Disubstituted pyrimidopyrrole analog and use thereof

Abstract

Disclosed are a disubstituted pyrimidopyrrole analog and the use thereof.

Description

Bisubstituted pyrimidine-pyrrole analogs and their applications

[0001] field

[0002] This disclosure generally relates to the field of medicinal chemistry, and more specifically, to bisubstituted pyrimidine-pyrrole analogs.

[0003] background

[0004] Currently, the incidence of cancer is increasing, with approximately 4.2 million people dying from cancer globally each year. In 2012, China accounted for nearly half of all cancer cases worldwide, ranking first. Cancer treatments mainly include cytotoxic drugs and molecularly targeted drugs. Cytotoxic drugs, also known as traditional chemotherapy drugs, primarily inhibit tumor growth by killing rapidly dividing tumor cells. However, cytotoxic drugs can also harm normally rapidly dividing cells, such as those in the bone marrow, gastrointestinal tract, and hair follicles, leading to common chemotherapy side effects such as bone marrow suppression, mucositis, and hair loss. Targeted therapy works by interfering with specific protein targets that affect tumor cell proliferation. An excellent protein or enzyme target has tumor cell-specific mutations or other genetic alterations that are absent in normal tissue cells, thus achieving specific cell selectivity. However, targeted drugs often fail in clinical trials due to limitations such as drug resistance and target-molecule-related toxicities, despite showing good efficacy in animal models. Combining targeted inhibitors with cytotoxic drugs can enhance efficacy through two different mechanisms of action, thereby allowing for a better efficacy / toxicity window by reducing the dosage.

[0005] Anaplastic lymphoma kinase (ALK) is a transmembrane protein tyrosine kinase belonging to the insulin receptor kinase subfamily. It was first discovered in anaplastic large cell lymphoma (ALCL) with a nucleophosphorus protein (NPM)-ALK fusion form, a T-cell non-Hodgkin lymphoma, often associated with chromosomal translocations. Since then, many cancers have been found to be associated with different forms of ALK fusions. These include non-small cell lung cancer (NSCLC, EML4-ALK), inflammatory myofibroblastic tumor (IMT, TPM3-ALK), and diffuse large B-cell lymphoma (DLBCL, CLTC-ALK). Furthermore, ALK gene amplification and mutations in wild-type ALK protein have been reported in various tumors.

[0006] Leukocyte receptor tyrosine kinase (LTK) and ALK belong to the same insulin receptor kinase subfamily and share high sequence homology, with kinase region identity reaching 79%. CLIP1, a member of the microtubule terminal tracer protein family, is fused with LTK to form CLIP1-LTK, a novel oncogenic driver in non-small cell lung cancer (NSCLC).

[0007] Overview

[0008] On the one hand, this disclosure relates to compounds represented by general formula (I) and pharmaceutically acceptable salts thereof:

[0009] in:

[0010] R1 is selected from any substituted aryl group or any substituted heteroaryl group;

[0011] X is selected from O, S, or NR3;

[0012] R2 is selected from any substituted hydrocarbon group, any substituted cyclic hydrocarbon group, any substituted heterocyclic hydrocarbon group, any substituted aryl group, or any substituted heteroaryl group; and

[0013] R3 is selected from hydrogen, any substituted hydrocarbon group, any substituted cyclic hydrocarbon group, any substituted heterocyclic hydrocarbon group, any substituted aryl group, or any substituted heteroaryl group.

[0014] On the other hand, this disclosure relates to compounds represented by general formula (II) and pharmaceutically acceptable salts thereof:

[0015] in:

[0016] R 11 Selected from any substituted aryl group or any substituted heteroaryl group;

[0017] A is selected from any substituted heterocyclic hydrocarbon group or any substituted heteroaryl group;

[0018] Y is HN- or does not exist;

[0019] R 22 Selected from hydrogen, any substituted hydrocarbon group, any substituted aryl group, or any substituted heteroaryl group; and

[0020] R 33 Selected from hydrogen, any substituted hydrocarbon group, any substituted aryl group, or any substituted heteroaryl group;

[0021] The premise is that the compound represented by general formula (II) is not (3S)-1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide and (3S)-1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide].

[0022] Furthermore, this disclosure relates to compounds and pharmaceutically acceptable salts thereof, wherein said compounds are selected from:

[0023] On the other hand, this disclosure relates to pharmaceutical compositions comprising the disclosed compounds or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0024] Furthermore, this disclosure relates to a method for preparing compounds of general formula (Ib):

[0025] It includes the following reactions:

[0026] in:

[0027] R1 is selected from any substituted aryl group or any substituted heteroaryl group;

[0028] B is selected from boric acid, borate ester, or halogen.

[0029] On the other hand, this disclosure relates to a method for preparing compounds of general formula (Ia),

[0030] It includes the following reactions:

[0031] in:

[0032] R1 is selected from any substituted aryl group or any substituted heteroaryl group;

[0033] X is selected from O, S, or NR3;

[0034] R2 is selected from any substituted hydrocarbon group, any substituted monocyclic aryl group, or any substituted heteroaryl group;

[0035] R3 is selected from hydrogen, any substituted hydrocarbon group, any substituted monocyclic aryl group, or any substituted heteroaryl group;

[0036] Alternatively, when X is NR3, R2, R3, and the N attached to them form any substituted heterocyclic hydrocarbon groups.

[0037] In another aspect, this disclosure relates to a method of inhibiting tyrosine kinase (TK), comprising contacting the tyrosine kinase (TK) with an inhibitory amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0038] In another aspect, this disclosure relates to methods for treating or preventing tyrosine kinase (TK)-mediated diseases or disease states, comprising administering to an individual in need of the method a therapeutically or preventively effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0039] On the other hand, this disclosure relates to the compounds of this disclosure and pharmaceutically acceptable salts thereof for inhibiting tyrosine kinase (TK).

[0040] In another aspect, this disclosure relates to compounds of the disclosure and pharmaceutically acceptable salts thereof for the treatment or prevention of tyrosine kinase (TK)-mediated diseases or disease states.

[0041] In another aspect, this disclosure relates to the use of the compounds of this disclosure and pharmaceutically acceptable salts thereof in the preparation of medicaments for inhibiting tyrosine kinase (TK).

[0042] On the other hand, this disclosure relates to the use of the compounds of this disclosure and pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of tyrosine kinase (TK)-mediated diseases or disease states.

[0043] Detailed Explanation

[0044] The following description includes certain specific details to provide a comprehensive understanding of the various disclosed embodiments. However, those skilled in the art will recognize that embodiments can be implemented without employing one or more of these specific details, but using other methods, components, materials, etc.

[0045] Unless otherwise required in this disclosure, throughout the specification and the claims, the words “comprising” and “including” shall be interpreted in an open-ended, inclusive sense, meaning “including but not limited to”.

[0046] Throughout this specification, the terms "an embodiment," "another embodiment," "an embodiment," or "certain embodiments" refer to including, in at least one embodiment, a specific reference element, structure, or feature related to that embodiment. Therefore, the phrases "an embodiment," "an embodiment," or "another embodiment" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in one or more embodiments in any suitable manner.

[0047] It should be understood that the singular article “a” (corresponding to the English words “a,” “an,” and “the”) used in this disclosure and the appended claims includes plural objects unless otherwise expressly stated herein. Thus, a pharmaceutical composition, for example, comprising “a compound of formula (I) or a pharmaceutically acceptable salt thereof”, includes one compound of formula (I) or a pharmaceutically acceptable salt thereof, or two or more compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0048] definition

[0049] Therefore, unless otherwise stated, the following terms used in the specification and appended claims shall have the following meanings:

[0050] The abbreviations preceding certain chemical groups in this disclosure indicate the total number of carbon atoms present in the indicated chemical group. For example, C1-C4 alkyl describes alkyl groups having a total of 1 to 4 carbon atoms as defined below, while C3-C... 10 Cycloalkyl groups are described below as having a total of 3 to 10 carbon atoms. The total number of carbons in the abbreviated symbols does not include carbons that may be present in substituents of the group.

[0051] In this disclosure, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0052] In this disclosure, the term "hydroxyl group" refers to the -OH group.

[0053] In this disclosure, the term "amino" refers to the -NH2 group.

[0054] In this disclosure, the term "cyano" refers to the -CN group.

[0055] In this disclosure, the term "hydrocarbon" refers to an aliphatic hydrocarbon group. The hydrocarbon moiety can be a "saturated hydrocarbon" group, meaning it does not contain any alkene or alkyne moiety. The hydrocarbon moiety can also be an "unsaturated hydrocarbon" moiety, meaning it contains at least one alkene or alkyne moiety. An "alkene" moiety refers to a straight-chain or branched hydrocarbon chain group consisting of two to eight carbon atoms and at least one carbon-carbon double bond, connected to the rest of the molecule by single bonds, such as vinyl, propenyl, butenyl, pentenyl, pent-1,4-dienyl, etc., and an "alkene" moiety refers to a straight-chain or branched hydrocarbon chain group consisting of two to eight carbon atoms and at least one carbon-carbon triple bond, connected to the rest of the molecule by single bonds. The hydrocarbon moiety, whether saturated or unsaturated, can be branched or straight-chain.

[0056] The hydrocarbon group may have 1 to 8 carbon atoms (whenever it appears in this disclosure, a numerical range such as “1 to 8” refers to every integer in the given range; such “1 to 8” means that the hydrocarbon group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc. up to and including 8 carbon atoms, although this definition also covers the occurrence of the term “hydrocarbon” where no numerical range is specified).

[0057] The hydrocarbon group can be substituted in any way, that is, substituted or unsubstituted. When substituted, the substituent is selected individually and independently from one or more of the following groups: cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfinylamide, N-sulfinylamide, C-carboxyl, O-carboxyl, isocyanato, cyanothio, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbon groups as defined in this disclosure) or amino groups including mono- and di-substituted amino groups, and their protected derivatives. Typically, hydrocarbon groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, ethynyl, propynyl, and butynyl. Whenever a substituent is described as "arbitrarily substituted," the substituent can be replaced by one of the substituents listed above.

[0058] In some embodiments, "C1-C4 hydrocarbon group" refers to a hydrocarbon group as defined above that contains one to four carbon atoms. The C1-C4 hydrocarbon group can be arbitrarily substituted as defined for hydrocarbon groups.

[0059] In some embodiments, "C1-C4 hydrocarbon group" can be a C1-C4 alkyl group. The C1-C4 alkyl group can be arbitrarily substituted as defined for the hydrocarbon group.

[0060] In some implementations, "C1-C6 hydrocarbon group" refers to a hydrocarbon group as defined above that contains one to six carbon atoms. The C1-C6 hydrocarbon group can be arbitrarily substituted as defined for hydrocarbon groups.

[0061] In some embodiments, "C1-C6 hydrocarbon group" can be a C1-C6 alkyl group. The C1-C6 alkyl group can be arbitrarily substituted as defined for the hydrocarbon group.

[0062] In some implementations, “C1-C” 12 "Hydrocarbon group" refers to a hydrocarbon group containing one to twelve carbon atoms as defined above. C1-C 12 Hydrocarbon groups can be arbitrarily substituted as defined for hydrocarbon groups.

[0063] In some implementations, “C1-C” 12 "Hydrocarbon group" can be C1-C 12 Alkyl groups. C1-C 12 Alkyl groups can be arbitrarily substituted as defined for hydrocarbon groups.

[0064] In some implementations, "C2-C6 hydrocarbon group" refers to a hydrocarbon group as defined above that contains two to six carbon atoms. The C2-C6 hydrocarbon group can be arbitrarily substituted as defined for hydrocarbon groups.

[0065] In some embodiments, "C2-C6 hydrocarbon group" can be a C2-C6 alkyl group. The C2-C6 alkyl group can be arbitrarily substituted as defined for hydrocarbon groups.

[0066] In some embodiments, "C2-C6 hydrocarbon group" can be a C2-C6 alkenyl group. The C2-C6 alkenyl group can be arbitrarily substituted as defined for hydrocarbon groups.

[0067] In some embodiments, "C2-C6 hydrocarbon group" can be a C2-C6 alkynyl group. The C2-C6 alkynyl group can be arbitrarily substituted as defined for hydrocarbon groups.

[0068] In some implementations, "C3-C6 hydrocarbon group" refers to a hydrocarbon group as defined above that contains three to six carbon atoms. The C3-C6 hydrocarbon group can be arbitrarily substituted as defined for hydrocarbon groups.

[0069] In some embodiments, "C3-C6 hydrocarbon group" can be a C3-C6 alkyl group. The C3-C6 alkyl group can be arbitrarily substituted as defined for hydrocarbon groups.

[0070] In some embodiments, "C3-C6 hydrocarbon group" can be a C3-C6 alkenyl group. The C3-C6 alkenyl group can be arbitrarily substituted as defined for hydrocarbon groups.

[0071] In some embodiments, "C3-C6 hydrocarbon group" can be a C3-C6 alkynyl group. The C3-C6 alkynyl group can be arbitrarily substituted as defined for hydrocarbon groups.

[0072] In some implementations, “C3-C” 12 "Hydrocarbon group" refers to a hydrocarbon group containing three to twelve carbon atoms as defined above. (C3-C) 12 Hydrocarbon groups can be arbitrarily substituted as defined for hydrocarbon groups.

[0073] In some implementations, “C3-C” 12 "Hydrocarbon group" can be C3-C 12 Alkyl group. C3-C 12 Alkyl groups can be arbitrarily substituted as defined for hydrocarbon groups.

[0074] In some implementations, “C3-C” 12 "Hydrocarbon group" can be C3-C 12 Alkenyl group. C3-C 12 Alkenyl groups can be arbitrarily substituted as defined for hydrocarbon groups.

[0075] In some implementations, “C3-C” 12 "Hydrocarbon group" can be C3-C 12 alkynyl group. C3-C 12 The alkynyl group can be arbitrarily substituted as defined for the hydrocarbon group.

[0076] In some implementations, “C6-C” 12 "Hydrocarbon group" refers to a hydrocarbon group as defined above, containing six to twelve carbon atoms. (C6-C) 12 Hydrocarbon groups can be arbitrarily substituted as defined for hydrocarbon groups.

[0077] In some implementations, “C6-C” 12 "Hydrocarbon group" can be C6-C 12 Alkyl group. C6-C 12 Alkyl groups can be arbitrarily substituted as defined for hydrocarbon groups.

[0078] In some implementations, “C6-C”12 "Hydrocarbon group" can be C6-C 12 Alkenyl group. C6-C 12 Alkenyl groups can be arbitrarily substituted as defined for hydrocarbon groups.

[0079] In some implementations, “C6-C” 12 "Hydrocarbon group" can be C6-C 12 alkynyl group. C6-C 12 The alkynyl group can be arbitrarily substituted as defined for the hydrocarbon group.

[0080] In some implementations, “C7-C” 12 "Hydrocarbon group" refers to a hydrocarbon group containing seven to twelve carbon atoms as defined above. (C7-C) 12 Hydrocarbon groups can be arbitrarily substituted as defined for hydrocarbon groups.

[0081] In some implementations, “C7-C” 12 "Hydrocarbon group" can be C7-C 12 Alkyl group. C7-C 12 Alkyl groups can be arbitrarily substituted as defined for hydrocarbon groups.

[0082] In some implementations, “C7-C” 12 "Hydrocarbon group" can be C7-C 12 Alkenyl group. C7-C 12 Alkenyl groups can be arbitrarily substituted as defined for hydrocarbon groups.

[0083] In some implementations, “C7-C” 12 "Hydrocarbon group" can be C7-C 12 alkynyl group. C7-C 12 The alkynyl group can be arbitrarily substituted as defined for the hydrocarbon group.

[0084] In this disclosure, the term "alkyloxy group" refers to the general formula -O-alkyl group, wherein the alkyl group is as defined in this disclosure. Exemplary examples of alkyloxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and tert-pentoxy.

[0085] In this disclosure, the term "aryl" refers to a carbon ring (all-carbon) or two or more fused rings (rings sharing two adjacent carbon atoms) having a fully delocalized Pi electron system. Aryl groups include, but are not limited to, fluorenyl, phenyl, and naphthyl. Aryl groups may, for example, have five to twelve carbon atoms. The aryl groups of this disclosure may be substituted or unsubstituted. When substituted, the hydrogen atom is replaced by one or more groups independently selected from the following substituents: alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, protected hydroxyl, alkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfinylamide, N-sulfinylamide, C-carboxyl, protected C-carboxyl, O-carboxyl, isocyanate, cyanothio, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are alkyl groups as defined in this disclosure), or protected amino. Whenever a substituent is described as "arbitrarily substituted," the substituent may be replaced by one of the above substituents.

[0086] In this disclosure, the term "heteroaryl" refers to a 5- to 18-membered aromatic cyclic group consisting of one to seventeen carbon atoms and one to ten heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Exemplary examples of heteroaryl groups include, but are not limited to, azirzolyl, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxazolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazolyl, 1,4-benzodioxane, benzonaphthuronyl, benzooxazolyl, benzodioxazolyl, benzodioxazolyl, benzodioxazolyl, benzodioxazolyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiophene, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenylyl, dibenzofuranyl, dibenzo[b][1,4]dioxazolyl, ... The heteroaryl groups disclosed herein may be substituted or unsubstituted. These heteroaryl groups include thiophene, furanyl, furanone, isothiazolyl, imidazolyl, indazole, indolyl, indazole, isoindolyl, indololinyl, isoquinolinyl, indolazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxozadiazolyl, oxazolyl, epoxyethyl, 1-phenyl-1H-pyrroleyl, phenanthazinyl, phenanthrethiazinyl, phenanthroxazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroleyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiopheneyl. When substituted, the hydrogen atom is replaced by one or more groups independently selected from the following substituents: alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, protected hydroxyl, alkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfinylamide, N-sulfinylamide, C-carboxyl, protected C-carboxyl, O-carboxyl, isocyanate, cyanothio, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are alkyl groups as defined in this disclosure), or protected amino. Whenever a substituent is described as "arbitrarily substituted," the substituent may be replaced by one of the above substituents.

[0087] In this disclosure, the term "cycloalkyl group" refers to a stable non-aromatic monocyclic or bicyclic hydrocarbon group consisting only of carbon and hydrogen atoms, having three to fifteen carbon atoms (in some embodiments, three to twelve carbon atoms), and being saturated or unsaturated, and connected to the rest of the molecule by single bonds, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodecyl, etc. Unless otherwise expressly stated in this disclosure, the term "cycloalkyl" is intended to include the above-defined cycloalkyl group arbitrarily substituted by one or more groups selected from the following substituents: cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acamido, N-acamido, S-sulfinylamino, N-sulfinylamino, C-carboxyl, O-carboxyl, isocyanate, cyanothio, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are alkyl groups as defined in this disclosure) or an amino group including mono- and di-substituted amino groups, and their protected derivatives.

[0088] In some embodiments, "C3-C6 cyclic hydrocarbon group" refers to a cyclic hydrocarbon group as defined above, having three to six carbon atoms. The C3-C6 cyclic hydrocarbon group can be arbitrarily substituted as defined above for cyclic hydrocarbon groups.

[0089] In some implementations, “C3-C” 10 "Cycloalkyl group" refers to a cycloalkyl group as defined above, having three to ten carbon atoms. (C3-C) 10 Cyclic hydrocarbon groups can be arbitrarily substituted as defined above for cyclic hydrocarbon groups.

[0090] In some implementations, “C3-C” 12 "Cycloalkyl group" refers to a cycloalkyl group as defined above, having three to twelve carbon atoms. (C3-C) 12 Cyclic hydrocarbon groups can be arbitrarily substituted as defined above for cyclic hydrocarbon groups.

[0091] In this disclosure, the term "heterocyclic hydrocarbon group" refers to a saturated or partially unsaturated 3-8 member monocyclic, 7-12 member bicyclic (fused, bridged, or spirocyclic), or 11-14 member tricyclic (fused, bridged, or spirocyclic) ring system having one or more heteroatoms (such as O, N, S, P, or Se), for example, 1 or 1 to 2 or 1 to 3 or 1 to 4 or 1 to 5 or 1 to 6 heteroatoms, or for example, 1, 2, 3, 4, 5, or 6 heteroatoms, said heteroatoms being independently selected from nitrogen, oxygen, and sulfur, unless otherwise stated. Examples of heterocyclic hydrocarbon groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, dioxazolidinyl, tetrahydrofuranyl, isoindololinyl, indololinyl, imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxacyclopropyl, aziridine, oxacyclobutyl, thiohexacyclobutyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiaranyl, 1,4-diazacycloheptyl, 1,4-oxazacycloheptyl, 2-oxa-5- Azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5 '-furano[3,4-b]pyridinyl]-yl, 3'H-spiro[cyclohexane-1,1'-furano[3,4-c]pyridinyl]-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexane-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8- Tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]octane-6-yl, 5,6-dihydro-4H-cyclopentadien[b]thiophene, etc. In the case of polycyclic heterocyclic hydrocarbon groups, only one ring in the heterocyclic hydrocarbon group needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).Unless otherwise expressly stated in this disclosure, the term "heterocyclic hydrocarbon group" is intended to include heterocyclic hydrocarbon groups as defined above, which are arbitrarily substituted by one or more groups selected from the following substituents: cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogenated, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acamido, N-acamido, S-sulfinylamino, N-sulfinylamino, C-carboxyl, O-carboxyl, isocyanate, cyanothio, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbon groups as defined in this disclosure) or amino groups including mono- and di-substituted amino groups, and their protected derivatives.

[0092] In this disclosure, the term “compound of the present disclosure or a pharmaceutically acceptable salt thereof” refers to the compounds represented by general formulas (I) and (II) of the present disclosure and their pharmaceutically acceptable salts, as well as any specific compound falling into general formulas (I) and (II) and its pharmaceutically acceptable salt.

[0093] In this disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cattle, sheep, horses, and humans. In some embodiments, mammals include humans.

[0094] In this disclosure, the term "patient" refers to animals (e.g., humans), companion animals (e.g., dogs, cats, or horses), and livestock (e.g., cattle, pigs, and sheep). In some embodiments, the patient is a mammal that includes both males and females. In some embodiments, the patient is a human.

[0095] In this disclosure, the term "drug-acceptable" means a carrier, delivery unit, diluent, excipient, and / or salt that must be compatible with other components of the formulation and not harmful to the recipient.

[0096] In this disclosure, the terms “arbitrary” or “optionally” mean that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition.

[0097] In this disclosure, the term "pharmaceutical-acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / coloring agent, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or animals and has no adverse effects on the composition of the pharmaceutical composition.

[0098] In this disclosure, the term "carrier" is defined as a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is commonly used as a carrier because it readily introduces certain organic compounds into the cells or tissues of an organism.

[0099] In this disclosure, the term "drug-acceptable salt" includes "acceptable acid adduct salt" and "acceptable base adduct salt".

[0100] In this disclosure, the term "acceptable acid adduct salt" refers to those salts that retain the biological validity and properties of a free base, said acid adduct salt being biologically or otherwise suitable and formed using inorganic or organic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and such organic acids as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, phenylcarboxylic acid, 4-acetamidophenylcarboxylic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexylaminosulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, etc. Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, viscous acid, gentian acid, glucoheponic acid, gluconic acid, glucuronic acid, glutamic acid, glutamate, 2-oxoglutamate, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lacturonic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, viscous acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanate, p-toluenesulfonic acid, trifluoroacetic acid, undecenoic acid, etc.

[0101] In this disclosure, the term "acceptable base addition salt" refers to those salts that retain the biological validity and properties of a free acid, said base addition salt being suitable for biological or other purposes. These salts are prepared by adding an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. In some embodiments, the inorganic salt is an ammonium, sodium, potassium, calcium, or magnesium salt. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, heparin, choline, betaine, benzylamine, phenylethylenediamine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, aminobutanetriol, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. In some embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0102] In this disclosure, the term "pharmaceutical composition" refers to an formulation formed by the compound described in this disclosure with a medium generally accepted in the art for delivering a bioactive compound to a mammal such as a human. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients.

