A ROCK inhibitor and its preparation method and use

Abstract

The present invention relates to the field of pharmaceutical technology, specifically to ROCK inhibitors represented by formula (I), their preparation methods, and uses. The compounds provided herein exhibit excellent ROCK inhibitory activity, particularly exhibiting good selective inhibition of ROCK2 kinase. Furthermore, the compounds of the present invention have good safety and metabolic stability, and high bioavailability. Finally, the compounds of the present invention are simple to prepare and easy to purify, thus possessing promising application prospects.

Description

[0001] This application claims priority to two prior applications, filed with the State Intellectual Property Office of China on July 14, 2020, and January 11, 2021, with patent application numbers 202010676711.6 and 202110040185.9, entitled “A ROCK Inhibitor, Its Preparation Method, and Use.” The entire contents of both applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of pharmaceutical technology, and in particular to a ROCK inhibitor, a preparation method and use thereof. Background Art

[0003] Idiopathic interstitial pulmonary fibrosis (IPF) is a chronic, diffuse interstitial lung disease of unknown etiology, characterized by changes in common interstitial pneumonia. Its histopathology and imaging often show manifestations of common interstitial pneumonia. Due to its complex pathogenesis and irreversible progression, early diagnosis is difficult. Patient survival rates decrease significantly over time after diagnosis, with a 3-year survival rate of 50% and a 5-year survival rate of only 20%. This rate is lower than that of most cancers (e.g., leukemia, breast cancer, colon cancer, uterine fibroids, and kidney cancer), earning it the nickname "a cancer that is not a cancer." Currently, there are no proven, effective treatments for IPF. Based on the results of recent randomized controlled clinical trials and in light of clinical practice in my country, drugs such as pirfenidone and nintedanib can be used as appropriate. Nintedanib is recommended only for IPF patients with mild to moderate pulmonary dysfunction. Whether nintedanib can benefit IPF patients with severe pulmonary dysfunction, as well as the appropriate duration of treatment, requires further investigation.

[0004] Rho GTPases (Rho GTPases) were discovered in 1985 and belong to the Ras superfamily, sharing 25% homology with Ras. Currently, the main Rho GTPase members found in mammalian tissue cells include Rho (A, B, C), Rac (1, 2, 3), Cdc42 (Cdc42Hs / G25K, TC10, Tcl), Rho D, Rho G, Chp (1, 2), Rnd (Rho E / Rnd3, Rnd1 / Rho6, Rnd2 / Rho7), Rho H / TTF, Rif, Wrch1, and Rho BTB (1, 2). Among them, Rho (A, B, C) is one of the most important members of the Rho GTPases. ROCK (Rho-associated protein kinase), also known as Rho kinase, is a serine / threonine protein kinase with a molecular mass of approximately 160 kD. It is the most thoroughly functionally studied downstream target of Rho. ROCK comprises two isoforms, ROCK1 (ROKβ, p160-ROCK) and ROCK2 (ROKα). These two isoforms share 65% amino acid sequence identity and exhibit high similarity (92% identity) in the kinase domain. ROCK is distributed throughout tissues. ROCK1 is more highly expressed in non-neural tissues (such as blood, small intestine, and thymus), while ROCK2 is more highly expressed in the brain, heart, and colon.

[0005] ROCK is involved in the development of a variety of cardiovascular and cerebrovascular diseases, including hypertension, atherosclerosis, ischemic stroke, heart disease, diabetic nephropathy, eye diseases, tumors, neurological diseases, radiation damage, and autoimmune diseases. For example, the Rho / ROCK signaling pathway is involved in the activation of NAD(P)H oxidase, inducing oxidative stress, cardiac microvascular damage, and C-reactive protein-induced atherosclerotic thrombosis. High glucose can activate the Rho / ROCK pathway, inducing the expression of visfatin and type I procollagen in cardiomyocytes, causing cardiomyocyte hyperproliferation and inducing diabetic cardiomyopathy. Activation of the Rho / ROCK signaling pathway can regulate the NF-κB signaling pathway, upregulating inflammatory genes and inducing diabetic nephropathy. The Rho / ROCK signaling pathway alters membrane permeability, affecting cancer cell metastasis. During spinal cord injury, Rho activation induces growth cone atrophy, leading to impaired axonal regeneration, while also inducing the inhibitory effects of chondroitin sulfate proteoglycans on neuronal growth.

[0006] In addition, the Rho / ROCK signaling pathway is also involved in the development and progression of fibrotic diseases. Activation of the Rho / ROCK signaling pathway can increase the level of myocardial fibrosis in ischemic myocardium, and the expression of Rho and ROCK in the heart tissue of rats with acute myocardial fibrosis is significantly increased. Activation of the Rho / ROCK signaling pathway can induce actin phosphorylation and trigger cellular fibrosis. In vivo and in vitro experimental results have demonstrated that cardiopulmonary physiological and pathological damage caused by radiation exposure for a period of time is associated with fibrosis induced by the Rho / ROCK pathway. Ionizing radiation-induced endothelial adhesion fibronectin and focal adhesion formation, decreased endothelial cell migration, and endothelial dysfunction are associated with actin cytoskeleton reorganization and stress fiber formation induced by Rho / ROCK signaling pathway activation.

[0007] Lung damage in IPF primarily targets alveolar epithelial cells (ACEs). ACE death triggers a wound-healing response, including innate immune activation, vascular leakage and extravascular coagulation, fibroblast recruitment, proliferation, and activation, extracellular matrix synthesis and cross-linking, alveolar collapse, and epithelial regeneration. ROCK signaling fundamentally regulates the activities of these cells involved in the healing response, particularly epithelial cells, endothelial cells, and fibroblasts. The crucial role of ROCK in these responses further suggests the potential of ROCK inhibitors for the treatment of pulmonary fibrosis.

[0008] Currently, there are no marketed drugs that inhibit the ROCK pathway to treat numerous conditions, including fibrosis. The development of new agents requires careful optimization of the chemical and biological properties of lead compounds. Furthermore, the compounds must possess the desired pharmacokinetic and pharmacodynamic characteristics. This arduous development process often requires extensive testing. In many cases, identifying the optimal compound often requires the preparation of thousands of structurally similar compounds. Therefore, improving ROCK kinase inhibitors and developing new backbone compounds with ROCK1 and / or ROCK2 kinase inhibitory activity have positive implications for the treatment of these diseases. Summary of the Invention

[0009] To improve the problems existing in the prior art, the present invention provides a compound represented by the following formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug:

[0010]

[0011] in,

[0012] Ring A is unsubstituted or optionally substituted by one, two or more Rc: 3-20 membered heterocyclyl, or 5-20 membered heteroaryl;

[0013] Ring B is unsubstituted or optionally substituted by one, two or more Rd: 3-20 Cycloalkyl, 3-20 membered heterocyclic group, C 6-20 Aryl, or 5-20 membered heteroaryl;

[0014] The ring A and the ring B form a fused ring with W and V as the connection sites;

[0015] Rc, Rd are the same or different and are independently selected from halogen, amino, hydroxy, formyl, or the following groups which are unsubstituted or optionally substituted with one, two or more Rs: 1-20 Alkyl, C 1-20 alkoxy;

[0016] W and V are each independently C or N, and W and V are not N at the same time;

[0017] X is -C(=O)-;

[0018] Y is OH, chemical bond, C 1-20 Alkoxy, C 1-20 Alkyl, -NH- or -N(C 1-20 Alkyl)-, -NH(C 1-20 alkyl), -NH(C 1-20 Alkoxy); the C 1-20 Alkoxy, C 1-20 Alkyl and "-N(C 1-20 Alkyl)-, -NH(C 1-20 alkyl), -NH(C 1-20 C in "alkoxy)" 1-20 Alkoxy, C 1-20 The alkyl group may be unsubstituted or optionally substituted with one, two or more Rs;

[0019] Can be present or absent;

[0020] The condition is that Y is OH, C 1-20 Alkoxy, C 1-20 Alkyl, -NH(C 1-20 alkyl), -NH(C 1-20 Alkoxy), does not exist;

[0021] When Y is a chemical bond, Selected from the following groups which are unsubstituted or optionally substituted by one, two or more Ra: 3-20 membered heterocyclyl, 5-20 membered heteroaryl, C 3-20 Cycloalkyl, or C 6-20 aryl;

[0022] When Y is -NH- or -N(C 1-20 alkyl)-, is selected from the following groups which are unsubstituted or optionally substituted with one, two or more Rb: C 1-20 Alkyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, C 3-20 Cycloalkyl, or C 6-20 aryl;

[0023] Said Ra, Rb are the same or different and are independently selected from halogen, CN, C which is unsubstituted or optionally substituted with one, two or more Rs 1-20 Alkyl, OH, 5-20 membered heteroaryl, halogenated 5-20 membered heteroaryl;

[0024] Ring D is unsubstituted or optionally substituted by one, two or more Re: 3-20 Cycloalkyl, 3-20 membered heterocyclic group, C 6-20 aryl, or 5-20 membered heteroaryl, and the ring A is connected to the ring D through an N atom;

[0025] Said Re is selected from halogen, CN, OH, the following groups which are unsubstituted or optionally substituted by one, two or more Rs: C 1-20 Alkyl, C 3-20 Cycloalkyl, C 1-20 Alkoxy, C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl;

[0026] Or when there are at least two Re substitutions on the ring D, the two adjacent Re and the D ring atoms to which they are bonded together form a C 3-20 Cycloalkyl or 3-20 membered heterocyclyl or 3-20 membered heteroaryl;

[0027] The Rs are selected from halogen, CN, OH, C 1-20 Alkyl, C 1-20 Alkoxy, C 6-20 aryl or 5-20 membered heteroaryl.

[0028] Z is -NH-;

[0029] Ring E is unsubstituted or optionally substituted by one, two or more Rf: 6-20 Aryl, or 5-20 membered heteroaryl;

[0030] Rf is selected from halogen, CN, OH, unsubstituted or optionally substituted by one, two or more Rg: C1-C 20 Alkyl, C 6-20 Aryl, or 5-20 membered heteroaryl;

[0031] Rg is selected from halogen, CN, OH, C1-C2 optionally substituted by one, two or more halogens 20 Alkyl, -O-5-20 membered heteroaryl, said -O-5-20 membered heteroaryl is optionally substituted with -C(O)-NH2.

[0032] According to an embodiment of the present invention, W is selected from N or C;

[0033] V is selected from C;

[0034] X is -C(=O)-;

[0035] Y is OH, chemical bond, C 1-6 Alkoxy, C 1-6 Alkyl, -NH- or -N(C 1-6 Alkyl)-, -NH(C 1-6 alkyl), -NH(C 1-6 Alkoxy); the C 1-6 Alkoxy, C 1-6 Alkyl and "-N(C 1-6 Alkyl)-, -NH(C 1-6 alkyl), -NH(C 1-6 C in "alkoxy)" 1-6 Alkoxy, C 1-6 The alkyl group may be unsubstituted or optionally substituted with one, two or more Rs;

[0036] The Rs are selected from halogen, CN, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-12 aryl or 5-12 membered heteroaryl.

[0037] According to an embodiment of the present invention,

[0038] When Y is a chemical bond, Selected from the following groups which are unsubstituted or optionally substituted by one, two or more Ra: 3-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0039] Said Ra is selected from F, Cl, CN, OH or C optionally substituted by one, two or more halogens 1-6 alkyl;

[0040] When Y is -NH- or -N(C 1-6 alkyl)-, is selected from the following groups which are unsubstituted or optionally substituted with one, two or more Rb: C 3-6 Cycloalkyl, C 1-6 Alkyl, 3-6 membered heterocyclyl, or 5-12 membered heteroaryl;

[0041] Rb is selected from F, Cl, CN, OH, F or Cl-substituted 5-12 membered heteroaryl;

[0042] In one embodiment, when Y is a chemical bond, the X is The heteroatoms of the 3-6 membered heterocyclic group represented by are connected;

[0043] Ring A is unsubstituted or optionally substituted by one, two or more Rc: 3-6 membered heterocyclyl, or 5-12 membered heteroaryl;

[0044] Ring B is unsubstituted or optionally substituted by one, two or more Rd: 3-6 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0045] The ring A and the ring B form a fused ring with the W and V as the connection sites;

[0046] Rc, Rd are the same or different and are independently selected from F, Cl, amino, hydroxy, formyl, C 1-6 Alkyl, the C 1-6 Alkyl is unsubstituted or optionally substituted with one, two or more halogens;

[0047] The ring D is unsubstituted or optionally substituted by one, two or more Re: 6-12 Aryl, or 5-12 membered heteroaryl; and, the ring A is connected to the ring D through an N atom;

[0048] Said Re is selected from halogen, CN, OH, the following groups which are unsubstituted or optionally substituted by one, two or more Rs: C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 6-12 Aryl, 3-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0049] Or when there are at least two Re substitutions on the ring D, the two adjacent Re and the D ring atoms to which they are bonded together form a C 3-6 Cycloalkyl or 3-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0050] The Rs are selected from halogen, CN, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-12 Aryl or 5-12 membered heteroaryl;

[0051] Z is -NH-;

[0052] The ring E is unsubstituted or optionally substituted with one, two or more Rf 6-12Aryl, or 5-12 membered heteroaryl;

[0053] Rf is selected from F, Cl, the following groups which are unsubstituted or optionally substituted by one, two or more Rg: 6-12 Aryl, or 5-12 membered heteroaryl;

[0054] Rg is selected from F, Cl, -O-5-12 membered heteroaryl, wherein the -O-5-12 membered heteroaryl is optionally substituted with -C(O)-NH2.

[0055] According to a preferred embodiment of the present invention, W is selected from N or C;

[0056] V is selected from C;

[0057] X is -C(=O)-;

[0058] Y is OH, a chemical bond, -NH- or -N(methyl)-, provided that when Y is OH, does not exist;

[0059] When Y is a chemical bond, Selected from the following groups: azetidine which is unsubstituted or substituted with one, two or more F; azetidine which is unsubstituted or substituted with one, two or more CN; azetidine which is unsubstituted or substituted with one, two or more CF2; azetidine which is unsubstituted or substituted with one, two or more CF3; azetidine which is unsubstituted or substituted with F and / or OH;

[0060] When Y is -NH- or -N(methyl)-, Selected from the following groups: cyclobutane which is unsubstituted or substituted with one, two or more F groups; isopropyl; pyridazinyl; azetidine which is unsubstituted or substituted with one, two or more CN groups; azetidine which is substituted with F and / or OH groups; ethyl which is unsubstituted or substituted with one, two or more F groups; -N-chloropyridine-piperidinyl; pyridinyl which is unsubstituted or substituted with one, two or more F groups;

[0061] In one embodiment, when Y is a chemical bond, the X is The heteroatoms of the heterocyclic groups represented by are connected;

[0062] In one embodiment, When absent, Y is methyl, ethyl, propyl, butyl, -CH2CF3, -NH-CH2CF3, -NHCH2(CH2)2, -OCH2CF3, -OCH2CH3;

[0063] According to an embodiment of the present invention, the ring A and the ring B constitute the following fused ring:

[0064]

[0065] According to an embodiment of the present invention, the ring D is unsubstituted or optionally substituted by one, two or more Re: or

[0066] Wherein, the Re is as defined above.

[0067] The ring D may be further selected from:

[0068]

[0069] According to an embodiment of the present invention, said Z is -NH-;

[0070] According to an embodiment of the present invention,

[0071] The ring E is

[0072]

[0073] According to an embodiment of the present invention, Selected from the following structures:

[0074]

[0075] According to an embodiment of the present invention, the Re is selected from halogen, CF3, CN, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, CHF2, CNCH2-, propylene oxide, oxetane, oxolane; or, when there are at least two Re substitutions on the ring D, the adjacent two Re and the D ring atoms to which they are bonded together form a C 5-6 Cycloalkyl or 5-6 membered heterocyclic group or 5-6 membered heteroaryl, for example, forming cyclopentyl, oxolanyl, oxanyl, pyrrolyl;

[0076] In some embodiments, the present invention provides a compound represented by the following formula (II), its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug:

[0077]

[0078] wherein W is selected from N or C;

[0079] A double line including solid and dashed lines represents a single bond or a double bond;

[0080] X1, X3, and X5 are each independently selected from N or C, and X1, X3, and X5 are not N at the same time;

[0081] X2, X4 are selected from C or a chemical bond;

[0082] X3 is selected from N or C;

[0083] Y1 is selected from N, O or S;

[0084] Y2 is selected from C, N or a chemical bond;

[0085] Y3 is selected from N or C;

[0086] Y2 and Y3 are not N at the same time;

[0087] m is 0, 1, 2, 3 or 4;

[0088] n is 0, 1, 2, or 3;

[0089] p is 0, 1, 2, 3, or 4;

[0090] q is 0, 1, 2, 3, or 4;

[0091] The remaining groups are as defined above.

[0092] In some embodiments, the present invention provides a compound represented by the following formula (III), its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug:

[0093]

[0094] wherein W is selected from N or C;

[0095] A double line including solid and dashed lines represents a single bond or a double bond;

[0096] Y2 and Y3 are each independently C or N, and Y2 and Y3 are not N at the same time;

[0097] m is 0, 1, 2, 3 or 4;

[0098] n is 0, 1, 2, or 3;

[0099] p is 0, 1, 2, 3, or 4;

[0100] q is 0, 1, 2, 3, or 4;

[0101] The remaining groups are as defined above.

[0102] In some embodiments, the present invention provides a compound represented by the following formula (IV), its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug:

[0103]

[0104] wherein W is selected from N or C;

[0105] Y2 is selected from N or C;

[0106] A double line including solid and dashed lines represents a single bond or a double bond;

[0107] Y is a chemical bond, -NH- or -N(C 1-6 Alkyl)-, -NH(C 1-6 alkyl);

[0108] The "-N(C 1-6 Alkyl)-, -NH(C 1-6 C in "alkyl)" 1-6 Alkoxy is unsubstituted or optionally substituted with one, two or more halogens;

[0109] When Y is a chemical bond, Selected from the following groups:

[0110] When Y is -NH- or -N(C 1-6 alkyl)-, Selected from the following groups:

[0111] When Y is -N(C 1-6 When (alkyl) does not exist;

[0112] Said Rc, Rd are the same or different and are independently selected from C 1-6 alkyl;

[0113] Said Re is selected from halogen, CN, OH, the following groups which are unsubstituted or optionally substituted by one, two or more Rs: C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 6-12 Aryl, 3-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0114] Alternatively, when there are at least two Re, the two adjacent Re and the ring atoms to which they are bonded together form a C 3-6 Cycloalkyl or 3-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0115] The Rs are selected from halogen, CN, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-12 aryl or 5-12 membered heteroaryl.

[0116] Rf 1 、Rf 2 The same or different, independently selected from Rf as defined above, preferably, independently selected from halogen, CN, OH;

[0117] m is 0, 1 or 2;

[0118] n is 0, 1 or 2;

[0119] p is 0, 1 or 2;

[0120] q' is independently 0, 1, or 2 at each occurrence.

[0121] In some embodiments, the present invention provides a compound, a racemate, stereoisomer, tautomer, isotopically labeled form, N-oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof, wherein Preferred are the following groups:

[0122] In some embodiments, the present invention provides a compound represented by the following formula (V), its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug:

[0123]

[0124] in,

[0125] Selected from the following groups:

[0126] Rc, Rd are the same or different and are independently selected from C 1-6 alkyl;

[0127] Said Re is selected from halogen, CN, OH, the following groups which are unsubstituted or optionally substituted by one, two or more Rs: C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 6-12 Aryl, 3-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0128] Or when there are at least two Re, the two adjacent Re and the ring atoms to which they are bonded together form a C3-6 Cycloalkyl or 3-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0129] The Rs are selected from halogen, CN, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-12 aryl or 5-12 membered heteroaryl.

[0130] Rf 1 、Rf 2 The same or different, independently selected from Rf as defined above, preferably, independently selected from halogen, CN, OH;

[0131] m is 0, 1 or 2;

[0132] n is 0, 1 or 2;

[0133] p is 0, 1 or 2;

[0134] q' is independently 0, 1, or 2 at each occurrence.

[0135] According to a preferred embodiment of the present invention,

[0136] In formula I, Selected from the following structures:

[0137]

[0138] X is -C(=O)-;

[0139] When Y is a chemical bond, Selected from the following groups:

[0140]

[0141] When Y is -NH- or -N(C 1-20 alkyl)-, Selected from the following groups:

[0142] or when When absent, Y is -NH-CH2CF3;

[0143] Ring D is selected from the following structures:

[0144]

[0145] Z is -NH-;

[0146] Ring E is selected from the following structures:

[0147]

[0148] According to a preferred embodiment of the present invention,

[0149] In formula I, Selected from the following structures:

[0150] X is -C(=O)-;

[0151] When Y is a chemical bond, Selected from the following groups: When Y is -NH- or -N(C 1-20 alkyl)-, Selected from the following groups:

[0152]

[0153] or when When absent, Y is -OCH2CF3;

[0154] Ring D is selected from the following structures:

[0155]

[0156] Z is -NH-;

[0157] Ring E is selected from the following structures:

[0158]

[0159] As an example, the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug, the compound of formula (I) can be selected from the following structures:

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173] The present invention also provides a method for preparing the compound represented by formula (I), comprising at least one of the following schemes:

[0174]

[0175] The compound represented by formula (I-1) reacts with the compound represented by formula (I-2) to obtain the compound represented by formula (I);

[0176] Among them, ring A, ring B, ring D, Rings E, W, V, X, Y, and Z are as defined above; and L is selected from a leaving group, such as halogen.

[0177] The present invention further provides intermediate compounds for preparing compounds represented by formula (I) of the present invention, including formula I-1, formula I-2, etc. In a preferred embodiment, formula (I-1) is selected from the following structures:

[0178]

[0179] Formula (I-2) is selected from the following structures:

[0180]

[0181] wherein each group is as defined above.

[0182] Further preferably, the formula (I-1) is selected from the following structures:

[0183]

[0184]

[0185] Further preferably, the formula (I-2) can be selected from the following structures:

[0186]

[0187] In some embodiments, the present invention further provides an intermediate compound for preparing the compound represented by formula (I) of the present invention, which can be selected from

[0188]

[0189] It will be understood by those skilled in the art that the compound shown in formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, isotope label can be used as a raw material or intermediate to prepare a prodrug or pharmaceutically acceptable salt of the compound shown in formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, isotope label. To this end, the present invention also provides the use of the compound shown in formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, isotope label in preparing a prodrug or pharmaceutically acceptable salt of the compound shown in formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, isotope label.

[0190] The present invention also provides the following compounds:

[0191]

[0192] The present invention also provides the use of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, isotope-labeled substance, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug in the preparation of a drug, wherein the drug is an inhibitor of protein kinase.

