HK1196125B - Pyrazol-4-yl-heterocyclyl-carboxamide compounds and methods of use - Google Patents

Description

Pyrazol-4-yl-heterocyclyl-carboxamide compounds and methods of use

Technical Field

The present invention relates generally to pyrazol-4-yl-heterocyclyl-carboxamide compounds that are useful for treating diseases mediated by Pim kinase (Pim-1, Pim-2, and/or Pim-3) inhibitors, and thus are useful as cancer therapeutics. The invention also relates to compositions, more particularly, pharmaceutical compositions comprising these compounds and methods of using them, alone or in combination, for the treatment of various forms of cancer and hyperproliferative disorders, as well as methods of using these compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells or associated pathological conditions.

Background

Pim kinases are three highly related families of serine and threonine protein kinases encoded by the genes Pim-1, Pim-2 and Pim-3. The gene name is derived from the phrase moloney proviral insert (ProviralInsertion，Moloney), a common integration site for mouse moloney virus, wherein said insertion results in Pim kinase overexpression and a dramatic acceleration of new T-Cell lymphoma or tumorigenesis in a transgenic Myc-driven lymphoma model (Cuypers et al (1984) Cell,37(1) 141-50; selten et al (1985) EMBO J.4(7) 1793-8; van der Lugt et al (1995) EMBO J.14(11) 2536-44; mikkers et al (2002) Nature Genetics,32(1) 153-9; van Lohuizen et al (1991) Cell,65(5) 737-52). These experiments revealed a synergistic effect with the oncogene c-Myc and indicate that inhibition of Pim kinase may have therapeutic benefit.

Mouse genetics indicates that antagonism of Pim kinase may have acceptable safety profiles; pim 1-/-; pim-2-/-, Pim-3-/-mouse gene knockouts are viable, although slightly smaller than wild-type littermates (Mikkers et al (2004) Molcell Biol24(13) 6104-154). The three genes produce six protein isoforms that contain a protein kinase domain and are apparently devoid of recognizable regulatory domains. All six isoforms are constitutively active protein kinases, which do not require post-translational modification of activity, and thus Pim kinases are predominantly regulated at the transcriptional level (Qian et al (2005) J Biol Chem,280(7) 6130-7). Pim kinase expression is highly inducible by cytokines and growth factor receptors, and Pim is a direct transcriptional target of Stat proteins, including Stat3 and Stat 5. For example, Pim-1 is required for gp 130-mediated Stat3 proliferation signaling (Aksoy et al (2007) Stem Cells,25(12) 2996-3004; Hirano et al (2000) Oncogene19(21) 2548-56; Shirogane et al (1999) Immunity11(6) 709-19).

Pim kinase acts parallel to the PI3k/Akt/mTOR signaling axis in cell proliferation and survival pathways (Hammerman et al (2005) Blood105(11) 4477-83). In fact, several phosphorylation targets of the PI3k axis, including Bad and eIF4E-BP1, are Cell growth and apoptosis regulators, and also phosphorylation targets of Pim kinase (Fox et al (2003) Genes Dev17(15) 1841-54; Macdonald et al (2006) Cell Biol 71; Aho et al (2004) FEBSletters571(1-3) 43-9; Tamburini et al (2009) Blood114(8) 1618-27). Pim kinase can affect cell survival, as phosphorylation of Bad increases Bcl-2 activity and thus promotes cell survival. Likewise, phosphorylation of eIF4E-BP1 by mTOR or Pim kinase results in inhibition of eIF4E, thereby promoting mRNA translation and cell growth. In addition, Pim-1 has been shown to promote Cell cycle progression by phosphorylating CDC25A, p21 and Cdc25C (Mochizuki et al (1999) J Biol Chem274(26) 18659-66; Bachmann et al (2006) Int J Biochem Cell Biol38(3) 430-43; Wang et al (2002) Biochim Biophys Acta1593(1) 45-55).

Pim kinase showed synergy with c-Myc-driven and Akt-driven tumors in transgenic mouse models (Verbeek et al (1991) Mol Cell Biol11(2) 1176-9; Allen et al Oncogene (1997)15(10) 1133-41; Hammerman et al (2005) Blood105(11) 4477-83). Pim kinase is involved in the transforming activity of oncogenes recognized in Acute Myeloid Leukemia (AML), including Flt3-ITD, BCR-abl and Tel-Jak 2. Expression of these oncogenes in BaF3 cells leads to upregulation of Pim-1 and Pim-2 expression, leading to IL-3 independent growth, and subsequent Pim inhibition leads to apoptosis and cell growth arrest (Adam et al (2006) Cancer Research66(7) 3828-35). Pim overexpression and dysregulation has also been noted as a frequent event in many hematopoietic cancers, including leukemias and lymphomas (Amson et al (1989) Proc Natl Acad Sci USA86(22) 8857-61); cohen et al (2004) Leuk Lymphoma45(5) 951-5; huttmann et al (2006) Leukemia20(10)1774-82) and multiple myeloma (Claudio et al (2002) Blood100(6) 2175-86). Pim1 has been shown to be overexpressed and associated with prostate cancer progression (Cibull et al (2006) JClin Pathol59(3) 285-8; Dhanasekaran et al (2001) Nature412(6849) 822-6). In the mouse model, Pim1 expression increased as the disease progressed (Kim et al (2002) Proc Natl Acad Sci USA99(5) 2884-9). Pim-1 was reported to be the most highly overexpressed mRNA in a subset of human prostate tumor samples with c-Myc driven gene signatures (Ellwood-Yen et al (2003) Cancer Cell4(3) 223-38). Pim-3 has also been shown to be overexpressed and functional in pancreatic and hepatocellular carcinomas (Li et al (2006) Cancer Research66(13) 6741-7; Fujii et al (2005) Int J Cancer,114(2) 209-18).

In addition to oncological therapeutic and diagnostic applications, Pim kinases can play an important role in normal immune system function, and Pim inhibition can have therapeutic roles for a number of different immunopathologies, including tumorigenesis (Nawijn et al (2011) Nature rev.11:23-34), inflammation, autoimmune disorders, allergy, and immunosuppression for organ transplantation (ahoe. al., (2005) Immunology116(1) 82-8).

Disclosure of Invention

The present invention relates to pyrazol-4-yl-heterocyclyl-carboxamide compounds, compounds of formula I, for the treatment of diseases mediated by Pim kinase (Pim-1, Pim-2 and/or Pim-3) inhibitors.

The compounds of formula I have the following structure:

wherein R is²Selected from the following structures:

wherein the wavy line represents the attachment site and the dashed line represents an optional double bond;

x is selected from the following structures:

and stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof. Each substituent including R¹、R²、R³、R⁴、R⁵、R⁶、R⁷And X are both as defined herein.

One aspect of the present invention is a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, glidant, diluent, or excipient. The pharmaceutical composition may further comprise a chemotherapeutic agent.

The invention includes a method of treating a disease or disorder comprising administering to a patient having a disease or disorder selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, and diseases or disorders mediated by Pim kinase, a therapeutically effective amount of a compound of formula I. The method further comprises administering an additional therapeutic agent selected from the group consisting of chemotherapeutic agents, anti-inflammatory agents, immunomodulatory agents, neurotropic factors, drugs for treating cardiovascular diseases, drugs for treating liver diseases, antiviral agents, drugs for treating blood disorders, drugs for treating diabetes, and drugs for treating immunodeficiency disorders.

The invention also encompasses the use of a compound of formula I in the manufacture of a medicament for the treatment of cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, wherein said medicament mediates Pim kinase.

The present invention includes a kit for treating a condition mediated by Pim kinase, comprising: a) a first pharmaceutical composition comprising a compound of formula I; and b) instructions for use.

The invention encompasses compounds of formula I for use as medicaments and for the treatment of diseases or disorders selected from the group consisting of cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, and diseases or disorders mediated by Pim kinase.

The invention includes a process for preparing a compound of formula I.

Drawings

FIG. 1 shows a schematic synthesis of 4-aminopyrazole compound 5 from nitro-1H-pyrazole 1.

FIG. 2 shows a schematic synthesis of 4-carboxy-thiazole 11 from hydroxyamide (hydroxamide) compound 6.

FIG. 3 shows a schematic synthesis of 2-substituted 4-carboxy-5-aminothiazole 11 by C-2 bromination 12 followed by the Suzuki reaction on 13.

FIG. 4 shows a schematic synthesis for the preparation of 5-azepanyl-N- (pyrazol-4-yl) thiazole-carboxamide compound 17 from the coupling of 4-amino, 5-azepanyl pyrazole compound 14 and 2-bromo, 4-carboxy-5-aminothiazole 11.

FIG. 5 shows a schematic synthesis for the preparation of 6-amino-N- (pyrazol-4-yl) pyridinyl-carboxamide compound 21 from the coupling of 4-amino, 5-azepanylpyrazole compound 14 and 2-bromo, 3-Boc-amino, 6-carboxy-pyridinyl compound 18.

FIG. 6 shows a coupling scheme for the synthesis of 6-amino-N- (pyrazol-4-yl) pyrazine-carboxamide compound 26 by coupling 4-amino, 5-diazepanyl pyrazole compound 22 and 2-bromo, 3-substituted, 6-carboxy-5-aminopyrazinyl compound 23.

FIG. 7 shows a schematic synthesis of 5-azido- (4-nitro-1H-pyrazol-5-yl) azepane 32 from 2,3,6, 7-tetrahydro-1H-azepine 27.

FIG. 8 shows a schematic synthesis of 5-Boc-amino- (4-nitro-1H-pyrazol-5-yl) azepane 39 from 6, 7-dihydro-1H-azepin-3 (2H) -one 33.

FIG. 9 shows a schematic synthesis of 5- (4-azido-1-fluorocycloheptyl) -4-nitro-1H-pyrazole 45 from 4-nitro-1H-pyrazole 2.

FIG. 10 shows a schematic synthesis of 3-fluoro-1- (4-nitro-1H-pyrazol-5-yl) azepan-4-amine 52 from 5-chloro-4-nitro-1H-pyrazole 3.

Detailed Description

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that the invention is not limited to these embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the cited documents, patents, and similar materials differ or contradict this application (including but not limited to defined terms, usage of terms, described techniques, etc.), this application controls.

Unless defined otherwise, 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 application belongs. Although methods and materials equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other documents referred to in this application are incorporated by reference herein in their entirety. The nomenclature used herein is based on the IUPAC systematic nomenclature, unless otherwise indicated.

Definition of

The term "one or more" when referring to the number of substituents refers to the range from one substituent to the highest possible number of substituents, i.e., one hydrogen is replaced by a substituent to all hydrogens. The term "substituent" means an atom, or group of atoms, that replaces a hydrogen atom on a parent molecule. The term "(substituted)" means that the specified group carries one or more substituents. While any group may carry multiple substituents and provide a variety of possible substituents, each substituent is independently selected and need not be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from the set of possible substituents. The term "one or more" when referring to the number of substituents refers to the range from one substituent to the highest possible number of substituents, i.e., one hydrogen is replaced by a substituent to all hydrogens.

The term "alkyl" as used herein refers to a compound having 1 to 12 carbon atoms (C)₁-C₁₂) Wherein the alkyl group may be optionally independently substituted with one or more substituents described below. In another embodiment, alkyl is 1 to 8 carbon atoms (C)₁-C₈) Or 1 to 6 carbon atoms (C)₁-C₆). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et-CH)₂CH₃) 1-propyl (n-Pr), n-propyl (n-propyl), -CH₂CH₂CH₃) 2-propyl (i-Pr), isopropyl (i-propyl), -CH (CH)₃)₂) 1-butyl (n-Bu), n-butyl (n-butyl), -CH₂CH₂CH₂CH₃) 2-methyl-1-propyl (isobutyl (i-Bu), isobutyl (i-butyl)), -CH₂CH(CH₃)₂) 2-butyl (s-butyl), sec-butyl (s-butyl), -CH (CH)₃)CH₂CH₃) 2-methyl-2-propyl (t-butyl (t-Bu), t-butyl (t-butyl)), -C (CH)₃)₃) 1-pentyl (n-pentyl, -CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-C)H₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) 1-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂)2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂)3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) 1-heptyl, 1-octyl, and the like.

The term "alkylene" as used herein refers to a group having 1 to 12 carbon atoms (C)₁-C₁₂) Wherein the alkylene group may be optionally independently substituted with one or more substituents described below. In another embodiment, the alkylene has one to eight carbon atoms (C)₁-C₈) Or one to six carbon atoms (C)₁-C₆). Examples of alkylene groups include, but are not limited to, methylene (-CH)₂-) ethylene (-CH₂CH₂-) propylene (-CH)₂CH₂CH₂-) and the like.

The term "alkenyl" refers to a group having 2 to 8 carbon atoms (C)₂-C₈) And having at least one site of unsaturation, i.e., a carbon-carbon sp²A double bond, wherein said alkenyl group may be optionally independently substituted with one or more substituents described herein and includes groups having "cis" and "trans" orientations (or "E" and "Z" orientations). Examples of the inventionIncluding but not limited to vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) And the like.

The term "alkenylene" refers to a compound having 2-8 carbon atoms (C)₂-C₈) And having at least one site of unsaturation, i.e., a carbon-carbon sp²A double bond, wherein said alkenylene group may be optionally independently substituted with one or more substituents described herein and includes groups having "cis" and "trans" orientations (or "E" and "Z" orientations). Examples include, but are not limited to, ethenylene (-CH-), allylene (-CH)₂CH-) and the like.

The term "alkynyl" refers to a compound having 2-8 carbon atoms (C)₂-C₈) And a straight or branched monovalent hydrocarbon group having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein said alkynyl group may be optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C ≡ CH), propynyl (propargyl, -CH)₂C.ident.CH) and the like.

The term "alkynylene" refers to a compound having 2-8 carbon atoms (C)₂-C₈) And a straight or branched chain divalent hydrocarbon radical having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein said alkynylene radical may be optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, ethynylene (-C ≡ C-), propynyl (propargylene, -CH)₂C.ident.C-), and the like.

The terms "carbocycle", "carbocyclyl", "carbocycle", and cycloalkyl "refer to a compound having 3 to 12 carbon atoms (C)₃-C₁₂) Monovalent non-aromatic saturated or partially unsaturated rings in the form of a single ring or in the form of a ring having 7 to 12 carbon atoms. Bicyclic carbocycles having 7 to 12 atoms may be arranged, for example, as bicyclo [4, 5]]System, bicyclo [5, 5]]System, bicyclo [5,6 ]]Systems or bicyclo [6,6 ]]Bicyclic carbocycles of a system and having 9 or 10 ring atoms may be arranged as a bicyclo [5,6 ]]Systems or bicyclo [6,6 ]]Systems or arrangements for bridging systems such as bicyclo [2.2.1]Heptane, ethyl acetate,Bicyclo [2.2.2]Octane and bicyclo [3.2.2]Nonane. Spiro moieties are also included within the scope of the invention. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-1-en-1-yl, cyclopent-2-en-1-yl, cyclopent-3-en-1-yl, cyclohexyl, cyclohex-1-en-1-yl, cyclohex-2-en-1-yl, cyclohex-3-en-1-yl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Carbocyclyl is optionally independently substituted with one or more substituents described herein.

"aryl" means having 6 to 20 carbon atoms (C)₆-C₂₀) A monovalent aromatic hydrocarbon group of (a), which is obtained by: one hydrogen atom is removed from one carbon atom in the parent aromatic ring system. Some aryl groups are represented in the exemplary structures as "Ar". Aryl includes bicyclic groups containing an aromatic ring fused to a saturated, partially unsaturated, or aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, groups derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, biphenyl (biphenyl), indene (indenyl), indan (indanyl), 1, 2-dihydronaphthalene, 1,2,3, 4-tetrahydronaphthalene (1,2,3, 4-tetrahydronaphthyl), and the like. Aryl groups may be optionally substituted independently with one or more substituents described herein.

"arylene" means having 6 to 20 carbon atoms (C)₆-C₂₀) A divalent aromatic hydrocarbon group of (a), which is obtained by: two hydrogen atoms are removed from two carbon atoms in the parent aromatic ring system. Some arylene groups are represented as "Ar" in the exemplary structures. Arylene includes bicyclic groups containing an aromatic ring fused to a saturated, partially unsaturated, or aromatic carbocyclic ring. Typical arylene groups include, but are not limited to, groups derived from benzene (phenylene), substituted benzenes, naphthalene, anthracene, biphenyl (biphenylene), indene (indenylene), indane (indanylene), 1, 2-dihydronaphthalene, 1,2,3, 4-tetrahydronaphthalene (1,2,3, 4-tetrahydronaphthalene subunit), and the like. The arylene group can be optionally substituted with one or more substituents described herein.

The terms "heterocycle (heterocyclic)", "heterocyclyl (heterocyclic)" and "heterocyclic" are used in this application to describe the heterocyclic ring and the heterocyclic ring of each otherUsed interchangeably and refers to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds in the ring) carbocyclic group of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, wherein one or more ring atoms are optionally independently substituted with one or more substituents described below. The heterocycle may be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P and S) or a bicyclic ring (e.g., bicyclo [4, 5] having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P and S)]System, bicyclo [5, 5]]System, bicyclo [5,6 ]]Systems or bicyclo [6,6 ]]A system). Heterocycles are described in Paquette, leoa.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York,1968) (in particular chapters 1,3, 4,6, 7 and 9); "The Chemistry of Heterocyclic Compounds, A series of monograms" (John Wiley&Sons, New York,1950to present) (especially volumes 13, 14, 16, 19 and 28); and J.am.chem.Soc. (1960)82: 5566. "Heterocyclyl" also includes groups in which a heterocyclyl group is fused to a saturated ring, a partially unsaturated ring, an aromatic carbocyclic ring, or an aromatic heterocyclic ring. Examples of heterocycles include, but are not limited to, morpholin-4-yl, piperidin-1-yl, piperazinyl, 2-oxo-piperazin-4-yl, 3-oxo-piperazin-4-yl, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azetidin-1-yl, octahydropyrido [1,2-a ] base]Pyrazin-2-yl, [1,4 ]]Diazepan-1-yl, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thiexacyclohexyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxaazazepanylRadical diazaThio-aza radicalA group, 2-pyrrolinyl group, 3-pyrrolinyl group, indolinyl group, 2H-pyranyl group, 4H-pyranyl group, dioxanyl group, 1, 3-dioxolanyl group, pyrazolinyl group, dithiacyclohexyl group, dithiocyclopentyl group, dihydropyranyl group, dihydrothienyl group, dihydrofuryl group, pyrazolidinyl group, imidazolinyl group, imidazolidinyl group, 3-azabicyclo [3.1.0] group]Hexyl, 3-azabicyclo [4.1.0]Heptyl, azabicyclo [2.2.2]Hexyl, 3H-indolyl, quinolizinyl and N-pyridylurea groups. Spirocyclic moieties are also included within the scope of this definition. Examples of heterocyclyl groups in which 2 ring atoms are substituted with an oxo (═ O) moiety are pyrimidinone groups and 1, 1-dioxo-thiomorpholinyl groups. The heterocyclyl groups of the present application are optionally independently substituted with one or more substituents described herein.

The term "heteroaryl" refers to a monovalent aromatic group in the form of a 5,6 or 7 membered ring containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur and includes fused ring systems (wherein at least one ring is aromatic) having 5 to 20 atoms. Examples of heteroaryl groups are pyridyl (including, for example, 2-hydroxypyridyl), imidazolyl, imidazopyridyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups are optionally independently substituted with one or more substituents described herein.

The heterocyclyl or heteroaryl group may be attached via carbon or via nitrogen, where applicable. For example, and without limitation, a carbon-linked heterocyclyl or heteroaryl group is attached at the following positions: 2,3,4, 5 or 6 position of pyridine; the 3,4, 5 or 6 position of pyridazine; 2,4, 5 or 6 positions of pyrimidine; 2,3, 5 or 6 position of pyrazine; 2,3,4 or 5 positions of furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole; 2,4 or 5 position of oxazole, imidazole or thiazole; the 3,4 or 5 position of isoxazole, pyrazole or isothiazole; 2 or 3 position of aziridine; the 2,3 or 4 position of azetidine; 2,3,4, 5,6, 7 or 8 positions of quinoline; or 1,3, 4,5, 6,7 or 8 positions of isoquinoline.

For example, but not limited to, a nitrogen-linked heterocyclyl or heteroaryl group is linked at the 1-position of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, or 1H-indazole; attached at the 2-position of isoindoline or isoindoline; attached at the 4-position of morpholine; and at the 9-position of the carbazole or β -carboline.

The term "treatment" refers to both therapeutic treatment and prophylactic measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (i.e., not worsening) of the disease state, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "treatment" may also mean an extended survival compared to the expected survival without treatment. Those in need of treatment include those already with the condition or disorder as well as those susceptible to the condition or disorder or those in which the condition or disorder is to be prevented.

The phrase "therapeutically effective amount" means (i) the amount of a compound of the present invention that treats or prevents the particular disease, condition, or disorder described herein; (ii) an amount of a compound of the invention that attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder described herein; or (iii) an amount of a compound of the invention that prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. For cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and/or relieve to some extent one or more symptoms associated with cancer. The drug may be cytostatic and/or cytotoxic if it can prevent the growth of cancer cells and/or kill existing cancer cells. For cancer treatment, efficacy can be measured, for example, by assessing time to disease progression (TTP) and/or determining Response Rate (RR).

The term "cancer" refers to or describes the physiological state in mammals that is typically characterized by dysregulated cell growth. A "tumor" includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of the above cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma); lung cancer, including small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung, and squamous carcinoma of the lung; peritoneal cancer; hepatocellular carcinoma; gastric or gastric cancer, including gastrointestinal cancer; pancreatic cancer; a glioblastoma; cervical cancer; ovarian cancer; liver cancer; bladder cancer; liver cancer; breast cancer; colon cancer; rectal cancer; colorectal cancer; endometrial or uterine cancer; salivary gland cancer; kidney cancer or renal cancer; prostate cancer; vulvar cancer; thyroid cancer; liver cancer; anal cancer; penile cancer; and head and neck cancer.

A "chemotherapeutic agent" is a compound useful in the treatment of cancer, regardless of the mechanism of action. Classes of chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolites, spindle toxic plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in "targeted therapy" and conventional chemotherapy. Examples of chemotherapeutic agents include erlotinib (erlotinib) (ll:)Genentech/OSI Pharm.), docetaxel (docetaxel)Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS No.51-21-8), gemcitabine (gemcitabine) (Lilly), PD-0325901(CAS No.391210-10-9, Pfizer), cisplatin (cisclinin) (cis-diamineplatinum (II) dichloride, CAS No.15663-27-1), carboplatin (CAS No.41575-94-4), paclitaxel (paclitaxel), (paclitaxel)Bristol-Myers Squibb Oncology, Princeton, N.J.), trastuzumab (trastuzumab) ((R)Genentech), temozolomide (temozolomide) (4-methyl-5-oxo-2, 3,4,6, 8-pentaazabicyclo [4.3.0 ]]Nonane-2, 7, 9-triene-9-carboxamide, CAS No.85622-93-1,schering Plough), tamoxifen ((Z) -2- [4- (1, 2-diphenylbut-1-enyl) phenoxy]-N, N-dimethylethylamine,) Doxorubicin (doxorubicin) ((d))) Akti-1/2, HPPD and rapamycin (rapamycin).

Other examples of chemotherapeutic agents include oxaliplatin (oxaliplatin) ((a))Sanofi), bortezomib (bortezomib), (b), (d), (Millennium Pharm.), sunitinib (sutent), (a mixture of them)SU11248, Pfizer), letrozole (letrozole), (L-Toxole)Novartis), imatinib mesylate (imatinib mesylate), (I) and (II) a pharmaceutically acceptable salt thereofNovartis), XL-518(MEK inhibitor, Exelixis, WO2007/044515), ARRY-886(MEK inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126(PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235(PI3K inhibitor, Novartis), XL-147(PI3K inhibitor, Exelixis), PTK787/ZK222584(Novartis), fulvestrant (fulvestrant) ((fulvestrant)AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus),wyeth), rapamycin analogues, mTOR inhibitors such as everolimus (everolimus), MEK inhibitors (GDC-0973), Bcl-2 inhibitors such as navitoclax (ABT-263) or ABT-199), lapatinib (lapatinib) ((Lapatinib)GSK572016,Glaxo Smith Kline)、lonafarnib(SARASAR^TMSCH66336, Schering Plough), Sorafenib (sorafenib) ((Schering Plough)BAY43-9006, Bayer Labs), gefitinib (gefitinib) ((B)AstraZeneca) Irinotecan (irinotecan) ((R))CPT-11,Pfizer)、tipifarnib(ZARNESTRA^TM,Johnson&Johnson)、ABRAXANE^TM(without Cremophor), albumin engineered nanoparticle formulations of paclitaxel (American pharmaceutical Partners, Schaumberg, Il), vandetanib (rINN, ZD6474,AstraZeneca), chlorambucil (chlorambucil), AG1478, AG1571(SU 5271; sugen), temsirolimus (Wyeth)、pazopanib(GlaxoSmithKline)、canfosfamide(Telik), thiotepa and cyclophosphamide (cyclophosphamide) ((Telik)) (ii) a Alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimine (ethylenimine) and methylaminoacridine (methyamelamine) groups including hexamethylmelamine (altretamine), triimizine (triethyleneamine), triethylenephosphoramide (triethylenephosphoramide), triethylenephosphoramide (triethylenethiophosphonamide), and trimethylomelamine; annonaceous acetogenins (especially bullatacin and bullatacin); camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin (adozelesin), carvelesin (carzelesin), and bizelesin (bizelesin) synthetic analogs); cryptophycins (especially cryptophycin1 and cryptophycin 8); dolastatin (dolastatin); duocarmycins (including the synthetic analogs KW-2189 and CB)1-TM 1); eiscosahol (eleutherobin); pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil (chlorambucil), chlorambucil (chlorenaphazine), chlorophosphamide (chlorophosphamide), estramustine (estramustine), ifosfamide (ifosfamide), mechlorethamine (mechlorethamine), mechlorethamine hydrochloride (mechlorethamine hydrochloride), melphalan (melphalan), neomustard (novembichin), benzene mustard cholesterol (pherenester), prednimustine (prednimustine), trofosfamide (trofosfamide), and uramustine (uracil mustard); nitroureas such as carmustine (carmustine), chlorouretocin (chlorozotocin), fotemustine (fotemustine), lomustine (lomustine), nimustine (nimustine) and ramustine (ranirnustine); antibiotics such as enediyne (enediyne) antibiotics (e.g., calicheamicin, including calicheamicin γ 1I and calicheamicin ω I1(Angew chem. intel. ed. Engl. (1994)33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; esperamicin (esperamicin), neooncostatin chromophore (neocarzinostatin chromophore) and related chromoprotein enediyne chromophore (related chromoprotein enediyne) antibiotics chromophore, aclacinomycin, carminomycin (acinomycin), actinomycin (actinomycin), carminomycin (carminomycin), actinomycin (carmycin), carminomycin (carminomycin), carminomycin (5-erythromycin), erythromycin (monocrotamycin-5), gentamycin (monocrotamycin-5-6), gentamycin (monocrotamycin), erythromycin (monocrotamycin-5-6), monocrotamycin (monocrotamycin-5-D), monocrotamycin (monocrotamycin-6-5), monocrotamycin (monocrotamycin-6-D), monocrotamycin (monocrotamycin-5-D), monocrotamycin (monocrotamycin, monocrotamycin-5-D), monocrotamycin (monocrotamycin-6-D), monocrotamycin (monocrotamycin-2-D), and a, Morpholino-doxorubicin (morpholino-doxorubicin), cyanomorpholino-doxorubicin (cyanomorpholo-doxorubicin), 2-pyrrolidino-doxorubicin (2-pyrrolino-doxorubicin), deoxydoxorubicin (deoxydoxorubicin), epirubicin (epirubicin), esorubicin (esorubicin), idarubicin (idarubicin), nemorubicin (nemorubicin), marijumycin (nemorubicin), mariomycin (marilomycin), mitomycin (mitomycin) classes such as mitomycin C (mitomycin C), mycophenolic acid (mycophenolic acid), norramycin (nogalamycin), olivomycin (olivomycin), peimineOxytetracycline (peplomycin), pofiomycin (porfiromycin), puromycin (puromycin), triiron doxorubicin (quelemycin), rodobicin (rodorubicin), streptonigrin (streptonigrin), streptozocin (streptozocin), tubercidin (tubicidin), ubenimex (ubenimex), azistin (zinostatin), and zorubicin (zorubicin); antimetabolites such as methotrexate (methotrexate) and 5-fluorouracil (5-fluorouracil) (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin and trimetrexate; purine analogs such as fludarabine (fludarabine), 6-mercaptopurine (6-mercaptopurine), thiamiprine (thiamiprine), and thioguanine (thioguanine); pyrimidine analogs such as ancitabine (ancitabine), azacitidine (azacitidine), 6-azauridine (6-azauridine), carmofur (carmofur), cytarabine (cytarabine), dideoxyuridine (dideoxyuridine), doxifluridine (doxifluridine), enocitabine (enocitabine), and floxuridine (floxuridine); androgens such as carposterone (calusterone), methyl androsterone propionate (dromostanolone propionate), epitioandrostanol (epitiostanol), mepiquitane (mepiquitane), and testolactone (testolactone); anti-adrenergic agents (anti-adrenals), such as aminoglutethimide, mitotane and trilostane; folic acid supplements such as folinic acid (frilic acid); acetoglucurolactone (acegultone); (ii) an aldophosphamide glycoside; aminolevulinic acid (aminolevulinic acid); eniluracil (eniluracil); amsacrine (amsacrine); bestrabuucil; bisantrene; idazot (edatraxate); desphosphamide (defofamine); colchicine (demecolcine); diazaquinone (diaziqutone); elfornitine; ammonium etitanium acetate; epothilone (epothilone); etoglut (etoglucid); gallium nitrate (gallium nitrate); hydroxyurea (hydroxyurea); lentinan (lentinan); lonidamine (lonidainine); maytansinol (maytansinoid) classes such as maytansinoid (maytansine) and ansamitocins (ansamitocins); mitoguazone (mitoguzone); mitoxantrone (mitoxantrone); mopidanmol; rhizobia (nitrarine); pentostatin (pentostatin); methionine mustard (phenamett); birou BianStar (pirarubicin); losoxantrone (losoxantrone); podophyllinic acid (podophyllic acid); 2-ethylhydrazine (2-ethylhydrazine); procarbazine (procarbazine);polysaccharide complex (A), (B)polysaccharidermplex) (JHS Natural Products, Eugene, OR); razoxane (rizoxane); rhizomycin (rhizoxin); sizofuran (sizofiran); germanium spiroamines (spirogyranium); tenuazonic acid (tenuazonic acid); triimine quinone (triaziquone); 2,2 ', 2' -trichlorotriethylamine (2,2 ', 2' -trichlorotriethylamine); trichothecenes (trichothecenes) (especially T-2 toxin, veracurin A, bacillocin A (roridin A) and anguidine); urethane (urethan); vindesine (vindesine); dacarbazine (dacarbazine); mannomustine (mannomustine); dibromomannitol (mitobronitol); dibromodulcitol (mitolactol); pipobromane (pipobroman); a polycytidysine; cytarabine (arabine) ("Ara-C"); cyclophosphamide; thiotepa; 6-thioguanine (6-thioguanine); mercaptopurine (mercaptoprine); methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine (vinblastine); etoposide (VP-16); ifosfamide; mitoxantrone (mitoxantrone); vincristine (vincristine); vinorelbine (vinorelbine) ((vinorelbine))) (ii) a Norfloxacin (novantrone); teniposide (teniposide); idazocide (edatrexate); daunorubicin (daunomycin); aminopterin (aminopterin); capecitabine (capecitabine) (capecitabine)Roche); ibandronate (ibandronate); CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids (retinoids), such as retinoic acid (retinocacid); and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

The following are also included in the definition of "chemotherapeutic agents": (i) anti-hormonal agents such as anti-estrogens (anti-estrogen) and Selective Estrogen Receptor Modulators (SERMs) including, for example, tamoxifen (includingTamoxifen citrate), raloxifene (raloxifene), droloxifene (droloxifene), 4-hydroxytamoxifen (4-hydroxytamoxifen), trioxifene (trioxifene), raloxifene (ketoxifene), LY117018, onapristone (onapristone), and(toremifene citrate); (ii) aromatase inhibitors which inhibit aromatase (aromatase regulates the production of estrogen in the adrenal gland), such as 4(5) -imidazoles, aminoglutethimide,(megestrol acetate)) (megestrol acetate),(exemestane; Pfizer), formestanie, fadrozole,(vorozole) and (C) a salt thereof,(letrozole; Novartis) and(anastrozole; AstraZeneca); (iii) anti-androgens (anti-androgens) such as flutamide (flutamide), nilutamide (nilutamide), bicalutamide (bicalutamide), leuprolide (leuprolide) and goserelin (goserelin), and troxacitabine (troxacitabine) (1,3-dioxolane nucleoside cytosine)Analogs (1, 3-dioxolone nucleotide analogs)), (iv) protein kinase inhibitors such as MEK inhibitors (WO2007/044515), (v) lipid kinase inhibitors, (vi) antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways involved in abnormal cell proliferation, e.g., PKC- α, Ralf, and H-Ras, such as oblimersen (R) ((R))Genta Inc.); (vii) ribozymes, such as VEGF expression inhibitors (e.g.) And inhibitors of HER2 expression; (viii) vaccines, such as gene therapy vaccines, e.g.AndrIL-2; topoisomerase 1 inhibitors, such asAndrmRH; (ix) anti-angiogenic agents, such as bevacizumab (bevacizumab) ((r))Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

Therapeutic antibodies are also included in the definition of "chemotherapeutic agents," such as alemtuzumab (alemtuzumab) ((r))) Bevacizumab (b), (c), (d), (Genentech); cetuximab (Imclone); palimumab (panitumumab) (panitumumab)Amgen), rituximab (Genentech/Biogen Idec), pertuzumab (OMNITARG)^TM2C4, Genentech), trastuzumab (Genentech), tositumomab (tositumomab) (Bexxar, Corixia, GlaxoSmithKline).

Humanized monoclonal antibodies that have therapeutic potential as chemotherapeutic agents for use in combination with the compounds of formula I of the present invention include alemtuzumab (alemtuzumab), aprezumab (apilizumab), alemtuzumab (aselizumab), atlizumab (atlizumab), bapineuzumab, bevacizumab, mabuzumab (bivatuzumab mertansine), moccantuzumab (cantuzumab mertansine), cetirizumab (cedelizumab), cetuximab (cetuzumab), certolizumab pegol (certolizumab pegol), cidfutuzumab (ciduzumab), daclizumab (daclizumab), eculizumab (eculizumab), efalizumab (efalizumab), epratuzumab (epuzumab), riluzumab (erlitumumab), panlizumab (fevinuzumab), arylpertuzumab (rituximab), polalizumab (ectuzumab), tumumab (epituzumab (rituzumab), rituzumab (rituximab), rituximab (rituximab), rituximab (aleb), rituximab (ale, Palivizumab (palivizumab), paclobuzumab (paclobuzumab), pecluzumab (pecluzumab), pertuzumab (petuzumab), pevizumab (pexelizumab), ralvizumab (ranibizumab), rayleigh mab (relivizumab), resyvizumab (roveluzumab), lulitumumab (ruplizumab), sibutrumab (sibutrumab), sibirizumab (sibilizumab), solurizumab (soluzumab), tatuzumab (tacatuzumab), taduzumab (taltuzumab tetraxetan), talucizumab (taluzumab), teluzumab (tebazumab), tuzumab (tocuzumab), tositumumab (tollizumab), tralizumab (toralizumab), trolizumab (taclizumab), trastuzumab (toralizumab), paclobuzumab (tuzumab), and wuxizumab (wuxituzumab).

A "metabolite" is a product produced by the in vivo metabolism of a particular compound or salt thereof. Metabolites of compounds can be identified using conventional techniques known in the art and their activity can be determined using the assays described herein. Such products may be derived, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method comprising contacting a compound of formula I of the present invention with a mammal for a period of time sufficient to produce a metabolite thereof.

The term "package insert" refers to instructions typically included in commercial packages of therapeutic products that contain information regarding the indications, usage, dosage, administration, contraindications, and/or precautions relating to the use of the therapeutic products described above.

The term "chiral" refers to a molecule that has a mirror image partner (mirror image partner) non-superimposability, while the term "achiral" refers to a molecule that can be superimposed with its mirror image partner.

The term "stereoisomers" refers to compounds having the same chemical composition but differing in the spatial arrangement of the atoms or groups.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography.

"enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

The stereochemical definitions and general knowledge used herein generally correspond to those of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. The present invention is intended to include all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers (atropisomers), and mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active form, i.e. they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l or (+) and (-) designate the symbols by which the compound rotates plane polarized light, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers and mixtures of the above isomers are often referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when a chemical reaction or process is not stereoselective or stereospecific. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, which are not optically active. Enantiomers can be separated from racemic mixtures by chiral separation methods such as supercritical liquid chromatography (SFC). The conformation of the separated enantiomers at the chiral center can be tentatively assigned and depicted in the table 1 structure for explanatory purposes while awaiting stereochemical determinations, such as X-ray crystallographic data.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert through a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.

The term "pharmaceutically acceptable salt" denotes a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include the addition salts and the base addition salts. The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith.

The term "pharmaceutically acceptable acid addition salts" denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, or organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic and sulfonic organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, methylenepamoic acid (embonic acid), phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

The term "pharmaceutically acceptable base addition salts" denotes those pharmaceutically acceptable salts formed with organic or inorganic bases. Acceptable inorganic bases include salts of sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, magnesium, and aluminum. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines, cyclic amines and basic ion exchange resins) such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine and polyamine resins.

"solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

The term "EC₅₀"refers to the half maximal effective concentration and refers to the plasma concentration of the particular compound required to achieve 50% of the maximal specific effect in vivo.

The term "Ki" is an inhibition constant and denotes the absolute binding affinity of a particular inhibitor to a receptor. It is measured using a competitive binding assay and is equal to the concentration at which a particular inhibitor occupies 50% of the receptors in the absence of a competitive ligand (e.g., a radioligand). Ki values can be logarithmically converted to pKi values (-log Ki), with higher values indicating exponentially greater potential.

The term "IC₅₀"is the half maximal inhibitory concentration and refers to the concentration of a particular compound required to obtain 50% inhibition of a biological process in vitro. IC (integrated circuit)₅₀The values can be logarithmically converted to pIC₅₀Value (-log IC)₅₀) Where a larger value indicates a larger potential exponentially. IC (integrated circuit)₅₀The values are not absolute values, but depend on experimental conditions such as the concentration used, and can be converted to absolute inhibition constants (Ki) using the Cheng-Prusoff equation (biochem. Pharmacol. (1973)22: 3099).

The terms "compounds of the invention" and "compounds of formula I" include compounds of formula I and stereoisomers, geometric isomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof.

Any formula or structural formula given herein, including the compounds of formula I, is also intended to represent hydrates, solvates, and polymorphs of the above compounds, and mixtures thereof.

Any formulae or structural formulae given herein, including compounds of formula I, are also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically-labeled compounds have the structure depicted in the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to²H (deuterium, D),³H (tritium),¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I. the invention includes various isotopically-labeled compounds of the invention, e.g., radioactive isotopes such as³H、¹³C and¹⁴those compounds of the present invention into which C is introduced. The isotopically labeled compounds described above are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution assays or in the treatment of patients with radioactivity. Therapeutic compounds of the invention labeled or substituted with deuterium may have improved DMPK (drug metabolism and pharmacokinetics) properties, including absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements). Warp beam¹⁸The F-labeled compounds are useful for PET or SPECT studies. Isotopically-labeled compounds of the present invention and prodrugs thereof can generally be prepared as follows: the procedures disclosed in the schemes or examples and preparations below were performed and the non-isotopically labeled reagents were replaced with readily available isotopically labeled reagents. In addition, with heavier isotopes, especially deuterium (i.e. deuterium)²H or D) may result in some therapeutic advantages (e.g. increased in vivo half-life or reduced dosage requirements or improved therapeutic index) due to better metabolic stabilityGood). It is to be understood that deuterium in the present application is considered as a substituent in the compounds of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. Any atom in the compounds of the present invention that is not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a location is specifically designated as "H" or "hydrogen," it is understood that the location has a concentration of hydrogen that is the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present invention, any atom specifically designated as deuterium (D) is intended to represent deuterium.

Pyrazol-4-yl-heterocyclyl-carboxamide compounds

The present invention provides pyrazol-4-yl-heterocyclyl-carboxamide compounds of formula I, including formula Ia-I and pharmaceutical formulations thereof, that are potentially useful for treating diseases, conditions, and/or disorders modulated by Pim kinase.

The compounds of formula I have the following structure:

and stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:

R¹selected from H, C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₆-C₂₀Aryl radical, C₃-C₁₂Carbocyclyl, C₂-C₂₀Heterocyclic group, C₁-C₂₀Heteroaryl and- (C)₁-C₁₂Alkylene group) - (C₂-C₂₀A heterocyclic group);

R²selected from the following structures:

wherein the wavy line indicates the attachment site and the dashed line indicates an optional double bond;

R³selected from H, -CH₃、-CH₂CH₃、-CH(CH₃)₂、-CH₂CH(CH₃)₂、-CH₂NH₂、-CH₂NHCH₃、-CH₂CH₂NH₂、-CH₂CHCH₂NH₂、-CH₂CH(CH₃)NH₂、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH(OH)CH(CH₃)₂、-C(CH₃)₂CH₂OH、-CH₂CH₂SO₂CH₃、-CN、-CF₃、-CO₂H、-COCH₃、-CO₂CH₃、-CO₂C(CH₃)₃、-COCH(OH)CH₃、-COCH₂NH₂、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-S(O)₂N(CH₃)₂、-SCH₃、-CH₂OCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;

R⁴independently selected from F, Cl, Br, I, -CH₃、-CH₂CH₃、-CH(CH₃)₂、-C(CH₃)₃、-CH₂CH(CH₃)₂、-CH＝CH₂、-CH＝C(CH₃)₂、＝CH₂、-CH₂F、-CHF₂、-CF₃、-CH₂OH、-CH₂OCH₃、-CH₂NH₂、-CH₂NHCH₃、-CH₂CH₂NH₂、-CH₂CHCH₂NH₂、-CH₂CH(CH₃)NH₂、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH(OH)CH(CH₃)₂、-C(CH₃)₂CH₂OH、-CH₂CH₂SO₂CH₃、-CN、-CO₂H、-COCH₃、-COCH₂NH₂、-CO₂CH₃、-CO₂C(CH₃)₃、-COCH(OH)CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CHF₂、-NHCH₂CF₃、-NHCH₂CH₂OH、-NHCOCH₃、-N(CH₃)COCH₃、-NHC(O)OCH₂CH₃、-NHC(O)OCH₂Cl₃、-NHC(O)OC₆H₅、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、＝O、-OH、-OCH₃、-OCHF₂、-OCH₂F、-OCH₂CH₃、-OCH(CH₃)₂、-OCH₂CH(CH₃)₂、-OC(CH₃)₃、-S(O)₂N(CH₃)₂、-SCH₃、-CH₂OCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, oxetan-3-ylmethylamino, (3-methyloxetan-3-yl) methylamino, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl) ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl and morpholino;

or wherein two geminal R are⁴The groups form a spiro ring selected from: cyclopropyl, cyclobutyl, cyclopentyl, cycloA hexyl, pyrrolidinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, or piperidinyl ring, wherein the spiro ring is optionally substituted with one or more groups independently selected from: -F, -OH, ═ O, -CH₃、-NH₂、-CH₂F、-CH₂OH、-CH₂OCH₃、-CH₂NH₂and-CF₃；

Or wherein two ortho-positions R⁴Group or R⁴Group and R³The groups form a five-or six-membered heterocyclyl-fused ring, wherein the heterocyclyl-fused ring is optionally substituted with one or more groups selected from: -F, -OH, ═ O, -CH₃、-NH₂、-CH₂F、-CH₂OH、-CH₂OCH₃、-CH₂NH₂and-CF₃；

n is 0, 1,2 or 3;

x is selected from the following structures:

wherein the wavy line represents the attachment site;

R⁵selected from H, Cl, Br, C₁-C₁₂Alkyl, - (C)₁-C₁₂Alkylene group) - (C₃-C₁₂Carbocyclyl), - (C)₁-C₁₂Alkylene group) - (C₂-C₂₀Heterocyclyl), - (C)₂-C8 alkenylene) - (C₃-C₁₂Carbocyclyl), - (C)₂-C8 alkenylene) - (C₂-C₂₀Heterocyclic group), C₆-C₂₀Aryl, - (C)₆-C₂₀Arylene group) - (C₂-C₂₀Heterocyclyl), - (C)₆-C₂₀Arylene group) - (C₁-C₁₂Alkylene group) - (C₂-C₂₀Heterocyclic group), C₃-C₁₂Carbocyclyl, C₂-C₂₀Heterocyclyl and C₁-C₂₀A heteroaryl group; wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups selected from: F. cl, Br, I, -CH₃、-CH₂CH₃、-CH(CH₃)₂、-CH₂CH(CH₃)₂、-CH₂NH₂、-CH₂CH₂NH₂、-CH₂CHCH₂NH₂、-CH₂CH(CH₃)NH₂、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH(OH)CH(CH₃)₂、-C(CH₃)₂CH₂OH、-CH₂CH₂SO₂CH₃、-CN、-CF₃、-CO₂H、-COCH₃、-CO₂CH₃、-CO₂C(CH₃)₃、-COCH(OH)CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-N(CH₃)COCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、＝O、-OH、-OCH₃、-S(O)₂N(CH₃)₂、-SCH₃、-CH₂OCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl) ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and

R⁶independently is H or-NH₂。

Exemplary embodiments of compounds of formula I include those wherein R¹Is H, C₁-C₁₂Alkyl radical(including-CH)₃、-CH₂CH₃)、-CH₂CHF₂and-CH₂CF₃、C₃-C₁₂Carbocyclyl or- (C)₁-C₁₂Alkylene group) - (C₂-C₂₀Heterocyclyl) (including oxetan-3-ylmethyl).

Exemplary embodiments of compounds of formula I include those wherein R¹Is H.

Exemplary embodiments of compounds of formula I include those wherein R¹Is C₁-C₁₂Alkyl or C₃-C₁₂A carbocyclic group.

Exemplary embodiments of compounds of formula I include those wherein R¹Is selected from-CH₃、-CH₂CH₃、-CH₂CHF₂and-CH₂CF₃。

Exemplary embodiments of compounds of formula I include those wherein R¹Is- (C)₁-C₁₂Alkylene group) - (C₂-C₂₀A heterocyclic group).

Exemplary embodiments of compounds of formula I include those wherein R¹Is oxetan-3-ylmethyl.

Exemplary embodiments of compounds of formula I include those wherein R³Is H or-CH₃。

Exemplary embodiments of compounds of formula I include those wherein R⁴Independently selected from F, Cl, -OH, -CH₃、-CH₂CH₃、-CF₃、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CHF₂、-NHCH₂CF₃、-CH₂NHCH₃and-OCH₃(ii) a And n is 1,2 or 3.

Exemplary embodiments of compounds of formula I include those wherein n is 1 or 2.

Exemplary embodiments of compounds of formula I include those wherein R⁵Is C₆-C₂₀Aryl radicals(including one or more F, especially phenyl substituted by one or two F).

Exemplary embodiments of compounds of formula I include those wherein R⁶is-NH₂.

Exemplary embodiments of the compounds of formula I include structures of formulae Ia-I:

biological evaluation

Determination of the Pim kinase activity of the compounds of formula I is feasible by a number of direct and indirect detection methods. Some of the exemplary compounds described herein were tested for Pim kinase binding activity (example 901) and in vitro activity against tumor cells (example 902) for some of them, including subtypes Pim-1, Pim-2 and Pim-3. Some exemplary compounds of the invention have a Pim binding activity IC of less than about 1 micromolar (μ M)₅₀The value is obtained. Some compounds of the invention have a tumor cell-based active EC of less than about 1 micromolar (μ M)₅₀The value is obtained. Has less than 1 μ MKi/IC in the assays described in examples 901 and 902₅₀/EC₅₀The compounds of formula (I) can be used therapeutically as Pim kinase inhibitors (Pim-1, Pim-2 and/or Pim-3).

Exemplary compounds of formula I in tables 1a and 1b were prepared, characterized and tested for Pim kinase inhibition according to the methods of the present invention and have the following structure and corresponding names (ChemBioDraw Ultra, version11.0, Cambridge soft corp., Cambridge MA). Some of the compounds in tables 1a and 1b having chiral atoms have not been fully characterized for their stereochemistry. Tentative assignments of stereochemistry or stereochemical relationships of related other groups can be shown in the structure. Means of separation and characterization of stereoisomers are given in the examples.

Table 1a.

Table 1b.

The present invention includes compositions (e.g., pharmaceutical compositions) comprising a compound of formula I, and/or solvates, hydrates, and/or salts thereof, and a carrier (pharmaceutically acceptable carrier). The present invention also includes compositions (e.g., pharmaceutical compositions) comprising a compound of formula I and/or solvates, hydrates, and/or salts thereof, and a carrier (pharmaceutically acceptable carrier), further comprising a second chemotherapeutic agent such as those described herein. The compositions of the invention are useful for inhibiting abnormal cell growth or treating hyperproliferative disorders, such as cancer, in a mammal (e.g., a human). For example, the compounds and compositions of the present invention are useful for treating multiple myeloma, lymphoma, acute myeloid leukemia, prostate cancer, breast cancer, hepatocellular carcinoma, pancreatic cancer, and/or colorectal cancer in a mammal (e.g., a human).

The present invention includes methods of inhibiting abnormal cell growth or treating a hyperproliferative disorder, such as cancer, in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of formula I, and/or solvates, hydrates, and/or salts thereof, or compositions thereof. For example, the present invention includes a method of treating multiple myeloma, lymphoma, acute myeloid leukemia, prostate cancer, breast cancer, hepatocellular carcinoma, pancreatic cancer, and/or colorectal cancer in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of formula I, and/or solvates, hydrates, and/or salts thereof), or a composition thereof.

The present invention includes methods of inhibiting abnormal cell growth or treating a hyperproliferative disorder, such as cancer, in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of formula I, and/or solvates, hydrates, and/or salts thereof, or compositions thereof, in combination with a second chemotherapeutic agent, such as those described herein. For example, the present invention includes a method of treating multiple myeloma, lymphoma, acute myeloid leukemia, prostate cancer, breast cancer, hepatocellular carcinoma, pancreatic cancer, and/or colorectal cancer in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of formula I, and/or solvates, hydrates, and/or salts thereof, or compositions thereof, in combination with a second chemotherapeutic agent, such as those described herein.

The present invention includes methods of treating lymphoma in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of formula I, and/or solvates, hydrates, and/or salts thereof, or compositions thereof, alone or in combination with a second chemotherapeutic agent, such as an anti-B-cell antibody therapeutic agent (e.g., Rituxan and/or Dacetuzumab), gemcitabine, a corticosteroid (e.g., prednisolone and/or dexamethasone), a chemotherapeutic drug cocktail (cocktail) (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), and/or ICE (isfosfamide, cyclophosphamide, etoposide)), a combination of a biologic and a chemotherapeutic drug (e.g., Rituxan-ICE, Dacetuzumab-Rituxan-ICE), or a combination thereof, R-Gem and/or D-R-Gem), Akt inhibitors, PI3K inhibitors (e.g., GDC-0941(Genentech) and/or GDC-0980(Genentech)), rapamycin analogs, mTOR inhibitors such as everolimus or sirolimus, MEK inhibitors (GDC-0973), and Bcl-2 inhibitors (ABT-263 or ABT-199).

The present invention includes methods of treating multiple myeloma in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of formula I, and/or solvates, hydrates, and/or salts thereof, or compositions thereof, alone or in combination with a second chemotherapeutic agent, such as melphalan, an "imide" (an immunomodulator, e.g., thalidomide, lenalidomide, and/or pomolidamide), a corticosteroid (e.g., dexamethasone and/or prednisolone), and bortezomib or other proteasome inhibitor.

The present invention includes a method of treating multiple myeloma, Chronic Lymphocytic Leukemia (CLL), or Acute Myeloid Leukemia (AML) in a mammal (e.g., a human), comprising administering to the mammal a therapeutically effective amount of a compound of formula I, and/or solvates, hydrates, and/or salts thereof, or compositions thereof, alone or in combination with a second chemotherapeutic agent, such as cytarabine (araC), an anthracycline (e.g., daunorubicin and/or idarubicin), an anti-myeloid antibody therapeutic drug (e.g., SGN-33), an anti-myeloid antibody-drug conjugate (e.g.,)。

the present invention includes a method of treating Chronic Lymphocytic Leukemia (CLL) in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of formula I, and/or solvates, hydrates and/or salts thereof, or compositions thereof, alone or in combination with a second chemotherapeutic agent, such as fludarabine, cyclophosphamide, an anti-B-cell antibody therapeutic (e.g., Rituxan and/or Dacetuzumab).

The present invention includes a method of treating Chronic Myeloid Leukemia (CML) in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of formula I, and/or solvates, hydrates and/or salts thereof, or compositions thereof, alone or in combination with a second chemotherapeutic agent, such as a BCR-abl inhibitor (e.g., imatinib, nilotinib, and/or dasatinib).

The present invention includes a method of treating Myelodysplastic Diseases (MDS) and myeloproliferative disorders, including Polycythemia Vera (PV), Essential Thrombocythemia (ET) or Myelofibrosis (MF), in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of formula I, and/or solvates, hydrates and/or salts thereof, or compositions thereof, alone or in combination.

The invention includes methods of using the compounds of the invention for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, tissues, or associated pathological conditions.

Administration of the compounds of the present invention (hereinafter "active compounds") can be carried out by any method that is capable of delivering the compound to the site of action. These methods include oral, intraduodenal, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, inhalation and rectal administration.

The amount of active compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition (disposition) of the compound, and the considerations of the prescribing physician. However, in a single dose or divided doses, an effective dose is from about 0.001 to about 100mg/kg body weight/day, preferably from about 1 to about 35 mg/kg/day. For a 70kg person, this will amount to about 0.05-7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be sufficient, while in other cases larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.

The active compounds may be administered as monotherapy or in combination with one or more chemotherapeutic drugs, such as those described herein. Such combination therapy may be achieved by administering the individual therapeutic components simultaneously, sequentially or separately.

The pharmaceutical compositions may, for example, be in a form suitable for oral administration as tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions, in a form suitable for parenteral injection as a sterile solution, suspension or emulsion, in a form suitable for topical administration as an ointment or cream, or in a form suitable for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage form suitable for single administration of the aforementioned dosages. The pharmaceutical compositions will contain conventional pharmaceutical carriers or excipients and the compounds of the invention as active ingredients. In addition, it may contain other pharmaceutical or pharmaceutic agents, carriers, adjuvants, and the like.

Exemplary parenteral administration forms include solutions or suspensions of the compounds of formula I in sterile aqueous solutions (e.g., aqueous propylene glycol or dextrose solutions). Such dosage forms may be suitably buffered if desired.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. If desired, the pharmaceutical compositions may contain additional ingredients such as flavoring agents, binders, excipients, and the like. Thus for oral administration, tablets containing various excipients such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binders such as sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often used for tableting purposes. Solid compositions of a similar type may also be used in soft and hard filled gelatin capsules. Thus, preferred materials include lactose (lactose) or lactose (milk sugar) and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring materials or dyes and, if desired, emulsifying or suspending agents as well as diluents such as water, ethanol, propylene glycol, glycerin or combinations thereof.

Use specialMethods for the quantitative preparation of active compounds for various pharmaceutical compositions are known or will be apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, MackPublishing Company, Ester, Pa.,15^thEdition(1975)。

Administering a compound of formula I

The compounds of formula I of the present invention may be administered by any route suitable for the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. For local immunosuppressive therapy, the compound may be administered by administration to the injury area (including perfusion or contacting the graft with an inhibitor prior to transplantation). It will be appreciated that the preferred route may vary, for example, with the condition of the receptor. When the compound is administered orally, it may be formulated with a pharmaceutically acceptable carrier or excipient into pills, capsules, tablets, and the like. When the compound is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle and into unit dosage injectable forms, as described below.

The dose for treating a human patient may be from about 10mg to about 1000mg of a compound of formula I. A typical dose may be from about 100mg to about 300mg of the compound. The dose may be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties of the particular compound, including absorption, distribution, metabolism, and excretion. In addition, toxicity factors can affect dosage and dosing regimens. When administered orally, the pills, capsules or tablets may be taken daily or less frequently for a prescribed period of time. The dosing regimen may be repeated for a number of treatment cycles.

Methods of treatment with compounds of formula I

The compounds of the invention are useful for treating hyperproliferative diseases, conditions and/or disorders, including but not limited to those characterized by overexpression of Pim kinases (e.g., Pim-1, Pim-2 and Pim-3 kinases). Accordingly, another aspect of the invention includes a method of treating or preventing a disease or condition that can be treated or prevented by inhibiting a Pim kinase. In one embodiment, the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I, or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, a human patient is treated with a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the compound of formula I is present in an amount that detectably inhibits Pim kinase activity.

Cancers that may be treated according to the methods of the invention include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular cancer, undifferentiated cancer, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, and cancer of the biliary tract, kidney cancer, myeloid disorders, lymphoid disorders, hairy cell cancer, oral and pharyngeal (oral) cancer, lip cancer, tongue cancer, mouth cancer, pharyngeal cancer, small intestine cancer, colon-rectal cancer, large intestine cancer, rectal cancer, brain cancer, and central nervous system cancer, and hodgkin's cancer and leukemia.

Another aspect of the invention provides a compound of the invention for use in treating a disease or condition described herein in a mammal, such as a human, suffering from such a disease or condition. The invention also provides the use of a compound of the invention in the manufacture of a medicament for use in the treatment of diseases and conditions described herein in a warm-blooded animal such as a mammal, e.g. a human, suffering from such diseases and conditions.

Pharmaceutical preparation

For the therapeutic treatment (including prophylactic treatment) of mammals (including humans) using compounds of formula I, they are generally formulated in accordance with standard pharmaceutical practice as pharmaceutical compositions. This aspect of the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier.

Typical formulations are prepared by mixing a compound of formula I with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include the following: such as carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc. The particular carrier, diluent or excipient employed will depend upon the mode and purpose for which the compounds of the present invention are to be employed. Solvents are generally selected based on the solvents (GRAS) that one skilled in the art would consider safe for administration to mammals. Generally, the safe solvent is a non-toxic aqueous solvent such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), and the like, and mixtures thereof. The formulation may further comprise one or more of the following: buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants, and other known additives to impart a superior appearance to a drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the preparation of a pharmaceutical product (i.e., a drug).

The formulations may be prepared using conventional dissolution and mixing operations. For example, a quantity of the drug substance, i.e., a stabilized form of a compound of the invention or a compound of formula I (e.g., a complex with a cyclodextrin derivative or other known complexing agent), is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the present invention are typically formulated into pharmaceutical dosage forms to provide easily controllable dosages of the drug and to enable patient compliance with prescribed dosing regimens.

Pharmaceutical compositions (or formulations) for administration can be packaged in a variety of ways, depending on the method of administration. Typically, the articles for dispensing comprise a container having disposed therein a pharmaceutical formulation in a suitable form. Suitable containers are well known to those skilled in the art and include the following: such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-resistant assembly that prevents inadvertent access to the contents of the package. In addition, the container has disposed thereon a label describing the contents of the container. The label may also include appropriate precautions.

Pharmaceutical formulations of the compounds of the present invention may be prepared for a variety of routes and types of administration. For example, a compound of formula I having the desired purity may be optionally admixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington's pharmaceutical Sciences (1980)16th edition, Osol, A.Ed.) in the form of a lyophilized formulation, a finely divided powder or an aqueous solution. The formulation can be carried out as follows: mixed at ambient temperature and at a suitable pH in the desired purity with a physiologically acceptable carrier, i.e. a carrier which is non-toxic to the recipient at the dosages and concentrations used. The pH of the formulation depends primarily on the particular use and concentration of the compound, but can range from about 3 to about 8. A formulation with a pH of 5 in acetate buffer is a suitable embodiment.

The compounds of the invention for use in the present application are preferably sterile. In particular, formulations for in vivo administration must be sterile. The above-mentioned sterilization is easily accomplished by filtration with a sterile filtration membrane.

The compounds can generally be stored in the form of solid compositions, lyophilized formulations or aqueous solutions.

The pharmaceutical compositions of the present invention comprising the compounds of formula I will be formulated, dosed and administered in a manner consistent with good medical practice, i.e., in amounts, concentrations, schedules, procedures, vehicles and routes of administration. Factors considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the drug, the method of administration, the timing of administration, and other factors known to medical practitioners. The "therapeutically effective amount" of the compound to be administered will depend on the above factors considered and is the minimum amount required to prevent, ameliorate or treat the disorder mediated by the coagulation factor. The above amount is preferably lower than an amount that is toxic to the host or renders the host significantly more susceptible to bleeding.

As a general proposition, the initial pharmaceutically effective amount of a compound of formula I administered parenterally will be about 0.01-100mg/kg, i.e., about 0.1 to 20mg/kg, patient body weight/day in each dose, with a typical initial range of 0.3 to 15 mg/kg/day for the compound used.

Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; chlorhexidine di-ammonium; benzalkonium chloride, benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; penta-3-ol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants, such as TWEEN^TM、PLURONICS^TMOr polyethylene glycol (PEG). The active pharmaceutical ingredient may also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. See Remington's Pharmaceutical Sciences16th edition, Osol, A.Ed. (1980).

Sustained release formulations of the compounds of formula I can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound of formula I, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl methacrylate) or poly (vinyl alcohol)), polylactide (U.S. Pat. No.3,773,919), copolymers of L-glutamic acid and γ -ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT^TM(microspheres for injection composed of lactic acid-glycolic acid copolymer and leuprorelin acetate) and poly D- (-) -3-hydroxybutyric acid.

Such formulations include those suitable for the routes of administration described herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally described in Remington's pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). The above method comprises the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. Typically, the formulations are prepared as follows: the active ingredient is mixed homogeneously and intimately with liquid carriers or finely divided solid carriers or with both carriers, and the product is then shaped as required.

Formulations of a compound of formula I suitable for oral administration may be prepared as discrete units, such as pills, capsules, cachets, or tablets each containing a predetermined amount of a compound of formula I.

Compressed tablets may be prepared as follows: the active ingredient is compressed with a suitable machine in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets may be prepared as follows: the mixture of powdered active ingredient moistened with an inert liquid diluent is moulded with a suitable machine. The tablets may optionally be coated or scored and optionally formulated to provide slow or controlled release of the active ingredient from the tablet.

Can be made into oral tablet, buccal tablet, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule such as gelatin capsule, syrup or elixir. Formulations of compounds of formula I intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic physiologically acceptable excipients which are suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

For the treatment of the eye or other external tissues such as the mouth and skin, the formulations may be applied in the form of a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the active ingredient may be employed with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream together with an oil-in-water cream base.

When desired, the aqueous phase in the cream base may include polyhydric alcohols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol, and polyethylene glycols (including PEG400) and mixtures thereof. Topical formulations may desirably include compounds that promote absorption or permeation of the active ingredient through the skin or other affected area. Examples of the above-mentioned skin permeation enhancers include dimethyl sulfoxide and the like.

The oily phase of the emulsions of the invention may be constituted by known ingredients in a known manner. Although the phase may comprise only emulsifiers, it is desirable that it comprises a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included with a lipophilic emulsifier as a stabilizer. It is also preferred to include both oil and fat. The emulsifier(s), with or without stabilizer(s), together constitute the so-called emulsifying wax and the wax together with the oil and fat constitutes the so-called emulsifying ointment base which forms the oily dispersed phase in the cream. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention includeStearyl/cetyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.

Aqueous suspensions of the compounds of formula I contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents such as naturally occurring phosphatides (e.g. lecithin), condensation products of an alkylene oxide with fatty acids (e.g. polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g. heptadecaethyleneoxyethanoyl hexadecanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (partial esters) (e.g. polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Pharmaceutical compositions of the compounds of formula I may be in the form of sterile injectable aqueous or oleaginous suspensions, such as sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the methods known in the art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in butane-1, 3-diol or as a lyophilized powder. Acceptable vehicles and solvents that may be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a timed release formulation intended for oral administration to humans may contain from about 1 to 1000mg of the active substance and a suitable and convenient amount of carrier material which may represent from about 5 to about 95% (weight: weight) of the total composition. Pharmaceutical compositions can be prepared to provide an easily measurable amount of the drug to be administered. For example, aqueous solutions intended for intravenous infusion may contain from about 3 to 500 μ g of active ingredient per mL of solution, so that an appropriate volume of infusion at a rate of about 30mL/hr may be performed.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The concentration of the active ingredient present in the above formulations is preferably from about 0.5 to 20% w/w, for example from about 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; lozenges comprising the active ingredient in an inert base (such as gelatin and glycerol or sucrose and acacia); and mouth washes comprising the active ingredient in a suitable liquid carrier.

Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration have, for example, a particle size in the range of 0.1 to 500 microns (including particle sizes in the range of 0.1 to 500 microns and in increments of microns such as 0.5, 1, 30, 35 microns, etc.), which are administered by rapid or oral inhalation through the nasal passages to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents, such as compounds heretofore used to treat or prevent the disorders described below.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules or vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water, for injections, immediately prior to use. Ready-to-use injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind described above. Preferred unit dosage formulations are those containing the active ingredient in a daily dose or unit daily sub-dose, or suitable fraction thereof, as herein described.

The invention also provides a veterinary composition, which therefore contains at least one active ingredient as described above and a veterinary carrier. Veterinary carriers are substances useful for the purpose of administering the composition and can be solid, liquid or gaseous substances which are either inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

Combination therapy

The compounds of formula I may be used alone or in combination with other therapeutic agents to treat diseases or disorders described herein, such as hyperproliferative disorders (e.g., cancer). In some embodiments, a compound of formula I is combined in a pharmaceutical combination preparation or in a dosing regimen that is a combination therapy with a second compound that is anti-hyperproliferative or useful for treating a hyperproliferative disorder (e.g., cancer). The second compound in the pharmaceutical combination formulation or dosing regimen preferably has complementary activity towards the compound of formula I such that they do not adversely affect each other. The amount of the above-mentioned compounds present in the combination is suitably an amount effective for the intended purpose. In one embodiment, the compositions of the present invention comprise a compound of formula I in combination with a chemotherapeutic agent as described herein.

The combination therapy may be administered on a simultaneous or sequential dosing schedule. When administered sequentially, the combination may be administered in two or more administrations. Co-administration includes simultaneous administration and sequential administration in any order using separate formulations or a single pharmaceutical formulation, wherein preferably both (or all) active agents exert their biological activities simultaneously over a period of time.

Suitable dosages for any of the above co-administered drugs are those currently used and may be reduced by the combined effect (synergy) of the newly identified drug and other chemotherapeutic agents or treatments.

Combination therapy may provide a "synergistic effect" and is demonstrated to be "synergistic", i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects obtained with each of these compounds. When the active ingredients (1) are co-formulated and administered or delivered simultaneously in the combined unit dosage formulation; (2) alternatively or in parallel in separate formulations; or (3) when administered by some other dosing regimen, a synergistic effect may be achieved. When delivered in alternation therapy, synergy may be achieved when the compounds are administered or delivered sequentially, e.g., by different injections in different syringes, separate pills or capsules, or separate infusions. Typically, an effective dose of each active ingredient is administered sequentially (i.e., sequentially) during alternation therapy, while in combination therapy, effective doses of two or more active ingredients are administered together.

In particular embodiments of anticancer therapy, the compounds of formula I, or stereoisomers, geometric isomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, can be used in combination with other chemotherapeutic agents, hormonal agents, or antibody agents (such as those described herein), as well as in combination with surgical therapy and radiation therapy. Accordingly, the combination therapies of the present invention include the administration of at least one compound of formula I, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and the use of at least one other cancer treatment method. The amount and relative timing of administration of the compound of formula I (or compounds of formula I) and the other pharmaceutically active chemotherapeutic agent (or agents) will be selected to achieve the desired combination therapeutic effect.

Metabolites of compounds of formula I

In vivo metabolites of formula I as described herein are also within the scope of the present invention. Such products may be derived, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound. Accordingly, the present invention includes metabolites of the compounds of formula I, including compounds produced by a method comprising contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolite thereof.

Metabolic productsThe substances are generally identified as follows: preparation of the Compounds of the invention radiolabeled (e.g.¹⁴C or³H) Isotopes, which are administered parenterally to an animal such as rat, mouse, guinea pig, monkey, or human at detectable doses (e.g., greater than about 0.5mg/kg), allowed a sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and then their conversion products isolated from urine, blood or other biological samples. These products are easy to isolate because they are labeled (other products are isolated by using antibodies that are capable of binding to epitopes of antigens that survive in the metabolite). The structure of the metabolite is determined in a conventional manner, for example by MS, LC/MS or NMR analysis. Typically, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites, so long as they are not otherwise present in the body, can be used in diagnostic assays for therapeutic administration of the compounds of the invention.

Article of manufacture

Another embodiment of the present invention provides an article of manufacture or "kit" comprising materials useful for the treatment of the diseases and disorders described above. The kit comprises a container comprising a compound of formula I. The kit may further comprise a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions typically included in commercial packages of therapeutic products containing information regarding the indications, usage, dosage, administration, contraindications and/or precautions relating to the use of the therapeutic products described above. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container may contain a compound of formula I or II or a formulation thereof effective to treat the condition and may have a sterile outlet (e.g., the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound of formula I. The label or package insert indicates that the composition can be used to treat a selected condition, such as cancer. In addition, the label or package insert may indicate that the patient to be treated is a patient suffering from a disorder such as a hyperproliferative disorder, neurodegeneration, cardiac hypertrophy, pain, migraine or a neurotrauma disease or event. In one embodiment, the label or package insert indicates that compositions comprising a compound of formula I are useful for treating disorders resulting from abnormal cell growth. The label or package insert may also indicate that the composition may be used to treat other disorders. Alternatively or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. It may also contain other substances as desired from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.

The kit may further comprise instructions for administering the compound of formula I and the second pharmaceutical formulation (if present). For example, if a kit comprises a first composition comprising a compound of formula I and a second pharmaceutical formulation, the kit may further comprise instructions for administering the first and second pharmaceutical compositions to a patient in need thereof simultaneously, sequentially or separately.

In another embodiment, the kit is suitable for delivering a solid oral form of a compound of formula I or II, such as a tablet or capsule. The kit preferably comprises a plurality of unit doses. The kit may comprise a card with a method of administration for its intended use. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dose forms. When desired, a memory aid may be provided, for example in the form of a number, letter or other indicia or with a calendar insert indicating those days in the treatment schedule on which administration may be performed.

According to one embodiment, a kit may comprise (a) a first container having a compound of formula I contained therein; and optionally (b) a second container having a second pharmaceutical formulation therein, wherein the second pharmaceutical formulation comprises a second compound having anti-hyperproliferative activity. Alternatively or additionally, the kit may further comprise a third container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. It may also contain other substances as desired from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.

In some other embodiments where the kit comprises a composition of formula I and a second therapeutic agent, the kit may comprise containers for holding separate compositions, such as separate bottles or separate foil packets, however, separate compositions may also be held in a single, undivided container. Typically, the kit contains instructions for administering the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral) or at different dosage intervals or when increasing the dosage of each of the components of the combination as desired by the prescribing physician.

Preparation of Compounds of formula I

The compounds of formula I can be synthesized by synthetic routes that include methods analogous to those well known in the chemical arts, specifically, in accordance with the descriptions contained herein, and the descriptions of other heterocycles in the following documents: comprehensive heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier,1997, e.g., Volume 3; liebigs Annalen der Chemie, (9):1910-16, (1985); helvetica Chimica Acta,41:1052-60, (1958); Arzneimittel-Forschung,40(12):1328-31, (1990), each of which is expressly incorporated herein by reference. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or can be readily prepared using methods well known to those skilled in the art (e.g., by the methods generally described in Louis F. Fieser and MaryFieser, Reagents for Organic Synthesis, v.1-23, Wiley, N.Y. (1967. and 2006ed.) or Beilsteins Handbuch der organischen Chemie,4, Aufl. ed. Springer-Verlag, Berlin (including the appendix) (also available from the Beilstein online database)).

Synthetic chemical transformations and protecting group methodologies (protection and deprotection) that may be employed in the synthesis of compounds of formula I, as well as the necessary reagents and intermediates, are known in the art and include, for example, those described in the following references: larock, Comprehensive Organic Transformations, VCH Publishers (1989); t.w.greene and p.g.m.wuts, Protective Groups in Organic Synthesis,3rd ed., john wiley and Sons (1999); and L.Patquette, ed., Encyclopedia of Reagents for organic Synthesis, John Wiley and Sons (1995) and subsequent versions thereof.

The compounds of formula I can be prepared individually or as libraries comprising at least 2, e.g. 5 to 1,000 or 10 to 100 compounds. Libraries of compounds of formula I can be prepared by procedures known to those skilled in the art using solution phase or solid phase chemistry by combinatorial 'split and mix' approaches or by multiple parallel syntheses. Accordingly, another aspect of the present invention provides a library of compounds comprising at least 2 compounds or pharmaceutically acceptable salts thereof.

The general procedures and examples provide exemplary methods for preparing compounds of formula I. It will be appreciated by those skilled in the art that other synthetic routes may be used to synthesize the compounds of formula I. Although specific starting materials and reagents have been shown and discussed in the figures, general procedures, and examples, other starting materials and reagents can be readily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the exemplary compounds prepared by the methods described can be further modified in light of this disclosure using conventional chemistry known to those skilled in the art.

When preparing compounds of formula I, it may be desirable to protect terminal functional groups (e.g., primary or secondary amines) in the intermediates. The need for such protection will vary with the nature of the terminal functional group and the conditions of the preparation process. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and fluoren-9-ylmethyl oxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting Groups and their use see t.w. greene, Protective Groups in organic Synthesis, John Wiley & Sons, New York, 1991.

Separation method

In the process for preparing compounds of the formula I, it may be advantageous to separate the reaction products from one another and/or from the starting materials. The desired product in each step or steps is isolated and/or purified to the desired homogeneity by techniques common in the art. Typically, such separation involves heterogeneous extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve any number of methods including, for example, reverse-phase and normal-phase, size exclusion, ion exchange, high, medium and low pressure liquid chromatography and apparatus, small scale analysis, Simulated Moving Bed (SMB) and preparative thin or thick layer chromatography, and small scale thin layer and flash chromatography techniques.

Another type of separation method involves treating the mixture with reagents selected to combine or isolate the desired product, unreacted starting materials, reaction by-products, etc. Such agents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, and the like. Alternatively, the reagent may be an acid (in the case of a basic substance), a base (in the case of an acidic substance), a binding agent such as an antibody, a binding protein, a selective chelating agent such as a crown ether, a liquid/liquid ion extraction agent (LIX), or the like. The choice of a suitable separation method depends on the nature of the substances involved, such as boiling point and molecular weight (in distillation and sublimation), presence or absence of polar functional groups (in chromatography), stability of the substances in acidic and basic media (in heterogeneous extraction), etc.

Mixtures of diastereomers may be separated into their individual diastereomers on the basis of their physical-chemical differences by methods well known to those skilled in the art, such as chromatography and/or fractional crystallization. Enantiomers can be separated as follows: mixtures of enantiomers are converted to mixtures of diastereomers by reaction with an optically active suitable compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), the diastereomers are separated, and the individual diastereomers are then converted (e.g., hydrolyzed) to the corresponding pure enantiomers. Additionally, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered to be part of the present invention. Enantiomers can also be separated by using a chiral HPLC column.

Individual stereoisomers, e.g. enantiomers substantially free of their stereoisomers, can be obtained by resolution of racemic mixtures using, for example, optically active resolving agents to form diastereomers (Eliel, E.and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994; Lochmuller, C.H., (1975) J.Chromatogr.,113 (283) (3): Bin 302). Racemic mixtures of chiral compounds of the invention can be separated by any suitable method, including (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other method; (2) forming a diastereomeric compound with a chiral derivatizing agent, separating the diastereomers and converting them to pure stereoisomers; and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions, e.g., by HPLC or SFC (supercritical fluid chromatography) on chiral adsorbents, see White and Burnett (2005) journal of Chrom. A1074: 175-185; "Drug Stereochemistry, Analytical Methods and Pharmacology", (1993) Irving W.Wainer, Ed., Marcel Dekker, Inc., New York.

In process (1), diastereomeric salts may be formed as follows: enantiomerically pure chiral bases such as strychnine, quinine, ephedrine, brucine, alpha-methyl-beta-phenylethylamine (amphetamine), and the like are reacted with asymmetric compounds having acidic functional groups such as carboxylic and sulfonic acids. Separation of diastereomeric salts can be achieved by fractional crystallization or ion chromatography. To separate the optical isomers of the amino compounds, chiral carboxylic or sulfonic acids such as camphorsulfonic, tartaric, mandelic or lactic acids are added, which can lead to the formation of diastereomeric salts.

Alternatively, the substrate to be resolved is coupled to chirality by method (2)One enantiomer of a compound reacts to form a diastereomer pair (Eliel, E.and Wilen, S. "stereoschemistry of organic Compounds", John Wiley&Sons, inc.,1994, p.322.) diastereoisomeric compounds may be formed by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing agent such as a menthyl derivative, followed by separation and hydrolysis of the diastereomers to yield pure or enriched enantiomers the method of determining optical purity involves preparing a chiral ester of the racemic mixture [ such as preparing a menthyl ester such as (-) -menthyl chloroformate in the presence of a base or preparing a Mosher ester, i.e., α -methoxy- α - (trifluoromethyl) phenyl acetate (Jacob iii.j.org.chem. (1982)47:4165)]And analyzed for the presence of two atropisomeric enantiomers or diastereomers¹H NMR spectrum. The stable diastereoisomers of atropisomeric compounds can be separated by normal and reverse phase chromatography according to the method for separating atropisomeric naphthyl-isoquinoline compounds (WO 1996/15111). In method (3), racemic mixtures of the two enantiomers can be separated by Chromatography using a Chiral stationary phase ("Chiral Liquid Chromatography" (1989) W.J.Lough, Ed., Chapman and Hall, New York; Okamoto, J.Chromatogr., 1990)513: 375-. Enriched or purified enantiomers can be distinguished by methods for distinguishing other chiral molecules with asymmetric carbon atoms, such as optical or circular dichroism (circular dichroism).

General preparation method

FIG. 1 shows an exemplary synthesis of 4-aminopyrazole compound 5. 4-nitro-1H-pyrazole 1 is converted to 2 by treatment with base, either neat or in a suitable solvent, followed by addition of an alkylating agent such as dimethyl sulfate. Compound 2 can be converted to 5-chloro-4-nitro-1H-pyrazole 3 by treatment with a base such as lithium hexamethyldisilazide or nBuLi in a suitable solvent at an appropriate temperature, such as THF at-78 deg.C. Compound 3 can be converted to compound 4 by direct SnAr or transition metal catalyzed cross coupling reactions such as suzuki, Sonogashira, Heck, Buchwald, Goldberg conditions in a known manner. 4-Aminopyrazole 5 can be synthesized from 4 by suitable synthesisReduction processes, e.g. treatment with zinc dust and ammonium formate in tetrahydrofuran, or with H₂And transition metal catalysts such as palladium on carbon hydride.

FIG. 2 shows a schematic synthesis of 4-carboxyoxy-thiazole 11 from the hydroxyamide compound 6. By dissolving in a suitable solvent such as Na₂S₂O₃Reduction of 6 in aqueous solution gives 7 which can be converted to 8 by an alkylating agent in a suitable solvent with a suitable base such as benzoyl chloride in dichloromethane and sodium bicarbonate. Compound 8 can be converted to 9 by thionic reagents in a suitable solvent such as pyridine and protected to 10 by a suitable Boc protecting group. Hydrolysis 10 using a suitable base and solvent such as LiOH and water esters in methanol gives 11.

FIG. 3 shows an exemplary 2-substituted 4-carboxyoxy-5-aminothiazole 11 by C-2 bromination 12 followed by Suzuki reaction of 13. Suzuki-type coupling reactions are used to attach heterocycles or heteroaryls by substituting the halide at the 2-position of the thiazole, pyridyl, pyrazinyl or pyrimidinyl ring in the synthesis of compounds of formula I. For example, 2-bromo (or chloro) thiazole 11 can be reacted with about 1.5 equivalents of an aryl, heterocyclyl, or heteroaryl boronic acid or ester reagent and an excess of aqueous sodium carbonate in acetonitrile. A catalytically metered or greater amount of a palladium suboxide reagent such as dichlorobis (triphenylphosphine) palladium (II) is added. Various boronic acids or esters may be used. Borate esters may be used. The borate ester includes pinacol (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) ester. Furthermore, the nitrogen of the heterocyclic or heteroaryl group may need to be protected, for example as N-THP. In some cases, potassium acetate was used in place of sodium carbonate to adjust the pH of the aqueous layer. The reaction may be heated under pressure to about 140 ℃ and 150 ℃ for 10-30 minutes in a microwave reactor such as a Biotage Optimizer (Biotage, Inc.). The contents are extracted with ethyl acetate or other organic solvent. After evaporation of the organic layer, the suzuki coupling product can be purified again on silica or by reverse phase HPLC.

Various palladium catalysts may be used during the suzuki coupling step to form exemplary compounds of formula I. The low-valence Pd (II) and Pd (0) catalysts can be used for suzuki coupling reaction, and comprisePdCl₂(PPh₃)₂、Pd(t-Bu)₃、PdCl₂dppfCH₂Cl₂、Pd(PPh₃)₄、Pd(Oac)/PPh₃、Cl₂Pd[(Pet₃)]₂、Pd(DIPHOS)₂、Cl₂Pd(Bipy)、[PdCl(PH₂PCH₂PPH₂)]₂、Cl₂Pd[P(o-tol)₃]₂、Pd₂(dba)₃/P(o-tol)₃、Pd₂(dba)/P (furyl)₃、Cl₂Pd [ P (furyl)₃]₂、Cl₂Pd(PmePH₂)₂、Cl₂Pd[P(4-F-Ph)₃]₂、Cl₂Pd[P(C₆F6)₃]₂、Cl₂Pd[P(2-COOH-Ph)(Ph)₂]₂、Cl₂Pd[P(4-COOH-Ph)(Ph)₂]₂And an encapsulated catalyst Pd EnCat^TM30、Pd EnCat^TMTPP30 and Pd (II) EnCat^TMBINAP30(US2004/0254066)。

FIG. 4 shows an exemplary synthesis of 5-azepanyl-N- (pyrazol-4-yl) thiazole-carboxamide compound 17 from the coupling of 4-amino, 5-azepanyl pyrazole compound 14 and 2-bromo, 4-carboxyoxy-5-aminothiazole 11. Compounds 14 and 11 can be coupled using amide coupling reagents such as HATU, HBTU in suitable solvents such as dichloromethane or DMF. The coupled intermediate 15 can then be purified by using the appropriate acid or base, K in solvents such as HCl in dioxane and trifluoroacetic acid or acetonitrile in water or dichloromethane₂CO₃Is converted into compound 17. In addition, when R is⁵In the case of a halogen group such as bromine, compound 15 can be subjected to Suzuki or Stille conditions to provide compound 16. K in a suitable solvent such as HCl in dioxane and trifluoroacetic acid or acetonitrile in water or dichloromethane with a suitable acid or base under acidic or basic conditions₂CO₃Wherein the protecting group of the compound of formula 16 is removed to give compound 17.

FIG. 5 shows the synthesis of 4-amino, 5-azepane pyrazole compound 14 and 2-bromo, 3-Boc-amino, 6-carboxyoxy-pyridinyl compound 18Exemplary synthesis of 6-amino-N- (pyrazol-4-yl) pyridinyl-carboxamide compound 21. Compounds 14 and 18 can be coupled using amide coupling reagents such as HATU, HBTU using suitable solvents such as dichloromethane or DMF. The coupled intermediate 19 can be subjected to suzuki or Stille conditions to afford compound 20. K in a suitable solvent such as HCl in dioxane and trifluoroacetic acid or acetonitrile in water or dichloromethane with a suitable acid or base under acidic or basic conditions₂CO₃The protecting group of compound 20 is removed to give compound 21.

FIG. 6 shows a schematic synthesis of 6-amino-N- (pyrazol-4-yl) pyrazine-carboxamide compound 26 from the coupling of 4-amino, 5-diazepanyl pyrazole compound 22 and 2-bromo, 3-substituted 6-carboxyoxy-5-aminopyrazinyl compound 23. Compounds 22 and 23 can be coupled using amide coupling reagents such as HATU, HBTU using suitable solvents such as dichloromethane or DMF. The coupled intermediate 24 can be subjected to suzuki or Stille conditions to provide compound 25. K in a suitable solvent such as HCl in dioxane and trifluoroacetic acid or acetonitrile in water or dichloromethane with a suitable acid or base under acidic or basic conditions₂CO₃Compound 26 can be obtained by removing the protecting group of compound 25.

FIG. 7 shows a schematic synthesis of 5-azido- (4-nitro-1H-pyrazol-5-yl) azepane 32 from 2,3,6, 7-tetrahydro-1H-azepine 27. Compound 27 can be converted to compound 28 by treatment with m-CPBA or similar methods in the literature. Compound 29 can be synthesized from compound 28 by ring-opening the epoxide with sodium azide according to literature procedures. The R protecting group of compound 29 can be removed by suitable acidic or basic or hydrogenation conditions or other known literature methods. Compound 30 can be reacted with compound 3 by heating with potassium fluoride in a suitable solvent such as dimethyl sulfoxide to provide compound 31. Compound 31 can be O-alkylated using sodium hydride or iodomethane or other methylation methods described in the literature to give 5-azido- (4-nitro-1H-pyrazol-5-yl) azepane compound 32. Compound 31 can be converted to 32 by a nucleophilic fluorinating agent such as DAST. Compound 31 can be converted to 32 by oxidation to a ketone followed by nucleophilic reaction with an organometallic reagent such as lithium or a Grignard reagent or followed by a nucleophilic fluorination reagent such as DAST.

FIG. 8 shows a schematic synthesis of 5-Boc-amino- (4-nitro-1H-pyrazol-5-yl) azepane 39 from 6, 7-dihydro-1H-azepin-3 (2H) -one 33. Compound 33 can be converted to 5-azido-azepan-3-one 34 by heating with TMS-azide and Amberlite IRA900F resin in a suitable solvent such as acetonitrile. Reduction of 34 ketone 34 using sodium borohydride in THF and water or other methods described in the literature gives 5-azido-azepan-3-ol 35. The R protecting group of compound 35 can be removed by suitable acidic or basic or hydrogenation conditions or other known literature methods. The resulting amine can be converted to 5-azido-1- (4-nitro-1H-pyrazol-5-yl) azepan-3-ol 36 by heating with 5-chloro-4-nitro-1H-pyrazole 3 and potassium fluoride in a solvent such as dimethyl sulfoxide. Compound 36 can be converted to 5- (N-Boc) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol 37 using Staudinger azide reduction with triphenylphosphine in THF and water, followed by protection of the resulting amine with a suitable protecting agent such as Boc protecting agent using methods described or those described in the literature. Oxidation of 37 by treatment with dess-martin reagent or methods described in the literature gives tert-butyl 1- (4-nitro-1H-pyrazol-5-yl) -6-oxoazepan-4-ylcarbamate 38. Compound 38 can be prepared byTreated in a suitable solvent such as dichloromethane or converted to 39 by methods described in the literature. Compound 38 can be converted to 39 by treatment with an organometallic reagent such as lithium or a grignard reagent or by methods described in the literature.

FIG. 9 shows a schematic synthesis of 5- (4-azido-1-fluorocycloheptyl) -4-nitro-1H-pyrazole 45 from 4-nitro-1H-pyrazole 2. Treatment of 4-nitro-1H-pyrazole 2 with (Z) -cyclohept-4-enone 40 and a base such as lithium hexamethyldisilazide in a suitable solvent such as THF at a suitable temperature or other methods described in the literature affords 1- (4-nitro-1H-pyrazol-5-yl) cyclohept-4-enol 41. To be provided withTreatment of 41 in a suitable solvent such as DCM or other methods described in the literature affords 5- (1-fluorocyclohept-4-enyl) -4-nitro-1H-pyrazole 42. Epoxidation of 42 with m-CPBA or by similar methods reported in the literature to give 5- (4-fluoro-8-oxabicyclo [5.1.0]Oct-4-yl) -4-nitro-1H-pyrazole 43. The epoxide of 43 was opened with sodium azide according to literature procedures to give 2-azido-5-fluoro-5- (4-nitro-1H-pyrazol-5-yl) cycloheptanol 44. O-alkylation of 44 using sodium hydride and methyl iodide or by other methylation methods described in the literature gives 45, where R is²Is O-alkyl and R³Is H. Compound 44 can be converted to 45 by nucleophilic fluorination with a reagent such as DAST, wherein R²And R³Is F. Compound 44 can be converted to 45 by oxidation to a ketone followed by nucleophilic fluorination with an organometallic reagent such as lithium or a Grignard reagent or followed by nucleophilic fluorination with a reagent such as DAST, where R²(R⁵) Is alkyl and R³Is F.

FIG. 10 shows a schematic synthesis of 3-fluoro-1- (4-nitro-1H-pyrazol-5-yl) azepan-4-amine 52 from 5-chloro-4-nitro-1H-pyrazole 3. With piperidin-4-one hydrochloride hydrate and potassium fluoride in a suitable solvent such as dimethylsulfoxide or using literature procedures to heat 3 to afford 1- (4-nitro-1H-pyrazol-5-yl) piperidin-4-one 46. Heating 46 with trimethylsilylchloride and triethylamine in a suitable solvent such as DMF or using methods described in the literature gives 1- (4-nitro-1H-pyrazol-5-yl) -4- (trimethylsilyloxy) -1,2,3, 6-tetrahydropyridine 47. Use ofFluorination of 47 in acetonitrile at a suitable temperature or using methods described in the literature gives 3-fluoro-1- (4-nitro-1H-pyrazol-5-yl) piperidin-4-one 48. Expansion of the 48-ring to 6-fluoro-1- (4-nitro-1H-pyrazol-5-yl) -5-oxoazepane-4-carboxylic acid ethyl ester 49 can be achieved using ethyl diazoacetate and boron trifluoride diethyl ether in a suitable solvent such as dichloromethane at a suitable temperature or using methods described in the literature. By passingDecarboxylation of 49 with hydrochloric acid, heated at a suitable temperature or by methods described in the literature, gives 3-fluoro-1- (4-nitro-1H-pyrazol-5-yl) azepan-4-one 50. Reductive amination of 50 by methods described in the literature gives 3-fluoro-1- (4-nitro-1H-pyrazol-5-yl) azepan-4-amine 51. The amine of 51 can be protected using a suitable protecting group such as trifluoroacetamide, trifluoroacetic anhydride and diisopropylethylamine in a suitable solvent such as dichloromethane, or other methods described in the literature to give amine-protected 52.

Examples

Example 15-chloro-1-methyl-4-nitro-1H-pyrazoles

To a 500mL round bottom flask containing 4-nitro-1-H-pyrazole (5g,44.2mmol) was added sodium hydroxide (1M,200mL) and dimethyl sulfate (31mL,330 mmol). The mixture was stirred at room temperature for 72 hours and the mixture was taken up with CH₂Cl₂(2X150 mL). The organic layer was separated and the solvent was distilled off to give 1-methyl-4-nitro-1H-pyrazole as a white solid (4.30g, 76%).

According to WO2007/99326, 1-methyl-4-nitro-1H-pyrazole (4.30g,33.8mmol) and THF (12mL) were added to a 500mL three-necked round bottom flask. The mixture was cooled to-78 ℃ and lithium hexamethyldisilazide (1M,88.4mL,90mmol) in THF was added dropwise over 20 minutes via the dropping funnel. The brown mixture was stirred for 30 minutes and warmed to-45 ℃ over 30 minutes. The mixture was cooled back to-78 ℃ and hexachloroethane (10.5g,44.2mmol) dissolved in THF (20mL) was added via dropping funnel over 15 minutes. The mixture was stirred for 2.5 hours, warmed from-78 ℃ to-40 ℃ and the reaction monitored by LCMS. When the reaction is complete, the reaction is saturated with NH₄The Cl solution (150mL) was quenched and ethyl acetate (100mL) was added. Separating the organic layerAnd the aqueous layer was quenched with ethyl acetate (100 mL). The combined organic layers were washed with water (150mL) and Na₂SO₄The organic solvent was dried and distilled off. The crude product was purified by flash Chromatography (CH)₂Cl₂MeOH/7%) to give 5-chloro-1-methyl-4-nitro-1H-pyrazole as a white solid (1.40)_g,20％)。¹H NMR(400MHz,CDCl₃)8.13(s,1H),3.92(s,3H)；ESIMS m/z＝162.0(M+1)

Example 2Tert-butyl 1- (4-amino-1-methyl-1H-pyrazol-5-yl) azepan-4-ylcarbamate.

To a10 mL microwave vial was added 5-chloro-1-methyl-4-nitro-1H-pyrazole (150mg,0.93mmol) from example 1, tert-butyl azepan-4-ylcarbamate (220mg,1.02 mmol). Ethanol (4mL) and diisopropylethylamine (1.00mL,8.00mmol) were added and the mixture was irradiated with microwaves at 130 ℃ for 60 minutes. The mixture was cooled, concentrated, and purified via flash chromatography (heptane/ethyl acetate 20% to 80%) to give a yellow oil (306mg, 97%).

To a 50mL round bottom flask were added nitro compound (306mg,0.90mmol), iron (202mg,3.61mmol), ammonium chloride (241mg,4.5mmol), ethanol (10mL), and water (1.5 mL). The mixture was stirred at 60 ℃ for 1 hour and the reaction was monitored by LCMS. Upon completion of the reaction, the mixture was filtered through a pad of celite and washed with ethyl acetate (30mL) and 10% K₃PO₄Was washed with aqueous solution (30 mL). The organic layer was washed with water (30mL) and Na₂SO₄Drying and distilling off the organic solvent gave 1- (4-amino-1-methyl-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester as a brown oil in the purity of>98％(264mg,95％)。ESIMS m/z＝310.1(M+1).

Practice ofExample 31- (1-methyl-4-amino-1H-pyrazol-5-yl) piperidin-4-ylcarbamic acid tert-butyl ester.

Following the procedure described in example 2, starting from tert-butyl piperidin-4-ylcarbamate, over two steps, tert-butyl 1- (1-methyl-4-amino-1H-pyrazol-5-yl) piperidin-4-ylcarbamate was obtained as a brown oil (173mg, 70%). ESIMS M/z 296.1(M +1).

Example 4(S) -1- (1-methyl-4-amino-1H-pyrazol-5-yl) piperidin-3-ylcarbamic acid tert-butyl ester.

Following the procedure described in example 2, starting from tert-butyl (S) -piperidin-3-ylcarbamate, over two steps, (S) -tert-butyl 1- (1-methyl-4-amino-1H-pyrazol-5-yl) piperidin-3-ylcarbamate was obtained as a brown oil (206mg, 75%). ESIMS M/z 296.1(M +1).

