JAK2 inhibitors

Abstract

The present invention relates to compounds of formula (I) - inhibitors of JAK2. The inhibitors described herein may be useful in treating diseases or disorders associated with JAK2, such as hematological disorders. In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit JAK2, methods for treating diseases or disorders associated with JAK2, and methods for synthesizing these compounds. JPEG2026502173000338.jpg63170

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and benefit of U.S. Provisional Patent No. 63 / 434,412, filed December 21, 2022, entitled "JAK2 Inhibitors," the disclosure of which is incorporated by reference in its entirety for all purposes.

[0002] FIELD OF THE INVENTION The present invention relates to inhibitors of JAK2. The inhibitors described herein may be useful for treating diseases or disorders associated with JAK2, such as hematological disorders. In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit JAK2, methods for treating diseases or disorders associated with JAK2, and methods for synthesizing these compounds. [Background technology]

[0003] (background) Myeloproliferative disorders (MPDs) are clonal disorders of hematopoietic progenitor cells and include the classic MPDs chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), as well as chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML), and systemic mastocytosis (SM). Although each MPD is recognized as a distinct clinicopathological entity, these diseases share fundamental features that distinguish them from other myeloid malignancies, namely myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).

[0004] Over the past 30 years, mutant alleles have been identified in CML, CMML, CEL, and SM, and in each case, the causative mutations result in constitutive activation of tyrosine kinase signaling. Perhaps most important from a clinical perspective, specific inhibition of these activated kinases has yielded dramatic clinical benefits in the treatment of MPDs. Together, these data demonstrate that tyrosine kinase activation is a common pathogenic mechanism in MPDs and that these mutated kinases serve as validated targets for the design of molecular-targeted therapies.

[0005] In 2005, multiple independent groups, using different experimental approaches, identified recurrent mutations in the JAK2 tyrosine kinase in most patients with PV, ET, or PMF. JAK2 is a member of the Janus family of cytoplasmic nonreceptor tyrosine kinases, which also includes JAK1, JAK3, and TYK2. This mutation is a guanine-to-thymidine substitution, resulting in a valine-to-phenylalanine substitution at codon 617 of JAK2 (JAK2V617F). This mutation is present in hematopoietic DNA but not in germline DNA in MPD patients, indicating that JAK2V617F is a somatic mutation acquired in the hematopoietic compartment. Furthermore, the JAK2V617F allele can be present in different hematopoietic compartments, including B and T lymphocytes. These findings suggested that the mutation may occur in pluripotent hematopoietic stem cells, and indeed, the JAK2V617F allele was recently identified in the hematopoietic stem cell (HSC) compartment of a PV patient.

[0006] JAKs are unique among tyrosine kinases in that they contain a pseudokinase domain immediately upstream of their C-terminal tyrosine kinase domain. Extensive biochemical and clinical data demonstrate that the pseudokinase domain of JAKs is important for maintaining a low basal (cytokine-free) level of tyrosine kinase activity. In particular, gain-of-function mutations in JAK genes, particularly V617F in the pseudokinase domain of JAK2, have been mapped in patients with hematological disorders, including myeloproliferative neoplasms and leukemia.

[0007] The tyrosine kinase domain (JH1) of JAKs is responsible for most, if not all, of the phosphorylation activity of JAKs. In particular, JH1 catalyzes the transphosphorylation of two tyrosine residues (Tyr1007 and Tyr1008 in JAK2) in the kinase activation loop, stabilizing the activated state. Transphosphorylation of these two tyrosines is a key step in JAK activation. The activated kinase domain then phosphorylates specific tyrosine residues in associated cytokine receptors and recruited STAT molecules, as well as other tyrosines in the JAK molecule.

[0008] Both biochemical and clinical evidence demonstrate the critical regulatory role of JH2 in JAK2, and 32 different mutations in JH2 of JAK2 have been shown to cause or be associated with hematological disorders. The most common somatic mutation, V617F, constitutively activates JAK2 and accounts for over 95% of cases of polycythemia vera and approximately 50% of cases of essential thrombocytosis and primary myelofibrosis. The mechanism(s) by which JH2 negatively regulates the tyrosine kinase activity of JH1 are currently unknown, but likely involve intramolecular interactions between JH2 and JH1.

[0009] Even if JAK2 inhibitor treatment can induce molecular and clinical remission in patients with PV, ET, or PMF, a proportion of patients will develop resistance to JAK2 inhibitor treatment, likely due to the emergence of resistance mutations, as observed in imatinib-resistant CML. The development of second-generation JAK2 inhibitors designed to inhibit specific resistance alleles represents a suitable approach to overcome this resistance. This strategy has been used to design second-generation ABL inhibitors for the treatment of imatinib-refractory CML.

[0010] (overview) A first aspect of the present invention is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: Ring G is a 5-10 membered monocyclic or bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S; R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, CN, NO, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, aryl, heteroaryl, wherein said C3-C 10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, OH, CN; R 2 is selected from H, C1-C6 alkyl; R 3 is hydrogen, C1-C6 alkyl, C3-C 10 cycloalkyl; R 4 is selected from H, C1-C6 alkyl; R 5 is selected from H, C1-C6 alkyl; Alternatively, R 4 and R 5 together with the atom to which they are attached and any intervening atoms form a 3- to 14-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; R 6 is selected from H, C1-C6 alkyl; Each R 7 is oxo, C1-C6 alkyl, C3-C10 Cycloalkyl, heterocyclyl, -NH-heteroaryl, -(CH2) m -NH-C(O)-R 8 , -(CH2) m -C(O)NH-R 8 , -(CH2) m -C(O)NH-heteroaryl, -(CH2) m -S(O)2N-R 8 , -(CH2) m -S(O)N-heterocyclyl, wherein said alkyl, cycloalkyl, heterocyclyl or heteroaryl is independently selected from halogen, -CN, -OH, N(R 8 )2, optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl; Each R 8 are independently H, C1-C6 alkyl, C3-C 10 cycloalkyl; n is an integer selected from 0, 1, 2, and 3; m is an integer selected from 0, 1, and 2; Cycloalkyl is a mono- or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spiro) or 11- to 14-membered tricyclic ring system (fused, bridged, or spiro) having one or more heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C.

[0011] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

[0012] Another aspect of the present invention relates to a method of treating a JAK2-associated disease or disorder, comprising administering to a patient in need of treatment for a JAK2-associated disease or disorder an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0013] Another aspect of the present invention relates to a method of inhibiting JAK2, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0014] Another aspect of the present invention relates to a method of inhibiting TYK2, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0015] Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting JAK2.

[0016] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof in the treatment of diseases associated with the inhibition of JAK2.

[0017] Another aspect of the present invention pertains to a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

[0018] Another aspect of the present invention relates to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0019] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0020] The present invention further provides a method of treating a disease or disorder associated with JAK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0021] The present invention provides inhibitors of JAK2 that are therapeutic agents in the treatment of diseases and disorders.

[0022] The present invention further provides compounds and compositions with improved efficacy and safety profiles compared to known inhibitors of JAK2. The present disclosure also provides agents with novel mechanisms of action against JAK2 in the treatment of various types of diseases.

[0023] The present invention further provides a method of treating a disease or disorder associated with JAK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0024] The present invention provides inhibitors of JAK2 that are therapeutic agents in the treatment of diseases and disorders.

[0025] The present invention further provides a method of treating a disease, disorder, or condition selected from polycythemia vera, essential thrombocytosis, thrombocytosis 3, primary myelofibrosis, chronic myelomonocytic leukemia, acute myeloid leukemia, myelodysplasia, acute myeloid leukemia, Budd-Chiari syndrome, the method comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0026] In some aspects, the disclosure provides compounds obtainable by or obtained by a method for preparing a compound described herein (e.g., a method comprising one or more steps described in the general procedures).

[0027] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in the methods for preparing the compounds described herein (e.g., the intermediates are selected from the intermediates described in Preparation Parts P1 to P84).

[0028] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0029] In some aspects, the present disclosure provides methods of preparing the compounds of the present disclosure, comprising one or more steps described herein.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular also includes the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. No reference cited herein is admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. In the event of a conflict between the chemical structure and name of a compound disclosed herein, the chemical structure will control.

[0031] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0032] (Detailed explanation) The present disclosure provides methods for treating, preventing, or ameliorating a disease or disorder associated with JAK2 by administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0033] Details of the present disclosure are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in practicing or testing the present disclosure, exemplary methods and materials are described here. Other features, objects, and advantages of the present disclosure will become apparent from the specification and claims. In this specification and the appended claims, the singular forms include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated herein by reference in their entirety. definition

[0034] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0035] In this disclosure, the term "and / or" means either "and" or "or" unless otherwise stated.

[0036] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For example, at any point along the chain, it can be bonded to a halogen atom, a hydroxyl group, or other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to include other functional groups, but does not necessarily have any additional functional groups. Suitable substituents for use in any substitution of the described groups include, but are not limited to, halogen, oxo, —OH, —CN, —COOH, —CHCN, —O—(C-C)alkyl, (C-C)alkyl, (C-C)alkoxy, (C-C)haloalkyl, (C-C)haloalkoxy, —O—(C-C)alkenyl, —O—(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, —OH, —OP(O )(OH), —OC(O)(C-C)alkyl, —C(O)(C-C)alkyl, —OC(O)O(C-C)alkyl, —NH, —NH((C-C)alkyl), —N((C-C)alkyl), —NHC(O)(C-C)alkyl, —C(O)NH(C-C)alkyl, —S(O)(C-C)alkyl, —S(O)NH(C-C)alkyl, and S(O)N((C-C)alkyl). Substituents may themselves be optionally substituted. As used herein, “optionally substituted” means substituted or unsubstituted, the meaning of which is described below.

[0037] As used herein, the term "substituted" means that a particular group or moiety has one or more suitable substituents, and the substituents may be linked to the particular group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl indicates that the cycloalkyl is linked to one atom of the aryl by a bond or by being fused to the aryl and sharing two or more common atoms.

[0038] As used herein, the term "unsubstituted" means that the particular group bears no substituents.

[0039] Unless otherwise defined, the term "aryl" refers to a cyclic, aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group can be attached at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group can be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C-C)alkyl, (C-C)alkyl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, -OH, -O-P(O)(OH), -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, -NH, -NH((C-C)alkyl), N((C-C)alkyl), -S(O)-(C-C)alkyl, -S(O)NH(C-C)alkyl, and -S(O)N((C-C)alkyl). Substituents may themselves be optionally substituted. Additionally, when containing two fused rings, aryl groups as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Examples of ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannurenyl, and the like.

[0040] Unless otherwise defined, "heteroaryl" refers to a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C. Polycyclic aromatic radicals can contain two or more fused rings and can further contain two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specified, "fused" refers to two rings that share two ring atoms. Unless otherwise specified, "spiro-fused" refers to two rings that share one ring atom. Heteroaryl, as defined herein, also refers to bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, or B. Heteroaryl, as defined herein, also refers to tricyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl, as defined herein, also refers to tetracyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, or B. Aromatic radicals may be independently substituted with one or more substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl ... lo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyridinyl Furo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl Lysinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,

[0023] In addition, when containing two or more fused rings, the heteroaryl group defined herein may have one or more saturated or partially unsaturated rings fused with one or more fully unsaturated aromatic rings. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated rings may be further fused with the saturated or partially unsaturated rings described herein. In addition, when containing three or more fused rings, the heteroaryl group defined herein may have one or more saturated or partially unsaturated rings spiro-fused. Any saturated or partially unsaturated ring described herein may be optionally substituted with one or more oxo. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyridin-7-on ... These include pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-onyl, or 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9'-onyl.

[0041] Halogen or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0042] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neo-pentyl, and isohexyl.

[0043] "Alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms including a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0044] "Alkenyl" refers to a straight- or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. As defined herein, alkenyl can be straight-chain or branched.

[0045] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0046] The term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by abstraction of a second hydrogen atom from the alkyl. As defined herein, alkylene can be a C1-C6 alkylene. Alkylene can further be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-, and the like.

[0047] "Cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring containing 3-18 carbon atoms. Polycyclic cycloalkyls may be fused bicyclic cycloalkyls, bridged bicyclic cycloalkyls, or spiro-fused bicyclic cycloalkyls. Polycyclic cycloalkyls contain at least one non-aromatic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0048] A "heterocyclyl," "heterocycle," or "heterocycloalkyl" contains 3-24 atoms, including carbon and one or more heteroatoms selected from N, O, S, P, or B, and is monocyclic or polycyclic, where the ring is not aromatic. The heterocycloalkyl ring structure may be substituted with one or more substituents. Polycyclic heterocycloalkyls contain at least one non-aromatic ring. Polycyclic heterocyclic compounds can be bridged, fused, or spirofused. The substituents may themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, homotropanyl, 2-oxa-5-azabicyclo[2.2.2]octane, and 2,6-diazaspiro[3.3]heptanyl.

[0049] The term "aromatic" refers to a planar ring with 4n+2 electrons in a conjugated system. As used herein, "conjugated system" refers to a system of linked p-orbitals with delocalized electrons, which may include lone pairs of electrons.

[0050] The term "haloalkyl," as used herein, refers to an alkyl group, as defined herein, that is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0051] The term "haloalkoxy" as used herein refers to an alkoxy group, as defined herein, substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0052] As used herein, the term "cyano" refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, i.e., C≡N.

[0053] "Spirocycloalkyl" or "spirocyclyl" refers to a carbon-based bicyclic ring system in which both rings are connected through a single atom. The rings may be different in size and nature or may be identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, and spirodecane. One or both of the spiro rings may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spiro ring may be replaced with a heteroatom (e.g., O, N, S, or P). (C3-C 12 ) A spirocycloalkyl is a spiro ring containing 3 to 12 carbon atoms. One or more carbon atoms may be replaced with a heteroatom.

[0054] The terms "spiroheterocycloalkyl," "spiroheterocycle," or "spiroheterocyclyl" are understood to mean a spirocycle in which at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperidinyl).

[0055] The term "solvate" refers to a complex of varying stoichiometry formed by a solute and a solvent. For purposes of this disclosure, such solvents may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0056] As used herein, the term "alkyl-aryl" (and variations thereof, e.g., C1-C6 alkyl-aryl) refers to a chemical moiety comprising an alkyl group covalently bonded to an aryl group, where the bond to the rest of the molecule is on the first group described, i.e., the alkyl group. Similarly, alkyl-alkoxy refers to a chemical moiety comprising an alkyl group covalently bonded to an alkoxy group, where the bond to the rest of the molecule is on the alkyl group. This nomenclature can also be used for, e.g., alkenyl-aryl, alkenyl-heteroaryl, alkynyl-aryl, alkynyl-heteroaryl. As a non-limiting example, C1 alkyl-phenyl is [ka] C2 alkenyl-furanyl refers to [ka] C1 alkyl-C2 alkoxy refers to [ka] For example, it refers to

[0057] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences may be in constitution (geometric isomers) or in ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0058] The present disclosure also provides isotopically labeled compounds of Formula I, such as 2 H and 14 C) are intended to be deuterated (i.e., 2 H or D) isotopes and carbon-14 (i.e., 14C) Isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium, may offer certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced required dose), and therefore may be preferred in some circumstances. Isotopically labeled compounds of Formula I can generally be prepared by replacing non-isotopically labeled reagents with appropriate isotopically labeled reagents in accordance with procedures similar to those disclosed in the following schemes and / or examples.

[0059] The present disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water-soluble salts and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, and hydrochloride. , hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, diacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0060] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, e.g., a monkey, chimpanzee, baboon, or rhesus monkey.

[0061] An "effective amount," when used in connection with a compound, is an amount effective to treat or prevent a disease in a subject as described herein.

[0062] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body of a subject to another organ or part of the body.

[0063] The term "treating" with respect to a subject refers to improving at least one symptom of the subject's disorder. Treating includes curing, ameliorating, or at least partially ameliorating the disorder.

[0064] In this disclosure, the term "disorder" is used to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise specified.

[0065] The terms "administer," "administering," or "administration," as used in this disclosure, refer to either administering a disclosed compound, or a pharmaceutically acceptable salt or composition of a disclosed compound, directly to a subject, or administering a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt or composition of the compound, to a subject, allowing an equivalent amount of active compound to form in the subject's body.

[0066] The term "prodrug," as used in this disclosure, means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to a disclosed compound.

[0067] The term "salt" means a pharmaceutically acceptable salt.

[0068] The term "pharmaceutically acceptable salt" also refers to a salt of a composition of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.

[0069] As used herein, "JAK2 inhibitor" refers to a compound of Formula I and / or a composition comprising a compound of Formula I that inhibits JAK2.

[0070] The amount of a compound of a composition described herein required to achieve a therapeutic effect can be empirically determined according to conventional procedures for a particular purpose. Generally, when administering a therapeutic agent (e.g., a compound of Formula I or a composition described herein (and / or additional agents)) for therapeutic purposes, the therapeutic agent is given in a pharmacologically effective dose. A "pharmacologically effective amount," "pharmacologically effective dose," "therapeutically effective amount," or "effective amount" refers to an amount sufficient to produce a desired physiological effect or achieve a desired result, particularly for treating a disorder or disease. As used herein, an effective amount includes, for example, an amount sufficient to delay the onset of symptoms of a disorder or disease, alter the course of symptoms of a disorder or disease (e.g., slow the progression of symptoms of the disease), reduce or eliminate one or more symptoms or signs of a disorder or disease, and reverse symptoms of a disorder or disease. For example, administering a therapeutic agent to a subject suffering from cancer provides a therapeutic effect not only if the underlying condition is eradicated or ameliorated, but also if the subject reports a decrease in the severity or duration of symptoms associated with the disease. A therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is achieved. Compounds of the Disclosure

[0071] In one aspect, the disclosure provides compounds of formula (I) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: [ka] where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , G, and n are as described herein.

[0072] For compounds of formula (I), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , G, and n may each be selected from groups described herein, where applicable; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 Any group described herein for any of R, G, and n, if applicable, 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 It is understood that one or more of the remaining groups, G, and n, can be combined with any group described herein.

[0073] In some embodiments, Ring G is a 5-10 membered monocyclic or bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S; R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, CN, NO, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, aryl, heteroaryl, wherein said C3-C 10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, OH, CN; R 2 is selected from H, C1-C6 alkyl; R 3 is hydrogen, C1-C6 alkyl, C3-C 10 cycloalkyl; R 4 is selected from H, C1-C6 alkyl; R 5 is selected from H, C1-C6 alkyl; Alternatively, R 4 and R 5 together with the atom to which they are attached and any intervening atoms form a 3- to 14-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; R 6 is selected from H, C1-C6 alkyl; Each R 7 is oxo, C1-C6 alkyl, C3-C 10 Cycloalkyl, heterocyclyl, -NH-heteroaryl, -(CH2) m -NH-C(O)-R 8 , -(CH2) m -C(O)NH-R 8 , -(CH2) m -C(O)NH-heteroaryl, -(CH2) m -S(O)2N-R 8 , -(CH2) m -S(O)N-heterocyclyl, wherein said alkyl, cycloalkyl, heterocyclyl or heteroaryl is independently selected from halogen, -CN, -OH, N(R 8)2, optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl; Each R 8 are independently H, C1-C6 alkyl, C3-C 10 cycloalkyl; n is an integer selected from 0, 1, 2, and 3; m is an integer selected from 0, 1, and 2.

[0074] In some embodiments, ring G contains 1-3 heteroatoms selected from N, O, and S, and optionally 1-3 R 7 is a 5-10 membered monocyclic or bicyclic heteroaryl substituted with

[0075] In some embodiments, ring G is a 5-membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S.

[0076] In some embodiments, ring G is a 5-membered monocyclic heteroaryl containing 1 heteroatom selected from N, O, and S.

[0077] In some embodiments, ring G is a 5-membered monocyclic heteroaryl containing two heteroatoms independently selected from N, O, and S.

[0078] In some embodiments, ring G is a 5-membered monocyclic heteroaryl containing 3 heteroatoms independently selected from N, O, and S.

[0079] In some embodiments, ring G is a 6-membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S.

[0080] In some embodiments, ring G is a 6-membered monocyclic heteroaryl containing 1 heteroatom selected from N, O, and S.

[0081] In some embodiments, ring G is a 6-membered monocyclic heteroaryl containing two heteroatoms independently selected from N, O, and S.

[0082] In some embodiments, ring G is a 6-membered monocyclic heteroaryl containing 3 heteroatoms independently selected from N, O, and S.

[0083] In some embodiments, ring G is a 9-membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S.

[0084] In some embodiments, ring G is a 9-membered bicyclic heteroaryl containing 1 heteroatom selected from N, O, and S.

[0085] In some embodiments, ring G is a 9-membered bicyclic heteroaryl containing two heteroatoms independently selected from N, O, and S.

[0086] In some embodiments, ring G is a 9-membered bicyclic heteroaryl containing 3 heteroatoms independently selected from N, O, and S.

[0087] In some embodiments, ring G is a 10-membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S.

[0088] In some embodiments, ring G is a 10-membered bicyclic heteroaryl containing 1 heteroatom selected from N, O, and S.

[0089] In some embodiments, ring G is a 10-membered bicyclic heteroaryl containing two heteroatoms independently selected from N, O, and S.

[0090] In some embodiments, ring G is a 10-membered bicyclic heteroaryl containing 3 heteroatoms independently selected from N, O, and S.

[0091] In some embodiments, ring G is [ka] is selected from.

[0092] In some embodiments, ring G is [ka] is.

[0093] In some embodiments, ring G is [ka] is.

[0094] In some embodiments, ring G is [ka] and n is selected from 0, 1 and 2.

[0095] In some embodiments, ring G is [ka] is.

[0096] In some embodiments, ring G is [ka] is.

[0097] In some embodiments, ring G is [ka] is.

[0098] In some embodiments, ring G is [ka] is.

[0099] In some embodiments, ring G is [ka] is.

[0100] In some embodiments, ring G is [ka] is selected from.

[0101] In some embodiments, ring G is [ka] is.

[0102] In some embodiments, ring G is [ka] is.

[0103] In some embodiments, ring G is [ka] is.

[0104] In some embodiments, ring G is [ka] is.

[0105] In some embodiments, ring G is [ka] is.

[0106] In some embodiments, ring G is [ka] is.

[0107] In some embodiments, ring G is [ka] [ka] is selected from.

[0108] In some embodiments, ring G is [ka] is.