[0193] In particular, the drug has the function of regulating Rho-kinase.

[0194] The drug can be used to prevent or treat diseases caused by high expression of one or more ROCKs or excessive activation of ROCKs, such as cardiovascular and cerebrovascular diseases, nervous system diseases, fibrotic diseases, eye diseases, tumors, arterial thrombosis, radiation damage, respiratory diseases, and autoimmune diseases, including atherosclerosis, acute coronary syndrome, hypertension, cerebral vasospasm, cerebral ischemia, ischemic stroke, restenosis, heart disease, heart failure, myocardial hypertrophy, myocardial ischemia-reperfusion injury, diabetes, diabetic nephropathy, cancer, neuronal degeneration (peripheral or central), nerve damage diseases, spinal cord injury, erectile dysfunction, platelet aggregation, leukocyte aggregation, glaucoma, ocular hypertension, asthma, osteoporosis, pulmonary fibrosis (such as idiopathic pulmonary fibrosis), liver fibrosis, renal fibrosis, COPD, renal dialysis (epithelial stability), glomerulosclerosis and neuronal degeneration inflammation, etc.

[0195] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, isotope-labeled substance, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug.

[0196] Preferably, the pharmaceutical composition may further optionally contain pharmaceutically acceptable excipients, such as carriers and excipients. For example, the excipients may be at least one selected from the following: disintegrants, glidants, lubricants, diluents or fillers, binders, and colorants.

[0197] The pharmaceutical composition of the present invention has the function of regulating Rho-kinase. The pharmaceutical composition can be used to prevent or treat diseases caused by the high expression or excessive activation of one or more ROCKs, such as cardiovascular and cerebrovascular diseases, nervous system diseases, fibrotic diseases, eye diseases, tumors, arterial thrombosis, radiation damage, respiratory diseases, and autoimmune diseases, including atherosclerosis, acute coronary syndrome, hypertension, cerebral vasospasm, cerebral ischemia, ischemic stroke, restenosis, heart disease, heart failure, myocardial hypertrophy, myocardial ischemia-reperfusion injury, diabetes, diabetic nephropathy, cancer, neuronal degeneration (peripheral or central), nerve damage diseases, spinal cord injury, erectile dysfunction, platelet aggregation, leukocyte aggregation, glaucoma, ocular hypertension, asthma, osteoporosis, pulmonary fibrosis (such as idiopathic pulmonary fibrosis), liver fibrosis, kidney fibrosis, COPD, renal dialysis (epithelial stability), glomerulosclerosis, and neuronal degeneration and inflammation.

[0198] The present invention also provides a method for regulating Rho-kinase function, comprising administering to an individual in need thereof an effective amount of a compound of formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, isotope-labeled form, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug, or pharmaceutical composition. The method can be used to prevent or treat diseases caused by overexpression of one or more ROCKs or overactivation of ROCKs.

[0199] The present invention also provides a method for preventing or treating diseases caused by high expression of one or more ROCKs or excessive activation of ROCKs, comprising administering to an individual in need thereof an effective amount of the compound represented by formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, isotope label, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition. The diseases include, for example, cardiovascular and cerebrovascular diseases, nervous system diseases, fibrotic diseases, eye diseases, tumors, arterial thrombosis, radiation damage, respiratory diseases, and autoimmune diseases, including atherosclerosis, acute coronary syndrome, hypertension, cerebral vasospasm, cerebral ischemia, ischemic stroke, restenosis, heart disease, heart failure, myocardial hypertrophy, myocardial ischemia-reperfusion injury, diabetes, diabetic nephropathy, cancer, neuronal degeneration (peripheral or central), nerve damage diseases, spinal cord injury, erectile dysfunction, platelet aggregation, leukocyte aggregation, glaucoma, ocular hypertension, asthma, osteoporosis, pulmonary fibrosis (such as idiopathic pulmonary fibrosis), liver fibrosis, renal fibrosis, COPD, renal dialysis (epithelial stability), glomerulosclerosis, and neuronal degeneration inflammation, etc.

[0200] In another aspect, provided herein are compounds of formula (I) for use in modulating Rho-kinase function, comprising administering to a subject in need thereof an effective amount of one or more compounds of the present invention, or a pharmaceutical composition comprising said compounds.

[0201] In another aspect, provided herein is a compound of formula (I) for use in a method of preventing or treating a disease caused by high expression of one or more ROCKs or overactivation of ROCKs, comprising administering to an individual in need thereof an effective amount of the compound of formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide, isotope label, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition. The diseases include, for example, cardiovascular and cerebrovascular diseases, nervous system diseases, fibrotic diseases, eye diseases, tumors, arterial thrombosis, radiation damage, respiratory diseases, and autoimmune diseases, including atherosclerosis, acute coronary syndrome, hypertension, cerebral vasospasm, cerebral ischemia, ischemic stroke, restenosis, heart disease, heart failure, myocardial hypertrophy, myocardial ischemia-reperfusion injury, diabetes, diabetic nephropathy, cancer, neuronal degeneration (peripheral or central), nerve damage diseases, spinal cord injury, erectile dysfunction, platelet aggregation, leukocyte aggregation, glaucoma, ocular hypertension, asthma, osteoporosis, pulmonary fibrosis (such as idiopathic pulmonary fibrosis), liver fibrosis, renal fibrosis, COPD, renal dialysis (epithelial stability), glomerulosclerosis, and neuronal degeneration inflammation, etc.

[0202] Definitions and Explanations of Terms

[0203] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0204] In this application description and claims, if This represents the connection site.

[0205] In the present specification and claims, "more" means three or more. The term "halogen" refers to F, Cl, Br, and I. In other words, F, Cl, Br, and I may be described as "halogen" in this specification.

[0206] The term "C 1-20 "Alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon group having 1 to 20 carbon atoms, preferably C 1-6 Alkyl. "C 1-12 “Alkyl” is understood as meaning preferably a linear or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0207] The term "C 1-20 Alkoxy" means "-OC 1-20 Alkyl" where C 1-20 Alkyl has the above definition. It is preferably "C 1-6 Alkoxy".

[0208] The term "C 3-20 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C 3-6 Cycloalkyl". The term "C 3-6 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms. 3-6The cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0209] The term "3-20 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O and S, preferably a "3-6 membered heterocyclyl". The term "3-6 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclyl may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclyl may include, but is not limited to, a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl. According to the present invention, the heterocyclyl is non-aromatic.

[0210] The term "C 6-20 "Aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6-12 Aryl". The term "C 6-12 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-12 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 "aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0211] The term "5-20 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-12 membered heteroaryl". The term "5-12 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in addition, in each case may be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or acininyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

[0212] Unless otherwise indicated, a heterocyclyl, heteroaryl, or heteroarylene group includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative, non-limiting examples, pyridyl or pyridylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene, and pyridin-4-ylene; thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-ylene, and thien-3-ylene.

[0213] It should be noted that the numerical ranges involved in the above group definitions, for example, C 1-20 ,3-20,C 6-20 Numerical ranges such as 5-20 represent the endpoints of the numerical range and any integer between the two endpoints, and are not limited to including only the two endpoints.

[0214] Unless otherwise indicated, the term "leaving group" as used herein shall mean a charged or uncharged atom or group that leaves during a substitution or displacement reaction. Suitable examples include, but are not limited to, H, F, Br, Cl, I, mesylate, tosylate, etc.

[0215] In any method for preparing the compounds of this invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any related molecule. This can be achieved by conventional protecting groups, such as those described in textbooks or reference books in this area. Protecting groups can be removed in a convenient subsequent stage using methods known in the art. Those skilled in the art will recognize that, depending on the specific protecting group, other reagents can be used for the deprotection step, including but not limited to Pd / C, Pd(OH) , PdCl , Pd(OAc) / Et SiH, Raney nickel, appropriately selected acid, appropriately selected base, fluoride, etc.

[0216] The target compound can be isolated according to known methods, for example, by extraction, filtration or column chromatography.

[0217] Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. These compounds may thus exist in racemic or optically active forms. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriate N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution can also be advantageously performed with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chirally derivatized methacrylate polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane / isopropanol / acetonitrile.

[0218] Those skilled in the art will appreciate that, since nitrogen needs to have an available lone pair of electrons for being oxidized to an oxide, not all nitrogen-containing heterocycles can form N-oxides; Those skilled in the art will recognize nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. The synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidizing heterocycles and tertiary amines with peroxyacids such as peracetic acid and metachloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature.

[0219] Pharmaceutically acceptable salts may be acid addition salts of compounds of the invention having a nitrogen atom in a chain or ring which are sufficiently basic, such as acid addition salts formed with inorganic acids such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or bisulfates, or acid addition salts formed with organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconolactic acid, benzoic acid, benzoyl ... Sugar acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.

[0220] In addition, another suitable pharmaceutically acceptable salt of the compound of the present invention having sufficient acidity is an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., calcium salt or magnesium salt), an ammonium salt, or a salt formed with an organic base that provides a physiologically acceptable cation, such as a salt formed with the following substances: sodium ion, potassium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol. As an example, the pharmaceutically acceptable salts include salts of -COOH group formed with the following substances: sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol.

[0221] In addition, basic nitrogen-containing groups can be quaternized using reagents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides, etc. As examples, pharmaceutically acceptable salts include hydrochlorides, sulfates, nitrates, bisulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates or meglumine salts, etc.

[0222] Since the compounds of the present invention may have multiple salt-forming sites, the "pharmaceutically acceptable salts" include not only salts formed at one of the salt-forming sites of the compounds of the present invention, but also salts formed at two, three, or all of the salt-forming sites. To this end, the molar ratio of the compound of formula (I) to the radical ion (anion) of the acid or cation of the base required for salt formation in the "pharmaceutically acceptable salt" may vary over a wide range, for example, from 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.

[0223] According to the present invention, pharmaceutically acceptable anions include anions selected from inorganic acids or organic acids ionized. The "inorganic acid" includes but is not limited to hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid. The "organic acid" includes but is not limited to formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid , itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.

[0224] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0225] The term "effective amount" or "therapeutically effective amount" refers to an amount of the compound of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the specific compound selected, the dosage regimen used, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system used.

[0226] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of excipients include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling characteristics of a pharmaceutical formulation, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression. Examples of typical pharmaceutically acceptable carriers suitable for the above-mentioned preparations are: sugars, such as lactose, sucrose, mannitol and sorbitol; starches, such as corn starch, tapioca starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and methyl cellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinyl pyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal salts of stearic acid, such as magnesium stearate and calcium stearate; stearic acid; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; ethylene glycol polymers; fatty alcohols; and cereal hydrolyzed solids and other non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, colorants and the like excipients commonly used in pharmaceutical preparations.

[0227] The beneficial effects of the present invention include:

[0228] The compounds provided by the present invention exhibit excellent ROCK inhibitory activity, particularly exhibiting good selective inhibition of ROCK2 kinase. Furthermore, the compounds of the present invention have good safety, metabolic stability, and high bioavailability. Finally, the compounds of the present invention are simple to prepare and easy to purify, thus possessing promising application prospects. DETAILED DESCRIPTION

[0229] The following will further describe in detail the general formula compounds of the present invention, their preparation methods, and applications with reference to specific examples. The following examples are intended only to illustrate and explain the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection intended by the present invention.

[0230] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0231] Nouns and representative reagents

[0232] The nouns used in the following experimental descriptions represent (unless otherwise specified) the following reagents:

[0233] DMF: N,N-dimethylformamide; DCM: dichloromethane; TEA: triethylamine; DMAP: 4-dimethylaminopyridine; DIEA: N,N-diisopropylethylamine; THF: tetrahydrofuran; DME: ethylene glycol dimethyl ether; CDI: N,N'-carbonyldiimidazole; MsCl: methanesulfonyl chloride; DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DMSO: dimethyl sulfoxide; EA: ethyl acetate; MeOH: methanol; EtOH: ethanol; MeCN: acetonitrile; NCS : N-chlorosuccinimide; n-BuOH: n-butanol; DCE: 1,2-dichloroethane; NMAC: N,N-dimethylacetamide; EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; IPA: isopropanol; mCPBA: m-chloroperbenzoic acid; nBuLi: n-butyllithium; NMP: N-methylpyrrolidone; TFA: trifluoroacetic acid; t-BuOK: potassium tert-butyl alcohol; t-BuOMe: methyl tert-butyl ether; xantphos: 5-bis(diphenylphosphino)-9,9-dimethylxanthene; DHP: 3,4-dihydro-2H-pyran.

[0234] <Preparation Example>

[0235] Preparation of Intermediate 1 3,3-difluoro-N-methylcyclobutane-1-amine hydrochloride (M001)

[0236]

[0237] (1) Preparation of compound (3,3-difluorocyclobutane)carbamic acid tert-butyl ester (M001-1)

[0238] 3,3-Difluorocyclobutane-1-amine (1.00 g, 9.34 mmol) was dissolved in a mixture of methanol (10 mL) and saturated aqueous sodium carbonate (10 mL). Di-tert-butyl dicarbonate (2.45 g, 11.20 mmol) was added to the mixture at room temperature. The reaction system was stirred at room temperature overnight. The product precipitated from the system. The filter cake was filtered and dried to give 1.35 g of crude tert-butyl (3,3-difluorocyclobutane)carbamate as a white solid, with a yield of 70.2%.

[0239] 1 H NMR (301MHz, CD3OD) δ3.89 (m, 1H), 2.93-2.74 (m, 2H), 2.58-2.38 (m, 2H), 1.42 (s, 9H).

[0240] (2) Preparation of compound (3,3-difluorocyclobutane)(methyl)carbamic acid tert-butyl ester (M001-2)

[0241] Under nitrogen, dissolve tert-butyl (3,3-difluorocyclobutane)carbamate (900 mg, 4.34 mmol) in anhydrous N,N-dimethylformamide (10 mL). Cool to 0°C and add sodium hydride (60%, 208 mg, 5.21 mmol) portionwise. Stir for 0.5 hours. Place in an ice-water bath, then add iodomethane (1.23 g, 8.69 mmol) dropwise. Stir the mixture overnight at room temperature. Slowly add water (30 mL) to quench the mixture. Extract with ethyl acetate (30 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 1.10 g of crude (tert-butyl (3,3-difluorocyclobutane)(methyl)carbamate) as a pale yellow solid.

[0242] 1 H NMR (301MHz, CD3OD) δ4.35-4.27 (m, 1H), 2.82 (s, 3H), 2.75 (dt, J = 15.5, 8.5Hz, 4H), 1.45 (s, 9H).

[0243] Dissolve tert-butyl (3,3-difluorocyclobutane)(methyl)carbamate (1.10 g, crude) in dichloromethane (10 mL), add a 33% ethanolic solution of hydrogen chloride (3 mL), and stir at room temperature overnight. Concentrate under reduced pressure to obtain 800 mg of a brownish-yellow solid, 3,3-difluoro-N-methylcyclobutane-1-amine hydrochloride. The crude product is overweight. LC-MS [M+H] + :122.1.

[0244] Intermediate 2 Preparation of tert-butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (M002)

[0245]

[0246] 1) Preparation of tert-butyl 4-(4-nitrophenyl)-1H-pyrazole-1-carboxylate (M002-1)

[0247] tert-Butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl)carboxylate (58.8 g, 0.2 mol), 1-bromo-4-nitrobenzene (20 g, 0.1 mol), anhydrous potassium carbonate (41.5 g, 0.3 mol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (7.3 g, 10 mmol) were added to a 30:1 mixture of 1,4-dioxane and water (207 mL). The atmosphere was replaced with nitrogen three times. The mixture was stirred in an oil bath at 100°C for 5 h. The reaction was stopped by TLC, filtered under reduced pressure, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give 16 g of a yellow solid in a 46% yield. MS (M+1-100) + =190.05, the hydrogen spectrum showed that it was the product M002-1.

[0248] 2) Preparation of tert-butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (M002)

[0249] tert-Butyl 4-(4-nitrophenyl)-1H-pyrazole-1-carboxylate (16 g, 55.3 mol) was dissolved in methanol (160 mL), palladium carbon (3.2 g) was added, and a hydrogen balloon was installed to replace the hydrogen. The mixture was reacted at 45°C for 16 h. After the reaction was complete after TLC detection, diatomaceous earth was added and filtered under reduced pressure. The filtrate was concentrated to obtain a yellow crude product. The product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 9.6 g of a light white solid with a yield of 60%. MS (M+1) + =260.15.

[0250] Intermediate 3 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)aniline (M003)

[0251]

[0252] 1) Preparation of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (M003-1)

[0253] Dissolve 4-bromopyrazole (5 g, 34.02 mmol) in 25 ml of 3,4-dihydro-2H-pyran and slowly add 387.9 mg (3.4 mmol) of trifluoroacetic acid dropwise. After the addition is complete, heat the mixture to 80°C and allow to react overnight. Samples were taken and monitored by LCMS, revealing a large amount of product. Post-treatment: Adjust the pH to approximately 8 with saturated aqueous NaHCO₃ solution, then extract three times with 20 ml of EA. Combine the organic phases, wash with saturated brine, dry, filter, and concentrate to yield a yellow oil, which was directly used in the next step. LC-MS [M+H] + =233.00.

[0254] 2) Preparation of 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)aniline (M003)

[0255] 4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (7.86 g, 34.01 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (8.94 g, 40.81 mmol), potassium carbonate (9.4 g, 68.02 mmol), and Pd(dppf)Cl2 (2.49 g, 3.4 mmol) were dissolved in dioxane / water (70 mL / 10 mL) and incubated at 80°C overnight under nitrogen. Samples were taken and sent to LCMS, indicating complete reaction. After completion of the reaction, ammonium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by silica gel column chromatography to obtain 5 g of a dark green solid (60% yield). LC-MS [M+H] + =244.15.

[0256] Preparation of Intermediates 4-tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (M004) and N-(4-(1H-pyrazol-4-yl)phenyl)-2-chloropyrimidin-4-amine (M004')

[0257]

[0258] 1) Preparation of compound tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (M004):

[0259] Dissolve tert-butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (5.64 g, 21.69 mmol) and 2,4-dichloropyrimidine (4.85 g, 1.44 mmol) in N,N-dimethylformamide (90 mL). Add N,N-diisopropylethylamine (8.39 g, 65.07 mmol) and react at 80°C under nitrogen for 8 hours. Pour the reaction solution into water (200 mL) and extract with ethyl acetate (100 mL x 2). The combined organic phases are washed with saturated brine (80 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product is separated by silica gel column chromatography (dichloromethane / ethyl acetate = 50:1-5:1) to obtain 4.40 g of a light yellow solid in a 54% yield. LC-MS [M+H] + :371.7.

[0260] 2) Preparation of N-(4-(1H-pyrazol-4-yl)phenyl)-2-chloropyrimidin-4-amine (M004')

[0261] Dissolve tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate in anhydrous dichloromethane, add 33% ethanolic hydrogen chloride solution, and stir at room temperature for 2 hours. Concentrate under reduced pressure to obtain N-(4-(1H-pyrazol-4-yl)phenyl)-2-chloropyrimidin-4-amine, MS (M+1) + =272.4.

[0262] Example 1. Preparation of Compound 1 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001)

[0263]

[0264] 1.1 Preparation of compound 3-(3-nitropyridin-4-yl)-2-oxopropionic acid ethyl ester (L001-1)

[0265] Under nitrogen, 4-methyl-3-nitropyridine (10.0 g, 72.0 mmol) was dissolved in diethyl oxalate (50 mL). DBU (12.7 g, 83.0 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction system was quenched by adding ice water (30.0 g). The pH was adjusted to 4-5 with 1N dilute hydrochloric acid and filtered. The filter cake was washed with ethyl acetate (100 ml x 2) and oven-dried to yield 18.0 g of a red solid, which was used directly in the next step. LC-MS [M+H] + :239.1.

[0266] 1.2 Preparation of compound 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (L001-2)

[0267] Under hydrogen protection, ethyl 3-(3-nitropyridin-4-yl)-2-oxopropanoate (17.0 g, 70.0 mmol) was dissolved in anhydrous dichloromethane (200 mL). Palladium on carbon (3.4 g) was added to the reaction mixture and allowed to stand at room temperature overnight. The mixture was filtered, concentrated under reduced pressure, and then separated by silica gel column chromatography (PE / EA = 1 / 1) to obtain 6.0 g of a yellow oily liquid, with a two-step yield of 43.8%. LC-MS [M+H] + :191.1.

[0268] 1.3 Preparation of compound 1-tert-butyloxycarbonyl-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (L001-3)

[0269] Under nitrogen, ethyl 1H-pyrrolo[2,3-c]pyridine-2-carboxylate (6.0 g, 31.5 mmol) was dissolved in anhydrous dichloromethane (50 mL). Boc anhydride (7.6 g, 34.7 mmol) and DMAP (384 mg, 3.2 mmol) were added to the reaction mixture and stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the crude product was separated by silica gel column chromatography (PE / EA = 3 / 1) to obtain 7.5 g of a yellow oily liquid. The yield was 82.4%. LC-MS [M+H] + :291.0.

[0270] 1.4 Preparation of compound 6-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (L001-4)

[0271] Under nitrogen, ethyl 1-tert-butoxycarbonyl-pyrrolo[2,3-c]pyridine-2-carboxylate (7.2 g, 24.7 mmol) was dissolved in anhydrous DMF (50 mL), followed by the addition of benzyl bromide (4.2 g, 24.7 mmol). The mixture was reacted at 80°C for 4 hours and concentrated under reduced pressure. The resulting solid was dissolved in ethanol (50 mL), and sodium borohydride (934 mg, 24.7 mmol) was added to the reaction mixture. The reaction mixture was allowed to react at room temperature for 3 hours. The mixture was quenched with water (100 mL), extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by silica gel column chromatography (PE / EA = 3 / 1) to obtain 3.5 g of a yellow oily liquid in a yield of 49.8%. LC-MS [M+H] + :285.1.

[0272] 1.5 Preparation of compound 6-tert-butoxycarbonyl-4,5,7-trihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (L001-5)

[0273] Dissolve ethyl 6-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (3.5 g, 12.3 mmol) in methanol (40 mL), add Boc anhydride (4.0 g, 18.5 mmol) and palladium on carbon (700 mg), and incubate under a hydrogen atmosphere at room temperature overnight. Filtration and concentration followed by silica gel column chromatography (PE / EA = 5 / 1) afforded 1.8 g of a yellow oily liquid in a 50.0% yield. MS [M / 2+H] + =295.1.

[0274] 1.6 Preparation of compound 6-tert-butoxycarbonyl-1-methyl-4,5,7-trihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (L001-6)

[0275] Under nitrogen, ethyl 6-tert-butoxycarbonyl-4,5,7-trihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (1.8 g, 6.1 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0°C. Sodium hydride (364 mg, 9.1 mmol, 60%) was added to the reaction system and stirred at this temperature for 30 minutes. Methyl iodide (1.7 g, 12.2 mmol) was added dropwise and the reaction was allowed to react at room temperature for 2 hours. The mixture was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.8 g of a yellow oily liquid (crude product). LC-MS [M+H] + :308.9.