[0103] In this disclosure, the term "therapeuticly effective amount" refers to the amount of a compound or combination of compounds that improves, reduces, or eliminates a particular disease or condition and its symptoms, or avoids or delays the onset of a particular disease or condition or its symptoms. The amount of the compound constituting a "therapeuticly effective amount" described in this disclosure will vary depending on the compound, the disease state and its severity, and the age, weight, etc., of the mammal to be treated; however, those skilled in the art can determine the amount of the compound described in this disclosure conventionally based on their own knowledge and this disclosure.

[0104] As used in this disclosure, "to treat" or "to treat" encompasses the treatment of a related disease or condition in mammals, such as humans, suffering from a related disease or ailment, and includes:

[0105] (i) To prevent the occurrence of disease or disease state in mammals, especially when the mammal is susceptible to the disease state but has not yet been diagnosed with the disease state;

[0106] (ii) Suppress the disease or disease state, that is, prevent it from occurring; or

[0107] (iii) Alleviate the disease or disease state, even if the disease or disease state subsides or does not progress.

[0108] In this disclosure, the term “prevention” means prevention of the onset, recurrence or spread of a disease or disease state, or one or more symptoms thereof.

[0109] In this disclosure, the term "preventively effective amount" refers to an amount of compound or combination of compounds sufficient to prevent a disease or disease state, or to prevent its recurrence or spread. The amount of the compound constituting a "preventively effective amount" described in this disclosure will vary depending on the compound, the disease state and its severity, and the age, weight, etc., of the mammal to be treated; however, those skilled in the art can conventionally determine the amount of the compound described in this disclosure based on their own knowledge and this disclosure.

[0110] As used in this disclosure, the terms “disease” and “disease state” may be used interchangeably or may be different, because a particular disease or disease state may not have a known causative agent (and therefore cannot be explained by etiology), and thus is not recognized as a disease, but rather as an undesirable disease state or symptom in which a clinician has identified a more or less specific set of symptoms.

[0111] In this disclosure, the term "leukocyte tyrosine kinase (LTK)" refers to a member of the tyrosine kinase insulin receptor superfamily, whose kinase domain shares nearly 80% identity with anaplastic lymphoma kinase (ALK). Detailed Implementation

[0112] On the one hand, this disclosure relates to compounds represented by general formula (I) and pharmaceutically acceptable salts thereof:

[0113] in:

[0114] R1 is selected from any substituted aryl group or any substituted heteroaryl group;

[0115] X is selected from O, S, or NR3;

[0116] R2 is selected from any substituted hydrocarbon group, any substituted cyclic hydrocarbon group, any substituted heterocyclic hydrocarbon group, any substituted aryl group, or any substituted heteroaryl group; and

[0117] R3 is selected from hydrogen, any substituted hydrocarbon group, any substituted cyclic hydrocarbon group, any substituted heterocyclic hydrocarbon group, any substituted aryl group, or any substituted heteroaryl group.

[0118] In some embodiments, R1 is selected from halogen, unsubstituted aryl, aryl-substituted alkyl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, aryl-substituted amino, sulfonamide-substituted aryl, unsubstituted heteroaryl, alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, aryl-substituted amino, or heterocyclic alkyl-substituted heteroaryl.

[0119] In some embodiments, R1 is selected from halogen, unsubstituted phenyl, arbitrarily substituted alkyl-substituted phenyl, arbitrarily substituted heterocyclic alkyl-substituted alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, arbitrarily substituted amino-substituted phenyl, sulfonamide-substituted phenyl, unsubstituted pyridyl, unsubstituted thiophenyl, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, arbitrarily substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocyclic alkyl-substituted amino-substituted pyrazolyl, or heterocyclic alkyl-substituted pyrazolyl.

[0120] In some embodiments, R1 is selected from halogen, unsubstituted aryl, alkyl-substituted aryl, halogen-substituted alkyl-substituted aryl, alkyl-substituted heterocyclic alkyl-substituted alkyl-substituted aryl, alkyl-substituted heterocyclic alkyl-substituted oxoalkyl-substituted aryl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, alkyl-substituted amino-substituted aryl, any-substituted heterocyclic alkyl-substituted amino-substituted aryl, sulfonamide-substituted phenyl, unsubstituted heteroaryl, any-substituted alkyl-substituted heteroaryl, any-substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocyclic alkyl-substituted amino-substituted heteroaryl, or heterocyclic alkyl-substituted heteroaryl.

[0121] In some embodiments, R1 is selected from iodine, phenyl, tolyl, isopropylphenyl, trifluoromethylphenyl, 4-(4-methylpiperazin-1-yl)methylphenyl, 4-(4-methylpiperazin-1-yl)oxomethylphenyl, methoxyphenyl, isopropoxyphenyl, bromophenyl, cyano-substituted phenyl, dimethylaminophenyl, 2-methyl-4-piperidinyl-substituted amino-substituted phenyl, 2-methyl-4-(N-methylpiperidinyl)-amino-substituted phenyl, 2-methyl-4-tetrahydropyrrolyl-substituted amino-substituted phenyl, 2-methyl-4-(N-methyltetrahydropyrrolyl)-amino-substituted phenyl, 2-methyl-4- The following are sulfonamide-substituted phenyl, pyridinyl, thiophene, pyrimidinyl, pyrazolyl, N-methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl, dimethylpyrazolyl, N-(hydroxyethyl)dimethylpyrazolyl, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolyl, N-(2-hydroxypropyl)dimethylpyrazolyl, N-pyranylamino-substituted N-methylpyrazolyl, N-piperidinyl-substituted pyrazolyl, N-piperidinyl-substituted dimethylpyrazolyl, cyano-aminomethyl-substituted N-methylpyrazolyl, cyano-N-methylaminomethyl-substituted N-methylpyrazolyl, or cyano-N-pyranylamino-substituted N-methylpyrazolyl.

[0122] In some implementations, R1 is selected from:

[0123] In some embodiments, R2 is selected from any substituted amino-substituted hydrocarbon group, halogen-substituted cyclic hydrocarbon group, any substituted carbonyl-substituted cyclic hydrocarbon group, any substituted amide-substituted cyclic hydrocarbon group, any substituted heterocyclic substituted cyclic hydrocarbon group, any substituted aminosulfonyl-substituted aryl group, unsubstituted heteroaryl group, any substituted alkyl-substituted heteroaryl group, alkoxy-substituted heteroaryl group, cyano-substituted heteroaryl group, any substituted amino-substituted heteroaryl group, or heterocyclic alkyl-substituted heteroaryl group.

[0124] In some embodiments, R2 is selected from any substituted alkyl, any substituted cycloalkyl, any substituted heterocycloalkyl, any substituted phenyl, unsubstituted pyridyl, unsubstituted thiophenyl, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, any substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocycloalkyl-substituted amino-substituted pyrazolyl, or heterocycloalkyl-substituted pyrazolyl.

[0125] In some embodiments, R2 is selected from any substituted amino-substituted alkyl, any substituted pyrrolealkyl, any substituted azabicycloalkyl, any substituted aminosulfonyl-substituted phenyl, unsubstituted heteroaryl, any substituted alkyl-substituted heteroaryl, any substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocyclic alkyl-substituted amino-substituted heteroaryl, or heterocyclic alkyl-substituted heteroaryl.

[0126] In some embodiments, R2 is selected from any substituted aryl-substituted amino-substituted alkyl, difluoropyrrolidinyl, N-tert-butyloxy-difluoropyrrolidinyl, N-(4-chlorophenylaminocarbonyl)-3,3-difluoro-pyrrolidinyl, N-(4-chlorophenylaminocarbonyl)-azabicyclo[3.2.1]octyl, any substituted hydrocarbon-substituted aminosulfonyl-substituted phenyl, pyridyl, thiophenyl, pyrimidinyl, pyrazolyl, N-methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl N-(hydroxyethyl)dimethylpyrazolyl, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolyl, N-(2-hydroxypropyl)dimethylpyrazolyl, N-pyranylamino-substituted N-methylpyrazolyl, N-piperidinyl-substituted pyrazolyl, N-piperidinyl-substituted dimethylpyrazolyl, cyano-aminomethyl-substituted N-methylpyrazolyl, cyano-N-methylaminomethyl-substituted N-methylpyrazolyl or cyano-N-pyranylamino-substituted N-methylpyrazolyl.

[0127] In some embodiments, R3 is selected from hydrogen, an aryl group with arbitrary substituted amino groups, a halogen-substituted cycloalkyl group, an aryl group with arbitrary substituted carbonyl groups, an aryl group with arbitrary substituted amide groups, an aryl group with arbitrary substituted heterocyclic groups, an aryl group with arbitrary substituted aminosulfonyl groups, an unsubstituted heteroaryl group, an aryl group with arbitrary substituted alkyl groups, an alkoxy-substituted heteroaryl group, a cyano-substituted heteroaryl group, an aryl group with arbitrary substituted amino groups, or an aryl group with heterocyclic alkyl groups.

[0128] In some embodiments, R3 is selected from hydrogen, any substituted alkyl, any substituted cycloalkyl, any substituted heterocycloalkyl, any substituted phenyl, unsubstituted pyridyl, unsubstituted thiophenyl, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, any substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocycloalkyl-substituted amino-substituted pyrazolyl, or heterocycloalkyl-substituted pyrazolyl.

[0129] In some embodiments, R3 is selected from hydrogen, any substituted amino-substituted alkyl, any substituted pyrrolealkyl, any substituted azabicycloalkyl, any substituted aminosulfonyl-substituted phenyl, unsubstituted heteroaryl, any substituted alkyl-substituted heteroaryl, any substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocyclic alkyl-substituted amino-substituted heteroaryl, or heterocyclic alkyl-substituted heteroaryl.

[0130] In some embodiments, R3 is selected from hydrogen, aryl-substituted amino-substituted alkyl groups, difluoropyrrolidinyl groups, N-tert-butyloxy-difluoropyrrolidinyl groups, N-(4-chlorophenylaminocarbonyl)-3,3-difluoro-pyrrolidinyl groups, N-(4-chlorophenylaminocarbonyl)-azabicyclo[3.2.1]octyl groups, alkyl-substituted aminosulfonyl-substituted phenyl groups, pyridyl, thiophenyl, pyrimidinyl, pyrazolyl, N-methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl Azolium, dimethylpyrazolium, N-(hydroxyethyl)dimethylpyrazolium, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolium, N-(2-hydroxypropyl)dimethylpyrazolium, N-pyranylamino-substituted N-methylpyrazolium, N-piperidinyl-substituted pyrazolium, N-piperidinyl-substituted dimethylpyrazolium, cyano-aminomethyl-substituted N-methylpyrazolium, cyano-N-methylaminomethyl-substituted N-methylpyrazolium, or cyano-N-pyranylamino-substituted N-methylpyrazolium.

[0131] In some implementations, R2 is selected from...

[0132] In some implementations, R3 is selected from hydrogen,

[0133] On the other hand, this disclosure relates to compounds represented by general formula (II) and pharmaceutically acceptable salts thereof:

[0134] in:

[0135] R 11 Selected from any substituted aryl group or any substituted heteroaryl group;

[0136] A is selected from any substituted heterocyclic hydrocarbon group or any substituted heteroaryl group;

[0137] Y is HN- or does not exist;

[0138] R 22 Selected from hydrogen, any substituted hydrocarbon group, any substituted aryl group, or any substituted heteroaryl group; and

[0139] R 33Selected from hydrogen, any substituted hydrocarbon group, any substituted aryl group, or any substituted heteroaryl group;

[0140] The premise is that the compound represented by general formula (II) is not (3S)-1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide and (3S)-1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide].

[0141] In some embodiments, A is selected from any substituted nitrogen-containing heterocyclic hydrocarbon group, any substituted oxygen-containing heterocyclic hydrocarbon group, or any substituted nitrogen-containing heteroaryl group.

[0142] In some embodiments, the nitrogen atom is attached to a pyrimidine-pyrrole group.

[0143] In some embodiments, A is selected from any substituted piperidinyl, substituted morpholinyl, any substituted azacycloheptyl, and any substituted azabicycloheptyl.

[0144] In some embodiments, A is selected from unsubstituted piperidinyl, amino-substituted piperidinyl, halogen-substituted piperidinyl, cyano-substituted piperidinyl, alkyl-substituted piperidinyl, deuterated alkyl-substituted piperidinyl, unsubstituted azaheptanyl, and unsubstituted azabicycloheptanyl.

[0145] In some embodiments, A is selected from unsubstituted piperidinyl, amino-substituted piperidinyl, fluorinated piperidinyl, cyano-substituted piperidinyl, methyl-substituted piperidinyl, deuterated methyl-substituted piperidinyl, unsubstituted azaheptanyl, and unsubstituted azabicycloheptanyl.

[0146] In some implementations, R 11 It is selected from halogen, unsubstituted aryl, aryl-substituted alkyl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, aryl-substituted amino, sulfonamide-substituted aryl, unsubstituted heteroaryl, alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, aryl-substituted amino, or heterocyclic alkyl-substituted heteroaryl.

[0147] In some implementations, R 11It is selected from halogen, unsubstituted phenyl, arbitrarily substituted alkyl-substituted phenyl, arbitrarily substituted heterocyclic alkyl-substituted alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, arbitrarily substituted amino-substituted phenyl, sulfonamide-substituted phenyl, unsubstituted pyridyl, unsubstituted thiophene, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, arbitrarily substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocyclic alkyl-substituted amino-substituted pyrazolyl, or heterocyclic alkyl-substituted pyrazolyl.

[0148] In some implementations, R 11 Selected from halogen, unsubstituted aryl, alkyl-substituted aryl, halogen-substituted alkyl-substituted aryl, alkyl-substituted heterocyclic alkyl-substituted alkyl-substituted aryl, alkyl-substituted heterocyclic alkyl-substituted oxoalkyl-substituted aryl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, alkyl-substituted amino-substituted aryl, any-substituted heterocyclic alkyl-substituted amino-substituted aryl, sulfonamide-substituted phenyl, unsubstituted heteroaryl, any-substituted alkyl-substituted heteroaryl, any-substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocyclic alkyl-substituted amino-substituted heteroaryl, or heterocyclic alkyl-substituted heteroaryl.

[0149] In some implementations, R 11 Selected from iodine, phenyl, tolyl, isopropylphenyl, trifluoromethylphenyl, 4-(4-methylpiperazin-1-yl)methylphenyl, 4-(4-methylpiperazin-1-yl)oxomethylphenyl, methoxyphenyl, isopropoxyphenyl, bromophenyl, cyano-substituted phenyl, dimethylaminophenyl, 2-methyl-4-piperidinyl-substituted amino-substituted phenyl, 2-methyl-4-(N-methylpiperidinyl)-amino-substituted phenyl, 2-methyl-4-tetrahydropyrrolyl-substituted amino-substituted phenyl, 2-methyl-4-(N-methyltetrahydropyrrolyl)-amino-substituted phenyl, 2-methyl-4-sulfonamide-substituted phenyl. The phenyl, pyridinyl, thiopheneyl, pyrimidinyl, pyrazolyl, N-methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl, dimethylpyrazolyl, N-(hydroxyethyl)dimethylpyrazolyl, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolyl, N-(2-hydroxypropyl)dimethylpyrazolyl, N-pyranylamino-substituted N-methylpyrazolyl, N-piperidinyl-substituted pyrazolyl, N-piperidinyl-substituted dimethylpyrazolyl, cyano-aminomethyl-substituted N-methylpyrazolyl, cyano-N-methylaminomethyl-substituted N-methylpyrazolyl or cyano-N-pyranylamino-substituted N-methylpyrazolyl.

[0150] In some implementations, R11 Selected from:

[0151] In some implementations, R 22 It is selected from hydrogen, any substituted amino-substituted hydrocarbon group, any substituted aminosulfonyl-substituted aryl group, unsubstituted heteroaryl group, any substituted alkyl-substituted heteroaryl group, alkoxy-substituted heteroaryl group, cyano-substituted heteroaryl group, any substituted amino-substituted heteroaryl group, or heterocyclic alkyl-substituted heteroaryl group.

[0152] In some implementations, R 22 It is selected from hydrogen, any substituted alkyl, any substituted phenyl, unsubstituted pyridyl, unsubstituted thiophene, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, any substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocyclic alkyl-substituted amino-substituted pyrazolyl, or heterocyclic alkyl-substituted pyrazolyl.

[0153] In some implementations, R 22 It is selected from hydrogen, any substituted amino-substituted alkyl, any substituted aminosulfonyl-substituted phenyl, unsubstituted heteroaryl, any substituted alkyl-substituted heteroaryl, any substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocyclic alkyl-substituted amino-substituted heteroaryl, or heterocyclic alkyl-substituted heteroaryl.

[0154] In some implementations, R 22 Selected from hydrogen, aryl-substituted amino-substituted alkyl, alkyl-substituted aminosulfonyl-substituted phenyl, pyridinyl, thiophene, pyrimidinyl, pyrazolyl, N-methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl, dimethylpyrazolyl, N-(hydroxyethyl)dimethylpyrazolyl, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolyl, N-(2-hydroxypropyl)dimethylpyrazolyl, N-pyranylamino-substituted N-methylpyrazolyl, N-piperidinyl-substituted pyrazolyl, N-piperidinyl-substituted dimethylpyrazolyl, cyano-aminomethyl-substituted N-methylpyrazolyl, cyano-N-methylaminomethyl-substituted N-methylpyrazolyl, or cyano-N-pyranylamino-substituted N-methylpyrazolyl.

[0155] In some implementations, R 33 It is selected from hydrogen, any substituted amino-substituted hydrocarbon group, any substituted aminosulfonyl-substituted aryl group, unsubstituted heteroaryl group, any substituted alkyl-substituted heteroaryl group, alkoxy-substituted heteroaryl group, cyano-substituted heteroaryl group, any substituted amino-substituted heteroaryl group, or heterocyclic alkyl-substituted heteroaryl group.

[0156] In some implementations, R 33 It is selected from hydrogen, any substituted alkyl, any substituted phenyl, unsubstituted pyridyl, unsubstituted thiophene, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, any substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocyclic alkyl-substituted amino-substituted pyrazolyl, or heterocyclic alkyl-substituted pyrazolyl.

[0157] In some implementations, R 33 It is selected from hydrogen, any substituted amino-substituted alkyl, any substituted aminosulfonyl-substituted phenyl, unsubstituted heteroaryl, any substituted alkyl-substituted heteroaryl, any substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocyclic alkyl-substituted amino-substituted heteroaryl, or heterocyclic alkyl-substituted heteroaryl.

[0158] In some implementations, R 33 Selected from hydrogen, aryl-substituted amino-substituted alkyl, alkyl-substituted aminosulfonyl-substituted phenyl, pyridinyl, thiophene, pyrimidinyl, pyrazolyl, N-methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl, dimethylpyrazolyl, N-(hydroxyethyl)dimethylpyrazolyl, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolyl, N-(2-hydroxypropyl)dimethylpyrazolyl, N-pyranylamino-substituted N-methylpyrazolyl, N-piperidinyl-substituted pyrazolyl, N-piperidinyl-substituted dimethylpyrazolyl, cyano-aminomethyl-substituted N-methylpyrazolyl, cyano-N-methylaminomethyl-substituted N-methylpyrazolyl, or cyano-N-pyranylamino-substituted N-methylpyrazolyl.

[0159] In some implementations, Selected from

[0160] Furthermore, this disclosure relates to compounds and pharmaceutically acceptable salts thereof, wherein said compounds are selected from:

[0161] In some embodiments, the compounds disclosed herein have potent inhibitory activity against LTK.

[0162] In some embodiments, the compounds disclosed herein exhibit excellent stability.

[0163] In some embodiments, the compounds disclosed herein exhibit excellent pharmacological efficacy.

[0164] On the other hand, this disclosure relates to pharmaceutical compositions comprising the compounds of this disclosure or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0165] Pharmaceutical Composition

[0166] In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0167] In some embodiments, the routes of administration of the compounds of this disclosure or pharmaceutically acceptable salts thereof to mammals for the treatment or prevention of tyrosine kinase (TK)-mediated diseases or disease states may be gastrointestinal or non-gastrointestinal.

[0168] In some embodiments, the route of administration of the compounds of this disclosure or pharmaceutically acceptable salts thereof to mammals for the treatment of diseases or disease states of tyrosine kinase (TK) may be oral.

[0169] In some embodiments, the route of administration of the compounds of this disclosure or pharmaceutically acceptable salts thereof to mammals for tyrosine kinase (TK)-mediated diseases or disease states may be rectal.

[0170] The compounds described in this disclosure can be obtained in any suitable form, such as tablets, capsules, powders, oral solutions, suspensions, rectal gels, rectal foams, rectal enemas, or rectal suppositories. Exemplary examples of the tablets include, but are not limited to, uncoated tablets, sugar-coated tablets, and film-coated tablets.

[0171] Examples of pharmaceutically acceptable excipients that can be used in the pharmaceutical compositions of this disclosure include, but are not limited to, any adjuvants, carriers, excipients, gliding agents, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or animals and are not intended to cause adverse effects on the composition of the pharmaceutical composition. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), the entire contents of which are incorporated herein by reference.

[0172] The pharmaceutical compositions of this disclosure can be administered by any method to achieve their intended purpose. For example, administration can be via oral, parenteral, local, enteral, intravenous, intramuscular, inhalation, nasal, intra-articular, intraspinal, tracheal, ocular, subcutaneous, intraperitoneal, percutaneous, or sublingual routes. Routes of administration can be non-gastrointestinal, oral, or rectal. The dosage administered will depend on the recipient's age, health condition, and weight, and if any, the type and frequency of concurrent treatments, as well as the nature of the desired effect.

[0173] Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, dragees, semi-solid preparations, powders, granules, suppositories, ointments, creams, lotions, inhalers, injections, muds, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, and emulsions, which can be prepared according to methods known in the art.

[0174] Particularly suitable for oral administration are plain tablets, sugar-coated tablets, film-coated tablets, pills, capsules, powders, granules, syrups, juices, or drops; suitable for rectal administration are suppositories; suitable for parenteral administration are solutions, which can also be oil-based solutions or aqueous solutions; in addition, there are suspensions, emulsions, or implants; suitable for topical use are ointments, creams, or powders. The products of this disclosure can also be lyophilized, and the resulting lyophilized products are used, for example, to prepare injections. The given formulations can be sterilized and / or contain assistants such as wetting agents, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for altering osmotic pressure, buffering substances, dyes, flavoring agents, and / or numerous other active ingredients, such as one or more vitamins.

[0175] In some embodiments, the pharmaceutical compositions of this disclosure are prepared as tablets, solutions, granules, patches, ointments, capsules, aerosols or suppositories for parenteral, dermal, mucosal, nasal, buccal, sublingual or oral use.

[0176] Preservatives, stabilizers, dyes, sweeteners, flavorings, and fragrances can be provided in pharmaceutical compositions. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid can be added as preservatives. Additionally, antioxidants and suspensions can be used.

[0177] In different implementation schemes, alcohols, esters, sulfated aliphatic alcohols, etc., can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicates, magnesium aluminate, magnesium aluminate methyl silicate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogen phosphate, calcium hydroxymethyl cellulose, etc., can be used as excipients; magnesium stearate, talc, hardened oil, etc., can be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, soybean oil, etc., can be used as suspensions or lubricants; cellulose acetate, as a derivative of sugars such as cellulose or sugar, or methyl acetate-isobutylene ester copolymer, as a derivative of polyethylene, can be used as suspensions; and plasticizers such as phthalates can be used as suspensions.

[0178] Suitable routes of administration may include, for example, oral administration, rectal administration, transmembrane administration, parenteral delivery, local administration, or enteral administration; parenteral delivery includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, intrathecal injection, direct intracardiac injection, intraperitoneal injection, intranasal injection, or intraocular injection. Compounds can also be administered at a predetermined rate and / or timed, pulsatilely in sustained-release or controlled-release dosage forms, including depot injections, osmotic pumps, pellets, and transdermal (including electromigration) patches.

[0179] The pharmaceutical compositions disclosed herein can be produced by known methods, such as conventional methods of mixing, dissolving, granulating, manufacturing tablets, grinding, emulsifying, encapsulating, retaining or compressing tablets.