[0109] In some embodiments, ring G is [ka] is.

[0110] In some embodiments, ring G is [ka] is.

[0111] In some embodiments, ring G is [ka] is.

[0112] In some embodiments, ring G is [ka] is.

[0113] In some embodiments, ring G is [ka] is.

[0114] In some embodiments, ring G is [ka] is.

[0115] In some embodiments, ring G is [ka] is.

[0116] In some embodiments, ring G is [ka] is.

[0117] In some embodiments, ring G is [ka] is.

[0118] In some embodiments, ring G is [ka] is.

[0119] In some embodiments, ring G is [ka] is.

[0120] In some embodiments, ring G is [ka] is.

[0121] In some embodiments, ring G is [ka] is.

[0122] In some embodiments, ring G is [ka] is.

[0123] In some embodiments, ring G is [ka] is.

[0124] In some embodiments, ring G is [ka] is.

[0125] In some embodiments, ring G is [ka] is.

[0126] In some embodiments, ring G is [ka] is.

[0127] In some embodiments, ring G is [ka] is.

[0128] In some embodiments, ring G is [ka] is.

[0129] In some embodiments, ring G is [ka] is.

[0130] In some embodiments, ring G is [ka] is.

[0131] In some embodiments, ring G is [ka] is.

[0132] In some embodiments, ring G is [ka] is.

[0133] In some embodiments, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, CN, NO, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, aryl, heteroaryl, wherein said C3-C 10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, OH, CN.

[0134] In some embodiments, R 1 is halogen, OH, N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10C1-C6 alkyl optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein said C3-C 10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, OH, CN.

[0135] In some embodiments, R 1 is C1-C6 alkyl.

[0136] In some embodiments, R 1 is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, i-pentyl, n-hexyl, i-hexyl.

[0137] In some embodiments, R 1 is methyl.

[0138] In some embodiments, R 1 is ethyl.

[0139] In some embodiments, R 1 is propyl.

[0140] In some embodiments, R 1 is n-propyl.

[0141] In some embodiments, R 1 is i-propyl.

[0142] In some embodiments, R 1 is n-butyl.

[0143] In some embodiments, R 1 is i-butyl.

[0144] In some embodiments, R1 is tert-butyl.

[0145] In some embodiments, R 1 is n-pentyl.

[0146] In some embodiments, R 1 is i-pentyl.

[0147] In some embodiments, R 1 is hexyl.

[0148] In some embodiments, R 1 is n-hexyl.

[0149] In some embodiments, R 1 is one or more N(R 8 )2 is a C1-C6 alkyl substituted with

[0150] In some embodiments, R 1 is one N(R 8 )2 is a C1-C6 alkyl substituted with

[0151] In some embodiments, R 1 is one N(R 8 ) methyl substituted with 2.

[0152] In some embodiments, R 1 is one or more R 8 is ethyl substituted with

[0153] In some embodiments, R 1 is one N(R 8 ) 2-substituted propyl.

[0154] In some embodiments, R 1 is one N(R 8 ) butyl substituted with 2.

[0155] In some embodiments, R 1 is one N(R 8 ) 2-substituted pentyl.

[0156] In some embodiments, R 1 is one N(R 8 )2-substituted hexyl.

[0157] In some embodiments, R 1 teeth, [ka] is.

[0158] In some embodiments, R 1 teeth, [ka] is.

[0159] In some embodiments, R 1 teeth, [ka] is.

[0160] In some embodiments, R 1 is a C1-C6 alkyl substituted with one or more C1-C6 alkoxy.

[0161] In some embodiments, R 1 is a C1-C6 alkyl substituted with one C1-C6 alkoxy.

[0162] In some embodiments, R 1 teeth, [ka] is.

[0163] In some embodiments, R 1 teeth, [ka] is.

[0164] In some embodiments, R 1 teeth, [ka] is.

[0165] In some embodiments, R 1 is C1-C6 alkyl optionally substituted with C1-C6 alkyl.

[0166] In some embodiments, R 1 is C1-C6 alkyl substituted with C1-C6 alkyl.

[0167] In some embodiments, R 1 is octyl.

[0168] In some embodiments, R 1 is n-octyl.

[0169] In some embodiments, R 1 is C3-C 10 It is a C1-C6 alkyl substituted with a cycloalkyl.

[0170] In some embodiments, R 1 is C3-C 10 It is methyl substituted with cycloalkyl.

[0171] In some embodiments, R 1 is methyl substituted with cyclopropyl.

[0172] In some embodiments, R 1 is methyl substituted with cyclobutyl.

[0173] In some embodiments, R 1is methyl substituted with cyclohexyl.

[0174] In some embodiments, R 1 is a methyl substituted with adamantyl.

[0175] In some embodiments, R 1 is a methyl substituted with 1-adamantyl.

[0176] In some embodiments, R 1 is C1-C6 alkyl optionally substituted with one or more halogens.

[0177] In some embodiments, R1 is C1-C6 alkyl optionally substituted with one or more F.

[0178] In some embodiments, R 1 teeth, [ka] is.

[0179] In some embodiments, R 1 is a C1-C6 alkyl substituted with one heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6 alkyl.

[0180] In some embodiments, R 1 is methyl substituted with one heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6 alkyl.

[0181] In some embodiments, R 1 is methyl substituted with one 5-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6 alkyl.

[0182] In some embodiments, R 1is methyl substituted with one 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6 alkyl.

[0183] In some embodiments, R 1 is methyl substituted with one 7-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6 alkyl.

[0184] In some embodiments, R 1 is methyl substituted with piperidinyl.

[0185] In some embodiments, R 1 is methyl substituted with 4-piperidinyl.

[0186] In some embodiments, R 1 is methyl substituted with 3-piperidinyl.

[0187] In some embodiments, R 1 is methyl substituted with 2-piperidinyl.

[0188] In some embodiments, R 1 teeth, [ka] is.

[0189] In some embodiments, R 1 is halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 C3-C optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl. 10 It is cycloalkyl.

[0190] In some embodiments, R 1 is C3-C 10It is cycloalkyl.

[0191] In some embodiments, R 1 is a monocyclic C3-C 10 It is cycloalkyl.

[0192] In some embodiments, R 1 is cyclopropyl.

[0193] In some embodiments, R 1 is cyclobutyl.

[0194] In some embodiments, R 1 is cyclopentyl.

[0195] In some embodiments, R 1 is cyclohexyl.

[0196] In some embodiments, R 1 is cycloheptyl.

[0197] In some embodiments, R 1 is cyclooctyl.

[0198] In some embodiments, R 1 is cyclononyl.

[0199] In some embodiments, R 1 is cyclodecyl.

[0200] In some embodiments, R 1 is a polycyclic C3-C 10 It is cycloalkyl.

[0201] In some embodiments, R 1 is adamantyl.

[0202] In some embodiments, R 1 is 1-adamantyl.

[0203] In some embodiments, R 1 is halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 and heterocyclyl optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.

[0204] In some embodiments, R 1 is halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 and 4-7 membered heterocyclyl optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.

[0205] In some embodiments, R 1 is a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and the heterocyclyl is selected from halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl.

[0206] In some embodiments, R 1 is a 4-membered heterocyclyl containing one heteroatom selected from N, O, S, and the heterocycle is preferably halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, aryl, heteroaryl.

[0207] In some embodiments, R 1 is a 5-membered heterocyclyl containing 1 to 2 heteroatoms selected from N, O, and S, and the heterocyclyl is selected from halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, aryl, heteroaryl.

[0208] In some embodiments, R 1 is a 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, and the heterocyclyl is selected from halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, aryl, heteroaryl.

[0209] In some embodiments, R 1 is a 6-membered heterocyclyl containing N, and heterocyclyl is a halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, aryl, heteroaryl.

[0210] In some embodiments, R 1 is piperidinyl.

[0211] In some embodiments, R 1 is 4-piperidinyl.

[0212] In some embodiments, R 1 is 3-piperidinyl.

[0213] In some embodiments, R 1 is 2-piperidinyl.

[0214] In some embodiments, R 1 teeth, [ka] is.

[0215] In some embodiments, R 1 is a 6-membered N-containing heterocyclyl, wherein the heterocyclyl is substituted with C1-C6 alkyl.

[0216] In some embodiments, R 1 teeth, [ka] is.

[0217] In some embodiments, R 1 teeth, [ka] is.

[0218] In some embodiments, R 1 teeth, [ka] is.

[0219] In some embodiments, R 1 teeth, [ka] is.

[0220] In some embodiments, R 1 is a 6-membered heterocyclyl containing O, and heterocyclyl is a halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, aryl, heteroaryl.

[0221] In some embodiments, R 1 is tetrahydropyran.

[0222] In some embodiments, R 1 is 4-tetrahydropyran.

[0223] In some embodiments, R 1 is 3-tetrahydropyran.

[0224] In some embodiments, R 1 is 2-tetrahydropyran.

[0225] In some embodiments, R 1 teeth, [ka] is.

[0226] In some embodiments, R 1 is a 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, and the heterocyclyl is selected from halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, aryl, heteroaryl.

[0227] In some embodiments, R 1 is halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10Aryl optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl.

[0228] In some embodiments, R 1 is halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 and phenyl optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.

[0229] In some embodiments, R 1 is phenyl.

[0230] In some embodiments, R 1 teeth, [ka] is.

[0231] In some embodiments, R 2 is selected from H, C1-C6 alkyl.

[0232] In some embodiments, R 2 is H.

[0233] In some embodiments, R 2 is C1-C6 alkyl.

[0234] In some embodiments, R 2 is methyl.

[0235] In some embodiments, R 3 is hydrogen, C1-C6 alkyl, C3-C 10 cycloalkyl.

[0236] In some embodiments, R3 is hydrogen.

[0237] In some embodiments, R 3 is C1-C6 alkyl.

[0238] In some embodiments, R 3 is C3-C 10 It is cycloalkyl.

[0239] In some embodiments, R 4 is selected from H, C1-C6 alkyl.

[0240] In some embodiments, R 4 is H.

[0241] In some embodiments, R 4 is C1-C6 alkyl.

[0242] In some embodiments, R 4 is methyl.

[0243] In some embodiments, R 5 is selected from H, C1-C6 alkyl.

[0244] In some embodiments, R 5 is H.

[0245] In some embodiments, R 5 is C1-C6 alkyl.

[0246] In some embodiments, R 5 is methyl.

[0247] In some embodiments, R 4 and R 5together with the atom to which they are attached and any intervening atoms form a 3- to 14-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy.

[0248] In some embodiments, R 6 is selected from H, C1-C6 alkyl.

[0249] In some embodiments, R 6 is H.

[0250] In some embodiments, R 6 is C1-C6 alkyl.

[0251] In some embodiments, R 6 is methyl.

[0252] In some embodiments, each R 7 is oxo, C1-C6 alkyl, C3-C 10 Cycloalkyl, heterocyclyl, -NH-heteroaryl, -(CH2) m -NH-C(O)-R 8 , -(CH2) m -C(O)NH-R 8 , -(CH2) m -C(O)NH-heteroaryl, -(CH2) m -S(O)2N-R 8 , -(CH2) m -S(O)N-heterocyclyl, wherein said alkyl, cycloalkyl, heterocyclyl or heteroaryl is independently selected from halogen, -CN, -OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, optionally substituted with one or more substituents independently selected from.

[0253] In some embodiments, R 7 is halogen, -OH, N(R 8)2, C1-C6 alkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl.

[0254] In some embodiments, R 7 is methyl.

[0255] In some embodiments, R 7 is halogen, -OH, N(R 8 )2, C3-C optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl 10 It is cycloalkyl.

[0256] In some embodiments, each R 8 are independently H, C1-C6 alkyl, C3-C 10 cycloalkyl.

[0257] In some embodiments, each R 8 is H.

[0258] In some embodiments, one R 8 is H and one R 8 is C1-C6 alkyl.

[0259] In some embodiments, each R 8 is C1-C6 alkyl.

[0260] In some embodiments, each R 8 is methyl.

[0261] In some embodiments, each R 8 is ethyl.

[0262] In some embodiments, each R 8 is propyl.

[0263] In some embodiments, each R 8is n-propyl.

[0264] In some embodiments, each R 8 is i-propyl.

[0265] In some embodiments, each R 8 is butyl.

[0266] In some embodiments, each R 8 is n-butyl.

[0267] In some embodiments, each R 8 is i-butyl.

[0268] In some embodiments, n is an integer selected from 0, 1, 2, and 3.

[0269] In some embodiments, n is 0.

[0270] In some embodiments, n is 1.

[0271] In some embodiments, n is 2.

[0272] In some embodiments, n is 3.

[0273] In some embodiments, m is an integer selected from 0, 1, and 2.

[0274] In some embodiments, m is 0.

[0275] In some embodiments, m is 1.

[0276] In some embodiments, m is 2.

[0277] In some embodiments, the compound is of formula (I-ABC): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and O, Y is selected from N, O, and CH, and a bond JPEG2026502173000066.jpg1121 is a single or double bond, and the bond JPEG2026502173000067.jpg819 is a single or double bond; however, when X is N, the bond JPEG2026502173000068.jpg1121 is a double bond, and the bond JPEG2026502173000069.jpg819 is a single bond, and when X is O, it is a bond JPEG2026502173000070.jpg1121 is a single bond, and the bond JPEG2026502173000071.jpg819 is a double bond; optionally, R 7 Two of the atoms, together with the atoms to which they are attached and any intervening atoms, form one to three R 7 and all other variables are as defined herein.

[0278] In some embodiments, the compound is of formula (IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0279] In some embodiments, the compound is of formula (IB): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0280] In some embodiments, the compound is of formula (IC): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0281] In some embodiments, the compound is of formula (IC*): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein all other variables are as defined herein, and n is selected from 0, 1, and 2, and all other variables are as defined herein.

[0282] In some embodiments, the compound is of formula (I-C'): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0283] In some embodiments, the compound is of formula (I-C″): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0284] In some embodiments, the compound is of formula (IC'"): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0285] In some embodiments, the compound is of formula (I-C''''): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0286] In some embodiments, the compound is of formula (I-DE): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Z is selected from N and C, and optionally R 7 two of which, together with the atom to which they are attached and any intervening atoms, form an aryl, and all other variables are as defined herein.

[0287] In some embodiments, the compound is of formula (ID): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0288] In some embodiments, the compound is of formula (IE): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0289] In some embodiments, the compound is of formula (IA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0290] In some embodiments, the compound is of formula (IA-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0291] In some embodiments, the compound is of formula (IA-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0292] In some embodiments, the compound is of formula (IA-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0293] In some embodiments, the compound is of formula (IA-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0294] In some embodiments, the compound is of formula (IBa): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0295] In some embodiments, the compound is of formula (IC-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0296] In some embodiments, the compound is of formula (IC-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0297] In some embodiments, the compound is of formula (IC-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0298] In some embodiments, the compound is of formula (IC-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0299] In some embodiments, the compound is of formula (IC-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0300] In some embodiments, the compound is of formula (IC-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0301] In some embodiments, the compound is of formula (IC-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0302] In some embodiments, the compound is of formula (IC-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0303] In some embodiments, the compound is of formula (IC-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0304] In some embodiments, the compound is of formula (IC-10): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0305] In some embodiments, the compound is of formula (IC-11): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0306] In some embodiments, the compound is of formula (I-C'-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0307] In some embodiments, the compound is of formula (I-C'-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0308] In some embodiments, the compound is of formula (I-C'-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0309] In some embodiments, the compound is of formula (I-C'-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0310] In some embodiments, the compound is of formula (I-C'-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0311] In some embodiments, the compound is of formula (I-C'-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0312] In some embodiments, the compound is of formula (I-C'-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0313] In some embodiments, the compound is of formula (I-C'-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0314] In some embodiments, the compound is of formula (I-C'-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0315] In some embodiments, the compound is of formula (I-C'-10): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0316] In some embodiments, the compound is of formula (I-C'-11): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0317] In some embodiments, the compound is of formula (I-C''-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0318] In some embodiments, the compound is of formula (I-C''-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0319] In some embodiments, the compound is of formula (I-C''-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0320] In some embodiments, the compound is of formula (I-C''-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0321] In some embodiments, the compound is of formula (I-C''-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0322] In some embodiments, the compound is of formula (I-C''-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0323] In some embodiments, the compound is of formula (I-C''-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0324] In some embodiments, the compound is of formula (I-C''-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0325] In some embodiments, the compound is of formula (I-C''-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0326] In some embodiments, the compound is of formula (I-C''-10): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0327] In some embodiments, the compound is of formula (I-C''-11): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0328] In some embodiments, the compound is of formula (I-C'''-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0329] In some embodiments, the compound is of formula (ID-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0330] In some embodiments, the compound is of formula (ID-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0331] In some embodiments, the compound is of formula (ID-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0332] In some embodiments, the compound is of formula (ID-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0333] In some embodiments, the compound is of formula (ID-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0334] In some embodiments, the compound is of formula (ID-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0335] In some embodiments, the compound is of formula (ID-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0336] In some embodiments, the compound is of formula (ID-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0337] In some embodiments, the compound is of formula (ID-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0338] In some embodiments, the compound is of formula (ID-10): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0339] In some embodiments, the compound is of formula (ID-11): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0340] In some embodiments, the compound is of formula (ID-12): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0341] In some embodiments, the compound is of formula (ID-13): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0342] In some embodiments, the compound is of formula (IE-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0343] In some embodiments, the compound is of formula (IE-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0344] In some embodiments, the compound is of formula (IE-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0345] In some embodiments, the compound is of formula (IE-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0346] In some embodiments, the compound is of formula (IE-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0347] In some embodiments, the compound is of formula (IE-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0348] In some embodiments, the compound is of formula (IA-2-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0349] In some embodiments, the compound is of formula (IA-2-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0350] In some embodiments, the compound is of formula (IA-2-IB): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0351] In some embodiments, the compound is of formula (IBaI): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0352] In some embodiments, the compound is of formula (IBIA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0353] In some embodiments, the compound is of formula (IBIB): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0354] In some embodiments, the compound is of formula (IC-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0355] In some embodiments, the compound is of formula (IC-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0356] In some embodiments, the compound is of formula (IC-1-IB): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0357] In some embodiments, the compound is of formula (ID-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0358] In some embodiments, the compound is of formula (ID-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0359] In some embodiments, the compound is of formula (ID-1-IB): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0360] In some embodiments, the compound is of formula (IE-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0361] In some embodiments, the compound is of formula (IE-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0362] In some embodiments, the compound is of formula (IE-1-IB): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0363] In some embodiments, the compound is of formula (I-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0364] In some embodiments, the compound is of formula (I-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0365] In some embodiments, the compound is of formula (I-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0366] In some embodiments, the compound is of formula (I-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0367] In some embodiments, the compound is of formula (I-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0368] In some embodiments, the compound is of formula (I-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0369] In some embodiments, the compound is of formula (I-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0370] In some embodiments, the compound is of formula (I-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0371] In some embodiments, the compound is of formula (I-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0372] In some embodiments, the compound is of formula (I-10): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0373] In some embodiments, the compound is of formula (I-11): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0374] In some embodiments, the compound is of formula (I-12): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0375] In some embodiments, the compound is of formula (I-13): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0376] In some embodiments, the compound is of formula (I-14): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0377] In some embodiments, the compound is of formula (I-15): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0378] In some embodiments, the compound is of formula (I-16): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0379] In some embodiments, the compound is of formula (I-17): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0380] In some embodiments, the compound is of formula (I-18): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0381] In some embodiments, the compound is of formula (I-19): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0382] In some embodiments, the compound is of formula (I-20): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0383] In some embodiments, the compound is of formula (I-21): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0384] In some embodiments, the compound is of formula (I-22): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0385] In some embodiments, the compound is of formula (I-23): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0386] In some embodiments, the compound is of formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each substituent is independently selected from Table 1.

[0387] JPEG2026502173000181.jpg246170JPEG2026502173000182.jpg240170JPEG2026502173000183.jpg238170JPEG2026502173000184.jpg28170

[0388] In some embodiments, the compound is selected from the compounds set forth in Table 2, and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.

[0389] In some embodiments, the compound is selected from the compounds set forth in Table 2, and pharmaceutically acceptable salts thereof.

[0390] In some embodiments, the compound is selected from prodrugs of the compounds set forth in Table 2 and pharmaceutically acceptable salts thereof.

[0391] In some embodiments, the compound is selected from the compounds listed in Table 2.

[0392] JPEG2026502173000185.jpg198170JPEG2026502173000186.jpg196170JPEG2026502173000187.jpg201170JPE G2026502173000188.jpg225170JPEG2026502173000189.jpg198170JPEG2026502173000190.jpg196170JPEG202 6502173000191.jpg189170JPEG2026502173000192.jpg197170JPEG2026502173000193.jpg232170JPEG2026502 173000194.jpg220170JPEG2026502173000195.jpg215170JPEG2026502173000196.jpg191170JPEG20265021730 00197.jpg220170JPEG2026502173000198.jpg229170JPEG2026502173000199.jpg219170JPEG20265021730002 00.jpg224170JPEG2026502173000201.jpg199170JPEG2026502173000202.jpg216170JPEG2026502173000203.j pg220170JPEG2026502173000204.jpg185170JPEG2026502173000205.jpg195170JPEG2026502173000206.jpg22 5170JPEG2026502173000207.jpg199170JPEG2026502173000208.jpg194170JPEG2026502173000209.jpg230170

[0393] In some embodiments, the compound is Compound 16: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0394] In some embodiments, the compound is 4-[3-(1,3-benzoxazol-2-yl)-2-methoxy-anilino]-2-[(1-isopropylpyrazol-4-yl)amino]pyrimidine-5-carboxamide, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0395] In some embodiments, the compound is the neutral form (ie, not a salt) of any one of the compounds listed in Table 2.

[0396] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 2.

[0397] In some embodiments, the compound is a lithium, sodium, potassium, calcium, or magnesium salt of any one of the compounds listed in Table 2.

[0398] In some embodiments, the compound is the sodium or potassium salt of any one of the compounds listed in Table 2.

[0399] In some embodiments, the compound is the sodium salt of any one of the compounds listed in Table 2.

[0400] In some embodiments, the compound is the potassium salt of any one of the compounds listed in Table 2.

[0401] In some embodiments, the compound is a salt of acetic acid and any one of the compounds listed in Table 2.

[0402] In some embodiments, the compound is a salt of adipic acid and any one of the compounds listed in Table 2.