[0276] 1.7 Preparation of compound 1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (L001-7)

[0277] Dissolve 6-tert-butoxycarbonyl-1-methyl-4,5,7-trihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (1.8 g, 5.8 mmol) in anhydrous dichloromethane (20 mL), add trifluoroacetic acid (5 mL), and react at room temperature for 3 hours. After concentration under reduced pressure, slowly add saturated sodium bicarbonate solution dropwise to adjust the pH to 8-9. Extract with dichloromethane (20 mL*3), wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate, and the crude product is purified by silica gel column chromatography (DCM / MeOH=15 / 1) to obtain 900 mg of a yellow oily liquid. The two-step yield is 71%, LC-MS [M+H] + :209.1.

[0278] 1.8 Preparation of compound 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (L001-8)

[0279] Tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (1342 mg, 3.6 mmol) was dissolved in n-butanol (10 mL). Ethyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (500 mg, 2.4 mmol) and DIEA (930 mg, 7.2 mmol) were added to the reaction solution. The temperature was raised to 120°C and the reaction was allowed to react overnight. The mixture was quenched with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (PE / EA = 1 / 1) to obtain 900 mg of a yellow oily liquid with a yield of 84.5%. LC-MS [M+H] + :444.1.

[0280] 1.9 Preparation of compound 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001)

[0281] Ethyl 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (800 mg, 1.5 mmol) was dissolved in tetrahydrofuran / methanol / water (3 / 1 / 1, 10 mL total). Sodium hydroxide (292 mg, 7.3 mmol) was added and the mixture was heated to 50°C for 1 hour. After concentration under reduced pressure, the pH was adjusted to 5-6 with 1N dilute hydrochloric acid and concentrated under reduced pressure to give 1.0 g of a white solid, crude product, containing sodium chloride. LC-MS [M+H] + :416.0.

[0282] Example 2. Preparation of compound 7-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (L002)

[0283]

[0284] 2.1 Preparation of compound imidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (L002-1)

[0285] Dissolve pyrazin-2-amine (3.5 g, 36.82 mmol) and ethyl 3-bromo-2-oxopropionate (7.0 g, 44.18 mmol) in ethylene glycol dimethyl ether (60 mL) and heat at 60°C overnight. Cool to room temperature, collect the filter cake by filtration, add ethanol (40 mL), and heat at 80°C for 3 hours. After concentration under reduced pressure, add saturated sodium bicarbonate solution (30 mL), extract with ethyl acetate (30 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified on a silica gel column (dichloromethane:ethyl acetate = 1:1) to obtain 1.15 g of a yellow oil, with a yield of 16.4%. LC-MS [M+H] + :192.0.

[0286] 2.2 Preparation of compound 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (L002-2)

[0287] Dissolve ethyl imidazo[1,2-a]pyrazine-2-carboxylate (1.1 g, 5.75 mmol) in anhydrous methanol (30 mL), add palladium-carbon catalyst (10%, 600 mg), introduce hydrogen, and stir overnight at room temperature. Filter and spin-dry the filtrate to obtain 800 mg of ethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate as a brownish-yellow oil, in a yield of 71.2%. LC-MS [M+H] + :196.0.

[0288] 2.3 Preparation of compound 7-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (L002-3)

[0289] Dissolve ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (310 mg, 1.59 mmol), tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (589 mg, 1.59 mmol), and N,N-diisopropylethylamine (570 mg, 4.42 mmol) in n-butanol (5 mL) and stir at 120°C for 5 hours. Dilute with water (20 mL) and extract with ethyl acetate (15 mL*3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product was purified on a silica gel column (dichloromethane:methanol = 5:1) to give 430 mg of the crude product, ethyl 7-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate, as a brown oil. Yield: 62.9%. LC-MS [M+H] + :431.1.

[0290] 2.4 Preparation of compound 7-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (L002)

[0291] Ethyl 7-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (430 mg, 1.00 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide monohydrate (126 mg, 3.00 mmol) was added and the reaction was stirred at room temperature overnight. The pH was adjusted to 2 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate (15 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. 350 mg of the crude product, 7-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid, was obtained as a gray solid in an 87.1% yield. LC-MS [M+H] + :403.0.

[0292] Example 3. Preparation of compound (5-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)(3,3-difluoroazetidine-1-yl)methanone (L003)

[0293]

[0294] 3.1 Preparation of compound 1-(2-((tert-Butoxycarbonyl)amino)ethyl)-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester (L003-1)

[0295] Dimethyl 1H-pyrazole-3,5-dicarboxylate (5.00 g, 27.10 mmol) was added to anhydrous N,N-dimethylformamide (60 mL), followed by potassium carbonate (5.61 g, 40.60 mmol). The mixture was placed in an ice-water bath under nitrogen protection. Tert-butyl (2-bromoethyl)carbamate (6.64 g, 29.80 mmol) was then added and stirred at room temperature for 3 h. Water (100 mL) was added for dilution, resulting in the precipitation of a large amount of solid. The solid was filtered and the filter cake washed with water (50 mL). The solid was collected and dried to yield 8.70 g of crude product, 70% purity, as a white solid in a 68% yield. MS [M+H] + =350.2.

[0296] 3.2 Preparation of compound 1-(2-((tert-Butyloxycarbonyl)amino)ethyl)-3-(methoxycarbonyl)-1H-pyrazole-5-carboxylic acid (L003-2)

[0297] Dissolve dimethyl 1-(2-((tert-Butoxycarbonyl)amino)ethyl)-1H-pyrazole-3,5-dicarboxylate (5.60 g, 17.10 mmol) in dichloromethane (30 mL) and methanol (30 mL). Add potassium hydroxide methanol solution (2.2 M, 5.4 mL, 11.9 mmol) dropwise and react at room temperature for 1 h. Dilute with water (60 mL) and back-extract with dichloromethane (50 mL*2). The aqueous phase is adjusted to pH 3 with dilute hydrochloric acid (1 N) and extracted with dichloromethane (50 mL*3). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 4.20 g of the crude product as a white solid. The yield is 78%. MS [M+H] + =336.2.

[0298] 3.3 Preparation of Compound 1-(2-((tert-Butoxycarbonyl)amino)ethyl)-5-(hydroxymethyl)-1H-pyrazole-3-carboxylic acid methyl ester (L003-3)

[0299] 1-(2-((tert-Butoxycarbonyl)amino)ethyl)-3-(methoxycarbonyl)-1H-pyrazole-5-carboxylic acid (2.00 g, 6.30 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). N,N'-carbonyldiimidazole (2.04 g, 12.6 mmol) (CDI) was added and stirred at 45°C for 1 h. Then, sodium borohydride (957 mg, 25.20 mmol) was added and stirred at room temperature overnight. The mixture was quenched with saturated ammonium chloride solution (20 mL), diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 3:1) to obtain 400 mg of a colorless, transparent oily liquid with a yield of 21%. MS [M+H] + =322.1.

[0300] 3.4 Preparation of Compound 1-(2-((tert-Butoxycarbonyl)amino)ethyl)-5-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-3-carboxylic acid methyl ester (L003-4)

[0301] Methyl 1-(2-((tert-Butoxycarbonyl)amino)ethyl)-5-(hydroxymethyl)-1H-pyrazole-3-carboxylate (400 mg, 1.33 mmol) was dissolved in anhydrous dichloromethane (5 mL), triethylamine (201 mg, 2.00 mmol) was added, and methylsulfonyl chloride (182 mg, 1.59 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 1.5 h. Saturated sodium bicarbonate (5 mL) was added to quench the mixture, and the mixture was diluted with water (10 mL). The mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 420 mg of a colorless, transparent oily liquid as a crude product with an 83% yield. MS (M-99) + =278.1.

[0302] 3.5 Preparation of Compound 5-tert-Butyloxycarbonyl-6,7-dihydropyrazolo[1,5-a]pyrazine-2,5(4H)-2-carboxylic acid methyl ester (L003-5)

[0303] Methyl 1-(2-((tert-Butoxycarbonyl)amino)ethyl)-5-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-3-carboxylate (420 mg, 1.11 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL) under nitrogen protection. Sodium hydride (76 mg, 1.89 mmol, 60%) was added at 0°C and stirred at room temperature for 1.5 h. After the reaction was completed, saturated ammonium chloride (10 mL) was added to quench the reaction, the mixture was diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 200 mg of a colorless, transparent oily liquid with a yield of 64%. MS [M+H] + =282.2.

[0304] 3.6 Preparation of compound 5-(tert-butyloxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (L003-6)

[0305] Methyl 5-tert-butoxycarbonyl-6,7-dihydropyrazolo[1,5-a]pyrazine-2,5(4H)-2-carboxylate (200 mg, 0.71 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL). Aqueous sodium hydroxide (2N, 1.4 mL, 2.80 mmol) was added dropwise and allowed to react at room temperature for 1 h. The mixture was diluted with water (5 mL) and back-extracted with ethyl acetate (5 mL*2). The aqueous phase was adjusted to pH 3 with dilute hydrochloric acid (1 N) and extracted with ethyl acetate (5 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 130 mg of the crude product as a white solid with a yield of 68%. MS (M+1) + =268.2.

[0306] 3.7 Preparation of Compound 2-(3,3-difluoroazetidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (L003-7)

[0307] 5-(tert-Butyloxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (130 mg, 0.49 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (205 mg, 0.54 mmol), N,N-diisopropylethylamine (255 mg, 1.96 mmol), and 3,3-difluorotrimethyleneimine hydrochloride (70 mg, 0.54 mmol) were added and stirred at room temperature for 2 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 3:1) to give 110 mg of a white solid with a yield of 65%. MS (M+1) + =343.2.

[0308] 3.8 Preparation of Compound (3,3-difluoroazetidin-1-yl)(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanone (L003-8)

[0309] Dissolve tert-butyl 2-(3,3-difluoroazetidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (110 mg, 0.32 mmol) in anhydrous dichloromethane (3 mL). Add 33% ethanolic hydrogen chloride solution (1 mL) and stir at room temperature for 2 h. Concentrate under reduced pressure to obtain 90 mg of the crude product as a white solid. MS (M+1) + =242.9.

[0310] 3.9 Preparation of Compound (5-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L003)

[0311] (3,3-Difluoroazetidin-1-yl)(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanone hydrochloride (90 mg, 0.32 mmol) was dissolved in n-butanol (3 mL), and tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (119 mg, 0.32 mmol) and N,N-diisopropylethylamine (255 mg, 1.96 mmol) were added. The mixture was refluxed and stirred overnight, diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 19.6 mg of a white solid by preparative purification. The two-step yield was 12%, MS (M+1). + =478.2.

[0312] 1 H NMR(400MHz,DMSO)δ12.91(brs,1H),9.42(s,1H),8.08-7.96(m,3H),7.63-7.58(m,4H),6.68(s,1H) ), 6.15 (d, J = 5.7Hz, 1H), 4.97 (s, 2H), 4.85 (t, J = 12.4Hz, 2H), 4.44 (t, J = 12.4Hz, 2H), 4.25 (s, 4H).

[0313] Example 4. Preparation of Compound 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-N-(3,3-difluorocyclobutyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (L004)

[0314]

[0315] 4.1 Preparation of Compound 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-N-(3,3-difluorocyclobutyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (L004)

[0316] 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001) (150 mg, 0.36 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (185 mg, 1.44 mmol), 3,3-difluorocyclobutane-1-amine hydrochloride (57 mg, 0.40 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (150 mg, 0.40 mmol) were added. The reaction was carried out at room temperature under nitrogen protection for 4 hours. After the reaction was completed, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified on a silica gel column using dichloromethane:methanol (20:1) as the eluent to obtain 40.8 mg of a white solid in a 22% yield. MS [M+H] + =504.9.

[0317] 1 H NMR(400MHz,MeOD)δ7.93(brs,2H),7.88(d,J=6.0Hz,1H),7.62(d,J=8.6Hz,2H ),7.55(d,J=8.7Hz,2H),6.63(s,1H),6.09(d,J=6.0Hz,1H),4.77(s,2H),4.28 -4.22(m,1H),4.02-3.96(m,2H),3.80(s,3H),2.95-2.87(m,2H),2.65-2.62(m,4H).

[0318] Example 5. Preparation of compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidine-1-yl)methanone (L005)

[0319]

[0320] 3,3-Difluoroazetidine (67 mg, 0.7 mmol) was dissolved in DMF (10 mL), and 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001) (200 mg, 0.5 mmol), HATU (547 mg, 1.4 mmol), and DIEA (186 mg, 1.4 mmol) were added. The reaction was allowed to react at room temperature for 2 hours. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 60 mg of a white solid. LC-MS [M+H] + :490.7.

[0321] 1 H NMR(400MHz,MeOD)δ7.96(s,2H),7.90(d,J=6.1Hz,1H),7.64(d,J=8.7Hz,2H),7.59(d,J=8.7Hz,2H),6.48(s,1H) ,6.15(d,J=6.1Hz,1H),4.82(s,2H),4.64-4.52(m,4H),4.03(t,J=5.7Hz,2H),3.83(s,3H),2.69(t,J=5.5Hz,2H).

[0322] Example 6. Preparation of Compound (6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L006)

[0323]

[0324] 6.1 Preparation of Compound N-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine (L006-1)

[0325] Under nitrogen, 2,4-dichloropyrimidine (1.48 g, 10.0 mmol) and 1H-indazol-5-amine (1.33 g, 10.0 mmol) were dissolved in anhydrous ethanol (10 mL). Triethylamine (1.01 g, 10.0 mmol) was added and the mixture was heated under reflux for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, diluted with 20 mL of water, and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spun down to obtain 1.30 g of N-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine (yield 53%) as a pink solid. MS [M+H] +=246.0.

[0326] 6.2 Preparation of compound 6-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L006-2)

[0327] Dissolve 6-tert-butoxycarbonyl-1-methyl-4,5,7-trihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (4.0 g, 12.9 mmol) in methanol (40 mL), add sodium hydroxide solution (38.7 mL, 1 N), and react at 50°C for 2 hours. Adjust the pH to 5-6 with dilute hydrochloric acid (1 N), extract with ethyl acetate (50 mL*3), wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, and evaporate under reduced pressure to obtain 3.2 g of a purple oily liquid. LC-MS [M+H] + :281.1.

[0328] 6.3 Preparation of Compound tert-Butyl 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-6(7H)-carboxylate (L006-3):

[0329] 6-(tert-Butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (2.4 g, 8.5 mmol) was dissolved in anhydrous DMF (20 mL). 3,3-Difluoroazetidine hydrochloride (1.2 g, 12.8 mmol), HATU (4.9 g, 12.8 mmol), and DIEA (3.3 g, 25.6 mmol) were added and reacted at room temperature for 1 hour. The mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, evaporated under reduced pressure, and concentrated by silica gel column chromatography (PE / EA = 3 / 1) to obtain 2.5 g of a yellow oily liquid. The yield was 83.3%. LC-MS [M+H] + :355.8.

[0330] 6.4 Preparation of Compound (3,3-difluoroazetidine-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L006-4):

[0331] Dissolve tert-butyl 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-6(7H)-carboxylate (1.8 g, 5.8 mmol) in anhydrous ethanol (20 mL). Add ethanolic hydrochloride (5 mL, 33% by mass) and allow to react at room temperature for 3 hours. Concentrate under reduced pressure by rotary evaporation to obtain 2.0 g of a yellow solid. LC-MS [M+H] + :256.0.

[0332] 6.5 Preparation of Compound (6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L006)

[0333] (3,3-Difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (50 mg, 0.20 mmol) and N-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine (73.7 mg, 0.30 mmol) were dissolved in n-butanol (1.0 mL). Diisopropylethylamine (53 mg, 0.41 mmol) was added and the mixture was reacted at 120°C for 15 hours. After the reaction, the mixture was cooled to room temperature, dried under reduced pressure, and purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:5) to obtain 20 mg of a white solid with a yield of 22%. MS [M+H] + =485.0.

[0334] 1 H NMR (400MHz, DMSO) δ12.97(s,1H),9.28(s,1H),8.13(s,1H),8.00(s,1H),7.94(d,J=5.7Hz,1H),7.51(d,J=8.9Hz,1H),7.44(dd,J=8.9,1 .6Hz,1H),6.46(s,1H),6.06(d,J=5.8Hz,1H),4.80(s,2H),4.62-4.48(m,4H),3.97(t,J=5.6Hz,2H),3.76(s,3H),2.56(t,J=5.5Hz,2H).

[0335] Example 7. Preparation of Compound 2-(4-((2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)pyrimidin-4-yl)amino)-2-fluorophenoxy)nicotinamide (L007)

[0336]

[0337] 7.1 Preparation of Compound 2-(4-amino-2-fluorophenoxy)nicotinamide (L007-1):

[0338] Dissolve 2-chloronicotinamide (3.00 g, 19.16 mmol) and 4-amino-2-fluorophenol (2.43 g, 19.16 mmol) in anhydrous dimethyl sulfoxide (50 mL), add cesium carbonate (18.68 g, 57.48 mmol), and stir at 100°C for 12 h. After the reaction is complete, add water (100 mL) and extract with ethyl acetate (100 mL*8). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin dry. The crude product is purified by silica gel column (dichloromethane:

[0339] Methanol = 10:1) to obtain 1.60 g of a brown solid product, 2-(4-amino-2-fluorophenoxy)nicotinamide, with a yield of 34%. LC-MS [M+H] + :248.1.

[0340] 7.2 Preparation of compound 2-(4-((2-chloropyrimidin-4-yl)amino)-2-fluorophenoxy)nicotinamide (L007-2):

[0341] 2-(4-Amino-2-fluorophenoxy)nicotinamide (300 mg, 1.21 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and 2,4-dichloropyrimidine (180 mg, 1.21 mmol) and N,N-diisopropylethylamine (470 mg, 3.63 mmol) were added. The system was heated to 80°C and reacted for 3 hours. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 1:1) to obtain 150 mg of 2-(4-((2-chloropyrimidin-4-yl)amino)-2-fluorophenoxy)nicotinamide as a light yellow solid in a 31% yield.

[0342] 7.3 Preparation of Compound 2-(4-((2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)pyrimidin-4-yl)amino)-2-fluorophenoxy)nicotinamide (L007):

[0343] 2-(4-((2-chloropyrimidin-4-yl)amino)-2-fluorophenoxy)nicotinamide (85 mg, 0.24 mmol) was dissolved in n-butanol (3 mL), and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone hydrochloride (60 mg, 0.24 mmol) and N,N-diisopropylethylamine (155 mg, 1.20 mmol) were added to the system. The system was heated to 120 ° C and stirred for 4 h. After completion of the reaction, water (10 mL) was added to quench the reaction, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 12.1 mg of 2-(4-((2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)pyrimidin-4-yl)amino)-2-fluorophenoxy)nicotinamide as a white solid product, with a yield of 8.8%. LC-MS [M+H] + :579.0.

[0344] 1 H NMR (301MHz, DMSO) δ9.58 (s, 1H), 8.23-8.13 (m, 2H), 8.05-7.98 (m, 1H), 7.92 (d, J = 13.6Hz, 1H), 7.82 (s, 2H), 7.38-7.29 (m, 2H), 7.26-7 .20(m,1H),6.44(s,1H),6.09(d,J=5.7Hz,1H),4.78(s,2H),4.53(t,J=7.1Hz,4H),3.99-3.92(m,2H),3.70(s,3H),2.58-2.50(m,2H).

[0345] Example 8. Preparation of compound 7-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-N-(3,3-difluorocyclobutyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide (L008)

[0346]

[0347] 7-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (L002) (100 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (5 mL). HATU (140 mg, 0.37 mmol), 3,3-difluorocyclobutane-1-amine hydrochloride (53 mg, 0.37 mmol), and N,N-diisopropylethylamine (160 mg, 1.25 mmol) were added. The mixture was stirred at room temperature overnight under nitrogen protection. Water (15 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (15 mL*3). The organic phases were combined, washed with saturated brine (15 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified on a silica gel column (dichloromethane:methanol = 10:1). The product was collected, concentrated, and then lyophilized to give 24.7 mg of a white solid product, 7-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-N-(3,3-difluorocyclobutyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide, in a yield of 20.1%. LC-MS [M+H] + :492.0.

[0348] 1 H NMR (400MHz, DMSO) δ12.87 (s, 1H), 9.41 (s, 1H), 8.49 (d, J = 7.7Hz, 1H), 8.20-7.85 (m, 3H), 7.66-7.56 (m,5H),6.14(d,J=5.8Hz,1H),4.91(s,2H),4.30-4.25(m,1H),4.20-4.08(m,4H),2.87-2.77(m,4H).

[0349] Example 9. Preparation of Compound 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-N-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (L009)

[0350]

[0351] 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001) (150 mg, 0.36 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (185 mg, 1.44 mmol), isopropylamine (57 mg, 0.40 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24 mg, 0.40 mmol) were added. The mixture was protected by nitrogen and reacted at room temperature for 4 hours. After the reaction was completed, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified to obtain 30.7 mg of a white solid with a yield of 18%. MS [M+H] + =457.2.

[0352] 1 H NMR (400MHz, DMSO) δ12.82(s,1H),9.31(s,1H),8.01(s,2H),7.96(d,J=5.7Hz,1H),7.65(d,J=8.6Hz,2H),7.58-7.55(m,3H) ,6.62(s,1H),6.07(d,J=5.8Hz,1H),4.76(s,2H),4.05-3.98(m,3H),3.78(s,3H),2.54-2.52(m,2H),1.10(d,J=6.6Hz,6H).

[0353] Example 10. Preparation of Compound 1-(6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)azetidine-3-carbonitrile (L010)

[0354]

[0355] 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001) (150 mg, 0.36 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (185 mg, 1.44 mmol), 3-cyano-azetidine hydrochloride (47 mg, 0.40 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (150 mg, 0.40 mmol) were added. The mixture was reacted at room temperature under nitrogen protection for 4 hours. After the reaction was complete, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified on a silica gel column using dichloromethane:methanol (20:1) as the eluent to obtain 58.6 mg of a white solid in a 34% yield. MS [M+H] + =479.9.

[0356] 1 H NMR(400MHz,MeOD)δ7.92(brs,2H),7.87(d,J=6.0,1H),7.61(d,J=8.6Hz,2H),7.54(d,J=8.6Hz,2H),6.38(s,1H),6.09 (d,J=6.0Hz,1H),4.75(s,2H),4.60-4.28(m,4H),4.00-3.96(m,2H),3.77(s,3H),3.75-3.68(m,1H),2.66-2.60(m,2H).

