CN107406427A - Alkynyl alcohols and methods of use thereof - Google Patents

Abstract

The invention relates to compounds of formula (I), wherein Q, A¹‑A⁸、R⁴And R⁵As defined herein. The compounds of formula (I) and pharmaceutical compositions thereof are useful in the treatment of diseases and disorders in which undesired or excessive activation of NF-kB signaling is observed.

Description

Alkynyl alcohols and methods of use thereof

Cross References to Related Applications

This application claims the benefit under 35 U.S.C. §119(a) of the international application PCT/CN2015/077176 filed on February 25, 2015, which is incorporated herein by reference in its entirety.

field of invention

The present invention relates to organic compounds useful in the treatment or prevention of mammals, in particular to NF-kB-inducible kinase (NIK) inhibitors useful in the treatment of cancer and inflammatory disorders.

Background of the invention

NF-kB-inducible kinase (NIK), also known as MAPK kinase kinase 14 (MAP3K14), is a serine/threonine kinase and a member of the MAPK family. It was originally identified as a binding partner of TNF receptor (TNFR)-associated factor 2 (TRAF2) in a two-hybrid screen [see Malinin, NL, et al., Nature, 1997, 385:540-4]. NIK overexpression leads to NF-kB activation, and a dominant-negative form of NIK lacking kinase activity is able to suppress NF-kB activation in response to TNF and IL-1 treatment. Thus, NIK has been identified as an important component of the NF-kB signaling pathway. Scientific research has demonstrated that blocking the NF-kB signaling pathway in cancer cells can cause such cells to stop proliferating to die, or to become more sensitive to other anticancer treatments. In addition, studies have demonstrated that NF-kB controls the expression of many genes involved in inflammation, and NF-kB signaling is found in many inflammatory disorders, such as lupus (including systemic lupus erythematosus), rheumatoid arthritis, inflammatory Chronically active in enteropathy, arthritis, sepsis, gastritis and asthma. Accordingly, organic compounds capable of inhibiting NIK and thereby inhibiting, attenuating or alleviating undesired or overactivation of the NF-kB signaling pathway may have utility in the treatment of where such undesired or overactivation of NF-kB signaling is observed. Therapeutic benefits of diseases and disorders.

Brief description of the invention

Alkynyl alcohol compounds as NIK kinase inhibitors, compositions containing these compounds, and methods for treating NIK kinase-mediated diseases such as cancer and inflammatory diseases are disclosed.

In one aspect, there is provided a compound of formula (I) or a stereoisomer, tautomer, solvate, prodrug or salt thereof:

in:

Ring A is a monocyclic or fused bicyclic ring;

Q is N or C, wherein when Q is N, then the bond between A1 and Q is not _a double bond and the bond between Q and _A4 is not a double bond;

A ₁ is NR ¹ , N, S, CR ¹ or CHR ¹ ;

A ₂ is NR ² , N, O, S, CR ² or CHR ² ;

A ₃ is N or C;

A ₄ is N; and

One, two or three of A ₁ -A ₄ are N, where:

Each R ¹ is independently selected from H, halogen, NR ^a R ^b , NHC(O)NR ^a R ^b , NHS(O) ₂ CH ₃ , C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₃ alkoxy and 3-11 membered heterocyclic group, wherein the alkyl of R ¹ is optionally replaced by F, OH, CN, SH, C ₁ -C ₃ alkoxy or 3-11 membered heterocyclic group Substituted; Cycloalkyl ^of R is optionally substituted by F, OH, CN, SH, CH, or CF _; Alkoxy ^of _R is optionally substituted by F, OH, CN, or SH; and Heterocycle ^of R The group is optionally substituted by F, OH, CN, SH, CF ₃ or C ₁ -C ₃ alkyl,

R ² are each independently selected from H, NR ^a R ^b , C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy, phenyl and 3-11 membered heterocyclyl , wherein R ² is optionally substituted by R ^c ; or

R ¹ and R ² together with the atoms they are connected to form a cyclic group selected from C ₃ -C ₇ cycloalkyl, phenyl and 3-11 membered heterocyclic groups, wherein the cyclic group is optionally replaced by ^Rd replaces;

R ⁴ is selected from H, C ₁ -C ₆ alkyl, CH ₂ F and CH ₂ OH;

R ⁵ is a 3-11 membered heterocyclyl, optionally substituted by ^Re or -C(=O)N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁴ and R ⁵ together form a C ₃ -C ₁₁ cycloalkyl optionally substituted by ^Re or a 3-11 membered heterocyclic group optionally substituted by ^Re ;

One of A ₅ -A ₈ is N and the rest is CR ⁶ or all are CR ⁶ ;

R ⁶ at each occurrence is independently selected from H, F, Cl, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , OH, OCH ₃ , OCHF ₂ , OCH ₂ F, OCF ₃ , SH, SCH ₃ , SCHF ₂ , SCH ₂ F, CN, CH ₃ , CHF ₂ , CH ₂ F, CH ₂ OH, CF ₃ , NO ₂ and N ₃ ;

R ^is selected from H and C ₁ -C ₆ alkyl optionally substituted by C ₁ -C ₃ alkoxy, F, OH, CN, SH, CH ₃ or CF ₃ ;

R ^b is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C(O)R ^g , phenyl and 3-11 membered heterocyclic groups, Wherein R ^b can be optionally substituted by C ₁ -C ₃ alkoxy, F, OH, CN, SH, CH ₃ or CF ₃ ;

R ^c and R ^d are each independently selected from halogen, -(X ¹ ) _0-1 -CN, -(X ¹ ) _0-1 -NO ₂ , -(X ¹ ) _0-1 -SF ₅ , -(X ¹ ) _0-1 -OH, -(X ¹ ) _0-1 -NH ₂ , -(X ¹ ) _0-1 -N(H)(R ^1a ), -(X ¹ ) _0-1 -N(R ^1b ) (R ^1a ), -(X ¹ ) _0-1 -CF ₃ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkane Oxygen, C ₁ -C ₆ alkylthio, oxo, -(X ¹ ) _0-1 -C ₁ -C ₆ alkyl, -(X ¹ ) _0-1 -C ₃ -C ₁₀ cycloalkane -OC ₃ -C ₁₀ cycloalkyl, -(X ¹ ) _0-1 -3-11 membered heterocyclyl, -(X ¹ ) _0-1 -C ₆ -C ₁₀ aryl, -C(= O)(X ¹ ) ₁ -C ₃ -C ₁₀ cycloalkyl, -C(=O)(X ¹ ) ₁ -3-11 membered heterocyclyl, -(X ¹ ) _0-1 -C(=Y ¹ )N(H)(R ^1a ), -(X ¹ ) _0-1 -C(=Y ¹ )NH ₂ , -(X ¹ ) _0-1 -C(=Y ¹ )N(R ^1a )( R ^1b ), -(X ¹ ) _0-1 -C(=Y ¹ )OR ^1a , -(X ¹ ) _0-1 -C(=Y ¹ )OH, -(X ¹ ) _0-1 -N( H)C(=Y ¹ )(R ^1a ), -(X ¹ ) _0-1 -N(R ^1b )C(=Y ¹ )(R ^1a ), -(X ¹ ) _0-1 -N(R ^1b )C(=Y ¹ )(H), -(X ¹ ) _0-1 -N(H)C(=Y ¹ )OR ^1a , -(X ¹ ) _0-1 -N(R ^1b )C( =Y ¹ )OR ^1a , -(X ¹ ) _0-1 -S(O) _1-2 R ^1a , -(X ¹ ) _0-1 -N(H)S(O) _1-2 R ^1a , - (X ¹ ) _0-1 -N(R ^1b )S(O) _1-2 R ^1a , -(X ¹ ) _0-1 -S(O) _0-1 N(H)(R ^1a ), -( X ¹ ) _0-1 -S(O) _0-1 N(R ^1b )(R ^1a ), -(X ¹ ) _0-1 -S(O) _{0- 1} NH ₂ , -(X ¹ ) _{0- 1} -S(=O)(=NR ^1b )R ^1a , -(X ¹ ) _0-1 -C(=Y ¹ )R ^1a , -(X ¹ ) _0-1 - C(=Y ¹ )H, -(X ¹ ) _0-1 -C(=NOH)R ^1a , -(X ¹ ) _0-1 -C(=NOR ^1b )R ^1a , -(X ¹ ) _{0- 1} -NHC(=Y ¹ )N(H)(R ^1a ), -(X ¹ ) _0-1 -NHC(=Y ¹ )NH ₂ , -(X ¹ ) _0-1 -NHC(=Y ¹ ) N(R ^1b )(R ^1a ), -(X ¹ ) _0-1 -N(R ^1a )C(=Y ¹ )N(H)(R ^1a ), -(X ¹ ) _0-1 -N( R ^1a )C(=Y ¹ )N(R ^1a )(R ^1b ), -(X ¹ ) _0-1 -N(R ^1a )C(=Y ¹ )NH ₂ , -(X ¹ ) _0-1 -OC(=Y ¹ )R ^1a , -(X ¹ ) _0-1 -OC(=Y ¹ )H, -(X ¹ ) _0-1 -OC(=Y ¹ )OR ^1a , -(X ¹ ) _0-1 -OP(=Y ¹ )(OR ^1a )(OR ^1b ), -(X ¹ )-SC(=Y ¹ )OR ^1a and -(X ¹ )-SC(=Y ¹ )N(R ^1a )(R ^1b ), wherein X ¹ is selected from C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₂ -C ₆ alkenylene, C ₂ -C ₆ alkynylene, C ₁ -C ₆ alkyleneoxy, C ₃ -C ₇ cycloalkylene, 3-11 membered heterocyclylene and phenylene; R ^1a and R ^1b are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, (C ₃ -C ₇ cycloalkylene) C ₁ -C ₆ alkyl, 3-11 membered hetero Cyclic group, (3-11 membered heterocyclylene) C ₁ -C ₆ alkyl, C ₆ aryl and (C ₆ -C ₁₀ arylene) C ₁ -C ₆ alkyl, or R ^1a and R ^1b When attached to the same nitrogen atom, optionally combined to form ^a 3-11 membered heterocyclyl containing 0-3 additional heteroatoms selected from N, O and S; Y is O, ^NR or S, where R ^1c is H or C ₁ -C ₆ alkyl; wherein any part of the R ^c or R ^d substituents, including R ^1a , R ^1b and R ^1c , are each independently further substituted at each occurrence with 0 to 4 R ^f substituent, the R ^f substituent is selected from halogen, CN, NO ₂ , SF ₅ , OH, NH ₂ , -N(C ₁ -C ₆ alkyl) ₂ , -NH(C ₁ -C ₆ alkyl ), oxo, C ₁ -C ₆ alkyl, -(C ₂ -C ₆ alkynylene) -(3-11 membered heterocyclyl, wherein the heterocyclyl is optionally substituted by ^Re ), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₃ -C ₇ cycloalkyl, 3-11 membered heterocycle radical, -C(=O)N(H)(C ₁ -C ₆ alkyl), -C(=O)N(C ₁ -C ₆ alkyl) ₂ , -C(=O)NH ₂ , - C(=O)OC ₁ -C ₆ alkyl, -C(=O)OH, -N(H)C(=O)(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkane group) C(=O)(C ₁ -C ₆ alkyl), -N(H)C(=O)OC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)C(=O )OC ₁ -C ₆ (halogenated) alkyl, -S(O) _1-2 C ₁ -C ₆ alkyl, -N(H)S(O) _{1- 2} C ₁ -C ₆ alkyl, - N(C ₁ -C ₆ alkyl)S(O) _1-2 C ₁ -C ₆ alkyl, -S(O) _0-1 N(H)(C ₁ -C ₆ alkyl), -S( O) _0-1 N(C ₁ -C ₆ alkyl) ₂ , -S(O) _0-1 NH ₂ , -C(=O)C ₁ -C ₆ alkyl, -C(=O)C ₃ -C ₇ cycloalkyl, -C(=NOH)C ₁ -C ₆ alkyl, -C(=NOC ₁ -C ₆ alkyl)C ₁ -C ₆ alkyl, -NHC(=O)N(H )(C ₁ -C ₆ alkyl), -NHC(=O)N(C ₁ -C ₆ alkyl) ₂ , -NHC(=O)NH ₂ , -N(C ₁ -C ₆ alkyl)C (=O)N(H)(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)C(=O)NH ₂ , -OC(=O)C ₁ -C ₆ alkyl , -OC(=O)OC ₁ -C ₆ alkyl, -OP(=O)(OC ₁ -C ₆ alkyl) ₂ , -SC(=O)OC ₁ -C ₆ alkyl and -SC(= O) N(C ₁ -C ₆ alkyl) ₂ , wherein any alkyl portion of R ^f is optionally substituted by halogen;