[0403] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds listed in Table 2.

[0404] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds listed in Table 2.

[0405] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds listed in Table 2.

[0406] In some embodiments, the compound is a salt of citric acid and any one of the compounds listed in Table 2.

[0407] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds listed in Table 2.

[0408] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds listed in Table 2.

[0409] In some embodiments, the compound is a salt of formic acid and any one of the compounds listed in Table 2.

[0410] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds listed in Table 2.

[0411] In some aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

[0412] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 2, as well as prodrugs and pharmaceutically acceptable salts thereof.

[0413] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 2 and pharmaceutically acceptable salts thereof.

[0414] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 2 and pharmaceutically acceptable salts thereof.

[0415] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2.

[0416] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by substituting isotopically labeled reagents for non-isotopically labeled reagents and by carrying out the procedures disclosed in the schemes and / or examples described herein.

[0417] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[0418] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0419] The term "isotopic derivative" as used herein refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of formula (I) is isotopically enriched or labeled with one or more isotopes compared to the corresponding compound of formula (I). In some embodiments, an isotopic derivative is 2 H, 13 C. 14 C. 15 N, 18 O. 29 Si, 31 P, and 34 In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., enriched or labeled with respect to one or more atoms selected from S). 2 H).

[0420] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 2, and prodrugs and pharmaceutically acceptable salts thereof.

[0421] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 2, and pharmaceutically acceptable salts thereof.

[0422] In some embodiments, the compound is a deuterium-labeled compound of any one of the prodrugs of the compounds listed in Table 2 and pharmaceutically acceptable salts thereof.

[0423] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds listed in Table 2.

[0424] A deuterium-labeled compound is understood to contain deuterium atoms having an abundance of deuterium substantially greater than the natural abundance of deuterium, which is 0.015%.

[0425] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation in each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term "deuterium enrichment factor" refers to the ratio of deuterium abundance to the natural abundance of deuterium.

[0426] It will be appreciated that deuterium-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein by substituting deuterium-labeled reagents for non-deuterium-labeled reagents.

[0427] Compounds of the present disclosure containing the deuterium atom(s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. 2 H) may confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0428] In some embodiments, the compound is 18 F-labeled compound.

[0429] In some embodiments, the compound is 123 I-labeled compound, 124 I-labeled compound, 125 I-labeled compound, 129 I-labeled compound, 131 I-labeled compound, 135 I-labeled compounds, or any combination thereof.

[0430] In some embodiments, the compound is 33 S-labeled compound, 34 S-labeled compound, 35 S-labeled compound, 36 S-labeled compounds, or any combination thereof.

[0431] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 It will be appreciated that S-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds generally utilize S-labeled compounds, instead of non-isotopic labeling reagents. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S,34 S, 35 S, and 36 S-labeled reagents can be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein.

[0432] the above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 Compounds of the present disclosure containing one or more S atom(s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 S) substitution can confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0433] For the avoidance of doubt, when a group is qualified herein by "as described herein," it is to be understood that said group encompasses the broadest definition appearing first, as well as each and every specific definition associated with that group.

[0434] The various functional groups and substituents that make up the compound of formula (I) are typically selected so that the molecular weight of the compound does not exceed 1000 daltons. More usually, the molecular weight of the compound is less than 900, for example, less than 800, or less than 750, or less than 700, or less than 650 daltons. More conveniently, the molecular weight is less than 600, for example, 550 daltons or less.

[0435] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of compounds of the present disclosure that are sufficiently basic, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0436] It will be understood that compounds of any one of the formulae disclosed herein, and any pharmaceutically acceptable salts thereof, include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of said compounds.

[0437] As used herein, the term "isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0438] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0439] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds with multiple chiral centers can exist as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture." When one chiral center is present, a stereoisomer is characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. Substituents attached to the chiral center are ranked according to the rules of Cahn, Ingold, and Prelog ordering. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0440] As used herein, the term "geometric isomer" refers to diastereomers that exist due to hindered rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, which indicate groups on the same or opposite sides of a double bond in a molecule, according to the Cahn-Ingold-Prelog rules.

[0441] It is understood that the compounds of the present disclosure may be represented as different chiral or geometric isomers, and when a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any isomeric form, and it is understood that not all isomers have the same level of activity.

[0442] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It should also be understood that not all atropic isomers have the same level of activity.

[0443] As used herein, the term "atropic isomer" refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers exist because of restricted rotation of large groups around a central bond, which prevents rotation. Such atropic isomers typically exist as mixtures, but recent advances in chromatographic techniques have made it possible to separate mixtures of two atropic isomers in selected cases.

[0444] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomers in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs when an aldehyde group (-CHO) of a sugar molecule reacts with one of the hydroxyl groups (-OH) of the same molecule to give a cyclic (ring-shaped) form, as shown in glucose.

[0445] It should be understood that the compounds of the present disclosure can be represented as different tautomers. When a compound has tautomeric forms, it should also be understood that all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form. It should be understood that certain tautomers may have a higher level of activity than other tautomers.

[0446] Compounds of any one of the formulas disclosed herein can exist in many different tautomeric forms, and a reference to a compound of formula (I) includes all such forms. For the avoidance of doubt, if a compound can exist in one of several tautomeric forms and only one is specifically described or illustrated, all others are nevertheless encompassed by formula (I) or (II). Examples of tautomeric forms include keto-, enol-, and enolate-forms, such as the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acid-nitro. [ka]

[0447] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are not superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers can exist. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, and are called dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0448] The compounds of the present disclosure may have one or more asymmetric centers; such compounds can be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemates or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or resolution of racemates (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present disclosure may have geometric isomer centers (E-isomers and Z-isomers). It should be understood that the present disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers and mixtures thereof that have inflammasome inhibitory activity.

[0449] The present disclosure also encompasses compounds of the disclosure as defined herein that contain one or more isotopic substitutions.

[0450] It should be understood that the compounds of any formula described herein include, if applicable, the compounds themselves, as well as their salts and solvates.For example, salts can be formed between an anion on the substituted compounds disclosed herein and a positively charged group (e.g., amino).Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0451] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on the substituted compounds disclosed herein and a negatively charged group (e.g., carboxylate). Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include salts containing quaternary nitrogen atoms.

[0452] It is understood that compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or unhydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc., and non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0453] As used herein, the term "solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amount of solvent.Some compounds tend to trap a certain molar ratio of solvent molecules in crystalline solid state to form solvates.When the solvent is water, the solvate that is formed is a hydrate; when the solvent is alcohol, the solvate that is formed is an alcoholate.Hydrate is formed by the combination of one molecule of a substance with one or more molecules of water, with water retaining its molecular state as H2O.

[0454] As used herein, the term "analog" refers to a compound that is structurally similar to another but has a slightly different composition (for example, the replacement of one atom with an atom of a different element, or the replacement of one atom with the presence of a specific functional group, or the replacement of one functional group with another functional group).Thus, an analog is a compound that is similar or equivalent in function and appearance, but different in structure or origin from the reference compound.

[0455] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0456] As used herein, the term "bioisomer" refers to a compound resulting from the exchange of an atom or group of atoms with another, broadly similar atom or group of atoms. The purpose of bioisosteric substitution is to generate a new compound with similar biological properties to the parent compound. Bioisosteric substitution can be based on physicochemical or topology. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0457] It should also be understood that any one particular compound of formula disclosed herein can exist in solvated form and unsolvated form, for example, hydrated form.Suitable pharmaceutically acceptable solvate is, for example, hydrate such as hemihydrate, monohydrate, dihydrate or trihydrate.It should be understood that the present disclosure encompasses all such solvated forms that have inflammasome inhibitory activity.

[0458] It should also be understood that any one particular compound of the formula disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms or mixtures thereof that have inflammasome inhibitory activity.It is generally known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetry, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy.The water content of such crystalline materials can be measured by Karl Fischer analysis.

[0459] Compounds of any one of the formulas disclosed herein containing an amine functional group can also form N-oxides. Herein, a reference to a compound of formula (I) or (II) containing an amine functional group also includes the N-oxide. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be generated by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid); see, for example, Advanced Organic Chemistry by Jerry March, 4th Edition, Wiley Interscience, pages 1977-1980. More specifically, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with metachloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0460] The compound of any one of the formulas disclosed herein can be administered in the form of a prodrug, which is broken down in the human or animal body to release the disclosed compound.Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compound of the present disclosure.When the compound of the present disclosure contains a suitable group or substituent to which a property-modifying group can be attached, a prodrug can be formed.Examples of prodrugs include derivatives of any one of the formulas disclosed herein that contain an alkyl or acyl substituent that can be cleaved in vivo on the ester or amide group.

[0461] Thus, the present disclosure includes those compounds of any of the above-defined formulas disclosed herein when made available by organic synthesis and when made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present disclosure also includes those compounds of any of the formulas disclosed herein produced by organic synthetic means, as well as such compounds produced in the human or animal body by metabolism of precursor compounds, and the compounds of any of the formulas disclosed herein may be synthetically produced compounds or metabolically produced compounds.

[0462] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein are those that are based on sound medical judgment and are suitable for administration to the human or animal body without undesirable pharmacological activity and undue toxicity. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACS Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0463] Suitable pharmaceutically acceptable prodrugs of compounds having a hydroxy group of any of the formulas disclosed herein are, for example, their in vivo cleavable esters or ethers. In vivo cleavable esters or ethers containing a hydroxy group of compounds of any of the formulas disclosed herein are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to generate the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include C1-C esters such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 C1-C groups such as alkanoyl groups, ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups 10 Examples of the ring substituents of the phenylacetyl group and the benzoyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0464] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having a carboxy group include, for example, an in vivo cleavable amide thereof, an amine such as ammonia, a C group such as methylamine, 1-4 alkylamines, (C1-C4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amides formed with amino acids such as glycine or its esters.

[0465] Suitable pharmaceutically acceptable prodrugs of any compound of the formulae disclosed herein having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C1-C2 acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 Examples of ring substituents for the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0466] The in vivo effects of a compound of any of the formulas disclosed herein may be exerted in part by one or more metabolites formed in the human or animal body after administration of a compound of any of the formulas disclosed herein. As mentioned above, the in vivo effects of a compound of any one of the formulas disclosed herein may also be exerted by metabolism of a precursor compound (prodrug). Compound synthesis method

[0467] The compounds of the invention may be made in a variety of ways, including standard chemistry. Suitable synthetic routes are illustrated in the schemes set out below.

[0468] Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, as defined in part by the synthetic schemes below. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art. The presence of a stereocenter in a compound of formula (I) will be recognizable by those skilled in the art by the selection process and reaction conditions and sequences. Accordingly, the present invention (unless specified in the synthesis) encompasses both possible stereoisomers, including not only racemates but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by separation of the final product or any convenient intermediate. Separation of the final product, an intermediate, or a starting material can be affected by any suitable method known in the art, see, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0469] The compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of compounds

[0470] The compounds of the present invention can be prepared in many ways well known to those skilled in the art of organic synthesis.For example, the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of organic synthetic chemistry, or modifications thereof that will be understood by those skilled in the art.Suitable methods include, but are not limited to, those methods described below.The compounds of the present invention can be synthesized according to the steps outlined in the general procedure, involving assembly intermediates or compounds of different sequences.The starting materials are commercially available or can be prepared by any of the known procedures reported in the literature, or as shown below. General Procedure

[0471] In general, compounds of formula (I) may be prepared using the reaction sequence shown below: [ka]

[0472] All reagents may be commercially available compounds themselves or synthetic products from commercially available reagents. The preparation of the final compounds and intermediates of formula (I) can use single-step or multi-step synthetic procedures, including but not limited to those described in the preparation part of this specification.

[0473] It will be apparent to those skilled in the art that any of the compounds of formula (I) obtained according to the above procedures may be subject to further transformations and modifications leading to other compounds of formula (I). Biological assays

[0474] Once compounds designed, selected, and / or optimized by the above methods are generated, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they have the expected activity, binding activity, and / or binding specificity.

[0475] Furthermore, high-throughput screening can be used to speed up the analysis using such assays. As a result, it is possible to rapidly screen the activity of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay technologies, including but not limited to those described below.

[0476] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure, including, but not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein. Pharmaceutical Composition

[0477] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound of each formula described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 2.

[0478] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts.

[0479] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each including sustained-release or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, etc. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0480] The formulation of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle.The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient.Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonicity agents, viscosity / suspension agents, buffering agents, and pH adjusting agents, and mixtures thereof.

[0481] Any suitable solubility enhancer can be used, including cyclodextrins selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0482] Any suitable chelating agent can be used, and examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, edetate disodium, edetate trisodium, and edetate tetrasodium, and mixtures thereof.

[0483] Any suitable preservative can be used. Examples of preservatives include quaternary ammonium salts, such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0484] In some embodiments, exemplary preservatives include quaternary ammonium salts, such as those selected from the group consisting of benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0485] The aqueous vehicle may also contain a tonicity agent to adjust tonicity (osmotic pressure). The tonicity agent may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof. In some embodiments, the tonicity agent is selected from the group consisting of glycols (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0486] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropyl methyl cellulose, and crosslinked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycols (Carbopols—e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0487] To adjust the formulation to an acceptable pH (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to a target acceptable pH range. Therefore, it is not necessary to use both an acid and a base; depending on the formulation, the mixture can be adjusted to the desired pH range by simply adding either an acid or a base.

[0488] The aqueous vehicle may also contain a buffer to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffer (such as boric acid or a salt thereof including disodium tetraborate), citrate buffer (such as citric acid or a salt thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0489] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0490] Oral compositions typically contain an inert diluent or an edible pharmaceutically acceptable carrier. They can also be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be mixed with an excipient and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is applied to the mouth, swished, and expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvants can be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; a filler such as starch or lactose, a disintegrating agent such as alginic acid, primogel or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, orange flavoring, and the like.

[0491] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0492] In some embodiments, the pharmaceutical compositions described herein can further comprise one or more additional pharmaceutically active agents.

[0493] The compositions of the disclosure may be in a form suitable for oral use (e.g., tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, powders or granules, syrups or elixirs), topical use (e.g., as a cream, ointment, gel, aqueous or oily solution or suspension), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by inhalation (e.g., as a finely divided powder) or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0494] The compositions of the present disclosure can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0495] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with a JAK2-associated condition referred to herein.

[0496] A therapeutically effective amount of a compound of the present disclosure for use in treatment is an amount sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with a JAK2-associated condition referred to herein.

[0497] The magnitude of a dose of a compound of formula (I) for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration, in accordance with well-known medical principles. How to use

[0498] In some aspects, the present disclosure provides a method of inhibiting JAK2 (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0499] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0500] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0501] In some embodiments, the disease or disorder is associated with JAK2. In some embodiments, the disease or disorder is a disease or disorder in which JAK2 is implicated.

[0502] The compounds of the present invention are inhibitors of JAK2. In some embodiments, the present invention relates to methods for inhibiting JAK2 by contacting JAK2 with a compound of the present invention. The contacting can be performed in vitro or in vivo. In some embodiments, the compounds of the present invention can bind to JAK2, thereby inhibiting JAK2. In some embodiments, the present invention provides methods for inhibiting the activity of JAK2 by contacting JAK2 with a compound of the present invention.

[0503] The compounds of the present invention are also useful in treating diseases associated with JAK2. For example, diseases and conditions treatable by the methods of the present invention include polycythemia vera, essential thrombocytosis, thrombocytosis 3, primary myelofibrosis, chronic myelomonocytic leukemia, acute myeloid leukemia, myelodysplasia, acute myeloid leukemia, and Budd-Chiari syndrome.

[0504] In some embodiments, the disease or disorder is polycythemia vera; essential thrombocytosis; thrombocytosis 3; primary myelofibrosis; chronic myelomonocytic leukemia; acute myeloid leukemia; myelodysplasia; acute myeloid leukemia; Budd-Chiari syndrome; familial erythrocytosis 1 (ECYT1); myeloproliferative neoplasms (MPD); polycythemia; acute lymphoblastic leukemia with lymphoma (LALL); essential thrombocytosis (ET); premature menopause; thrombocytosis; hypereosinophilic syndrome (HES); splenomegaly; acute leukemia; thrombosis; portal hypertension; papilloma; acquired polycythemia; systemic mastocytosis (SMCD); chronic myelomonocytic leukemia (CMML); primary polycythemia; hereditary neutrophil leukemia. Neutropenia; Thrombosis; Leukemia; Blood Cancer; Myeloid Anemia; Erythroid Leukemia; Myeloid Leukemia; Antithrombin III Deficiency (AT3D); Severe Congenital Neutropenia; Leukemia, Chronic Myeloid (CML); Fibrosarcoma; Mastocytosis; Myelodysplastic Syndrome (MDS); Chronic Eosinophilic Leukemia; Bone Marrow Cancer; Behcet's Syndrome (BD); Pancreatic Adenocarcinoma; Adenocarcinoma; Stress Polycythemia; B-Cell Lymphoma; Myelodysplastic / Myeloproliferative Neoplasms; Hemangioblastoma; Atypical Chronic Myeloid Leukemia, Bcr-Abl1 Negative (ACML); Chronic Neutrophilic Leukemia (CNL); Gastrointestinal Stromal Tumor (GIST); Beta-Thalassemia (B-THAL); Acquired Von Willebrand syndrome (AVWS); splenic infarction; B-lymphoblastic leukemia / lymphoma, Bcr-Abl1-like; classical Hodgkin lymphoma (CHL); Down syndrome; Wernicke's encephalopathy; hepatic vasculopathy; primary mediastinal B-cell lymphoma; hyperglycemia; chronic leukemia (CLL); portal vein thrombosis; Diamond-Blackfan anemia (BDA); leptin deficiency or dysfunction (LEPD); deficiency anemia; hepatocellular carcinoma (HCC); Sm-Ahnmd; acute lymphoblastic leukemia (ALL); sagittal sinus thrombosis; blood coagulation disorders Acute erythroid leukemia; immunodeficiency disorder 35 (IMD35); thrombocytopenia; colorectal cancer (CRC); platelet disorders; temporal arteritis (GCA); congenital erythropenia (CAMT); inflammatory bowel disease; venous disease; erythrocytosis; familial polycythemia 2 (ECYT2); prostate cancer (PC); familial polycythemia 6 (ECYT6); aggressive systemic mastocytosis (ASM); myeloid and lymphoid neoplasms with pdgfra rearrangements; pancreatic cancer (PNCA); ovarian cancer (OC); juvenile myelomonocytic leukemia (JMML); breast cancer (BC);The disease is selected from the group consisting of gastric cancer (GASC); medulloblastoma (MDB); familial non-Hodgkin's lymphoma (NHL); myocardial infarction (MCI1); body mass index quantitative trait locus 11 (BMIQ11); acute salpingo-salpingitis; autism spectrum disorder (ASD); esophageal cancer (ESCR); chronic lymphocytic leukemia (CLL); multiple myeloma (MM); essential hypertension (EHT); type 2 diabetes (T2D); skin disease; lasopathy; connective tissue disease; peripheral nervous system disease; and nervous system disease.

[0505] In some embodiments, the disease or disorder is polycythemia vera.

[0506] In some embodiments, the disease or disorder is essential thrombocytosis.

[0507] In some embodiments, the disease or disorder is thrombosis3.

[0508] In some embodiments, the disease or disorder is primary myelofibrosis.

[0509] In some embodiments, the disease or disorder is chronic myelomonocytic leukemia.

[0510] In some embodiments, the disease or disorder is acute myeloid leukemia.

[0511] In some embodiments, the disease or disorder is Budd-Chiari syndrome.

[0512] In some embodiments, the disease or disorder is familial erythrocytosis 1 (ECYT1).

[0513] In some embodiments, the disease or disorder is a myeloproliferative neoplasm (MPD).

[0514] In some embodiments, the disease or disorder is polycythemia.

[0515] In some embodiments, the disease or disorder is acute lymphoblastic leukemia with lymphomatous features (LALL).

[0516] In some embodiments, the disease or disorder is essential thrombocytosis (ET).

[0517] In some embodiments, the disease or disorder is premature ovarian failure.

[0518] In some embodiments, the disease or disorder is thrombocytosis.

[0519] In some embodiments, the disease or disorder is hypereosinophilic syndrome (HES).

[0520] In some embodiments, the disease or disorder is splenomegaly.

[0521] In some embodiments, the disease or disorder is acute leukemia.

[0522] In some embodiments, the disease or disorder is thrombosis.

[0523] In some embodiments, the disease or disorder is portal hypertension.

[0524] In some embodiments, the disease or disorder is papilledema.

[0525] In some embodiments, the disease or disorder is acquired polycythemia.

[0526] In some embodiments, the disease or disorder is systemic mast cell disease (SMCD).

[0527] In some embodiments, the disease or disorder is chronic myelomonocytic leukemia (CMML).

[0528] In some embodiments, the disease or disorder is primary polycythemia.

[0529] In some embodiments, the disease or disorder is NEUTROPHILIA.

[0530] In some embodiments, the disease or disorder is thrombophilia.

[0531] In some embodiments, the disease or disorder is leukemia.

[0532] In some embodiments, the disease or disorder is a hematological cancer.

[0533] In some embodiments, the disease or disorder is myelophthisic anemia.

[0534] In some embodiments, the disease or disorder is erythroleukemia.

[0535] In some embodiments, the disease or disorder is myeloid leukemia.

[0536] In some embodiments, the disease or disorder is antithrombin III deficiency (AT3D).

[0537] In some embodiments, the disease or disorder is severe congenital neutropenia.

[0538] In some embodiments, the disease or disorder is chronic myeloid leukemia (CML).

[0539] In some embodiments, the disease or disorder is fibrosarcoma.

[0540] In some embodiments, the disease or disorder is mastocytosis.

[0541] In some embodiments, the disease or disorder is myelodysplastic syndrome (MDS).

[0542] In some embodiments, the disease or disorder is chronic eosinophilic leukemia.

[0543] In some embodiments, the disease or disorder is multiple myeloma.

[0544] In some embodiments, the disease or disorder is Behcet's disease (BD).

[0545] In some embodiments, the disease or disorder is pancreatic adenocarcinoma.

[0546] In some embodiments, the disease or disorder is adenocarcinoma.

[0547] In some embodiments, the disease or disorder is stress hypertension.

[0548] In some embodiments, the disease or disorder is B-cell lymphoma.

