,or* 1 -NHC(O)-** 1 ; R a , R b and R c are independently hydrogen, deuterium, or -C 1-8 Alkyl or C 3-8 Cycloalkyl, such as -C 1-8 Alkyl or C 3-8 Each of the cycloalkyl groups is optionally substituted by OR f Replacement; R f are each independently hydrogen or -C 1-8 Alkyl; or R a and R b Together with the carbon atoms to which they are attached, they form a 3- to 5-membered ring.

3. The compound according to claim 2, wherein R a , R b and R c Each is independently hydrogen, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, butyl, pentyl or hexyl; each methyl, ethyl, propyl, isopropyl, 2-methylpropyl, butyl, pentyl or hexyl is optionally substituted with OH.

4. The compound according to claim 1, wherein L 1 Selected from single bond, -O-, * 1 -CH2-O-** 1 ,* 1 -NHC(O)-** 1 ,* 1 -CHCH3-O-** 1 ,* 1 -CH2-NH-** 1 ,* 1 -CH2-N(CH3)-** 1 ,* 1 -C(CH3)2-O-** 1 ,or* 1 -CF2-O-** 1 .

5. The compound according to claim 1, wherein m=1; R 1 Selected from hydrogen, -C 1-8 Alkyl, OR a 、-NR a R b , or halogen, the -C 1-8 The alkyl group is optionally substituted with at least one halogen; R a and R b are each independently hydrogen or -C 1-8 alkyl.

6. The compound according to claim 1, wherein m=1; R 1 Selected from hydrogen, methyl, OR a 、-NR a R b , or halogen, the methyl group is optionally substituted by at least one halogen; R a and R b are each independently hydrogen or -C 1-8 alkyl. The compound according to claim 1 , wherein n=0.

8. The compound according to claim 1, wherein formula (I) is formula (Ia) or formula (Ib) R 1 , R 4 , R 3 ,t,Cy 1 , L 1 As defined in formula (I).

9. The compound according to claim 8, wherein R 1 Selected from hydrogen, -CH3, OCH3, -NHCH3, -NHCH2CH3, CHF2 or -CF3.

10. The compound according to claim 7, wherein formula (I) is formula (Ic) or (Id) 11. The compound according to claim 10, wherein formula (Ic) is selected from Where R 4 ,t,Cy 1 is as defined in formula (I); and R c is hydrogen or -C 1-8 alkyl.

12. The compound according to claim 11, wherein R c is hydrogen or methyl.

13. A compound according to any one of claims 1 to 12, wherein Cy 1 is selected from 3- to 8-membered monocyclic heterocyclic groups containing one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, wherein Cy 1 Optionally, -(R 4 ) t replace.

14. A compound according to any one of claims 1 to 12, wherein Cy 1 is selected from the group consisting of oxiranyl, aziridinyl, thiirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azocanyl, azetidinyl, dihydropyridinyl, tetrahydropyridinyl, pyranyl, homopiperidinyl, homopiperazinyl, azepanyl, oxetanyl, thiepanyl, oxathianyl, 1,4-oxathianyl, 1,4-dioxetanyl, 1,4-oxathianyl, 1,4-oxazepanyl, 1,4-dithianyl, 1,4-thiazepanyl, 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepanyl, Base, diazepine Thiazepine 1,1-dioxo-1,2-dioxolanyl, 1,3-dioxolanyl, pyrazolyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinyl, or 1,1-dioxo-1,2-dioxomorpholinyl, wherein Cy is 1 Optionally defined as -(R 4 ) t replace.

15. The compound according to claim 14, wherein Cy 1 is selected from piperidinyl, dihydropyridinyl or pyrrolidinyl; t=0 or 1, each R 4 Selected from hydrogen, oxo, or -C 1-8 alkyl.

16. The compound according to claim 15, wherein the pyrrolidinyl group is pyrrolidin-1-yl, pyrrolidin-2-yl, or pyrrolidin-3-yl; 1-8 The alkyl group is methyl.

17. The compound according to claim 14, wherein Selected from 18. A compound according to any one of claims 1 to 12, wherein Cy 1 is optionally defined as -(R 4 ) t Substituted monocyclic or bicyclic aryl groups.

19. The compound according to claim 18, wherein Cy 1 is naphthyl or phenyl; t=0, 1, 2 or 3; each R 4 are independently selected from hydrogen, halogen, optionally substituted with halogen or -OR f Replaced-C 1-8 Alkyl, -CN, -COOR a 、-OR a 、-CONR a R b , or -NR a R b , where R a , R b and R f are independently hydrogen, -C 1-8 Alkyl, -C 3-6 Cycloalkyl, or -C 3-6 Heterocyclic group, or R a and R b Together with the nitrogen atom to which they are attached they form a 3- to 12-membered ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members.

20. The compound according to claim 19, wherein each R 4 It is hydrogen, chlorine, fluorine, methoxy, -COOH, -CON(CH3)2, -CF3, -CH2-OCH3, -CN, pyrrolidin-1-ylcarbonyl, morpholinocarbonyl, or N-cyclopropylaminocarbonyl.

21. The compound according to claim 19, wherein Selected from 22. A compound according to any one of claims 1 to 12, wherein Cy 1 is optionally defined as -(R 4 ) t Substituted 5-membered or 6-membered heteroaryl.