Example 4a1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -3- (trifluoromethyl) piperidine

Following the procedure for intermediate 22, starting from 5-chloro-1-methyl-4-nitro-1H-pyrazole and 3- (trifluoromethyl) piperidine, 107 was obtained as a yellow oil (499mg, 97%).¹H NMR(400MHz,CDCl₃)8.03(s,1H),3.77(s,3H),3.41-3.32(m,1H),3.31-3.18(m,2H),3.07-2.97(m,1H),2.54-2.40(m,1H),2.13-2.06(m,1H),1.97-1.90(m,1H),1.80-1.60(m,2H).

Example 5(S) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) pyrrolidin-3-ylcarbamic acid tert-butyl ester

Following the procedure described in example 2, starting from tert-butyl (S) -pyrrolidin-3-ylcarbamate, over two steps, (S) -tert-butyl 1- (4-amino-1-methyl-1H-pyrazol-5-yl) pyrrolidin-3-ylcarbamate was obtained as a brown oil (162mg, 62%). ESIMS M/z 282.1(M +1).

Example 64- ((4-amino-1-methyl-1H-pyrazol-5-yloxy) methyl) piperidine-1-carboxylic acid tert-butyl ester

To a 50mL round bottom flask was added 5-chloro-1-methyl-4-nitro-1H-pyrazole from example 1 (100mg,0.60mmol), 4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester (200mg,0.93mmol), and DMF (10 mL). NaH (37mg,1.55mmol) was added slowly and the mixture was stirred for 1 hour. The mixture was concentrated and purified via flash chromatography (heptane/ethyl acetate 20% to 80%) to give an oil (150mg, 70%).

To a 50mL round bottom flask was added the nitro compound (150mg,0.44mmol), iron (173mg,3.10mmol), ammonium chloride (199mg,3.71mmol), ethanol (10mL), and water (1.5 mL). The mixture was stirred at 60 ℃ for 1 hour and the reaction was monitored by LCMS. Upon completion of the reaction, the mixture was filtered through a pad of celite and washed with ethyl acetate (30mL) and 10% K₃PO₄Aqueous (30mL) wash. The organic layer was washed with water (30mL) and Na₂SO₄Drying and distilling off the organic solvent to give 4- ((4-amino-1-methyl)-1H-pyrazol-5-yloxy) methyl) piperidine-1-carboxylic acid tert-butyl ester as a brown oil in purity>98％(135mg,99％)。ESIMS m/z＝311.1(M+1).

Example 7(R) -1- (1-methyl-4-amino-1H-pyrazol-5-yl) piperidin-3-ylcarbamic acid tert-butyl ester

Following the procedure described in example 2, starting from tert-butyl (R) -piperidin-3-ylcarbamate, over two steps, (R) -tert-butyl 1- (1-methyl-4-amino-1H-pyrazol-5-yl) piperidin-3-ylcarbamate was obtained as a brown oil (187mg, 68%). ESIMS M/z 296.1(M +1).

Example 84- (4-amino-1-methyl-1H-pyrazol-5-yloxy) piperidine-1-carboxylic acid tert-butyl ester

Following the procedure described in example 6, starting from tert-butyl 4-hydroxypiperidine-1-carboxylate, over two steps, tert-butyl 4- (4-amino-1-methyl-1H-pyrazol-5-yloxy) piperidine-1-carboxylate was obtained as a brown oil (102mg, 50%). ESIMS M/z 297.1(M +1)

Example 9(R) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) pyrrolidin-3-ylcarbamic acid tert-butyl ester

Following the procedure described in example 2, starting from tert-butyl (R) -pyrrolidin-3-ylcarbamate, over two steps, (R) -tert-butyl 1- (4-amino-1-methyl-1H-pyrazol-5-yl) pyrrolidin-3-ylcarbamate was obtained as a brown oil (159mg, 61%). ESIMS M/z 282.1(M +1).

Example 104- ((4-amino-1-methyl-1H-pyrazol-5-ylamino) methyl) piperidine-1-carboxylic acid tert-butyl ester

Following the procedure described in example 2, starting from tert-butyl 4- (aminomethyl) piperidine-1-carboxylate, over two steps, tert-butyl 4- ((4-amino-1-methyl-1H-pyrazol-5-ylamino) methyl) piperidine-1-carboxylate was obtained as a brown oil (124mg, 43%). ESIMS M/z 310.1(M +1).

Example 11(S) - (1- (4-amino-1-methyl-1H-pyrazol-5-yl) pyrrolidin-3-yl) methylcarbamic acid tert-butyl ester

Following the procedure described in example 2, starting from tert-butyl (R) -pyrrolidin-3-ylmethyl carbamate, over two steps, (S) - (1- (4-amino-1-methyl-1H-pyrazol-5-yl) pyrrolidin-3-yl) methyl carbamate was obtained as a brown oil (230mg, 84%). ESIMS M/z 296.1(M +1)

Example 12(R) - (1- (4-amino-1-methyl-1H-pyrazol-5-yl) pyrrolidin-3-yl) methylcarbamic acid tert-butyl ester

Following the procedure described in example 2, starting from tert-butyl (S) -pyrrolidin-3-ylmethyl carbamate, over two steps, (R) - (1- (4-amino-1-methyl-1H-pyrazol-5-yl) pyrrolidin-3-yl) methyl carbamate was obtained as a brown oil (200mg, 73%). ESIMS M/z 296.1(M +1).

Example 13(1- (4-amino-1H-pyrazol-5-yl) piperidin-4-yl) methylcarbamic acid tert-butyl ester

Following the procedure described in example 2, starting from tert-butyl piperidin-4-ylmethylcarbamate, over two steps, tert-butyl (1- (4-amino-1H-pyrazol-5-yl) piperidin-4-yl) methylcarbamate was obtained as a brown oil (270mg, 98%). ESIMS M/z 310.1(M +1).

Example 14(S) - (1- (4-amino-1-methyl-1H-pyrazol-5-yl) piperidin-3-yl) methylcarbamic acid tert-butyl ester

Following the procedure described in example 2, starting from tert-butyl (R) -piperidin-3-ylmethyl carbamate, over two steps, (S) - (1- (4-amino-1-methyl-1H-pyrazol-5-yl) piperidin-3-yl) methyl carbamate was obtained as a brown oil (270mg, 98%). ESIMS M/z 310.1(M +1).

Example 15(R) - (1- (4-amino-1-methyl-1H-pyrazol-5-yl) piperidin-3-yl) methylcarbamic acid tert-butylEsters

Following the procedure described in example 2, starting from tert-butyl (S) -piperidin-3-ylmethyl carbamate, over two steps, (R) - (1- (4-amino-1-methyl-1H-pyrazol-5-yl) piperidin-3-yl) methyl carbamate was obtained as a brown oil (268mg, 98%). ESIMS M/z 310.1(M +1)

Example 16(R) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid benzyl ester

Starting from benzyl (R) -azepan-4-ylcarbamate, following the procedure described in example 2, over two steps, benzyl (R) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) azepan-4-ylcarbamate was obtained as a brown oil (191mg, 60%). ESIMS M/z 344.1(M +1).

Example 17(S) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid benzyl ester

Starting from (S) -azepan-4-ylcarbamic acid benzyl following the procedure described in example 2, two steps were performed to give (S) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid benzyl ester as a brown oil (220mg, 63%). ESIMS M/z 344.1(M +1).

Example 183- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-azabicyclo [3.1.0]6-Hexanecarboxylic acid tert-butyl ester

Following the procedure described in example 2, starting from tert-butyl 3-azabicyclo [3.1.0] hex-6-ylcarbamate, over two steps, tert-butyl 3- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-azabicyclo [3.1.0] hex-6-ylcarbamate was obtained as a brown oil (130mg, 48%). ESIMS M/z 294.1(M +1).

Example 192-amino-2-cyanoacetic acid ethyl ester

(E) A stirred solution of ethyl (E) -2-cyano-2- (hydroxyimino) acetate (20g,0.14mol) in water (250mL) was added NaHCO₃Then Na was added thereto (160mL) to prepare a saturated aqueous solution₂S₂O₄(60g,0.423 mol). The reaction mixture was warmed to 35 ℃ and stirred for an additional 2 hours. Then saturated with NaCl (150g) and extracted with DCM (3 × 350 mL). The combined organic layers were washed with brine, over Na₂SO₄Drying, filtration and concentration in vacuo gave ethyl 2-amino-2-cyanoacetate as a red oil (7.8g, 43%) which was used in the next step without additional purification.¹H-NMR(CDCl₃,500MHz)(ppm):4.45(s,1H),4.34(q,J＝7.0Hz,2H),1.36(t,J＝7.0Hz,3H)；MS(ESI)m/z:129[M+H+]。

Example 202-Benzamido-2-cyanoacetic acid ethyl ester

To a stirred solution of compound ethyl 2-amino-2-cyanoacetate (0.64g,5mmol) in DCM (15mL) was added NaHCO₃Saturated aqueous solution (15 mL). With vigorous stirring, benzoyl chloride (0.84g,6mmol) was added. The reaction mixture was stirred at room temperature for an additional 30 minutes, at which time it was extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄Drying, filtering and vacuum concentrating. The resulting residue was purified by silica gel column chromatography (5:1PE/EtOAc) to give ethyl 2-benzamide-2-cyanoacetate (0.25g, 22%) as a white solid:¹H-NMR(CDCl₃,500MHz)(ppm):7.83-7.85(m,2H),7.59(t,J＝7.5Hz,1H),7.49(t,J＝7.5Hz,2H),7.02(d,J＝7.0Hz,1H),5.72(d,J＝7.5Hz,1H),4.40(q,J＝7.5Hz,2H),1.39(t,J＝7.0Hz,3H)；MS(ESI)m/z:233[M+H+]。

example 215-amino-2-phenylthiazole-4-carboxylic acid ethyl ester

A stirred solution of the compound ethyl 2-benzamide-2-cyanoacetate (0.46g,2mmol) in pyridine (20mL) was added with Lawesson's reagent (0.81g,2 mmol). The reaction mixture was heated at reflux for 15 hours. It was then concentrated and diluted with EtOAc (40 mL). The diluted mixture was washed with water (3 × 20mL), brine (10mL), and Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (10:1PE/EtOAc) to give ethyl 5-amino-2-phenylthiazole-4-acetate (0.2g, 40%) as a yellow solid:¹H-NMR(CDCl₃,500MHz)(ppm):7.80(d,J＝6.5Hz,1H),7.36-7.41(m,3H),4.43(q,J＝7.0Hz,2H),1.44(t,J＝7.0Hz,3H)；MS(ESI)m/z:249[M+H+]。

example 225- (tert-Butoxycarbonylamino) -2-phenylthiazole-4-acetic acid ethyl ester

To the compound ethyl 5-amino-2-phenylthiazole-4-acetate (248mg,1mmol) in CH₃DMAP (6mg,0.05mmol) was added to a solution of CN (10mL), followed by addition of (Boc)₂O (262mg,1.2 mmol). The reaction mixture was kept at ambient temperature for a further 30 minutes. The mixture was then evaporated in vacuo to give 5- (tert-butoxycarbonylamino) -2-phenylthiazole-4-acetic acid ethyl ester as a red solid (340mg, 95%), which was used in the next step without further purification.

Example 235- (tert-Butoxycarbonylamino) -2-phenylthiazole-4-carboxylic acid

To the compound ethyl 5- (tert-butoxycarbonylamino) -2-phenylthiazole-4-carboxylate (348mg,1mmol) in MeOH/H₂Solution in O (10mL,1:1) LiOH. H was added₂O (20mg,5 mmol). The reaction mixture was heated at 50-55 ℃ until the starting material disappeared from TLC. It was cooled at about 0-4 ℃ and concentrated HCl was added dropwise until the pH was about 5. The resulting mixture was then extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, (2 × 20mL) over Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (50:1DCM: MeOH) to give 5- (tert-butoxycarbonylamino) -2-phenylthiazole-4-carboxylic acid (0.22g, 68%) as a white solid:¹H-NMR(CDCl₃,500MHz)(ppm):9.69(s,1H),7.89-7.91(m,2H),7.46-7.47(m,3H),1.57(s,9H)；MS(ESI)m/z:321[M+H+]

example 245- (tert-Butoxycarbonylamino) -2- (2-fluorophenyl) thiazole-4-carboxylic acid

Following examples 19-23 and the procedure shown in FIG. 2, 2-fluorobenzoyl chloride was converted to 5- (tert-butoxycarbonylamino) -2- (2-fluorophenyl) thiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.70(s,1H),8.19-8.23(m,1H),7.42-7.45(m,1H),7.20-7.30(m,2H),1.57(s,9H)；MS(ESI)m/z:339[M+H+]

example 255- (tert-Butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid

According to examples 19-23 and the procedure shown in FIG. 2, 6-difluorobenzoyl chloride was converted to 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid:¹H-NMR(CD3OD,500MHz)(ppm):7.42-7.46(m,1H),7.06(t,J＝8.5Hz,2H),1.47(s,9H)；MS(ESI)m/z:355[M+H+]。

example 265- (tert-Butoxycarbonylamino) -2- (2-chlorophenyl) thiazole-4-carboxylic acid

Following examples 19-23 and the procedure shown in FIG. 2, 2-chlorobenzoyl chloride was converted to 5- (tert-butoxycarbonylamino) -2- (2-chlorophenyl) thiazole-4-carboxylic acid:¹H-NMR(DMSO,500MHz)(ppm):13.57(s,1H),10.05(s,1H),8.14-8.17(m,1H),7.63-7.65(m,1H),7.49-7.51(m,2H),1.53(s,9H)；MS(ESI)m/z:355[M+H+]。

example 272- (5-bromo-2-fluorophenyl) -5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid

Following examples 19-23 and the procedure shown in figure 2, 5-bromo-2-fluorobenzoyl chloride was converted to 2- (5-bromo-2-fluorophenyl) -5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.70(s,1H),8.32-8.34(m,1H),7.49-7.52(m,1H),7.09-7.13(m,1H),1.57(s,9H)；MS(ESI)m/z:418[M+H+]。

example 282- (5-bromo-2-chlorophenyl) -5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid

Following examples 19-23 and the procedure shown in FIG. 2, 5-bromo-2-chlorobenzoyl chloride was converted to 2- (5-bromo-2-chlorophenyl) -5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.70(s,1H),8.31(d,J＝2.5Hz,1H),7.47(dd,J＝2.5Hz,J＝8.5Hz,1H),7.35(d,J＝9.0Hz,1H),1.57(s,9H)；MS(ESI)m/z:433[M+H+]。

example 292- (3-bromophenyl) -5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid

According to examples 19-23 and the procedure shown in FIG. 2, 3-bromobenzoyl chloride is converted to 2- (3-bromophenyl) -5- (tert-butoxycarbonylamino)Thiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.68(s,1H),8.08(s,1H),7.78(d,J＝8.0Hz,1H),7.56(d,J＝8.0Hz,1H),7.32(t,J＝8.0Hz,1H),1.57(s,9H)；MS(ESI)m/z:399[M+H+]

example 302- (4-bromo-2-fluorophenyl) -5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid

Following examples 19-23 and the procedure shown in figure 2, 4-bromo-2-fluorobenzoyl chloride was converted to 2- (4-bromo-2-fluorophenyl) -5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.67(s,1H),8.07(t,J＝8.0Hz,1H),7.42(d,J＝9.5Hz,1H),1.57(s,9H)；MS(ESI)m/z:417[M+H+]

example 315- (tert-Butoxycarbonylamino) -2- (pyridin-2-yl) thiazole-4-carboxylic acid

To a solution of picolinic acid (1.23g,10mmol), EDC.HCl (1.91g,10mmol) and HOBT (1.35g,10mmol) in THF (80mL) at ambient temperature was added DIPEA (3.6g,30 mmol). The reaction mixture was held at the same temperature for 1 hour, at which time a solution of ethyl 2-amino-2-cyanoacetate (1.28g,10mmol) in THF (5mL) was added. The reaction mixture was stirred at room temperature for an additional 6 hours. It was then concentrated and the residue was purified by silica gel column chromatography (5:1PE/EtOAc) to give ethyl 2-cyano-2- (picolinamido) acetate (0.7g, 30%) as a yellow solid.

Following the procedures shown in examples 19-23 and FIG. 2, ethyl 2-cyano-2- (picolinamido) acetate was converted to 5- (tert-butoxycarbonylamino) -2- (pyridine-2-Yl) thiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.72(s,1H),8.61(d,J＝4.5Hz,1H),8.09(d,J＝8.0Hz,1H),7.81(t,J＝7.5Hz,1H),7.34(dd,J＝5.5Hz,J＝7.0Hz,1H),1.57(s,9H)；MS(ESI)m/z:322[M+H+]。

example 325- (tert-Butoxycarbonylamino) -2-isopropylthiazole-4-carboxylic acid

According to the procedures shown in examples 19-23 and in FIG. 2, isobutyryl chloride was converted to 5- (tert-butoxycarbonylamino) -2-isopropylthiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.54(s,1H),3.16-3.21(m,1H),1.54(s,9H),1.37(d,J＝7.0Hz,6H)；MS(ESI)m/z:287[M+H+]。

example 335- (tert-Butoxycarbonylamino) -2-cyclohexylthiazole-4-carboxylic acid

Following the procedures shown in examples 19-23 and in FIG. 2, cyclohexane carboxylic acid chloride was converted to 5- (tert-butoxycarbonylamino) -2-cyclohexylthiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.53(s,1H),2.84-2.89(m,1H),2.08-2.12(m,2H),1.84(dd,J＝3.5Hz,J＝10.0Hz,2H),1.73(d,J＝13.0Hz,1H),1.53(s,9H),1.35-1.50(m,4H),1.25-1.27(m,1H)；MS(ESI)m/z:327[M+H+]。

example 345- (tert-Butoxycarbonylamino) -2-o-tolylthiazole-4-carboxylic acid

Following examples 19-23 and the procedure shown in FIG. 2, 2-methylbenzoyl chloride was converted to 5- (tert-butoxycarbonylamino) -2-o-tolylthiazole-4-carboxylic acid:¹H-NMR(CD3OD,500MHz)(ppm):7.34(s,1H),7.13-7.22(m,3H),2.32(s,3H),1.43(s,9H)；MS(ESI)m/z:335[M+H+]。

example 355- (tert-Butoxycarbonylamino) -2- (2-methoxyphenyl) thiazole-4-carboxylic acid

Following the procedures shown in examples 19-23 and in FIG. 2, 2-methoxybenzoyl chloride was converted to 5- (tert-butoxycarbonylamino) -2- (2-methoxyphenyl) thiazole-4-carboxylic acid:¹H-NMR(CD3OD,500MHz)(ppm):9.63(s,1H),8.27(d,J＝7.5Hz,1H),7.42(t,J＝8.0Hz,1H),7.09(t,J＝7.5Hz,1H),7.04(d,J＝9.0Hz,1H),1.57(s,9H)；MS(ESI)m/z:351[M+H+]

example 365- (tert-Butoxycarbonylamino) -2- (2- (trifluoromethyl) phenyl) thiazole-4-carboxylic acid

Following examples 19-23 and the procedure shown in figure 2,2- (trifluoromethyl) benzoyl chloride was converted to 5- (tert-butoxycarbonylamino) -2- (2- (trifluoromethyl) phenyl) thiazole-4-carboxylic acid:¹H-NMR(CD3OD,500MHz)(ppm):7.76(d,J＝7.5Hz,1H),7.58-7.64(m,3H),1.46(s,9H)；MS(ESI)m/z:389[M+H+]。

example 375- (tert-butyl) benzeneOxycarbonylamino) -2-methylthiazole-4-carboxylic acid

According to the procedures shown in examples 19-23 and FIG. 2, acetyl chloride was converted to 5- (tert-butoxycarbonylamino) -2-methylthiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.62(s,1H),2.62(s,3H),1.54(s,9H)；MS(ESI)m/z:259[M+H+]

example 385- (tert-Butoxycarbonylamino) thiazole-4-carboxylic acid

Under nitrogen atmosphere (N)₂) HCOOH (2.44g,53mmol) was added to AC at 0 deg.C₂O (6.48g,63.6 mmol). After warming to ambient temperature, the reaction was heated at 50 ℃ for 15 hours. It was cooled to ambient temperature. The mixed anhydride was then added dropwise to a solution of ethyl 2-amino-2-cyanoacetate (128mg,1mmol) in anhydrous THF (5mL) at 0 deg.C. After removal of the cooling bath, the reaction was held at ambient temperature for an additional 1 hour. The reaction mixture was concentrated and purified by silica gel column chromatography (5:1PE/EtOAc) to give ethyl 2-cyano-2-carboxamidoacetate (110mg, 70%) as a white solid.

Following the procedures shown in examples 19-23 and in figure 2, ethyl acetate, 2-cyano-2-carboxamide base was converted to 5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.70(s,1H),8.29(s,1H),1.55(s,9H)；MS(ESI)m/z:245[M+H+]

example 392-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid

To a solution of 5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid (1.72g,10mmol) in DCM (50mL) was added NBS (1.95g,11mmol) in three portions; the reaction mixture was stirred at ambient temperature for 1 hour. Carrying out vacuum concentration reaction; the resulting residue was purified by silica gel column chromatography (6:1 petroleum ether-EtOAc) to give 2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid (1.75g, 70%) as a white solid:¹H-NMR(CDCl₃,500MHz)(ppm):13.65(s,1H),10.03(s,1H),1.49(s,9H)。MS(ESI)m/z:324[M+H+]

example 405- (tert-Butoxycarbonylamino) -2- (2, 5-difluorophenyl) thiazole-4-carboxylic acid

According to examples 19-23 and the procedure shown in FIG. 2, 5-difluorobenzoyl chloride was converted to 5- (tert-butoxycarbonylamino) -2- (2, 5-difluorophenyl) thiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.68(s,1H),7.87-7.91(m,1H),7.15-7.26(m,1H),7.08-7.13(m,1H),1.57(s,9H)；MS(ESI)m/z:357[M+H+]

EXAMPLE 415- (tert-Butoxycarbonylamino) -2- (2, 4-difluorophenyl) thiazole-4-carboxylic acid

According to examples 19-23 and the procedure shown in FIG. 2, 4-difluorobenzoyl chloride was converted to 5- (tert-butoxycarbonylamino) -2- (2, 4-difluorophenyl) thiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.66(s,1H),8.16-8.21(m,1H),6.95-7.04(m,2H),1.62(s,9H)；MS(ESI)m/z:357[M+H+]

example 425- (tert-Butoxycarbonylamino) -2- (2, 3-difluorophenyl) thiazole-4-carboxylic acid

According to examples 19-23 and the procedure shown in FIG. 2, 3-difluorobenzoyl chloride was converted to 5- (tert-butoxycarbonylamino) -2- (2, 3-difluorophenyl) thiazole-4-carboxylic acid:¹H-NMR(CD3OD,400MHz)(ppm):7.45(s,1H),7.07-7.16(m,2H),1.42(s,9H)；MS(ESI)m/z:357[M+H+]。

example 432-benzyl-5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid

Following examples 19-23 and the procedure shown in FIG. 2, 2-phenylacetyl chloride was converted to 2-benzyl-5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.63(s,1H),7.27-7.35(m,5H),4.25(s,2H),1.50(s,9H)；MS(ESI)m/z:335[M+H+]。

example 445- (tert-Butoxycarbonylamino) -2- (quinolin-7-yl) thiazole-4-carboxylic acid

Following the procedures shown in examples 19-23 and in FIG. 2, quinoline-7-carbonyl chloride was converted to 5- (tert-butoxycarbonylamino) -2- (quinolin-7-yl) thiazole-4-carboxylic acid:¹H-NMR(DMSO,500MHz)(ppm):10.14(s,1H),9.11(d,J＝5Hz,1h),8.68(s,1H),8.55(s,1H),8.21-8.25(m,2H),7.75-7.77(m,1H),1.54(s,9H)；MS(ESI)m/z:372[M+H+]

example 455- (tert-Butoxycarbonylamino) -2- (imidazo [1, 2-a)]Pyridin-2-yl) thiazole-4-carboxylic acid

Imidazo [1,2-a ] according to the procedures shown in examples 19-23 and in FIG. 2]Conversion of pyridine-2-carbonyl chloride to 5- (tert-butoxycarbonylamino) -2- (imidazo [1, 2-a)]Pyridin-2-yl) thiazole-4-carboxylic acid:¹H-NMR(DMSO,500MHz)(ppm):10.12(s,1H),8.58(d,5Hz,1H),8.45(s,1H),7.61(d,5Hz,1H),7.31-7.34(m,1H),6.97-6.99(m,1H),1.53(s,9H)；MS(ESI)m/z:361[M+H+]。

example 465- (tert-Butoxycarbonylamino) -2-tert-butylthiazole-4-carboxylic acid

Following the procedures shown in examples 19-23 and in FIG. 2, pivaloyl chloride was converted to 5- (tert-butoxycarbonylamino) -2-tert-butylthiazole-4-carboxylic acid:¹H-NMR(CDCl₃,500MHz)(ppm):9.55(s,1H),1.55(s,9H),1.42(s,9H)；MS(ESI)m/z:301[M+H+]。

example 475- (tert-Butoxycarbonylamino) -2- (3-chlorophenyl) thiazole-4-carboxylic acid

Following examples 19-23 and the procedure shown in FIG. 2, 3-chlorobenzoyl chloride was converted to 5- (tert-butoxycarbonylamino) -2- (3-chlorophenyl) thiazole-4-carboxylic acid:¹H-NMR(DMSO,500MHz)(ppm):9.67(s,1H),7.91(s,1H),7.72(d,J＝7Hz,1H),7.38-7.40(m,2H),1.56s,9H)；MS(ESI)m/z:355[M+H+]。

example 485- (tert-Butoxycarbonylamino) -2- (4-chlorophenyl) thiazole-4-carboxylic acid

Following examples 19-23 and the procedure shown in FIG. 2, 4-chlorobenzoyl chloride was converted to 5- (tert-butoxycarbonylamino) -2- (4-chlorophenyl) thiazole-4-carboxylic acid:¹H-NMR(DMSO,500MHz)(ppm):9.66(s,1H),7.81(d,J＝8.5Hz,2H),7.42(d,J＝8.5Hz,2H),1.56(s,9H)；MS(ESI)m/z:355[M+H+]。

example 495-amino-N- (1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

Following the procedure described in example 113, 1-methyl-1H-pyrazol-4-amine, 5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid were reacted to give 5-amino-N- (1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide as a white solid (13mg, 32%) over two steps. ESIMS M/z 336.1(M +1)

Example 503- (4-amino-1-methyl-1H-pyrazol-5-yl) phenylcarbamic acid tert-butyl ester

To a10 mL microwave vial was added 5-chloro-1-methyl-4-nitro-1H-pyrazole from example 1 (150mg,0.93mmol), 3- (tert-butoxycarbonylamino) phenylboronic acid (440mg,1.86mmol), dichloro [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) (152mg,0.019mmol), Na₂CO₃A1: 1M solution of/KOAc (1mL) and acetonitrile (4 mL). The mixture was irradiated to 130 ℃ using microwaves for 40 minutes, cooled, concentrated and purified via flash chromatography, heptane/ethyl acetate 20% to 95% to give a yellow oil. To a 50mL round bottom flask was added the nitro compound (120mg,0.90mmol), iron (156mg,2.8mmol), ammonium chloride (200mg,3.7mmol), ethanol (10mL), and water (1.5 mL). The mixture was stirred for 1 hour and the reaction was monitored by LCMS. Upon completion of the reaction, the mixture was filtered through a pad of celite and washed with ethyl acetate (30mL) and 10% K₃PO₄Aqueous (30mL) wash. The organic layer was washed with water (30mL) and Na₂SO₄Drying and distilling off the organic solvent to obtain 3- (4-amino-1-methyl-1H-pyrazol-5-yl) phenyl carbamic acid tert-butyl ester as brown oil with purity of>98％(120mg,45％)。ESIMS m/z＝289.1(M+1)

Example 511-methyl-5-o-tolyl-1H-pyrazol-4-amine

Following the procedure described in example 2, starting from o-tolylboronic acid, in two steps, 1-methyl-5-o-tolyl-1H-pyrazol-4-amine was obtained as a brown oil (148mg, 85%). ESIMS M/z 188.1(M +1)

Example 522- (4-cyclopropyl-2-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane

Step 1 trifluoromethanesulfonic acid 3-fluoro-4-nitrophenyl ester

To a stirred solution of 3-fluoro-4-nitrophenol (10.00g,63.65mmol) and trifluoromethanesulfonic anhydride (20.0mL,119mmol,1.87 equiv.) in anhydrous DCM (100.0mL) was added triethylamine (33.27mL,238.7mmol,3.75 equiv.) dropwise at 0 deg.C. The resulting brown reaction mixture was stirred at 0 ℃ for 2 hours and then at ambient temperature for 16 hours. The reaction mixture was slowly quenched with water and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (1 ×), and over Na₂SO₄Dried, filtered, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography eluting with 0-5% DCM/hexanes to give 15.67g (85.1%) of 3-fluoro-4-nitrophenyl trifluoromethanesulfonate as an oil.¹H NMR(500MHz,CDCl₃)8.23(t,J＝8.52Hz,1H),7.34-7.27(m,2H).

Step 2-4-cyclopropyl-2-fluoro-1-nitrobenzene

3-fluoro-4-nitrophenyl trifluoromethanesulfonate (7.15g,24.73mmol), cyclopropylboronic acid (2.55g,29.67mmol), [1,1' -bis (diphenylphosphino) -ferrocene]A mixture of palladium (II) dichloride (complexed with dichloromethane (1:1)) (1.62g,1.98mmol) and 2M cesium carbonate in water (19.8mL,39.56mmol) was degassed in toluene (39.5mL) for 20 minutes. At 90 ℃ in N₂The reaction mixture was stirred for 2.5 hours. The reaction was cooled to RT, diluted with ethyl acetate (200mL) and filtered through a pad of Celite. The filtrate was washed with brine, over Na₂SO₄Dried, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography eluting with 0-75% DCM/hexanes to give 4.11g (91.7%) of 4-cyclopropyl-2-fluoro-1-nitrobenzene as an oil.¹H NMR(400MHz,MeOD)7.98(dd,J＝10.2,6.6Hz,1H),7.12-7.02(m,2H),2.11-1.97(m,1H),1.20-1.11(m,2H),0.89-0.82(m,2H).

Step 3-4-cyclopropyl-2-fluoroaniline

4-cyclopropyl-2-fluoro-1-nitrobenzene (3.36g,18.55mmol), iron powder (4.35g,77.9mmol) and 2M ammonium chloride in water (19.8mL) and 3:2:1v/v EtOH: THF: H₂Mixture in O (86mL) at reflux under N₂Stirred for 17 hours. The reaction mixture was cooled to RT and filtered through a pad of Celite. The Celite pad was rinsed well with ethyl acetate (-50 mL). Saturated NaHCO₃An aqueous solution was slowly added to the filtrate to neutralize the reaction mixture. The reaction mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with water and brine, over Na₂SO₄Dried, filtered, and concentrated under reduced pressure. The crude residue was purified via flash column chromatography eluting with 0-75% ethyl acetate/hexanes to give 2.80g (99%) of an orange oil which solidified at 20 ℃.¹H NMR(400MHz,CDCl₃)6.75-6.63(m,3H),3.57(s,2H),1.87-1.72(m,1H),0.93-0.83(m,2H),0.64-0.51(m,2H)；MS(ESI)m/z:152.3[M+H]+.

Step 4-4-cyclopropyl-2-fluoro-1-iodobenzene

To a stirred mixture of 4-cyclopropyl-2-fluoroaniline (1.63g,10.78mmol) in water (20mL) was added concentrated sulfuric acid (8.6mL,15.0 equivalents) dropwise at 0 deg.C, while keeping the temperature constant at 0 deg.C. A solution of sodium nitrite (781.0mg,11.32mmol,1.05 eq) in water (2.7mL) was added and stirred for 5 minutes. The reaction mixture was then added to a solution of potassium iodide (3.76g,22.64mmol,2.1 equivalents) in water (9.7mL) and the reaction mixture was stirred at 60 ℃ for 3 hours. DCM (400mL) was added to the cooled reaction. The two phase layers were separated and the aqueous layer was extracted with DCM (2 × 150 mL). The combined organic layers were saturated with Na₂S₂O₄Aqueous solution, water and brine, over Na₂SO₄Dried, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography eluting with 100% heptane to give 2.01g (71.28%) of 4-cyclopropyl-2-fluoro-1-iodobenzene as a clear oil.¹H NMR(400MHz,CDCl₃)7.57(dd,J＝8.0,6.9Hz,1H),6.76(dd,J＝9.4,1.9Hz,1H),6.64(dd,J＝8.2,1.9Hz,1H),1.94-1.77(m,1H),1.09-0.95(m,2H),0.79-0.56(m,2H).

Step 5, putting 4-cyclopropyl into the high-pressure pipe-2-fluoro-1-iodo-benzene (1.32g,5.04mmol), boronic acid pinacol ester (1.53g,6.04mmol), potassium acetate (1.98g,20.15mmol), [1,1' -bis (diphenylphosphino) ferrocene]Dichloropalladium (II) (368.5mg,0.50mmol) and N, N-dimethylformamide (35 mL). Reaction mixture with N₂Degassing for 15 minutes. The vial was sealed and the reaction mixture was stirred at 90 ℃ for 16 hours. The cooled reaction mixture was diluted with ethyl acetate (75mL) and water (25mL) and then filtered through a pad of Celite. The two phase layers were separated and the organic layer was washed with water and brine, over Na₂SO₄Dried, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography eluting with 0-75% EA in heptane to give 859.0mg (65.1%) of 2- (4-cyclopropyl-2-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane as a clear oil.¹HNMR(400MHz,CDCl₃)7.58(s,1H),6.83(d,J＝7.7Hz,1H),6.68(d,J＝10.8Hz,1H),1.91-1.81(m,1H),1.33(s,12H),0.98(dd,J＝8.3,2.0Hz,2H),0.74-0.66(m,2H)

Example 53 ((R) -1- {4- [ (2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl) -amino ] -2-methyl-2H-pyrazol-3-yl } -perhydro-azepin-4-yl) -carbamic acid benzyl ester

To 2-bromo-5- (isopropoxycarbonylamino) -thiazole-4-carboxylic acid (650.0mg,2.01mmol) and [ (R) -1- (4-amino-2-methyl-2H-pyrazol-3-yl) -azepan-4-yl]A stirred solution of benzyl carbamate (828.9mg,2.41mmol,1.2 equiv.) in dry N, N-dimethylformamide (22mL) was added HATU (1.07g,2.81mmol,1.4 equiv.), followed by N, N-diisopropylethylamine (0.88mL,5.03mmol,2.5 equiv.), and at RT in N₂The reaction mixture was stirred for 7 days. The reaction mixture was diluted with ethyl acetate (150 mL). The organic layer was washed with 50% brine/water, water and brine, over Na₂SO₄Dried, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography eluting with 45-100% ethyl acetate in heptane to give 1.30g of (A) ((R))79.7%) of ((R) -1- {4- [ (2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl) -amino)]-2-methyl-2H-pyrazol-3-yl } -perhydro-azepin-4-yl) -carbamic acid benzyl ester as viscous gel.¹H NMR(400MHz,CDCl₃)10.28(s,1H),8.39(s,1H),7.74(s,1H),7.33(s,5H),5.09(s,2H),4.98(s,1H),3.89(s,1H),3.72(s,3H),3.36-3.21(m,2H),3.16-3.03(m,2H),2.19-2.01(m,2H),2.00-1.61(m,4H),1.51(s,9H)

Example 54N- (5, 5-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide

Dess-martin oxidizer (2.3g,5.4mmol) was added in portions to a solution of benzyl 4-azido-5-hydroxyazepan-1-carboxylate (1.3g,4.5mmol) in DCM (25 mL). After stirring at room temperature for 18 h, the mixture was diluted with DCM and with NaHCO₃Aqueous solution (40mL) followed by Na₂S₂O₃Aqueous solution (20%, 40mL) was quenched. The resulting mixture was stirred for 20 minutes. Separating the organic layer over Na₂SO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-50% EtOAc/isohexane) afforded benzyl 4-azido-5-oxoazepane-1-carboxylate (1.10g, 84%) as a clear oil. To a solution of this oil (1.10g,3.8mmol) in DCM (10mL) was added(50% in THF, 3.5mL,9.5mmol) and the mixture stirred at room temperature for 18 h. The mixture was diluted with DCM, cooled in an ice/water bath and saturated NaHCO was added dropwise₃Aqueous solution (20 mL). Bubbling was observed. The resulting mixture was stirred for 10 minutes. Separating the organic layer over Na₂SO₄Dried and the solvent removed under reduced pressure. The crude product was purified by silica gel column chromatography (0-40% EtOAc/isohexane) to give 5-azido-4, 4-difluoroazepane-Benzyl 1-carboxylate (0.65g, 56%) as a clear oil. The oil was dissolved in THF (10mL) and water (2mL) and triphenylphosphine (0.58g,2.2mmol) were added. After stirring and heating at 60 ℃ for 18 hours, the mixture was concentrated under reduced pressure. The crude product was dissolved in DCM and the organic layer was washed with water, separated, over Na₂SO₄Dried and the solvent removed under reduced pressure. To the crude product (cooled in a water/ice bath) in DCM (20mL) was added DIPEA (1.1mL,6.36mmol) followed by the dropwise addition of trifluoroacetic anhydride (0.75mL,5.3 mmol). The mixture was warmed to room temperature, stirred for 18 hours and diluted with DCM. Adding water and separating the organic layer over Na₂SO₄The solvent was dried and removed under reduced pressure. The residue was purified by silica gel column chromatography (0-60% EtOAc/isohexane) to give benzyl 4, 4-difluoro 5- (2,2, 2-trifluoroacetamide) azepane-1-carboxylate (0.59g, 73%) as a clear oil. The trifluoroacetamide (0.57g,1.5mmol) was dissolved in MeOH (50mL) and passed through(all H)₂Mode,70 ℃ C., flow rate 1 mL/min, 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give crude N- (5, 5-difluoroazepan-4-yl) -2,2, 2-trifluoroacetamide. To a solution of azepane (0.37g,1.5mmol) in EtOH (4mL) was added 5-chloro-1-methyl-4-nitro-1H-pyrazole from example 1 (0.73g,4.5mmol) and DIPEA (0.65mL,3.8 mmol). The mixture was heated in a microwave at 130 ℃ for 6 hours. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (0-50% EtOAc/isohexane) to give N- (5, 5-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide as a light yellow oil (0.31g, 56%).¹H NMR(400MHz,CDCl₃)8.05(s,1H),6.77(d,J＝9.0Hz,1H),4.72-4.58(m,1H),3.80(s,3H),3.55-3.39(m,2H),3.33-3.18(m,2H),2.52-2.17(m,3H),2.14-2.04(m,1H).

Example 554- (5- (4, 4-difluoro-5- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-ylcarbamic acid tert-butyl ester

A solution of N- (5, 5-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide (0.29g,0.78mmol) in MeOH (20mL) was passed through(all H)₂Mode,70 ℃ C., flow rate 1 mL/min, 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give the crude amine. To a solution of this amine (0.26g,0.78mmol) in DCM (15mL) was added DIPEA (0.68mL,3.9mmol), PyBOP (0.61g,1.17mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 (0.30g,0.86mmol) and the mixture was stirred at rt for 18 h. The mixture was diluted with DCM and washed with water. Separating the organic layer over Na₂SO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) gave tert-butyl 4- (5- (4, 4-difluoro-5- (2,2, 2-trifluoroacetamide) -azepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-ylcarbamate as a white solid (0.37g, 69%).¹H NMR(400MHz,CDCl₃)10.28(s,1H),8.71(s,1H),7.82(s,1H),7.42-7.33(m,1H),7.11-7.01(m,2H),6.72(d,J＝9.0Hz,1H),4.73-4.57(m,1H),3.77(s,3H),3.51-3.37(m,2H),3.36-3.25(m,2H),2.49-2.36(m,2H),2.25-2.03(m,2H),1.55(s,9H).

Example 563, 3-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidine

5-chloro-1-methyl-4-nitro-1H-pyrazole from example 1 (0.1g,4.5mmol), 3-difluoropiperidine hydrochloride (0.14g,0.93mmol) and DIPEA (0.5mL,2.8mmol) in EtOH (3mL)The mixture of (a) was heated at 130 ℃ for 1 hour in a microwave. Additional DIPEA (0.5mL,2.8mmol) and 3, 3-difluoropiperidine hydrochloride (0.29g,1.8mmol) were added and heated in a microwave at 130 ℃ for 2 hours. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (0-60% EtOAc/isohexane) to give 3, 3-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidine as a yellow oil (127mg, 83%).¹H NMR(400MHz,CDCl₃)8.04(s,1H),3.80(s,3H),3.41-3.29(m,2H),3.26-3.04(m,2H),2.17-2.03(m,2H),1.97-1.88(m,2H).

Example 572- (2, 6-difluorophenyl) -4- (5- (3, 3-difluoropiperidin-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester

Starting from 3, 3-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidine and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazol-4-carboxylic acid from example 25, according to the procedure of example 55, tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (3, 3-difluoropiperidin-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate was obtained as a milky solid (57mg, 20%).¹H NMR(400MHz,CDCl₃)10.33(s,1H),8.67(s,1H),7.71(s,1H),7.41-7.32(m,1H),7.11-7.01(m,2H),3.76(s,3H),3.32(t,J＝11.0Hz,2H),3.19-3.13(m,2H),2.10-1.97(m,2H),1.94-1.85(m,2H),1.53(s,9H).

Example 583- (methyl (1-methyl-4-nitro-1H-pyrazol-5-yl) amino) propylcarbamic acid tert-butyl ester

5-chloro-1-methyl-4-nitro from example 1A mixture of-1H-pyrazole (0.81g,5mmol), tert-butyl 3-aminopropylcarbamate (0.85g,4.88mmol) and DIPEA (1.8mL,10.5mmol) in EtOH (5mL) was heated in a microwave at 130 ℃ for 90 min. On cooling, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl 3- (1-methyl-4-nitro-1H-pyrazol-5-ylamino) propylcarbamate as a yellow gum (1.27g, 85%). The gum (0.3g,1mmol), K₂CO₃A mixture of (0.41g,3mmol) and methyl iodide (0.1mL,1.58mmol) in DMF (5mL) was stirred at 60 ℃ for 18 h. More methyl iodide (0.1mL,1.58mmol) was added and stirring continued at 60 ℃ for 24 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was triturated with DCM (100mL), filtered and the filtrate concentrated under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) afforded tert-butyl 3- (methyl (1-methyl-4-nitro-1H-pyrazol-5-yl) amino) propylcarbamate as a light yellow gum (0.122g, 38%).¹H-NMR(400MHz,CDCl₃)8.03(s,1H),4.60(s,1H),3.77(s,3H),3.20-3.14(m,4H),2.86(s,3H),1.72-1.61(m,2H),1.42(s,9H).

Example 592- (2, 6-difluorophenyl) -4- (5- (tert-butyl- (3-methylamino) propylcarbamoyl-3-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester

Solution of tert-butyl 3- (methyl (1-methyl-4-nitro-1H-pyrazol-5-yl) amino) propylcarbamate (122mg,0.39mmol) in MeOH (15mL) was purified by(all H)₂Mode,50 ℃ C., flow rate 1 mL/min, 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give a red oil (0.12 g). To a solution of this oil in DCM (10mL) was added 5- (tert-butoxycarbonylamino) -2- (2, 6) from example 25-difluorophenyl) thiazole-4-carboxylic acid (166mg,0.47mmol), PyBOP (0.33g,0.64mmol) and DIPEA (0.5mL,2.86mmol) and the mixture was stirred at room temperature for 66 h. Water (20ml) was added and stirring continued for 30 min. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (tert-butyl- (3-methylamino) propylcarbamoyl-3-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate as a white solid (207mg, 90%).¹H-NMR(400MHz,CDCl₃)10.37(s,1H),8.74(s,1H),7.87(s,1H),7.42-7.32(m,1H),7.10-7.02(m,2H),4.65(s,1H),3.75(s,3H),3.20-3.14(m,2H),3.10(t,J＝7Hz,2H),2.85(s,3H),1.76-1.66(m,2H),1.55(s,9H),1.39(s,9H).

Example 605-chloro-1-ethyl-4-nitro-1H-pyrazole

Following the procedure of example 1, starting from 1-ethyl-4-nitropyrazole, 5-chloro-1-ethyl-4-nitro-1H-pyrazole was obtained as a colorless solid (1.3g, 74%).¹H-NMR(400MHz,CDCl₃)8.16(s,1H),4.26(q,J＝7Hz,2H),1.50(t,J＝7Hz,3H).

Example 615-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole

Starting from 1-cyclopropylmethyl-4-nitropyrazole, 5-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole was obtained as a colorless oil (1.16g, 56%) according to the procedure of example 1.¹H-NMR(400MHz,CDCl₃)8.17(s,1H),4.07(d,J＝7Hz,2H),1.39-1.28(m,1H),0.66-0.59(m,2H),0.50-0.40(m,2H).

Example 625-chloro-1-cyclopropyl-4-nitro-1H-pyrazole

Starting from 1-cyclopropyl-4-nitropyrazole, 5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole was obtained as a colorless solid (0.23g, 63%) according to the procedure of example 1.¹H-NMR(400MHz,CDCl₃)8.09(s,1H),3.62-3.54(m,1H),1.38-1.28(m,2H),1.25-1.13(m,2H).

Example 63 (R) -N- (azepan-4-yl) -2,2, 2-trifluoroacetamide

A solution of tert-butyl (R) -4- (benzyloxycarbonylamino) azepane-1-carboxylate (3.25g,0.33mmol) in MeOH (100mL) was stirred at room temperature under hydrogen at atmospheric pressure in the presence of 10% Pd/C (1g) for 1.5 h. The mixture was filtered and the solvent removed under reduced pressure to give (R) -4- (2,2, 2-trifluoroacetamide) azepane-1-carboxylic acid tert-butyl ester as a light gray oil (2g, 100%). To a stirred solution of this oil (1.8g,8.4mmol) and DIPEA (3mL,17.18mmol) in DCM (100mL) was added trifluoroacetic anhydride (1.31mL,9.27mmol) dropwise over 5 min at RT and the resulting pale yellow solution was stirred for 18 h. Saturated aqueous sodium bicarbonate (150mL) was added and stirring continued for 1 hour. The layers were separated and the organics passed through a phase separation cartridge and the solvent removed under reduced pressure to give (R) -4- (2,2, 2-trifluoroacetamide) azepane-1-carboxylic acid tert-butyl ester as a light yellow oil (2.61g, 100%). To a solution of this oil (2.6g,8.38mmol) in DCM (50mL) was added trifluoroacetic acid (25mL) at room temperature and the mixture was stirred for 2 h. Removing the solvent under reduced pressure and remainingThe residue was dissolved in DCM and passed through an SCX column, washed with DCM and MeOH, and eluted with 1N ammonia (MeOH). The solvent was removed under reduced pressure to give (R) -N- (azepan-4-yl) -2,2, 2-trifluoroacetamide as a light yellow oil (1.3g, 74%).¹H-NMR(400MHz,CDCl₃)7.83(s,1H),4.44-4.37(m,1H),3.13-3.03(m,2H),2.88(dt,J＝13.2,6.6Hz,1H),2.65-2.55(m,1H),2.03-1.79(m,3H),1.75(s,1H),1.69-1.58(m,3H).

Example 64 (S) -N- (azepan-4-yl) -2,2, 2-trifluoroacetamide

Following the procedure of example 510, starting from tert-butyl (S) -4- (benzyloxycarbonylamino) azepane-1-carboxylate, give (S) -N- (azepan-4-yl) -2,2, 2-trifluoroacetamide as a light yellow oil (1.35g, 75% over three steps).¹H-NMR(400MHz,CDCl₃)7.86(s,1H),4.44-4.37(m,1H),3.15-3.03(m,2H),2.92-2.81(m,1H),2.67-2.55(m,1H),2.02-1.81(m,4H),1.76-1.56(m,3H).

Example 64a tert-butyl 3-fluoro-5- (4-methoxybenzyloxy) azepane-1-carboxylate

A solution of tert-butyl (Z) -3-oxo-2, 3,6, 7-tetrahydro-1H-azepine-1-carboxylate (2g,9.48mmol), (4-methoxyphenyl) methanol (6.55g,47.4mmol) and DBU (0.14mL,0.95mmol) in acetonitrile (10mL) was heated at 60 ℃ for 23H. The solvent was removed under reduced pressure. Purification by silica gel column chromatography (0-40% EtOAc/isohexane) afforded tert-butyl 5- (4-methoxybenzyloxy) -3-oxoazepane-1-carboxylate as a clear oil (1.99 g). To this oil (1.33g,3.8mmol) was addedSolution in Water/THF (20mL/20mL) NaBH was added₄And the mixture was stirred for 1.5 hours. THF was removed under reduced pressure and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. Purification by silica gel column chromatography (0-60% EtOAc/isohexane) afforded tert-butyl 3-hydroxy-5- (4-methoxybenzyloxy) azepane-1-carboxylate (1.30g) as a clear oil. The oil (1.15g,3.28mmol) was dissolved in DCM (20mL) and added(50% in THF, 5.93mL,16.4 mmol). The mixture was stirred at room temperature for 18 h, diluted with DCM (30mL), cooled in an ice/water bath and passed through a low-valent saturated NaHCO₃Aqueous solution (50mL) was quenched. The resulting mixture was stirred for 10 minutes. Separating the organic layer over Na₂SO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-30% EtOAc/isohexane) afforded tert-butyl 3-fluoro-5- (4-methoxybenzyloxy) azepane-1-carboxylate (746mg, 39%, over three steps) as a clear oil.¹H NMR(400MHz,CDCl₃)7.36-7.30(m,2H),6.95(d,J＝8.2Hz,2H),5.19-4.64(m,1H),4.65-4.43(m,2H),4.06-3.20(m,8H),2.35-1.67(m,4H),1.55-1.50(m,9H).

Example 64b 3-fluoro-5- (4-methoxybenzyloxy) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepane

To a solution of 3-fluoro-5- (4-methoxybenzyloxy) azepan-1-carboxylic acid tert-butyl ester (740mg,0.21mmol) in MeOH (5mL) was added HCl (4M in1, 4-dioxane, 5.3mL,21mmol) and the solution was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7N ammonia (in MeOH). The solvent was removed under reduced pressure to give a yellow oil. To a solution of this oil in anhydrous DMSO (15mL) were added potassium fluoride (0.32g,8.4mmol) and5-chloro-1-methyl-4-nitro-1H-pyrazole (372mg,2.31mmol) and the mixture was heated at 65 ℃ for 16H. After cooling to room temperature, the mixture was diluted with water (300mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (3 × 50mL) and the solvent was removed under reduced pressure. Purification via silica gel column chromatography (20-100% EtOAc/isohexane) afforded 3-fluoro-5- (4-methoxybenzyloxy) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepane as a yellow oil (300g, 55% over two steps).¹H NMR(400MHz,CDCl₃)7.33-7.23(m,3H),6.89-6.86(m,2H),4.82-4.66(m,2H),4.49-3.93(m,1H),3.81(s,3H),3.30-2.99(m,4H),2.95-2.74(m,4H),2.35-2.03(m,2H),1.98-1.83(m,2H).

Example 65N- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide

Following the procedure of example 503, starting from 5-chloro-1-ethyl-4-nitro-1H-pyrazole and 2,2, 2-trifluoro-N- (hexahydro-1H-azepin-4-yl) -acetamide, N- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide was obtained as a light yellow gum (0.136g, 55%).¹H-NMR(400MHz,CDCl₃)8.07(s,1H),6.39-6.37(m,1H),4.22-4.19(m,1H),4.12(q,J＝7Hz,2H),3.42-3.35(m,1H),3.27-3.18(m,3H),2.25-2.05(m,2H),2.00-1.75(m,4H),1.47(t,J＝7Hz,3H).

Example 66 (R) -N- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide

By operation of example 503 from 5-chloro-1-ethyl-4-nitro-1H-pyrazole and (R) -2,2, 2-trifluoro-N- (hexahydroxy-1H-azepin-4-yl) -acetamide (0.1g,0.476mmol) to give (R) -N- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide as a light yellow gum (0.1g, 60%).¹H-NMR(400MHz,CDCl₃)8.07(s,1H),6.39-6.36(m,1H),4.23-4.19(m,1H),4.12(q,J＝7Hz,2H),3.42-3.35(m,1H),3.27-3.18(m,3H),2.25-2.05(m,2H),2.00-1.75(m,4H),1.47(t,J＝7Hz,3H).

Example 67 (S) -N- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide

Following the procedure of example 503, starting from 5-chloro-1-ethyl-4-nitro-1H-pyrazole and (S) -2,2, 2-trifluoro-N- (hexahydro-1H-azepin-4-yl) -acetamide, the (S) -N- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide was obtained as a light yellow gum (0.12g, 44%).¹H-NMR(400MHz,CDCl₃)8.07(s,1H),6.42-6.40(m,1H),4.22-4.18(m,1H),4.12(q,J＝7Hz,2H),3.42-3.35(m,1H),3.27-3.18(m,3H),2.25-2.05(m,2H),2.00-1.75(m,4H),1.47(t,J＝7Hz,3H).

Example 68 (R) -N- (1- (1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide

Following the procedure of example 503, starting from 5-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole and (R) -2,2, 2-trifluoro-N- (hexahydro-1H-azepin-4-yl) -acetamide, there is obtained (R) -N- (1- (1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl)Azepan-4-yl) -2,2, 2-trifluoroacetamide as a light yellow gum (0.98g, 55%).¹H-NMR(400MHz,CDCl₃)8.08(s,1H),6.42-6.39(m,1H),4.22-4.14(m,1H),4.00-3.85(m,2H),3.44-3.32(m,1H),3.30-3.15(m,3H),2.25-2.05(m,2H),2.00-1.75(m,4H),1.30-1.20(m,1H),0.70-0.62(m,2H),0.50-0.35(m,2H).

Example 69 (R) -N- (1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide

Following the procedure of example 503, starting from 5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole and (R) -2,2, 2-trifluoro-N- (hexahydro-1H-azepin-4-yl) -acetamide, the (R) -N- (1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide was obtained as a light yellow gum (0.105g, 61%).¹H-NMR(400MHz,CDCl₃)7.96(s,1H),6.55-6.38(m,1H),4.30-4.15(m,1H),3.65-3.53(m,1H),3.55-3.25(m,4H),2.25-2.05(m,6H),1.35-1.05(m,4H).

Example 702- (2, 6-difluorophenyl) -4- (1-ethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester

A solution of N- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide (136mg,0.39mmol) in MeOH (15mL) was passed through(70bar,25 ℃, flow rate: 1 mL/min, 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give the crude amine as a purple gum (121 mg). To a solution of the amine in DCM (10mL) was added 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (149mg,0.42mmol), HATU (0.43g,1.14mmol) and DIPEA (1mL,5.72mmol) from example 25. The mixture was stirred at room temperature for 18 hours. Water (30ml) was added and stirring was continued for 15 minutes. The layers were separated and the aqueous layer was extracted with DCM. The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl 2- (2, 6-difluorophenyl) -4- (1-ethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate as a colorless solid (170mg, 68%).¹H-NMR(400MHz,CDCl₃)10.39(s,1H),8.75(s,1H),7.95(s,1H),7.42-7.33(m,1H),7.12-7.02(m,2H),6.35(d,J＝8Hz,1H),4.25-4.13(m,1H),4.05(q,J＝7Hz,2H),3.45-3.25(m,2H),3.23-3.10(m,2H),2.25-1.65(m,6H),1.56(s,9H),1.45(t,J＝7Hz,3H).

Example 71 tert-butyl (R) -2- (2, 6-difluorophenyl) -4- (1-ethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

Starting from (R) -N- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25, according to the procedure of example 517, give tert-butyl (R) -2- (2, 6-difluorophenyl) -4- (1-ethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate, as a milky solid (0.148g, 76%).¹H-NMR(400MHz,CDCl₃)10.40(s,1H),8.76(s,1H),7.95(s,1H),7.43-7.34(m,1H),7.12-7.02(m,2H),6.37(d,J＝8Hz,1H),4.23-4.16(m,1H),4.05(q,J＝7Hz,2H),3.43-3.31(m,2H),3.25-3.15(m,2H),2.22-2.05(m,2H),2.03-1.89(m,2H),1.89-1.72(m,2H),1.57(m,12H).

Example 72 tert-butyl (S) -2- (2, 6-difluorophenyl) -4- (1-ethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

Starting from (S) -N- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25, according to the procedure of example 517, give tert-butyl (S) -2- (2, 6-difluorophenyl) -4- (1-ethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate, as a milky solid (151mg, 66%).¹H-NMR(400MHz,CDCl₃)10.40(s,1H),8.75(s,1H),7.95(s,1H),7.45-7.34(m,1H),7.12-7.02(m,2H),6.37(d,J＝8Hz,1H),4.23-4.16(m,1H),4.05(q,J＝7Hz,2H),3.43-3.31(m,2H),3.25-3.15(m,2H),2.22-2.05(m,2H),2.03-1.89(m,2H),1.89-1.72(m,2H),1.55(s,9H),1.46(t,J＝7Hz,3H).

Example 73 tert-butyl (R) -2- (2, 6-difluorophenyl) -4- (1-cyclopropylmethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

(R) -N- (1- (1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid to obtain (R) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acidFluorophenyl) -4- (1-cyclopropylmethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester as a milky solid (136mg, 77%).¹H-NMR(400MHz,CDCl₃)10.39(s,1H),8.75(s,1H),7.95(s,1H),7.41-7.36(m,1H),7.10-7.02(m,2H),6.37(d,J＝8Hz,1H),4.25-4.10(m,1H),3.90-3.83(m,2H),3.43-3.31(m,2H),3.30-3.15(m,2H),2.25-2.05(m,2H),2.03-1.70(m,4H),1.57(s,9H)1.35-1.20(m,1H),0.64-0.59(m,2H),0.43-0.38(m,2H).

Example 74 tert-butyl (R) -2- (2, 6-difluorophenyl) -4- (1-cyclopropyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

(R) -N- (1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 to give (R) -tert-butyl 2- (2, 6-difluorophenyl) -4- (1-cyclopropyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate, as a milky solid (142mg, 73%).¹H-NMR(400MHz,CDCl₃)10.40(s,1H),8.76(s,1H),7.87(s,1H),7.41-7.34(m,1H),7.10-7.00(m,2H),6.39(d,J＝8Hz,1H),4.25-4.15(m,1H),3.45-3.36(m,3H),3.35-3.15(m,2H),2.25-2.12(m,1H),2.10-1.70(m,5H),1.55(s,9H),1.35-1.15(m,2H),1.10-1.00(m,2H).

Example 75 tert-butyl (R) -2- (2-fluorophenyl) -4- (1-ethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

Following the procedure of example 506, starting from (R) -N- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonylamino) -2- (2-fluorophenyl) thiazole-4-carboxylic acid, the tert-butyl (R) -2- (2-fluorophenyl) -4- (1-ethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate was obtained as a milky solid (330mg, 72%).¹H-NMR(400MHz,CDCl₃)10.37(s,1H),8.66(s,1H),8.15-8.05(m,1H),7.45-7.35(m,1H),7.30-7.15(m,3H),6.31(d,J＝8Hz,1H),4.25-4.15(m,1H),4.07(q,J＝7Hz,2H),3.43-3.31(m,2H),3.25-3.15(m,2H),2.25-2.10(m,2H),2.10-1.70(m,4H),1.57(s,9H)1.47(t,J＝7Hz,3H).

Example 76 tert-butyl (R) -2- (2-fluorophenyl) -4- (1-cyclopropylmethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

Starting from (R) -N- (1- (1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide 5- (tert-butoxycarbonylamino) -2- (2-fluorophenyl) thiazole-4-carboxylic acid, the procedure according to example 506 gave (R) -tert-butyl 2- (2-fluorophenyl) -4- (1-cyclopropylmethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate, as a milky solid (350mg, 70%).¹H-NMR(400MHz,CDCl₃)10.36(s,1H),8.66(s,1H),8.15-8.05(m,1H),7.45-7.35(m,1H),7.28-7.15(m,3H),6.31(d,J＝7.5Hz,1H),4.25-4.15(m,1H),3.95-3.85(m,2H),3.43-3.30(m,2H),3.28-3.15(m,2H),2.25-2.08(m,2H),2.08-1.70(m,4H),1.55(s,9H),1.35-1.20(m,1H),0.70-0.60(m,2H),0.50-0.35(m,2H).

Example 77 (R) -tert-butyl 2- (2-fluorophenyl) -4- (1-cyclopropyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

Starting from (R) -N- (1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonylamino) -2- (2-fluorophenyl) thiazole-4-carboxylic acid, according to the procedure of example 506, tert-butyl (R) -2- (2-fluorophenyl) -4- (1-cyclopropyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate was obtained, as a milky solid (370mg, 76%).¹H-NMR(400MHz,CDCl₃)10.36(s,1H),8.69(s,1H),8.12-8.00(m,1H),7.45-7.30(m,1H),7.28-7.15(m,3H),6.40-6.27(m,1H),4.30-4.15(m,1H),3.43-3.15(m,5H),2.25-1.75(m,6H),1.55(s,9H),1.35-1.15(m,2H),1.10-0.95(m,2H).

Example 78 (1- (4-amino-1-methyl-1H-pyrazol-5-yl) piperidin-4-yl) methylcarbamic acid tert-butyl ester

A solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole from example 1 (1.9g,11.77mmol), 4- (boc-aminomethyl) piperidine (3.78g,17.66mmol) and DIPEA (6.15mL,35.31mmol) in EtOH (20mL) was heated in a microwave at 130 ℃ for 1H. The solvent was removed under reduced pressure and the residue redissolved in DCM. The organic layer was washed with water, passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl (1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-yl) methylcarbamate as yellowA colored solid (3.95g, 98%). A solution of the solid (3.84g,11.30mmol) in MeOH (125mL) was added with 10% Pd/C (0.42g,3.96mmol) and ammonium formate (2.85g,45.2 mmol). The mixture was heated at 80 ℃ for 2.5 hours. The mixture was concentrated under reduced pressure and the residue was redissolved in EtOAc and washed with water. The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure to give tert-butyl (1- (4-amino-1-methyl-1H-pyrazol-5-yl) piperidin-4-yl) methylcarbamate as a brown oil (3.49g, 99%).¹H NMR(400MHz,CDCl₃)7.04(s,1H),4.63(s,1H),3.64(s,3H),3.11-3.07(m,6H),2.67(s,2H),1.77(d, J ═ 12.8Hz,2H),1.45(s,9H),1.39-1.26(m,2H).1H are hidden by the water peak.

Example 794- (5- (4- (butoxycarbonylaminomethyl) piperidin-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) -2-bromothiazol-5-ylcarbamic acid tert-butyl ester

A solution of PyBOP (2.84g,5.46mmol) and 2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid (1.39g,4.29mmol) in DCM (10mL) was stirred at room temperature for 30 min. A solution of tert-butyl (1- (4-amino-1-methyl-1H-pyrazol-5-yl) piperidin-4-yl) methylcarbamate (1.2g,3.90mmol) and DIPEA (1.1mL,6.24mmol) in DCM (20mL) was added and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM and washed with water. The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl 4- (5- (4- (butoxycarbonylaminomethyl) piperidin-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) -2-bromothiazol-5-ylcarbamate as a pink solid (2.32g, 96%).¹H NMR(400MHz,d6-DMSO)10.62(s,1H),9.64(s,1H),7.23(s,1H),6.86(t,J＝5.8Hz,1H),3.62(s,3H),3.07(d,J＝11.4Hz,2H),2.95(t,J＝11.5Hz,2H),2.87(t,J＝6.3Hz,2H),1.67(d,J＝12.3Hz,2H),1.52(s,9H),1.45(s,1H),1.40(s,9H),1.27-1.16(m,2H).

Example 805- (tert-Butoxycarbonylamino) -2- (2, 6-difluoro-3-methoxyphenyl) thiazole-4-carboxylic acid

Following the procedures of examples 19-23, starting from 2, 6-difluoro-3-methoxybenzoyl chloride, 5- (tert-butoxycarbonylamino) -2- (2, 6-difluoro-3-methoxyphenyl) thiazole-4-carboxylic acid was obtained as a light yellow solid (120mg, 70%).¹HNMR(400MHz,d6-DMSO)7.32-7.23(m,1H),7.22-7.15(m,1H),3.88(s,3H),1.49(s,9H).

EXAMPLE 81 benzyl (R) -1- (4- (5-tert-butoxycarbonyl-amino-2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) azepan-4-ylcarbamate

A solution of PyBOP (1.31g,2.52mmol) and 2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid (0.61g,1.89mmol) in DCM (20mL) was stirred at room temperature for 30 min. A solution of benzyl (R) -azepan-4-ylcarbamate (0.62g,1.80mmol) and DIPEA (0.5mL,2.88mmol) in DCM (20mL) was added and the mixture stirred at room temperature for 16 h. The mixture was diluted with DCM and washed with water. The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% EtOAc/hexanes) to give benzyl (R) -1- (4- (5-tert-butoxycarbonyl-amino-2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) azepan-4-ylcarbamate as a pink solid (1.04g, 89%).¹H NMR(400MHz,CDCl₃)10.28(s,1H),8.40(s,1H),7.75(s,1H),7.38-7.27(m,5H),5.09(s,2H),5.00-4.92(m,1H),3.91-3.84(m,1H),3.73(s,3H),3.36-3.24(m,2H),3.15-3.04(m,2H),2.19-2.03(m,2H),1.96-1.79(m,3H),1.75-1.63(m,1H),1.52(s,9H).

Example 82 tert-butyl (R) -2-bromo-4- (1-methyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid and (R) -N- (azepan-4-yl) -2,2, 2-trifluoroacetamide were linked to give tert-butyl (R) -2-bromo-4- (1-methyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate as a pale orange solid (500mg, 74%).¹HNMR(400MHz,CDCl₃)10.27(s,1H),8.38(s,1H),7.74(s,1H),6.41(d,J＝8.2Hz,1H),4.23-4.15(m,1H),3.75(s,3H),3.38-3.29(m,2H),3.22-3.08(m,2H),2.22-2.08(m,2H),2.03-1.93(m,2H),1.88-1.69(m,2H),1.52(s,9H).

Example 83 (R) -4- (Benzyloxycarbonylamino) azepane or (S) -4- (benzyloxycarbonylamino) azepane

To a 250mL three-necked round bottom flask was added tert-butyl 4-amino azepane-1-carboxylate (8.80g,41.0mmol), triethylamine (29mL,0.21mol), and dichloromethane (20 mL). The mixture was cooled to-20 ℃ and benzyl chloroformate (8.4g,49mmol) was added dropwise over 10 minutes via syringe. The heterogeneous mixture was warmed to room temperature and stirred for 2 hours. The reaction was monitored by LCMS and when the reaction was complete, the solvent was distilled off and the crude product was purified by flash chromatography, heptane/ethyl acetate 10% to 30% to give a white solid (6.0g, 42%).

Racemic azepines were purified using chiral SFC (Supercritical liquid chromatography, see White and Burnett (2005) Jour. of Chrom. A1074:175-₂The resolution was carried out at a flow rate of 200 ml/min, a pressure of 100bars and at 40 ℃ for 5 minutes. Two enantiomers ((R) -4- (benzyloxycarbonylamino) azepane-1-carboxylic acid tert-butyl ester and (S) -4- (benzyloxycarbonylamino) azepane-1-carboxylic acid tert-butyl ester) were obtained.

To a 100mL round bottom flask was added one of the enantiomers, dioxane (20mL) and 12N HCl (4 mL). The mixture was stirred for 2 hours and the solvent was distilled off. The product, an HCl salt, (2.2g, 37%) isomer 1 and (2.4g, 40%) isomer 2 were used directly in the next step.

Example 845-azido-3-hydroxy-3-methylazepane-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl (Z) -3-oxo-2, 3,6, 7-tetrahydro-1H-azepine-1-carboxylate (15g,71.1mmol) in acetonitrile (25mL) was added trimethylsilylazide (28.2mL,213mmol) followed by Amberlite IRA900F values (loading: 2-3mmol/g,18g) and the mixture was heated at 60 ℃ for 4 hours. After 16 h at room temperature, the values were removed by filtration, washed with acetonitrile and the solvent was removed under reduced pressure to give a yellow oil. To this oil (813mg,3.2mmol) in anhydrous Et over 10 min₂Solution in O (20ml) (cooled in an ice-salt bath) Methyllithium solution (1.6M in Et) was added dropwise₂In O, 2.1mL,3.36 mmol). After stirring for another 1.5 hours, saturated NaHCO was added₃(10mL) and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were over MgSO₄Drying and removal of the solvent under reduced pressure gave a green oil (0.8g, 81% over four steps).¹H NMR(400MHz,CDCl₃)4.00-2.65(m,6H),2.30-1.60(m,4H),1.55-1.20(m,12H).

Example 84a 5-azido-3-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol

A solution of tert-butyl 5-azido-3-hydroxy-3-methylazepane-1-carboxylate (0.8g,3mmol) in DCM (15mL) and trifluoroacetic acid (5mL) was stirred at room temperature for 1.5 h, then concentrated under reduced pressure. The residue was dissolved in a minimum volume of DCM, loaded onto a SCX column, washed with DCM and MeOH and eluted with 1N ammonia (in MeOH). The solvent was removed under reduced pressure. To a solution of the residue in anhydrous DMSO (10mL) was added 5-chloro-1-methyl-4-nitro-1H-pyrazole (574mg,3.56mmol) and potassium fluoride (675mg,12.7 mmol). The mixture was heated at 70 ℃ for 16 hours under nitrogen, then cooled and poured into water (300 mL). The mixture was extracted with EtOAc (3X150mL) and the combined organic layers were separated with water (100mL) and brine (50mL), over MgSO₄Dried and concentrated to give a brown gum. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded 5-azido-3-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol as a mixture of four diastereomers (0.38g, 47%, over 2 steps).¹H NMR(400MHz,CDCl₃)8.04(s,1H),4.12-3.90(m,1H),3.85and3.74(2s,3H),3.60-3.40(m,1H),3.40-3.30(m,1H),3.25-3.10(m,1H),3.00-2.60(m,2H),2.30-2.10(m,2H),2.00-1.70(m,2H),1.35-1.15(m,3H)。LCMS(ES+)m/z296(M+1).

The mixture was separated into two pairs of diastereomers via silica gel column chromatography (0-50% EtOAc/isohexane) to give:

less polar pair of diastereomers (111A)¹H NMR(400MHz,CDCl₃)8.04(s,1H),4.12-3.95(m,1H),3.83(s,3H),3.60-3.50(m,1H),3.45-3.30(m,1H),3.25-3.10(m,1H),2.95-2.85(m,1H),2.55(br s,1H),2.30-2.10(m,2H),2.00-1.70(m,2H),1.25(s,3H)。LCMS(ES+)m/z296(M+1).

Larger polar pair of diastereomers (111B)¹H NMR(400MHz,CDCl₃)8.04(s,1H),4.00-3.92(m,1H),3.90(s,3H),3.55-3.45(m,1H),3.40-3.30(m,1H),3.25-3.15(m,1H),3.00-2.85(m,1H),2.83(s,1H),2.30-2.10(m,3H),1.95-1.85(m,1H),1.20(s,3H)。LCMS(ES+)m/z296(M+1).

Example 84b tert-butyl 6-fluoro-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate

Triphenylphosphine (338mg,1.29mmol) was added to a stirred solution of 5-azido-3-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol (380mg,1.29mmol) in THF (15mL) and water (3mL) and the mixture was heated at 60 ℃ for 16H. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (20mL) and DIPEA (0.67mL,3.86mmol) and di-tert-butyl dicarbonate (565mg,3.58mmol) were added. The mixture was stirred at room temperature for 20 h, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give a pale orange solid (0.4 g). To a solution of the solid (0.4g,1.29mmol) in DCM (10mL) was added(1.2mL,3.31mmol, 50% in THF) and the mixture stirred at room temperature for 20 h. Saturated NaHCO₃(30mL) was added and stirring continued for 15 minutes. The aqueous layer was extracted with DCM (30mL) and the combined organic layers were MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded tert-butyl 6-fluoro-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate as a pale orange gum (315mg, 64%, over three steps).¹H NMR(400MHz,CDCl₃)8.04(s,1H),5.30-4.90(m,1H),4.75-4.15(m,1H),3.90-3.75(m,3H),3.65-3.00(m,4H),2.55-1.75(m,4H),1.48(s,9H),1.45-1.25(m,3H)。LCMS(ES+)m/z394(M+Na).

Example 84c tert-butyl 6-hydroxy-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (less polar pair of diastereomers)

Triphenylphosphine (113mg,0.43mmol) was added to a stirred solution of 5-azido-3-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol (less polar pair of diastereomers) (103mg,0.35mmol) in THF (5mL) and water (1mL) and the mixture was heated at 60 ℃ for 16H. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM (10mL) and DIPEA (0.19mL,1.09mmol), followed by the addition of di-tert-butyl dicarbonate (153mg,0.70 mmol). The mixture was stirred at room temperature for 3 hours and then with saturated NaHCO₃(15mL) washing. The organic layer was passed through a phase separation cartridge and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give a light orange gum (110mg, 86% over two steps).¹H NMR(400MHz,CDCl₃)8.02(s,1H),4.62(br s,1H),4.2-4.10(m,1H),3.87(s,3H),3.60-3.45(m,1H),3.35-3.10(m,2H),2.90-2.80(m,1H),2.73(br s,1H),2.25-2.10(m,1H),2.05-1.90(m,1H),1.80-1.65(m,2H),1.45(s,9H),1.19(s,3H)。LCMS(ES+)m/z370(M+1).

Example 84d 6-hydroxy-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester (larger polar pair of diastereomers)

Following the procedure for intermediate 113, starting from 5-azido-3-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol, the more polar pair of diastereomers, gave tert-butyl 6-hydroxy-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate, the more polar pair of diastereomers, as a pale orange gum (100mg, 97%).¹H NMR(400MHz,CDCl₃)8.03(s,1H),4.70(br s,1H),4.05-3.90(m,1H),3.88(s,3H),3.60-3.50(m,1H),3.35-3.25(m,1H),3.15-3.05(m,1H),2.95-2.85(m,1H),2.30-2.10(m,1H),2.10-1.80(m,4H),1.45(s,9H),1.26(s,3H)。LCMS(ES+)m/z370(M+1).

Example 84e 6-methoxy-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester (less polar pair of diastereomers)

To a solution of 5-azido-3-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol (less polar pair of diastereomers) (115mg,0.53mmol) in anhydrous DMF (2mL) was added sodium hydride (25mg,0.63mmol, 60% suspension in oil) at room temperature under nitrogen and the mixture was stirred at room temperature for 10 min. Methyl iodide (0.05mL,0.80mmol) was added and the mixture was stirred at room temperature for 1 hour. Ice-water (50mL) was added and the mixture was extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (20mL), separated, and MgSO₄Dried and the solvent removed under reduced pressure. The residue was dissolved in THF (5mL) and water (1mL) and triphenylphosphine (102mg,0.39mmol) was added. The reaction mixture was heated at 60 ℃ for 16 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (10mL) and DIPEA (0.2mL,1.15mmol) and di-tert-butyl dicarbonate (170mg,0.78mmol) were added. The mixture was stirred at room temperature for 3 hours, then with saturated NaHCO₃(15mL) washing. The organic layer was passed through a phase separation cartridge and the solvent was removed under reduced pressure. Through a silica gel columnChromatography (0-100% EtOAc/isohexane) afforded tert-butyl 6-methoxy-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (less polar pair of diastereomers) as a light orange gum (118mg, 79%, over three steps).¹H NMR(400MHz,CDCl₃)8.02(s,1H),4.55(br s,1H),4.20-4.10(m,1H),3.88(s,3H),3.45-3.25(m,2H),3.20(s,3H),3.20-2.95(m,2H),2.30-2.10(m,2H),1.80-1.50(m,2H),1.45(s,9H),1.08(s,3H)。LCMS(ES+)m/z384(M+1).

Example 84f tert-butyl 6-methoxy-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (diastereomer B)

Following the procedure for intermediate 115, starting from 5-azido-3-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol (the more polar pair of diastereomers) gave tert-butyl 6-methoxy-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (the more polar pair of diastereomers) as a pale orange gum (110mg, 68%, over three steps).¹H NMR(400MHz,CDCl₃)8.03(s,1H),5.70(br s,1H),4.05-3.90(m,1H),3.88(s,3H),3.50-3.25(m,2H),3.15(s,3H),3.10-2.90(m,2H),2.25-2.05(m,2H),2.00-1.85(m,1H),1.75-1.60(m,1H),1.45(s,9H),1.14(s,3H)。LCMS(ES+)m/z384(M+1).

Example 855- (Benzylaminooxy) -3, 3-difluoroazepane-1-carboxylic acid tert-butyl ester

(Z) -3-oxo-2, 3,6, 7-tetrahydro-1H-azepine-1-carboxylic acid tert-butyl ester (330mg,1.56mmol), (E) -benzaldoxime (286mg,2.36mmol) and DBU (0.007mL,0.05mmol) were combined in MeCN (0.5mL) and the mixture was stirred at room temperature for 48H. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give tert-butyl 5- (benzylideneaminooxy) -3-oxoazepane-1-carboxylate as a brown oil (127 mg).

A solution of this oil (125mg,0.37mmol) in DCM (20mL) was prepared(50% in THF, 0.67mL,1.86mmol) and the mixture stirred at room temperature for 18 h. The mixture was diluted with DCM (20mL), cooled in an ice/water bath and purified by dropwise addition of saturated NaHCO₃Aqueous solution (30mL) was quenched. The resulting mixture was stirred for 10 minutes. Separating the organic layer over Na₂SO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) afforded tert-butyl 5- (benzylideneaminooxy) -3, 3-difluoroazepane-1-carboxylate (101mg, 18%, over two steps) as a clear oil.¹H NMR(400MHz,CDCl₃)8.11-8.03(m,1H),7.61-7.55(m,2H),7.40-7.36(m,3H),4.52-4.42(m,1H),4.02-3.56(m,3H),3.51-3.27(m,1H),2.67-2.51(m,1H),2.42-2.21(m,2H),2.09-1.91(m,1H),1.50-1.45(m,9H).

Example 85a benzaldehyde O-6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl oxime

Starting from tert-butyl 5- (benzylideneaminooxy) -3, 3-difluoroazepane-1-carboxylate, following the procedure of intermediate 109, the benzaldehyde O-6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazole- 5-yl) azepan-4-yloxime as a yellow oil (52mg, 33%).¹H NMR(400MHz,CDCl₃)8.21-7.98(m,1H),8.05(s,1H),7.63-7.58(m,2H),7.41-7.36(m,3H),4.71-4.62(m,1H),3.85(s,3H),3.80-3.65(m,1H),3.47-3.39(m,2H),3.26-3.23(m,1H),2.77(q,J＝13.2Hz,1H),2.58-2.29(m,2H),2.23-2.10(m,1H).

Intermediates

Intermediate 1Methyl ((1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-yl) methyl) carbamic acid tert-butyl ester

A solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (0.2g,1.23mmol), methyl (piperidin-4-ylmethyl) carbamic acid tert-butyl ester (0.29g,1.36mmol) and DIPEA (1mL,5.7mmol) in EtOH (3mL) from example 1 was heated in a microwave at 130 ℃ for 2 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (40% EtOAc/isohexane) to give tert-butyl (1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-yl) methylcarbamate as a yellow oil (0.34g, 80%). To a solution of this oil (0.15mg,0.44mmol) in DMF (5mL) (cooled to 0 deg.C) was added sodium hydride (27mg,0.66mmol, 60% in mineral oil) and the mixture was stirred at 0 deg.C for 15 min. Methyl iodide (0.03mL,0.53mmol) was added and the mixture was stirred at 0 ℃ for 30 min. Additional sodium hydride (14mg,0.33mmol) and methyl iodide (0.02mL,0.78mmol) were added and the reaction mixture was warmed to 10 ℃ and stirred for 1 hour. Water (10mL) was added and the mixture was extracted with EtOAc (60 mL). The organic layer was washed with water (7 × 10mL), washed with brine (10mL), separated, and over MgSO₄Dried and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (30% EtOAc/isohexane) to give tert-butyl methyl ((1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-yl) methyl) carbamate as a yellow oil (148mg, 95%).¹HNMR(400MHz,CDCl₃)8.01(s,1H),3.74(s,3H),3.38-3.26(m,2H),3.25-3.15(m,2H),3.12-2.95(m,2H),2.89(s,3H),1.90-1.71(m,3H),1.60-1.32(m,2H),1.47(s,9H).

Intermediate 26, 6-difluoro-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester

A solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (1.62g,10.0mmol), 1, 4-diazepan-6-ol (4.18g,15.0mmol) and DIPEA (6.6mL) in EtOH (6mL) was heated in a microwave at 130 ℃ for 3 hours. The solvent was removed under reduced pressure, and the residue was dissolved in DCM (60mL) and DMF (10 mL). Di-tert-butyl dicarbonate (8.73g,40mmol) and DIPEA (3.48mL) were added and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl 6-hydroxy-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepane-1-carboxylate (2.13g) as a yellow oil. To a solution of this oil (2.13g,6.2mmol) in DCM (20mL) was added bose-martin oxidant (3.18g,7.49mmol) in portions. After stirring at room temperature for 18 h, the mixture was diluted with DCM (20mL) and saturated NaHCO₃The aqueous solution (40mL) was then quenched with 20% aqueous sodium thiosulfate (40 mL). The resulting mixture was stirred for 20 minutes. Separating the organic layer over Na₂SO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) afforded tert-butyl 4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -6-oxo-1, 4-diazepan-1-carboxylate (1.6g) as a viscous yellow oil. To a solution of this oil (0.49g,1.43mmol) in DCM (10mL) was added(50% in THF, 1.3mL,3.6mmol) and the mixture stirred at room temperature for 18 h. The mixture was diluted with DCM (30mL), cooled in an ice/water bath and purified by dropwise addition of saturated NaHCO₃Aqueous solution (50mL) was quenched. The resulting mixture was stirred for 10 minutes. Separating the organic layer over Na₂SO₄Dried and the solvent removed under reduced pressure. The crude product was passed through a silica gel columnChromatography (0-60% EtOAc/isohexane) afforded tert-butyl 6, 6-difluoro-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylate (467mg, 42% over four steps) as a clear oil.¹H NMR(400MHz,CDCl₃)8.04(s,1H),4.05-3.27(m,11H),1.50(s,9H).

Intermediate 34- (4- (2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 6, 6-difluoro-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylate (467mg,1.29mmol) in MeOH (30mL) was passed through(70bar,60 ℃ C., flow rate: 1 mL/min, 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give a red oil (428 mg). To a solution of this oil in DCM (15mL) was added 2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid (459mg,1.42mmol), PyBOP (1.0g,1.94mmol) and DIPEA (0.57mL,3.22mmol) and the mixture was stirred at room temperature for 16 h. Water (20mL) was added and the mixture was diluted with DCM (100 mL). The organic layer was washed with water (20mL), separated, and MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) afforded 4- (4- (2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester as a beige foam (565mg, 69%, over two steps).¹H NMR(400MHz,CDCl₃)10.23(s,1H),8.31(s,1H),7.62(s,1H),4.07-3.95(m,2H),3.76(s,3H),3.64(s,2H),3.56-3.42(m,2H),3.38-3.28(m,2H),1.53(s,9H),1.49(s,9H).

Intermediate 4(R) -N- (azepan-4-yl) -2,2, 2-trifluoroacetamide

A solution of tert-butyl (R) -4- (benzyloxycarbonylamino) azepane-1-carboxylate (3.25g,0.33mmol) in MeOH (100mL) was stirred at room temperature under hydrogen at atmospheric pressure in the presence of 10% palladium on carbon (1g) for 1.5 h. By passingThe mixture was filtered and the solvent removed under reduced pressure to give (R) -4- (2,2, 2-trifluoroacetamide) azepane-1-carboxylic acid tert-butyl ester as a light gray oil (2g, 100%). To a stirred solution of this oil (1.8g,8.4mmol) and DIPEA (3mL,17.2mmol) in DCM (100mL) was added trifluoroacetic anhydride (1.31mL,9.3mmol) dropwise over 5 min at room temperature and the resulting pale yellow solution was stirred for 18 h. Addition of saturated NaHCO₃Aqueous solution (150mL) and stirring continued for 1 hour, the layers were separated and the organics passed through a phase separation cartridge and the solvent removed under reduced pressure to give (R) -4- (2,2, 2-trifluoroacetamide) azepane-1-carboxylic acid tert-butyl ester as a light yellow oil (2.61g, 100%). To a solution of this oil (2.6g,8.38mmol) in DCM (50mL) was added trifluoroacetic acid (25mL) at room temperature and the mixture was stirred for 2 h. The solvent was removed under reduced pressure, and the residue was dissolved in DCM and passed through a SCX column, washed with DCM and MeOH, and eluted with 1N ammonia (MeOH). The solvent was removed under reduced pressure to give (R) -N- (azepan-4-yl) -2,2, 2-trifluoroacetamide as a light yellow oil (1.3g, 74%).¹H-NMR(400MHz,CDCl₃)7.83(s,1H),4.44-4.37(m,1H),3.13-3.03(m,2H),2.88(dt,J＝13.2,6.6Hz,1H),2.65-2.55(m,1H),2.03-1.79(m,3H),1.75(s,1H),1.69-1.58(m,3H).

Intermediate 55-chloro-1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazole

To a stirred solution (cooled) of 1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazole (1.0g,5.13mmol) in anhydrous THF (20mL)To-70 ℃ a solution of lithium hexamethyldisilazide (1M in THF, 8.47mL,8.47mmol) was added dropwise. After stirring at-70 ℃ for 40 minutes, the reaction mixture was warmed to-55 ℃ over 20 minutes. After additional cooling to-70 ℃ a solution of perchloroethane (1.74g,7.34mmol) in THF (10mL) was added slowly and the reaction mixture was stirred at-70 ℃ for 1.5 h. Saturated aqueous ammonium chloride (30mL) was added, followed by water (15mL) and the mixture extracted with EtOAc (3 × 100 mL). The combined organic layers were over MgSO₄Dried and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give 5-chloro-1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazole as an off-white solid (438mg, 37%).¹H NMR(400MHz,CDCl₃)8.24(s,1H),6.18(tt,J＝54.8,4.2Hz,1H),4.58(td,J＝12.8,4.2Hz,2H).

Intermediate 6(R) -N- (1- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoro-N-methylacetamide

A solution of 5-chloro-1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazole (438mg,2.07mmol), (R) -N- (azepan-4-yl) -2,2, 2-trifluoroacetamide (438mg,2.07mmol) and DIPEA (1mL) in EtOH (4mL) was heated in a microwave at 155 ℃ for 5H. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give (R) -N- (1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide as a light orange gum (518 mg). One portion of this gum (39mg,0.10mmol) was treated with sodium hydride (60% in mineral oil, 5mg,0.12mmol) in anhydrous THF (2 mL). After stirring at room temperature for 10 min, iodomethane (0.01mL,0.20mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction was repeated on the remaining (R) -N- (1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide. Water (50mL) was added carefully and the mixture was extracted with EtOAc (2 × 100 mL). The organic layers were combined and MgSO₄Drying and removing the solvent under reduced pressure,this gave (R) -N- (1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoro-N-methylacetamide as a light yellow gum (518 mg). The gum (514mg,1.29mmol) was dissolved in MeOH (20mL) and treated with ammonium formate (325mg,6.15mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 85 ℃ for 2 hours. After cooling to room temperature, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between DCM (50mL) and water (30mL) and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure to give (R) -N- (1- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoro-N-methylacetamide as a light yellow gum (348mg, 46%, over three steps).¹H NMR(400MHz,CDCl₃)7.13(s,1H),6.19(tq,J＝55.4,4.4Hz,1H),4.65-4.15(m,3H),3.40-3.10(m,4H),3.10and2.97(2s,3H),2.80(brs,2H),2.10-1.70(m,6H).

Intermediate 7(R) -tert-butyl 2-bromo-4- (1- (2, 2-difluoroethyl) -5- (4- (2,2, 2-trifluoro-N-methylacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

To a solution of (R) -N- (1- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoro-N-methylacetamide (248mg,0.67mmol) in DCM (20mL) were added DIPEA (1.0mL,5.7mmol), PyBOP (700mg,1.34mmol) and 2-bromo-5- (tert-butoxycarbonylamino) -thiazole-4-carboxylic acid (282mg,0.87mmol) and the mixture was stirred at room temperature for 20 hours. Water (50mL) was added and stirring continued for 1 hour. The mixture was extracted with DCM (50mL), the combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification by column chromatography on silica gel (0-100% EtOAc/isohexane) afforded (R) -tert-butyl 2-bromo-4- (1- (2, 2-difluoroethyl) -5- (4- (2,2, 2-trifluoro-N-methylacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate as a light yellow gum (405mg, 90%).¹H NMR(400MHz,CDCl₃)10.27and10.26(2s,1H),8.32and8.27(2s,1H),7.88and7.85(2s,1H),6.36-6.02(m,1H),4.67-4.11(m,2H),3.41-3.08(m,5H),3.08and2.95(2s,3H),2.22-1.71(m,4H),1.31-1.18(m,2H).

Intermediate 81- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) azepan-4-ol

A solution of 5-chloro-1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazole (470mg,2.22mmol), azepan-4-ol (281mg,2.44mmol) and DIPEA (1mL) in EtOH (3mL) was heated in a microwave at 155 ℃ for 5H. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give 1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) azepan-4-ol as a light orange gum (400 mg). The gum (390mg,1.35mmol) was dissolved in MeOH (25mL) and treated with ammonium formate (340mg,5.38mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 85 ℃ for4 hours. After standing overnight at room temperature, more ammonium formate (205mg,3.25mmol) and 10% palladium on carbon (50mg) were added to the reaction mixture, which was then heated at 85 ℃ for 1 hour. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between DCM (30mL) and water (20 mL). The organic layer was passed through a phase separation cartridge and the solvent was removed under reduced pressure to give 1- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) azepan-4-ol as an orange solid (265mg, 42%, over two steps).¹H NMR(400MHz,CDCl₃)7.17(s,1H),6.27-5.91(m,1H),4.39-4.23(m,2H),4.16-4.04(m,1H),3.30-3.11(m,4H),2.60(br s,3H),2.55(s,2H),2.08-1.81(m,3H),1.80-1.71(m,1H).

Intermediate 92-bromo-4- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester

Following the procedure for intermediate 7, starting from 1- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) azepan-4-ol and 2-bromo-5- (tert-butoxycarbonylamino) -thiazole-4-carboxylic acid, tert-butyl 2-bromo-4- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate was obtained as a colorless solid (265mg, 69%).¹H NMR(400MHz,CDCl₃)10.39(s,1H),9.14(s,1H),8.02(s,1H),6.18(tt,J＝55.9,4.5Hz,1H),4.38-4.27(m,2H),3.33-3.12(m,5H),2.20(br s,1H),2.35-1.58(m,4H),1.70-1.48(m,2H).

Intermediate 10(R) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester

To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (355mg,2.2mmol) from example 1 and potassium fluoride (511mg,8.8mmol) in anhydrous DMSO (20mL) was added (R) -tert-butyl 3-methylpiperazine-1-carboxylate (507mg,2.53mmol) and the mixture was heated in a microwave at 100 ℃ for 10 hours. The mixture was partitioned between water (40mL) and EtOAc (100mL) and the organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) gave (R) -tert-butyl 3-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperazine-1-carboxylate as an orange gum (627 mg). To a solution of this gum (179mg,0.55mmol) and ammonium formate (256mg,4.4mmol) in MeOH (10mL) under nitrogen was added 10% palladium on carbon (59mg,0.55 mmol). The mixture was heated at 70 ℃ for4 hours, then cooled, filtered and concentrated under reduced pressure. The residue was partitioned between water (20mL) and DCM (60mL) and the organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give (R) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester as a brown gum (150mg, 80% over two steps). LCMS (ES +) M/z296(M +1).

Intermediate 11(S) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-ethylpiperazine-1-carboxylic acidTert-butyl ester

Starting from 5-chloro-1-methyl-4-nitro-1H-pyrazole and (S) -3-ethylpiperazine-1-carboxylic acid tert-butyl ester from example 1 according to the procedure for intermediate 10, we obtained (S) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-ethylpiperazine-1-carboxylic acid tert-butyl ester as an orange gum (110mg, 65% over two steps). LCMS (ES +) M/z310(M +1).

Intermediate 12(R) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-ethylpiperazine-1-carboxylic acid tert-butyl ester

Starting from 5-chloro-1-methyl-4-nitro-1H-pyrazole and (R) -3-ethylpiperazine-1-carboxylic acid tert-butyl ester from example 1 according to the procedure for intermediate 10, we obtained (R) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-ethylpiperazine-1-carboxylic acid tert-butyl ester as an orange gum (118mg, 67% over two steps). LCMS (ES +) M/z310(M +1).

Intermediate 13 (S) -N- (azepan-4-yl) -2,2, 2-trifluoroacetamide

Following the procedure for intermediate 4, starting from tert-butyl (S) -4- (benzyloxycarbonylamino) azepane-1-carboxylate, (S) -N- (azepan-4-yl) -2,2, 2-trifluoroacetamide is obtained as a light yellow oil (1.35g, 75% over three steps).¹H-NMR(400MHz,CDCl₃)7.86(s,1H),4.44-4.37(m,1H),3.15-3.03(m,2H),2.92-2.81(m,1H),2.67-2.55(m,1H),2.02-1.81(m,4H),1.76-1.56(m,3H).

Intermediate 14 (S) -N- (1- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoro-N-methylacetamide

Starting from (S) -N- (azepan-4-yl) -2,2, 2-trifluoroacetamide and 5-chloro-1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazole, following the procedure for intermediate 6, gave (S) -N- (1- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoro-N-methylacetamide as a pale red gum (100mg, 32%, over three steps).¹H NMR(400MHz,CDCl₃)7.13(s,1H),6.19(tq,J＝55.4,4.4Hz,1H),4.65-4.15(m,3H),3.40-3.10(m,4H),3.10and2.97(2s,3H),2.80(br s,2H),2.10-1.70(m,6H).

Intermediate 15 (S) -tert-butyl 2-bromo-4- (1- (2, 2-difluoroethyl) -5- (4- (2,2, 2-trifluoro-N-methylacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

Starting from (S) -N- (1- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoro-N-methylacetamide and 2-bromo-5- (tert-butoxycarbonylamino) -thiazole-4-carboxylic acid, tert-butyl (S) -2-bromo-4- (1- (2, 2-difluoroethyl) -5- (4- (2,2, 2-trifluoro-N-methylacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamate) was obtained according to the procedure for intermediate 7, as a pale pink gum (80mg 57%).¹H NMR(400MHz,CDCl₃)10.27(s,1H),8.31and8.27(2s,1H),7.88and7.85(2s,1H),6.34-6.05(m,1H),4.41-4.31(m,2H),3.42-3.29(m,5H),3.10and2.95(2s,3H),2.08-1.75(m,4H),1.40-1.15(m,2H).