[0549] In some embodiments, the disease or disorder is a myelodysplastic / myeloproliferative neoplasm.

[0550] In some embodiments, the disease or disorder is hemangioblastoma.

[0551] In some embodiments, the disease or disorder is Bcr-Abl1-negative atypical chronic myeloid leukemia (ACML).

[0552] In some embodiments, the disease or disorder is chronic neutrophilic leukemia (CNL).

[0553] In some embodiments, the disease or disorder is gastrointestinal stromal tumor (GIST).

[0554] In some embodiments, the disease or disorder is beta-thalassemia (B-THAL).

[0555] In some embodiments, the disease or disorder is acquired von Willebrand syndrome (AVWS).

[0556] In some embodiments, the disease or disorder is splenic infarction.

[0557] In some embodiments, the disease or disorder is B-lymphoblastic leukemia / lymphoma, Bcr-Abl1-like.

[0558] In some embodiments, the disease or disorder is classical Hodgkin's lymphoma (CHL).

[0559] In some embodiments, the disease or disorder is Down's syndrome.

[0560] In some embodiments, the disease or disorder is Wernicke's encephalopathy.

[0561] In some embodiments, the disease or disorder is hepatic vascular disease.

[0562] In some embodiments, the disease or disorder is primary mediastinal B-cell lymphoma.

[0563] In some embodiments, the disease or disorder is hyperglycemia.

[0564] In some embodiments, the disease or disorder is chronic leukemia (CLL).

[0565] In some embodiments, the disease or disorder is portal vein thrombosis.

[0566] In some embodiments, the disease or disorder is Diamond-Blackfan Anemia (BDA).

[0567] In some embodiments, the disease or disorder is leptin deficiency or dysfunction (LEPD).

[0568] In some embodiments, the disease or disorder is deficiency anemia.

[0569] In some embodiments, the disease or disorder is hepatocellular carcinoma (HCC).

[0570] In some embodiments, the disease or disorder is Sm-Ahnmd; acute lymphoblastic leukemia (ALL).

[0571] In some embodiments, the disease or disorder is sagittal sinus thrombosis.

[0572] In some embodiments, the disease or disorder is a blood clotting disorder.

[0573] In some embodiments, the disease or disorder is acute erythroid leukemia.

[0574] In some embodiments, the disease or disorder is immunodeficiency 35 (IMD35).

[0575] In some embodiments, the disease or disorder is thrombocytopenia.

[0576] In some embodiments, the disease or disorder is colorectal cancer (CRC).

[0577] In some embodiments, the disease or disorder is a platelet disorder.

[0578] In some embodiments, the disease or disorder is temporal arteritis (GCA).

[0579] In some embodiments, the disease or disorder is congenital cytotoxic thrombocytopenia (CAMT).

[0580] In some embodiments, the disease or disorder is inflammatory bowel disease.

[0581] In some embodiments, the disease or disorder is venous disease.

[0582] In some embodiments, the disease or disorder is polycythemia.

[0583] In some embodiments, the disease or disorder is familial erythrocytosis 2 (ECYT2).

[0584] In some embodiments, the disease or disorder is prostate cancer (PC).

[0585] In some embodiments, the disease or disorder is familial erythrocytosis 6 (ECYT6).

[0586] In some embodiments, the disease or disorder is aggressive systemic mastocytosis (ASM).

[0587] In some embodiments, the disease or disorder is myeloid and lymphoid neoplasia associated with pdgfra gene rearrangements.

[0588] In some embodiments, the disease or disorder is pancreatic cancer (PNCA).

[0589] In some embodiments, the disease or disorder is ovarian cancer (OC).

[0590] In some embodiments, the disease or disorder is juvenile myelomonocytic leukemia (JMML).

[0591] In some embodiments, the disease or disorder is breast cancer (BC).

[0592] In some embodiments, the disease or disorder is gastric cancer (GASC).

[0593] In some embodiments, the disease or disorder is medulloblastoma (MDB).

[0594] In some embodiments, the disease or disorder is familial non-Hodgkin's lymphoma (NHL).

[0595] In some embodiments, the disease or disorder is myocardial infarction (MCI1).

[0596] In some embodiments, the disease or disorder is body mass index quantitative trait locus 11 (BMIQ11).

[0597] In some embodiments, the disease or disorder is acute salpingitis; autism spectrum disorder (ASD).

[0598] In some embodiments, the disease or disorder is esophageal cancer (ESCR).

[0599] In some embodiments, the disease or disorder is chronic lymphocytic leukemia (CLL).

[0600] In some embodiments, the disease or disorder is multiple myeloma (MM).

[0601] In some embodiments, the disease or disorder is essential hypertension (EHT).

[0602] In some embodiments, the disease or disorder is type 2 diabetes (T2D).

[0603] In some embodiments, the disease or disorder is a skin condition.

[0604] In some embodiments, the disease or disorder is a rasopathy.

[0605] In some embodiments, the disease or disorder is a connective tissue disease.

[0606] In some embodiments, the disease or disorder is a peripheral nervous system disorder.

[0607] In some embodiments, the disease or disorder is a nervous system disease.

[0608] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0609] In some aspects, the present disclosure provides a method of treating or preventing leukemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0610] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0611] In some aspects, the present disclosure provides a method of treating leukemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0612] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in inhibiting JAK2 (e.g., in vitro or in vivo).

[0613] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder disclosed herein.

[0614] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0615] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in a subject in need thereof.

[0616] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing leukemia in a subject in need thereof.

[0617] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof.

[0618] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating leukemia in a subject in need thereof.

[0619] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting JAK2 (e.g., in vitro or in vivo).

[0620] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0621] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0622] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

[0623] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing leukemia in a subject in need thereof.

[0624] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0625] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating leukemia in a subject in need thereof.

[0626] The present disclosure provides compounds that function as inhibitors of JAK2 (e.g., in vitro or in vivo). Accordingly, the present disclosure provides methods of JAK2 in vitro or in vivo, the methods comprising contacting a cell with a therapeutically effective amount of a compound, as defined herein, or a pharmaceutically acceptable salt thereof.

[0627] In some embodiments, the JAK2 inhibitor is a compound of the present disclosure.

[0628] The efficacy of the compounds of the present disclosure can be determined by industry-accepted assays / disease models as described in the art and as found in the current general knowledge.

[0629] The present disclosure also provides a method of treating a disease or disorder in which JAK2 is implicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0630] In some embodiments, the subject is a mammal, hi some embodiments, the subject is a human. Administration route

[0631] The compounds of the present disclosure or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., to the desired site of action).

[0632] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, bandages, etc.); transmucosal (including, e.g., by patches, bandages, etc.); intranasal (e.g., nasal spray); ophthalmic (e.g., by eye drops); pulmonary (e.g., through the mouth or nose, e.g., using aerosols, e.g., inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral by injection, such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, intradermal, intraarticular, subarachnoid, intrasternal, etc.;

[0633] Abbreviations used in the following examples and elsewhere in this specification are as follows: JPEG2026502173000213.jpg183170 Example General Synthetic Procedures and Examples of Compound Preparation. Building Block Synthesis Synthesis of 4-[(2-methoxy-3-pyridin-2-ylphenyl)amino]-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxylic acid (P6) [ka]

[0634] Preparation 1. 2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (P1). Under argon, a mixture of 1-bromo-2-methoxy-3-nitrobenzene (11.1 g, 47.8 mmol), tetrakis(triphenylphosphine)palladium(0) (2.76 g, 2.4 mmol), potassium acetate (11.7 g, 119 mmol), and 2,2'-oxybis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in 1,4-dioxane (200 mL) was stirred overnight at 100 °C. The precipitate was then filtered, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / EtO 4:1) to give product P1 (6.3 g, 47% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 7.97 (dd, J = 8.0, 1.2 Hz, 1H), 7.86 (dd, J = 7.4, 1.2 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 3.87 (s, 3H), 1.32 (s, 12H).

[0635] Preparation 2. 2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (P2). A mixture of P1 (6.3 g, 22.6 mmol) and 10% Pd / C (0.63 g, 0.1 mass) in EtOH (100 ml) was stirred at room temperature under a stream of H for 12 h. The Pd / C was then filtered and the solvent removed under reduced pressure to give product P2 (5.4 g, 96% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 7.28 - 6.43 (m, 3H), 4.79 (s, 2H), 3.64 (s, 3H), 1.28 (s, 12H).

[0636] Preparation 3. (2-Methoxy-3-pyridin-2-ylphenyl)amine (P3). Under argon, a mixture of P2 (3.5 g, 14 mmol), 2-chloropyridine (1.6 g, 14 mmol), tetrakis(triphenylphosphine)palladium(0) (0.81 g, 0.7 mmol), and cesium carbonate (11.4 g, 5 mmol) in 1,4-dioxane (100 ml) and water (30 ml) was stirred overnight at 100 °C. Then, 300 ml of water was added, the product was extracted with DCM (2 × 100 ml), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / Et2O 2:1, 1:1) to give product P3 (2 g, 71% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 8.64 (d, J = 4.1 Hz, 1H), 7.81 (ddd, J = 17.6, 11.9, 4.8 Hz, 2H), 7.31 (ddd, J = 7.2, 4.8, 1.4 Hz, 1H), 6.90 (t, J = 7.7 Hz, 1H), 6.84 (dd, J = 7.7, 1.8 Hz, 1H), 6.76 (dd, J = 7.6, 1.8 Hz, 1H), 5.00 (s, 2H), 3.41 (s, 3H).

[0637] Preparation 4. Ethyl 2-chloro-4-[(2-methoxy-3-pyridin-2-ylphenyl)amino]pyrimidine-5-carboxylate (P4). A mixture of P3 (2 g, 10 mmol), ethyl 2,4-dichloropyrimidine-5-carboxylate (2.21 g, 10 mmol), and DIPEA (3.5 mL, 20 mmol) in acetonitrile (50 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was dissolved in DCM (50 mL). The resulting solution was washed with water, dried over NaSO, and the solvent was removed under reduced pressure. The residue was washed with EtO and dried to give product P4 (2.4 g, 62% yield). 1H NMR (400 MHz, DMSO-d6), δ: 11.02 (s, 1H), 8.86 (s, 1H), 8.72 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.00 - 7.80 (m, 2H), 7.48 (d, J = 7.9 Hz, 1H), 7.44 - 7.37 (m, 1H), 7.33 (t, J = 8.1 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.52 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H).

[0638] Preparation 5. Ethyl 4-[(2-methoxy-3-pyridin-2-ylphenyl)amino]-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxylate (P5). Under an argon atmosphere, a mixture of P4 (1.2 g, 3.12 mmol), 1-methyl-1H-pyrazol-4-amine (1.25 g, 9.36 mmol), palladium acetate (0.15 g, 0.668 mmol), Xantphos (0.45 g, 0.778 mmol), and cesium carbonate (1.52 g, 4.66 mmol) in dioxane (50 mL) was stirred at 100 °C overnight. The mixture was cooled and filtered through a pad of Celite, and the solvent was removed from the mother liquor under reduced pressure. The residue was purified by silica gel column chromatography (2%, 5%, 10% MeOH in DCM) to give product P5 (0.39 g, 28% yield). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min) m / z 446.4 [M + H] + ; Rt = 1.16 minutes.

[0639] Preparation 6. 4-[(2-Methoxy-3-pyridin-2-ylphenyl)amino]-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxylic acid (P6). A solution of lithium hydroxide monohydrate (0.184 g, 4.38 mmol) in water (10 ml) was added to a suspension of P5 (0.39 g, 0.875 mmol) in THF (20 ml) at room temperature. The reaction mixture was stirred overnight, the solvent was removed under reduced pressure, the residue was dissolved in water (10 ml), the resulting solution was acidified to pH 5-6 with 10% HCl, the formed precipitate was filtered, washed with water, and dried under reduced pressure to give product P6 (0.36 g, 99%). LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min) m / z 418.8 [M + H] + ; Rt = 1.10 minutes. Synthesis of 4-{[2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxylic acid (P13) [ka]

[0640] Preparation 7. tert-Butyl 2-(2-methoxy-3-nitrobenzoyl)hydrazinecarboxylate (P7). A mixture of 2-methoxy-3-nitrobenzoic acid (4.2 g, 21.3 mmol), tert-butyl hydrazinecarboxylate (2.814 g, 21.3 mmol), TBTU (10.2 g, 32 mmol), and DIPEA (5.7 mL, 32 mmol) in DCM (200 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / EtO 1:1) to give product P7 (5.8 g, 78% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 10.16 (s, 1H), 9.05 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 6.8 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 3.89 (s, 3H), 1.43 (s, 9H).

[0641] Preparation 8. 2-Methoxy-3-nitrobenzohydrazide (P8). To a solution of P7 (4.4 g, 14.1 mmol) in DCM / MeOH 1:1 (100 ml) was added a solution of HCl in 1,4-dioxane (3 M, 20 ml), and the reaction mixture was stirred at room temperature for 48 h. The resulting precipitate was filtered, washed with EtO, and air-dried to give product P8 (2.5 g, 84% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 11.60 (s, 1H), 8.09 (dd, J = 8.1, 1.7 Hz, 1H), 7.80 (dd, J = 7.7, 1.7 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 3.88 (s, 3H).

[0642] Preparation 9. 2-(2-Methoxy-3-nitrophenyl)-5-methyl-1,3,4-oxadiazole (P9). A mixture of P8 (2 g, 9.48 mmol), 1,1,1-trimethoxyethane (50 ml), and ammonium chloride (0.152 g, 2.84 mmol) was stirred overnight at 150° C. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / EtOAc 2:1, 1:1) to give product P9 (0.943 g, 42% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 8.18 (dd, J = 17.2, 8.0 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H), 3.89 (s, 3H), 2.62 (s, 3H).

[0643] Preparation 10. 2-Methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)aniline (P10). A mixture of P9 (1.075 g, 4.57 mmol) and 10% Pd / C (0.1 g, 0.1 mass) in EtOH (50 ml) was stirred at room temperature under a stream of H for 12 h. The Pd / C was then filtered and the solvent removed under reduced pressure to give the product P10 (0.926 g, 99% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 6.99 - 6.95 (m, 2H), 6.93 - 6.88 (m, 1H), 5.26 (s, 2H), 5.26 (s, 2H), 3.69 (s, 3H), 2.57 (s, 3H).

[0644] Preparation 11. Ethyl 2-chloro-4-{[2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}pyrimidine-5-carboxylate (P11). A mixture of P10 (0.926 g, 4.52 mmol), ethyl 2,4-dichloropyrimidine-5-carboxylate (0.998 g, 4.52 mmol), and DIPEA (1.6 mL, 9.04 mmol) in acetonitrile (50 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was dissolved in DCM (50 mL). The resulting solution was washed with water and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was washed with Et2O and dried to give product P11 (1.365 g, 77% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 10.99 (s, 1H), 8.89 (s, 1H), 8.60 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 4.42 (q, J = 7.0 Hz, 2H), 3.85 (s, 3H), 2.60 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[0645] Preparation 12. Ethyl 4-{[2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxylate (P12). Under argon, a mixture of P11 (1 g, 2.57 mmol), 1-methyl-1H-pyrazol-4-amine (1.03 g, 7.74 mmol), palladium acetate (0.15 g, 0.66 mmol), Xantphos (0.45 g, 0.78 mmol), and cesium carbonate (0.514 g, 3.85 mmol) in 1,4-dioxane (50 mL) was stirred at 100 °C overnight. The mixture was cooled, filtered through a pad of Celite, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (2%, 5%, 10% MeOH in DCM) to give product P12 (0.5 g, 43% yield). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min) m / z 451.0 [M + H] + ; Rt = 5.16 minutes.

[0646] Preparation 13. 4-{[2-Methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxylic acid (P13). A solution of lithium hydroxide monohydrate (0.14 g, 3.3 mmol) in water (10 ml) was added to a suspension of P12 (0.5 g, 1.1 mmol) in THF (25 mL) at room temperature. The reaction mass was stirred overnight. The solvent was removed under reduced pressure, the residue was dissolved in water (10 ml), and the resulting solution was acidified to pH 5-6 with 10% HCl. The formed precipitate was filtered, washed with water, and dried under reduced pressure to give product P13 (0.4 g, 87%). LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min) m / z 423.4 [M + H] + ; Rt = 0.94 min. Synthesis of tert-butyl 4-{4-[(5-(aminocarbonyl)-4-{[3-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]amino}pyrimidin-2-yl)amino]-1H-pyrazol-1-yl}piperidine-1-carboxylate (P18) [ka]

[0647] Preparation 14. 3-(1,3-Benzoxazol-2-yl)-2-methoxyaniline (P14). Under an argon atmosphere, a mixture of P2 (1 g, 4 mmol), 2-chloro-1,3-benzoxazole (0.614 g, 4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.2 mmol), and cesium carbonate (3.25 g, 119 mmol) in 1,4-dioxane (50 mL) and water (20 mL) was stirred overnight at 100 °C. Then, 200 mL of water was added, and the product was extracted with DCM (2 × 100 mL). The solvent from the mother liquor was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / EtO 2:1, 1:1) to give product P14 (0.594 g, 62% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 7.84 - 7.74 (m, 2H), 7.46 - 7.37 (m, 2H), 7.23 (dd, J = 7.7, 1.4 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.94 (dd, J = 7.9, 1.5 Hz, 1H), 5.26 (s, 2H), 3.78 (s, 3H).

[0648] Preparation 15. Ethyl 4-{[3-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-chloropyrimidine-5-carboxylate (P15). A mixture of P14 (1.248 g, 5.2 mmol), ethyl 2,4-dichloropyrimidine-5-carboxylate (1.149 g, 5.2 mmol), and DIPEA (1.84 mL, 10.4 mmol) in acetonitrile (5 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was dissolved in DCM (50 mL). The resulting solution was washed with water and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was washed with Et2O and dried to give product P15 (1.529 g, 69% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 11.04 (s, 1H), 8.89 (s, 1H), 8.62 (d, J = 8.2 Hz, 1H), 7.93 - 7.78 (m, 3H), 7.46 (dt, J = 13.0, 7.7 Hz, 3H), 4.43 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H).

[0649] Preparation 16. Ethyl 4-{[3-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-({1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1H-pyrazol-4-yl}amino)pyrimidine-5-carboxylate (P16) Under argon, a mixture of P15 (0.5 g, 1.18 mmol), tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.941 g, 3.54 mmol), palladium acetate (0.08 g, 0.356 mmol), Xantphos (0.25 g, 0.432 mmol), and cesium carbonate (0.57 g, 1.77 mmol) in dioxane (25 mL) was stirred at 100 °C overnight. The mixture was cooled and filtered through a pad of Celite, and the solvent was removed from the mother liquor under reduced pressure. The residue was purified by silica gel column chromatography (2%, 5%, 10% MeOH in DCM) to give product P16 (0.235 g, 30% yield). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min) m / z 655.7 [M + H] + ; Rt = 1.97 minutes.

[0650] Preparation 17. 4-{[3-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-({1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1H-pyrazol-4-yl}amino)pyrimidine-5-carboxylic acid (P17) A solution of lithium hydroxide monohydrate (0.151 g, 3.6 mmol) in water (10 ml) was added to a suspension of P16 (0.235 g, 0.36 mmol) in THF (10 ml) at room temperature. The reaction mixture was stirred overnight, the solvent was removed under reduced pressure, the residue was dissolved in water (10 ml), the resulting solution was acidified to pH 6-7 with 3% HCl, the formed precipitate was filtered, washed with water, and dried under reduced pressure to give product P17 (0.22 g, 99%). LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min) m / z 627.7 [M + H] + ; Rt = 1.534 minutes.

[0651] Preparation 18. tert-Butyl 4-{4-[(5-(aminocarbonyl)-4-{[3-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]amino}pyrimidin-2-yl)amino]-1H-pyrazol-1-yl}piperidine-1-carboxylate (P18). Ammonia solution (7N in MeOH, 3 mL), TBTU (0.173 g, 0.54 mmol), and DIPEA (0.2 mL, 1.08 mmol) were added to a solution of P17 (0.22 g, 0.36 mmol) in DMF (10 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, then 50 mL of water was added, and the product was extracted with DCM (3 × 30 mL). The combined organic layers were dried over NaSO, the solvent was removed under reduced pressure, and the residue was washed with EtO and dried to give product P18 (0.17 g, 75% yield). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5–87%, 3 min) m / z 626.3 [M + H] + ; Rt = 1.48 minutes. Synthesis of 4-{[3-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-({1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}amino)pyrimidine-5-carboxylic acid (P20) [ka]

[0652] Preparation 19. Ethyl 4-{[3-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-({1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}amino)pyrimidine-5-carboxylate (P19). Under argon, a mixture of P15 (0.5 g, 1.18 mmol), 1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-amine (0.545 g, 3.54 mmol), palladium acetate (0.08 g, 0.356 mmol), Xantphos (0.25 g, 0.432 mmol), and cesium carbonate (0.57 g, 1.77 mmol) in dioxane (25 mL) was stirred at 100 °C overnight. The mixture was cooled and filtered through a pad of Celite, and the solvent was removed from the mother liquor under reduced pressure. The residue was purified by silica gel column chromatography (2%, 5%, 10% MeOH in DCM) to give product P19 (0.2 g, 31% yield). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5–87%, 3 min) m / z 543.8 [M + H] + ; Rt = 1.4 minutes.

[0653] Preparation 20. 4-{[3-(1,3-Benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-({1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}amino)pyrimidine-5-carboxylic acid (P20). A solution of lithium hydroxide monohydrate (0.151 g, 3.6 mmol) in water (10 ml) was added to a suspension of P19 (0.2 g, 0.369 mmol) in THF (10 mL) at room temperature. The reaction mass was stirred overnight. The solvent was removed under reduced pressure, the residue was dissolved in water (10 ml), the resulting solution was acidified to pH 5-6 with 10% HCl, and the formed precipitate was filtered, washed with water, and dried under reduced pressure to give product P20 (0.19 g, 99%). LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min) m / z 515.8 [M + H] + ; Rt = 1.11 minutes. Synthesis of 4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-ylamino)pyrimidine-5-carboxylic acid (P23) [ka]

[0654] Preparation 21. Ethyl 2-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylate (P21). Ethyl 2,4-dichloropyrimidine-5-carboxylate (490 mg, 2.22 mmol) was dissolved in ACN (5 mL), and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (450 mg, 2.20 mmol) and DIPEA (1.0 mL) were added at room temperature. The reaction mixture was stirred for 3 hours, and then concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc:DCM = 3:2) to give P21 (785 mg, 92% yield) as a white solid. 1 H NMR (400 MHz, CDCl3), δ: 11.22 (s, 1H), 8.85 (s, 1H), 8.67 (dd, J = 8.0, 1.6 Hz, 1H), 8.12 (s, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 4.02 (s, 3H), 3.87 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H).