[0180] Therefore, according to this disclosure, the pharmaceutical compositions used can be formulated using conventional methods with one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the treatment of the active compound into a pharmaceutically usable formulation. Suitable formulations depend on the chosen route of administration. Any known techniques, carriers, and excipients can be used as suitably understood and appreciated in the art.

[0181] Injectable formulations can be prepared in the following conventional forms: as solutions or suspensions, solid dosage forms suitable for preparation as solutions or suspensions prior to injection, or as emulsions. Suitable excipients include, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, monosodium glutamate, cysteine ​​hydrochloride, etc. Additionally, if desired, the injectable pharmaceutical composition may contain small amounts of non-toxic excipients, such as wetting agents, pH buffers, etc. Physiologically suitable buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer. If desired, absorption-enhancing agents (e.g., liposomes) may be used.

[0182] For oral administration, the active compound can be readily formulated by combining it with a pharmaceutically acceptable carrier known in the art. Such a carrier allows the disclosed compounds to be formulated as tablets, pills, lozenges, capsules, liquids, gels, syrups, ointments, suspensions, solutions, powders, etc., for oral ingestion by mixing the active compound with a solid excipient, grinding the resulting mixture as desired, and processing the granular mixture, if necessary, after adding a suitable excipient to obtain a tablet or lozenge core. Suitable excipients are particularly fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). Disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginate or alginate such as sodium alginate can be added if desired. The tablet core is appropriately coated. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, shellac solution, and suitable organic solvents or solvent mixtures. To identify or characterize different combinations of active compound dosages, dyes or pigments may be added to the tablet or tablet coating. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, shellac solution, and suitable organic solvents or solvent mixtures.

[0183] Oral pharmaceutical formulations include push-in capsules made of gelatin, and soft, sealed capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-in capsules may contain the active ingredient mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All oral formulations should be administered at a dose suitable for this administration.

[0184] In some embodiments, the pharmaceutical compositions of this disclosure may comprise 0.1% to 95% of the compounds of this disclosure or pharmaceutically acceptable salts thereof.

[0185] In some embodiments, the pharmaceutical compositions of this disclosure may comprise 1% to 70% of the compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0186] In any case, the composition or formulation to be administered will contain an amount of the compound disclosed herein, its stereoisomer or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating the disease / condition of the subject being treated.

[0187] Administration method

[0188] At least one compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of the present disclosure or a pharmaceutically acceptable salt thereof, may be administered to a patient by any suitable systemic and / or local method of delivery of the compound of the present disclosure or a pharmaceutically acceptable salt thereof. Non-limiting examples of administration methods include (a) oral administration, including administration in capsule, tablet, granule, spray, syrup or other such forms; (b) non-oral administration, such as rectal, vaginal, urethral, ​​intraocular, intranasal or intraauricular administration, including administration in aqueous suspension, oily preparations or in drops, spray, suppositories, ointments, creams or ointments; (c) administration by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intracapsular injection, intraspinal injection, intrasternal injection, etc., including delivery by infusion pump; (d) localized administration, such as direct injection into the renal or cardiac region, for example by reservoir implantation; and (e) topically administration; as would be considered appropriate by those skilled in the art, is contact between the compounds described in this disclosure and living tissue.

[0189] The most suitable route depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining the method of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, appropriate pharmaceutical excipients, and other matters relating to the delivery of the compound, its stereoisomers, or pharmaceutically acceptable salts thereof to the recipient.

[0190] Suitable pharmaceutical compositions for administration include compositions containing an effective amount of the active ingredient to achieve their intended effect. The required therapeutically effective dose of the pharmaceutical composition described in this disclosure depends on the route of administration, the type of animal being treated (including humans), and the physical characteristics of the specific animal under consideration. The dose can be adjusted to achieve the desired effect, but this will depend on factors such as body weight, diet, concurrent drug treatment, and other factors recognized by those skilled in the art. More specifically, a therapeutically effective dose refers to the amount of compound that effectively prevents, alleviates, or improves disease symptoms, or prolongs the lifespan of the treated individual. The actual ability of those skilled in the art can well determine a therapeutically effective dose, particularly in accordance with the detailed disclosure provided herein.

[0191] As will be apparent to those skilled in the art, the dosage and specific route of administration for in vivo administration will vary depending on age, weight, the species of mammal being treated, the specific compound used, and the specific purpose of those compounds. Those skilled in the art can determine the effective dose level—that is, the dose level necessary to determine the desired effect—using conventional pharmacological methods. Typically, human clinical application of the product is initiated at a lower dose level, increasing the dose level until the desired effect is achieved. Alternatively, established pharmacological methods can be used to establish the effective dose and route of administration of the compositions identified by this method using acceptable in vitro studies.

[0192] In non-human animal studies, the application of a potential product begins at a higher dose level and is gradually reduced until the desired effect is no longer achieved or adverse side effects disappear. The dose range can be broad, depending on the expected effect and therapeutic indication. Typically, the dose can range from about 10 μg / kg body weight to 1000 mg / kg body weight, and in some embodiments from about 100 μg / kg body weight to 300 mg / kg body weight. Alternatively, as those skilled in the art will understand, the dose can be based on and calculated according to the patient's body surface area.

[0193] Physicians can select the exact formulation, route of administration, and dosage of the pharmaceutical compositions described in this disclosure based on the patient's condition. Typically, the dosage range of the composition administered to a patient can be from about 0.5 mg / kg to 1000 mg / kg of patient body weight. Depending on the patient's needs, the dosage may be given once or twice or more over a day or several days. Where the human dosage of the compound has been established under at least certain conditions, this disclosure will use those same dosages, or dosage ranges from about 0.1% to 500% of the established human dosage, and in some embodiments, dosage ranges from 25% to 250% of the established human dosage. In the absence of a determined human dosage, such as in the case of a newly discovered pharmaceutical compound, an appropriate human dosage can be inferred from the median effective dose or median infectious dose, or other suitable values ​​from in vitro or in vivo studies, as quantified in toxicity studies and efficacy studies in animals.

[0194] It should be noted that, due to toxicity and organ dysfunction, the attending physician will know and when to terminate, interrupt, or adjust medication. Conversely, if the clinical response is inadequate (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. The dosage administered in the treatment of the condition of interest will vary depending on the severity of the disease state and the route of administration. For example, the severity of the disease state can be assessed in part using standard prognostic methods. Furthermore, the dosage and possible dosing frequency will also vary based on the individual patient's age, weight, and response. Protocols equivalent to those discussed above can be used in veterinary medicine.

[0195] While an exact dosage can be determined based on drug-by-drug analysis, in most cases, some generalizations about the dosage can be made. Daily dosing regimens for adult patients are, for example, oral doses of 0.1 mg to 2000 mg of each active ingredient, or in some embodiments, 1 mg to 2000 mg of each active ingredient, such as 5 mg to 1500 mg of each active ingredient. In other embodiments, the intravenous, subcutaneous, or intramuscular dose of each active ingredient used is 0.01 mg to 1000 mg, or in some embodiments, 0.1 mg to 1000 mg, such as 1 mg to 800 mg. In the case of administering acceptable saline solutions, the dosage can be calculated based on free base. In some embodiments, the composition is administered 1 to 4 times daily. Alternatively, the compositions described in this disclosure can be administered by continuous intravenous infusion, or in some embodiments, at doses of up to 2000 mg of each active ingredient daily. As those skilled in the art will understand, in certain situations, it is necessary to administer the compounds described in this disclosure in amounts exceeding or far exceeding the above-described dosage range for the effective and rapid treatment of a rapidly progressing disease or infection. In some embodiments, the compounds are administered during continuous treatment, for example, for one or several weeks, or for several months or years.

[0196] Dosage and dosing intervals can be individually adjusted to provide plasma levels sufficient to maintain the modulated effect or minimum effective concentration (MEC) of the active moiety. The MEC varies for each compound, but it can be assessed from in vitro data. The required dose to achieve the MEC depends on individual characteristics and route of administration. However, plasma concentrations can be determined using HPLC (high-performance liquid chromatography) or bioassays.

[0197] The MEC value can also be used to determine the dosing interval. The composition should be administered using a treatment regimen that maintains plasma levels above the MEC for 10-90% of the time, 30-90% of the time in some embodiments, and 50-90% of the time in some embodiments.

[0198] In cases of local administration or selective absorption, the effective local concentration of a drug is independent of its plasma concentration.

[0199] Of course, the amount of the administered composition depends on the individual being treated, the individual's weight, the severity of their pain, the route of administration, and the prescribing physician's judgment.

[0200] The efficacy and toxicity of the compounds described in this disclosure can be evaluated using known methods. For example, the toxicology of a particular compound or a subset of compounds sharing certain chemical motifs can be established by determining the toxicity of cell lines in vitro, such as mammalian cell lines and, in some embodiments, human cell lines. The results of such studies can generally predict toxicity in animals such as mammals, or more specifically, toxicity in humans. Alternatively, the toxicity of a particular compound in animal models such as mice, rats, rabbits, or monkeys can be determined using known methods. The efficacy of a particular compound can be determined using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for almost every type of disease state, including but not limited to cancer, cardiovascular disease, and various immune disorders. Similarly, acceptable animal models can be used to determine the efficacy of chemical agents for treating these disease states. When selecting a model to determine efficacy, a person skilled in the art can choose an appropriate model, dosage, route of administration, and treatment regimen under the guidance of prior art. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0201] If desired, the composition may be placed in a packaging or dispensing device, which may contain one or more unit dosage forms containing the active ingredient. The packaging may include, for example, metal or plastic foil, such as blister packs. The packaging or dispensing device may include instructions for use. The packaging or dispensing device may also include precautions related to the container, prescribed by a government agency regulating the production, use, or sale of the drug, reflecting that the drug form has been approved by that agency for human or animal administration. Such precautions may, for example, be labels approved for prescription drugs by the National Food and Drug Administration or the U.S. Food and Drug Administration, or approved product instructions. Compositions containing the compounds of this disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof may also be prepared in suitable containers, formulated in compatible drug carriers, and labeled for the treatment of specified disease states.

[0202] Furthermore, this disclosure relates to a method for preparing compounds of general formula (Ib), comprising:

[0203] It includes the following reactions:

[0204] in:

[0205] R1 is selected from any substituted aryl group or any substituted heteroaryl group;

[0206] B is selected from boric acid, borate ester, or halogen.

[0207] In some embodiments, the reaction for preparing the compound represented by general formula (Ib) is carried out in the presence of a palladium catalyst and a base.

[0208] In some embodiments, exemplary examples of palladium catalysts that can be used in this disclosure include, but are not limited to, palladium, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(OAc)2, and Pd(dppf)Cl. 2、 Pd(amphost)Cl2, Xphos-Pd-G3, or any mixture thereof.

[0209] In some embodiments, exemplary examples of bases that can be used in this disclosure include, but are not limited to, alkali metal salts, organic bases, or any mixtures thereof.

[0210] In some embodiments, exemplary examples of alkali metal salts that can be used in this disclosure include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium fluoride, potassium fluoride, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof.

[0211] In some embodiments, exemplary examples of alcohols that can be used in this disclosure include, but are not limited to, methanol, ethanol, or tert-butanol.

[0212] In some embodiments, exemplary examples of organic bases that can be used in this disclosure include, but are not limited to, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

[0213] In some embodiments, exemplary examples of boronic esters that can be used in this disclosure include, but are not limited to, bis(pinacol)diboron (Bpin), Bcat, or any mixture thereof.

[0214] In some embodiments, exemplary examples of halogens that can be used in this disclosure include, but are not limited to, chlorine, bromine, iodine, or any mixture thereof, and the reaction is carried out in the presence of bis(pinacol)diboron.

[0215] On the other hand, this disclosure relates to a method for preparing compounds of general formula (Ia),

[0216] It includes the following reactions:

[0217] in:

[0218] R1 is selected from any substituted aryl group or any substituted heteroaryl group;

[0219] X is selected from O, S, or NR3;

[0220] R2 is selected from any substituted hydrocarbon group, any substituted monocyclic aryl group, or any substituted heteroaryl group;

[0221] R3 is selected from hydrogen, any substituted hydrocarbon group, any substituted monocyclic aryl group, or any substituted heteroaryl group;

[0222] Alternatively, when X is NR3, R2, R3, and the N attached to them form any substituted heterocyclic hydrocarbon groups.

[0223] In some embodiments, the method for preparing the compound represented by general formula (Ia) is carried out in the presence of a base.

[0224] In some embodiments, exemplary examples of bases that can be used in this disclosure include, but are not limited to, alkali metal salts, organic bases, or any mixtures thereof.

[0225] In some embodiments, exemplary examples of alkali metal salts that can be used in this disclosure include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium fluoride, potassium fluoride, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof.

[0226] In some embodiments, exemplary examples of alcohols that can be used in this disclosure include, but are not limited to, methanol, ethanol, or tert-butanol.

[0227] In some embodiments, exemplary examples of organic bases that can be used in this disclosure include, but are not limited to, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

[0228] In some cases, the above synthesis steps can be reversed and performed separately.

[0229] In another aspect, this disclosure relates to a method of inhibiting tyrosine kinase (TK), comprising contacting the tyrosine kinase (TK) with an inhibitory amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0230] In some embodiments, the tyrosine kinase (TK) is contacted in vitro with an inhibitory amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0231] In some embodiments, it can be used with the tyrosine kinase disclosed herein. Exemplary examples of kinases (TKs) include, but are not limited to, anaplastic lymphoma kinase (ALK), ROS1 oncogene receptor tyrosine kinase (ROS1), leukocyte receptor tyrosine kinase (LTK), epidermal growth factor receptor (EGFR), platelet growth factor receptor (PDGF), ABL tyrosine kinase, fibroblast growth factor receptor (FGFR), interleukin receptor-associated kinase (IRAK), human tyrosine kinase receptor (FLT), V-raf mouse sarcoma virus oncogene homolog B (BRAF), vascular endothelial growth factor receptor 2 (KDR), vascular endothelial growth factor (VEGFR), transfection rearrangement kinase (RET), Bruton's tyrosine kinase (BTK), B-lymphotyrosine kinase (BLK), cytoplasmic tyrosine protein kinase (BMX), human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 4 (HER4), isocitrate dehydrogenase (IDH), discoid domain receptor 1 (DDR1), interleukin 2-induced T cell kinase (ITK), and human protein tyrosine kinase 4 (TXK).

[0232] In another aspect, this disclosure relates to methods for treating or preventing tyrosine kinase (TK)-mediated diseases or disease states, comprising administering to an individual in need of said method a therapeutically or preventively effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0233] Exemplary examples of individuals who can use the methods disclosed herein for treating or preventing tyrosine kinase (TK)-mediated diseases or disease states include, but are not limited to, mammals.

[0234] In some implementations, the individual is a human being.

[0235] In some embodiments, it can be used with the tyrosine kinase disclosed herein. Exemplary examples of kinases (TKs) include, but are not limited to, anaplastic lymphoma kinase (ALK), ROS1 oncogene receptor tyrosine kinase (ROS1), leukocyte receptor tyrosine kinase (LTK), epidermal growth factor receptor (EGFR), platelet growth factor receptor (PDGF), ABL tyrosine kinase, fibroblast growth factor receptor (FGFR), interleukin receptor-associated kinase (IRAK), human tyrosine kinase receptor (FLT), V-raf mouse sarcoma virus oncogene homolog B (BRAF), vascular endothelial growth factor receptor 2 (KDR), vascular endothelial growth factor (VEGFR), transfection rearrangement kinase (RET), Bruton's tyrosine kinase (BTK), B-lymphotyrosine kinase (BLK), cytoplasmic tyrosine protein kinase (BMX), human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 4 (HER4), isocitrate dehydrogenase (IDH), discoid domain receptor 1 (DDR1), interleukin 2-induced T cell kinase (ITK), and human protein tyrosine kinase 4 (TXK).

[0236] In some embodiments, exemplary examples of diseases or disease states that can be used for the methods of treating or preventing tyrosine kinase (TK)-mediated diseases or disease states disclosed herein include, but are not limited to, non-small cell lung cancer, lymphoma, blastoma, sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, pancreatic islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia, lymphoid malignancies, lung cancer, squamous cell carcinoma of the lung, peritoneal cancer, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, biliary tract tumors, head and neck cancers, and hematologic malignancies.

[0237] In some embodiments, a method for treating or preventing tyrosine kinase (TK)-mediated diseases or disease states includes administering 1 mg to 10 g of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to an individual in need of the method.

[0238] In some embodiments, a method for treating or preventing tyrosine kinase (TK)-mediated diseases or disease states includes administering 10 mg to 3000 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to an individual requiring the method.

[0239] In some embodiments, a method for treating or preventing tyrosine kinase (TK)-mediated diseases or disease states includes administering 100 mg to 1000 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to an individual in need of the method.

[0240] In some embodiments, a method of treating or preventing tyrosine kinase (TK)-mediated diseases or disease states includes administering to an individual requiring the method 100 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, or 1000 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, the methods of treating or preventing tyrosine kinase (TK)-mediated diseases or disease states disclosed herein further include administering additional active agents to the individual.

[0242] In some embodiments, examples of active agents capable of being used in methods of treating or preventing tyrosine kinase (TK)-mediated diseases or disease states disclosed herein include, but are not limited to, nitrogen mustard, aziridine, methyl melamine, alkyl sulfonates, nitrosourea, triazine, folic acid analogs, pyrimidine analogs, purine analogs, vinca alkaloids, epipodophyllotoxin, antibiotics, topoisomerase inhibitors, anticancer vaccines, acyclovir, azorubicin, acodaazole hydrochloride, acroline, adorine, interleukin, ambroxol, amyronone acetate, aminoglutethimide, acridine, anastrozole, atrazoxyphenidyl, asparaginase, and triamcinolone. Acetaminophen, azacitidine, azatepa, azomycin, palmastat, benzothiazide, bicalutamide, bifenthrin hydrochloride, bis(2-naphthyl)fadyl mesylate, bizolexin, bleomycin sulfate, busulfan, actinomycin C, capprotestone, carbetamide, carbetin, carboplatin, carmustine, carrubicin hydrochloride, chlorambucil, siromycin, cladribine, cristatol mesylate, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin hydrochloride, decitabine, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifen, epirubicin hydrochloride Esomeprazole hydrochloride, estradiol, etorizine, etoposide, fluorouracil, fluorouracil, fluoxetine, gemcitabine, edabrine hydrochloride, ifosfamide, interleukin II, interferon α-2a, interferon α-2b, irinotecan hydrochloride, letrozole, mercaptopurine, methotrexate, chlorpheniramine, serinemycin, mitoxantrone, paclitaxel, procarbazine, sertepa, vincristine, vinblastine, angiogenesis inhibitors, camptothecin, dexamethasone, aspirin, acetaminophen, indomethacin, ibuprofen, ketoprofen, meloxicam, corticosteroids, and adrenocortical steroids.

[0243] On the other hand, this disclosure relates to the compounds of this disclosure and pharmaceutically acceptable salts thereof for inhibiting tyrosine kinase (TK).

[0244] In another aspect, this disclosure relates to compounds of the disclosure and pharmaceutically acceptable salts thereof for the treatment or prevention of tyrosine kinase (TK)-mediated diseases or disease states.

[0245] In another aspect, this disclosure relates to the use of the compounds of this disclosure and pharmaceutically acceptable salts thereof in the preparation of medicaments for inhibiting tyrosine kinase (TK).

[0246] On the other hand, this disclosure relates to the use of the compounds of this disclosure and pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of tyrosine kinase (TK)-mediated diseases or disease states.

[0247] In the following sections, this disclosure will be explained in detail through the following embodiments to provide a better understanding of the various aspects of this application and its advantages. However, it should be understood that the following embodiments are non-limiting and are only used to illustrate certain implementations of this disclosure.

[0248] Example

[0249] The reagents and equipment used in the embodiments of this disclosure are all conventional and commercially available. For example:

[0250] Preparation Example 1

[0251] Preparation of N-(4-chlorophenyl)-N'-[6-[2-methyl-4-(piperidin-4-ylamino)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]butane-1,4-diamine (compound 1)

[0252] Step a: Synthesis of tert-butyl 4-((4-chlorophenyl)amino)-4-oxobutyl)carbamate

[0253] To a mixture of p-chloroaniline (2.03 g, 10 mmol) in DCM (35 mL, 0.3 M), EDCI (3.834 g, 20 mmol), HOBT (1.35 g, 10 mol), DIPEA (2.585 g, 20 mol), and 4-((tert-Butoxycarbonyl)amino)butyric acid (1.28 g, 10 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with DCM (20 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude product, which was further purified by silica column chromatography to give a colorless oily compound (1.641 g, 52%).

[0254] Step b: Synthesis of 4-amino-N-(4-chlorophenyl)butyramide

[0255] DCM / TFA (24 mL / 24 mL, 0.1 M) was added to tert-butyl 4-((4-chlorophenyl)amino)-4-oxobutyl)carbamate (1.50 g, 4.8 mmol). The reaction mixture was stirred at room temperature for 1 hour, and TLC showed no starting material residue. The reaction mixture was concentrated to remove most of the DCM and TFA. The crude product was pumped with an oil pump and milled with Et2O to obtain the TFA salt. It was then extracted with EA, and the pH was adjusted to 12 to convert the compound to a free amine. Further purification was performed by silica gel column chromatography to give the desired product (818.6 mg, 79%) as a white solid.

[0256] Step c: N 1 Synthesis of 1,4-(4-chlorophenyl)butane-1,4-diamine

[0257] BH3-Me2S (2.5 mL, 5 mmol, 2 M in THF) was added to a mixture of 4-amino-N-(4-chlorophenyl)butyramide (425.4 mg, 2 mmol) in THF (2 mL, 1 M). The reaction was stirred at 67 °C for 1 hour, and TLC showed no residue of starting material. The reaction was quenched with MeOH, and the solvent was removed. The reaction was purified by silica column chromatography to give the desired product (233.5 mg, 59%) as a white solid.

[0258] Step d: Synthesis of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[0259] To a mixture of 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 17.9 mmol) in THF (60 mL), NaH (1.08 g, 27 mmol, 60%) was added, and the mixture was stirred at 0 °C for 30 min. SEMCl (3.58 g, 3.8 mL, 8.64 mmol) was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 2 h, quenched with saturated NH4Cl solution. Extraction was performed with EtOAc (60 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was further purified by silica gel column chromatography to obtain the desired product (5.72 g, 78%).

[0260] Step e: Synthesis of N-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)piperidine-4-amine

[0261] In a reaction flask containing 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (4.1 g, 10 mmol), Pd(dppf)Cl2 (205 mg, 0.5 mmol), K2CO3 (2.76 g, 20 mmol), and N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)piperidin-4-amine (3.86 g, 12 mmol) were added. The mixture was purged with nitrogen three times, and then stirred at 100 °C for 4 hours in a dioxane / water mixture (45 mL / 5 mL). The mixture was extracted with EA, washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to give the desired product (3.055 g, 65%).

[0262] Step f: N 1 -(4-Chlorophenyl)-N 4 Synthesis of -(6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)butane-1,4-diamine

[0263] Add N-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)piperidin-4-amine (0.613 g, 1.3 mmol), Cs₂CO₃ (0.643 g, 1.974 mmol), and N to a 100 mL round-bottom flask. 1 1,4-(4-chlorophenyl)butane-1,4-diamine (0.299 g, 1.5 mmol) was prepared in NMP (6 mL, 0.2 M). The atmosphere was replaced with nitrogen three times, and then stirred overnight at 100 °C. The mixture was concentrated and purified by silica gel column chromatography to give the desired intermediate (585 mg, 71%).

[0264] Step g: N 1 -(4-Chlorophenyl)-N 4 Synthesis of 1,4-(6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)butane-1,4-diamine (PPC-006-022)

[0265] To N 1DCM / TFA (4 mL / 4 mL, 0.1 M) was added to (4-chlorophenyl)-N4-(6-(2-methyl-4-(piperidin-4-ylamino)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)butane-1,4-diamine (0.63 g, 1 mmol). The reaction was stirred at room temperature. After 1 hour, TLC showed no starting material residue. Most of the DCM and TFA were removed by concentration. Et2O was added to give the TFA salt of the product. Extraction was performed with EA, and the pH was adjusted to 12 to make the compound a free amine. The crude product was further purified by silica gel column chromatography to give title compound 1 (153.7 mg, 30%) as a white solid.