Intermediate 163-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-one

Three equivalent solutions of piperidin-4-one hydrochloride hydrate (1.84g,12.0mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole from example 1 (1.3g,8.0mmol) and potassium fluoride (1.86g,32mmol) in anhydrous DMSO (20mL) were heated in a microwave at 100 ℃ for 12H. The mixture was combined, poured into water (700mL) and extracted into EtOAc (3 × 100 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (0-5% MeOH/DCM) gave 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-one as a yellow solid (1.97g, 36%). To a solution of the ketone in DMF (40mL) was added NEt₃(3.05mL,21.9mmol) and chlorotrimethylsilane (1.55mL,12.3 mmol). The reaction vessel was sealed and the mixture was heated at 90 ℃ for 16 hours. The mixture was cooled and the product extracted into EtOAc (2 × 50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Chromatography on silica gel column (0-100% Et)₂O/isohexane) to give 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -4- (trimethylsilyloxy) -1,2,3, 6-tetrahydropyridine as a yellow gum (1.53g, 59%). The gum was dissolved in MeCN (130mL) and cooled to 0 ℃. Dropwise adding over 20 minutesA solution of (1.99g,5.61mmol) in 2:1MeCN DMF (10mL) and the mixture was stirred between-5 ℃ and 0 ℃ for 2 h. The solvent was removed under reduced pressure and the residue partitioned between EtOAc (50mL) and water (40 mL). The product was extracted into EtOAc (50mL) and DCM (50mL) and the combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) afforded 3-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-one as a pale yellow solid (1.23g, 99%).¹H NMR(400MHz,CDCl₃)8.07(s,1H),5.04(ddd,J＝48.3,8.2,5.7Hz,1H),3.89(s,3H),3.77-3.64(m,2H),3.64-3.51(m,1H),3.50-3.43(m,1H),2.88-2.72(m,2H).

Intermediate 172, 2, 2-trifluoro-N- (3-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide

To a solution of 3-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-one (1.07g,4.40mmol) in DCM (10mL) was added dropwise a solution of boron trifluoride diethyl ether (0.71mL,5.72mmol) in DCM (1mL) at-5 ℃. The mixture was stirred for 30 min, then a solution of ethyl diazoacetate (0.60mL,5.72mmol) in DCM (1mL) was added. The mixture was stirred at-5 ℃ for 1 hour and then warmed to room temperature. Water (5mL) was added and the mixture stirred for 30 min. The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) afforded ethyl 6-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -5-oxoazepane-4-carboxylate as a yellow gum (0.85g, 58%). The gum was redissolved in 3M hydrochloric acid (30mL) and heated at 100 ℃ for4 hours. The mixture was concentrated under reduced pressure, redissolved in DCM (30mL) and washed with water (20 mL). The organic phase was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded 3-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-one as a pale yellow solid (0.30g, 45%). To a solution of the solid (0.30g,1.15mmol) in anhydrous MeOH (6mL) and DCM (6mL) was added ammonium acetate (0.709g,9.20mmol) and triturated by activationAnd (3) a molecular sieve. The mixture was heated at 55 ℃ for4 hours and then cooled to room temperature. Sodium cyanoborohydride (80mg,1.27mmol) was added in portions and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was redissolved in DCM (10mL) and washed with 10% aqueous NaOH (10 mL). The aqueous solution was extracted with EtOAc (3 × 20mL) and the combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via amine-functionalized silica gel column chromatography (0-100% EtOAc/isohexane) afforded 3-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-amine as a yellow gum (0.205g, 69%). To the jellyA solution of (0.20g,0.79mmol) and DIPEA (0.37mL,2.13mmol) in DCM (5mL) was added trifluoroacetic anhydride (0.11mL,0.78mmol) dropwise. The mixture was stirred at room temperature for 16 hours, then washed with water (10 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded 3-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl carbamic acid tert-butyl ester as a light yellow solid (140mg, 55%). LCMS (ES +) M/z354(M +1).

Intermediate 185-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol

To a solution of (Z) -3-oxo-2, 3,6, 7-tetrahydro-1H-azepine-1-carboxylic acid butyl ester (2.0g,9.5mmol) in acetonitrile (3mL) was added trimethylsilyl azide (3.76mL,28.4mmol) followed by addition ofIRA900F resin (Loading amount: 2-3 mmoleg)^-12.4g) and the resulting mixture is heated after an explosion-proof barrier at 60 ℃ for 16 hours. After cooling to room temperature, the solution was filtered, the resin was washed with acetonitrile and the filtrate was concentrated under reduced pressure (bath temperature)<5-azido-3-oxoazepane-1-carboxylic acid tert-butyl ester was obtained at 40 ℃ as a yellow liquid (2.21 g). To a solution of azide (2.2g,8.70mmol) in THF/water (1/1,40mL) was added NaBH in portions₄(0.82mg,21.8mmol) and the mixture stirred at room temperature for 2 h. The mixture was diluted with water (100mL) and extracted with EtOAc (100 mL). The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. Purification by column chromatography on silica gel (0-60% EtOAc/isohexane) afforded 5-azido-3-hydroxyazepan-1-carboxylic acid tert-butyl ester as an oil (2.01 g). A solution of this oil (2.0g,7.8mmol) in MeOH (20mL) was added HCl (4M in1, 4-dioxane, 43mL,173mmol) and the solution was stirred at rt for 16 h. The solvent was removed under reduced pressure and the crude residue was dissolved in MeOH and passed through an SCX column, washed with MeOH and washed with 7NAmmonia (in MeOH) eluted to 5-azidoazepan-3-ol as a yellow oil. To this oil in anhydrous DMSO (20mL) was added potassium fluoride (1.68g,28.9mmol) and 5-chloro-1-methyl-4-nitro-1H-pyrazole from example 1 (1.17g,7.2mmol) and the mixture was heated at 65 ℃ for 16H. The mixture was diluted with water (300mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (3 × 20mL), separated, and over MgSO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-30% EtOAc/isohexane) afforded 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol as a viscous yellow oil (1.9g, 72% over four steps).¹H NMR(400MHz,CDCl₃)8.06and8.02(2s,1H),4.15-3.97(m,2H),3.95-3.83(m,4H),3.58-3.46(m,1H),3.39-3.16(m,3H),2.29-1.91(m,4H).

Intermediate 196, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester

To a solution of 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol, intermediate 18(3.4g,16mmol) in THF (40mL) and water (8mL) was added triphenylphosphine (1.89g,7.2mmol) and the mixture was heated at 65 ℃ after the explosion-proof barrier for 16 hours. The solvent was removed under reduced pressure to give 5-amino-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol (contaminated with triphenylphosphine oxide) as a viscous oil. To the amine in DCM (40mL) was added di-tert-butyl dicarbonate (4.49g,20.6mmol) and DIPEA (4.78mL,27.4mmol) and the mixture was stirred at room temperature for 60 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl 6-hydroxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate as a yellow oil (1.2 g). To a solution of this oil (1.2g) in DCM (25mL) was added portionwise bose-martin oxidant (1.72g,1.51 mmol). After stirring at room temperature for 16 h, the mixture was diluted with DCM (25mL) and saturated NaHCO₃Aqueous solution (40mL) followed by 20% aqueous sodium thiosulfate solution (40 mL). The resulting mixture was stirred for 20 minutes. Separating the organic layer over Na₂SO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-60% EtOAc/isohexane) afforded tert-butyl 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -6-oxoazepan-4-ylcarbamate (0.56g) as a yellow oil. To a solution of this oil (0.51g,1.46mmol) in DCM (15mL) was added(50% in THF, 1.85mL,5.1mmol) and the mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM (30mL), cooled in an ice/water bath and purified by dropwise addition of saturated NaHCO₃Aqueous solution (30mL) was quenched. The resulting mixture was stirred for 10 minutes. Separating the organic layer over Na₂SO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) afforded tert-butyl 6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (510mg, 64% over four steps) as an oil.¹H NMR(400MHz,CDCl₃)8.04(s,1H),4.18-4.01(m,1H),3.84(s,3H),3.79-3.19(m,4H),2.56-2.42(m,1H),2.38-1.99(m,4H),1.46(s,9H).

Intermediate 206-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester

To a solution of 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol, intermediate 18(3.4g,16mmol) in THF (40mL) and water (8mL) was added triphenylphosphine (1.89g,7.2mmol) and the mixture was heated at 65 ℃ for 16H. The solvent was removed under reduced pressure to give 5-amino-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol (contaminated with triphenylphosphine oxide) as a viscous oil. To the amine in DCM (40mL) was added di-tert-butyl dicarbonate (4.49g,20.6mmol) and DIPEA (4.78mL,27.4mmol) and the mixture was stirredThe mixture was stirred at room temperature for 60 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl 6-hydroxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate as a yellow oil (2.6 g). To a solution of this oil (2.6g,10.2mmol) in DCM (50mL) was added(50% in THF, 6.7mL,18.6mmol) and stirred at room temperature for 16 h. The mixture was diluted with DCM (30mL), cooled in an ice/water bath and purified by dropwise addition of saturated NaHCO₃Aqueous solution (30mL) was quenched. The resulting mixture was stirred for 10 minutes. Separating the organic layer over Na₂SO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) afforded tert-butyl 6-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (1.07g, 66% over three steps) as a light yellow oil.¹H NMR(400MHz,CDCl₃)8.14-7.97(m,1H),5.04-4.46(m,3H),3.96-2.99(m,6H),2.42-1.64(m,5H),1.70-1.22(m,9H).

Intermediate 21 (S) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester

Starting from 5-chloro-1-methyl-4-nitro-1H-pyrazole and (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester from example 1 according to the procedure for intermediate 10, we obtained (S) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester as an orange gum (134mg, 73% over two steps). LCMS (ES +) M/z296(M +1).

Intermediate 228- (1-methyl-4-nitro-1H-pyrazol-5-yl) -2, 8-diazaspiro [4.5] silane-2-carboxylic acid tert-butyl ester

5-chloro-1-methyl-4-nitro-1H-pyrazole from example 1 (150mg,0.93mmol), 2, 8-diazaspiro [4.5]]A mixture of silane-2-carboxylic acid tert-butyl ester (244mg,1.02mmol) and DIPEA (1mL) in EtOH (3mL) was heated in a microwave at 130 ℃ for 2 hours. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (50% EtOAc/isohexane) to give 8- (1-methyl-4-nitro-1H-pyrazol-5-yl) -2, 8-diazaspiro [4.5]]Tert-butyl silane-2-carboxylate as a yellow oil (245mg, 72%).¹H NMR(400MHz,CDCl₃)8.02(s,1H),3.76(s,3H),3.49-3.39(m,2H),3.30-3.00(m,6H),1.90-1.60(m,6H),1.55(s,9H).

Intermediate 23 (S) -5- (2, 4-dimethylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-amine

To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (355mg,2.2mmol) from example 1 and potassium fluoride (511mg,8.8mmol) in anhydrous DMSO (20mL) was added (R) -tert-butyl 3-methylpiperazine-1-carboxylate (1.15 equivalents, 2.53mmol) and the mixture was heated in a microwave at 100 ℃ for 10 hours. The mixture was partitioned between water (40mL) and EtOAc (100mL), and the organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (S) -tert-butyl 3-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperazine-1-carboxylate as an orange gum (627 mg). To a solution of this gum (212mg,0.65mmol) in DCM (9mL) was added trifluoroacetic acid (3mL) and the mixture was stirred at rt for4 h. The mixture was concentrated under reduced pressure and the residue was partitioned between water (20mL) and DCM (30 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure to give (S) -2-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperazine as a yellow gum (120 mg). To a solution of this gum (119mg,0.53mmol) and acetic acid (0.12mL,2.12mmol) in MeOH (10mL) was added aqueous formaldehyde (37 wt% in water, 0.17mL,2.12mmol) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (83mg,1.33 m) was then addedmol) and the mixture was stirred at room temperature for 70 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between water (20mL) and DCM (30 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure to give (S) -2, 4-dimethyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperazine as a yellow gum (109 mg). To a solution of this gum (108mg,0.45mmol) and ammonium formate (209mg,3.6mmol) in MeOH (10mL) under nitrogen was added 10% palladium on carbon (48mg,0.45 mmol). The mixture was heated at 70 ℃ for4 hours, then cooled, filtered and concentrated under reduced pressure. The residue was partitioned between water (20mL) and DCM (50mL) and the organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give (S) -5- (2, 4-dimethylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-amine as a brown gum (94mg, 62% over four steps).¹HNMR(400MHz,CDCl₃)7.07(s,1H),3.66(s,3H),3.51-3.41(m,1H),3.36(td, J ═ 5.7,2.6Hz,1H),2.94-2.84(m,3H),2.36(s,3H),2.28(td, J ═ 5.6,3.0Hz,1H),1.92(dd, J ═ 11.2,9.8Hz,1H),0.86(d, J ═ 6.3Hz,3H). No exchangeable NH was observed₂。

Intermediate 24 (R) -5- (2, 4-dimethylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-amine

Starting from 5-chloro-1-methyl-4-nitro-1H-pyrazole and (R) -3-methyl-piperazine-1-carboxylic acid tert-butyl ester from example 1, following the procedure of intermediate 23, was obtained (R) -5- (2, 4-dimethylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-amine as a brown solid (94mg, 62% over four steps).¹H NMR(400MHz,CDCl₃)7.07(s,1H),3.66(s,3H),3.59-3.44(m,2H),2.99-2.86(m,3H),2.46-2.31(m,4H),2.03(t, J ═ 10.7Hz,1H),0.87(d, J ═ 6.3Hz,3H), no exchangeable NH was observed₂。

Intermediate 255-chloro-1-cyclopropyl-4-nitro-1H-pyrazole

Following the procedure for intermediate 5, starting from 1-cyclopropyl-4-nitropyrazole, 5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole was obtained as a colorless solid (0.23g, 63%).¹H-NMR(400MHz,CDCl₃)8.09(s,1H),3.62-3.54(m,1H),1.38-1.28(m,2H),1.25-1.13(m,2H).

Intermediate 264- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester

Following the procedure for intermediate 2, starting from 5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole, after silica gel column chromatography (0-100% EtOAc/isohexane), tert-butyl 4- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylate was obtained as a yellow oil (520mg, 9% over four steps).¹H NMR(400MHz,CDCl₃)7.96(s,1H),4.07-3.34(m,9H),1.49(s,9H),1.34-1.17(m,2H),1.08-1.01(m,2H).

Intermediate 274- (4- (2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxamide) -1-cyclopropyl-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester

Following the procedure for intermediate 3, starting from tert-butyl 4- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylate, after column chromatography on silica gel (0-50% EtOAc/isohexane), tert-butyl 4- (4- (2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxamide) -1-cyclopropyl-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylate was obtained as an off-white foam (573mg, 62% over four steps).¹H NMR(400MHz,CDCl₃)10.23(s,1H),8.43(s,1H),7.65(s,1H),3.71-3.63(m,4H),3.45-3.10(m,5H),1.49(s,9H),1.44(s,9H),1.27-1.18(m,2H),1.06-0.99(m,2H).

Intermediate 284-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol

To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (390mg,2.4mmol) from example 1 and 4-hydroxy-4-methylazepane hydrochloride (0.48g,2.9mmol) in EtOH (9.5mL) was added DIPEA (1.9mL,10.9 mmol). The reaction mixture was heated at 130 ℃ for 1 hour in a microwave. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-5% MeOH/DCM) to give 4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol as a colorless oil (410mg, 66%).¹H NMR(400MHz,CDCl₃)8.03(s,1H),3.77(s,3H),3.56-3.47(m,1H),3.28-3.20(m,2H),3.08-3.04(m,1H),2.17-2.03(m,1H),1.95-1.81(m,4H),1.78-1.67(m,1H),1.56(br s,1H),1.25(s,3H).

Intermediate 292-bromo-4- (5- (4-hydroxy-4-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester

To a solution of 4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (212mg,0.83mmol) in MeOH (15mL) was added ammonium formate (386mg,5.63mmol) and 10% palladium on carbon (88mg,0.83mmol) and the mixture was heated at 80 deg.C for 18H. By passingThe mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between DCM (20mL) and water (20mL) and the aqueous layer was re-extracted with DCM (3 × 20 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure to give 1- (4-amino-1-methyl-1H-pyrazol-5-yl) -4-methylazepinAlk-4-ol as a red oil. To a solution of this oil (140mg,0.623mmol) in DCM (25mL) was added 2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid (241mg,0.75mmol), PyBOP (454mg,1.94mmol) and DIPEA (0.17mL,1.0mmol) and the mixture was stirred at room temperature for 16 h. Water (20mL) was added and the mixture was diluted with DCM (100 mL). The organic layer was washed with water (20mL), separated, and MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded tert-butyl 2-bromo-4- (5- (4-hydroxy-4-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate as an off-white solid (280mg, 63%, over two steps).¹H NMR(400MHz,CDCl₃)10.49(s,1H),9.41(s,1H),7.95(s,1H),3.71(s,3H),3.41-3.30(m,1H),3.24-3.11(m,3H),2.39(br s,1H),2.07-1.75(m,5H),1.84-1.78(m,1H),1.52(s,9H),1.43(s,3H).

Intermediate 304- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester

Following the procedure for intermediate 2, starting from 5-chloro-1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazole, 4- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester was obtained as a pale green gum (11% over four steps).¹H NMR(400MHz,CDCl₃)8.13and8.12(2s,1H),6.33-6.02(m,1H),4.60-4.40(m,2H),4.10-3.30(m,8H),1.48(s,9H).

Intermediate 314- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -6-hydroxy-1, 4-diazepan-1-carboxylic acid tert-butyl ester

5-chloro-1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazoleA mixture of (800mg,3.78mmol), 1, 4-diazepan-6-ol dihydrobromide salt (1.58g,5.67mmol) and DIPEA (2.5mL,14.35mmol) in EtOH (6mL) was heated in a microwave at 130 ℃ for 3 hours. The solvent was removed under reduced pressure and the residue was passed through a SCX column, washed with DCM and 1:1MeOH: DCM and MeOH and eluted with 1N ammonia in MeOH to give 1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-6-ol as a light yellow gum (1.0 g). The gum (1.0g,3.44mmol) was dissolved in DCM (100mL) and treated with di-tert-butyl dicarbonate (2.25g,10.31mmol) and DIPEA (2.4mL,13.75 mmol). The reaction mixture was stirred at room temperature for 1.5 hours and saturated NaHCO₃Aqueous (100mL) wash. The organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100%) EtOAc/isohexane gave tert-butyl 4- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -6-hydroxy-1, 4-diazepan-1-carboxylate as a pale green gum (46% over two steps).¹H NMR(400MHz,CDCl₃)8.11(s,1H),6.18(tdd,J＝55.6,5.6,3.2Hz,1H),4.49-4.31(m,2H),4.19-2.95(m,10H),1.60-1.40(m,9H).

Intermediate 325-chloro-1- (4-methoxybenzyl) -4-nitro-1H-pyrazole

Following the procedure for intermediate 5, starting from 1- (4-methoxybenzyl) -4-nitro-1H-pyrazole, to give 5-chloro-1- (4-methoxybenzyl) -4-nitro-1H-pyrazole as a yellow solid (536mg, 46%).¹H NMR(400MHz,CDCl₃)8.17(s,1H),7.25(d,J＝8.3Hz,2H),6.89(d,J＝8.3Hz,2H),5.30(s,2H),3.80(s,3H).

Intermediate 33 (S) -4- (4-amino-1- (4-methoxybenzyl) -1H-pyrazol-5-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester

To a solution of 5-chloro-1- (4-methoxybenzyl) -4-nitro-1H-pyrazole (268mg,1.0mmol) and potassium fluoride (232mg,4.0mmol) in anhydrous DMSO (20mL) was added (S) -tert-butyl 3-methylpiperazine-1-carboxylate (230mg,1.15mmol) and the mixture was heated in a microwave at 100 ℃ for 8 hours. The mixture was partitioned between water (30mL) and EtOAc (50mL) and the organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (S) -tert-butyl 4- (1- (4-methoxybenzyl) -4-nitro-1H-pyrazol-5-yl) -3-methylpiperazine-1-carboxylate as a yellow gum (380 mg). To a solution of this gum (371mg,0.86mmoL) in ethanol/water (20mL/2mL) were added ammonium chloride (230mg,4.3mmoL) and iron powder (192mg,3.44mmoL) and the mixture was heated at 80 ℃ for 1.5 h. The mixture is passed throughFiltered and concentrated under reduced pressure. The residue was partitioned between water (30mL) and DCM (40mL) and the organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-5% MeOH/DCM) gave (S) -4- (4-amino-1- (4-methoxybenzyl) -1H-pyrazol-5-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester as a red gum (330mg, 84%, over two steps).¹H NMR(400MHz,CDCl₃)7.17-7.11(m,3H),6.82(d,J＝8.6Hz,2H),5.34(d,J＝14.4Hz,1H),5.17(d,J＝14.4Hz,1H),3.98-3.80(m,2H),3.78(s,3H),3.23(ddd,J＝9.9,6.4,3.3Hz,1H),3.01(td,J＝11.4,3.0Hz,1H),2.92-2.83(m,1H),2.66(s,1H),2.57(s,1H),1.47(s,9H),0.81(d,J＝6.3Hz,3H).

Intermediate 344- (4-amino-1- (4-methoxybenzyl) -1H-pyrazol-5-yl) piperazine-1-carboxylic acid tert-butyl ester

Starting from 5-chloro-1- (4-methoxybenzyl) -4-nitro-1H-pyrazole and (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester according to the procedure of intermediate 33, the (R) -4- (4-amino-1- (4-methoxybenzyl) -1H-pyrazol-5-yl) -3-methylpiperazine-1-carboxylic acid was obtainedTert-butyl ester as a red gum (325mg, 81%, over two steps).¹H NMR(400MHz,CDCl₃)7.16-7.11(m,3H),6.82(d,J＝8.6Hz,2H),5.16(d,J＝14.8Hz,1H),5.05(d,J＝14.8Hz,1H),4.10-3.80(m,2H),3.78(s,3H),3.26-3.19(m,1H),3.01(td,J＝11.4,3.0Hz,1H),2.86(t,J＝13.2Hz,1H),2.66(s,2H),2.57(s,2H),1.47(s,9H),0.81(d,J＝6.3Hz,3H).

Intermediate 35 (S) -5- (2-ethyl-4-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-amine

Following the procedure for intermediate 24, starting from (S) -3-ethyl-piperazine-1-carboxylic acid tert-butyl ester, (S) -5- (2-ethyl-4-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-amine was obtained as a brown solid (100mg, 86% over four steps).¹HNMR(400MHz,CDCl₃)8.38(s,1H),7.08(s,1H),3.75-3.55(m,5H),3.29(dt,J＝11.4,2.4Hz,1H),3.22(ddd,J＝6.0,5.5,2.6Hz,1H),2.95(dt,J＝12.5,2.8Hz,1H),2.64(dd,J＝11.8,3.6Hz,1H),2.61(s,3H),2.29(t,J＝10.9Hz,1H),1.48-1.31(m,1H),1.26-1.11(m,1H),0.82(t,J＝7.6Hz,3H).NH₂And (4) partial exchange.

Intermediate 36 (R) -5- (2-ethyl-4-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-amine

Following the procedure for intermediate 24, starting from (R) -3-ethyl-piperazin-1-tert-butyl ester, (R) -5- (2-ethyl-4-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-amine was obtained as a brown solid (100mg, 86% over four steps).¹H NMR(400MHz,CDCl₃)8.40(s,1H),7.07(s,1H),3.65(s,3H),3.66-3.46(m,2H),3.24(dt,J＝11.3,2.4Hz,1H),3.16(ddd,J＝5.8,5.6,2.7Hz,1H),2.94(dt,J＝12.3,2.8Hz,1H),2.77-2.34(m,4H),2.21(t,J＝10.8Hz,1H),1.47-1.32(m,1H),1.27-1.10(m,1H),0.81(t,J＝7.5Hz,3H).NH₂And (4) partial exchange.

Intermediate 374- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -6-fluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester

To a solution of 4- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -6-hydroxy-1, 4-diazepan-1-carboxylic acid tert-butyl ester (370mg,0.95mmol) in DCM (10mL) was added(50% solution in THF, 1.0mL,2.37mmol) and the mixture stirred at room temperature for 18 h. Slowly add saturated NaHCO₃Aqueous solution (10mL) and the mixture was stirred for 15 minutes. The aqueous layer was extracted with DCM (10mL), the combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification by column chromatography on silica gel afforded 4- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -6-fluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester as a pale green gum (366mg, 74%).¹H NMR(400MHz,CDCl₃)8.12(s,1H),6.34-6.00(m,1H),5.08-2.75(m,11H),1.48(s,9H).

Intermediate 386, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl (methyl) carbamic acid tert-butyl ester

To a cooled (ice water bath) solution of tert-butyl 6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (190mg,0.51mmol) in THF (10mL) was added lithium bis (trimethylsilyl) amide (1M in THF, 0.8mL,0.8mmol) and the mixture was stirred for 30 minutes. Methyl iodide (0.06mL,1.02mmol) was added and the mixture was stirred at room temperature for 16 h. Water (2mL) was added and the mixture was extracted with EtOAc (30 mL). Separating the organic layer over Na₂SO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-70% EtOAc/isohexane) gave tert-butyl 6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl (methyl) carbamate (180mg, 90%) as a yellow oil.¹H NMR(400MHz,CDCl₃)8.09-7.99(m,1H),4.57-4.38(m,1H),3.85(s,3H),3.84-3.53(m,1H),3.45-3.15(m,3H),2.81(s,3H),2.53-2.29(m,2H),2.16-2.01(m,2H),1.48(s,9H).

Intermediate 395-bromo-4-nitro-1- (2,2, 2-trifluoroethyl) -1H-pyrazole

To a stirred solution of 1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-amine (990mg,6.0mmol) in acetic acid (5mL) was added dropwise acetic anhydride (0.57mL,6.0mmol) and the mixture was stirred at room temperature for 16 hours. More acetic anhydride (0.57mL,6.0mmol) was added to the reaction mixture, which was cooled in an ice bath for dropwise addition of fuming nitric acid (0.28mL,6 mmol). The reaction mixture was stirred at room temperature for 7 hours and the solvent was removed under reduced pressure. The residue was dissolved in EtOH (15mL) and concentrated hydrochloric acid (10mL) was added. The mixture was heated at reflux for 16 hours. After concentration under reduced pressure, the residue was taken up in DCM (50mL) and 5% NaHCO₃The aqueous solution (100mL) was partitioned. The mixture was filtered and the aqueous layer was extracted with DCM (100 mL). The organic layers were combined and MgSO₄Drying and removal of the solvent under reduced pressure gave a pale orange solid (540 mg). The solid (540mg,2.57mmol) was dissolved in bromoform (2.9mL,33mmol) and tert-butyl nitrite (0.92mL,7.71mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 15 minutes and then heated at 145 ℃ for 1.5 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give 5-bromo-4-nitro-1- (2,2, 2-trifluoroethyl) -1H-pyrazole as a pale yellow solid (536mg, 33% over four steps).¹H NMR(400MHz,CDCl₃)8.30(s,1H),4.86(q,J＝7.8Hz,2H).

Intermediate 40 (R) -N- (1- (4-amino-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide

Following the procedure for intermediate 8, starting from 5-bromo-4-nitro-1- (2,2, 2-trifluoroethyl) -1H-pyrazole (150mg,0.55mmol) and (R) -N- (azepan-4-yl) -2,2, 2-trifluoroacetamide (115mg,0.55mmol), we obtained (R) -N- (1- (4-amino-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide as a colourless gum (110mg, 53%).¹H NMR(400MHz,CDCl₃)7.25(s,1H),7.11(br s,1H),4.54(q,J＝8.5Hz,2H),4.35-4.22(m,1H),3.40-3.23(m,2H),3.21-3.08(m,2H),2.62(brs,2H),2.17-2.08(m,1H),2.06-1.91(m,1H),1.92-1.71(m,4H).

Intermediate 414- (4-Nitro-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester

Following the procedure for intermediate 22, starting from 5-bromo-4-nitro-1- (2,2, 2-trifluoroethyl) -1H-pyrazole and tert-butyl 1, 4-diazepan-1-carboxylate, 4- (4-nitro-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylate was obtained as a light yellow gum (197mg, 91%).¹H NMR(400MHz,CDCl₃)8.19-8.12(m,1H),4.76-4.66(m,2H),3.65-3.49(m,4H),3.32-3.23(m,4H),1.92-1.78(m,2H),1.52-1.47(m,9H).

Intermediate 424-hydroxy-5- (2,2, 2-trifluoroacetamide) azepane-1-carboxylic acid benzyl ester

To benzyl 4-azido-5-hydroxyazetidine-1-carboxylate(1.4g,4.83mmol) in THF/water (30mL/6mL) triphenylphosphine (1.26g,4.83mmol) was added and the reaction mixture was heated at 60 ℃ for 16 h. EtOAc (100mL) was added and the mixture was washed with water (20 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. The resulting oil is in Et₂The resulting solid was filtered off by trituration in O and the filtrate was concentrated under reduced pressure to give a yellow oil. To a solution of this oil in DCM (20mL) was added DIPEA (2.5mL,14.4mmol) and trifluoroacetic anhydride (1.0mL,7.22mmol) at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 16 hours. Water (20mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel column chromatography (50% EtOAc/isohexane) afforded benzyl 4-hydroxy-5- (2,2, 2-trifluoroacetamide) azepane-1-carboxylate as a golden yellow viscous oil (934mg, 54% over 2 steps).¹H NMR(400MHz,CDCl₃)7.40-7.29(m,5H),6.49(s,1H),5.20-5.11(m,2H),3.94-3.25(m,6H),2.35-1.65(m,5H).

Intermediate 43N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-hydroxyazepan-4-yl) -2,2, 2-trifluoroacetamide

A solution of benzyl 4-hydroxy-5- (2,2, 2-trifluoroacetamide) azepane-1-carboxylate (935mg,3.0mmol) in MeOH (100mL) was passed through(all H)₂50 ℃ C., flow rate 1 mL/min, 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give 4-hydroxy-5- (2,2, 2-trifluoroacetamide) azepane as a pale yellow solid (514 mg). To a solution of this solid (500mg,2.21mmol) in anhydrous DMSO (10mL) were added 5-chloro-1-methyl-4-nitro-1H-pyrazole from example 1 (150mg,0.93mmol) and potassium fluoride (513mg,8.85 mmol). The reaction mixture was heated at 65 ℃ for 16 hours. The mixture was poured into water (200mL) and extracted with EtOAc (5 × 50 mL). The combined organic layers were over MgSO₄Drying and reducing pressureAnd (5) concentrating. The residue was purified by silica gel column chromatography (70% EtOAc/isohexane) to give 2,2, 2-trifluoro-N- (5-hydroxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide as a yellow solid (640 mg). A portion of this solid (200mg,0.57mmol) was dissolved in MeOH (25mL) and passed through(all H)₂50 ℃ C., flow rate 1 mL/min, 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-hydroxyazepan-4-yl) -2,2, 2-trifluoroacetamide as an orange foam (172mg, 68% over three steps).¹H NMR (400MHz, DMSO)9.22(d, J ═ 8.1Hz,1H),6.83(s,1H),4.84(d, J ═ 5.0Hz,1H),3.91-3.73(m,2H),3.32(s,3H),3.28-2.96(m,4H),2.00-1.75(m, 4H). Exchangeable NH not observed₂。

Intermediate 446-hydroxy-6-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester

To a cooled solution (ice-water bath) of 6-oxo-1, 4-diazepan-1, 4-dicarboxylic acid di-tert-butyl ester (570mg,1.82mmol) in THF (10mL) was added dropwise a solution of methyl magnesium bromide (3M in Et₂O, 0.79mL,2.36 mmol). The mixture was warmed to room temperature and stirred for 16 hours. Saturated aqueous ammonium chloride (5mL) was added and the mixture was diluted with EtOAc (30mL) and water (30 mL). The layers were separated and the organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (0-70% EtOAc/isohexane) afforded di-tert-butyl 6-hydroxy-6-methyl-1, 4-diazepan-1, 4-dicarboxylate as an oil (0.45 g). To a solution of this oil (0.45g,1.36mmol) in MeOH (2mL) was added HCl in1, 4-dioxane (4M,6.8mL,27.3mmol) and the solution was stirred at rt for 16 h. The solvent was removed under reduced pressure. The residue was dissolved in MeOH and passed through an SCX column, washed with MeOH and eluted with 1N ammonia (in MeOH). Removing the solvent under reduced pressure to obtain 6-methyl-1, 4-bisAzepan-6-ol as an oil. To the amine (in EtOH (3mL)) was added 5-chloro-1-methyl-4-nitro-1H-pyrazole from example 1 (209mg,1.29mmol) and DIPEA (0.9mL,5.44mmol) and the mixture was heated in a microwave at 130 ℃ for 3H. The solvent was removed under reduced pressure. To crude 6-hydroxy-6-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester (in DCM (10mL) was added di-tert-butyl dicarbonate (1.18g,5.44mmol) and DIPEA (0.9mL,5.44 mmol). The mixture was stirred at room temperature for 16 h, the solvent was removed under reduced pressure, and the residue was dissolved in DCM (30 mL). Water (20mL) was added and the organic layer was separated over Na₂SO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-80% EtOAc/isohexane) afforded tert-butyl 6-hydroxy-6-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylate (235mg, 22% over four steps) as a yellow oil.¹H NMR(400MHz,CDCl₃)8.03(s,1H),4.16-3.79(m,7H),3.52-2.81(m,4H),1.70-1.80(br s,1H),1.51(s,9H),1.16(s,3H).

Intermediate 456-fluoro-6-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 6-hydroxy-6-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylate (100mg,0.28mmol) in DCM (5mL) was added(50% in THF, 0.26mL,0.7mmol) and the mixture stirred at room temperature for 18 h. The mixture was diluted with DCM (30mL), cooled in an ice-water bath and purified by dropwise addition of saturated NaHCO₃Aqueous solution (40mL) was quenched. The resulting mixture was stirred for 10 minutes. Separating the organic layer over Na₂SO₄Drying and reducing pressureThe solvent was removed. The crude product was purified by silica gel column chromatography (0-50% EtOAc/isohexane) to give tert-butyl 6-fluoro-6-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylate (70mg, 70%) as a clear colorless oil.¹H NMR(400MHz,CDCl₃)8.03(s,1H),3.80(s,3H),3.73-3.32(m,6H),3.26-3.03(m,2H),1.50(s,9H),1.32(d,J＝20.1Hz,3H).

Intermediate 466, 6-difluoro-4- (4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester

5-chloro-4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole (815mg,2.93mmol), 1, 4-diazepan-6-ol (510mg,4.39mmol) and DIPEA (2.55mL,14.6mmol) were combined in EtOH (10mL) and heated in a microwave at 130 ℃ for 1 hour and the solvent was removed under reduced pressure to give 1- (4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) -1, 4-diazepan-6-ol. To the amine was added di-tert-butyl dicarbonate (2.56g,11.7mmol) and DIPEA (2.55mL,14.6 mmol). After stirring at room temperature for 16 h, the solvent was removed under reduced pressure and the residue was dissolved in DCM (30 mL). Water (20mL) was added and the organic layer was separated over Na₂SO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-50% EtOAc/isohexane) afforded tert-butyl 6-hydroxy-4- (4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylate as an oil (590 mg). To a solution of this oil (570mg,1.26mmol) in DCM (10mL) was added portionwise bose-martin oxidant (0.68g,1.51 mmol). After stirring at room temperature for 16 h, the mixture was diluted with DCM and saturated NaHCO₃Aqueous solution (40mL) followed by 20% aqueous sodium thiosulfate (30 mL). The resulting mixture was stirred for 20 minutes. Separating the organic layer over Na₂SO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-50% EtOAc/isohexane) affordedTert-butyl 4- (4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) -6-oxo-1, 4-diazepan-1-carboxylate (0.36g) as an oil. To a solution of this oil (0.35g,0.76mmol) in DCM (5mL) was added(50% in THF, 0.69mL,1.91mmol) and the mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM (30mL), cooled in an ice/water bath and purified by dropwise addition of saturated NaHCO₃Aqueous solution (30mL) was quenched. The resulting mixture was stirred for 10 minutes. Separating the organic layer over Na₂SO₄Dried and the solvent removed under reduced pressure. The crude product was purified by silica gel column chromatography (0-50% EtOAc/isohexane) to give 6, 6-difluoro-4- (4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester (280mg, 19% over four steps) as a yellow oil.¹HNMR(400MHz,CDCl₃)8.12-8.03(m,1H),5.61-5.34(m,2H),4.01-3.41(m,6H),3.59-3.09(m,4H),1.67-1.34(m,9H),0.94-0.86(m,2H),SiMe₃Masked by the internal standard TMS peak.

Intermediate 476-methoxy-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester

A solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (1.62g,10.0mmol), 1, 4-diazepan-6-ol (4.18g,15.0mmol) and DIPEA (6.6mL) from example 1 in EtOH (6mL) was heated in a microwave at 130 ℃ for 3 hours. The solvent was removed under reduced pressure, and the residue was dissolved in DCM (60mL) and DMF (10 mL). Di-tert-butyl dicarbonate (8.73g,40mmol) and DIPEA (3.48mL) were added and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl 6-hydroxy-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylate as a yellow oil (2.13 g). To the oilA solution of material (205mg,0.6mmol) in THF (5ml) was added sodium hydride (60% in mineral oil, 24mg,0.6mmol) at 0 deg.C. After 30 min, iodomethane (0.04mL,0.6mmol) was added and the resulting mixture was warmed to room temperature over 1.5 h. The mixture was diluted with DCM (20mL) and with water (20mL) and saturated NaHCO₃Aqueous (20mL) wash. The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded tert-butyl 6-methoxy-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylate as a yellow gum (116mg, 33%, over two steps). LCMS (ES +) M/z356(M +1).

Intermediate 485-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol

Trifluoroacetic acid (20mL) was added to a solution of 4-azido-5-hydroxyazetidine-1-carboxylic acid tert-butyl ester (7.43g,29.0mmol) in DCM (70mL) and the mixture was heated after an explosion-proof barrier at 35 ℃ for4 hours. The solvent was removed under reduced pressure and the residue redissolved in MeOH and passed through an SCX column, washed with DCM and MeOH and eluted with 3-10% 7N ammonia in MeOH/DCM to give 5-azidoazepan-4-ol as a yellow oil (4.38g,28.0mmol) which was dissolved in anhydrous DMSO (100 mL). To 5-chloro-1-methyl-4-nitro-1H-pyrazole (5.20g,32.2mmol) from example 1 was added potassium fluoride (6.51g,112 mmol). The mixture was heated at 70 ℃ for 16 h, cooled to room temperature, poured into water (1000mL) and extracted into EtOAc (4X250 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol as a yellow gum (7.27g, 77% over two steps).¹H NMR(400MHz,CDCl₃)8.04(s,1H),3.94-3.66(m,4H),3.65(td,J＝9.7,3.8Hz,1H),3.44-3.18(m,4H),2.50(d,J＝2.8Hz,1H),2.24-2.12(m,2H),2.02-1.89(m,2H).

Intermediate 48a 4-azido-5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepane

To a solution of 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (4.0g,14.2mmol) in anhydrous DCM (100mL) (cooled to 0 deg.C) was slowly added triethylamine (4.0mL,28.5mmol), followed by the addition of DMAP (175mg,1.42mmol) and 4-methylbenzene-1-sulfonyl chloride (4.1g,21.4mmol) in portions. The reaction mixture was warmed to room temperature and stirred for 18 hours. More 4-methylbenzene-1-sulfonyl chloride (1.4g,7.12mmol) was added to the reaction mixture, which was stirred at room temperature for an additional 24 hours. Water (40mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (30-70% EtOAc/isohexane) afforded 4-methylbenzenesulfonic acid 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl ester as a dark milky solid (2.81 g). The solid (2.3g,5.29mmol) was treated with a solution of TBAF (1.0M in THF, 21mL,21.1mmol) and the reaction mixture was heated at 60 ℃ for 2 h. After cooling to room temperature, water (30mL) was added and the mixture was extracted with EtOAc (2 × 150 mL). The combined organic layers were over MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (30-40% EtOAc/isohexane) afforded 4-azido-5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepane as a yellow viscous oil (804mg, 20% over two steps).¹H NMR(400MHz,CDCl₃)8.04(s,1H),5.06(ddt,J＝46.2,8.1,2.5Hz,1H),4.00(dd,J＝20.8,8.1Hz,1H),3.79(s,3H),3.43-3.34(m,2H),3.26-3.11(m,2H),2.43-2.30(m,1H),2.30-2.18(m,1H),2.12-1.92(m,2H).

Intermediate 49N- ((4S,5S) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide

To a solution of 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (7.26g,25.8mmol) in anhydrous DCM (100ml) was added dropwise(12.1mL,32.84mmol, 50% in THF) and the mixture stirred at room temperature for 16 h. The mixture was cooled in an ice bath and saturated NaHCO was added slowly₃Aqueous (40mL) (bubbling was observed) and the mixture was extracted with DCM (150 mL). The organic layer was saturated NaHCO₃The aqueous solution (2 × 30mL) was washed, separated, passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% EtOAc/isohexane) to give 4-azido-5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepane as a yellow gum (5.55 g). Sufficient reaction provides additional material. A solution of this gum (6.40g,22.6mmol) in THF/water (120mL/24mL) was treated with triphenylphosphine (5.93g,22.6mmol) and the mixture was heated at 60 ℃ for 16 h. The mixture was partitioned between EtOAc (150mL) and water (20mL) and the organic layer was separated, washed with brine (20mL), passed through a phase separation cartridge and concentrated under reduced pressure. The residue was redissolved in MeOH and passed through an SCX column, washed with MeOH and eluted with 3-10% 7N ammonia in MeOH/DCM to give 5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-amine as a yellow oil (5.70 g). To a solution of this oil (5.7g,22.1mmol) and DIPEA (11.5mL,66.3mmol) in DCM (50mL) was added trifluoroacetic anhydride (3.38mL,24.3mmol) dropwise and the mixture was stirred at room temperature for 16 h. Water (15mL) was added and the organic phase was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give 2,2, 2-trifluoro-N- (5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide as a yellow gum (7.8 g). To a solution of this gum (7.8g,22.0mmol) and ammonium formate (10.23g,176.0mmol) in MeOH (100mL) under nitrogen was added 10% palladium on carbon (585mg,5.5 mmol). The mixture was heated at 70 ℃ for4 hours, then cooled, filtered and concentrated under reduced pressure. The residue was partitioned between water (20mL) and DCM (100mL) and the organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give N- ((4S,5S) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamideAs a brown solid (4.72g, 49% over four steps).¹HNMR(400MHz,CDCl₃)9.03(s,1H),7.19(s,1H),4.90-4.76(m,2H),3.66(s,3H),3.52-3.43(m,2H),3.12(td, J ═ 11.9,5.4Hz,1H),2.96(dt, J ═ 14.8,4.2Hz,1H),2.43-2.31(m,1H),2.13-1.85(m, 3H). No exchangeable NH observed₂。

Intermediate 49a N- ((4S,5R) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide

A solution of 4-azido-5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepane (1.4g,4.95mmol) in THF/water (30mL/6mL) was treated with triphenylphosphine (1.3g,4.95mmol) and the mixture was heated at 60 ℃ after the explosion-proof barrier for4 hours. The mixture was washed with EtOAc (200mL) and saturated NaHCO₃The aqueous solution (30mL) was partitioned. The aqueous layer was extracted with EtOAc (50mL) and the combined organic layers were MgSO₄Dried and concentrated under reduced pressure. The resulting oil was triturated with diethyl ether, the resulting solid was filtered and the filtrate was concentrated under reduced pressure to give 5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-amine (contaminated with triphenylphosphine oxide as a yellow oil to a solution of this oil (1.27g,4.95mmol) in anhydrous DCM (40mL) was slowly added DIPEA (2.6mL,14.8mmol) at 0 deg.C, then trifluoroacetic anhydride (0.83mL,5.94mmol) was added dropwise, the reaction mixture was warmed to room temperature and stirred for 18 hours, water (40mL) was added and the mixture was extracted with DCM (150mL), the organic layer was separated, MgSO 2₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (40% EtOAc/isohexane) afforded 2,2, 2-trifluoro-N- (5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide as a yellow viscous oil (1.4 g). To a solution of this oil (1.4g,3.97mmol) and ammonium formate (2.5g,39.7mmol) in MeOH (40mL) under nitrogen was added 10% palladium on carbon (140 mg). The mixture was heated at 70 ℃ for 30 minutes, then cooled, filtered and concentrated under reduced pressure. The residue was partitioned between water (30mL) and DCM (75 mL). The aqueous layer was extracted with DCM (2X75mL) and combinedThe organic layer was separated and MgSO₄Drying and concentration under reduced pressure gave N- ((4S,5R) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide as an orange yellow glass (1.1g, 69%, over three steps).¹H NMR(400MHz,CDCl₃)7.47(s,1H),7.12(s,1H),5.02-4.85(m,1H),4.69-4.55(m,1H),3.66(s,3H),3.42-3.20(m,3H),3.11(ddd, J ═ 14.4,6.7,3.3Hz,1H),2.36-2.22(m,1H),2.23-1.94(m,2H),1.90-1.82(m, 1H). No NH observed₂。

Intermediate 49b 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol

To a solution of anti-5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (1.75g,6.23mmol) in DCM (40mL) was added Toiss-martin oxidant (3.2g,7.47 mmol). An exotherm was observed and the mixture was cooled in a cold water bath. The reaction mixture was stirred at room temperature for 18 hours. Addition of saturated NaHCO₃Aqueous (50mL) and the mixture was extracted with DCM (200mL) the organic layer was successively saturated with aqueous sodium thiosulfate (2 × 50mL) and saturated NaHCO₃Aqueous (2 × 50mL) washes. The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (30-60% EtOAc/isohexane) afforded 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-one as a yellow solid (1.55 g). To a solution of the solid (1.5g,5.38mmol) in dry THF (40mL) under nitrogen (cooled to-78 deg.C) was added dropwiseWas added (1M in THF,6.5mL,6.45mmol) and the reaction mixture was stirred at-78 deg.C for 90 minutes. The mixture was warmed to room temperature and water (30mL) was added. The mixture was extracted with EtOAc (2 × 100mL) and the combined organic layers were MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel column chromatography (50-70% EtOAc/isohexane) afforded syn-5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol as an orange-yellow oil (845mg, 50%, over two steps).¹H NMR(400MHz,CDCl₃)8.07-8.01(m,1H),4.21-4.16(m,1H),3.98-3.92(m,1H),3.80(s,2H),3.44-3.30(m,2H),3.28-3.19(m,1H),3.14(ddd, J ═ 13.3,7.4,4.0Hz,1H),2.33-2.22(m,1H),2.21-2.09(m,1H),2.07(d, J ═ 5.1Hz,1H),2.01-1.86(m,2H). no OH was observed.

Intermediate 49c tert-butyl 5-methoxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate

To a solution of 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (420mg,1.49mmol) in anhydrous DMF (15mL) (cooled to 0 deg.C) was added sodium hydride (60% in mineral oil, 90mg,2.24 mmol). After stirring for 15 min, iodomethane (0.14mL,2.24mmol) was added and the reaction mixture was warmed to room temperature and stirred for 1 h. Water (20mL) was added and the mixture was extracted with EtOAc (150 mL). The organic layer was washed with water (6 × 30mL) and brine (20mL), separated, and over MgSO₄Dried and concentrated under reduced pressure. Purification by column chromatography on silica gel afforded 4-azido-5-methoxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepane as a yellow oil (350 mg). A solution of this oil (350mg,1.19mmol) in THF/water (15mL/3mL) was treated with triphenylphosphine (311mg,1.19mmol) and the reaction mixture was heated at 60 ℃ after an explosion-proof barrier for 18 h. Water (2mL) was added and the mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were over MgSO₄Dried and concentrated under reduced pressure. The resulting oil is in Et₂Trituration with O, filtration of the resulting solid and concentration of the filtrate under reduced pressure afforded a yellow oil. To a solution of this oil (319mg,1.19mmol) in dry DCM (10mL) was added a solution of di-tert-butyl dicarbonate (310mg,1.42mmol) in DCM (10mL) and DIPEA (1.0mL,5.93mmol) at 0 deg.C. The reaction mixture was warmed to room temperature and stirred for 72 hours. Water (20mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was separated over MgSO₄Drying and reducing pressureAnd (5) concentrating. Purification via silica gel column chromatography (40-50% EtOAc/isohexane) afforded tert-butyl 5-methoxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate as a yellow oil (355mg, 64%, over three steps).¹H NMR(400MHz,CDCl₃)8.02(s,1H),5.14(d,J＝8.9Hz,1H),4.00-3.90(m,1H),3.78(s,3H),3.68-3.60(m,1H),3.48(t,J＝12.6Hz,1H),3.39(s,3H),3.33-3.23(m,1H),3.19-3.11(m,1H),3.04-2.95(m,1H),2.25-2.06(m,2H),1.88-1.76(m,2H),1.45(s,9H).

Intermediate 49d 5-hydroxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester

A solution of syn-5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (420mg,1.49mmol) in THF/water (15mL/3mL) was treated with triphenylphosphine (392mg,1.49mmol) and the reaction mixture was heated at 60 ℃ for 9H. Brine (5mL) was added and the mixture was extracted with EtOAc (2 × 75mL), the combined organic layers were over MgSO₄Dried and concentrated under reduced pressure. The resulting oil was treated with Et₂Trituration with O, filtration of the resulting solid and concentration of the filtrate under reduced pressure afforded a yellow solid. To a solution of the solid in anhydrous DCM (10mL) was added a solution of di-tert-butyl dicarbonate (391mg,1.79mmol) in DCM (10mL) and DIPEA (1.3mL,7.47 mmol). The reaction mixture was warmed to room temperature and stirred for 18 hours. Water (10mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (60-75% EtOAc/isohexane) afforded tert-butyl 5-hydroxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (contaminated with triphenylphosphine oxide) as a yellow oil (172 mg).¹H NMR(400MHz,CDCl₃)8.03(s,1H),5.20(br s,1H),4.19(br s,1H),3.98-3.90(m,1H),3.79(s,3H),3.52-3.42(m,1H),3.34-3.05(m,3H),2.72(br s,1H),2.23-2.10(m,1H),2.04-1.95(m,2H),1.92-1.80(m,1H),1.46(s,9H).

Intermediate 505-azido-1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) azepan-4-ol

Following the procedure for intermediate 48, starting from tert-butyl 4-azido-5-hydroxyazepan-1-carboxylate and 5-chloro-1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazole, 5-azido-1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) azepan-4-ol was obtained as a yellow gum (1.16g, 50% over two steps).¹H NMR(400MHz,CDCl₃)8.14-8.09(m,1H),6.11(tt,J＝27.8,4.4Hz,1H),4.50-4.39(m,2H),3.83(tt,J＝8.8,3.1Hz,1H),3.67(td,J＝4.7,3.6Hz,1H),3.45-3.21(m,4H),2.37(d,J＝2.9Hz,1H),2.25-2.12(m,2H),2.03-1.91(m,2H).

Intermediate 51N- (1- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide

Following the procedure for intermediate 49, starting from 5-azido-1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) azepan-4-ol, N- (1- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide was obtained as a red gum (720mg, 50%, over four steps). LCMS (ES +) M/z374(M +1).

Intermediate 526, 6-difluoro-N, N-dimethyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-amine

To 6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylaminoTert-butyl formate (0.96g,2.56mmol) in MeOH (3mL) was added HCl in1, 4-dioxane (4M,12.8mL,51.2mmol) and the solution stirred at rt for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM (30 mL). The organic layer was saturated NaHCO₃Washed with aqueous solution (30mL) over Na₂SO₄Drying and removal of the solvent under reduced pressure gave 6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-amine. The amine was dissolved in MeOH/THF (1:1,50mL) and treated with formaldehyde (38% in water,0.45mL,6.21 mmol). After 5 min, sodium cyanoborohydride (0.39g,6.21mmol) was added in portions and the resulting mixture was stirred for 5 h. Additional formaldehyde (38% in water,0.45mL,6.21mmol) and sodium cyanoborohydride (0.39g,6.21mmol) were added and the resulting mixture was stirred for 60 hours. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (0-10% MeOH/DCM) to give 6, 6-difluoro-N, N-dimethyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-amine as a yellow oil (0.64g, 82% over two steps).¹H NMR(400MHz,CDCl₃)8.07-8.03(m,1H),3.82(s,3H),3.70-3.57(m,2H),3.42-3.29(m,1H),3.24-3.05(m,1H),3.04-2.98(m,1H),2.51-2.40(m,1H),2.35-2.29(m,6H),2.20-2.01(m,2H),1.97-1.82(m,1H).

Intermediate 536-methoxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester

To a solution of 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol, intermediate 18(0.85g,3.0mmol) in DMF (5mL) (cooled to 0 ℃) was added sodium hydride (60% in mineral oil, 133mg,3.3mmol) under nitrogen and the resulting mixture was stirred for 10 min. Methyl iodide (0.37mL,6.0mmol) was added and the mixture was stirred at room temperature for 16 h. Water (200mL) was added and the mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with Na₂SO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-50% EtOAc/isohexane) afforded 5-azido-3-methoxy-1- (1-methyl-4)-nitro-1H-pyrazol-5-yl) azepane as an oil (0.76 g). The azide (0.76g,2.6mmol) was treated with triphenylphosphine (0.71g,2.7mmol) in THF (15mL) and water (3 mL). The mixture was heated at 65 ℃ for 16H and the solvent was removed under reduced pressure to give 6-methoxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-amine. The amine was suspended in DCM (40mL) and di-tert-butyl dicarbonate (1.13g,5.2mmol) and DIPEA (1.36mL,7.8mmol) were added. After stirring at room temperature for 16 h, the solvent was removed under reduced pressure and the residue was dissolved in DCM (40 mL). Water (20ml) was added and the organic layer was separated over Na₂SO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-50% EtOAc/isohexane) afforded tert-butyl 6-methoxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (0.84g, 74%, over three steps) as an oil.¹H NMR(400MHz,CDCl₃)8.03(d,J＝4.3Hz,1H),5.39(d,J＝7.9Hz,1H),4.21-3.94(m,1H),3.84(s,3H),3.56-3.42(m,2H),3.35-3.03(m,6H),2.28-1.89(m,4H),1.46(s,9H).

Intermediate 53a N- (1- (4-amino-1-cyclopropyl-1H-pyrazol-5-yl) -6-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide

To a solution of 5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol (0.69g,2.25mmol) in DCM (30mL) was added(50% in THF, 1.06mL,2.86mmol) and the mixture stirred at room temperature for 62 h. The mixture was diluted with DCM (30mL), cooled in an ice/water bath and purified by dropwise addition of saturated NaHCO₃Aqueous solution (100mL) was quenched. The resulting mixture was stirred for 10 minutes. The organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification by column chromatography on silica gel (0-100% EtOAc/isohexane) afforded 5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -3, 3-difluoroazepane (410mg) as a viscous yellow colored gelAn oil. To a solution of this oil (400mg,1.3mmol) in THF (10mL) and water (2mL) was added triphenylphosphine (341mg,1.3mmol) and the mixture was heated at 60 ℃ after an explosion-proof barrier for 16 h. The mixture was washed with EtOAc (30mL) and water (3 × 20 mL). The organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. The residue was passed through an SCX column, washed with DCM and MeOH and eluted with 3-10% 1N ammonia in MeOH/DCM to give 1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-amine (555mg) (contaminated with triphenylphosphine oxide) as a viscous yellow oil. To a solution of this oil (360mg,1.28mmol) and DIPEA (0.67mL,3.84mmol) in DCM (20mL) was added trifluoroacetic anhydride (0.2mL,1.41mmol) and the mixture was stirred at rt for 16 h. The organic layer was washed with water (2 × 20mL), separated and passed through a phase separation cartridge. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give N- (1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -6-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide (280mg) as a viscous yellow oil.

To this oil (276mg,0.73mmol) and ammonium formate (340mg,5.84mmol) in MeOH (15mL) under nitrogen was added 10% palladium on carbon (31mg,0.29 mmol). The mixture was heated at 80 ℃ for4 hours, then cooled, filtered and concentrated under reduced pressure. The residue was partitioned between water (10mL) and DCM (50 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give N- (1- (4-amino-1-cyclopropyl-1H-pyrazol-5-yl) -6-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide (210mg, 28%, over 4 steps) as a viscous red oil. LCMS (ES +) M/z350(M +1).

Intermediate 54N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-methoxyazepan-4-yl) -2,2, 2-trifluoroacetamide

To a solution of 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (500mg,1.78mmol) in anhydrous DMF (15mL) (cooled to ℃ C.) was added hydrogenSodium cyanide (60% in mineral oil, 107mg,2.67 mmol). After stirring for 15 min, iodomethane (0.17mL,2.67mmol) was added and the reaction mixture was warmed to room temperature and stirred for 90 min. Water (20mL) was added and the mixture was extracted with EtOAc (200mL), washed with water (6 × 20mL) and brine (20 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure to give 4-azido-5-methoxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepane as a yellow oil (484 mg). A solution of this oil (480mg,1.63mmol) in THF/water (15mL/3mL) was treated with triphenylphosphine (426mg,1.63mmol) and the reaction mixture was heated at 60 ℃ for 5 h. EtOAc (100mL) was added and the mixture was saturated NaHCO₃Aqueous (20mL) wash. The aqueous layer was extracted with EtOAc (50mL) and the combined organic layers were MgSO₄Dried and concentrated under reduced pressure. The resulting oil is in Et₂Trituration with O, filtration of the resulting solid and concentration of the filtrate under reduced pressure afforded a yellow oil. To a solution of this oil in anhydrous DCM (20mL) was added DIPEA (0.85mL,4.88mmol) and trifluoroacetic anhydride (0.27mL,1.95mmol) at 0 ℃. The reaction mixture was warmed to room temperature and stirred for4 hours. Water (20mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (40-50% EtOAc/isohexane) afforded 2,2, 2-trifluoro-N- (5-methoxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide as a yellow oil (530 mg). A solution of this oil (520mg,1.42mmol) in MeOH (20mL) was treated with ammonium formate (900mg,14.2mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 65 ℃ for 1 hour. After cooling to room temperature, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was taken up in saturated NaHCO₃Partition between aqueous solution (20mL) and DCM (50 mL). The aqueous layer was extracted with DCM (3 × 50mL) and the combined organic layers were over MgSO₄Dried and concentrated under reduced pressure to give N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-methoxyazepan-4-yl) -2,2, 2-trifluoroacetamide as an orange foam (486mg, 82% over 4 steps).¹H NMR(400MHz,CDCl₃)8.85(br s,1H),7.17(s,1H),4.64(dd,J＝14.5,7.2Hz,1H),3.65(s,3H),3.57-3.36(m,2H),3.41(s,3H),3.15-3.05(m,1H),2.93-2.85(m,1H),2.61(br s,2H),2.43-2.33(m,1H),1.92-1.77(m,4H).

Intermediate 555-azido-1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) azepan-3-ol

Following the procedure for intermediate 18, starting from tert-butyl (Z) -3-oxo-2, 3,6, 7-tetrahydro-1H-azepine-1-carboxylate, 5-azido-1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) azepan-3-ol was obtained as a light brown gum (88% over four steps).¹H NMR(400MHz,CDCl₃)8.11(s,1H),6.36-5.99(m,1H),4.89-4.70(m,1H),4.55-4.23(m,1H),4.18-4.00(m,1H),3.96-3.76(m,1H),3.73-3.44(m,2H),3.42-3.12(m,2H),2.32-1.95(m,5H).

Intermediate 561- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-ylcarbamic acid tert-butyl ester

Following the procedure for intermediate 19, starting from 5-azido-1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) azepan-3-ol, we obtained tert-butyl 1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-ylcarbamate as a pale green gum (1.34g, 46% over four steps).¹H NMR(400MHz,CDCl₃)8.17-8.06(m,1H),6.34-6.00(m,1H),4.72-4.30(m,3H),4.12-3.95(m,1H),3.66-3.10(m,4H),2.59-2.03(m,4H),1.45-1.41(m,9H).

Intermediate 57 (R) -N- (1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide

Following the procedure for intermediate 28, starting from 5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole and (R) -2,2, 2-trifluoro-N- (hexahydro-1H-azepin-4-yl) -acetamide, the (R) -N- (1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide was obtained as a light yellow gum (105mg, 61%).¹H-NMR(400MHz,CDCl₃)7.96(s,1H),6.55-6.38(m,1H),4.30-4.15(m,1H),3.65-3.53(m,1H),3.55-3.25(m,4H),2.25-2.05(m,6H),1.35-1.05(m,4H).

Intermediate 57a 5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol

To a solution of (Z) -3-oxo-2, 3,6, 7-tetrahydro-1H-azepine-1-carboxylic acid tert-butyl ester (15.0g,71.1mmol) in acetonitrile (25mL) was added trimethylsilylazide (28.2mL,213mmol) followed by Amberlite IRA900F resin (loading: 2-3mmol/g,18g) and the resulting mixture was heated at 60 ℃ for 16 hours after the explosion-proof barrier. After cooling to room temperature, the solution was filtered, the resin was washed with acetonitrile and the filtrate was concentrated under reduced pressure (bath temperature)<5-azido-3-oxoazepane-1-carboxylic acid tert-butyl ester was obtained at 40 ℃ as a light orange oil. To a solution of this oil in THF/water (150mL/150mL) (cooled in an ice bath) was added NaBH in portions over 15 minutes₄(6.73g,178mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was extracted with EtOAc (2x400mL), the combined organic layers were washed with water (2x250mL) and brine (150mL), separated, and over MgSO₄Drying and removal of the solvent under reduced pressure gave tert-butyl 5-azido-3-hydroxyazepane-1-carboxylate as a colorless oil (19.2 g). To a solution of this oil (4.0g,15.6mmol) in DCM (60mL) was added TFA (30mL) and the solution was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude residue was dissolved in DCM and passed through a SCX column, washed with DCM, 1:1MeOH/DCM and MeOH and eluted with 1N ammonia in MeOH to give 5-azidoazepan-3-ol as a light yellow gum (2.36 g). To the gum (1.17g,7.48mmol) in anhydrous DMSO (25mL)To the solution in (1.74g,29.9mmol) was added potassium fluoride and 5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole (1.61g,8.6mmol) and the mixture was heated at 70 ℃ for 16 hours. The mixture was diluted with water (100mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (3 × 20mL), separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) afforded 5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol as a viscous yellow oil (2.24g, 81% over four steps). LCMS (ES +) M/z308(M +1).

Intermediate 57b N- (1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-yl) -2,2, 2-trifluoroacetamide

To a solution of 5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-3-ol (1.54g,5.0mmol) in DCM (50mL) was added portionwise bose-martin oxidant (2.54g,6.0 mmol). After stirring at room temperature for 3 hours, the mixture was diluted with DCM (25mL) and saturated NaHCO₃Aqueous solution (50mL) was quenched followed by saturated aqueous sodium thiosulfate solution (50 mL). The resulting mixture was stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted with more EtOAc (3 × 30 mL). The combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) afforded 5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-3-one (1.22g) as a light yellow solid. To a solution of the solid (1.22g,4.0mmol) in DCM (60mL) was added(50% in THF, 2.68mL,7.3mmol) and the mixture stirred at room temperature for 62 h. The mixture was diluted with DCM (30mL), cooled in an ice/water bath and purified by dropwise addition of saturated NaHCO₃Aqueous solution (100mL) was quenched. The resulting mixture was stirred for 10 minutes. The organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Chromatography on silica gel (0-100% EtOAc/isoHexane) to give 5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -3, 3-difluoroazepane (860mg) as a viscous yellow oil. To a solution of this oil (0.85g,2.6mmol) in THF (20mL) and water (4mL) was added triphenylphosphine (682mg,2.6mmol) and the mixture was heated at 60 ℃ for 16 h after your explosion proof barrier. The mixture was washed with EtOAc (30mL) and water (3 × 20 mL). The organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. The residue was passed through an SCX column, washed with DCM and 1:1MeOH: DCM and MeOH and eluted with 1N ammonia in MeOH to give 1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-amine (783mg) (contaminated with triphenylphosphine oxide) as a thick dark yellow oil. To a solution of this oil (0.78g,2.60mmol) and DIPEA (1.36mL,7.80mmol) in DCM (20mL) was added trifluoroacetic anhydride (0.4mL,2.86mmol) and the mixture was stirred at room temperature for 16 h. The organic layer was washed with water (2 × 20mL), separated and passed through a phase separation cartridge. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give N- (1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-yl) -2,2, 2-trifluoroacetamide as a yellow solid (880mg, 44%, over 4 steps).¹H NMR(400MHz,CDCl₃)7.99-7.95(m,1H),6.55(d,J＝8.0Hz,1H),4.59-4.50(m,1H),3.74-3.62(m,3H),3.44-3.34(m,2H),2.55-2.44(m,2H),2.31-2.14(m,2H),1.39-1.07(m,4H).

Intermediate 58 (R) -tert-butyl 2-bromo-4- (1-cyclopropyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

To a solution of (R) -N- (1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide (0.725g,2.00mmol) in MeOH (20mL) was added 10% palladium on carbon (0.75g,7.07mmol) and ammonium formate (0.507g,8.03 mmol). The mixture was heated at 80 ℃ for 3 hours. By passingThe mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was redissolved in DCM (20mL) and 2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxylic acid (0.74g,2.29mmol), PyBOP (1.57g,3.01mmol) and DIPEA (1mL,5.6mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. Water (20mL) was added and stirring continued for 10 min. The layers were separated and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give (R) -tert-butyl 2-bromo-4- (1-cyclopropyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate as a light brown solid (0.98g, 77% over two steps).¹HNMR(400MHz,CDCl₃)10.26(s,1H),8.43(s,1H),7.71(s,1H),6.47(d,J＝8.3Hz,1H),4.25-4.15(m,1H),3.47-3.35(m,3H),3.29-3.13(m,2H),2.46-1.57(m,6H),1.52(s,9H),1.23-1.17(m,2H),1.12-0.96(m,2H).

Intermediate 58a 5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol

Following the procedure for intermediate 48, starting from tert-butyl 4-azido-5-hydroxyazepan-1-carboxylate, 5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol was obtained as a yellow gum (1.2g, 72%).¹H NMR(400MHz,CDCl₃)7.96(s,1H),3.82(tt,J＝8.5,4.8Hz,1H),3.65(ddd,J＝10.0,8.5,3.8Hz,1H),3.62-3.54(m,1H),3.52-3.37(m,2H),3.31(tdd,J＝14.1,5.7,3.8Hz,2H),2.50(d,J＝3.1Hz,1H),2.24-2.13(m,2H),2.04-1.92(m,2H),1.31-1.20(m,2H),1.14-1.05(m,2H).

Intermediate 58b N- (1- (4-amino-1-cyclopropyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide

Following the procedure for intermediate 49, starting from 5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol, N- (1- (4-amino-1-cyclopropyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide was obtained as an orange gum (900mg, 67%, over four 4 steps). LCMS (ES +) M/z350(M +1).

Intermediate 595-chloro-1-ethyl-4-nitro-1H-pyrazole

Following the procedure for intermediate 5, starting from 1-ethyl-4-nitropyrazole, 5-chloro-1-ethyl-4-nitro-1H-pyrazole was obtained as a colorless solid (1.3g, 74%).¹H-NMR(400MHz,CDCl₃)8.16(s,1H),4.26(q,J＝7Hz,2H),1.50(t,J＝7Hz,3H).

Intermediate 60N- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide

Following the procedure for intermediate 28, starting from 5-chloro-1-ethyl-4-nitro-1H-pyrazole and 2,2, 2-trifluoro-N- (hexahydro-1H-azepin-4-yl) -acetamide, N- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide was obtained as a light yellow gum (136mg, 55%).¹H-NMR(400MHz,CDCl₃)8.07(s,1H),6.39-6.37(m,1H),4.22-4.19(m,1H),4.12(q,J＝7Hz,2H),3.42-3.35(m,1H),3.27-3.18(m,3H),2.25-2.05(m,2H),2.00-1.75(m,4H),1.47(t,J＝7Hz,3H).

Intermediate 61 (R) -tert-butyl 2-bromo-4- (1-ethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

Starting from (R) -N- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide according to the procedure for intermediate 58, tert-butyl (R) -2-bromo-4- (1-ethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate was obtained as a light brown solid (186mg, 31% over two steps).¹H NMR(400MHz,CDCl₃)10.30(s,1H),8.41(s,1H),7.81(s,1H),6.44(d,J＝8.2Hz,1H),4.25-4.17(m,1H),4.06(q,J＝7.2Hz,2H),3.40-3.32(m,2H),3.23-3.10(m,2H),2.23-2.09(m,2H),2.06-1.94(m,2H),1.91-1.68(m,2H),1.54(s,9H),1.48(t,J＝7.2Hz,3H).

Intermediate 621- ((3-Methylooxetan-3-yl) methyl) -1H-pyrazol-4-amine

4-Nitropyrazole (1.13g,10mmol) and K₂CO₃A mixture of (3.4g,25mmol) in MeCN (50mL) was stirred at room temperature for 15 minutes, then 3- (bromomethyl) -3-methyloxetane (1.8g,11mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, filtered and the filter cake was washed with MeCN. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) gradient to give 1- ((3-methyloxetan-3-yl) methyl) -4-nitro-1H-pyrazole as a colorless solid (1.43g, 73%). A portion of the solid (206mg,1.04mmol) (dissolved in MeOH (20 mL)) was treated with ammonium formate (260mg,4.13mmol) and 10% palladium on carbon (50 mg). Heating the mixture at 80 deg.C for 1.5 hr, cooling, and passing throughFiltration and concentration of the filtrate under reduced pressure gave 1- ((3-methyloxetan-3-yl) methyl) -1H-pyrazol-4-amine as a pale pink gumMaterial (160mg, 92%).¹H NMR(400MHz,CDCl₃)7.15(s,1H),6.97(s,1H),4.66(d,J＝6.1Hz,2H),4.37(d,J＝6.1Hz,2H),4.19(s,2H),2.91(s,2H),1.23(s,3H).

Intermediate 634- (1-methyl-4-nitro-1H-pyrazol-5-yl) but-3-ynylcarbamic acid tert-butyl ester

A solution of tert-butyl 3-butyn-1-ylcarbamate (123mg,0.728mmol) in NEt3(4mL) was treated with 5-bromo-1-methyl-4-nitro-1H-pyrazole (100mg,0.485mmol) and copper (I) bromide-dimethylsulfide complex (10mg,0.049 mmol). The mixture was degassed four times by evacuation and refilling with nitrogen, then tetrakis (triphenylphosphine) -palladium (0) (28mg,0.024mmol) was added. Degassing was repeated twice and the reaction mixture was stirred at room temperature for 20 hours. More tert-butyl 3-butyn-1-ylcarbamate (123mg,0.728mmol) and copper (I) bromide dimethylsulfide complex (10mg,0.049mmol) were added and the mixture degassed three times. Tetrakis (triphenylphosphine) palladium (0) (28mg,0.024mmol) was added and the reaction mixture stirred at room temperature for 48 h. The mixture was washed with EtOAc (100mL) and with water (20mL) and brine (20 mL). The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (30-40% EtOAc/isohexane) to give tert-butyl 4- (1-methyl-4-nitro-1H-pyrazol-5-yl) but-3-ynylcarbamate as a yellow oil (112mg, 78%).¹H NMR(400MHz,CDCl₃)8.05(s,1H),5.03(s,1H),3.94(s,3H),3.46(q,J＝6.4Hz,2H),2.79(t,J＝6.4Hz,2H),1.67-1.27(m,9H).

Intermediate 645-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole

Starting from 1-cyclopropylmethyl-4-nitropyrazole, according to the procedure of intermediate 5, 5-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole as a colorless oil (1.16g, 56%).¹H-NMR(400MHz,CDCl₃)8.17(s,1H),4.07(d,J＝7Hz,2H),1.39-1.28(m,1H),0.66-0.59(m,2H),0.50-0.40(m,2H).

Intermediate 65 (R) -N- (1- (1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide

Following the procedure for intermediate 28, starting from 5-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole and (R) -2,2, 2-trifluoro-N- (hexahydro-1H-azepin-4-yl) -acetamide, the (R) -N- (1- (1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide was obtained as a light yellow gum (0.98g, 55%).¹H-NMR(400MHz,CDCl₃)8.08(s,1H),6.42-6.39(m,1H),4.22-4.14(m,1H),4.00-3.85(m,2H),3.44-3.32(m,1H),3.30-3.15(m,3H),2.25-2.05(m,2H),2.00-1.75(m,4H),1.30-1.20(m,1H),0.70-0.62(m,2H),0.50-0.35(m,2H).

Intermediate 66 (R) -tert-butyl 2-bromo-4- (1- (cyclopropylmethyl) -5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

Starting from (R) -N- (1- (1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoroacetamide according to the procedure for intermediate 58, was obtained (R) -tert-butyl 2-bromo-4- (1-cyclopropylmethyl-5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate as a light brown solid (310mg, 57% over two steps).¹H NMR(400MHz,CDCl₃)10.28(s,1H),8.39(s,1H),7.83-7.75(m,1H),6.40(d,J＝8.2Hz,1H),4.22-4.14(m,1H),3.90-3.80(m,2H),3.39-3.30(m,2H),3.23-3.11(m,2H),2.02-1.91(m,3H),1.89-1.67(m,4H),1.52(s,9H),0.65-0.59(m,2H),0.47-0.37(m,2H).

Intermediate 675-amino-N- (5-chloro-1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

Following the procedure of example 110, starting from 3-chloro-1-methyl-1H-pyrazol-4-amine, 5-amino-N- (5-chloro-1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide was obtained as an off-white solid (146mg, 46% over three steps).¹H NMR(400MHz,d6-DMSO)8.89(s,1H),7.74(s,1H),7.60-7.50(m,3H),7.28(t,J＝8.6Hz,2H),3.80(s,3H)。LCMS(ES+)m/z370(M+1).

Intermediate 685-amino-2- (2, 6-difluorophenyl) -N- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

Following the procedure of example 107, purification by preparative HPLC gave 5-amino-2- (2, 6-difluorophenyl) -N- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) thiazole-4-carboxamide (0.14g, 28% over two steps) as a milky solid. 1H (400MHz, d6-DMSO)9.75(s,1H),7.97(s,1H),7.67(s,1H),7.58-7.52(m,3H),7.30-7.25(m,2H),4.09(t, J ═ 17.0Hz,2H),3.27(s,3H),3.23(t, J ═ 15.4Hz,2H),1.98-1.93(m, 2H). LCMS (ES +) M/z394(M +1)

Intermediate 695-amino-2- (2, 6-difluorophenyl) -N- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

Following the procedure of example 107, purification by preparative HPLC gave 5-amino-2- (2, 6-difluorophenyl) -N- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide (0.17g, 43% over two steps) as a light brown solid. 1H (400MHz, d6-DMSO)9.75(s,1H),8.03(s,1H),7.70(s,1H),7.58-7.52(M,3H),7.29-7.25(M,2H),4.40-4.36(M,1H),3.97-3.93(M,2H),3.49-3.43(M,2H),1.97-1.87(M,4H) LCMS (ES +) M/z406(M +1).

Intermediate 2018- (1-methyl-4-nitro-1H-pyrazol-5-yl) -5, 8-diazaspiro [2.6] nonane-5-carboxylic acid tert-butyl ester

To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (323mg,2.0mmol), triethylamine (0.7mL,5.0mmol) and potassium fluoride (581mg,10.0mmol) in anhydrous DMSO (20mL) was added 5, 8-diazaspiro [2.6]]Nonane dihydrobromide (686mg,2.4mmol) and the mixture were heated in a microwave oven at 65 ℃ for4 hours. The mixture was washed with EtOAc (30mL) and with saturated NaHCO₃Aqueous (3 × 20mL) washes. The aqueous layer was extracted with DCM (3 × 20mL) and the combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The residue was loaded onto an SCX-2 column, which was washed with MeOH and eluted with 3% 7M ammonia (in MeOH/DCM) and concentrated under reduced pressure to give 5- (1-methyl-4-nitro-1H-pyrazol-5-yl) -5, 8-diazaspiro [2.6]]Nonane as a yellow gum (153 mg). To a solution of this intermediate in DCM (10mL) was added di-tert-butyl dicarbonate (157mg,0.72mmol) and DMAP (4mg,0.03mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was washed with water (3X10mL) and the organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give 8- (1-methyl-4-nitro-1H-pyrazol-5-yl) -5, 8-diazaspiro [2.6]]Tert-butyl nonane-5-carboxylate as a yellow gum (200mg, 28%, over two steps).¹H NMR(400MHz,CDCl₃)8.02and8.00(2s,1H),3.85-3.77(m,3H),3.75-3.67(m,2H),3.47-3.27(m,4H),3.29-2.97(m,2H),1.49(s,9H),0.73-0.55(m,2H),0.47-0.38(m,2H).

Intermediate 2021- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-2-one

A mixture of azepan-2-one (136mg,1.2mmol), 5-bromo-1-methyl-4-nitro-1H-pyrazole (206mg,1.0mmol), Xantphos (116mg,0.20mmol) and cesium carbonate (456mg,1.40mmol) in dioxane (4mL) was degassed by bubbling nitrogen for 15 minutes. Tris (dibenzylideneacetone) dipalladium (0) (46mg,0.05mmol) was then added and the mixture degassed for a further 10 minutes and then heated in a microwave at 140 ℃ for 3 hours. Water (10mL) was added and the mixture was extracted into EtOAc (3 × 10 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% EtOAc/isohexane) to give 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-2-one as a brown gum (107mg, 44%).¹H NMR(400MHz,CDCl₃)8.11(s,1H),3.96(dd,J＝15.2,10.0Hz,1H),3.76(s,3H),3.53(dd,J＝15.2,7.2Hz,1H),2.82-2.74(m,2H),2.13-1.96(m,3H),1.83-1.67(m,3H).

Intermediate 2034- (1-methyl-4-nitro-1H-pyrazol-5-yl) -5-oxo-1, 4-diazepan-1-carboxylic acid tert-butyl ester

Following the procedure for intermediate 202, starting from 5-bromo-1-methyl-4-nitro-1H-pyrazole and tert-butyl 5-oxo-1, 4-diazepan-1-carboxylate, 4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -5-oxo-1, 4-diazepan-1-carboxylate was obtained as a brown gum (136mg, 33%).¹H NMR(400MHz,d4-MeOD)8.18(s,1H),4.04-3.72(m,5H),3.90-3.62(m,4H),3.02-2.86(m,2H),1.52(s,9H).

Intermediate 2044- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-oxazepan-5-one

Following the procedure for intermediate 202, starting from 5-bromo-1-methyl-4-nitro-1H-pyrazole and 1, 4-oxazepan-5-one, 4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-oxazepan-5-one was obtained as an orange solid (40mg, 13%).¹H NMR(400MHz,CDCl₃)8.11(s,1H),4.18(dd,J＝13.3,6.4Hz,1H),4.12-3.99(m,2H),3.96-3.82(m,2H),3.77(s,3H),3.64(dd,J＝15.7,6.4Hz,1H),3.08(ddd,J＝15.6,8.5,2.1Hz,1H),2.94(ddd,J＝15.6,7.5,1.8Hz,1H).

Intermediate 2055-azido-1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol

To a solution of 5-azidoazepan-4-ol (2.5g,16.0mmol) dissolved in anhydrous DMSO (20mL) were added 5-chloro-1-methyl-4-nitro-1H-pyrazole (2.70g,15.4mmol) and potassium fluoride (3.71g,64 mmol). The mixture was heated at 60 ℃ for 16 h, cooled to room temperature, poured into water (300mL) and extracted into EtOAc (2 × 50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification by column chromatography on silica gel (0-100% EtOAc/isohexane) afforded 5-azido-1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol as a yellow gum (2.5g, 53%).¹H NMR(400MHz,CDCl₃)8.18-7.95(m,1H),4.16-4.07(m,2H),3.80(tt,J＝9.1,3.1Hz,1H),3.67-3.59(m,1H),3.42-3.18(m,4H),2.51(d,J＝2.9Hz,1H),2.24-2.12(m,2H),2.07-1.87(m,2H),1.46(t,J＝7.3Hz,3H).

Intermediate 2061- (1-ethyl-4-nitro-1H-pyrazol-5-yl) -5-fluoroazepan-4-ylcarbamic acid tert-butyl ester

To a solution of 5-azido-1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (1.25g,4.2mmol) in anhydrous DCM (20ml) was added dropwise(3.8mL,10.6mmol, 50% in THF) and the mixture stirred at room temperature for 16 h. The mixture was cooled in an ice bath and saturated NaHCO was added slowly₃Aqueous solution (40mL) (bubbling was observed) and the mixture was extracted with DCM (2 × 20 mL). The organic layer was saturated NaHCO₃The aqueous solution (2 × 10mL) was washed, passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% EtOAc/isohexane) to give 4-azido-5-fluoro-1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepane as a yellow gum (0.91 g). A solution of this gum (0.9g,3.0mmol) in THF/water (20mL/4mL) was treated with triphenylphosphine (0.8g,3.0mmol) and the mixture was heated at 60 ℃ for 16 h. The mixture was cooled and concentrated under reduced pressure to 4mL, diluted with EtOAc (30mL) and extracted with 1M HCl (4 × 10 mL). The combined aqueous extracts were washed with EtOAc (20mL) and then basified with 6N NaOH and extracted with DCM (3 × 20mL), the combined organic layers were separated, over MgSO₄Drying and concentration under reduced pressure gave 5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-amine as a yellow oil (0.82 g). To a solution of this oil (0.8g,2.9mmol) and DIPEA (0.77mL,4.4mmol) in DCM (25mL) was added di-tert-butyl dicarbonate (0.97g,4.4mmol) and the mixture was stirred at room temperature for 16 h. Water (15mL) was added and the organic phase was separated over MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded tert-butyl 1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) -5-fluoroazepan-4-ylcarbamate as a yellow solid (1.1g, 70%, over three steps).¹H NMR(400MHz,CDCl₃)8.07(s,1H),4.96(s,1H),4.74(td,J＝7.4,3.6Hz,1H),4.65-4.58(m,1H),4.16-4.05(m,3H),3.42-3.29(m,2H),3.16(d,J＝11.4Hz,2H),2.31-2.18(m,2H),2.20-2.06(m,2H),1.94-1.82(m,1H),1.60-1.45(m,10H).

Intermediate 2071- (1-ethyl-4-nitro-1H-pyrazol-5-yl) -5-methoxy azepan-4-ylcarbamic acid tert-butyl ester

Following the procedure for intermediate 120, starting from 5-azido-1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol, tert-butyl 1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) -5-methoxyazepan-4-ylcarbamate was obtained as a yellow gum (0.59g, 70%, over three steps).¹H NMR(400MHz,CDCl₃)8.09-8.03(m,1H),4.21-3.99(m,4H),3.54-3.30(m,4H),3.33-3.05(m,4H),2.40-2.30(m,1H),2.08-1.98(m,1H),1.95-1.78(m,2H),1.50-1.40(m,12H).

Intermediate 2081- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -5-methoxyazepan-4-ylcarbamic acid tert-butyl ester

Following the procedure for intermediate 120, starting from 5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol, 1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -5-methoxyazepan-4-ylcarbamic acid tert-butyl ester was obtained as a yellow gum (0.67g, 70%, over three steps).¹H NMR(400MHz,CDCl₃)7.96(s,1H),5.38(m,1H),4.15-4.08(m,1H),3.68-3.31(m,7H),3.28-3.18(m,1H),3.07(ddd,J＝14.1,6.2,3.1Hz,1H),2.42-2.32(m,1H),2.05-1.92(m,2H),1.93-1.80(m,1H),1.48(s,9H),1.26-1.13(m,4H).

Intermediate 209 syn-5-azido-1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) azepan-4-ol

According to the operation of intermediate 119, from anti-5-azido-1- (1- (2, 2-difluoroethyl)) -4-nitro-1H-pyrazol-5-yl) azepan-4-ol to give syn-5-azido-1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) azepan-4-ol as a brown gum (0.57g, 92% over two steps).¹H NMR(400MHz,CDCl₃)8.15-8.07(m,1H),6.35-6.02(m,1H),4.55-4.35(m,2H),3.83(tt,J＝8.8,2.9Hz,1H),3.70-3.62(m,1H),3.37(t,J＝11.8Hz,1H),3.32-3.18(m,3H),2.46(d,J＝2.9Hz,1H),2.25-2.12(m,2H),2.11-1.85(m,2H).

Intermediate 2101- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -5-hydroxyazepan-4-ylcarbamic acid tert-butyl ester

Following the procedure for intermediate 112, starting from 5-azido-1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) azepan-4-ol, tert-butyl 1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -5-hydroxyazepan-4-ylcarbamate was obtained as a yellow gum (0.33g, 47%, over two steps).¹H NMR(400MHz,CDCl₃)8.12(s,1H),6.32-6.05(m,1H),5.06(d,J＝7.9Hz,1H),4.64-4.40(m,2H),4.23(m,1H),3.89(m,1H),3.45-3.29(m,2H),3.18-3.09(m,2H),2.60(m,1H),2.20-1.93(m,3H),1.86(dd,J＝14.1,5.4Hz,1H),1.44(s,9H).

Intermediate 211 syn-5-azido-1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol

Following the procedure for intermediate 119, starting from anti-5-azido-1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol, syn-5-azido-1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol was obtained as a brown gum (0.5g, 81%, over two steps).¹H NMR(400MHz,CDCl₃)8.08-8.04(m,1H),4.25-4.07(m,2H),3.44-3.28(m,1H),3.27-3.09(m,1H),2.32-2.21(m,1H),2.23-2.09(m,1H),1.99-1.84(m,2H),1.42-1.14(m,5H),1.10-0.84(m,3H).

Intermediate 2121- (1-ethyl-4-nitro-1H-pyrazol-5-yl) -5-methoxyazepan-4-ylcarbamic acid tert-butyl ester

Following the procedure for intermediate 120, starting from syn-5-azido-1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol, 1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) -5-methoxyazepan-4-ylcarbamic acid tert-butyl ester was obtained as a yellow gum (0.46g, 70%, over three steps).¹H NMR(400MHz,CDCl₃)8.06(s,1H),5.11(t,J＝8.8Hz,1H),4.14(q,J＝7.3Hz,2H),3.94(m,1H),3.65-3.61(m,1H),3.59-3.18(m,4H),3.31-3.20(m,1H),3.18-3.10(m,1H),2.99(d,J＝13.4Hz,1H),2.26-2.02(m,2H),1.88-1.76(m,2H),1.45-1.35(m,12H).

Intermediate 2133- (1-methyl-4-nitro-1H-pyrazol-5-yl) -8-oxa-3-azabicyclo [3.2.1] octane

8-oxa-3-azabicyclo [3.2.1]Octane hydrochloride (150mg,1.0mmol) and DIPEA (0.26mL,1.5mmol) were stirred in DMSO (4mL) at room temperature for 5 minutes. 5-chloro-1-methyl-4-nitro-1H-pyrazole (150mg,0.95mmol) and potassium fluoride (170mg,3mmol) were then added and the reaction mixture was heated at 70 ℃ for 18H. The mixture was cooled to room temperature and poured into water (4 mL). The aqueous solution was extracted with EtOAc (3 × 10mL) and the combined organic layers were washed with brine (10mL), separated, over MgSO₄Drying and concentrating under reduced pressure to give 3- (1-methyl-4-nitro-1H-pyrazol-5-yl) -8-oxa-3-azabicyclo [3.2.1]Octane (220mg, 92%).¹H NMR(400MHz CDCl₃)8.04(s,1H),4.43(s,2H),3.86(s,3H),3.73-3.70(m,2H),2.61-2.58(m2H),2.09-2.07(m,4H).

Intermediate 2143- (1-methyl-4-nitro-1H-pyrazol-5-yl) -3-azabicyclo [3.2.1] octane

Following the procedure of intermediate 213 from (1R,5S) -3-azabicyclo [3.2.1]Octane hydrochloride to give 3- (1-methyl-4-nitro-1H-pyrazol-5-yl) -3-azabicyclo [3.2.1]Octane as an off-white solid (290mg, 99%).¹H NMR(400MHz CDCl₃)8.03(s,1H),3.81(s,3H),3.44(d,J＝10.1Hz,2H),2.66-2.59(m,2H),2.29(br s,2H),1.78-1.71(m,4H),1.64-1.59(m,2H).

Intermediate 2154- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-thiazepane 1, 1-dioxide

1, 4-Thiazacycloheptane hydrochloride (153mg,1mmol) and DIPEA (0.26mL,1.5mmol) in DMSO (4mL) was stirred at room temperature for 15 min. 5-chloro-1-methyl-4-nitro-1H-pyrazole (150mg,0.95mmol) and potassium fluoride (170mg,3mmol) were then added and the reaction mixture was heated at 70 ℃ for 18H. The mixture was cooled to room temperature and poured into water (4 mL). The aqueous solution was extracted with EtOAc (3 × 10mL) and the combined organic layers were washed with brine (10mL), separated, over MgSO₄Drying and concentrating under reduced pressure to give 3- (1-methyl-4-nitro-1H-pyrazol-5-yl) -8-oxa-3-azabicyclo [3.2.1]Octane (220mg, 92%). This intermediate was dissolved in DCM (10mL), cooled to 0 ℃, treated with m-chloroperbenzoic acid (400mg,1.9mmol) and the resulting mixture stirred at rt for 16 h. The resulting precipitate was filtered off and washed with cold DCM (5 mL). The filtrate was washed with 2M NaOH (5mL) and brine (5mL), passed through a phase separation cartridge and concentrated under reduced pressure to give 4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-thiaazepane 1, 1-dioxide (280mg, 97%, over two steps) as a yellow solid.¹H NMR(400MHz,CDCl₃)8.14(s,1H),3.87(s,3H),3.59-3.55(m,2H),3.41-3.36(m,6H),2.29-2.24(m,2H).

Intermediate 218 (Z) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-4-enol

To a solution of 1-methyl-4-nitro-1H-pyrazole (1.5g,11.8mmol) and (Z) -cyclohept-4-enone (1.4g,13.0mmol) in dry THF (30mL) (cooled to-78 deg.C) was added dropwise a solution of lithium hexamethyldisilazide (1.0M in THF, 30mL,29.5mmol) under nitrogen. The reaction mixture was warmed to-40 ℃ and stirred for 90 minutes. Saturated aqueous ammonium chloride (30mL) was added (dropwise first) and the mixture was warmed to room temperature and extracted with EtOAc (150 mL). The organic layer was washed with water (30mL), brine (20mL), separated, and MgSO₄Dried and concentrated under reduced pressure. Purification by column chromatography on silica gel (20-25% EtOAc) afforded (Z) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-4-enol as an oil (1.37g, 49%).¹H NMR(400MHz,CDCl₃)8.03(s,1H),5.96-5.86(m,2H),4.13(s,3H),3.70(s,1H),2.63-2.54(m,2H),2.41-2.31(m,2H),2.16-2.03(m,2H),2.00-1.92(m,2H).

Intermediate 2195- ((1E,4Z) -cyclohepta-1, 4-dienyl) -1-methyl-4-nitro-1H-pyrazole

To a solution of (Z) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-4-enol (1.35g,5.70mmol) in anhydrous DCM (60mL) was added dropwiseSolution (50% in THF, 6.2mL,17.1mmol) and reaction mixture stirred at rt for 90 min. The mixture was cooled to 0 ℃ and saturated NaHCO was first added dropwise₃Aqueous solution (70mL) and extracted with DCM (1)00mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel column chromatography (15-20% EtOAc/hexanes) afforded 5- ((1E,4Z) -cyclohepta-1, 4-dienyl) -1-methyl-4-nitro-1H-pyrazole as a light yellow oil (523mg, 42%).¹H NMR(400MHz,CDCl₃)8.06(s,1H),5.90(t,J＝5.6Hz,1H),5.88-5.79(m,1H),5.71-5.63(m,1H),3.82(s,3H),3.14-3.08(m,2H),2.62-2.55(m,2H),2.44-2.37(m,2H).

Intermediate 220 (Z) -5- (1-fluorocyclohept-4-enyl) -1-methyl-4-nitro-1H-pyrazole

Following the procedure for intermediate 219, (Z) -5- (1-fluorocyclohept-4-enyl) -1-methyl-4-nitro-1H-pyrazole was obtained as an off-white solid (615mg, 45%).¹H NMR(400MHz,CDCl₃)8.03and8.02(2s,1H),5.98-5.94(m,2H),4.10and4.08(2s,3H),2.67-2.54(m,3H),2.49(t,J＝13.6Hz,1H),2.10-1.93(m,4H).

Intermediate 221 (E) -2-azido-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-4-enol

To a solution of 5- ((1E,4Z) -cyclohepta-1, 4-dienyl) -1-methyl-4-nitro-1H-pyrazole (520mg,2.37mmol) in DCM (20mL) was cooled to 0 ℃ and m-CPBA (70%, 646mg,2.61mmol) was added in portions. The reaction mixture was warmed to room temperature and stirred for 90 minutes. Addition of saturated NaHCO₃Aqueous (30mL) and the mixture extracted with DCM (100 mL). The organic layer was washed with 2M NaOH solution (3 × 30mL), separated, over MgSO₄Dried and concentrated under reduced pressure to give a pale yellow solid (595 mg). The solid (590mg,2.51mmol) was treated with MeOH/water (16mL/4mL), ammonium chloride (333mg,6.28mmol) and sodium azide (816mg,12.6 mmol). The reaction mixture was heated at 70 ℃ for 18 hours. MeOH was removed under reduced pressure, the residue diluted with water (20mL) andextract with EtOAc (100 mL). The organic layer was washed with brine (20mL), separated, and MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel column chromatography (50-60% EtOAc/isohexane) gave (E) -2-azido-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-4-enol as a pale yellow oil (294mg, 42% over two steps).¹H NMR(400MHz,CDCl₃)8.06(s,1H),5.96(dd,J＝8.3,4.9Hz,1H),3.84-3.70(m,4H),3.56-3.47(m,1H),2.71(ddd,J＝15.5,8.3,2.3Hz,1H),2.61-2.36(m,4H),2.23-2.14(m,1H),1.89-1.76(m,1H).