[0655] Preparation 22. Ethyl 4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-ylamino)pyrimidine-5-carboxylate (P22). 1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-amine (600 mg, 3.3 mmol), cesium carbonate (390 mg, 1.2 mmol), Xantphos (23 mg, 0.04 mmol), and palladium acetate (9 mg, 0.04 mmol) were added to a solution of P21 (150 mg, 0.38 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH 10:1) to give P22 (110 mg, 54% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.53 (br. s, 1H),9.88 (s, 1H), 8.80 (d, J = 6.8 Hz, 1H), 8.56 (s, 1H), 8.15 (d, 1H), 7.83 (s, 1H), 7.66-7.59 (m, 1H), 7.38 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 4.08-4.03 (m, 1H), 3.95 (s, 3H), 3.75 (s, 3H), 2.05-1.85 (m, 11H), 1.34 (t, J = 7.2 Hz, 3H).

[0656] Preparation 23. 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-ylamino)pyrimidine-5-carboxylic acid (P23). A solution of P22 (110 mg, 0.207 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (86 mg, 2.07 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P23 (107 mg, 99% yield) as a yellow solid. LCMS (ESI) (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 3 min), m / z: 505.5 [M + H] + ; Rt = 0.75 min. Synthesis of 2-(1-cyclohexyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P25) [ka]

[0657] Preparation 24. Ethyl 2-(1-cyclohexyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate (P24). 1-Cyclohexyl-1H-pyrazol-4-amine (318 mg, 1.93 mmol), cesium carbonate (502 mg, 1.54 mmol), Xantphos (23 mg, 0.04 mmol), and palladium acetate (9 mg, 0.04 mmol) were added to a solution of P21 (150 mg, 0.38 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 50:50) to give P24 (56 mg, 28% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.50 (br. s, 1H), 9.84 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 8.13 (d, 1H), 7.69-7.52 (m, 1H), 7.39 (s, 1H), 7.23 (t, J = 8.0 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 4.16-4.09 (m, 1H), 3.95 (s, 3H), 3.78 (s, 3H), 2.20-2.10 (m, 2H), 1.93-1.88 (m, 2H), 1.77-1.66 (m, 6H), 1.32 (t, J = 7.2 Hz, 3H).

[0658] Preparation 25. 2-(1-Cyclohexyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P25). A solution of P24 (56 mg, 0.107 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (27 mg, 0.65 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P25 (44 mg, 83% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 10 min) m / z 490.8 [M + H] + ; Rt = 4.99 minutes. Synthesis of 4-((3-(1,3-benzoxazol-2-yl)-2-methoxyphenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxylic acid (P27) [ka]

[0659] Preparation 26. Ethyl 4-((3-(1,3-benzoxazol-2-yl)-2-methoxyphenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxylate (P26). 1-Methyl-1H-pyrazol-4-amine (100 mg, 1.03 mmol), cesium carbonate (300 mg, 0.92 mmol), Xantphos (27 mg, 0.04 mmol), and palladium acetate (10 mg, 0.04 mmol) were added to a solution of P15 (200 mg, 0.47 mmol) in dioxane (10 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 50:50) to give P26 (140 mg, 61% yield) as a white solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min) m / z 486.5 [M + H] + ; Rt = 1.70 minutes.

[0660] Preparation 27. 4-((3-(1,3-Benzoxazol-2-yl)-2-methoxyphenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxylic acid (P27). A solution of P26 (142 mg, 0.29 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (70 mg, 1.7 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P27 (130 mg, 97% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 3 min) m / z 458.9 [M + H] + ; Rt = 1.31 minutes. Synthesis of 2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P29) [ka]

[0661] Preparation 28. Ethyl 2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate (P28). 1,3-Dimethyl-1H-pyrazol-4-amine (900 mg, 8.1 mmol), cesium carbonate (600 mg, 1.85 mmol), Xantphos (44 mg, 0.07 mmol), and palladium acetate (16 mg, 0.07 mmol) were added to a solution of P21 (300 mg, 0.77 mmol) in dioxane (50 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 50:50) to give P28 (70 mg, 19% yield) as a white solid. 1 H NMR (400 MHz, CDCl3), δ: 10.78 (br. s, 1H), 8.78 (d, J = 6.8 Hz, 1H), 8.25 (br. s, 1H), 8.12 (s, 1H), 7.75 (d, J = 7.1 Hz 1H), 7.65 (s, 1H), 7.14 (t, J = 7.0 Hz, 1H),6.88 (s, 1H), 4.38 (q, J = 7.2 Hz, 2H), 4.03 (s, 3H), 3.86 (s, 3H), 3.79 (s, 3H), 1.63(s, 3H), 1.41 (t, J = 7.2 Hz, 3H).

[0662] Preparation 29. 2-(1,3-Dimethyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P29). A solution of P28 (70 mg, 0.15 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (63 mg, 1.51 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P29 (66 mg, 97% yield) as a yellow solid. LCMS (ESI) (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 3 min), m / z: 436.4 [M + H] + ; Rt = 1.11 min. Synthesis of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidine (P31) [ka]

[0663] Preparation 30. Ethyl 4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylamino)pyrimidine-5-carboxylate (P30). 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (1291 mg, 7.7 mmol), cesium carbonate (1000 mg, 3.07 mmol), Xantphos (70 mg, 0.07 mmol), and palladium acetate (17 mg, 0.07 mmol) were added to a solution of P21 (300 mg, 0.77 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 50:50) to give P30 (144 mg, 36% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.60 (br. s, 1H), 9.89 (s, 1H), 8.70 (s, 1H), 8.55 (s, 1H), 8.20 (d, J = Hz, 1H), 7.68-7.66 (m, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.92-3.88 (m, 5H), 3.78 (s, 3H), 3.48-3.39 (m, 3H), 1.99-1.93 (m, 2H), 1.85-1.75 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H).

[0664] Preparation 31. 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylamino)pyrimidine-5-carboxylic acid (P31). A solution of P30 (144 mg, 0.257 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (108 mg, 2.57 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P31 (62 mg, 51% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 10 min) m / z 492.2 [M + H] + ; Rt = 4.28 minutes. Synthesis of 4-{[3-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-[(1-isopropyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxylic acid (P33) [ka]

[0665] Preparation 32. Ethyl 4-{[3-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-[(1-isopropyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxylate (P32). Under argon, a mixture of P15 (0.5 g, 1.18 mmol), 1-isopropyl-1H-pyrazol-4-amine (0.442 g, 3.54 mmol), palladium acetate (0.08 g, 0.356 mmol), Xantphos (0.25 g, 0.432 mmol), and cesium carbonate (0.54 g, 1.77 mmol) in dioxane (25 mL) was stirred at 100 °C overnight. The mixture was cooled and filtered through a pad of Celite, and the solvent was removed from the mother liquor under reduced pressure. The residue was purified by silica gel column chromatography (2%, 5%, 10% MeOH in DCM) to give product P32 (0.23 g, 38% yield). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 3 min) m / z 514.5 [M + H] +; Rt = 1.78 minutes.

[0666] Preparation 33. 4-{[3-(1,3-Benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-[(1-isopropyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxylic acid (P33). A solution of lithium hydroxide monohydrate (0.223 g, 4.48 mmol) in water (10 ml) was added to a suspension of P32 (0.23 g, 0.448 mmol) in THF (10 mL) at room temperature. The reaction mass was stirred overnight. The solvent was removed under reduced pressure, the residue was dissolved in water (10 ml), and the resulting solution was acidified to pH 5-6 with 10% HCl. The formed precipitate was filtered, washed with water, and dried under reduced pressure to give product P33 (0.2 g, 92%). LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min) m / z 486.5 [M + H] + ; Rt = 1.39 minutes. Synthesis of 4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1,3,5-trimethyl-1H-pyrazol-4-ylamino)pyrimidine-5-carboxylic acid (P35) [ka]

[0667] Preparation 34. Ethyl 4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1,3,5-trimethyl-1H-pyrazol-4-ylamino)pyrimidine-5-carboxylate (P34). 1,3,5-Trimethyl-1H-pyrazol-4-amine (483 mg, 3.86 mmol), cesium carbonate (390 mg, 2.5 mmol), Xantphos (23 mg, 0.04 mmol), and palladium acetate (9 mg, 0.04 mmol) were added to a solution of P21 (150 mg, 0.386 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 2:1) to give P34 (150 mg, 81% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.91 (br. s, 1H), 9.06 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 6.5 Hz, 1H), 6.86 (t, J = 8.0 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.93 (s, 3H), 3.76 (s, 3H), 3.50 (s, 3H), 2.04 ((s, 3H), 1.95 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H).

[0668] Preparation 35. 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1,3,5-trimethyl-1H-pyrazol-4-ylamino)pyrimidine-5-carboxylic acid (P35). A solution of P34 (150 mg, 0.314 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (132 mg, 3.14 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P35 (140 mg, 98% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 10 min) m / z 450.2 [M + H] + ; Rt = 4.14 minutes. Synthesis of 2-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P37) [ka]

[0669] Preparation 36. Ethyl 2-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate (P36). 1-Ethyl-3,5-dimethyl-1H-pyrazol-4-amine (514 mg, 3.70 mmol), cesium carbonate (812 mg, 2.5 mmol), Xantphos (35 mg, 0.06 mmol), and palladium acetate (13 mg, 0.06 mmol) were added to a solution of P21 (150 mg, 0.386 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 1:1) to give P36 (206 mg, 65% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.93 (br. s, 1H), 9.04 (s, 1H), 8.71 (s, 1H), 8.54 (s, 1H), 8.23 ​​(d, J = 8.0 Hz, 1H), 7.43 (d, J = 6.5 Hz, 1H), 6.83 (t, J = 8.0 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.84 (q, J = 7.2 Hz, 2H), 3.77 (s, 3H), 2.05 (s, 3H), 1.96 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H).

[0670] Preparation 37. 2-(1-Ethyl-3,5-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P37). A solution of P36 (200 mg, 0.40 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (132 mg, 3.14 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P37 (100 mg, 54% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 10 min) m / z 464.5 [M + H] + ; Rt = 4.30 minutes. Synthesis of 2-(3,5-dimethyl-1-propyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P39) [ka]

[0671] Preparation 38. Ethyl 2-(1-propyl-3,5-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate (P38). 3,5-Dimethyl-1-propyl-1H-pyrazol-4-amine (979 mg, 6.40 mmol), cesium carbonate (812 mg, 2.5 mmol), Xantphos (35 mg, 0.06 mmol), and palladium acetate (13 mg, 0.06 mmol) were added to a solution of P21 (250 mg, 0.64 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 1:1) to give P38 (206 mg, 63% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.95 (br. s, 1H), 9.05 (s, 1H), 8.71 (s, 1H), 8.52 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 6.5 Hz, 1H), 6.82 (t, J = 8.0 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.75 (t, J = 7.0 Hz, 2H), 3.77 (s, 3H), 2.05 (s, 3H), 1.97 (s, 3H), 1.64-1.55 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H), 0.80 (t, J = 7.2 Hz, 3H).

[0672] Preparation 39. 2-(3,5-Dimethyl-1-propyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P39). A solution of P38 (206 mg, 0.40 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (132 mg, 3.14 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P38 (190 mg, 95% yield) as a yellow solid. LCMS (ESI) (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 3 min), m / z: 478.3 [M + H] + ; Rt = 1.02 min. Synthesis of 2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P41) [ka]

[0673] Preparation 40. Ethyl 2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate (P40). 1-Isopropyl-3,5-dimethyl-1H-pyrazol-4-amine (787 mg, 5.15 mmol), cesium carbonate (747 mg, 2.3 mmol), Xantphos (29 mg, 0.05 mmol), and palladium acetate (11 mg, 0.05 mmol) were added to a solution of P21 (200 mg, 0.515 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 1:1) to give P40 (150 mg, 57% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.95 (br. s, 1H), 9.05 (s, 1H), 8.71 (s, 1H), 8.52 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 6.5 Hz, 1H), 6.82 (t, J = 8.0 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.81 (q, J = 7.0 Hz, 1H), 3.77 (s, 3H), 2.05 (s, 3H), 1.97 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H), 1.21 (d, J = 7.2 Hz, 6H).

[0674] Preparation 41. 2-(1-Isopropyl-3,5-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P41). A solution of P40 (150 mg, 0.30 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (124 mg, 3.0 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P41 (130 mg, 84% yield) as a yellow solid. LCMS (ESI) (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 3 min), m / z: 478.4 [M + H] + ; Rt = 1.04 min. Synthesis of 2-[(1-cyclopropyl-1H-pyrazol-4-yl)amino]-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}pyrimidine-5-carboxylic acid (P43) [ka]

[0675] Preparation 42. Ethyl 2-[(1-cyclopropyl-1H-pyrazol-4-yl)amino]-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}pyrimidine-5-carboxylate (P42). Under an argon atmosphere, a mixture of P21 (0.25 g, 0.643 mmol), 1-cyclopropyl-1H-pyrazol-4-amine (0.236 g, 6.43 mmol), palladium acetate (0.05 g, 0.222 mmol), Xantphos (0.15 g, 0.259 mmol), and cesium carbonate (0.314 g, 0.964 mmol) in dioxane (25 mL) was stirred at 100 °C overnight. The mixture was cooled and filtered through a pad of Celite, and the solvent was removed from the mother liquor under reduced pressure. The residue was purified by silica gel column chromatography (2%, 5%, 10% MeOH in DCM) to give product P42 (0.242 g, 79% yield). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5–87%, 3 min) m / z 476.3 [M + H] + ; Rt = 1.23 minutes.

[0676] Preparation 43. 2-[(1-Cyclopropyl-1H-pyrazol-4-yl)amino]-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}pyrimidine-5-carboxylic acid (P43). A solution of lithium hydroxide monohydrate (0.213 g, 5.09 mmol) in water (10 mL) was added to a suspension of P42 (0.242 g, 0.509 mmol) in THF (10 mL) at room temperature. The reaction mixture was stirred overnight, the solvent was removed under reduced pressure, the residue was dissolved in water (10 mL), the resulting solution was acidified to pH 5-6 with 10% HCl, the formed precipitate was filtered, washed with water, and dried under reduced pressure to give product P43 (0.227 g, 100%). LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min) m / z 447.4 [M + H]+ ; Rt = 1.07 minutes. Synthesis of 2-(1-(cyclohexylmethyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P45) [ka]

[0677] Preparation 44. Ethyl 2-(1-(cyclohexylmethyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate (P44). 1-(Cyclohexylmethyl)-1H-pyrazol-4-amine (1145 mg, 6.4 mmol), cesium carbonate (975 mg, 3.00 mmol), Xantphos (35 mg, 0.06 mmol), and palladium acetate (13 mg, 0.06 mmol) were added to a solution of P21 (250 mg, 0.64 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 50:50) to give P44 (312 mg, 91% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.40 (br. s, 1H), 9.83 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.06 (d, 1H), 7.83 (s, 1H), 7.70 (d, J = 6.7 Hz, 1H), 7.38 (s, 1H), 7.21 (t, J = 8.0 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 3.80-3.74(m, 5H), 1.66-1.41 (m, 5H), 1.34 (t, J = 7.2 Hz, 3H), 1.20-1.09 (m, 4H), 0.97-0.79 (m, 2H).

[0678] Preparation 45. 2-(1-(cyclohexylmethyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P45). A solution of P44 (300 mg, 0.531 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (238 mg, 5.65 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P45 (230 mg, 81% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5–87%, 10 min) m / z 504.5 [M + H] + ; Rt = 5.14 minutes. Synthesis of 2-(1-(adamantylmethyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P47) [ka]

[0679] Preparation 46. Ethyl 2-(1-(adamantylmethyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate (P46). 1-(Adamantylmethyl)-1H-pyrazol-3-amine (952 mg, 4.12 mmol), cesium carbonate (660 mg, 2.03 mmol), Xantphos (30 mg, 0.05 mmol), and palladium acetate (11 mg, 0.05 mmol) were added to a solution of P21 (200 mg, 0.515 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 2:1) to give P46 (243 mg, 81% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.35 (br. s, 1H), 9.87 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 8.02 (d, J = Hz, 1H), 7.74-7.69 (m, 1H), 7.50 (s, 1H), 7.39 (s, 1H), 7.24 (t, J = 8.0 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 3.93 (s, 3H), 3.73 (s, 3H), 3.57 (s, 2H), 1.91 (br. s, 4H), 1.65-1.62 (m, 3H), 1.57-1.51 (m, 3H), 1.44-1.42 (m, 5H), 1.34 (t, J = 7.2 Hz, 3H).

[0680] Preparation 47. 2-(1-(Adamantylmethyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P47). A solution of P46 (300 mg, 0.51 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (216 mg, 5.10 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P47 (210 mg, 74% yield) as a yellow solid. LCMS (ESI) (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 3 min), m / z: 556.5 [M + H] + ; Rt = 1.43 minutes. Synthesis of 2-(1-isopentyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P49) [ka]

[0681] Preparation 48. Ethyl 2-(1-isopentyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate (P48). 1-Isopentyl-1H-pyrazol-4-amine (985 mg, 6.44 mmol), cesium carbonate (812 mg, 2.5 mmol), Xantphos (40 mg, 0.07 mmol), and palladium acetate (16 mg, 0.07 mmol) were added to a solution of P21 (250 mg, 0.64 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 2:1) to give P48 (250 mg, 77% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.54 (br. s, 1H), 9.87 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 8.19 (d, J = Hz, 1H), 7.74-7.69 (m, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.93-3.95 (m, 5H), 3.76 (s, 3H), 1.69-1.64 (m, 2H), 1.57-1.49 (m, 1H), 1.34 (t, J = 7.2 Hz, 3H), 0.90 (d, J = 6.6 Hz, 6H).

[0682] Preparation 49. 2-(1-Isopentyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P49). A solution of P48 (200 mg, 0.49 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (206 mg, 4.9 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P49 (110 mg, 58% yield) as a yellow solid. LCMS (ESI) (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 3 min), m / z: 478.4 [M + H] + ; Rt = 1.25 minutes. Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-((1-octyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxylic acid (P51) [ka]

[0683] Preparation 50. Ethyl 4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}-2-{methyl[(1-phenyl-1H-pyrazol-4-yl)methyl]amino}pyrimidine-5-carboxylate (P50). To a solution of P21 (150 mg, 0.38 mmol) in dioxane (10 mL, degassed) was added 1-octyl-1H-pyrazol-4-amine (150 mg, 0.76 mmol), cesium carbonate (0.5 g, 1.53 mmol), Xantphos (25 mg, 0.04 mmol), and palladium acetate (10 mg, 0.04 mmol) at room temperature under an argon atmosphere. After stirring the solution at 100 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH = 95:5) to give P50 (180 mg, 86% yield) as a white solid. LCMS (ESI), m / z: 548.8 [M + H] + ; Rt = 1.74 minutes.

[0684] Preparation 51. 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-((1-octyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxylic acid (P51). To a solution of P50 (140 mg, 0.25 mmol) in THF (8.5 mL) was added water (8.5 mL) and lithium hydroxide (100 mg, 2.38 mmol) at room temperature. After stirring overnight, the mixture was concentrated and then acidified with dilute HCl. The precipitated solid was filtered and air-dried to give a yellow solid. Yield 0.075 g (56%). LCMS (ESI), m / z: 520.8 [M + H] + ; Rt = 1.41 minutes. Synthesis of 2-((1-hexyl-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylic acid (P53) [ka]

[0685] Preparation 52. Ethyl 2-((1-hexyl-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylate (P52). To a solution of P21 (150 mg, 0.38 mmol) in dioxane (10 mL, degassed) was added 1-hexyl-1H-pyrazol-4-amine (120 mg, 0.72 mmol), cesium carbonate (0.5 g, 1.53 mmol), Xantphos (25 mg, 0.04 mmol), and palladium acetate (10 mg, 0.04 mmol) at room temperature under an argon atmosphere. After stirring the solution at 100 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH = 95:5) to give P52 (96 mg, 47% yield) as a white solid. LCMS (ESI), m / z: 520.5 [M + H] + ; Rt = 1.52 minutes.

[0686] Preparation 53. 2-((1-Hexyl-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylic acid (P53). To a solution of P52 (96 mg, 0.18 mmol) in THF (8.5 mL) was added water (8.5 mL) and lithium hydroxide (91 mg, 2.16 mmol) at room temperature. After stirring overnight, the mixture was concentrated and then acidified with dilute HCl. The precipitated solid was filtered and air-dried to give a yellow solid. Yield 0.083 g (91%). LCMS (ESI), m / z: 492.4 [M + H] + ; Rt = 1.26 minutes. Synthesis of 4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(2-(1-methylpiperidin-2-yl)ethyl)-1H-pyrazol-4-ylamino)pyrimidine-5-carboxylic acid (P55) [ka]

[0687] Preparation 54. Ethyl 4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(2-(1-methylpiperidin-2-yl)ethyl)-1H-pyrazol-4-ylamino)pyrimidine-5-carboxylate (P54). 1-(2-(1-Methylpiperidin-2-yl)ethyl)-1H-pyrazol-4-amine (1071 mg, 5.14 mmol), cesium carbonate (812 mg, 2.5 mmol), Xantphos (30 mg, 0.05 mmol), and palladium acetate (11 mg, 0.05 mmol) were added to a solution of P21 (250 mg, 0.64 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH / EtN 100:5:0.5) to give P54 (170 mg, 47% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.54 (br. s, 1H), 9.87 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 8.19 (d, J = Hz, 1H), 7.74-7.69 (m, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.93-3.95 (m, 5H), 3.76 (s, 3H), 2.78-2.71 (m, 1H), 2.56-2.53 (m, 2H), 2.19-2.10 (m, 4H), 2.01-1.86 (m, 2H),1.63-1.46 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H), 1.26-1.15 (m, 3H).