[0357] Example 11. Preparation of the compound (2-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-2H-indazol-5-yl)(3,3-difluoroazetidine-1-yl)methanone (L011)

[0358]

[0359] 11.1 Preparation of Compound (3,3-difluoroazetidin-1-yl)(1H-indazol-5-yl)methanone (L011-1)

[0360] 1H-Indazole-5-carboxylic acid (1.50 g, 9.26 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 mL). 3,3-Difluorotrimethyleneimine hydrochloride (1.31 g, 10.18 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.86 g, 10.18 mmol), and N,N-diisopropylethylamine (4.78 g, 37.04 mmol) were added and stirred at room temperature for 4 h. Water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EA) to yield 1.40 g of a white solid in a 63% yield. LC-MS [M+H] + :237.9.

[0361] 11.2 Preparation of Compound N-(4-bromophenyl)-2-chloropyrimidin-4-amine (L011-2)

[0362] Dissolve 2,4-dichloropyrimidine (500 mg, 3.38 mmol) in acetonitrile (5 mL), add 4-bromoaniline (577 mg, 3.38 mmol) and N,N-diisopropylethylamine (872 mg, 6.76 mmol), and heat under reflux for 24 hours. After concentration under reduced pressure, the crude product was separated by silica gel column chromatography (PE / EA = 2 / 1) to obtain 800 mg of a white solid, with a yield of 83%. LC-MS [M+H] + :283.9.

[0363] 11.3 Preparation of Compound (2-(4-((4-bromophenyl)amino)pyrimidin-2-yl)-2H-indazol-5-yl)(3,3-difluoroazetidine-1-yl)methanone (L011-3)

[0364] N-(4-bromophenyl)-2-chloropyrimidin-4-amine (800 mg, 2.82 mmol) was dissolved in acetonitrile (5 mL), and (3,3-difluoroazetidin-1-yl)(1H-indazol-5-yl)methanone (735 mg, 3.10 mmol) and acetic acid (0.1 mL) were added. The mixture was stirred in a microwave oven at 140°C for 1 h. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (EA) to obtain 250 mg of compound L011-3 as a colorless oil, with a yield of 18%. LC-MS [M+H] + :484.8.

[0365] 11.4 Preparation of Compound (2-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-2H-indazol-5-yl)(3,3-difluoroazetidin-1-yl)methanone (L011)

[0366] Under nitrogen protection, (2-(4-((4-bromophenyl)amino)pyrimidin-2-yl)-2H-indazol-5-yl)(3,3-difluoroazetidine-1-yl)methanone (250 mg, 0.51 mmol) was dissolved in dioxane (6 mL) and water (1 mL), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (180 mg, 0.61 mmol), potassium carbonate (140 mg, 10.2 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (37 mg, 0.051 mmol) were added, and the mixture was stirred at 80 °C for 3 h. The mixture was returned to room temperature, quenched with water (20 mL), extracted with ethyl acetate (10 mL*3), and the organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. 23 mg of a white solid was obtained by preparative separation. The yield was 10%. LC-MS [M+H] + :=472.8.

[0367] 1 H NMR (400MHz, DMSO) δ12.93(s,1H),10.16(s,1H),9.31(s,1H),8.41(d,J=5.9Hz,1H),8.30(s,1H),8.19(s,1H),7.94 (s,1H),7.83-7.76(m,3H),7.68(d,J=8.6Hz,2H),7.63(dd,J=9.2,1.5Hz,1H),6.86(d,J=5.9Hz,1H),4.72(brs,4H).

[0368] Example 12. Preparation of Compound 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-N-(pyridazin-4-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (L012)

[0369]

[0370] Pyridazin-4-amine (34 mg, 0.36 mmol) was dissolved in DMF (4 mL), and 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001) (100 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol), and DIEA (93 mg, 0.72 mmol) were added. The mixture was reacted at room temperature under nitrogen for 2 hours. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was preparatively isolated and purified to yield 2 mg of a white solid.

[0371] LC-MS[M+H] + :492.7.

[0372] 1 H NMR (400MHz, DMSO) δ12.98(s,1H),10.23(s,1H),9.47(s,1H),9.35(s,1H),8.99(d,J=5.8Hz,1H),8.34(s,1H),8.08-7.94(m,3H),7.66(d ,J=8.2Hz,2H),7.58(d,J=8.1Hz,2H),7.04(s,1H),6.09(d,J=6.0Hz,1H),4.85(s,2H),4.05-3.97(m,2H),3.85(s,3H),3.54-3.46(m,2H).

[0373] Example 13. Preparation of Compound 2-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylic acid (L013)

[0374]

[0375] 13.1 Preparation of Compound 1H-pyrrole-2,4-dicarboxylic acid diethyl ester (L013-1)

[0376] Under nitrogen, ethyl 2-isocyanatoacetate (5.0 g, 44.2 mmol) was dissolved in methyl tert-butyl ether (50 mL). Ethyl propiolate (4.3 g, 44.2 mmol) was added to the reaction mixture. Potassium tert-butoxide (6.9 g, 61.9 mmol) was added to the reaction system under ice-salt bath, then warmed to room temperature and stirred for 2 hours. The mixture was quenched with water (50 mL) and extracted with methyl tert-butyl ether (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain 2.5 g of a yellow oily liquid with a yield of 26.9%. LC-MS [M+H] + :212.0.

[0377] 13.2 Preparation of Compound 1-(2-((tert-Butoxycarbonyl)amino)ethyl)-1H-pyrrole-2,4-dicarboxylic Acid Diethyl Ester (L013-2)

[0378] Under hydrogen protection, diethyl 1H-pyrrole-2,4-dicarboxylate (2.5 g, 11.8 mmol) was dissolved in anhydrous DMSO (20 mL). Tert-butyl (2-bromoethyl)carbamate (7.9 g, 35.4 mmol) and potassium carbonate (4.9 g, 35.4 mmol) were added and stirred at 80°C overnight. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (PE / EA = 5 / 1) to obtain 2.0 g of a yellow oily liquid with a yield of 47.9%. LC-MS [M+Na] + :376.9.

[0379] 13.3 Preparation of Compound 1-(2-aminoethyl)-1H-pyrrole-2,4-dicarboxylic Acid Diethyl Ester (L013-3)

[0380] Under nitrogen, diethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-2,4-dicarboxylate (2.0 g, 5.6 mmol) was dissolved in anhydrous ethanol (10 mL). 33% ethanolic hydrogen chloride solution (5 mL) was added and stirred at room temperature for 2 hours. After concentration, 2.2 g of a yellow oily liquid was obtained, which was used directly in the next reaction. LC-MS [M+H] + :255.1.

[0381] 13.4 Preparation of Compound 1-Carboxylic Acid Ethyl 1-Carboxylate (L013-4)

[0382] Under nitrogen, diethyl 1-(2-aminoethyl)-1H-pyrrole-2,4-dicarboxylate (1.5 g, 5.9 mmol) was dissolved in anhydrous ethanol (15 mL), potassium carbonate (4.1 g, 29.5 mmol) was added, and the mixture was refluxed for 12 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE / EA = 1 / 1) to obtain 600 mg of a colorless oily liquid, with a yield of 48.9%. LC-MS [M+H] + :209.1.

[0383] 13.5 Preparation of Compound 1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylic acid ethyl ester (L013-5)

[0384] Under hydrogen protection, ethyl 1-carbonyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (600 mg, 3.1 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and borane (12.4 mL, 12.4 mmol) was added. The mixture was stirred at 80°C for 3 hours. After returning to room temperature, methanol (2 mL) was slowly added dropwise to quench the mixture. After stirring for 20 minutes, 1N dilute hydrochloric acid (20 mL) was slowly added dropwise. The mixture was stirred for 20 minutes, and water (10 mL) was added. After extraction with ethyl acetate (20 mL), the aqueous phase was adjusted to pH 9 with 1N NaOH solution and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain 200 mg of a colorless oil. The yield was 33.1%, MS [M / 2+H] + = 195.1.

[0385] 13.6 Preparation of Compound 2-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylic acid ethyl ester (L013-6)

[0386] Under nitrogen protection, ethyl 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (200 mg, 1.0 mmol) was dissolved in n-butanol (5 mL), and tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (408 mg, 1.1 mmol) and DIEA (400 mg, 3.1 mmol) were added. The mixture was stirred at 120°C for 12 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified on a silica gel column (DCM / MeOH = 20 / 1) to give 200 mg of a light yellow solid with a yield of 46.5%. LC-MS [M+H] + :430.1.

[0387] 13.7 Preparation of Compound 2-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylic acid (L013)

[0388] Dissolve ethyl 2-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (200 mg, 0.5 mmol) in methanol / water / tetrahydrofuran (1 / 1 / 3 = 10 mL). Add lithium hydroxide (100 mg, 2.5 mmol) and allow to react at room temperature overnight. After concentration under reduced pressure, adjust the pH to 5-6 with 1N dilute hydrochloric acid and concentrate under reduced pressure to yield 400 mg of a yellow solid as a crude product. LC-MS [M+H] + :402.0.

[0389] Example 14. Preparation of Compound 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-N-(3,3-difluorocyclobutyl)-N,1-dimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (L014)

[0390]

[0391] Dissolve 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001) (200 mg, 0.71 mmol) in N,N-dimethylformamide (6 mL). Add HATU (274 mg, 0.72 mmol), 3,3-difluoro-N-methylcyclobutane-1-amine hydrochloride (M001) (87 mg, 0.72 mmol), and N,N-diisopropylethylamine (248 mg, 1.92 mmol). Stir at room temperature overnight. Quench with water (20 mL) and extract with ethyl acetate (10 mL*3). Combine the organic phases, wash with saturated brine (10 mL*3), dry over anhydrous sodium sulfate, filter, and concentrate. The crude product was purified on a silica gel column (dichloromethane:ethyl acetate = 1:1), and the collected product was lyophilized to give 24.4 mg of a white solid product, 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-N-(3,3-difluorocyclobutyl)-N,1-dimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, in a yield of 9.8%. LC-MS [M+H] + :519.1.

[0392] 1 H NMR (400MHz, DMSO) δ12.85(brs,1H),10.20(brs,1H)8.05(s,2H),7.94(d,J=6.5Hz,1H),7.64(s,4H),6.28-6.24(m,2H ),4.83(s,2H),4.70-4.60(m,1H),4.02-3.96(m,2H),3.58(s,3H),3.00(s,3H),2.95-2.80(m,4H),2.66-2.60(m,2H).

[0393] Example 16. Preparation of the compound (3,3-difluoroazetidin-1-yl)(6-(4-((3-fluoro-4-(3-fluoro-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone

[0394]

[0395] 16.1 Preparation of Compound N-(4-bromo-3-fluorophenyl)-2-chloropyrimidin-4-amine (L016-1):

[0396] Under nitrogen protection, 2,4-dichloropyrimidine (1000 mg, 6.7 mmol) was dissolved in n-butanol (5 mL), 4-bromo-3-fluoroaniline (1274 mg, 6.7 mmol) and DIEA (2601 mg, 20.1 mmol) were added, the temperature was raised to 120°C, and the reaction was carried out for 8 hours. The mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL*3), the organic phases were combined, washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether /

[0397] Ethyl acetate = 5 / 1) to obtain 600 mg of yellow solid, with a yield of 29.6%, LC-MS [M+H] + :301.9 / 303.9.

[0398] 16.2 Preparation of Compound (6-(4-((4-bromo-3-fluorophenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidine-1-yl)methanone (L016-2):

[0399] Dissolve N-(4-bromo-3-fluorophenyl)-2-chloropyrimidin-4-amine (500 mg, 1.6 mmol) in n-butanol (5 mL), add (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (421 mg, 1.6 mmol) and DIEA (639 mg, 4.9 mmol), heat to 120°C, and react for 8 hours. Quench with water (20 mL), extract with ethyl acetate (20 mL*3), combine the organic phases, wash with saturated brine (20 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 450 mg of a yellow solid. LC-MS [M+H] + :520.7.

[0400] 16.3 Preparation of Compound (3,3-difluoroazetidin-1-yl)(6-(4-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L016-3):

[0401] (6-(4-((4-bromo-3-fluorophenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidine-1-yl)methanone (500 mg, 0.9 mmol) was dissolved in 1,4-dioxane (10 mL), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (366 mg, 1.4 mmol), Pd(dppf)Cl2 (70 mg, 0.09 mmol) and potassium acetate (282 mg, 2.9 mmol) were added. The mixture was protected by nitrogen and reacted at 80°C for 12 hours. Dilute with water (10 mL), extract with ethyl acetate (20 mL*3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate the crude product by wet silica gel column chromatography (PE / EA=5 / 1) to obtain 500 mg of a brown oily liquid. MS [M+H] + =569.2.

[0402] 16.4 Preparation of Compound (3,3-difluoroazetidin-1-yl)(6-(4-((3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L016-4):

[0403] (3,3-Difluoroazetidine-1-yl)(6-(4-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (500 mg, 0.9 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL), and 4-bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (426 mg, 1.4 mmol), Pd(PPh3)4 (111 mg, 0.09 mmol) and potassium carbonate (398 mg, 2.9 mmol) were added. The mixture was protected by nitrogen and reacted at 90°C for 4 hours. Dilute with water (20 mL), extract with ethyl acetate (20 mL*3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate the crude product by silica gel column chromatography (PE / EA=1 / 1) to obtain 100 mg of a yellow oily liquid. MS [M+H] + =657.0.

[0404] 16.5 Preparation of Compound (3,3-difluoroazetidin-1-yl)(6-(4-((3-fluoro-4-(3-fluoro-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L016):

[0405] Dissolve (3,3-difluoroazetidin-1-yl)(6-(4-((3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (150 mg, 0.2 mmol) in ethanol (5 mL). Add ethanolic hydrochloric acid solution (2 mL, 33% by mass) and react at room temperature under nitrogen for 2 hours. Concentrate under reduced pressure and obtain 7.6 mg of a white solid. MS [M+H] + =527.0.

[0406] MS[M+H] + =527.0.1H NMR (400MHz, DMSO) δ12.68(s,1H),9.63(s,1H),8.03(d,J=5.7Hz,1H),7.99-7.91(m,2H),7.51(t,J=8.6Hz,1H),7.34(d,J=6.9Hz ,1H),6.47(s,1H),6.12(d,J=5.7Hz,1H),4.81(s,2H),4.65-4.65(m,4H),3.99(t,J=5.6Hz,2H),3.77(s,3H),2.61-2.55(m,2H).

[0407] Example 17. Preparation of Compound 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-N-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (L017)

[0408]

[0409] 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (70 mg, 0.17 mmol) was dissolved in nitrogen-dimethylformamide (5 mL), and 2,2,2-trifluoroethane-1-amine (25 mg, 0.25 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (96 mg, 0.25 mmol) and nitrogen-diisopropylethylamine (110 mg, 0.84 mmol) were added sequentially, and the reaction was stirred at room temperature overnight. After completion, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified on a silica gel column (4 g, dichloromethane:methanol = 20:1) and lyophilized to obtain 6.7 mg of a white solid product with a yield of 5.39%. LC-MS [M+H] + :497.0.

[0410] 1 H NMR (301MHz, CD3OD) δ8.00 (s, 2H), 7.92 (d, J = 5.9Hz, 1H), 7.74-7.56 (m, 4H), 6.72 (s, 1H), 6 .20(d,J=6.1Hz,1H),4.85(s,2H),4.03(dd,J=18.8,9.1Hz,4H),3.88(s,3H),2.72(s,2H).

[0411] Example 19. Preparation of Compound (3,3-difluoroazetidin-1-yl)(6-(4-(4-(3-fluoro-1H-pyrazol-4-yl)benzyl)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L019)

[0412]

[0413] 19.1 Preparation of Compound (6-(4-((4-bromophenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidine-1-yl)methanone (L019-1):

[0414] Dissolve N-(4-bromophenyl)-2-chloropyrimidin-4-amine (150 mg, 0.5 mmol) in n-butanol (5 mL), add (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (127 mg, 0.5 mmol) and DIEA (129 mg, 1 mmol), heat to 120 ° C, and react for 8 hours. Quench with water (20 mL), extract with ethyl acetate (20 mL * 3), combine the organic phases, wash with saturated brine (20 mL * 2), dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 500 mg of a yellow solid. LC-MS [M+H] + :503.0.

[0415] 19.2 Preparation of Compound (3,3-difluoroazetidin-1-yl)(1-methyl-6-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)pyrimidin-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L019-2):

[0416] (6-(4-((4-bromophenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (200 mg, 0.4 mmol) was dissolved in 1,4-dioxane (10 mL), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (152 mg, 0.6 mmol), Pd(dppf)Cl2 (29 mg, 0.04 mmol) and potassium acetate (78 mg, 0.8 mmol) were added. The mixture was reacted at 80°C under nitrogen protection for 12 hours. Dilute with water (10 mL), extract with ethyl acetate (20 mL*3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate the crude product by wet silica gel column chromatography (PE / EA=5 / 1) to obtain 200 mg of a brown oily liquid. MS [M+H] + =551.2.

[0417] 19.3 Preparation of Compound (3,3-difluoroazetidin-1-yl)(6-(4-((4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L019-3):

[0418] (3,3-Difluoroazetidine-1-yl)(1-methyl-6-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)pyrimidin-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (200 mg, 0.4 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL), and 4-bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (177 mg, 0.6 mmol), Pd(PPh3)4 (46 mg, 0.04 mmol) and potassium carbonate (110 mg, 0.8 mmol) were added. The mixture was protected by nitrogen and reacted at 90 ° C for 4 hours. Dilute with water (20 mL), extract with ethyl acetate (20 mL*3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate the crude product by silica gel column chromatography (PE / EA=5 / 1) to obtain 100 mg of a yellow oily liquid. MS [M+H] + =639.0.

[0419] 19.4 Preparation of Compound (3,3-difluoroazetidin-1-yl)(6-(4-(4-(3-fluoro-1H-pyrazol-4-yl)benzyl)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L019):

[0420] Dissolve (3,3-difluoroazetidin-1-yl)(6-(4-((4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (100 mg, 0.2 mmol) in ethanol (5 mL). Add ethanolic hydrochloric acid solution (2 mL, 33% by mass) under nitrogen protection and react at room temperature for 2 hours. Concentrate under reduced pressure and obtain 3.5 mg of a white solid by preparative isolation. MS [M+H] + =509.0.

[0421] 1 H NMR(400MHz,MeOD)δ7.95(d,J=2.3Hz,1H),7.81(d,J=7.1Hz,1H),7.64(s,4H),6.49(s,1H),6.34(d, J=7.0Hz,1H),4.84(s,1H),4.65-4.48(m,4H),4.06-3.98(m,2H),3.80(s,3H),2.75(t,J=5.5Hz,2H).

[0422] Example 20. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidine-1-yl)methanone (L020)

[0423]

[0424] 20.1 Preparation of Compound Ethyl 4-Formyl-1H-pyrrole-2-carboxylate (L020-1):

[0425] Ethyl pyrrole-2-carboxylate (6.9 g, 49.6 mmol) and aluminum trichloride (13.2 g, 99.2 mmol) were added to 1,2-dichloroethane-nitromethane (1:1, 100 mL). The temperature was lowered to -20°C, and dichloro(methoxy)methane (11.4 g, 99.2 mmol) was added dropwise. Stirring was continued for 1 hour, and the mixture was allowed to stand at -20°C overnight. The reaction mixture was poured into 100 mL of ice water, and the organic phase was separated. The aqueous layer was extracted with DCM (3 x 100 mL), washed with aqueous ammonia (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 5.0 g of ethyl 4-formyl-1H-pyrrole-2-carboxylate as a yellow solid in a 54% yield. MS: [M+H] + =168.0.

[0426] 20.2 Preparation of Compound 4-((Dimethylamino)methyl)-1H-pyrrole-2-carboxylic acid ethyl ester (L020-2):

[0427] Ethyl-4-formyl-1H-pyrrole-2-carboxylate (5.0 g, 29.9 mmol) and dimethylamine (2N in THF) were mixed at room temperature.

[0428] 0.45 ml) was added to MeOH (3 mL), sodium triacetoxyborohydride (381.5 mg, 1.8 mmol) was added portionwise, and the mixture was stirred for 16 hours. The mixture was concentrated under reduced pressure, washed with water (100 mL), extracted with DCM (3 x 50 mL), adjusted to pH 12 with Na2CO3, and extracted with DCM (3 x 50 mL) to obtain 4.3 g of ethyl 4-((dimethylamino)methyl)-1H-pyrrole-2-carboxylate as a colorless oily liquid. MS: [M+H] + =197.1.

[0429] 20.3 Preparation of Compound 1-(5-(Ethoxycarbonyl)-1H-pyrrol-3-yl)-N,N,N-trimethylformamide (L020-3):

[0430] At room temperature, ethyl 4-((dimethylamino)methyl)-1H-pyrrole-2-carboxylate (4.3 g, 21.9 mmol) was dissolved in 80 ml of a solvent (THF:DCM = 1:1). Methyl iodide (15.5 g, 11.0 mmol) was added and stirred for 15 hours. The mixture was concentrated under reduced pressure, and ethyl acetate was added and stirred for 1 hour. Filtration afforded 4.7 g of a white solid, 1-(5-(ethoxycarbonyl)-1H-pyrrol-3-yl)-N,N,N-trimethylformamide, in a 63% yield. MS: [M+H] + =211.0.

[0431] 20.4 Preparation of Compound 4-(Cyanomethyl)-1H-pyrrole-2-carboxylic Acid Ethyl Ester (L020-4):

[0432] 1-(5-(Ethoxycarbonyl)-1H-pyrrol-3-yl)-N,N,N-trimethylformamide (4.67 g, 13.8 mmol) was added to ethanol (30 mL), followed by the addition of NaCN (2.6 g, 53.1 mmol). The mixture was heated to 78°C and refluxed for 15 h. The mixture was concentrated under reduced pressure, washed with water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The organic phase was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain 2.0 g of ethyl 4-(cyanomethyl)-1H-pyrrole-2-carboxylate as a colorless oily liquid in an 81% yield. MS: [M+H] + =179.0.

[0433] 20.5 Preparation of Compound 4-(2-cyanopropane-2-yl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (L020-5):

[0434] Under nitrogen, ethyl 4-(cyanomethyl)-1H-pyrrole-2-carboxylate (300 mg, 1.68 mmol) was added to N,N-dimethylformamide (5 mL). The temperature was cooled to -50°C, sodium hydride (336.0 g, 8.4 mmol) was added, and iodomethane (1.19 g, 8.4 mmol) was added dropwise. After stirring for 0.5 hour, the reaction mixture was warmed to -5°C and stirred for 3 hours. Saturated NH4Cl (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The mixture was concentrated and the crude product was chromatographed on a silica gel column (PE:EtOAc = 10:1) to obtain 250 mg of ethyl 4-(2-cyanopropan-2-yl)-1-methyl-1H-pyrrole-2-carboxylate as a colorless oily liquid in a 67% yield. MS: [M+H] + =221.0.