Intermediate 2222- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester (diastereomer 1)

To a solution of (E) -2-azido-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-4-enol (450mg,1.62mmol) in anhydrous DCM (20mL) was added dropwise under nitrogenSolution (50% in THF, 1.5mL,4.05mmol) and the mixture stirred at room temperature for 2 h. Addition of saturated NaHCO₃Aqueous (20mL) and the mixture extracted with DCM (75 mL). Organic layer with NaHCO₃The solution (20mL) was washed, separated, and MgSO₄Dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-40% EtOAc/isohexane) to give a light yellow oil (260 mg). A solution of this oil (250mg,0.89mmol) in THF/water (10mL/2mL) was treated with triphenylphosphine (234mg,0.89mmol) and the mixture was heated at 60 ℃ for 6 h. More triphenylphosphine (24mg,0.09mmol) was added to the reaction mixture, which was heated at 60 ℃ for 1 hour. The mixture was washed with EtOAc (75mL) and saturated NaHCO₃The organic layer was partitioned between aqueous solutions (10mL) and separated over MgSO₄Dried and concentrated under reduced pressure to give a yellow oil. To the oil (227mg,0.89mmol) and DIPEA (0.47mL,2.69mmol) in DCM (10mL)Trifluoroacetic anhydride (0.15mL,1.07mmol) was added dropwise and the mixture was stirred at room temperature for 72 hours. Water (20mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure to give a pale yellow viscous oil (240 mg). A solution of this oil (240mg,0.69mmol) in MeOH (50mL) was passed through(all H)₂Flow rate 1 mL/min, 10% Pd/C cartridge, 70 ℃). The solvent was removed under reduced pressure to give a pale yellow foam (195 mg). To a solution of this foam (190mg,0.59mmol) in DCM (20mL) was added DIPEA (1.0mL), PyBOP (767mg,1.48mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (231mg,0.65mmol) and the mixture was stirred at room temperature for 18 h. Water (30mL) was added and the mixture was extracted with DCM (100mL and 30 mL). The organic layers were combined and MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (60-70% EtOAc/isohexane) followed by chiral preparative HPLC gave tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (diastereomer 1) as an off-white solid (53mg, 5% over five steps).¹H NMR(400MHz,CDCl₃)10.31(s,1H),8.70(s,1H),7.79(s,1H),7.40-7.33(m,1H),7.10-7.01(m,2H),6.41(d,J＝7.3Hz,1H),4.81-4.62(m,1H),4.17-4.06(m,1H),3.86(s,3H),2.90-2.79(m,1H),2.40-2.28(m,1H),2.22-1.89(m,5H),1.79-1.67(m,1H),1.60-1.48(m,10H).

Intermediate 2232- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester (diastereomer 2)

The procedure described for intermediate 222 gave 2- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazole-4-Ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester (diastereomer 2) as a white solid (28mg, 3%, over five steps).¹H NMR(400MHz,CDCl₃)10.31(s,1H),8.70(s,1H),7.79(s,1H),7.41-7.32(m,1H),7.12-7.02(m,2H),6.50(d,J＝7.4Hz,1H),4.81-4.63(m,1H),4.18-4.05(m,1H),3.86(s,3H),2.87-2.79(m,1H),2.38-2.25(m,1H),2.21-1.91(m,5H),1.68-1.50(m,2H),1.54(s,9H).

Intermediate 2242- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester (diastereomer 3 and diastereomer 4)

Following the procedure for intermediate 222, after purification by silica gel column chromatography, tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (diastereomer 3 and diastereomer 4) was obtained as a racemic mixture of enantiomers as an off-white solid (82mg, 8%, over 5 steps).¹H NMR(400MHz,CDCl₃)10.35(s,1H),8.56(s,1H),7.78(s,1H),7.44-7.35(m,1H),7.11-7.01(m,2H),6.46(d,J＝8.0Hz,1H),4.64-4.44(m,1H),4.26-4.19(s,1H),3.85(s,3H),3.05-2.95(s,1H),2.36-2.27(m,1H),2.09-1.84(m,7H),1.54(s,9H).

Intermediate 2252- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester (diastereomer 5)

The procedure described for intermediate 222 gave 2- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester (diastereomer 5) as a white solid (28mg, 3%, over five steps).¹H NMR(400MHz,CDCl₃)10.31(s,1H),8.74(s,1H),7.84(s,1H),7.40-7.33(m,1H),7.14-7.04(m,2H),6.63(d,J＝8.5Hz,1H),5.06-4.88(m,1H),4.30-4.16(m,1H),3.85(s,3H),3.09-2.99(m,1H),2.35-1.88(m,8H),1.54(s,9H).

Intermediate 2262- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester (diastereomer 6, diastereomer 7, and diastereomer 8)

The procedure according to intermediate 222 gave tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (diastereomer 6, diastereomer 7 and diastereomer 8) as a white solid (76mg, 7% over five steps).¹H NMR(400MHz,CDCl₃)10.35and10.31(2s,1H),8.74and8.61(2s,1H),7.84and7.75(2s,1H),7.41-7.34(m,1H),7.12-7.02(m,2H),6.73-6.58(m,1H),4.31-4.11(m,1H),3.86and3.85(2s,3H),3.08-2.97(m,1H),2.44-1.71(m,9H),1.55(s,9H).

Intermediate 227 (E) -5- (6, 6-difluorocyclohept-1-enyl) -1-methyl-4-nitro-1H-pyrazole

(E) 3-Oxocyclo-1-enyl trifluoromethanesulfonate (1.8g,6.98mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (2.42g,9.52mmol), potassium acetate (1.56g,15.8mmol) and Pd (dppf) Cl₂DCM complex (0.32g,0.39mmol) was suspended in degassed dioxane (20mL) and mixedThe mass was heated to 80 ℃ for 16 hours. After cooling, the mixture was filtered and the filter cake was washed with dioxane (3 × 20 mL). The solution was degassed by bubbling nitrogen for 10 minutes and a degassed aqueous potassium acetate/sodium carbonate solution (1M,1:1,20.9mL,20.9mmol), Pd (dppf) Cl was added thereto₂DCM complex (0.32g,0.39mmol) and 5-chloro-1-methyl-4-nitro-1H-pyrazole (1.54g,9.51 mmol). The mixture was heated to 110 ℃ for 24 hours, cooled to room temperature and passedAnd (5) filtering. The filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAC (30mL) and washed with water (3 × 20 mL). The organic layer was passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) afforded an oil (460 mg). A solution of this oil (440mg,1.86mmol) in DCM (8mL) was prepared(50% solution in THF, 1.57mL,4.34mmol) and the reaction mixture stirred at room temperature for 16 h. The mixture was diluted with DCM (20mL), cooled in an ice-water bath and saturated NaHCO₃The aqueous solution (50mL) was carefully quenched. The organic layer was washed with water (2 × 20mL), passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-40% EtOAc/isohexane) afforded (E) -5- (6, 6-difluorocyclohept-1-enyl) -1-methyl-4-nitro-1H-pyrazole as an oil (0.16g, 33% over three steps).¹H NMR(400MHz,CDCl₃)8.06(s,1H),6.24-6.16(m,1H),3.84(s,3H),2.49-2.31(m,4H),1.88-1.75(m,3H),1.60(d,J＝6.5Hz,1H).

Intermediate 228N- (4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide

4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (610mg,2.40mmol) was dissolved in acetonitrile (4mL) and cooled to 0 deg.C, and concentrated sulfuric acid (S) (N, N-methyl-N-ethyl-N-propyl ether)2.1 mL). The reaction was warmed to room temperature and stirred for 1 hour, then poured onto ice (150g), basified with KOH and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (20mL), passed through a phase separation cartridge and concentrated under reduced pressure to give N- (4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide as a yellow solid (660mg, 93%).¹H NMR(400MHz,CDCl₃)8.05-7.98(m,1H),5.31(s,1H),3.81-3.73(m,3H),3.35(ddd,J＝14.2,9.3,2.2Hz,1H),3.22(t,J＝5.9Hz,2H),3.09(ddd,J＝14.2,7.6,2.5Hz,1H),2.43-2.31(m,2H),2.05-1.95(m,3H),1.89-1.74(m,4H),1.53-1.36(m,3H).

Intermediate 229N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-ethoxyazepan-4-yl) -2,2, 2-trifluoroacetamide

Following the procedure for intermediate 54, starting from 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol and iodoethane, N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-ethoxyazepan-4-yl) -2,2, 2-trifluoroacetamide was obtained as a pink gum (151mg, 60%, over four steps).¹H NMR(400MHz,CDCl₃)8.73(s,1H),7.16(s,1H),4.60-4.53(m,1H),3.69-3.36(m,8H),3.16-3.05(m,1H),2.90(dt,J＝14.4,4.4Hz,1H),2.64-2.27(m,3H),1.89-1.76(m,3H),1.22(t,J＝7.0Hz,3H).

Intermediate 230 syn-5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol

Following the procedure for intermediate 119, starting from anti-5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol, we obtained syn-5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol as a brown oil (560)mg, 78%, over two steps).¹H NMR(400MHz,CDCl₃)7.97-7.92(m,1H),3.94(dt, J ═ 9.0,2.7Hz,1H),3.73-3.62(m,1H),3.53-3.22(m,5H),2.24-2.12(m,2H),2.02-1.88(m,2H),1.28-1.23(m,2H),1.15-1.05(m,2H).

Intermediate 2311- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -5-methoxyazepan-4-ylcarbamic acid tert-butyl ester

Following the procedure for intermediate 120, starting from syn-5-azido-1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol, 1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -5-methoxyazepan-4-ylcarbamic acid tert-butyl ester was obtained as a yellow oil (440mg, 61%, over three steps).¹H NMR(400MHz,CDCl₃)7.95(s,1H),5.21(d,J＝9.0Hz,1H),4.00(d,J＝10.3Hz,1H),3.73-3.51(m,3H),3.56-3.27(m,4H),3.26-3.18(m,1H),3.10(d,J＝13.5Hz,1H),2.28-2.16(m,1H),2.15-2.06(m,1H),1.93-1.79(m,2H),1.46(s,9H),1.37-1.03(m,4H).

Intermediate 2321- (1-methyl-4-nitro-1H-pyrazol-5-yl) -4- (trifluoromethyl) azepan-4-ol

To a solution of benzyl 4-oxoazepane-1-carboxylate (2.0g,8.08mmol) in trifluoromethyl trimethylsilane (1.42mL,9.70mmol) was added cesium fluoride (70.4mg,0.40 mmol). The reaction mixture was stirred at room temperature until it was passed¹⁹F NMR observed complete depletion of trifluoromethyltrimethylsilane and quenched with 1M HCl solution (50 mL). The mixture was extracted with EtOAc (3 × 50mL) and the combined organic layers were washed with brine (50mL), separated, over MgSO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) afforded 4-hydroxy-4- (trifluoromethyl)) Benzyl azepane-1-carboxylate as a yellow oil (1.48 g). To a solution of this oil (1.3g,4.1mmol) in ethanol (20mL) was added methylcyclohexadiene (4.6mL) and 10% palladium on carbon (0.13 g). The reaction mixture was heated at reflux for 30 minutes, then cooled to room temperature, and passed throughFiltered, washed with MeOH and concentrated under reduced pressure. The residue was dissolved in DMSO (10mL) and 5-chloro-1-methyl-4-nitro-1H-pyrazole (637mg,3.94mmol) and potassium fluoride (916mg,15.76mmol) were added. The reaction mixture was heated at 70 ℃ for 16 h, quenched with water (50mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (100mL) and brine (100mL), separated, and over MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -4- (trifluoromethyl) azepan-4-ol as a yellow solid (1.06g, 40%, over three steps).¹H NMR(400MHz,CDCl₃)8.04(s,1H),3.78(s,3H),3.71(ddd,J＝14.7,10.5,2.0Hz,1H),3.31(dt,J＝11.8,4.4Hz,1H),3.14(td,J＝11.3,4.6Hz,1H),3.06(ddd,J＝14.7,5.7,2.9Hz,1H),2.31-2.13(m,1H),2.14-1.94(m,5H),1.92-1.83(m,1H).

Intermediate 233 (E) -7-azido-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohepta-3-enol

Following the procedure of intermediate 221, (E) -7-azido-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-3-enol was obtained as a pale yellow oil (244mg, 35% over two steps).¹H NMR(400MHz,CDCl₃)8.06(s,1H),5.95(dd, J ═ 8.2,5.1Hz,1H),3.80(s,3H),3.69 to 3.61(m,2H),2.74 to 2.63(m,1H),2.61 to 2.41(m,3H),2.28 to 2.19(m,1H),1.97 to 1.86(m,1H). no OH was observed.

Intermediate 234 (E) -tert-butyl 2-methoxy-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-4-enylcarbamate

Following the procedure for intermediate 120, starting from (E) -7-azido-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-3-enol, (E) -tert-butyl 2-methoxy-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-4-enylcarbamate was obtained as a light yellow solid (360mg, 62%, over three steps).¹H NMR(400MHz,CDCl₃)8.05(s,1H),5.82(t,J＝6.5Hz,1H),4.77(s,1H),3.93(s,1H),3.82(s,3H),3.42(s,3H),3.37(t,J＝7.6Hz,1H),2.71-2.44(m,3H),2.34(t,J＝11.7Hz,1H),2.22-2.11(m,1H),1.86-1.74(m,1H),1.47(s,9H).

Intermediate 2354-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester

To a solution of benzyl 4-oxoazepane-1-carboxylate (2.0g,8.09mmol) in diethyl ether (18mL) (cooled to-78 deg.C) was added dropwise a solution of methyllithium-lithium bromide complex (1.5M in Et₂O, 10.8mL,16.17 mmol). The reaction mixture was stirred at-78 ℃ for 30 minutes and then quenched with a saturated solution of ammonium chloride (50 mL). The reaction was warmed to rt and extracted with EtOAc (3 × 50 mL). The combined organic layers were over MgSO₄Dried and the solvent removed under reduced pressure. Purification by column chromatography on silica gel (0-50% EtOAc/isohexane) afforded benzyl 4-hydroxy-4-methylazepane-1-carboxylate as a pale yellow oil (1.94 g). A solution of this oil (884mg,3.36mmol) in MeOH (10mL) was passed through(all H)₂50 ℃ C., flow rate 1 mL/min, 30mm 10% Pd/C cartridge) and the solvent was removed under reduced pressure. The residue was dissolved in DMSO (10mL) and 5-chloro-1-methyl-4-nitro-1H-pyrazole (521mg,3.23mmol) and potassium fluoride (potassium fluoride) (DMSO) were added750mg,12.91 mmol). The reaction mixture was heated at 75 ℃ for 16 h and then quenched with water (30 mL). The mixture was extracted with EtOAc (3 × 30mL) and the combined organic layers were washed with water (20mL), separated, over MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded 4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol as a yellow oil (290 mg). Concentrated sulfuric acid (308mL,3.15mmol) was added dropwise to a solution of the oil (260mg,1.04mmol) and chloroacetonitrile (139mL,2.09mmol) in acetic acid (1.0mL) at 0 ℃. The reaction mixture was warmed to room temperature and stirred for an additional 2 hours, then quenched with 2m naoh aqueous solution (10mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were separated over MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) afforded 2-chloro-N- (4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide as a yellow oil (264 mg). To a solution of this oil (264mg,0.80mmol) in ethanol (1.4mL) and acetic acid (0.6mL) was added thiourea (73mg,0.96 mmol). The reaction mixture was heated at reflux for 16 h, quenched with 1M NaOH solution (5mL) and extracted with EtOAc (10 mL). The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. The residue was passed through an SCX column at 1M NH₃Elution (in MeOH) afforded 4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-amine as a gum (172 mg). To a solution of this gum (166mg,0.65mmol) in DCM (5mL) was added DIPEA (0.57mL,3.27mmol) followed by di-tert-butyl dicarbonate (171mg,0.78 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with water (10mL) and extracted with DCM (3 × 10 mL). The combined organic layers were passed through a phase separator and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded tert-butyl 4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate as a yellow oil (188mg, 14%, over 6 steps).¹H NMR(400MHz,CDCl₃)8.03(s,1H),4.53(s,1H),3.78(s,3H),3.38-3.28(m,1H),3.28-3.16(m,2H),3.11-3.03(m,1H),2.28-2.12(m,2H),1.90-1.69(m,4H),1.44(d,J＝7.2Hz,12H).

Intermediate 2365- (4-fluoro-8-oxabicyclo [5.1.0] oct-4-yl) -1-methyl-4-nitro-1H-pyrazole

To a solution of (Z) -5- (1-fluorocyclohept-4-enyl) -1-methyl-4-nitro-1H-pyrazole (900mg,3.77mmol) in DCM (30mL) was added m-chloroperoxybenzoic acid (1.0g,4.14mmol) in portions at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 90 minutes, then quenched with a saturated solution of sodium bicarbonate (30 mL). The mixture was extracted with DCM (100mL), washed with 2m naoh aqueous solution (2 × 50mL) and brine (30 mL). The organic layer was separated over MgSO₄Drying and concentrating under reduced pressure to obtain 5- (4-fluoro-8-oxabicyclo [ 5.1.0)]Oct-4-yl) -1-methyl-4-nitro-1H-pyrazole as a colorless solid (982mg, quantitative) as a 2:5 ratio diastereomer.¹H NMR(400MHz,CDCl₃)8.07and8.01(2s,1H),4.12-4.00(m,3H),3.27-3.11(m,2H),2.90-2.63(m,2H),2.24-1.74(m,6H).

Intermediate 2372-azido-5-fluoro-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cycloheptanol

5- (4-fluoro-8-oxabicyclo [ 5.1.0)]A solution of oct-4-yl) -1-methyl-4-nitro-1H-pyrazole (260mg,1.02mmol) in DMF/water (10mL/1mL) was treated with ammonium chloride (135mg,2.55mmol) and sodium azide (332mg,5.1mmol) and the mixture was heated at 100 ℃ for 48H. The reaction mixture was extracted with EtOAc (100mL) and the organic layer was washed with water (7 × 20mL), washed with brine (20mL), separated, over MgSO₄Dried and concentrated under reduced pressure. Purification by column chromatography on silica gel (40% EtOAc/isohexane) afforded 2-azido-5-fluoro-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cycloheptanol as a white solid (145mg, 48%).¹H NMR(400MHz,CDCl₃)8.06and8.05(2s,1H),4.08and4.06(2s,3H),3.83(dd,J＝10.7,8.2Hz,1H),3.65-3.58(m,1H),2.87-2.55(m,2H),2.33-2.21(m,2H),2.17-1.98(m,3H),1.98-1.84(m,2H).

Intermediate 2385-fluoro-2-methoxy-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cycloheptylcarbamic acid tert-butyl ester

Following the procedure for intermediate 120, starting from 2-azido-5-fluoro-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cycloheptanol, tert-butyl 5-fluoro-2-methoxy-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cycloheptylcarbamate was obtained as an off-white solid (155mg, 53%, over three steps).¹H NMR(400MHz,CDCl₃)8.06(s,1H),4.08and4.06(2s,3H),3.82(d,J＝8.8Hz,1H),3.39(s,3H),2.98-2.62(m,1H),2.16-1.84(m,7H),1.61-1.49(m,2H),1.47(s,9H).

Intermediate 2391- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-ylcarbamic acid tert-butyl ester

To a solution of 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (5.4g,19.2mmol) in DCM (150mL) was added dropwise over 15 minutes at 0 deg.CSolution in THF (18.5mL,51.1 mmol). The reaction was allowed to warm to room temperature over 18 hours. The mixture was then cooled to 0 ℃ and then a saturated solution of sodium bicarbonate (300mL) was added dropwise. The reaction mixture was stirred for 1 hour, then the layers were separated and the aqueous layer was extracted with DCM (200mL). The combined organic layers were over MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded 4-azido-5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepane as a pale green gum (3.66 g). To a solution of this gum (3.66g,12.9mmol) in THF (200mL) and water (20mL) was added triphenylphosphine (3.38g,12.9 mmol). The reaction mixture was heated at 60 ℃ for 18 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was then diluted with EtOAc (500mL), quenched with 1N aqueous HCl (100mL) and washed with water (2 × 100 mL). The combined organic layers were washed with EtOAc (300mL), then basified with solid sodium hydroxide to pH14 and extracted with DCM (3 × 250 mL). The combined organic layers were over MgSO₄Drying and removal of the solvent under reduced pressure gave 5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-amine as a pale green gum (3.1 g). To a solution of this gum (3.1g,12.0mmol) in DCM (150mL) was added triethylamine (4mL,28.6mmol), followed by di-tert-butyl dicarbonate (3.95g,18.0 mmol). The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded tert-butyl-5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate as a light yellow solid (3.7g, 86%). To a solution of this solid (1.5g,4.19mmol) in MeOH (100mL) was added ammonium formate (1.95g,33.58mmol) followed by 10% palladium on carbon (178mg,1.68mmol) and the mixture heated at 75 deg.C for 2 h. By passingThe mixture was filtered and dissolved and concentrated under reduced pressure. The residue was dissolved in water (100mL) and extracted with DCM (3 × 100 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure to give tert-butyl 1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-ylcarbamate as a purple solid (1.37g, 54% over four steps).¹H NMR(400MHz,CDCl₃)7.13(s,1H),6.28(s,1H),4.75(d,J＝46.1Hz,1H),4.26(s,1H),3.66(s,3H),3.49-3.30(m,2H),3.13-2.88(m,2H),2.62(s,2H),2.29-2.15(m,1H),2.10-1.97(m,1H),1.89-1.80(m,1H),1.75-1.54(m,1H),1.45(s,9H).

Intermediate 2401- (4- (5- (tert-butoxy-carbonyl) -amino-2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-ylcarbamic acid tert-butyl ester

A solution of PyBOP (3.06g,5.03mmol) and 2-bromo-5- (tert-butoxycarbonyl-amino) thiazole-4-carboxylic acid (1.63g,5.04mmol) in DCM (50mL) was stirred at room temperature for 15 min. Tert-butyl 1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-ylcarbamate (1.37g,4.20mmol) and DIPEA (1.17mL,6.71mmol) were added and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with DCM (50mL) and washed with water (3 × 50 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl 1- (4- (5-amino-2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-ylcarbamate as a pink solid (2.50g, 94%).¹H NMR(400MHz,CDCl₃)10.27(s,1H),8.27(s,1H),7.64(s,1H),5.01(s,1H),4.86-4.60(m,1H),3.81-3.64(m,3H),3.44-3.27(m,2H),3.15-3.07(m,2H),2.28-2.10(m,3H),1.92-1.70(m,2H),1.52(s,9H),1.44(s,9H).

Intermediate 240a 6-azido-6-methyl-cyclohex-3-en-1-ol

Sodium bicarbonate (7.5g,89mmol) and m-chloroperbenzoic acid (20g,89mmol) were added in portions to a solution of 1-methylcyclohexa-1, 4-diene (8.4g,89mmol) in DCM (250mL), cooled to-15 deg.C, and the mixture was stirred for 30 minutes. The reaction was quenched with 20% sodium sulfite solution (100mL) and warmed to room temperature. The aqueous layer was extracted with DCM (3 × 100mL) and the combined organic layers aqueous sodium sulfite (100mL), NaHCO₃The aqueous solution (100mL), water (100mL) and brine (100mL) were washed, passed through a phase separation cartridge and concentrated under reduced pressure to give an epoxide as a colorless oil. Epoxide (2.1g,19.1mmol) was added slowly to a mixture of sodium azide (6.2g,95mmol) in acetic acid (5mL) and water (25mL) (stirring at 30 ℃), the resulting mixture was stirred for 16 hours, and any hydrazoic acid generated in situ above the condenser was taken into the bleached solution. The mixture was cooled to room temperature and washed with waterNaHCO₃Aqueous solution (20mL) was quenched. The mixture was extracted with ether (3 × 50mL) and the combined organics were washed with 2N aqueous NaOH (50mL), separated, and over MgSO₄Drying and concentration under reduced pressure gave 6-azido-6-methyl-cyclohex-3-en-1-ol as a yellow oil (1.8g, 82% over two steps).¹H NMR(400MHz,CDCl₃)5.58-5.55(m,2H),3.77-3.73(m,1H),2.46(d,J＝6.5Hz,1H),2.30-2.27(m,2H),2.10(s,3H),2.06-2.03(m,2H).

Intermediate 2415-azido-1-benzyl-5-methylazepan-4-ol

A solution of 6-azido-6-methylcyclohex-3-enol (3.9g,25mmol) in MeOH/DCM (100mL/20mL) (cooled to-78 deg.C) was degassed by bubbling nitrogen for 5 minutes. Ozone was then bubbled through the reaction mixture until a grayish blue color remained. Nitrogen was again bubbled through the cold reaction mixture until only the light color remained. A solution of benzylamine (2.7g,25mmol) dissolved in MeOH (5mL) was added, followed by NaCNBH3(6.4g,101.5mmol) in MeOH (10 mL). The mixture was warmed to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3 × 50mL) and the combined organic layers were washed with brine (40mL), separated, over MgSO₄Dried and concentrated under reduced pressure. The residue was chromatographed on silica gel (1-10% 7M NH)₃Purification (in MeOH)/DCM) afforded 5-azido-1-benzyl-5-methylazepan-4-ol as a viscous yellow oil (4.8g, 73%).¹H NMR(400MHz,CDCl₃)7.25-7.34(m,5H),3.69-3.62(m,2H),3.51-3.47(m,2H),2.96-2.89(m,1H),2.69-2.62(m,3H),2.19-2.11(m,1H),1.99-1.85(m,1H),1.78-1.68(m,1H),1.61-1.57(m,1H),1.43(s,3H).

Intermediate 2425-amino-1-benzyl-5-methylazepan-4-ol

To a solution of 5-azido-1-benzyl-5-methylazepan-4-ol (1.5g,5.76mmol) in THF (12mL) and water (4mL) was slowly added a solution of trimethylphosphine (1M in toluene, 28mL,28.9mmol) and the reaction stirred at 65 ℃ for 18 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1M HCl (30mL) and extracted with EtOAc (2 × 25 mL). The aqueous layer was basified with 6m naoh aqueous solution to pH14 and extracted with DCM (3 × 30 mL). The combined organic layers were concentrated under reduced pressure through a phase separation cartridge. Chromatography on silica gel (1-10% 7M NH)₃Purification (in MeOH)/DCM) afforded 5-amino-1-benzyl-5-methylazepan-4-ol as a viscous yellow oil (1.2g, 89%).¹H NMR(400MHz,CDCl₃)7.34-7.20(m,5H),3.60-3.52(m,2H),3.50-3.46(m,2H),2.80-2.79(m,1H),2.70-2.45(m,4H),2.15-1.95(m,1H),1.79-1.72(m,2H),1.49-1.40(m,2H),1.19(s,3H).

Intermediate 243N- (1-benzyl-5-hydroxy-4-methylazepan-4-yl) -2,2, 2-trifluoroacetamide

To 5-amino-1-benzyl-5-methylazepan-4-ol (1.2g,5.12mmol) and Et at 0 deg.C₃A solution of N (0.77g,7.68mmol) in THF (20mL) was added trifluoroacetic anhydride (1.18g,5.63mmol,0.78mL) dropwise. The reaction mixture was warmed to room temperature and stirred for 3 hours. The mixture was partitioned between EtOAc (10mL) and water (10mL) and the aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (30mL) over MgSO₄Dried and concentrated under reduced pressure. Chromatography on silica gel (1-5% (7M NH)₃MeOH)/DCM) to give N- (1-benzyl-5-hydroxy-4-methylazepan-4-yl) -2,2, 2-trifluoroacetamide (0.8g, 47%) as a yellow gum.¹H NMR(400MHz,CDCl₃)7.34-7.28(m,5H),6.65(br s,1H),4.22-4.15(m,1H),3.60(dd,J＝9.6,9.7Hz,2H),2.90-2.75(m,1H),2.70-2.65(m,1H),2.60-2.49(m,2H),2.20-2.10(m,1H),1.95-1.80(m,2H),1.75-1.55(m,2H),1.58(s,3H).

Intermediate 2442, 2, 2-trifluoro-N- (5-hydroxy-4-methylazepan-4-yl) acetamide

To a solution of N- (1-benzyl-5-hydroxy-4-methylazepan-4-yl) -2,2, 2-trifluoroacetamide (1.7g,5.0mmol) in MeOH (30mL) was added 1M HCl (1mL) and palladium hydroxide on carbon (0.25 g). The mixture was shaken under a hydrogen atmosphere (40psi) for 72 hours. By passingThe mixture was filtered and washed with MeOH (30 mL). The solvent was removed under reduced pressure and the residue passed through an SCX column at (1-10% (7M NH)₃Elution (in MeOH)/DCM) gave 2,2, 2-trifluoro-N- (5-hydroxy-4-methylazepan-4-yl) acetamide as a yellow gum (0.8g, 66%). 1H (400MHz, CDCl)₃)6.90(brs,1H),4.22-4.16(m,1H),3.70-3.60(m,1H),3.40-3.35(m,1H),3.15-2.99(m,1H),2.90-2.75(m,2H),2.20-2.05(m,1H),1.99-1.75(m,4H),1.53(s,3H).

Intermediate 2452, 2, 2-trifluoro-N- (5-hydroxy-4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide

Following the procedure for intermediate 213, starting from 2,2, 2-trifluoro-N- (5-hydroxy-4-methylazepan-4-yl) acetamide, 2,2, 2-trifluoro-N- (5-hydroxy-4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide was obtained as a white solid (400mg, 88%).¹H NMR(400MHz,CDCl₃)8.03(s,1H),3.77(s,2H),3.54(dd,J＝10.2,3.2Hz,1H),3.49(s,3H),3.41-3.32(m,1H),3.30-3.22(m,1H),3.13(dt,J＝13.1,4.7Hz,2H),2.22-2.00(m,1H),1.95-1.72(m,2H),1.24-1.15(m,3H),1.08(d,J＝7.0Hz,1H).

Intermediate 2461- (4- (5- (tert-butoxycarbonyl-amino) -2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-ylcarbamic acid tert-butyl ester

To a solution of tert-butyl 6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (2.5g,6.67mmol) in ethanol (100mL) and water (10mL) was added ammonium chloride (3.5g,65.0mmol) and iron powder (3.0g,53.7 mmol). The reaction mixture was heated at 100 ℃ for 2.5 hours and then cooled down at room temperature byFilter, wash with MeOH and concentrate the filtrate under reduced pressure. The residue was dissolved in DCM (200mL), quenched with a saturated solution of sodium bicarbonate (300mL) and 10% sodium sulfite solution (100mL) and the mixture was stirred for 30 min. The layers were separated and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were over MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) afforded tert-butyl 1- (4-amino-1-methyl-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-ylcarbamate as an orange foam (2.12 g). A solution of PyBOP (1.92g,3.70mmol) and 2-bromo-5- (tert-butoxycarbonyl-amino) thiazole-4-carboxylic acid (795mg,2.46mmol) in DCM (50mL) was stirred at room temperature for 15 min. Tert-butyl 1- (4-amino-1-methyl-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-ylcarbamate (850mg,2.46mmol) and DIPEA (2.0mL,11.4mmol) were added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (50mL) and washed with a saturated solution of sodium bicarbonate (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl 1- (4- (5- (tert-butoxycarbonyl-amino) -2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-ylcarbamate as a light yellow foam (1.35g, 77% over two steps).¹H NMR(400MHz,CDCl₃)10.24(s,1H),8.37(s,1H),7.65(s,1H),4.88(s,1H),4.04(s,1H),3.77(s,3H),3.63-3.43(m,2H),3.38-3.24(m,2H),2.52-2.40(m,2H),2.13-2.05(m,1H),1.99(s,1H),1.53(s,9H),1.43(s,9H).

Intermediate 2471- (4- (5- (tert-butoxy-carbonyl-amino) -2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6-methoxy-6-methylazepan-4-ylcarbamic acid tert-butyl ester

Starting from tert-butyl 6-methoxy-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate according to the procedure for intermediate 245, tert-butyl 1- (4- (5- (tert-butoxy-carbonyl-amino) -2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6-methoxy-6-methylazepan-4-ylcarbamate was obtained as a light yellow foam (530mg, 79% over two steps).¹H NMR(400MHz,CDCl₃)10.43(s,1H),9.25(s,1H),7.92(s,1H),4.60(s,1H),4.03(d,J＝10.5Hz,1H),3.71(s,3H),3.38(s,3H),3.39-3.19(m,4H),3.06(d,J＝14.5Hz,1H),2.36(d,J＝14.2Hz,1H),2.16(d,J＝13.4Hz,1H),1.77(d,J＝12.1Hz,1H),1.52(s,9H),1.43(s,9H),1.12(s,3H).

Intermediate 248 (E) -3- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohepta-2-enone

To a solution of heptane-1, 3-dione (10g,79.3mmol) in DCM (500mL) was added pyridine (12.8mL,158.6 mmol). The solution was cooled at-78 deg.C and then trifluoromethanesulfonic anhydride (13.2mL,95.1mmol) was added dropwise. The mixture was warmed to 0 ℃ and left to stir for4 hours, then quenched with 1M HCl (150 mL). The organic layer was washed with a saturated solution of sodium bicarbonate (200mL), passed through a phase separation cartridge and concentrated under reduced pressure to give (E) -trifluoromethanesulfonic acid 3-oxocyclohept-1-eneEsterester as brown oil. To a solution of this oil (1.8g,6.97mmol) in degassed dioxane (200mL) was added potassium acetate (15.6g,158.6mmol), bis (pinacolato) diboron (24.2g,95.1mmol) and [1,1' -bis (diphenylphosphino) -ferrocene]A complex of palladium (II) dichloride in dichloromethane (3.24g,3.97mmol) and the mixture was heated at 90 ℃ for 18 hours. The mixture was cooled to room temperature and passed throughFiltration, washing with MeOH (50mL) and removal of solvent under reduced pressure. The residue was dissolved in degassed dioxane (200mL) and then 5-chloro-1-methyl-4-nitro-1H-pyrazole (15.4g,95.1mmol) was added followed by the addition of [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (complex with dichloromethane) (3.24mg,3.97mmol) and sodium/potassium carbonate/acetate (63mL,3.8M) in 1/1 aqueous solution. The mixture was heated at 105 ℃ for 3 hours. The mixture was cooled to room temperature and filteredFiltered and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (50mL) and washed with water (50 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave (E) -3- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-2-enone as a light brown solid (7.2g, 39%, over three steps).¹H NMR(400MHz,CDCl₃)8.08(s,1H),6.09(s,1H),3.83(s,3H),2.81-2.77(m,2H),2.71-2.67(m,2H),2.07-1.97(m,4H).

Intermediate 249 (2E,6Z) -3- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohepta-2, 6-dienone

To a solution of LiHMDS (1M in THF, 1.28mL,1.28mmol) was added (E) -3- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-2-enone (150mg,0.64mmol) at-78 deg.C and the mixture was stirred for 1 hour at-78 deg.C. Adding phenylselenium bromide (453mg,1.92mmol) in THF (THF: (THF) ((THF)), (0.5mL) and the reaction mixture was warmed to 0 ℃ and stirred for 45 minutes, then quenched with saturated aqueous ammonium chloride (2 mL). The mixture was extracted with EtOAc (3 × 5mL) and the combined organic layers were MgSO₄Drying and concentrating under reduced pressure to give (E) -3- (1-methyl-4-nitro-1H-pyrazol-5-yl) -7- (phenylselenoalkyl) cyclohept-2-enone as an oil. This oil was dissolved in DCM (3mL) and pyridine (0.1mL,1.28mmol) was added followed by hydrogen peroxide (30 wt% in water, 0.37mL,3.34 mmol). The reaction mixture was stirred at room temperature for 18 hours. 1MHCl (10mL) was added and the mixture was extracted with DCM (2X5 mL). The combined organic layers were washed with 1M HCl (5mL), water (5mL) and brine (5mL) over MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded (2E,6Z) -3- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohepta-2, 6-dienone as a yellow oil (26mg, 17%, over three steps).¹H NMR(400MHz,CDCl₃)8.11(s,1H),6.88-6.82(m,1H),6.26-6.23(dd,J＝12.0,1.6Hz,1H),6.19(d,J＝2.0Hz,1H),3.87(s,3H),2.82-2.73(m,4H).

Intermediate 250 (E) -tert-butyl 5- (1-methyl-4-nitro-1H-pyrazol-5-yl) -3-oxocyclohept-4-enylcarbamate

To a solution of (2E,6Z) -3- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohepta-2, 6-dienone (690mg,2.95mmol) in acetonitrile (10mL) was added trimethylsilylazide (1mL,7.57mmol) and Amberlite^TMIRA900F resin (590mg,1.47 mmol). The reaction mixture was stirred at 40 ℃ for 5 hours, cooled to room temperature, filtered and concentrated under reduced pressure to give (E) -6-azido-3- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-2-enone as a yellow oil. To a solution of this oil (810mg,2.93mmol) in THF (20mL) and water (6mL) was added sodium borohydride (166mg,4.40 mmol). The mixture was stirred at room temperature for 18 hours, then diluted with water (50 mL). The mixture was extracted with EtOAc (100mL) and the organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. Through a silica gel columnPurification by chromatography (0-100% EtOAc/isohexane) afforded (E) -6-azido-3- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-2-enol as a yellow oil. This oil (810mg,2.91mmol) was dissolved in THF (15mL) and added to a suspension of polymer-supported triphenylphosphine (3.1g,5.76mmol) in THF (45mL) and water (1.5 mL). The mixture was gently stirred at 60 ℃ for 18 h, cooled to room temperature and concentrated under reduced pressure. The residue was diluted in DCM (30mL) and di-tert-butyl dicarbonate (754mg,3.46mmol) and DIPEA (1.51mL,8.64mmol) were added. The mixture was stirred at room temperature for 5 hours, diluted with DCM (50mL) and quenched with a saturated solution of sodium bicarbonate (50 mL). The organic layer was washed with water (50mL), separated, and MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) afforded (E) -tert-butyl 5- (1-methyl-4-nitro-1H-pyrazol-5-yl) -3-oxocyclohept-4-enylcarbamate as a white foam (620mg, 59%, over three steps).¹H NMR(400MHz,CDCl₃)8.05(s,1H),6.03-5.99(m,1H),4.82-4.60(m,2H),3.86-3.82(m,4H),2.82-2.34(m,1H),2.29-2.35(m,1H),2.34-2.20(m,2H),2.15-2.04(m,1H),1.85-1.51(m,2H),1.45(s,9H).

Intermediate 251 (Z) -tert-butyl 2- (2, 6-difluorophenyl) -4- (1-methyl-5- (2,3,6, 7-tetrahydro-1H-azepin-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

To a solution of (Z) -2,3,6, 7-tetrahydro-1H-azepine hydrochloride (32.3g,0.24mmol) in DMSO (650mL) was added 3-chloro-1-methyl-4-nitro-1H-pyrazole (37.2g,0.23mmol) followed by DIPEA (64mL,0.36mmol) and potassium fluoride (56.2g,0.96 mmol). The reaction mixture was heated at 75 ℃ for 25 h, then cooled to room temperature, poured into water (1.5L) and extracted with EtOAc (4 × 500 mL). The combined organic layers were washed with water (400mL) and brine (300mL), separated, and over MgSO₄Dried and concentrated under reduced pressure to give (Z) -1- (1-methyl-4-nitro-1H-pyrazol-3-yl) -2,3,6, 7-tetrahydro-1H-azepine as a light brown solid (50.7 g). To the solid (1.80 g)8.1mmol) in ethanol (80mL) and water (8mL) was added ammonium chloride (2.15g,40.1mmol) as fine iron powder (1.77g,31.8 mmol). The reaction mixture was heated at 80 ℃ for 1.5 hours, then cooled to room temperature, and filteredFiltered and concentrated under reduced pressure. The residue was dissolved in DCM (200mL) and washed with water (200mL). The aqueous layer was extracted with DCM (100mL) and the combined organic layers were MgSO₄Dried and concentrated under reduced pressure to give (Z) -1-methyl-3- (2,3,6, 7-tetrahydro-1H-azepin-1-yl) -1H-pyrazol-4-amine as a brown oil (1.36g, 87%). A solution of HATU (3.22g,8.47mmol), 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acid (2.52g,7.07mmol), (Z) -1-methyl-3- (2,3,6, 7-tetrahydro-1H-azepin-1-yl) -1H-pyrazol-4-amine (1.36g,7.07mmol) and DIPEA (2.48mL,14.2mmol) in DMF (30mL) was stirred at room temperature for 18H. The reaction mixture was diluted with DCM (50mL) and washed with water (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-80% 10% MeOH in DCM/DCM) to give (Z) -tert-butyl 2- (2, 6-difluorophenyl) -4- (1-methyl-5- (2,3,6, 7-tetrahydro-1H-azepin-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate as a brown solid (2.71g, 72% over two steps).¹H NMR(400MHz,CDCl₃)10.39(s,1H),8.82(s,1H),7.85(s,1H),7.40-7.30(m,1H),7.08-6.99(m,2H),5.93-5.84(m,2H),3.77(s,3H),3.19(t,J＝5.1Hz,4H),2.42-2.37(m,4H),1.58-1.48(m,9H).

Intermediate 2521- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-one

To a solution of 3-chloro-1-methyl-4-nitro-1H-pyrazole (1.0g,6.17mmol) in ethanol (10mL) was added DIPEA (2mL,11.4mmol) followed by 4-hydroxypyridine (686mg,6.79 mmol). The reaction mixture was heated at 130 ℃ for 60 minutes in a microwave and then the solvent was removed under reduced pressure. The residue was chromatographed over silica gel column (75-100% EtOAc/isohexane)Alkane) to give 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-ol as a bright yellow oil (1.46 g). To a solution of this oil (1.40g,6.17mmol) in DCM (40mL) was added visas-martin oxidant (3.1g,7.41mmol) in portions. The reaction mixture was stirred at room temperature for 3 hours, diluted with DCM (100mL) and washed with saturated aqueous sodium bicarbonate solution (30mL), followed by saturated aqueous sodium thiosulfate solution (30mL), saturated aqueous sodium bicarbonate solution (30mL) and brine (30 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (50-75% EtOAc/isohexane) afforded 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-one as a yellow solid (1.32g, 95% over two steps).¹H NMR(400MHz,CDCl₃)8.06(s,1H),3.86(s,3H),3.54(t,J＝6.0Hz,4H),2.65(t,J＝6.0Hz,4H).

Intermediate 2534- (azidomethyl) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-ol

Sodium hydride (255mg,6.38mmol) was added in portions to DMSO (15mL) at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 15 minutes, then trimethylsulfonium iodide (1.34g,6.09mmol) was added. After stirring at room temperature for 90 minutes, a solution of 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-one (1.3g,5.80mmol) in DMSO (15mL) was added. The mixture was heated at 55 ℃ for 2h, then poured into water (200mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were over MgSO₄Drying and concentrating under reduced pressure to obtain 6- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1-oxa-6-azaspiro [2.5]Octane as an orange liquid. To a solution of this liquid (1.38g,5.80mmol) in MeOH (25mL) and water (5mL) was added ammonium chloride (768mg,14.4mmol) followed by sodium azide (1.9g,29.2 mmol). The reaction mixture was heated at 70 ℃ for 18 h, cooled to room temperature and MeOH removed under reduced pressure. The residue was diluted with water (20mL) and extracted with EtOAc (150 mL). The organic layer was washed with water (20mL) and brine (20mL), separated, and over MgSO₄Dried and concentrated under reduced pressure. Chromatography on silica gel (50-75)% EtOAc/isohexane) to give 4- (azidomethyl) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-ol as a yellow oil (1.03g, 63% over two steps).¹H NMR(400MHz,CDCl₃)8.03(s,1H),3.76(s,3H),3.64-3.54(m,2H),3.42(s,2H),3.05-2.96(m,2H),1.92(s,1H),1.81-1.77(m,4H).

Intermediate 254 (tert-butyl 4-methoxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-yl) methylcarbamate

Following the procedure for intermediate 120, starting from 4- (azidomethyl) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-ol, tert-butyl (4-methoxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-yl) methylcarbamate was obtained as a yellow oil (330mg, 88%, over three steps).¹H NMR(400MHz,CDCl₃)8.01(s,1H),4.72(s,1H),3.74(s,3H),3.51(t,J＝11.8Hz,2H),3.28(d,J＝5.9Hz,2H),3.25(s,3H),2.92(d,J＝11.8Hz,2H),1.91(d,J＝13.5Hz,2H),1.66(t,J＝13.5Hz,2H),1.45(s,9H).

Intermediate 2552, 2, 2-trifluoro-N- (5-fluoro-2-hydroxy-5- (2-methyl-4-nitro-pyrazol-3-yl) cycloheptyl) acetamide

A solution of 2-azido-5-fluoro-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cycloheptanol (280mg,094mmol) in THF/water (20mL/4mL) was treated with triphenylphosphine (270g,1.03mmol) and the mixture was heated at 60 ℃ after the explosion-proof barrier for 18 hours. The solvent was removed under reduced pressure and the residue was purified via SCX cartridge, washed with MeOH and washed with 3N NH₃Elution (in MeOH) gave 2-amino-5-fluoro-5- (2-methyl-4-nitro-pyrazol-3-yl) cycloheptanol as a colorless oil. To a solution of this oil (256mg,0.94mmol) in anhydrous DCM (20mL) at 0 deg.C was slowly added DIPEA (0.49 mmol)mL,2.82mmol), followed by the dropwise addition of trifluoroacetic anhydride (0.16mL,1.13 mmol). The reaction mixture was warmed to room temperature and stirred for 18 hours. Water (20mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (30-50% EtOAc/isohexane) afforded 2,2, 2-trifluoro-N- (5-fluoro-2-hydroxy-5- (2-methyl-4-nitro-pyrazol-3-yl) cycloheptyl) acetamide as a light yellow oil (130mg, 38% over two steps).¹H NMR(400MHz,CDCl₃)8.07and8.06(2s,1H),6.53(s,1H),4.08and4.06(2s,3H),4.05-3.92(m,2H),3.06-2.69(m,3H),2.32-1.89(m,6H).

Intermediate 2574- (aminomethyl) -1- (2-methyl-4-nitro-pyrazol-3-yl) piperidin-4-ol

Sodium hydride (60% in mineral oil, 200mg,4.9mmol) was added in portions to DMSO (15mL) at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 15 minutes, then trimethylsulfonium iodide (1.0g,4.6mmol) was added. After stirring at room temperature for 90 minutes, a solution of 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-one (1.0g,4.45mmol) in DMSO (15mL) was added. The mixture was heated at 55 ℃ for 3h, then poured into water (50mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were over MgSO₄Drying and concentrating under reduced pressure to obtain 6- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1-oxa-6-azaspiro [2.5]Octane as an orange liquid. To a solution of this liquid (0.4g,1.67mmol) in the reaction tube was added NH₃A 7M solution in MeOH (20mL) and the mixture was stirred in a sealed tube at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel (1-10% 7M NH)₃In MeOH/DCM) to give 4- (aminomethyl) -1- (2-methyl-4-nitro-pyrazol-3-yl) piperidin-4-ol as a yellow solid (350mg, 60% over two steps).¹H NMR(400MHz,CDCl₃)8.02(s,1H),3.76(s,3H),3.64-3.54(m,2H),3.09-3.03(m,2H),2.72(s,2H),1.73-1.62(m, 4H). Exchangeable groups are not observed.

Intermediate 258N- ((tert-butyl 4-hydroxy-1- (2-methyl-4-nitro-pyrazol-3-yl) -4-piperidinyl) methyl) carbamate

To a solution of 4- (aminomethyl) -1- (2-methyl-4-nitro-pyrazol-3-yl) piperidin-4-ol (150mg,0.58mml), triethylamine (0.12mL,0.88mmol), and DMAP (17mg,0.15mmol) in DCM (10mL) (cooled to 0 ℃) was slowly added a solution of di-tert-butyl dicarbonate (140mg,0.65mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 16 hours. Water (10mL) was added and the aqueous layer was extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine (15mL), passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (1-10% MeOH/DCM) gave tert-butyl N- ((4-hydroxy-1- (2-methyl-4-nitro-pyrazol-3-yl) -4-piperidinyl) methyl) carbamate as a yellow solid (140mg, 68%).¹HNMR(400MHz,CDCl₃)8.02(s,1H),5.10-5.03(m,1H),3.76(s,3H),3.61-3.49(m,2H),3.25(d, J ═ 6.3Hz,2H),3.08-2.96(m,2H),1.77-1.72(m,4H),1.46(s, 9H). No OH was observed.

Intermediate 2593- (2-methyl-4-nitro-pyrazol-3-yl) -11-oxa-3, 8-diazaspiro [5.5] undecane-8-carboxylic acid tert-butyl ester

To a solution of 4- (aminomethyl) -1- (2-methyl-4-nitro-pyrazol-3-yl) piperidin-4-ol (0.5g,1.95mmol) in THF (25mL) was added K₂CO₃(0.68g,4.98mmol) (dissolved in water (10 mL)). After cooling to 0 deg.C, chloroacetyl chloride (0.19mL,2.45mmol) was added slowly. The mixture was warmed to rt and stirred for 16 h, partitioned between water (15mL) and EtOAc (15mL) and the aqueous layer extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (20mL) over MgSO₄Dried and concentrated under reduced pressure to give a yellow solid. Dissolving it in tert-butanol (1)5mL) and THF (3mL) and potassium tert-butoxide (0.34g,2.9mmol) was added. The mixture was heated at 85 ℃ for 16 hours. After cooling to room temperature, the mixture was partitioned between water (20mL) and EtOAc (20mL) and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were over MgSO₄Dried and concentrated under reduced pressure. Purification by column chromatography on silica gel (1-10% MeOH/DCM) afforded a yellow solid (0.47 g). The solid was dissolved in THF (15mL) and borane solution (1M in THF, 10mL) was added. The reaction mixture was heated at 66 ℃ for 72 hours and then cooled to room temperature. The reaction was quenched with 1M hydrochloric acid (5mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20mL) over MgSO₄Dried and concentrated under reduced pressure. To a solution of the resulting intermediate (200mg) in DCM (10mL) was added triethylamine (0.12mL,0.85mmol) and DMAP (20mg,0.14 mmol). The mixture was cooled to 0 ℃ and a solution of di-tert-butyl dicarbonate (0.18g,0.85mmol) in DCM (2mL) was added slowly. The mixture was warmed to room temperature and stirred for 16 hours. Water (5mL) was added and the mixture was extracted with DCM (3 × 10 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (10-100%, EtOAc/isohexane) afforded 3- (2-methyl-4-nitro-pyrazol-3-yl) -11-oxa-3, 8-diazaspiro [5.5]]Tert-butyl undecane-8-carboxylate as an off-white solid (110mg, 44%, over three steps).¹H NMR(400MHz,CDCl₃)8.02(s,1H),3.82-3.59(m,5H),3.50-3.32(m,4H),2.00-1.85(m,4H),1.82-1.69(m,4H),1.44(s,9H).

Intermediate 2655- ((4-methoxyphenyl) methoxy) -1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-ol

To a solution of (Z) -2,3,6, 7-tetrahydro-1H-azepine hydrochloride (5.0g,25.38mmol) in MeOH (25mL) was added HCl in dioxane (4M,0.10mol,25mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 5 minutes, warmed to room temperature and stirred for a further 3.5 hours. The mixture was concentrated under reduced pressure and the crude residue was dissolved in DMSO (90 mL). DIPEA (8.80mL,50.52mmol) was added followed by 5-chloro-1-methyl-4-nitro-pyrazole (4.1g,25.37mmol) and potassium fluoride (5.9g,101.54mmol) and the mixture was heated at 70 ℃ for 18 h. After cooling to room temperature, the reaction was quenched with water (500mL) and extracted with EtOAc (3 × 200mL). The combined organic layers were washed with water (200mL) and brine (200mL), separated, and over MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel chromatography (0-100% EtOAc/isohexane) afforded a light yellow solid (5.22 g). To a solution of this solid (3.13g,14.10mmol) in DCM (50mL) was added 3-chloroperbenzoic acid (7.30g,21.10mmol) and the mixture was stirred at room temperature for 1.5 h. The mixture was diluted with DCM (250mL) and saturated NaHCO₃Aqueous (250mL) and 1M NaOH aqueous (150 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) afforded a light yellow solid (3.03 g). To a solution of the solid (1.29g,5.42mmol) and p-methoxybenzyl alcohol (3.74g,27.10mmol) in DCM (30mL) was added copper (II) trifluoromethanesulfonate (0.20g,0.54mmol) and the mixture was stirred at room temperature for 18 h. Copper (II) trifluoromethanesulfonate (0.10g,0.26mmol) was added and the mixture was stirred for a further 48 h. The mixture was quenched with water (250mL) and extracted with DCM (2 × 250 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (20-90% EtOAc/isohexane, then 0-20% EtOAc/DCM) gave 5- ((4-methoxyphenyl) methoxy) -1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-ol as a light yellow gum (800mg, 8% over four steps).¹H NMR(400MHz,CDCl₃)8.03(t,J＝3.4Hz,1H),7.31-7.25(m,2H),6.92-6.87(m,2H),4.65(d,J＝11.0Hz,1H),4.49-4.38(m,1H),3.98-3.67(m,4H),3.73(s,3H),3.57-3.44(m,1H),3.34-3.23(m,2H),3.22-3.12(m,2H),2.95(d,J＝1.3Hz,1H),2.25-2.10(m,2H),1.91-1.75(m,2H).

Intermediate 266 tert-butyl N- (2- (2, 6-difluorophenyl) -4- ((5- (4-hydroxy-5- ((4-methoxyphenyl) methoxy) azepan-1-yl) -1-methyl-pyrazol-4-yl) carbamoyl) thiazol-5-yl ] carbamate

To a solution of 5- ((4-methoxyphenyl) methoxy) -1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-ol (0.80g,2.18mmol) in EtOH (30mL) and water (3mL) was added iron powder (0.90g,16.11 mmol). The reaction mixture was heated at 100 ℃ for 2 hours, cooled to room temperature, and filteredFiltered and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM (50mL) and washed with water (50 mL). The aqueous layer was extracted with DCM (50mL) and the combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure to give a light orange gum. To a solution of this gum (0.55g,1.60mmol) in DMF (5mL) was added 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (0.62g,1.76mmol), HATU (0.85g,2.40mmol) and DIPEA (0.56mL,3.20 mmol). The reaction mixture was stirred at room temperature for 66 hours, with saturated NaHCO₃Aqueous solution (200mL) quenched and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (100mL), separated, and MgSO₄Dried and concentrated under reduced pressure. Purification by column chromatography on silica gel (0-10% MeOH/EtOAc) afforded N- (2- (2, 6-difluorophenyl) -4- ((5- (4-hydroxy-5- ((4-methoxyphenyl) methoxy) azepan-1-yl) -1-methyl-pyrazol-4-yl) carbamoyl) thiazol-5-yl]Tert-butyl carbamate as a pale pink solid (530mg, 35% over two steps).¹H NMR(400MHz,CDCl₃)10.44(s,1H),9.02(s,1H),7.91(s,1H),7.38-7.28(m,1H),7.25(d,J＝8.2Hz,2H),7.00(t,J＝8.7Hz,2H),6.92-6.84(m,2H),4.61(d,J＝11.1Hz,1H),4.40(d,J＝11.1Hz,1H),3.91(t,J＝8.6Hz,1H),3.81(s,3H),3.73(s,3H),3.55(td,J＝8.4,3.4Hz,1H),3.34-3.13(m,4H),3.10(s,1H),2.22-2.14(m,2H),1.93-1.77(m,2H),1.62-1.50(m,9H).

Intermediate 2675-azido-4-methoxy-4-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepane

To 4-azido-5-hydroxy-azepaneA stirred solution of tert-butyl alkane-1-carboxylate (2.4g,9.38mmol) in DCM (100mL) was added as one portion with Toiss-Martin oxidant (5.16g,12.19mmol) and the mixture stirred at room temperature for 2 h. DCM (100mL) was added, followed by saturated NaHCO₃(100mL) and 10% Na2S2O3(30 mL). Stirring was continued for 30 minutes. The layers were separated and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) gave a colorless oil (1.99 g). To this oil under nitrogen over 15 min in anhydrous Et₂Ice-cooled solution in O (30mL) was slowly added the lithium methyl bromide complex in Et₂Solution in O (1.5M,5.8mL,8.62 mmol). The mixture was cooled under stirring on ice for 1 hour, warmed to room temperature and stirred for 18 hours. After cooling in ice, saturated brine (100mL) was added. The mixture was extracted with EtOAc (3 × 100mL) and the combined extracts were over MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel column chromatography (20-40% EtOAc/isohexane) gave a colorless oil (0.92 g). The oil was dissolved in anhydrous DMF (5mL) under nitrogen, cooled in ice and sodium hydride (60% dispersion in mineral oil, 203mg,5.08mmol) was added in portions over 15 minutes. After cooling with ice for 15 minutes under stirring, iodomethane (1.06mL,16.94mmol) was added dropwise and the mixture was cooled with ice under stirring for 30 minutes. The reaction mixture was warmed to room temperature and stirred for4 hours. Saturated brine (100mL) was added and the mixture was taken up in Et₂O (3 × 100 mL). The combined organic layers were over MgSO₄The solvent was removed under reduced pressure by drying to give a pale green oil (1.05 g). The oil was dissolved in MeOH (10mL) and a solution of HCl in dioxane (4M,10mL) was added. The solution was warmed to 40 ℃ and stirred for 2.5 hours. Concentration under reduced pressure gave a light brown gum (1.03g) which was dissolved in DMSO (10 mL). To this solution was added 5-chloro-1-methyl-4-nitro-pyrazole (712mg,4.41mmol), potassium fluoride (720mg,13.56mmol) and DIPEA (1.2mL,6.78mmol) and the mixture was heated at 70 ℃ under nitrogen for 19 hours. The mixture was cooled, poured into water (300mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with water (150mL) and brine (150mL), separated, and over MgSO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) afforded 5-dAza-4-methoxy-4-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepane as a pale yellow solid (830mg, 11%, over four steps).¹H NMR(400MHz,CDCl₃)8.03(s,1H),3.79(s,3H),3.47-3.35(m,2H),3.32-3.20(m,5H),3.06-2.95(m,1H),2.60-2.40(m,1H),2.18-2.08(m,1H),2.06-1.92(m,1H),1.80-1.65(m,1H),1.39(s,3H).

Intermediate 268 tert-butyl N- (5-methoxy-5-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl) carbamate

Following the procedure for intermediate 112, starting from 5-azido-4-methoxy-4-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepane, tert-butyl N- (5-methoxy-5-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl) carbamate was obtained as a yellow gum (780mg, 75% over two steps).¹H NMR(400MHz,CDCl₃)8.02(s,1H),5.25-5.15(m,1H),3.75(s,3H),3.74-3.65(m,1H),3.65-3.50(m,1H),3.48-3.35(m,1H),3.20(s,3H),3.19-3.10(m,1H),3.00-2.85(m,1H),2.45-2.30(m,1H),2.20-2.05(m,1H),1.90-1.70(m,2H),1.46(s,9H),1.28(s,3H).

Intermediate 269G 02693495N- (tert-butyl 1- (4- ((5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl) amino) -2-methyl-pyrazol-3-yl) -5-methoxy-5-methyl-azepan-4-yl ] carbamate

10% Palladium on carbon (0.2g) was added under nitrogen to a stirred solution of tert-butyl N- (5-methoxy-5-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl) carbamate (0.77g,2.01mmol) and ammonium formate (1.6g,25mmol) in MeOH (30mL) and the mixture was heated at reflux for 2 hours. After cooling to room temperature, byThe mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up in DCM (100mL) and saturated NaHCO₃The aqueous solution (150mL) was partitioned and the aqueous layer was extracted with DCM (100 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure to give a light brown gum (700 mg). The gum was dissolved in DCM (10mL) and DMF (10mL) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (0.84g,2.2mmol), HATU (1.14g,3mmol) and DIPEA (0.7mL,4mmol) were added. The mixture was stirred at room temperature for 18 hours. DCM was removed under reduced pressure and saturated NaHCO was added₃(300 mL). The mixture was extracted with EtOAc (3 × 200mL), the combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification by column chromatography on silica gel (0-100% EtOAc/isohexane) afforded N- (1- (4- ((5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl) amino) -2-methyl-pyrazol-3-yl) -5-methoxy-5-methyl-azepan-4-yl)]Tert-butyl carbamate as a pale yellow solid (540mg, 39%, over two steps).¹H NMR(400MHz,CDCl₃)10.39(s,1H),8.77(s,1H),7.89(s,1H),7.45-7.30(m,1H),7.12-6.95(m,2H),5.30-5.20(m,1H),3.73(s,3H),3.72-3.65(m,1H),3.50-3.28(m,2H),3.25-3.15(m,1H),3.14(s,3H),3.05-2.95(m,1H),2.40-2.20(m,1H),2.18-2.05(m,1H),1.95-1.70(m,2H),1.55(s,9H),1.45(s,9H),1.22(s,3H).

Intermediate 270 tert-butyl N- ((4R,5S) -5-hydroxy-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl) carbamate

A racemic mixture of tert-butyl 5-hydroxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (5.13g,14.13mmol) was subjected to chiral SFC to separate the enantiomers and give tert-butyl N- ((4R,5S) -5-hydroxy-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl) carbamate as a yellow gum (2.08g, 98.3% ee, 40%).¹H NMR(400MHz,CDCl₃)8.03(s,1H),5.12(s,1H),4.19(s,1H),3.93(t,J＝8.6Hz,1H),3.79(s,3H),3.52-3.44(m,1H),3.33-3.26(m,1H),3.22-3.08(m,2H),2.53(s,1H),2.19-2.11(m,1H),2.02-1.95(m,2H),1.92-1.82(m,1H),1.46(s,9H).

Intermediate 271N- ((4S,5R) -5-hydroxy-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl) carbamic acid tert-butyl ester

A racemic mixture of tert-butyl 5-hydroxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (5.13g,14.13mmol) was subjected to chiral SFC to separate the enantiomers and give tert-butyl N- ((4S,5R) -5-hydroxy-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl) carbamate as a yellow gum (2.02g, 97.6% ee, 39%).¹H NMR(400MHz,CDCl₃)8.03(s,1H),5.12(s,1H),4.19(s,1H),3.93(t,J＝8.6Hz,1H),3.79(s,3H),3.52-3.44(m,1H),3.33-3.26(m,1H),3.22-3.08(m,2H),2.53(s,1H),2.19-2.11(m,1H),2.02-1.95(m,2H),1.92-1.82(m,1H),1.46(s,9H).

Intermediate 272 tert-butyl N- ((4R,5S) -1- (4- ((5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl) amino) -2-methyl-pyrazol-3-yl) -5-hydroxy-azepan-4-yl ] carbamate

To a solution of tert-butyl N- ((4R,5S) -5-hydroxy-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl) carbamate (1.92g,5.40mmol) in methanol (40mL) was added 10% palladium on carbon (37mg,0.35mmol) and the reaction mixture was stirred at room temperature under hydrogen at 600psi atmosphere for 6 hours. By passingThe mixture and filtrate were filtered and concentrated under reduced pressure to give crude amino-pyrazole (1.5 g). A solution of PyBOP (3.35g,6.44mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (1.8g,5.06mmol) in DCM (50mL) was stirred at room temperature for 30 min. A solution of crude amino-pyrazole (1.5g,4.60mmol) and DIPEA (1.28mL,7.36mmol) in DCM (50mL) was added and the mixture stirred at room temperature for 70 h. The reaction mixture was diluted with DCM (50mL) and washed with water (3 × 50 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purify via silica gel chromatography (0-3% MeOH/DCM) and dry Et₂O was then triturated with hot MeCN to give N- ((4R,5S) -1- (4- ((5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl) amino) -2-methyl-pyrazol-3-yl) -5-hydroxy-azepan-4-yl]Tert-butyl carbamate as an off-white solid (1.85g, 51% over two steps).¹H NMR(400MHz,CDCl₃)10.67(s,1H),9.76(s,1H),8.03(s,1H),7.41-7.34(m,1H),7.09(t,J＝8.8Hz,2H),5.00(d,J＝8.4Hz,1H),4.25(s,1H),3.83(s,1H),3.72(s,3H),3.45-3.25(m,4H),3.20-3.12(m,1H),2.20-1.84(m,3H),1.84-1.78(m,1H),1.55(s,9H),1.42(s,9H).

Intermediate 273N- ((4S,5R) -tert-butyl 4N- ((4S,5R) -1- (4- ((5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl) amino) -2-methyl-pyrazol-3-yl) -5-hydroxy-azepan-4-yl ] carbamate

Starting from tert-butyl N- ((4S,5R) -5-hydroxy-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl) carbamate according to the procedure for intermediate 272, N- ((4S,5R) -1- (4- ((5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl) amino) -2-methyl-pyrazol-3-yl) -5-hydroxy-azepan-4-yl) amino) -2-methyl-pyrazol-3-yl]Tert-butyl carbamate as a white solid (1.34g, 37% over two steps).¹H NMR(400MHz,CDCl₃)10.67(s,1H),9.76(s,1H),8.03(s,1H),7.41-7.34(m,1H),7.09(t,J＝8.8Hz,2H),5.00(d,J＝8.4Hz,1H),4.25(s,1H),3.83(s,1H),3.72(s,3H),3.45-3.25(m,4H),3.20-3.12(m,1H),2.20-1.84(m,3H),1.84-1.78(m,1H),1.55(s,9H),1.42(s,9H).

Intermediate 274 anti-7-azido-4- (2-methyl-4-nitro-pyrazol-3-yl) cyclohept-3-en-1-ol

Following the procedure of intermediate 221, anti-7-azido-4- (2-methyl-4-nitro-pyrazol-3-yl) cyclohept-3-en-1-ol was also obtained as a light yellow oil (294mg, 42% yield).¹H NMR(400MHz,CDCl₃)8.06(s,1H),5.96(dd,J＝8.3,4.9Hz,1H),3.82(s,3H),3.80-3.73(m,1H),3.56-3.48(m,1H),2.71(ddd,J＝15.5,8.3,2.3Hz,1H),2.58-2.39(m,4H),2.24-2.14(m,1H),1.86-1.73(m,1H).

Intermediate 275 syn-7-azido-4- (2-methyl-4-nitro-pyrazol-3-yl) cyclohept-3-en-1-ol

Following the procedure for intermediate 119, starting from anti-7-azido-4- (2-methyl-4-nitro-pyrazol-3-yl) cyclohept-3-en-1-ol, syn-7-azido-4- (2-methyl-4-nitro-pyrazol-3-yl) cyclohept-3-en-1-ol was obtained as a yellow oil (346mg, 67% over two steps).¹H NMR(400MHz,CDCl₃)8.06(s,1H),5.93-5.85(m,1H),3.94-3.88(m,1H),3.85(s,3H),2.98(ddd,J＝15.2,9.5,6.4Hz,1H),2.65(dd,J＝15.7,9.0Hz,1H),2.41(dd,J＝15.2,6.9Hz,1H),2.30(dd,J＝15.9,9.4Hz,1H),2.04-1.87(m,4H).

Intermediate 276 tert-butyl N- (-2-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) cyclohept-4-en-1-yl) carbamate

Following the procedure for intermediate 120, starting from syn-7-azido-4- (2-methyl-4-nitro-pyrazol-3-yl) cyclohept-3-en-1-ol, tert-butyl N- (-2-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) cyclohept-4-en-1-yl) carbamate was obtained as a colorless oil (189mg, 89%, over three steps).¹H NMR(400MHz,CDCl₃)8.05(s,1H),5.92(ddd,J＝8.4,4.7,1.6Hz,1H),5.23(s,1H),3.91-3.81(m,1H),3.80(s,3H),3.66-3.62(m,1H),3.41(s,3H),2.93(ddd,J＝15.1,11.1,4.7Hz,1H),2.78(t,J＝12.9Hz,1H),2.23(dd,J＝15.1,8.5Hz,1H),2.15-1.82(m,3H),1.46(s,9H).

Intermediate 277G 02693497N- (tert-butyl 5- (4- ((5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl) amino) -2-methyl-pyrazol-3-yl ] -2-methoxy-cycloheptyl ] carbamate

A solution of tert-butyl N- (-2-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) cyclohept-4-en-1-yl) carbamate (180mg,0.49mmol) in MeOH (30mL) was purified by(all H)₂Flow rate 1 mL/min, 30mm 20% Pd/C cartridge, 70 ℃). The solvent was removed under reduced pressure to give a colorless oil. To a solution of this oil in DCM (30mL) was added DIPEA (2.00mL,11.48mmol) and 5- (tert-butoxycarbonylamino) -2- (2-fluorophenyl) thiazole-4-carboxylic acid (171mg,0.50mmol) followed by PyBOP (596mg,1.15mmol) and the mixture stirred at rt for 16 h and quenched with water (20mL) and extracted with DCM (80 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel chromatography (70-80% EtOAc/isohexane) afforded N- (5- (4- ((5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl) amino) -2-methyl-pyrazol-3-yl)]-2-methoxy-cycloheptyl]Tert-butyl carbamate, a mixture of the four diastereomers, was an off-white solid (175mg, 54%, over two steps).¹H NMR(400MHz,CDCl₃)10.39and10.36(2s,1H),8.69and8.62(2s,1H),8.32-8.28and8.21-8.14(2m,1H),7.85and7.75(2s,1H),7.43-7.36(m,1H),7.32(t,J＝7.6Hz,1H),7.25-7.17(m,1H),5.19and5.08(2d,J＝8.8Hz,1H),3.84(s,3H),3.78-3.54(m,2H),3.37and3.27(2s,3H),3.11-2.94(m,1H),2.32-1.30(m,8H),1.55(s,9H),1.43(s,9H).

Intermediate 2784-methyl-6-oxo-3, 7-dihydro-2H-azepine-1-carboxylic acid tert-butyl ester

A stirred solution of N- (3-methyl-3-buten-1-yl) -1, 1-dimethylethyl ester (2.14g,11.57mmol) in anhydrous THF (30mL) was added dropwise over 10 min of N-butyllithium in hexane (2.5M,5.1mL,12.75mmol) at room temperature under nitrogen. After 1.25 h, 1-chloro-3- (triphenyl-. lamda.5-phosphinylidene) propan-2-one (4.07g,11.57mmol) was added in portions over 15 min and stirring continued at room temperature for 18 h. Water (100mL) was added carefully and the reaction mixture was extracted with EtOAc (3x150 mL). The combined organic layers were over MgSO₄Dried and the solvent removed under reduced pressure. Purification by column chromatography on silica gel (0-10% MeOH/DCM) gave a pale orange gum (5.7 g). This was dissolved in anhydrous THF (60mL) and acetaldehyde (6.4mL) was added. The reaction mixture was stirred at room temperature for 20 hours. The solvent was removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded a light orange solid (2.18 g). The oil was dissolved in DCM (30mL) deoxygenated with nitrogen and Grubbs2 added^ndCatalyst (335mg,0.34mmol) was produced. The mixture was heated under nitrogen at reflux for 20 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) afforded 4-methyl-6-oxo-3, 7-dihydro-2H-azepine-1-carboxylic acid tert-butyl ester as a dark brown oil (1.23g, 47% over three steps).¹H NMR(400MHz,CDCl₃)5.30(s,1H),4.30-4.10(m,2H),3.65-3.50(m,2H),2.70-2.55(m,2H),2.05-1.90(m,3H),1.48and1.44(2s,9H).

Intermediate 2795-azido-5-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-3-ol

Following the procedure for intermediate 18, starting from tert-butyl 4-methyl-6-oxo-3, 7-dihydro-2H-azepine-1-carboxylate, 5-azido-5-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-3-ol was obtained as a pale green gum (720mg, 64% over three steps).¹H NMR(400MHz,CDCl₃)8.04-8.03(m,1H),4.25-3.90(m,1H),3.88and3.84(2s,3H),3.75-3.45(m,1H),3.45-2.90(m,3H),2.30-2.18(m,1H),2.15-1.75(m,4H),1.55(2s,3H).

Intermediate 280N- (6, 6-difluoro-4-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl) carbamic acid tert-butyl ester

To a solution of 5-azido-5-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-3-ol (720mg,2.44mmol) in DCM (100mL) was added bose-martin oxidant (1.35g,3.17mmol) in one portion. The reaction mixture was stirred at room temperature for 1 hour, diluted with DCM (100mL) and saturated NaHCO₃Aqueous solution (200mL) followed by 20% Na₂S₂O₃Aqueous solution (100mL) was quenched. The resulting mixture was stirred for 15 min, the organic layer was separated and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure to give a pale green gum (720 mg). To a solution of the gum in DCM (50mL) was added(50% in THF, 3.12mL,8.6mmol) and the mixture stirred at room temperature for 20 h. Adding more(3.1mL) and mixingThe mixture was heated at 40 ℃ for 28 hours. The mixture was cooled and saturated NaHCO was added dropwise₃Aqueous solution (200mL) was quenched and diluted with DCM (100 mL). The organic layer was separated and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded a light yellow gum (626 mg). The gum was dissolved in THF (20mL) and water (4mL) and triphenylphosphine (522mg,2mmol) was added. The mixture was heated at 70 ℃ for 16 hours after the explosion-proof barrier. More triphenylphosphine (500mg) was added and heating continued for a further 5 hours. The solvent was removed under reduced pressure and the residue was dissolved in DCM (30 mL). To the solution was added di-tert-butyl dicarbonate (1.08g,5mmol) and DIPEA (0.7mL,4mmol) and the mixture was stirred at room temperature for 66 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl N- (6, 6-difluoro-4-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl) carbamate as a colorless solid (540mg, 57% over four steps).¹H NMR(400MHz,CDCl₃)8.04(s,1H),4.92(s,1H),3.84(s,3H),3.82-3.55(m,1H),3.52-3.05(m,3H),2.70-2.45(m,2H),2.30-2.05(m,1H),2.04-1.85(m,1H),1.52(s,3H),1.45(s,9H).

Intermediate 281N- (4- ((5- (5- (tert-butoxycarbonylamino) -3, 3-difluoro-5-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl) carbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-yl ] carbamic acid tert-butyl ester

Following the procedure for intermediate 269, starting from tert-butyl N- (6, 6-difluoro-4-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl) carbamate, tert-butyl N- (4- ((5- (5- (tert-butoxycarbonylamino) -3, 3-difluoro-5-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl) carbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-yl) carbamate was obtained as a yellow solid (409mg, 58% over two steps).¹H NMR(400MHz,CDCl₃)10.39(s,1H),8.79(s,1H),7.88(s,1H),7.45-7.30(m,1H),7.15-7.00(m,2H),5.12(br s,1H),3.78(s,3H),3.75-3.42(m,2H),3.40-3.10(m,2H),2.70-2.45(m,2H),2.40-2.15(m,1H),1.95-1.70(m,1H),1.55(s,9H),1.46(s,3H),1.33(s,9H).

Intermediate 2853-Ethyl-1- (2-methyl-4-nitro-pyrazol-3-yl) piperidin-4-one

To a solution of 380mg,1.67mmol) of 3-ethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester in DCM (15mL) was added TFA (3mL) at rt and the reaction mixture was stirred at rt for4 h. The mixture was concentrated under reduced pressure to give ethylpiperidinone as its trifluoroacetate salt. A mixture of the salt (410mg,1.7mmol), 5-chloro-1-methyl-4-nitro-pyrazole (330mg,2.0mmol) and DIPEA (0.75mL,4.2mmol) in EtOH (15mL) was heated at 130 ℃ for 2h under microwave conditions. The reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (10-50% EtOAc/isohexane) afforded 3-ethyl-1- (2-methyl-4-nitro-pyrazol-3-yl) piperidin-4-one as a light yellow solid (250mg, 58% over two steps).¹H NMR(400MHz,CDCl₃)8.05(s,1H),3.87(s,3H),3.65-3.54(m,1H),3.53-3.41(m,2H),3.36-3.21(m,1H),2.78-2.64(m,1H),2.64-2.49(m,2H),2.01-1.87(m,1H),1.44-1.29(m,1H),0.94(t,J＝7.5Hz,3H).

Intermediate 2864- (azidomethyl) -3-ethyl-1- (2-methyl-4-nitro-pyrazol-3-yl) piperidin-4-ol

Following the procedure for intermediate 253, starting from 3-ethyl-1- (2-methyl-4-nitro-pyrazol-3-yl) piperidin-4-one, 4- (azidomethyl) -3-ethyl-1- (2-methyl-4-nitro-pyrazol-3-yl) piperidin-4-ol was obtained as a yellow gum (170mg, 66% over two steps).¹H NMR(400MHz,CDCl₃)8.03(s,1H),3.76(s,3H),3.62-3.53(m,2H),3.40(d,J＝12.2Hz,1H) 3.34-3.15(m,1H),3.06-2.94(m,2H),1.97-1.77(m,3H),1.37-1.15(m,2H),0.92(t, J ═ 7.4Hz,3H).

Intermediate 287N- ((3-Ethyl-4-methoxy-1- (2-methyl-4-nitro-pyrazol-3-yl) -4-piperidinyl) methyl) carbamic acid tert-butyl ester

Following the procedure for intermediate 120, starting from 4- (azidomethyl) -3-ethyl-1- (2-methyl-4-nitro-pyrazol-3-yl) piperidin-4-ol, tert-butyl N- ((3-ethyl-4-methoxy-1- (2-methyl-4-nitro-pyrazol-3-yl) -4-piperidinyl) methyl) carbamate was obtained as a light yellow solid (110mg, 70%, over three steps).¹H NMR(400MHz,CDCl₃)8.02(s,1H),4.95-4.35(m,1H),3.76(s,3H),3.53-3.43(m,2H),3.36-3.09(m,7H),2.07-1.93(m,1H),1.44-1.10(m,4H),0.96-0.81(m,12H).

Intermediate 2923- (2-methyl-4-nitro-pyrazol-3-yl) -8-oxa-3-azabicyclo [3.2.1] oct-6-ol

To 7-oxabicyclo [2.2.1]A solution of hept-2-en-5-ol (0.7g,6.2mmol) in MeOH/DCM (25mL/5mL) (cooled to-78 deg.C) was degassed by bubbling nitrogen for 5 min. Ozone was bubbled through the reaction mixture until the developed blue color remained. Nitrogen was again bubbled through the cold reaction mixture until only the light color remained. Add a solution of benzylamine (0.67g,6.2mmol) dissolved in MeOH (5mL) followed by the addition of NaCNBH in MeOH (10mL)₃(1.6g,25 mmol). The mixture was warmed to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (30mL) and water (30 mL). The aqueous layer was extracted with EtOAc (3 × 50mL) and the combined organic layers were washed with brine (20mL), over MgSO₄Drying and concentration under reduced pressure gave the benzyl protected amine. It was dissolved in EtOH (40mL) andthen 2M aqueous HCl (1mL) and Pd (OH) were added₂C (0.2 g). The mixture was stirred under 600psi of hydrogen at 70 ℃ for 18 hours. The reaction mixture was cooled to room temperature, filtered through celite, and washed with EtOH (40 mL). The filtrate was concentrated under reduced pressure to give the debenzylated product as hydrochloride. To a suspension of the hydrochloride salt (1.1g,6.6mmol) in DMSO (15mL) was added 5-chloro-1-methyl-4-nitro-pyrazole (1.2g,7.3mmol), DIPEA (1.7mL,9.7mmol) and potassium fluoride (1.1g,20mmol) and the reaction was heated at 85 ℃ for 16 h. The mixture was cooled to room temperature, partitioned between water (25mL) and EtOAc (25mL) and the aqueous layer extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (25mL), separated, and MgSO₄Dried and concentrated under reduced pressure. Purification by column chromatography on silica gel (10-50% EtOAc/isohexane) afforded 3- (2-methyl-4-nitro-pyrazol-3-yl) -8-oxa-3-azabicyclo [3.2.1]Oct-6-ol as an off-white solid (550mg, 62%, over three steps).¹H NMR(400MHz,CDCl₃)8.06(s,1H),4.66-4.57(m,1H),4.38(d,J＝7.6Hz,1H),4.19(d,J＝6.3Hz,1H),3.94(s,3H),3.82-3.73(m,1H),3.68(dd,J＝11.1,2.8Hz,1H),3.12(d,J＝11.1Hz,1H),2.71-2.59(m,2H),2.38(d,J＝7.0Hz,1H),1.97(dd,J＝12.9,3.9Hz,1H).

Intermediate 2936-azido-3- (2-methyl-4-nitro-pyrazol-3-yl) -8-oxa-3-azabicyclo [3.2.1] octane

3- (2-methyl-4-nitro-pyrazol-3-yl) -8-oxa-3-azabicyclo [3.2.1]Oct-6-ol (500mg,1.96mmoL) was dissolved in DCM (15mL) and triethylamine (0.41mL,2.95mmoL) was added. After cooling to 0 ℃, methanesulfonyl chloride (0.19mL,2.45mmol) was added slowly and the reaction mixture was warmed to room temperature and stirred for 18 hours. The mixture was diluted with DCM (10mL), quenched with water (10mL) and the aqueous layer extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (10mL), passed through a phase separation cartridge and concentrated under reduced pressure to give a light brown solid. The solid (450mg,1.35mmol) was dissolved in DMF (20mL), sodium azide (450mg,6.8mmol) was added and the mixture was exposed to 150 ℃ at explosion-proof screenAfter-barrier heating for 18 hours. After the mixture was cooled to room temperature, the mixture was partitioned between water (20mL) and EtOAc (20mL) and the aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (20mL) over MgSO₄Dried and concentrated under reduced pressure. Purification by column chromatography on silica gel (10-50%, EtOAc/isohexane) afforded 6-azido-3- (2-methyl-4-nitro-pyrazol-3-yl) -8-oxa-3-azabicyclo [3.2.1]Octane as a brown gum (25mg, 68% over two steps).¹H NMR(400MHz,CDCl₃)8.05(s,1H),4.65(d,J＝7.4Hz,1H),4.34(s,1H),4.28(dd,J＝8.0,3.2Hz,1H),3.82(s,3H),3.75-3.70(m,2H),2.83-2.73(m,1H),2.64-2.49(m,2H),2.20(ddd,J＝13.4,7.3,3.2Hz,1H).

Intermediate 294 tert-butyl N- (3- (2-methyl-4-nitro-pyrazol-3-yl) -8-oxa-3-azabicyclo [3.2.1] oct-6-yl) carbamate

To 6-azido-3- (2-methyl-4-nitro-pyrazol-3-yl) -8-oxa-3-azabicyclo [3.2.1]Octane (250g,0.8mmol) in THF (10mL) and water (2mL) was added trimethylphosphine (1M solution in toluene, 5mL,4.47mmol) and the mixture was heated at 65 ℃ for 16 h. The solvent was removed under reduced pressure and the resulting residue was dissolved (2M,15mL) and washed with EtOAc (2 × 10 mL). The aqueous layer was basified with 5m naoh aqueous solution to pH14 and extracted with DCM (3 × 20 mL). The combined DCM layers were passed through a phase separation cartridge and concentrated under reduced pressure to give a milky solid (220 mg). To a solution of the amine in DCM (10mL) was added triethylamine (0.18mL1.3mmol) and DMAP (26mg,0.22 mmol). The mixture was cooled to 0 ℃ and a solution of di-tert-butyl dicarbonate (0.28g,1.3mmol) in DCM (2mL) was added slowly. The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with DCM (10mL) and washed with water (10 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification by column chromatography on silica gel (1-10% MeOH/DCM) gave N- (3- (2-methyl-4-nitro-pyrazol-3-yl) -8-oxa-3-azabicyclo [3.2.1]Oct-6-yl) carbamic acid tert-butyl ester as an off-white solid (110mg, 66%, over two steps).¹H NMR(400MHz,CDCl₃)8.03(s,1H),4.64-4.52(m,1H),4.20(s,1H),3.85(s,3H),3.50-3.41(m,4H),2.69-2.46(m,3H),1.84-1.76(m,1H),1.45(s,9H).

Intermediate 295N- (5-fluoro-2-hydroxy-5- (2-methyl-4-nitro-pyrazol-3-yl) cycloheptyl) carbamic acid tert-butyl ester

Following the procedure for intermediate 294, starting from 2-azido-5-fluoro-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cycloheptanol, tert-butyl N- (5-fluoro-2-hydroxy-5- (2-methyl-4-nitro-pyrazol-3-yl) cycloheptyl) carbamate was obtained as a colorless solid (572mg, 61%, over two steps).¹H NMR(400MHz,CDCl₃)8.06and8.05(2s,1H),4.70(br s,1H),4.07and4.06(2s,3H),3.86-3.67(m,3H),2.96(ddd,J＝40.6,15.3,10.4Hz,1H),2.74(dt,J＝44.6,13.8Hz,1H),2.25-2.04(m,2H),2.01-1.79(m,3H),1.72-1.63(m,1H),1.47(s,9H).

Intermediate 3025-hydroxy-4-methyl-azepane-1, 4-dicarboxylic acid O1-benzyl ester O4-ethyl ester

To 1- (benzyloxycarbonyl) -4-piperidone (20.0g,85.80mmol) in Et at 0 deg.C₂To a solution in O (200mL) was added boron trifluoride diethyl ether (12.0mL,94.40mmol) followed by ethyl diazoacetate (11.7mL,94.40mmol) maintaining the temperature below 7 ℃. The reaction mixture was stirred for 1 hour, quenched with 2M aqueous sodium carbonate (150mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were over MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) afforded a light yellow oil. This oil (10g,31.30mmol) was dissolved in DMF (75mL) at 0 deg.C and sodium hydride (60% dispersion in mineral oil, 1.38g,34.50mmol) was added in portions. The reaction mixture was stirred at 0 ℃ for 1 hour, then shop-owned methyl iodide (2.15mL, 34.50)mmol). The reaction wasallowed to warm to room temperature and stir for 18 hours. The mixture is mixed with Et₂O (100mL) was diluted and quenched with water (100 mL). Aqueous layer with Et₂O (3x75mL) extracted and combined organic layers were washed with water (2x100mL) and brine (2x100mL), separated, over MgSO₄Dried and concentrated under reduced pressure. Chromatography on silica gel (50% Et)₂O/isohexane) to give a pale yellow oil. A portion of this oil (0.90g,2.70mmol) was dissolved in MeOH (4mL) and added to NaBH at 0 deg.C₄(0.12g,3.24mmol) in MeOH (5 mL). The reaction mixture was stirred at 0 ℃ for 3 hours and then quenched with 1M aqueous HCl (5 mL). The aqueous layer was extracted with DCM (3 × 10mL) and the combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (25-100% EtOAc/isohexane) afforded 5-hydroxy-4-methyl-azepane-1, 4-dicarboxylic acid O1-benzyl ester O4-ethyl ester as a colorless oil (480mg, 1%, via three steps).¹H NMR(400MHz,CDCl₃)7.37-7.28(m,5H),5.17-5.10(m,2H),4.20-4.07(m,2H),3.78-3.20(m,7H),2.32-2.24(m,1H),2.07-1.86(m,3H),1.73-1.62(m,1H),1.30-1.19(m,3H). Exchangeable does not observe OH.

Intermediate 3033 a-methyl-2-oxo-3, 4,5,7,8,8 a-hexahydroxyoxazolo [4,5-d ] azepine-6-carboxylic acid benzyl ester

To a solution of 5-hydroxy-4-methyl-azepane-1, 4-dicarboxylic acid O1-benzyl ester O4-ethyl ester (0.48g,1.43mmol) in dioxane (5mL) was added 1M aqueous NaOH solution (2.9mL,2.87mmol) and the reaction was stirred at room temperature for 16 h. The mixture was acidified to pH3 with 2M aqueous HCl and Et₂O (10mL) and DCM (10 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) gave a colorless oil (0.42 g). A portion of this oil (0.21g,0.68mmol), diphenylphosphoryl azide (0.17mL,0.82mmol) and triethylamine (0.12mL,0.88mmol) were dissolved in toluene (7mL) and the reaction mixture was stirred at room temperature for40 minute and heating after the explosion-proof barrier at 90 ℃ for 40 minutes. Tert-butanol (0.05mL,0.56mmol) was added and the reaction mixture was heated under reflux for 16 hours after the explosion-proof barrier. The reaction mixture was cooled to room temperature and saturated NaHCO₃Aqueous solution (10mL) was quenched. The mixture was extracted with EtOAc (15mL) and the organic layer was washed with water (10mL) and brine (10mL), separated, and over MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) afforded 3 a-methyl-2-oxo-3, 4,5,7,8,8 a-hexahydroxyoxazolo [4,5-d]Benzyl azepine-6-carboxylate as a yellow oil (100mg, 22% over two steps).¹H NMR(400MHz,CDCl₃)7.38-7.28(m,5H),5.26-4.97(m,3H),4.51(s,1H),3.98-3.76(m,1H),3.43-3.06(m,2H),2.17(s,1H),1.96-1.77(m,3H),1.58(s, 3H). No displaceable groups were observed.

Intermediate 3043 a-methyl-6- (2-methyl-4-nitro-pyrazol-3-yl) -3,4,5,7,8,8 a-hexahydroxyoxazolo [4,5-d ] azepin-2-one

3 a-methyl-2-oxo-3, 4,5,7,8,8 a-hexahydroxyoxazolo [4,5-d ] under nitrogen]Benzyl azepin-6-carboxylate (305mg,1.0mmol) and 1-methyl-1, 4-cyclohexadiene (1.1mL,10.00mmol) in EtOH (10mL) was added 10% palladium on carbon (53mg,0.50mmol) and the mixture was heated at 60 ℃ for 2 h. The mixture was cooled to room temperature and filteredFiltered and concentrated under reduced pressure. To a solution of the residue (170mg,1.00mmol) in DMSO (5mL) was added 5-chloro-1-methyl-4-nitro-pyrazole (178mg,1.10mmol) and potassium fluoride (232mg,4.00mmol) and the mixture was heated in a microwave at 110 ℃ for4 h. The reaction was quenched with water (20mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification by chromatography on silica gel (0-5% MeOH/DCM) gave a yellow solid (220mg, 74%, over two steps). This material was combined in another batch to give 350mg for preparative HPLC on reversed phaseThe diastereoisomers are separated. The major diastereomer was isolated as a yellow solid (196mg, 67% over two steps).¹H NMR (400MHz, d6-DMSO)8.11(s,1H),7.72(s,1H),4.48(dd, J ═ 6.6,2.7Hz,1H),3.74(s,3H),3.10-3.01(m,2H),2.20-1.96(m,3H),1.85(dd, J ═ 15.2,7.8Hz,1H),1.32(s, 3H). Two protons are under the water peak. LCMS (ES +) M/z296(M +1).

Intermediate 3058- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-dioxaspiro [4.5] decan-8-ol

Starting from 1-methyl-4-nitro-1H-pyrazole and 1, 4-cyclohexanedione monoacetal, following the procedure of intermediate 218, 8- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-dioxaspiro [4.5] spiro]Decan-8-ol as a pale beige solid (3.68g, 83%).¹H NMR(400MHz,CDCl₃)8.06(s,1H),4.45(s,1H),4.12(s,3H),4.04-3.93(m,4H),2.44-2.34(m,2H),2.23-1.95(m,4H),1.75-1.67(m,2H).

Intermediate 3064-fluoro-4- (2-methyl-4-nitro-pyrazol-3-yl) cyclohexanone

To 8- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-dioxaspiro [4.5] under nitrogen]A solution of decan-8-ol (3.68g,13.0mmol) in anhydrous DCM (80mL) was added dropwise(50% in THF, 14.1mL,39.0 mmol). The reaction mixture was stirred at room temperature for 1 hour. After cooling to 0 ℃ saturated NaHCO was first added dropwise₃Aqueous solution (100mL) and the mixture extracted with DCM (2 × 75 mL). The combined organic layers were over MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (30-50% EtOAc/isohexane) afforded a light yellow oil. A portion of this oil (780mg,2.74 mmol)) Dissolved in THF (20mL) and treated with 2M aqueous HCl (3 mL). The reaction mixture was stirred at room temperature for4 hours, heated at 60 ℃ for 7 hours, and stirred at room temperature for 18 hours. Water (10mL) was added and the mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine (20mL), separated, and MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (25-40% EtOAc/isohexane) afforded 4-fluoro-4- (2-methyl-4-nitro-pyrazol-3-yl) cyclohexanone as a white solid (490mg, 30%, over two steps).¹H NMR(400MHz,CDCl₃)8.10and8.09(2s,1H),4.17and4.15(2s,3H),3.16-2.94(m,2H),2.84-2.72(m,2H),2.51(dd,J＝15.4,5.6Hz,2H),2.43-2.33(m,2H).

Intermediate 307 tert-butyl N- [ [ 4-fluoro-1-hydroxy-4- (2-methyl-4-nitro-pyrazol-3-yl) cyclohexyl ] methyl ] carbamate

Sodium hydride (60% dispersion in mineral oil, 183mg,4.56mmol) was added in portions to anhydrous DMSO (15mL) at 0 ℃ under nitrogen. The reaction mixture was warmed to room temperature and stirred for 15 minutes, then trimethylsulfonium iodide (0.96g,4.36mmol) was added in portions. After stirring at room temperature for 90 minutes, a solution of 4-fluoro-4- (2-methyl-4-nitro-pyrazol-3-yl) cyclohexanone (1.0g,4.15mmol) in DMSO (15mL) was added dropwise. The mixture was heated at 55 ℃ for 2h, cooled to room temperature, poured into water (200mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were over MgSO₄Dried and concentrated under reduced pressure to give a gum. The gum (1.1g,4.15mmol) was placed in 7M NH₃The solution in (5) was stirred in MeOH (30mL) and DCM (10mL) for4 days at room temperature. The solvent was removed under reduced pressure and the resulting yellow oil (1.1g,4.15mmol) was dissolved in DCM (30mL) and DIPEA (3.6mL),20.7 mmol). The solution was treated with a solution of di-tert-butyl dicarbonate (1.1g,4.98mmol) in DCM (20mL) and the reaction mixture was stirred at room temperature for 18 h. Water (20mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purifying by silica gel column chromatography (50% EtOAC/gasoline 40-60) to obtain N- [ [ 4-fluoro-1-hydroxy-4- (2-Methyl-4-nitro-pyrazol-3-yl) cyclohexyl]Methyl radical]Tert-butyl carbamate as a milky foam (858mg, 56% in three steps).¹H NMR(400MHz,CDCl₃)8.07and8.06(2s,1H),5.05-4.95(m,1H),4.09and4.07(2s,3H),3.21(d,J＝6.3Hz,2H),2.95-2.72(m,2H),2.54(s,1H),1.99-1.87(m,2H),1.85-1.65(m,4H),1.45(s,9H).

Intermediate 308 tert-butyl N- [ (4R) -6, 6-difluoro-4-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl ] carbamate

Intermediate 280 was further purified via chiral SFC to give N- [ (4R) -6, 6-difluoro-4-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl ] carbamic acid tert-butyl ester (first eluting isomer) (440mg) ee 100%. LCMS (ES +) M/z412(M +23).

Intermediate 309 tert-butyl N- [ (4S) -6, 6-difluoro-4-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl ] carbamate

Following the procedure for intermediate 308, further elution provided tert-butyl N- [ (4S) -6, 6-difluoro-4-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl ] carbamate (second eluting isomer) (430mg) ee 93%. LCMS (ES +) M/z412(M +23).

Intermediate 310 tert-butyl N- [4- [ [5- [ (5R) -5- (tert-butoxycarbonylamino) -3, 3-difluoro-5-methyl-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] carbamoyl ] -2- (2, 6-difluorophenyl) thiazol-5-yl ] carbamate

Following the procedure for intermediate 269, starting from N- [ (4R) -6, 6-difluoro-4-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl]Starting from tert-butyl carbamate, N- [4- [ [5- [ (5R) -5- (tert-butoxycarbonylamino) -3, 3-difluoro-5-methyl-azepan-1-yl)]-1-methyl-pyrazol-4-yl]Carbamoyl radical]-2- (2, 6-difluorophenyl) thiazol-5-yl]Tert-butyl carbamate as a light brown solid (210mg, 57%) ee 98.6%.¹H NMR(400MHz,CDCl₃)10.39(s,1H),8.79(s,1H),7.88(s,1H),7.45-7.30(m,1H),7.15-7.00(m,2H),5.12(br s,1H),3.78(s,3H),3.75-3.40(m,2H),3.35-3.10(m,2H),2.70-2.45(m,2H),2.40-2.15(m,1H),1.95-1.70(m,1H),1.55(s,9H),1.46(s,3H),1.33(s,9H).