R ^is selected from halogen, OH, C ₁ -C ₆ alkyl and oxo; and

R ^g is selected from C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, wherein R ^g can optionally be replaced by C ₁ -C ₃ alkoxy, F, OH, CN, SH, CH ₃ or CF ₃ replace;

With the proviso that said compound is not a compound selected from compounds 1x-199x of Table 1x.

In some embodiments, Q is C and the compound has formula (II):

Wherein rings A, A ₁ , A ₂ , A ₃ , A ₄ , A ₅ , A ₆ , A ₇ , A ₈ , R ⁴ and R ⁵ are as defined in formula (I).

In some embodiments, ring B is substituted phenyl, and Q is C; and the compound has formula (III):

wherein ring A, A ₁ , A ₂ , A ₃ , A ₄ , R ⁴ and R ⁵ are as defined in formula (II), n is 0, 1 or 2, and R ⁶ is each independently selected from F, Cl, _OCH3 , _CH3 and _CF3 .

In some embodiments of the compound of formula (I), (II) or (III), wherein

defined as (E.g ),

in:

A ₉ is O, NR ¹¹ or CR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are each independently selected from H, halogen, OH and C ₁ -C ₃ alkyl;

^R7 and ^R8 are each independently selected from halogen, OH, _C1 - _C6 alkyl, or ^R7 and ^R8 together form =O, and

R ⁹ and R ¹⁰ are each independently selected from H and R ^e , or R ⁹ and R ¹⁰ together with the atoms to which they are attached form a C ₅ -C ₆ cycloalkyl group optionally substituted by ^Re or optionally substituted by R ^e Substituted 5-6 membered heterocyclyl.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II) or (III) and a pharmaceutically acceptable carrier, diluent or excipient.

In another aspect, the present invention provides a compound of formula (I), (II) or (III) or a pharmaceutical composition thereof for use in therapy. In another embodiment, the present invention provides the use of a compound or pharmaceutical composition for the manufacture of a medicament for the treatment of an inflammatory disorder.

In another aspect, the present invention provides compounds of formula (I), (II) or (III) and pharmaceutical compositions thereof for use in the treatment of diseases and disorders, including cancer, inflammatory conditions and autoimmune diseases and the like.

In another aspect, the present invention provides methods (or uses) of compounds of formula (I), (II) or (III) or pharmaceutical compositions thereof for treating diseases and disorders, such as cancer, inflammatory disorders or autoimmune diseases and the like.

In another aspect, the present invention provides a compound of formula (I), (II) or (III) for use in the manufacture of a medicament for the treatment of cancer, inflammatory disorders or autoimmune diseases and the like.

In another aspect, the present invention provides compound intermediates useful in the synthesis of compounds of formula (I), (II) or (III).

Detailed description of the invention

The present invention provides, inter alia, compounds of formula (I), (II) or (III) and variants thereof, pharmaceutical compositions comprising compounds of formula (I), (II) or (III) and the use of such compounds and compositions Methods of treating diseases and disorders associated with undesired or excessive activation of the NF-kB signaling pathway, such as certain cancers and inflammatory disorders.

definition

The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group, wherein the alkyl group may be optionally and independently substituted with one or more substituents as described herein. In one example, an alkyl group has 1 to 18 carbon atoms (C ₁ -C ₁₈ ). In another example, the alkyl group is C ₀ -C ₆ , C ₀ -C ₅ , C ₀ -C ₃ , C ₁ -C ₁₂ , C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ - C ₆ , C ₁ -C ₅ , C ₁ -C ₄ or C ₁ -C ₃ . C ₀ alkyl refers to a bond. Examples of alkyl groups include methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, -CH ₂ CH ₂ CH ₃ ) , 2-propyl (i-Pr, isopropyl, -CH(CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl -1-propyl (i-Bu, isobutyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (s-Bu, sec-butyl, -CH(CH ₃ )CH ₂ CH ₃ ) , 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2- Hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl ( -C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl group (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3- Pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-Dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3 -Dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ , 1-heptyl, and 1-octyl. In some embodiments, for "optionally substituted alkyl" Substituents include F, Cl, Br, I, OH, SH, CN, NH ₂ , NO ₂ , N ₃ , COOH, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ring Propyl, Methoxy, Ethoxy, Propoxy, Oxo, Trifluoromethyl, Difluoromethyl, Sulfonylamino, Methanesulfonate ₁ to 6 examples of acylamino, SO, SO2, phenyl, piperidinyl, piperazinyl or pyrimidinyl, wherein the alkyl, aryl and heterocyclic moieties thereof may be optionally substituted.

_The term "alkylene" by itself or as part of another substituent denotes a divalent group derived from an _alkane , _exemplified by _{-CH2CH2CH2CH2-} . Typically, an alkyl (or alkylene) group will have 1 to 12 carbon atoms, eg 1-8, 1-6 or 1-3 carbon atoms. "Alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having double or triple bonds respectively, usually having 2 to 12 carbon atoms, e.g. 2-8, 2-6 or 2-3 carbon atoms. "Alkylene", "alkenylene" and "alkynylene" groups can be optionally substituted.

The term "heteroalkyl" refers to a straight or branched chain monovalent hydrocarbon radical consisting of the indicated number of carbon atoms or, if not indicated, up to 18 carbon atoms and 1 to 5 heteroatoms selected from O, N, Si and S , wherein the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen heteroatoms can be optionally quaternized. In some embodiments, the heteroatom is selected from O, N, and S, wherein the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. A heteroatom can be at any internal position within a heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule (eg -O- _CH2 - _CH3 ). Examples include -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -O-CF ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ ) -CH ₃ , -CH ₂ -S-CH ₂ -CH ₃ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -Si(CH ₃ ) ₃ , - _CH2 -CH=N- _OCH3 and _-OCF3 . Up to two heteroatoms can be linked, eg -CH ₂ -NH-OCH ₃ and -CH ₂ -O-Si(CH ₃ ) ₃ . Heteroalkyl groups can be optionally substituted. In some embodiments, substituents for "optionally substituted heteroalkyl" include F, _Cl , Br, I, OH, SH, CN, _NH2 , _NO2 , N3, COOH, methyl, ethyl , propyl, isopropyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methyl 1 to ₄ examples of sulfonylamino, SO, SO2, phenyl, piperidinyl, piperazinyl, and pyrimidinyl, wherein the alkyl, aryl, and heterocyclic moieties may be optionally substituted.

The term "heteroalkylene" refers to a divalent group derived from a heteroalkyl group, examples of which are -CH ₂ CH ₂ SCH ₂ CH ₂ , -CH ₂ SCH ₂ CH ₂ NHCH ₃ and -OCH ₂ CH ₃ . For heteroalkylene groups, heteroatoms may also occupy one or both chain termini (eg, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). A heteroalkylene group can be optionally substituted.

"Cycloalkyl" means a non-aromatic saturated or partially unsaturated hydrocarbon ring group in which the cycloalkyl group may be optionally substituted with one or more substituents described herein. In one example, a cycloalkyl group has 3 to 12 carbon atoms (C ₃ -C ₁₂ ). In other examples, cycloalkyl is C ₃ -C ₆ , C ₃ -C ₈ , C ₃ -C ₁₀ , or C ₅ -C ₁₀ . In other examples, a cycloalkyl group that is a monocycle is C ₃ -C ₈ , C ₃ -C ₆ , or C ₅ -C ₆ . In another example, a cycloalkyl group that is a bicyclic ring is C ₇ -C ₁₂ . In another example, a cycloalkyl group that is a spiro ring system is C ₅ -C ₁₂ . Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, Cyclohexyl, fully tritiated cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclohexyl Octyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems . Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[4.1.0]heptane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo [4.1.0] Heptane and Bicyclo[3.2.2] Nonane. Examples of spirocycloalkyl groups include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane. In some embodiments, substituents for "optionally substituted cycloalkyl" include F, _Cl , Br, I, OH, SH, CN, _NH2 , _NO2 , N3, COOH, methyl , ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonyl 1 to 4 examples of amino, methanesulfonylamino, SO, SO ₂ , phenyl, piperidinyl, piperazinyl (piperizinyl) and pyrimidinyl, wherein the alkyl, aryl and heterocyclic moieties can be optionally was replaced.

The term "cycloalkylene" refers to a divalent radical derived from a cycloalkyl group. Cycloalkylene groups can be optionally substituted.