[0435] 20.6 Preparation of Compound 4-(1-amino-2-methylpropane-2-yl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (L020-6):

[0436] Ethyl 4-(1-cyano-1-methylethyl)-1-methylpyrrole-2-carboxylate (50 mg, 0.23 mmol) was added to formic acid (2 mL), followed by Ni (0.3 mL), heated to 100°C, and stirred for 2 h. After returning to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 50 mg of ethyl 4-(1-amino-2-methylpropane-2-yl)-1-methyl-1H-pyrrole-2-carboxylate as a colorless oil. MS: [M+H] + =225.0.

[0437] 20.7 Preparation of Compound 1,4,4-Trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (L020-7):

[0438] At room temperature, 4-(1-amino-2-methylpropane-2-yl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (50 mg, 0.22 mmol) and trifluoroacetic acid (50.17 mg, 0.44 mmol) were added to dichloromethane (1 mL), and aqueous formaldehyde solution (13 mg, 0.45 mmol) was added, stirred for 4 h, and concentrated under reduced pressure to obtain 50 mg of colorless oily liquid 1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester. MS: [M+H] + =237.0.

[0439] 20.8 Preparation of Compound 6-(tert-Butyloxycarbonyl)-1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L020-8):

[0440] At room temperature, ethyl 1,4,4-trimethyl-5H,6H,7H-pyrrolo[2,3-c]pyridine-2-carboxylate (50 mg, 0.21 mmol) was dissolved in methanol (2 mL). 5 mL of lithium hydroxide (1N, dissolved in water) was added and stirred for 20 hours. The mixture was concentrated under reduced pressure, and Boc2O (137.5 mg, 0.63 mmol) was added and stirred for 12 hours. The mixture was extracted with ethyl acetate (2 x 2 mL). The mixture was adjusted to pH = 5 with hydrochloric acid, extracted with DCM (3 x 5 mL), and concentrated under reduced pressure to obtain 70 mg of 6-(tert-butyloxycarbonyl)-1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid as a colorless oil. MS: [M+Na] + =331.0.

[0441] 20.9 Preparation of Compound 2-(3,3-difluoroazetidine-1-carbonyl)-1,4,4-trimethyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (L020-9):

[0442] At room temperature, 6-(tert-butyl-1'{3}-oxy)-1,4,4-trimethyl-5H,7H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (70 mg, 0.23 mmol), 3,3-difluoroazetidine (44.50 mg, 0.345 mmol) and HATU (131.2) were added to 1,2-dichloroethane (3 mL), DIEA (89.2 mg, 0.7 mmol) was added, and stirred for 15 hours. After the reaction was completed, water (5 mL) was added for washing, and the mixture was extracted with ethyl acetate (3x5 mL), concentrated under reduced pressure, and purified by thin layer chromatography (petroleum ether / ethyl acetate) = (1:1) to obtain 35 mg. tert-Butyl 2-(3,3-difluoroazetidine-1-carbonyl)-1,4,4-trimethyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carboxylate, colorless oily liquid, yield 49%. MS: [M+H] + =384.0.

[0443] Preparation of 20.10 Compound (3,3-difluoroazetidin-1-yl)(1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L020-10):

[0444] At room temperature, tert-butyl 2-(3,3-difluoroazetidine-1-carbonyl)-1,4,4-trimethyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carboxylate (35 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL). 1 mL of 4N HCl (dissolved in 1,4-dioxane) was added and stirred for 1 hour. The mixture was concentrated under reduced pressure to give 30 mg of (3,3-difluoroazetidine-1-yl)(1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone as a white solid. MS: [M+H] + =284.0.

[0445] Preparation of 20.11(6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L020):

[0446] Under nitrogen protection, (3,3-difluoroazetidin-1-yl)(1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (30 mg, 0.11 mmol) and N-(4-(1H-pyrazol-4-yl)phenyl)-2-chloropyrimidin-4-amine (61.52 mg, 0.165 mmol) were dissolved in n-butanol (0.5 mL), and DIEA (71.08 mg, 0.11 mmol) was added. The mixture was stirred at 120°C for 5 hours, concentrated under reduced pressure, and purified by high-performance liquid chromatography to obtain 6.5 mg of (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1,4,4-trimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone as a white solid in a yield of 12%. MS: [M+H] + =519.31.

[0447] 1 H NMR (400MHz, DMSO) δ9.32(s,1H),8.26(s,1H),8.02(s,2H),7.69(d,J=8.6Hz,2H),7.56(d,J

[0448] =8.6Hz,2H),6.60(s,1H),6.07(d,J=5.7Hz,1H),4.74(s,2H),4.58(s,4H),3.76(d,J=3.4Hz,5H),1.18(s,6H).

[0449] The preparation of compound L015 and compound L022 was carried out by referring to the methods described in Example 2 and Example 8 above.

[0450] Compound L018 was prepared by referring to the method described in Example 20 above.

[0451] The preparation of compound L021, compound L023, and compound L024 was carried out by referring to the methods described in Examples 1, 4, 5, 9, 10, 12, and 14 above.

[0452] The characterization data of each compound are shown in the following table:

[0453]

[0454]

[0455] Example 25. Preparation of Compound (2-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)(3,3-difluoroazetidin-1-yl)methanone (L025)

[0456]

[0457] Under nitrogen protection, the crude product 2-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylic acid (L013) (200 mg) was dissolved in DMF (10 mL), and 3,3-difluorotrimethyleneimine hydrochloride (39 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol), and DIEA (129 mg, 1.0 mmol) were added. The reaction was allowed to react at room temperature for 2 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (DCM / MeOH = 10 / 1) to obtain 15 mg of a white solid.

[0458] LC-MS[M+H] + :476.9.

[0459] 1 H NMR (400MHz, DMSO) δ12.86 (s, 1H), 8.04 (brs, 2H), 7.96 (d, J = 6.3Hz, 1H), 7.75-7.57 (m, 4H) ,7.32(s,1H),6.30(s,1H),6.24(s,1H),4.86(s,2H),4.71-4.41(m,4H),4.17-4.05(m,4H).

[0460] Example 26. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-methoxypyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidine-1-yl)methanone (L026)

[0461]

[0462] 26.1 Preparation of Compound N-(4-(1H-pyrazol-4-yl)phenyl)-2-chloro-5-methoxypyrimidin-4-amine (L026-1)

[0463] 2,4-Dichloro-5-methoxypyrimidine (300 mg, 1.68 mmol) was dissolved in isopropanol (5 mL), and tert-butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (436 mg, 1.68 mmol) and N,N-diisopropylethylamine (1.30 g, 10.08 mmol) were added. The reaction was stirred at 120°C for 16 h under nitrogen. After completion of the reaction, water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (DCM / MeOH = 20 / 1) to yield 450 mg of a white solid with a yield of 88%. LC-MS [M+H] + :301.9.

[0464] 26.2 Preparation of the compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-methoxypyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone

[0465] N-(4-(1H-pyrazol-4-yl)phenyl)-2-chloro-5-methoxypyrimidin-4-amine (100 mg, 0.33 mmol) was dissolved in isopropanol (0.5 mL), and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone hydrochloride (116 mg, 0.40 mmol) and N,N-diisopropylethylamine (155 mg, 1.20 mmol) were added. Under nitrogen protection, the mixture was heated to 140°C in a microwave oven for 2 hours. After completion of the reaction, water (5 mL) was added for dilution, and the mixture was extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 26.2 mg of a white solid with a yield of 15%. LC-MS [M+H] + :520.9.

[0466] 1 H NMR (400MHz, DMSO) δ12.88(s,1H),8.72(s,1H),8.15(s,1H),7.90(s,1H),7.83-7.78(m,3H),7.56(d,J=8.7Hz,2H) ,6.45(s,1H),4.71(s,2H),4.65-4.48(m,4H),3.89(t,J=5.5Hz,2H),3.82(s,3H),3.75(s,3H),2.58-2.52(m,2H).

[0467] Example 27. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L027)

[0468]

[0469] 27.1 Preparation of Compound tert-Butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (L027-1):

[0470] Tert-butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (M002) (1.8 g, 6.9 mmol) was dissolved in ethanol (20 mL), and 2,4-dichloro-5-fluoropyrimidine (2.3 g, 13.8 mmol) and DIEA (3.6 g, 27.6 mmol) were added sequentially. The mixture was stirred at 40°C for 2 hours. After completion, the reaction was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (15 mL*3). The organic phases were combined and washed with saturated brine (30 mL*2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified on a silica gel column (PE / EA = 3 / 1) to obtain 2.3 g of a brown solid product with a yield of 85.2%. LC-MS [M+H] + :389.9

[0471] 27.2 Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L027):

[0472] Tert-butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (1.6 g, 12.3 mmol) was dissolved in n-butanol (16 mL), and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone hydrochloride (784 mg, 3.1 mmol) and DIEA (1.2 g, 3.1 mmol) were added to the system and stirred at 120°C overnight. After the reaction was completed and cooled to room temperature, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined and washed with saturated brine (20 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and dried, and the crude product was lyophilized after silica gel column chromatography (DCM / MeOH=20 / 1) to give 600 mg of a white solid. LC-MS[M+H] +:508.7

[0473] 1 H NMR (400MHz, DMSO) δ12.90(s,1H),9.34(s,1H),8.16(s,1H),8.06(d,J=3.7Hz,1H),7.91(s,1H),7.76(d,J=8.7Hz,2H), 7.59(d,J=8.7Hz,2H),6.46(s,1H),4.73(s,2H),4.56(s,4H),3.92(t,J=5.5Hz,2H),3.74(s,3H),2.55(t,J=5.2Hz,2H).

[0474] Example 28. Preparation of the compound (2-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(3,3-difluoroazetidin-1-yl)methanone (L028)

[0475]

[0476] 28.1 Preparation of compound tert-butyl 7-(3,3-difluoroazetidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (L028-1) 2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (300 mg, 1.08 mmol) was dissolved in nitrogen-dimethylformamide (10 mL), and 3,3-difluoroazetidine (210 mg, 1.62 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (615 mg, 1.62 mmol) and nitrogen-diisopropylethylamine (557 mg, 4.32 mmol) were added in sequence, and the reaction was stirred at room temperature overnight. After completion, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with saturated brine (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified on a silica gel column (4 g, petroleum ether:ethyl acetate = 3:1) to obtain 350 mg of tert-butyl 7-(3,3-difluoroazetidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a white solid, with a yield of 91.80%. LC-MS [M+H] + :375.0.

[0477] 28.2 Preparation of Compound (3,3-difluoroazetidin-1-yl)(1,2,3,4-tetrahydroisoquinolin-7-yl)methanone hydrochloride (L028-2)

[0478] Tert-butyl 7-(3,3-difluoroazetidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (300 mg, 0.85 mmol) was dissolved in dichloromethane (3 mL). A hydrochloric acid / dioxane solution (33%, 1 mL) was added to the mixture and stirred at room temperature for 3 hours. After the reaction was complete, the mixture was dried to give 270 mg of the crude brown solid (3,3-difluoroazetidine-1-yl)(1,2,3,4-tetrahydroisoquinolin-7-yl)methanone hydrochloride. The crude product was used directly in the next reaction. LC-MS [M+H] + :253.0.

[0479] 28.3 Preparation of Compound (2-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(3,3-difluoroazetidin-1-yl)methanone (L028)

[0480] (3,3-Difluoroazetidin-1-yl)(1,2,3,4-tetrahydroisoquinolin-7-yl)methanone hydrochloride (100 mg, 0.27 mmol) was dissolved in n-butanol (5 mL), and tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (81 mg, 0.32 mmol) and nitrogen, nitrogen-diisopropylethylamine (105 mg, 0.81 mmol) were added, and the reaction was carried out at room temperature of 120°C overnight. After completion, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The crude product was purified on a silica gel column (4 g, dichloromethane:methanol = 20:1) and lyophilized to obtain 32.6 mg of the white solid product (2-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(3,3-difluoroazetidin-1-yl)methanone) in a yield of 24.74%. LC-MS [M+H] + :488.0.

[0481] 1 H NMR (301MHz, DMSO) δ12.84(s,1H),9.38(s,1H),8.16-7.91(m,3H),7.66(d,J=8.7Hz,2H),7.62-7.52(m,3H),7.49(d,J=7.9Hz,1H) ,7.28(d,J=7.9Hz,1H),6.07(d,J=5.8Hz,1H),4.90(s,2H),4.78(s,2H),4.47(s,2H),3.98(t,J=5.7Hz,2H),2.92(t,J=5.4Hz,2H).

[0482] Example 30. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidine-1-yl)methanone (L030)

[0483]

[0484] 30.1 Preparation of Compound tert-Butyl 4-(4-((2,6-difluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (L030-1)

[0485] Tert-butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (500 mg, 1.93 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). 2,4,6-trifluoropyrimidine (258 mg, 1.93 mmol), nitrogen, and nitrogen-diisopropylethylamine (747 mg, 5.79 mmol) were added sequentially. The reaction was stirred at 0°C overnight. After completion, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (15 mL*3). The organic phases were combined and washed with saturated brine (30 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified on a silica gel column (4 g, petroleum ether:ethyl acetate = 3:1) to obtain 200 mg of tert-butyl 7-(3,3-difluoroazetidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a white solid in a yield of 27.70%. LC-MS[M+H] + :374.0.

[0486] 30.2 Preparation of Compound tert-Butyl 4-(4-((2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-6-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (L030-2)

[0487] Tert-butyl 4-(4-((2,6-difluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (120 mg, 0.32 mmol) was dissolved in acetonitrile (5 mL), and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone hydrochloride (140 mg, 0.48 mmol), nitrogen, nitrogen-diisopropylethylamine (156 mg, 1.21 mmol) were added to the system and stirred at 50°C overnight. After completion, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined and washed with saturated brine (20 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified on a silica gel column (4 g, dichloromethane:methanol = 20:1) and lyophilized to obtain 130 mg of tert-butyl 4-(4-((2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-6-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate as a white solid, with a yield of 66.71%. LC-MS [M+H] + :609.0.

[0488] 30.3 Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L030)

[0489] Tert-Butyl 4-(4-((2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-6-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (130 mg, 0.21 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added to the system, and the mixture was stirred at room temperature overnight. After the reaction was complete, the system was dried by spin drying. The crude product was purified by preparative chromatography (column: Gemini-C18 150 x 21.2 mm, 5 μm mobile phase: ACN-H2O (0.1% FA), gradient: 20-35) and lyophilized to obtain 81.9 mg of the white solid product (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone, with a yield of 76.19%. LC-MS [M+H] + :509.0.

[0490] 1 H NMR(301MHz,DMSO)δ9.58(s,1H),8.01(s,2H),7.57(s,4H),6.46(s,1H),5.62(s, 1H), 4.76 (s, 2H), 4.55 (t, J = 11.6Hz, 4H), 3.94 (s, 2H), 3.75 (s, 3H), 2.56 (s, 2H).

[0491] Example 31. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L031)

[0492]

[0493] 31.1 Preparation of Compound 2-chloro-N-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (L031-1):

[0494] 2,4-Dichloro-7,8-dihydro-5H-pyrano[4,3-D]pyrimidine (150 mg, 0.732 mmol) and 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)aniline (178 mg, 0.732 mmol) were dissolved in n-butanol (10 mL). DIPEA (189 mg, 1.464 mmol) was added, and the atmosphere was replaced with N2 three times. The reaction was stirred at 110°C for 48 hours. LCMS indicated the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. Purification by column chromatography (PE / EA = 3:1 to 1:3) afforded 140 mg of a tan solid. LC-MS: [M+H] + =412.15.

[0495] 31.2 Preparation of Compound (3,3-difluoroazetidin-1-yl)(1-methyl-6-(4-((4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L031-2):

[0496] L031-1 (140 mg, 0.341 mmol), (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (104 mg, 0.409 mmol), Pd2(dba)3 (31 mg, 0.034 mmol), Xantsphos (39 mg, 0.068 mmol), and Cs2CO3 (222 mg, 0.682 mmol) were weighed separately. 1,4-dioxane was added, the nitrogen atmosphere was displaced, and the reaction was allowed to proceed at 90°C overnight. LCMS indicated the reaction was complete. The reaction solution was cooled to room temperature and the 1,4-dioxane was dried by spin drying. The mixture was diluted with H2O (30 mL) and extracted three times with EA (50 mL). The EA phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column (DCM / MeOH=20:1) to obtain 44 mg of yellow solid product. LC-MS: [M+H] + =631.25.

[0497] 31.3 Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L031):

[0498] L031-2 (39 mg, 0.063 mmol) and acidic resin (40 mg) were weighed into a 25 mL round-bottom flask. Methanol (8 mL) and 4M HCl / dioxane (0.4 mL) were added and allowed to react at room temperature for 1 h. LCMS showed that the reaction was complete. The pH was adjusted to 8 with triethylamine and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated by prep-HPLC and lyophilized to obtain a white solid product (2.0 mg, purity 95.573%). LC-MS: [M+H] + =547.25.

[0499] 1 H NMR (400MHz, DMSO) δ8.05 (s, 1H), 7.60 (d, J = 9.4Hz, 2H), 6.46 (s, 1H), 4.74 (s, 1H), 4 .56(d,J=10.3Hz,3H),3.91(t,J=5.5Hz,2H),3.70(s,1H),2.71(s,1H),2.57(s,1H).

[0500] Example 32. Preparation of Compound 2,2,2-trifluoroethyl 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L032)

[0501]

[0502] 32.1 Preparation of Compound 6-tert-Butyl 2-(2,2,2-trifluoroethyl) 1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-2,6(7H)-dicarboxylate (L032-1)

[0503] 6-(tert-Butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (90 mg, 0.32 mmol) was dissolved in anhydrous dichloromethane (5 mL), and 2,2,2-trifluoroethanol (38 mg, 0.38 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73 mg, 0.38 mmol) and 4-dimethylaminopyridine (47 The product was stirred at room temperature for 4 h under nitrogen atmosphere, diluted with water (10 mL), extracted with dichloromethane (5 mL*2), and the combined organic phases were washed with dilute hydrochloric acid (1N) (5 mL*2), saturated sodium bicarbonate (5 mL*2), and then saturated brine (10 mL). The product was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (PE / EA=20 / 1) to obtain 90 mg of a colorless oily liquid with a yield of 77%. LC-MS [M+H] + :362.9.

[0504] 32.2 Preparation of Compound 2,2,2-Trifluoroethyl 1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L032-2)

[0505] Dissolve 6-tert-butyl 2-(2,2,2-trifluoroethyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-2,6(7H)-dicarboxylate (90 mg, 0.25 mmol) in anhydrous dichloromethane (3 mL). Add dioxane hydrochloride (1 mL) and react at room temperature under nitrogen for 2 hours. After the reaction, concentrate to obtain 80 mg of the crude product as a light yellow solid. LC-MS [M+H] + :262.8.

[0506] 32.3 Preparation of Compound 2,2,2-trifluoroethyl 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L032)

[0507] Crude 2,2,2-trifluoroethyl 1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate hydrochloride (80 mg, 0.25 mmol) was dissolved in n-butanol (2 mL). N,N-diisopropylethylamine (97 mg, 0.75 mmol) and N-(4-(1H-pyrazol-4-yl)phenyl)-2-chloropyrimidin-4-amine (94 mg, 0.33 mmol) were added. The mixture was heated to 120°C under nitrogen for 4 hours. After completion of the reaction, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified to yield 47.9 mg of a white solid, with a two-step yield of 38%. LC-MS [M+H] + :497.8.

[0508] 1 H NMR (400MHz, DMSO) δ10.54 (s, 1H), 8.08 (s, 2H), 7.96 (d, J = 6.9Hz, 2H), 7.72-7.60 (m, 4H), 6.85 (s, 1H), 6.34 (d, J = 6.8Hz, 1H), 4.95-4.82 (m, 4H), 4.03-3.93 (m, 2H), 3.80 (s, 3H), 2.72-2.63 (m, 2H).

[0509] Example 34. Preparation of Compound 4-((4-(1H-pyrazol-4-yl)phenyl)amino)-2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)pyrimidine-5-carbonitrile (L034)

[0510]

[0511] 34.1 Preparation of Compound 2-(methylthio)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidine-5-carbonitrile (L034-1)

[0512] 4-Chloro-2-(methylthio)pyrimidine-5-carbonitrile (300 mg, 1.62 mmol) was dissolved in n-butanol (4 mL), and 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)aniline (468 mg, 1.62 mmol) and N,N-diisopropylethylamine (418 mg, 3.24 mmol) were added. The reaction was carried out at 90°C for 4 h under nitrogen. After completion of the reaction, water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (PE / EA = 5 / 1) to obtain 540 mg of a white solid with a yield of 76%. LC-MS [M+H] + :438.9.

[0513] The preparation of 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)aniline (M005) was carried out by referring to the preparation method of L038-1 described in Example 38 below.

[0514] 34.2 Preparation of Compound 2-(Methanesulfonyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidine-5-carbonitrile (L034-2)

[0515] 2-(Methylthio)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidine-5-carbonitrile (200 mg, 0.46 mmol) was dissolved in anhydrous dichloromethane (5 mL), and m-chloroperbenzoic acid (280 mg, 1.38 mmol) was added. The mixture was reacted under nitrogen for 2 hours at room temperature. After completion of the reaction, saturated sodium bicarbonate solution (10 mL) was added to quench the aqueous phase until the pH value was approximately 10. The mixture was extracted with dichloromethane (10 mL*2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (PE / EA = 3 / 1) to obtain 110 mg of a white solid with a yield of 51%. LC-MS [M+H] + :471.2.

[0516] 34.3 Preparation of Compound 2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidine-5-carbonitrile (L034-3)

[0517] 2-(Methylsulfonyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidine-5-carbonitrile (110 mg, 0.23 mmol) was dissolved in n-butanol (3 mL) and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone hydrochloride (80 mg, The product was reacted with 1,2-diisopropylethylamine (89 mg, 0.69 mmol) and N,N-diisopropylethylamine (89 mg, 0.69 mmol) at 120°C under nitrogen for 4 hours. After completion of the reaction, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (PE / EA=5 / 1) to obtain 100 mg of a yellow solid with a yield of 65%. LC-MS [M+H] + :645.8.