[0688] Preparation 55. 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(2-(1-methylpiperidin-2-yl)ethyl)-1H-pyrazol-4-ylamino)pyrimidine-5-carboxylic acid (P55) A solution of P54 (170 mg, 0.30 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (127 mg, 3.0 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P55 (160 mg, 99% yield) as a yellow solid. LCMS (ESI) (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 3 min), m / z: 533.3 [M + H] + ; Rt = 0.83 min. Synthesis of 2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P57) [ka]

[0689] Preparation 56. Ethyl 2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate (P56). 1-(3-(dimethylamino)propyl)-1H-pyrazol-4-amine (1075 mg, 6.4 mmol), cesium carbonate (975 mg, 3.0 mmol), Xantphos (35 mg, 0.06 mmol), and palladium acetate (13 mg, 0.06 mmol) were added to a solution of P21 (250 mg, 0.64 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH / EtN 100:5:0.5) to give P56 (120 mg, 63% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.56 (br. s, 1H), 9.86 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 8.19 (d, J = Hz, 1H), 7.66-7.64 (m, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.12-4.04 (m, 2H), 3.98-3.91 (m, 5H), 3.76 (s, 3H), 1.85-1.77 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H), 1.06 (d, J = 6.2 Hz, 6H).

[0690] Preparation 57. 2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P57). A solution of P56 (120 mg, 0.23 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (97 mg, 2.3 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P57 (110 mg, 99% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 10 min) m / z 493.8 [M + H] + ; Rt = 3.66 minutes. Synthesis of 2-(1-(2-(diisobutylamino)ethyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P59) [ka]

[0691] Preparation 58. Ethyl 2-(1-(2-(diisobutylamino)ethyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate (P58). 1-(2-(diisobutylamino)ethyl)-1H-pyrazol-4-amine (1533 mg, 6.4 mmol), cesium carbonate (975 mg, 3.0 mmol), Xantphos (35 mg, 0.06 mmol), and palladium acetate (13 mg, 0.06 mmol) were added to a solution of P21 (250 mg, 0.64 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / THF 50:50) to give P58 (215 mg, 57% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.60 (br. s, 1H), 9.89 (s, 1H), 8.70 (s, 1H), 8.55 (s, 1H), 8.20 (d, J = Hz, 1H), 7.68-7.66 (m, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.16-4.11 (m, 2H), 3.95 (s, 3H), 3.80 (s, 3H), 2.83 (t, 2H), 2.17-2.12 (m, 4H), 1.67-1.63 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H), 0.84 (d, J = 6.2 Hz, 12H).

[0692] Preparation 59. 2-(1-(2-(diisobutylamino)ethyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P59). A solution of P58 (300 mg, 0.51 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (119 mg, 2.8 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P59 (200 mg, 70% yield) as a yellow solid. LCMS (ESI) (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 3 min), m / z: 563.8 [M + H] + ; Rt = 1.01 min. Synthesis of 2-[(1-isopropyl-1H-pyrazol-4-yl)amino]-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}pyrimidine-5-carboxylic acid (P61) [ka]

[0693] Preparation 60. Ethyl 2-[(1-isopropyl-1H-pyrazol-4-yl)amino]-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}pyrimidine-5-carboxylate (P60). Under argon, a mixture of P21 (0.778 g, 2 mmol), 1-isopropyl-1H-pyrazol-4-amine (2.5 g, 20 mmol), palladium acetate (0.15 g, 0.668 mmol), Xantphos (0.45 g, 0.778 mmol), and cesium carbonate (0.977 g, 3 mmol) in dioxane (75 mL) was stirred at 100 °C overnight. The mixture was cooled and filtered through a pad of Celite, and the solvent was removed from the mother liquor under reduced pressure. The residue was purified by silica gel column chromatography (2%, 5%, 10% MeOH in DCM) to give product P60 (0.8 g, 83% yield). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5–87%, 3 min) m / z 478.3 [M + H]+ ; Rt = 1.32 minutes.

[0694] Preparation 61. 2-[(1-Isopropyl-1H-pyrazol-4-yl)amino]-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}pyrimidine-5-carboxylic acid (P61). A solution of lithium hydroxide monohydrate (1 g, 20 mmol) in water (20 ml) was added to a suspension of P60 (0.8 g, 1.675 mmol) in THF (50 ml) at room temperature. The reaction mixture was stirred overnight, the solvent was removed under reduced pressure, the residue was dissolved in water (50 ml), the resulting solution was acidified to pH 5-6 with 10% HCl, the formed precipitate was filtered, washed with water, and dried under reduced pressure to give product P61 (0.75 g, 100%). LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min) m / z 450.5 [M + H] + ; Rt = 0.97 min. Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxylic acid (P63) [ka]

[0695] Preparation 62. Ethyl 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxylate (P62). 1-Methyl-1H-pyrazol-4-amine (240 mg, 2.47 mmol), cesium carbonate (600 mg, 1.85 mmol), Xantphos (44 mg, 0.07 mmol), and palladium acetate (16 mg, 0.07 mmol) were added to a solution of P21 (300 mg, 0.77 mmol) in dioxane (50 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 50:50) to give P62 (100 mg, 37% yield) as a white solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min) m / z 450.6 [M + H] + ; Rt = 4.91 minutes.

[0696] Preparation 63. 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxylic acid (P63). A solution of P62 (100 mg, 0.22 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (50 mg, 1.2 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P63 (60 mg, 64% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5–87%, 10 min) m / z 422.3 [M + H] + ; Rt = 3.96 minutes. Synthesis of 2-((1-isopropyl-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylic acid (P65) [ka]

[0697] Preparation 64. Ethyl 2-((1-isopropyl-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylate (P64). 1-Isopropyl-1H-pyrazol-4-amine (460 mg, 3.67 mmol), cesium carbonate (2178 mg, 6.68 mmol), Xantphos (580 mg, 1.00 mmol), and palladium acetate (225 mg, 1.00 mmol) were added to a solution of P21 (1300 mg, 3.34 mmol) in dioxane (150 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 50:50) to give P64 (93 mg, 6% yield) as a white solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min) m / z 478.2 [M + H] + ; Rt = 5.04 minutes.

[0698] Preparation 65. 2-((1-Isopropyl-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylic acid (P65). A solution of P64 (93 mg, 0.195 mmol) in THF (15 mL) was mixed with water (5 mL) and lithium hydroxide (82 mg, 1.950 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P65 (87 mg, 99% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 10 min) m / z 450.3 [M + H] + ; Rt = 4.39 minutes. Synthesis of 2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylic acid (P67) [ka]

[0699] Preparation 66. Ethyl 2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylate (P66). 1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-amine (436 mg, 2.83 mmol), cesium carbonate (1676 mg, 5.14 mmol), Xantphos (447 mg, 0.77 mmol), and palladium acetate (173 mg, 0.77 mmol) were added to a solution of P21 (1000 mg, 2.57 mmol) in dioxane (150 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 50:50) to give P66 (37 mg, 3% yield) as a white solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min) m / z 507.9 [M + H] + ; Rt = 3.95 minutes.

[0700] Preparation 67. 2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylic acid (P67). A solution of P66 (37 mg, 0.073 mmol) in THF (15 mL) was mixed with water (5 mL) and lithium hydroxide (31 mg, 0.730 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P67 (35 mg, 100% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 10 min) m / z 479.4 [M + H] + ; Rt = 3.41 minutes. Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-((1-phenyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxylic acid (P69) [ka]

[0701] Preparation 68. Ethyl 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-((1-phenyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxylate (P68). 1-Phenyl-1H-pyrazol-4-amine (409 mg, 2.57 mmol), cesium carbonate (1676 mg, 5.14 mmol), Xantphos (447 mg, 0.77 mmol), and palladium acetate (173 mg, 0.77 mmol) were added to a solution of P21 (1000 mg, 2.57 mmol) in dioxane (150 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / THF 50:50) to give P68 (194 mg, 15% yield) as a white solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min) m / z 512.3 [M + H] + ; Rt = 6.04 minutes.

[0702] Preparation 69. 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-((1-phenyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxylic acid (P69). A solution of P68 (194 mg, 0.379 mmol) in THF (20 mL) was mixed with water (5 mL) and lithium hydroxide (159 mg, 3.790 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P69 (100 mg, 55% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5–87%, 10 min) m / z 484.4 [M + H] + ; Rt = 5.05 minutes. Synthesis of tert-butyl 4-(4-((5-carbamoyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (P71) [ka]

[0703] Preparation 70. Ethyl 2-((1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylate (P70). To a solution of P21 (600 mg, 1.54 mmol) in dioxane (150 mL, degassed) was added tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (411 mg, 1.54 mmol), cesium carbonate (1.01 g, 3.09 mmol), Xantphos (268 mg, 0.46 mmol), and tris(dibenzylideneacetone)dipalladium(0) (104 mg, 0.46 mmol) at room temperature under an argon atmosphere. The solution was stirred at 100 °C overnight, and the mixture was cooled and filtered through a pad of Celite®. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 95:5) to give P70 (131 mg, 14% yield) as a white solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min) m / z 619.6 [M + H] + ; Rt = 5.82 minutes.

[0704] Preparation 71. 2-((1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylic acid (P71). To a solution of P70 (131 mg, 0.212 mmol) in THF (20 mL) was added water (5 mL) and lithium hydroxide (89 mg, 2.12 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 7 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P71 (125 mg, 99% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5–87%, 10 min) m / z 591.6 [M + H] + ; Rt = 5.10 minutes. Synthesis of 2-((1-(1-adamantyl)-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylic acid (P73) [ka]

[0705] Preparation 72. Ethyl 2-((1-(1-adamantyl)-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylate (P72). To a solution of P21 (150 mg, 0.38 mmol) in dioxane (10 mL, degassed) was added 1-(1-adamantyl)-1H-pyrazol-4-amine (P76, 160 mg, 0.73 mmol), cesium carbonate (0.5 g, 1.53 mmol), Xantphos (25 mg, 0.04 mmol), and palladium acetate (10 mg, 0.04 mmol) at room temperature under an argon atmosphere. After stirring the solution at 100 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH = 95:5) to give P72 (159 mg, 72% yield) as a white solid. LCMS (ESI), m / z: 570.5 [M + H] + ; Rt = 1.65 minutes.

[0706] Preparation 73. 2-((1-(1-Adamantyl)-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylic acid (P73). To a solution of P72 (159 mg, 0.25 mmol) in THF (8.5 mL) was added water (8.5 mL) and lithium hydroxide (120 mg, 2.85 mmol) at room temperature. After stirring overnight, the mixture was concentrated and then acidified with dilute HCl. The precipitated solid was filtered and air-dried to give a yellow solid. Yield 0.143 g (94%). LCMS (ESI), m / z: 542.8 [M + H] + ; Rt = 1.30 minutes. Synthesis of 1-(1-adamantyl)-1H-pyrazol-4-amine (P76) [ka]

[0707] Preparation 74. 1-(1-Adamantyl)-1H-pyrazole (P74). 1-Bromoadamantane (0.6 g, 2.79 mmol) and 1H-pyrazole (0.6 g, 8.81 mmol) were dissolved at 190 °C for 2 h. The reaction mixture was cooled to room temperature and then partitioned between aqueous NaHCO3 and DCM. The organic phase was separated and the aqueous phase was extracted with DCM (2 x 5 ml). The combined organic phases were dried over MgSO4 and concentrated. The product was purified by silica chromatography using CHCl3 as the eluent. Yield 0.45 g (79%). 1 H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.53 (d, J = 2.1 Hz, 1H), 6.25 (t, J = 2.0 Hz, 1H), 2.24 (s, 3H), 2.19 (d, J = 2.6 Hz, 6H), 1.84 - 1.73 (m, 6H).

[0708] Preparation 75. 1-(1-Adamantyl)-4-nitro-1H-pyrazole (P75). Compound P74 (0.61 g, 3.0 mmol) was added portionwise to ice-cold concentrated H2SO4 (2 mL), followed by dropwise addition of 70% HNO3 (0.25 mL). The mixture was heated at 50 °C for 2 h and then poured onto ice. The product was extracted with DCM (3 x 10 mL). The organic phase was dried over MgSO4 and concentrated. Yield 0.67 g (89%). 1 H NMR (400 MHz, CDCl3), δ: 8.23 ​​(s, 1H), 8.12 (s, 1H), 2.29 (s, 2H), 2.29 (s, 2H), 2.19 - 2.07 (m, 7H), 1.87 - 1.72 (m, 6H).

[0709] Preparation 76. 1-(1-Adamantyl)-1H-pyrazol-4-amine (P76). To a solution of compound P75 (0.6 g, 2.42 mmol) in MeOH (10 ml) was added 10% Pd-C (0.06 g). The reaction mixture was flushed with argon and hydrogenated at room temperature overnight. The catalyst was filtered and washed with MeOH, and the combined organic phases were evaporated to dryness. The product was used in the next step without further purification. Yield 0.49 g (93%). 1 H NMR (400 MHz, CDCl3), δ: 7.20 (s, 1H), 7.17 (s, 1H), 3.75 (s, 2H), 2.21 (s, 2H), 2.11 (s, 5H), 1.86 (s, 2H), 1.75 (s, 6H). Synthesis of tert-butyl 4-bromopiperidine-1-carboxylate (P77) [ka]

[0710] Preparation 77. tert-Butyl 4-bromopiperidine-1-carboxylate (P77). 4-Bromopiperidine hydrobromide (10 g, 40.8 mmol) was dissolved in DMF (50 ml), DIPEA (14.2 ml, 10.55 g, 81.7 mmol) was added, and the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was cooled to 0 °C, and di-tert-butyl bicarbonate (13.36 g, 61.2 mmol) was added in small portions. The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was poured into water (250 ml), adjusted to a weakly acidic pH, and extracted with DCM (3 × 50 ml). The combined organic phases were washed with water (100 ml) and dried over Na2SO4. The solvent was evaporated under vacuum, and the product P77 was used further without further purification. Yield 10.2 g (95%). 1 H NMR (400 MHz, DMSO-d6), δ: 4.55-4.50 (tt, J=7.7, 3.8 Hz, 1H), 3.60-3.53 (m, 2H), 3.23-3.17 (m, 2H), 2.09-2.04 (m, 2H), 1.81-1.73 (m, 2H), 1.47 (s, 9H). Synthesis of amines P80, P82, and P84 [ka]

[0711] Preparation 78. 4-Nitro-1H-pyrazole (P78). Pyrazole (10 g, 147.05 mmol) was dissolved in concentrated sulfuric acid (60 ml) and the reaction mixture was cooled to -5°C. Nitric acid (6.74 ml, 161.6 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 18 hours, then poured onto 250 g of ice and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with 10% sodium bicarbonate solution until CO evolution ceased, then dried over NaSO and concentrated. Yield 13.35 g (81%). 1 H-NMR (400 MHz, DMSO-d6), δ: 13.98 (br. s, 1H), 8.59 (br. s, 2H).

[0712] Preparation 79. 1-Cyclohexyl-4-nitro-1H-pyrazole (P79). 4-Nitro-1H-pyrazole P78 (10 g, 88.5 mmol) and cesium carbonate (57.62 g, 176.86 mmol) were suspended in DMF, and cyclohexyl bromide (14.42 g, 88.5 mmol) was added. The reaction mixture was stirred at 80 °C for 15 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4, and concentrated. The residue was purified by column chromatography using ethyl acetate / hexane (1:4) to give P79. Yield: 9.1 g (53%). 1 H-NMR (400 MHz, DMSO-d6), δ: 8.89 (s, 1H), 8.24 (s, 1H), 4.17-4.27 (m, 1H), 1.99-2.04 (d, J=12.6 Hz, 2H), 1.63-1.83 (m, 5H), 1.33-1.43 (dd, J=13.0 Hz, 2H), 1.14-1.25 (m, 1H).

[0713] Preparation 80. 1-Cyclohexyl-1H-pyrazol-4-amine (P80). 1-Cyclohexyl-4-nitro-1H-pyrazole P79 (9.1 g, 46.67 mmol) was dissolved in dry methanol and 0.496 g of 10% Pd / C was added. The reaction mixture was stirred under a hydrogen atmosphere (20 atm) at 25° C. for 15 hours. The reaction mixture was filtered through a Celite pad and evaporated to give product P80. Yield 7.67 g (99%). 1 H-NMR (400 MHz, DMSO-d6), δ: 7.03 (s, 1H), 6.88 (s, 1H), 3.85-3.93 (m, 1H), 3.70 (br. s, 2H), 1.90-1.93 (d, J=12.3 Hz, 2H), 1.74-1.84 (d, J=13.7 Hz, 2H), 1.53-1.64 (m, 3H), 1.28-1.40 (dd, J=12.7 Hz, 2H), 1.10-1.23 (m, 1H).

[0714] Preparation 81. tert-Butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (P81). 4-Nitro-1H-pyrazole P78 (2 g, 17.7 mmol) and cesium carbonate (11.53 g, 35.37 mmol) were suspended in DMF, tert-butyl 4-bromopiperidine-1-carboxylate P77 (4.67 g, 17.7 mmol) was added, and the reaction mixture was stirred at 80 °C for 15 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4, and concentrated. The residue was purified by column chromatography using ethyl acetate / hexane (1:9). Yield of P81: 2.21 g (42%). 1 H-NMR (400 MHz, DMSO-d6), δ: 8.94 (s, 1H), 8.26 (s, 1H), 4.42-4.51 (m, 1H), 3.99-4.01 (m, 2H), 2.82-2.98 (m, 2H), 2.01-2.06 (d, J=12.3 Hz, 2H), 1.75-1.87 (m, 2H), 1.41 (s, 9H).

[0715] Preparation 82. tert-Butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (P82). tert-Butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate P81 (1.15 g, 3.88 mmol) was dissolved in dry methanol and 0.041 g of 10% Pd / C was added. The reaction mixture was stirred under a hydrogen atmosphere at 20 atmospheres and 25° C. for 15 hours. The reaction mass was filtered through a Celite pad and evaporated to give product P82. Yield 1.03 g (99%). 1H NMR (400 MHz, CDCl3), δ: 7.16 (s, 1H), 7.03 (s, 1H), 4.22 (br. s, 2H), 4.09-4.17 (m, 1H), 2.83-2.90 (m, 2H), 2.78 (br. s, 2H), 2.05-2.09 (d, J=12.2 Hz, 2H), 1.78-1.89 (m, 2H), 1.47 (s, 9H).

[0716] Preparation 83. 1-Isopropyl-4-nitro-1H-pyrazole (P83). 4-Nitro-1H-pyrazole P78 (3 g, 26.53 mmol) and cesium carbonate (17.29 g, 49 mmol) were suspended in DMF, and isopropyl chloride (2.42 mL, 2.08 g, 26.53 mmol) was added dropwise. The reaction mixture was stirred at 80 °C for 15 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4, and concentrated. The residue was purified by column chromatography using ethyl acetate / hexane (3:6) to give P83. Yield: 2.67 g (65%). 1 H-NMR (400 MHz, DMSO-d6), δ: 8.91 (s, 1H), 8.25 (s, 1H), 4.53-4.64 (m, 1H), 1.43-1.45 (d, J=6.7 Hz, 6H).

[0717] Preparation 84. 1-Isopropyl-1H-pyrazol-4-amine (P84) 1-Isopropyl-4-nitro-1H-pyrazole P83 (14.35 g, 92.48 mmol) was dissolved in dry methanol and 0.984 g of 10% Pd / C was added. The reaction mixture was stirred under hydrogen atmosphere (20 atm) at 25° C. for 15 hours. The reaction mass was filtered through a pad of Celite and evaporated to give product P84. Yield 11.37 g (99%). 1H NMR (400 MHz, DMSO-d6), δ: 7.03 (s, 1H), 6.90 (s, 1H), 4.22-4.32 (m, 1H), 3.73 (br s, 2H), 1.31-1.33 (d, J=6.6 Hz, 6H).

[0718] Table 3 shows some examples of key intermediates.

[0719] JPEG2026502173000247.jpg224170JPEG2026502173000248.jpg204170JPEG2026502173000249.jpg236170JPEG2026502173000250.jpg183170JPEG2026502173000251.jpg218170JPEG2026502173000252.jpg218170JPEG2026502173000253.jpg210170JPEG2026502173000254.jpg198170JPEG2026502173000255.jpg226170Example of final compound

[0720] Table 4 shows certain non-limiting examples of compounds of formula (I).

[0721] JPEG2026502173000256.jpg181170JPEG2026502173000257.jpg179170JPEG2026502173000258.jpg185170JPEG2026502173000259.jpg184170JPEG2026502173000260.jpg185170JPEG2026502173000261.jpg190170JPEG2026502173000262.jpg179170JPEG2026502173000263.jpg179170JPEG2026502173000264.jpg99170Synthesis of Representative Example Compounds

[0722] Example 1. 4-[(2-Methoxy-3-pyridin-2-ylphenyl)amino]-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide (Compound 2). [ka] Ammonia solution (7N in MeOH, 3 mL) and TBTU (0.207 g, 0.646 mmol) were added to a solution of P6 (0.18 g, 0.43 mmol) in DMF (20 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, concentrated under reduced pressure, and the residue was purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μL TFA, B: 1000 mL CH3CN) to give compound 2 (71 mg, 40% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.13 (s, 1H), 9.86 (s, 1H), 8.97 (s, 1H), 8.87 - 8.73 (m, 1H), 8.67 (s, 1H), 8.42 - 7.85 (m, 4H), 7.76 - 7.34 (m, 4H), 7.29 (t, J = 7.8 Hz, 1H), 3.80 (s, 3H), 3.50 (s, 3H). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min): m / z 417.3 [M + H] + ; Rt = 3.58 minutes.

[0723] Example 2. 4-{[2-Methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide (Compound 3). [ka] Ammonia solution (7N in MeOH, 3 ml), TBTU (0.091 g, 0.21 mmol), and DIPEA (0.05 ml, 0.285 mmol) were added to a solution of P13 (0.08 g, 0.19 mmol) in DMF (15 ml) at room temperature. The reaction mass was stirred overnight at room temperature, the mixture was concentrated under reduced pressure, and the residue was purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 ml HO - 226 μl TFA, B: 1000 ml CH3CN) to give compound 3 (28 mg, 35% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.09 (s, 1H), 9.68 (s, 1H), 8.87 - 8.62 (m, 1H), 8.47 (s, 1H), 8.22 - 7.83 (m, 2H), 7.72 - 7.37 (m, 3H), 7.32 (t, J = 8.0 Hz, 1H), 3.80 (s, 6H), 2.61 (s, 3H). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min): m / z 422.2 [M + H] + ; Rt = 3.08 minutes.