[0266] 1 H NMR (400MHz, DMSO-d6) δ11.44(s,1H),8.06(s,1H),7.30-7.27(m,1H),7.21(d,J= 8.2Hz,1H),7.04(d,J=8.8Hz,2H),6.54(d,J=8.8Hz,2H),6.51-6.42(m,3H),5.80- 5.77(m,1H),5.58(d,J=8.2Hz,1H),3.52-3.48(m,2H),3.04-2.97(m,4H),2.62-2 .56(m,2H),2.45-2.32(m,1H),2.33(s,3H),1.93-1.82(m,2H),1.70-1.57(m,4H).

[0267] MS(ESI) measurement value: [M+H + 505.16

[0268] Preparation Example 2

[0269] Preparation of N-ethyl-4-[[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]oxy]benzenesulfonamide (compound 2)

[0270] Step h: Synthesis of N-ethyl-4-methoxybenzenesulfonamide

[0271] A solution of DCM containing triethylamine (1.2 g, 12 mmol) and ethylamine (0.5 g, 11 mmol) was slowly added dropwise to a solution of 4-methoxybenzenesulfonyl chloride (2.1 g, 10 mmol) in 20 mL of DCM. The reaction was stirred at room temperature for 5 hours, and TLC showed no starting material residue. Most of the solvent was removed by concentration, and the crude product was further purified by silica gel column chromatography to give the desired product (1.68 g, 78%).

[0272] Step i: Synthesis of N-ethyl-4-hydroxybenzenesulfonamide

[0273] Boron tribromide (2.5 g, 10 mmol) was slowly added dropwise to a dry DCM (10 mL) solution of N-ethyl-4-methoxybenzenesulfonamide (1.08 g, 5 mmol). The reaction was stirred at room temperature for 3 hours, and TLC showed no starting material residue. Most of the solvent was removed by concentration, and the crude product was further purified by silica gel column chromatography to give the desired product (0.64 g, 63%).

[0274] Then, using a method similar to that in Example 1, N-ethyl-4-hydroxybenzenesulfonamide was used to replace N. 1 -(4-chlorophenyl)butane-1,4-diamine, through steps f and g, yielded the title compound 2.

[0275] 1 H NMR (400MHz, DMSO-d6) δ12.26 (s, 1H), 8.30 (s, 1H), 7.87 (d, J = 8.2Hz, 2H), 7.6 7-7.55(m,1H),7.51(d,J=8.2Hz,2H),7.29(d,J=8.2Hz,1H),6.60-6.45(m,2H) ,6.39(s,1H),5.73(d,J=8.2Hz,1H),3.17(m,1H),2.90-2.70(m,4H),2.35(s, 3H), 2.20 (s, 3H), 2.15-1.85 (m, 4H), 1.50-1.35 (m, 2H), 1.02 (t, J = 7.2Hz, 3H).

[0276] HRMS (ESI-TOF) measurement: [M+H + 521.2332

[0277] Preparation Example 3

[0278] Preparation of N-(4-chlorophenyl)-1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]azacycloheptane-3-carboxamide (compound 10)

[0279] Step 1: Synthesis of tert-butyl 3-((4-chlorophenyl)carbamoyl)aza-1-carboxylic acid

[0280] The reaction flask containing 1-(tert-butyloxycarbonyl)azabenzene-3-carboxylic acid (5 g, 20 mmol), p-chloroaniline (3.2 g, 25 mmol), and HATU (8.4 g, 22 mmol) was purged with nitrogen three times, and a DCM solution of DIPEA (3.3 g, 25 mmol) was added. The reaction was stirred at room temperature for 4 hours, and TLC showed no starting material residue. The product was extracted with EA, washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to give the desired product (4.3 g, 61%).

[0281] Then, using a method similar to that in Example 1, 4-((4-chlorophenyl)carbamoyl)aza-1-carboxylic acid tert-butyl ester was substituted with 3-((4-chlorophenyl)amino)-4-oxobutyl)carbamoyl ester, and N-(4-(4-chlorophenyl)amino)-4-oxobutyl)carbamoyl ester was substituted with 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine. The title compound 10 was prepared by substituting N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)piperidine-4-amine with pyrimidin-6-yl)-3-methylphenyl)piperidine-4-amine via steps b, f, e, and g.

[0282] 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),10.21(s,1H),8.12(s,1H),7.66(d,J=8.8Hz,2H),7.37(d,J=8. 8Hz,2H),7.22(d,J=8.3Hz,1H),6.47(s,1H),6.44(d,J=8.3Hz,1H),6.47(s,1H),5.62-5.56(m,1H),5 .35-5.31(m,1H),4.56-4.46(m,1H),4.42-4.30(m,1H),3.70-3.58(m,2H),3.03-2.95(m,1H),2.87-2 .77(m,1H),2.70-2.65(m,1H),2.35-2.32(m,1H),2.28(s,3H),2.03-1.63(m,6H),1.52-1.35(m,4H).

[0283] HRMS (ESI-TOF) measurement: 572.2902

[0284] Preparation Example 4

[0285] Preparation of 1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-methyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 15)

[0286] Step m: Synthesis of (S)-1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide

[0287] Using a method similar to that in Example 1, (S)-piperidine-3-carboxylic acid methyl ester hydrochloride was used to replace N1-(4-chlorophenyl)butane-1,4-diamine, 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine to replace N-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)piperidine-4-amine, DIPEA to replace Cs2CO3, and acetonitrile to replace NMP. After step f, (S)-1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acid methyl ester was obtained.

[0288] Methyl (S)-1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-carboxylic acid ester (1.3 g, 2 mmol) and TBD (0.56 g, 0.4 mmol) were purged with argon three times, and (4-(trifluoromethoxy)phenyl)methylamine was added. The mixture was then stirred overnight at 90 °C. The solution was concentrated and purified by silica gel column chromatography to give the desired product (0.74 g, 54%).

[0289] Step n: Synthesis of (S)-1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-methyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide

[0290] Iodomethane (0.14 g, 1 mmol) was added to a solution of (S)-1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (0.34 g, 0.5 mmol) and potassium carbonate (84 mg, 0.6 mmol) in DMF (2 mL). The reaction was stirred at room temperature for 4 hours, and TLC showed no starting material residue. The product was extracted with EA, washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to give the desired product (114 mg, 33%).

[0291] Then, using a method similar to that in Example 1, N-(3-methyl-4-(4,4,5,5-tetramethyl-1H-pyrazol-4-yl)boronic acid was substituted for N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-4-amine and (S)-1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-methyl-N-(4-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide) was substituted for 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidinium, through steps e and g, to obtain title compound 15.

[0292] 1 H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.25-7.17(m,2H),7.03-6.95(m,2H),6.89( s,1H),5.48(dt,J=12.5,1.2Hz,1H),4.17(dt,J=12.4,7.0Hz,1H),3.94(dd,J=12. 6,7.0Hz,1H),3.74(d,J=12.3Hz,1H),3.38-3.20(m,2H),2.84(s,3H),2.67(p,J= 6.9Hz,1H),2.44(s,6H),2.05-1.91(m,1H),1.88-1.75(m,1H),1.77-1.52(m,2H).

[0293] MS(ESI) measurement value: [M+H + 528.47

[0294] Preparation Example 5

[0295] Preparation of 1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 27)

[0296] Step o: Synthesis of 1-(tert-butyl)-3-ethyl 5-dimethyl-4-oxoperidin-1,3-dicarboxylic acid

[0297] 1-BOC-3,3-dimethyl-4-oxopiperidine (10.0 g, 44.0 mmol) was dissolved in tetrahydrofuran (100 mL), purged three times with nitrogen, and cooled to -40 °C. 52.8 mL (52.8 mmol) of lithium bis(trimethylsilylamino)amine was slowly added dropwise. The mixture was stirred at -40 °C for 30 min, and then ethyl cyanoformate (4.8 g, 48.4 mmol) was slowly added. The mixture was stirred at -40 °C for 2 hours, allowed to rise naturally to room temperature, and the TLC reaction was completed. The reaction was quenched with saturated NH4Cl solution. The mixture was extracted with EtOAc (100 mL × 2), the organic phases were combined, washed with 100 mL of water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was further purified by silica gel column chromatography to obtain the desired product as a pale yellow liquid (13.0 g, 98%).

[0298] Step p: Synthesis of 1-(tert-butyl)-3-ethyl-4-hydroxy-5,5-dimethylpiperidine-1,3-dicarboxylate

[0299] 3.2 g (86.8 mmol) of sodium borohydride was slowly added dropwise to 1-(tert-butyl)-3-ethyl 5-dimethyl-4-oxopiperidin-1,3-dicarboxylic acid (13.0 g, 43.4 mmol) in methanol (150 mL) under ice-water bath. After the addition was complete, the mixture was allowed to rise to room temperature and stirred for 2 hours. The reaction was completed by TLC and quenched with saturated NH4Cl solution. The mixture was extracted with EtOAc (100 mL × 2), and the organic phases were combined, washed with 100 mL of water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was further purified by silica gel column chromatography to obtain the desired product, a pale yellow liquid (6.9 g, 53%).

[0300] Step q: Synthesis of 1-(tert-butyl)-3-ethyl 5,5-dimethyl-4-(toluenesulfonyloxy)piperidine-1,3-dicarboxylate

[0301] 27.5 mL (27.5 mmol) of bis(tert-butyl)silylaminolithium was slowly added dropwise to 1-(tert-butyl)-3-ethyl-4-hydroxy-5,5-dimethylpiperidine-1,3-dicarboxylate (6.9 g, 22.9 mmol) in tetrahydrofuran (70 mL) under ice-water bath. After stirring in the ice-water bath for 30 min, 5.2 g (27.5 mmol) of p-toluenesulfonyl chloride was slowly added. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 2 hours. The reaction was completed by TLC and quenched with saturated NH4Cl solution. The mixture was extracted with EtOAc (100 mL × 2), the organic phases were combined, washed with 100 mL of water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography to obtain the desired product as a pale yellow liquid (9.7 g, 93%).

[0302] Step r: Synthesis of 1-(tert-butyl)-3-ethyl 5-dimethyl-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid

[0303] 16.2 g (106.5 mmol) of 1,8-diazacyclo[5,4,0]undecene-7 (DBU) was added to 1-(tert-butyl)-3-ethyl-5,5-dimethyl-4-(toluenesulfonyloxy)piperidine-1,3-dicarboxylate (9.7 g, 21.3 mmol) in toluene (100 mL). After the addition was complete, the mixture was heated to 80 °C and stirred for 5 hours. The reaction was completed by TLC and quenched with saturated NH4Cl solution. The mixture was extracted with EtOAc (100 mL × 2), and the organic phases were combined, washed with 100 mL of water, ammonium chloride solution, and saturated brine. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography to obtain the desired product as a pale yellow liquid (4.7 g, 78%).

[0304] Step s: Synthesis of 1-(tert-butyl)-3-ethyl 5-dimethylpiperidine-1,3-dicarboxylic acid

[0305] 4.7 g (16.6 mmol) of 1-(tert-butyl)-3-ethyl 5-dimethyl-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid was added to methanol (60 mL), followed by the addition of 2.4 g (10% palladium on carbon). The mixture was purged with hydrogen five times and stirred at rt for 12 hours. After the reaction was completed by TLC, the mixture was filtered, washed with 20 mL of methanol, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. This crude product was further purified by silica gel column chromatography to obtain the desired product, which was a pale yellow liquid (4.7 g, 99%).

[0306] Step m: Synthesis of tert-butyl 3,3-dimethyl-5-((4-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate

[0307] 4.7 g (16.5 mmol) of 1-(tert-butyl)-3-ethyl 5-dimethylpiperidine-1,3-dicarboxylic acid was added to 4.1 g (21.5 mmol) of 4-(trifluoromethoxy)benzylamine, followed by the addition of 3.4 g (24.8 mmol) of 1,5,7-triazabicyclo[4.4.0]decen-5-ene (TBD). After the addition was complete, the mixture was heated to 80 °C and stirred for 12 hours. The reaction was completed by TLC, cooled, and quenched with saturated NH4Cl solution. The mixture was extracted with EtOAc (100 mL × 2), and the organic phases were combined, washed with 100 mL of water, ammonium chloride solution, and saturated brine. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was further purified by silica gel column chromatography to obtain the desired product, a pale yellow liquid (6.2 g, 88%).

[0308] Step t: Synthesis of 5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide

[0309] 3,3-Dimethyl-5-((4-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (6.2 g, 14.4 mmol) was added to dioxane (30 mL) in 30 mL of 4M HCl solution. The mixture was stirred at rt for 2 hours. After the reaction was completed by LC-MS, the mixture was concentrated under reduced pressure to dryness to obtain the crude product, which was a white solid (4.3 g, 91%).

[0310] Step f: Synthesis of 1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide

[0311] 4.3 g (13.0 mmol) of 5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide was added sequentially to acetonitrile (50 mL) along with 5.3 g (13.0 mmol) of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine and 3.4 g (26.0 mmol) of N,N-diisopropylethylamine (DIPEA). After the addition was complete, the mixture was heated to 120 °C and stirred for 12 hours. The reaction was completed by TLC, cooled, and quenched with saturated NH4Cl solution. Extracted with EtOAc (100 mL × 2), the organic phases were combined, washed with 100 mL of water, then with ammonium chloride aqueous solution, then with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product, which was further purified by silica gel column chromatography to obtain the desired product as a pale yellow solid (3.8 g, 90%).

[0312] Step u: Synthesis of tert-butyl 4-(4-(3,3-dimethyl-5-((4-(trifluoromethoxy)benzyl)carbamoyl)piperidin-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazole-1-carboxylic acid

[0313] 0.1 g (0.14 mmol) of 1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (4 mL) was added sequentially to acetonitrile (4 mL). Then, 57.0 mg (0.18 mmol) of BOC-3,5-dimethylpyrazol-4-phenanthrol borate, 36.7 mg (28.0 mmol) of N,N-diisopropylethylamine (DIPEA), 6 mg (0.07 mmol) of Xphos-Pd-G3, 39.0 mg (0.28 mmol) of potassium carbonate, and 1 mL of water were added. After the addition was complete, the mixture was purged with nitrogen three times, and the temperature was raised to 100 °C with stirring for 12 hours. The reaction was completed by TLC, cooled, and quenched with saturated NH4Cl solution. Extracted with EtOAc (30 mL × 2), the organic phases were combined, washed with 50 mL of water and saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product, which was further purified by silica gel column chromatography to obtain the desired product as a pale yellow solid (0.06 g, 54.7%).

[0314] Step v: Synthesis of 1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 27)

[0315] 0.06 g (0.078 mmol) of 4-(4-(3,3-dimethyl-5-((4-(trifluoromethoxy)benzyl)carbamoyl)piperidin-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazole-1-carboxylic acid tert-butyl ester was added to dichloromethane (2 mL), followed by the addition of 2 mL of trifluoroacetic acid. The mixture was stirred at rt for 2 hours. After the reaction was completed by LCMS, the product was concentrated to dryness under reduced pressure. The product was dissolved in 2 mL of methanol, and ammonia was slowly added until alkaline. The mixture was stirred for another 2 hours. After the reaction was completed by LCMS, the product was concentrated to dryness under reduced pressure to obtain the crude target product. Further purification yielded a white solid (0.028 g, 67%).

[0316] 1 H NMR (400MHz, Methanol-d4) δ8.13 (s, 1H), 7.41 (d, J = 8.6Hz, 2H), 7.28-7.14 (m, 2H), 6.45 (s, 1H), 4.54-4.32 (m, 3H), 3.37 (s, 1H), 3.15 (dd, J=13.3,11.4Hz,1H),2.99(d,J=13.2Hz,1H),2.86(ddd,J=8.9,6.8,4.3Hz,1H),2.33(s,6H),1.78-1.72(m,2H),1.06(s,3H),0.94(s,3H).

[0317] MS(ESI) measurement value: [M+H + 542.08

[0318] Preparation Example 6

[0319] Preparation of 1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-difluoro-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 25)

[0320] Using a method similar to that in Example 5, methyl 1-BOC-5,5-difluoropiperidine-3-carboxylate was used to replace 3,3-dimethyl-5-((4-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate, and the title compound 25 was prepared by steps t, f, m, u, and v.

[0321] 1H NMR (400MHz, DMSO-d6) δ12.43 (s, 1H), 11.83-11.67 (m, 1H), 8.81 (t, J = 5.9Hz, 1H ),8.20(s,1H),7.60-7.09(m,4H),6.43(d,J=1.9Hz,1H),4.93(t,J=12.6Hz,1H) ,4.78(d,J=13.4Hz,1H),4.35(t,J=5.8Hz,2H),3.58(dd,J=32.3,13.7Hz,1H),3 .27(dd,J=13.4,11.4Hz,1H),2.96-2.84(m,1H),2.44-2.33(m,2H),2.25(s,6H).

[0322] MS(ESI) measurement value: [M+H + 550.37

[0323] Preparation Example 7

[0324] Preparation of 1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-bis(trideutermethyl)-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 55)

[0325] Step w: Synthesis of tert-butyl 3,3-bis(d3-methyl)-4-oxoperidin-1-carboxylate

[0326] 4.4 g (100.4 mmol) of NaH was slowly added to 1-BOC-4-piperidinone (10.0 g, 50.2 mmol) in DMF (100 mL) under ice-water bath conditions. After the addition was complete, the mixture was stirred for 30 minutes, followed by the slow dropwise addition of 15.3 g (105.4 μL) of deuterated iodomethane. The mixture was allowed to rise to room temperature for 2 h. The reaction was completed by TLC and quenched with saturated NH4Cl solution. The mixture was extracted with EtOAc (100 mL × 2), and the organic phases were combined, washed with 100 mL of water, ammonium chloride solution, and saturated brine. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was further purified by silica gel column chromatography to obtain the desired product as a pale yellow liquid (7.1 g, 61%).

[0327] Then, using a method similar to that in Example 5, 1-BOC-3,3-dimethyl-4-oxopiperidinium-1-carboxylic acid tert-butyl ester was substituted for 3,3-bis(d3-methyl)-4-oxopiperidinium-1-carboxylic acid, and the title compound 55 was prepared by steps o, p, q, r, s, m, t, f, u, and v.

[0328] 1H NMR (400MHz, Methanol-d4) δ8.13 (s, 1H), 7.49-7.30 (m, 2H), 7.23 (d, J = 8.2Hz, 2H), 6.44 (s, 1H), 4.91 (m, 1H), 4.51-4 .30(m,3H),3.15(dd,J=13.3,11.4Hz,1H),2.99(d,J=13.3Hz,1H),2.92-2.79(m,1H),2.33(s,6H),1.81-1.68(m,2H).

[0329] MS(ESI) measurement value: [M+H + 548.42

[0330] Preparation Example 8

[0331] Preparation of 5,5-dimethyl-1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide (compound 28)

[0332] Using a method similar to that in Example 5, the title compound 28 was prepared by replacing BOC-3,5-dimethylpyrazol-4-boronic acid ester with 1-methyl-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-4-amine with 1-methyl-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-4-amine via steps e and v.

[0333] 1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.45-7.36(m,2H),7.30-7.19(m,3H),6.66-6.56(m,2H),6.44 (s,1H),4.86(d,J=4.7Hz,1H),4.51-4.33(m,3H),3.48(ddd,J=10.3,6.4,3.4Hz,1H),3.16-3.09(m, 2H),2.86(dtd,J=11.8,8.9,8.4,3.9Hz,1H),2.83-2.53(m,5H),2.36(s,3H),2.14(dd,J=13.7,3.7 Hz,2H),1.75(d,J=8.2Hz,2H),1.64(d,J=11.6Hz,2H),1.51-1.35(m,2H),1.05(s,3H),0.95(s,3H).

[0334] MS(ESI) measurement value: [M+H + 650.30

[0335] Preparation Example 9

[0336] Preparation of 5,5-difluoro-1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide (compound 26)

[0337] Using a method similar to that of Example 6, the title compound 26 was prepared by replacing BOC-3,5-dimethylpyrazol-4-boronic acid ester with 1-methyl-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-4-amine with 1-methyl-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-4-amine via steps e and v.

[0338] 1 H NMR (400MHz, DMSO-d6) δ11.91-11.75(m,1H),8.82(t,J=5.9Hz,1H),8.19(s,1H),7.46-7.20(m,5H),6 .55-6.37(m,3H),5.63(d,J=8.0Hz,1H),4.95(t,J=12.5Hz,1H),4.76(d,J=13.4Hz,1H),4.51-4.20(m, 2H),3.55(dd,J=32.2,13.9Hz,1H),3.33-3.16(m,2H),2.97-2.83(m,1H),2.76(d,J=11.4Hz,2H),2.38 (d,J=12.7Hz,2H),2.29(s,3H),2.19(s,3H),2.10-1.99(m,2H),1.94-1.84(m,2H),1.48-1.33(m,2H).

[0339] MS(ESI) measurement value: [M+H + ]658.19

[0340] Preparation Example 10

[0341] Preparation of (3S)-1-[6-iodo-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]piperidine-3-carboxylic acid methyl ester (compound 6)

[0342] Using a method similar to that in Example 5, methyl (S)-piperidine-3-carboxylate was used to replace 3,3-dimethyl-5-((4-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate, and the title compound 6 was prepared by step f.

[0343] MS(ESI) measurement value: [M+H + 517.21

[0344] Preparation Example 11

[0345] Preparation of (S)-1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide (compound 5)

[0346] Using a method similar to that of Example 5, methyl (S)-piperidine-3-carboxylate was used instead of 3,3-dimethyl-5-((4-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate tert-butyl ester, and 1-methyl-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-4-amine was used instead of BOC-3,5-dimethylpyrazol-4-phenanthrol boronic acid ester, and the title compound 5 was prepared through steps f, m, and e.

[0347] 1 H NMR(400MHz,Chloroform-d)δ8.18(s,1H),7.81(s,1H),7.28(s,1H),7.26(d,J=2.1Hz,1H),7.19-7.09(m ,3H),6.56-6.46(m,2H),6.38(s,1H),5.37(s,2H),4.52(dd,J=14.8,5.9Hz,1H),4.37(m,2H),4.02-3.86( m,3H),3.45(dd,J=9.7,7.3Hz,2H),2.87(d,J=11.5Hz,2H),2.64(m,2H),2.35(s,4H),2.20(t,J=11.3Hz,2 H),2.14(s,5H),1.93(m,1H),1.72-1.64(m,2H),1.56(d,J=11.2Hz,2H),0.89-0.78(m,2H),-0.06(s,9H).

[0348] MS(ESI) measurement value: [M+H + 752.41

[0349] Preparation Example 12

[0350] Preparation of (3S)-1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide (compound 7)

[0351] Using a method similar to that in Example 5, methyl (S)-piperidine-3-carboxylate was used instead of 3,3-dimethyl-5-((4-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate tert-butyl ester, and 1-methyl-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-4-amine was used instead of BOC-3,5-dimethylpyrazol-4-phenanthrol boronic acid ester, and the title compound 7 was prepared by steps f, m, e, and v.

[0352] 1 H NMR (400MHz, DMSO-d6) δ11.70(d,J=2.1Hz,1H),8.54(t,J=6.0Hz,1H),8.13(s,1H),7.36(d,J=8.7Hz,2H),7.2 9(d,J=5.6Hz,2H),7.21(d,J=8.1Hz,1H),6.54-6.44(m,2H),6.40(d,J=2.1Hz,1H),5.63(d,J=8.1Hz,1H),4.7 0(d,J=13.0Hz,1H),4.61(d,J=13.2Hz,1H),4.39-4.20(m,3H),4.12(m,1H),3.24-3.14(m,4H),3.10(t,J=12. 6Hz,1H),2.81(m,2H),2.29(s,3H),2.24(s,3H),1.92(d,J=5.0Hz,3H),1.82-1.73(m,2H),1.49-1.34(m,2H).