"Heterocyclic group", "heterocyclic", "heterocycle", "heterocyclyl" or "heterocycle" are used interchangeably to refer to any monocyclic, bicyclic or spirocyclic saturated or unsaturated, aromatic (heteroaryl) or non-aromatic (eg heterocycloalkyl) ring systems wherein the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. A ring system is a heterocycle if any ring atom of the ring system is a heteroatom, regardless of the point of attachment of the ring system to the rest of the molecule. In one example, a heterocyclyl group includes 3-11 ring atoms ("membered", ie, a 3-11 membered heterocycle) and includes monocyclic, bicyclic, and spiro ring systems, wherein the ring atoms are carbon and the ring or ring At least one atom in the system is a heteroatom selected from nitrogen, sulfur or oxygen. In one example, a heterocyclyl group includes 1 to 4 heteroatoms. In another example, heterocyclyl includes 3- to 7-membered monocyclic rings having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, heterocyclyl includes 4- to 6-membered monocyclic rings having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, heterocyclyl includes 3-membered monocyclic rings. In another example, heterocyclyl includes 4-membered monocyclic rings. In another example, heterocyclyl includes 5-6-membered monocyclic rings. In one example, a heterocyclic group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom can be optionally oxidized (eg NO, SO, SO ₂ ) and any nitrogen heteroatom can be optionally quaternized (eg [NR ₄ ] ⁺ Cl ⁻ , [NR ₄ ] ⁺ OH ⁻ ). In another example, heterocyclyl includes 3- to 9-membered spirocycles having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. Examples of heterocycles are oxiranyl, aziridinyl, thiiridine, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl , 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuryl, tetrahydrofuryl, dihydrothiophenyl, tetrahydrothiophenyl, imidazolidinyl, piperidinyl, Piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, Hexahydrothiopyranyl, Hexahydropyrimidinyl, Oxazepanyl, Thiazinyl, Thioxanyl, Homopiperazinyl, Homopiperidinyl, Azepanyl, Oxepeptyl base, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, Thiaazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxaisothiazolidinyl, oxa Oxazolidinone, imidazolidinone, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazole 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl , Dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrole Linyl, 3-pyrrolinyl, indolinyl, thiopyranyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolanyl, pyrazoline , pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinone, pyrimidinedione, pyrimidine-2,4-dione, piperazinone, piperazinedione, pyrazolidine Imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.1]heptyl, Bicyclo[3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-azabicyclo[3.2.1]octyl, 8-azabicyclo [3.2.1] Octyl, 2-azabicyclo[2.2.2]octyl, 8-azabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptane, azaspiro [3.5]nonyl, azaspiro[2.5]octyl, azaspiro[4.5]decane, 1-azaspiro[4.5]decane-2-onyl, azaspiro[5.5]undecyl , tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxahexahydrothiopyranyl. Examples of 5-membered heterocycles containing sulfur or oxygen atoms and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxides; thiadiazolyl, including 1,3, 4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl; oxazolyl such as oxazol-2-yl; and oxadiazolyl such as 1,3,4-oxadi Azol-5-yl and 1,2,4-oxadiazol-5-yl. Examples of 5-membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl such as imidazol-2-yl; triazolyl such as 1,3,4-triazol-5-yl, 1,2,3-tri oxazol-5-yl, 1,2,4-triazol-5-yl; and tetrazolyl such as 1H-tetrazol-5-yl. Examples of benzo-fused 5-membered heterocycles are benzoxazol-2-yl, benzothiazol-2-yl and benzimidazol-2-yl. Examples of 6-membered heterocyclic rings contain one to three nitrogen atoms and optionally sulfur or oxygen atoms, such as pyridyl, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; pyrimidinyl, such as pyrimidine -2-yl and pyrimidin-4-yl; triazinyl, such as 1,3,4-triazinyl-2-yl and 1,3,5-triazinyl-4-yl; pyridazinyl, especially pyridazin-3-yl; and pyrazinyl. Pyridine N-oxide and pyridazine N-oxide and pyridyl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazinyl and 1,3,4-pyridazinyl 2-yl groups are heterocyclic groups other instances of . Heterocycles can be optionally substituted. For example, substituents for "optionally substituted heterocycle" include F, _Cl , Br, I, OH, SH, CN, _NH2 , _NO2 , N3, COOH, methyl, ethyl, propane, radical, isopropyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methylsulfonyl ₁ to 6 examples of amino, SO, SO2, phenyl, piperidinyl, piperazinyl, and pyrimidinyl, wherein the alkyl, aryl, and heterocyclic moieties thereof may be optionally substituted.

The term "heterocyclylene" refers to a divalent group derived from a heterocyclic group. A heterocyclylene group can be optionally substituted.

"Heteroaryl" means any mono-, bi- or tricyclic ring system in which at least one ring is a 5- or 6-membered aromatic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, in In an exemplary embodiment, at least one heteroatom is nitrogen. See eg Lang's Handbook of Chemistry (ed. Dean, JA) 13th ed. Table 7-2 [1985]. Included in the definition are any bicyclic groups in which any of the aforementioned heteroaryl rings is fused to an aryl ring, wherein the aryl ring or heteroaryl ring is attached to the remainder of the molecule. In one embodiment, heteroaryl includes 4-6 membered monocyclic aromatic groups in which one or more ring atoms are nitrogen, sulfur or oxygen. In another embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups wherein one or more ring atoms are nitrogen, sulfur or oxygen. Examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl , tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl , imidazo[1,2-a]pyrimidinyl and purinyl and benzo-fused derivatives such as benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzo Triazolyl, benzimidazolyl and indolyl. Heteroaryl groups can be optionally substituted. In some embodiments, substituents for "optionally substituted heteroaryl" include F, _Cl , Br, I, OH, SH, CN, _NH2 , _NO2 , N3, COOH, methyl , ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonyl 1 to 6 examples of amino, methanesulfonylamino, SO, SO ₂ , phenyl, piperidinyl, piperazinyl (piperizinyl) and pyrimidinyl, wherein the alkyl, aryl and heterocyclic moieties can be optionally was replaced.

In certain embodiments, the heterocyclic group is attached at a carbon atom of the heterocyclic group. By way of example, carbon-bonded heterocyclic groups include the following bonding arrangements: 2, 3, 4, 5, or 6 of the pyridine ring, 3, 4, 5, or 6 of the pyridazine ring, 2, 4, or 4 of the pyrimidine ring. , 5 or 6 positions, 2, 3, 5 or 6 positions of pyrazine ring, 2, 3, 4 or 5 positions of furan, tetrahydrofuran, thiocene, thiophene, pyrrole or tetrahydropyrrole ring, oxazole, imidazole or thiazole 2, 4 or 5 positions of the ring, 3, 4 or 5 positions of the isoxazole, pyrazole or isothiazole ring, 2 or 3 positions of the aziridine ring, 2, 3 or 4 positions of the azetidine ring , the 2, 3, 4, 5, 6, 7 or 8 position of the quinoline ring, or the 1, 3, 4, 5, 6, 7 or 8 position of the isoquinoline ring.

In some embodiments, a heterocyclic group is N-attached. By way of example, nitrogen-bonded heterocyclyl or heteroaryl groups include the following bonding arrangements: aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, Imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole 1-position of isoindole or isoindoline, 2-position of morpholine, 9-position of carbazole or β-carboline.

The term "alkoxy" refers to an alkyl group attached to the rest of the molecule through an oxygen atom. Non-limiting examples include methoxy, ethoxy and propoxy. Alkoxy groups may be optionally substituted, for example by halogen.

The term "alkylthio" refers to an alkyl group attached to the rest of the molecule via a sulfur atom. Non-limiting examples include -SCH ₃ , -SCH ₂ CH ₃ , and -SCH ₂ CH ₂ CH ₃ . Alkylthio groups may be optionally substituted, for example by halogen.

The term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine or iodine atom unless otherwise indicated. The term "haloalkyl" is intended to include both "alkyl" and "haloalkyl" substituents. Additionally, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl.

The term "oxo" refers to =O or (=O) ₂ .

The term "aryl" refers to a polyunsaturated, usually aromatic, hydrocarbon ring group, which may be a single ring or multiple rings (up to three rings) fused together, having the stated number of aryl ring atoms, otherwise Unless stated otherwise. Aryl groups can be optionally substituted.

A "phenylene" group refers to a divalent radical derived from a phenyl group. A phenylene group may be optionally substituted.

"Optionally substituted" means that a group may be unsubstituted or substituted with one or more (eg 0, 1, 2, 3, 4 or 5 or more) of the substituents listed for that group, wherein The substituents may be the same or different, unless otherwise specified. That is, each occurrence of an optionally substituted substituent is independent. In an embodiment, an optionally substituted group has 1 substituent. In other embodiments, an optionally substituted group has 2 substituents. In other embodiments, an optionally substituted group has 3 substituents. In other embodiments, optionally substituted groups have 4 substituents.

Optional substituents for alkyl and cycloalkyl groups can be a variety of groups including, but not limited to, halogen, oxo, CN, NO2, _N3 , OR _' , perfluoro _{- C1-4} Alkoxy, unsubstituted cycloalkyl, unsubstituted aryl (eg phenyl), unsubstituted heterocyclyl, NR'R", SR', SiR'R"R"', OC(O)R ', C(O)R', CO ₂ R', CONR'R", OC(O)NR'R", NR"C(O)R', NR"'C(O)NR'R", NR "C(O) ₂ R', S(O) ₂ R', S(O) ₂ NR'R", NR'S(O) ₂ R", NR"'S(O) ₂ NR'R", amidino , Guanidine, (CH ₂ ) _1-4 OR', (CH ₂ ) _1-4 NR'R″, (CH ₂ ) _1-4 SR', (CH ₂ ) _1-4 SiR'R″R″', (CH ₂ ) _1-4 OC(O)R', (CH ₂ ) _1-4 C(O)R', (CH ₂ ) _1-4 CO ₂ R' and (CH ₂ ) _1-4 CONR'R " or combinations thereof, the number is from 0 to (2m'+1), wherein m' is the total number of carbon atoms in the group. R', R" and R"' each independently refer to groups including, for example: Hydrogen; unsubstituted C ₁ - ₆ alkyl; unsubstituted heteroalkyl; unsubstituted aryl; aryl substituted by 1-3 halogen, unsubstituted C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxy or C ₁ -C ₆ thioalkoxy groups, unsubstituted aryl-C ₁ -C ₄ alkyl groups and unsubstituted heteroaryl groups. When R' and R" are connected to When the nitrogen atoms are the same, they can be combined with nitrogen atoms to form 3-, 4-, 5-, 6- or 7-membered rings, wherein the ring atoms are optionally substituted by N, O or S. For example, NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl.

Similarly, optional substituents are different for aryl and heterocyclic groups. In some embodiments, substituents for aryl and heterocyclic groups are selected from groups including, but not limited to, halogen, OR', OC(O)R', NR'R", SR', R', CN, NO ₂ , CO ₂ R', CONR'R", C(O)R', OC(O)NR'R", NR"C(O)R', NR"C(O) ₂ R', NR'C(O)NR"R"', S(O)R', S(O) ₂ R', S(O) ₂ NR'R", NR'S(O) ₂ R", N ₃ , perfluoro-C ₁ -C ₄ alkoxy, perfluoro-C ₁ -C ₄ alkoxy, (CH ₂ ) _1-4 OR', (CH ₂ ) _1-4 NR'R″, (CH ₂ ) _1-4 SR', (CH ₂ ) _1-4 SiR'R″R″', (CH ₂ ) _1-4 OC(O)R', (CH ₂ ) _1-4 C(O)R', (CH ₂ ) _1-4 CO ₂ R', (CH ₂ ) _1-4 CONR'R" or a combination thereof in an amount ranging from 0 to the total number of open valence bonds on the aromatic ring; and wherein R', R" and R″' is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, unsubstituted aryl and unsubstituted Substituted Heteroaryl. Other suitable substituents include each of the aforementioned aryl substituents attached to a ring atom through an alkylene chain of 1 to 4 carbon atoms.