Intermediate 311 tert-butyl N- [4- [ [5- [ (5S) -5- (tert-butoxycarbonylamino) -3, 3-difluoro-5-methyl-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] carbamoyl ] -2- (2, 6-difluorophenyl) thiazol-5-yl ] carbamate

Following the procedure of intermediate 269, starting from N- [ (4S) -6, 6-difluoro-4-methyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl]Starting from tert-butyl carbamate (intermediate 309) gave a pale brown solid (246 mg). It is further purified by chiral SFC to give N- [4- [ [5- [ (5S) -5- (tert-butoxycarbonylamino) -3, 3-difluoro-5-methyl-azepan-1-yl ] -e]-1-methyl-pyrazol-4-yl]Carbamoyl radical]-2- (2, 6-difluorophenyl) thiazol-5-yl]Tert-butyl carbamate as a light brown solid (190mg, 51%) ee 98.5%.¹H NMR(400MHz,CDCl₃)10.39(s,1H),8.79(s,1H),7.88(s,1H),7.45-7.30(m,1H),7.15-7.00(m,2H),5.12(br s,1H),3.78(s,3H),3.75-3.40(m,2H),3.35-3.10(m,2H),2.70-2.45(m,2H),2.40-2.15(m,1H),1.95-1.70(m,1H),1.55(s,9H),1.46(s,3H),1.33(s,9H).

Intermediate 3125- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6] non-8-ene

To a solution of zirconocene chloride (20.8g,71mmol) in THF (300mL) at-78 deg.C was added ethyl magnesium bromide (1M in THF, 142mL,142mmol) slowly and the mixture was stirred at-78 deg.C for 30 min then warmed to 0 deg.C. Stirring was continued until a red solution was obtained. The mixture was stirred for an additional 30 minutes. Tert-butyl 6-oxo-3, 7-dihydro-2H-azepine-1-carboxylate (15g,71mmol) in THF (100mL) was added slowly and the mixture warmed to room temperature and stirred for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in DCM (150 mL). Titanium tetrachloride (8mL,71mmol) was added and the mixture was stirred at room temperature for 16 h. Saturated ammonium chloride solution (100mL) was slowly added to the reaction mixture to give a white suspension. The layers were separated and the aqueous layer was extracted with DCM (3 × 200mL). The combined organic layers were washed with saturated NaHCO₃The aqueous solution (200mL) and brine (200mL) were washed over MgSO₄Dried and concentrated under reduced pressure. Chromatography on silica gel column (10-50% Et)₂O/isohexane) to afford the desired Boc-protected material. This was dissolved in DCM (50mL), TFA (10mL) was added and the mixture was taken up at 40 ℃ for4 h. The solvent was removed under reduced pressure to give the amine as trifluoroacetate salt. This was dissolved in DMSO (50mL) and DIPEA (6.2mL,35mmol), potassium fluoride (3.1g,19.1mmol) and 5-chloro-1-methyl-4-nitro-pyrazole (3.0g,19.1mmol) were added. The mixture was heated at 85 ℃ for 16 hours and then cooled to room temperature. The mixture was partitioned between water (50mL) and EtOAc (50mL), the aqueous layer was extracted with EtOAc (3X50mL) and the combined organics were washed with brine (50mL), separated, over MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel column chromatography (10-50% EtOAc/isohexane) afforded 5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6]Non-8-ene as an off-white solid (2.0g, 56%, over three steps).¹H NMR(400MHz,CDCl₃)8.00(s,1H),5.69(dt,J＝11.2,5.4Hz,1H),5.22-5.11(m,1H),3.82(s,3H),3.47-3.38(m,2H),3.18(s,2H),2.55-2.48(m,2H),0.72-0.61(m,4H).

Intermediate 3138-azido-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6] nonan-9-ol

To 5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6]A solution of non-8-ene (1.0g,4.1mmol) in DCM (25mL) was added m-CPBA (1.1g,4.8mmol) and the resulting mixture was stirred at room temperature for 16 h. Addition of saturated NaHCO₃Aqueous (15mL) and aqueous layer extracted with DCM (3 × 20 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (10-50%, EtOAc/isohexane) afforded the intermediate epoxide as a yellow solid. This was dissolved in DMSO (30mL) and acetic acid (3mL) and sodium azide was added. The mixture was heated at 110 ℃ for 16 hours after the explosion-proof barrier. After cooling to room temperature, the mixture was taken up in saturated NaHCO₃Partition between aqueous (10mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 × 20mL) and the combined organic layers were washed with brine (20mL), separated, over MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel column chromatography (10-50%, EtOAc/isohexane) afforded 8-azido-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [ 2.6%]Nonan-9-ol as a yellow gum (160mg, 54%, over two steps).¹H NMR(400MHz,CDCl₃)8.01(s,1H),3.80(s,3H),3.79-3.72(m,1H),3.55(dd,J＝7.4,2.4Hz,1H),3.51-3.34(m,1H),3.31-3.18(m,2H),2.92(d,J＝13.4Hz,1H),2.33-2.24(m,1H),2.20(d,J＝2.7Hz,1H),2.09-1.98(m,1H),1.00-0.94(m,1H),0.81-0.71(m,1H),0.53-0.44(m,2H).

Intermediate 3149-azido-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6] nonan-8-ol

According to the procedure of intermediate 313, 9-azido-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6] is also obtained]Nonan-8-ol was a yellow gum (350mg, 68%, over two steps).¹H NMR(400MHz,CDCl₃)8.02(s,1H),3.99-3.92(m,1H),3.79(s,3H),3.53-3.20(m,4H),2.76(d,J＝13.7Hz,1H),2.61(d,J＝5.9Hz,1H),2.35-2.15(m,1H),2.17-1.82(m,1H),0.94-0.73(m,2H),0.61-0.51(m,2H).

Intermediate 3158-azido-9-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6] nonane

To 8-azido-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6]A solution of nonan-9-ol (200mg,0.67mmol) in DCM (10mL) was added portionwise with Toiss-Martin oxidant (340mg,0.80 mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with DCM (50mL) and saturated NaHCO was added₃Aqueous (50mL) and the mixture extracted with DCM (50 mL). The combined organic layers were washed with brine (20mL), passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (10-50% EtOAc/isohexane) afforded the intermediate ketone. To a solution of this ketone (190mg,0.62mmol) in anhydrous THF (7mL) under nitrogen (cooled to-78 deg.C) was added dropwise a solution of lithium tri-sec-butylborohydride (L-selectride) (1M in THF, 0.8mL,0.78mmol) and the reaction mixture was stirred at-78 deg.C for 2 h. The mixture was warmed to room temperature and water (10mL) was added. The mixture was extracted with EtOAc (2 × 30mL) and the combined organic layers were washed with brine (20mL), over MgSO₄Drying and concentrating under reduced pressure to obtain intermediate alcohol. To a solution of the alcohol (160mg,0.52mmol) in anhydrous DMF (5mL) (cooled to 0 deg.C) was added sodium hydride (60% in mineral oil, 25mg,0.62 mmol). After stirring for 15 min, iodomethane (0.05mL,0.78mmol) was added and the reaction mixture was warmed to room temperature and stirred for 18 h. The mixture was concentrated under reduced pressure and the residue was partitioned between water (30mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (30mL) and the combined organic layers were washed with brine (20mL), separated, and over MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel column chromatography (10-50% EtOAc/isohexane) afforded 8-azido-9-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6]Nonane as an off-white solid (120mg, 55%, over three steps).¹H NMR(400MHz,CDCl₃)8.02(s,1H),3.84(s,3H),3.84-3.72(m,1H),3.58(s,3H),3.57-3.47(m,2H),3.22-3.15(m,1H),2.93(s,1H),2.40-2.28(m,1H),2.24(d,J＝12.5Hz,1H),2.07-1.91(m,1H),0.79-0.72(m,1H),0.67-0.46(m,3H).

Intermediate 3169-azido-8-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6] nonane

Following the procedure of intermediate 315, starting from 9-azido-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6]]Starting with nonan-8-ol to give 9-azido-8-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6]]Nonane as a yellow gum (170mg, 62%, over three steps).¹H NMR(400MHz,CDCl₃)8.02(s,1H),3.90(d,J＝13.4Hz,1H),3.84(s,2H),3.73-3.67(m,1H),3.45-3.36(m,1H),3.41(s,3H),3.28(s,1H),3.21-3.14(m,2H),2.32-2.15(m,2H),2.09-1.99(m,1H),0.82-0.74(m,1H),0.69-0.51(m,3H).

Intermediate 317N- [ 9-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6] nonan-8-yl ] carbamic acid tert-butyl ester

8-azido-9-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6]A solution of nonane (120mg,0.37mmol) in THF/water (5mL/1mL) was treated with trimethylphosphine (1.0M in toluene, 1.8mL,1.8mmol) and the reaction mixture was heated at 70 ℃ after an explosion-proof barrier for4 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was acidified with 1M aqueous HCl and washed with EtOAc (2 × 20 mL). The aqueous layer was basified with 6M NaOH acid solution to pH14 and extracted with DCM (2 × 30 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure to give a light brown gum. To a solution of the gum (80mg,0.27mmol) in anhydrous DCM (5mL) was added DIPE at 0 deg.CA (0.1mL,0.54mmol) was added followed by a solution of di-tert-butyl dicarbonate (90mg,0.41mmol) in DCM (5 mL). The reaction mixture was warmed to room temperature and stirred for4 hours. Water (5mL) was added and the mixture was extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (10mL), passed through a phase separation cartridge and concentrated under reduced pressure. Purification by column chromatography on silica gel (10-50% EtOAc/isohexane) afforded N- [ 9-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6]Non-8-yl]Tert-butyl carbamate as a yellow gum (110mg, 72%, over three steps).¹H NMR(400MHz,CDCl₃)8.00(s,1H),5.08(d,J＝8.9Hz,1H),3.97-3.86(m,2H),3.81(s,3H),3.60(ddd,J＝13.6,10.5,2.8Hz,1H),3.51(s,3H),3.12-3.04(m,1H),2.74(s,1H),2.16(d,J＝12.6Hz,1H),2.25-1.86(m,1H),1.95-1.85(m,1H),1.45(s,9H),0.77-0.57(m,4H).

Intermediate 318 tert-butyl N- [ 8-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6] non-9-yl ] carbamate

Following the procedure of intermediate 317, starting from 9-azido-8-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6]]Nonane to give N- [ 8-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6]Non-9-yl]Tert-butyl carbamate as a yellow gum (160mg, 67%, over two steps).¹H NMR(400MHz,CDCl₃)8.01(s,1H),5.12(d,J＝8.8Hz,1H),3.82(s,3H),3.68-3.57(m,2H),3.52-3.38(m,1H),3.36(s,3H),3.32(d,J＝12.7Hz,1H),3.21-3.14(m,1H),2.74(d,J＝12.8Hz,1H),2.13-1.88(m,2H),1.47(s,9H),0.91-0.81(m,1H),0.68-0.53(m,2H),0.43-0.36(m,1H).

Tables 1a and 1b Compounds of formula I101-531

Example 1015-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (4- ((methylamino) methyl) piperidin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 101

Intermediate tert-butyl 1, methyl ((1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-yl) methyl) carbamate (145mg,0.41mmol) in MeOH (40mL) was passed through(all H)₂50 ℃ C., flow rate 1 mL/min, 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give crude tert-butyl (1- (4-amino-1-methyl-1H-pyrazol-5-yl) piperidin-4-yl) methyl (methyl) carbamate as a red-brown oil (117 mg). To a solution of this amine (115mg,0.36mmol) in DCM (20mL) was added DIPEA (1.0mL), PyBOP (0.46g,0.89mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 (127mg,0.36mmol) and the mixture was stirred at rt for 18 h. The mixture was diluted with DCM (80mL) and washed with water (20 mL). The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (75% EtOAc/isohexane) gave tert-butyl (1- (4- (5-tert-butoxycarbonylamino-2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) piperidin-4-yl) methyl (methyl) carbamate as a pale purple foam (200 mg). The foam (200mg,0.30mmol) was stirred with HCl in1, 4-dioxane (4M,3.8mL,15.1mmol) in MeOH (5mL) for 3 days at room temperature. The solvent was removed under reduced pressure and the crude residue was redissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7N ammonia in MeOH to give 101 as a beige solid (99mg, 53% over three steps).¹H NMR(400MHz,d6-DMSO)8.75(s,1H),7.59-7.49(m,3H),7.44(s,1H),7.32-7.22(m,2H),6.90(br s,1H),3.63(s,3H),3.14-2.96(m,4H),2.66(d,J＝6.8Hz,2H),2.45(s,3H),1.77(d,J＝12.6Hz,2H),1.78-1.55(m,1H),1.36-1.22(m,2H)。LCMS(ES+)m/z462(M+1).

Example 102 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (3-methylpiperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 102

(±) -2-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperazine-1-carboxylic acid tert-butyl ester.

A mixture of 2-methylpiperazine (1g,6.2mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole from example 1 (2.48g,12.4mmol), DIPEA (2.4g,18.6mmol) in EtOH (10mL) was heated in a microwave at 140 ℃ for 5H. The solvent was removed under reduced pressure to give a residue. The residue was purified by silica gel chromatography using MeOH/DCM (10:1) as eluting solvent to give (±) -2-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperazine-1-carboxylic acid tert-butyl ester (1.0g, 40%) as a yellow solid.¹H NMR(500MHz,CDCl₃)(ppm):8.03(s,1H),4.38(s,1H),3.99-3.68(m,1H),3.83(s,3H),3.67-3.65(m,1H),3.46-3.41(m,1H),3.31-3.25(m,1H),2.90-2.88(d,J＝9.6Hz,1H),2.71-2.68(d,J＝9.2Hz,1H),1.49(s,9H),1.36-1.34(d,J＝5.2Hz,3H).

(±) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester.

To (±) -2-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperazine-1-carboxylic acid tert-butyl ester (500mg,1.54mmol) in MeOH (20mL) and H₂To a solution in O (5mL) were added zinc (845mg,13mmol) and NH₄Cl (1.4g,26 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and filtered through Celite. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography PE/EtOAc (10/1-1/10) as the eluting solvent to give (±) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (650mg,. about.100%) as a red solid.¹H NMR(500MHz,CD3OD)(ppm):7.22(s,1H),4.35-4.33(m,1H),4.12-4.11(m,1H),3.94(s,3H),3.43-3.46(m,1H),3.25-3.30(m,2H),3.01-3.00(m,1H),2.89-2.87(d,J＝12Hz,1H),1.49(s,9H),1.34-1.36(d,J＝5.6Hz,3H)；MS(ESI)m/z＝296(M+H+).

Step C. (±) -4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester.

To a solution of tert-butyl (±) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylate (400mg,2.05mmol), 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (630mg,2.46mmol), HATU (0.83g,8.19mmol) in DMF (15mL) was added TEA (1.5mL), the reaction mixture was stirred at 25 ℃ for 20 hours and poured into water (100mL), the mixture was extracted (50mL × 2) ·, the combined organic layers were washed with water (50mL × 2) and brine (30mL × 2), washed with Na₂SO₄Dried, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using DCM/MeOH (1:1) as the eluting solvent to give tert-butyl (±) -4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylate (280mg, 52%) as a white solid.¹H NMR(500MHz,CDCl₃)(ppm):10.32(s,1H),8.70(s,1H),7.80(s,1H),7.38-7.35(m,1H),7.06-7.03(m,2H),4.34(s,1H),3.94-3.97(m,1H),3.81(s,3H),3.67-3.40(m,1H),3.20-3.25(m,2H),3.04-3.06(m,1H),2.88-2.90(m,1H),1.55(s,9H),1.47(s,9H),1.34-1.36(d,J＝6.4Hz,3H)；MS(ESI)m/z＝434(M+H+).

Step d. (R) -tert-butyl 4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylate and (S) -tert-butyl 4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylate.

Chiral separation of (. + -.) -4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -2-methyl-piperazine-1-carboxylic acid tert-butyl ester (280mg) by using preparative HPLC to give (S) -4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (80mg) and (R) -4- (4- (5- (tert-butoxycarbonylamino) -2-methyl-1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester Tert-butyl- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylate (80 mg).

Step E. (R) -4- (4- (5- (tert-butoxy)A solution of aminocarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (80mg,0.126mmol) in TFA (1mL) and DCM (4mL) was stirred at ambient temperature for 3 hours. The mixture was adjusted to about pH 8-9 by adding ammonia and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give 102(40mg, 73%).¹H NMR(500MHz,CDCl₃)(ppm):8.48(s,1H),8.33(s,1H),7.69(s,1H),7.30-7.36(m,1H),7.03-7.07(m,2H),6.14-6.17(m,2H),3.78(s,3H),3.53-3.48(m,1H),2.90-3.34(m,6H),1.32(d,J＝6.5Hz,3H)；MS(ESI)m/z＝434(M+1+).

Example 103 (S) -5-amino-N- (5- (3-aminoazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 103

Chiral separation of the racemic mixture by SFC gave 103 as a single enantiomer.¹H NMR(400MHz,DMSO)7.77(s,1H),7.60-7.43(m,3H),7.27(dd,J＝14.5,5.8Hz,2H),6.39(tt,J＝55.3,4.2Hz,1H),4.54-4.28(m,2H),3.23-3.02(m,4H),3.00-2.90(m,2H),1.85-1.40(m,6H)。MS(ESI)m/z:498.2[M+H+]。

Example 104 (R) -5-amino-N- (5- (3-Aminoazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 104

Chiral separation of the racemic mixture by SFC gave 104 as a single enantiomer.¹H NMR(400MHz,DMSO)7.78(s,1H),7.60-7.42(m,3H),7.34-7.21(m,2H),6.39(tt,J＝55.3,4.1Hz,1H),4.54-4.29(m,2H),3.25-3.02(m,4H),3.00-2.90(m,2H),1.87-1.36(m,8H)。MS(ESI)m/z:498.2[M+H+]。

Example 1055-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 105

Intermediate 3,4- (4- (2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester (283mg,0.44mmol), Na₂CO₃A mixture of (93mg,0.88mmol) and 2-fluoro-5-methylphenylboronic acid (95mg,0.62mmol) in DME (4.9mL) and water (1.6mL) was degassed by gently bubbling nitrogen through the mixture for 10 minutes. Then [1,1' -bis (diphenylphosphino) ferrocene ] is added]Dichloro-palladium (II) (36mg,0.04mmol), and the mixture was degassed for a further 10 minutes and then heated in a microwave at 120 ℃ for 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in DCM (50mL) and washed with water (2 × 20 mL). The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (0-80% EtOAc/isohexane) to give 4- (4- (5-tert-butoxycarbonylamino-2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester (179mg) and 4- (4- (5-amino-2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester (50 mg). The isolated intermediates were combined and suspended in MeOH (2mL) and a solution of HCl in1, 4-dioxane (4M,1.7mL,6.75mmol) was added thereto and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was dissolved in EtOAc (50mL) and washed with 1M NaOH solution (20 mL). The residue was purified by column chromatography on silica gel (0-10% MeOH/DCM) to give 105 as a beige solid (59mg, 30% over two steps).¹H NMR(400MHz,CDCl₃)8.98(s,1H),7.90(dd,J＝7.0,2.5Hz,1H),7.80(s,1H),7.16-7.11(m,1H),7.09-7.01(m,1H),6.09(s,2H),3.77(s,3H),3.63(t,J＝13.5Hz,2H),3.46-3.29(m,4H),3.06(t,J＝5.5Hz,2H),2.39(s,3H),1.95(s,1H)。LCMS(ES+)m/z466(M+1).

Example 1065-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 106

In accordance with the operation of the embodiment 105,4- (4- (2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester and 2, 5-difluorophenylboronic acid reacted to give 106 as an off-white solid (57mg, 28% over two steps).¹H NMR(400MHz,CDCl₃)8.90(s,1H),7.88-7.81(m,2H),7.18-7.10(m,1H),7.06-6.99(m,1H),6.16(s,2H),3.78(s,3H),3.70-3.56(m,2H),3.44(t,J＝14.0Hz,2H),3.35(t,J＝5.5Hz,2H),3.11-3.05(m,2H),1.95(s,1H)。LCMS(ES+)m/z470(M+1).

Example 107 (R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4- (methylamino) azepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 107

To a solution of (R) -N- (1- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) azepan-4-yl) -2,2, 2-trifluoro-N-methylacetamide (100mg,0.28mmol) in DCM (10mL) were added DIPEA (0.5mL,2.87mmol), PyBOP (293mg,0.56mmol) and 5- (tert-butoxycarbonylamino) -2-cyclopropylthiazole-4-carboxylic acid (125mg,0.35mmol) and the mixture was stirred at room temperature for 20 hours. The mixture was diluted with DCM (50mL) and washed with water (10 mL). The organic layer was separated by a phase separation cartridge and the solvent was removed under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) gave (R) -tert-butyl 4- (1- (2, 2-difluoroethyl) -5- (4- (2,2, 2-trifluoro-N-methylacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-ylcarbamate as a light yellow solid (172 mg). The gum (170mg,0.24mmol) was strained in HCl in1, 4-dioxane (4M,5mL) and MeOH (5mL) at50 ℃ for4 h. The solvent and residue were removed under reduced pressure and purified by preparative HPLC to give 107 as the mono-formate salt as a white solid (62mg, 41% over two steps).¹H NMR(400MHz,d4-MeOD)8.56(s,1H),7.72(s,1H),7.49(tt,J＝8.5,6.2Hz,1H),7.20-7.12(m,2H),6.24(tt,J＝55.5,4.2Hz,1H),4.48(td,J＝14.0,4.2Hz,2H),3.40-3.20(m,5H),2.68(s,3H),2.28-1.74(m,6H)。LCMS(ES+)m/z512(M+1).

Example 108 (R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4- (methylamino) azepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 108

(R) -tert-butyl 2-bromo-4- (1- (2, 2-difluoroethyl) -5- (4- (2,2, 2-trifluoro-N-methylacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (200mg,0.29mmol), Na₂CO₃A mixture of (62mg,0.59mmol) and 2, 5-difluorophenylboronic acid (66mg,0.41mmol) in DME (3mL) and water (1mL) was degassed by gently bubbling nitrogen through the mixture for 5 minutes. Then [1,1' -bis (diphenylphosphino) ferrocene ] is added]Dichloro-palladium (II) (30mg,0.037mmol) and the mixture was heated in a microwave at 120 ℃ for 60 minutes. The solvent was removed under reduced pressure and the residue was dissolved in HCl in1, 4-dioxane (4M,5mL) and MeOH (5mL) and stirred at 70 ℃ for 48 hours. The solvent was removed under reduced pressure, and the residue was dissolved in MeOH/DCM and passed through an SCX cartridge, washed with DCM and MeOH and eluted with 1N ammonia (in MeOH). The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 108 as the mono-formate salt as a light brown solid (21mg, 14% over two steps).¹H NMR(400MHz,d4-MeOD)8.53(s,1H),8.15-7.95(m,1H),7.58(s,1H),7.35-7.05(m,2H),6.25(tt,J＝55.6,4.1Hz,1H),4.54-4.43(m,2H),3.43-3.22(m,5H),2.68(s,3H),2.28-1.74(m,6H)。LCMS(ES+)m/z512(M+1).

Example 109 (R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4- (methylamino) azepan-1-yl) -1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 109

Following the procedure of example 108, (R) -tert-butyl 2-bromo-4- (1- (2, 2-difluoroethyl) -5- (4- (2,2, 2-trifluoro-N-methylacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (200mg,0.29mmol) and 2-fluoro-5-methylbenzeneboronic acid (63mg,0.41mmol) were reacted to give 109 as a monoformate salt as a light brown solid (67mg, 45% over two steps).¹H NMR(400MHz,d4-MeOD)8.56(s,1H),8.07(dd,J＝7.3,2.2Hz,1H),7.61(s,1H),7.26-7.20(m,1H),7.12(dd,J＝11.4,8.4Hz,1H),6.25(tt,J＝55.6,4.2Hz,1H),4.48(td,J＝13.9,4.2Hz,2H),3.41-3.33(m,3H),3.30-3.13(m,2H),2.58(s,3H),2.40(s,3H),2.23-1.72(m,6H)。LCMS(ES+)m/z508(M+1).

Example 1105-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 110

To a solution of 1- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) azepan-4-ol (100mg,0.39mmol) in DCM (20mL) was added DIPEA (0.5mL,2.87mmol), PyBOP (300mg,0.58mmol) and 5- (tert-butoxycarbonylamino) -2-cyclopropylthiazole-4-carboxylic acid (164mg,0.46mmol) and the mixture was stirred at room temperature for 18H. The mixture was diluted with DCM (100mL) and washed with water (20 mL). The organic layer was separated by a phase separation cartridge and the solvent was removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 4- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-ylcarbamate as a colorless solid (145 mg). The solid (145mg,0.24mmol) was stirred in HCl in1, 4-dioxane (4M,5mL) at room temperature for 20 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 110 as a milky solid (80mg, 44% over two steps).¹H NMR(400MHz,d4-MeOD)7.81(s,1H),7.46(tt,J＝8.5,6.2Hz,1H),7.19-7.11(m,2H),6.22(tt,J＝55.6,4.2Hz,1H),4.45(td,J＝13.9,4.2Hz,2H),4.01-3.93(m,1H),3.32-3.15(m,5H),2.10-1.90(m,3H),1.87-1.65(m,3H)。LCMS(ES+)m/z499(M+1).

Example 1115-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 111

EXAMPLE 105 procedure from 2-bromo-4- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazole-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester (0.13g,0.23mmol) and 2-fluoro-5-methylbenzeneboronic acid (53mg,0.35mmol) were started to give 111 as a black solid (56mg, 50% over two steps).¹H NMR(400MHz,d6-DMSO)8.93(s,1H),8.08(d,J＝7.4Hz,1H),7.66(s,1H),7.42(s,2H),7.24(d,J＝8.7Hz,2H),6.39(tt,J＝55.3,4.2Hz,1H),4.55(d,J＝3.8Hz,1H),4.42(td,J＝14.5,4.2Hz,2H),3.86-3.80(m,1H),3.29-3.03(m,4H),2.37(s,3H),1.94-1.84(m,3H),1.77-1.55(m,3H)。LCMS(ES+)m/z495(M+1).

Example 112 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (2-methylpiperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 112

A solution of PyBOP (313mg,0.60mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 (153mg,0.43mmol) in DCM (10mL) was stirred at room temperature for 30 min. A solution of (R) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (133mg,0.45mmol) and DIPEA (0.12mL,0.68mmol) in DCM (10mL) was added and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM (50mL) and washed with water (20 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. The isolated intermediate was redissolved in DCM (6mL) and TFA (2mL) was added. The mixture was stirred at room temperature for4 hours. The mixture was concentrated under reduced pressure and the residue was redissolved in DCM (50mL) and saturated NaHCO₃Aqueous washes (2 × 10 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification by preparative HPLC gave 112 as a white solid (41mg, 22% over two steps).¹H NMR(400MHz,CDCl₃)8.66(s,1H),7.92(s,1H),7.38-7.25(m,1H),7.03(t, J ═ 9.0Hz,2H),6.20(s,2H),3.77(s,3H),3.27-3.15(m,2H),3.10-2.93(m,4H),2.59(dd, J ═ 12.5,9.5Hz,1H),0.88(d, J ═ 6.3Hz,3H). No alkyl NH was observed. LCMS (ES +) M/z434(M +1).

Example 113 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2-ethylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 113

Following the procedure of example 112, tert-butyl (S) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-ethylpiperazine-1-carboxylate and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 were reacted to give 113 as a white solid (27mg, 19% over two steps).¹H NMR(400MHz,CDCl₃)8.68(s,1H),7.91(s,1H),7.31(t, J ═ 7.7Hz,1H),7.03(t, J ═ 9.2Hz,2H),6.20(s,2H),3.77(s,3H),3.24 to 3.14(m,2H),3.12 to 2.93(m,4H),2.60(t, J ═ 10.8Hz,1H),1.48 to 1.28(m,1H),1.28 to 1.16(m,1H),0.79(t, J ═ 7.6Hz,3H). LCMS (ES +) M/z448(M +1).

Example 114 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2-ethylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 114

Following the procedure of example 112, tert-butyl (R) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-ethylpiperazine-1-carboxylate and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 were reacted to give 114 as a white solid (30mg, 21% over two steps).¹H NMR(400MHz,CDCl₃)8.68(s,1H),7.91(s,1H),7.36-7.27(m,1H),7.02(t, J ═ 8.9Hz,2H),6.24(s,2H),3.76(s,3H),3.25-3.15(m,2H),3.11-2.90(m,4H),2.58(t, J ═ 5.5Hz,1H),1.41-1.31(m,1H),1.28-1.14(m,1H),0.79(t, J ═ 7.5Hz,3H). LCMS (ES +) M/z448(M +1).

Example 115 (R) -5-amino-N- (5- (4-aminoazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-cyclopropyl-2, 6-difluorophenyl) thiazole-4-carboxamide 115

Step A. tert-butyl 2- (5-cyclopropyl-2-fluorophenyl) -4- (1-methyl-5- (4- (benzyloxycarbonylamino) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate

Tert-butyl 2- (5-chloro-2-fluorophenyl) -4- (1-methyl-5- (4- (benzyloxycarbonylamino) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (309mg,0.44mmol), potassium cyclopropyltrifluoroborate (98mg,0.66mmol), palladium acetate (20.0mg,0.088mmol), butyl-di-1-adamantylphosphine (50.1mg,0.133mmol), and cesium carbonate (437mg,1.33mmol) were charged to a 40mL reaction vial and flushed under vacuum with nitrogen three times. Toluene (10.8mL) and water (1.2mL) were added and the mixture was heated at 105 ℃ for four days and monitored by LCMS. The reaction was filtered through Celite and washed thoroughly with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with 0-100% ethyl acetate/heptane, to give tert-butyl 2- (5-cyclopropyl-2-fluorophenyl) -4- (1-methyl-5- (4- (benzyloxycarbonylamino) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (192mg, 62%).

Step B. removal of Cbz and Boc groups from tert-butyl 2- (5-cyclopropyl-2-fluorophenyl) -4- (1-methyl-5- (4- (benzyloxycarbonylamino) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate gave 115.¹H NMR(400MHz,DMSO)8.83(br,1H),7.59(s,1H),7.48(br,2H),7.20-7.05(m,2H),3.65(d,J＝4.6Hz,3H),3.18-3.04(m,4H),3.3.05-2.95(m,1H),2.1.-2.02(m,1H),1.85-1.75(m,3H),1.68-1.43(m,3H),0.98(dt,J＝8.4,3.1Hz,2H),0.79-0.68(m,2H)。MS(ESI)m/z:488.2[M+H+]。

Example 116 (R) -5-amino-N- (5- (4-Aminoazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluoro-3-methylphenyl) thiazole-4-carboxamide 116

Compound 116 was prepared according to the procedure in example 115.¹H NMR(400MHz,DMSO)8.81(s,1H),7.58(s,1H),7.47(s,2H),7.40(dd,J＝15.0,8.5Hz,1H),7.17(t,J＝9.3Hz,1H),3.64(s,3H),3.19-2.93(m,5H),2.27(s,3H),1.93-1.72(m,3H),1.67-1.43(m,3H)。MS(ESI)m/z:462.2[M+H+]。

Example 117 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (3-methylpiperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 117

Following the procedure of example 102, (S) -4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester reacted to give 117 as a white solid (40mg, 73%).¹H NMR(500MHz,DMSO-d6)(ppm):8.81(s,1H),8.17(s,1H),7.51-7.57(m,3H),7.36(s,1H),7.25-7.29(m,2H),3.65(s,3H),3.17-3.19(m,3H),2.91-3.14(m,4H),1.10(d,J＝5.2Hz,3H)；MS(ESI)m/z＝434(M+1+).

Example 1185-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 118

Following the procedure of example 105, tert-butyl 2-bromo-4- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (130mg,0.23mmol) and 2, 5-difluorophenylboronic acid (55mg,0.35mmol) reacted to give 118 as a dark green solid (66mg, 57% in two steps).¹H NMR(400MHz,d4-MeOD)8.10-8.00(m,1H),7.68(s,1H),7.30-7.20(m,1H),7.19-7.11(m,1H),6.24(tt,J＝55.6,4.2Hz,1H),4.51-4.40(m,2H),4.01-3.92(m,1H),3.45-3.30(m,2H),3.31-3.16(m,3H),2.13-1.91(m,2H),1.90-1.67(m,2H)。LCMS(ES+)m/z499(M+1).

Example 119 (S) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4- (methylamino) azepan-1-yl) -1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 119

Following the procedure of example 108, (R) -2-bromo-4- (1- (2, 2-difluoroethyl) -5- (4- (2,2, 2-trifluoro-N-methylacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbam meAcyl) Thiazol-5-ylcarbamic acid tert-butyl ester (80mg,0.12mmol) and 2-fluoro-5-methylbenzeneboronic acid (30mg,0.20mmol) reacted to give 119 as the monoformate salt as a pale pink solid (11mg, 19% over two steps).¹H NMR(400MHz,d4-MeOD)8.56(s,1H),8.08(dd,J＝7.3,2.2Hz,1H),7.60(s,1H),7.26-7.20(m,1H),7.12(dd,J＝11.4,8.4Hz,1H),6.41-6.08(m,1H),4.54-4.43(m,2H),3.40-3.33(m,3H),3.32-3.24(m,2H),2.64(s,3H),2.41(s,3H),2.33-1.94(m,3H),1.91-1.76(m,3H)。LCMS(ES+)m/z508(M+1).

Example 1205-amino-N- (5- (4-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 120

To a solution of intermediate 17,2,2, 2-trifluoro-N- (3-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide (70mg,0.20mmol) and ammonium formate (101mg,1.60mmol) in MeOH (5mL) was added 10% palladium on carbon (21mg,0.20mmol) under nitrogen. The mixture was heated at 70 ℃ for 3 hours, then cooled, filtered and concentrated under reduced pressure. The residue was partitioned between water (10mL) and DCM (50 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide as a red gum (64 mg). A solution of PyBOP (146mg,0.28mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 (78mg,0.22mmol) in DCM (3mL) was stirred at room temperature for 30 min. A solution of N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide (65mg,0.20mmol) and DIPEA (56 μ L,0.32mmol) in DCM (2mL) was added and the mixture stirred at room temperature for 30H. Additional DCM (50mL) was added and the mixture was washed with water (20 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Chromatography on silica gel column (0-100% Et)₂O/DCM) to give 2- (2, 6-difluorophenyl) -4- (5- (3-fluoro-4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester as a racemic mixture of four diastereomers as a white solid(82mg) form. The solid was redissolved in a mixture of DCM (12mL) and TFA (2mL) and the mixture was stirred at rt for4 h. The solvent was removed under reduced pressure. The residue was then redissolved in 7N ammonia (in MeOH (20 mL)) and heated at 55 ℃ for 24 hours. The solvent was removed under reduced pressure and purified by silica gel column chromatography (0-5% 7N ammonia in MeOH/DCM) to give two separate enantiomeric pairs of tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (3-fluoro-4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate. One of the enantiomeric pairs 120 was obtained as a white solid (41 mg).¹HNMR(400MHz,d4-MeOD)7.60(s,1H),7.53-7.43(m,1H),7.15(t,J＝8.8Hz,2H),4.48-4.30(m,1H),3.83-3.72(m,3H),3.57(d,J＝4.4Hz,1H),3.59-3.45(m,1H),3.37-3.29(m,2H),3.14(td,J＝11.4,5.2Hz,1H),1.95-1.84(m,3H),1.82-1.71(m,1H)。LCMS(ES+)m/z466(M+1).

Example 1215-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 121

Following the procedure of example 101, intermediate 19, 6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester, after dissolution in 5% MeOH/DCM (350mL), was purified by saturated NaHCO₃Washed (50mL) with water (4x50mL) and the solvent removed under reduced pressure to give 121 as a beige solid (1.1g, 34% over three steps).¹H NMR(400MHz,d6-DMSO)8.83(s,1H),7.57-7.47(m,4H),7.31-7.22(m,2H),3.78-3.45(m,4H),3.45-3.02(m,3H),2.25-2.06(m,2H),1.92-1.55(m,5H)。LCMS(ES+)m/z484(M+1).

Example 1225-amino-N- (5- ((3S,5S) -5-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 122

Following the procedure of example 101, intermediate 20, 6-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylaminoTert-butyl benzoate and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 gave, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7N ammonia in MeOH), a white solid (93mg, 7% over three steps). Chiral separation of the racemic mixture from SFC afforded compound 122 as a single enantiomer.¹HNMR(400MHz,CDCl₃)8.51(s,1H),7.88(s,1H),7.38-7.28(m,2H),7.08-6.98(m,3H),6.18-6.07(m,2H),4.83-4.66(m,1H),4.30-4.21(m,1H),4.16-4.09(m,1H),3.74(s,3H),3.40-3.16(m,3H),3.11(m,1H),2.98-2.89(m,1H),1.95-1.76(m,2H)。LCMS(ES+)m/z466(M+1).

Example 123 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (2-methylpiperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 123

Following the procedure of example 112, starting from (S) -4- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acid tert-butyl ester, 123 was obtained as a white solid (61mg, 32% over two steps).¹H NMR(400MHz,CDCl₃)8.66(s,1H),7.92(s,1H),7.34-7.27(m,1H),7.03(t, J ═ 8.8Hz,2H),6.11(s,2H),3.77(s,3H),3.28-3.16(m,2H),3.08-2.93(m,4H),2.59(dd, J ═ 12.4,9.5Hz,1H),0.88(d, J ═ 6.3Hz,3H). LCMS (ES +) M/z434(M +1).

Example 1245-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (2, 8-diazaspiro [4.5] decan-8-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 124

Following the procedure of example 101, from 8- (1-methyl-4-nitro-1H-pyrazol-5-yl) -2, 8-diazaspiro [4.5]]Silane-2-carboxylic acid tert-butyl ester to give 124 as a beige solid (140mg, 47% over three steps).¹H NMR(400MHz,d6-DMSO)¹H NMR8.85(br s,1H),8.81(s,1H),7.61-7.45(m,4H),7.29(t,J＝8.8Hz,2H),3.64(s,3H),3.22(t,J＝7.5Hz,2H),3.14-2.96(m,6H),1.81(t,J＝7.5Hz,2H),1.73-1.60(m,4H)。LCMS(ES+)m/z474(M+1).

Example 1255-amino-N- (5- (4-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 125

Following the procedure of example 121, enantiomer pair 125 was also given as an off-white solid (37 mg).¹H NMR(400MHz,d4-MeOD)7.73(s,1H),7.53-7.41(m,1H),7.14(t,J＝8.8Hz,2H),4.78-4.56(m,1H),3.75(s,3H),3.55(t,J＝15.3Hz,1H),3.51-3.31(m,2H),3.20-2.97(m,2H),2.14(q,J＝12.2Hz,1H),2.05-1.83(m,1H),1.78-1.69(m,2H)。LCMS(ES+)m/z466(M+1).

Example 1265-amino-N- (5- ((3R,5R) -5-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 126

Following the procedure of example 101, starting from intermediate 20, 6-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7N ammonia in MeOH), a white solid was obtained (273mg, 19% over three steps). Chiral separation of the racemic mixture from SFC affords compound 126 as a single enantiomer.¹H NMR(400MHz,CDCl₃)8.52(s,1H),7.80(s,1H),7.37-7.28(m,2H),7.08-6.98(m,3H),6.13(s,2H),4.83-4.78and4.72-4.68(2m,1H),3.79-3.72(m,3H),3.54-3.30(m,3H),3.24-3.12(m,2H),2.31-2.22(m,1H),2.18-2.07(m,1H),1.93-1.76(m,2H)。LCMS(ES+)m/z466(M+1).

Example 1275-amino-N- (5- ((3S,5R) -3-amino-5-fluoropiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 127

(3S,5R) -1- (4- (5- (tert-Butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acidA mixture of tert-butyl amine) -1-methyl-1H-pyrazol-5-yl) -5-fluoropiperidin-3-ylcarbamate (100mg,0.15mmol) in HCl/MeOH (10mL) was stirred at ambient temperature for 20 hours and concentrated under reduced pressure to give a residue. The residue was diluted with MeOH (10mL), neutralized with 28% ammonia solution, and concentrated to give the crude product. The crude product was purified by preparative HPLC to give 127(40mg, 59%).¹H-NMR(500MHz,CD3OD)(ppm):7.51-7.49(m,2H),7.17-7.12(m,2H),4.95-4.86(m,2H),3.75(s,3H),3.31-3.25(m,3H),2.97-2.90(m,1H),2.31-2.23(m,1H),1.64-1.48(m,1H)；MS(ESI)m/z:452[M+H+]。

Example 128N- (5- (1, 4-Diazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -5-amino-2- (2, 6-difluorophenyl) thiazole-4-carboxamide 128

Removal of the Boc group from 4- (4- (5-amino-2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1- (oxetan-3-ylmethyl) -1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester in 1:1 dichloromethane: TFA gave 128.¹H NMR(400MHz,DMSO)11.57(s,1H),8.57(s,1H),7.65(s,2H),7.61-7.43(m,1H),7.29(t,J＝8.7Hz,2H),5.21-5.03(m,1H),4.58-4.36(m,2H),4.26-4.04(m,2H),3.59(s,2H),3.46-3.36(m,2H),2.98(t,J＝6.1Hz,2H),2.79(t,J＝5.7Hz,2H),1.60-1.40(m,2H)。MS(ESI)m/z:490.2[M+H+]。

Example 129N- (5- (1, 4-diazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -5-amino-2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 129

Removal of the Boc group from 4- (4- (5-amino-2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide) -1- (oxetan-3-ylmethyl) -1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester in 1:1 dichloromethane: TFA afforded 129.¹H NMR(400MHz,DMSO)10.78(s,1H),8.49(s,1H),8.41(s,2H),7.90(d,J＝7.4Hz,1H),7.55(s,2H),7.26(d,J＝9.0Hz,2H),4.61-4.42(m,2H),4.27-4.11(m,2H),3.70-3.54(m,2H),3.00(t,J＝5.4Hz,2H),2.84(t,J＝5.5Hz,2H),2.36(s,3H),1.71-1.57(m,2H)。MS(ESI)m/z:486.2[M+H+]。

Example 130N- (5- (1, 4-Diazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -5-amino-2- (2, 5-difluorophenyl) thiazole-4-carboxamide 130

Removal of the Boc group from 4- (4- (5-amino-2- (2, 5-difluorophenyl) thiazole-4-carboxamide) -1- (oxetan-3-ylmethyl) -1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester in 1:1 dichloromethane: TFA afforded 130.¹H NMR(400MHz,DMSO)10.43(s,1H),8.42(s,1H),8.36(s,2H),8.06-7.94(m,1H),7.60(s,2H),7.51-7.37(m,1H),7.36-7.24(m,1H),4.56(dd,J＝10.5,8.2Hz,1H),4.47(dd,J＝11.2,8.1Hz,1H),4.25(dd,J＝10.7,5.5Hz,1H),4.18(dd,J＝11.2,5.7Hz,1H),3.60-3.36(m,7H),2.94(t,J＝5.5Hz,2H),2.83-2.74(m,2H),1.75-1.56(m,2H)。MS(ESI)m/z:486.2[M+H+]。

Example 131 (R) -5-amino-2- (2-fluorophenyl) -N- (5- (4-hydroxy-4-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 131

Chiral separation of the racemic mixture by SFC gave 131 as a single enantiomer.¹H NMR(400MHz,DMSO)8.85(s,1H),8.33-8.20(m,1H),7.53(s,1H),7.50-7.24(m,5H),4.24(s,1H),3.65(s,3H),3.43-3.32(m,1H),3.28-3.17(m,1H),3.11-2.98(m,1H),2.96-2.83(m,1H),2.05-1.88(m,1H),1.84-1.64(m,4H),1.63-1.45(m,1H),1.17(s,3H)。MS(ESI)m/z:445.2[M+H+]。

Example 132 (S) -5-amino-2- (2-fluorophenyl) -N- (5- (4-hydroxy-4-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 132

Chiral separation of the racemic mixture by SFC gave 132 as a single enantiomer.¹H NMR(400MHz,DMSO)8.85(s,1H),8.33-8.22(m,1H),7.53(s,1H),7.50-7.23(m,5H),4.24(s,1H),3.65(s,3H),3.42-3.33(m,1H),3.27-3.19(m,1H),3.11-2.98(m,1H),2.96-2.80(m,1H),2.06-1.89(m,1H),1.80-1.63(m,4H),1.63-1.47(m,1H),1.17(s,3H)。MS(ESI)m/z:445.2[M+H+]。

Example 133 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (5- (trifluoromethyl) -1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 133

Chiral separation of the racemic mixture by SFC gave 133 as a single enantiomer.¹H NMR(400MHz,DMSO)11.98(s,1H),7.90(s,1H),7.64-7.39(m,3H),7.37-7.21(m,2H),3.62(s,3H),3.22-2.97(m,6H),2.89(dd,J＝14.6,10.5Hz,1H),2.79-2.60(m,1H),2.25(dd,J＝12.4,10.6Hz,1H),1.83-1.59(m,1H),0.68(d,J＝6.7Hz,3H)。MS(ESI)m/z:448.2[M+H+]。

Example 134 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (5- (trifluoromethyl) -1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 134

Chiral separation of the racemic mixture by SFC gave 134 as a single enantiomer.¹H NMR(400MHz,DMSO)11.98(s,1H),7.90(s,1H),7.64-7.39(m,3H),7.37-7.21(m,2H),3.62(s,3H),3.22-2.97(m,6H),2.89(dd,J＝14.6,10.5Hz,1H),2.79-2.60(m,1H),2.25(dd,J＝12.4,10.6Hz,1H),1.83-1.59(m,1H),0.68(d,J＝6.7Hz,3H)。MS(ESI)m/z:448.2[M+H+]。

Example 135 (S) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 135

Chiral separation of the racemic mixture by SFC gave 135 as a single enantiomer.¹H NMR(400MHz,DMSO)8.69(s,1H),7.69(s,1H),7.59-7.43(m,3H),7.27(t,J＝8.7Hz,2H),6.37(tt,J＝55.3,4.1Hz,1H),4.41(td,J＝14.5,4.1Hz,2H),3.79(d,J＝7.8Hz,1H),3.24-2.94(m,4H),1.96-1.75(m,3H),1.73-1.48(m,3H)。MS(ESI)m/z:499.1[M+H+]。

Example 136 (R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 136

Chiral separation of the racemic mixture by SFC gave 136 as a single enantiomer.¹H NMR(400MHz,DMSO)8.69(s,1H),7.69(s,1H),7.58-7.42(m,3H),7.27(t,J＝8.7Hz,2H),6.37(tt,J＝55.3,4.0Hz,1H),4.47(d,J＝3.8Hz,1H),4.40(td,J＝14.5,4.1Hz,2H),3.87-3.72(m,1H),3.23-2.94(m,4H),1.92-1.76(m,3H),1.73-1.46(m,3H)。MS(ESI)m/z:499.1[M+H+]。

Example 137 (S) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 137

Chiral separation of the racemic mixture by SFC gave 137 as a single enantiomer.¹H NMR(400MHz,DMSO)8.91(s,1H),8.07(d,J＝7.5Hz,1H),7.65(s,1H),7.41(s,2H),7.23(d,J＝9.0Hz,2H),6.38(tt,J＝55.4,4.1Hz,1H),4.53(s,1H),4.42(td,J＝14.5,4.1Hz,2H),3.89-3.76(m,1H),3.27-2.98(m,4H),2.36(s,3H),1.95-1.79(m,3H),1.79-1.48(m,3H)。MS(ESI)m/z:495.2[M+H+]。

Example 138 (R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 138

Chiral separation of the racemic mixture by SFC gave 138 as a single enantiomer.¹H NMR(400MHz,DMSO)8.91(s,1H),8.07(d,J＝7.5Hz,1H),7.66(s,1H),7.41(s,2H),7.23(d,J＝9.0Hz,2H),6.38(tt,J＝55.4,4.1Hz,1H),4.53(d,J＝3.8Hz,1H),4.42(td,J＝14.5,4.1Hz,2H),3.93-3.74(m,1H),3.27-3.00(m,4H),2.37(s,3H),1.97-1.78(m,3H),1.78-1.49(m,3H)。MS(ESI)m/z:495.2[M+H+]。

Example 1395-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 139

Step A to a solution of benzyl 4-azido-5-hydroxyazepan-1-carboxylate (1.0g,3.45mmol) in anhydrous DCM (10ml) was added(1.6mL,8.62mmol, 50% in THF) and the mixture stirred at room temperature for 18 h. Addition of saturated NaHCO₃Aqueous (20mL) and the mixture extracted with DCM (100 mL). The organic layer was saturated NaHCO₃The aqueous solution (20mL) was washed, separated, and MgSO₄Dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% EtOAc/isohexane) to give benzyl 4-azido-5-fluoroazepan-1-carboxylate as a mixture of syn and anti isomers as a light yellow oil (0.76 g).

Step B A solution of benzyl 4-azido-5-fluoroazepan-1-carboxylate (0.5g,1.71mmol) in THF/water (10mL/2mL) was treated with triphenylphosphine (0.45g,1.71mmol) and the mixture was heated at 60 ℃ for 24 h. The mixture was partitioned between EtOAc (100mL) and water (20mL) and treated with brine (20 mL). The organic layer was separated over MgSO ₄Dried and concentrated under reduced pressure to give a colorless oil. The oil is in Et₂Trituration in O, filtration of the resulting solid, purification with Et₂O wash and concentrate the filtrate under reduced pressure to give a colorless oil. The reaction was repeated on a general scale and the combined batches were dissolved in anhydrous DCM (20mL) and washed with di-tert-butyl dicarbonate (1.1g,5.11mmol) and NEt₃(1.1mL,7.67 mmol). The mixture was stirred at room temperature for 18 hours. Water (10mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel column chromatography (40% EtOAc/isohexane) afforded 4- (tert-butoxycarbonylamino)Benzyl 5-fluoroazepan-1-carboxylate as a mixture of syn and anti isomers as a colorless oil (0.55 g).

Step C benzyl 4- (tert-Butoxycarbonylamino) -5-fluoroazepan-1-carboxylate (0.55g,1.50mmol) in MeOH (75mL) was passed through(all H)₂50 ℃ C., flow rate 1 mL/min, 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give tert-butyl 5-fluoroazepan-4-ylcarbamate as a mixture of syn and anti isomers as a colorless oil (317 mg).

Step D to a solution of tert-butyl 5-fluoroazepan-4-ylcarbamate (310mg,1.34mmol) in EtOH (4mL) was added DIPEA (1mL,5.7mmol) and 5-chloro-1-methyl-4-nitro-1H-pyrazole (216mg,1.34 mmol). The reaction mixture was heated in a microwave at 130 ℃ for 8 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (30-40% EtOAc/isohexane) to give the two trans isomers, tert-butyl 5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate and tert-butyl 5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate, as yellow glasses (65mg), contaminated with some of the syn isomers.

Step E tert-butyl 5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate and tert-butyl 5-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (65mg,0.182mmol) in MeOH (20mL) was purified by(all H)₂50 ℃ C., flow rate 1 mL/min, 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give the free amine as a pale yellow glass (51 mg).

Step F to a solution of the amine (51mg,0.156mmol) in DCM (10mL) was added 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (56mg,0.156mmol), PyBOP (203mg,0.39 mmol)l) and DIPEA (0.5mL,2.9mmol) and the reaction mixture was stirred at room temperature for 18 h. Water (10mL) was added and the mixture was extracted with DCM (40 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60% EtOAc/isohexane) to give the two trans isomers of tert-butyl 4- (5- (4-Boc-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-ylcarbamate as a pale purple solid (36mg) with little contamination of the syn (cis) isomer.

Step G a solution/suspension of 4- (5- (4-Boc-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-ylcarbamic acid tert-butyl ester (35mg,0.053mmol) in MeOH (2mL) was treated with a solution of HCl in dioxane (4M,0.65mL,2.63mmol) and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 5-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide as an off-white solid (3mg, 0.16% over eight steps). The 4-amino and 5-fluoro groups are trans. The¹H NMR(400MHz,CDCl₃)8.81(s,1H),7.88(s,1H),7.38-7.27(m,1H),7.08-6.98(m,2H),6.14(s,2H),4.92-4.77(m,1H),3.73(s,3H),3.50-3.29(m,3H),3.18-3.05(m,2H),2.29-2.24(m,1H),2.11-1.76(m,3H). No alkyl NH was observed₂。LCMS(ES+)m/z466(M+1)

Chiral separation of 5-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide by SFC afforded 139 as a single enantiomer.¹H NMR(400MHz,DMSO)8.82(s,1H),7.59-7.42(m,4H),7.26(t,J＝8.7Hz,2H),4.55-4.31(m,1H),3.63(s,3H),3.23-3.03(m,5H),2.20-2.02(m,1H),2.02-1.88(m,1H),1.88-1.76(m,1H),1.67-1.52(m,1H)。MS(ESI)m/z:466.1[M+H+]。

Example 1405-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 140

Following the procedure of example 139, 5-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide, in which the 4-amino and 5-fluoro groups are cis, was obtained. Chiral separation of the racemic mixture by SFC gave 140 as a single enantiomer.¹H NMR(400MHz,DMSO)8.82(s,1H),7.59-7.42(m,4H),7.26(t,J＝8.7Hz,2H),4.55-4.31(m,1H),3.63(s,3H),3.23-3.03(m,5H),2.20-2.02(m,1H),2.02-1.88(m,1H),1.88-1.76(m,1H),1.67-1.52(m,1H)。MS(ESI)m/z:466.1[M+H+]。

Example 141 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (2-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 141

Following the procedure of example 112, (S) -5- (2, 4-dimethylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-amine and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 reacted to give 141 as a pink solid (86mg, 46% over two steps).¹H NMR(400MHz,CDCl₃)8.59(s,1H),7.88(s,1H),7.35-7.28(m,1H),7.02(t,J＝8.7Hz,2H),6.13(s,2H),3.77(s,3H),3.43-3.31(m,2H),2.98(d,J＝11.6Hz,1H),2.83(t,J＝11.4Hz,2H),2.35(s,3H),2.32-2.25(m,1H),1.96(t,J＝10.2Hz,1H),0.90(d,J＝6.3Hz,3H)。LCMS(ES+)m/z448(M+1).

Example 142 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (2-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 142

Following the procedure of example 110, (R) -5- (2, 4-dimethylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-amine and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 reacted to give 142 as a white solid (54mg, 29% over two steps).¹H NMR(400MHz,CDCl₃)8.59(s,1H),7.88(s,1H),7.36-7.25(m,1H),7.02(t,J＝8.7Hz,2H),6.12(s,2H),3.77(s,3H),3.43-3.30(m,2H),2.98(dt,J＝11.5,2.8Hz,1H),2.83(t,J＝11.4Hz,2H),2.35(s,3H),2.42-2.20(m,1H),1.96(t,J＝10.2Hz,1H),0.92(d,J＝8.6Hz,3H)。LCMS(ES+)m/z448(M+1).

Example 1435-amino-N- (1-cyclopropyl-5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 143

Following the procedure of example 105, 4- (4- (2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxamide) -1-cyclopropyl-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester and 2, 5-difluoro-phenylboronic acid reacted to give 143 as a beige foam (60mg, 42% in two steps).¹H NMR(400MHz,CDCl₃)8.92(s,1H),7.92-7.84(m,2H),7.17-7.08(m,1H),7.07-6.99(m,1H),6.15(s,2H),3.68(t,J＝13.2Hz,2H),3.52-3.32(m,5H),3.11(t,J＝5.4Hz,2H),1.95(s,1H),1.26-1.20(m,2H),1.08-1.00(m,2H)。LCMS(ES+)m/z496(M+1).

Example 1445-amino-N- (1-cyclopropyl-5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 144

Following the procedure of example 105, 4- (4- (2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxamide) -1-cyclopropyl-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester and 2-fluoro-5-methylphenylboronic acid reacted to give 144 as a beige foam (75mg, 53% in two steps).¹H NMR(400MHz,CDCl₃)8.99(s,1H),7.92(dd,J＝7.2,2.2Hz,1H),7.84-7.79(m,1H),7.16-7.11(m,1H),7.10-7.00(m,1H),6.09(s,2H),3.69(t,J＝13.3Hz,2H),3.51-3.35(m,5H),3.09(t,J＝5.5Hz,2H),2.39(s,3H),2.05-1.80(m,1H),1.29-1.19(m,2H),1.09-0.98(m,2H)。LCMS(ES+)m/z492(M+1).

Example 1455-amino-N- (1-cyclopropyl-5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 145

A mixture of 4- (4- (2-bromo-5- (tert-butoxycarbonylamino) thiazole-4-carboxamide) -1-cyclopropyl-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester (191mg,0.29mmol), potassium fluoride dihydrate (90mg,0.96mmol) and 2, 6-difluoro-phenylboronic acid (137mg,0.87mmol) in THF (3mL) was degassed by bubbling nitrogen gently through the mixture for 15 minutes. Then a mixture of tris (dibenzylideneacetone) dipalladium/tri-tert-butylphosphonium tetrafluoroborate (molar ratio: 1/1.2) (35mg,0.029mmol) was added and the degassed mixture was heated in a microwave at 100 ℃ for 2 hours. The solvent was removed under reduced pressure. Water (5mL) was added and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were over MgSO₄Dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-60% EtOAc/isohexane) to give 4- (4- (5-tert-butoxycarbonylamino-2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-cyclopropyl-1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylic acid tert-butyl ester as an orange solid (95mg,0.13mmol) dissolved in a solution of HCl in 1, 4-dioxane (4M,0.7mL,2.73mmol) and MeOH (0.2mL) and stirred at 70 ℃ for 48H. The solvent was removed under reduced pressure, and the residue was dissolved in MeOH/DCM and passed through an SCX cartridge, washed with DCM and MeOH, and eluted with 1N ammonia (MeOH). Purification by silica gel column chromatography (0-10% MeOH/DCM) gave 145 as a beige solid (35mg, 25% over two steps).¹H NMR(400MHz,CDCl₃)9.42(s,1H),7.87(s,1H),7.38-7.28(m,1H),7.08-6.97(m,2H),6.20(s,2H),3.71-3.56(m,3H),3.46-3.35(m,4H),3.12-3.06(m,2H),1.25-1.19(m,2H),1.06-0.97(m,2H). AlkylNH was not observed. LCMS (ES +) M/z496(M +1).

Example 1465-amino-2- (2, 6-difluorophenyl) -N- (5- (4-hydroxy-4-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 146

To 4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (212mg,0.83mmol) under nitrogenAnd ammonium formate (386mg,6.6mmol) in MeOH (15mL) 10% palladium on carbon (88mg,0.83mmol) was added. The mixture was heated at 80 ℃ for 16 hours, then cooled, and then filteredFiltered and concentrated under reduced pressure. The residue was partitioned between water (20mL) and DCM (40mL) and the organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give 1- (4-amino-1-methyl-1H-pyrazol-5-yl) -4-methylazepan-4-ol as a red oil which was used without further purification. To a solution of DIPEA (0.06mL,0.33mmol), PyBOP (151mg,0.29mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acid (89mg,0.25mmol) in DCM (10mL) (pre-stirred for 30 min) was added 1- (4-amino-1-methyl-1H-pyrazol-5-yl) -4-methylazepan-4-ol (47mg,0.21mmol) and the mixture was stirred at rt for 16H. The mixture was diluted with DCM (30mL) and water (20 mL). The organic layer was passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4-hydroxy-4-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate as an off-white solid (109 mg). The solid was stirred in HCl in 1, 4-dioxane (4M,5mL,20mmol) in MeOH (5mL) at room temperature for 16 h. The solvent was removed under reduced pressure and the residue redissolved in MeOH and passed through a SCX column, washed with DCM and MeOH and eluted with 3-10% 7N ammonia (in cancer MeOH/DCM). Purification via silica gel column chromatography (0-5% MeOH/DCM) gave 146 as an off-white solid (36mg, 37% over three steps).¹H NMR (400MHz, d4-MeOD)7.68(s,1H),7.52-7.43(m,1H),7.17-7.10(m,2H),3.74(s,3H),3.56-3.44(m,1H),3.19-3.10(m,1H),3.04-2.96(m,1H),2.14-2.02(m,1H),1.94-1.80(m,4H),1.74-1.64(m,1H),1.23(s,3H) (1 proton coincides with the solvent peak). LCMS (ES +) M/z463(M +1).

Example 1475-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 147

Step A to a solution of 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (784mg,2.2mmol) in DCM (40mL) was added PyBOP (1.46g,2.8mmol) and the mixture was stirred at room temperature for 30 min. A solution of N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide (647mg,2.0mmol) and DIPEA (0.59mL,3.4mmol) in DCM (40mL) was then added and the mixture stirred at room temperature for 16H. The mixture was diluted with DCM (60mL) and washed with water (30 mL). The organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) afforded tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate as an off-white solid (1.32 g).

Step B tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate was suspended in MeOH (20mL) in a pressure bottle and a solution of HCl in 1, 4-dioxane (4M,20mL,80.0mmol) was added thereto. The vial was sealed and the mixture was heated at 60 ℃ for 16 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-10% 7N ammonia in MeOH/DCM) to give 5-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide as a light brown solid (653mg, 70% over two steps). The 4-amino group and the 5-fluoro group are cis.¹H NMR(400M Hz,CDCl₃)8.63(s,1H),7.84(s,1H),7.37-7.29(m,1H),7.03(t, J ═ 8.7Hz,2H),6.13(s,2H),4.48(dtd, J ═ 47.9,8.6,3.6Hz,1H),3.72(s,3H),3.37-3.15(m,5H),2.23-1.92(m,3H),1.75-1.67(m,1H) · no alkyl NH was observed₂. LCMS (ES +) M/z466(M +1). Chiral separation of the racemic mixture by SFC gave 147 as a single enantiomer.¹H NMR(400MHz,DMSO)9.04(s,1H),7.59(s,1H),7.56-7.43(m,3H),7.26(dd,J＝14.5,5.9Hz,2H),4.82(dd,J＝47.0,7.4Hz,1H),3.63(s,3H),3.29-3.15(m,4H),3.08-2.91(m,2H),2.24-2.06(m,1H),1.91-1.76(m,2H),1.74-1.59(m,1H)。MS(ESI)m/z:466.1[M+H+]。

Example 148 (S) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 148

Chiral separation of the racemic mixture by SFC gave 148 as a single enantiomer.¹H NMR(400MHz,DMSO)9.10(s,1H),8.15(ddd,J＝9.3,5.7,3.3Hz,1H),7.55(s,1H),7.51-7.36(m,3H),7.27(tt,J＝7.4,3.6Hz,1H),6.38(tt,J＝55.4,4.1Hz,1H),4.50(d,J＝3.8Hz,1H),4.42(td,J＝14.5,4.1Hz,2H),3.87-3.71(m,1H),3.25-2.97(m,4H),1.92-1.76(m,3H),1.73-1.47(m,3H)。MS(ESI)m/z:499.1[M+H+]。

EXAMPLE 149 (R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 149

Chiral separation of the racemic mixture by SFC gave 149 as a single enantiomer.¹H NMR(400MHz,DMSO)9.10(s,1H),8.15(ddd,J＝9.3,5.7,3.3Hz,1H),7.55(s,1H),7.51-7.36(m,3H),7.27(tt,J＝7.4,3.6Hz,1H),6.38(tt,J＝55.4,4.1Hz,1H),4.50(d,J＝3.8Hz,1H),4.42(td,J＝14.5,4.1Hz,2H),3.87-3.71(m,1H),3.25-2.97(m,4H),1.92-1.76(m,3H),1.73-1.47(m,3H)。MS(ESI)m/z:499.1[M+H+]。

Example 1505-amino-N- (5- ((4R,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 150

Obtained according to the procedure of example 147, 5-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide, wherein the 4-amino and the 5-fluoro groups are cis. Chiral separation of the racemic mixture by SFC gave 150 as a single enantiomer.¹H NMR(400MHz,DMSO)9.05(s,1H),7.59(s,1H),7.57-7.47(m,3H),7.27(t,J＝8.7Hz,2H),4.82(dd,J＝47.0,7.2Hz,1H),3.63(s,3H),3.30-3.15(m,4H),3.08-2.94(m,2H),2.26-2.09(m,1H),1.93-1.74(m,2H),1.74-1.60(m,1H)。MS(ESI)m/z:466.1[M+H+]。

Example 1515-amino-2- (2, 6-difluorophenyl) -N- (5- (6-fluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 151

Compound 151 was prepared according to the procedure described for the preparation of example 102 using 6-fluoro-1, 4-diazepan.¹HNMR(400MHz,DMSO)8.74(s,1H),8.17(s,1H),7.59-7.46(m,3H),7.43(s,1H),7.27(t,J＝8.7Hz,2H),4.47-4.37(m,1H),4.30(dd,J＝5.2,2.3Hz,1H),3.64(s,3H),3.08-2.73(m,8H)。MS(ESI)m/z:452.1[M+H+]。

Example 152 (R) -5-amino-N- (5- (4-aminoazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 152

Compound 152 was prepared according to the procedure described herein.

Example 1535-amino-N- (5- ((3S,5R) -5-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 153

Following the procedure of example 101, intermediate 20, 6-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 gave, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7N ammonia in MeOH), a white solid (273mg, 19% over three steps). SFC chiral separation of the racemic mixture gave compound 153 as a single enantiomer.¹HNMR(400MHz,DMSO)8.77(s,1H),7.61-7.41(m,4H),7.27(dd,J＝14.5,5.8Hz,2H),4.84-4.56(m,1H),3.67(d,J＝7.4Hz,3H),3.44-3.34(m,2H),3.21-2.86(m,3H),2.22-2.07(m,1H),1.87(ddt,J＝34.3,21.1,7.4Hz,3H),1.70-1.53(m,1H)。MS(ESI)m/z:466.1[M+H+]。

Example 1545-amino-N- (5- (5-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 154

Following the procedure of example 101, intermediate 20, 6-fluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 were obtained by chromatography on silica gel column (0-10% MeOH/DCM, 1% 7N ammonia in MeOH) as a white solid (273mg, 19% over three steps). SFC chiral separation of the racemic mixture gave compound 154 as a single enantiomer.¹HNMR(400MHz,DMSO)8.77(s,1H),7.61-7.41(m,4H),7.27(dd,J＝14.5,5.8Hz,2H),4.84-4.56(m,1H),3.67(d,J＝7.4Hz,3H),3.44-3.34(m,2H),3.21-2.86(m,3H),2.22-2.07(m,1H),1.87(ddt,J＝34.3,21.1,7.4Hz,3H),1.70-1.53(m,1H)。MS(ESI)m/z:466.1[M+H+]。

Example 1555-amino-N- (5- ((3R,4S) -4-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 155

Following the procedure of example 101 or 112, compound 155 was obtained as a single enantiomer from a racemic mixture by chiral separation of SFC.¹H NMR(400MHz,DMSO)8.77(s,1H),7.60-7.44(m,4H),7.26(dd,J＝14.4,5.8Hz,2H),4.34-4.10(m,1H),3.66(s,3H),3.54-3.33(m,2H),3.17-2.93(m,3H),1.96-1.50(m,5H)。MS(ESI)m/z:466.1[M+H+]。

Example 1565-amino-N- (5- ((3S,4R) -4-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 156

Exo-extinction from chiral separation of SFCs according to the procedure of examples 101 or 112The mixture was then mixed by rotation to give compound 156 as a single enantiomer.¹H NMR(400MHz,DMSO)8.77(s,1H),7.60-7.44(m,4H),7.26(dd,J＝14.4,5.8Hz,2H),4.34-4.10(m,1H),3.66(s,3H),3.54-3.33(m,2H),3.17-2.93(m,3H),1.96-1.50(m,5H)。MS(ESI)m/z:466.1[M+H+]。

Example 1575-amino-N- (5- ((3R,4R) -4-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 157

Following the procedure of example 101 or 112, chiral separation of the racemic mixture from SFC afforded compound 157 as a single enantiomer.¹H NMR(400MHz,DMSO)8.77(s,1H),7.61-7.41(m,4H),7.26(dd,J＝14.4,5.8Hz,2H),4.33-4.09(m,1H),3.66(s,3H),3.51-3.32(m,2H),3.06(m,3H),1.87-1.49(m,4H)。MS(ESI)m/z:466.2[M+H+]。

Example 1585-amino-N- (5- ((3S,4S) -4-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 158

Compound 158 was obtained as a single enantiomer from sfc according to the procedure of example 101 or 112¹H NMR(400MHz,DMSO)8.77(s,1H),7.61-7.41(m,4H),7.26(dd,J＝14.4,5.8Hz,2H),4.33-4.09(m,1H),3.66(s,3H),3.51-3.32(m,2H),3.06(m,3H),1.87-1.49(m,4H)。MS(ESI)m/z:466.2[M+H+]。

Example 1595-amino-N- (5- ((3R,5R) -3-amino-5-fluoropiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 159

A mixture of tert-butyl (3R,5R) -1- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -5-fluoropiperidin-3-ylcarbamate (150mg,0.23mmol) in HCl/MeOH (10mL) was stirred at ambient temperature for 20 hours and concentrated under reduced pressure to give a residue. Disabled personThe residue was diluted with MeOH (10mL), neutralized with 28% ammonia solution, and concentrated to give the crude product. The crude product was purified by preparative HPLC to give 159 as a light colored solid (77mg, 74%).¹H NMR(500MHz,CD3OD)(ppm):7.74(s,1H),7.48-7.42(m,1H),7.14-7.11(m,2H),5.36-5.24(m,1H),4.00-3.94(m,1H),3.83-3.72(m,4H),3.42-3.37(m,1H),2.74-2.62(m,2H),2.50-5.42(m,1H),2.02-1.88(m,1H)；MS(ESI)m/z:452[M+H+]。

Example 1605-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 160

Compound 160 was prepared according to example 162.¹H NMR(400MHz,DMSO)10.13(s,1H),9.14(s,1H),8.51(s,1H),7.60-7.45(m,1H),7.27(t,J＝8.4Hz,2H),5.17(s,1H),4.55(t,J＝8.2Hz,2H),4.33-4.10(m,2H),3.77(t,J＝12.8Hz,2H),3.69-3.51(m,2H),3.47-3.36(m,2H),3.19(t,J＝14.3Hz,2H),3.03-2.81(m,3H)。MS(ESI)m/z:526.2[M+H+]。

Example 161 (R) -5-amino-N- (5- (4-aminoazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 161

Reaction of 5-chloro-1- (2, 2-difluoroethyl) -4-nitro-pyrazole with benzyl (R) -azepan-4-ylcarbamate according to example 101 gave 161.¹H NMR(400MHz,DMSO)9.12(s,1H),8.18-8.06(m,1H),7.57(s,1H),7.52-7.35(m,3H),7.34-7.18(m,1H),6.39(tt,J＝55.3,4.2Hz,1H),4.42(td,J＝14.5,4.2Hz,2H),3.21-3.03(m,4H),3.03-2.91(m,1H),1.91-1.71(m,3H),1.64-1.36(m,3H)。MS(ESI)m/z:498.2[M+H+]。

Example 1625-amino-2- (2, 6-difluorophenyl) -N- (5- (4-hydroxyazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 162

Step A. Oxetan-3-ylmethyl methanesulfonate

Oxetan-3-ylmethanol (1.85g,21.0mmol) was dissolved in dichloromethane and cooled to 0 ℃. Triethylamine (5.31g,52.2mmol) was added, followed by slow addition of methanesulfonyl chloride (2.89g,25.2 mmol). The mixture was warmed to ambient temperature for 2 hours and quenched with saturated sodium bicarbonate (14 mL). The aqueous solution was extracted 3x with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude oxetan-3-ylmethyl methanesulfonate (quantitative).

Step B.4-Nitro-1- (Oxetan-3-ylmethyl) pyrazole

A mixture of 4-nitropyrazole (1000mg,8.80mmol), oxetan-3-ylmethyl methanesulfonate (1.90g,11.0mmol), cesium carbonate (8.70g,27.0mmol) and acetonitrile (13mL) was heated at 100 ℃ for 3 h. The mixture was cooled to room temperature and saturated ammonium chloride was added. The mixture was extracted 3x with dichloromethane. The combined organics were dried (Na)₂SO₄) And the solvent was removed under reduced pressure. The crude product was purified by flash chromatography eluting with 0-70% ethyl acetate in heptane to give 4-nitro-1- (oxetan-3-ylmethyl) pyrazole (1.60g, 99%).

Step C.5-chloro-4-nitro-1- (oxetan-3-ylmethyl) -1H-pyrazole

To a solution of 4-nitro-1- (oxetan-3-ylmethyl) pyrazole (3200mg,17.47mmol) in THF (80mL) was added LHMDS (1M in THF) dropwise over 15 min at-78 deg.C22.7mL,22.7 mmol). The resulting mixture was stirred at-78 ℃ for 30 minutes. Hexachloroethane (5.38g,22.7mmoL) in THF (20mL) was added dropwise at-78 ℃. The resulting mixture was stirred at-78 ℃ for an additional 40 minutes. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (X3). The combined organic layers were washed with Na₂SO₄Dried and concentrated under reduced pressure. The crude material was purified by column chromatography with 0-75% ethyl acetate/heptane as eluent to give 5-chloro-4-nitro-1- (oxetan-3-ylmethyl) -1H-pyrazole (3.60g, 95%).

Step d. starting from 5-chloro-4-nitro-1- (oxetan-3-ylmethyl) -1H-pyrazole and azepan-4-ol and using TFA instead of 4N HCl in dioxane in the final deprotection step, according to example 101, 162 was obtained.¹H NMR(400MHz,DMSO)9.25(s,1H),8.27(s,1H),7.65-7.48(m,3H),7.26(dd,J＝14.3,5.8Hx,2H),5.18(t,J＝5.2Hz,1H),4.65-4.52(m,2H),4.41(dd,J＝11.0,8.2Hz,1H),4.27(dd,J＝10.5,5.8hZ,1H),4.10(dd,J＝11.1,6.1Hz,1H),3.80-3.66(m,1H),3.63-3.43(m,5H),3.43-3.32(m,1H),1.95-1.78(m,2H),1.77-1.52(m,4H)。MS(ESI)m/z:505.1[M+H+]。

Example 1635-amino-2- (2-fluoro-5-methylphenyl) -N- (5- (4-hydroxyazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 163

According to the operation of the embodiment 162, 163 is obtained.¹H NMR(400MHz,DMSO)8.85(s,1H),8.05(d,J＝7.6Hz,1H),7.56(s,1H),7.40(s,2H),7.23(d,J＝9.1Hz,2H),4.72-4.61(m,2H),4.53(d,J＝3.8Hz,1H),4.46(t,J＝6.2Hz,2H),4.25(d,J＝7.4Hz,2H),3.90-3.76(m,1H),3.49-3.36(m,1H),3.28-2.97(m,4H),2.37(s,3H),1.99-1.81(m,3H),1.78-1.53(m,3H)。MS(ESI)m/z:501.1[M+H+]。

Example 164 (R) -5-amino-N- (5- (4-Aminoazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 164

Following the procedure of example 162, 164 was obtained.¹H NMR(400MHz,DMSO)9.09(s,1H),8.31(s,1H),8.29(s,1H),7.66-7.45(m,2H),7.27(td,J＝8.4,5.9Hz,2H),5.17(s,1H),4.59(dd,J＝18.0,7.8Hz,1H),4.48-4.35(m,1H),4.32-4.18(m,1H),4.16-4.02(m,1H),3.67-3.38(m,6H),2.97-2.84(m,1H),1.91-1.30(m,6H)。MS(ESI)m/z:504.1[M+H+]。

Example 1655-amino-2- (2, 6-difluorophenyl) -N- (5- (6-fluoro-1, 4-diazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

Following the procedure of example 162, 165 was obtained. MS (ESI) M/z 508.2[ M + H + ].

Example 166 (S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 166

Following the procedure of examples 101 and 112, chiral separation of the racemic mixture from SFC afforded compound 166 as a single enantiomer.¹H NMR(400MHz,DMSO)8.83(s,1H),7.59-7.43(m,4H),7.28(t,J＝8.6Hz,2H),3.75-3.54(m,4H),3.25-3.01(m,4H),2.29-2.09(m,2H),1.90-1.77(m,1H),1.77-1.62(m,1H)。MS(ESI)m/z:484.1[M+H+]。

Example 167 (R) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

Following the procedure of examples 101 and 112, chiral separation of the racemic mixture from SFC afforded compound 167 as a single enantiomer.¹H NMR(400MHz,DMSO)8.84(s,1H),7.59-7.44(m,4H),7.28(t,J＝8.7Hz,2H),3.73-3.57(m,4H),3.26-2.96(m,4H),2.30-2.09(m,2H),1.91-1.79(m,1H),1.79-1.60(m,1H)。MS(ESI)m/z:484.1[M+H+]。

Example 168 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (3- (trifluoromethyl) piperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 168

Example 169 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (3- (trifluoromethyl) piperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 169

Step A. (+ -) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -3- (trifluoromethyl) piperazine

A mixture of (. + -.) -2- (trifluoromethyl) piperazine (1g,6.2mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole (2.1g,13mmol), DIPEA (2.4g,18.6mmol) in EtOH (10mL) was heated in a microwave oven at 140 ℃ for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was chromatographed on silica gel using DCM/MeOH (10:1) as the eluting solvent to give (±) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -3- (trifluoromethyl) piperazine as a yellow oil (1.8g, 99%). MS (ESI) M/z 280[ M + H + ].

Step B. (+ -) -1-methyl-5- (3- (trifluoromethyl) piperazin-1-yl) -1H-pyrazol-4-amine

To (. + -.) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -3- (trifluoromethyl) piperazine (420mg,1.5mmol) in MeOH (20mL) and H₂To a solution in O (5mL) were added zinc (590mg,4mmol) and NH₄Cl (805mg,10 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and filtered through Celite. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using PE/EtOAc (10/1-1/10) as the eluting solvent to give (+ -) -1-methyl-5- (3- (trifluoro-phenyl) -ethylMethyl) piperazin-1-yl) -1H-pyrazol-4-amine (340mg, 90%) as a red solid.¹H NMR(500MHz,DMSO-d6)(ppm):6.84(s,1H),3.38-3.52(m,5H),3.13-3.17(m,2H),2.94-3.00(m,2H),2.50-2.78(s,3H),1.98(m,1H)；MS(ESI)m/z:250(M+1+).

Step C. (+ -) -2- (2, 6-difluorophenyl) -4- (1-methyl-5- (3- (trifluoromethyl) piperazin-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester

To a solution of (±) -1-methyl-5- (3- (trifluoromethyl) piperazin-1-yl) -1H-pyrazol-4-amine (300mg,2.05mmol), 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 (516mg,1.73mmol), HATU (0.54g,1.73mmol) in DMF (15mL) was added TEA (1.1mL), the reaction mixture was stirred at 25 ℃ for 20 hours, EtOAc was poured into water (100mL), and extracted (50mL × 2) · the combined organic layers were washed with water (50mL × 2) and brine (30mL × 2), washed over Na₂SO₄Dried, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by chromatography on silica gel using DCM/MeOH (1:1) as eluting solvent to give tert-butyl (±) -2- (2, 6-difluorophenyl) -4- (1-methyl-5- (3- (trifluoromethyl) piperazin-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (380mg, 52%) as a white solid. MS (ESI) M/z588(M +1+).

Step D. chiral separation of tert-butyl (. + -.) -2- (2, 6-difluorophenyl) -4- (1-methyl-5- (3- (trifluoromethyl) piperazin-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (380mg) by using preparative HPLC to give tert-butyl (S) -2- (2, 6-difluorophenyl) -4- (1-methyl-5- (3- (trifluoromethyl) piperazin-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (123mg) and (R) -2- (2, 6-difluorophenyl) -4- (1-methyl-5- (3-, (2, 6-difluorophenyl) -4- (1-methyl-5- (3-) ( Trifluoromethyl) piperazin-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester (120mg).

Step E. (S) -2- (2, 6-difluorobenzeneA mixture of tert-butyl yl) -4- (1-methyl-5- (3- (trifluoromethyl) piperazin-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (80mg,0.126mmol) in TFA (1mL) and DCM (4mL) was stirred at ambient temperature for 3 hours. The mixture was adjusted to a pH of about 8-9 by adding ammonia and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give 168 formate (40mg, 73%) as a white solid.¹HNMR(500MHz,DMSO-d6)(ppm):8.85(s,1H),7.50-7.56(m,3H),7.37(s,1H),7.25-7.28(m,2H),3.65(s,3H),3.46-3.48(m,1H),3.02-3.14(m,3H),2.92-2.97(m,2H),2.78(m,1H),1.23(s,1H)；MS(ESI)m/z＝488.1(M+1+).

A mixture of (R) -tert-butyl 2- (2, 6-difluorophenyl) -4- (1-methyl-5- (3- (trifluoromethyl) piperazin-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (80mg,0.126mmol) in TFA (1mL) and DCM (4mL) was stirred at ambient temperature for 3 hours. The mixture was adjusted to about pH 8-9 by adding ammonia and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give 169 formate salt (40mg, 73%) as a white solid.¹H NMR(500MHz,DMSO-d6)(ppm):8.84(s,1H),7.50-7.55(m,3H),7.37(s,1H),7.25-7.28(m,2H),3.47(s,3H),3.36-3.48(m,1H),3.07-3.16(m,3H),2.94-2.96(m,2H),2.78-2.80(m,1H),1.24(s,1H)；MS(ESI)m/z＝488.1(M+1+).

Example 170 (S) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (3-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 170

Following the procedure of example 101 or 112, chiral separation of the racemic mixture from SFC afforded compound 170 as a single enantiomer.¹H NMR(400MHz,DMSO)8.84(s,1H),7.71(s,1H),7.56-7.52(m,1H),7.51(s,2H),7.27(m,2H),6.39(tt,J＝55.4,4.1Hz,1H),4.63(d,J＝3.9Hz,1H),4.60-4.50(m,1H),4.42-4.31(m,1H),3.70(d,J＝3.8Hz,1H),3.18(ddd,J＝17.8,12.9,4.7Hz,2H),3.11-3.02(m,2H),1.91-1.82(m,1H),1.77(dd,J＝17.4,10.6Hz,1H),1.67(m,2H),1.60-1.47(m,2H).ESIMS m/z＝499.1(M+1).

Example 171 (R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (3-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 171

Following the procedure of example 101 or 112, chiral separation of the racemic mixture from SFC afforded compound 171 as a single enantiomer.¹H NMR(400MHz,DMSO)8.84(s,1H),7.72(s,1H),7.56-7.52(m,1H),7.51(s,2H),7.27(m,2H),6.39(tt,J＝55.4,4.1Hz,1H),4.63(d,J＝3.9Hz,1H),4.52(m,1H),4.43-4.32(m,1H),3.75-3.66(m,1H),3.18(ddd,J＝17.8,12.9,4.7Hz,2H),3.11-3.02(m,2H),1.91-1.82(m,1H),1.77(dd,J＝17.4,10.6Hz,1H),1.67(m,2H),1.45(m,2H).ESIMS m/z＝499.1(M+1).

Example 1725-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 172

Following the procedure of example 149, starting from tert-butyl 4- (4-nitro-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) -6, 6-difluoro-1, 4-diazepan-1-carboxylate (64mg,0.16mmol), compound 172 was obtained as a light orange solid (13mg, 16%, over three steps).¹H NMR (400MHz, d6-DMSO)9.45(s,1H),7.72(s,1H),7.60-7.47(m,3H),7.29(t, J ═ 8.7Hz,2H),6.53-6.21(m,1H),4.45(td, J ═ 14.5,4.0Hz,2H),3.56(t, J ═ 13.6Hz,2H),3.31-3.14(m,3H),2.89(s,3H). no alkyl NH was observed. LCMS (ES +) M/z520(M +1).

Example 1735-amino-N- (5- (6-hydroxy-1, 4-diazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 173

Following the procedure of example 149, starting from tert-butyl 4- (4-nitro-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) -6-hydroxy-1, 4-diazepan-1-carboxylate (18mg,0.46mmol), gave 173 as colorlessSolid (78mg, 34%, over three steps).¹H NMR (400MHz, d6-DMSO)11.42(s,1H),8.01(s,1H),7.60(s,2H),7.59-7.48(m,1H),7.30(t, J ═ 8.7Hz,2H),6.37(tt, J ═ 55.4,4.2Hz,1H),4.72(s,1H),4.55-4.30(m,2H),3.65-3.50(m,1H),3.10-2.93(m,4H),2.73-2.63(m,2H),2.45(dd, J ═ 12.7,8.8Hz,1H). LCMS (ES +) M/z500(M +1).

Example 174 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 174

A solution of PyBOP (328mg,0.63mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 (176mg,0.50mmol) in DCM (5mL) was stirred at room temperature for 30 min. A solution of intermediate 33(S) -tert-butyl 4- (4-amino-1- (4-methoxybenzyl) -1H-pyrazol-5-yl) -3-methylpiperazine-1-carboxylate (181mg,0.45mmol) and DIPEA (0.13mL,0.72mmol) in DCM (5mL) was added and the mixture was stirred at room temperature for 65 hours. The mixture was diluted with DCM (40mL) and washed with water (15 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/isohexane) gave (S) -tert-butyl 4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1- (4-methoxybenzyl) -1H-pyrazol-5-yl) -3-methylpiperazine-1-carboxylate as a yellow solid (150 mg). The solid was redissolved in DCM (10mL) and TFA (2mL) was added, followed by heating at 65 ℃ for 2.5 hours. The mixture was concentrated under reduced pressure, then redissolved in 7N ammonia in MeOH (20mL) and heated in a sealed pressure tube at 55 ℃ for 16 hours after the explosion barrier. The mixture was concentrated under reduced pressure, redissolved in MeOH and passed through a SCX column, washed with DCM and MeOH and eluted with 3-10% 7N ammonia in MeOH/DCM to give 174 as an off-white solid (60mg, 32% over two steps).¹H NMR(400MHz,d4-MeOD)8.03(s,1H),7.51-7.41(m,1H),7.16(t,J＝8.9Hz,2H),3.20-3.14(m,1H),3.08-2.98(m,5H),2.64(dd,J＝12.7,9.4Hz,1H),0.93(d,J＝6.2Hz,3H)。LCMS(ES+)m/z420(M+1).

Example 175 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 175

Following the procedure of example 174, tert-butyl 4- (4-amino-1- (4-methoxybenzyl) -1H-pyrazol-5-yl) piperazine-1-carboxylate and 5- (tert-butoxycarbonyl-amino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid gave 175 as a white solid (29mg, 15% over two steps).¹H NMR(400MHz,d4-MeOD)8.03(s,1H),7.50-7.44(m,1H),7.16(t,J＝8.9Hz,2H),3.20-3.14(m,1H),3.09-2.99(m,5H),2.64(dd,J＝12.6,9.3Hz,1H),0.93(d,J＝6.2Hz,3H)。LCMS(ES+)m/z420(M+1).

Example 176 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2-ethyl-4-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 176

Following the procedure of example 110, starting from (S) -5- (2-ethyl-4-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-amine and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25, 176 was obtained as a pale purple solid (53mg, 31%).¹H NMR(400MHz,CDCl₃)8.58(s,1H),7.88(s,1H),7.37-7.27(m,1H),7.01(t,J＝8.8Hz,2H),6.16(s,2H),3.76(s,3H),3.32(t,J＝11.3Hz,1H),3.22(t,J＝9.3Hz,1H),2.96(t,J＝12.9Hz,2H),2.79(d,J＝11.0Hz,1H),2.42-2.22(m,4H),1.96(t,J＝10.2Hz,1H),1.41-1.33(m,1H),1.29-1.15(m,1H),0.80(t,J＝7.5Hz,3H)。LCMS(ES+)m/z462(M+1).

Example 176 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2-ethyl-4-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 176

Following the procedure of example 110, (R) -5- (2-ethyl-4-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-amine and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 gave 176 as a white solid (47mg, 28% over two steps).¹H NMR(400MHz,CDCl₃)8.58(s,1H),7.87(s,1H),7.37-7.25(m,1H),7.01(t,J＝8.8Hz,2H),6.17(s,2H),3.76(s,3H),3.33(t,J＝11.3Hz,1H),3.22(t,J＝9.2Hz,1H),2.97(t,J＝12.7Hz,2H),2.79(d,J＝11.0Hz,1H),2.41-2.22(m,4H),1.96(t,J＝10.2Hz,1H),1.41-1.33(m,1H),1.28-1.13(m,1H),0.80(t,J＝7.5Hz,3H)。LCMS(ES+)m/z462(M+1).

Example 1785-amino-2- (2-fluoro-5-methylphenyl) -N- (5- (4-hydroxy-4-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 178

Following the procedure of example 105, starting from tert-butyl 2-bromo-4- (5- (4-hydroxy-4-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate, 178 was obtained as an off-white solid (60mg, 25%, in two steps)¹H NMR (400MHz, d4-MeOD)8.06(d, J ═ 7.3Hz,1H),7.59(s,1H),7.24-7.19(m,1H),7.11(dd, J ═ 11.4,8.4Hz,1H),3.75(s,3H),3.51-3.48(m,1H),3.26-3.17(m,1H),3.09-3.01(m,1H),2.41(s,3H),2.16-2.04(m,1H),1.96-1.83(m,4H),1.78-1.68(m,1H),1.26(s,3H) (1 proton consistent with the solvent peak). LCMS (ES +) M/z459(M +1).

Example 1795-amino-N- (5- (6-fluoro-1, 4-diazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 179

Following the procedure of example 149, starting from tert-butyl 4- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) -6-fluoro-1, 4-diazepan-1-carboxylate (366mg,0.93mmol), gave 179 as a light yellow solid (40mg, 10%, over three steps).¹H NMR (400MHz, d6-DMSO)10.26(s,1H),7.88(s,1H),7.66-7.52(m,3H),7.34(t, J ═ 8.9Hz,2H),6.42(t, J ═ 55.3Hz,1H),4.71(d, J ═ 47.8Hz,1H),3.61-3.41(m,2H),3.42-3.04(m,4H),3.05(t, J ═ 16.5Hz,1H),2.83-2.57(m,3H). LCMS (ES +) M/z502(M +1).

Example 180 (R) -3-amino-N- (5- (4-Aminoazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -6- (2-fluorophenyl) picolinamide 180

Following the procedure of example 101 or 112, (R) -3-amino-6-bromo-N- (1- (2, 2-difluoroethyl) -5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-yl) picolinamide was prepared. In a microwave reaction tube, (R) -3-amino-6-bromo-N- (1- (2, 2-difluoroethyl) -5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-yl) picolinamide (284mg,0.51mmol), (2-fluorophenyl) boronic acid (215mg,1.54mmol) and Pd (dppf)₂Cl2(37mg,0.051mmol) was dissolved in acetonitrile (4 mL). 1.0M potassium acetate (0.77mL,0.77mmol) and 1.0M sodium carbonate (0.77mL,0.77mmol) were added. The mixture was irradiated under microwave at 120 ℃ for 30 minutes. It was cooled and filtered through Celite and washed with methanol. The filtrate was concentrated and purified by flash chromatography eluting with 0-10% methanol in dichloromethane to give (R) -3-amino-N- (1- (2, 2-difluoroethyl) -5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-yl) -6- (2-fluorophenyl) picolinamide (98mg, 33%).

(R) -3-amino-N- (1- (2, 2-difluoroethyl) -5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-yl) -6- (2-fluorophenyl) methylpyridinamide (98mg,0.17mmol) was stirred with potassium carbonate (144mg,1.03mmol) in methanol (5mL) at 50 ℃ overnight. The mixture was filtered and the filtrate was purified by reverse phase HPLC to afford 180.¹H NMR(400MHz,DMSO)9.81(s,1H),8.00(td,J＝8.3,1.8Hz,1H),7.86(s,1H),7.74(dd,J＝8.7,2.2Hz,1H),7.43(dt,J＝7.2,3.8Hz,1H),7.38-7.20(m,4H),7.08(s,2H),6.38(tt,J＝55.3,4.1Hz,1H),4.43(td,J＝14.5,4.1Hz,2H),3.55(s,1H),3.21-3.07(m,4H),2.92(dd,J＝19.4,10.4Hz,1H),1.89-1.69(m,3H),1.69-1.37(m,3H)。MS(ESI)m/z:474.2[M+H+]。

Example 181 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-hydroxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 181

Compound 181 was prepared according to the procedures described herein.¹H NMR(400MHz,DMSO)8.78(s,1H),7.59(s,1H),7.51(d,J＝12.3Hz,3H),7.27(t,J＝8.7Hz,2H),4.55(d,J＝4.1Hz,1H),3.68(m,1H),3.66(s,3H),3.20-3.10(m,2H),3.05(dd,J＝13.6,7.4Hz,2H),、2.07-1.55(m,6H).ESIMS m/z＝449.1(M+1).

Example 182 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-hydroxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 182

Compound 182 was prepared according to the procedures described herein.¹H NMR(400MHz,DMSO)8.78(s,1H),7.59(s,1H),7.49(m,3H),7.28(d,J＝8.8Hz,2H),4.55(d,J＝4.0Hz,1H),3.68(m,1H)3.66(s,3H),3.23-3.11(m,2H),3.05(dd,J＝13.6,7.4Hz,2H),1.95-1.82(m,1H),1.81-1.61(m,3H),1.61-1.47(m,2H).ESIMS m/z＝449.1(M+1).

Example 1835-amino-N- (5- (3, 3-difluoro-5- (methylamino) azepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 183

Following the procedure of example 101, starting from tert-butyl 6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl (methyl) carbamate, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7N ammonia in MeOH) gave 183 as a white solid (122mg, 48% over three steps).¹H NMR (400MHz, d6-DMSO)8.85(s,1H),7.59-7.49(m,4H),7.33-7.23(m,2H),3.80-3.57(m,4H),3.48-3.24(m,2H),3.14-3.03(m,1H),2.90-2.80(m,1H),2.50-2.04(m,5H),1.95(d, J ═ 13.9Hz,1H),1.77-1.65(m,1H). no alkyl NH was observed. LCMS (ES +) M/z498(M +1).

Example 1845-amino-N- (5- ((3R,5S) -3-amino-5-fluoropiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 184

A mixture of tert-butyl (3R,5S) -1- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -5-fluoropiperidin-3-ylcarbamate (200mg,0.31mmol) in HCl/MeOH (10mL) was stirred at ambient temperature for 20 hours and concentrated under reduced pressure to give a residue. The residue was diluted with MeOH (10mL), neutralized with 28% ammonia solution, and concentrated to give the crude product. The crude product was purified by preparative HPLC to give 184 as a light colored solid (138mg, 99%).¹H NMR(500MHz,CD3OD)(ppm):7.60(s,1H),7.50-7.45(m,1H),7.14-7.11(m,2H),5.36-5.23(m,1H),3.84-3.74(m,4H),3.63-3.49(m,2H),2.72-2.62(m,2H),2.54-5.41(m,1H),2.16-2.05(m,1H)；MS(ESI)m/z:452[M+H+]。

Example 185 (R) -5-amino-N- (5- (4-Aminoazepan-1-yl) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 185

Following the procedure of example 107, starting from tert-butyl (R) -2- (2, 6-difluorophenyl) -4- (5- (4- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (148mg,0.21mmol), 185 was obtained as an orange solid (69mg, 65% over two steps).¹H NMR (400MHz, d6-DMSO)9.0(br s,1H),7.79(s,1H),7.60-7.48(m,3H),7.33-7.25(m,2H),4.84(q, J ═ 9.1Hz,2H),3.15-3.10(m,4H),3.04-2.97(m,1H),1.88-1.73(m,3H),1.65-1.45(m,3H). no alkyl NH was observed₂。LCMS(ES+)m/z516(M+1).