[0353] MS(ESI) measurement value: [M+H + ]622.18

[0354] Preparation Example 13

[0355] Preparation of 5-methyl-1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide (compound 8)

[0356] Using a method similar to that in Example 5, methyl 5-methylpiperidin-3-carboxylate hydrochloride was used instead of 3,3-dimethyl-5-((4-(trifluoromethoxy)benzyl)carbamoyl)piperidin-1-carboxylate tert-butyl ester, and 1-methyl-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-4-amine was used instead of BOC-3,5-dimethylpyrazol-4-phenanthrol boronic acid ester, through steps f, m, e, and v, to prepare title compound 8.

[0357] 1 H NMR (400MHz, DMSO-d6) δ11.71(d,J=2.0Hz,1H),8.54(t,J=6.0Hz,1H),8.14(s,1H),7.37(d,J=8.7Hz,2H),7.30(d,J=8 .3Hz,2H),7.22(d,J=8.1Hz,1H),6.48(d,J=11.2Hz,2H),6.38(d,J=2.1Hz,1H),5.62(d,J=8.1Hz,1H),4.78(d,J=13.1H z,1H),4.66(d,J=12.9Hz,1H),4.39-4.23(m,2H),4.13(q,J=5.3Hz,1H),3.17(d,J=5.1Hz,2H),3.03(t,J=12.3Hz,1H), 2.80-2.71(m,2H),2.71-2.57(m,1H),2.29(s,3H),2.19(s,3H),2.08-1.83(m,5H),1.43(m,3H),0.96(d,J=6.6Hz,3H).

[0358] MS(ESI) measurement value: [M+H + 636.54

[0359] Preparation Example 14

[0360] Preparation of N-(4-chlorophenyl)-4-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]morpholine-2-carboxamide (compound 9)

[0361] Using a method similar to that in Example 5, methyl 2-morpholinocarboxylate was used to replace tert-butyl 3,3-dimethyl-5-((4-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate, and 1-methyl-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-4-amine was used to replace BOC-3,5-dimethylpyrazol-4-phenanthrol boronic acid ester, and the title compound 9 was prepared by steps f, m, e, and v.

[0362] 1 H NMR(400MHz,DMSO-d6)δ11.79(d,J=2.0Hz,1H),10.03(s,1H),8.20(s,1H),7.83-7.70(m,2H),7.43-7.3 1(m,2H),7.21(d,J=8.3Hz,1H),6.57-6.39(m,3H),5.62(d,J=8.1Hz,1H),4.76(d,J=12.9Hz,1H),4.41(d ,J=12.9Hz,1H),4.32-4.22(m,1H),4.16-4.08(m,2H),3.85-3.72(m,1H),3.17(d,J=5.1Hz,2H),2.73(d ,J=11.5Hz,2H),2.33(s,3H),2.17(s,3H),2.01(t,J=11.0Hz,2H),1.91-1.84(m,2H),1.43-1.30(m,2H).

[0363] MS(ESI) measurement value: [M+H + 560.35

[0364] Preparation Example 15

[0365] Preparation of tert-butyl 3,3-difluoro-4-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]oxopyrrolidine-1-carboxylate (compound 12)

[0366] Using a method similar to that in Example 1, N-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)-1-methylpiperidin-4-amine was substituted for N-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)piperidin-4-amine was substituted for N-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)piperidin-4-amine, and tert-butyl 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate was substituted for N-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)piperidin-4-amine ... 1-(4-chlorophenyl)butane-1,4-diamine, through step f, yields title compound 12.

[0367] 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H),7.06(d,J=8.3Hz,1H),6.54(s,1H),6.49(d,J=8.3Hz,1H),6.44(s,1H),6.03(s,1H),5 .77-5.72(m,1H),5.36(s,2H),4.07-3.75(m,4H),3.54(m,2H),3.35-3.10(m,4H),2.77-2.70(m,2H),2.17(s,3H),2.07(s, 3H),2.03-1.97(m,2H),1.90-1.78(m,2H),1.42(s,9H),0.74-0.67(m,2H),-0.13(s,9H).

[0368] MS(ESI) measurement value: [M+H + 673.35

[0369] Preparation Example 16

[0370] Preparation of N-[4-[4-(4,4-difluoropyrrolidine-3-yl)oxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3-methylphenyl]-1-methylpiperidin-4-amine (compound 11)

[0371] Using a method similar to that in Example 1, N-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)-1-methylpiperidin-4-amine was substituted for N-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)piperidin-4-amine was substituted for N-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)piperidin-4-amine, and tert-butyl 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate was substituted for N-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)piperidin-4-amine ... 1 -(4-chlorophenyl)butane-1,4-diamine, through steps f and g, yielded the title compound 11.

[0372] 1H NMR (400MHz, DMSO-d6) δ12.10(s,1H),8.34(s,1H),7.27(d,J=8.2Hz,1H),6.55-6.47(m,2H),6.36(s,1H),5.82-5.69(m,2H),3 .70-3.53(m,1H),3.08(m,1H),2.97-2.82(m,1H),2.51(s,3H),2.35(s,3H),2.05-1.96(m,2H),1.92(m,2H),1.54-1.39(m,4H).

[0373] MS (ESI) measurement: [M+H+] 443.32

[0374] Preparation Example 17

[0375] Preparation of 1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]piperidin-3-amine (compound 3)

[0376] Using a method similar to that in Example 1, N-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)-1-methylpiperidin-4-amine was substituted with N-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)piperidin-4-amine, and 3-tert-butoxycarbonylaminopiperidine was substituted with N- 1 -(4-chlorophenyl)butane-1,4-diamine, through steps f and g, yielded the title compound 3.

[0377] 1 H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.14(s,1H),7.20(d,J=8.2Hz,1H),6 .59-6.42(m,3H),5.60(d,J=8.1Hz,1H),4.62(d,J=11.8Hz,1H),4.41(d,J=1 3.1Hz,1H),3.27-2.98(m,5H),2.76(d,J=11.4Hz,2H),2.33(s,3H),2.20(s ,3H),2.13-1.94(m,3H),1.93-1.77(m,2H),1.54(m,2H),1.48-1.34(m,2H).

[0378] MS(ESI) measurement value: [M+H + 420.16

[0379] Preparation Example 18

[0380] Preparation of 1-(4-chlorophenyl)-3-[1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-3-yl]urea (compound 4)

[0381] Step a4: Synthesis of 1-(4-chlorophenyl)-3-[1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-3-yl]urea (compound 4)

[0382] 0.26 g (0.6 mmol) of 1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]piperidin-3-amine (2 mL) was added to DMF, along with 0.11 g (7.2 mmol) of p-chlorophenyl isocyanate and 0.15 g (1.2 mmol) of N,N-diisopropylethylamine. The mixture was stirred at rt for 2 hours. After the reaction was completed by LC-MS, the reaction was quenched with saturated NH4Cl solution. The mixture was extracted with EtOAc (50 mL × 2), and the organic phases were combined, washed with 50 mL of water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was further purified by silica gel column chromatography to prepare the title compound 4 as a pale yellow solid (0.27 g, 78%).

[0383] 1 H NMR (400MHz, DMSO-d6) δ11.63(d,J=2.0Hz,1H),8.58(s,1H),8.11(s,1H),7.46-7.36(m,2H),7.32-7.11(m,3H),6.62(d, J=2.3Hz,1H),6.50(d,J=2.3Hz,1H),6.47-6.36(m,2H),5.59(d,J=8.1Hz,1H),4.29(m,1H),4.09(m,1H),3.75(m,1H),3.58(m,1H),3.45(m 1H),3.20(m,2H),2.77(m,2H),2.32(s,3H),2.20(s,3H),2.07(m,2H),1.97-1.86(m,3H),1.60(m,2H),1.49-1.34(m,2H).

[0384] MS(ESI) measurement value: [M+H + 573.24

[0385] Preparation Example 19

[0386] Preparation of N-(4-chlorophenyl)-3,3-difluoro-4-[[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]oxy]pyrrolidin-1-carboxamide (compound 14)

[0387] Using a method similar to that of Example 18, 1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]piperidin-3-amine was prepared by step a4, replacing 1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]piperidin-3-amine.

[0388] MS(ESI) measurement value: [M+H + 597.34

[0389] Preparation Example 20

[0390] Preparation of N-(4-chlorophenyl)-3-[[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]-8-azabicyclo[3.2.1]octane-8-carboxamide (compound 13)

[0391] Using a method similar to that in Examples 17 and 18, 3-tert-butoxycarbonylaminopiperidine was replaced with 3-fluoro-6-methyl-2-pyridinecarboxaldehyde, and the title compound 13 was prepared by steps f, g, and a4.

[0392] 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),8.72(s,1H),8.32(s,1H),7.59(d,J=8.9Hz,2H),7.37-7.27(m,2H),7.23(d,J=8.1H z,2H),6.69(s,1H),6.50(s,1H),6.30(d,J=2.1Hz,1H),5.81(m,1H),5.69(m,1H),5.33(m,3H),4.52(m,2H),3.17(m,1H), 2.67(m,3H),2.32(m,3H),2.00(m,9H),1.85(m,3H).

[0393] MS(ESI) measurement value: [M+H + 600.42

[0394] Preparation Example 21

[0395] Preparation of (S)-N-methyl-1-[6-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide (compound 16)

[0396] Using a method similar to that of Example 5, 1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-methyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide was substituted for 1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide, and 1-methyl-4-[4-(tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-pyrazol-1-yl]piperidine was substituted for BOC-3,5-dimethylpyrazol-4-pinacol boronic acid ester, through steps u and v, to obtain title compound 16.

[0397] 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),8.29(s,1H),8.11(s,1H),8.07-7.95(m,1H),7.43-7.28(m,3H),7.26-7.22(m,1H),6.76(s,1H),4. 85-4.48(m,5H),4.28-4.22(m,1H),3.80-3.30(m,4H),3.22-3.06(m, 1H),3.03(s,3H),2.37(m,4H),2.16-1.94(m,5H),1.85-1.70(m,3H).

[0398] MS(ESI) measurement value: [M+H + 597.37

[0399] Preparation Example 22

[0400] Preparation of (S)-1-[6-[1-(1-ethylpiperidin-4-yl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-methyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide (compound 17)

[0401] Using a method similar to that in Example 5, 1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-methyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide was substituted for 1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide, and 1-ethyl-4-[4-(tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-pyrazol-1-yl]piperidine was substituted for BOC-3,5-dimethylpyrazol-4-pinacol boronic acid ester, through steps u and v, to obtain title compound 17.

[0402] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.29(s,1H),8.12(s,1H),8.08-7.95 (m,1H),7.45-7.30(m,3H),7.28-7.24(m,1H),6.76(s,1H),4.85-4.46(m,4H ),4.37-4.22(m,1H),3.58(m,5H),3.24-2.96(m,6H),2.71-2.61(m,2H),2.2 4-2.09(m,4H),2.02-1.89(m,1H),1.86-1.73(m,2H),1.13(t,J=7.3Hz,3H).

[0403] MS(ESI) measurement value: [M+H + 611.37

[0404] Preparation Example 23

[0405] Preparation of (S)-N-methyl-1-[6-[4-(4-methylpiperazin-1-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 18)

[0406] Using a method similar to that of Example 5, 1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-methyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide was replaced with (S)-1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide and BOC-3,5-dimethylpyrazol-4-boronic acid pinacol ester was replaced with 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid pinacol ester, and the title compound 18 was prepared by steps e and v.

[0407] 1 H NMR (400MHz, Chloroform-d) δ12.05(s,1H),8.35(s,1H),7.80(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,2H),7.30(m,2H),7.21(d,J=5.7Hz,2H),6.84( s,1H),4.98(m,1H),4.77(m,1H),4.59(m,1H),3.85(m,2H),3.55(m,2H) ,3.33(m,3H),3.11(s,3H),2.45(m,4H),2.37(s,3H),2.11-1.92(m,4H).

[0408] MS(ESI) measurement value: [M+H + 636.42

[0409] Preparation Example 24

[0410] Preparation of (S)-1-[6-[4-(4-ethylpiperazine-1-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-methyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 19)

[0411] Using a method similar to that of Example 5, 1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-methyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide was substituted for 1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide, and 4-(4-ethylpiperazine-1-carbonyl)pinazone ester was substituted for BOC-3,5-dimethylpyrazol-4-pinazone ester, through steps e and v, to obtain title compound 19.

[0412] 1 H NMR(400MHz,DMSO-d6)δ12.28(s,1H),8.15(s,1H),7.98(m,2H),7.44(m,2H),7.34(m,3H),7.20(m,2H),4.96-4.56(m,4H),3. 54(m,5H),3.20(m,1H),3.03(m,1H),2.83(m,1H),2.37(m,7H),1.89(m,1H),1.79(m,2H),1.17(m,2H),1.01(t,J=7.1Hz,3H).

[0413] MS(ESI) measurement value: [M+H + 650.41

[0414] Preparation Example 25

[0415] Preparation of (S)-N-methyl-1-[6-[4-(morpholin-4-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 20)

[0416] Using a method similar to that of Example 5, 1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-methyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide was replaced with (S)-1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide and 4-(morpholino-4-carbonyl)phenylboronic acid was replaced with BOC-3,5-dimethylpyrazol-4-phenanol borate, and the title compound 20 was prepared by steps e and v.

[0417] 1 H NMR(400MHz,DMSO-d6)δ12.29(s,1H),8.15(s,1H),8.03(m,2H),7.47(m,2H),7.34(m,3H),7.25(m,2H),4.89-4.64(m,2H), 4.56(m,1H),3.61(m,9H),3.20(m,2H),3.03(s,2H),2.92(m,1H),2.83(m,1H),1.96(m,1H),1.82(m,2H),1.68-1.43(m,1H).

[0418] MS(ESI) measurement value: [M+H + 623.15

[0419] Preparation Example 26

[0420] Preparation of (S)-N-methyl-1-[6-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 21)

[0421] Using a method similar to that in Example 5, 1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-methyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide was replaced with (S)-1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide and (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid was replaced with BOC-3,5-dimethylpyrazol-4-phenazol boronic acid ester, and the title compound 21 was prepared by steps e and v.

[0422] 1 H NMR (400MHz, DMSO-d6) δ12.16(s,1H),8.13(s,1H),7.85(m,2H),7.32(m,5H),7.23(m,1H),7.05(m,1H),4.76(m,2H),4.56( q,J=15.0Hz,1H),3.43(m,5H),3.19(s,3H),3.03(s,2H),2.82(m,1H),2.36(m,6H),2.17(s,3H),1.99(m,2H),1.80(m,2H).

[0423] MS(ESI) measurement value: [M+H + ]622.22

[0424] Preparation Example 27

[0425] Preparation of 1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]azacycloheptane-4-carboxamide (compound 22)

[0426] Using a method similar to that in Example 5, methyl 5-dimethylpiperidine-1,3-dicarboxylic acid 1-(tert-butyl)-3-ethyl ester was replaced with methyl aziridine-4-carboxylate, and the title compound 22 was prepared by steps m, t, f, u, and v.

[0427] 1 H NMR(400MHz, DMSO-d6)δ8.12(s,1H),7.35(d,J=8.7Hz,2H),7.27-7.18(m,2H),6.45(s,1H),4.35(s,2H),4.20-4.05(m,2 H),3.97(m,1H),3.82(m,1H),2.42(m,1H),2.33(s,6H),2.29-2.00(m,2H),2.00-1.81(m,2H),1.73(m,1H),1.35(m,1H).

[0428] MS(ESI) measurement value: [M+H + 527.43

[0429] Preparation Example 28

[0430] Preparation of 1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]azacycloheptane-4-carboxamide (compound 23)

[0431] Using a method similar to that in Example 5, methyl aziridine-4-carboxylate was used to replace 1-(tert-butyl)-3-ethyl 5-dimethylpiperidine-1,3-dicarboxylate and 1-methyl-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-4-amine to replace BOC-3,5-dimethylpyrazol-4-phenanthrol boronic acid ester, and the title compound 23 was prepared by steps m, t, f, e, and v.

[0432] 1H NMR (400MHz, DMSO-d6) δ11.60(d,J=2.1Hz,1H),8.35(t,J=6.0Hz,1H),8.08(s,1H),7.36-7.25(m,4H),7.20(d,J=8.2 Hz,1H),6.55-6.44(m,2H),6.39(d,J=2.1Hz,1H),5.58(d,J=8.1Hz,1H),4.23(d,J=5.9Hz,2H),4.02(td,J=15.3,14. 9,5.3Hz,2H),3.86(ddd,J=14.0,8.8,4.3Hz,1H),3.73(ddd,J=14.3,9.9,4.6Hz,1H),3.30-3.11(m,1H),2.83-2.73( m,2H),2.32(s,3H),2.22(s,3H),2.16-1.96(m,4H),1.95-1.85(m,3H),1.77(m,2H),1.63-1.49(m,1H),1.43(m,2H).

[0433] MS(ESI) measurement value: [M+H + 636.38

[0434] Preparation Example 29

[0435] Preparation of (3S)-1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 24)

[0436] Using a method similar to that in Example 5, methyl (S)-piperidine-3-carboxylate was used to replace 1-(tert-butyl)-3-ethyl 5-dimethylpiperidine-1,3-dicarboxylate, and the title compound 24 was prepared by steps m, t, f, u, and v.

[0437] 1H NMR (400MHz, DMSO-d6) δ12.40(s,1H),11.60(d,J=2.0Hz,1H),8.54(t,J=5.9Hz,1H ),8.14(s,1H),7.54-7.19(m,4H),6.38(d,J=1.8Hz,1H),4.72(dt,J=13.4,2.5Hz,1 H),4.59(d,J=13.1Hz,1H),4.31(d,J=5.8Hz,2H),3.16(ddd,J=34.3,12.7,10.4Hz ,2H),2.47(s,1H),2.25(s,6H),2.01-1.91(m,1H),1.85-1.68(m,2H),1.50(m,1H).

[0438] MS(ESI) measurement value: [M+H + 514.39

[0439] Preparation Example 30

[0440] Preparation of 3-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]-3-azabicyclo[3.1.1]heptane-1-carboxamide (compound 29)

[0441] Using a method similar to that in Example 5, 1-(tert-butyl)-3-ethyl 5-dimethylpiperidine-1,3-dicarboxylic acid was prepared by replacing ethyl 3-azabicyclo[3.1.1]heptane-1-carboxylate with 1-ethyl 3-dimethylpiperidine-1,3-dicarboxylate, followed by steps m, t, f, u, and v, to obtain title compound 29.

[0442] 1 H NMR (400MHz, DMSO-d6) δ12.40(s,1H),11.58(s,1H),8.48(t,J=6.0Hz,1H),8.16(s,1H),7.50-7.20(m,4H),6.48(s,1H),4.35(d,J=5.9H z,2H),4.15(d,J=5.2Hz,1H),3.19(d,J=4.3Hz,3H),2.56(d,J=6.5Hz,1H),2.41-2.31(m,2H),2.26(s,6H),1.67(dd,J=6.8,2.6Hz,2H).

[0443] MS(ESI) measurement value: [M+H + 526.28

[0444] Preparation Example 31

[0445] Preparation of 1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidine-3-nitrile (compound 30)

[0446] Using a method similar to that in Example 5, the title compound 30 was prepared by replacing 5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide with piperidine-3-nitrile through steps f, u, and v.

[0447] 1 H NMR(400MHz,DMSO-d6)δ12.39(s,1H),11.64(m,1H),8.18(s,1H),6.44(d,J=1.9Hz,1H),4 .21(m,1H),4.05(m,2H),3.70(m,1H),3.14(m,1H),2.27(s,6H),1.97(m,2H),1.70(m,2H).

[0448] MS(ESI) measurement value: [M+H + 322.21

[0449] Preparation Example 32

[0450] Preparation of 1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[2-fluoro-4-(trifluoromethoxy)phenyl]methyl]-5,5-dimethylpiperidin-3-carboxamide (compound 31)

[0451] Using a method similar to that in Example 5, 4-(trifluoromethoxy)benzylamine was replaced with 2-fluoro-4-(trifluoromethoxy)benzylamine, and the title compound 31 was prepared through steps m, t, f, u, and v.

[0452] 1H NMR (400MHz, DMSO-d6) δ12.41 (s, 1H), 11.67-11.52 (m, 1H), 8.59 (t, J = 5.7Hz, 1H), 8.13 (s, 1H), 7 .46(t,J=8.5Hz,1H),7.36(dd,J=10.2,2.4Hz,1H),7.23(dd,J=8.4,2.3Hz,1H),6.37(d,J=1.6Hz, 1H),4.86(dd,J=12.7,3.8Hz,1H),4.47-4.29(m,3H),2.95(t,J=12.3Hz,1H),2.85(d,J=13.1Hz,1 H),2.75(ddt,J=11.4,6.9,4.3Hz,1H),2.27(s,6H),1.69-1.56(m,2H),1.00(s,3H),0.87(s,3H).

[0453] MS(ESI) measurement value: [M+H + 560.35

[0454] Preparation Example 33

[0455] Preparation of N-[[2-fluoro-4-(trifluoromethoxy)phenyl]methyl]-5,5-dimethyl-1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-3-carboxamide (compound 32)

[0456] Using a method similar to that in Example 5, 4-(trifluoromethoxy)benzylamine was replaced with (2-fluoro-4-(trifluoromethoxy)phenyl)methylamine and BOC-3,5-dimethylpyrazol-4-boronic acid ester was replaced with 1-methyl-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-4-amine, and the title compound 32 was prepared through steps m, t, f, e, and v.

[0457] 1H NMR (400MHz, DMSO-d6) δ11.70(d,J=2.1Hz,1H),8.60(t,J=5.8Hz,1H),8.11(s,1H),7.45(t,J=8.5Hz,1H),7.36(dd,J= 10.2,2.3Hz,1H),7.23(d,J=8.1Hz,2H),6.50(d,J=8.7Hz,2H),6.40(d,J=2.1Hz,1H),5.65(d,J=8.0Hz,1H),4.91-4.75 (m,1H),4.41(d,J=13.3Hz,1H),4.36-4.28(m,2H),3.30-3.25(m,1H),2.98-2.95(m,1H),2.88-2.82(m,3H),2.75(m,1H ),2.31(s,3H),2.23(s,3H),2.21(m,2H),1.92(m,2H),1.71-1.54(m,2H),1.53-1.38(m,2H),1.00(s,3H),0.86(s,3H).

[0458] MS(ESI) measurement value: [M+H + 668.41

[0459] Preparation Example 34

[0460] Preparation of 1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[4-(trifluoromethoxy)phenyl]methyl]-2,6-dihydropyridine-3-carboxamide (compound 33)

[0461] Using a method similar to that in Example 5, 5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide was prepared by replacing 5-dimethyl-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid 1-(tert-butyl)-3-ethyl ester with 5-dimethyl-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid 1-(tert-butyl)-3-ethyl ester, through steps m, t, f, u, and v, to obtain title compound 33.

[0462] 1 H NMR(400MHz,Methanol-d4)δ8.16(s,1H),7.52-7.37(m, 2H),7.22(d,J=8.2Hz,2H),6.68-6.38(m,2H),4.65(d,J=2.0Hz,2H),4.48(s,2H),3.84(s,2H),2.33(s,6H),1.17(s,6H).

[0463] MS(ESI) measurement value: [M+H +540.27

[0464] Preparation Example 35

[0465] Preparation of 5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]-1-[6-(1,3,5-trimethylpyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidine-3-carboxamide (compound 34)

[0466] Using a method similar to that in Example 5, the title compound 34 was prepared by replacing BOC-3,5-dimethylpyrazole-4-phenazine borate with 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole, followed by steps u and v.

[0467] 1 H NMR (400MHz, Methanol-d4) δ8.12(s,1H),7.40(d,J=8.3Hz,2H),7.22(d,J=8.2Hz,2H),6.42(s,1H),4.87(d,J=3.9Hz,1H),4.52-4.32(m,3H),3.77(s, 3H),3.13(dd,J=13.2,11.4Hz,1H),2.96(d,J=13.2Hz,1H),2.85(dt,J=6.7 ,3.0Hz,1H),2.28(s,6H),1.74(d,J=8.6Hz,2H),1.04(s,3H),0.93(s,3H).