The term "heteroatom" as used herein is intended to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). In some embodiments, a heteroatom refers to O, N, or S. In some embodiments, a heteroatom refers to O or N.

The term "chiral" as used herein refers to a molecule that has the property of being non-superimposable with a mirror image partner, while the term "achiral" refers to a molecule that is superimposable with a non-mirror image partner.

The term "stereoisomer" as used herein refers to compounds that have the same chemical composition but differ in the arrangement of the atoms or groups in space. "Diastereoisomers" refer to stereoisomers that have 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 reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography.

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

Stereochemical definitions and conventions used herein generally follow S.P. Parker ed., McGraw-Hill Dictionary 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 present invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures, are intended to form part of the invention. Many organic compounds exist in optically active forms, ie they have the ability to rotate the plane of plane polarized light. In 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(s). The prefixes d and 1 or (+) and (-) are used to designate the sign that the compound rotates plane polarized light, where (-) or 1 indicates that the compound is levorotatory. 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 such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, which is optically inactive.

The term "tautomer" or "tautomeric form" as used herein refers to structural isomers with different energies that are interconvertible through a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-enamine isomerization. Bonded tautomers include interconversions by recombination of some of the bonding electrons.

In the structures shown herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers are contemplated and included as compounds of the invention. When stereochemistry is indicated by a solid wedge or dashed line indicating a particular configuration, then that stereoisomer is so indicated and defined. Where solid wedges or dashed lines are used, relative stereoisomers are indicated unless otherwise indicated. If there is an inconsistency between the structure and the name, the structure takes precedence.

The term "solvate" as used herein refers to an association or complex of one or more solvent molecules with a compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

The term "protecting group" as used herein refers to substituents commonly used to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino function in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" is a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy protecting group" refers to a carboxyl blocking or substituent protecting the carboxyl functional group. Common carboxyl protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-( p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis, 4th ed., Wiley-Interscience, New York, 2006.

The term "mammal" as used herein includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs and sheep.

A "subject", "individual" or "patient" is a vertebrate. In some embodiments, the vertebrate is a mammal. A subject, individual or patient may be in need of a compound of the invention.

The term "pharmaceutically acceptable salt" as used herein is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found in the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganous, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include those of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethyl Piperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, proca Because, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonic acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrogen phosphoric acid, Sulfuric acid, hydroiodic acid or phosphorous acid, etc., and salts derived from relatively nontoxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginine salts and the like and salts of organic acids such as glucuronic or galactunoric acids and the like (see, e.g., Berge, S.M. et al., "Pharmaceutical Salts", J.Pharm.Sci. ., 1977, 66, 1-19). Certain specific compounds of the invention contain both basic and acidic functionalities, which allow the compounds to be converted into base or acid addition salts.

Neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents, but the salts and the parent form of the compound are equivalent for the purposes of the present invention.

In addition to salt forms, the present invention also provides compounds in prodrug form. The term "prodrug" as used herein refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Alternatively, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vitro environment. For example, prodrugs can be slowly converted to compounds of the invention when placed in a transdermal patch depot with a suitable enzyme or chemical reagent.

Prodrugs of the present invention include those wherein an amino acid residue or a polypeptide chain having two or more (eg two, three or four) amino acid residues is covalently linked to the compound of the present invention via an amide or ester bond. Compounds with amino, hydroxyl or carboxylic acid groups. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly designated by 3-letter symbols, and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, Demosine, isodemosine, γ-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statin, 1,2,3,4-tetrahydroiso Quinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, Homoserine, methyl-alanine, p-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert-butylglycine.

Additional types of prodrugs are also contemplated. For example, free carboxyl groups of compounds of the invention may be derivatized as amides or alkyl esters. As a further example, compounds of the invention that contain free hydroxyl groups can be derivatized as prodrugs by converting the hydroxyl group into a compound such as, but not limited to, phosphate, hemisuccinate, dimethylaminoacetate, or phospho A group of acyloxymethyloxycarbonyl groups as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by use of Prodrugs Advanced Drug Delivery Reviews, 19:115. Also included are carbamate prodrugs of hydroxy and amino groups, as do carbonate prodrugs, sulfonates and sulfates of hydroxy groups. Also included are the derivatization of hydroxyl groups to (acyloxy)methyl and (acyloxy)ethyl ethers, where the acyl groups can be optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups Substituted alkyl esters, or amino acid esters wherein the acyl group is as described above. Prodrugs of this type are described in J. Med. Chem., (1996), 39:10. More specific examples include the replacement of a hydrogen atom of an alcohol group by a group such as: (C ₁ -C ₆ )alkanoyloxymethyl, 1-((C ₁ -C ₆ )alkanoyloxy)ethyl , 1-methyl-1-((C ₁ -C ₆ )alkanoyloxy)ethyl, (C ₁ -C ₆ )alkoxycarbonyloxymethyl, N-(C ₁ -C ₆ )alkane Oxycarbonylaminomethyl, succinyl, (C ₁ -C ₆ )alkanoyl, α-amino(C _1-4 )alkanoyl, aryl acyl and α-aminoacyl or α-aminoacyl-α-aminoacyl , wherein the α-aminoacyl groups are each independently selected from naturally occurring L-amino acids, P(O)(OH) ₂ , -P(O)(O(C _1-6 )alkyl) ₂ or glycosyl ( The group resulting from the removal of the hydroxyl group from the hemiacetal form of the carbohydrate).

Further examples of prodrug derivatives see e.g. a) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985) ); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", H. Bundgaard, pp. 113-191 (1991); c) H. Bundgaard , Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N.Kakeya, et al., Chem.Pharm.Bull ., 32:692 (1984), each of which is expressly incorporated herein by reference.

Additionally, the invention provides metabolites of compounds of the invention. A "metabolite" as used herein refers to a product produced in vivo by the metabolism of a specific compound or a salt thereof. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound.

Typically, metabolites are identified by preparing a radiolabeled (eg ¹⁴ C or ³ H) isotope of a compound of the invention and administering it to animals such as rats, mice Rats, guinea pigs, monkeys, or humans are allowed time sufficient for metabolism to occur (usually about 30 seconds to 30 hours), and their transformation products are isolated from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies capable of binding epitopes present in the metabolites). Metabolite structures are determined in a conventional manner, eg by MS, LC/MS or NMR analysis. In general, metabolite analysis is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites are useful in diagnostic assays for the therapeutic administration of the compounds of the invention, as long as they are not found in vivo.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. The compounds of the invention may exist in various crystalline or amorphous forms. In general, all physical forms are intended to be within the scope of the present invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the invention also includes isotopically labeled variants of the invention that are identical to those described herein, but where one or more atoms are labeled with an atomic mass or mass number different from that found naturally in nature. atomic replacement. All isotopes of any particular atom or element mentioned are contemplated within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ² H(D), ³ H, ¹¹ C, ¹³ C, respectively. ^14C , ^13N , ^15N , ^15O , ^17O , ^18O , ^32P , ^33P , ^35S , ^18F , ^36Cl , ^123I and ^125I . Some isotopically labeled compounds of the invention (eg, those labeled ^{with3H and14C} ) are useful in compound or substrate tissue distribution assays. Tritiated ( ³ H) and carbon-14 ( ¹⁴ C) isotopes are useful because of their ease of preparation and detectability. Moreover, substitution with heavier isotopes such as deuterium (ie,2H ⁾ may afford some therapeutic benefits resulting from greater metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and thus may be preferred in some circumstances. Positron-emitting isotopes such as ¹⁵ O, ¹³ N, ¹¹ C and ¹⁸ F can be used in positron emission tomography (PET) studies to detect substrate acceptor occupancy. Isotopically labeled compounds of the invention can generally be prepared following methods analogous to those disclosed in the Schemes and Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. A non-limiting example of an isotopically substituted moiety is as follows:

Unless otherwise indicated, the term "compound of the present invention" and the like includes compounds of formula (I), (II) or (III) and stereoisomers (including atropisomers), geometric isomers, tautomers Isomers, solvates, metabolites, isotopes, salts (eg, pharmaceutically acceptable salts), and prodrugs. In some embodiments, solvates, metabolites, isotopes or prodrugs or any combination thereof are excluded.

"Treatment" (and variations thereof such as "treatment") refers to clinical intervention to alter the natural course of the treated individual or cell, either for prophylaxis or during a clinical condition. Anticipated therapeutic effects include arresting the onset or recurrence of the disease, relieving symptoms, eliminating any direct or indirect pathological consequences of the disease, stabilizing (i.e., not worsening) the disease state, reducing the rate of disease progression, ameliorating or palliation of the disease state, and, if not Expected survival with treatment compared to prolonged survival and spare or improved prognosis. In some embodiments, compounds of the invention are used to delay the development of a disease or disorder or to slow the progression of a disease or disorder. Those in need of treatment include those already with the condition or disorder as well as those who are predisposed to have the condition or disorder (eg, through a genetic mutation) or in which the condition or disorder is intended to be prevented. In some embodiments, prophylaxis is excluded from the definition of "treatment."

The phrase "therapeutically effective amount" or "effective amount" refers to an amount of a compound of the invention that (i) treats or prevents a particular disease, condition or disorder, (ii) alleviates, ameliorates or eliminates a particular disease, condition or disorder. or multiple symptoms, or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition or disorder as described herein. For cancer therapy, efficacy can be determined, for example, by assessing time to disease progression (TTP) or determining response rate (RR). In immunological diseases, the therapeutically effective amount is sufficient to reduce or alleviate the symptoms of allergic disorders, autoimmune or inflammatory disorders (such as psoriasis or inflammatory bowel disease), or the symptoms of acute inflammatory reactions (such as asthma) quantity. In some embodiments, a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly reduce B-cell activity or number.

The terms "inhibit" and "reduce" or any variation of these terms include any measurable decrease or complete inhibition to achieve the desired result. For example, it can be reduced by about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% compared to normal %, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more or any range derivable therein reduces activity (eg NIK activity).

The term "bioavailability" refers to the systemic availability (ie, blood/plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term indicating the time (rate) and total amount (extent) of a drug reaching the systemic circulation from an administered dosage form.

An "inflammatory condition" as used herein refers to any disease, disorder or condition in which an excessive or uncontrolled inflammatory response results in excessive inflammatory symptoms, host tissue damage or loss of tissue function.