[0518] 34.4 Preparation of Compound 4-((4-(1H-pyrazol-4-yl)phenyl)amino)-2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)pyrimidine-5-carbonitrile (L034)

[0519] 2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidine-5-carbonitrile (100 mg, 0.15 mmol) was dissolved in dichloromethane (3 mL) and hydrochloric acid 1, A 4-dioxane solution (1 mL) was reacted at room temperature under nitrogen for 2 hours. After completion of the reaction, the mixture was diluted with water (5 mL) and extracted with dichloromethane (5 mL*2). The pH of the aqueous phase was adjusted to approximately 10 with sodium hydroxide (2N), and the mixture was extracted with dichloromethane (5 mL*2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified to obtain 43 mg of a white solid with a yield of 55%. LC-MS [M+H] + :515.8.

[0520] 1H NMR(300MHz,DMSO)δ9.01(s,1H),8.38(s,1H),7.92(s,2H),7.60-7.49(m,4H),6.39(s,1H),4 .79(s,2H),4.50(t,J=12.5Hz,4H),3.99(t,J=5.8Hz,2H),3.69(s,3H),2.56(t,J=5.6Hz,2H).

[0521] Example 35. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L035)

[0522]

[0523] 35.1 Preparation of Compound tert-Butyl 4-(4-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (L035-1)

[0524] Dissolve 2,4-dichloro-5-(trifluoromethyl)pyrimidine (100 mg, 0.46 mmol) in n-butanol (2 mL) and add N,N-diisopropylethylamine (118 mg, 0.92 mmol). Under nitrogen, lower the temperature to -20°C and slowly add tert-butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (143 mg, 0.55 mmol). Stir for 1 hour, then warm to room temperature and stir for 5 hours. After the reaction is complete, dilute with water (5 mL) and extract with ethyl acetate (5 mL x 2). The combined organic phases are washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (PE / EA = 8 / 1) to yield 120 mg of a white solid (containing isomers). LC-MS [M+H] + :439.8.

[0525] 35.2 Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L035)

[0526] Tert-butyl 4-(4-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (including isomers) (120 mg, 0.27 mmol) was dissolved in n-butanol (2 mL), and N,N-diisopropylethylamine (106 mg, 0.82 mmol) and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone carbonate (94 mg, 0.33 mmol) were added. The reaction was heated to 120°C under nitrogen protection for 4 hours. After completion of the reaction, water (5 mL) was added for dilution and extraction with ethyl acetate (5 mL*2) was performed. The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified to give 30.2 mg of a white solid, with a two-step yield of 20%. LC-MS[M+H] + :558.9.

[0527] 1 H NMR (400MHz, DMSO) δ12.93(s,1H),8.61(d,J=29.9Hz,1H),8.32(s,1H),8.20(s,1H),7.93(s,1H),7.61(d,J=8.6Hz,2H), 7.51(s,2H),6.45(s,1H),4.90-4.65(m,2H),4.60-4.42(m,4H),4.12-3.80(m,2H),3.76-3.50(m,3H),2.56-2.52(m,2H).

[0528] Example 36. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L036)

[0529]

[0530] 36.1 Preparation of Compound 4-(4-(((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (L036-1):

[0531] 2,4-Dichloro-1,3,5-triazine (120 mg, 0.80 mmol) and tert-butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (219 mg, 0.84 mmol) were added to ethanol (3 mL), followed by diisopropylethylamine (517 mg, 4.0 mmol). The mixture was stirred at 70°C for 5 h. Liquid chromatography-mass spectrometry confirmed the reaction was complete and the resulting mixture was filtered to give 100 mg of tert-butyl 4-(4-(((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazole-1-carboxylate as a white solid in a 31.43% yield. MS (M+H) + =372.7.

[0532] 36.2 Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L036):

[0533] tert-Butyl 4-(4-(((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (50 mg, 0.13 mmol) and 3,3-difluoro-1-((1-methyl-4H,5H,6H,7H-pyrrolo(2,3-c)pyridin-2-yl)carbonyl)azetidine (34 mg, 0.13 mmol) were added to n-butanol (2 mL) and diisopropylethylamine (86 mg, 0.7 mmol) and stirred at 120°C for 5 h. After the reaction was complete, the product was prepared by liquid chromatography-mass spectrometry to obtain 24.2 mg of (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone as a white solid in a yield of 36.55%. MS (M+H) + =492.2.

[0534] 1 H NMR (400MHz, DMSO) δ12.89(s,1H),9.74(s,1H),8.30(s,1H),8.13(s,1H),7.88(s,1H),7.76-7.67(m,J=8.6Hz,2H),7.61-7 .51(m,2H),6.49(s,1H),4.86(s,2H),4.57(s,4H),4.03(t,J=5.5Hz,2H),3.82-3.71(m,J=14.8Hz,3H),2.63-2.56(m,2H).

[0535] Example 37. Preparation of Compound (6-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L037)

[0536]

[0537] 37.1 Preparation of Compound 4-(4-(((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (L037-1):

[0538] 3,5,6-Trichloro-1,2,4-triazine (205 mg, 1.4 mmol) and tert-butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (353 mg, 1.4 mmol) were added to ethanol (5 mL), followed by diisopropylethylamine (350 mg, 2.7 mmol). The mixture was stirred at room temperature for 1 hour. Liquid chromatography-mass spectrometry confirmed the reaction was complete, and the mixture was concentrated to yield 600 mg of crude tert-butyl 4-(4-(((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)-1H-pyrazole-1-carboxylate.

[0539] MS(M+H) + =406.8.

[0540] 37.2 Preparation of Compound (6-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-chloro-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L037-2):

[0541] 4-(4-(((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (400 mg, 0.98 mmol) and 3,3-difluoro-1-((1-methyl-4H,5H,6H,7H-pyrrolo(2,3-c)pyridin-2-yl)carbonyl)azetidine (286 mg, 0.98 mmol) were added to n-butanol (10 mL) and diisopropylethylamine (63 3 mg, 4.9 mmol), stirred at 120°C for 2 h. After the reaction was complete, a portion was taken for preparation by liquid chromatography-mass spectrometry to obtain 127.7 mg of (6-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-chloro-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone as a white solid. MS (M+H) + =526.0.

[0542] 37.3 Preparation of Compound (6-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L037):

[0543] (6-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-chloro-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (the product of the previous step) was dissolved in methanol (10 mL), palladium carbon (50 mg) was added, stirred evenly, and triethylamine (1 mL) was added. A hydrogen balloon was installed. , replace hydrogen, stir at room temperature for 10 hours, detect the reaction completion, filter, concentrate the filtrate, and obtain a white solid (6-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-1,2,4-triazine-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidine-1-yl)methanone 36.6 mg, MS (M+H) + =491.8.

[0544] 1HNMR(400MHz,)δ12.88(s,1H),9.96(s,1H),8.22-7.87(m,3H),7.71(d,J=8.6Hz,2H),7.64(d,J=8 .7Hz,2H),6.48(s,1H),4.86(s,2H),4.57(s,4H),4.01(s,2H),3.78(s,3H),2.60(t,J=5.4Hz,2H).

[0545] Example 38. Preparation of Compound (6-(5-chloro-4-((4-(3-fluoro-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L038)

[0546]

[0547] 38.1 Preparation of Compound 4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)aniline (L038-1):

[0548] 4-Bromo-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (500 mg, 1.70 mmol) was dissolved in dioxane (5 mL) and water (1 mL), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (446 mg, 2.04 mmol), potassium carbonate (73 mg, 0.38 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (124 mg, 0.17 mmol) were added. The mixture was protected by nitrogen and heated to 90°C and stirred for 4 h. The mixture was filtered and diluted with water (10 mL). The mixture was extracted with ethyl acetate (10 mL*2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (PE / EA=5 / 1) to give 300 mg of a white solid with a yield of 57%. LC-MS[M+H] + :307.8.

[0549] 38.2 Preparation of Compound 2,5-dichloro-N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)pyrimidin-4-amine (L038-2):

[0550] 4-(5-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)aniline (70 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 2,4,5-trichloropyrimidine (63 mg, 0.34 mmol) and N,N-diisopropylethylamine (89 mg, 0.69 mmol) were added. The mixture was reacted at room temperature under nitrogen for 5 hours. Water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (PE / EA = 4 / 1) to obtain 90 mg of a yellow solid with a yield of 86%. LC-MS [M+H] + :453.8.

[0551] 38.3 Preparation of Compound (6-(5-chloro-4-((4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L038-3):

[0552] 2,5-Dichloro-N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)pyrimidin-4-amine (90 mg, 0.19 mmol) was dissolved in n-butanol (2 mL), and N,N-diisopropylethylamine (73 mg, 0.57 mmol) and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone hydrochloride (66 mg, 0.23 mmol) were added. Under nitrogen protection, the temperature was raised to 120 ° C and the reaction was carried out for 4 hours. After the reaction, water (5 mL) was added for dilution, and the mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (PE / EA = 2 / 1) to obtain 110 mg of a white solid with a yield of 86%. LC-MS [M+H] + :672.8.

[0553] 38.4 Preparation of Compound (6-(5-chloro-4-((4-(3-fluoro-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L038):

[0554] (6-(5-chloro-4-((4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidine-1-yl)methanone (110 mg, 0.16 mmol) was dissolved in anhydrous dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added to the reaction solution, and the reaction was carried out at room temperature under nitrogen protection for 2 hours. After the reaction, water (5 mL) was added for dilution, and the mixture was extracted with dichloromethane (5 mL*2). The aqueous phase was adjusted to a pH of approximately 10 with a 2N sodium hydroxide solution and extracted with dichloromethane (5 mL*2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 45.3 mg of a white solid with a yield of 52%. LC-MS [M+H] + :542.8.

[0555] 1 H NMR (400MHz, DMSO) δ12.65(s,1H),8.86(s,1H),8.15(d,J=2.0Hz,1H),8.10(s,1H),7.71(d,J=8.6Hz,2H),7.55( d,J=8.5Hz,2H),6.45(s,1H),4.72(s,2H),4.68-4.48(s,4H),3.98-3.90(m,2H),3.71(s,3H),2.55-2.53(m,2H).

[0556] Example 39. Preparation of Compound (3-(difluoromethyl)azetidin-1-yl)(6-(5-fluoro-4-((4-(3-fluoro-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L039)

[0557]

[0558] 39.1 Preparation of Compound tert-Butyl 2-(3-(difluoromethyl)azetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-6(7H)-carboxylate (L039-1):

[0559] 6-(tert-Butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (300 mg, 1.07 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and 3-(difluoromethyl)azetidine hydrochloride (183 mg, 1.28 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (487 mg, 1.28 mmol) and N,N-diisopropylethylamine (414 mg, 3.21 mmol) were added. The mixture was stirred at room temperature for 4 h under nitrogen protection, diluted with water (10 mL), and extracted with ethyl acetate (10 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (PE / EA=3 / 1) to obtain 280 mg of a colorless oily liquid with a yield of 71%. LC-MS[M+H] + :369.9.

[0560] 39.2 Preparation of Compound (3-(difluoromethyl)azetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L039-2):

[0561] Dissolve tert-butyl 2-(3-(difluoromethyl)azetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-6(7H)-carboxylate (280 mg, 0.75 mmol) in anhydrous dichloromethane (6 mL). Add trifluoroacetic acid (2 mL) and react under nitrogen at room temperature for 2 hours. After the reaction, dilute with water (10 mL) and extract with dichloromethane (10 mL x 2). The aqueous phase is adjusted to a pH of approximately 10 with aqueous sodium hydroxide (2 N) and extracted with dichloromethane (10 mL x 2). The organic phases are combined and concentrated to yield 160 mg of the crude product as a yellow solid. LC-MS [M+H] + :269.8.

[0562] 39.3 Preparation of Compound 2-chloro-5-fluoro-N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)pyrimidin-4-amine (L039-3):

[0563] 4-(5-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)aniline (80 mg, 0.26 mmol) was dissolved in anhydrous ethanol (3 mL), and N,N-diisopropylethylamine (100 mg, 0.78 mmol) and 2,4-dichloro-5-fluoropyrimidine (86 mg, 0.52 mmol) were added. The reaction was heated to 40°C under nitrogen for 2 hours. After completion of the reaction, water (10 mL) was added for dilution and extraction with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (PE / EA = 3 / 1) to obtain 100 mg of a white solid with a yield of 88%. LC-MS [M+H] + :438.2.

[0564] 39.4 Preparation of Compound (3-(difluoromethyl)azetidin-1-yl)(6-(5-fluoro-4-((4-(3-fluoro-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L039):

[0565] 2-Chloro-5-fluoro-N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)pyrimidin-4-amine (100 mg, 0.22 mmol) was dissolved in n-butanol (3 mL), and N,N-diisopropylethylamine (85 mg, 0.66 mmol) and (3-(difluoromethyl)azetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (71 mg, 0.26 mmol) were added to the reaction solution. The mixture was protected by nitrogen and heated to 120 °C for 12 hours. After the reaction was completed, water (10 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (10 mL*2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and prepared to obtain 10.9 mg of a white solid with a yield of 10%. LC-MS [M+H] + :541.2.

[0566] NMR(400MHz,)DMSOδ12.51(s,1H),9.36(s,1H),8.10(t,J=2.0Hz,1H),8.03(d,J=3. 7Hz,1H),7.75(d,J=1.9Hz,2H),7.50(d,J=8.6Hz,2H),6.44(d,J=4.4Hz,0.25H),6. 33(s,1H),6.29(d,J=4.3Hz,0.5H),6.15(d,J=4.4Hz,0.25H),4.68(s,2H),4.35-4. 00(m,4H),3.87(t,J=5.6Hz,2H),3.69(s,3H),3.15-3.04(m,1H),2.53-2.46(m,2H).

[0567] Example 40. Preparation of Compound (6-(5-fluoro-4-((2-fluoro-4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L040)

[0568]

[0569] 40.1 Preparation of Compound 4-(3-fluoro-4-nitrophenyl)-1H-pyrazole (L040-1):

[0570] 4-Bromo-2-fluoro-1-nitrobenzene (4.0 g, 18.18 mmol), tert-butyl (4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl)carboxylate (8.02 g, 27.27 mmol), Pd(dppf)Cl2 (1.99 g, 2.732 mmol), and K2CO3 (7.54 g, 54.55 mol) were weighed and added to 1,4-dioxane (90 mL) and water (9 mL). The atmosphere was replaced with nitrogen and the mixture was heated to 100°C for 3 hours. The reaction was complete by TLC. The reaction solution was cooled and filtered, the solvent was evaporated, and purification was performed by silica gel column chromatography (PE / EA = 20 / 1 to 3 / 1). 2.3 g of a yellow solid powder was obtained.

[0571] 40.2 Preparation of Compound 4-(4-amino-3-fluorophenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (L040-2):

[0572] L040-1 (500 mg, 2.41 mmol) and Pd / C (150 mg) were weighed separately and added to 5 mL of methanol. The atmosphere was replaced with hydrogen and heated to 40°C for 2 hours. LCMS indicated the reaction was complete. The mixture was filtered and the solvent was dried to give 320 mg of a yellow oily liquid. LC-MS: [M+H] + =278.30.

[0573] Preparation of 40.3 Compound tert-butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3-fluorophenyl)-1H-pyrazole-1-carboxylate (L040-3):

[0574] 2,4-Dichloro-5-fluoropyrimidine (390 mg, 2.37 mmol) and L040-2 (540 mg, 1.95 mmol) were weighed into a 50 mL eggplant-shaped flask and dissolved in n-butanol. DIEA (1.01 g, 7.8 mmol) was added and heated to 120°C for 3 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 20 / 1 to 5 / 1), followed by scraping and purifying with pure DCM to obtain 70 mg of the product as a yellow solid. LC-MS: [M+H] + =308.04.

[0575] 40.4 Preparation of Compound (6-(5-fluoro-4-((2-fluoro-4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L040):

[0576] L040-3 (70 mg, 0.23 mmol) and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (70 mg, 0.27 mmol) were weighed into a 35 mL sealed tube and dissolved in n-butanol (2 ml). DIEA (119 mg, 0.92 mmol) was added and allowed to react at 120°C overnight. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated by prep-HPLC using a H2O / ACN system and lyophilized to obtain a white solid product (7.2 mg, 95.736% purity). LC-MS: [M+H] + =527.10.

[0577] 1H-NMR(400MHz,dmso)δ8.97(d,J=0.6Hz,1H),8.60(d,J=4.2Hz,1H),8.31(d,J =0.6Hz,1H),7.52(dd,J=12.8,1.8Hz,1H),7.34(dd,J=8.2,1.9Hz,1H),6.79(d d,J=9.5,8.3Hz,1H),6.48(s,1H),5.25(s,2H),4.83(s,2H),4.54(t,J=11.8H z, 4H), 4.06 (t, J = 5.3Hz, 2H), 3.78 (s, 3H), 2.60 (t, J = 5.3Hz, 2H), 2.05 (s, 1H).

[0578] Example 41. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-(trifluoromethyl)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L041)

[0579]

[0580] 41.1 Preparation of Compound tert-Butyl 4-(4-((2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (L041-1):

[0581] 2,4-Dichloro-6-trifluoromethylpyrimidine (100 mg, 0.46 mmol) and tert-butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (119.52 mg, 0.46 mmol) were weighed separately into a 5 mL sample vial, dissolved in 1 mL of n-butanol, and then DIEA (297.8 mg, 1.15 mmol) was added. The mixture was stirred at 70°C for 2 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated to obtain 233 mg of crude product as a light yellow solid. LC-MS: [M+H] + =440.10.

[0582] 41.2 Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-(trifluoromethyl)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L041):

[0583] L041-1 (200 mg, 0.454 mmol) and (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (116 mg, 0.454 mmol) were weighed separately into a 25 mL eggplant-shaped flask. 5 mL of n-butanol was added for dissolution, followed by DIEA (294 mg, 2.27 mmol). The mixture was stirred at 120°C for 2 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated to obtain the crude product. The crude product was then lyophilized to obtain a white solid product (56.1 mg, 96.192% purity). LC-MS: [M+H] + =559.15.

[0584] 1 H NMR(600MHz,DMSO-d6)δ12.86(s,1H),9.82(s,1H),8.33-7.81(m,1H),7.64(dd,J=28.2,8.0Hz,2H), 6.48(s,1H),6.43(s,1H),4.82(s,1H),4.56(s,2H),4.01(t,J=5.0Hz,1H),3.77(s,2H),2.59(s,1H).

[0585] Example 43. Preparation of Compound (6-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-methoxy-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L043)

[0586]

[0587] (6-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-chloro-1,2,4-triazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo(2,3-c)pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (300 mg, 0.570 mmol) was placed in a 35 mL sealed tube and dissolved in methanol (10 ml). Sodium methoxide (308 mg, 5.703 mmol) was added and the mixture was reacted at 100°C for 11 h. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated by prep-HPLC using a H2O / ACN system and lyophilized to obtain a white solid product (15.0 mg, 97.816% purity). LC-MS: [M+H] + =522.20.

[0588] 1 H NMR(400MHz,DMSO-d)δ9.46(s,1H),8.14(s,1H),8.05(s,2H),7.84(d,J=8.6Hz,2H),7.63(dd,J=8.6,1.7Hz,2H) ,6.46(s,1H),4.72(s,2H),4.56(t,J=11.8Hz,4H),4.01(s,3H),3.89(t,J=5.5Hz,2H),3.76(s,3H),2.58(s,2H).

[0589] Example 45. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)-1-(difluoromethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L045)

[0590]

[0591] 45.1 Preparation of Compound 6-(tert-butyl)-2-ethyl-1-(difluoromethyl)-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-2,6-dicarboxylic acid (L045-1):

[0592] 6-(tert-Butyl)-2-ethyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-2,6-dicarboxylic acid (2.0 g, 6.8 mmol) and diethyl bromofluoromethylphosphonate (2.7 g, 10.2 mmol) were weighed into a 100 mL eggplant-shaped flask. Acetonitrile (20 mL) was added to dissolve the mixture. KF (1.2 g, 20.4 mmol) was then added and allowed to react at room temperature for 16 h. TLC confirmed the reaction was complete, and the reaction was stopped. The mixture was filtered under reduced pressure, and the filtrate was concentrated to obtain the crude product, which was then separated by silica gel column chromatography (PE:EA = 10:1-4:1) to yield 800 mg of an off-white solid. LC-MS: [2M+H] + =689.30.

[0593] 45.2 Preparation of Compound 2-(3,3-difluoroazetidine-1-carbonyl)-1-(difluoromethyl)-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (L045-2):

[0594] L045-1 (720 mg, 2.0 mmol) was weighed into a 50 mL eggplant-shaped flask and dissolved in THF (20 mL) and water (4 mL). Solid NaOH (0.4 g, 10 mmol) was added and allowed to react at room temperature for 4 h. LCMS indicated the reaction was complete. The pH was adjusted to 5-6 with acetic acid in an ice bath. The solid was filtered and the filtrate was dried to obtain the product. The product was dissolved in DCM (20 mL). DIEA (1 mL, 6.0 mmol), HATU (1.5 g, 4.0 mmol), and 3,3-difluorotrimethyleneimine (389 mg, 3.0 mmol) were added and allowed to react at room temperature for 3 h. LCMS indicated that the reaction was complete, and the reaction was stopped. The filtrate was filtered under reduced pressure and concentrated to obtain the crude product, which was then separated by silica gel column chromatography (PE:EA = 4:1) to obtain 900 mg of a light yellow solid.

[0595] LC-MS: [M+H-56] + =336.05.

[0596] Preparation of 45.3 Compound (3,3-difluoroazetidine-1-yl)(1-(difluoromethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L045-3):

[0597] L045-2 (900 mg, 2.3 mmol) was weighed into a 50 mL eggplant flask and dissolved in methanol (20 mL). Then, 20 mL of a 4M HCl solution in 1,4-dioxane was added. The mixture was allowed to react at room temperature for 5 h. LCMS indicated the reaction was complete. The solvent was then dried and the HCl was removed with DCM to obtain 700 mg of the hydrochloride salt of L045-3 as a yellow solid. LC-MS: [M+H] + =292.05.

[0598] 45.4 Preparation of Compound 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)-1-(difluoromethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L045):

[0599] tert-Butyl 4-(4-(((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (100 mg, 0.268 mmol) and L045-03 (78 mg, 0.268 mmol) were weighed into a 25 mL eggplant flask and dissolved in 2 mL of n-butanol. DIEA (173 mg, 1.34 mmol) was then added and stirred at 120°C for 2 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated to obtain the crude product. The crude product was then lyophilized to obtain a white solid product (70.4 mg, 98.524% purity). LC-MS: [M+H] + =528.15.

[0600] 1 H NMR(400MHz,DMSO-d6)δ12.84(s,1H),9.74(s,1H),8.40-7.74(m,2H),7.68(s,1H),7.52(dd,J =31.2,7.6Hz,1H),6.72(s,1H),5.06(s,1H),4.62(s,2H),4.06(t,J=5.6Hz,1H),2.60(s,1H).