[0468] MS(ESI) measurement value: [M+H + 556.18

[0469] Preparation Example 36

[0470] Preparation of 1-[6-(2,4-dimethylpyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 35)

[0471] Using a method similar to that in Example 5, the title compound 35 was prepared by replacing BOC-3,5-dimethylpyrazole-4-pinacol ester with 1,4-dimethylpyrazole-5-boronate pinacol ester through steps u and v.

[0472] 1H NMR (400MHz, Methanol-d4) δ8.19 (s, 1H), 7.51-7.34 (m, 3H), 7.23 (d, J = 8.2Hz, 2H), 6.74 (s, 1H), 4.99-4.93 (m, 1H), 4.53-4. 34(m,3H),3.84(s,3H),3.16(dd,J=13.3,11.4Hz,1H),3.00(d,J=13.2Hz,1H),2.85(m,1H),2.10(s,3H),1.80-1.70(m,2H), 1.06(s,3H),0.94(s,3H).

[0473] MS(ESI) measurement value: [M+H + 542.28

[0474] Preparation Example 37

[0475] Preparation of 5,5-dimethyl-1-[6-(2-methylpyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 36)

[0476] Using a method similar to that in Example 5, the title compound 36 was prepared by replacing BOC-3,5-dimethylpyrazole-4-phenazine borate with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester through steps u and v.

[0477] 1 H NMR (400MHz, DMSO-d6) δ12.17(s,1H),8.59(t,J=5.9Hz,1H),8.18(s,1H),7.48(d,J=1.8Hz,1H ),7.40(d,J=8.5Hz,2H),7.33(d,J=8.3Hz,2H),6.82(s,1H),6.69(d,J=1.8Hz,1H),4.89(d,J= 13.5Hz,1H),4.46(d,J=13.2Hz,1H),4.33(d,J=5.8Hz,2H),3.97(s,3H),3.02(t,J=12.4Hz,1H ),2.91(d,J=13.2Hz,1H),2.81-2.68(m,1H),1.66(d,J=8.4Hz,2H),1.03(s,3H),0.85(s,3H).

[0478] MS(ESI) measurement value: [M+H + 528.31

[0479] Preparation Example 38

[0480] Preparation of 1-[6-[1-(2-cyanoethyl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 37)

[0481] Using a method similar to that in Example 5, the title compound 37 was prepared by replacing BOC-3,5-dimethylpyrazole-4-pinacol boronic acid ester with 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrazole-1-propionitrile and proceeding through steps u and v.

[0482] 1 H NMR (400MHz, DMSO-d6) δ12.09-11.97(m,1H),8.58(t,J=5.9Hz,1H),8.26(s,1H),8.08(d, J=24.3Hz,2H),7.54-7.23(m,4H),6.73(d,J=1.9Hz,1H),4.96-4.83(m,1H),4.54-4.20(m, 5H),3.10(t,J=6.3Hz,2H),3.01-2.84(m,2H),2.79-2.66(m,1H),1.72-1.56(m,2H),1.04(s,3H),0.88(s,3H).

[0483] MS(ESI) measurement value: [M+H + 567.32

[0484] Preparation Example 39

[0485] Preparation of 5,5-dimethyl-1-[6-(1,3-thiazolyl-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 38)

[0486] Using a method similar to that in Example 5, the title compound 38 was prepared by replacing BOC-3,5-dimethylpyrazole-4-pinacol boronic acid ester with 5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)thiazole with 5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)thiazole, through steps u and v.

[0487] 1H NMR (400MHz, DMSO-d6) δ12.45(s,1H),9.07(s,1H),8.63(t,J=5.9Hz,1H),8. 36(s,1H),8.17(s,1H),7.41(d,J=8.7Hz,2H),7.34(d,J=8.3Hz,2H),6.91(s, 1H),4.92-4.76(m,1H),4.49-4.41(m,1H),4.33(d,J=5.8Hz,2H),3.06-2.82 (m,2H),2.78-2.74(m,1H),1.64(d,J=11.5Hz,2H),1.03(s,3H),0.84(s,3H).

[0488] MS(ESI) measurement value: [M+H + 531.23

[0489] Preparation Example 40

[0490] Preparation of 5,5-dimethyl-1-[6-[2-(2-methylpropyl)pyrazol-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 39)

[0491] Using a method similar to that in Example 5, the title compound 39 was prepared by replacing BOC-3,5-dimethylpyrazole-4-pyrrolidone ester with 1-(2-methylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1hpyrazole with 1-(2-methylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1hpyrazole, following steps u and v.

[0492] 1 H NMR (400MHz, DMSO-d6) δ12.19(s,1H),8.62(t,J=5.9Hz,1H),8.19(s,1H),7.52(d,J=1.9H z,1H),7.44-7.26(m,4H),6.79-6.63(m,2H),4.93-4.91(m,1H),4.44-4.17(m,4H),4.13- 4.09(m,1H),3.06-2.88(m,2H),2.79-2.68(m,1H),2.11-2.08(m,1H),1.73-1.54(m,2H),1.02(s,3H),0.86(s,3H),0.83-0.77(m,6H).

[0493] MS(ESI) measurement value: [M+H + 570.13

[0494] Preparation Example 41

[0495] Preparation of 1-[6-(3,5-dimethyl-1,2-oxazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 40)

[0496] Using a method similar to that in Example 5, the title compound 40 was prepared by replacing BOC-3,5-dimethylpyrazole-4-boronic acid pinacol ester with 3,5-dimethylisoxazole-4-boronic acid pinacol ester through steps u and v.

[0497] 1 H NMR(400MHz, Methanol-d4)δ8.16(s,1H),7.48-7.35(m,2H),7.25(d,J=8.2Hz,2H),6.62(s,1H),4.97-4.93(m,1H),4.50-4.33(m,3 H),3.21-3.14(m,1H),3.09-3.00(m,1H),2.88-2.84(m,1H),2.49(s,3H),2.33(s,3H),1.81-1.68(m,2H),1.07(s,3H),0.94(s,3H).

[0498] MS(ESI) measurement value: [M+H + 543.35

[0499] Preparation Example 42

[0500] Preparation of 1-[6-(2-ethylpyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 41)

[0501] Using a method similar to that in Example 5, BOC-3,5-dimethylpyrazole-4-pinacol ester was replaced with 1-ethylpyrazole-5-boronic acid pinacol ester, and the title compound 41 was prepared by steps u and v.

[0502] 1H NMR (400MHz, Methanol-d4) δ8.19 (s, 1H), 7.58 (d, J = 2.0Hz, 1H), 7.46-7.38 (m, 2H), 7.25 ( d,J=8.2Hz,2H),6.78(s,1H),6.61(d,J=2.0Hz,1H),4.95-4.90(m,1H),4.47-4.29(m,5H), 3.19-1.15(m,1H),3.10-3.03(m,1H),2.89-2.85(m,1H),1.77(d,J=8.3Hz,2H),1.41(t,J=7.2Hz,3H),1.08(s,3H),0.95(s,3H).

[0503] MS(ESI) measurement value: [M+H + 542.36

[0504] Preparation Example 43

[0505] Preparation of 1-[6-(1-cyclohexylpyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 42)

[0506] Using a method similar to that in Example 5, the title compound 42 was prepared by replacing BOC-3,5-dimethylpyrazole-4-pyrrolidone ester with 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole, followed by steps u and v.

[0507] 1 H NMR (400MHz, Methanol-d4) δ8.13(s,1H),8.11(s,1H),7.91(s,1H),7.43(d,J=8.3Hz,2H),7.26(d,J=8.1Hz,2H),6.71(s,1H),4.62(m,1H),4.43(m, 3H),4.18(m,1H),3.13(m,1H),3.00(m,1H),2.82(m,1H),2.17(m,2H),1.9 4(m,2H),1.75(m,4H),1.51(m,2H),1.33(m,2H),1.08(s,3H),0.94(s,3H).

[0508] MS(ESI) measurement value: [M+H + 596.39

[0509] Preparation Example 44

[0510] Preparation of 5,5-dimethyl-1-[6-[1-(oxopentyl-3-yl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 43)

[0511] Using a method similar to that in Example 5, the title compound 43 was prepared by replacing BOC-3,5-dimethylpyrazole-4-boronic acid pinacol ester with 1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-boronic acid pinacol ester through steps u and v.

[0512] 1 H NMR (400MHz, Methanol-d4) δ8.15(s,1H),8.10(s,1H),7.94(s,1H),7.43(d,J=8.4Hz,2H),7.26(d,J=8.4Hz,2H),6.73(s,1H), 5.09(m,1H),4.62(m,1H),4.45(m,3H),4.17(m,1H),4.10(m,2H),3.99(m,1H),3.13(m,1H),3.00(m,1H),2.82(m,1H),2.55(m, 1H),2.36(m,1H),1.75(m,2H),1.31(m,2H),1.08(s,3H),0.94(s,3H).

[0513] MS(ESI) measurement value: [M+H + 584.36

[0514] Preparation Example 45

[0515] Preparation of 1-[6-(1-tert-butylpyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 44)

[0516] Using a method similar to that in Example 5, the title compound 44 was prepared by replacing BOC-3,5-dimethylpyrazole-4-pyrrolidone ester with 1-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyrazole with 1-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyrazole, through steps u and v.

[0517] 1H NMR(400MHz,Methanol-d4)δ8.23(s,1H),8.10(s,1H),7.94(s,1H),7.40(m,2H),7.26(m,2H),6.73(s,1H),4.87 (m,1H),4.43(m,3H),3.13(m,1H),3.00(m,1H),2.86(m,1H),1.75(m,2H),1.65(s,9H),1.08(s,3H),0.94(s,3H).

[0518] MS(ESI) measurement value: [M+H + 570.37

[0519] Preparation Example 46

[0520] Preparation of 5,5-dimethyl-1-[6-(1-prop-2-phenylpyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 45)

[0521] Using a method similar to that in Example 5, the title compound 45 was prepared by replacing BOC-3,5-dimethylpyrazole-4-pinacol boronic acid ester with 1-(2-propen-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole in steps u and v.

[0522] 1 H NMR (400MHz, Methanol-d4) δ8.09(s,1H),8.06(s,1H),7.94(s,1H),7.42(d,J=8.2Hz,2H),7.25(d,J=8.2Hz,2H),6.72(s,1H),6.09 (m,1H),5.26(m,2H),4.91-4.69(m,3H),4.42(m,3H),3.11(m,1H),2.99(m,1H),2.84(m,1H),1.74(m,2H),1.07(s,3H),0.92(s,3H).

[0523] MS(ESI) measurement value: [M+H + 554.30

[0524] Preparation Example 47

[0525] Preparation of 5,5-dimethyl-1-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 46)

[0526] Using a method similar to that in Example 5, the title compound 46 was prepared by replacing BOC-3,5-dimethylpyrazole-4-phenazine boronic acid with [1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid through steps e and v.

[0527] MS(ESI) measurement value: [M+H + 529.71

[0528] Preparation Example 48

[0529] Preparation of 1-[6-[1-(2-fluoroethyl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 47)

[0530] Using a method similar to that in Example 5, the title compound 47 was prepared by replacing BOC-3,5-dimethylpyrazole-4-pinacol ester with 1-(2-fluoroethyl)-4-pyrazoleboronic acid pinacol ester through steps u and v.

[0531] 1 H NMR(400MHz,Methanol-d4)δ8.11(s,1H),8.10(s,1H),7.97(s,1H),7.43(d, J=8.7Hz,2H),7.32-7.17(m,2H),6.73(s,1H),4.89-4.82(m,1H),4.76-4.73 (m,1H),4.57-4.54(m,1H),4.49-4.41(m,5H),3.15-3.09(m,1H),3.05-3.00 (m,1H),2.86-2.84(m,1H),1.75(d,J=8.3Hz,2H),1.08(s,3H),0.94(s,3H).

[0532] MS(ESI) measurement value: [M+H + 560.27

[0533] Preparation Example 49

[0534] Preparation of 1-[6-[1-(2,2-difluoroethyl)pyrazol-4-yl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 48)

[0535] Using a method similar to that in Example 5, the title compound 48 was prepared by replacing BOC-3,5-dimethylpyrazole-4-phenazine boronic acid ester with 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole in steps u and v.

[0536] 1 H NMR(400MHz,Methanol-d4)δ8.13(s,1H),8.11(s,1H),8.00(s,1H),7.51-7.39(m,2 H),7.32-7.23(m,2H),6.75(s,1H),6.24(tt,J=55.1,3.7Hz,1H),4.93-4.79(m,1H) ,4.70-4.57(m,2H),4.43(d,J=13.6Hz,3H),3.14(dd,J=13.2,11.4Hz,1H),3.01(d, J=13.2Hz,1H),2.92-2.77(m,1H),1.76(d,J=8.3Hz,2H),1.09(s,3H),0.94(s,3H).

[0537] MS(ESI) measurement value: [M+H + 578.34

[0538] Preparation Example 50

[0539] Preparation of 5,5-dimethyl-1-[6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 49)

[0540] Using a method similar to that in Example 5, the title compound 49 was prepared by replacing BOC-3,5-dimethylpyrazole-4-phenazine boronic acid ester with 1-(oxecyclobutane-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronide-2-yl)-1H-pyrazole in steps u and v.

[0541] 1H NMR(400MHz, Methanol-d4)δ8.23(s,1H),8.11(s,1H),8.04(s,1H),7.53-7. 37(m,2H),7.27(d,J=8.2Hz,2H),6.75(s,1H),5.69-5.51(m,1H),5.15-5.07 (m,4H),4.89-4.83(m,1H),4.49-4.38(m,3H),3.20-3.13(m,1H),3.07-3.01 (m,1H),2.89-2.85(m,1H),1.76(d,J=8.4Hz,2H),1.08(s,3H),0.94(s,3H).

[0542] MS(ESI) measurement value: [M+H + 570.28

[0543] Preparation Example 51

[0544] Preparation of 1-[6-(1,3-dimethylpyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 50)

[0545] Using a method similar to that in Example 5, the title compound 50 was prepared by replacing BOC-3,5-dimethylpyrazole-4-boronic acid pinacol ester with 1,3-dimethylpyrazole-4-boronic acid pinacol ester through steps u and v.

[0546] 1 H NMR (400MHz, Methanol-d4) δ8.13(d,J=4.5Hz,1H),7.87(d,J=4.1Hz,1H),7.44(d,J=8.5Hz ,2H),7.27(d,J=7.9Hz,2H),6.53(d,J=4.0Hz,1H),4.87(m,1H),4.46(q,J=6.5,4.4Hz,3H) ,3.90(d,J=4.1Hz,3H),3.17(t,J=12.7Hz,1H),3.00(d,J=13.1Hz,1H),2.90-2.85(m,1H), 2.41(d,J=4.2Hz,3H), 1.78(d,J=7.4Hz,2H), 1.08(d,J=4.1Hz,3H), 0.95(d,J=4.2Hz,3H).

[0547] MS(ESI) measurement value: [M+H + 542.32

[0548] Preparation Example 52

[0549] Preparation of 1-[6-[1-(1,3-dioxolane-2-ylmethyl)pyrazol-4-yl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 51)

[0550] Using a method similar to that in Example 5, the title compound 51 was prepared by replacing BOC-3,5-dimethylpyrazole-4-boronic acid pinacol ester with 1-((1,3-dioxolane-2-yl-)-methyl-1-hydro-pyrazole-4-boronic acid pinacol ester through steps u and v.

[0551] 1 H NMR (400MHz, Methanol-d4) δ8.10(s,2H),7.94(s,1H),7.43(d,J=8.5,2H),7.27(d,J=8.1,2H),6.73(s,1H),5.23(m,1H),4.87(m,1H),4.44(m,2 H),4.35(m,2H),3.88(s,4H),3.19-3.08(m,1H),2.99(d,J=13.1,1H),2 .86(dd,J=11.9,7.5,1H),1.75(d,J=8.4,2H),1.08(s,3H),0.93(s,3H).

[0552] MS(ESI) measurement value: [M+H + 600.37

[0553] Preparation Example 53

[0554] Preparation of 1-[6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 52)

[0555] Using a method similar to that in Example 5, the title compound 52 was prepared by replacing BOC-3,5-dimethylpyrazole-4-pyrazole borate with 1-(2-hydroxy-2-methyl-propyl)pyrazole-4-yl]boronic acid ester, followed by steps u and v.

[0556] 1H NMR (400MHz, Methanol-d4) δ8.10(s,2H),7.93(s,1H),7.43(d,J=8.3Hz,2H),7.27(d,J=8.3Hz,2H),6.72(s,1H),4.88(m,1H),4.48-4.43(m,3H), 4.15(s,2H),3.18-3.08(m,1H),3.05-2.97(m,1H),2.88-2.83(m,1H),1. 75(d,J=8.5Hz,2H),1.31(m,1H),1.22(s,6H),1.08(s,3H),0.94(s,3H).

[0557] MS(ESI) measurement value: [M+H + 586.38

[0558] Preparation Example 54

[0559] Preparation of 5,5-dimethyl-1-[6-[1-(oxan-4-yl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 53)

[0560] Using a method similar to that in Example 5, the title compound 53 was prepared by replacing BOC-3,5-dimethylpyrazole-4-boronic acid pinacol ester with 1-(tetrahydropyran-4-yl)-1H-pyrazole-4-boronic acid pinacol ester through steps u and v.

[0561] 1 H NMR (400MHz, Methanol-d4) δ8.16(s,1H),8.10(s,1H),7.94(s,1H),7.42(d,J=8. 6Hz,2H),7.26(d,J=8.2Hz,2H),6.73(s,1H),4.87(m,1H),4.50-4.38(m,4H),4.13 -4.05(m,2H),3.66-3.56(m,2H),3.17-3.09(m,1H),3.00(d,J=13.2Hz,1H),2.90 -2.80(m,1H),2.15-2.09(m,4H),1.75(d,J=8.3Hz,2H),1.08(s,3H),0.94(s,3H).

[0562] MS(ESI) measurement value: [M+H + 598.39

[0563] Preparation Example 55

[0564] Preparation of 5,5-dimethyl-1-[6-[1-(2-morpholin-4-ylethyl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 54)

[0565] Using a method similar to that in Example 5, the title compound 54 was prepared by replacing BOC-3,5-dimethylpyrazole-4-boronic acid pinacol ester with 1-(2-morpholinoethyl)-1H-pyrazole-4-boronic acid pinacol ester through steps u and v.

[0566] 1 H NMR (400MHz, Methanol-d4) δ8.10 (s, 2H), 7.93 (s, 1H), 7.43 (d, J = 8.4Hz, 2H), 7.26(d,J=8.4Hz,2H),6.71(s,1H),4.88(m,1H),4.49-4.40(m,3H),4.34(t,J =6.5Hz,2H),3.72-3.66(m,4H),3.19-3.06(m,1H),3.00(m,1H),2.85(t,J=6. 5Hz,3H),2.56-2.48(m,4H),1.75(d,J=8.4Hz,2H),1.08(s,3H),0.94(s,3H).

[0567] MS(ESI) measurement value: [M+H + 627.44

[0568] Preparation Example 56

[0569] Preparation of 1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3,3-dimethyl-4-oxo-N-[[4-(trifluoromethoxy)phenyl]methyl]-2H-pyridine-5-carboxamide (compound 56)

[0570] Using a method similar to that in Example 5, 5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide was replaced with 1-(tert-butyl)-3-ethyl 5-dimethyl-4-oxopiperidinium-1,3-dicarboxylic acid, and the title compound 56 was prepared by steps m, t, f, u, and v.

[0571] 1H NMR(400MHz,Methanol-d4)δ9.45(s,1H),8.56(s,1H),7.50-7.39(m,2H),7.29-7.1 9(m,2H),6.69(s,1H),4.32(s,2H),3.36(d,J=3.5Hz,2H),2.39(s,6H),1.24(s,6H).

[0572] MS(ESI) measurement value: [M+H + 554.26

[0573] Preparation Example 57

[0574] Preparation of 1-[6-(3,5-dimethyl-1-piperidin-4-ylpyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide (compound 57)

[0575] Using a method similar to that of Example 5, the title compound 57 was prepared by replacing BOC-3,5-dimethylpyrazol-4-phenazolyl borate with 4-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)piperidine, through steps u and v.

[0576] 1 H NMR (400MHz, Methanol-d4) δ8.13 (s, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8. 2Hz,2H),6.44(s,1H),4.92(m,1H),4.55-4.36(m,4H),3.51-3.43(m,2H),3.2 1-3.06(m,3H),3.00(m,1H),2.86(m,1H),2.38(s,3H),2.28(s,3H),2.27-2.1 5(m,2H),2.13-2.04(m,2H),1.75(d,J=8.4Hz,2H),1.08(s,3H),0.94(s,3H).

[0577] MS(ESI) measurement value: [M+H + 625.51

[0578] Preparation Example 58

[0579] Preparation of 5,5-dimethyl-1-[6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 58)

[0580] Using a method similar to that in Example 5, the title compound 58 was prepared by replacing BOC-3,5-dimethylpyrazole-4-boronic acid pinacol ester with 3-methyl-5-(trifluoromethyl)-1H-pyrazole-4-boronic acid pinacol ester through steps u and v.

[0581] 1 H NMR (400MHz, Methanol-d4) δ8.16 (s, 1H), 7.44-7.34 (m, 2H), 7.23 (d, J = 8.2Hz, 2H), 6.57 (s, 1H), 4.93 (m, 1H), 4.51 -4.33(m,3H),3.15(m,1H),3.01(m,1H),2.85(m,1H),2.38(s,3H),1.76(d,J=8.6Hz,2H),1.06(s,3H),0.95(s,3H).

[0582] MS(ESI) measurement value: [M+H + 596.31

[0583] Preparation Example 59

[0584] Preparation of 1-[6-[3,5-dimethyl-1-(oxan-4-yl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 59)

[0585] Using a method similar to that in Example 5, the title compound 59 was prepared by replacing BOC-3,5-dimethylpyrazole-4-pyrrolidone ester with 3,5-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole in steps u and v.

[0586] 1H NMR(400MHz, Methanol-d4)δ8.13(s,1H),7.45-7.37(m,2H),7.24(dt,J=7.7,1.1Hz,2H),6.43(s,1H),4.91(m,1H),4.51-4.34(m,4H),4.10(m ,2H),3.62(m,2H),3.15(m,1H),2.99(m,1H),2.86(m,1H),2.36(s,3H), 2.28(m,5H),1.85(m,2H),1.80-1.67(m,2H),1.06(s,3H),0.94(s,3H).

[0587] MS(ESI) measurement value: [M+H + 626.52

[0588] Preparation Example 60

[0589] Preparation of 1-[6-[2-(1,2-dihydroxypropyl-2-yl)-4-methyl-1,3-thiazolyl-5-yl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 60)

[0590] Step x: Synthesis of 2-(5-bromo-4-methylthiazol-2-yl)prop-2-ol

[0591] 5.6 g (35.6 mmol) of 2-(4-methylthiazol-2-yl)prop-2-ol was added to dichloromethane (100 mL) and cooled to 0 °C. 7.0 g (39.2 mmol) of N-bromosuccinimide (NBS) was slowly added, and the reaction was stirred for 2 hours after the addition was complete. The reaction was quenched by TLC with saturated NH4Cl solution after completion. The mixture was extracted with DCM (100 mL × 2), and the organic phases were combined, washed with 100 mL of water, ammonium chloride solution, and saturated brine. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was further purified by silica gel column chromatography to obtain the desired product as a white solid (8.2 g, 98%).

[0592] Step y: Synthesis of 5-bromo-4-methyl-2-(prop-1-en-2-yl)thiazole

[0593] 3.7 g (38.2 mmol) of concentrated sulfuric acid was slowly added to 80 mL of glacial acetic acid to 2-(5-bromo-4-methylthiazo-2-yl)prop-2-ol (8.2 g, 34.7 mmol). The mixture was heated to 85 °C and reacted overnight. After the reaction was completed by TLC, the mixture was poured into ice water and the pH was adjusted to 7 with sodium carbonate aqueous solution. The mixture was extracted with EtOAc (100 mL × 2). The organic phases were combined, washed with 100 mL of water, ammonium chloride aqueous solution, and saturated brine. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography to obtain the desired product as a yellow liquid (3.2 g, 42%).