Example 186N- (5- (1, 4-diazepan-1-yl) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -5-amino-2- (2, 6-difluorophenyl) thiazole-4-carboxamide 186

Following the procedure of example 145, starting from tert-butyl 4- (4-nitro-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylate (197mg,0.5mmol) in 5% MeOH (in Et)₂O) to yield 186 as di-hydrochloride and orangeSolid (48mg, 19%, over three steps).¹H NMR (400MHz, d6-DMSO)9.22(br s,2H),8.91(s,1H), 7.60-7.52(m,3H),7.34-7.24(m,2H),5.02(q, J ═ 9.1Hz,2H),3.43-3.12(m,8H),2.02-1.95(m, 2H). LCMS (ES +) M/z502(M +1). No alkyl NH was observed.

Example 1875-amino-N- (5- (4-amino-5-hydroxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 187

Following the procedure of example 107, starting from N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-hydroxyazepan-4-yl) -2,2, 2-trifluoroacetamide, gave 187 as an off-white solid (119mg, 49%, over two steps).¹H NMR(400MHz,d6-DMSO)8.83(s,1H),7.60-7.47(m,4H),7.28(t,J＝8.8Hz,2H),3.64(s,3H),3.50-3.05(m,8H),2.81(t,J＝8.7Hz,1H),2.00-1.84(m,2H),1.78-1.67(m,1H),1.65-1.56(m,1H)。LCMS(ES+)m/z464(M+1).

Example 1885-amino-N- (5- (3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 188

Compound 188 was prepared according to the procedures described herein.¹H NMR(400MHz,DMSO)8.74(s,1H),7.56(s,1H),7.52-7.46(m,2H),7.31-7.23(m,2H),3.67(s,3H),3.52(t,J＝13.2Hz,2H),3.16(t,J＝6.0Hz,2H),2.23-2.09(m,2H),1.82-1.68(m,4H).ESIMS m/z＝469.1(M+1)

Example 1895-amino-N- (5- ((3S,5S) -3-amino-5-fluoropiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 189

A mixture of (3S,5S) -1- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -5-fluoropiperidin-3-ylcarbamic acid tert-butyl ester (208mg,0.32mmol) in HCl/MeOH (10mL) was stirred at ambient temperature for 20HConcentrated under reduced pressure to give a residue. The residue was diluted with MeOH (10mL), neutralized with 28% ammonia solution, and concentrated to give the crude product. The crude product was purified by preparative HPLC to give 189(130mg, 90%) as a solid.¹H NMR(500MHz,DMSO)(ppm):8.82(s,1H),7.56-7.51(m,3H),7.41(s,1H),7.30-7.26(m,2H),4.80-4.65(m,1H),3.64(s,3H),3.06-2.98(m,2H),2.89-2.84(m,1H),2.70-2.66(m,1H),2.23-2.18(m,1H),1.72(br s,3H),1.41-1.32(m,1H)；MS(ESI)m/z:452[M+H+]。

Example 1905-amino-2- (2, 6-difluorophenyl) -N- (5- (6-hydroxy-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 190

To a solution of intermediate 44, 6-hydroxy-6-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester (70mg,0.20mmol) in MeOH (5mL) was added 10% palladium on carbon (10mg) and the mixture was in H₂Stir under ambient (60psi) for 16 hours. By passingThe mixture was filtered and the solvent was removed under reduced pressure to give 4- (4-amino-1-methyl-1H-pyrazol-5-yl) -6-hydroxy-6-methyl-1, 4-diazepan-1-carboxylic acid tert-butyl ester as an oil. To a solution of the amine in DCM (5mL) was added DIPEA (0.1mL,9.6mmol), PyBOP (0.16g,0.3mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acid (78mg,0.22mmol) and the mixture was stirred at rt for 18 h. The mixture was diluted with DCM (30mL) and washed with water (10 mL). The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-60% EtOAc/isohexane) afforded 4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6-hydroxy-6-methyl-1, 4-diazepan-1-carboxylic acid tert-butyl ester as a solid (122 mg). To the solid (122mg,0.18mmol) in MeOH (1mL) was added HCl solution (4M in 1, 4-dioxane, 3.2mL,12.9mmol) and the resulting solution was stirred at rt for 16 h. The solvent was removed under reduced pressure and the crude residue dissolvedIn MeOH and loaded onto SCX column. The column was washed with MeOH and eluted with 7N ammonia (in MeOH). Purification by preparative HPLC gave 190 as an off-white solid (40mg, 44%, over three steps).¹HNMR (400MHz, d6-DMSO)9.19(s,1H),8.24(s,1H),7.59-7.48(m,3H),7.33-7.23(m,2H),3.69(s,3H),3.26-3.02(m,4H),2.98-2.73(m,4H),1.01(s, 3H). No alkyl NH and OH were observed. LCMS (ES +) M/z464(M +1).

Example 1915-amino-2- (2, 6-difluorophenyl) -N- (5- (6-fluoro-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 191

Following the procedure of example 101, starting from tert-butyl 6-fluoro-6-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylate, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7N ammonia in MeOH), 191 was obtained as a beige solid (51mg, 39%, over three steps).¹H NMR(400MHz,d6-DMSO)9.37(s,1H),7.62-7.48(m,4H),7.34-7.24(m,2H),3.68(s,3H),3.16(t,J＝6.4Hz,4H),3.03-2.79(m,4H),1.21(d,J＝21.2Hz,3H)。LCMS(ES+)m/z466(M+1).

Example 1925-amino-2- (2, 6-difluorophenyl) -N- (5- (6-methoxy-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 192

To a cooled (ice-water bath) solution of intermediate 44, 6-hydroxy-6-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester (70mg,0.20mmol) in DMF (1mL) was added sodium hydride (60% in mineral oil, 9.5mg,0.24mmol) under nitrogen and the mixture was stirred for 10 min. Methyl iodide (0.04mL,0.6mmol) was added and the mixture was stirred at room temperature for 16 h. Sodium hydride (60% in mineral oil, 9.5mg,0.24mmol) was added and the mixture stirred for 30 minutes, then more methyl iodide (0.04mL,0.6mmol) was added. After 5h, water (30mL) was added and the mixture was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with Na₂SO₄Drying, and removing solvent under reduced pressure6-methoxy-6-methyl-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester was obtained as an oil. A solution of this oil in MeOH (4mL) was passed through(all H)₂60 ℃ C., flow rate 1 mL/min, 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give 4- (4-amino-1-methyl-1H-pyrazol-5-yl) -6-methoxy-6-methyl-1, 4-diazepan-1-carboxylic acid tert-butyl ester as an oil. To a solution of this amine in DCM (10mL) was added DIPEA (0.1mL,9.6mmol), PyBOP (160mg,0.30mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 (78mg,0.22mmol) and the mixture was stirred at rt for 18 h. The mixture was diluted with DCM (30mL) and washed with water (20 mL). The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (75% EtOAc/isohexane) afforded 4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6-methoxy-6-methyl-1, 4-diazepan-1-carboxylic acid tert-butyl ester as an off-white solid (123 mg). The solid (120mg,0.30mmol) was stirred with HCl in 1, 4-dioxane (4M,2.3mL,9.1mmol) in MeOH (1mL) at rt for 16 h. The solvent was removed under reduced pressure and the crude residue was redissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7N ammonia (in MeOH), and the residue was purified by silica gel column chromatography (0-10% MeOH/DCM, 1% 7N ammonia in MeOH). Further purification by preparative HPLC gave 192 as the mono-formate salt as an off-white solid (19mg, 20% over four steps).¹H NMR (400MHz, d6-DMSO)9.38(s,1H),8.21(s,1H),7.66(s,1H),7.60-7.48(m,3H),7.33-7.23(m,2H),3.67(t, J ═ 4.9Hz,3H),3.29-2.69(m,11H),0.97(s,3H). LCMS (ES +) M/z477(M +1).

Example 1935-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 193

According toOperation of example 101, starting from tert-butyl 6, 6-difluoro-4- (4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylate, after column chromatography on silica gel (0-10% MeOH/DCM, 1% 7N ammonia in MeOH) and preparative HPLC gave 193 as an off-white solid (86mg, 25% over three steps).¹H NMR(400MHz,d6-DMSO)11.99(s,1H),8.53(s,1H),7.85(s,1H),7.59-7.47(m,3H),7.32-7.24(m,2H),3.70(t,J＝13.9Hz,2H),3.22-3.10(m,4H),2.96-2.91(m,2H),2.80-2.73(s,1H)。LCMS(ES+)m/z456(M+1).

Example 1945-amino-2- (2, 6-difluorophenyl) -N- (5- (6-methoxy-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 194

Intermediate 47, 6-methoxy-4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester (114mg,0.32mmol) in MeOH (15mL) was purified by(all H)₂Flow rate 1 mL/min, 30mm 10% Pd/C cartridge, 70 ℃). The solvent was removed under reduced pressure to give 4- (4-amino-1-methyl-1H-pyrazol-5-yl) -6-methoxy-1, 4-diazepan-1-carboxylic acid tert-butyl ester as a pink solid (100 mg). To a solution of this solid in DCM (5mL) was added DIPEA (0.84mL,48mmol), PyBOP (219mg,0.42mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 (118mg,0.33mmol) and the mixture was stirred at rt for 65 h. The mixture was diluted with DCM (50mL) and washed with water (10 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (0-5% MeOH/DCM) gave tert-butyl 4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6-methoxy-1, 4-diazepan-1-carboxylate as a pink solid (160 mg). The solid (159mg,0.24mmol) was dissolved in HCl (4M,3mL,12.0mmol) and MeOH (3mL) in 1, 4-dioxane and heated after an explosion-proof barrier in a sealed pressure vessel for 16 hours at 60 ℃. Removing under reduced pressureThe solvent and crude residue were redissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 0-10% 7N ammonia in MeOH/DCM to give 194 as a light brown solid (53mg, 36%, three steps).¹H NMR(400MHz,CDCl₃)11.35(s,1H),8.13(s,1H),7.39-7.29(m,1H),7.04(t, J ═ 8.6Hz,2H),6.33(s,2H),3.74(s,3H),3.41-3.28(m,4H),3.36-3.00(m,6H),2.88-2.77(m,1H),2.69(dd, J ═ 12.7,7.6Hz, 1H). No alkyl NH was observed. LCMS (ES +) M/z464(M +1).

Example 1955-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide 195

Intermediate 49, N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonyl-amino) -2- (2-fluorophenyl) thiazole-4-carboxylic acid, gave 195 as a brown solid (368mg, 69% over two steps) according to the procedure described herein.¹H NMR(400MHz,CDCl₃)8.49(s,1H),8.13(td, J ═ 7.7,1.8Hz,1H),7.79(s,1H),7.39-7.31(m,1H),7.33-7.17(m,1H),7.17(dd, J ═ 11.4,8.3Hz,1H),6.09(s,2H),4.50 (dd, J ═ 48.0,8.7,3.8Hz,1H),3.73(s,3H),3.36-3.19(m,5H),2.34-2.23(m,1H),2.14-2.05(m,1H),2.01-1.93(m,1H),1.78-1.67(m,1H), no alkyl NH was observed₂。LCMS(ES+)m/z448(M+1).

Example 1965-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 196

A solution of PyBOP (1.82g,3.5mmol) and 2-bromo-5- (tert-butoxycarbonyl-amino) thiazole-4-carboxylic acid (889mg,2.75mmol) in DCM (40mL) was stirred at room temperature for 30 min. A solution of N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide (808mg,2.50mmol) and DIPEA (0.74mL,4.25mmol) in DCM (40mL) was added and the mixture was stirred at room temperature for 16H. The mixture was diluted with DCM (50mL) and washed with water (10 m)L). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification by column chromatography on silica gel (0-5% MeOH/DCM) gave tert-butyl 2-bromo-4- (5- (4-fluoro-5- (tert-butoxycarbonylamino) azepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate as a pale brown solid (1.57 g). The solid (786mg,1.25mmol), Na₂CO₃A mixture of (265mg,2.50mmol) and 2-fluoro-5-methylphenylboronic acid (250mg,1.63mmol) in DME (12mL) and water (4mL) was degassed by gently bubbling nitrogen through the mixture for 30 minutes. Then [1,1' -bis (diphenylphosphino) ferrocene ] is added]Dichloro-palladium (II) (102mg,0.125mmol) and the mixture degassed for a further 10 minutes and then heated in a microwave at 100 ℃ for 4 hours. Water (10mL) was added and the mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (0-5% MeOH/DCM) gave tert-butyl 4- (5- (4-fluoro-5- (tert-butoxycarbonylamino) azepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) -2- (2-fluoro-5-methylphenyl) thiazol-5-ylcarbamate as a brown solid (600 mg). The solid (591mg,0.9mmol) was dissolved in HCl (4M,10mL,40.0mmol) and MeOH (10mL) in 1, 4-dioxane and heated at 60 ℃ for 16 hours after an explosion-proof barrier in a sealed pressure vessel. The solvent was removed under reduced pressure and the residue redissolved on MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 0-10% 7N ammonia in MeOH/DCM to give 196 as a light brown solid (235mg, 41% over three steps).¹H NMR(400MHz,CDCl₃)8.44(s,1H),7.87(dd, J ═ 7.2,2.2Hz,1H),7.74(s,1H),7.18-7.12(m,1H),7.05(dd, J ═ 11.0,8.4Hz,1H),6.08(s,2H),4.49(dtd, J ═ 48.0,8.5,3.7Hz,1H),3.74(s,3H),3.38-3.19(m,5H),2.40(s,3H),2.31-2.20(m,1H),2.15-2.09(m,1H),2.01-1.94(m,1H),1.74-1.68(m,1H), no alkyl NH was observed₂。LCMS(ES+)m/z462(M+1).

Example 197 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (4- (2,2, 2-trifluoroethylamino) azepan-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 197

(R) -4- (5- (4-Aminoaza)Cycloheptan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-ylcarbamic acid tert-butyl ester (112mg,0.204mmol) and 2,2, 2-trifluoroethyl trifluoromethanesulfonate (95mg,0.409mmol) were dissolved in dichloromethane/DMF (1.5mL/1.5 mL). N, N-diisopropylethylamine (132mg,1.02mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove DMF, redissolved in ethyl acetate and washed with brine. The aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were concentrated and purified by flash chromatography eluting with 0-100% ethyl acetate/heptane to give tert-butyl (R) -2- (2, 6-difluorophenyl) -4- (1-methyl-5- (4- (2,2, 2-trifluoroethylamino) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (96mg, 75%) which was deprotected by 4N HCl (in dioxane) and purified on reverse phase HPLC to give 197.¹H NMR(400MHz,DMSO)8.65(s,1H),7.59-7.43(m,4H),7.25(t,J＝8.7Hz,2H),3.64(s,3H),3.24-3.01(m,6H),2.81(s,1H),2.14(d,J＝6.1Hz,1H),1.96-1.74(m,3H),1.65-1.48(m,3H)。MS(ESI)m/z:530.2[M+H+]。

Example 1983-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) picolinamide 198

Compound 198 was prepared according to the procedure for example 180.¹H NMR(400MHz,DMSO)9.81(s,1H),8.03(dd,J＝11.2,4.9Hz,1H),7.72(dd,J＝8.7,2.3Hz,1H),7.64(s,1H),7.42(ddd,J＝7.4,6.1,1.8Hz,1H),7.36-7.24(m,3H),7.07(s,2H),3.70(s,3H),3.59(t,J＝13.8Hz,2H),3.17(dt,J＝18.1,9.7Hz,4H),2.89(s,2H),2.78(s,1H)。MS(ESI)m/z:446.2[M+H+]。

Example 199 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 199

Compound 199 was prepared according to the procedure described in this application.¹H NMR(400MHz,DMSO)8.72(s,1H),7.55(s,1H),7.55-7.50(m,1H),7.48(s,2H),7.28(d,J＝8.8Hz,2H),4.85-4.64(m,1H),3.66(s,3H),3.50-3.33(m,2H),3.18-3.05(m,2H),1.96(ddd,J＝23.4,9.2,4.8Hz,2H),1.74(ddt,J＝20.0,14.0,7.3Hz,3H),1.60-1.46(m,1H).ESIMS m/z＝451.1(M+1)

Example 200 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 200

Compound 200 was prepared according to the procedures described herein.¹H NMR(400MHz,DMSO)8.72(s,1H),7.55(s,1H),7.55-7.50(m,1H),7.48(s,2H),7.30-7.23(m,2H),4.91-4.60(m,1H),3.66(s,3H),3.50-3.33(m,2H),3.17-3.08(m,2H),2.01-1.89(m,2H),1.89-1.72(m,2H),1.67(dd,J＝15.2,9.1Hz,1H),1.60-1.47(m,1H).ESIMS m/z＝451.1(M+1)

Example 2015-amino-2- (2, 6-difluorophenyl) -N- (5- (3-hydroxy-3-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 201

Compound 201 was prepared according to the procedures described herein.¹H NMR(400MHz,DMSO)8.85(s,1H),7.60(s,1H),7.56-7.50(m,1H),7.48(s,2H),7.26(m,2H),4.19(s,1H),3.66(s,3H),3.09(t,J＝6.1Hz,2H),3.03(s,2H),1.85-1.57(m,5H),1.50(dd,J＝14.0,8.1Hz,1H),1.05(s,3H).ESIMS m/z＝463.2(M+1)

Example 2025-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 202

Compound 202 was prepared as an off-white solid (212mg, 36% over three steps) according to the procedure described herein.¹H NMR(400MHz,CDCl₃)8.41(s,1H),7.84(ddd,J＝9.1,5.8,3.2Hz,1H),7.78(s,1H),7.13(td,J＝9.7,4.4Hz,1H),7.07-7.00(m,1H),6.15(s,2H),4.50(dtd,J＝47.9,8.7,3.8Hz,1H),3.74(s,3H),3.37-3.21(m,5H)2.32-2.21(m,1H),2.15-1.96(m,2H),1.76-1.70(m,1H)₂。LCMS(ES+)m/z466(M+1).

Example 2035-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 203

A solution of PyBOP (692mg,1.33mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25 (372mg,1.05mmol) in DCM (40mL) was stirred at room temperature for 30 min. A solution of intermediate 51, N- (1- (4-amino-1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide (354mg,0.95mmol) and DIPEA (0.28mL,1.62mmol) in DCM (40mL) was added and the mixture stirred at room temperature for 16H. The mixture was diluted with DCM (50mL) and washed with water (20 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave tert-butyl 4- (1- (2, 2-difluoroethyl) -5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1H-pyrazol-4-ylcarbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-ylcarbamate as an off-white solid (600mg,0.84mmol) dissolved in HCl (4M,10mL,40.0mmol) and MeOH (10mL) in 1, 4-dioxane and heated in a sealed pressure vessel after an explosion-proof barrier at 60 ℃ for 16 hours. The solvent was removed under reduced pressure and the residue redissolved on MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 0-10% 7N ammonia (in MeOH/DCM) to give 203 as an off-white solid (197mg, 40%, over two steps).¹H NMR(400MHz,CDCl₃)8.75(s,1H),8.00(s,1H),7.37-7.29(m,1H),7.09-6.99(m,2H),6.31-6.01(m,3H),4.56-4.28(m,3H),3.39-3.13(m,5H),2.32-2.17(m,1H),2.14-1.94(m,2H),1.77-1.64(m, 1H). No alkyl NH was observed₂。LCMS(ES+)m/z516(M+1).

Example 204 (R) -5-amino-N- (5- (4- (2, 2-difluoroethylamino) azepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 204

Compound 204 was prepared according to the procedure for example 197.¹H NMR(400MHz,DMSO)8.66(s,1H),7.61-7.40(m,4H),7.25(dd,J＝14.5,5.8Hz,2H),5.89(tt,J＝56.6,4.3Hz,1H),3.64(s,3H),3.22-3.01(m,4H),2.91-2.73(m,3H),1.97-1.75(m,3H),1.64-1.46(m,3H)。MS(ESI)m/z:512.2[M+H+]。

Example 2055-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (5-methyl-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 205

Racemic compound 205 was prepared according to the procedures described in this application.¹H NMR(400MHz,DMSO)12.03(s,1H),7.91(s,1H),7.63-7.46(m,3H),7.35-7.21(m,2H),3.60(s,3H),3.22-2.99(m,5H),2.85-2.64(m,3H),1.52-1.35(m,1H),1.31-1.11(m,1H),0.89(d,J＝6.3Hz,3H)。MS(ESI)m/z:448.2[M+H+]。

Example 206 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-fluoro-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 206

Compound 206 was prepared by chiral separation on SFC from its racemic mixture according to the procedures described herein.¹H NMR(400MHz,DMSO)9.37(s,1H),7.62(s,1H),7.56-7.52(m,1H),7.51(s,2H),7.26(dd,J＝14.5,5.8Hz,2H),3.66(s,3H),3.34(s,1H),3.12(dd,J＝13.6,3.1Hz,3H),2.99-2.87(m,2H),2.87-2.73(m,2H),1.19(d,J＝21.2Hz,4H).ESIMS m/z＝466.1(M+1)

Example 207 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-hydroxy-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 207

Compound 207 was separated from its racemic mixture on SFC by chirality according to procedures described herein.¹H NMR(400MHz,DMSO)9.20(s,1H),7.60(s,1H),7.54(dd,J＝8.3,6.3Hz,1H),7.49(s,2H),7.27(m,2H),4.30(s,1H),3.67(s,3H),3.08(m,5H),2.89(dt,J＝11.7,5.7Hz,1H),2.84-2.76(m,1H),2.74(s,2H),0.99(s,3H).ESIMS m/z＝464.2(M+1)

Example 208 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-hydroxy-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 208

Compound 208 was separated from its racemic mixture on SFC by chirality according to the procedures described herein.¹H NMR(400MHz,DMSO)9.20(s,1H),7.60(s,1H),7.53(m,1H)7.50(s,2H),7.27(m,2H),4.30(s,1H),3.67(s,3H),3.16-3.00(m,5H),2.89(dt,J＝11.8,5.8Hz,1H),2.83-2.77(m,1H),2.74(s,2H),0.99(s,3H).ESIMS m/z＝464.2(M+1)

Example 209 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-fluoro-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 209

Compound 209 was separated from its racemic mixture by chirality on SFC according to the procedures described herein.¹H NMR(400MHz,DMSO)9.37(s,1H),7.62(s,1H),7.56-7.52(m,1H),7.52(s,2H),7.26(dd,J＝14.5,5.8Hz,2H),3.66(s,3H),3.34(s,1H),3.11(dd,J＝13.6,3.1Hz,3H),2.98-2.87(m,2H),2.87-2.73(m,2H),1.18(d,J＝21.2Hz,4H).ESIMS m/z＝466.1(M+1)

Example 2105-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 210

Compound 210 is separated from its racemic mixture on SFC by chirality according to procedures described herein.¹H NMR(400MHz,DMSO)8.91(s,1H),8.22(s,1H),7.68(s,1H),7.53(m,1H),7.50(s,2H),7.27(t,J＝8.7Hz,2H),6.36(m,1H),4.42(dd,J＝14.3,4.0Hz,2H),3.25-3.07(m,6H),2.21-2.04(m,1H),1.94(ddd,J＝41.1,22.7,8.9Hz,2H),1.75-1.53(m,1H).ESIMS m/z＝516.1(M+1)

Example 2115-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 211

Compound 211 was separated from its racemic mixture on SFC by chirality according to the procedures described herein.¹H NMR(400MHz,DMSO)8.90(s,1H),8.22(s,1H),7.68(s,1H),7.53(m,1H),7.51(s,2H),7.27(t,J＝8.7Hz,2H),6.36(m,1H),4.42(dd,J＝14.3,4.0Hz,2H),3.25-3.09(m,6H),2.21-2.04(m,1H),1.94(ddd,J＝41.1,22.7,8.9Hz,2H),1.75-1.55(m,1H).ESIMS m/z＝516.1(M+1)

Example 2125-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 212

Compound 212 was separated from its racemic mixture on SFC by chiral separation according to procedures described herein.¹H NMR(400MHz,DMSO)8.95(s,1H),8.07(d,J＝7.7Hz,1H),7.46(s,1H),7.39(s,2H),7.23(d,J＝9.3Hz,2H),4.48(dtd,J＝48.1,8.3,3.6Hz,1H),3.65(s,3H),3.15(ddd,J＝13.5,8.5,3.3Hz,5H),2.36(s,3H),2.22-2.06(m,1H),2.06-1.92(m,1H),1.91-1.78(m,1H),1.64(m,1H).ESIMS m/z＝462.2(M+1)

Example 2135-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 213

Compound 213 was separated from its racemic mixture on SFC by chirality according to the procedures described in the present application.¹H NMR(400MHz,DMSO)8.95(s,1H),8.07(d,J＝7.7Hz,1H),7.45(s,1H),7.39(s,2H),7.23(d,J＝9.3Hz,2H),4.51(dtd,J＝48.1,8.3,3.6Hz,1H),3.65(s,3H),3.15(ddd,J＝13.5,8.5,3.3Hz,5H),2.36(s,3H),2.22-2.06(m,1H),2.06-1.92(m,1H),1.91-1.78(m,1H),1.64(m,1H).ESIMS m/z＝462.2(M+1)

Example 2143-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide 214

Compound 214 was prepared according to the procedure for example 180.¹H NMR(400MHz,DMSO)9.93(s,1H),8.67(s,1H),8.12(t,J＝7.9Hz,1H),7.73(s,2H),7.58(s,1H),7.52-7.40(m,1H),7.35(dd,J＝13.3,5.6Hz,2H),3.70(s,3H),3.58(t,J＝13.8Hz,3H),2.89(s,2H),2.78(s,1H)。MS(ESI)m/z:447.2[M+H+]。

Example 2155-amino-2- (2, 6-difluorophenyl) -N- (5- (5- (dimethylamino) -3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 215

Following the procedure of example 101, starting from 6, 6-difluoro-N, N-dimethyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-amine, after purification by preparative HPLC, 215 was obtained as a white solid (119mg, 12%).¹H NMR(400MHz,d6-DMSO)8.72(s,1H),7.58-7.48(m,4H),7.31-7.21(m,2H),3.75-3.50(m,3H),3.53-3.22(m,2H),3.16-3.06(m,1H),2.89-2.81(m,1H),2.37-2.19(m,2H),2.10-2.05(m,6H),1.89-1.74(m,3H)。LCMS(ES+)m/z512(M+1).

Example 2165-amino-N- (5- (5-amino-3-methoxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 216

Following the procedure of example 101, starting from tert-butyl 6-methoxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate, after purification by preparative HPLC, 216 was obtained as the mono-formate saltWhite solid (480mg, 39%, over three steps).¹H NMR (400MHz, d6-DMSO)8.92and8.79(2br s,1H),8.43(s,1H),7.61-7.46(m,4H),7.36-7.25(m,2H),3.67and3.66(2s,3H),3.54-2.99(m,9H),2.26-2.18(m,1H),2.05-1.91(m,1H),1.86-1.69(m, 2H). To observe alkyl NH₂。LCMS(ES+)m/z478(M+1).

Example 2175-amino-N- (5- ((4S,5S) -4-amino-5-methoxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 217

To a solution of intermediate 54, N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-methoxyazepan-4-yl) -2,2, 2-trifluoroacetamide (150mg,0.45mmol) in DCM (20mL) were added DIPEA (1.0mL), PyBOP (580mg,1.12mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acid (159mg,0.45mmol) and the mixture was stirred at room temperature for 18H. The mixture was diluted with DCM (100mL) and washed with water (20 mL). The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (70-80% EtOAc/isohexane) afforded 2- (2, 6-difluorophenyl) -4- (5- (4-methoxy-5- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamic acid tert-butyl ester as an off-white solid (260mg,0.39mmol) stirred in HCl in 1, 4-dioxane (4M,4.8mL,19.3mmol) in MeOH (5mL) for 3 days at room temperature. The solvent was removed under reduced pressure, and the resulting solid was dissolved in MeOH/water (10mL/10mL) and K was added thereto₂CO₃(267mg,19.3 mmol). The reaction mixture was heated at 65 ℃ for 3 hours. MeOH was removed under reduced pressure and the aqueous residue was diluted with water (5mL) and extracted with 5% MeOH in DCM (2 × 75 mL). The organic layers were combined and MgSO₄Dried and concentrated under reduced pressure to give 217 as a beige solid (144mg, 67%, over three steps).¹H NMR(400MHz,CDCl₃)8.62(s,1H),7.84(s,1H),7.38-7.28(m,1H),7.02(t, J ═ 8.8Hz,2H),6.15(s,2H),3.72(s,3H),3.37(s,3H),3.36-3.25(m,2H),3.22-3.08(m,3H),3.07-2.99(m,1H),2.17-2.10(m,1H),2.02-1.93(m,1H),1.88-1.65(m,2H). no alkyl NH was observed₂。LCMS(ES+)m/z478(M+1).

Example 2185-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide 218

Following the procedure of example 145, starting from intermediate 19,6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester, 218 was obtained as a yellow solid (560mg, 60%, over two steps).¹H NMR(400MHz,CDCl₃)8.54(s,1H),8.18(td, J ═ 3.9,1.8Hz,1H),7.74(s,1H),7.39-7.33(m,1H),7.33-7.17(m,1H),7.17(ddd, J ═ 11.4,8.2,1.2Hz,1H),6.09(s,2H),3.76(s,3H),3.73-3.61(m,1H),3.53-3.36(m,3H),3.26(td, J ═ 11.6,4.9Hz,1H),2.41-2.25(m,2H),2.02-1.91(m,1H),1.88-1.78(m,1H), no alkyl NH was observed₂。LCMS(ES+)m/z466(M+1).

Example 2195-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 219

Following the procedure of example 145, starting from intermediate 19,6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester, 219 was obtained as a yellow solid (665mg, 70%, over two steps).¹H NMR(400MHz,CDCl₃)8.52(s,1H),7.95(d, J ═ 7.3Hz,1H),7.72(s,1H),7.14(s,1H),7.04(dd, J ═ 11.1,8.5Hz,1H),6.09(s,2H),3.86-3.51(m,4H),3.57-3.37(m,3H),3.33-3.23(m,1H),2.53-2.15(m,5H),2.02-1.90(m,1H),1.87-1.74(m, 1H). No alkyl NH was observed₂。LCMS(ES+)m/z480(M+1).

Example 2205-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 220

According to embodiment 145Operation, starting from intermediate 19,6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamic acid tert-butyl ester, gave 220 as a yellow solid (570mg, 59%, over two steps).¹H NMR(400MHz,CDCl₃)8.62(s,1H),7.95-7.88(m,1H),7.85(s,1H),7.13(td, J ═ 9.7,4.4Hz,1H),7.07-6.98(m,1H),6.15(s,2H),3.81-3.58(m,4H),3.56-3.36(m,3H),3.30-3.20(m,1H),2.51-2.39(m,1H),2.38-2.21(m,1H),2.05-1.94(m,1H),1.91-1.79(m,1H). no alkyl NH was observed₂。LCMS(ES+)m/z484(M+1).

Example 2215-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 221

Compound 221 was prepared by chiral separation on SFC from its racemic mixture according to the procedures described in the present application.¹H NMR(400MHz,DMSO)9.08(s,1H),8.15(s,1H),7.45(d,J＝11.0Hz,2H),7.43(s,2H),7.27(t,J＝8.3Hz,1H),4.45(dtd,J＝48.2,8.4,3.6Hz,1H),3.65(s,3H),3.15(ddd,J＝25.1,17.1,8.5Hz,5H),2.20-2.03(m,1H),2.02-1.90(m,1H),1.88-1.77(m,1H),1.71-1.53(m,1H).ESIMS m/z＝466.1(M+1)

Example 2225-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 222

Compound 222 was prepared from its racemic mixture by chiral separation on SFC according to the procedures described herein.¹H NMR(400MHz,DMSO)9.08(s,1H),8.15(s,1H),7.46(d,J＝11.0Hz,2H),7.43(s,2H),7.28(t,J＝8.3Hz,1H),4.45(dtd,J＝48.2,8.4,3.6Hz,1H),3.66(s,3H),3.15(ddd,J＝25.1,17.1,8.5Hz,5H),2.20-2.03(m,1H),2.02-1.90(m,1H),1.89-1.78(m,1H),1.71-1.53(m,1H).ESIMS m/z＝466.1(M+1)

Example 2235-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (pyridin-2-yl) thiazole-4-carboxamide 223

Compound 223 was prepared according to the procedures described herein.¹H NMR(400MHz,DMSO)9.12(s,1H),8.54(d,J＝4.7Hz,1H),8.08(d,J＝8.0Hz,1H),7.92(td,J＝7.8,1.5Hz,1H),7.56(s,2H),7.47(s,1H),7.38(dd,J＝7.0,5.3Hz,1H),3.68(s,3H),3.59(t,J＝13.9Hz,2H),3.24-3.16(m,2H),2.97-2.86(m,2H)。MS(ESI)m/z:435.1[M+H+]。

Example 2245-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxamide 224

Compound 224 was prepared according to the procedures described herein.¹H NMR(400MHz,DMSO)9.37(s,1H),8.44(d,J＝4.6Hz,1H),7.86(dd,J＝11.1,8.5Hz,1H),7.68(d,J＝2.8Hz,3H),7.48(dt,J＝8.4,4.2Hz,1H),3.68(s,3H),3.57(t,J＝13.4Hz,2H),3.27-3.18(m,3H),3.07-2.89(m,3H),2.07(s,2H)。MS(ESI)m/z:453.1[M+H+]。

Example 225 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (5-methyl-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 225

Compound 225 was prepared as a single enantiomer by chiral separation on SFC from its racemic mixture 205 according to procedures described herein.¹H NMR(400MHz,DMSO)11.81(s,1H),8.20(s,1H),7.88(s,1H),7.62-7.46(m,3H),7.35-7.21(m,2H),3.60(s,3H),3.21-3.01(m,5H),2.90-2.69(m,3H),1.48(d,J＝11.6Hz,1H),1.35-1.17(m,1H),0.92(d,J＝6.3Hz,3H)。MS(ESI)m/z:448.1[M+H+]。

Example 226 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (5-methyl-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 226

Compound 226 is prepared as a single enantiomer by chiral separation on SFC from its racemic mixture 205 according to procedures described herein.¹H NMR(400MHz,DMSO)11.83(s,1H),8.23(s,1H),7.88(s,1H),7.61-7.47(m,3H),7.33-7.23(m,2H),3.60(s,3H),3.26-2.98(m,6H),2.84-2.67(m,3H),1.48(d,J＝11.9Hz,1H),1.32-1.12(m,1H),0.92(d,J＝6.3Hz,3H)。MS(ESI)m/z:448.1[M+H+]。

Example 227 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-hydroxy-3-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 227

Compound 227 was prepared according to the procedures described herein.¹H NMR(400MHz,DMSO)8.85(s,1H),7.61(s,1H),7.56-7.50(m,1H),7.48(s,2H),7.26(m,2H),4.19(s,1H),3.67(s,3H),3.09(t,J＝6.1Hz,2H),3.03(s,2H),1.85-1.58(m,5H),1.50(dd,J＝14.0,8.1Hz,1H),1.05(s,3H).ESIMS m/z＝463.2(M+1)

Example 228 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-hydroxy-3-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 228

Compound 228 was prepared according to the procedures described herein.¹H NMR(400MHz,DMSO)8.85(s,1H),7.61(s,1H),7.56-7.50(m,1H),7.48(s,2H),7.26(m,2H),4.19(s,1H),3.67(s,3H),3.09(t,J＝6.1Hz,2H),3.03(s,2H),1.85-1.57(m,5H),1.50(dd,J＝14.0,8.1Hz,1H),1.05(s,3H).ESIMS m/z＝463.2(M+1)

Example 2295-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide 229

Compound 229 is prepared by chiral separation on SFC from its racemic mixture according to procedures described hereinAs a single enantiomer.¹H NMR(400MHz,DMSO)8.93(s,1H),8.29(m,1H),7.48(s,1H),7.43(m,1H),7.41(s,2H),7.33(d,J＝7.9Hz,2H),4.48(dtd,J＝47.9,8.5,3.5Hz,1H),3.65(s,3H),3.23-3.10(m,5H),2.14(ddd,J＝19.7,8.6,3.1Hz,1H),1.98(ddd,J＝18.3,9.4,4.9Hz,1H),1.86(dd,J＝18.4,13.0Hz,1H),1.63(dtd,J＝14.3,9.5,4.6Hz,1H).ESIMS m/z＝448.2(M+1)

Example 2305-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide 230

Compound 230 was prepared as a single enantiomer by chiral separation on SFC from its racemic mixture according to the procedures described herein.¹H NMR(400MHz,DMSO)8.94(s,1H),8.29(m,1H),7.47(s,1H),7.43(m,1H),7.41(s,2H),7.34(d,J＝7.9Hz,2H),4.48(dtd,J＝47.9,8.5,3.5Hz,1H),3.65(s,3H),3.23-3.10(m,5H),2.14(ddd,J＝19.7,8.6,3.1Hz,1H),1.98(ddd,J＝18.3,9.4,4.9Hz,1H),1.86(dd,J＝18.4,13.0Hz,1H),1.65(dtd,J＝14.3,9.5,4.6Hz,1H).ESIMS m/z＝448.2(M+1)

Example 2313-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) methylpyridine amide 231

Racemic compound 231 was prepared according to the procedures described in the present application.¹H NMR(400MHz,DMSO)9.73(s,1H),8.01(dd,J＝11.3,4.8Hz,1H),7.73(dd,J＝8.7,2.1Hz,1H),7.67(s,1H),7.43(ddd,J＝7.2,6.2,1.7Hz,1H),7.37-7.24(m,3H),7.06(s,2H),4.40(dtd,J＝48.0,8.2,3.6Hz,1H),3.67(s,3H),3.28-3.00(m,5H),2.21-2.04(m,1H),2.04-1.89(m,1H),1.83(dd,J＝9.3,5.6Hz,1H),1.76-1.54(m,3H)。MS(ESI)m/z:442.2[M+H+]。

Example 2323-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide 232

Racemic compound 232 was prepared according to the procedures described in this application.¹H NMR(400MHz,DMSO)9.76(s,1H),8.68(d,J＝2.4Hz,1H),8.12(td,J＝8.2,1.8Hz,1H),7.73(s,2H),7.57(s,1H),7.46(dt,J＝7.2,3.7Hz,1H),7.41-7.27(m,2H),4.39(dtd,J＝48.0,8.2,3.6Hz,1H),3.66(s,3H),3.26-2.97(m,5H),2.19-1.87(m,2H),1.87-1.74(m,1H),1.69-1.51(m,3H)。MS(ESI)m/z:443.2[M+H+]。

Example 233 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-methylpiperazin-1-yl) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

Step A. (+ -) -2-methyl-4- (4-nitro-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) piperazine-1-carboxylic acid tert-butyl ester

A solution of intermediate 39, 5-bromo-4-nitro-1- (2,2, 2-trifluoroethyl) -1H-pyrazole (550mg,2.01mmol), (±) 2-methylpiperazine-1-carboxylic acid tert-butyl ester (403mg,2.01mmol), DIPEA (2mL) in EtOH (6mL) was stirred in a microwave oven at 130 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using PE: EtOAc (1:1) as the eluting solvent to give (±) -2-methyl-4- (4-nitro-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (377mg, 48%). MS (ESI) M/z 394[ M + H + ].

(±) -4- (4-amino-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) -2-methyl-piperazine-1-carboxylic acid tert-butyl ester

To (±) 2-methyl-4- (4-nitro-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) piperazineOxazine-1-carboxylic acid tert-butyl ester (370mg,0.94mmol) in MeOH (15mL) and H₂To a solution in O (3mL) were added zinc (362mg,5.6mmol) and NH₄Cl (400mg,7.5 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, filtered through Celite, and evaporated under reduced pressure to give (±) -4- (4-amino-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester as a yellow solid (300mg, 88%). MS (ESI) M/z:364[ M + H +]。

Step C. (+ -) -4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester

To a solution of t-butyl (±) -4- (4-amino-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylate (300mg,0.83mmol), 5- (t-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (294mg,0.83mmol), HATU (410mg,1.08mmol) in DMF (15mL) was added TEA (2 mL.) the mixture was stirred at 30 ℃ for 20H, poured into water (100mL) and extracted with water (50mL × 2) and brine (30mL × 2), the combined organic layers were washed with Na (× 3) and brine (30mL ×)₂SO₄Dried, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give (±) -4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester as a white solid (190mg, 33%). MS (ESI) M/z 702[ M + H +]。

Step d. chiral separation of (±) -4- (4- (5- (tert-butoxy-carbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (190mg) by preparative HPLC gave about 80mg of the (R) enantiomer and the (S) enantiomer, respectively.

Step E a mixture of (R) -4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (82mg,0.12mmol) in HCl/MeOH (10mL) was stirred at ambient temperature for 20H. The reaction mixture was concentrated under reduced pressureAnd (4) condensing to obtain a residue. The residue was diluted with MeOH (30mL), neutralized with 28% ammonia solution, concentrated and purified by preparative HPLC to give 233 as a white solid (32mg, 56%).¹H-NMR(500MHz,CD3OD)(ppm):7.69(s,1H),7.51-7.45(m,1H),7.17-7.12(m,2H),4.84-4.78(m,2H),3.22.-3.17(m,1H),3.05-2.86(m,6H),1.08(d,J＝6Hz,3H)；MS(ESI)m/z:502[M+H+]。

Example 2345-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 234

Following the procedure of example 145, starting from intermediate 56, tert-butyl 1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-ylcarbamate (1.33g,3.13mmol), 234 was obtained as a pale yellow solid (300mg, 36% over three steps).¹H NMR(400MHz,d6-DMSO)8.95(s,1H),7.67(s,1H),7.59-7.48(m,3H),7.29(t,J＝8.7Hz,2H),6.38(tt,J＝55.2,4.2Hz,1H),4.44(td,J＝14.4,4.2Hz,2H),3.75-3.58(m,1H),3.50-3.05(m,6H),2.29-2.06(m,2H),1.92-1.80(m,1H),1.77-1.63(m,1H)。LCMS(ES+)m/z534(M+1).

Example 2355-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) pyrimidine-4-carboxamide 235

Compound 235 was prepared according to the procedure for example 237.¹H NMR(400MHz,DMSO)9.78(s,1H),8.61(s,1H),8.13-8.00(m,1H),7.67(s,1H),7.53-7.39(m,1H),7.35-7.23(m,2H),7.00(s,2H),4.51-4.29(m,1H),3.29-2.98(m,5H),2.23-2.04(m,1H),2.04-1.87(m,1H),1.87-1.72(m,1H),1.72-1.51(m,1H)。MS(ESI)m/z:447.1[M+H+]。

Example 2365-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) pyrimidine-4-carboxamide 236

Compound 236 was prepared according to the procedure provided in example 237.¹H NMR(400MHz,DMSO)9.95(s,1H),8.61(s,1H),8.08-7.94(m,2H),7.66(s,1H),7.55-7.40(m,1H),7.35-7.21(m,2H),7.00(s,2H),3.58-3.44(m,2H),3.23-3.10(m,4H),2.96-2.81(m,2H)。MS(ESI)m/z:447.1[M+H+]。

Example 2375-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) pyrimidine-4-carboxamide 237

Sodium ethoxide (21 mass% in ethanol; 8.69mL,23.268mmol) was added to an ice-bath cooled mixture of 2-fluorobenzamidine (2.71g,15.512mmol) in ethanol (100 mL). The resulting mixture was warmed to room temperature and stirred at rt (room temperature) under nitrogen for 30 minutes. To the reaction mixture was added a solution of (E) -2, 3-dibromo-4-oxo-but-2-enoic acid (2.00g,7.7561mmol) in ethanol (20 ml). The mixture was heated at 50 ℃ for 3 hours. After cooling to RT, the reaction was concentrated in vacuo. Water and 1M NaOH (. about.50 ml) were added and the aqueous mixture was extracted with EtOAc. The aqueous phase was acidified to pH4 with 1N HCl (ca. 30ml) and then extracted 3X with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give 5-bromo-2- (2-fluorophenyl) pyrimidine-4-carboxylic acid, 770 mg.

Mixing CuSO₄(having 5H)₂O,65mg) was added to a mixture of 5-bromo-2- (2-fluorophenyl) pyrimidine-4-carboxylic acid (770mg,2.59 mmol) prepared above and 28% aqueous ammonium hydroxide solution (12 ml). The reaction was heated in a microwave reactor at 110 ℃ for 30 minutes. It was cooled to RT and concentrated in vacuo. The residue was diluted with 1N HCl (20mL) and extracted 3X with EtOAc. The combined organic extracts were dried over sodium sulfate and filtered and concentrated to give 5-amino-2- (2-fluorophenyl) pyrimidine-4-carboxylic acid (320mg, 53%).

1- (4-amino-1-methyl-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-amine (99mg,0.29mmol), 5-amino-2- (2-fluorophenyl) pyrimidine-4-carboxylic acid (87mg,0.37mmol), PyBop (304mg,0.57mmol), and diisopropylethylamine (222mg,1.72mmol) were dissolved in dichloromethane (10mL) and stirred at room temperature overnight. The reaction mixture was concentrated and purified by flash chromatography eluting with 0-100% ethyl acetate/heptane to give tert-butyl 1- (4- (5-amino-2- (2-fluorophenyl) pyrimidine-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-ylcarbamate (157mg, 97%).

Tert-butyl 1- (4- (5-amino-2- (2-fluorophenyl) pyrimidine-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-ylcarbamate (157mg) was stirred with 4N HCl in dioxane (6mL) at room temperature for 1 hour. The reaction mixture was concentrated to dryness, basified with saturated aqueous sodium bicarbonate and extracted 3x with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified on reverse phase HPLC to afford 237. MS (ESI) M/z 461.1[ M + H + ].

Example 241 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (3- (trifluoromethyl) piperidin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 241

Following the procedure of example 101, starting from enantiomerically pure 1-methyl-5- (3- (trifluoromethyl) piperidin-1-yl) -1H-pyrazol-4-amine and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid from example 25, compound 241 was obtained as a single enantiomer.¹H NMR(400MHz,DMSO)8.80(s,1H),7.62-7.47(m,1H),7.45(s,1H),7.32-7.14(m,2H),3.65(s,3H),3.23(dd,J＝11.5,3.8Hz,1H),3.15-2.91(m,3H),2.71-2.55(m,1H),1.95(dd,J＝12.8,3.3Hz,1H),1.79(d,J＝13.2Hz,1H),1.70-1.51(m,1H),1.39(ddd,J＝24.5,12.2,4.1Hz,1H)。MS(ESI)m/z:487.3[M+H+]。

Example 242 (R) -5-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [ 1-methyl-5- (3-trifluoromethyl-piperidin-1-yl) -1H-pyrazol-4-yl ] -amide 242

Following the procedure of example 101, from enantiomerically pure 1-methyl-5- (3- (trifluoromethyl) piperidin-1-yl) -1H-pyrazol-4-amine and 5 from example 25- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid gave compound 242 as a single enantiomer.¹H NMR(400MHz,DMSO)8.80(s,1H),7.62-7.47(m,1H),7.45(s,1H),7.32-7.14(m,2H),3.65(s,3H),3.23(dd,J＝11.5,3.8Hz,1H),3.15-2.91(m,3H),2.71-2.55(m,1H),1.95(dd,J＝12.8,3.3Hz,1H),1.79(d,J＝13.2Hz,1H),1.70-1.51(m,1H),1.39(ddd,J＝24.5,12.2,4.1Hz,1H)。MS(ESI)m/z:487.3[M+H+]。

Example 2433-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide 243

SFC chiral separation of parent racemic compound 232 gave chiral diastereomer 243, peak 2.¹H NMR(400MHz,DMSO)9.76(s,1H),8.68(d,J＝2.5Hz,1H),8.22(s,1H),8.13(td,J＝8.2,1.9Hz,1H),7.71(s,2H),7.55(s,1H),7.50-7.40(m,1H),7.40-7.24(m,2H),4.58-4.35(m,1H),3.67(s,3H),3.28-3.02(m,5H),2.23-2.05(m,1H),2.05-1.92(m,1H),1.92-1.77(m,1H),1.71-1.57(m,1H)。MS(ESI)m/z:443.1[M+H+]。

Example 2443-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide 244

SFC chiral separation of parent racemic compound 232 gave chiral diastereomer 244, peak 1.¹H NMR(400MHz,DMSO)9.75(s,1H),8.68(d,J＝2.5Hz,1H),8.12(td,J＝8.1,1.9Hz,1H),7.72(s,2H),7.56(s,1H),7.52-7.40(m,1H),7.40-7.27(m,2H),4.53-4.28(m,2H),3.67(s,3H),3.23-2.97(m,5H),2.19-2.03(m,1H),2.03-1.90(m,1H),1.90-1.74(m,1H),1.67-1.52(m,1H)。MS(ESI)m/z:443.1[M+H+]。

Example 2453-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) picolinamide 245

SFC chiral separation of the parent racemic compound 231 gave chiral diastereomer 245, peak 2.¹H NMR(400MHz,DMSO)9.72(s,1H),8.01(td,J＝8.0,1.8Hz,1H),7.73(dd,J＝8.7,2.2Hz,1H),7.67(s,1H),7.48-7.37(m,1H),7.37-7.21(m,3H),7.05(s,2H),4.39(dtd,J＝48.0,8.2,3.7Hz,1H),3.67(s,3H),3.24-2.98(m,5H),2.19-2.04(m,1H),1.97(dtd,J＝19.7,9.8,4.8Hz,1H),1.89-1.77(m,1H),1.73-1.53(m,2H)。MS(ESI)m/z:442.1[M+H+]。

Example 2463-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) methylpyridine amide 246

Chiral separation of the parent racemic compound 231 by SFC gave chiral diastereomer 246, peak 1.¹H NMR(400MHz,DMSO)9.72(s,1H),8.01(td,J＝8.0,1.8Hz,1H),7.73(dd,J＝8.7,2.2Hz,1H),7.67(s,1H),7.47-7.37(m,1H),7.38-7.22(m,3H),7.05(s,2H),4.39(dtd,J＝48.0,8.2,3.7Hz,1H),3.67(s,3H),3.25-2.97(m,5H),2.21-2.03(m,1H),2.03-1.88(m,1H),1.88-1.75(m,1H),1.75-1.52(m,2H)。MS(ESI)m/z:442.1[M+H+]。

Example 247 (S) -3-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide 247

SFC chiral separation of parent racemate 293 yielded enantiomer 247, peak 2.¹H NMR(400MHz,DMSO)9.78(s,1H),8.68(d,J＝2.5Hz,1H),8.15(dd,J＝11.3,4.9Hz,1H),7.73(s,2H),7.54(s,1H),7.51-7.41(m,1H),7.35(dd,J＝16.1,7.7Hz,2H),3.79-3.59(m,4H),3.53-3.37(m,2H),3.19-3.10(m,1H),2.37-2.15(m,2H),1.98-1.67(m,2H)。MS(ESI)m/z:461.1[M+H+]。

Example 248 (R) -3-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide 248

SFC chiral separation of parent racemate 293 yielded enantiomer 248, peak 1.¹H NMR(400MHz,DMSO)9.76(s,1H),8.68(d,J＝2.5Hz,1H),8.17-8.04(m,1H),7.73(s,2H),7.59(s,1H),7.54-7.41(m,1H),7.41-7.25(m,2H),3.77-3.55(m,4H),3.50-3.34(m,1H),3.21-3.04(m,2H),2.27-2.03(m,2H),1.92-1.64(m,3H)。MS(ESI)m/z:461.1[M+H+]。

Example 2493-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) methylpyridine amide 249

SFC chiral separation of the parent racemic compound 292 gave enantiomer 249, peak 2.¹H NMR(400MHz,DMSO)9.71(s,1H),8.07-7.96(m,1H),7.71(dd,J＝8.7,2.3Hz,1H),7.66(s,1H),7.48-7.38(m,1H),7.38-7.23(m,3H),7.06(s,2H),3.78-3.58(m,4H),3.50-3.33(m,1H),3.19-3.02(m,2H),2.24-1.97(m,2H),1.88-1.78(m,1H),1.78-1.63(m,1H),1.63-1.42(m,1H)。MS(ESI)m/z:460.1[M+H+]。

Example 250 (R) -3-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) methylpyridine amide 250

SFC chiral separation of parent racemic compound 292 gave enantiomer 250, peak 1.¹H NMR(400MHz,DMSO)9.71(s,1H),8.06-7.96(m,1H),7.71(dd,J＝8.7,2.3Hz,1H),7.66(s,1H),7.48-7.37(m,1H),7.37-7.25(m,3H),7.06(s,2H),3.76-3.59(m,4H),3.51-3.33(m,1H),3.18-3.04(m,2H),2.25-2.01(m,2H),1.91-1.77(m,1H),1.77-1.64(m,1H),1.64-1.43(m,2H)。MS(ESI)m/z:460.1[M+H+]。

Example 2525-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide 252

Following the procedure of example 145, starting from tert-butyl 6-methoxy-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (the more polar pair of diastereomers), after purification by preparative HPLC, gave 252 as the monoformate salt as a light yellow solid (116mg, 53% over three steps).¹H NMR(400MHz,d6-DMSO)8.83(br s,1H),8.43(s,1H),7.60-7.45(m,4H),7.35-7.20(m,2H),3.68(s,3H),3.30-3.15(m,5H),3.10-2.85(m,5H),2.15-1.65(m,4H),1.02(s,3H)。LCMS(ES+)m/z492(M+1)

Example 2535-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3-hydroxy-3-methyl-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide 253

Following the procedure of example 145, starting from tert-butyl 6-hydroxy-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (the more polar pair of diastereomers), purification by preparative HPLC gave 253 as the mono-formate salt as a light yellow solid (37mg, 19% over three steps).¹H NMR(400MHz,d6-DMSO)8.70(br s,1H),8.44(s,1H),7.58-7.45(m,4H),7.35-7.20(m,2H),3.70(s,3H),3.60-2.80(m,8H),2.05-1.60(m,4H),1.14(s,3H)。LCMS(ES+)m/z478(M+1)

Example 2545-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide 254

Following the procedure of example 145, starting from tert-butyl 6-methoxy-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (less polar pair of diastereomers), after purification by preparative HPLC, gave 254 as the mono-formate salt as a light yellow solid (78mg, 34%).¹H NMR(400MHz,d6-DMSO)8.84(s,1H),8.44(s,1H),7.63(s,1H),7.60-7.45(m,3H),7.35-7.20(m,2H),3.67(s,3H),3.60-3.15(m,5H),3.15-2.90(m,5H),2.15-1.55(m,4H),1.01(s,3H)。LCMS(ES+)m/z492(M+1)

Example 2555-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3-hydroxy-3-methyl-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide 255

Following the procedure of example 145, starting from tert-butyl 6-hydroxy-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate (less polar pair of diastereomers), purification by preparative HPLC gave 255 as the monoformate salt as a light yellow solid (39mg, 18%, over three steps).¹H NMR(400MHz,d6-DMSO)8.88(s,1H),8.42(s,1H),7.60-7.45(m,4H),7.35-7.20(m,2H),3.68(s,3H),3.67-3.55(m,2H),3.30-2.80(m,6H),2.05-1.60(m,4H),1.06(s,3H)。LCMS(ES+)m/z478(M+1)

Example 2565-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3-fluoro-3-methyl-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide 256

Following the procedure of example 145, starting from tert-butyl 6-fluoro-6-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate, 256 was obtained as a light brown solid (110mg, 27%, over three steps).¹HNMR(400MHz,CDCl₃)8.64-8.56(m,1H),7.89and7.80(2s,1H),7.40-7.26(m,1H),7.06-6.99(m,2H),6.22(br s,2H),3.77and3.64(2s,3H),3.67-2.99(m,5H),2.45-2.05(m,1H),2.05-1.60(m,5H),1.45-1.25(m,3H)。LCMS(ES+)m/z480(M+1)

Example 2575-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (3-fluoro-5-hydroxy-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide 257

Prepared by following the procedure of example 145, starting from 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -3- (trifluoromethyl) piperidineAfter purification by sexual HPLC, 257 was obtained as a beige solid (222mg, 41%, over three steps).¹H NMR(400MHz,CDCl₃)9.08and8.66(2s,1H),7.93and7.83(s,1H),7.33(ddd, J ═ 8.6,5.9,2.7Hz,1H),7.07-6.99(m,2H),6.22and6.16(2s,2H),4.96-4.73(m,1H),4.45and4.12(2s,1H),3.76and3.74(2s,3H),3.60-3.17(m,4H),2.44-1.90(m, 4H). No OH was observed. LCMS (ES +) M/z467(M +1)

Example 2585-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [ 1-methyl-5- (3-trifluoromethyl-piperidin-1-yl) -1H-pyrazol-4-yl ] -amide 258

Following the procedure of example 101, starting from 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -3- (trifluoromethyl) piperidine, after purification by silica gel column chromatography (20-100% EtOAc/isohexane), 258 was obtained as an off-white foam (415mg, 48%, over three steps).¹H NMR(400MHz,CDCl₃)8.52(s,1H),7.77(s,1H),7.37-7.26(m,1H),7.07-6.97(m,2H),6.13(s,2H),3.73(s,3H),3.32(dd,J＝11.5,3.8Hz,1H),3.17-3.04(m,3H),2.54-2.40(m,1H),2.10-2.04(m,1H),1.94-1.84(m,1H),1.84-1.43(m,2H)。LCMS(ES+)m/z487(M+1)

Example 261 (S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (pyridin-2-yl) thiazole-4-carboxamide 261

SFC chiral separation of the parent racemic compound gives enantiomer 261.¹H NMR(400MHz,DMSO)8.92(s,1H),8.54(d,J＝4.7Hz,1H),8.12(d,J＝8.0Hz,1H),7.93(t,J＝7.7Hz,1H),7.53(d,J＝14.5Hz,3H),7.42-7.35(m,1H),3.68(s,3H),3.50-3.37(m,2H),3.20-3.09(m,2H),2.36-2.16(m,3H),1.90(d,J＝18.9Hz,1H),1.83-1.68(m,1H).ESIMS m/z＝449.1(M+1)

Example 262 (R) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (pyridin-2-yl) thiazole-4-carboxamide 262

SFC chiral separation of the parent racemic compound gives enantiomer 262.¹H NMR(400MHz,DMSO)8.92(s,1H),8.54(d,J＝4.7Hz,1H),8.12(d,J＝8.0Hz,1H),7.93(t,J＝7.7Hz,1H),7.53(d,J＝14.5Hz,3H),7.42-7.35(m,1H),3.68(s,3H),3.50-3.37(m,2H),3.20-3.09(m,2H),2.36-2.16(m,3H),1.90(d,J＝18.9Hz,1H),1.83-1.68(m,1H).ESIMS m/z＝449.1(M+1)

Example 2635-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (pyridin-2-yl) thiazole-4-carboxamide 263

SFC chiral separation of the parent racemic compound gave enantiomer 263.¹H NMR(400MHz,DMSO)8.88(s,1H),8.53(d,J＝4.7Hz,1H),8.14(d,J＝7.9Hz,1H),7.89(d,J＝1.4Hz,1H),7.54(s,2H),7.49(s,1H),7.40-7.35(m,1H),4.49(dtd,J＝48.0,8.5,3.6Hz,1H),3.65(s,3H),3.22-3.11(m,5H),2.22-2.08(m,1H),2.08-1.95(m,1H),1.93-1.79(m,1H),1.63(dtd,J＝14.3,9.5,4.5Hz,1H).ESIMS m/z＝431.1(M+1)

Example 264 (S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxamide 264

SFC chiral separation of the parent racemic compound gave enantiomer 264.¹H NMR(400MHz,DMSO)8.69(s,1H),8.43(d,J＝4.5Hz,1H),8.27(s,2H),7.88(dd,J＝10.9,8.6Hz,1H),7.67(s,2H),7.61(s,1H),7.48(dt,J＝8.3,4.1Hz,1H),3.68(s,3H),3.20-2.99(m,3H),2.32(t,J＝19.9Hz,3H),1.93(d,J＝13.3Hz,1H),1.82(dd,J＝14.8,9.4Hz,2H).ESIMS m/z＝467.1(M+1)

Example 2655-amino-N- (5- ((4R,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 265

SFC chiral separation of the parent racemic compound gives enantiomer 265.¹H NMR(400MHz,DMSO)9.16(s,1H),8.05(s,1H),7.51(s,1H),7.40(s,2H),7.23(d,J＝9.0Hz,2H),4.88(dd,J＝47.4,7.4Hz,1H),3.65(s,3H),3.09(m,3H),2.36(s,3H),2.20(ddd,J＝10.8,7.3,3.4Hz,1H),2.00-1.80(m,3H),1.78-1.67(m,1H).ESIMS m/z＝462.1(M+1)

Example 2665-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 266

SFC chiral separation of the parent racemic compound gives enantiomer 266.¹H NMR(400MHz,DMSO)9.21(s,1H),8.28(s,2H),8.12(ddd,J＝9.3,5.7,3.3Hz,1H),7.47(s,2H),7.40(m,2H),7.27(tt,J＝7.4,3.5Hz,1H),4.88(d,J＝40.8Hz,2H),3.67(s,3H),3.09(d,J＝4.0Hz,1H),2.25-2.09(m,2H),2.06-1.82(m,3H),1.82-1.66(m,2H).ESIMS m/z＝466.1(M+1)

Example 2675-amino-N- (5- ((4R,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide 267

SFC chiral separation of the parent racemic compound gave enantiomer 267.¹H NMR(400MHz,DMSO)9.11(s,1H),8.26(dd,J＝14.8,6.9Hz,1H),7.51(s,1H),7.41(s,3H),7.39-7.29(m,2H),4.88(dd,J＝47.4,7.1Hz,1H),3.65(s,3H),3.12-3.03(m,5H),2.26-2.12(m,1H),2.00-1.80(m,2H),1.79-1.67(m,1H).ESIMS m/z＝448.1(M+1)

Example 2685-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxamide 268

SFC chiral separation of the parent racemic compound gave enantiomer 268.¹H NMR(400MHz,DMSO)8.79(s,1H),8.43(d,J＝4.6Hz,1H),7.85(dd,J＝11.0,8.6Hz,1H),7.63(d,J＝13.0Hz,3H),7.47(dt,J＝8.3,4.1Hz,1H),4.49(dtd,J＝47.9,8.1,3.6Hz,1H),3.65(s,3H),3.18-3.07(m,4H),2.21-2.04(m,1H),1.98(dt,J＝9.5,7.4Hz,1H),1.94-1.83(m,1H),1.76-1.50(m,1H),1.72-1.57(m,1H).ESIMS m/z＝449.1(M+1)

Example 2695-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxamide 269

SFC chiral separation of the parent racemic compound gives enantiomer 269.¹H NMR(400MHz,DMSO)8.79(s,1H),8.43(d,J＝4.6Hz,1H),7.85(dd,J＝11.0,8.6Hz,1H),7.63(d,J＝13.0Hz,3H),7.47(dt,J＝8.3,4.1Hz,1H),4.49(dtd,J＝47.9,8.1,3.6Hz,1H),3.65(s,3H),3.18-3.07(m,4H),2.21-2.04(m,1H),1.98(dt,J＝9.5,7.4Hz,1H),1.94-1.83(m,1H),1.76-1.50(m,1H),1.72-1.57(m,1H).ESIMS m/z＝449.1(M+1)

Example 2705-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide 270

SFC chiral separation of the parent racemic compound gives enantiomer 270.¹H NMR(400MHz,DMSO)9.11(s,1H),8.26(dd,J＝14.8,6.9Hz,1H),7.51(s,1H),7.41(s,3H),7.39-7.29(m,2H),4.88(dd,J＝47.4,7.1Hz,1H),3.65(s,3H),3.12-3.03(m,5H),2.26-2.12(m,1H),2.00-1.80(m,2H),1.79-1.67(m,1H).ESIMS m/z＝448.1(M+1)

Example 2715-amino-N- (5- ((4R,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 271

SFC chiral separation of the parent racemic compound gives enantiomer 271.¹H NMR(400MHz,DMSO)9.21(s,1H),8.28(s,2H),8.12(ddd,J＝9.3,5.7,3.3Hz,1H),7.47(s,2H),7.40(m,2H),7.27(tt,J＝7.4,3.5Hz,1H),4.88(d,J＝40.8Hz,2H),3.67(s,3H),3.09(d,J＝4.0Hz,1H),2.25-2.09(m,2H),2.06-1.82(m,3H),1.82-1.66(m,2H).ESIMS m/z＝466.1(M+1)

Example 2725-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 272

SFC chiral separation of the parent racemic compound gives enantiomer 272.¹H NMR(400MHz,DMSO)9.16(s,1H),8.05(s,1H),7.51(s,1H),7.40(s,2H),7.23(d,J＝9.0Hz,2H),4.88(dd,J＝47.4,7.4Hz,1H),3.65(s,3H),3.09(m,3H),2.36(s,3H),2.20(ddd,J＝10.8,7.3,3.4Hz,1H),2.00-1.80(m,3H),1.78-1.67(m,1H).ESIMS m/z＝462.1(M+1)

Example 273 (R) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxamide 273

SFC chiral separation of the parent racemic compound gives enantiomer 273.¹H NMR(400MHz,DMSO)8.69(s,1H),8.43(d,J＝4.5Hz,1H),8.27(s,2H),7.88(dd,J＝10.9,8.6Hz,1H),7.67(s,2H),7.61(s,1H),7.48(dt,J＝8.3,4.1Hz,1H),3.68(s,3H),3.20-2.99(m,3H),2.32(t,J＝19.9Hz,3H),1.93(d,J＝13.3Hz,1H),1.82(dd,J＝14.8,9.4Hz,2H).ESIMS m/z＝467.1(M+1)

Example 2745-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (pyridin-2-yl) thiazole-4-carboxamide 274

SFC chiral separation of the parent racemic compound gives enantiomer 274.¹H NMR(400MHz,DMSO)8.88(s,1H),8.53(d,J＝4.7Hz,1H),8.14(d,J＝7.9Hz,1H),7.89(d,J＝1.4Hz,1H),7.54(s,2H),7.49(s,1H),7.40-7.35(m,1H),4.49(dtd,J＝48.0,8.5,3.6Hz,1H),3.65(s,3H),3.22-3.11(m,5H),2.22-2.08(m,1H),2.08-1.95(m,1H),1.93-1.79(m,1H),1.63(dtd,J＝14.3,9.5,4.5Hz,1H).ESIMS m/z＝431.1(M+1)

Example 2755-amino-2- (2, 6-difluoro-3-iodo-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3, 3-difluoro-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide 275

Following the procedure of example 145, starting from tert-butyl 6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate, 275 was obtained as an off-white solid (220mg, 34%, over three steps).¹H NMR(400MHz,d4-MeOD)7.93-7.85(m,1H),7.64(s,1H),7.04(ddd,J＝10.3,8.8,1.4Hz,1H),3.77(s,3H),3.74-3.62(m,1H),3.55-3.36(m,3H),3.30-3.23(m,1H),2.41-2.22(m,2H),2.06-1.95(m,1H),1.91-1.80(m,1H)。LCMS(ES+)m/z610(M+1)

Example 2765-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 276

Following the procedure of example 107, starting from N- (1- (4-amino-1-cyclopropyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonyl-amino) -2- (2, 5-difluorophenyl) thiazole-4-carboxylic acid, 276 was obtained as a mono-formate salt as an off-white solid (170mg, 40% over two steps).¹H NMR(400MHz,d4-MeOD)8.54(s,1H),8.06(ddd,J＝9.4,5.8,3.2Hz,1H),7.39(s,1H),7.28(td,J＝9.9,4.4Hz,1H),7.19-7.11(m,1H),4.86(dtd,J＝49.0,9.3,3.6Hz,1H),3.62-3.49(m,2H),3.50-3.38(m,4H),2.45-2.31(m,1H),2.26-2.06(m,2H),1.99-1.86(m,1H),1.21-1.12(m,2H),1.15-1.05(m,2H)。LCMS(ES+)m/z492(M+1)

Example 2775-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 277

Following the procedure of example 107, starting from N- (1- (4-amino-1-cyclopropyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonyl-amino) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxylic acid, 277 is obtained as a yellow solid (228mg, 55% over two steps).¹H NMR(400MHz,d4-MeOD)8.07(dd,J＝7.3,2.3Hz,1H),7.48(s,1H),7.24-7.19(m,1H),7.11(dd,J＝11.4,8.4Hz,1H),4.49(dtd,J＝48.3,8.8,3.8Hz,1H),3.56-3.48(m,1H),3.47-3.34(m,4H),3.23-3.13(m,1H),2.41(s,3H),2.35-2.21(m,1H),2.19-2.06(m,1H),2.01-1.91(m,1H),1.84-1.72(m,1H),1.19-1.10(m,2H),1.11-1.04(m,2H)。LCMS(ES+)m/z488(M+1)

Example 2785-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 278

Following the procedure of example 107, starting from N- (1- (4-amino-1-cyclopropyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid, purification by preparative HPLC gave 278 as the monoformate salt as an off-white solid (209mg, 50% in two steps).¹H NMR(400MHz,d4-MeOD)8.54(s,1H),7.52(s,1H),7.51-7.44(m,1H),7.19-7.12(m,2H),4.86(dtd,J＝48.0,9.3,3.0Hz,1H),3.61-3.47(m,2H),3.48-3.36(m,4H),2.46-2.32(m,1H),2.26-2.05(m,2H),1.99-1.86(m,1H),1.23-1.11(m,2H),1.13-1.05(m,2H)。LCMS(ES+)m/z492(M+1)

Example 2795-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3, 3-difluoro-azepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl ] -amide 279

Following the procedure of example 145, starting from N- (1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-yl) -2,2, 2-trifluoroacetamide, gave 279 as a monoformate salt as an off-white solid (166mg, 16%, in three steps))。¹H NMR(400MHz,d4-MeOD)8.55(s,1H),7.55-7.43(m,2H),7.19-7.12(m,2H),3.87-3.71(m,1H),3.69-3.45(m,4H),3.44-3.39(m,1H),2.70-2.45(m,2H),2.24-2.13(m,1H),2.08-1.95(m,1H),1.24-1.11(m,2H),1.14-1.05(m,2H)。LCMS(ES+)m/z510(M+1)

Example 280 (R) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 280

SFC chiral separation of the parent racemic compound gave enantiomer 280.¹H NMR(400MHz,DMSO)8.92(s,1H),7.66(s,1H),7.52(d,J＝8.0Hz,3H),7.28(t,J＝8.6Hz,2H),6.37(m,2H),4.43(d,J＝4.1Hz,3H),3.64(dt,J＝27.0,13.5Hz,2H),2.26(s,3H),1.92-1.80(m,1H),1.71(tt,J＝19.7,10.0Hz,1H),1.49(dd,J＝8.3,6.7Hz,1H),0.98(d,J＝2.4Hz,1H).ESIMS m/z＝534.1(M+1)

Example 281 (S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 281

SFC chiral separation of the parent racemic compound gives enantiomer 281.¹H NMR(400MHz,DMSO)8.92(s,1H),7.66(s,1H),7.52(d,J＝8.0Hz,3H),7.28(t,J＝8.6Hz,2H),6.37(m,2H),4.43(d,J＝4.1Hz,3H),3.64(dt,J＝27.0,13.5Hz,2H),2.26(s,3H),1.92-1.80(m,1H),1.71(tt,J＝19.7,10.0Hz,1H),1.49(dd,J＝8.3,6.7Hz,1H),0.98(d,J＝2.4Hz,1H).ESIMS m/z＝534.1(M+1)

Example 282 (S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 282

SFC chiral separation of the parent racemic compound gives enantiomer 282.¹H NMR(400MHz,DMSO)9.11(s,1H),8.13(s,1H),7.48(s,2H),7.44(s,1H),7.43(m,1H),7.28(tt,J＝7.5,3.6Hz,1H),3.68(s,3H),3.67-3.62(m,1H),3.48-3.35(m,2H),3.19-3.06(m,2H),2.23(ddd,J＝35.9,24.1,14.0Hz,3H),1.92-1.82(m,1H),1.73(ddd,J＝20.0,12.7,8.0Hz,1H).ESIMS m/z＝484.1(M+1)

Example 283 (R) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 283

SFC chiral separation of the parent racemic compound gives enantiomer 283.¹H NMR(400MHz,DMSO)9.11(s,1H),8.13(s,1H),7.48(s,2H),7.44(s,1H),7.43(m,1H),7.28(tt,J＝7.5,3.6Hz,1H),3.68(s,3H),3.67-3.62(m,1H),3.48-3.35(m,2H),3.19-3.06(m,2H),2.23(ddd,J＝35.9,24.1,14.0Hz,3H),1.92-1.82(m,1H),1.73(ddd,J＝20.0,12.7,8.0Hz,1H).ESIMS m/z＝484.1(M+1)

Example 284 (S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 284

SFC chiral separation of the parent racemic compound gives enantiomer 284.¹H NMR(400MHz,DMSO)8.98(s,1H),8.318.08(d,J＝7.4Hz,1H),7.49(s,1H),7.41(s,2H),7.23(d,J＝9.0Hz,2H),3.68(s,3H),3.64(d,J＝14.5Hz,1H),3.45(ddd,J＝19.7,15.1,9.3Hz,2H),3.21-3.11(m,2H),2.37(s,3H),2.28(dd,J＝31.2,15.2Hz,2H),1.88(d,J＝15.3Hz,1H),1.81-1.66(m,1H).ESIMS m/z＝480.1(M+1)

Example 285 ((R) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 285

SFC chiral separation of the parent racemic compound gives enantiomer 285.¹H NMR(400MHz,DMSO)8.98(s,1H),8.318.08(d,J＝7.4Hz,1H),7.49(s,1H),7.41(s,2H),7.23(d,J＝9.0Hz,2H),3.68(s,3H),3.64(d,J＝14.5Hz,1H),3.45(ddd,J＝19.7,15.1,9.3Hz,2H),3.21-3.11(m,2H),2.37(s,3H),2.28(dd,J＝31.2,15.2Hz,2H),1.88(d,J＝15.3Hz,1H),1.81-1.66(m,1H).ESIMS m/z＝480.1(M+1)

Example 286 (S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide 286

SFC chiral separation of the parent racemic compound gives enantiomer 286.¹H NMR(400MHz,DMSO)8.99(s,1H),8.30(dd,J＝14.7,6.9Hz,1H),7.51(s,1H),7.48-7.40(m,3H),7.40-7.32(m,2H),3.68(s,3H),3.50-3.37(m,3H),3.16(m,2H),2.35-2.17(m,2H),1.87(m,1H),1.76(m,1H).ESIMS m/z＝466.1(M+1)

Example 287 (R) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide 287

SFC chiral separation of the parent racemic compound gives enantiomer 287.¹H NMR(400MHz,DMSO)8.99(s,1H),8.30(dd,J＝14.7,6.9Hz,1H),7.51(s,1H),7.48-7.40(m,3H),7.40-7.32(m,2H),3.68(s,3H),3.50-3.37(m,3H),3.16(m,2H),2.35-2.17(m,2H),1.87(m,1H),1.76(m,1H).ESIMS m/z＝466.1(M+1)

Example 2885-amino-N- (5- ((4S,5S) -4-amino-5-methoxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 288

SFC chiral separation of the parent racemic compound gives enantiomer 288.¹H NMR(400MHz,DMSO)8.79(s,1H),8.31(s,1H),7.53-7.49(m,4H),7.26(t,J＝8.7Hz,2H),3.63(s,3H),3.25(s,3H),3.24-3.13(m,4H),3.06(m,2H),1.69(m,2H).ESIMS m/z＝478.2(M+1)

Example 2895-amino-N- (5- ((4R,5R) -4-amino-5-methoxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 289

SFC chiral separation of the parent racemic compound gives enantiomer 289.¹H NMR(400MHz,DMSO)8.79(s,1H),8.31(s,1H),7.53-7.49(m,4H),7.26(t,J＝8.7Hz,2H),3.63(s,3H),3.25(s,3H),3.24-3.13(m,4H),3.06(m,2H),1.69(m,2H).ESIMS m/z＝478.2(M+1)

Example 290 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (5- (dimethylamino) -3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 290

SFC chiral separation of the parent racemic compound gives enantiomer 290.¹H NMR(400MHz,DMSO)8.70(s,1H),8.18(s,1H),7.54(s,1H),7.50(m,2H),7.25(t,J＝8.6Hz,2H),3.68(s,3H),3.65-3.51(m,2H),2.84(s,1H),2.24(m,4H),2.07(s,6H),1.96-1.76(m,2H).ESIMS m/z＝512.1(M+1)

Example 2923-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) picolinamide 292

Compound 292 was prepared according to the procedure for example 180.¹H NMR(400MHz,DMSO)9.72(s,1H),8.02(t,J＝7.3Hz,1H),7.72(dd,J＝8.7,2.1Hz,1H),7.66(s,1H),7.49-7.38(m,1H),7.38-7.25(m,3H),7.07(s,2H),3.80-3.58(m,4H),3.51-3.33(m,2H),3.20-3.03(m,2H),2.25-2.09(m,1H),1.90-1.76(m,1H),1.76-1.61(m,1H),1.54-1.37(m,1H)。MS(ESI)m/z:460.2[M+H+]。

Example 2933-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide 293

According to the factCompound 293 was prepared by the procedure of example 180.¹H NMR(400MHz,DMSO)9.79(s,1H),8.68(d,J＝2.3Hz,1H),8.25(s,1H),8.12(t,J＝8.1Hz,1H),7.74(s,2H),7.60-7.52(m,1H),7.52-7.41(m,1H),7.41-7.28(m,2H),3.77-3.57(m,5H),3.18-2.96(m,3H),2.31-2.15(m,2H),1.94-1.81(m,1H),1.81-1.62(m,1H)。MS(ESI)m/z:461.2[M+H+]。

Example 291 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (5- (dimethylamino) -3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 291

SFC chiral separation of the parent racemic compound gives enantiomer 291.¹H NMR(400MHz,DMSO)8.70(s,1H),8.18(s,1H),7.54(s,1H),7.50(m,2H),7.25(t,J＝8.6Hz,2H),3.68(s,3H),3.65-3.51(m,2H),2.84(s,1H),2.24(m,4H),2.07(s,6H),1.96-1.76(m,2H).ESIMS m/z＝512.1(M+1)

Example 2945-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide 294

Following the procedure of example 221, starting from N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonyl-amino) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxylic acid, after purification by silica gel column chromatography (5% MeOH/DCM containing 1% 7N ammonia in MeOH), 294 was obtained as a milky solid (107mg, 48%).¹H NMR(400MHz,CDCl₃)8.73(s,1H),7.90-7.84(m,1H),7.82(s,1H),7.17-7.11(m,1H),7.04(dd, J ═ 11.1,8.4Hz,1H),6.10(s,2H),4.95-4.78(m,1H),3.74(s,3H),3.49-3.33(m,3H),3.24-3.11(m,2H),2.40(s,3H),2.40-2.26(m,1H),2.09-1.91(m,2H),1.87-1.77(m, 1H). Alkyl NH not visible₂。LCMS(ES+)m/z462(M+1)

Example 2955-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 295

Following the procedure of example 221, starting from N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonyl-amino) -2- (2, 5-difluorophenyl) thiazole-4-carboxylic acid, 295 was obtained as a dark milky solid (166mg, 73% over three steps).¹H NMR(400MHz,CDCl₃)8.65(s,1H),7.87-7.81(m,2H),7.17-7.09(m,1H),7.07-7.01(m,1H),6.16(s,2H),4.90(dd, J ═ 47.1,6.7Hz,1H),3.74(s,3H),3.49-3.32(m,3H),3.23-3.09(m,2H),2.36-2.28(m,1H),2.18-1.81(m,3H) alkyl NH₂not seen。LCMS(ES+)m/z466(M+1)

Example 2965-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide 296

Following the procedure of example 221, starting from N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonyl-amino) -2- (2-fluorophenyl) thiazole-4-carboxylic acid, after purification by silica gel column chromatography (5-7% MeOH/DCM containing 1% 7N ammonia in MeOH), 296 was obtained as a milky solid (128mg, 59%, over three steps).¹H NMR(400MHz,CDCl₃)8.72(s,1H),8.13-8.08(m,1H),7.84(s,1H),7.40-7.32(m,1H),7.29-7.20(m,1H),7.17(dd, J ═ 11.4,8.3Hz,1H),6.10(s,2H),4.89(dd, J ═ 47.0,7.0Hz,1H),3.74(s,3H),3.50-3.31(m,3H),3.22-3.09(m,2H),2.37-2.27(m,1H),2.12-1.89(m,2H),1.86-1.78(m, 1H). Alkyl NH not visible₂。LCMS(ES+)m/z448(M+1)

Example 2975-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxamide 297

By following the procedure of example 107, starting from N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-oneYl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonylamino) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxylic acid to give 297 as a pale brown solid (424mg, 72% over 2 steps).¹H NMR(400MHz,CDCl₃)8.70(s,1H),8.39(dt, J ═ 4.6,1.4Hz,1H),7.86(s,1H),7.52(ddd, J ═ 10.8,8.3,1.4Hz,1H),7.32-7.26(m,1H),6.32(s,2H),4.51(dtd, J ═ 47.9,8.5,3.6Hz,1H),3.73(s,3H),3.40-3.17(m,5H),2.34-2.19(m,1H),2.16-1.96(m,2H),1.79-1.66(m,1H), alkyl NH₂not seen。LCMS(ES+)m/z449(M+1)

Example 2985-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (pyridin-2-yl) thiazole-4-carboxamide 298

Following the procedure of example 107, starting from N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonylamino) -2- (pyridin-2-yl) thiazole-4-carboxylic acid, 298 was obtained as a light yellow solid (418mg, 74%, over 2 steps).¹H NMR(400MHz,CDCl₃)8.54(d, J ═ 4.9Hz,1H),8.40(s,1H),8.06(d, J ═ 8.0Hz,1H),7.78-7.73(m,2H),7.28-7.23(m,1H),6.26(s,2H),4.51(dtd, J ═ 48.0,8.8,3.8Hz,1H),3.73(s,3H),3.37-3.20(m,5H),2.35-2.21(m,1H),2.18-2.04(m,1H),2.02-1.92(m,1H),1.79-1.66(m,1H). alkyl NH₂not seen。LCMS(ES+)m/z431(M+1)

Example 2995-amino-2- (3-fluoro-pyridin-2-yl) -thiazole-4-carboxylic acid [5- (5-amino-3, 3-difluoro-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide 299

Following the procedure of example 145, starting from tert-butyl 6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate, 299 was obtained as a pale yellow solid (350mg, 43%, via three steps).¹HNMR(400MHz,CDCl₃)8.56(s,1H),8.39(dt,J＝4.6,1.4Hz,1H),7.81(s,1H),7.52(ddd,J＝10.8,8.3,1.4Hz,1H),7.32-7.26(m,1H),6.32(s,2H),3.76(s,3H),3.71-3.57(m,1H),3.54-3.35(m,3H),3.33-3.24(m,1H),2.41-2.26(m,2H),2.03-1.92(m,1H),1.90-1.78(m,1H),1.34(br s,2H)。LCMS(ES+)m/z467(M+1)

Example 3005-amino-2-pyridin-2-yl-thiazole-4-carboxylic acid [5- (5-amino-3, 3-difluoro-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide 300

Following the procedure of example 145, starting from tert-butyl 6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate, 300 was obtained as a light yellow solid (519mg, 66%, over three steps).¹HNMR(400MHz,CDCl₃)8.55(d, J ═ 4.9Hz,1H),8.41(s,1H),8.07(d, J ═ 8.0Hz,1H),7.76(t, J ═ 7.8Hz,1H),7.69(s,1H),7.33 to 7.20(m,1H),6.25(s,2H),3.77(s,3H),3.74 to 3.59(m,1H),3.55 to 3.36(m,3H),3.33 to 3.23(m,1H),2.43 to 2.28(m,2H),2.03 to 1.92(m,1H),1.88 to 1.77(m,1H), no alkyl NH was seen₂not seen。LCMS(ES+)m/z449(M+1).

Example 301 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-methylpiperazin-1-yl) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 301

Following the procedure of example 233, starting from tert-butyl (S) -4- (4- (5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-5-yl) -2-methylpiperazine-1-carboxylate, 301 was obtained as a white solid (25mg, 50%).¹H-NMR(500MHz,CD3OD)(ppm):7.69(s,1H),7.51-7.45(m,1H),7.16-7.12(m,2H),4.90-4.78(m,2H),3.22.-3.17(m,1H),3.05-2.86(m,6H),1.08(d,J＝6Hz,3H)；MS(ESI)m/z:502[M+H+]

Example 3045-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (3, 3-difluoro-5-hydroxy-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide 304

According to example 101Starting from benzaldehyde O-6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl oxime from example 85a, purification by preparative HPLC gave 304 as a white solid (37mg, 27% over three steps).¹H NMR(400MHz,CDCl₃)8.77(s,1H),7.84(s,1H),7.39-7.29(m,1H),7.09-6.99(m,2H),6.19(s,2H),4.30(s,1H),3.75(s,3H),3.66-3.36(m,3H),3.34-3.24(m,1H),2.57-2.40(m,2H),2.10-2.02(m,3H)。LCMS(ES+)m/z485(M+1)

Example 3055-amino-N- (5- ((4S,5R) -4-amino-5-methoxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 305

Following the procedure of example 101, starting from tert-butyl 5-methoxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate from example 49, 305 was obtained as an apricot-colored foam (286mg, 66%, over three steps).¹H NMR(400MHz,CDCl₃)8.94(s,1H),7.90(s,1H),7.38-7.28(m,1H),7.02(t, J ═ 8.7Hz,2H),6.16(s,2H),3.72(s,3H),3.49-3.44(m,1H),3.45-3.18(m,6H),3.20-3.06(m,2H),2.17-2.06(m,1H),2.06-1.96(m,1H),1.85-1.65(m,2H). no alkyl NH was observed₂。LCMS(ES+)m/z478(M+1)

Example 3065-amino-N- (5- ((3R,5R) -5-amino-3-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 306

Following the procedure of example 107, starting from N- (1- (4-amino-1-cyclopropyl-1H-pyrazol-5-yl) -6-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide from example 53a, purification by chiral preparative HPLC gave 306 as an off-white solid (7.6mg, 2% over 2 steps).¹H NMR(400MHz,d4-MeOD)7.63(s,1H),7.51-7.42(m,1H),7.20-7.11(m,2H),4.89-4.85(m,1H),3.63-3.46(m,4H),3.45-3.27(m,2H),2.34-2.18(m,1H),2.10-1.90(m,2H),1.80-1.66(m,1H),1.25-1.15(m,1H),1.17-1.00(m,3H)。LCMS(ES+)m/z492(M+1)

Example 3075-amino-N- (5- ((3S,5S) -5-amino-3-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 307

Following the procedure of example 107, starting from N- (1- (4-amino-1-cyclopropyl-1H-pyrazol-5-yl) -6-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide from example 53a, after purification by chiral preparative HPLC, gave 307 as an off-white solid (7.8mg, 2% over 2 steps).¹H NMR(400MHz,d4-MeOD)7.63(s,1H),7.51-7.42(m,1H),7.20-7.11(m,2H),4.89-4.85(m,1H),3.63-3.46(m,4H),3.45-3.27(m,2H),2.34-2.18(m,1H),2.10-1.90(m,2H),1.80-1.66(m,1H),1.25-1.15(m,1H),1.17-1.00(m,3H)。LCMS(ES+)m/z492(M+1)

Example 3085-amino-N- (5- ((3S,5R) -5-amino-3-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 308

Following the procedure of example 107, starting from N- (1- (4-amino-1-cyclopropyl-1H-pyrazol-5-yl) -6-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide from example 53a, after purification by manual preparative HPLC, gave 308 as an off-white solid (2.6mg, 1%, over 2 steps).¹H NMR(400MHz,d4-MeOD)7.58(s,1H),7.52-7.44(m,1H),7.21-7.11(m,2H),4.87-4.86(m,1H),3.61-3.49(m,4H),3.38-3.30(m,1H),3.12(t,J＝5.8Hz,1H),2.32-2.23(m,1H),2.21-2.07(m,1H),2.03-1.93(m,1H),1.93-1.83(m,1H),1.22-1.04(m,4H)。LCMS(ES+)m/z492(M+1)

Example 3095-amino-N- (5- ((3R,5S) -5-amino-3-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 309

Following the procedure of example 107, from N- (1- (4-amino-1-cyclopropyl-1H-pyrazole-5) from example 53aStarting from-yl) -6-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide, purification by chiral preparative HPLC gave 309 as an off-white solid (2.5mg, 1% over 2 steps).¹H NMR(400MHz,d4-MeOD)7.58(s,1H),7.52-7.44(m,1H),7.21-7.11(m,2H),4.87-4.86(m,1H),3.61-3.49(m,4H),3.38-3.30(m,1H),3.12(t,J＝5.8Hz,1H),2.32-2.23(m,1H),2.21-2.07(m,1H),2.03-1.93(m,1H),1.93-1.83(m,1H),1.22-1.04(m,4H)。LCMS(ES+)m/z492(M+1)

Example 3105-amino-N- (5- ((4S,5R) -4-amino-5-hydroxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 310

Following the procedure of example 101, starting from tert-butyl 5-hydroxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate from example 49d, 310 was obtained as a pale beige solid (106mg, 68%, over three steps).¹H NMR (400MHz, d6-DMSO)9.05(br s,1H),7.60-7.47(m,4H),7.28(t, J ═ 8.8Hz,2H),3.90-3.82(s,1H),3.70-3.58(m,3H),3.40-3.20(m,3H),3.08-2.92(m,2H),1.99-1.83(m,2H),1.70-1.55(m,2H), no alkyl NH was observed₂And OH. LCMS (ES +) M/z464(M +1)

Example 3135-amino-N- [5- (5, 8-diazaspiro [2.6] non-8-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 313

Following the procedure in example 101, starting from 8- (1-methyl-4-nitro-1H-pyrazol-5-yl) -5, 8-diazaspiro [2.6]]Nonane-5-carboxylic acid tert-butyl ester to give 313 as a pale yellow solid (90mg, 35%, over three steps).¹H NMR(400MHz,CDCl₃)12.25(s,1H),8.15(s,1H),7.41-7.22(m,1H),7.02(t, J ═ 8.6Hz,2H),6.34(s,2H),3.66(s,3H),3.38(t, J ═ 6.3Hz,2H),3.11(t, J ═ 6.3Hz,2H),2.97(s,2H),2.74(s,2H),0.33(t, J ═ 5.3Hz,2H),0.13(t, J ═ 5.3Hz,2H). LCMS (ES +) M/z460(M +1)

EXAMPLE 3145-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 314

Chiral separation of racemic 5-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-methyl-pyrazol-4-yl by SFC]-2- (2, 6-difluorophenyl) thiazole-4-carboxamide to give 314.¹H NMR(400MHz,DMSO)9.28(s,1H),7.64(s,1H),7.61-7.40(m,4H),7.32-7.17(m,2H),3.62(s,3H),3.40(d,J＝8.4Hz,1H),3.20(s,3H),3.18-3.07(m,2H),3.07-2.92(m,3H),2.13-1.93(m,1H),1.83-1.74(m,1H),1.74-1.56(m,2H)。LCMS(ES+)m/z478(M+1)

Example 3155-amino-N- (5- ((4S,5R) -4-amino-5-hydroxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 315

Chiral separation of racemic 5-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-methyl-pyrazol-4-yl by SFC]-2- (2, 6-difluorophenyl) thiazole-4-carboxamide gave 315.¹H NMR(400MHz,DMSO)9.28(s,1H),7.64(s,1H),7.60-7.42(m,4H),7.31-7.20(m,2H),3.62(s,3H),3.44-3.36(m,1H),3.19(s,3H),3.18-3.07(m,2H),3.02(dt,J＝13.0,3.8Hz,3H),2.12-1.95(m,1H),1.86-1.73(m,1H),1.73-1.57(m,2H)。LCMS(ES+)m/z478(M+1)

Example 3185-amino-2- (2, 6-difluorophenyl) -N- [ 1-methyl-5- (2-oxoazepan-1-yl) pyrazol-4-yl ] thiazole-4-carboxamide 318

Following the procedure in example 101, starting from 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-2-one, 318 was obtained as a white solid (51mg, 26%, over three steps).¹H NMR(400MHz,CDCl₃)8.40(s,1H),7.95(s,1H),7.35-7.28(m,1H),7.01(t,J＝8.9Hz,2H),6.14(s,2H),3.78-3.58(m,5H),2.76(d,J＝7.4Hz,2H),1.92-1.75(m,6H)。LCMS(ES+)m/z447(M+1)

Example 3195-amino-2- (2, 6-difluorophenyl) -N- [ 1-methyl-5- (7-oxo-1, 4-diazepan-1-yl) pyrazol-4-yl ] thiazole-4-carboxamide 319

Following the procedure in example 101, starting from tert-butyl 4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -3-oxo-1, 4-diazepan-1-carboxylate, 319 was obtained as a white solid (35mg, 20%, over three steps).¹H NMR(400MHz,CDCl₃)8.70(s,1H),7.96(s,1H),7.36-7.28(m,1H),7.02(t, J ═ 8.7Hz,2H),6.16(s,2H),3.83(ddd, J ═ 15.2,8.3,2.4Hz,1H),3.72(s,3H),3.64(ddd, J ═ 15.2,6.1,2.5Hz,1H),3.22-3.02(m,4H),2.96-2.84(m,2H), no exchangeable NH was observed. LCMS (ES +) M/z448(M +1)

Example 3225-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2-pyridyl) thiazole-4-carboxamide 322

Following the procedure of example 101, tert-butyl ((4R,5R) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-methoxyazepan-4-yl) carbamate was reacted with 5- ((tert-butoxycarbonyl) amino) -2- (pyridin-2-yl) thiazole-4-carboxylic acid to give racemic 322(58.4mg, 41% over two steps).¹H NMR(400MHz,DMSO)8.89(s,1H),8.54(d,J＝4.7Hz,1H),8.17(d,J＝8.0Hz,1H),7.89(t,J＝7.7Hz,1H),7.62-7.47(m,3H),7.43-7.31(m,1H),3.64(s,3H),3.27(s,3H),3.23-2.91(m,6H),2.15-2.00(m,1H),1.92-1.80(m,1H),1.79-1.55(m,2H)。LCMS(ES+)m/z443(M+1)

Example 3235-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (3-fluoro-2-pyridinyl) thiazole-4-carboxamide 323

In accordance with the procedure of example 101, tert-butyl ((4R,5R) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-methoxyazepan-4-yl) carbamate and 5- ((tert-butoxycarbonyl) amino) Reaction of (E) -2- (3-fluoro-pyridin-2-yl) thiazole-4-carboxylic acid gave racemic 323(35.8mg, 24% over two steps).¹H NMR(400MHz,DMSO)8.84(s,1H),8.43(d,J＝4.6Hz,1H),7.89-7.78(m,1H),7.66(s,2H),7.62(s,1H),7.48(dt,J＝8.3,4.1Hz,1H),3.65(s,3H),3.28(d,J＝7.5Hz,5H),3.26-2.95(m,8H),2.07(dd,J＝10.6,4.4Hz,1H),1.92(dd,J＝10.6,7.4Hz,1H),1.79-1.55(m,2H)。LCMS(ES+)m/z461(M+1)

Example 3245-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2-fluorophenyl) thiazole-4-carboxamide 324

Following the procedure of example 101, tert-butyl ((4R,5R) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-methoxyazepan-4-yl) carbamate and 5- ((tert-butoxycarbonyl) amino) -2- (2-fluorophenyl) thiazole-4-carboxylic acid were reacted to give 324(118mg, 63% over two steps).¹H NMR(400MHz,DMSO)8.94(s,1H),8.30(t,J＝8.2Hz,1H),7.51(s,1H),7.48-7.39(m,3H),7.39-7.27(m,2H),3.64(s,3H),3.27(s,4H),3.24-2.90(m,7H),2.14-2.01(m,1H),1.91-1.81(m,1H),1.77-1.54(m,2H)。LCMS(ES+)m/z460(M+1)

Example 3255-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2-fluoro-5-methyl-phenyl) thiazole-4-carboxamide 325

Following the procedure of example 101, tert-butyl ((4R,5R) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-methoxyazepan-4-yl) carbamate and 5- ((tert-butoxycarbonyl) amino) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxylic acid were reacted to give 325(70.8mg, 40% over two steps).¹H NMR(400MHz,DMSO)8.98(s,1H),8.07(d,J＝7.4Hz,1H),7.48(s,1H),7.40(s,2H),7.23(d,J＝9.0Hz,2H),3.64(s,3H),3.24(s,4H),3.23-2.86(m,8H),2.37(s,3H),2.11-1.95(m,1H),1.91-1.79(m,1H),1.79-1.53(m,2H)。LCMS(ES+)m/z474(M+1).