"Inflammation" as used herein refers to a local protective response caused by tissue damage or destruction, which serves to destroy, dilute or strip (separate) noxious substances and damaged tissue. Inflammation is notably accompanied by leukocyte influx or neutrophil chemotaxis. Inflammation can arise from infection by pathogenic organisms and viruses as well as from non-inflammatory means such as trauma or reperfusion after myocardial infarction or stroke, immune responses to exogenous antigens and autoimmune responses.

The terms "cancer" and "cancer" relate to or describe the physiological condition in mammals that is often characterized by uncontrolled cell growth or proliferation. 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.

"Autoimmune disease" as used herein refers to any collection of disorders in which tissue damage is associated with humoral or cell-mediated responses to the body's own components.

It is specifically contemplated that any limitations discussed with respect to one embodiment of the invention may be applied to any other embodiment of the invention. Furthermore, any compound or composition of the invention can be used in any method of the invention, and any method of the invention can be used to produce or utilize any compound or composition of the invention.

Although the definition of open support refers to alternatives and "and/or" only, the use of the term "or" is used to mean "and/or" unless expressly indicated that only alternatives or alternatives are mutually exclusive .

Throughout this application, the term "about" is used to indicate that a value includes the standard error of the device or method used to determine the value.

As used herein, "a", "an" or entity means one or more unless the context clearly indicates otherwise. "Other" as used herein refers to at least a second or more.

The headings used in this article are for organization only.

NIK inhibitor

One aspect of the present invention provides a compound of formula (I) or a stereoisomer, tautomer, solvate, prodrug or salt thereof:

in:

Ring A is a monocyclic or fused bicyclic ring;

Q is N or C, wherein when Q is N, then the bond between A1 and Q is not _a double bond and the bond between Q and _A4 is not a double bond;

A ₁ is NR ¹ , N, S, CR ¹ or CHR ¹ ;

A ₂ is NR ² , N, O, S, CR ² or CHR ² ;

A ₃ is N or C;

A ₄ is N; and

One, two or three of A ₁ -A ₄ are N, where:

Each R ¹ is independently selected from H, halogen, NR ^a R ^b , NHC(O)NR ^a R ^b , NHS(O) ₂ CH ₃ , C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₃ alkoxy and 3-11 membered heterocyclic group, wherein the alkyl of R ¹ is optionally replaced by F, OH, CN, SH, C ₁ -C ₃ alkoxy or 3-11 membered heterocyclic group Substituted; Cycloalkyl ^of R is optionally substituted by F, OH, CN, SH, CH, or CF _; Alkoxy ^of _R is optionally substituted by F, OH, CN, or SH; and Heterocycle ^of R The group is optionally substituted by F, OH, CN, SH, CF ₃ or C ₁ -C ₃ alkyl,

R ² are each independently selected from H, NR ^a R ^b , C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy, phenyl and 3-11 membered heterocyclyl , wherein R ² is optionally substituted by R ^c ; or

R ¹ and R ² together with the atoms they are connected to form a cyclic group selected from C ₃ -C ₇ cycloalkyl, phenyl and 3-11 membered heterocyclic groups, wherein the cyclic group is optionally replaced by ^Rd replaces;

R ⁴ is selected from H, C ₁ -C ₆ alkyl, CH ₂ F and CH ₂ OH;

R ⁵ is a 3-11 membered heterocyclic ring optionally substituted by ^Re or -C(=O)N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁴ and R ⁵ together form a C ₃ -C ₁₁ cycloalkyl optionally substituted by ^Re or a 3-11 membered heterocyclic group optionally substituted by ^Re ;

One of A ₅ -A ₈ is N and the rest is CR ⁶ or all are CR ⁶ ;

R ⁶ at each occurrence is independently selected from H, F, Cl, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , OH, OCH ₃ , OCHF ₂ , OCH ₂ F, OCF ₃ , SH, SCH ₃ , SCHF ₂ , SCH ₂ F, CN, CH ₃ , CHF ₂ , CH ₂ F, CH ₂ OH, CF ₃ , NO ₂ and N ₃ ;

R ^is selected from H and C ₁ -C ₆ alkyl optionally substituted by C ₁ -C ₃ alkoxy, F, OH, CN, SH, CH ₃ or CF ₃ ;

R ^b is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C(O)R ^g , phenyl and 3-11 membered heterocyclic groups, Wherein R ^b can be optionally substituted by C ₁ -C ₃ alkoxy, F, OH, CN, SH, CH ₃ or CF ₃ ;

R ^c and R ^d are each independently selected from halogen, -(X ¹ ) _0-1 -CN, -(X ¹ ) _0-1 -NO ₂ , -(X ¹ ) _0-1 -SF ₅ , -(X ¹ ) _0-1 -OH, -(X ¹ ) _0-1 -NH ₂ , -(X ¹ ) _0-1 -N(H)(R ^1a ), -(X ¹ ) _0-1 -N(R ^1b ) (R ^1a ), -(X ¹ ) _0-1 -CF ₃ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkane Oxygen, C ₁ -C ₆ alkylthio, oxo, -(X ¹ ) _0-1 -C ₁ -C ₆ alkyl, -(X ¹ ) _0-1 -C _3- C ₁₀ cycloalkane radical, -OC _3- C ₁₀ cycloalkyl, -(X ¹ ) _0-1 -3-11 membered heterocyclyl, -(X ¹ ) _0-1 -C ₆ -C ₁₀ aryl, -C(= O)(X ¹ ) ₁ -C _3- C ₁₀ cycloalkyl, -C(=O)(X ¹ ) ₁ -3-11 membered heterocyclyl, -(X ¹ ) _0-1 -C(=Y ¹ )N(H)(R ^1a ), -(X ¹ ) _0-1 -C(=Y ¹ )NH ₂ , -(X ¹ ) _0-1 -C(=Y ¹ )N(R ^1a )( R ^1b ), -(X ¹ ) _0-1 -C(=Y ¹ )OR ^1a , -(X ¹ ) _0-1 -C(=Y ¹ )OH, -(X ¹ ) _0-1 -N( H)C(=Y ¹ )(R ^1a ), -(X ¹ ) _0-1 -N(R ^1b )C(=Y ¹ )(R ^1a ), -(X ¹ ) _0-1 -N(R ^1b )C(=Y ¹ )(H), -(X ¹ ) _0-1 -N(H)C(=Y ¹ )OR ^1a , -(X ¹ ) _0-1 -N(R ^1b )C( =Y ¹ )OR ^1a , -(X ¹ ) _0-1 -S(O) _1-2 R ^1a , -(X ¹ ) _0-1 -N(H)S(O) _1-2 R ^1a , - (X ¹ ) _0-1 -N(R ^1b )S(O) _1-2 R ^1a , -(X ¹ ) _0-1 -S(O) _0-1 N(H)(R ^1a ), -( X ¹ ) _0-1 -S(O) _0-1 N(R ^1b )(R ^1a ), -(X ¹ ) _0-1 -S(O) _{0- 1} NH ₂ , -(X ¹ ) _{0- 1} -S(=O)(=NR ^1b )R ^1a , -(X ¹ ) _0-1 -C(=Y ¹ )R ^1a , -(X ¹ ) _0-1 - C(=Y ¹ )H, -(X ¹ ) _0-1 -C(=NOH)R ^1a , -(X ¹ ) _0-1 -C(=NOR ^1b )R ^1a , -(X ¹ ) _{0- 1} -NHC(=Y ¹ )N(H)(R ^1a ), -(X ¹ ) _0-1 -NHC(=Y ¹ )NH ₂ , -(X ¹ ) _0-1 -NHC(=Y ¹ ) N(R ^1b )(R ^1a ), -(X ¹ ) _0-1 -N(R ^1a )C(=Y ¹ )N(H)(R ^1a ), -(X ¹ ) _0-1 -N( R ^1a )C(=Y ¹ )N(R ^1a )(R ^1b ), -(X ¹ ) _0-1 -N(R ^1a )C(=Y ¹ )NH ₂ , -(X ¹ ) _0-1 -OC(=Y ¹ )R ^1a , -(X ¹ ) _0-1 -OC(=Y ¹ )H, -(X ¹ ) _0-1 -OC(=Y ¹ )OR ^1a , -(X ¹ ) _0-1 -OP(=Y ¹ )(OR ^1a )(OR ^1b ), -(X ¹ )-SC(=Y ¹ )OR ^1a and -(X ¹ )-SC(=Y ¹ )N(R ^1a )(R ^1b ), wherein X ¹ is selected from C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₂ -C ₆ alkenylene, C ₂ -C ₆ alkynylene, C ₁ -C ₆ alkyleneoxy, C _3- C ₇ cycloalkylene, 3-11 membered heterocyclylene and phenylene; R ^1a and R ^1b are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C _3- C ₇ cycloalkyl, (C _3- C ₇ cycloalkylene) C ₁ -C ₆ alkyl, 3-11 membered hetero Cyclic group, (3-11 membered heterocyclylene) C ₁ -C ₆ alkyl, C ₆ aryl and (C ₆ -C ₁₀ arylene) C ₁ -C ₆ alkyl, or R ^1a and R ^1b When attached to the same nitrogen atom, optionally combined to form ^a 3-11 membered heterocyclyl containing 0-3 additional heteroatoms selected from N, O and S; Y is O, ^NR or S, where R ^1c is H or C ₁ -C ₆ alkyl; wherein any part of the R ^c or R ^d substituents, including R ^1a , R ^1b and R ^1c , are each independently further substituted at each occurrence with 0 to 4 R ^f substituent, the R ^f substituent is selected from halogen, CN, NO ₂ , SF ₅ , OH, NH ₂ , -N(C ₁ -C ₆ alkyl) ₂ , -NH(C ₁ -C ₆ alkyl) , oxo, C ₁ -C ₆ alkyl, -(C ₂ -C ₆ alkynylene) -(3-11 membered heterocyclyl, wherein the heterocyclyl is optionally substituted by ^Re ), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C _3- C ₇ cycloalkyl, 3-11 membered heterocycle radical, -C(=O)N(H)(C ₁ -C ₆ alkyl), -C(=O)N(C ₁ -C ₆ alkyl) ₂ , -C(=O)NH ₂ , - C(=O)OC ₁ -C ₆ alkyl, -C(=O)OH, -N(H)C(=O)(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkane group) C(=O)(C ₁ -C ₆ alkyl), -N(H)C(=O)OC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)C(=O )OC ₁ -C ₆ (halo)alkyl, -S(O) _1-2 C ₁ -C ₆ alkyl, -N(H)S(O) _1-2 C ₁ -C ₆ alkyl, - N(C ₁ -C ₆ alkyl)S(O) _1-2 C ₁ -C ₆ alkyl, -S(O) _0-1 N(H)(C ₁ -C ₆ alkyl), -S( O) _0-1 N(C ₁ -C ₆ alkyl) ₂ , -S(O) _0-1 NH ₂ , -C(=O)C ₁ -C ₆ alkyl, -C(=O)C ₃ -C ₇ cycloalkyl _, -C(=NOH)C ₁ -C ₆ alkyl, -C(=NOC ₁ -C ₆ alkyl)C ₁ -C ₆ alkyl, -NHC(=O)N(H )(C ₁ -C ₆ alkyl), -NHC(=O)N(C ₁ -C ₆ alkyl) ₂ , -NHC(=O)NH ₂ , -N(C ₁ -C ₆ alkyl)C (=O)N(H)(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)C(=O)NH ₂ , -OC(=O)C ₁ -C ₆ alkyl , -OC(=O)OC ₁ -C ₆ alkyl, -OP(=O)(OC ₁ -C ₆ alkyl) ₂ , -SC(=O)OC ₁ -C ₆ alkyl and -SC(= O) N(C ₁ -C ₆ alkyl) ₂ , wherein any alkyl portion of R ^f is optionally substituted by halogen;

R ^is selected from halogen, OH, C ₁ -C ₆ alkyl and oxo; and

R ^g is selected from C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, wherein R ^g can optionally be replaced by C ₁ -C ₃ alkoxy, F, OH, CN, SH, CH ₃ or CF ₃ replace.