[0594] Step z: Synthesis of 2-(5-bromo-4-methylthiazol-2-yl)propane-1,2-diol

[0595] 14.5 g of AD-mix-α was added to 5-bromo-4-methyl-2-(prop-1-en-2-yl)thiazole (3.2 g, 14.7 mmol) in tetrahydrofuran (15 mL), tert-butanol (15 mL), and water (15 mL). The reaction was carried out overnight at room temperature. After the reaction was completed by TLC, the mixture was extracted with EtOAc (100 mL × 2). The organic phases were combined, washed with 100 mL of water, ammonium chloride aqueous solution, and saturated brine. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography to obtain the desired product as a white solid (2.9 g, 78%).

[0596] Step a1: Synthesis of 1-(6-(2-(1,2-dihydroxypropyl-2-yl)-4-methylthiazolyl-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide

[0597] To prepare 2-(5-bromo-4-methylthiazolyl-2-yl)propane-1,2-diol (35.8 mg, 0.14 mmol), in methanol (6 mL) and water (1 mL), add 100 mg (0.14 mmol) of 1-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide and 10.0 mg (0.014 mmol) of dichlorodi-tert-butyl-(4-dimethyl)propane-1,2-diol (35.8 mg, 0.14 mmol) in methanol (6 mL) and water (1 mL), respectively. Aminophenyl)phosphine palladium(II), 53.2 mg (0.35 mmol) cesium fluoride, and 88.9 mg (0.35 mmol) pinacol diborate (B2Pin2) were reacted at 60 °C for 3 hours. After the reaction was completed by TLC, the mixture was cooled and extracted with EtOAc (60 mL × 2). The organic phases were combined, washed with 50 mL of water, ammonium chloride aqueous solution, and saturated brine, and dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography to obtain the desired product as a white solid (88.4 mg, 83%).

[0598] Step v: Synthesis of 1-[6-[2-(1,2-dihydroxypropyl-2-yl)-4-methyl-1,3-thiazolyl-5-yl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 60)

[0599] 1-(6-(2-(1,2-dihydroxypropyl-2-yl)-4-methylthiazolyl-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,5-dimethyl-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (88.4 mg, 0.12 mmol) was added to 2 mL of dichloromethane, and the mixture was stirred at rt for 2 hours. After the reaction was completed by LCMS, the mixture was concentrated to dryness under reduced pressure, dissolved in 2 mL of methanol, and ammonia was slowly added until alkaline. The mixture was stirred for another 2 hours. After the reaction was completed by LCMS, the mixture was concentrated to dryness under reduced pressure to obtain the crude target product, which was further purified to a white solid (44.5 mg, 61%).

[0600] 1H NMR (400MHz, Methanol-d4) δ8.16(s,1H),7.42(d,J=8.6Hz,2H),7.25(d,J=8.2Hz,2H),6.67(s,1H),4.93(m,1H),4.43(m, 3H),3.91-3.66(m,2H),3.15(m,1H),3.00(m,1H),2.86(m,1H),2.52(s,3H),1.84-1.71(m,2H),1.61(s,3H),1.07(s,3H),0.94(s,3H).

[0601] MS(ESI) measurement value: [M+H + 619.42

[0602] Preparation Example 61

[0603] Preparation of 1-[6-[1-(2-hydroxyethyl)-3,5-dimethylpyrazol-4-yl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 61)

[0604] Using a method similar to that in Example 5, the title compound 61 was prepared by replacing BOC-3,5-dimethylpyrazol-4-phenazol boronic acid ester with 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)ethanol-1-ol.

[0605] 1 H NMR (400MHz, Methanol-d4) δ8.13(s,1H),7.52-7.34(m,2H),7.28-7.12(m,2H),6.43(s,1H),4.94-4.90(m,1H),4.47-4.38(m,3H),4.18(t,J=5.5 Hz,2H),3.91(t,J=5.5Hz,2H),3.15(m,1H),2.99(m,1H),2.86(m,1H),2. 37(s,3H),2.28(s,3H),1.75(d,J=8.9Hz,2H),1.05(s,3H),0.94(s,3H).

[0606] MS(ESI) measurement value: [M+H + 586.31

[0607] Preparation Example 62

[0608] Preparation of 5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]-1-[6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidine-3-carboxamide (compound 62)

[0609] Using a method similar to that in Example 5, 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine was replaced with 4-chloro-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine, and the title compound 62 was prepared by step f.

[0610] 1 H NMR(400MHz, DMSO-d6)δ12.96(s,1H),8.61(t,J=6.0Hz,1H),8.25(s,1H),7.55-7.26(m,4H),7.18(s,1H),4.86(m,1H), 4.51-4.30(m,3H),3.08-2.86(m,2H),2.78-2.68(m,1H),1.69-1.55(m,2H),1.02(s,3H),0.83(s,3H).

[0611] MS(ESI) measurement value: [M+H + 516.08

[0612] Preparation Example 63

[0613] Preparation of 1-[6-[3,5-dimethyl-1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide (compound 63)

[0614] Using a method similar to that in Example 5, the title compound 63 was prepared by replacing BOC-3,5-dimethylpyrazol-4-phenazine boronic acid ester with 4-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)-1-methylpiperidine in steps u and v.

[0615] 1H NMR (400MHz, Methanol-d4) δ8.13 (s, 1H), 7.42 (d, J = 8.6Hz, 2H), 7.29-7.17 (m ,2H),6.42(s,1H),4.93-4.90(m,1H),4.50-4.36(m,3H),4.25-4.13(m,1H),3. 17-3.06(m,3H),3.00(m,1H),2.86(m,1H),2.41(s,3H),2.34(d,J=5.7Hz,6H) ,2.27(s,4H),1.98-1.90(m,2H),1.80-1.72(m,2H),1.07(s,3H),0.95(s,3H).

[0616] MS(ESI) measurement value: [M+H + 639.23

[0617] Preparation Example 64

[0618] Preparation of 1-[6-(1-ethyl-3,5-dimethylpyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 64)

[0619] Using a method similar to that in Example 5, the title compound 64 was prepared by replacing BOC-3,5-dimethylpyrazole-4-pinacol boronic acid ester with 1-ethyl-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrazole, followed by steps u and v.

[0620] 1 H NMR (400MHz, Methanol-d4) δ8.13 (s, 1H), 7.41 (d, J = 8.6Hz, 2H), 7.30-7.13 (m, 2H), 6.43 (s, 1H), 4.96-4.86 (m, 1H), 4.52 -4.31(m,3H),4.13(q,J=7.2Hz,2H),3.16(m,1H),3.00(m,1H),2.86(m,1H),2.34(s, 3H),2.27(s,3H),1.78-1.69(m,2H),1.40(t,J=7.2Hz,3H),1.07(s,3H),0.95(s,3H).

[0621] MS(ESI) measurement value: [M+H + 570.31

[0622] Preparation Example 65

[0623] Preparation of 1-[6-[1-(2-fluoroethyl)-3,5-dimethylpyrazol-4-yl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 65)

[0624] Step a2: Synthesis of 1-[6-[1-(2-fluoroethyl)-3,5-dimethylpyrazol-4-yl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 65)

[0625] 1-[6-[1-(2-hydroxyethyl)-3,5-dimethylpyrazol-4-yl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (18 mg, 0.03 mmol) was added to dichloromethane (0.5 mL), and 0.2 mL of diethylaminotrifluoride (DAST) was added. The mixture was stirred at rt for 1 hour. After the reaction was completed by LCMS, the mixture was concentrated to dryness under reduced pressure and further purified to obtain the target product (7.2 mg, 41%).

[0626] 1 H NMR (400MHz, Methanol-d4) δ8.13 (s, 1H), 7.47-7.37 (m, 2H), 7.24 (dt, J = 7. 7,1.1Hz,2H),6.45(s,1H),4.94-4.90(m,1H),4.81(t,J=4.7Hz,1H),4.69(t ,J=4.7Hz,1H),4.53-4.28(m,5H),3.15(m,1H),2.99(m,1H),2.91-2.77(m, 1H),2.35(s,3H),2.29(s,3H),1.82-1.72(m,2H),1.06(s,3H),0.95(s,3H).

[0627] MS(ESI) measurement value: [M+H + 588.14

[0628] Preparation Example 66

[0629] Preparation of 5,5-dimethyl-N-[[4-(trifluoromethylthio)phenyl]methyl]-1-[6-(1,3,5-trimethylpyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidine-3-carboxamide (compound 66)

[0630] Using a method similar to that in Example 5, 4-(trifluoromethoxy)benzylamine was replaced with 4-trifluoromethylthiobenzylamine and BOC-3,5-dimethylpyrazole-4-phenazolyl boronic acid ester was replaced with 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrazole, and the title compound 66 was prepared by steps m, t, f, u, and v.

[0631] 1 H NMR (400MHz, Methanol-d4) δ8.13(s,1H),7.64(d,J=8.2Hz,2H),7.43(d,J=8.2Hz,2H),6.42(s,1H),4.96-4.87(m,1H),4.56-4.38(m ,3H),3.78(s,3H),3.15(m,1H),2.97(m,1H),2.87(m,1H),2.32(s,3H),2.26(s,3H),1.76(d,J=8.2Hz,2H),1.05(s,3H),0.94(s,3H).

[0632] MS(ESI) measurement value: [M+H + 572.17

[0633] Preparation Example 67

[0634] Preparation of 1-[6-(5-cyano-1,3-dimethylpyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 67)

[0635] Using a method similar to that in Example 5, the title compound 67 was prepared by replacing BOC-3,5-dimethylpyrazol-4-phenazol boronic acid ester with 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-5-carboxynitrile in steps u and v.

[0636] 1 H NMR(400MHz, Methanol-d4)δ8.23(s,1H),7.46-7.37(m,2H),7.25(dt,J=7.7,1.1Hz,2H),7.04(s,1H),4.97(m,1H),4.53-4.3 7(m,3H),3.94(s,3H),3.19(m,1H),3.05(m,1H),2.91-2.82(m,1H),2.40(s,3H),1.82-1.75(m,2H),1.09(s,3H),0.95(s,3H).

[0637] MS(ESI) measurement value: [M+H + 567.18

[0638] Preparation Example 68

[0639] Preparation of 1-[6-(2,5-dimethylpyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 68)

[0640] Using a method similar to that in Example 5, the title compound 68 was prepared by replacing BOC-3,5-dimethylpyrazole-4-pinacol ester with 1,3-dimethyl-1H-pyrazole-5-boronic acid pinacol ester through steps u and v.

[0641] 1 H NMR (400MHz, Methanol-d4) δ8.18(s,1H),7.42(d,J=8.7Hz,2H),7.26(dd,J=8.8,1.1Hz,2H),6.80(s,1H),6.41(s,1H),4.94(m,1H),4 .52-4.41(m,3H),3.94(s,3H),3.18(m,1H),3.03(m,1H),2.92-2.81(m,1H),2.28(s,3H),1.81-1.74(m,2H),1.08(s,3H),0.94(s,3H).

[0642] MS(ESI) measurement value: [M+H + 542.28

[0643] Preparation Example 69

[0644] Preparation of N-[[2-fluoro-4-(trifluoromethoxy)phenyl]methyl]-5,5-dimethyl-1-[6-(1,3,5-trimethylpyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidine-3-carboxamide (compound 69)

[0645] Using a method similar to that in Example 5, 4-(trifluoromethoxy)benzylamine was replaced with (2-fluoro-4-(trifluoromethoxy)phenyl)methylamine and BOC-3,5-dimethylpyrazol-4-pyrazole was replaced with 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrazole, and the title compound 69 was prepared through steps m, t, f, u, and v.

[0646] 1H NMR(400MHz, Methanol-d4)δ8.12(s,1H),7.47(m,1H),7.14-6.99(m,2H),6.41(s,1H),4.85(m,1H),4.58-4.32(m,3H),3.77(s ,3H),3.12(m,1H),2.95(m,1H),2.88-2.78(m,1H),2.31(s,3H),2.26(s,3H),1.73(d,J=8.4Hz,2H),1.03(s,3H),0.92(s,3H).

[0647] MS(ESI) measurement value: [M+H + 574.17

[0648] Preparation Example 70

[0649] Preparation of 5,5-bis(trideutermethyl)-1-[6-(1,3,5-trimethylpyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (compound 70)

[0650] Using a method similar to that in Example 7, the title compound 70 was prepared by replacing BOC-3,5-dimethylpyrazole-4-pyrrolidone ester with 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrazole, followed by steps u and v.

[0651] 1 H NMR(400MHz, Methanol-d4)δ8.13(s,1H),7.40(d,J=8.6Hz,2H),7.29-7.16(m,2H),6.42(s,1H),4.87(m,1H),4.53- 4.30(m,3H),3.78(s,3H),3.14(m,1H),2.97(m,1H),2.91-2.73(m,1H),2.31(s,3H),2.26(s,3H),1.78-1.68(m,2H).

[0652] MS(ESI) measurement value: [M+H + 562.07

[0653] Preparation Example 71

[0654] Preparation of N-[[2-fluoro-4-(trifluoromethoxy)phenyl]methyl]-5,5-bis(trideuterylmethyl)-1-[6-(1,3,5-trimethylpyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidine-3-carboxamide (compound 71)

[0655] Using a method similar to that of Example 7, 4-(trifluoromethoxy)benzylamine was replaced with (2-fluoro-4-(trifluoromethoxy)phenyl)methylamine and BOC-3,5-dimethylpyrazole-4-pyrazole was replaced with 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrazole, and the title compound 71 was prepared by steps m, t, f, u, and v.

[0656] 1 H NMR(400MHz, Methanol-d4)δ8.14(s,1H),7.48(m,1H),7.11(m,2H),6.43(s,1H),4.86(m,1H),4.54-4.37(m, 3H),3.79(s,3H),3.21-3.12(m,1H),2.99(m,1H),2.85(m,1H),2.33(s,3H),2.27(s,3H),1.78-1.69(m,2H).

[0657] MS(ESI) measurement value: [M+H + 580.33

[0658] Preparation Example 72

[0659] 6-[3,5-Dimethyl-1-[2-(4-methylphenyl)sulfonyloxyethyl]-1H-pyrazol-4-yl]-4-[3,3-Dimethyl-5-[4-(trifluoromethoxy)benzyl]carbamoyl]piperidin-1-yl]

[0660] Preparation steps of pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (compound 72): a3: Synthesis of 6-[3,5-dimethyl-1-[2-(4-methylphenyl)sulfonyloxyethyl]-1H-pyrazol-4-yl]-4-[3,3-dimethyl-5-[4-(trifluoromethoxy)benzyl]carbamoyl]piperidin-1-yl]pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (compound 72)

[0661] 1-[6-[1-(2-hydroxyethyl)-3,5-dimethylpyrazol-4-yl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-5,5-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide (58 mg, 0.1 mmol) was added to dichloromethane (0.5 mL) along with catalytic amounts of 4-dimethylaminopyridine, triethylamine (17 μL, 0.12 mmol), and TsCl (21 μL, 0.11 mmol). The mixture was stirred at rt for 6 hours. After the reaction was completed by LCMS, the product was concentrated to dryness under reduced pressure and further purified to obtain the target product (21.2 mg, 25%).

[0662] 1 H NMR(400MHz, Methanol-d4)δ8.29(s,1H),7.80-7.71(m,2H),7.52-7.33(m,4H),7.25-7.17(m,2H),6.63(s,1H),4.96-4.89(m,1H),4.47-4.27(m,7 H),3.16(m,1H),3.00(m,1H),2.92-2.81(m,1H),2.45(s,3H),2.19(s,3H ),2.06(s,3H),1.79-1.68(m,2H),1.35(s,9H),1.05(s,3H),0.92(s,3H).

[0663] MS(ESI) measurement value: [M+H + 840.31

[0664] Biological Examples

[0665] Biological Example 1

[0666] kinase inhibitory activity

[0667] Kinase inhibition assay (taking ALK kinase inhibition activity as an example): Dilute 1 volume of protein culture medium 4-fold and add 50 μM dithiothreitol as the culture medium. Add different concentrations of the test compound to a 384-well plate (10 μM as the starting concentration, 3-fold dilution, 10 concentrations, replicates). Seal the 384-well plate and centrifuge at 1000g for 1 minute. Mix 2x ALK protein (test protein) with 1x protein culture medium thoroughly, and add 2.5 μL of the protein mixture to each well. Centrifuge at 1000g for 30 seconds, incubate at room temperature for 10 minutes. Simultaneously, mix 2x substrate and ATP with 1x protein culture medium. Add 2.5 μL of the substrate and ATP mixture to each well, centrifuge at 1000g for 30 seconds, seal the plate, and incubate at room temperature for 1 hour. After the reaction, add 5 μL of ADP-Glo ​​reagent to each well and incubate at room temperature for 40 minutes. Next, 10 μL of protein detection reagent was added, and the reaction was carried out at room temperature for 40 min. Finally, the fluorescence value was obtained using an Envision 2104, and the corresponding protein inhibition rate was calculated.

[0668] Table 1. Inhibitory activity (IC50) of the compounds disclosed herein against kinases. 50 (Unit: nM)

[0669] Biological Example 2

[0670] Tumor cell growth inhibitory activity

[0671] Cytotoxicity assay (using stable transgenic Ba / F3-CLIP1-LTK cells as an example): Cell proliferation activity was evaluated in the Ba / F3-CLIP1-LTK cell line using the MTT assay. Ba / F3-CLIP1-LTK cell suspension was prepared using IL-3-free RPMI-1640 medium, and 90 μL (10⁻⁶ m³ / well) was seeded into each well of a 96-well plate. 4 Cells were incubated in a cell culture incubator for 2 hours, followed by the addition of 10 μL of a concentration gradient compound or DMSO. After 72 hours of incubation, 10 μL of MTT (5 mg / ml) was added to each well, and after 4 hours of incubation, 100 μL of SDS-HCl-PBS triple buffer was added and incubated overnight. The absorbance of each well at 570 nm was measured using a microplate reader. After data processing, a dose-response curve of compound concentration versus cell viability was fitted to obtain the quantitative anti-cell proliferation activity value (IC50) of the compound. 50 ).

[0672] Table 2. Inhibition rate of tumor cell growth of the compounds disclosed herein (IC50) 50 (Unit: nM)

[0673] Biological Example 3

[0674] Tumor cell growth inhibitory activity

[0675] Cytotoxicity assay (using Kelly cells as an example): Kelly cells were cultured in the supplier-recommended medium (containing 10% fetal bovine serum). 1 × 10⁶ cells were added to each 96-well plate. 3 / well, cultured overnight at 37℃ and 5% CO2. Then, culture medium containing different concentrations of the test compound (10 μM as the initial concentration, 3-fold dilution, 10 concentrations, replicates) was added to each well, and cultured for another 72 h. After trypan blue staining, the viability of cells reached over 95%. Four h before the end of culture, 20 μL of MTT solution (5 mg / mL) was added to each well, and incubation continued for another 4 h. The culture medium was discarded, and 150 μL of dimethyl sulfoxide was added, followed by shaking for 15 min. The absorbance (A value) was measured using a microplate reader at 570 nm, and the proliferation inhibition rate was calculated. The compound incubation time for Kelly cells was 72 h, and for KP-N-RT-BM-1 cells, it was 120 h.

[0676] Table 3. Inhibition rate (IC50) of the compounds disclosed herein against the growth of ALK-mutant tumor cells. 50 (Unit: nM)

[0677] In this disclosure, relational terms such as first and second are used merely to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations.

[0678] As will be understood from the foregoing, although specific embodiments of this disclosure have been described for illustrative purposes, various modifications or alterations can be made by those skilled in the art without departing from the spirit and scope of this disclosure. All such modifications or alterations should fall within the scope of the appended claims.

Claims

1. Compounds represented by general formula (I), and their pharmaceutically acceptable salts: in: R1 is selected from any substituted aryl group or any substituted heteroaryl group; X is selected from O, S, or NR3; R2 is selected from any substituted hydrocarbon group, any substituted cyclic hydrocarbon group, any substituted heterocyclic hydrocarbon group, any substituted aryl group, or any substituted heteroaryl group; and R3 is selected from hydrogen, any substituted hydrocarbon group, any substituted cyclic hydrocarbon group, any substituted heterocyclic hydrocarbon group, any substituted aryl group, or any substituted heteroaryl group.

2. The compound of general formula (I) as claimed in claim 1, and its pharmaceutically acceptable salt, wherein R1 is selected from halogen, unsubstituted aryl, aryl-substituted alkyl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, aryl-substituted amino, sulfonamide-substituted aryl, unsubstituted heteroaryl, alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, aryl-substituted amino, or heterocyclic alkyl-substituted heteroaryl.

3. The compound of general formula (I) as claimed in claim 1 or 2, and its pharmaceutically acceptable salt, wherein R1 is selected from halogen, unsubstituted phenyl, arbitrarily substituted alkyl-substituted phenyl, arbitrarily substituted heterocyclic alkyl-substituted alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, arbitrarily substituted amino-substituted phenyl, sulfonamide-substituted phenyl, unsubstituted pyridyl, unsubstituted thiophenyl, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, arbitrarily substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocyclic alkyl-substituted amino-substituted pyrazolyl, or heterocyclic alkyl-substituted pyrazolyl.

4. The compound of general formula (I) as claimed in any one of claims 1 to 3, and its pharmaceutically acceptable salt, wherein R1 is selected from halogen, unsubstituted aryl, alkyl-substituted aryl, halogen-substituted alkyl-substituted aryl, alkyl-substituted heterocyclic alkyl-substituted alkyl-substituted aryl, alkyl-substituted heterocyclic alkyl-substituted oxoalkyl-substituted aryl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, alkyl-substituted amino-substituted aryl, any-substituted heterocyclic alkyl-substituted amino-substituted aryl, sulfonamide-substituted phenyl, unsubstituted heteroaryl, any-substituted alkyl-substituted heteroaryl, any-substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocyclic alkyl-substituted amino-substituted heteroaryl, or heterocyclic alkyl-substituted heteroaryl.

5. The compound of general formula (I) as claimed in any one of claims 1 to 4, and its pharmaceutically acceptable salt, wherein R1 is selected from iodine, phenyl, tolyl, isopropylphenyl, trifluoromethylphenyl, 4-(4-methylpiperazin-1-yl)methylphenyl, 4-(4-methylpiperazin-1-yl)oxomethylphenyl, methoxyphenyl, isopropoxyphenyl, bromophenyl, cyano-substituted phenyl, dimethylaminophenyl, 2-methyl-4-piperidinyl-substituted amino-substituted phenyl, 2-methyl-4-(N-methylpiperidinyl)-amino-substituted phenyl, 2-methyl-4-tetrahydropyrrolyl-substituted amino-substituted phenyl, 2-methyl-4-(N-methyltetrahydropyrrolyl) )-Amino-substituted phenyl, 2-methyl-4-sulfonamido-substituted phenyl, pyridinyl, thienyl, pyrimidinyl, pyrazolyl, N-methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl, dimethylpyrazolyl, N-(hydroxyethyl)dimethylpyrazolyl, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolyl, N-(2-hydroxypropyl)dimethylpyrazolyl, N-pyranylamino-substituted N-methylpyrazolyl, N-piperidinyl-substituted pyrazolyl, N-piperidinyl-substituted dimethylpyrazolyl, cyano-aminomethyl-substituted N-methylpyrazolyl, cyano-N-methylaminomethyl-substituted N-methylpyrazolyl or cyano-N-pyranylamino-substituted N-methylpyrazolyl.

6. The compound of general formula (I) as claimed in any one of claims 1 to 5, and a pharmaceutically acceptable salt thereof, wherein R1 is selected from:

7. The compound of general formula (I) as claimed in any one of claims 1 to 6, and its pharmaceutically acceptable salt, wherein R2 is selected from any substituted amino-substituted hydrocarbon group, halogen-substituted cycloalkyl group, any substituted carbonyl-substituted cycloalkyl group, any substituted amide-substituted cycloalkyl group, any substituted heterocyclic-substituted cycloalkyl group, any substituted aminosulfonyl-substituted aryl group, unsubstituted heteroaryl group, any substituted alkyl-substituted heteroaryl group, alkoxy-substituted heteroaryl group, cyano-substituted heteroaryl group, any substituted amino-substituted heteroaryl group, or heterocyclic alkyl-substituted heteroaryl group.