Example 3265-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 5-difluorophenyl) thiazole-4-carboxamide 326

Following the procedure of example 101, tert-butyl ((4R,5R) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-methoxyazepan-4-yl) carbamate and 5- ((tert-butoxycarbonyl) amino) -2- (2, 5-difluorophenyl) thiazole-4-carboxylic acid were reacted to give 326(64.2mg, 33.6% over two steps).¹H NMR(400MHz,DMSO)9.08(s,1H),8.22-8.10(m,1H),7.46(d,J＝9.7Hz,2H),7.45-7.35(m,2H),7.34-7.18(m,1H),3.64(s,3H),3.23(d,J＝12.0Hz,4H),3.21-2.89(m,6H),2.10-1.97(m,1H),1.89-1.79(m,1H),1.78-1.53(m,2H)。LCMS(ES+)m/z478(M+1)

Example 3275-amino-N- [5- (4-amino-5-hydroxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 327

Chiral separation of racemic 5-amino-N- [5- (4-amino-5-hydroxy-azepan-1-yl) -1-methyl-pyrazol-4-yl by SFC]-2- (2, 6-difluorophenyl) thiazole-4-carboxamide to give the single enantiomer 327.¹H NMR(400MHz,DMSO)9.14(s,1H),7.60(s,1H),7.57-7.41(m,3H),7.27(t,J＝8.7Hz,2H),3.77(d,J＝7.1Hz,1H),3.62(s,3H),3.25-2.91(m,5H),1.96-1.78(m,2H),1.72-1.55(m,2H)。LCMS(ES+)m/z464(M+1)

Example 3285-amino-N- [5- (4-amino-5-hydroxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 328

Following the procedure of example 333, and starting from 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol, which is the second eluting peak of chiral separation, gave 328 (18%).¹H NMR(400MHz,DMSO)8.85(s,1H),7.60-7.39(m,4H),7.27(t,J＝8.7Hz,2H),3.63(s,3H),3.22-3.01(m,5H),2.81-2.68(m,1H),1.97-1.78(m,2H),1.76-1.62(m,1H),1.62-1.45(m,1H)。LCMS(ES+)m/z464(M+1)

Example 3315-amino-N- [5- (4-amino-5-fluoro-azepan-1-yl) -1-cyclopropyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 331

Racemic trans-N- [1- (2-cyclopropyl-4-nitro-pyrazol-3-yl) -5-fluoro-azepan-4-yl]Carbamic acid tert-butyl ester on AD column at 20% methanol w/0.1% NH₄And (4) performing OH chiral separation. Following the procedure of example 369, the second elution peak was converted to 331.¹H NMR(400MHz,DMSO)8.83(s,1H),7.59-7.40(m,4H),7.26(t,J＝8.7Hz,2H),4.44(dtd,J＝47.9,8.3,3.7Hz,1H),3.54(tt,J＝7.5,3.9Hz,1H),3.27-3.05(m,5H),2.23-2.09(m,1H),2.01-1.77(m,4H),1.70-1.53(m,1H),1.03(dd,J＝7.4,3.8Hz,2H),0.94(dd,J＝6.8,4.6Hz,2H)。LCMS(ES+)m/z492(M+1)

Example 3325-amino-N- [5- (4-amino-5-fluoro-azepan-1-yl) -1-cyclopropyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 332

Upon separation at 331, the first eluting peak was converted to the single enantiomer 332.¹H NMR(400MHz,DMSO)8.81(s,1H),8.25(s,1H),7.95(s,1H),7.60-7.42(m,3H),7.27(t,J＝8.7Hz,2H),4.64-4.42(m,1H),3.59-3.49(m,1H),3.32-3.10(m,5H),2.24-2.07(m,1H),2.03-1.85(m,2H),1.74-1.59(m,1H),1.04(dd,J＝8.3,4.1Hz,2H),0.96(dd,J＝10.3,5.8Hz,2H)。LCMS(ES+)m/z492(M+1)

Example 3335-amino-N- [5- (4-amino-5-hydroxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 333

Step A solution of 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (502mg,1.78mmol) (first elution peak on chiral separation) in THF/water (15mL/3mL) at triphenylphosphine (476mg,1.78mmol)The reaction mixture was heated at 60 ℃ for 5 hours. EtOAc (100mL) was added and the mixture was saturated NaHCO₃Aqueous (20mL) wash. The aqueous layer was extracted with EtOAc (50mL) and the combined organic layers were MgSO₄Dried and concentrated under reduced pressure to give an oil. To a solution of this oil in anhydrous DCM (20mL) was added DIPEA (0.85mL,4.88mmol) and trifluoroacetic anhydride (0.29mL,2.05mmol) at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 4 hours. Water (20mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/heptane) afforded 2,2, 2-trifluoro-N- (5-hydroxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide as a yellow oil (626mg, 88%). A solution of this oil (554mg,1.57mmol) in MeOH (20mL) was treated with ammonium formate (1002mg,15.7mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 65 ℃ for 1 hour. After cooling to room temperature, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was taken up in saturated NaHCO₃Partition between aqueous solution (20mL) and DCM (50 mL). The aqueous layer was extracted with DCM (3 × 50mL) and the combined organic layers were over MgSO₄Dried and concentrated under reduced pressure to give N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-hydroxyazepan-4-yl) -2,2, 2-trifluoroacetamide as an orange foam.

Step B to a solution of N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-hydroxyazepan-4-yl) -2,2, 2-trifluoroacetamide (504mg,1.57mmol) in DCM (20mL) was added DIPEA (1.65mL,9.42mmol), PyBOP (1.17mg,2.20mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acid (559mg,1.57mmol) and the mixture was stirred at room temperature for 18H. The mixture was diluted with DCM (100mL) and washed with water (20 mL). The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/heptane) afforded tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4-hydroxy-5- (2,2, 2-trifluoroacetamide) azepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate as an off-white solid (240mg, 23%). The solid (240mg,0.36mmol) was stirred with HCl in 1, 4-dioxane (4M,6mL,24mmol) in MeOH (5mL) at room temperature for 18 hours. ReducingThe solvent was removed under pressure with saturated NaHCO₃Basified and extracted with ethyl acetate (3 ×). The combined organic layers were over MgSO₄The solvent was removed under reduced pressure by drying and the residue was purified by preparative HPLC to give 333. LCMS (ES +) M/z464(M +1)

Example 3345-amino-2- (2, 6-difluorophenyl) -N- [ 1-methyl-5- [ (4S) -4- [ (3-methyloxetan-3-yl) methylamino ] azepan-1-yl ] pyrazol-4-yl ] thiazole-4-carboxamide 334

To a solution of tert-butyl (S) - (4- ((5- (4-aminoazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) carbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-yl) carbamate (103mg,0.19mmol) in acetonitrile (2mL) and THF (2mL) was added 3- (iodomethyl) -3-methyl-oxetane (78mg,0.38mmol) and potassium carbonate (130mg,0.94 mmol). The mixture was heated at 65 ℃ for 3 days. After cooling to room temperature, water (20mL) was added and the mixture was extracted with DCM (50mLx 3). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. Purification by silica gel column chromatography (0-15% methanol/DCM) gave N- [2- (2, 6-difluorophenyl) -4- [ [ 1-methyl-5- [ (4R) -4- [ (3-methyloxetan-3-yl) methylamino ]]Azepan-1-yl]Pyrazol-4-yl]Carbamoyl radical]Thiazol-5-yl]Tert-butyl carbamate (130mg, quantitative). The solid (130mg,0.21mmol) was stirred with TFA (3mL) and DCM (3mL) at room temperature for 1 h. The solvent was removed under reduced pressure to saturate NaHCO₃Basified and extracted with ethyl acetate (3 ×). The combined organic layers were over MgSO₄The solvent was removed under reduced pressure by drying and the residue was purified by preparative HPLC to give 334(55.7mg, 51%).¹H NMR(400MHz,DMSO)8.66(s,1H),8.18(s,1H),7.56(s,1H),7.55-7.41(m,3H),7.26(t,J＝8.7Hz,2H),4.28(d,J＝5.6Hz,2H),4.12(d,J＝5.5Hz,2H),3.65(s,3H),3.23-3.00(m,4H),2.83-2.70(m,1H),2.70-2.58(m,2H),1.99-1.77(m,3H),1.68-1.51(m,3H),1.17(s,3H)。LCMS(ES+)m/z532(M+1)

Example 3355-amino-2- (2, 6-difluorophenyl) -N- [5- [ (4S) -4- (2-hydroxyethylamino) azepan-1-yl ] -1-methyl-pyrazol-4-yl ] thiazole-4-carboxamide 335

Following the procedure in example 334, except substituting 3- (iodomethyl) -3-methyl-oxetane with 2-iodoethanol, N- [2- (2, 6-difluorophenyl) -4- [ [5- [ (4R) -4- (2-hydroxyethylamino) azepan-1-yl ] azepan-1-yl]-1-methyl-pyrazol-4-yl]Carbamoyl radical]Thiazol-5-yl]Carbamic acid tert-butyl ester (37mg, 38%) and N- [4- [ [5- [ (4R) -4- [ bis (2-hydroxyethyl) amino]Azepan-1-yl]-1-methyl-pyrazol-4-yl]Carbamoyl radical]-2- (2, 6-difluorophenyl) thiazol-5-yl]Tert-butyl carbamate (10mg, 9.6%). Following the deprotection procedure in example 334, N- [2- (2, 6-difluorophenyl) -4- [ [5- [ (4R) -4- (2-hydroxyethylamino) azepan-1-yl]-1-methyl-pyrazol-4-yl]Carbamoyl radical]Thiazol-5-yl]Tert-butyl carbamate was converted to 335(16.7mg, 31%).¹H NMR(400MHz,DMSO)8.69(s,1H),8.27(s,1H),7.59-7.41(m,4H),7.27(t,J＝8.7Hz,2H),3.65(s,3H),3.50-3.42(m,2H),3.24-3.03(m,5H),2.98-2.83(m,1H),2.73-2.57(m,2H),1.89(m,3H),1.68-1.49(m,3H)。LCMS(ES+)m/z492(M+1)

Example 3365-amino-N- [5- [ (4S) -4- [ bis (2-hydroxyethyl) amino ] azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 336

In the preparation of 335, N- [4- [ [5- [ (4R) -4- [ bis (2-hydroxyethyl) amino]Azepan-1-yl]-1-methyl-pyrazol-4-yl]Carbamoyl radical]-2- (2, 6-difluorophenyl) thiazol-5-yl]Deprotection of tert-butyl carbamate following the procedure in example 334 gave 336(6mg, 71%).¹H NMR(400MHz,DMSO)8.63(s,1H),8.24(s,1H),7.56(s,1H),7.55-7.41(m,3H),7.27(t,J＝8.7Hz,2H),3.65(s,3H),3.19-3.02(m,7H),2.85-2.71(m,2H),2.46(t,J＝6.2Hz,4H),1.92-1.75(m,3H),1.67-1.50(m,3H)。LCMS(ES+)m/z536(M+1)

Example 3375-amino-N- [5- (4-amino-5-hydroxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 337

SFC chiral separation of 5-amino-N- [5- (4-amino-5-hydroxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide gave the single enantiomer 337. LCMS (ES +) M/z464(M +1)

Example 3405-amino-2- (2, 6-difluorophenyl) -N- [ 1-methyl-5- (5-oxo-1, 4-oxazepan-4-yl) pyrazol-4-yl ] thiazole-4-carboxamide 340

Following the procedure in example 101, starting from 4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-oxazepan-5-one, 340 was obtained as a white solid (45mg, 70%, over three steps).¹H NMR(400MHz,CDCl₃)8.38(s,1H),7.86(s,1H),7.36-7.27(m,1H),7.06-6.98(m,2H),6.12(s,2H),4.01-3.86(m,5H),3.80-3.62(m,4H),3.03-2.94(m,2H)。LCMS(ES+)m/z449(M+1)

Example 3415-amino-2- (2, 6-difluorophenyl) -N- [ 1-methyl-5- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) pyrazol-4-yl ] thiazole-4-carboxamide 341

Following the procedure in example 101, from 3- (1-methyl-4-nitro-1H-pyrazol-5-yl) -8-oxa-3-azabicyclo [3.2.1]Octane started to give 341 as a white solid (49mg, 40%, over three steps).¹H NMR(400MHz,d6-DMSO)8.71(s,1H),7.56-7.52(m,3H),7.47(s,1H),7.30-7.24(m,2H),4.27(br s,2H),3.68(s,3H),3.35-3.32(m,2H),2.68(d,J＝10.9Hz,2H),2.09-1.97(m,2H),1.82-1.79(m,2H)。LCMS(ES+)m/z447(M+1)

Example 3425-amino-2- (2, 6-difluorophenyl) -N- [ 1-methyl-5- [ (4S) -4- (oxetan-3-ylmethyl-amino) azepan-1-yl ] pyrazol-4-yl ] thiazole-4-carboxamide 342

Following the procedure of example 334, except substituting 3- (iodomethyl) -3-methyl-oxetane for 3- (iodomethyl) oxetane, tert-butyl N- [2- (2, 6-difluorophenyl) -4- [ [ 1-methyl-5- [ (4R) -4- (oxetan-3-ylmethyl amino) azepan-1-yl ] pyrazol-4-yl ] carbamoyl ] thiazol-5-yl ] carbamate (17mg, 25.5%) and N- [4- [ [5- [ (4R) -4- [ bis (oxetan-3-ylmethyl) amino ] azepan-1-yl ] -1-methyl-pyrazol-4-yl ] carbamoyl ] -2-yl ] carbamate were obtained (17mg, 25.5%) Tert-butyl (2, 6-difluorophenyl) thiazol-5-yl ] carbamate (19mg, 25.6%). Tert-butyl N- [2- (2, 6-difluorophenyl) -4- [ [ 1-methyl-5- [ (4R) -4- (oxetan-3-ylmethylamino) azepan-1-yl ] pyrazol-4-yl ] carbamoyl ] thiazol-5-yl ] carbamate was converted to 342(4.1mg, 29%) according to the deprotection procedure in example 334. LCMS (ES +) M/z518(M +1)

Example 3435-amino-N- [5- [ (4S) -4- [ bis (oxetan-3-ylmethyl) amino ] azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 343

In preparation of 342, tert-butyl N- [4- [ [5- [ (4R) -4- [ bis (oxetan-3-ylmethyl) amino ] azepan-1-yl ] -1-methyl-pyrazol-4-yl ] carbamoyl ] -2- (2, 6-difluorophenyl) thiazol-5-yl ] carbamate is deprotected according to the procedure in example 334 to give 343. LCMS (ES +) M/z588(M +1)

Example 3485-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-ethyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 348

Following the procedure in example 101, starting from tert-butyl 1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) -5-fluoroazepan-4-ylcarbamate, 348 was obtained as a white solid (37mg, 23%, over three steps).¹H NMR(400MHz,CDCl₃)8.64(s,1H),7.88(s,1H),7.39-7.26(m,1H),7.03(t,J＝8.7Hz,2H),6.17(s,2H),4.48(dtd,J＝48.0,8.7,3.6Hz,1H),4.02(q,J＝7.2Hz,2H),3.38-3.13(m,6H),2.32-2.18(m,1H),2.14-1.93(m,2H),1.85-1.79(m,1H),1.83-1.57(m,1H),1.43(t,J＝7.2Hz,3H)。LCMS(ES+)m/z480(M+1)

Example 3495-amino-N- [5- (3-azabicyclo [3.2.1] oct-3-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 349

Following the procedure of example 101, from 3- (1-methyl-4-nitro-1H-pyrazol-5-yl) -3-azabicyclo [3.2.1]Octane started to give 349 as an off-white solid (80mg, 30% over three steps).¹H NMR(400MHz,CDCl₃)8.57(s,1H),7.86(s,1H,)7.39-7.22(m,1H),7.04-6.99(m,2H),6.12(br s,2H),3.76(s,3H),3.25(d J＝10.4Hz,2H),2.81-2.78(dd J＝10.4,3.4Hz,2H)2.24(br s,2H),1.86(d,J＝7.7Hz,2H),1.72-1.69(m,2H),1.60(br s,2H)。LCMS(ES+)m/z445(M+1)

Example 3505-amino-2- (2, 6-difluorophenyl) -N- [5- (1, 1-dioxo-1, 4-thiazepan-4-yl) -1-methyl-pyrazol-4-yl ] thiazole-4-carboxamide 350

Following the procedure of example 101, starting from 4- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1, 4-thiaazepane 1, 1-dioxide, 350 was obtained as an off-white solid (52mg, 20%, over three steps).¹H NMR(400MHz,CDCl₃)8.45(s,1H),7.74(s,1H),7.36-7.32(m,1H),7.07-7.01(m,2H),6.12(br s,2H),3.79(s,3H),3.59-3.56(m,2H),3.47-3.43(m,2H),3.38-3.35(m,2H),3.30-3.27(m,2H),2.24-2.18(m,2H)。LCMS(ES+)m/z483(M+1)

Example 3525-amino-N- [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 352

Chiral separation of 5-amino-N- [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl group by SFC]-2- (2, 6-difluorophenyl) thiazole-4-carboxamide gave the single enantiomer 352.¹H NMR(400MHz,DMSO)8.85(s,1H),8.46(s,1H),7.64(s,1H),7.60-7.44(m,3H),7.29(t,J＝8.7Hz,2H),3.65(s,3H),3.27-3.14(m,3H),3.07(dd,J＝10.9,5.5Hz,1H),3.02(s,3H),2.97(d,J＝14.4Hz,1H),2.00(d,J＝14.3Hz,1H),1.92-1.82(m,1H),1.71-1.57(m,1H),1.48(dd,J＝14.3,10.8Hz,1H),0.99(s,3H)。LCMS(ES+)m/z492(M+1)

EXAMPLE 3535-amino-N- [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 353

Chiral separation of 5-amino-N- [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl group by SFC]-2- (2, 6-difluorophenyl) thiazole-4-carboxamide gave a single enantiomer 353.¹H NMR(400MHz,DMSO)8.85(s,1H),8.47(s,1H),7.64(s,1H),7.59-7.45(m,3H),7.29(t,J＝8.7Hz,2H),3.65(s,3H),3.28-3.12(m,3H),3.11-3.03(m,1H),3.02(s,3H),2.97(d,J＝14.3Hz,1H),2.00(d,J＝14.2Hz,1H),1.93-1.80(m,1H),1.71-1.57(m,1H),1.48(dd,J＝14.3,10.8Hz,1H),0.99(s,3H)。LCMS(ES+)m/z492(M+1)

EXAMPLE 3545-amino-2- (2, 6-difluorophenyl) -N- [ 1-methyl-5- (9-oxa-3, 7-diazabicyclo [3.3.1] non-3-yl) pyrazol-4-yl ] thiazole-4-carboxamide 354

Step A. to a microwave reaction vial was added 5-chloro-1-methyl-4-nitro-1H-pyrazole (141mg,0.88mmol), 9-oxa-3, 7-diazabicyclo [3.3.1] nonane-3-carboxylic acid tert-butyl ester (200mg,0.88 mmol). Ethanol (8mL) and diisopropylethylamine (0.92mL,5.25mmol) were added and the mixture was irradiated with microwaves at 130 ℃ for 60 minutes. The mixture was cooled, concentrated and purified via flash chromatography, ethyl acetate/heptane 0% to 100% to give 7- (2-methyl-4-nitro-pyrazol-3-yl) -9-oxa-3, 7-diazabicyclo [3.3.1] nonane-3-tert-butyl ester as a yellow oil (202mg, 65%).

Step B A solution of the above yellow oil in MeOH (30mL)(60bar,60 ℃, flow rate: 1 mL/min, 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give 7- (4-amino-2-methyl-pyrazol-3-yl) -9-oxa-3, 7-diazabicyclo [3.3.1]Tert-butyl nonane-3-carboxylate as a brown oil. To a solution of this oil in DCM (10mL) was added 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (260mg,0.74mmol), PyBOP (480g,0.91mmol) and DIPEA (0.60mL,3.40mmol) and the mixture was stirred at rt for 16 h. Water (20mL) was added and the mixture was diluted with DCM (100 mL). The organic layer was washed with water (20mL), separated, and MgSO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/heptane) afforded 7- [4- [ [5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl]Amino group]-2-methyl-pyrazol-3-yl]-9-oxa-3, 7-diazabicyclo [3.3.1]Tert-butyl nonane-3-carboxylate (380mg, quantitative).

Step C the solid (380mg,0.57mmol) was stirred with TFA (7mL) and DCM (10mL) at room temperature for 1 h. The solvent was removed under reduced pressure to saturate NaHCO₃Basified and extracted with ethyl acetate (3 ×). The combined organic layers were over MgSO₄The solvent was removed under reduced pressure by drying and the residue was purified by preparative HPLC to give 354(82mg, 29%).¹H NMR(400MHz,DMSO)9.58(s,1H),7.63-7.40(m,4H),7.27(t,J＝8.6Hz,2H),3.66(s,3H),3.62(d,J＝19.8Hz,3H),3.20-2.86(m,7H)。LCMS(ES+)m/z462(M+1)

Example 3575-amino-N- (5- ((4R,5R) -4-amino-5-fluorocycloheptyl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 357

To a solution/suspension of tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (diastereomer 1) (49mg,0.074mmol) in MeOH (2mL) was added a solution of HCl in dioxane (4M,1.9mL,7.42mmol) and the mixture was heated at 60 ℃ for 72 hours. The solvent was removed under reduced pressure and the residueDissolved in MeOH/water (5mL/5mL) and washed with K₂CO₃(51mg,0.37 mmol). The mixture was heated at 65 ℃ for 18 hours. MeOH was removed under reduced pressure and the aqueous residue was extracted with 5% MeOH/DCM (2X30 mL). The organic layers were combined and MgSO₄Dried and concentrated under reduced pressure. The residue was dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH, eluted with 3N ammonia in MeOH and the solvent was removed under reduced pressure to give 357 (diastereomer 1) as a beige solid (10mg, 29%, over two steps).¹H NMR(400MHz,CDCl₃)8.44(s,1H),7.76(s,1H),7.35-7.28(m,1H),7.07-6.99(m,2H),6.11(s,2H),4.46-4.29(m,1H),3.83(s,3H),3.23-3.13(m,1H),2.84-2.76(m,1H),2.26-1.81(m,6H),1.60-1.40(m,2H). No alkyl NH was observed₂。LCMS(ES+)m/z465(M+1)

Example 3585-amino-N- (5- ((4R,5R) -4-amino-5-fluorocycloheptyl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 358

To a suspension of tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (diastereomer 2) (28mg,0.042mmol) in MeOH (2mL) was added a solution of HCl in dioxane (4M,1.1mL,4.24mmol) and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in MeOH/water (3mL/3mL) in K₂CO₃(29mg,0.21mmol) and heated at 60 ℃ for 18 h. MeOH was removed under reduced pressure and the aqueous residue was extracted with 5% MeOH/DCM (2X40 mL). The organic layers were combined, passed through a phase separation cartridge and concentrated under reduced pressure to give 358 (diastereomer 2) as an off-white solid (17mg, 86% over two steps).¹H NMR(400MHz,CDCl₃)8.44(s,1H),7.76(s,1H),7.34-7.29(m,1H),7.03(t, J ═ 8.7Hz,2H),6.11(s,2H),4.47-4.29(m,1H),3.83(s,3H),3.23-3.12(m,1H),2.86-2.75(m,1H),2.25-1.84(m,6H),1.60-1.40(m,2H), no alkyl NH was observed₂。LCMS(ES+)m/z465(M+1)

Example 3595-amino-N- [5- (2, 6-diazaspiro [3.4] oct-6-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 359

Following the procedure in example 354, 9-oxa-3, 7-diazabicyclo [3.3.1]Replacement of nonane-3-carboxylic acid tert-butyl ester with 2, 7-diazaspiro [3.4]]Tert-butyl octane-2-carboxylate, 359.¹H NMR(400MHz,DMSO)8.70(s,1H),8.44(s,1H),7.58-7.44(m,3H),7.39(s,1H),7.26(t,J＝8.6Hz,2H),3.61(s,5H),3.56(d,J＝8.2Hz,4H),3.21(t,J＝6.8Hz,2H),2.10(t,J＝6.9Hz,2H)。LCMS(ES+)m/z446(M+1)

Example 3605-amino-2- (2, 6-difluorophenyl) -N- [ 1-methyl-5- (1-oxo-2, 8-diazaspiro [4.5] decan-8-yl) pyrazol-4-yl ] thiazole-4-carboxamide 360

Following the procedure in example 354, 9-oxa-3, 7-diazabicyclo [3.3.1]Replacement of nonane-3-carboxylic acid tert-butyl ester with 3, 8-diazaspiro [4.5]]Decan-4-one, to afford 360.¹H NMR(400MHz,DMSO)8.78(s,1H),7.58-7.43(m,4H),7.26(t,J＝8.7Hz,2H),3.64(s,3H),3.21-3.07(m,4H),3.07-2.92(m,2H),1.97(t,J＝6.8Hz,2H),1.86-1.74(m,3H),1.41(d,J＝12.9Hz,2H)。LCMS(ES+)m/z488(M+1)

Example 3615-amino-N- [5- (2, 7-diazaspiro [3.4] oct-2-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 361

Following the procedure in example 354, 9-oxa-3, 7-diazabicyclo [3.3.1]Replacement of nonane-3-carboxylic acid tert-butyl ester with 2, 7-diazaspiro [3.4]]Octane-7-carboxylic acid tert-butyl ester; oxalic acid to give 361.¹H NMR(400MHz,DMSO)8.73(s,1H),7.60-7.43(m,3H),7.27(t,J＝8.6Hz,2H),7.15(s,1H),4.04(d,J＝7.0Hz,2H),3.97(d,J＝7.0Hz,2H),3.57(s,3H),3.11(t,J＝7.3Hz,2H),2.89(s,1H),2.73(s,1H),2.14(t,J＝7.3Hz,2H),2.07(s,2H)。LCMS(ES+)m/z446(M+1)

Example 3625-amino-N- [5- [4- (azetidin-3-yl) -1, 4-diazepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 362

Step A to a microwave reaction vial was added 5-chloro-1-methyl-4-nitro-1H-pyrazole (500mg,3.10mmol), 1, 4-diazepan-1-carboxylic acid tert-butyl ester (744mg,3.72 mmol). Ethanol (15mL) and diisopropylethylamine (3.23mL,18.57mmol) were added and the mixture was irradiated with microwaves at 130 ℃ for 60 minutes. The mixture was cooled, concentrated and purified via flash chromatography, ethyl acetate/heptane 0% to 100% to give 4- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester as a yellow oil (690mg, 69%).

Step B A solution of 4- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester (200mg,0.61mmol) in DCM (4mL) and TFA (4mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to saturate NaHCO₃Basified and extracted with ethyl acetate (3 ×). The combined organic layers were over MgSO₄The solvent was removed under reduced pressure by drying and the residue was purified by silica gel column chromatography (0-10% methanol/DCM) to give 1- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-diazepane (88mg, 64%). This was dissolved in acetonitrile (3 mL). Tert-butyl 3-iodoazetidine-1-carboxylate (221mg,0.78mmol) and DIPEA (5 equiv.) were added and the mixture was heated at 75 ℃ for 7 days, with additional iodide and DIPEA added on days 2and 3. The reaction mixture was cooled to room temperature, water (20mL) was added and the mixture was extracted with DCM (50 mL). The organic layer was washed with water (20mL), separated, and MgSO₄Dried and the solvent removed under reduced pressure. Purification by column chromatography on silica gel (0-10% methanol in DCM) gave 3- [4- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-diazepan-1-yl]Azetidine-1-carboxylic acid tert-butyl ester (144mg, 97%).

Step C3- [4- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-diazepan-1-yl ] -was prepared according to the procedure in example 354]Tert-butyl azetidine-1-carboxylate was converted to 362.¹H NMR(400MHz,DMSO)8.71(s,1H),8.36(s,1H),7.62-7.41(m,4H),7.29(t,J＝8.7Hz,2H),4.12-3.96(m,1H),3.89-3.75(m,1H),3.66(s,3H),3.59(dd,J＝17.1,10.1Hz,4H),3.41(dd,J＝14.3,7.1Hz,2H),3.21(t,J＝5.4Hz,4H),2.68-2.54(m,2H),1.91-1.73(m,2H)。LCMS(ES+)m/z489(M+1)

Example 3635-amino-N- [5- (3, 3-difluorocycloheptyl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 363

(E) Solution of (E) -5- (6, 6-difluorocyclohept-1-enyl) -1-methyl-4-nitro-1H-pyrazole (0.14g,0.54mmol) in MeOH (10mL) was purified by(all H)₂At 65 ℃ and a flow rate of 1 mL/min in a 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give an oil. This was dissolved in DCM (20mL) and DIPEA (0.28mL) and PyBOP (0.42g,0.81mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (211mg,0.59mmol) were added. The mixture was stirred at room temperature for 18 h, diluted with DCM (30mL) and washed with water (10 mL). The organic layer was separated and the solvent was removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) afforded a foam (210 mg). A solution of the foam (200mg) in MeOH (2mL) was treated with a solution of HCl in dioxane (4M,2.7mL,10.8mmol) and the mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and the residue was dissolved in EtOAC (25mL) and saturated NaHCO₃Aqueous solution (2 × 20mL) and water (20 mL). The organic layer was passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification via chiral preparative HPLC gave 363 (enantiomer 1) as a white solid (6.3mg, 5% over three steps).¹H NMR(400MHz,CDCl₃)8.49(s,1H),7.79(s,1H),7.40-7.30(m,1H),7.10-7.00(m,2H),6.13(s,2H),3.88(s,3H),3.19-3.07(m,1H),2.68-2.37(m,2H),2.30-1.94(m,6H),1.89-1.57(m,2H)

Example 3645-amino-N- (5- ((4S,5S) -4-amino-5-methoxyazepan-1-yl) -1-ethyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 364

Following the procedure as in example 101, starting from tert-butyl 1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) -5-methoxyazepan-4-ylcarbamate, 364 was obtained as a monoformate salt as a white solid (70mg, 64% over three steps).¹H NMR (400MHz, d6-DMSO)8.41(s,1H),7.59-7.45(m,2H),7.27(t, J ═ 8.8Hz,2H),3.96(q, J ═ 7.2Hz,2H),3.33-3.27(m,4H),3.23-3.04(m,5H),2.13(d, J ═ 14.4Hz,1H),1.96(d, J ═ 14.4Hz,1H),1.75-1.67(m,2H),1.32(t, J ═ 7.2Hz, 3H). No displaceable groups (exchanges) were found. LCMS (ES +) M/z492(M +1)

Example 3655-amino-N- (5- ((4S,5S) -4-amino-5-methoxyazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 365

Following the procedure as in example 101, starting from tert-butyl 1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -5-methoxyazepan-4-ylcarbamate, 365 was obtained as a monoformate salt as a white solid (68mg, 64% over three steps).¹H NMR (400MHz, d6-DMSO)8.40(s,1H),7.58-7.47(m,1H),7.43(s,1H),7.26(t, J ═ 8.7Hz,2H),3.55-3.47(m,1H),3.36-3.08(m,9H),2.15(d, J ═ 14.4Hz,1H),2.02-1.94(m,1H),1.83-1.66(m,2H),1.07-0.94(m, 4H). No displaceable groups were seen. LCMS (ES +) M/z504(M +1)

Example 3665-amino-N- [5- (3, 3-difluorocycloheptyl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 366

Obtained 366 (enantiomer 2) as a white solid following the procedure in example 363 (6.6mg, 5%).¹HNMR(400MHz,CDCl₃)8.49(s,1H),7.80(s,1H),7.39-7.30(m,1H),7.10-7.00(m,2H),6.13(s,2H),3.88(s,3H),3.17-3.06(m,1H),2.64-2.33(m,2H),2.30-1.94(m,6H),1.85-1.57(m,2H)

Example 367 (S) -5-amino-2- (2, 6-difluorophenyl) -N- [ 1-methyl-5- (2-oxo-1, 9-diazaspiro [4.6] undecan-9-yl) pyrazol-4-yl ] thiazole-4-carboxamide 367

Following the procedure in example 508, preparation 367, as a single enantiomer.¹H NMR(400MHz,DMSO-d6)8.64(s,1H),7.99(s,1H),7.59-7.50(m,2H),7.48(s,2H),7.27(t,J＝8.7Hz,2H),3.65(s,2H),3.30(s,3H),3.31-3.15(m,2H),3.11-2.96(m,2H),2.15-2.05(m,2H),1.80(m,6H)。MS(ESI)m/z:502.1[M+H+]

Example 368 (R) -5-amino-2- (2, 6-difluorophenyl) -N- [ 1-methyl-5- (2-oxo-1, 9-diazaspiro [4.6] undecan-9-yl) pyrazol-4-yl ] thiazole-4-carboxamide 368

Prepared 368 according to the procedure in example 508 as a single enantiomer.¹H NMR(400MHz,DMSO-d6)8.64(s,1H),7.99(s,1H),7.59-7.50(m,2H),7.48(s,2H),7.27(t,J＝8.7Hz,2H),3.65(s,2H),3.30(s,3H),3.31-3.15(m,2H),3.11-2.96(m,2H),2.15-2.05(m,2H),1.80(m,6H)。MS(ESI)m/z:502.1[M+H+]

Example 3695-amino-N- [5- (4-amino-5-fluoro-azepan-1-yl) -1-ethyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 369

Racemic tert-butyl trans- (1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) carbamate was purified on an AD column with 20% methanol w/0.1% NH₄And (4) performing OH chiral separation. Following the procedure of example 354, the first elution peak was converted to 369.¹H NMR(400MHz,DMSO)8.82(s,1H),7.60(s,1H),7.57-7.43(m,3H),7.26(t,J＝8.7Hz,2H),4.42(dtd,J＝47.8,8.2,3.6Hz,1H),3.95(q,J＝7.2Hz,2H),3.24-3.04(m,5H),2.18-1.76(m,3H),1.66-1.51(m,1H),1.32(t,J＝7.2Hz,3H)。LCMS(ES+)m/z480(M+1)

Example 3705-amino-N- [5- (4-amino-5-fluoro-azepan-1-yl) -1-ethyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 370

In preparation of 369, the second elution peak is converted to 370.¹H NMR(400MHz,DMSO)8.82(s,1H),7.60(s,1H),7.57-7.44(m,3H),7.26(t,J＝8.7Hz,2H),4.42(dd,J＝47.9,3.6Hz,1H),3.95(q,J＝7.2Hz,2H),3.24-3.02(m,5H),2.19-2.03(m,1H),2.00-1.77(m,2H),1.67-1.52(m,1H),1.32(t,J＝7.2Hz,3H)。LCMS(ES+)m/z480(M+1)

Example 3715-amino-N- [5- (3, 3-difluoro-5-hydroxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 371

Racemic N- [6, 6-difluoro-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl]Oxy-1-phenyl-azomethine on AD column at 35% methanol w/0.1% NH₄And (4) performing OH chiral separation. Following the procedure in example 369, the first eluting peak was converted to 371.¹H NMR(400MHz,DMSO)8.76(s,1H),7.61-7.40(m,4H),7.26(t,J＝8.6Hz,2H),4.90(d,J＝3.8Hz,1H),4.06-3.90(m,1H),3.74-3.57(m,4H),3.47-3.34(m,1H),3.34-3.20(m,1H),3.17-3.01(m,1H),2.43-2.23(m,2H),2.00-1.73(m,2H)。LCMS(ES+)m/z485(M+1)

Example 3725-amino-N- [5- (3, 3-difluoro-5-hydroxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 372

In the preparation of 371, the second eluting peak was converted to the single enantiomer 372.¹H NMR(400MHz,DMSO)8.76(s,1H),7.60-7.42(m,4H),7.26(t,J＝8.6Hz,2H),4.90(d,J＝3.9Hz,1H),4.00(s,1H),3.75-3.54(m,4H),3.46-3.34(m,1H),3.34-3.23(m,1H),3.16-3.03(m,1H),2.45-2.23(m,2H),2.01-1.70(m,2H)。LCMS(ES+)m/z485(M+1)

Example 3735-amino-N- [5- (4-amino-5-fluoro-azepan-1-yl) -1-ethyl-pyrazol-4-yl ] -2- (2-fluorophenyl) thiazole-4-carboxamide 373

Following the procedure in example 369, the first eluting peak was converted to the single enantiomer 373.¹H NMR(400MHz,DMSO)8.92(s,1H),8.28(t,J＝7.9Hz,1H),7.56(s,1H),7.51-7.27(m,5H),4.56-4.32(m,1H),3.96(q,J＝7.2Hz,2H),3.24-3.06(m,5H),2.20-2.04(m,1H),2.04-1.90(m,1H),1.90-1.77(m,1H),1.77-1.54(m,3H),1.33(t,J＝7.2Hz,3H)。LCMS(ES+)m/z462(M+1)

Example 3745-amino-N- [5- (4-amino-5-fluoro-azepan-1-yl) -1-ethyl-pyrazol-4-yl ] -2- (2-fluorophenyl) thiazole-4-carboxamide 374

In the preparation of 373, the second eluting peak was converted to the single enantiomer 374.¹H NMR(400MHz,DMSO)8.92(s,1H),8.28(t,J＝7.7Hz,1H),7.56(s,1H),7.50-7.23(m,5H),4.56-4.33(m,1H),3.96(q,J＝7.2Hz,2H),3.25-3.04(m,5H),2.21-2.05(m,1H),2.05-1.90(m,1H),1.90-1.79(m,1H),1.79-1.50(m,3H),1.33(t,J＝7.2Hz,3H)。LCMS(ES+)m/z462(M+1)

Example 3755-amino-N- (5- ((4S,5R) -4-amino-5-hydroxyazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 375

Following the procedure of example 101, starting from tert-butyl 1- (1- (2, 2-difluoroethyl) -4-nitro-1H-pyrazol-5-yl) -5-hydroxyazepan-4-ylcarbamate, 375 was obtained as a monoformate salt as a light brown solid (58mg, 47%, over three steps).¹H NMR (400MHz, d6-DMSO)8.42(s,1H),7.65(s,1H),7.58-7.48(m,1H),7.28(t, J ═ 8.8Hz,2H),6.36(tt, J ═ 55.3,4.1Hz,1H),4.43(td, J ═ 14.5,4.2Hz,2H),4.04(s,1H),3.40-3.29(m,2H),3.26-3.18(m,1H),3.12-3.02(m,1H),2.95(dt, J ═ 13.7,4.7Hz,1H),2.14-2.02(m,1H),1.93-1.66(m,2H),1.77-1.67(m, 1H). No displaceable groups were observed. LCMS (ES +) M/z514(M +1)

Example 3765-amino-N- (5- ((4S,5R) -4-amino-5-methoxyazepan-1-yl) -1-ethyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 376

Following the procedure of example 101, starting from tert-butyl 1- (1-ethyl-4-nitro-1H-pyrazol-5-yl) -5-methoxyazepan-4-ylcarbamate, 376 was obtained as the monoformate salt as a light brown solid (60mg, 51% over three steps).¹H NMR (400MHz, d6-DMSO)8.41(s,1H),7.59(s,1H),7.58-7.45(m,1H),7.27(t, J ═ 8.8Hz,2H),3.96(q, J ═ 7.2Hz,2H),3.42(dt, J ═ 9.8,3.0Hz,1H),3.70-3.60(m,1H),3.50-2.94(m,5H),3.09-3.00(m,1H),3.00-2.91(m,1H),2.13-2.04(m,1H),2.03-1.91(m,1H),1.79-1.65(m,2H),1.31(t, J ═ 7.2, 3H). No displaceable groups were observed. LCMS (ES +) M/z492(M +1)

Example 3775-amino-N- (5- ((4R,5S) -4-amino-5-fluorocycloheptyl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 377

Following the procedure in example 358, starting from tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (diastereomer 5) gave 377 (diastereomer 5) as an off-white solid (16mg, 79% over two steps).¹H NMR(400MHz,CDCl₃)8.46(s,1H),7.79(s,1H),7.38-7.28(m,1H),7.03(t, J ═ 8.8Hz,2H),6.14(s,2H),4.88-4.71(m,1H),3.82(s,3H),3.25-3.14(m,1H),3.06-2.96(m,1H),2.20-1.83(m,7H),1.78-1.63(m,1H) · no alkyl NH was observed₂。LCMS(ES+)m/z465(M+1)

Example 378N- [5- (4-acetylamino-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -5-amino-2- (2, 6-difluorophenyl) thiazole-4-carboxamide 378

To N- (4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl)To a stirred solution of acetamide (330mg,1.11mmol) in a mixture of EtOH (25mL) and water (2.5mL) were added ammonium chloride (300mg,5.55mmol) and iron powder (250mg,4.44 mmol). The reaction mixture was heated at 100 ℃ for 2 hours, then cooled, and then filteredFiltered and concentrated under reduced pressure. The residue was partitioned between water (20mL) and DCM (40mL) and the organic layer was separated, washed with brine (20mL), passed through a phase separation cartridge and concentrated under reduced pressure to give N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -4-methylazepan-4-yl) acetamide as a brown solid which was used without further purification. Using this intermediate and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acid, according to the procedure of example 149, 378 was obtained as an off-white foam (54mg, 19% over three steps).¹H NMR(400MHz,CDCl₃)8.52(s,1H),7.86(s,1H),7.39-7.29(m,1H),7.07-6.99(m,2H),6.15(s,2H),5.38(s,1H),3.74(s,3H),3.30-3.18(m,4H),3.12(ddd,J＝13.6,6.6,3.1Hz,1H),2.30-2.19(m,2H),2.00-1.72(m,6H),1.45(s,3H)。LCMS(ES+)m/z504(M+1)

Example 3795-amino-N- (5- ((4R,5R) -4-amino-5-fluorocycloheptyl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 379

Following the procedure in example 358, starting from tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (diastereomer 3and diastereomer 4) gave 379 (diastereomer 3and diastereomer 4) as the racemic pair of enantiomers after preparative HPLC purification and an off-white solid (4mg, 7% over two steps).¹H NMR(400MHz,CDCl₃)8.41(s,1H),7.76(s,1H),7.38-7.28(m,1H),7.03(t, J ═ 8.7Hz,2H),6.12(s,2H),4.33-4.18(m,1H),3.83(s,3H),3.14-3.05(m,1H),2.96-2.88(m,1H),2.32-2.20(m,1H),2.00-1.69(m, 7H). No alkyl NH was observed₂。LCMS(ES+)m/z465(M+1)

Example 3805-amino-N- (5- ((4R,5S) -4-amino-5-fluorocycloheptyl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 380

Following the procedure in example 358, starting from tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (diastereomer 6, diastereomer 7and diastereomer 8), after purification by preparative HPLC, 380 (diastereomer 6and diastereomer 7) was obtained as a white foam (8mg, 15% over two steps).¹H NMR(400MHz,CDCl₃)8.47(s,1H),7.75(s,1H),7.38-7.29(m,1H),7.02(t, J ═ 8.9Hz,2H),6.13(s,2H),4.77(dd, J ═ 47.1,6.6Hz,1H),3.83(s,3H),3.18(dd, J ═ 23.9,8.0Hz,1H),2.93-2.85(m,1H),2.42-2.32(m,1H),2.18-1.55(m, 7H). No alkyl NH was observed₂。LCMS(ES+)m/z465(M+1)

Example 3815-amino-N- (5- ((4R,5S) -4-amino-5-fluorocycloheptyl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 381

Following the procedure in example 358, starting from tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4-fluoro-5- (2,2, 2-trifluoroacetamide) cycloheptyl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (diastereomer 6, diastereomer 7and diastereomer 8), after purification by preparative HPLC, gave 381 (diastereomer 8) as an off-white solid (9mg, 17% over two steps).¹H NMR(400MHz,CDCl₃)8.46(s,1H),7.80(s,1H),7.36-7.29(m,1H),7.03(t, J ═ 8.8Hz,2H),6.11(s,2H),4.88-4.72(m,1H),3.82(s,3H),3.24-3.15(m,1H),3.05-2.97(m,1H),2.13-1.82(m,7H),1.74-1.67(m, 1H). No alkyl NH was observed₂。LCMS(ES+)m/z465(M+1)

Example 3835-amino-N- (5-cycloheptyl-1-methyl-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 383

(Z) -5- (1-Fluorocyclohept-4-enyl) -1-methyl-4-nitro-1H-pyrazole (100mg,0.42mmol) in MeOH (30mL) by(all H)₂Flow rate 1 mL/min, 10% Pd/C cartridge, 70 ℃). The solvent was removed under reduced pressure to give a red gum (81 mg). To a solution of the amine (80mg,0.41mmol) in DCM (20mL) was added DIPEA (1mL), PyBOP (606mg,1.17mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (183mg,0.51mmol) and the mixture was stirred at room temperature for 18 h. The mixture was diluted with DCM (100mL) and washed with water (20 mL). The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (30-40% EtOAc/isohexane) afforded tert-butyl 4- (5-cycloheptyl-1-methyl-1H-pyrazol-4-ylcarbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-ylcarbamate as a milky solid (140 mg). The solid (130mg,0.25mmol) was stirred with HCl in dioxane (4M,3.1mL,12.2mmol) in MeOH (3mL) at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH, eluted with 2N ammonia (in MeOH) and the solvent was removed under reduced pressure. Prepared via preparative HPLC to give 383 as a milky solid (45mg, 25% over three steps).¹H NMR(400MHz,CDCl₃)8.59(s,1H),7.85(s,1H),7.35-7.29(m,1H),7.02(t,J＝8.9Hz,2H),6.10(s,2H),3.83(s,3H),2.92-2.81(m,1H),1.97-1.83(m,6H),1.72-1.50(m,6H)。LCMS(ES+)m/z432(M+1)

EXAMPLE 384N- [5- (4-acetylamino-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -5-amino-2- (3-fluoro-2-pyridyl) thiazole-4-carboxamide 384

Following the procedure in example 378, starting from N- (4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide and 5- (tert-butoxycarbonylamino) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxylic acid,384 was obtained as an off-white foam (80mg, 29%, over three steps).¹H NMR(400MHz,CDCl₃)8.57(s,1H),8.41(d,J＝4.3Hz,1H),7.90(s,1H),7.52(t,J＝9.7Hz,1H),7.31(dt,J＝8.4,4.3Hz,1H),6.32(s,2H),5.75(s,1H),3.74(s,3H),3.33-3.15(m,4H),2.38-2.21(m,2H),2.02-1.84(m,4H),1.82-1.74(m,3H),1.51(s,3H)。LCMS(ES+)m/z487(M+1)

Example 3855-amino-N- [5- (4-amino-5-ethoxy-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 385

Following the procedure of example 107, starting from N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-ethoxyazepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acid, 385 was obtained as a brown solid (127mg, 60% over two steps).¹H NMR(400MHz,CDCl₃)8.61(s,1H),7.85(s,1H),7.42-7.28(m,1H),7.04(t,J＝8.9Hz,2H),6.19(s,2H),3.78-3.58(m,4H),3.47-3.35(m,1H),3.38-3.25(m,2H),3.25-3.16(m,3H),3.09-3.01(m,1H),2.13(d,J＝14.7Hz,1H),2.00(d,J＝14.7Hz,1H),1.92-1.82(m,1H),1.84-1.58(m,3H),1.22(t,J＝7.0Hz,3H)。LCMS(ES+)m/z492(M+1)

Example 3865-amino-N- (5- ((4S,5R) -4-amino-5-methoxyazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 386

Following the procedure of example 101, starting from tert-butyl 1- (1-cyclopropyl-4-nitro-1H-pyrazol-5-yl) -5-methoxyazepan-4-ylcarbamate and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acid, 386 was obtained as an off-white solid (29mg, 23% over three steps).¹H NMR(400MHz,CDCl₃)8.96(s,1H),7.86(s,1H),7.36-7.28(m,1H),7.02(t,J＝8.9Hz,2H),6.19-6.10(m,2H),3.50-3.35(m,4H),3.33(s,3H),3.25-3.11(m,2H),2.19-2.05(m,1H),2.03-1.96(m,1H),2.01-1.60(m,2H),1.57(s,3H),1.27-1.12(m,2H),0.97(d,J＝7.1Hz,2H)。LCMS(ES+)m/z504(M+1)

Example 3875-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (pyridin-2-yl) thiazole-4-carboxamide 387

Following the procedure of example 107, starting from N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonylamino) -2- (pyridin-2-yl) thiazole-4-carboxylic acid, 387 was obtained as an off-white solid (106mg, 68% over two steps).¹H NMR(400MHz,CDCl₃)8.65(s,1H),8.54(d, J ═ 4.6Hz,1H),8.04(d, J ═ 7.9Hz,1H),7.81(s,1H),7.76(t, J ═ 7.9Hz,1H),7.29 to 7.20(m,1H),6.27(s,2H),4.90(d, J ═ 47.2Hz,1H),3.73(s,3H),3.58 to 3.33(m,3H),3.23 to 3.11(m,2H),2.44 to 2.22(m,1H),2.11 to 1.92(m,2H),1.87 to 1.76(m, 1H). No exchangeable NH observed₂。LCMS(ES+)m/z431(M+1)

Example 3885-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxamide 388

Following the procedure of example 107, starting from N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-yl) -2,2, 2-trifluoroacetamide and 5- (tert-butoxycarbonylamino) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxylic acid, 388 was obtained as an off-white solid (120mg, 74% over two steps).¹H NMR (400MHz, d6-DMSO)8.42(s,1H),7.85(t, J ═ 9.8Hz,1H),7.64(s,1H),7.50-7.44(m,1H),4.85(d, J ═ 47.3Hz,1H),3.64(s,3H),3.40-3.22(m,3H),3.23-2.83(m,2H),2.31-2.01(m,1H),2.04-1.66(m,2H),1.92-1.48(m, 1H). No exchangeable NH observed₂(x2) and NH. LCMS (ES +) M/z449(M +1)

Example 3895-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-ethyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 389

Racemic trans-N- [1- (2-ethyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl]Tert-butyl carbamate was chirally separated on an AD column with 15% methanol. Following the procedure in example 369, trans-N- [1- (2-ethyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl]The first eluting peak of tert-butyl carbamate was converted to 389.¹H NMR(400MHz,DMSO)8.88(s,1H),7.63(s,1H),7.58-7.40(m,3H),7.26(t,J＝8.7Hz,2H),3.95(q,J＝7.2Hz,2H),3.24(s,3H),3.22-2.97(m,5H),2.94-2.82(m,1H),2.07-1.95(m,1H),1.90-1.49(m,3H),1.32(t,J＝7.2Hz,3H)。LCMS(ES+)m/z492(M+1)

Example 3905-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-ethyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 390

Preparation according to 389, trans-N- [1- (2-ethyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl]The second eluted peak of tert-butyl carbamate left conversion to 390 of SFC chiral separation.¹H NMR(400MHz,DMSO)8.88(s,1H),7.63(s,1H),7.59-7.43(m,3H),7.26(t,J＝8.7Hz,2H),3.95(q,J＝7.2Hz,2H),3.24(s,3H),3.22-2.98(m,5H),2.94-2.83(m,1H),2.08-1.95(m,1H),1.90-1.47(m,3H),1.32(t,J＝7.2Hz,3H)。LCMS(ES+)m/z492(M+1)

Example 3915-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-ethyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 391

Preparation according to 389, trans-N- [1- (2-ethyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl]The first eluting peak of tert-butyl carbamate leaves the conversion of SFC chiral separation 391.¹H NMR(400MHz,DMSO)8.92(s,1H),8.30(t,J＝8.0Hz,1H),7.60(s,1H),7.49-7.39(m,3H),7.39-7.27(m,2H),3.96(q,J＝7.2Hz,2H),3.26(s,3H),3.24-3.02(m,5H),2.99-2.88(m,1H),2.13-2.01(m,1H),1.91-1.78(m,1H),1.78-1.51(m,2H),1.33(t,J＝7.2Hz,3H)。LCMS(ES+)m/z474(M+1)

Example 3925-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-ethyl-pyrazol-4-yl ] -2- (2-fluorophenyl) thiazole-4-carboxamide 392

Following the procedure of 390, trans-N- [1- (2-ethyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl]The second eluted peak of tert-butyl carbamate left conversion to 392 of SFC chiral separation.¹H NMR(400MHz,DMSO)8.92(s,1H),8.30(t,J＝8.0Hz,1H),7.60(s,1H),7.50-7.38(m,3H),7.33(t,J＝7.7Hz,2H),3.96(q,J＝7.2Hz,2H),3.26(s,3H),3.23-3.03(m,5H),2.98-2.89(m,1H),2.13-2.01(m,1H),1.91-1.50(m,3H),1.33(t,J＝7.2Hz,3H)。LCMS(ES+)m/z474(M+1)

Example 3935-amino-N- [5- [ (4S) -4-aminoazepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (6-hydroxy-2-pyridinyl) thiazole-4-carboxamide 393

Step A N- [4- [ [5- [ (4S) -4- (benzyloxycarbonylamino) azepan-1-yl ] in a microwave reaction vial]-1-methyl-pyrazol-4-yl]Carbamoyl radical]-2-bromo-thiazol-5-yl]Tert-butyl carbamate (200mg,0.31mmol), 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-ol (205mg,0.93mmol), and PDCL2(DPPF) (23mg,0.031mmol) were dissolved in acetonitrile (8 mL). Potassium acetate (1.0M,0.46mL,0.46mmol) and sodium carbonate (1.0M,0.46mL,0.46mmol) were added and the mixture was irradiated with microwaves at 120 ℃ for 30 minutes. Cooling the mixture over Na₂SO₄And Celite filtered, concentrated and purified by flash chromatography in methanol/DCM 0% to 10% to give N- [4- [ [5- [ (4S) -4- (benzyloxycarbonylamino) azepan-1-yl]-1-methyl-pyrazol-4-yl]Carbamoyl radical]-2- (6-hydroxy-2-pyridyl) thiazol-5-yl]Tert-butyl carbamate.

Step B, in a round-bottom flask, the N- [4- [ [5- [ (4S) -4- (benzyloxycarbonyl) groupAmino) azepan-1-yl]-1-methyl-pyrazol-4-yl]Carbamoyl radical]-2- (6-hydroxy-2-pyridyl) thiazol-5-yl]Tert-butyl carbamate was dissolved in DCM (10 mL). Boron tribromide (1.0m in DCM, 2.2mL,2.21mmol) was added slowly and the mixture was stirred at rt for 4 h. The reaction was concentrated under reduced pressure. The residue was taken up in saturated NaHCO₃Basified and extracted 3x with EA. The combined organic layers were over MgSO₄The solvent was removed under reduced pressure by drying and the residue was purified by preparative HPLC to give 393(10.3mg, 7.6% over two steps).¹H NMR(400MHz,DMSO)8.98(s,1H),7.60(t,J＝7.8Hz,1H),7.50(s,2H),7.47(s,1H),7.16(d,J＝7.2Hz,1H),6.49(d,J＝8.4Hz,1H),3.65(s,3H),3.21-2.98(m,5H),1.96-1.71(m,3H),1.71-1.45(m,3H)。LCMS(ES+)m/z429(M+1)

Example 3945-amino-N- [5- [4- (2-aminoacetyl) -1, 4-diazepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 394

Step A: in preparation of 362, 1- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-diazepane (105mg,0.47mmol), 2- (tert-butoxycarbonylamino) acetic acid (106mg,0.61mmol), and PyBOP (396mg,0.75mmol) were dissolved in DCM (6 mL). DIPEA (0.49ml,2.80mmol) was added and the mixture stirred at room temperature for 18 h. The crude reaction mixture was concentrated and the residue was purified by silica gel column chromatography (0-100% EA/heptane) to give N- [2- [4- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-diazepan-1-yl ] -2-oxo-ethyl ] carbamic acid tert-butyl ester (quantitative yield).

Step B N- [2- [4- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-diazepan-1-yl ] according to the procedure of 354]-2-oxo-ethyl]Tert-butyl carbamate was converted to 394(85mg, 24%, over three steps).¹H NMR(400MHz,DMSO)8.72(d,J＝8.0Hz,1H),7.59-7.39(m,4H),7.27(t,J＝8.7Hz,2H),3.70-3.58(m,5H),3.58-3.45(m,2H),3.35(d,J＝18.5Hz,2H),3.28-3.22(m,1H),3.22-3.08(m,3H),1.89-1.70(m,2H)。LCMS(ES+)m/z491(M+1)

Example 3955-amino-N- [5- [4- (2-aminoethyl) -1, 4-diazepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 395

Step A in preparation for 362, 1- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-diazepane (105mg,0.47mmol) and tert-butyl N- (2-bromoethyl) carbamate (209mg,0.93mmol) were dissolved in acetonitrile (3 mL). DIPEA (0.41mL,2.33mmol) was added and the mixture was heated at 80 ℃ for 18 h. The crude reaction mixture was concentrated and the residue was purified by silica gel column chromatography (0-100% EA/heptane) to give tert-butyl N- [2- [4- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-diazepan-1-yl ] ethyl ] carbamate (quantitative yield).

Step B N- [2- [4- (2-methyl-4-nitro-pyrazol-3-yl) -1, 4-diazepan-1-yl ] according to the procedure of 354]Ethyl radical]The tert-butyl carbamate was converted to 395(17 mg).¹H NMR(400MHz,DMSO)8.74(s,1H),8.33(s,2H),7.58-7.43(m,4H),7.28(t,J＝8.7Hz,2H),3.66(s,3H),3.21(t,J＝5.4Hz,4H),2.82-2.68(m,6H),2.62(t,J＝6.1Hz,2H),1.91-1.76(m,2H)。LCMS(ES+)m/z477(M+1)

Example 396N- [5- (3,4,4a,5,6,8,9,9 a-octahydro-2H- [1,4] oxazino [2,3-d ] azepin-7-yl) -1-methyl-pyrazol-4-yl ] -5-amino-2- (2, 6-difluorophenyl) thiazole-4-carboxamide 396

In a microwave reaction vial, (4aR,9aR) -2,3,4,4a,5,6,7,8,9,9 a-decahydro- [1,4]]Oxazino [2,3-d]Azepine dihydrochloride (509 mg; 2.22mmol) and 5-chloro-1-methyl-4-nitro-pyrazole (322mg,2.00mmol) were dissolved in acetonitrile (16 mL). DIPEA (3.11mL,17.77mmol) was added and the mixture was irradiated with microwaves at 130 ℃ for 60 minutes. The reaction mixture was diluted with water and extracted 3x with EA. The combined organic layers were washed with Na₂SO₄Drying and concentrating to obtain trans-7- (2-methyl-4-nitro-pyrazol-3-yl) -3,4,4a,5,6,8,9,9 a-octahydro-2H- [1,4]Oxazino [2,3-d]And (3) azepine. To a solution of this compound in DCM (15mL) were added di-tert-butyl dicarbonate (727mg,3.33mmol) and DIPEA (1.16mL,6.66 mmol). The mixture was stirred at room temperature for 18 hours. The crude reaction mixture was concentrated and the residue was purified by silica gel column chromatography (0-100% EA/heptane) to give racemic trans-7- (2-methyl-4-nitro-pyrazol-3-yl) -2,3,4a,5,6,8,9,9 a-octahydro- [1,4]Oxazino [2,3-d]Azepin-4-carboxylic acid tert-butyl ester on AD column at 20% methanol w/0.1% NH₄And (4) performing OH chiral separation. Following the procedure of example 354, trans-tert-butyl-7- (2-methyl-4-nitro-pyrazol-3-yl) -2,3,4a,5,6,8,9,9 a-octahydro- [1, 4-octahydro- [ 3-methyl-4-nitro-pyrazol-3-yl ] -leaving the chiral separation of SFC]Oxazino [2,3-d]The first eluting peak of tert-butyl azepin-4-carboxylate was converted to 396.¹H NMR(400MHz,DMSO)8.63(s,1H),7.55(s,1H),7.54-7.43(m,3H),7.26(t,J＝8.7Hz,2H),3.64(s,3H),3.24-3.13(m,4H),3.13-2.95(m,3H),2.65(d,J＝5.6Hz,2H),2.60-2.52(m,1H),1.82-1.68(m,3H),1.64-1.53(m,2H)。LCMS(ES+)m/z490(M+1)

Example 397N- [5- (3,4,4a,5,6,8,9,9 a-octahydro-2H- [1,4] oxazino [2,3-d ] azepin-7-yl) -1-methyl-pyrazol-4-yl ] -5-amino-2- (2, 6-difluorophenyl) thiazole-4-carboxamide 397

Trans-7- (2-methyl-4-nitro-pyrazol-3-yl) -2,3,4a,5,6,8,9,9 a-octahydro- [1,4] separated chirally from SFC according to preparation 396]Oxazino [2,3-d]The second eluting peak of tert-butyl azepin-4-carboxylate was converted to 397.¹H NMR(400MHz,DMSO)8.63(s,1H),7.55(s,1H),7.53-7.40(m,3H),7.26(t,J＝8.7Hz,2H),3.64(s,3H),3.23-3.13(m,4H),3.13-2.94(m,3H),2.65(d,J＝6.8Hz,2H),2.60-2.52(m,1H),1.86-1.65(m,3H),1.65-1.54(m,2H)。LCMS(ES+)m/z490(M+1)

Example 3985-amino-N- [5- (4-amino-5-hydroxy-azepan-1-yl) -1- (2, 2-difluoroethyl) pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 398

Racemic cis-N- [1- [2- (2, 2-difluoroethyl) -4-nitro-pyrazol-3-yl]-5-hydroxy-azepan-4-yl]Chiral separation of tert-butyl carbamate on AD column using 30% methanolAnd (5) separating. Following the procedure in example 369, cis-N- [1- [2- (2, 2-difluoroethyl) -4-nitro-pyrazol-3-yl leaving the chiral separation of SFC]-5-hydroxy-azepan-4-yl]The first eluting peak of tert-butyl carbamate was converted to 398.¹H NMR(400MHz,DMSO)9.30(s,1H),7.76(s,1H),7.59-7.41(m,3H),7.27(t,J＝8.7Hz,2H),6.55-6.17(m,1H),4.56(s,1H),4.45-4.28(m,2H),3.76(d,J＝7.8Hz,1H),3.26-3.13(m,2H),3.13-2.93(m,3H),1.95-1.77(m,2H),1.73-1.55(m,2H)。LCMS(ES+)m/z514(M+1)

Example 3995-amino-N- [5- (4-amino-5-hydroxy-azepan-1-yl) -1- (2, 2-difluoroethyl) pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 399

The preparation according to 398 of the SFC chiral separation of cis-N- [1- [2- (2, 2-difluoroethyl) -4-nitro-pyrazol-3-yl]-5-hydroxy-azepan-4-yl]The second eluted peak of tert-butyl carbamate was converted to 399.¹H NMR(400MHz,DMSO)9.29(s,1H),7.76(s,1H),7.62-7.41(m,3H),7.27(t,J＝8.7Hz,2H),6.55-6.19(m,1H),4.58(s,1H),4.45-4.31(m,2H),3.76(d,J＝7.9Hz,1H),3.25-3.13(m,2H),3.13-2.93(m,3H),1.94-1.77(m,2H),1.71-1.55(m,2H)。LCMS(ES+)m/z514(M+1)

Example 4015-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-cyclopropyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 401

Racemic cis-N- [1- (2-cyclopropyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl]Tert-butyl carbamate was chirally separated on an AD column with 30% methanol. Following the preparation of example 369, cis-N- [1- (2-cyclopropyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl leaving the SFC chiral separation]The first eluting peak of tert-butyl carbamate was converted to 401.¹H NMR(400MHz,DMSO)9.38(s,1H),7.64(s,1H),7.58-7.44(m,3H),7.27(t,J＝8.7Hz,2H),3.58-3.45(m,1H),3.39(d,J＝8.3Hz,1H),3.27-3.20(m,1H),3.27-3.21(m,1H),3.19(s,3H),3.07(dd,J＝11.4,6.5Hz,2H),2.13-1.96(m,1H),1.85-1.58(m,4H),1.08-0.86(m,4H)。LCMS(ES+)m/z504(M+1)

EXAMPLE 4025-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-cyclopropyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 402

Following preparation 401, cis-N- [1- (2-cyclopropyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl) chirally separated from SFC]The second eluted peak of tert-butyl carbamate was converted to 402.¹H NMR(400MHz,DMSO)9.38(s,1H),7.64(s,1H),7.58-7.41(m,3H),7.27(t,J＝8.6Hz,2H),3.60-3.46(m,1H),3.40(d,J＝8.6Hz,1H),3.33-3.27(m,1H),3.27-3.21(m,1H),3.19(s,3H),3.15-2.99(m,2H),2.11-1.97(m,1H),1.85-1.61(m,4H),1.09-0.87(m,4H)。LCMS(ES+)m/z504(M+1)

Example 4035-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-cyclopropyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 403

Racemic trans-N- [1- (2-cyclopropyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl]Tert-butyl carbamate was chirally separated on an AD column with 15% methanol. Following the procedure in example 369, trans-N- [1- (2-cyclopropyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl leaving the chiral separation of SFC]The first eluting peak of tert-butyl carbamate was converted to 403.¹H NMR(400MHz,DMSO)8.92(s,1H),7.60-7.39(m,4H),7.27(t,J＝8.7Hz,2H),3.59-3.45(m,1H),3.29-3.02(m,8H),2.96-2.85(m,1H),2.10-1.96(m,1H),1.93-1.83(m,1H),1.78-1.65(m,1H),1.65-1.49(m,1H),1.10-0.85(m,4H)。LCMS(ES+)m/z504(M+1)

EXAMPLE 4045-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-cyclopropyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 404

According to the preparation 403, trans-N- [1- (2-cyclopropyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl) chirally separated off the SFC]The second eluted peak of tert-butyl carbamate was converted to 404.¹H NMR(400MHz,DMSO)8.92(s,1H),7.62-7.41(m,4H),7.27(t,J＝8.7Hz,2H),3.53(t,J＝5.4Hz,1H),3.28-2.99(m,8H),2.96-2.83(m,1H),2.10-1.97(m,1H),1.92-1.80(m,1H),1.79-1.64(m,1H),1.64-1.46(m,1H),1.10-0.82(m,4H).LCMS(ES+)m/z504(M+1)

EXAMPLE 4055-amino-2- (2, 6-difluorophenyl) -N- [5- [ 4-hydroxy-4- (trifluoromethyl) azepan-1-yl ] -1-methyl-pyrazol-4-yl ] thiazole-4-carboxamide 405

Following the procedure of example 101, starting from 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -4- (trifluoromethyl) azepan-4-ol and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acid, 405 was obtained as a light brown solid (53mg, 29% over three steps).¹H NMR(400MHz,CDCl₃)8.95(s,1H),7.94(s,1H),7.39-7.28(m,1H),7.02(t,J＝8.7Hz,2H),6.21(s,2H),3.73(s,3H),3.46(ddd,J＝13.7,8.5,5.0Hz,1H),3.29-3.18(m,3H),2.95(s,1H),2.15-1.97(m,5H),1.87-1.77(m,1H)。LCMS(ES+)m/z517(M+1)

EXAMPLE 4065-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-ethyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 406

Racemic cis-N- [1- (2-ethyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl]Tert-butyl carbamate was chirally separated on an AD column with 30% methanol. Following the procedure of example 369, cis-N- [1- (2-ethyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl leaving the SFC chiral separation]The first eluting peak of tert-butyl carbamate was converted to 406.¹H NMR(400MHz,DMSO)9.20-9.01(s,1H),8.39-8.28(s,1H),7.69-7.60(s,1H),7.60-7.45(m,3H),7.35-7.19(t,J＝8.7Hz,2H),4.01-3.89(q,J＝8.1,7.7Hz,2H),3.56-3.47(d,J＝6.9Hz,1H),3.26-3.20(s,3H),3.21-2.88(m,1H),2.15-1.98(s,0H),1.96-1.80(s,0H),1.76-1.60(m,2H),1.37-1.27(t,J＝7.2Hz,3H)。LCMS(ES+)m/z492(M+1)

EXAMPLE 4075-amino-N- [5- (4-amino-5-methoxy-azepan-1-yl) -1-ethyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 407

According to the preparation of 406, the cis-N- [1- (2-ethyl-4-nitro-pyrazol-3-yl) -5-methoxy-azepan-4-yl radical separated chirally from the SFC is isolated]The second eluted peak of tert-butyl carbamate was converted to 407.¹H NMR(400MHz,DMSO)9.23-9.02(s,1H),8.40-8.32(s,1H),7.70-7.61(s,1H),7.59-7.45(m,3H),7.35-7.20(t,J＝8.7Hz,2H),4.01-3.90(m,2H),3.56-3.44(d,J＝7.1Hz,1H),3.27-3.20(s,3H),3.21-2.91(m,1H),2.13-1.99(m,1H),1.94-1.79(m,1H),1.77-1.60(m,2H),1.36-1.27(t,J＝7.2Hz,3H)。LCMS(ES+)m/z492(M+1)

Example 4105-amino-N- (5- ((4S,5S) -5-amino-4-methoxycyclohept-1-enyl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 410

Following the procedure in example 378, starting from (E) -tert-butyl 2-methoxy-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-4-enylcarbamate and 5- (tert-butoxycarbonylamino) -2-cyclopropylthiazole-4-carboxylic acid, 410 was obtained as a monoformate salt as an off-white foam (13mg, 4% over three steps).¹H NMR(400MHz,d6-DMSO)8.63(s,1H),8.35(s,1H),7.80(s,1H),7.59-7.43(m,3H),7.26(t,J＝8.8Hz,2H),5.93(t,J＝6.4Hz,1H),3.70(s,3H),3.26(s,3H),3.02-2.96(m,1H),2.91(t,J＝9.3Hz,1H),2.68-2.60(m,1H),2.42-2.24(m,4H),1.98-1.89(m,2H),1.48-1.37(m,1H)。LCMS(ES+)m/z475(M+1)

Example 4115-amino-N- [5- (4-amino-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 411

Following the procedure of example 101, starting from tert-butyl 4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acid, 411 was obtained as a light brown solid (68mg, 55% over three steps).¹H NMR(400MHz,CDCl₃)8.98(s,1H),7.91(s,1H),7.38-7.25(m,1H),7.02(t, J ═ 8.7Hz,2H),6.20(s,2H),3.73(s,3H),3.34-3.26(m,1H),3.33-3.08(m,2H),3.17-3.09(m,1H),1.95-1.78(m,2H),1.77-1.66(m,4H),1.19(s,3H). no exchangeable NH was observed₂。LCMS(ES+)m/z462(M+1)

EXAMPLE 4125-amino-N- [5- (4-amino-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2-fluorophenyl) thiazole-4-carboxamide 412

Following the procedure of example 101, starting from tert-butyl 4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ylcarbamate and 5- (tert-butoxycarbonyl-amino) -2- (2-fluorophenyl) thiazole-4-carboxylic acid, 412 was obtained as a light brown solid (87mg, 74%, over three steps).¹H NMR(400MHz,CDCl₃)8.73(s,1H),8.13(t, J ═ 7.7Hz,1H),7.85(s,1H),7.39-7.30(m,1H),7.26-7.11(m,2H),6.11(s,2H),3.75(s,3H),3.40-3.18(m,3H),3.17-3.09(m,1H),1.98-1.89(m,1H),1.90-1.71(m,5H),1.23(s, 3H). No exchangeable NH observed₂。LCMS(ES+)m/z444(M+1)

Example 4135-amino-N- (5- ((4S,5S) -4-amino-5-methoxycycloheptyl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide 413

A solution of tert-butyl 5-fluoro-2-methoxy-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cycloheptylcarbamate (430mg,1.27mmol) in MeOH (50mL) was purified by(all H)₂Flow rate 1 mL/min, 30mm 10% Pd/C cartridge, 70 ℃). The solvent was removed under reduced pressure to give an orange foam. The foam was then dissolved in MeOH (70mL) and 10% palladium on carbon (45mg) was added. Then at H₂The mixture was stirred at room temperature for 3 hours under an atmosphere (400psi) overFiltration and removal of solvent under reduced pressure gave a complex mixture as an orange foam (378mg) containing tert-butyl 5- (4-amino-1-methyl-1H-pyrazol-5-yl) -2-methoxycycloheptylcarbamate. To a solution of this mixture (378mg,1.13mmol) in DCM (30mL) was added DIPEA (1.0mL,5.74mmol), PyBOP (1.5g,2.81mmol) and 5- (tert-butoxycarbonyl-amino) -2- (2-fluorophenyl) thiazole-4-carboxylic acid (418mg,1.24mmol) and the mixture was stirred at rt for 18 h. The mixture was diluted with DCM (150mL) and washed with water (30 mL). The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (70-80% EtOAc/isohexane) afforded a mixture of four diastereomers as a peach-colored solid (240mg), which was isolated by preparative HPLC. Each diastereomer (25mg,0.03mmol) was then stirred with HCl in dioxane (4M,0.95mL,3.80mmol) in MeOH (1mL) at room temperature for 18 hours. The solvent was removed under reduced pressure and the crude residue was redissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7N ammonia in MeOH to give 413 (diastereomer 1) as an off-white solid (13mg, 2%, over three steps).¹H NMR(400MHz,CDCl₃)8.43(s,1H),8.21(td,J＝7.7,1.9Hz,1H),7.79(s,1H),7.38-7.32(m,1H),7.26-7.21(m,1H),7.16(dd,J＝11.4,8.3Hz,1H),6.09(s,2H),3.84(s,3H),3.36(s,3H),3.11-2.99(m,2H),2.91-2.84(m,1H),2.13-2.02(m,2H),1.98-1.91(m,2H),1.85(t,J＝12.3Hz,4H),1.58-1.46(m,2H)。LCMS(ES+)m/z459(M+1)

Example 4145-amino-N- (5- ((4S,5S) -4-amino-5-methoxycycloheptyl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide 414

Obtained 414 (diastereomer 2) as an off-white solid according to the procedure in example 413 (16mg, 2% in three steps).¹H NMR(400MHz,CDCl₃)8.39(s,1H),8.22-8.15(m,1H),7.76(s,1H),7.38-7.31(m,1H),7.27-7.20(m,1H),7.15(dd,J＝11.4,8.3Hz,1H),6.10(s,2H),3.83(s,3H),3.35(s,3H),3.16-3.12(m,1H),3.05(t,J＝9.2Hz,1H),2.95-2.82(m,1H),2.15-2.00(m,2H),1.98-1.80(m,5H),1.64-1.50(m,1H)。LCMS(ES+)m/z459(M+1)

Example 4155-amino-N- (5- ((4S,5S) -4-amino-5-methoxycycloheptyl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide 415

Following the procedure in example 413, 415 (diastereomer 3) was obtained as a beige solid (15mg, 2%, over three steps).¹H NMR(400MHz,CDCl₃)8.37(s,1H),8.17(t,J＝7.8Hz,1H),7.72(s,1H),7.38-7.31(m,1H),7.26-7.12(m,2H),6.11(s,2H),3.84(s,3H),3.36(s,3H),2.99(d,J＝6.6Hz,2H),2.92(t,J＝7.6Hz,1H),2.17(dd,J＝14.1,7.0Hz,1H),2.13-1.79(m,7H),1.47(d,J＝13.7Hz,2H)。LCMS(ES+)m/z459(M+1).

Example 4165-amino-N- (5- ((4S,5S) -4-amino-5-methoxycycloheptyl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide 416

Obtained 416 (diastereomer 4) as an off-white solid (14mg, 2% in three steps) according to the procedure in example 413.¹H NMR(400MHz,CDCl₃)8.37(s,1H),8.17(td,J＝7.7,1.9Hz,1H),7.72(s,1H),7.39-7.31(m,1H),7.26-7.12(m,2H),6.10(s,2H),3.84(s,3H),3.36(s,3H),3.02-2.96(m,2H),2.96-2.87(m,1H),2.22-2.11(m,1H),2.13-1.78(m,7H),1.54-1.41(m,2H)。LCMS(ES+)m/z459(M+1)

Example 4175-amino-N- [5- [ (4S) -4-aminoazepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2-fluoro-4-pyridinyl) thiazole-4-carboxamide 417

Step A N- [ (4S) -1- (4-amino-2-methyl-pyrazol-3-yl) azepan-4-yl ] -2,2, 2-trifluoro-acetamide (733mg,2.40mmol), 2-bromo-5- (tert-butoxycarbonylamino) -1H-imidazole-4-carboxylic acid (955mg,3.12mmol) and PyBOP (2020mg,3.84mmol) were dissolved in DCM (40mL) in a round bottom flask. DIPEA (2.51mL,14.4mmol) was added and the mixture stirred at room temperature for 18 h. The mixture was concentrated and purified via flash chromatography EA/heptane 0% to 100% to give tert-butyl N- [ 2-bromo-4- [ [ 1-methyl-5- [ (4S) -4- [ (2,2, 2-trifluoroacetyl) amino ] azepan-1-yl ] pyrazol-4-yl ] carbamoyl ] thiazol-5-yl ] carbamate (1.39g, 95%).

Step B N- [ 2-bromo-4- [ [ 1-methyl-5- [ (4S) -4- [ (2,2, 2-trifluoroacetyl) amino ] in a microwave reaction vial]Azepan-1-yl]Pyrazol-4-yl]Carbamoyl radical]Thiazol-5-yl]Tert-butyl carbamate (100mg,0.16mmol), 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (110mg,0.49mmol), and PD (DPPF) CL2(12mg,0.016mmol) were dissolved in acetonitrile (3 mL). 1.0M KOAc (0.25mL,0.25mmol) and 1.0M Na were added₂CO₃(0.25mL,0.25mmol) and the reaction was irradiated with microwaves at 120 ℃ for 30 minutes. The mixture was cooled, filtered through Celite, concentrated and purified by flash chromatography EA/heptane 0% to 100% to give N- [2- (2-fluoro-4-pyridinyl) -4- [ [ 1-methyl-5- [ (4S) -4- [ (2,2, 2-trifluoroacetyl) amino]Azepan-1-yl]Pyrazol-4-yl]Carbamoyl radical]Thiazol-5-yl]Tert-butyl carbamate (60mg, 58%). the compound was stirred in 4n hcl in dioxane (3mL,12mmol) and methanol (2mL) at rt for 3 h. The solvent was removed under reduced pressure. The residue was dissolved in methanol (3mL) and water (1mL), potassium carbonate (67mg,0.48mmol) was added, and the mixture was heated at 60 ℃ for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted 3x with EA. The combined organic layers were over MgSO₄The solvent was removed under reduced pressure by drying and the residue was purified by preparative HPLC to give 417.¹H NMR(400MHz,DMSO)9.04(s,1H),8.29(d,J＝5.3Hz,1H),7.74(d,J＝5.3Hz,3H),7.59(s,1H),7.42(s,1H),3.66(s,3H),3.24-3.01(m,5H),1.94-1.73(m,3H),1.67-1.48(m,3H)。LCMS(ES+)m/z431(M+1)

Example 4185-amino-N- [5- [ (4S) -4-aminoazepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2-methoxy-3-pyridinyl) thiazole-4-carboxamide 418

Preparation 418 was prepared according to the procedure of 417, substituting 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine for (2-methoxy-3-pyridinyl) boronic acid.¹H NMR(400MHz,DMSO)8.97(s,1H),8.64(d,J＝7.6Hz,1H),8.22(d,J＝4.6Hz,1H),7.40(s,1H),7.32(s,2H),7.22-7.13(m,1H),4.05(s,3H),3.66(s,3H),3.25-2.98(m,5H),2.04-1.79(m,3H),1.77-1.54(m,3H)。LCMS(ES+)m/z443(M+1)

Example 4195-amino-N- [5- [ (4S) -4-aminoazepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (1-methylpyrazol-4-yl) thiazole-4-carboxamide 419

Following the procedure of 417, substituting 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine for 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole, produced 419.¹HNMR(400MHz,DMSO)8.73(s,1H),8.18(d,J＝47.7Hz,1H),7.81(d,J＝11.8Hz,1H),7.53(d,J＝24.5Hz,1H),7.24(s,2H),3.87(s,3H),3.64(s,3H),3.21-3.01(m,5H),1.96-1.77(m,3H),1.72-1.48(m,3H)。LCMS(ES+)m/z416(M+1)

Example 4205-amino-N- [5- [ (4S) -4-aminoazepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (5-fluoro-3-pyridinyl) thiazole-4-carboxamide 420

Following the procedure of 417, 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine was substituted with 3-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine to prepare 420.¹HNMR(400MHz,DMSO)9.01(s,1H),8.90(s,1H),8.58(d,J＝2.4Hz,1H),8.20(d,J＝10.0Hz,1H),7.61(s,2H),7.39(s,1H),3.66(s,3H),3.22-3.03(m,5H),1.99-1.75(m,3H),1.69-1.51(m,3H)。LCMS(ES+)m/z431(M+1)

Example 4215-amino-N- [5- [ (4S) -4-Aminoazepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (3, 5-dimethylisoxazol-4-yl) thiazole-4-carboxamide 421

Preparation 421 was prepared according to the procedure of 417, substituting 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine for (3, 5-dimethylisoxazole 4-yl) boronic acid.¹H NMR(400MHz,DMSO)8.60(s,1H),8.41(s,1H),7.50(s,1H),7.39(s,2H),3.66(s,3H),3.26-2.98(m,5H),2.65(s,3H),2.47(s,3H),2.04-1.75(m,3H),1.72-1.50(m,3H)。LCMS(ES+)m/z431(M+1)

Example 4225-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-4-yl) thiazole-4-carboxamide 422

To a solution of tert-butyl 1- (4- (5- (tert-butoxy-carbonyl) -amino-2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-ylcarbamate (100mg,0.16mmol) in dioxane (1.6mL) was added 3-fluoro-4- (tributylstannyl) pyridine (90mg,0.23mmol), tetrakis (triphenylphosphine) palladium (0) (9mg,0.008mmol), copper (I) iodide (9mg,0.05mmol), and lithium chloride (20mg,0.48 mmol). The mixture was degassed for 5 minutes and then heated in a microwave at 120 ℃ for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-10% MeOH/DCM) to give a brown oil (100mg, 96%). To a solution of this oil (100mg,0.15mmol) in dioxane (3mL) was added HCl in dioxane (4M,3mL,12.0mmol) and the mixture was stirred at room temperature for 36 hours. Prepared via preparative HPLC to give 422 as a mono-formate salt as a yellow solid (24mg, 35%).¹H NMR (d6-DMSO)9.11(s,1H),8.70(d, J ═ 2.76Hz,1H),8.51(d, J ═ 5.10Hz,1H),8.33 to 8.20(m,2H),7.69(s,2H),7.49 to 7.38(m,1H),4.78 to 4.44(m,1H),3.66(s,3H),3.30 to 3.10(m,5H),2.22 to 2.05(m,1H),2.05 to 1.96(m,1H),1.95 to 1.90(m,1H),1.75 to 1.62(m, 1H). No exchangeable NH observed₂。LCMS(ES+)m/z449(M+1)

Example 4235-amino-2- (2-fluorophenyl) -N- [5- (2-methoxy-8-azabicyclo [3.2.1] oct-5-yl) -1-methyl-pyrazol-4-yl ] thiazole-4-carboxamide 423

Obtained 423 according to the procedure in example 413 as a beige solid (109mg, 18% in three steps).¹H NMR(400MHz,CDCl₃)10.96(s,1H),8.27(t,J＝7.7Hz,2H),7.37-7.29(m,1H),7.22-7.11(m,2H),6.06(s,2H),3.91(s,3H),3.62-3.56(m,1H),3.44(s,3H),2.37-2.28(m,1H),2.19-2.00(m,5H),1.89-1.73(m,3H),1.52-1.39(m,1H)。LCMS(ES+)m/z457(M+1)

Example 4245-amino-N- (5- ((4S,5S) -4-amino-5-hydroxy-4-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 424

To a solution of 2,2, 2-trifluoro-N- (5-hydroxy-4-methyl-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide (200mg,0.55mmol) and ammonium formate (700mg,2.74mmol) in MeOH (10mL) was added 10% palladium on carbon (50mg,0.13mmol) under nitrogen. The mixture was heated at 65 ℃ for 2 hours then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between water (10mL) and DCM (50 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-hydroxy-4-methylazepan-4-yl) -2,2, 2-trifluoroacetamide as a red gum (140 mg). A solution of PyBOP (330mg,0.62mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (160mg,0.45mmol) in DCM (3mL) was stirred at room temperature for 30 min. A solution of N- (1- (4-amino-1-methyl-1H-pyrazol-5-yl) -5-hydroxy-4-methylazepan-4-yl) -2,2, 2-trifluoroacetamide (140mg,0.41mmol) and DIPEA (140. mu.L, 0.83mmol) in DCM (2mL) was added and the mixture stirred at room temperature for 18H. Additional DCM (50mL) was added and the mixture was washed with water (20 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. The residue was dissolved in THF (2mL), MeOH (MeOH)2mL) and water (1mL) and potassium carbonate (200mg,1.44mmol) was added. The reaction mixture was heated at 60 ℃ for 18 h, cooled to room temperature, filtered and concentrated under reduced pressure. The residue was then dissolved in DCM (3mL) and trifluoroacetic acid (1mL) was added. The mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure and purified via preparative HPLC to give 424 as the mono-formate salt as a white solid (5mg, 2%, over three steps).¹H NMR(400MHz,d4-MeOD)8.56(s,1H),7.57(s,1H),7.53-7.44(m,1H),7.15(t,J＝8.8Hz,2H),3.86-3.72(m,5H),3.45-3.35(m,2H),3.26-3.14(m,1H),2.15-1.90(m,4H),1.46(s,3H)。LCMS(ES+)m/z478(M+1)

Example 4255-amino-N- [5- [ (4S) -4-Aminoazepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2-fluoro-5-methyl-3-pyridinyl) thiazole-4-carboxamide 425

Following the procedure of 417, 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine was substituted with 2-fluoro-5-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine to afford 425.¹H NMR(400MHz,DMSO)9.00(s,1H),8.55(d,J＝9.7Hz,1H),8.06(s,1H),7.51(s,2H),7.44(s,1H),3.66(s,3H),3.22-2.95(m,5H),2.38(s,3H),1.92-1.77(m,3H),1.67-1.42(m,3H)。LCMS(ES+)m/z445(M+1)

Example 4265-amino-N- [5- (5-amino-3, 3-difluoro-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (3-fluoro-4-pyridinyl) thiazole-4-carboxamide 426

Following the procedure of example 422, starting from tert-butyl 1- (4- (5- (tert-butoxycarbonylamino) -2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-ylcarbamate, 426 was obtained as a mono-formate salt as a white solid (76mg, 51% over two steps).¹H NMR (400MHz, d6-DMSO)9.16(s,1H),8.71(d, J ═ 2.8Hz,1H),8.54(d, J ═ 5.2Hz,1H),8.32-8.19(m,2H),7.70(s,2H),7.45(s,1H),3.69(s,3H, under the water peak), 3.56-3.34(m,3H, under the water peak), 3.37-3.24(m,1H),3.22-3.11(m,1H),2.44 (m,1H), 8.71(d, J ═ 2.8Hz,1H), 7.70(s,2H),7.45(s,1H),3.69(s,3H2.31(m,2H),2.03-1.91(m,1H),1.90-1.80(m,1H). No exchangeable NH was observed₂。LCMS(ES+)m/z467(M+1)

Example 4285-amino-N- [5- [ (4R,5R) -4-amino-5-fluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (4-methyl-3-pyridinyl) thiazole-4-carboxamide 428

Step A tert-butyl N- [ (4R,5R) -1- (4-amino-2-methyl-pyrazol-3-yl) -5-fluoro-azepan-4-yl ] carbamate (1240mg,3.80mmol), 2-bromo-5- (tert-butoxycarbonylamino) -1H-imidazole-4-carboxylic acid (1510mg,4.94mmol) and PyBOP (3.20g,6.08mmol) were dissolved in DCM (50mL) in a round bottom flask. DIPEA (3.97mL,22.8mmol) was added and the mixture stirred at room temperature for 18 h. The mixture was concentrated and purified via flash chromatography EA/heptane 0% to 100% to tert-butyl N- [ 2-bromo-4- [ [5- [ (4R,5R) -4- (tert-butoxycarbonylamino) -5-fluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] carbamoyl ] thiazol-5-yl ] carbamate (2.23g, 93%).