In some embodiments, the compound of formula (I) is not compound 1-199 in PCT/EP2014/067872 filed August 22, 2014 or an intermediate disclosed therein. In some embodiments, the compound of Formula (I) is not a compound selected from compounds 1x-199x in Table 1x.

Table 1x

In some embodiments, the compound has Formula (I), wherein Q is C. In some embodiments, the compound is of formula (I), wherein Q is C, with the proviso that the compound is not a compound selected from compounds 1x-146x and 148x-199x.

In some embodiments, compounds of formula (I) are further defined as compounds of formula (II):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein:

Ring A is a monocyclic or fused bicyclic ring;

A ₁ is NR ¹ , N, S, CR ¹ or CHR ¹ ;

A ₂ is NR ² , N, O, S, CR ² or CHR ² ;

A ₃ is N or C;

A ₄ is N; and

One, two or three of A ₁ -A ₄ are N, where:

Each R ¹ is independently selected from H, halogen, NR ^a R ^b , NHC(O)NR ^a R ^b , NHS(O) ₂ CH ₃ , C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₃ alkoxy and 3-11 membered heterocyclic group, wherein the alkyl of R ¹ is optionally replaced by F, OH, CN, SH, C ₁ -C ₃ alkoxy or 3-11 membered heterocyclic group Substituted; Cycloalkyl ^of R is optionally substituted by F, OH, CN, SH, CH, or CF _; Alkoxy ^of _R is optionally substituted by F, OH, CN, or SH; and Heterocycle ^of R The group is optionally substituted by F, OH, CN, SH, CF ₃ or C ₁ -C ₃ alkyl,

R ² are each independently selected from H, NR ^a R ^b , C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy, phenyl and 3-11 membered heterocyclyl , wherein R ² is optionally substituted by R ^c ; or

R ¹ and R ² together with the atoms they are connected to form a cyclic group selected from C ₃ -C ₇ cycloalkyl, phenyl and 3-11 membered heterocyclic groups, wherein the cyclic group is optionally replaced by ^Rd replaces;

R ⁴ is selected from H, C ₁ -C ₆ alkyl, CH ₂ F and CH ₂ OH;

R ⁵ is a 3-11 membered heterocyclyl, optionally substituted by ^Re or -C(=O)N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁴ and R ⁵ together form a C ₃ -C ₁₁ cycloalkyl optionally substituted by ^Re or a 3-11 membered heterocyclic group optionally substituted by ^Re ;

One of A ₅ -A ₈ is N and the rest is CR ⁶ or all are CR ⁶ ;

R ⁶ at each occurrence is independently selected from H, F, Cl, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , OH, OCH ₃ , OCHF ₂ , OCH ₂ F, OCF ₃ , SH, SCH ₃ , SCHF ₂ , SCH ₂ F, CN, CH ₃ , CHF ₂ , CH ₂ F, CH ₂ OH, CF ₃ , NO ₂ and N ₃ ;

R ^is selected from H and C ₁ -C ₆ alkyl optionally substituted by C ₁ -C ₃ alkoxy, F, OH, CN, SH, CH ₃ or CF ₃ ;

R ^b is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C(O)R ^g , phenyl and 3-11 membered heterocyclic groups, Wherein R ^b can be optionally substituted by C ₁ -C ₃ alkoxy, F, OH, CN, SH, CH ₃ or CF ₃ ;

R ^c and R ^d are each independently selected from halogen, -(X ¹ ) _0-1 -CN, -(X ¹ ) _0-1 -NO ₂ , -(X ¹ ) _0-1 -SF ₅ , -(X ¹ ) _0-1 -OH, -(X ¹ ) _0-1 -NH ₂ , -(X ¹ ) _0-1 -N(H)(R ^1a ), -(X ¹ ) _0-1 -N(R ^1b ) (R ^1a ), -(X ¹ ) _0-1 -CF ₃ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkane Oxygen, C ₁ -C ₆ alkylthio, oxo, -(X ¹ ) _0-1 -C ₁ -C ₆ alkyl, -(X ¹ ) _0-1 -C _3- C ₁₀ cycloalkane radical, -OC _3- C ₁₀ cycloalkyl, -(X ¹ ) _0-1 -3-11 membered heterocyclyl, -(X ¹ ) _0-1 -C ₆ -C ₁₀ aryl, -C(= O)(X ¹ ) ₁ -C _3- C ₁₀ cycloalkyl, -C(=O)(X ¹ ) ₁ -3-11 membered heterocyclyl, -(X ¹ ) _0-1 -C(=Y ¹ )N(H)(R ^1a ), -(X ¹ ) _0-1 -C(=Y ¹ )NH ₂ , -(X ¹ ) _0-1 -C(=Y ¹ )N(R ^1a )( R ^1b ), -(X ¹ ) _0-1 -C(=Y ¹ )OR ^1a , -(X ¹ ) _0-1 -C(=Y ¹ )OH, -(X ¹ ) _0-1 -N( H)C(=Y ¹ )(R ^1a ), -(X ¹ ) _0-1 -N(R ^1b )C(=Y ¹ )(R ^1a ), -(X ¹ ) _0-1 -N(R ^1b )C(=Y ¹ )(H), -(X ¹ ) _0-1 -N(H)C(=Y ¹ )OR ^1a , -(X ¹ ) _0-1 -N(R ^1b )C( =Y ¹ )OR ^1a , -(X ¹ ) _0-1 -S(O) _1-2 R ^1a , -(X ¹ ) _0-1 -N(H)S(O) _1-2 R ^1a , - (X ¹ ) _0-1 -N(R ^1b )S(O) _1-2 R ^1a , -(X ¹ ) _0-1 -S(O) _0-1 N(H)(R ^1a ), -( X ¹ ) _0-1 -S(O) _0-1 N(R ^1b )(R ^1a ), -(X ¹ ) _0-1 -S(O) _{0- 1} NH ₂ , -(X ¹ ) _{0- 1} -S(=O)(=NR ^1b )R ^1a , -(X ¹ ) _0-1 -C(=Y ¹ )R ^1a , -(X ¹ ) _0-1 - C(=Y ¹ )H, -(X ¹ ) _0-1 -C(=NOH)R ^1a , -(X ¹ ) _0-1 -C(=NOR ^1b )R ^1a , -(X ¹ ) _{0- 1} -NHC(=Y ¹ )N(H)(R ^1a ), -(X ¹ ) _0-1 -NHC(=Y ¹ )NH ₂ , -(X ¹ ) _0-1 -NHC(=Y ¹ ) N(R ^1b )(R ^1a ), -(X ¹ ) _0-1 -N(R ^1a )C(=Y ¹ )N(H)(R ^1a ), -(X ¹ ) _0-1 -N( R ^1a )C(=Y ¹ )N(R ^1a )(R ^1b ), -(X ¹ ) _0-1 -N(R ^1a )C(=Y ¹ )NH ₂ , -(X ¹ ) _0-1 -OC(=Y ¹ )R ^1a , -(X ¹ ) _0-1 -OC(=Y ¹ )H, -(X ¹ ) _0-1 -OC(=Y ¹ )OR ^1a , -(X ¹ ) _0-1 -OP(=Y ¹ )(OR ^1a )(OR ^1b ), -(X ¹ )-SC(=Y ¹ )OR ^1a and -(X ¹ )-SC(=Y ¹ )N(R ^1a )(R ^1b ), wherein X ¹ is selected from C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₂ -C ₆ alkenylene, C ₂ -C ₆ alkynylene, C ₁ -C ₆ alkyleneoxy, C _3- C ₇ cycloalkylene, 3-11 membered heterocyclylene and phenylene; R ^1a and R ^1b are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C _3- C ₇ cycloalkyl, (C _3- C ₇ cycloalkylene) C ₁ -C ₆ alkyl, 3-11 membered hetero Cyclic group, (3-11 membered heterocyclylene) C ₁ -C ₆ alkyl, C ₆ aryl and (C ₆ -C ₁₀ arylene) C ₁ -C ₆ alkyl, or R ^1a and R ^1b When attached to the same nitrogen atom, optionally combined to form ^a 3-11 membered heterocyclyl containing 0-3 additional heteroatoms selected from N, O and S; Y is O, ^NR or S, where R ^1c is H or C ₁ -C ₆ alkyl; wherein any part of the R ^c or R ^d substituents, including R ^1a , R ^1b and R ^1c , are each independently further substituted at each occurrence with 0 to 4 R ^f substituent, the R ^f substituent is selected from halogen, CN, NO ₂ , SF ₅ , OH, NH ₂ , -N(C ₁ -C ₆ alkyl) ₂ , -NH(C ₁ -C ₆ alkyl) , oxo, C ₁ -C ₆ alkyl, -(C ₂ -C ₆ alkynylene) -(3-11 membered heterocyclyl, wherein the heterocyclyl is optionally substituted by ^Re ), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C _3- C ₇ cycloalkyl, 3-11 membered heterocycle radical, -C(=O)N(H)(C ₁ -C ₆ alkyl), -C(=O)N(C _1- C ₆ alkyl) ₂ , -C(=O)NH ₂ , - C(=O)OC ₁ -C ₆ alkyl, -C(=O)OH, -N(H)C(=O)(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkane group) C(=O)(C ₁ -C ₆ alkyl), -N(H)C(=O)OC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)C(=O )OC ₁ -C ₆ (halo)alkyl, -S(O) _1-2 C ₁ -C ₆ alkyl, -N(H)S(O) _1-2 C ₁ -C ₆ alkyl, - N(C ₁ -C ₆ alkyl)S(O) _1-2 C ₁ -C ₆ alkyl, -S(O) _0-1 N(H)(C ₁ -C ₆ alkyl), -S( O) _0-1 N(C ₁ -C ₆ alkyl) ₂ , -S(O) _0-1 NH ₂ , -C(=O)C ₁ -C ₆ alkyl, -C(=O)C ₃ -C ₇ cycloalkyl _, -C(=NOH)C ₁ -C ₆ alkyl, -C(=NOC ₁ -C ₆ alkyl)C ₁ -C ₆ alkyl, -NHC(=O)N(H )(C ₁ -C ₆ alkyl), -NHC(=O)N(C ₁ -C ₆ alkyl) ₂ , -NHC(=O)NH ₂ , -N(C ₁ -C ₆ alkyl)C (=O)N(H)(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)C(=O)NH ₂ , -OC(=O)C ₁ -C ₆ alkyl , -OC(=O)OC ₁ -C ₆ alkyl, -OP(=O)(OC ₁ -C ₆ alkyl) ₂ , -SC(=O)OC ₁ -C ₆ alkyl and -SC(= O) N(C ₁ -C ₆ alkyl) ₂ , wherein any alkyl portion of R ^f is optionally substituted by halogen;

R ^is selected from halogen, OH, C ₁ -C ₆ alkyl and oxo; and

R ^g is selected from C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, wherein R ^g can optionally be replaced by C ₁ -C ₃ alkoxy, F, OH, CN, SH, CH ₃ or CF ₃ replace.