[0724] Example 3. 4-{[3-(1,3-Benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-[(1-piperidin-4-yl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide (Compound 8). [ka] A mixture of P18 (0.05 g, 0.08 mmol) in MeOH (5 ml) and a 3 M solution of HCl in 1,4-dioxane (5 ml) was stirred at room temperature overnight. EtO (20 ml) was then added, and the formed precipitate was filtered, dissolved in water, and a saturated solution of NaHCO was added to pH 8. The formed precipitate was filtered, washed with water, and dried under reduced pressure to give compound 8 (23 mg, 55% yield) as a white solid.1 H NMR (400 MHz, DMSO-d6), δ: 12.04 (s, 1H), 9.59 (s, 1H), 9.16 (s, 1H), 8.74 (s, 1H), 8.44 (s, 1H), 8.16 - 7.65 (m, 5H), 7.62 - 7.13 (m, 5H), 4.41 - 3.95 (m, 1H), 3.89 (s, 3H), 3.09 - 2.87 (m, 2H), 2.69 - 2.55 (m, 2H), 2.13 - 1.54 (m, 4H). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5–87%, 10 min) m / z 526.5 [M + H]+; Rt = 4.07 min.

[0725] Example 4. 4-{[3-(1,3-Benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-({1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}amino)pyrimidine-5-carboxamide (Compound 9). [ka] Ammonia solution (7N in MeOH, 3 mL), TBTU (0.178 g, 0.55 mmol), and DIPEA (0.2 mL, 1.08 mmol) were added to a solution of P20 (0.19 g, 0.36 mmol) in DMF (10 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, concentrated under reduced pressure, and the residue was purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μL TFA, B: 1000 mL CH3CN) to give compound 9 (CF3COOH salt) (150 mg, 20% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 12.19 (s, 1H), 9.78 (s, 1H), 9.42 (s, 1H), 9.13 (s, 1H), 8.74 (s, 1H), 8.22 - 8.03 (m, 1H), 7.91 - 7.72 (m, 3H), 7.72 - 7.61 (m, 1H), 7.55 - 7.41 (m, 3H), 7.36 (t, J = 8.1 Hz, 1H), 4.57 - 4.43 (m, 2H), 3.90 (s, 3H), 3.56 (s, 2H), 2.81 (s, 6H). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min) m / z 514.5 [M + H] + ; Rt = 4.81 minutes.

[0726] Example 5. 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-ylamino)pyrimidine-5-carboxamide (compound 10). [ka] A solution of NH3, TBTU (104 mg, 0.32 mmol), and DIPEA (129 mg, 1.0 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P23 (104 mg, 0.21 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μL TFA, B: 1000 mL CH3CN) to give compound 10 (39 mg, 37% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 11.90 (s, 1H), 9.88 - 9.33 (m, 2H), 8.69 (s, 1H), 8.56 (s, 1H), 8.35 - 7.84 (m, 2H), 7.84 - 7.33 (m, 3H), 7.19 (t, J = 7.9 Hz, 1H), 4.53 - 4.32 (m, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.57 (d, J = 12.3 Hz, 2H), 3.27 - 3.04 (m, 2H), 2.84 (s, 3H), 2.37 - 1.97 (m, 4H). LCMS (ESI), m / z: 504.5 [M + H] + ; Rt = 3.55 minutes.

[0727] Example 6. 2-(1-Cyclohexyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxamide (Compound 11). [ka] A solution of NH3, TBTU (51 mg, 0.135 mmol), and DIPEA (46 mg, 0.356 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P25 (44 mg, 0.09 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μl TFA, B: 1000 mL CH3CN) to give compound 11 (10 mg, 23% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 11.96 (s, 1H), 9.84 (s, 1H), 8.91 (s, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.19 - 7.89 (m, 2H), 7.76 - 7.34 (m, 3H), 7.30 - 7.08 (m, 1H), 4.33 - 4.12 (m, 1H), 3.95 (s, 3H), 3.75 (s, 3H), 2.12 - 1.04 (m, 10H). LCMS (ESI), m / z: 489.5 [M + H] + ; Rt = 4.59 minutes.

[0728] Example 7. 4-((3-(1,3-Benzoxazol-2-yl)-2-methoxyphenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide (Compound 12). [ka] A solution of NH3, TBTU (130 mg, 0.34 mmol), and DIPEA (70 mg, 0.546 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P27 (130 mg, 0.28 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μl TFA, B: 1000 mL CH3CN) to give compound 12 (3 mg, 2% yield) as a white solid. LCMS (ESI), m / z: 457.5 [M + H] + ; Rt = 5.49 minutes.

[0729] Example 8. 2-(1,3-Dimethyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxamide (Compound 13). [ka] A solution of NH3, TBTU (120 mg, 0.32 mmol), and DIPEA (64 mg, 0.5 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P29 (66 mg, 0.15 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μL TFA, B: 1000 mL CH3CN) to give compound 13 (39 mg, 59% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.24 (s, 1H), 9.48 (s, 1H), 8.88 (s, 1H), 8.76 - 8.36 (m, 3H), 8.36 - 7.95 (m, 2H), 7.95 - 7.42 (m, 3H), 7.42 - 6.90 (m, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 2.08 (d, J = 6.0 Hz, 3H). LCMS (ESI), m / z: 435.4 [M + H] + ; Rt = 4.08 minutes.

[0730] Example 9. 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylamino)pyrimidine-5-carboxamide (compound 14). [ka] A solution of NH3, TBTU (72 mg, 0.189 mmol), and DIPEA (32 mg, 0.252 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P31 (62 mg, 0.126 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μl TFA, B: 1000 mL CH3CN) to give compound 14 (30 mg, 48% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.27 - 11.81 (m, 1H), 9.82 (s, 1H), 8.66 (s, 1H), 8.56 (s, 1H), 8.24 - 7.84 (m, 2H), 7.84 - 7.32 (m, LCMS (ESI), m / z: 491.3 [M + H] + ; Rt = 4.32 minutes.

[0731] Example 10. 4-{[3-(1,3-Benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-[(1-isopropyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide (Compound 16). [ka] Ammonia solution (7N in MeOH, 3 mL), TBTU (0.198 g, 0.618 mmol), and DIPEA (0.1 mL, 0.618 mmol) were added to a solution of P33 (0.2 g, 0.412 mmol) in DMF (10 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, concentrated under reduced pressure, and the residue was added with DCM. The precipitate formed was filtered, washed with DCM, and recrystallized from EtOH to give compound 16 (112 mg, 56% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.08 (s, 1H), 9.58 (s, 1H), 8.89 - 8.40 (m, 2H), 8.13 - 7.65 (m, 5H), 7.65 - 7.16 (m, 5H), 4.60 - 4.24 (m, 1H), 3.90 (s, 3H), 1.53 - 1.17 (m, 6H). LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min): m / z 485.5 [M + H]. + ; Rt = 5.93 minutes.

[0732] Example 11. 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1,3,5-trimethyl-1H-pyrazol-4-ylamino)pyrimidine-5-carboxamide (Compound 17). [ka] A solution of NH3, TBTU (152 mg, 0.467 mmol), and DIPEA (90 mg, 0.70 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P35 (140 mg, 0.32 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μL TFA, B: 1000 mL CH3CN) to give compound 17 (13 mg, 10% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.50 (s, 1H), 9.41 - 8.48 (m, 2H), 8.38 (s, 1H), 8.21 - 8.04 (m, 1H), 7.96 - 7.39 (m, 3H), 7.39 - 6.77 (m, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.73 (s, 3H), 2.16 - 1.95 (m, 6H). LCMS (ESI), m / z: 449.4 [M + H] + ; Rt = 3.93 minutes.

[0733] Example 12. 2-(1-Ethyl-3,5-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxamide (Compound 18). [ka] A solution of NH3, TBTU (350 mg, 1.08 mmol), and DIPEA (263 mg, 2.08 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P37 (100 mg, 0.21 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μL TFA, B: 1000 mL CH3CN) to give compound 18 (24 mg, 25% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.59 (s, 1H), 8.94 - 8.51 (m, 2H), 8.48 - 8.02 (m, 2H), 8.02 - 7.43 (m, 3H), 7.28 (t, J = 8.0 Hz, 1H), 4.11 - 3.98 (m, 2H), 3.95 (s, 3H), 3.78 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H). LCMS (ESI), m / z: 463.9 [M + H] + ; Rt = 4.04 minutes.

[0734] Example 13. 2-(3,5-Dimethyl-1-propyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxamide (Compound 19). [ka] A solution of NH3, TBTU (350 mg, 1.08 mmol), and DIPEA (263 mg, 2.08 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P39 (190 mg, 0.39 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μl TFA, B: 1000 mL CH3CN) to give compound 19 (18 mg, 9% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.63 (s, 1H), 8.90 - 8.61 (m, 2H), 8.58 - 8.12 (m, 2H), 8.02 - 7.53 (m, 3H), 7.22 (t, J = 8.0 Hz, 1H), 4.11 - 3.98 (m, 2H), 3.95 (s, 3H), 3.78 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H), 1.85 (m, 2H), 1.38 (t, J = 7.3 Hz, 3H). LCMS (ESI), m / z: 477.2 [M+H] + ; Rt = 4.47 minutes.

[0735] Example 14. 2-(1-Isopropyl-3,5-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxamide (Compound 20). [ka] A solution of NH3, TBTU (209 mg, 0.644 mmol), and DIPEA (116 mg, 0.90 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P41 (130 mg, 0.27 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μL TFA, B: 1000 mL CH3CN) to give compound 20 (12 mg, 9% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.58 (s, 1H), 8.88 - 8.51 (m, 2H), 8.52 - 8.16 (m, 2H), 8.09 - 7.47 (m, 3H), 7.26 (t, J = 8.0 Hz, 1H), 4.54 - 4.43 (m, 1H), 3.95 (s, 3H), 3.78 (s, 3H), 2.12 (s, 3H), 2.04 (s, 3H), 1.47 - 1.28 (m, 6H). LCMS (ESI), m / z: 477.2 [M + H] + ; Rt = 4.46 minutes.

[0736] Example 15. 2-[(1-Cyclopropyl-1H-pyrazol-4-yl)amino]-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}pyrimidine-5-carboxamide (Compound 21). [ka] Ammonia solution (7N in MeOH, 1 ml), TBTU (0.245 g, 0.763 mmol), and DIPEA (0.27 ml, 1.52 mmol) were added to a solution of P43 (0.12 g, 0.277 mmol) in DMF (5 ml) at room temperature. The reaction mass was stirred overnight at room temperature, the mixture was concentrated under reduced pressure, and the residue was purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 ml HO - 226 μl TFA, B: 1000 ml CH3CN) to give compound 21 (78 mg, 34% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6), δ: 11.99 (s, 1H), 9.75 (s, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.23 ​​(s, 1H), 8.11 - 7.70 (m, 2H), 7.70 - 7.34 (m, 3H), 7.20 (t, J = 8.0 Hz, 1H), 3.94 (s, 3H), 3.76 (s, 3H), 3.69 - 3.51 (m, 1H), 1.08 - 0.82 (m, 4H). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min) m / z 447.2 [M + H] + ; Rt = 4.14 minutes.

[0737] Example 16. 2-(1-(Cyclohexylmethyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxamide (Compound 22). [ka] A solution of NH3, TBTU (193 mg, 0.595 mmol), and DIPEA (109 mg, 0.794 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P45 (200 mg, 0.397 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μL TFA, B: 1000 mL CH3CN) to give compound 22 (151 mg, 76% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 11.87 (s, 1H), 9.84 (s, 1H), 8.66 (s, 1H), 8.56 (s, 1H), 8.21 - 7.85 (m, 2H), 7.73 - 7.34 (m, 4H), 7.25 - 7.13 (m, 1H), 3.95 (s, 3H), 3.84 - 3.68 (m, 6H), 1.89 - 1.28 (m, 5H), 1.25 - 0.72 (m, 5H). LCMS (ESI), m / z: 503.4 [M + H] + ; Rt = 5.14 minutes.

[0738] Example 17. 2-(1-(Adamantylmethyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxamide (Compound 23). [ka] A solution of NH3, TBTU (215 mg, 0.57 mmol), and DIPEA (98 mg, 0.76 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P47 (210 mg, 0.38 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μL TFA, B: 1000 mL CH3CN) to give compound 23 (38 mg, 20% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 11.79 (s, 1H), 9.81 (s, 1H), 8.66 (s, 1H), 8.56 (s, 1H), 8.24 - 7.63 (m, 3H), 7.63 - 7.32 (m, 3H), 7.21 (t, J = 8.0 Hz, 1H), 3.94 (s, 3H), 3.73 (s, 3H), 3.60 (s, 2H), 1.98 - 1.72 (m, 3H), 1.68 - 1.38 (m, 9H), 1.38 - 1.20 (m, 3H). LCMS (ESI), m / z: 555.3 [M + H] + ; Rt = 5.12 minutes.

[0739] Example 18. 2-(1-Isopentyl-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxamide (Compound 24). [ka] A solution of NH3, TBTU (105 mg, 0.324 mmol), and DIPEA (103 mg, 0.816 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P49 (103 mg, 0.216 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μl TFA, B: 1000 mL CH3CN) to give 24 (60 mg, 59% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 11.97 (s, 1H), 9.84 (s, 1H), 8.66 (s, 1H), 8.56 (s, 1H), 8.31 - 7.82 (m, 3H), 7.82 - 7.33 (m, 3H), 7.33 - 7.02 (m, 1H), 4.15 - 3.98 (m, 2H), 3.95 (s, 3H), 3.76 (s, 3H), 1.79 - 1.36 (m, 3H), 0.86 (d, J = 8.1 Hz, 6H). LCMS (ESI), m / z: 477.4[M+H] + ; Rt = 4.18 minutes.

[0740] Example 19. 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-((1-octyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide (Compound 25). [ka] To a solution of P51 (75 mg, 0.14 mmol) in DMF (2 mL) was added TBTU (75 mg, 0.19 mmol) and DIPEA (0.14 mL, 101 mg, 0.8 mmol). The mixture was stirred at room temperature for 2 h, and then ammonia solution (7N in MeOH, 0.5 mL, 3.5 mmol) was added. After stirring overnight, the mixture was directly purified on a C18 reverse-phase column (5–100% MeOH in water) to give 25 (50 mg, 66% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.02 (s, 1H), 9.91 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 8.31 - 7.87 (m, 3H), 7.77 - 7.31 (m, 3H), 7.31 - 7.00 (m, 1H), 4.15 - 4.01 (m, 2H), 3.95 (s, 3H), 3.76 (s, 3H), 1.88 - 1.61 (m, 2H), 1.32 - 1.10 (m, 10H), 0.90 - 0.75 (m, 3H). LCMS (C18 column 20 x 2 mm, 2.5 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min, retention time 5.84 min). LCMS (ESI), m / z: 519.8 [M+H] + .

[0741] Example 20. 2-((1-Hexyl-1H-pyrazol-4-yl)amino(-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino)pyrimidine-5-carboxamide (Compound 26). [ka] To a solution of P53 (83 mg, 0.16 mmol) in DMF (2 mL) was added TBTU (83 mg, 0.22 mmol) and DIPEA (0.14 mL, 101 mg, 0.8 mmol). The mixture was stirred at room temperature for 2 h, and then ammonia solution (7N in MeOH, 0.5 mL, 3.5 mmol) was added. After stirring overnight, the mixture was directly purified on a C18 reverse-phase column (5-100% MeOH in water) to give compound 26 (26 mg, 31% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.02 (s, 1H), 9.91 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 8.31 - 7.87 (m, 3H), 7.77 - 7.31 (m, 3H), 7.31 - 7.00 (m, 1H), 4.15 - 4.01 (m, 2H), 3.95 (s, 3H), 3.76 (s, 3H), 1.88 - 1.61 (m, 2H), 1.42 - 1.14 (m, 6H), 0.90 - 0.75 (m, 3H). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min, retention time 5.21 min). LCMS (ESI), m / z: 491.5 [M+H] + .

[0742] Example 21. 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(2-(1-methylpiperidin-2-yl)ethyl)-1H-pyrazol-4-ylamino)pyrimidine-5-carboxamide (Compound 27) [ka] A solution of NH3, TBTU (147 mg, 0.45 mmol), and DIPEA (116 mg, 0.9 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P55 (160 mg, 0.3 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μL TFA, B: 1000 mL CH3CN) to give compound 27 (58 mg, 36% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 11.88 (s, 1H), 9.67 (s, 1H), 9.18 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.37 - 7.67 (m, 3H), 7.67 - 7.29 (m, 3H), 7.20 (t, J = 7.9 Hz, 1H), 4.36 - 4.06 (m, 1H), 3.95 (s, 3H), 3.77 (s, 6H), 3.26 - 2.88 (m, 1H), 2.88 - 2.60 (m, 3H), 2.18 - 1.23 (m, 8H). LCMS (ESI), m / z: 532.7 [M + H]+; Rt = 3.91 minutes.

[0743] Example 22. 2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxamide (Compound 28) [ka] A solution of NH3, TBTU (171 mg, 0.53 mmol), and DIPEA (180 mg, 1.4 mmol) in MeOH (1 mL, 7 mmol) was added to a solution of P57 (113 mg, 0.23 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μL TFA, B: 1000 mL CH3CN) to give compound 28 (80 mg, 71% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.00 (s, 1H), 9.76 (s, 1H), 9.41 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.41 - 7.81 (m, 2H), 7.81 - 7.34 (m, 3H), 7.24 - 7.14 (m, 1H), 4.30 - 4.03 (m, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 3.17 - 2.90 (m, 2H), 2.76 (s, 6H), 2.19 - 1.99 (m, 3H). LCMS (ESI), m / z: 492.8 [M + H] + ; Rt = 3.57 minutes. Example 23. 2-(1-(2-(diisobutylamino)ethyl)-1H-pyrazol-4-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxamide (Compound 29). [ka] A solution of NH3, TBTU (173 mg, 0.53 mmol), and DIPEA (180 mg, 1.4 mmol) in MeOH (2 mL, 14 mmol) was added to a solution of P59 (200 mg, 0.35 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μL TFA, B: 1000 mL CH3CN) to give compound 29 (117 mg, 58% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.00 (s, 1H), 9.80 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 8.39 - 7.79 (m, 3H), 7.73 - 7.31 (m, 3H), 7.20 (t, J = 8.0 Hz, 1H), 4.67 - 4.47 (m, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 3.63 (s, 2H), 3.03 (s, 4H), 2.07 (s, 2H), 1.07 - 0.79 (m, 12H). LCMS (ESI), m / z: 562.9 [M + H] + ; Rt = 4.07 minutes.

[0744] Example 24. 2-[(1-Isopropyl-1H-pyrazol-4-yl)amino]-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}-N,N-dimethylpyrimidine-5-carboxamide (Compound 31). [ka] Dimethylamine hydrochloride (0.186 g, 2.28 mmol), TBTU (0.732 g, 2.28 mmol), and DIPEA (0.88 mL, 5 mmol) were added to a solution of P61 (0.75 g, 1.668 mmol) in DMF (25 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A-B (A: 1000 mL HO - 226 μL TFA, B: 1000 mL CH3CN) to give compound 31 (CF3COOH salt) (122 mg, 12% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.05 (s, 1H), 9.90 (s, 1H), 8.56 (s, 1H), 8.22 (s, 1H), 8.03 - 7.30 (m, 4H), 7.22 (t, J = 8.0 Hz, 1H), 4.58 - 4.22 (m, 1H), 3.94 (s, 3H), 3.74 (s, 3H), 3.08 (s, 6H), 1.52 - 1.16 (m, 6H). LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min). 477.1 [M + H] + ; Rt = 4.32 minutes.

[0745] Example 25. 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide (Compound 1). [ka] A solution of 8 M NH3, TBTU (68 mg, 0.213 mmol), and DIPEA (55 mg, 0.426 mmol) in MeOH (1 mL, 8 mmol) was added to a solution of P63 (60 mg, 0.142 mmol) in DMF (4 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μl TFA, B: 1000 mL CH3CN) to give compound 1 (10 mg, 16% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6), δ: 12.27 (s, 1H), 10.61 (s, 1H), 8.80 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.16 (s, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.61 (s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 3.95 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H). LCMS (ESI), m / z: 421.4 [M + H] + ; Rt = 4.10 minutes.

[0746] Example 26. 2-((1-Isopropyl-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxamide (Compound 4) [ka] A solution of 8 M NH3, TBTU (94 mg, 0.293 mmol), and DIPEA (126 mg, 0.975 mmol) in MeOH (1 mL, 8 mmol) was added to a solution of P65 (87 mg, 0.195 mmol) in DMF (10 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μl TFA, B: 1000 mL CH3CN) to give compound 4 (30 mg, 34% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.10 (s, 1H), 9.79 (s, 1H), 8.92 (s, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 8.32 - 7.87 (m, 2H), 7.70 - 7.41 (m, 3H), 7.15 (s, 1H), 4.53 - 4.32 (m, 1H), 3.95 (s, 3H), 3.77 (s, 3H), 1.45 - 1.32 (m, 6H). LCMS (ESI), m / z: 449.4 [M + H] + ; Rt = 4.07 minutes.

[0747] Example 27. 2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxamide (Compound 5) [ka] A solution of 8 M NH3, TBTU (35 mg, 0.110 mmol), and DIPEA (57 mg, 0.438 mmol) in MeOH (1 mL, 8 mmol) was added to a solution of P67 (35 mg, 0.073 mmol) in DMF (10 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μl TFA, B: 1000 mL CH3CN) to give compound 5 (22 mg, 63% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.01 (s, 1H), 9.80 (s, 1H), 9.44 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 8.28 (s, 0H), 8.20 - 7.75 (m, 2H), 7.71 - 7.34 (m, 3H), 7.22 (t, J = 8.1 Hz, 1H), 4.60 - 4.32 (m, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 3.55 (s, 2H), 2.81 (s, 6H). LCMS (ESI), m / z: 478.6 [M + H] + ; Rt = 3.45 minutes.