[0601] Example 46. Preparation of Compound (6-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-1,3,4-oxadiazol-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L046)

[0602]

[0603] 46.1 Preparation of Compound 4-(4-isothiocyanatophenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (L046-1)

[0604] tert-Butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (M002) (520 mg, 2.005 mmol) was weighed and dissolved in tetrahydrofuran (10 mL). CS2 (1.522 g, 20.050 mmol) and NaH (200 mg, 5.013 mmol) were then added, followed by reaction at 50°C overnight. LCMS indicated that the reaction was complete. Boc2O (437 mg, 2.005 mmol) and DMAP (25 mg, 0.205 mmol) were then added to the reaction system, and the mixture was allowed to react at room temperature for 5 hours. LCMS showed the reaction was complete. The mixture was diluted with an appropriate amount of water and extracted with EA (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (PE:EA = 8:1) to obtain 650 mg of tert-butyl 4-(4-isothiocyanatophenyl)-1H-pyrazole-1-carboxylate as a light yellow solid. LC-MS: [M+H] + =302.05.

[0605] 46.2 Preparation of Compound 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carbonyl chloride (L046-2)

[0606] (3,3-Difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (500 mg, 1.961 mmol) and DIEA (2.529 g, 19.610 mmol) were weighed into a 50 mL eggplant flask and dissolved in DCM (10 mL). The mixture was stirred at room temperature for 10 minutes. A DCM solution of solid triphosgene (1.741 g, 5.883 mmol) was added dropwise under an ice bath. After completion, the mixture was allowed to react at room temperature for 5 hours. LCMS indicated the reaction was complete. The mixture was diluted with water and extracted with DCM (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 1 g of crude product as a brown oil. LC-MS: [M+H] + =318.00.

[0607] 46.3 Preparation of DMSO Solution of Compound 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carbohydrazide (L046-3)

[0608] L046-2 (1.0 g, 3.147 mmol) was weighed into a 50 mL eggplant-shaped flask and dissolved in DMSO (10 mL). Hydrazine hydrate (1.6 g, 31.474 mmol) was slowly added dropwise under an ice bath. After completion of the addition, the mixture was allowed to react overnight at room temperature. LCMS indicated the reaction was complete. This yielded 10 mL of a pale yellow DMSO solution of L046-3. LC-MS: [M+H] + =314.10.

[0609] 46.4 Compound tert-Butyl 2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-6-carbonyl)hydrazine-1-carboxylate (L046-4)

[0610] To the 10 mL DMSO solution obtained in the previous step, add 10 mL of water, THF (10 mL), K2CO3 (2 g), and Boc2O (5 mL) and allow to react overnight at room temperature. LCMS indicated the reaction was complete. Dilute with an appropriate amount of water and extract with EA (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was separated by silica gel column chromatography (PE:EA = 1:2) to afford 380 mg of an off-white solid. LC-MS: [M+H] + =414.20.

[0611] 46.5 Preparation of Compound 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carbohydrazide (L046-3)

[0612] L046-4 (380 mg, 0.921 mmol) was weighed into a 50 mL eggplant flask and dissolved in DCM (4 mL). Trifluoroacetic acid (2 mL) was added and the mixture was allowed to react at room temperature for 1 hour. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure to yield 380 mg of the crude product as a light yellow oil. LC-MS: [M+H] + =314.15.

[0613] 46.6 Compound tert-butyl 4-(4-(2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-6-carbonyl)hydrazine-1-thioamino)phenyl)-1H-pyrazole-1-carboxylate (L046-5)

[0614] The crude product L046-3 (300 mg, 0.958 mmol) was weighed into a 50 mL eggplant-shaped flask, DIEA (248 mg, 1.916 mmol) was added, and the mixture was dissolved in dichloromethane (10 mL). The mixture was stirred at room temperature for 10 minutes. A dichloromethane solution of L046-1 (288 mg, 0.958 mmol) was added dropwise. After completion of the addition, the mixture was allowed to react at room temperature overnight. LCMS indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to give the crude product, which was then separated by silica gel column chromatography (DCM:MeOH = 1:1-1:3) to afford 360 mg of a light yellow solid. LC-MS: [M+H] + =615.15.

[0615] Preparation of Compound 46.7: Tert-Butyl 4-(4-((5-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1,3,4-oxadiazol-2-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (L046-6)

[0616] L046-5 (360 mg, 0.586 mmol) was weighed into a 50 mL eggplant-shaped flask, EDCI (1.122 g, 5.856 mmol) was added, and NMP (20 mL) was added for dissolution. The mixture was stirred at 60°C for 5 hours. LCMS indicated the reaction was complete. The mixture was diluted with water and extracted with EA (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (DCM:MeOH = 20:1 to 10:1) to yield 280 mg of a pale yellow solid.

[0617] 46.8 Preparation of Compound (6-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-1,3,4-oxadiazol-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L046)

[0618] L046-6 (260 mg, 0.448 mmol) was weighed into a 50 mL eggplant flask and dissolved in DCM (16 mL). Trifluoroacetic acid (4 mL) was added and the mixture was allowed to react at room temperature for 2 h. LCMS indicated the reaction was complete. The solvent was concentrated under reduced pressure, and the residue was diluted with water. The pH was adjusted to 9 with saturated NaHCO₃. The mixture was extracted with EA (50 mL x 3). The organic phase was collected to obtain the crude product, which was separated by prep-HPLC and lyophilized to yield a white solid (28.0 mg, 98.641% purity). LC-MS: [M+H] + =481.15.

[0619] 1 H-NMR(400MHz,DMSO-d)δ10.07(s,1H),7.94(s,1H),7.52(d,J=8.7Hz,1H),7.45(d,J=8.7Hz,1H), 6.47(s,1H),4.55(s,1H),4.47(s,1H),3.70(s,1H),3.59(t,J=5.6Hz,1H),2.62(t,J=5.5Hz,1H).

[0620] Example 47. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-(difluoromethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L047)

[0621]

[0622] Tert-butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (190 mg, 0.49 mmol) was weighed into a 50 mL eggplant-shaped flask and dissolved in n-BuOH (10 mL). DIEA (0.40 mL, 2.45 mmol) and L045-3 hydrochloride (192 mg, 0.59 mmol) were then added and reacted at 120°C for 16 h. TLC analysis indicated the reaction was complete, and the reaction was stopped. The solvent was concentrated under reduced pressure, washed with water (50 mL x 3), and extracted with EA (50 mL x 3). The organic phase was collected to obtain the crude product, which was separated by prep-HPLC and lyophilized to yield a white solid (38.0 mg, 98.251% purity). LC-MS: [M+H] + =545.15.

[0623] 1 H NMR(400MHz,dmso)δ12.83(s,1H),9.33(s,1H),8.36(s,0H),8.21(s,1H),8.04(t,J=13.2Hz,3H),7.75(d,J=8.7H z, 2H), 7.54 (d, J = 8.6Hz, 2H), 6.69 (s, 1H), 4.97 (s, 2H), 4.62 (s, 4H), 3.94 (t, J = 5.6Hz, 2H), 2.58 (t, J = 5.1Hz, 2H).

[0624] Example 48. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-ethyl-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L048)

[0625]

[0626] 48.1 Preparation of compound 2,4-dichloro-6-ethyl-1,3,5-triazine (L048-1):

[0627] 2,4,6-Trichloro-1,3,5-triazine (1.84 g, 10.0 mmol) was dissolved in 20 mL of DCM and cooled to -10°C using a dry ice / acetonitrile bath. 11.0 mmol of ethylmagnesium bromide solution was added dropwise. The mixture was allowed to react at low temperature for 0.5 h. After the mixture was allowed to warm to room temperature, the reaction was quenched with ammonium chloride. The mixture was extracted with an EA / water system, dried over anhydrous sodium sulfate, and dried to dryness to obtain 1.4 g of the product as a yellow solid, which was used directly in the next reaction. LC-MS: [M+H] + =178.00.

[0628] 48.2 Preparation of Compound tert-Butyl 4-(4-((4-chloro-6-ethyl-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (L048-2):

[0629] 2,4-Dichloro-6-ethyl-1,3,5-triazine (534 mg, 3.0 mmol) and tert-butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (932 mg, 3.6 mmol) were weighed separately into a 50 mL eggplant-shaped flask. Dissolved in 30 mL of ethanol, DIEA (1.5 mL, 9.0 mmol) was added, and stirred at 60°C overnight. TLC indicated completion of the reaction and the reaction could be stopped. The reaction solution was concentrated under reduced pressure and extracted with EA / water to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 4:1) to yield 1.4 g of a yellow solid. LC-MS: [M+H] + =401.10.

[0630] 48.3 Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-ethyl-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L048):

[0631] L048-2 (400.87 mg, 1 mmol) and 3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (255.27 mg, 1 mmol) were weighed separately into a 25 mL single-necked flask, dissolved in 5 mL of n-butanol, and then added with DIEA (646.2 mg, 5 mmol). The mixture was stirred at 120°C for 3 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated to obtain a crude product. The crude product was then lyophilized to obtain a white solid product (135 mg, purity 97.309%). LC-MS: [M+H] + =520.20.

[0632] 1 H-NMR (400MHz, DMSO-d) δ12.87(s,1H),9.62(s,1H),8.11(s,1H),7.88(s,1H),7.74(d,J=8.6Hz,1H),7.54(d,J=8.3Hz,1H),6.48(s ,1H),4.86(d,J=11.9Hz,1H),4.56(t,J=11.3Hz,2H),4.04(s,1H),3.77(d,J=9.9Hz,1H),2.64-2.52(m,2H),1.23(t,J=7.6Hz,2H).

[0633] Example 50. Preparation of Compound 1-(6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-methyl-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)azetidine-3-carbonitrile (L050)

[0634]

[0635] 50.1 Preparation of Compound tert-Butyl 4-(4-((4-chloro-6-methyl-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (L050-1)

[0636] 2,4-Dichloro-6-methyl-1,3,5-triazine (150 mg, 0.915 mmol) and tert-butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (237 mg, 0.915 mmol) were weighed separately in a 25 mL single-necked flask. 5 mL of n-butanol was added to dissolve the mixture, followed by DIEA (591 mg, 4.573 mmol). The mixture was stirred at 70°C for 3 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated to yield 350 mg of the crude product as a light yellow solid. LC-MS: [M+H] + =387.10.

[0637] 50.2 Preparation of Compound Ethyl 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-methyl-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L050-2)

[0638] L050-1 (300 mg, 0.776 mmol) and ethyl 1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (162 mg, 0.776 mmol) were weighed separately into a 25 mL single-necked flask. 5 mL of n-butanol was added for dissolution, followed by DIEA (502 mg, 3.88 mmol). The mixture was stirred at 130°C for 6 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated to yield 1.46 g of crude product as a light yellow solid. LC-MS: [M+H] + =459.20.

[0639] 50.3 Preparation of Compound 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-methyl-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L050-3)

[0640] L050-2 (1.36 g, 2.966 mmol), NaOH (356 mg, 8.898 mmol), and MeOH / H₂O (12 ml / 3 ml) were weighed separately into a 50 mL eggplant flask and stirred at 55°C for 12 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H₂O. The organic phase was separated, dried, and concentrated to yield 600 g of crude product as a light yellow solid. LC-MS: [M+H] + =387.15.

[0641] 50.4 Preparation of Compound 1-(6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-methyl-1,3,5-triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)azetidine-3-carbonitrile (L050)

[0642] L050-3 (200 mg, 0.465 mmol), 3-acetonitrile cyclobutylamine hydrochloride (83 mg, 0.697 mmol), and HATU (354 mg, 0.93 mmol) were weighed separately into a 25 mL eggplant flask and dissolved in 3 mL of DCM. DIEA (181 mg, 1.395 mmol) was then added and stirred at room temperature for 12 hours. LCMS indicated the reaction was complete. The reaction solution was extracted twice with DCM / H2O. The organic phase was separated, dried, and concentrated to obtain the crude product. The crude product was then lyophilized to yield a white solid (15.8 mg, 98.055% purity). LC-MS: [M+H] + =495.15.

[0643] 1 H NMR (400MHz, DMSO-d) δ12.81(s,1H),9.63(s,1H),8.01(s,1H),7.72(d,J=8.7Hz,1H),7.54(d,J=8.2Hz,1H),6.39(s,1H),4.8 4(s,1H),4.35(d,J=40.3Hz,2H),4.02(t,J=5.3Hz,1H),3.85-3.78(m,1H),3.75(d,J=10.7Hz,1H),2.57(s,1H),2.27(s,1H).

[0644] Example 51. Preparation of Compound 2-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1,3,5-triazin-2-yl)acetonitrile (L051)

[0645]

[0646] 51.1 Preparation of Compound (6-(4,6-dichloro-1,3,5-triazine-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidine-1-yl)methanone (L051-1):

[0647] Dissolve 2,4,6-trichloro-1,3,5-triazine (184 mg, 1.0 mmol) in 4 mL of acetone, add 248 mg (3.0 mmol) of sodium bicarbonate, and add (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone hydrochloride (292 mg (1.0 mmol)) in portions over ice. After addition, react at room temperature for 3 h. LCMS shows the product as the main peak. The reaction solution is extracted with EA / water, dried, and spun down to give 400 mg of a yellow solid, which is used directly in the next step. LC-MS: [M+H] + =403.05

[0648] 51.2 Preparation of Compound tert-butyl 2-(4-chloro-6-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c)]pyridin-6-yl)-1,3,5-triazin-2-yl)-2-cyanoacetate (L051-2):

[0649] To a 25 mL reaction flask, add L051-1 (320 mg, 0.8 mmol) and 3 mL of tetrahydrofuran and stir at room temperature. To another 25 mL reaction flask, add tert-butyl cyanoacetate (128 mg, 0.88 mmol) and 3 mL of tetrahydrofuran. Add 40 mg of NaH in batches and react at room temperature for 30 minutes. Add the mixture dropwise to the tetrahydrofuran solution of L051-1. After addition, react at room temperature for 4.0 hours. LCMS shows that the reaction is complete. Quench the reaction with ammonium chloride, extract with EA / water system, dry and spin dry to obtain 400 mg of crude product as a yellow solid product, which is directly used in the next step. LC-MS: [M+H] + =508.15.

[0650] 51.3 Preparation of Compound 2-(4-chloro-6-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1,3,5-triazin-2-yl)acetonitrile (L051-3):

[0651] Weigh L051-2 (400 mg, 0.79 mmol) and dissolve it in 4 mL of dichloromethane. Then add 1 mL of trifluoroacetic acid and allow to react at room temperature for 2 hours. LCMS indicates the reaction is complete. Workup: Dilute the reaction with 20 mL of dichloromethane, neutralize with sodium bicarbonate, and extract with a dichloromethane / water system. Dry, concentrate, and purify by column chromatography to obtain 200 mg of a white solid product. LC-MS: [M+H] + =408.10.

[0652] 51.4 Preparation of Compound 2-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1,3,5-triazin-2-yl)acetonitrile (L051):

[0653] L051-3 (180 mg, 0.44 mmol), tert-butyl 4-(4-aminophenyl)-1H-pyrazole-1-carboxylate (148 mg, 0.57 mmol), KF (38 mg, 0.66 mmol), and DIEA (170 mg, 1.32 mmol) were weighed into a reaction flask and dissolved in n-butanol (3 ml). The mixture was reacted at 90°C overnight. LCMS indicated the reaction was complete. After concentration under reduced pressure, the mixture was extracted with EA / water and concentrated to dryness to obtain the crude product. The crude product was lyophilized to obtain a white solid product (68.0 mg, 98.924% purity). LC-MS: [M+H] + =531.25.

[0654] 1 H NMR (400MHz, DMSO-d6) δ12.85(s,1H),9.85(s,1H),7.98(d,J=88.1Hz,2H),7.71(d,J=8.4Hz,2H),7.53(s,2H) ,6.46(d,J=4.1Hz,1H),4.85(d,J=10.2Hz,2H),4.53(s,4H),4.02(s,4H),3.73(d,J=19.2Hz,3H),2.55(s,2H).

[0655] Example 52. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-(oxetane-3-yl)-1,3,5-triazine-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidine-1-yl)methanone (L052)

[0656]

[0657] 52.1 Preparation of Compound 2,4-Dichloro-6-(Oxetane-3-yl)-1,3,5-triazine (L052-1):

[0658] Dissolve 3-bromooxetane (411 mg, 3.0 mmol) in 4 mL of tetrahydrofuran, cool to -78°C using a dry ice / ethyl acetate bath, and add 3.0 mmol of n-butyllithium solution dropwise. Allow to react at low temperature for half an hour.

[0659] In a separate reaction flask, weigh 2,4,6-trichloro-1,3,5-triazine (607 mg, 3.3 mmol), add 6.0 mL of tetrahydrofuran, and cool to -78°C in a dry ice / ethyl acetate bath. Add the above 3-bromooxetane solution dropwise. Allow to react at low temperature for half an hour after addition, then naturally warm to room temperature and stir for 1 hour. LCMS shows approximately 50% product. The reaction solution is quenched with ammonium chloride and extracted with an EA / water system. Dry and spin-dry to obtain 500 mg of a yellow solid, which is used directly in the next step. LC-MS: [M+H] + =206.00.

[0660] 52.2 Preparation of Compound tert-Butyl 4-(4-((4-chloro-6-(oxetane-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (L052-2):

[0661] 2,4-Dichloro-6-(oxetane-3-yl)-1,3,5-triazine (206 mg, 1.0 mmol) and M002 (260 mg, 1.0 mmol) were weighed separately into a 50 mL eggplant-shaped flask, dissolved in ethanol, and then added with DIEA (390 mg, 3.0 mmol). The mixture was stirred at 50°C overnight. LCMS indicated the reaction was complete. The reaction solution was concentrated under reduced pressure and extracted with EA / water to obtain 400 mg of crude product as a yellow solid, which was directly used in the next step. LC-MS: [M+H] + =429.15.

[0662] 52.3 Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6-(oxetane-3-yl)-1,3,5-triazine-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L052):

[0663] tert-Butyl 4-(4-((4-chloro-6-(oxetane-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (400 mg, 0.93 mmol), L006-4 hydrochloride (298 mg, 1.02 mmol), and DIEA (360 mg, 2.79 mmol) were weighed into a reaction flask and dissolved in n-butanol (5 ml). The mixture was reacted at 100°C overnight. LCMS showed that the reaction was complete. After concentration under reduced pressure, the mixture was extracted with EA / water and concentrated to dryness to obtain the crude product. The crude product was lyophilized to obtain a white solid product (68.0 mg, purity 96.727%). LC-MS: [M+H] + =548.20.

[0664] Example 53. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6,7-dihydro-5H-cyclopentadienyl[d]pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L053)

[0665]

[0666] 53.1 Preparation of Compound 2-Chloro-N-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (L053-1):

[0667] 2,4-Dichloro-6,7-dihydro-5H-cyclopentadi[d]pyrimidine (189.04 mg, 1 mmol) and 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)aniline (243.31 mg, 1 mmol) were weighed separately into a 25 mL eggplant-shaped flask. 5 mL of n-butanol was added to dissolve the mixture, followed by DIEA (646.2 mg, 5 mmol). The mixture was stirred at 100°C for 12 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated. After concentration, the mixture was separated by silica gel column chromatography (PE / EA = 4 / 1) to yield 176 mg of a light yellow solid. LC-MS: [M+H] + =396.15.

[0668] Preparation of 53.2 Compound (3,3-difluoroazetidin-1-yl)(1-methyl-6-(4-((4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)amino)-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L053-2):

[0669] L053-1 (150 mg, 0.379 mmol), (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (110 mg, 0.379 mmol), Pd2dba3 (69.4 mg, 0.0758 mmol), xantphos (43.8 mg, 0.0758 mmol), and Cs2CO3 (246 mg, 0.758 mmol) were weighed into a 25 mL single-necked flask. Dissolved in 5 mL of dioxane, the atmosphere was purged with nitrogen three times, and stirred at 100°C for 12 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated. After concentration, the product was separated by silica gel column chromatography (PE / EA = 3 / 1) to yield 100 mg of a pale yellow solid. LC-MS: [M+H] + =615.25.

[0670] 53.3 Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-6,7-dihydro-5H-cyclopentadienyl[d]pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L053):

[0671] L053-2 (100 mg, 0.163 mmol), acidic resin (20 mg), and HCl / Dioxane solution (0.4 ml) were weighed separately into a 25 mL eggplant flask. 3 ml of methanol was added for dissolution and stirred at room temperature for 2 hours. LCMS indicated the reaction was complete. The reaction solution was filtered and concentrated to obtain the crude product, which was then lyophilized to yield a white solid (5 mg, 98.148% purity). LC-MS: [M+H] + =531.20.

[0672] 1 H NMR (400MHz, DMSO-d) δ12.85(s,1H),8.46(s,1H),8.11(s,1H),7.90(s,1H),7.72(d,J=8.7Hz,2H),7.55(d,J=8.6Hz,2H),6.45(s,1H) ,4.76(s,2H),4.55(t,J=11.8Hz,4H),3.94(t,J=5.6Hz,2H),3.75(s,3H),2.75-2.67(m,4H),2.54(d,J=5.5Hz,2H),2.01-1.96(m,2H).

[0673] Example 56. Preparation of Compound 1-(6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)azetidine-3-carbonitrile (L056)

[0674]

[0675] 56.1 Preparation of Compound Ethyl 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (L056-1):

[0676] Weigh 450 mg, 1.154 mmol, of tert-butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate and ethyl 1-methyl-1,4,5,7-tetrahydro-6-(2-pyrrolo[2,3-c]pyridine-2-carboxylate (240 mg, 1.154 mmol) into a 50 mL single-necked flask. Dissolve the mixture in 6 ml of n-butanol, then add DIEA (746 mg, 5.770 mmol) and stir at 140°C for 4 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated. After concentration, the mixture was separated by silica gel column chromatography (PE / EA = 5 / 1) to yield 406 mg of a light yellow solid. LC-MS: [M+H] + =462.15.

[0677] 56.2 Preparation of Compound 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L056-2):

[0678] L056-1 (406 mg, 0.880 mmol), NaOH (352 mg, 8.80 mmol), and MeOH / H₂O (5 ml / 5 ml) were weighed separately in a 50 mL single-necked flask and stirred at 155°C for 12 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H₂O. The organic phase was separated, dried, and concentrated to yield 140 mg of crude product as a light yellow solid. LC-MS: [M+H] + =434.15.