In some embodiments, the compound has Formula (II), with the proviso that the compound is not a compound selected from compounds 1x-146x and 148x-199x.

In some embodiments, Ring A is a monocyclic ring. A ₁ is N or CHR ¹ . In some embodiments, A ₁ is N. _In some embodiments, A1 is N, _A2 is _S , and A3 is C. ^In some embodiments, A2 is N, O, or _CHR2 . In some embodiments, _A is N. In some embodiments, A ₁ is S, A ₂ is N, and A ₃ is C. _In some embodiments, A2 is O, A1 is _CR1 , ^A2 is _O , and _A3 is C.

In some embodiments, A ₁ is CHR ¹ and A ₂ is CHR ² and Ring A is a non-aromatic heterocycle. In some embodiments, A ₁ is CHR ¹ and A ₂ is CHR ² and Ring A is a non-aromatic monocyclic heterocycle. In some embodiments, A ₁ is CHR ¹ and A ₂ is CHR ² and Ring A is a fused bicyclic non-aromatic heterocycle. In some embodiments, A ₁ is CHR ¹ ; A ₂ is CHR ² ; and R ¹ and R ² together with the atoms to which they are attached form a C ₃ -C ₇ cycloalkyl optionally substituted with R ^d or optionally 3-11 membered heterocyclic group substituted by ^Rd . ^In some embodiments, R and R are taken together to form the following cyclic group, wherein the asterisk indicates the point of ring fusion to Ring ^A , and each of the cyclic groups is ^optionally substituted with R:

^In some embodiments, R and R together with the atoms to which they are attached form a moiety having the following structure ^: It is optionally substituted with ^Rd , where the asterisk indicates the point of ring fusion to ring A.

In some embodiments, A ₁ is CR ¹ , wherein R ¹ is selected from NHC(O)NR ^a R ^b ;

NHS(O) ₂ CH ₃ ; C ₁ -C ₃ alkyl substituted by C ₁ -C ₃ alkoxy or 3-11 membered heterocyclic group; and 3-11 membered substituted by C ₁ -C ₃ alkyl heterocyclyl. In some embodiments, A ₁ is CR ¹ , wherein R ¹ is NHC(O)NR ^a R ^b . In some of these embodiments, R ^a and R ^b are independently selected from H and C ₁ -C ₆ alkyl.

In some embodiments, A ₁ is CR ¹ , wherein R ¹ is NHS(O) ₂ CH ₃ . In some embodiments, A ₁ is CR ¹ , wherein R ¹ is 3-11 membered heterocyclyl substituted with C ₁ -C ₃ alkyl. In some embodiments, A ₁ is CR ¹ , wherein R ¹ is C ₁ -C ₃ alkyl substituted by C ₁ -C ₃ alkoxy or 3-11 membered heterocyclyl.

In some embodiments, A ₁ is CR ¹ , wherein R ¹ is selected from:

Wherein the wavy line represents the connection point of R in formula ( ^I ) or (II).

In some embodiments of formula (I) or (II), A ₁ is NR ¹ , S, or CR ¹ ; and A ₂ is NR ² , S, or CR ² . In some embodiments, A is a monocyclic ring.

In some embodiments, A ₁ is NR ¹ . In some embodiments, A ₁ is NR ¹ , A ₂ is CR ² and A ₃ is C. In some of these embodiments, R ¹ is H or C ₁ -C ₃ alkyl. In some embodiments, A ₁ is CR ¹ . In some embodiments, A ₁ is CR ¹ , A ₂ is CR ² and A ₃ is N. In some embodiments, A ₁ is CR ¹ and A ₆ is CR ⁶ . In some of these embodiments, A ₂ is CR ² , wherein R ² is H or —OCH ₃ .

In some embodiments, A ₁ is CR ¹ , A ₂ is S and A ₃ is C. In some ^of these embodiments, R1 is not _-NH2 or _-CH3 .

In some embodiments, R ¹ is H, F or Cl.

In some embodiments, R ¹ is NR ^a R ^b . In some of these embodiments, R ^a is H or C ₁ -C ₆ alkyl. In some of these embodiments, ^R is H; C ₁ -C ₆ alkyl optionally substituted with C ₁ -C ₃ alkoxy, F, OH, CN, SH, CH ₃ , or CF ₃ ; or optionally A 3-11 membered heterocyclic group substituted by C ₁ -C ₃ alkoxy, F, OH, CN, SH, CH ₃ or CF ₃ . In some of these embodiments, ^Rb is C(O) ^Rg . In some embodiments, R ^g is C ₃ -C ₆ cycloalkyl optionally substituted with F.

In some embodiments, R ¹ is C ₁ -C ₃ alkyl optionally substituted by F, OH, CN, SH, C ₁ -C ₃ alkoxy, or 3-11 membered heterocyclyl; optionally substituted by F , OH, CN, SH, CH ₃ or CF ₃ substituted C ₃ -C ₇ cycloalkyl; or C ₁ -C ₃ alkoxy.

In some embodiments, R ¹ is 3-11 membered heterocyclyl optionally substituted with F, OH, CN, SH, CF ₃ , or C ₁ -C ₃ alkyl.

In some embodiments, R ¹ is 5-6 membered heteroaryl optionally substituted with F, OH, CN, SH, CF ₃ or C ₁ -C ₃ alkyl.

^In some embodiments, R is selected from:

H, -CH ₃ , -CH ₂ CH ₃ ,

Wherein the wavy line represents the connection point of R in formula ( ^I ) or (II).

_In some embodiments, A1 is S. In some embodiments, A ₁ is S, A ₂ is CR ² and A ₃ is C. In some embodiments, R ² is H. In some embodiments,

In some embodiments, A ₁ is NR ¹ or CR ¹ ; and A ₂ is NR ² or CR ² .

In some embodiments, A ₁ is NR ¹ or CR ¹ ; A ₂ is NR ² or CR ² ; and R ¹ and R ² together with the atoms to which they are attached form C ₃ -C ₇ ^optionally substituted by R Cycloalkyl, or 3-11 membered heterocyclyl optionally substituted by ^Rd . ^In some ^of these embodiments, R and R, together with the atoms to which they are attached, form a moiety selected from:

where the asterisk indicates the point of ring fusion to ring A.

In some embodiments, A ₇ is CR ⁶ , wherein R ⁶ is H. In some embodiments, A ₈ is CR ⁶ , wherein R ⁶ is H or F. In some embodiments, A ₅ is CR ⁶ , wherein R ⁶ is H. In some embodiments, A ₆ is CR ⁶ , wherein R ⁶ is selected from H, F, OCH ₃ and CH ₃ . In some embodiments, A ⁵ , A ⁶ , A ⁷ and A ⁸ are each independently CR ⁶ , wherein R ⁶ at each occurrence is independently selected from H, F, OCH ₃ and CH ₃ , and n is 0 .

In some embodiments, the compound of formula (I) is further defined as a compound of formula (III):

wherein rings A, A ₁ , A ₂ , A ₃ , A ₄ , R ⁴ and R ⁵ are as defined in formula (II) or any of the modified forms detailed herein, n is 0, 1 or 2, and R ⁶ Each is independently selected from F, Cl, OCH ₃ , CH ₃ and CF ₃ . In some embodiments, the compound has Formula (III), with the proviso that the compound is not selected from compounds 1x-3x, 12x-14x, 16x, 18x-50x, 53x, 57x, 67x-70x, 73x-77x in Table 1x , 84x-140x, 143x-164x and 167x-199x compounds.

In some embodiments of compounds of formula (I), (II) or (III), R ⁴ and R ⁵ together with the carbon to which they are attached form a C ₈ -C ₁₀ cycloalkyl optionally substituted with ^Re . ^In some embodiments, R and R are ^taken together with the carbon to which they are attached to form a 4-9 membered heterocyclyl optionally substituted with ^Re .

In some embodiments of the compound of formula (I), (II) or (III), wherein the following moiety:

is defined as

in:

A ₉ is O, NR ¹¹ or CR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are each independently selected from H, halogen, OH and C ₁ -C ₃ alkyl;

^R7 and ^R8 are each independently selected from halogen, OH, _C1 - _C6 alkyl, or ^R7 and ^R8 together form =O, and

R ⁹ and R ¹⁰ are each independently selected from H and R ^e , or R ⁹ and R ¹⁰ together with the atoms to which they are attached form a C ₅ -C ₆ cycloalkyl group optionally substituted by ^Re or optionally substituted by R ^e Substituted 5-6 membered heterocyclyl.

In some of these embodiments, R ⁷ and R ⁸ are taken together to form =O; R ⁹ and R ¹⁰ are each H; and A ₉ is NR ¹¹ , wherein R ¹¹ is C ₁ -C ₃ alkyl.

In some embodiments, some selected from:

In some embodiments, some yes

It is intended and understood that each and every variation of _A to _A described for formula (I), ( ^II ) or (III), including variations ^of R and R when applicable, may be with each and each variant of A ₅ -A ₈ described for formula (I), (II) or (III) and with R ⁴ described for formula (I), (II) or (III) Each and each variation of and R5 is incorporated as if each and each combination ^were individually recited. For example, in some embodiments, Ring A is a monocyclic ring, A ₁ is NR ¹ , A ₅ , A ₆ , A ₇ and A ₈ are each independently CR ⁶ , and -C(R ⁴ )(R ⁵ )OH Part is 3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl. In some embodiments, Ring A is a monocyclic ring, A ₁ is CR ¹ , wherein R ¹ is not -NH ₂ or -CH ₃ , A ₂ is S, A ₃ is C, A ₅ , A ₆ , A ₇ and A ₈ are each independently CR ⁶ , and the moiety —C(R ⁴ )(R ⁵ )OH is 3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl. In some embodiments, ring A is a monocyclic ring, A ₁ is CR ¹ , A ₂ is CR ² , A ₃ is N, A ₆ is CR ⁶ , and the -C(R ⁴ )(R ⁵ )OH moiety is 3 -Hydroxy-1-methyl-2-oxopyrrolidin-3-yl.