[0748] Example 28. 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-((1-phenyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide (Compound 6). [ka] A solution of 8 M NH3, TBTU (90 mg, 0.279 mmol), and DIPEA (120 mg, 0.930 mmol) in MeOH (1 mL, 8 mmol) was added to a solution of P69 (90 mg, 0.186 mmol) in DMF (10 mL) at room temperature. The solution was stirred overnight at room temperature and evaporated under vacuum. The mixture was directly purified on a C18 reverse-phase column (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 mL HO - 226 μl TFA, B: 1000 mL CH3CN) to give compound 6 (14 mg, 16% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 11.93 (s, 1H), 9.93 (s, 1H), 8.73 (s, 1H), 8.57 (s, 1H), 8.41 (s, 1H), 8.29 - 8.03 (m, 2H), 7.95 - 7.39 (m, 7H), 7.29 (t, J = 7.4 Hz, 1H), 7.02 (s, 1H), 3.95 (s, 3H), 3.78 (s, 3H). LCMS (ESI), m / z: 483.8 [M + H] + ; Rt = 4.98 minutes.

[0749] Example 29. 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide 2,2,2-trifluoroacetate (Compound 7) [ka] To a solution of P71 (125 mg, 0.212 mmol) in DMF (15 mL) was added 8 M NH3 in MeOH (1 mL, 8 mmol), TBTU (102 mg, 0.318 mmol), and DIPEA (164 mg, 1.27 mmol) at room temperature. The solution was stirred at room temperature for 12 h. The solvent was removed, and the crude product P71a was used further without further purification. LCMS (C18 column 20 × 2 mm, 2.5 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5–87%, 10 min, retention time 4.78 min). MS (ESI), m / z: 590.7 [M−H] + A solution of compound P71a (0.120 g, 0.204 mmol) in a mixture of isopropanol-DCM (10%, 5 ml) was treated with a 3 M solution of HCl in dioxane (0.5 ml). The reaction mixture was evaporated under vacuum and treated with concentrated aqueous NaHCO (1 ml). The product 7 was extracted with DCM, concentrated, and purified by HPLC under acidic conditions (YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, 12 nm, gradient A solution - B solution (A: 1000 ml H2O - 226 μl TFA, B: 1000 ml CH3CN)). Yield 0.065 g (65%). 1 H NMR (400 MHz, DMSO-d6), δ: 11.93 (s, 1H), 9.79 (s, 1H), 8.92 (s, 1H), 8.68 (s, 1H), 8.56 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.76 - 7.43 (m, 3H), 7.19 (s, 1H), 4.37 - 4.29 (m, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.47 - 3.34 (m, 2H), 3.07 (q, J = 11.9 Hz, 2H), 2.22 - 2.00 (m, 4H). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min, retention time 3.77 min). LCMS (ESI), m / z: 490.6 [M−H] + .

[0750] Example 30. 2-((1-(1-Adamantyl)-1H-pyrazol-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxamide (Compound 30). [ka] To a solution of P73 (143 mg, 0.26 mmol) in DMF (2 mL) was added TBTU (150 mg, 0.39 mmol) and DIPEA (0.14 mL, 101 mg, 0.8 mmol). The mixture was stirred at room temperature for 2 h, and then ammonia solution (7N in MeOH, 0.5 mL, 3.5 mmol) was added. After stirring overnight, the mixture was directly purified on a C18 reverse-phase column (5-100% MeOH in water) to give compound 30 (85 mg, 59% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 9.84 (s, 1H), 12.05 (s, 1H), 8.66 (s, 1H), 8.56 (s, 1H), 8.25 - 7.70 (m, 3H), 7.70 - 7.32 (m, 3H), 7.31 - 6.98 (m, 1H), 3.94 (s, 3H), 3.76 (s, 3H), 2.23 - 2.04 (m, 6H), 2.04 - 1.90 (m, 4H), 1.79 - 1.60 (m, 5H). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5-87%, 10 min, retention time 5.09 min). LCMS (ESI), m / z: 541.4 [M+H] + . Biological assays

[0751] Example A. JAK2 Assay Enzyme Protocol. material: ·Dilution plate: Diamond well plate (Axygen, Cat#P-384-120SQ-CS); Compound plate: Diamond well plate (Axygen, Cat#P-384-120SQ-CS); Reaction plate: 384w, NBS, white (Corning, Cat#4513). Reagents and concentrations in the reaction: ·DMSO: 1%; · Kinase: JAK2 0.1ng / μL (SignalChem, Cat#J02-11G); ·Substrate:PolyE4Y1 0.2ng / μL(Sigma-Aldrich, Cat#P0275); ATP: 5 μM (Promega, ADP-Glo™ Kinase Assay, Cat# V9102). Assay buffer 1x: 40mM Tris-HCl pH 7.4-7.6 20mM MgCl2 0.05mM DTT 0.1mg / ml BSA procedure: 1. Prepare 100x solutions of compounds in DMSO in the compound plate; 2. Prepare 2x JAK2-PolyE4Y1 mix with 1x assay buffer and negative control solution (PolyE4Y1 only). Add 4 μL of 2x JAK2-PolyE4Y1 mix and negative control to the reaction plate per well; 3. Centrifuge the plate at 200g for 1 minute; 4. Prepare the dilution plate by adding 49 μL per well of 2x ATP in assay buffer; 5. Using the Biomek workstation, add compounds to the reaction plate by performing the following steps: transfer 1 μL of 100× compound from the compound plate to the dilution plate (containing 49 μL of 2× ATP solution), mix well, and then transfer 4 μL from the dilution plate to the reaction plate containing 4 μL of 2× JAK2-PolyE4Y1 mix; 6. Centrifuge the plate at 200g for 1 minute; 7. Incubate at room temperature for 1 hour; 8. Add 4 μL of ADP-Glo ​​reagent (Promega, ADP-Glo™ Kinase Assay, Cat#V9102) per well; 9. Centrifuge the plate at 200g for 1 minute; 10. Incubate at room temperature for 30 minutes; 11. Add 8 μL of kinase detection reagent (Promega, ADP-Glo™ Kinase Assay, Cat#V9102) per well; 12. Centrifuge the plate at 200g for 1 minute; 13. Measure luminescence using a microplate reader (BMG ClarioStar Plus). The results of this assay are shown in Table A. IC 50 The values ​​are indicated by letters A to D: A ≤ 0.1 μM; 0.1 μM <B≦0.5μM;0.5μM<C≦1μM;1 <d>1.

[0752] Example B. JAK2 JH2 TR-FRET Assay Protocol. Assay buffer 1x: · 20mM HEPES pH 7.2-7.4; ·10mM MgCl2; ·0.015% Brij-35; 2mM DTT; 0.05mg / ml BSA. Final assay concentration: ·DMSO: 0.25%; ·Streptavidin Tb-cryptate (Cisbio, Cat#610SATLB) 0.2nM; Enzyme: JAK2 JH2, His-Avi-Tag, biotin-labeled (BPS Bioscience, Cat#79074) 1nM; Probe: Tracer ZE84-0003 (ChemRar) 10 nM. material: Reaction plate: ProxiPlate-384 Plus White Plate (PerkinElmer); ·Dilution plate: Diamond well plate (Axygen, Cat#P-384-120SQ-CS); Compound plate: Diamond well plate (Axygen, Cat#P-384-120SQ-CS). Assay Protocol: 1. Prepare a 400x solution of compounds in DMSO in the compound plate; 2. Prepare the dilution plate: add 39 μL of 1x assay buffer per well of the dilution plate; 3. Prepare 2x Tb-cryptate mix with 1x assay buffer. Add 10 µL of 2x Tb-cryptate mix to K- (Tb-cryptate and probe without enzyme) and blank (Tb-cryptate and probe without enzyme) wells; 4. Add JAK2 JH2 to the remaining 2x Tb-cryptate mix to create a 2x JAK2 JH2 + Tb-cryptate mix. Add 10 μL per well to the reaction plate; 5. Centrifuge the plate at 200g for 1 minute; 6. Dilute 1 μL of 400× compound with 39 μL 1× concentration assay buffer in the dilution plate; 7. Add 2 μL of 10× compound from the dilution plate to the reaction plate containing 10 μL of JAK2 JH2+Tb-cryptate mix; 8. Centrifuge the plate at 200g for 1 minute; 9. Pre-incubate the reaction plate with compounds for 15 minutes; 10. Prepare 2.5x tracer mix; 11. Add 8 μL of 2.5× tracer mix to the appropriate wells of the reaction plate; 12. Centrifuge the plate at 800g for 1 minute; 13. Incubate at room temperature for 15 minutes; 14. Measure fluorescence using a microplate reader (e.g., TR, Em1 / Em2:482 / 520). The results of this assay are shown in Table B. EC 50 The values ​​are indicated by letters A to D, where A≦0.01 μM; <B≦0.05μM;0.05μM<C≦0.1μM;D> 0.1.

[0753] JPEG2026502173000295.jpg21785JPEG2026502173000296.jpg20798*-EC 50 Half-maximal effective concentration: The concentration of a compound that induces a response halfway between the baseline and maximum after a specific exposure time; EC 50 : A ≤ 0.01 μM; 0.01 μM <B≦0.05μM;0.05μM<C≦0.1μM;D> 0.1

[0754] Example C. Assessment of STAT5 phosphorylation by immunoblotting. Ba / F3 Jak2 wild-type cells (ABM, T3076) and Ba / F3 Jak2 V617F cells (WuXiAppTec) were cultured in RPMI-1640 (Paneco, cat. #C330) supplemented with 10% FBS (Hyclone Laboratories Inc, cat. #SV30160.03), 1x antibiotic-antimycotic (Gibco, cat. #15240-062), 2x sodium pyruvate (Paneco, cat. #F023), 2x essential amino acids (Paneco, cat. #F115 / 100), and 1x non-essential amino acids (Paneco, cat. #F116) at 37°C in a 5% CO atmosphere. Ba / F3 Jak2 wild-type or Ba / F3 Jak2 V617F cells were seeded in 24-well CELLSTAR® cell culture polystyrene sterile plates (Greiner, cat. #662160) at a density of 2,500,000 cells per well with 1 ml of cell suspension per well, with or without 10 ng / ml rmIL-3 (RD systems, USA, Cat. #403-ML-025). A 1000x compound stock in DMSO (Sigma Cat# D2650) was prepared and added to complete culture medium in a 96-well V-bottom plate (Thermo Scientific, cat# 249946) to create a 25x compound solution. 40 μl of the 25x compound solution was then added to the 24-well plate containing the cell suspension, resulting in a final DMSO concentration of 0.1%. Treated cells were incubated at 37°C in a 5% CO2 atmosphere for 3 hours. After incubation, cells were harvested by centrifugation at 500 g for 5 minutes, washed once with PBS (Thermo Scientific, cat. #28372), and lysed using RIPA buffer (ProteinSimple, cat. #040-483) supplemented with 1x Halt™ protease and phosphatase inhibitor cocktail (Thermo Scientific, cat. #78440) at 30 μl / well. The cell lysate was then incubated on ice for 20 minutes and centrifuged at 20,000 g for 20 minutes at 4°C. The supernatant was then aspirated and used for protein analysis. The protein concentration in the prepared cell lysates was measured using a Pierce™ Coomassie (Bradford) Protein Assay Kit (Thermo Scientific, cat. #23200) in a 96-well flat-bottom polystyrene plate (Greiner, cat. #655061) and a microplate reader (CLARIOStar). The cell lysates were diluted to a concentration of 1.25 μg / μl with 0.1× sample buffer (ProteinSimple, cat. #042-195). 10 μl of the diluted lysate was mixed with 2.5 μl of master mix (ProteinSimple, cat. #PS-ST01EZ-8) and heated at 95°C for 5 minutes. Phospho-Stat5 (Tyr694) rabbit antibody (1:400) (Cell Signaling, cat. #9351S) and beta-Actin mouse antibody (1:200) (R&D Systems, cat. #MAB8929) were diluted in milk-free diluent (ProteinSimple, cat. #043-524). 20x anti-rabbit HRP antibody (ProteinSimple, cat. #043-426) was diluted to 1x with anti-mouse secondary HRP antibody (ProteinSimple, cat. #042-205). Jess plates (ProteinSimple, cat. #SM-W004) were loaded according to the manufacturer's instructions, and phosphorylated Stat5 levels in the lysates were measured using Jess (ProteinSimple).

[0755] Example D. Growth Inhibition Assay. Ba / F3(JAK2wt) (ABM, T3076) and Ba / F3(JAK2 V617F) (WuXi AppTec) cells were cultured in RPMI-164 (Gibco, cat. no. 21870) supplemented with 10% FBS (Hyclone Laboratories Inc., cat. no. SV30160.03), 1x antibiotic-antimycotic (Gibco, cat. no. 15240-062), 2x sodium pyruvate (Paneco, cat. no. F023), 2x essential amino acids (Paneco, cat. no. F115 / 100), and 1x non-essential amino acids (Paneco, cat. no. F116) at 37°C in a 5% CO atmosphere. For growth inhibition assays, Ba / F3(JAK2wt) and Ba / F3(JAK2 V617F) cells were seeded into CellBIND® 384-well flat clear bottom black polystyrene microplates (Corning, USA, Cat#3770) at a density of 4000 cells per well in complete culture medium with or without 10 ng / ml rmIL-3 (RD systems, USA, Cat#403-ML-02) using a Biomek FX / NX (384) liquid handler, with 45 μl of cell suspension per well in complete culture medium. 500x compound stocks in DMSO (Sigma Cat# D2650) were prepared in a compound plate (Diamond Well Plate, Axigen, Cat# P-384-120SQ-CS) using a Biomek 2000. 1 μl of 500x compound stock was added to 49 μl of complete culture medium in a dilution plate (Diamond Well Plate, Axigen, Cat# P-384-120SQ-CS), mixed, and then 5 μl of 10x compound solution was transferred to the cells using a Biomek FX / NX (384) liquid handler. Cells were then centrifuged at 100g for 1 minute in an Eppendorf 5810. The final DMSO concentration in the assay was 0.2%. All treatments were performed in technical and biological duplicates. Treated cells were incubated at 37°C in 5% CO2 for 72 hours. After 3 days of incubation, a CellTiter-Glo luminescent cell viability assay (Promega) was performed. Using a Biomek FX / NX (384) liquid handler, 10 μl of CellTiter-Glo (Promega, CAT# G7572) was added to the cells. The assay plate was centrifuged at 100 g for 1 minute, and the luminescent signal was measured using a microplate reader (CLARIOStar).

[0756] JPEG2026502173000297.jpg251170JPEG2026502173000298.jpg160170 equivalent

[0757] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed by the claims.< / d>

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: Ring G is a 5-10 membered monocyclic or bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S; R １ is C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １０ cycloalkyl, heterocycle, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, CN, NO ２ , OH, N(R ８ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclyl, aryl, heteroaryl, ３ -C １０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl is C １ -C ６ optionally substituted with one or more substituents independently selected from alkyl, halogen, OH, CN; R ２ is H, C １ -C ６ alkyl; R ３ is hydrogen, C １ -C ６ Alkyl, C ３ -C １０ cycloalkyl; R ４ is H, C １ -C ６ alkyl; R ５ is H, C １ -C ６ alkyl; Or, R ４ and R ５ together with the atoms to which they are attached and any intervening atoms, represent a halogen, C １ -C ６ Alkyl, and C １ -C ６ forming a 3- to 14-membered heterocycle optionally substituted with one or more substituents independently selected from alkoxy; R ６ is H, C １ -C ６ alkyl; Each R ７ is oxo, C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, heterocyclyl, -NH-heteroaryl, -(CH ２ ) ｍ -NH-C(O)-R ８ , -(CH ２ ) ｍ —C(O)NH—R ８ , -(CH ２ ) ｍ -C(O)NH-heteroaryl, -(CH ２ ) ｍ -S(O) ２ N-R ８ , -(CH ２ ) ｍ -S(O) ２ and N-heterocyclyl, wherein said alkyl, cycloalkyl, heterocyclyl or heteroaryl is independently selected from halogen, —CN, —OH, N(R ８ ) ２ , C １ -C ６ Alkyl, C １ -C ６ optionally substituted with one or more substituents independently selected from alkoxy, cycloalkyl; Each R ８ are independently H, C １ -C ６ Alkyl, C ３ -C １０ cycloalkyl; n is an integer selected from 0, 1, 2, and 3; m is an integer selected from 0, 1, and 2; Cycloalkyl is a mono- or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro) or 11-14 membered tricyclic ring system (fused, bridged, or spiro) having one or more heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C.

2. The compound has the formula (IA): 【Chemistry 2】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

3. The compound has the formula (IB): 【Transformation 3】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

4. The compound has the formula (IC): 【Chemistry 4】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

5. The compound has the formula (ID): 【Transformation 5】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

6. The compound has the formula (IE): 【Transformation 6】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

7. The compound is of formula (I-ABC): 【Transformation 7】 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein X is selected from N and O, Y is selected from N, O, and C, and 【change】 is a single or double bond, and the bond 【change】 is a single or double bond; provided that when X is N, 【change】 is a double bond, and the bond 【change】 is a single bond, and when X is O, 【change】 is a single bond, and the bond 【change】 is a double bond; optionally, R ７ two of which, together with the atoms to which they are attached and any intervening atoms, form one to three R ７ 10. The compound of claim 1, wherein R 1 is an optionally substituted aryl group, and R 2 is an optionally substituted aryl group, and all other variables are as defined herein.

8. The compound has the formula (I-DE): 【Transformation 8】 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein Z is selected from N and C, and optionally R ７ and two of, taken together with the atom to which they are attached and any intervening atoms, form an aryl, and all other variables are as defined herein.

9. A compound selected from: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

10. 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, and a pharmaceutically acceptable carrier.

11. 11. The pharmaceutical composition of claim 10, further comprising one or more additional pharmaceutically active agents.

12. 12. A method of inhibiting JAK2 in a cell, comprising contacting said cell with a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11.

13. 14. The method of claim 12 or 13, wherein the contacting is in vitro or in vivo.

14. A method for the treatment or prevention of a disease or disorder associated with JAK2, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 9, or a pharmaceutical composition according to claim 10 or 11.

15. The disease or disorder may be polycythemia vera; essential thrombocytosis; thrombocytosis 3; primary myelofibrosis; chronic myelomonocytic leukemia; acute myeloid leukemia; myelodysplasia; Budd-Chiari syndrome; Familial erythrocytosis 1 (ECYT1); Myeloproliferative neoplasms (MPD); Polycythemia; Acute lymphoblastic leukemia with lymphoma (LALL); Essential thrombocytosis (ET); Premature menopause; Thrombocytosis; Hypereosinophilic syndrome (HES); Splenomegaly; Acute leukemia; Thrombosis; Portal hypertension; Papilloma; Acquired polycythemia; Systemic mastocytosis (SMCD); Chronic myelomonocytic leukemia (CMML); Primary polycythemia; Hereditary neutrophilia (NEUTROPHILIA); Thrombosis; Leukemia; Blood cancers; myeloid anemia; erythroid leukemia; myeloid leukemia; antithrombin III deficiency (AT3D); severe congenital neutropenia; leukemia, chronic myeloid (CML); fibrosarcoma; mastocytosis; myelodysplastic syndrome (MDS); chronic eosinophilic leukemia; bone marrow cancer; Behcet's syndrome (BD); pancreatic adenocarcinoma; adenocarcinoma; stress polycythemia; B-cell lymphoma; myelodysplastic / myeloproliferative neoplasm; hemangioblastoma; atypical chronic myeloid leukemia, Bcr-Abl1 negative (ACML); chronic neutrophilic leukemia (CNL); gastrointestinal stromal tumor (GIST); beta-thalassemia (B-THAL); acquired von Willebrand syndrome (AVWS); splenic infarction; B-lymphoblastic leukemia / lymphoma, Bcr-Abl1-like; classical Hodgkin's lymphoma (CHL); Down's syndrome; Wernicke's encephalopathy; hepatic vasculopathy; primary mediastinal B-cell lymphoma; hyperglycemia; chronic lymphocytic leukemia (CLL); portal vein thrombosis; Diamond-Blackfan anemia (BDA); leptin deficiency or dysfunction Deficiency anemia; Hepatocellular carcinoma (HCC); Sm-Ahnmd; Acute lymphoblastic leukemia (ALL); Sagittal sinus thrombosis; Blood coagulation disorders; Acute erythroid leukemia; All symptoms 35 (IMD35); thrombocytopenia; colorectal cancer (CRC); platelet disease; temporal arteritis (GCA); congenital erythrocytopenia (CAMT); inflammatory bowel disease; venous disease; erythromelalgia; Familial erythrocytosis 2 (ECYT2); prostate cancer (PC); familial erythrocytosis 6 (ECYT6); aggressive systemic mastocytosis (ASM); myeloid and lymphoid neoplasms with pdgfra rearrangements; pancreatic cancer (PNCA); ovarian cancer (OC); juvenile myelomonocytic leukemia (JMML); breast cancer (BC); gastric cancer (GASC); medulloblastoma (MDB); familial non-Hodgkin's lymphoma (NHL); myocardial infarction ( 15. The method of claim 14, wherein the disease is selected from the group consisting of: MCI1); body mass index quantitative trait locus 11 (BMIQ11); acute salpingitis; autism spectrum disorder (ASD); esophageal cancer (ESCR); chronic lymphocytic leukemia (CLL); multiple myeloma (MM); essential hypertension (EHT); type 2 diabetes mellitus (T2D); skin diseases; rasopathy; connective tissue diseases; peripheral nervous system diseases; and nervous system diseases.

16. 15. The method of claim 14, wherein the disease or disorder is leukemia.

17. Leukemias include chronic myelomonocytic leukemia; acute myeloid leukemia; acute lymphoblastic leukemia with lymphomatous features (LALL); acute leukemia; chronic myelomonocytic leukemia (CMML); myeloid leukemia; chronic myelogenous leukemia (CML); chronic eosinophilic leukemia; atypical chronic myelogenous leukemia, Bcr-Abl1 negative (ACML); chronic neutrophilic leukemia ( 17. The method of claim 16, wherein the leukemia is selected from: Bcr-Abl1-like B lymphoblastic leukemia / lymphoma; chronic leukemia (CLL); Bcr-Abl1-like B lymphoblastic leukemia / lymphoma; chronic leukemia (CLL); deficiency anemia; hepatocellular carcinoma (HCC); Sm-Ahnmd; leukemia, acute lymphoblastic (ALL); acute erythroid leukemia; juvenile myelomonocytic leukemia (JMML); leukemia, chronic lymphocytic (CLL).

18. The method of any one of claims 12 to 17, wherein the subject is a mammal.

19. 20. The method of claim 18, wherein the subject is a human.

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