[0679] 56.3 Preparation of Compound 1-(6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)azetidine-3-carbonitrile (L056):

[0680] L056-2 (140 mg, 0.323 mmol), 3-acetonitrile cyclobutylamine hydrochloride (58 mg, 0.484 mmol), and HATU (246 mg, 0.646 mmol) were weighed separately into a 25 mL eggplant flask and dissolved in 3 mL of DCM. DIEA (126 mg, 0.969 mmol) was added and stirred at room temperature for 12 hours. LCMS indicated the reaction was complete. The reaction solution was extracted twice with DCM / H2O. The organic phase was separated, dried, and concentrated to obtain the crude product. The crude product was then lyophilized to yield a white solid (22.4 mg, 99.220% purity). LC-MS: [M+H] + =498.25.

[0681] 1 H NMR(400MHz, DMSO-d)δ12.83(s,1H),9.31(s,1H),8.05(d,J=3.7Hz,1H),7.79-7.72(m,1H),7.61-7.55(m,1H),6.37(s,1H), 4.72 (s, 1H), 4.34 (d, J = 41.2Hz, 2H), 3.91 (t, J = 5.6Hz, 1H), 3.80 (tt, J = 9.2, 6.1Hz, 1H), 3.73 (s, 1H), 2.55 (t, J = 5.3Hz, 1H).

[0682] Example 57. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L057)

[0683]

[0684] 57.1 Preparation of Compound 2-chloro-N-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (L057-1):

[0685] 2,4-Dichloropyrrolo[2,1-f][1,2,4]triazine (400 mg, 2.128 mmol) and 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)aniline (518 mg, 2.128 mmol) were weighed separately into a 50 mL eggplant-shaped flask. 10 mL of n-butanol was added for dissolution, followed by DIEA (1375 mg, 10.64 mmol). The mixture was stirred at 40°C for 12 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated. After concentration, the mixture was separated by silica gel column chromatography (PE / EA = 4 / 1) to yield 579 mg of a light yellow solid. LC-MS: [M+H] + =395.15.

[0686] 57.2 Preparation of Compound (3,3-difluoroazetidin-1-yl)(1-methyl-6-(4-((4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (L057-2):

[0687] L057-1 (360 mg, 0.912 mmol), (3,3-difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (265 mg, 0.912 mmol), Pd2dba3 (168 mg, 0.1824 mmol), dit-Bu-xphos (78 mg, 0.1824 mmol), and t-BuONa (176 mg, 1.824 mmol) were weighed into a 50 mL single-necked flask. Dissolved in 10 mL of dioxane, the atmosphere was purged with nitrogen three times, and stirred at 100°C for 18 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated. After concentration, the product was separated by silica gel column chromatography (PE / EA = 3 / 1) to yield 83.6 mg of a pale yellow solid. LC-MS: [M+H] + =614.25.

[0688] 57.3 Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L057):

[0689] L057-2 (80 mg, 0.130 mmol), acidic resin (100 mg), and HCl / Dioxane solution (0.1 ml) were weighed separately in a 25 mL eggplant flask. 3 ml of methanol was added to dissolve the mixture and stirred at room temperature for 2 hours. LCMS indicated the reaction was complete. The reaction solution was filtered and concentrated to obtain the crude product, which was then lyophilized to yield a white solid (3 mg, 98.796% purity). LC-MS: [M+H] + =530.15.

[0690] 1 H-NMR(400MHz,DMSO-d)δ12.91(s,1H),9.70(s,1H),8.19(s,1H),7.93(s,1H) ,7.82(d,J=8.7Hz,1H),7.65(d,J=8.7Hz,1H),7.49(dd,J=2.3,1.7Hz,1H),7.0 2(dd,J=4.4,1.5Hz,1H),6.51(dd,J=4.4,2.5Hz,1H),6.46(s,1H),4.67(s,1H) ,4.63-4.45(m,2H),3.88(t,J=5.5Hz,1H),3.76(s,1H),2.59(t,J=5.4Hz,1H).

[0691] Example 58. Preparation of Compound (6-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-1,3,4-thiadiazol-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L058)

[0692]

[0693] 58.1 Preparation of Compound 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carbosulfhydrazide (L058-1)

[0694] (3,3-Difluoroazetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (400 mg, 1.568 mmol) and KOH (176 mg, 3.137 mmol) were weighed separately into a 100 mL eggplant-shaped flask and dissolved in ethanol. An ethanolic solution of CS2 (238 mg, 3.137 mmol) was then added dropwise under an ice bath. After completion, the mixture was reacted at below 10°C for 5 hours. A mixed solution of chloroacetic acid (298 mg, 3.137 mmol) and KOH (176 mg, 3.137 mmol) in ethanol was added and allowed to react overnight at room temperature. After the reaction of the starting materials was complete, as monitored by LCMS, hydrazine hydrate (784 mg, 15.683 mmol) was added to the reaction mixture and allowed to react at 65°C for 4 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate (50 mL x 3). The organic phase was collected to obtain a crude product, which was then separated by silica gel column chromatography (DCM / MeOH = 50:1-20:1) to obtain 350 mg of an off-white solid product. LC-MS: [M+H] + =330.05.

[0695] 58.2 Preparation of Compound tert-Butyl 4-(4-(2-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-6-carbonylsulfonyl)hydrazine-1-carbonylsulfonylamino)phenyl)-1H-pyrazole-1-carboxylate (L058-2)

[0696] L058-1 (330 mg, 1.001 mmol) was weighed into a 100 mL eggplant-shaped flask, DIEA (258 mg, 2.002 mmol) was added, and the mixture was dissolved in dichloromethane (10 mL). The mixture was stirred at room temperature for 10 minutes. A dichloromethane solution of L046-1 (241 mg, 0.801 mmol) was added dropwise. After completion of the addition, the mixture was allowed to react at room temperature overnight. LCMS indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to yield the crude product, which was then separated by silica gel column chromatography (DCM:MeOH = 20:1) to afford 150 mg of a yellow solid. LC-MS: [M+H] + =631.15.

[0697] 58.3 Preparation of Compound tert-Butyl 4-(4-((5-(2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1,3,4-thiadiazol-2-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (L058-3)

[0698] L058-2 (100 mg, 0.156 mmol) was weighed into a 50 mL eggplant-shaped flask, EDCI (303 mg, 1.561 mmol) was added, and NMP (10 mL) was added for dissolution. The mixture was stirred at 50°C for 5 hours. LCMS indicated the reaction was complete. The mixture was diluted with water and extracted with EA (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (DCM:MeOH = 50:1-20:1) to obtain 80 mg of the product as a yellow oil. LC-MS: [M+H] + =597.20.

[0699] 58.4 Preparation of Compound (6-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-1,3,4-thiadiazol-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L058)

[0700] L058-3 (80 mg, 0.134 mmol) was weighed into a 25 mL eggplant-shaped flask and dissolved in DCM (6 mL). Trifluoroacetic acid (2 mL) was added and the mixture was allowed to react at room temperature for 1 h. LCMS indicated the reaction was complete. The solvent was concentrated under reduced pressure, and the residue was diluted with water. The pH was adjusted to 9 with saturated NaHCO₃. The mixture was extracted with EA (20 mL x 3). The organic phase was collected to obtain the crude product, which was separated by prep-HPLC and lyophilized to yield a white solid (11.0 mg, 98.435% purity). LC-MS: [M+H] + =497.10.

[0701] 1 H NMR(400MHz,DMSO-d)δ12.83(s,1H),9.81(s,1H),8.08(s,1H),7.84(s,1H),7.50(td,J=8.9,2.2Hz,2H) ,6.48(s,1H),4.54(d,J=13.2Hz,2H),3.73(s,1H),3.61(t,J=5.7Hz,1H),2.65(dt,J=11.1,3.7Hz,1H).

[0702] Example 59. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-3-chloro-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoropyrrolidin-1-yl)methanone (L059)

[0703]

[0704] 59.1 Preparation of Compound 3-chloro-2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (L059-1):

[0705] tert-Butyl 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-4,5-dihydro-1H-pyrrolo[2,3-c]pyridine-6(7H)-carboxylate (810 mg, 2.279 mmol) and NCS (304 mg, 2.279 mmol) were weighed separately in a 50 mL single-necked flask. 10 mL of MeCN was added and stirred at room temperature for 2 hours. LCMS indicated completion of the reaction, with a product yield of 20%. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated. After concentration, the mixture was separated by silica gel column chromatography (PE / EA = 4 / 1) to yield 200 mg of a light yellow solid. LC-MS: [M+H] + =390.10.

[0706] Preparation of 59.2 Compound (3-chloro-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoroazetidine-1-yl)methanone (L059-2):

[0707] L059-1 (200 mg, 0.513 mmol), HCl / dioxane solution (5 ml), and DCM (2 ml) were weighed separately in a 50 mL single-necked flask and stirred at room temperature for 2 hours. LCMS indicated the reaction was complete, with a product content of 20%. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated to yield 177.6 mg of crude product as a light yellow solid. LC-MS: [M+H] + =290.05.

[0708] 59.3 Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-3-chloro-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3,3-difluoropyrrolidin-1-yl)methanone (L059):

[0709] L059-2 (145 mg, 0.445 mmol) and tert-butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (174 mg, 0.445 mmol) were weighed separately into a 25 mL eggplant-shaped flask. 3 mL of n-butanol was added for dissolution, followed by DIEA (288 mg, 2.225 mmol). The mixture was stirred at 120°C for 2 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and extracted twice with EA / H2O. The organic phase was separated, dried, and concentrated to obtain the crude product. The crude product was then lyophilized to obtain a white solid (33 mg, 97.663% purity). LC-MS: [M+H] + =543.15.

[0710] 1 H NMR (400MHz, DMSO-d) δ12.89(s,1H),9.34(s,1H),8.15(s,1H),8.06(d,J=3.7Hz,1H),7.90(s,1H),7.77-7.72(m,1H ),7.62-7.57(m,1H),4.74(s,1H),4.52(t,J=11.9Hz,2H),3.93(t,J=5.6Hz,1H),3.59(s,2H),2.52(d,J=1.9Hz,1H).

[0711] Example 60. Preparation of Compound (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)(3-(difluoromethyl)azetidin-1-yl)methanone (L060)

[0712]

[0713] (3-(Difluoromethyl)azetidin-1-yl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (55 mg, 0.20 mmol) was dissolved in n-butanol (2 mL), and N,N-diisopropylethylamine (77 mg, 0.60 mmol) and tert-butyl 4-(4-((2-chloropyrimidin-4-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (89 mg, 0.24 mmol) were added. The mixture was heated to 120°C under nitrogen protection for 4 hours. After completion of the reaction, water (5 mL) was added for dilution, and the mixture was extracted with ethyl acetate (5 mL*2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified to give 44.5 mg of a white solid, with a two-step yield of 36%. LC-MS [M+H] + :504.9.

[0714] 1 H NMR (400MHz, DMSO) δ12.84(s,1H),9.31(s,1H),8.01(s,2H),7.96(d,J=5.7Hz,1H),7.6 5(d,J=8.7Hz,2H),7.56(d,J=8.7Hz,2H),6.48(d,J=4.3Hz,0.25H),6.38(s,1H),6.34(d ,J=4.3Hz,0.5H),6.20(d,J=4.4Hz,0.25H),6.07(d,J=5.7Hz,1H),4.79(s,2H),4.65-4. 05(m,4H),3.98(t,J=5.5Hz,2H),3.76(s,3H),3.19-3.09(m,1H),2.55(t,J=6.6Hz,2H).

[0715] Compound L029 was prepared by referring to the method described in Example 28 above.

[0716] Compound L033 was prepared by referring to the method described in Example 39 above.

[0717] Compound L042 was prepared by referring to the method described in Example 41 above.

[0718] Compound L044 was prepared by referring to the method described in Example 36 above.

[0719] Compound L049 was prepared by referring to the method described in Example 48 above.

[0720] Compound L054 was prepared by referring to the method described in Example 53 above.

[0721] Compound L055 was prepared by referring to the method described in Example 11 above.

[0722] With reference to the corresponding synthesis methods of the above examples, the characterization data of the synthesized compounds are shown in the following table:

[0723] Compound number <![CDATA[LC-MS:[M+H] + ]]> L029 488.0 L033 522.5 L042 516.1 L044 506.2 L049 534.2 L054 523.2 L055 472.8

[0724] <Biological Activity Test>

[0725] In some embodiments, experiments conducted using conventional methods in the art have revealed that the compounds of the present invention inhibit kinases in vitro and / or in vivo, particularly ROCK1 and / or ROCK2 kinases. Furthermore, the compounds of the present invention have been found to exhibit low cytotoxicity and good pharmacokinetic properties. Experiments have also demonstrated that the compounds of the present invention possess suitable metabolic stability and have promising prospects for drug development.

[0726] 1. In vitro evaluation of ROCK2 kinase activity

[0727] ROCK2 activity screening. ROCK2 activity was measured using a 96-well (Cisbio) time-resolved fluorescence assay. The ROCK2 assay was run in the following assay buffer: 5 mM MgCl2 (Sigma), 1 mM DTT (Sigma), and 1X kinase buffer. Using kinase buffer, 7.5 μL of ROCK2 kinase (Invitrogen, PV3759) was added to a 96-well microplate to a final concentration of 0.4 ng / μL. Then, 0.25 μL of the test compound was added in 1% DMSO (volume fraction) and incubated at room temperature for 0.5 h. To initiate the reaction, ATP (Aladdin) and the substrate STK-substrate 2-biotin were mixed in kinase buffer. 7.5 μL of this mixture was added to the microplate to a final concentration of 6.739 μM and 1 μM, respectively. The reaction was incubated at room temperature for 2 h. 5 mL of detection buffer was mixed with STK Antibody-Cryptate, and then an appropriate volume was mixed with an equal volume of Streptavidin-XL665. 10 μL of this mixture was added to the microplate to terminate the reaction. After incubation for approximately 1 hour, the plate was read on a Molecular Devices Spectra Maxi3x multi-function microplate reader. Kinase buffer, STK-Substrate 2-Biotin, detection buffer, STK Antibody-Cryptate, and Streptavidin-XL665 were all from the HTRF KinEASE-STK kit (Cisbio, 1000 tests, 61GSTXLA).

[0728] 2. In vitro evaluation of ROCK1 kinase selectivity

[0729] ROCK1 activity was measured using a 96-well (Cisbio) time-resolved fluorescence assay. The ROCK1 assay was run in the following assay buffer: 5 mM MgCl2 (Sigma), 1 mM DTT (Sigma), and 1X kinase buffer. 7.5 μL of ROCK1 kinase (Invitrogen) diluted in kinase buffer was added to a 96-well microplate to a final concentration of 0.4 ng / μL. Then, 0.25 μL of the test compound was added in 1% DMSO and incubated at room temperature for 0.5 h. To initiate the reaction, ATP (Aladdin) and the substrate STK-substrate 2-biotin were mixed in kinase buffer, and 7.5 μL of this mixture was added to the microplate to final concentrations of 3.53 μM and 1 μM, respectively. The reaction was incubated at room temperature for another 2 h. 5 mL of assay buffer was mixed with STK antibody-Cryptate, and an appropriate volume was then mixed with an equal volume of streptavidin-XL665. The reaction was terminated by adding 10 μL of this mixture. After incubation for approximately 1 hour, the plate was read on a Molecular Devices SpectraMax i3x multi-function microplate reader. Kinase buffer, STK-substrate 2-biotin, detection buffer, STK antibody-Cryptate, and streptavidin-XL665 were all from the HTRF KinEASE-STK kit (Cisbio, 1000 tests, 61GSTXLA).

[0730] Example 61

[0731] The above-mentioned in vitro kinase activity evaluation experiment was carried out on the compounds of the present invention to determine the inhibitory activity of each compound on ROCK1 / 2. It was found that the compounds of the present invention all had good activity. Some compounds had IC values ​​of 100 for the two kinases. 50 Below 10 μM, some compounds had IC values ​​for both kinases. 50 ≤50nM (activity level A), IC of some compounds for both kinases 50 >50 nM and ≤500 nM (activity level B), IC of some compounds for both kinases 50 >500 nM and ≤4.5 μM (activity level C), IC of some compounds for both kinases 50 >4.5 μM (activity level D).

[0732] Among them, the representative compound IC 50 The values ​​are reported in Table 1 below: Note: (A: ≤50 nM; B: >50 nM and ≤500 nM; C: >500 nM and ≤4.5 μM; D: >4.5 μM; ND: not detected)

[0733] Table 1: Inhibition of ROCK1 and ROCK2 by the compounds of the present invention

[0734]

[0735]

[0736] Example 62 In vitro cytotoxicity test of the compounds of the present invention

[0737] The in vitro cytotoxicity test of the compounds of the present invention was determined in HepG2 cells using the CCK-8 method. HepG2 cells in the logarithmic phase were collected (Beina Biotech), the cell suspension concentration was adjusted, and 50,000 cells / well were plated in a 96-well cell culture plate. The cells were placed in a 5% cell culture incubator at 37°C and incubated overnight. After the cell fusion in the plate reached 80-90%, the solution was changed and the test compound or solvent (DMSO) of each concentration gradient was added. The cells were incubated in a 5% cell culture incubator at 37°C for 48 hours. After the treatment, the culture medium in the plate was discarded, the plate was washed twice with PBS, 100 μL of CCK-8 working solution (Biyuntian Biotechnology) was added to each well, and the plate was incubated in the dark at 37°C for 1.5 hours. The OD was detected on an enzyme reader. 450nm The absorbance value of each well was measured and the CC of each compound was analyzed and calculated. 50 .

[0738] The above experiments were conducted on the example compounds of the present invention, and the results showed that the compounds of the present invention have good safety. 50 The range is >10μM, some preferred compounds CC 50 >30μM, more preferably CC 50 >50μM. CC of representative compounds 50 Shown in Table 2 below.

[0739] Table 2. CC obtained for each compound 50

[0740] Compound <![CDATA[HepG2 CC 50 (μM)]]> L005 >100 L017 33.38 L026 >100 L027 >100 L030 >100 L031 33.38 L032 28.43 L033 >100 L036 >100 L037 >100 L042 27.95 L043 >100 L044 58.12 L045 >100 L047 >100 L048 100.3 L050 >100 L051 >100 L056 >100 L057 >100 L060 >100

[0741] Example 63 In vitro metabolic stability test of the compounds of the present invention

[0742] The in vitro metabolic stability of the compounds of the present invention is determined using various liver microsome incubation methods. An appropriate amount of the test compound is added to the liver microsome reaction system (1 mg / mL liver microsomal protein, 25 U / mL 6-phosphate glucose dehydrogenase, 1 mM NADP, 6 mM D-6-phosphate glucose, 5 mM MgCl2), and the reaction is started by incubating in a 37°C water bath. At each time point, 100 μL of the reaction solution is added to a centrifuge tube containing 400 μL of a 0°C pre-cooled internal standard working solution (an acetonitrile solution containing 200 ng / mL dexamethasone, diclofenac, tolbutamide, and labetalol), the reaction is terminated, and the mixture is centrifuged at 10,000 g for 10 minutes at 4°C. The supernatant is then analyzed and detected by LC-MS to obtain the in vitro metabolic half-life of the test compound in various liver microsomes. The T values ​​obtained using the above method are as follows: 1 / 2 Shown in Table 3.

[0743] Table 3. Metabolic half-life of each compound in liver microsomal protein

[0744]

[0745] The above experiments were conducted on the example compounds of the present invention, and it was found that the compounds of the present invention have good metabolic stability in humans, rats, and mice, preferably in human liver microsomes. 1 / 2 >30 min, more preferably in human liver microsomes T 1 / 2 The inventors also conducted a comparative experiment on the ROCK inhibitor KD-025, which has entered the clinical stage, and found that the preferred compound of the present invention has better in vitro stability than KD-025.

[0746] Example 29 Pharmacokinetic study of the compound of the present invention in mice

[0747] SPF mice (Beijing Sibeifu Biotechnology Co., Ltd.) were acclimated and fasted overnight (without water deprivation) before being administered 3 mg / kg of the compounds of this invention by oral gavage and tail vein bolus injection, respectively. Plasma was collected at specific time points after administration, and compound concentrations in plasma were determined by LC-MS / MS (AB SCIEX Qtrap4500). PK parameters for each compound were statistically analyzed and calculated (WinNonlin V5.2, Pharsight) to demonstrate the pharmacokinetic properties of the compounds of this invention in mice.

[0748] The above experiments conducted on the compounds of the present invention demonstrate that the compounds exhibit favorable pharmacokinetic properties in mice, achieving high in vivo exposure and oral bioavailability at relatively low doses. Some compounds exhibited oral bioavailability exceeding 30%, and some exhibited oral bioavailability exceeding 50%. Table 4 below presents experimental data for representative compounds.

[0749] Table 4: PK test of the compounds of the present invention on mice

[0750]

[0751] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0752] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound represented by the following formula (II), its tautomer or pharmaceutically acceptable salt: in, The formula (II) is selected from the following structures:

2. An intermediate for preparing the compound of formula (II) according to claim 1, characterized in that: The intermediate is selected from the following structures: Each group thereof is as defined in claim 1.

3. The intermediate according to claim 2, characterized in that The intermediate is selected from the following structures:

4. Use of at least one of the compound represented by formula (II) according to claim 1, its tautomers or pharmaceutically acceptable salts in the preparation of a medicament for preventing or treating diseases caused by overexpression of one or more ROCKs or overactivation of ROCKs.

5. The use according to claim 4, characterized in that The diseases are: cardiovascular and cerebrovascular diseases, nervous system diseases, fibrotic diseases, eye diseases, tumors, radiation damage, respiratory diseases or autoimmune diseases.

6. The use according to claim 4, characterized in that The diseases are: peripheral or central neuronal degeneration, idiopathic pulmonary fibrosis.

7. The use according to claim 4, characterized in that The diseases are: arterial thrombosis, atherosclerosis, acute coronary syndrome, hypertension, cerebral vasospasm, cerebral ischemia, restenosis, heart failure, myocardial hypertrophy, myocardial ischemia-reperfusion injury, diabetes, diabetic nephropathy, cancer, neurological damage, spinal cord injury, erectile dysfunction, platelet aggregation, leukocyte aggregation, glaucoma, ocular hypertension, asthma, osteoporosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, COPD, glomerulosclerosis and neuronal degeneration and inflammation.

8. The use according to claim 4, characterized in that The diseases are: heart disease and ischemic stroke.

9. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound of formula (II) according to claim 1, its tautomers or pharmaceutically acceptable salts.

10. The pharmaceutical composition according to claim 9, characterized in that The pharmaceutical composition comprises a pharmaceutically acceptable carrier and an excipient.

11. The pharmaceutical composition according to claim 9, characterized in that The pharmaceutical composition comprises pharmaceutically acceptable excipients, which are selected from at least one of the following: a disintegrant, a lubricant, a filler, a binder, and a colorant.

12. The pharmaceutical composition according to claim 9, characterized in that The pharmaceutical composition comprises pharmaceutically acceptable excipients, wherein the excipients are selected from at least one of the following: a glidant and a diluent.

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