23. A compound according to any one of claims 1 to 12, wherein Cy 1 is selected from the group consisting of pyridyl, cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furanyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, oxadiazolyl, phthalazinyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, wherein Cy 1 Optionally defined as -(R 4 ) t replace.

24. The compound according to claim 22, wherein Cy 1 is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl, thien-2-yl, thien-3-yl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl.

25. The compound according to claim 23, wherein Cy 1 Selected from Among them, Cy 1 Optionally defined as -(R 4 ) t Replace each R 4 are independently selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, oxo, -CN, -OR a 、-CONR a R b 、-NR a COR b , or -NR a R b , the -C 1-8 Alkyl, -C 2-8 Each of the alkynyl, cycloalkyl or heterocyclyl groups is optionally substituted by at least one R d Substitution, where R d Independently -C 1-8 Alkyl, cycloalkyl, aryl, heteroaryl, -SO2R f or-CONR f R g , the -C 1-8 Each of the alkyl, cycloalkyl, aryl, or heteroaryl groups is optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR i , or -NR i R j substituted by a substituent; and wherein R f , R g , R i and R j are each independently hydrogen or -C 1-8 alkyl.

26. The compound according to claim 25, wherein t = 0, 1, 2 or 3, provided that the valence bond theory is satisfied.

27. The compound according to claim 25, wherein t=1 or 2.

28. The compound according to claim 25, wherein the -C 2-8 Alkynyl is ethynyl.

29. The compound according to claim 25, wherein R d is cyclopropyl, cyclohexyl, pyridyl, pyrazolyl or thiazolyl, each of which is optionally substituted by at least one selected from halogen, -C 1-8 Alkyl, -OR i , or -NR i R j substituted by a substituent; and wherein R f , R g , R i and R j are each independently hydrogen or -C 1-8 alkyl.

30. The compound of claim 29, wherein the pyridyl group is pyridin-3-yl or pyridin-4-yl; and the pyrazolyl group is 1H-pyrazol-3-yl or 1H-pyrazol-5-yl.

31. The compound according to claim 23, wherein Each R 4 is -C optionally substituted by at least one halogen or cyano 1-8 alkyl.

32. The compound according to claim 23, wherein Each R 4 is -C optionally substituted by at least one fluoro or cyano group 1-8 alkyl.

33. The compound according to claim 23, wherein Each R 4 is optionally cyano, -C 1-8 Alkyl or hydroxy-substituted cycloalkyl.

34. The compound according to claim 23, wherein Each R 4 is optionally substituted by halogen or -C 1-8 Alkyl substituted heterocyclic group.

35. The compound according to claim 25, wherein Each R 4 is optionally represented by at least one R d Replaced-C 2-8 Alkynyl.

36. The compound according to claim 25, wherein Each R 4 is optionally represented by at least one R d Substituted ethynyl.

37. The compound according to claim 25, wherein Each R 4 Yes-OR a 、-CONR a R b , or -NR a R b , where R a and R b Each is hydrogen, -C 1-8 alkyl, cycloalkyl, aryl or heterocyclic group, wherein the -C 1-8 The alkyl group is optionally selected from cycloalkyl, aryl or heterocyclic R e Substituted, each cycloalkyl, aryl or heterocyclyl is optionally substituted with at least one -CO-NR i R j Substitution, where R i and R j are each independently hydrogen or -C 1-8 Alkyl; or R a and R b Together with the nitrogen atom to which they are attached, they form a 3- to 12-membered ring containing 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring being optionally substituted with at least one substituent R e replace.

38. The compound according to claim 23, wherein Selected from 39. according to the compound described in any one of claims 1-12, wherein Cy 1 is selected from 7- to 12-membered bicyclic fused heteroaryl or heterocyclyl groups containing, as one or more ring members, one or two or three heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, wherein Cy 1 Optionally, -(R 4 ) t replace.

40. The compound according to claim 39, wherein Cy 1 is selected from indazole, benzimidazole, quinoline, pyridoxazine, pyrrolopyridine, isoquinoline, benzoxazine, quinoxaline, isochromene, pyranopyrazole, pyranopyridine, benzodioxole, quinazoline, benzoxazole, indole, pyrrolopyrazine, pyrrolopyrimidine, imidazopyrimidine, or thienopyridine, wherein one or two carbon-carbon double bonds or carbon-nitrogen double bonds are optionally hydrogenated, wherein Cy 1 Optionally defined as -(R 4 ) t Replace; each R 4 It is halogen, -C 1-8 Alkyl, oxo, or -OR a , the -C 1-8 The alkyl group is optionally substituted with halogen, hydroxy or alkoxy, and wherein R a is hydrogen or -C 1-8 alkyl.

41. The compound of claim 40, wherein t is 0, 1, or 2.

42. The compound according to claim 39, wherein Cy 1 Selected from Among them, Cy 1 Optionally defined as -(R 4 ) t replace.

43. The compound according to claim 42, wherein Selected from 44. A compound selected from or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

45. A pharmaceutical composition comprising a compound according to any one of claims 1 to 44 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

46. ​​Use of a compound according to any one of claims 1 to 44, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancer.

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