8. The compound of general formula (I) as claimed in any one of claims 1 to 7, and its pharmaceutically acceptable salt, wherein R2 is selected from any substituted alkyl, any substituted cycloalkyl, any substituted heterocycloalkyl, any substituted phenyl, unsubstituted pyridyl, unsubstituted thiophenyl, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, any substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocycloalkyl-substituted amino-substituted pyrazolyl, or heterocycloalkyl-substituted pyrazolyl.

9. The compound of general formula (I) as claimed in any one of claims 1 to 8, and its pharmaceutically acceptable salt, wherein R2 is selected from any substituted amino-substituted alkyl, any substituted pyrrolidinyl, any substituted azabicycloalkyl, any substituted aminosulfonyl-substituted phenyl, unsubstituted heteroaryl, any substituted alkyl-substituted heteroaryl, any substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocyclic alkyl-substituted amino-substituted heteroaryl, or heterocyclic alkyl-substituted heteroaryl.

10. The compound of general formula (I) as claimed in any one of claims 1 to 9, and a pharmaceutically acceptable salt thereof, wherein R2 is selected from any substituted aryl-substituted amino-substituted alkyl, difluoropyrrolidinyl, N-tert-butyloxy-difluoropyrrolidinyl, N-(4-chlorophenylaminocarbonyl)-3,3-difluoro-pyrrolidinyl, N-(4-chlorophenylaminocarbonyl)-azabicyclo[3.2.1]octyl, any substituted hydrocarbon-substituted aminosulfonyl-substituted phenyl, pyridyl, thiophenyl, pyrimidinyl, pyrazolyl, N- Methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl, dimethylpyrazolyl, N-(hydroxyethyl)dimethylpyrazolyl, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolyl, N-(2-hydroxypropyl)dimethylpyrazolyl, N-pyranylamino-substituted N-methylpyrazolyl, N-piperidinyl-substituted pyrazolyl, N-piperidinyl-substituted dimethylpyrazolyl, cyano-aminomethyl-substituted N-methylpyrazolyl, cyano-N-methylaminomethyl-substituted N-methylpyrazolyl or cyano-N-pyranylamino-substituted N-methylpyrazolyl.

11. The compound of general formula (I) as claimed in any one of claims 1 to 10, and its pharmaceutically acceptable salt, wherein R3 is selected from hydrogen, an aryl group with arbitrary substituted amino, a halogen-substituted cycloalkyl, an aryl group with arbitrary substituted carbonyl, an aryl group with arbitrary substituted amide, an aryl group with arbitrary substituted heterocyclic, an aryl group with arbitrary substituted aminosulfonyl, an unsubstituted heteroaryl, an aryl group with arbitrary substituted alkyl, an alkoxy, a heteroaryl, a heteroaryl, an aryl group with arbitrary substituted amino or a heterocyclic alkyl.

12. The compound of general formula (I) as claimed in any one of claims 1 to 11, and its pharmaceutically acceptable salt, wherein R3 is selected from hydrogen, any substituted alkyl, any substituted cycloalkyl, any substituted heterocycloalkyl, any substituted phenyl, unsubstituted pyridyl, unsubstituted thiophenyl, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, any substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocycloalkyl-substituted amino-substituted pyrazolyl, or heterocycloalkyl-substituted pyrazolyl.

13. The compound of general formula (I) as claimed in any one of claims 1 to 12, and its pharmaceutically acceptable salt, wherein R3 is selected from hydrogen, any substituted amino-substituted alkyl, any substituted pyrrolidinyl, any substituted azabicycloalkyl, any substituted aminosulfonyl-substituted phenyl, unsubstituted heteroaryl, any substituted alkyl-substituted heteroaryl, any substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocyclic alkyl-substituted amino-substituted heteroaryl, or heterocyclic alkyl-substituted heteroaryl.

14. The compound of general formula (I) as claimed in any one of claims 1 to 13, and its pharmaceutically acceptable salt, wherein R3 is selected from hydrogen, any substituted aryl-substituted amino-substituted alkyl, difluoropyrrolidinyl, N-tert-butyloxy-difluoropyrrolidinyl, N-(4-chlorophenylaminocarbonyl)-3,3-difluoro-pyrrolidinyl, N-(4-chlorophenylaminocarbonyl)-azabicyclo[3.2.1]octyl, any substituted hydrocarbon-substituted aminosulfonyl-substituted phenyl, pyridyl, thiophenyl, pyrimidinyl, pyrazolyl, N-methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl, dimethylpyrazolyl, N-(hydroxyethyl)dimethylpyrazolyl, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolyl, N-(2-hydroxypropyl)dimethylpyrazolyl, N-pyranylamino-substituted N-methylpyrazolyl, N-piperidinyl-substituted pyrazolyl, N-piperidinyl-substituted dimethylpyrazolyl, cyano-aminomethyl-substituted N-methylpyrazolyl, cyano-N-methylaminomethyl-substituted N-methylpyrazolyl or cyano-N-pyranylamino-substituted N-methylpyrazolyl.

15. The compound of formula (I) as claimed in any one of claims 1 to 14, and a pharmaceutically acceptable salt thereof, wherein R2 is selected from...

16. The compound of general formula (I) as claimed in any one of claims 1 to 15, and a pharmaceutically acceptable salt thereof, wherein R3 is selected from hydrogen, 17. Compounds represented by general formula (II) and their pharmaceutically acceptable salts: in: R 11 Selected from any substituted aryl group or any substituted heteroaryl group; A is selected from any substituted heterocyclic hydrocarbon group or any substituted heteroaryl group; Y is HN- or does not exist; R 22 Selected from hydrogen, any substituted hydrocarbon group, any substituted aryl group, or any substituted heteroaryl group; and R 33 Selected from hydrogen, any substituted hydrocarbon group, any substituted aryl group, or any substituted heteroaryl group; The premise is that the compound represented by general formula (II) is not (3S)-1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide and (3S)-1-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-3-carboxamide].

18. The compound of general formula (II) as claimed in claim 17, and its pharmaceutically acceptable salt, wherein A is selected from any substituted nitrogen-containing heterocyclic hydrocarbon group, any substituted oxygen-containing heterocyclic hydrocarbon group, or any substituted nitrogen-containing heteroaryl group.

19. The compound of formula (II) as claimed in claim 18, and its pharmaceutically acceptable salt, wherein the nitrogen atom is attached to a pyrimidine-pyrrole group.

20. The compound of general formula (II) as claimed in any one of claims 17 to 19, and a pharmaceutically acceptable salt thereof, wherein A is selected from any substituted piperidinyl, substituted morpholinyl, any substituted azacycloheptyl, and any substituted azabicycloheptyl.

21. The compound of general formula (II) as claimed in any one of claims 17 to 20, and its pharmaceutically acceptable salt, wherein A is selected from unsubstituted piperidinyl, amino-substituted piperidinyl, halogen-substituted piperidinyl, cyano-substituted piperidinyl, alkyl-substituted piperidinyl, deuterated alkyl-substituted piperidinyl, unsubstituted azaheptanyl, and unsubstituted azabicycloheptanyl.

22. The compound of general formula (II) as claimed in any one of claims 17 to 21, and its pharmaceutically acceptable salt, wherein A is selected from unsubstituted piperidinyl, amino-substituted piperidinyl, fluorinated piperidinyl, cyano-substituted piperidinyl, methyl-substituted piperidinyl, deuterated methyl-substituted piperidinyl, unsubstituted azacycloheptyl, and unsubstituted azabicycloheptyl.

23. The compound of general formula (II) as claimed in any one of claims 17 to 22, and a pharmaceutically acceptable salt thereof, wherein R 11 It is selected from halogen, unsubstituted aryl, aryl-substituted alkyl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, aryl-substituted amino, sulfonamide-substituted aryl, unsubstituted heteroaryl, alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, aryl-substituted amino, or heterocyclic alkyl-substituted heteroaryl.

24. The compound of general formula (II) as claimed in any one of claims 17 to 23, and a pharmaceutically acceptable salt thereof, wherein R 11 It is selected from halogen, unsubstituted phenyl, arbitrarily substituted alkyl-substituted phenyl, arbitrarily substituted heterocyclic alkyl-substituted alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, arbitrarily substituted amino-substituted phenyl, sulfonamide-substituted phenyl, unsubstituted pyridyl, unsubstituted thiophene, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, arbitrarily substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocyclic alkyl-substituted amino-substituted pyrazolyl, or heterocyclic alkyl-substituted pyrazolyl.

25. The compound of general formula (II) as claimed in any one of claims 17 to 24, and a pharmaceutically acceptable salt thereof, wherein R 11 Selected from halogen, unsubstituted aryl, alkyl-substituted aryl, halogen-substituted alkyl-substituted aryl, alkyl-substituted heterocyclic alkyl-substituted alkyl-substituted aryl, alkyl-substituted heterocyclic alkyl-substituted oxoalkyl-substituted aryl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, alkyl-substituted amino-substituted aryl, any-substituted heterocyclic alkyl-substituted amino-substituted aryl, sulfonamide-substituted phenyl, unsubstituted heteroaryl, any-substituted alkyl-substituted heteroaryl, any-substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocyclic alkyl-substituted amino-substituted heteroaryl, or heterocyclic alkyl-substituted heteroaryl.

26. The compound of general formula (II) as claimed in any one of claims 17 to 25, and a pharmaceutically acceptable salt thereof, wherein R 11 Selected from iodine, phenyl, tolyl, isopropylphenyl, trifluoromethylphenyl, 4-(4-methylpiperazin-1-yl)methylphenyl, 4-(4-methylpiperazin-1-yl)oxomethylphenyl, methoxyphenyl, isopropoxyphenyl, bromophenyl, cyano-substituted phenyl, dimethylaminophenyl, 2-methyl-4-piperidinyl-substituted amino-substituted phenyl, 2-methyl-4-(N-methylpiperidinyl)-amino-substituted phenyl, 2-methyl-4-tetrahydropyrrolyl-substituted amino-substituted phenyl, 2-methyl-4-(N-methyltetrahydropyrrolyl)-amino-substituted phenyl, 2-methyl-4-sulfonamide-substituted phenyl. The phenyl, pyridinyl, thiopheneyl, pyrimidinyl, pyrazolyl, N-methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl, dimethylpyrazolyl, N-(hydroxyethyl)dimethylpyrazolyl, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolyl, N-(2-hydroxypropyl)dimethylpyrazolyl, N-pyranylamino-substituted N-methylpyrazolyl, N-piperidinyl-substituted pyrazolyl, N-piperidinyl-substituted dimethylpyrazolyl, cyano-aminomethyl-substituted N-methylpyrazolyl, cyano-N-methylaminomethyl-substituted N-methylpyrazolyl or cyano-N-pyranylamino-substituted N-methylpyrazolyl.

27. The compound of general formula (II) as claimed in any one of claims 17 to 26, and a pharmaceutically acceptable salt thereof, wherein R 11 Selected from:

28. The compound of general formula (II) as claimed in any one of claims 17 to 27, and a pharmaceutically acceptable salt thereof, wherein R 22 It is selected from hydrogen, any substituted amino-substituted hydrocarbon group, any substituted aminosulfonyl-substituted aryl group, unsubstituted heteroaryl group, any substituted alkyl-substituted heteroaryl group, alkoxy-substituted heteroaryl group, cyano-substituted heteroaryl group, any substituted amino-substituted heteroaryl group, or heterocyclic alkyl-substituted heteroaryl group.

29. The compound of general formula (II) as claimed in any one of claims 17 to 28, and a pharmaceutically acceptable salt thereof, wherein R 22 It is selected from hydrogen, any substituted alkyl, any substituted phenyl, unsubstituted pyridyl, unsubstituted thiophene, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, any substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocyclic alkyl-substituted amino-substituted pyrazolyl, or heterocyclic alkyl-substituted pyrazolyl.

30. The compound of general formula (II) as claimed in any one of claims 17 to 29, and its pharmaceutically acceptable salt, wherein R 22 It is selected from hydrogen, any substituted amino-substituted alkyl, any substituted aminosulfonyl-substituted phenyl, unsubstituted heteroaryl, any substituted alkyl-substituted heteroaryl, any substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocyclic alkyl-substituted amino-substituted heteroaryl, or heterocyclic alkyl-substituted heteroaryl.

31. The compound of general formula (II) as claimed in any one of claims 17 to 30, and its pharmaceutically acceptable salt, wherein R 22 Selected from hydrogen, aryl-substituted amino-substituted alkyl, alkyl-substituted aminosulfonyl-substituted phenyl, pyridinyl, thiophene, pyrimidinyl, pyrazolyl, N-methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl, dimethylpyrazolyl, N-(hydroxyethyl)dimethylpyrazolyl, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolyl, N-(2-hydroxypropyl)dimethylpyrazolyl, N-pyranylamino-substituted N-methylpyrazolyl, N-piperidinyl-substituted pyrazolyl, N-piperidinyl-substituted dimethylpyrazolyl, cyano-aminomethyl-substituted N-methylpyrazolyl, cyano-N-methylaminomethyl-substituted N-methylpyrazolyl, or cyano-N-pyranylamino-substituted N-methylpyrazolyl.

32. The compound of general formula (II) as claimed in any one of claims 17 to 31, and its pharmaceutically acceptable salt, wherein R 33 It is selected from hydrogen, any substituted amino-substituted hydrocarbon group, any substituted aminosulfonyl-substituted aryl group, unsubstituted heteroaryl group, any substituted alkyl-substituted heteroaryl group, alkoxy-substituted heteroaryl group, cyano-substituted heteroaryl group, any substituted amino-substituted heteroaryl group, or heterocyclic alkyl-substituted heteroaryl group.

33. The compound of general formula (II) as claimed in any one of claims 17 to 32, and its pharmaceutically acceptable salt, wherein R 33 It is selected from hydrogen, any substituted alkyl, any substituted phenyl, unsubstituted pyridyl, unsubstituted thiophene, unsubstituted pyrimidinyl, unsubstituted pyrazolyl, any substituted alkyl-substituted pyrazolyl, amino-substituted alkyl-substituted pyrazolyl, alkyl-substituted amino-substituted alkyl-substituted pyrazolyl, alkoxy-substituted pyrazolyl, cyano-substituted pyrazolyl, heterocyclic alkyl-substituted amino-substituted pyrazolyl, or heterocyclic alkyl-substituted pyrazolyl.

34. The compound of general formula (II) as claimed in any one of claims 17 to 33, and a pharmaceutically acceptable salt thereof, wherein R 33 It is selected from hydrogen, any substituted amino-substituted alkyl, any substituted aminosulfonyl-substituted phenyl, unsubstituted heteroaryl, any substituted alkyl-substituted heteroaryl, any substituted amino-substituted alkyl-substituted heteroaryl, alkoxy-substituted heteroaryl, cyano-substituted heteroaryl, heterocyclic alkyl-substituted amino-substituted heteroaryl, or heterocyclic alkyl-substituted heteroaryl.

35. The compound of general formula (II) as claimed in any one of claims 17 to 34, and a pharmaceutically acceptable salt thereof, wherein R 33 Selected from hydrogen, aryl-substituted amino-substituted alkyl, alkyl-substituted aminosulfonyl-substituted phenyl, pyridinyl, thiophene, pyrimidinyl, pyrazolyl, N-methylpyrazolyl, cyanopyrazolyl, isopropoxypyrazolyl, dimethylpyrazolyl, N-(hydroxyethyl)dimethylpyrazolyl, N-(2-hydroxy-2-methylpropyl)dimethylpyrazolyl, N-(2-hydroxypropyl)dimethylpyrazolyl, N-pyranylamino-substituted N-methylpyrazolyl, N-piperidinyl-substituted pyrazolyl, N-piperidinyl-substituted dimethylpyrazolyl, cyano-aminomethyl-substituted N-methylpyrazolyl, cyano-N-methylaminomethyl-substituted N-methylpyrazolyl, or cyano-N-pyranylamino-substituted N-methylpyrazolyl.

36. The compound of general formula (II) as claimed in any one of claims 17 to 35, and a pharmaceutically acceptable salt thereof, wherein Selected from 37. A compound, and a pharmaceutically acceptable salt thereof, wherein said compound is selected from:

38. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or a compound of formula (II) according to any one of claims 17 to 36 or a pharmaceutically acceptable salt thereof, or a compound of claim 37 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

39. The pharmaceutical composition of claim 38, wherein it is prepared as a tablet, solution, granule, patch, ointment, gel, capsule, aerosol or suppository for parenteral, dermal, mucosal, nasal, buccal, sublingual or oral use.

40. A method for preparing compounds of general formula (Ib), comprising: It includes the following reactions: in: R1 is selected from any substituted aryl group or any substituted heteroaryl group; B is selected from boric acid, borate ester, or halogen.

41. The method of claim 40, wherein the reaction is carried out in the presence of a palladium catalyst and a base.

42. The method of claim 41, wherein the palladium catalyst is selected from palladium, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(OAc)2, Pd(dppf)Cl 2、 Pd(amphost)Cl2, Xphos-Pd-G3, or any mixture thereof.

43. The method of claim 41 or 42, wherein the base is selected from alkali metal salts, organic bases, or any mixture thereof; the alkali metal salt is preferably potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium fluoride, potassium fluoride, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof, wherein the alcohol is preferably methanol, ethanol, or tert-butanol; the organic base is preferably triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

44. The method according to any one of claims 40 to 43, wherein the borate ester is selected from bis(pinacol)diboron (Bpin), Bcat, or any mixture thereof.

45. The method according to any one of claims 40 to 44, wherein the halogen is selected from chlorine, bromine, iodine or any mixture thereof, and the reaction is carried out in the presence of bis(pinacol)diboron.

46. ​​A method for preparing compounds of general formula (Ia), It includes the following reactions: in: R1 is selected from any substituted aryl group or any substituted heteroaryl group; X is selected from O, S, or NR3; R2 is selected from any substituted hydrocarbon group, any substituted monocyclic aryl group, or any substituted heteroaryl group; R3 is selected from hydrogen, any substituted hydrocarbon group, any substituted monocyclic aryl group, or any substituted heteroaryl group; Alternatively, when X is NR3, R2, R3, and the N attached to them form any substituted heterocyclic hydrocarbon groups.

47. The method of claim 46, wherein the reaction is carried out in the presence of a base.

48. The method of claim 47, wherein the base is selected from alkali metal salts, organic bases, or any mixture thereof, wherein the alkali metal salt is preferably potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium fluoride, potassium fluoride, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof, wherein the alcohol is selected from methanol, ethanol, or tert-butanol, and the organic base is preferably triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

49. A method of inhibiting tyrosine kinase (TK), comprising contacting the tyrosine kinase (TK) with an inhibitory effective amount of a compound of formula (I) of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or a compound of formula (II) of any one of claims 17 to 36 or a pharmaceutically acceptable salt thereof, or a compound of claim 37 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 38 or 39.

50. The method of claim 49, wherein the tyrosine kinase (tyrosine kinase) The kinase (TK) is selected from anaplastic lymphoma kinase (ALK), ROS1 oncogene receptor tyrosine kinase (ROS1), leukocyte receptor tyrosine kinase (LTK), epidermal growth factor receptor (EGFR), platelet growth factor receptor (PDGF), ABL tyrosine kinase, fibroblast growth factor receptor (FGFR), interleukin receptor-associated kinase (IRAK), human tyrosine kinase receptor (FLT), V-raf mouse sarcoma virus oncogene homolog B (BRAF), vascular endothelial growth factor receptor 2 (KDR), vascular endothelial growth factor (VEGFR), transfection rearrangement kinase (RET), Bruton's tyrosine kinase (BTK), B-lymphotyrosine kinase (BLK), cytoplasmic tyrosine protein kinase (BMX), human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 4 (HER4), isocitrate dehydrogenase (IDH), discoid domain receptor 1 (DDR1), interleukin 2-induced T cell kinase (ITK), and human protein tyrosine kinase 4 (TXK).

51. The method of claim 49 or 50, wherein the contact is performed in vitro.

52. A method for treating or preventing tyrosine kinase (TK)-mediated diseases or disease states, comprising administering to an individual in need of the method a therapeutically or preventively effective amount of a compound of formula (I) as claimed in any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof of a compound of formula (II) as claimed in any one of claims 17 to 36, or a compound of claim 37, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 38 or 39.

53. The method of claim 52, wherein the individual is a mammal, preferably a human.

54. The method of claim 52 or 53, wherein the disease or disease state is selected from non-small cell lung cancer, lymphoma, blastoma, sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia, lymphoid malignancy, lung cancer, squamous cell carcinoma of the lung, peritoneal carcinoma, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, biliary tract tumor, head and neck cancer, and hematologic malignancies.

55. The method of any one of claims 52 to 54, further comprising administering other active agents to the individual.

56. The method of claim 55, wherein the active agent is selected from nitrogen mustard, aziridine, methylmelamine, alkyl sulfonates, nitrosourea, triazine, folic acid analogs, pyrimidine analogs, purine analogs, vinca alkaloids, epipodophyllotoxin, antibiotics, topoisomerase inhibitors, anticancer vaccines, acyclovir, azorubicin, acodazole hydrochloride, acronin, adorine, interleukin, ambroxol, amyronin, amantadine acetate, aminoglutethimide, acridine, anastrozole, atrazomycin, asparaginase, astragalin, azacitidine, azatepeptide, azotocin, palmastat, benzothiopeia, bicalutamide, bifenthrin hydrochloride, bis(2-naphthyl)fadyl mesylate, bizole, bleomycin sulfate, busulfan, actinomycin C, capprotestone, carvacrol, carbetin, carboplatin, carmustine, carrubicin hydrochloride, chlorbutazone. Mustard, Sirloin, Cladribine, Clinapordine Mesylate, Cyclophosphamide, Cytarabine, Dacarbazine, Actinomycin D, Daunorubicin Hydrochloride, Decitabine, Docetaxel, Doxorubicin, Doxorubicin Hydrochloride, Droloxifene, Epirubicin Hydrochloride, Exorubicin Hydrochloride, Estrostine, Etacozide, Etoposide, Fluorouracil, Fluorouracil, Fluoxetine, Gemcitabine, Idarubicin Hydrochloride, Ifosfamide, Interleukin Interferon II, interferon α-2a, interferon α-2b, irinotecan hydrochloride, letrozole, mercaptopurine, methotrexate, chlorpheniramine, serine, mitoxantrone, paclitaxel, procarbazine, sertepa, vincristine, vinblastine, angiogenesis inhibitors, camptothecin, dexamethasone, aspirin, acetaminophen, indomethacin, ibuprofen, ketoprofen, meloxicam, corticosteroids, and adrenocortical steroids.

57. A compound of formula (I) according to any one of claims 1 to 16 and a pharmaceutically acceptable salt thereof for inhibiting tyrosine kinase (TK), or a compound of formula (II) according to any one of claims 17 to 36 and a pharmaceutically acceptable salt thereof, or a compound of claim 37 and a pharmaceutically acceptable salt thereof.

58. A compound of formula (I) according to any one of claims 1 to 16 and a pharmaceutically acceptable salt thereof, or a compound of formula (II) according to any one of claims 17 to 36 and a pharmaceutically acceptable salt thereof, or a compound of claim 37 and a pharmaceutically acceptable salt thereof, for the treatment or prevention of tyrosine kinase (TK) mediated diseases or disease states.

59. [Amended 24.01.2025 according to Rule 26] Use of the compound of formula (I) of any one of claims 1 to 16 and a pharmaceutically acceptable salt thereof, or the compound of formula (II) of any one of claims 17 to 36 and a pharmaceutically acceptable salt thereof, or the compound of claim 37 and a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting tyrosine kinase (TK).

60. [Amended 24.01.2025 according to Rule 26] Use of the compound of formula (I) of any one of claims 1 to 16 and a pharmaceutically acceptable salt thereof, or the compound of formula (II) of any one of claims 17 to 36 and a pharmaceutically acceptable salt thereof, or the compound of claim 37 and a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment or prevention of tyrosine kinase (TK) mediated diseases or disease states.

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