Step B N- [ 2-bromo-4- [ [5- [ (4R,5R) -4- (tert-butoxycarbonylamino) -5-fluoro-azepan-1-yl ] in a microwave reaction vial]-1-methyl-pyrazol-4-yl]Carbamoyl radical]Thiazol-5-yl]Tert-butyl carbamate (161mg,0.25mmol), (4-methyl-3-pyridinyl) boronic acid (105mg,0.76) and pd (dppf) CL2(19mg,0.025mmol) were dissolved in acetonitrile (3 mL). 1.0M KOAc (0.38mL,0.38mmol) and 1.0M Na were added₂CO₃(0.38mL,0.38mmol) and the reaction was irradiated with microwaves at 125 ℃ for 30 minutes. The mixture was cooled, filtered through Celite, concentrated and purified by flash chromatography EA/heptane 0% to 100% to give N- [4- [ [5- [ (4R,5R) -4- (tert-butoxycarbonylamino) -5-fluoro-azepan-1-yl ] -a]-1-methyl-pyrazol-4-yl]Carbamoyl radical]-2- (4-methyl-3-pyridyl) thiazol-5-yl]Tert-butyl carbamate (95mg, 58%). The compound was stirred with 4N HCl in dioxane (3mL,12mmol) and methanol (2mL) at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was taken up in saturated NaHCO₃Basified and extracted 3x with EA. The combined organic layers were over MgSO₄Drying under reduced pressure to remove the solvent and passing the residue throughPreparative HPLC purification gave 428(38mg, 58%).¹H NMR(400MHz,DMSO)8.83(s,1H),8.79(s,1H),8.43(d,J＝5.0Hz,1H),7.49(s,2H),7.47(s,1H),7.37(d,J＝4.9Hz,1H),4.42(dt,J＝8.4,5.0Hz,1H),3.64(s,3H),3.26-3.02(m,5H),2.63(s,3H),2.18-2.02(m,1H),2.02-1.88(m,1H),1.87-1.75(m,1H),1.66-1.53(m,1H)。LCMS(ES+)m/z445(M+1)

Example 4295-amino-N- [5- [ (4R,5R) -4-amino-5-fluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (1, 5-dimethylpyrazol-4-yl) thiazole-4-carboxamide 429

By following the procedure of 428, 429 was prepared by substituting (4-methyl-3-pyridyl) boronic acid with 1, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole.¹H NMR(400MHz,DMSO)8.61(s,1H),7.69(s,1H),7.54(s,1H),7.23(s,2H),4.46(dt,J＝48.2,6.6Hz,1H),3.78(s,3H),3.64(s,3H),3.25-3.04(m,5H),2.56(s,3H),2.21-2.03(m,1H),2.03-1.91(m,1H),1.91-1.76(m,1H),1.71-1.55(m,1H)。LCMS(ES+)m/z448(M+1)

Example 4305-amino-N- [5- [ (4R,5R) -4-amino-5-fluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2-methyl-3-pyridinyl) thiazole-4-carboxamide 430

Following the procedure of 428, 430 was prepared substituting (4-methyl-3-pyridyl) boronic acid with (2-methyl-3-pyridyl) boronic acid.¹H NMR(400MHz,DMSO)8.76(s,1H),8.47(d,J＝4.7Hz,1H),8.04(d,J＝7.9Hz,1H),7.49(s,2H),7.40-7.28(m,1H),4.56-4.34(m,1H),3.64(s,3H),3.26-3.02(m,5H),2.82(s,3H),2.22-2.03(m,1H),2.03-1.89(m,1H),1.89-1.76(m,1H),1.70-1.51(m,1H)。LCMS(ES+)m/z445(M+1)

Example 4315-amino-N- [5- [ (4R,5R) -4-amino-5-fluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2-methyl-4-pyridinyl) thiazole-4-carboxamide 431

According to428, substituting (4-methyl-3-pyridyl) boronic acid with (2-methyl-4-pyridyl) boronic acid, preparation 431.¹H NMR(400MHz,DMSO)8.97(s,1H),8.48(d,J＝5.2Hz,1H),7.64(d,J＝6.5Hz,3H),7.58(d,J＝5.2Hz,1H),7.45(s,1H),4.61-4.37(m,1H),3.65(s,3H),3.26-3.06(m,5H),2.22-2.06(m,1H),2.06-1.93(m,1H),1.93-1.76(m,1H),1.70-1.54(m,1H)。LCMS(ES+)m/z445(M+1)

Example 4325-amino-N- [5- [ (4R,5R) -4-amino-5-fluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (6-cyano-2-pyridinyl) thiazole-4-carboxamide 432

Following the procedure of 428, substituting (4-methyl-3-pyridinyl) boronic acid with 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-carbonitrile, preparation 432.¹H NMR(400MHz,DMSO)9.03(s,1H),8.44(d,J＝8.2Hz,1H),8.14(t,J＝7.9Hz,1H),8.00(d,J＝7.6Hz,1H),7.74(s,2H),7.44(s,1H),4.67-4.41(m,1H),3.65(s,3H),3.28-3.05(m,5H),2.23-2.06(m,1H),2.06-1.94(m,1H),1.94-1.77(m,1H),1.75-1.57(m,1H)。LCMS(ES+)m/z456(M+1)

Example 4335-amino-N- [5- (4-amino-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2-fluorophenyl) thiazole-4-carboxamide 433

Chiral separation of racemic 412 by SFC gave the single enantiomer 433.¹H NMR(400MHz,DMSO)9.02(s,1H),8.42(s,1H),8.29(t,J＝7.8Hz,1H),7.45(d,J＝7.2Hz,3H),7.42-7.26(m,2H),3.66(s,3H),3.24-2.95(m,4H),1.95-1.53(m,6H),1.23(s,3H)。LCMS(ES+)m/z444(M+1)

Example 4345-amino-N- [5- (4-amino-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2-fluorophenyl) thiazole-4-carboxamide 434

Chiral separation 412 by SFC afforded 434.¹H NMR(400MHz,DMSO)9.03(s,1H),8.42(s,1H),8.28(t,J＝7.9Hz,1H),7.45(d,J＝11.1Hz,3H),7.41-7.25(m,2H),3.66(s,3H),3.24-2.98(m,4H),1.96-1.52(m,6H),1.21(s,3H)。LCMS(ES+)m/z444(M+1)

Example 4355-amino-N- [5- (4-amino-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 435

Chiral separation of racemic 411 by SFC gave the single enantiomer 435.¹H NMR(400MHz,DMSO)8.96(s,1H),7.58(s,1H),7.56-7.43(m,2H),7.27(t,J＝8.7Hz,2H),3.65(s,3H),3.23-2.94(m,5H),1.97-1.48(m,6H),1.15(s,3H)。LCMS(ES+)m/z462(M+1)

Example 4365-amino-N- [5- (4-amino-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 436

Obtained 436 by SFC chiral separation 411.¹H NMR(400MHz,DMSO)8.96(s,1H),7.57(s,1H),7.56-7.44(m,2H),7.27(t,J＝8.7Hz,2H),3.65(s,3H),3.25-2.90(m,5H),1.93-1.51(m,6H),1.15(s,3H)。LCMS(ES+)m/z462(M+1)

Example 4375-amino-N- [5- [ (4R,5R) -4-amino-5-fluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (1, 3-dimethylpyrazol-4-yl) thiazole-4-carboxamide 437

In accordance with the procedure of example 428, 437 is prepared by substituting (4-methyl-3-pyridinyl) boronic acid with 1, 3-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole.¹H NMR(400MHz,DMSO)8.55(s,1H),8.08(s,1H),7.57(s,1H),7.22(s,2H),4.46(dt,J＝48.3,6.7Hz,1H),3.78(s,3H),3.65(s,3H),3.26-3.03(m,5H),2.42(s,3H),2.23-2.05(m,1H),2.05-1.92(m,1H),1.92-1.77(m,1H),1.70-1.53(m,1H)。LCMS(ES+)m/z448(M+1)

Example 4385-amino-N- [5- (5-amino-3, 3-difluoro-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (3, 5-difluoro-4-pyridinyl) thiazole-4-carboxamide 438

Following the procedure of example 422, starting from tert-butyl 1- (4- (5- (tert-butoxycarbonyl-amino) -2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-ylcarbamate and3, 5-difluoro-4- (tributylstannyl) pyridine, 438 was obtained as a white solid (68mg, 43% over two steps).¹H NMR(400MHz,d6-DMSO)8.83(s,1H),8.67(s,2H),7.78(s,2H),7.61-7.56(m,1H),3.79-3.56(m,4H),3.46-3.33(m,1H),3.37-3.16(m,2H),3.16-3.06(m,1H),2.35-2.08(m,2H),1.91-1.78(m,1H),1.81-1.60(m,3H)。LCMS(ES+)m/z485(M+1)

Example 4395-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3, 5-difluoropyridin-4-yl) thiazole-4-carboxamide 439

Following the procedure of example 422, starting from tert-butyl 1- (4- (5- (tert-butoxy-carbonyl) -amino-2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -5-fluoroazepan-4-ylcarbamate and3, 5-difluoro-4- (tributylstannyl) pyridine, 439 was obtained as a white solid (42mg, 28%, over two steps).¹H NMR(400MHz,d6-DMSO)8.84(s,1H),8.65(s,2H),7.75(s,2H),7.58(s,1H),4.44(dtd,J＝47.9,8.0,3.6Hz,1H),3.65(s,3H),3.26-3.08(m,5H),2.19-2.05(m,1H),2.04-1.79(m,2H),1.73-1.50(m,3H)。LCMS(ES+)m/z467(M+1)

Example 4405-amino-N- [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (3, 5-difluoro-4-pyridinyl) thiazole-4-carboxamide 440

Following the procedure of example 422, from 1- (4- (5- (tert-butoxy-carbonyl-amino) -2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6-methoxy-6-methylazepan-4-ylcarbamic acid tert-butyl acidStarting with 3, 5-difluoro-4- (tributylstannyl) pyridine, 440 was obtained as the mono-formate salt as a white solid (67mg, 43% over two steps).¹H NMR(400MHz,d6-DMSO)8.84(s,1H),8.70(s,2H),8.45(s,1H),7.82(s,2H),7.70(s,1H),3.68(s,3H),3.52(t,J＝11.2Hz,2H),3.36-3.19(m,3H),3.13-3.04(m,1H),3.04(s,3H),2.98(d,J＝14.4Hz,1H),2.18(d,J＝14.2Hz,1H),2.12-1.98(m,1H),1.85-1.75(m,1H),1.68-1.57(m,1H),1.03(s,3H)。LCMS(ES+)m/z493(M+1)

Example 4415-amino-N- [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (3-fluoro-4-pyridinyl) thiazole-4-carboxamide 441

Following the procedure of example 422, starting from tert-butyl 1- (4- (5- (tert-butoxy-carbonyl-amino) -2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6-methoxy-6-methylazepan-4-ylcarbamate, 441 was obtained as the mono-formate salt as a white solid (72mg, 48% over two steps).¹H NMR (400MHz, d6-DMSO)9.15(s,1H),8.71(d, J ═ 2.7Hz,1H),8.58(d, J ═ 5.1Hz,1H),8.41(s,1H),8.23(dd, J ═ 5.2,6.4Hz,1H),7.72(s,2H),7.59(s,1H),3.69(s,3H),3.54(t, J ═ 10.6Hz,1H),3.33 to 3.21(m,2H),3.25 to 2.91(m,5H),2.22 to 1.95(m,2H),1.82 to 1.72(m,1H),1.74 to 1.61(m,1H),1.05(s, 3H). No exchangeable NH observed₂。LCMS(ES+)m/z475(M+1)

Example 4425-amino-N- [5- [ (4R,5R) -4-amino-5-fluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (5-cyano-2-fluoro-phenyl) thiazole-4-carboxamide 442

Following the procedure of example 428, 442 was prepared substituting (4-methyl-3-pyridinyl) boronic acid with (5-cyano-2-fluoro-phenyl) boronic acid.¹H NMR(400MHz,DMSO)9.22(s,1H),8.86(d,J＝6.8Hz,1H),7.91(s,1H),7.67-7.57(m,1H),7.53(s,2H),7.35(s,1H),4.56-4.34(m,1H),3.65(s,3H),3.24-3.00(m,5H),2.20-2.03(m,1H),2.03-1.89(m,1H),1.79(s,1H),1.67-1.50(m,1H)。LCMS(ES+)m/z473(M+1)

Example 4435-amino-N- [5- [ (4R,5R) -4-amino-5-fluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-dimethyl-4-pyridinyl) thiazole-4-carboxamide 443

Following the procedure of example 428, substituting (4-methyl-3-pyridinyl) boronic acid with 2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine prepares 443.¹H NMR(400MHz,DMSO)8.95(s,1H),7.63(s,2H),7.45(s,1H),7.44(s,2H),4.60-4.35(m,1H),3.65(s,3H),3.27-3.00(m,5H),2.47(s,6H),2.23-2.06(m,1H),2.06-1.90(m,1H),1.90-1.76(m,1H),1.71-1.54(m,1H)。LCMS(ES+)m/z459(M+1).

Example 4445-amino-N- [5- [ (4R,5R) -4-amino-5-fluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (5-cyano-3-pyridinyl) thiazole-4-carboxamide 444

Following the procedure of example 428, substituting (4-methyl-3-pyridinyl) boronic acid with 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-3-carbonitrile produces 444.¹H NMR(400MHz,DMSO)9.29(s,1H),9.03(s,1H),8.97(s,1H),8.74(s,1H),7.64(s,2H),7.41(s,1H),4.44(dtd,J＝11.5,8.2,3.2Hz,1H),3.64(s,3H),3.27-3.00(m,5H),2.20-2.04(m,1H),2.04-1.89(m,1H),1.89-1.78(m,1H),1.66-1.52(m,1H)。LCMS(ES+)m/z456(M+1)

Example 4455-amino-N- [5- [ (4R,5R) -4-amino-5-fluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2, 5-dimethyl-3-pyridinyl) thiazole-4-carboxamide 445

Following the procedure of example 428, substituting (4-methyl-3-pyridinyl) boronic acid with 2, 5-dimethyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine, preparation 445.¹H NMR(400MHz,DMSO)8.70(s,1H),7.92(d,J＝8.0Hz,1H),7.51(s,1H),7.42(s,2H),7.19(d,J＝8.0Hz,1H),4.43(dt,J＝47.9,6.1Hz,1H),3.64(s,3H),3.27-2.99(m,5H),2.77(s,3H),2.47(s,3H),2.16-2.05(m,1H),2.04-1.89(m,1H),1.87-1.69(m,3H),1.68-1.52(m,1H)。LCMS(ES+)m/z459(M+1)

Example 4465-amino-N- [5- [ (5S) -5-amino-3, 3-difluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (3-fluoro-4-pyridinyl) thiazole-4-carboxamide 446

Chiral separation of racemic 426 by SFC gives a single enantiomer 446.¹H NMR(400MHz,DMSO)9.09(s,1H),8.70(d,J＝2.4Hz,1H),8.54(d,J＝5.1Hz,1H),8.22(t,J＝5.9Hz,1H),7.68(s,2H),7.49(s,1H),3.78-3.57(m,4H),3.53-3.35(m,1H),3.29-3.04(m,3H),2.37-2.11(m,2H),1.95-1.67(m,4H)。LCMS(ES+)m/z467(M+1)

Example 4475-amino-N- [5- [ (5R) -5-amino-3, 3-difluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (3-fluoro-4-pyridinyl) thiazole-4-carboxamide 447

Chiral separation of racemic 426 by SFC gave single enantiomer 447.¹H NMR(400MHz,DMSO)9.11(s,1H),8.70(d,J＝2.6Hz,1H),8.53(d,J＝5.1Hz,1H),8.27(s,1H),8.26-8.16(m,1H),7.68(s,2H),7.47(s,1H),3.79-3.62(m,4H),3.51-3.08(m,3H),2.40-2.19(m,2H),2.02-1.86(m,1H),1.86-1.70(m,1H)。LCMS(ES+)m/z467(M+1)

Example 4485-amino-N- [5- (6-amino-1-oxa-9-azaspiro [3.6] decan-9-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 448

Step A Methyltriphenylphosphonium bromide (3.09g,8.49mmol) was suspended in toluene (25 mL). Potassium tert-butoxide (1.0mol/L) in THF (7.07mL,7.074mmol) was added and the mixture turned bright yellow. It was stirred at room temperature for 4 hours, then tert-butyl N- [ (4S) -1- (2-methyl-4-nitro-pyrazol-3-yl) -6-oxo-azepan-4-yl ] carbamate (1000mg,2.83mmol) (second eluting peak in chiral separation) (in 5mL toluene) was added. The mixture was stirred at RT for 30 min, quenched with saturated aluminum chloride, and extracted 3x with EA. The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (0-100% EA/heptane) to give tert-butyl N- [ (4R) -6-methylene-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl ] carbamate (699mg, 70%).

Step B MCPBA (335mg,1.49mmol, 77% by mass) was added to N- [ (4R) -6-methylene-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl]Tert-butyl carbamate (350mg,1.00mmol) in a stirred solution in DCM (12 mL). The mixture was stirred at room temperature overnight. The reaction was saturated NaHCO₃Quench and extract 3x with DCM. The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (0-100% EA/heptane) to give N- [ (5S) -8- (2-methyl-4-nitro-pyrazol-3-yl) -2-oxa-8-azaspiro [2.6]]Non-5-yl]Tert-butyl carbamate (316mg, 86%).

Step C to a stirred suspension of sodium hydride (115mg,2.87mmol,60 mass%) in DMSO (5mL) was added trimethylsulfonium iodide (644mg,2.87mmol) and the suspension was stirred at 60 ℃ for 2 hours to give a clear solution. Epoxy N- [ (5S) -8- (2-methyl-4-nitro-pyrazol-3-yl) -2-oxa-8-azaspiro [2.6] non-5-yl ] carbamic acid tert-butyl ester (320mg,0.87mmol) was dissolved in DMSO (2mL) and added to the reaction mixture. The resulting clear solution was stirred at 65 ℃ for two days. After cooling to room temperature, the reaction was quenched with water and extracted 3x with EA. The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (0-100% EA/heptane) to give tert-butyl ((9S) -6- (1-methyl-4-nitro-1H-pyrazol-5-yl) -1-oxa-6-azaspiro [3.6] decan-9-yl) carbamate (114mg, 34%).

Step D: solution of the above compound in MeOH (30mL) was passed(50bar,50 ℃, flow rate: 1 mL/min, 30mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give ((9S) -6- (4-amino-1-methyl-1H-pyrazol-5-yl) -1-oxa-6-azaspiro [ 3.6)]Decan-9-yl) carbamic acid tert-butyl esterEsterester as brown oil. To a solution of this oil in DCM (10mL) was added 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (131mg,0.39mmol), PyBOP (251g,0.48mmol) and DIPEA (0.31mL,1.79mmol) and the mixture was stirred at rt for 16 h. Water (20mL) was added and the mixture was diluted with DCM (100 mL). The organic layer was washed with water (20mL), separated, and MgSO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc/heptane) afforded N- [ (6S) -9- [4- [ [5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl]Amino group]-2-methyl-pyrazol-3-yl]-3-oxa-9-azaspiro [3.6]Decan-6-yl]Tert-butyl carbamate (185mg, 90%).

Step E the above compound was stirred with TFA (5mL) and DCM (5mL) for 30 min at room temperature. The solvent was removed under reduced pressure to saturate NaHCO₃Basified and extracted with ethyl acetate (3 ×). The combined organic layers were over MgSO₄The solvent was removed under reduced pressure by drying and the residue was purified by preparative HPLC to give 448(11mg, 8.4%).¹H NMR(400MHz,DMSO)7.60(s,1H),7.58-7.43(m,3H),7.30(t,J＝8.7Hz,2H),4.39-4.19(m,2H),3.66(s,3H),3.44(d,J＝13.9Hz,1H),3.24-3.13(m,1H),3.09-2.89(m,3H),2.48-2.38(m,1H),2.34-2.20(m,2H),1.90-1.74(m,2H),1.69-1.51(m,1H)。LCMS(ES+)m/z490(M+1)

Example 4495-amino-N- [5- [ (5R) -5-amino-3-methylene-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 449

In preparation of 448, N- [ (4R) -6-methylene-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl]Tert-butyl carbamate was converted to 449.¹H NMR(400MHz,DMSO)8.73(s,1H),7.56(s,1H),7.55-7.41(m,3H),7.26(t,J＝8.7Hz,2H),4.89(d,J＝9.7Hz,2H),3.86-3.71(m,2H),3.67(s,3H),3.16-3.05(m,1H),3.05-2.92(m,1H),2.85(s,1H),2.44-2.28(m,1H),1.82-1.69(m,2H),1.53-1.35(m,1H)。LCMS(ES+)m/z460(M+1)

Example 4505-amino-N- [5- [ (4S,5S) -4-amino-5-fluoro-azepan-1-yl ] -1- (trideuteromethyl) pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 450

Following the procedure in example 147, 5-chloro-1-trideuteromethyl-4-nitro-1H-pyrazole was converted to 450.¹HNMR(400MHz,DMSO)8.83(s,1H),7.62-7.41(m,4H),7.26(t,J＝8.7Hz,2H),4.41(dtd,J＝47.9,8.2,3.6Hz,1H),3.24-3.02(m,5H),2.18-2.02(m,1H),2.02-1.89(m,1H),1.89-1.78(m,1H),1.69(br,2H),1.64-1.49(m,1H)。LCMS(ES+)m/z469(M+1)

Example 4515-amino-N- [5- [ (4R,5R) -4-amino-5-fluoro-azepan-1-yl ] -1- (trideuteromethyl) pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 451

Following the procedure in example 150, 5-chloro-1-trideuteromethyl-4-nitro-1H-pyrazole was converted to 451.¹HNMR(400MHz,DMSO)8.83(s,1H),7.60-7.40(m,4H),7.26(t,J＝8.7Hz,2H),4.41(dtd,J＝48.0,8.2,3.6Hz,1H),3.24-3.02(m,5H),2.19-2.03(m,1H),2.03-1.88(m,1H),1.88-1.77(m,1H),1.69(br,2H),1.66-1.52(m,1H)。LCMS(ES+)m/z469(M+1)

Example 4525-amino-N- [5- (6-amino-1-oxa-9-azaspiro [3.6] decan-9-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 452

Following the procedure in example 448, the first eluting peak, tert-butyl N- [ (4R) -1- (2-methyl-4-nitro-pyrazol-3-yl) -6-oxo-azepan-4-yl ] carbamate, was converted to 452. LCMS (ES +) M/z490(M +1)

Example 4535-amino-N- [5- (5-amino-3-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 453

In the preparation of 448, N- [ (4R) -6-methylene-1- (2-Methyl-4-nitro-pyrazol-3-yl) azepan-4-yl]Tert-butyl carbamate was converted to 453.¹H NMR(400MHz,DMSO)8.65(s,1H),8.41(s,1H),7.61-7.43(m,4H),7.28(td,J＝8.8,2.0Hz,2H),3.66(d,J＝3.0Hz,4H),3.33-3.01(m,3H),2.96-2.77(m,2H),2.19-1.58(m,4H),1.49(dd,J＝24.1,11.2Hz,1H),0.86(dd,J＝15.5,6.8Hz,3H)。LCMS(ES+)m/z462(M+1)

Example 4545-amino-N- [5- [ (5S) -5-amino-3, 3-difluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (3, 5-difluoro-4-pyridinyl) thiazole-4-carboxamide 454

Chiral separation of racemic 438 by SFC gave single enantiomer 454.¹H NMR(400MHz,DMSO)8.81(s,1H),8.66(d,J＝1.1Hz,2H),7.76(s,2H),7.60(s,1H),3.76-3.59(m,4H),3.49-3.34(m,1H),3.28-3.02(m,3H),2.37-2.09(m,2H),1.92-1.61(m,2H)。LCMS(ES+)m/z485(M+1)

Example 4555-amino-N- [5- [ (5R) -5-amino-3, 3-difluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (3, 5-difluoro-4-pyridinyl) thiazole-4-carboxamide 455

Chiral separation of racemic 438 by SFC gave single enantiomer 455.¹H NMR(400MHz,DMSO)8.79(s,1H),8.66(s,2H),8.28(s,1H),7.76(s,2H),7.58(s,1H),3.78-3.60(m,4H),3.51-3.23(m,3H),3.18-3.05(m,1H),2.42-2.15(m,2H),1.99-1.73(m,2H)。LCMS(ES+)m/z485(M+1)

Example 4565-amino-N- [5- (5-amino-3-hydroxy-3-methyl-cycloheptyl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 456

(E) (iii) -3-hydroxy-5- (1-methyl-4-nitro-1H-pyrazol-5-yl) cyclohept-4-enylcarbamic acid tert-butyl ester (620mg,1.76mmol) in MeOH (40mL) by(all H)₂Flow rate 1 mL/min, 30mm 10% Pd/C cartridge, 70 ℃). The solvent was removed under reduced pressure to give tert-butyl 5- (4-amino-1-methyl-1H-pyrazol-5-yl) -3-hydroxycycloheptylcarbamate as a yellow oil. To a solution of the amine in DCM (50mL) was added DIPEA (0.92mL,5.28mmol), PyBOP (1.37g,2.64mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (690mg,1.94mmol) and the mixture was stirred at rt for 18 h. The mixture was diluted with DCM (100mL) and washed with water (50 mL). The organic layer was separated over MgSO₄Dried and the solvent removed under reduced pressure. Purification by silica gel column chromatography (75% EtOAc/isohexane) afforded (tert-butyl 5- (4- (5-tert-butoxycarbonylamino-2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -3-hydroxycycloheptylcarbamate as a yellow foam (890 mg.) this foam (890mg,1.34mmol) was dissolved in DCM (50mL) and dess-martin oxidant (684mg,1.61mmol) was added and the mixture stirred at room temperature for 1.5H. the mixture was then purified with 20% sodium thiosulfate/saturated NaHCO₃The aqueous solution (100mL) was quenched with 1/1 aqueous solution, and the layers were extracted over MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded a light yellow solid (500 mg). A portion of this solid (356mg,0.54mmol) was dissolved in dry THF (5mL) and cooled at 0 deg.C, then a solution of methylmagnesium bromide (3M in Et) was added dropwise₂0.72mL,2.15mmol) in O. The mixture was stirred at 0 ℃ for 3 hours, then an additional amount of methylmagnesium bromide (3M in Et)₂0.3mL,0.9mmol) in O. The mixture was stirred for an additional 6 hours, quenched with a saturated solution of ammonium chloride (30mL), extracted with EtOAc (50mL) and washed with water. The combined organic layers were over MgSO₄Dried and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) afforded a light yellow oil. The four diastereomers obtained were separated by preparative HPLC to give diastereomer 1 as a white solid (22mg, 2% over five steps). The solid (22mg,0.03mmol) was dissolved in HCl in dioxane (4M,1mL,4.0mmol) and MeOH (1mL) and stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and the crude residue was purified by preparative HPLC to give 456 as an orange solid (15 mg),96％)。¹H NMR(400MHz,d6-DMSO)8.79(s,1H),8.45(s,2H),7.59-7.50(m,2H),7.33-7.25(m,2H),3.78(s,3H),3.58-3.05(m,1H),3.17(s,1H),2.85-2.77(m,1H),2.08-1.92(m,4H),1.88-1.78(m,5H),1.55-1.44(m,1H),1.17(s,3H)。LCMS(ES+)m/z477(M+1)

Example 4575-amino-2- (2, 6-difluorophenyl) -N- (5- ((4R,5S) -4, 5-dihydroxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 457

To a solution of (Z) -tert-butyl 2- (2, 6-difluorophenyl) -4- (1-methyl-5- (2,3,6, 7-tetrahydro-1H-azepin-1-yl) -1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate (1.28g,2.41mmol) in tert-butanol (35mL) was added a solution of N-methylmorpholine-N-oxide (0.80g,6.80mmol) in water (35mL), followed by a solution of osmium tetroxide (2.5 wt% in tert-butanol, 2.5 mL). The reaction mixture was stirred at room temperature for 72 h, then diluted with DCM (100mL) and quenched with a saturated solution of sodium dithionite (50mL), and the organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification by silica gel column chromatography (0-10% MeOH/DCM) gave tert-butyl 2- (2, 6-difluorophenyl) -4- (5- (4, 5-syn-dihydroxyazepan-1-yl) -1-methyl-1H-pyrazol-4-ylcarbamoyl) thiazol-5-ylcarbamate as a brown gum (0.12 g). The gum (0.12g,0.21mmol) was dissolved in HCl (4M,10mL,40.0mmol) and MeOH in dioxane (2mL) and stirred at room temperature for 20 hours. The solvent was removed under reduced pressure and the crude residue was purified by preparative HPLC to give 457 as a white solid (36mg, 3% over two steps).¹H NMR(400MHz,d6-DMSO)8.74(s,1H),7.60-7.50(m,4H),7.34-7.26(m,2H),4.41(d,J＝4.1Hz,2H),3.91(t,J＝4.7Hz,2H),3.67(s,3H),2.96(ddd,J＝12.8,7.7,4.4Hz,2H),2.55-2.52(m,2H),2.02-1.92(m,2H),1.72-1.64(m,2H)。LCMS(ES+)m/z465(M+1)

Example 4585-amino-N- [5- [4- (aminomethyl) -4-methoxy-1-piperidinyl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 458

Following the procedure of example 101, starting from tert-butyl (4-methoxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-4-yl) methylcarbamate and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acid, 458 was obtained as an off-white solid (30mg, 7% over three steps).¹H NMR(400MHz,d4-MeOD)8.56(s,1H),7.56-7.42(m,2H),7.15(t,J＝8.7Hz,2H),3.74(s,3H),3.42-3.33(m,4H),3.23(s,2H),3.12-2.95(m,3H),1.97(d,J＝13.6Hz,2H),1.76-1.66(m,2H)。LCMS(ES+)m/z478(M+1)

Example 4595-amino-N- [5- (5-amino-3, 3-difluoro-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluoro-4-methoxy-phenyl) thiazole-4-carboxamide 459

To a solution of tert-butyl 1- (4- (5- (tert-butoxycarbonyl-amino) -2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-ylcarbamate (200mg,0.31mmol) in dimethyl ether (3mL) was added 2, 6-difluoro-4-methoxyphenylboronic acid (101mg,0.54mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (complex with dichloromethane (50mg,0.06 mmol)), sodium carbonate (67mg,0.63mmol) and water (1 mL). The mixture was degassed for 5 minutes and then heated in a microwave at 120 ℃ for 2.5 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give a brown oil. To a solution of this oil in MeOH (10mL) was added HCl in dioxane (4M,10mL,40.0mmol) and the mixture was heated at 40 ℃ for 3 hours. Prepared via preparative HPLC to afford 459 as a white solid (10mg, 6% over two steps).¹H NMR(400MHz,d6-DMSO)8.82(s,1H),7.54(s,1H),7.43(s,2H),6.99-6.88(m,2H),3.85(s,3H),3.79-3.50(m,4H),3.47-3.33(m,1H),3.29-3.16(m,2H),3.15-3.05(m,1H),2.29-2.09(m,2H),1.90-1.78(m,1H),1.77-1.65(m,1H),1.62(s,2H)。LCMS(ES+)m/z514(M+1)

Example 4605-amino-N- [5- (5-amino-3, 3-difluoro-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (1, 5-dimethylpyrazol-4-yl) thiazole-4-carboxamide 460

Following the procedure in example 459, starting from tert-butyl 1- (4- (5- (tert-butoxycarbonyl-amino) -2-bromothiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -6, 6-difluoroazepan-4-ylcarbamate, 460 was obtained as a red solid (13mg, 8% over two steps).¹H NMR(400MHz,d6-DMSO)8.63(s,1H),7.74-7.65(m,1H),7.59-7.52(m,1H),7.25(s,2H),3.79(s,3H),3.82-3.55(m,4H),3.48-3.34(m,1H),3.29-3.05(m,3H),2.57(s,3H),2.28-2.05(m,2H),1.92-1.80(m,1H),1.84-1.56(m,3H)。LCMS(ES+)m/z466(M+1)

Example 4615-amino-N- [5- [ (5R) -5-amino-3, 3-difluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (6-cyano-2-pyridinyl) thiazole-4-carboxamide 461

Step A tert-butyl (R) - (6, 6-difluoro-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) carbamate was converted to tert-butyl N- [ 2-bromo-4- [ [5- [ (5R) -5- (tert-butoxycarbonylamino) -3, 3-difluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] carbamoyl ] thiazol-5-yl ] carbamate according to the procedure in example 166.

Step B tert-butyl N- [ 2-bromo-4- [ [5- [ (5R) -5- (tert-butoxycarbonylamino) -3, 3-difluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] carbamoyl ] thiazol-5-yl ] carbamate was reacted with 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-carbonitrile according to the procedure in example 428 to give 461. LCMS (ES +) M/z474(M +1)

Example 4625-amino-N- [5- [ (5R) -5-amino-3, 3-difluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (1, 3-dimethylpyrazol-4-yl) thiazole-4-carboxamide 462

According to the procedure in example 461, preparation 462.¹H NMR(400MHz,DMSO)8.57(s,1H),8.07(s,1H),7.57(s,1H),7.22(s,2H),3.79(s,3H),3.74-3.57(m,4H),3.49-3.34(m,1H),3.26-3.04(m,3H),2.43(d,J＝9.1Hz,3H),2.31-2.04(m,2H),1.86(d,J＝14.1Hz,1H),1.82-1.59(m,3H)。LCMS(ES+)m/z466(M+1)

Example 4635-amino-N- [5- [ (5R) -5-amino-3, 3-difluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (1, 5-dimethylpyrazol-4-yl) thiazole-4-carboxamide 463

According to the procedure in example 461, 463 was prepared.¹H NMR(400MHz,DMSO)8.62(s,1H),8.28(s,1H),7.68(s,1H),7.53(s,1H),7.23(s,2H),3.78(s,3H),3.75-3.58(m,4H),3.52-3.35(m,1H),3.35-3.23(m,2H),3.21-3.06(m,1H),2.56(s,3H),2.37-2.18(m,2H),1.92(d,J＝13.3Hz,1H),1.80(dd,J＝14.9,9.7Hz,1H)。LCMS(ES+)m/z466(M+1)

Example 4645-amino-N- [5- [ (5R) -5-amino-3, 3-difluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2-methyl-4-pyridinyl) thiazole-4-carboxamide 464

Pursuant to the procedure in example 461, 464 was prepared.¹H NMR(400MHz,DMSO)8.99(s,1H),8.50(d,J＝5.2Hz,1H),8.27(s,1H),7.64(d,J＝5.6Hz,3H),7.57(d,J＝5.2Hz,1H),7.47(s,1H),3.75-3.60(m,4H),3.54-3.37(m,1H),3.37-3.22(m,2H),3.22-3.05(m,1H),2.53(s,3H),2.41-2.22(m,2H),1.99-1.87(m,1H),1.87-1.70(m,1H)。LCMS(ES+)m/z463(M+1)

Example 4655-amino-N- [5- (5-amino-3-hydroxy-3-methyl-cycloheptyl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 465

Chiral separation of racemic mixture N- [5- [4- [ [5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl ] by SFC]Amino group]-2-methyl-pyrazol-3-yl]-3-hydroxy-3-methyl-cycloheptyl]T-butyl carbamate was then deprotected with 4N HCl in dioxane to give 465 as a single enantiomer.¹H NMR(400MHz,DMSO)8.66(s,1H),8.44(s,1H),7.56(s,1H),7.53(t,J＝8.4Hz,1H),7.47(s,2H),7.27(t,J＝8.8Hz,2H),3.77(s,3H),3.53-3.10(m,2H),2.11-1.99(m,1H),1.99-1.78(m,4H),1.72-1.53(m,3H),1.15(s,3H)。LCMS(ES+)m/z477(M+1)

Example 4665-amino-N- [5- (5-amino-3-hydroxy-3-methyl-cycloheptyl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 466

Racemic mixture N- [5- [4- [ [5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl ] amino ] -2-methyl-pyrazol-3-yl ] -3-hydroxy-3-methyl-cycloheptyl ] carbamic acid tert-butyl ester was chirally separated by SFC and then deprotected with 4N HCl in dioxane to give 466 as single enantiomer. LCMS (ES +) M/z477(M +1)

Example 4675-amino-N- [5- (5-amino-3-hydroxy-3-methyl-cycloheptyl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 467

Racemic mixture N- [5- [4- [ [5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl ] amino ] -2-methyl-pyrazol-3-yl ] -3-hydroxy-3-methyl-cycloheptyl ] carbamic acid tert-butyl ester was separated chirally by SFC and passed through HCl in 4N in dioxane to give 467 as a single enantiomer. LCMS (ES +) M/z477(M +1)

Example 4685-amino-N- [5- (5-amino-3-hydroxy-3-methyl-cycloheptyl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 468

Chiral separation of racemic mixture N- [5- [4- [ [5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl ] by SFC]Amino group]-2-methyl-pyrazol-3-yl]-3-hydroxy-3-methyl-cycloheptyl]T-butyl carbamate was then deprotected with 4N HCl (in dioxane) to afford 468 as a single enantiomer.¹H NMR(400MHz,DMSO)8.70(s,1H),7.85(s,2H),7.60-7.49(m,1H),7.46(s,1H),7.28(t,J＝8.7Hz,2H),3.78(s,3H),3.72-3.42(m,1H),2.99-2.84(m,1H),2.10-1.94(m,3H),1.94-1.74(m,4H),1.65(d,J＝13.6Hz,1H),1.26(s,3H).LCMS(ES+)m/z477(M+1)

Example 4695-amino-N- [5- (5-amino-3-hydroxy-3-methyl-cycloheptyl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 469

Chiral separation of racemic mixture N- [5- [4- [ [5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl ] by SFC]Amino group]-2-methyl-pyrazol-3-yl]-3-hydroxy-3-methyl-cycloheptyl]T-butyl carbamate was then deprotected with 4N HCl (in dioxane) to afford 469 as a single enantiomer.¹H NMR(400MHz,DMSO)8.70(s,1H),7.85(s,2H),7.60-7.50(m,1H),7.46(s,1H),7.28(t,J＝8.7Hz,2H),3.79(s,3H),3.74-3.43(m,1H),2.99-2.84(m,1H),2.12-1.95(m,3H),1.95-1.71(m,4H),1.65(d,J＝13.5Hz,1H),1.26(s,3H)。LCMS(ES+)m/z477(M+1)

Example 4705-amino-N- [5- (5-amino-3-hydroxy-3-methyl-cycloheptyl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 470

Chiral separation of racemic mixture N- [5- [4- [ [5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl ] by SFC]Amino group]-2-methyl-pyrazol-3-yl]-3-hydroxy-3-methyl-cycloheptyl]Tert-butyl carbamate was then deprotected with 4N HCl (in dioxane) to give 470 as a single enantiomer.¹H NMR(400MHz,DMSO)8.66(s,1H),8.43(s,1H),7.56(s,1H),7.53(dd,J＝11.6,5.2Hz,1H),7.48(s,2H),7.27(t,J＝8.8Hz,2H),3.76(s,3H),3.51-3.29(m,2H),2.13-2.00(m,1H),2.00-1.79(m,4H),1.72-1.54(m,3H),1.16(s,3H)。LCMS(ES+)m/z477(M+1)

Example 4715-amino-N- [5- [ (4S,5S) -4-amino-5-fluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (3, 5-difluoro-4-pyridinyl) thiazole-4-carboxamide 471

Chiral separation of racemic 439 by SFC gave a single enantiomer 471.¹H NMR(400MHz,DMSO)8.81(s,1H),8.64(d,J＝0.9Hz,2H),7.73(s,2H),7.58(s,1H),4.57-4.34(m,1H),3.65(s,3H),3.26-3.04(m,5H),2.20-1.78(m,5H),1.71-1.51(m,1H)。LCMS(ES+)m/z467(M+1)

Example 4725-amino-N- [5- [ (4S,5S) -4-amino-5-fluoro-azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (3, 5-difluoro-4-pyridinyl) thiazole-4-carboxamide 472

Chiral separation of racemic 439 by SFC gave single enantiomer 472.¹H NMR(400MHz,DMSO)8.82(s,1H),8.64(d,J＝1.1Hz,2H),7.73(s,2H),7.58(s,1H),4.44(dtd,J＝47.9,8.2,3.6Hz,1H),3.65(s,3H),3.24-3.04(m,5H),2.23-1.71(m,5H),1.68-1.51(m,1H)。LCMS(ES+)m/z467(M+1)

Example 4735-amino-N- [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (3, 5-difluoro-4-pyridinyl) thiazole-4-carboxamide 473

Chiral separation of racemic 440 by SFC yields a single enantiomer 473.¹H NMR(400MHz,DMSO)8.85(s,1H),8.67(s,2H),7.76(s,2H),7.70(s,1H),3.66(s,3H),3.31-3.23(m,2H),3.24-3.13(m,1H),3.12-2.92(m,5H),2.00(d,J＝14.1Hz,1H),1.88-1.75(m,1H),1.70-1.55(m,1H),1.42(dd,J＝14.3,10.6Hz,1H),0.99(s,3H)。LCMS(ES+)m/z493(M+1)

Example 4745-amino-N- [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (3, 5-difluoro-4-pyridinyl) thiazole-4-carboxamide 474

Chiral separation of racemic 440 by SFC to give a single enantiomerAnd a body 474.¹H NMR(400MHz,DMSO)8.85(s,1H),8.67(s,2H),7.76(s,2H),7.70(s,1H),3.66(s,3H),3.29-3.11(m,3H),3.12-2.89(m,5H),2.00(d,J＝14.1Hz,1H),1.89-1.76(m,1H),1.67-1.55(m,1H),1.41(dd,J＝14.4,10.5Hz,1H),0.99(s,3H)。LCMS(ES+)m/z493(M+1)

Example 4755-amino-N- [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (3-fluoro-4-pyridinyl) thiazole-4-carboxamide 475

Racemic 441 was chirally separated by SFC to give the single enantiomer 475.¹H NMR(400MHz,DMSO)9.20(s,1H),8.69(d,J＝2.8Hz,1H),8.57(d,J＝5.0Hz,1H),8.31-8.16(m,1H),7.69(s,2H),7.68(s,1H),3.67(s,3H),3.46(t,J＝10.2Hz,1H),3.36-3.18(m,2H),3.09-2.91(m,5H),2.09(d,J＝14.0Hz,1H),1.94-1.81(m,1H),1.77-1.59(m,1H),1.50(dd,J＝14.2,10.7Hz,1H),1.02(s,3H)。LCMS(ES+)m/z475(M+1)

Example 4765-amino-N- [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (3-fluoro-4-pyridinyl) thiazole-4-carboxamide 476

Chiral separation of racemic 441 by SFC gave single enantiomer 476.¹H NMR(400MHz,DMSO)9.20(s,1H),8.69(d,J＝2.8Hz,1H),8.57(d,J＝5.1Hz,1H),8.29-8.21(m,1H),7.69(s,2H),7.68(s,1H),3.67(s,3H),3.46(t,J＝10.3Hz,1H),3.38-3.21(m,2H),3.09-2.94(m,5H),2.09(d,J＝14.2Hz,1H),1.95-1.82(m,1H),1.75-1.63(m,1H),1.50(dd,J＝14.2,10.7Hz,1H),1.02(s,3H)。LCMS(ES+)m/z475(M+1)

Example 4775-amino-2- (2-fluorophenyl) -N- [ 1-methyl-5- (1-oxa-6, 9-diazaspiro [3.6] decan-6-yl) pyrazol-4-yl ] thiazole-4-carboxamide 477

Following the procedure in example 448, 4- (2-methyl-4-nitro-pyrazol-3-yl) -6-oxo-1, 4-diAzepane-1-carboxylic acid tert-butyl ester was converted to racemic 477.¹H NMR(400MHz,DMSO)9.46(s,1H),8.35(t,J＝6.9Hz,1H),7.63(s,1H),7.51-7.27(m,5H),4.28(dt,J＝15.1,6.3Hz,2H),3.67(s,3H),3.45(q,J＝14.5Hz,2H),3.23-3.02(m,4H),2.88-2.74(m,2H),2.42-2.29(m,1H),2.29-2.14(m,1H)。LCMS(ES+)m/z458(M+1).

Example 4785-amino-2- (2, 6-difluorophenyl) -N- [ 1-methyl-5- (1-oxa-6, 9-diazaspiro [3.6] decan-6-yl) pyrazol-4-yl ] thiazole-4-carboxamide 478

Following the procedure in example 448, tert-butyl 4- (2-methyl-4-nitro-pyrazol-3-yl) -6-oxo-1, 4-diazepan-1-carboxylate was converted to racemic 478.¹H NMR(400MHz,DMSO)9.73(s,1H),7.67(s,1H),7.61-7.41(m,3H),7.29(t,J＝8.7Hz,2H),4.30-4.15(m,2H),3.66(s,3H),3.48-3.33(m,2H),3.21-2.98(m,4H),2.81(t,J＝5.8Hz,2H),2.38-2.25(m,1H),2.25-2.09(m,1H)。LCMS(ES+)m/z458(M+1).

Example 4795-amino-N- [5- [4- (aminomethyl) -4-hydroxy-1-piperidinyl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 479

Operating according to example 101, from N- [ [ 4-hydroxy-1- (2-methyl-4-nitro-pyrazol-3-yl) -4-piperidinyl]Methyl radical]Starting with tert-butyl carbamate, 479 was obtained as a milky solid (37mg, 35% in three steps).¹H NMR(400MHz,d4-MeOD)8.55(s,1H),7.52-7.43(m,2H),7.20-7.10(m,2H),3.74(s,3H),3.49-3.38(m,2H),3.09-3.03(m,2H),2.92(s,2H),1.85-1.73(m,4H)。LCMS(ES+)m/z464(M+1)

Example 480 (R) -5-amino-2- (2-fluorophenyl) -N- [ 1-methyl-5- (1-oxa-6, 9-diazaspiro [3.6] decan-6-yl) pyrazol-4-yl ] thiazole-4-carboxamide 480

Chiral separation of racemic 5-amino-2- (2-fluorophenyl) -N- [ 1-methyl group by SFC-5- (1-oxa-6, 9-diazaspiro [3.6]]Dec-6-yl) pyrazol-4-yl]Thiazole-4-carboxamide 477 gave 480 (first eluting peak).¹H NMR(400MHz,DMSO)9.46(s,1H),8.41-8.32(m,1H),7.63(s,1H),7.51-7.30(m,5H),4.36-4.19(m,2H),3.67(s,3H),3.45(q,J＝14.5Hz,2H),3.26-3.04(m,4H),2.88-2.71(m,2H),2.42-2.29(m,1H),2.29-2.16(m,1H)。LCMS(ES+)m/z458(M+1).

Example 481 (S) -5-amino-2- (2-fluorophenyl) -N- [ 1-methyl-5- (1-oxa-6, 9-diazaspiro [3.6] decan-6-yl) pyrazol-4-yl ] thiazole-4-carboxamide

Chiral separation of racemic mixture 5-amino-2- (2-fluorophenyl) -N- [ 1-methyl-5- (1-oxa-6, 9-diazaspiro [3.6] by SFC]Dec-6-yl) pyrazol-4-yl]Thiazole-4-carboxamide 477 gave 481 (the second eluting peak).¹H NMR(400MHz,DMSO)9.46(s,1H),8.36(dd,J＝11.1,4.8Hz,1H),7.63(s,1H),7.52-7.31(m,5H),4.36-4.21(m,2H),3.67(s,3H),3.45(q,J＝14.5Hz,2H),3.21-3.05(m,4H),2.91-2.72(m,2H),2.41-2.31(m,1H),2.26-2.14(m,1H)。LCMS(ES+)m/z458(M+1)

Example 482 (R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (1-oxa-6, 9-diazaspiro [3.6] decan-6-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 482

Chiral separation of racemic mixture 478 by SFC gave 482 (first eluting peak).¹H NMR(400MHz,DMSO)9.71(s,1H),7.67(s,1H),7.60-7.44(m,3H),7.28(dd,J＝14.5,5.9Hz,2H),4.30-4.16(m,2H),3.66(s,3H),3.40(q,J＝14.7Hz,2H),3.19-3.00(m,4H),2.82(t,J＝5.8Hz,2H),2.38-2.26(m,1H),2.23-2.13(m,1H)。LCMS(ES+)m/z458(M+1).

Example 483 (S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (1-oxa-6, 9-diazaspiro [3.6] decan-6-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 483

Chiral separation of racemic mixtures by SFCCompound 478 gave 483 (second elution peak).¹H NMR(400MHz,DMSO)9.71(s,1H),8.22(s,1H),7.66(s,1H),7.62-7.44(m,3H),7.29(t,J＝8.7Hz,2H),4.30-4.17(m,2H),3.66(s,3H),3.48-3.31(m,2H),3.20-2.99(m,4H),2.82(t,J＝5.7Hz,2H),2.38-2.25(m,1H),2.25-2.12(m,1H)。LCMS(ES+)m/z458(M+1).

Example 4845-amino-2- (2, 6-difluorophenyl) -N- [ 1-methyl-5- (1-oxa-4, 9-diazaspiro [5.5] undecan-9-yl) pyrazol-4-yl ] thiazole-4-carboxamide 484

Following the procedure of example 121, starting from 3- (2-methyl-4-nitro-pyrazol-3-yl) -11-oxa-3, 8-diazaspiro [5.5]]Tert-butyl undecane-8-carboxylate to give 484 as an off-white solid (15mg, 30% over three steps).¹HNMR(400MHz,CDCl₃)8.56(s,1H),7.80(s,1H),7.39-7.16(m,1H),7.06-6.96(m,2H),6.12(s,2H),3.75(s,3H),3.69(t, J ═ 4.8Hz,2H),3.40-3.30(m,2H),2.99-2.92(m,2H),2.88-2.83(m,2H),2.79(s,2H),2.11-2.00(m,2H),1.74-1.63(m, 2H). No alkyl NH was observed. LCMS (ES +) M/z490(M +1)

EXAMPLE 4855-amino-N- [5- (5-amino-4-methoxy-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 485

To N- (1- (4- ((5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl) amino) -2-methyl-pyrazol-3-yl) -5-methoxy-5-methyl-azepan-4-yl)]A solution of tert-butyl carbamate (0.12g,0.17mmol) in MeOH (10mL) was added HCl in dioxane (4M,10mL,0.04 mol). The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. Prepared via preparative HPLC to yield 485 as a light yellow solid (64mg, 74%).¹H NMR(400MHz,d6-DMSO)9.63(s,1H),7.69(s,1H),7.59-7.48(m,3H),7.31-7.22(m,2H),3.61(s,3H),3.31-3.25(m,1H),3.14-3.03(m,2H),3.03(s,3H),2.99-2.89(m,1H),2.11-2.02(m,1H),1.92-1.82(m,1H),1.79-1.59(m,4H),1.47(dd,J＝14.5,6.2Hz,1H),1.19(s,3H)。LCMS(ES+)m/z492(M+1)

Example 486N- [5- [ (3aR,8aS) -2-oxo-3 a,4,5,7,8,8 a-hexahydro-3H-oxazolo [4,5-d ] azepin-6-yl ] -1-methyl-pyrazol-4-yl ] -5-amino-2- (2, 6-difluorophenyl) thiazole-4-carboxamide 486

To a stirred solution of tert-butyl N- ((4R,5S) -1- (4- ((5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl) amino) -2-methyl-pyrazol-3-yl) -5-hydroxy-azepan-4-yl) carbamate (199mg,0.30mmol) in DMF (2mL) was added sodium hydride (60% suspension in oil, 26mg,0.66mmol) at 0 ℃. The mixture was warmed to room temperature over 2 hours, quenched with water (3mL) and the resulting precipitate filtered off and dried under reduced pressure. The aqueous layer was extracted with EtOAc (3 × 3mL) and the combined organic layers were passed through a phase separation cartridge, concentrated under reduced pressure and the residue was combined in the earlier collected precipitate. A solution of this material (159mg,0.27mmol) in HCl in dioxane (4M,10mL) and MeOH (5mL) was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. Prepared via preparative HPLC to give 486 as a white solid (55mg, 41% over two steps).¹HNMR(400MHz,CDCl₃)8.50(s,1H),7.79(s,1H),7.37-7.28(m,1H),7.05(t,J＝8.8Hz,2H),6.14(s,2H),5.08-5.00(m,1H),4.87(s,1H),4.26(td,J＝9.3,3.5Hz,1H),3.75(s,3H),3.45-3.33(m,2H),3.16-3.07(m,2H),2.34-2.27(m,2H),2.20-2.09(m,1H),2.06-1.97(m,1H)。LCMS(ES+)m/z490(M+1)

Example 487 [ (4S,5R) -5-amino-1- [4- [ [ 5-amino-2- (2, 6-difluorophenyl) thiazole-4-carbonyl ] amino ] -2-methyl-pyrazol-3-yl ] azepan-4-yl ] acetate 487

To a mixture of N- ((4R,5S) -1- (4- ((5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl) amino) -2-methyl-pyrazol-3-yl) -5-hydroxy-azepan-4-yl]Tert-butyl carbamate (200mg,0.3mmol) and DMAP (55mg,0.45mmol) in DCM (2mL) acetic anhydride (0.43mL,0.45mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (3mL) and extracted with EtOAc (3X3mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-5% MeOH/DCM) to afford an off-white solid. A solution of the solid (176mg,0.25mmol) in HCl in dioxane (4M,10mL) and MeOH (5mL) was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was purified via preparative HPLC and purified by chromatography on silica gel (0-10% 7M NH₃In MeOH/DCM) to afford 487 as a white solid (52mg, 41% over two steps).¹H NMR(400MHz,d4-MeOD)7.64(s,1H),7.51-7.42(m,1H),7.15(t,J＝8.7Hz,2H),4.19(dt,J＝10.1,2.6Hz,1H),4.13-4.09(m,1H),3.76(s,3H),3.53(ddd,J＝13.5,9.7,3.3Hz,1H),3.35-3.20(m,2H),3.17-3.09(m,1H),2.29-2.18(m,1H),2.09-1.86(m,5H),1.78-1.69(m,1H)。LCMS(ES+)m/z506(M+1)

Example 488N- [5- [ (3aS,8aR) -2-oxo-3 a,4,5,7,8,8 a-hexahydro-3H-oxazolo [4,5-d ] azepin-6-yl ] -1-methyl-pyrazol-4-yl ] -5-amino-2- (2, 6-difluorophenyl) thiazole-4-carboxamide 488

Following the procedure of example 486, starting from tert-butyl N- ((4S,5R) -1- (4- ((5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl) amino) -2-methyl-pyrazol-3-yl) -5-hydroxy-azepan-4-yl) carbamate gave 488 as a white solid (69mg, 52% over two steps).¹H NMR(400MHz,CDCl₃)8.50(s,1H),7.79(s,1H),7.37-7.28(m,1H),7.05(t,J＝8.8Hz,2H),6.14(s,2H),5.08-5.00(m,1H),4.87(s,1H),4.26(td,J＝9.3,3.5Hz,1H),3.75(s,3H),3.45-3.33(m,2H),3.16-3.07(m,2H),2.34-2.27(m,2H),2.20-2.09(m,1H),2.06-1.97(m,1H)。LCMS(ES+)m/z490(M+1)

EXAMPLE 489 [ (4R,5S) -5-amino-1- [4- [ [ 5-amino-2- (2, 6-difluorophenyl) thiazole-4-carbonyl ] amino ] -2-methyl-pyrazol-3-yl ] azepan-4-yl ] acetate 489

By the procedure of example 487, from N- ((4S,5R) -1- (4- ((5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl) amino) -2-methyl-pyrazol-3-yl) -5-hydroxy-azepan-4-yl]Starting with tert-butyl carbamate, 489 was obtained as a white solid (40mg, 31% over two steps).¹H NMR(400MHz,d4-MeOD)7.64(s,1H),7.51-7.42(m,1H),7.15(t,J＝8.7Hz,2H),4.19(dt,J＝10.1,2.6Hz,1H),4.13-4.09(m,1H),3.76(s,3H),3.53(ddd,J＝13.5,9.7,3.3Hz,1H),3.35-3.20(m,2H),3.17-3.09(m,1H),2.29-2.18(m,1H),2.09-1.86(m,5H),1.78-1.69(m,1H)。LCMS(ES+)m/z506(M+1)

Example 4905-amino-2- (2, 6-difluorophenyl) -N- (5- ((4R,5R) -4, 5-dihydroxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide 490

To a solution of tert-butyl N- (2- (2, 6-difluorophenyl) -4- ((5- (4-hydroxy-5- ((4-methoxyphenyl) methoxy) azepan-1-yl) -1-methyl-pyrazol-4-yl) carbamoyl) thiazol-5-yl) carbamate (0.50g,0.73mmol) in MeOH (25mL) was added 10% Pd/C (0.20 g). The mixture was stirred at room temperature for 18 hours under a 50psi hydrogen atmosphere. Reaction byThe mixture was filtered and the filtrate was concentrated under reduced pressure to give a colorless solid. The crude solid was dissolved in DCM (10mL) and TFA (10mL) was added. The reaction mixture was stirred at room temperature for 18 h, concentrated under reduced pressure and the crude residue was dissolved in 1/1 mixture of aqueous MeOH/2M NaOH (40mL) and heated at 50 ℃ for 18 h. The reaction mixture was concentrated under reduced pressure, diluted with water (30mL) and extracted with DCM (50mL) and EtOAc (2 × 50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Preparative HPLC preparation 490 as a pale yellow solid (86mg, 25%, over two steps).¹H NMR(400MHz,d6-DMSO)8.72-8.63(m,1H),7.61-7.45(m,4H),7.31-7.23(m,2H),4.57(s,2H),3.63(s,3H),3.52(d,J＝6.5Hz,2H),3.20-3.05(m,4H),1.94-1.86(m,2H),1.74-1.64(m,2H)。LCMS(ES+)m/z465(M+1)

Example 4915-amino-N- [5- [ 4-amino-5- (trideuteromethoxy) azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2-fluorophenyl) thiazole-4-carboxamide 491

Following the procedures in examples 101 and 333, starting from trideuteromethyl iodide, 491 was obtained.¹H NMR(400MHz,DMSO)8.93(s,1H),8.30(t,J＝7.9Hz,1H),7.52(s,1H),7.50-7.27(m,5H),3.64(s,3H),3.24-3.03(m,5H),3.02-2.87(m,1H),2.13-2.01(m,1H),1.92-1.79(m,1H),1.78-1.53(m,2H)。LCMS(ES+)m/z463(M+1)

Example 4925-amino-N- [5- [ 4-amino-5- (trideuteromethoxy) azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 492

Following the procedure in examples 101 and 333, starting from a trideuteromethyl group, 492 was obtained.¹H NMR(400MHz,DMSO)8.87(s,1H),7.63-7.41(m,4H),7.26(t,J＝8.7Hz,2H),3.63(s,3H),3.25-2.98(m,5H),2.98-2.84(m,1H),2.07-1.93(m,1H),1.95-1.80(m,1H),1.79-1.63(m,1H),1.63-1.49(m,1H)。LCMS(ES+)m/z481(M+1)

Example 4935-amino-N- [5- [ (5S) -5-amino-3, 3-difluoro-azepan-1-yl ] -1- (trideuteromethyl) pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 493

Following the procedure of examples 101 and 112, 5-chloro-1-trideuteromethyl-4-nitro-1H-pyrazole was converted to 493.¹H NMR(400MHz,DMSO)8.82(s,1H),7.61-7.40(m,4H),7.28(t,J＝8.7Hz,2H),3.72-3.56(m,1H),3.50-3.33(m,1H),3.27-3.03(m,3H),2.29-2.08(m,2H),1.91-1.78(m,1H),1.78-1.46(m,3H)。LCMS(ES+)m/z487(M+1)

Example 4945-amino-N- [5- [ (5R) -5-amino-3, 3-difluoro-azepan-1-yl ] -1- (trideuteromethyl) pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 494

Following the procedure of examples 101 and 112, 5-chloro-1-trisDeuterated methyl-4-nitro-1H-pyrazole is converted to 494.¹H NMR(400MHz,DMSO)8.82(s,1H),7.60-7.40(m,4H),7.28(t,J＝8.7Hz,2H),3.72-3.55(m,1H),3.48-3.33(m,1H),3.27-3.02(m,3H),2.29-2.05(m,2H),1.90-1.78(m,1H),1.78-1.49(m,3H)。LCMS(ES+)m/z487(M+1)

Example 4955-amino-N- [5- (5-amino-3, 3-difluoro-5-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 495

To a solution of tert-butyl N- (4- ((5- (5- (tert-butoxycarbonylamino) -3, 3-difluoro-5-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl) carbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-yl) carbamate (0.36g,0.51mmol) in MeOH (5mL) was added HCl in dioxane (4M,0.02mol,5 mL). The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. Purify via SCX cartridge, wash with 1/1MeOH/DCM (250mL) followed by MeOH (250mL) and 1NNH₃Elution (in MeOH (200 mL)) gave 495 as a pale yellow foam (250mg, 87%).¹H NMR(400MHz,CDCl₃)8.92(s,1H),7.85(s,1H),7.33(tt, J ═ 8.4,6.1Hz,1H),7.07-6.99(m,2H),6.28-6.06(m,2H),3.78-3.74(m,3H),3.65-3.40(m,3H),3.29-3.20(m,1H),2.41-2.16(m,2H),1.96-1.85(m,1H),1.77(dt, J ═ 14.7,4.6Hz,1H),1.26(s, 3H). No displaceable groups were observed. LCMS (ES +) M/z498(M +1)

Example 4965-amino-N- (5- ((3S,4R) -4- (aminomethyl) -3-ethyl-4-methoxypiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 496

Following the procedure of example 101, starting from tert-butyl N- ((3-ethyl-4-methoxy-1- (2-methyl-4-nitro-pyrazol-3-yl) -4-piperidinyl) methyl) carbamate, 496 was obtained as a white solid (21mg, 33%, over three steps).¹H NMR(400MHz,CDCl₃)8.52(s,1H),7.80(s,1H),7.36-7.27(m,1H),7.07-6.97(m,2H),6.15(s,2H),3.75(s,3H),3.18(s,3H),3.20-3.03(m,4H),3.03(d,J＝13.8Hz,1H),2.91(d,J＝13.8Hz,1H),1.89-1.74(m,2H),1.72-1.45(m,5H),0.89(t,J＝7.5Hz,3H)。LCMS(ES+)m/z506(M+1)

Example 4975-amino-N- [5- (5-amino-1-oxa-8-azaspiro [3.6] decan-8-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 497

Step A solution of 5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (502mg,1.78mmol) (second eluting peak on chiral separation) in THF/water (15mL/3mL) was treated with triphenylphosphine (476mg,1.78mmol) and the reaction mixture was heated at 60 ℃ for 5H. EtOAc (100mL) was added and the mixture was saturated NaHCO₃Aqueous (20mL) wash. The aqueous layer was extracted with EtOAc (50mL) and the combined organic layers were MgSO₄Dried and concentrated under reduced pressure to give an oil. To a solution of this oil in anhydrous DCM (20mL) was added DIPEA (0.85mL,4.88mmol) and trifluoroacetic anhydride (0.29mL,2.05mmol) at 0 deg.C. The reaction mixture was warmed to room temperature and stirred for 4 hours. Water (20mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/heptane) afforded 2,2, 2-trifluoro-N- (5-hydroxy-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-yl) acetamide as a yellow oil (626mg, 88%).

Step B, to a solution of this oil in DCM was added bose-martin oxidant (1.0 eq) and sodium bicarbonate (4.0 eq). The mixture was stirred at room temperature overnight, then water and the mixture were added and extracted with DCM (100 mL). The organic layer was separated over MgSO₄Dried and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/heptane) afforded (S) -2,2, 2-trifluoro-N- (1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -5-oxoazepan-4-yl) acetamide.

Step C according to the procedure in example 448, (S) -2,2, 2-trifluoro-N- (1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -5-oxoazepan-4-yl) acetamide was converted into 2,2, 2-trifluoro-N- [ (10S) -7- (2-methyl-4-nitro-pyrazol-3-yl) -3-oxa-7-azaspiro [3.6]Decan-10-yl]An acetamide. Two peaks were obtained as single enantiomers by SFC chiral separation. Deprotection of the second eluting peak according to the procedure described in example 417 gave 497.¹HNMR(400MHz,DMSO)8.72-8.61(m,1H),7.56(s,1H),7.54-7.40(m,2H),7.25(t,J＝8.6Hz,2H),3.65(s,3H),3.44-3.33(m,2H),3.08-2.86(m,4H),2.73-2.57(m,1H),1.93-1.66(m,5H),1.66-1.53(m,1H)。LCMS(ES+)m/z490(M+1)

Example 4985-amino-N- [5- (5-amino-1-oxa-8-azaspiro [3.6] decan-8-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 498

In the preparation of 497, 2,2, 2-trifluoro-N- [ (10S) -7- (2-methyl-4-nitro-pyrazol-3-yl) -3-oxa-7-azaspiro [3.6] chiral separated from SFC]Decan-10-yl]The first eluting peak of acetamide was converted to 498.¹H NMR(400MHz,DMSO)8.67(s,1H),7.60-7.41(m,3H),7.25(t,J＝8.6Hz,2H),3.65(s,3H),3.44-3.33(m,2H),3.08-2.86(m,4H),2.65-2.54(m,1H),1.91-1.69(m,5H),1.65-1.50(m,1H)。LCMS(ES+)m/z490(M+1)

Example 4995-amino-N- (5- ((1R,5R,6S) -6-amino-8-oxa-3-azabicyclo [3.2.1] oct-3-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 499

By operating according to example 101 from N- [3- (2-methyl-4-nitro-pyrazol-3-yl) -8-oxa-3-azabicyclo [3.2.1]]Oct-6-yl]Starting with tert-butyl carbamate, 499 was obtained as a formate salt as an off-white solid (12mg, 28%, over three steps).¹H NMR(400MHz,CDCl₃)8.41(s,1H),8.10(s,1H),7.75(s,1H),7.38-7.29(m,1H),7.08-6.97(m,2H),6.14(s,2H),4.53(d, J ═ 7.2Hz,1H),4.00(s,1H),3.87(d, J ═ 7.8Hz,1H),3.77(s,3H),3.51-3.40(m,2H),2.86(d, J ═ 11.2Hz,1H),2.68-2.53(m, 3H). No alkyl NH was observed₂。LCMS(ES+)m/z462(M+1)

EXAMPLE 5005-amino-N- [5- [ 5-amino-4-hydroxy-4- (2-hydroxyethyl) azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 500

Step A5-azido-1- (1-methyl-4-nitro-1H-pyrazol-5-yl) azepan-4-ol (502mg,1.78mmol) (first eluting peak on chiral separation) was converted to (R) -2,2, 2-trifluoro-N- (1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -5-oxoazepan-4-yl) acetamide according to the procedure in example 498.

Step B (R) -2,2, 2-trifluoro-N- (1- (1-methyl-4-nitro-1H-pyrazol-5-yl) -5-oxoazepan-4-yl) acetamide was converted to 2,2, 2-trifluoro-N- [ (10R) -7- (2-methyl-4-nitro-pyrazol-3-yl) -3-oxa-7-azaspiro [3.6] according to the procedure in example 448]Decan-10-yl]An acetamide. Two peaks were obtained as single enantiomers by SFC chiral separation. The first eluting peak was converted to 500 (oxetane ring-opened product) according to the procedure described in example 448 and the trifluoroacetamide deprotection procedure described in example 417.¹H NMR(400MHz,DMSO)9.14(s,1H),8.21(s,1H),7.61-7.41(m,4H),7.25(t,J＝8.6Hz,2H),3.64(s,3H),3.47-3.37(m,2H),3.22-2.83(m,5H),2.72(s,1H),2.34-2.17(m,2H),1.94-1.82(m,1H),1.82-1.59(m,2H),1.59-1.37(m,2H)。LCMS(ES+)m/z508(M+1)

Example 5015-amino-N- [5- (5-amino-1-oxa-8-azaspiro [3.6] decan-8-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 501

Following the procedure in example 498, 2,2, 2-trifluoro-N- [ (10S) -7- (2-methyl-4-nitro-pyrazol-3-yl) -3-oxa-7-azaspiro [3.6] leaving the SFC chiral separation]Decan-10-yl]The second eluting peak of acetamide was converted to 501.¹H NMR(400MHz,DMSO)8.67(s,1H),8.39(s,1H),7.61-7.38(m,4H),7.26(t,J＝8.7Hz,2H),3.66(s,3H),3.52-3.17(m,2H),3.12-2.93(m,4H),2.92-2.78(m,1H),2.00-1.77(m,5H),1.72-1.57(m,1H)。LCMS(ES+)m/z490(M+1)

Example 5025-amino-N- [5- (5-amino-4-methoxy-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 502

Chiral separation of racemic mixture N- [1- [4- [ [5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl by SFC]Amino group]-2-methyl-pyrazol-3-yl]-5-methoxy-5-methyl-azepan-4-yl]Tert-butyl carbamate was then deprotected with 4N HCl (in dioxane) to give 502 as a single enantiomer.¹H NMR(400MHz,DMSO)9.56(s,1H),7.68(s,1H),7.61-7.43(m,3H),7.26(t,J＝8.6Hz,2H),3.61(s,3H),3.18-3.05(m,3H),3.02(s,3H),2.91(t,J＝8.2Hz,1H),2.15-2.02(m,1H),1.96-1.82(m,1H),1.78-1.63(m,1H),1.55-1.40(m,1H),1.18(s,3H)。LCMS(ES+)m/z492(M+1)

Example 5035-amino-N- [5- (5-amino-4-methoxy-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 503

Chiral separation of racemic mixture N- [1- [4- [ [5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl by SFC]Amino group]-2-methyl-pyrazol-3-yl]-5-methoxy-5-methyl-azepan-4-yl]Tert-butyl carbamate was then deprotected with 4N HCl (in dioxane) to give 503 as a single enantiomer.¹H NMR(400MHz,DMSO)9.54(s,1H),7.68(s,1H),7.60-7.41(m,3H),7.26(t,J＝8.6Hz,2H),3.61(s,3H),3.18-3.05(m,3H),3.01(s,3H),2.92(d,J＝7.1Hz,1H),2.13-2.00(m,1H),1.96-1.81(m,1H),1.76-1.62(m,1H),1.56-1.40(m,1H),1.19(s,3H)。LCMS(ES+)m/z492(M+1)

EXAMPLE 5045-amino-N- [5- (5-amino-4-methoxy-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 504

Chiral separation of racemic mixture N- [5- [4- [ [5- (tert-butoxycarbonylamino) -2- (2-fluorophenyl) thiazole-4-carbonyl ] by SFC]Amino group]-2-methyl-pyrazol-3-yl]-2-methoxy-cycloheptyl]T-butyl carbamate was then deprotected with 4N HCl (in dioxane) to give 504 as a single enantiomer.¹H NMR(400MHz,DMSO)8.88(s,1H),8.32(s,1H),7.52(s,1H),7.49-7.26(m,4H),7.03-6.91(m,1H),6.70-6.58(m,1H),3.76(s,3H),3.24(s,3H),3.17-3.10(m,1H),3.02-2.91(m,1H),2.27-2.12(m,1H),2.07-1.84(m,3H),1.76-1.62(m,2H),1.57-1.42(m,3H)。LCMS(ES+)m/z459(M+1)

Example 5055-amino-N- [5- (5-amino-4-methoxy-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 505

Chiral separation of racemic mixture N- [5- [4- [ [5- (tert-butoxycarbonylamino) -2- (2-fluorophenyl) thiazole-4-carbonyl ] by SFC]Amino group]-2-methyl-pyrazol-3-yl]-2-methoxy-cycloheptyl]T-butyl carbamate was then deprotected with 4N HCl (in dioxane) to give 505 as a single enantiomer.¹H NMR(400MHz,DMSO)8.89(s,1H),8.27(s,1H),7.53-7.24(m,5H),7.03-6.91(m,1H),6.67-6.51(m,1H),3.75(s,3H),3.24(s,3H),3.12-2.93(m,2H),2.00-1.61(m,7H),1.58-1.39(m,2H)。LCMS(ES+)m/z459(M+1)

Example 5065-amino-N- [5- (5-amino-4-methoxy-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 506

Chiral separation of racemic mixture N- [5- [4- [ [5- (tert-butoxycarbonylamino) -2- (2-fluorophenyl) thiazole-4-carbonyl ] by SFC]Amino group]-2-methyl-pyrazol-3-yl]-2-methoxy-cycloheptyl]T-butyl carbamate was then deprotected with 4N HCl (in dioxane) to give 506 as a single enantiomer.¹H NMR(400MHz,DMSO)8.89(s,1H),8.27(s,1H),7.55-7.24(m,5H),7.05-6.91(m,1H),6.67-6.54(m,1H),3.75(s,3H),3.24(s,3H),3.12-2.96(m,2H),1.97-1.62(m,7H),1.60-1.36(m,2H)。LCMS(ES+)m/z459(M+1)

Example 5075-amino-N- [5- (5-amino-4-methoxy-4-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 507

Chiral separation of racemic mixture N- [5- [4- [ [5- (tert-butoxycarbonylamino) -2- (2-fluorophenyl) thiazole-4-carbonyl ] by SFC]Amino group]-2-methyl-pyrazol-3-yl]-2-methoxy-cycloheptyl]Tert-butyl carbamate was then deprotected with 4N HCl (in dioxane) to give 507 as a single enantiomer.¹H NMR(400MHz,DMSO)8.87(s,1H),8.33(s,1H),7.52(s,1H),7.48-7.26(m,4H),7.02-6.89(m,1H),6.66-6.55(m,1H),3.76(s,3H),3.24(s,3H),3.17-3.07(m,1H),3.02-2.89(m,1H),2.26-2.09(m,1H),2.12-1.86(m,3H),1.77-1.60(m,2H),1.61-1.40(m,3H)。LCMS(ES+)m/z459(M+1)

Example 5085-amino-N- [5- (2, 6-diazaspiro [3.5] non-6-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 508

Step A5-chloro-1-methyl-4-nitro-pyrazole (0.16 g; 0.99mmol) and tert-butyl 2, 8-diazaspiro [3.5] nonane-2-carboxylate (0.2 g; 0.88mmol) were suspended in butan-1-ol (2mL) followed by the addition of DIPEA (0.7 mL; 3.9616 mmol). The reaction mixture was heated at 120 ℃ for 2 days. All solvents were evaporated and the crude mixture was purified on silica gel eluting with a gradient of 0-30% ethyl acetate/dichloromethane. Tert-butyl 6- (1-methyl-4-nitro-1H-pyrazol-5-yl) -2, 6-diazaspiro [3.5] nonane-2-carboxylate (200mg) was obtained as a yellow oil in 57% yield. MS (ESI) M/z 352.2[ M + H + ].

Step B tert-butyl 8- (2-methyl-4-nitro-pyrazol-3-yl) -2, 8-diazaspiro [3.5] nonane-2-carboxylate (200mg,0.57mmol) was dissolved in methanol (20 mL). The solution was subjected to hydrogenation using H-Cube through a Pd/C cartridge at 50 ℃ under a hydrogen pressure of 50bar and a flow rate of 1 mL/min. The reaction was completed after four cycles through the system (flow rate 1 mL/min, 80 min). After evaporation, the desired product, tert-butyl 6- (4-amino-1-methyl-1H-pyrazol-5-yl) -2, 6-diazaspiro [3.5] nonane-2-carboxylate (184mg, 100%) was obtained as a light brown solid. MS (ESI) M/z 322.3[ M + H + ].

Step C5- (tert-Butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carboxylic acid (224.4mg,0.63mmol) was suspended in dichloromethane (2mL), followed by the addition of HATU (269.3mg,0.69mmol), DIPEA (299.0mg,2.3mmol) and 8- (4-amino-2-methyl-pyrazol-3-yl) -2, 8-diazaspiro [3.5]]Nonane-2-carboxylic acid tert-butyl ester (184mg,0.57mmol) (in dichloromethane (2 mL)). The suspension was stirred at room temperature for 16 hours. Saturated NaHCO₃(5mL) was added to the reaction mixture. After separation, the aqueous layer was extracted with dichloromethane (5mL × 2). The combined organic layers were washed with Na₂SO₄Dried, filtered and evaporated. The resulting crude mixture was purified on a silica gel column eluting with a gradient of 0-6% methanol in dichloromethane. White solid (336mg, 89%) was obtained as the desired product, 6- (4- (5- ((tert-butoxycarbonyl) amino) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide) -1-methyl-1H-pyrazol-5-yl) -2, 6-diazaspiro [ 3.5%]Nonane-2-carboxylic acid tert-butyl ester. MS (ESI) M/z 674.5[ M + Na +].

Step D8- [4- [ [5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) thiazole-4-carbonyl]Amino group]-2-methyl-pyrazol-3-yl]-2, 8-diazaspiro [3.5]Tert-butyl nonane-2-carboxylate (336mg,0.51mmol) was dissolved in methanol (2mL) and dichloromethane (2mL), followed by the addition of 4M hydrogen chloride (in 1, 4-dioxane (2 mL)). The solution was stirred at room temperature for 16 hours. After evaporation, the crude mixture was obtained as an off-white solid (345 mg). The crude mixture was purified by reverse phase HPLC to give 508 as a white solid (66mg, 28%).¹H NMR(400MHz,DMSO-d6)8.70(s,1H),7.55-7.45(m,4H),7.26(t,J＝8.8Hz,2H),3.66(s,3H),3.54(s,1H),3.22(s,4H),3.12(s,2H),2.94(t,J＝5.3Hz,2H),1.68-1.60(m,2H),1.58-1.50(m,2H)。MS(ESI)m/z:460.2[M+H+]。

Example 5095-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- ((3aR,8aS) -3 a-methyl-2-oxotetrahydro-2H-oxazolo [5,4-d ] azepin-6 (7H,8H,8aH) -yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide 509

3 a-methyl-6- (2-methyl-4-nitro-pyrazol-3-yl) -3,4,5,7,8,8 a-hexahydroxyoxazolo [4,5-d ] under nitrogen]A solution of azepin-2-one (195mg,0.66mmol) and 1-methyl-1, 4-cyclohexadiene (0.52mL,4.60mmol) in MeOH (10mL) was added 10% palladium on carbon (35mg,0.33mmol) and the mixture was heated at 60 deg.C for 2 h. TLC indicated a major starting material so the catalyst was filtered off and fresh 10% palladium on carbon (35mg,0.33mmol) was added. The mixture was heated at 65 ℃ for 16 hours. TLC indicated that the starting material was predominant, so the catalyst was filtered off, the volume reached 14mL of MeOH and the mixture was passed through(perhydro mode, 75 ℃, flow rate: 1 mL/min, 30mm 10% Pd/C). The solvent was removed under reduced pressure to give crude amino-pyrazole (175 mg). A solution of HATU (351mg,0.92mmol) and 5- (tert-butoxycarbonylamino) -2- (2, 6-difluorophenyl) -thiazole-4-carboxylic acid (259mg,0.73mmol) in DMF (5mL) was stirred at room temperature for 30 min. A solution of crude amino-pyrazole (175mg,0.66mmol) and DIPEA (0.18mL,1.06mmol) in DMF (5mL) was added and the mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue triturated with DCM then MeOH. The resulting solid was suspended in DMSO (3mL) and methanol (5mL), a solution of HCl in dioxane (4M,15mL) was added and the mixture was stirred at 50 ℃ for 16 hours. The volatile solvents were removed under reduced pressure and the remaining DMSO solution was subjected to purification via preparative HPLC to give 509 as a yellow solid (13mg, 4% over three steps).¹H NMR(400MHz,d6-DMSO)8.78(s,1H),7.66(s,1H),7.57-7.47(m,4H),7.27(t,J＝8.8Hz,2H),4.45(dd,J＝6.8,3.8Hz,1H),4.02(s,1H),3.66(s,3H),3.31-3.29(m,1H),3.23-3.15(m,1H),3.07-2.95(m,2H),2.09-2.02(m,2H),1.90(t,J＝5.1Hz,2H),1.30(s,3H)。LCMS(ES+)m/z504(M+1)

Example 5105-amino-N- [5- (5-amino-1-oxa-8-azaspiro [3.6] decan-8-yl) -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 510

To N- [2- (2, 6-difluorophenyl) -4- [ [ 1-methyl-5- [ (10R) -10- [ (2,2, 2-trifluoroacetyl) amino group]-3-oxa-7-azaspiro [3.6]Decan-7-yl]Pyrazol-4-yl]Carbamoyl radical]Thiazol-5-yl]To a solution of tert-butyl carbamate (30mg,0.044mmol) in methanol (2mL) and water (2mL) was added potassium carbonate (67mg,0.48 mmol). The mixture was heated at 65 ℃ for 8 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted 3x with EA. The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated. The residue was stirred with DCM (4mL) and TFA (2mL) for 20 min and concentrated under reduced pressure to saturate NaHCO₃Basified and extracted with ethyl acetate (3 ×). The combined organic layers were over MgSO₄The solvent was removed under reduced pressure by drying and the residue was purified by preparative HPLC to give 510. LCMS (ES +) M/z490(M +1).

Example 5115-amino-N- [5- [ 4-amino-5- (difluoromethyl) azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 511

Step A (methoxymethyl) triphenylphosphonium chloride (5.59g,15.8mmol) (dried overnight under vacuum before use) was suspended in diethyl ether (65 mL). The suspension was cooled to-15 ℃. Potassium tert-butoxide (1.0mol/L) (12.6mL,12.6mmol) in THF was added slowly and the bright orange suspension was stirred at-25 ℃ ester-10 ℃ for 1 hour while maintaining the color. 2,2, 2-trifluoro-N- [ (4R) -1- (2-methyl-4-nitro-pyrazol-3-yl) -5-oxo-azepan-4-yl ] acetamide (1.38g,3.95mmol) was dissolved in THF (12mL) and added to the ylide at-15 ℃. The mixture was slowly warmed to room temperature and stirred overnight then quenched with saturated aluminum chloride and quenched 3x with EA. The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (0-100% EA/heptane) to give 2,2, 2-trifluoro-N- [ (4R) -5- (methoxymethylene) -1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl ] acetamide.

Step B to a solution of 2,2, 2-trifluoro-N- [ (4R) -5- (methoxymethylene) -1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl ] acetamide (1060mg,2.81mmol) in chloroform (90mL) was added trichloroacetic acid (1.84g,11.24 mmol). The mixture was heated at 70 ℃ overnight and another portion of trichloroacetic acid (1.84g,11.24mmol) was added and heating continued for 6 hours. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate and extracted 3x with DCM. The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (0-100% EA/heptane) to give 2,2, 2-trifluoro-N- [ (4R) -5-formyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl ] acetamide (896mg, 88%).

Step C of adding 2,2, 2-trifluoro-N- [ (4R) -5-formyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl]A solution of acetamide (190mg,0.52mmol) in DCM (5mL) was slowly added DEOXO-FLUOR (R) (1.16g,2.62mmol,50 mass% in toluene). The mixture was stirred at room temperature for 1.5 h, with saturated NaHCO₃Quench and extract 3x with DCM. The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (0-100% EA/heptane) to give N- [ (4R) -5- (difluoromethyl) -1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl]-2,2, 2-trifluoro-acetamide (121mg, 60%). Chiral separation of the compound by SFC gives two single enantiomers. Chiral separation of N- [ (4R) -5- (difluoromethyl) -1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl from SFC]The first eluting peak of-2, 2, 2-trifluoro-acetamide was converted to 511 according to the procedure described in example 497. LCMS (ES +) M/z498(M +1)

Example 5125-amino-N- [5- [ 4-amino-5- (difluoromethyl) azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 512

N- [ (4R) -5- (difluoromethyl) -1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl chirally separated from SFC according to preparation 511]-a second eluent of 2,2, 2-trifluoro-acetamide is converted to 512.¹H NMR(400MHz,DMSO)8.72(s,1H),7.60-7.36(m,4H),7.30-7.17(m,2H),6.30(t,J＝58.2Hz,1H),3.64(s,3H),3.29-3.21(m,2H),3.21-3.05(m,3H),2.92-2.79(m,1H),2.05-1.87(m,2H),1.79-1.55(m,4H)。LCMS(ES+)m/z498(M+1)

Example 5135-amino-N- [5- [ 4-amino-5- (hydroxymethyl) azepan-1-yl ] -1-methyl-pyrazol-4-yl ] -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 513

Step A in preparation of 511, 2,2, 2-trifluoro-N- [ (4R) -5-formyl-1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl]Acetamide (192mg,0.53mmol) was dissolved in methanol (5mL) and cooled in an ice bath. Sodium borohydride (41mg,1.06mmol) was added, warmed to room temperature, and stirred for 40 minutes. The reaction was saturated NaHCO₃Quench and extract 3x with EA. The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (0-100% EA/heptane) to give 2,2, 2-trifluoro-N- [ (4R) -5- (hydroxymethyl) -1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl]Acetamide (120mg, 62%).

Step B2, 2, 2-trifluoro-N- [ (4R) -5- (hydroxymethyl) -1- (2-methyl-4-nitro-pyrazol-3-yl) azepan-4-yl]Acetamide is converted to 513.¹H NMR(400MHz,DMSO)8.72(s,1H),7.60-7.36(m,4H),7.30-7.17(m,2H),6.30(t,J＝58.2Hz,1H),3.64(s,3H),3.29-3.21(m,2H),3.21-3.05(m,3H),2.92-2.79(m,1H),2.05-1.87(m,2H),1.79-1.55(m,4H)。LCMS(ES+)m/z478(M+1)

Example 5165-amino-N- (5- ((8R,9S) -8-amino-9-methoxy-5-azaspiro [ 2.6)]Nonan-5-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 516

Following the procedure of example 101, from N- [ 9-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6 ]]Non-8-yl]Starting with tert-butyl carbamate, 516 was obtained as a white solid (10mg, 58%, over three steps).¹HNMR(400MHz,CDCl₃)8.77(s,1H),7.94(s,1H),7.38-7.28(m,1H),7.08-6.98(m,2H),6.17(s,2H),3.77(dd,J＝12.7,1.7Hz,1H),3.71(s,3H),3.45(s,3H),3.43-3.37(m,1H),3.19-3.12(m,2H),2.65(d,J＝2.3Hz,1H),2.26(d,J＝12.7Hz,1H),2.12-2.00(m,1H),1.79-1.70(m,1H),0.68-0.62(m,1H),0.60-0.43(m,3H). No alkyl NH was observed₂。LCMS(ES+)m/z504(M+1)

Example 5175-amino-N- (5- ((8R,9S) -9-amino-8-methoxy-5-azaspiro [ 2.6)]Nonan-5-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 517

Following the procedure of example 101, from N- [ 8-methoxy-5- (2-methyl-4-nitro-pyrazol-3-yl) -5-azaspiro [2.6 ]]Non-9-yl]Starting with tert-butyl carbamate, 517 was obtained as a white solid (5mg, 51% over three steps).¹HNMR(400MHz,CDCl₃)9.77(s,1H),8.02(s,1H),7.38 to 7.28(m,1H),7.07 to 6.97(m,2H),6.24(s,2H),3.97(d, J ═ 13.2Hz,1H),3.69(s,3H),3.58 to 3.50(m,1H),3.34 to 3.25(m,1H),3.22(s,3H),3.23 to 3.15(m,1H),2.57(d, J ═ 2.8Hz,1H),2.31 to 2.16(m,2H),1.85 to 1.78(m,1H),0.64 to 0.53(m,2H),0.49 to 0.41(m,1H),0.39 to 0.32(m,1H), no alkyl group was observed₂。LCMS(ES+)m/z504(M+1)

Example 518(R) -5-amino-N- (5- (5-amino-3, 3-difluoro-5-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 518

To N- (4- ((5R- (5- (tert-butoxycarbonylamino) -3, 3-difluoro-5-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl) carbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-yl]Tert-butyl carbamate (205mg,0.294mmol) solution in MeOH (10mL) was added HCl in dioxane (4M,0.04mol,10 mL). The reaction mixture was stirred at 40 ℃ for 1 hour and concentrated under reduced pressure to give 518 as the hydrochloride salt as a light brown solid (145mg, 92%).¹H NMR(400MHz,d₆-DMSO)8.81(s,1H),8.39(br s,3H),7.65-7.53(m,1H),7.51(s,1H),7.35-7.20(m,2H),3.90-3.75(m,1H),3.74-3.60(m,4H),3.55-3.42(m,2H),3.40-3.30(m,1H),3.25-3.10(m,1H),2.70-2.45(m,2H),2.35-2.15(m,1H),2.00-1.85(m,1H),1.48(s,3H)。LCMS(ES+)m/z498(M+1)

Example 526(S) -5-amino-N- (5- (5-amino-3, 3-difluoro-5-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide 526

Following the procedure of example 520, from N- (4- ((5S- (5- (tert-butoxycarbonylamino) -3, 3-difluoro-5-methyl-azepan-1-yl) -1-methyl-pyrazol-4-yl) carbamoyl) -2- (2, 6-difluorophenyl) thiazol-5-yl]Starting with tert-butyl carbamate, 526 was obtained as the hydrochloride salt as a light brown solid (147mg, 98%).¹H NMR(400MHz,d₆-DMSO)8.81(s,1H),8.37(br s,3H),7.65-7.53(m,1H),7.52(s,1H),7.35-7.20(m,2H),3.90-3.75(m,1H),3.74-3.65(m,4H),3.60-3.42(m,2H),3.40-3.30(m,1H),3.25-3.10(m,1H),2.70-2.45(m,2H),2.35-2.15(m,1H),2.00-1.85(m,1H),1.46(s,3H)。LCMS(ES+)m/z498(M+1)

Example 901Pim kinase binding Activity

PIM-1, -2 and-3 enzymes were generated as fusion proteins expressed in bacteria and purified by IMAC column chromatography (Sun, X., Chiu, J.F., and He, Q.Y. (2005) Expertrev. proteomics,2: 649-one 657). Fluorescently labeled Pim-specific Peptide substrates were custom synthesized by the American Peptide Company (Sunnyvale, Calif.). The reaction buffer contained 10mM HEPES, pH7.2,10mM MgCl₂0.01% Tween20,2mM DTT. The stop buffer contained 190mM HEPES, pH7.2, 0.015% Brij-35, 0.2% coating reagent 3(Caliper Life Sciences, Hopkinton, Mass.), 20mM EDTA. The isolation buffer contained 100mM HEPES, pH7.2, 0.015% Brij-35, 0.1% coating reagent 3,1:200 coating reagent 8(Caliper Life Sciences, Hopkinton, Mass.), 10mM EDTA and 5% DMSO.

The PIM reaction was performed in 384 well plates at a final volume of 10 μ L/well. A standard enzymatic reaction was initiated by adding 5. mu.L of 2X ATP and test compound to 5. mu.L of 2 Xase and FAM-peptide (containing 20pM PIM1,50pM PIM2 or 55pMPIM3, 1. mu.M FAM-peptide, and 10. mu.M ATP in buffer). After 90 min incubation at room temperature, the phosphorylation reaction was stopped by adding 10. mu.L of stop buffer.The product and substrate in each individual reaction were applied to a 12-pipette microfluidic chip (Caliper Life sciences, Hopkinton, Mass.) (in Caliper)(run on Caliper Life Sciences, Hopkinton, Mass.). The separated product and substrate were optimized by selecting voltage and pressure using Caliper's Optimizer software (Hopkinton, MA). The separation conditions used a downstream voltage of-500V, an upstream voltage of-2150V, and a screening pressure of-1.2 psi. The product and substrate fluorophores are excited at 488nm and detected at 530 nm. Substrate conversion was calculated from the electropherograms using HTS WellAnalyzer software (Caliper Life Sciences, Hopkinton, MA). The Ki values of the test compounds were calculated. Representative PIM1LC of exemplary Compounds₃K Ki (unit: micromolar) is shown in Table 1.

Example 902In vitro cell proliferation efficacy test

BaF₃Parental lines were obtained from the DSMZ library. Generation of BaF transfected with PIM1 or PIM2₃Is described. Mouse IL-3 from R&DSystems. G418 was purchased from Clontech. BaF₃Parental lines medium containing RPMI, 10% FBS,2mM L-glutamine, 2ng/mL mIL-3. BaF₃PIM1&Line 2 vehicle contains RPMI, 10% FBS,2mM L-glutamine, 250. mu.g/mL. The medium of the MM1.S (multiple myeloma cell) line contained RPMI, 10% FBS,2mM L-glutamine.

BaF₃Murine interleukin-3 dependent pre-B cell line, parental cell, BaF₃PIM1 cells, BaF₃PIM2 cells, and mm1.s (multiple myeloma) cells were seeded at 2 k/well, 5 k/well, and 10 k/well, 45 μ L/well, respectively, in 384-well plates. At 5. mu.L/well. Test Compound addition BaF₃Cells (parental and transfection) were incubated overnight while MM1.S cells were incubated at 37 ℃ in 5% CO₂Incubate for 72 hours. CELL TITER was added at 50. mu.L/wellReagent (Promega), respective plate temperatureIncubate for 30 min and take their luminescence readings on HT analysts. Calculating IC of test Compound₅₀/EC₅₀The value is obtained.

Representative compounds of the invention were tested as described above and found to exhibit Ki/IC as shown in tables 2a and 2b below₅₀/EC₅₀。

Table 2a.

Table 2b.

The words "comprise," "comprising," "include," and "including" when used in this specification and the appended claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the description and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific documents cited in this application are expressly incorporated by reference in their entirety.

Claims (4)

1. A compound selected from:

5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (4- ((methylamino) methyl) piperidin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (3-methylpiperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(S) -5-amino-N- (5- (3-aminoazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-N- (5- (3-aminoazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

5-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4- (methylamino) azepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4- (methylamino) azepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4- (methylamino) azepan-1-yl) -1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (2-methylpiperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2-ethylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2-ethylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-N- (5- (4-aminoazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-cyclopropyl-2, 6-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-N- (5- (4-aminoazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluoro-3-methylphenyl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (3-methylpiperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

(S) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4- (methylamino) azepan-1-yl) -1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

5-amino-N- (5- (4-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3S,5S) -5-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (2-methylpiperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (2, 8-diazaspiro [4.5] decan-8-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-N- (5- (4-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3R,5R) -5-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3S,5R) -3-amino-5-fluoropiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

N- (5- (1, 4-diazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -5-amino-2- (2, 6-difluorophenyl) thiazole-4-carboxamide

N- (5- (1, 4-diazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -5-amino-2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

N- (5- (1, 4-diazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -5-amino-2- (2, 5-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-2- (2-fluorophenyl) -N- (5- (4-hydroxy-4-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(S) -5-amino-2- (2-fluorophenyl) -N- (5- (4-hydroxy-4-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (6-methyl-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (6-methyl-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(S) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(S) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

(R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2, 4-dimethylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2, 4-dimethylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-N- (1-cyclopropyl-5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (1-cyclopropyl-5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

5-amino-N- (1-cyclopropyl-5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluorophenyl) -N- (5- (4-hydroxy-4-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(S) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (4-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4R,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-fluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-N- (5- (4-aminoazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3S,5R) -5-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3R,5S) -5-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3R,4S) -4-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3S,4R) -4-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3R,4R) -4-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3S,4S) -4-amino-3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3R,5R) -3-amino-5-fluoropiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-N- (5- (4-aminoazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluorophenyl) -N- (5- (4-hydroxyazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-2- (2-fluoro-5-methylphenyl) -N- (5- (4-hydroxyazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-N- (5- (4-aminoazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-fluoro-1, 4-diazepan-1-yl) -1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (3- (trifluoromethyl) piperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (3- (trifluoromethyl) piperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(S) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (3-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-N- (1- (2, 2-difluoroethyl) -5- (3-hydroxyazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (1- (2, 2-difluoroethyl) -5- (6-hydroxy-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2-methylpiperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2-methylpiperazin-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2-ethyl-4-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (2-ethyl-4-methylpiperazin-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-2- (2-fluoro-5-methylphenyl) -N- (5- (4-hydroxy-4-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-N- (1- (2, 2-difluoroethyl) -5- (6-fluoro-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(R) -3-amino-N- (5- (4-aminoazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -6- (2-fluorophenyl) picolinamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-hydroxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-hydroxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-N- (5- (3, 3-difluoro-5- (methylamino) azepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3R,5S) -3-amino-5-fluoropiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-N- (5- (4-aminoazepan-1-yl) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

N- (5- (1, 4-diazepan-1-yl) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -5-amino-2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- (4-amino-5-hydroxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- (3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3S,5S) -3-amino-5-fluoropiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-hydroxy-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-fluoro-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-methoxy-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-methoxy-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (4- (2,2, 2-trifluoroethylamino) azepan-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

3-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) picolinamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-hydroxy-3-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-N- (5- (4- (2, 2-difluoroethylamino) azepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (5-methyl-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-fluoro-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-hydroxy-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-hydroxy-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (6-fluoro-6-methyl-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

3-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide

5-amino-2- (2, 6-difluorophenyl) -N- (5- (5- (dimethylamino) -3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-N- (5- (5-amino-3-methoxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5S) -4-amino-5-methoxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (pyridin-2-yl) thiazole-4-carboxamide

5-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (5-methyl-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (5-methyl-1, 4-diazepan-1-yl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-hydroxy-3-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-hydroxy-3-methylazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide

3-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) picolinamide

3-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-methylpiperazin-1-yl) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) pyrimidine-4-carboxamide

5-amino-N- (5- (6, 6-difluoro-1, 4-diazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) pyrimidine-4-carboxamide

5-amino-2- (2-fluoro-phenyl) -pyrimidine-4-carboxylic acid [5- (5-amino-3, 3-difluoro-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (1-methyl-5- (3- (trifluoromethyl) piperidin-1-yl) -1H-pyrazo l-4-yl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [ 1-methyl-5- (3-trifluoromethyl-piperidin-1-yl) -1H-pyrazol-4-yl ] -amide

3-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide

3-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide

3-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) picolinamide

3-amino-N- (5- (4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) picolinamide

(S) -3-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide

(R) -3-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide

(S) -3-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) picolinamide

(R) -3-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) picolinamide

5-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid (1-oxetan-3-ylmethyl-5-piperazin-1-yl-1H-pyrazol-4-yl) -amide

5-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide

5-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3-hydroxy-3-methyl-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide

5-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3-fluoro-3-methyl-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide

5-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (3-fluoro-5-hydroxy-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide

5-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [ 1-methyl-5- (3-trifluoromethyl-piperidin-1-yl) -1H-pyrazol-4-yl ] -amide

(S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (pyridin-2-yl) thiazole-4-carboxamide

(R) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (pyridin-2-yl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (pyridin-2-yl) thiazole-4-carboxamide

(S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxamide

5-amino-N- (5- ((4R,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4R,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4R,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

(R) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxamide

5-amino-N- (5- ((4R,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (pyridin-2-yl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluoro-3-iodo-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3, 3-difluoro-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide

5-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3, 3-difluoro-azepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl ] -amide

(R) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -2, 2-difluoroethyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

(S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -2, 2-difluoroethyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

(S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

(R) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

(S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

((R) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

(S) -5-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide

5-amino-2- (2-fluoro-phenyl) -thiazole-4-carboxylic acid [5- ((R) -5-amino-3, 3-difluoro-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide

5-amino-N- (5- ((4S,5S) -4-amino-5-methoxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4R,5R) -4-amino-5-methoxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (5- (dimethylamino) -3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

(R) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (5- (dimethylamino) -3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide

3-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) picolinamide

3-amino-N- (5- (5-amino-3, 3-difluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -6- (2-fluorophenyl) pyrazine-2-carboxamide

5-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluoro-5-methylphenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 5-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (3-fluoropyridin-2-yl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5S) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (pyridin-2-yl) thiazole-4-carboxamide

5-amino-2- (3-fluoro-pyridin-2-yl) -thiazole-4-carboxylic acid [5- (5-amino-3, 3-difluoro-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide

5-amino-2-pyridin-2-yl-thiazole-4-carboxylic acid [5- (5-amino-3, 3-difluoro-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide

(S) -5-amino-2- (2, 6-difluorophenyl) -N- (5- (3-methylpiperazin-1-yl) -1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (3-amino-azepan-1-yl) -1- (2,2, 2-trifluoro-ethyl) -1H-pyrazol-4-yl ] -amide

5-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (3, 3-difluoro-5-hydroxy-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide

5-amino-N- (5- ((4S,5R) -4-amino-5-methoxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3R,5R) -5-amino-3-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3S,5S) -5-amino-3-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3S,5R) -5-amino-3-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((3R,5S) -5-amino-3-fluoroazepan-1-yl) -1-cyclopropyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-N- (5- ((4S,5R) -4-amino-5-hydroxyazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide

5-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3-methoxy-3-methyl-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide

5-amino-2- (2, 6-difluoro-phenyl) -thiazole-4-carboxylic acid [5- (5-amino-3-hydroxy-3-methyl-azepan-1-yl) -1-methyl-1H-pyrazol-4-yl ] -amide.

2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient, further comprising a chemotherapeutic agent.

3. The pharmaceutical composition of claim 2, for treating a disease or disorder selected from: cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.

4. The use of a compound of claim 1 in the manufacture of a medicament for the treatment of: cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, wherein the drug mediates Pim kinase.