In some embodiments, a compound of formula (I), (II) or (III), wherein ring A is a monocyclic ring; A ₁ is NR ¹ , S or CR ¹ ; and A ₂ is NR ² , S or CR ² . In some embodiments, a compound of formula (I), (II) or (III), wherein ring A is a monocyclic ring; A ₁ is NR ¹ , S or CR ¹ ; and A ₂ is NR ² , S or CR ² ; With the proviso that the compound is not a compound selected from compounds 55x, 78x-83x, 89x, 195x and 197x.

In some embodiments, the compound has Formula (I), (II) or (III), wherein the -C(R ⁴ )(R ⁵ )OH moiety is 3-hydroxy-1-methyl-2-oxopyrrolidine -3-base. In some embodiments, the compound has Formula (I), (II) or (III), wherein the -C(R ⁴ )(R ⁵ )OH moiety is 3-hydroxy-1-methyl-2-oxopyrrolidine -3-yl; provided that the compound is not selected from the group of compounds - Compounds of 169x, 173x-180x, 182x-184x, 186x, 188x-199x.

In some embodiments, one of A ₁ -A ₄ is N. _In some embodiments, A4 is N. In some embodiments, two of A ₁ -A ₄ are N. For example, in some embodiments, each _of A1 and _A4 is N. _In other embodiments, A3 and _A4 are each N. In any such embodiment, ring B can be phenyl or phenyl independently substituted with one or two R ⁶ . In some embodiments, A ¹ is CR ¹ , A ² is CR ² , A ³ is N, and A ⁴ is N.

In some embodiments, R ¹ is selected from H, F and Cl. _In some embodiments, R2 is selected from H, ^NH2 , _CH3 , and cyclopropyl. In other embodiments, R ² is C ₃ -C ₁₁ heterocycloalkyl. ^In some embodiments, R and R are taken together to form the following cyclic groups, where the asterisk indicates the point of ring fusion to Ring ^A , each cyclic group ^optionally substituted with R:

^In some embodiments, R and R are taken together to form the following cyclic group, wherein the asterisk indicates the point of ring fusion to Ring ^A , and each cyclic group is ^optionally substituted with R:

^In some embodiments, R and R are taken together to form ^an unsubstituted cyclic group.

In some embodiments, R ^d is selected from OH, CN, F, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-phenyl, NR ^a R ^b , 4-6 membered heterocyclyl, C(O)R ^g , C(O) ₂ R ^g and C ₁ -C ₆ alkyl optionally substituted by OH, CN, or 4-6 membered heterocyclyl.

In some embodiments, Ring B is phenyl.

In some embodiments, R ^c and R ^d are each independently selected from halogen, -(X ¹ ) _0-1 -CN, -(X ¹ ) _0-1 -NO ₂ , -(X ¹ ) _0-1 - SF ₅ , -(X ¹ ) _0-1 -OH, -(X ¹ ) _0-1 -NH ₂ , -(X ¹ ) _0-1 -N(H)(R ^1a ), -(X ¹ ) _{0 -1} -N(R ^1b )(R ^1a ), -(X ¹ ) _0-1 -CF ₃ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, oxo, -(X ¹ ) _0-1 -C ₁ -C ₆ alkyl, -(X ¹ ) _0-1 -C _3- C ₇ cycloalkyl, -(X ¹ ) _0-1 -3-11 membered heterocyclyl (such as 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl), -(X ¹ ) _{0 -1} -C ₆ -C ₁₀ aryl, -C(=O)(X ¹ ) ₁ -C _3- C ₇ cycloalkyl, -C(=O)(X ¹ ) ₁ -3-11 membered heterocycle radical, -(X ¹ ) _0-1 -C(=Y ¹ )N(H)(R ^1a ), -(X ¹ ) _0-1 -C(=Y ¹ )NH ₂ , -(X ¹ ) _{0 -1} -C(=Y ¹ )N(R ^1a )(R ^1b ), -(X ¹ ) _0-1 -C(=Y ¹ )OR ^1a , -(X ¹ ) _0-1 -C(=Y ¹ )OH, -(X ¹ ) _0-1 -N(H)C(=Y ¹ )(R ^1a ), -(X ¹ ) _0-1 -N(R ^1b )C(=Y ¹ )(R ^1a ), -(X ¹ ) _0-1 -N(R ^1b )C(=Y ¹ )(H), -(X ¹ ) _0-1 -N(H)C(=Y ¹ )OR ^1a , - (X ¹ ) _0-1 -N(R ^1b )C(=Y ¹ )OR ^1a , -(X ¹ ) _0-1 -S(O) _1-2 R ^1a , -(X ¹ ) _0-1 - N(H)S(O) _1-2 R ^1a , -(X ¹ ) _0-1 -N(R ^1b )S(O) _1-2 R ^1a , -(X ¹ ) _0-1 -S(O ) _0-1 N(H)(R ^1a ), -(X ¹ ) _0-1 -S(O) _0-1 N(R ^1b )(R ^1a ), -(X ¹ ) _0-1 -S( O) _0-1 NH ₂ , -(X ¹ ) _0-1 -S(=O)(=NR ^1b )R ^1a , -(X ¹ ) _0-1 -C(=Y ¹ )R ^1a and -( x ¹ ) _0-1 -C(=Y ¹ )H, wherein X ¹ is selected from C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₂ -C ₆ alkenylene, C ₂ - C ₆ alkynylene, C ₁ -C ₆ alkyleneoxy, C _3- C ₇ cycloalkylene, 3-11 membered heterocyclylene and phenylene; R ^1a and R ^1b are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C _3- C ₇ cycloalkyl, 3-11 membered heterocyclyl and phenyl, or R ^1a and R ^1b is optionally combined when attached to the same nitrogen atom to form a 3-11 membered heterocyclyl group containing 0-3 additional heteroatoms selected from N, O and S (eg 4-7 membered heterocycloalkyl or 5 -6-membered heteroaryl); Y ¹ is O, NR ^1c or S, wherein R ^1c is H or C ₁ -C ₆ alkyl; wherein R ^c or R ^d substituting any part, including R ^1a , R ^1b and R ^1c are each independently further substituted at each occurrence with 0 to 4 R ^f substituents selected from the group consisting of halogen, CN, NO ² , OH, NH ₂ , -N _{(C 1 -C 6} alkyl) ₂ , -NH(C ₁ -C ₆ alkyl), oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - C ₆ heteroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C _3- C ₇ cycloalkyl, or 3-11 membered heterocyclic group (such as 4-7 membered heterocyclic alkyl or 5-6 membered heteroaryl).

In some embodiments, a heterocyclic group contains one to three nitrogen atoms, one oxygen atom, or one sulfur atom, or any combination thereof.

In some embodiments, compounds of the invention are defined as one or more of the following:

Some embodiments provide pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient. The compounds or pharmaceutical compositions described herein are useful in therapy, e.g., inflammatory disorders (e.g. lupus, e.g. systemic lupus erythematosus, extrarenal lupus or lupus nephritis, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and transplant rejection). Also provided is the use of a compound or pharmaceutical composition described herein in the manufacture of an inflammatory disorder (e.g. lupus, e.g. systemic lupus erythematosus, extrarenal lupus or lupus nephritis, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and transplant rejection).

Also provided is a method of treating an inflammatory disorder in a patient, the method comprising administering to the patient an effective amount of a compound or pharmaceutical composition as described herein. The inflammatory condition may be selected from lupus such as systemic lupus erythematosus, extrarenal lupus or lupus nephritis, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and transplant rejection .

Also provided are processes for the preparation of compounds of formula (I):

wherein Q, A ₁ , A ₂ , A ₃ , A ₄ , A ₅ , A ₆ , A ₇ , A ₈ , R ⁴ and R ⁵ are as defined above, in (a)(i) palladium(0) catalyst or Under the existence of (a) (ii) copper catalyst and (b) base, make formula (A) compound under Suzuki reaction condition:

wherein X is Cl, Br or I,

contact with a compound of formula (B),

where [M] is boric acid, borate ester or trifluoroborate,

A compound of formula (I) is obtained.

Those skilled in the art are familiar with Suzuki reactions and the reagents employed in such reactions. See, eg, Suzuki, J. Organometallic Chem., 576:147-168 (1999). Non-limiting examples of palladium catalysts include Pd(PPh ₃ ) ₄ , Pd(OAc) ₂ and Pd(PPh ₃ ) ₂ Cl ₂ . A non-limiting example of a copper catalyst is copper(II) acetate. Non-limiting examples of bases include sodium carbonate, potassium carbonate and cesium carbonate or mixtures thereof. In some embodiments, copper(II) acetate and pyridine as the base are employed under Chan-Lam coupling conditions, as known in the art. For example, the carbon nitrogen bond in indazole or azaindazole can be formed using Chan-Lam coupling conditions. A variety of organic solvents can be used, including toluene, THF, dioxane, 1,2-dichloroethane, DMF, DMSO, and acetonitrile. The reaction temperature varies depending on conditions, but is usually room temperature to 150°C.

In some embodiments, the invention provides compounds of Table 1A and Table 1B:

Table 1A

Table 1B

In some embodiments, the present invention provides compounds of the Examples.

In some embodiments, the compound is selected from compounds 1-69 and salts thereof. In some embodiments, the compound is selected from compounds 4, 5, 12, 16, 20, 26, 37, 43, 49, 52, 55, 65, and 67, and salts thereof.

Synthesis of NIK inhibitors

Methods for preparing intermediates and compounds of the invention are given in the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the invention. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives or reaction conditions. Additionally, most of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

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 outlined in: Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, Vol. 1-23, Wiley, N.Y. (ed. 1967-2006), or Beilsteins Handbuchder organischen Chemie, 4, edited by Aufl., Springer-Verlag, Berlin, including supplements, included via the Beilstein online database).

In the preparation of compounds of formula (I), (II) or (III), protection of remote functional groups (eg primary or secondary amines) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation method. The need for such protection is readily determined by those skilled in the art. Exemplary protecting groups are provided herein. For a general description of protecting groups and their uses, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physicochemical differences by methods well known to those skilled in the art, for example by chromatography or fractional crystallization. Enantiomers can be separated by converting an enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g. a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomeric enantiomers, and the conversion (eg hydrolysis) of individual diastereomers into the corresponding pure enantiomers. Also, some of the compounds of the present invention may be atropisomers (eg substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by using chiral HPLC columns or supercritical fluid chromatography.

Individual stereoisomers, e.g., enantiomers, substantially free of their stereoisomers may be obtained by separation of a racemic mixture by methods such as diastereoisomer formation using an optically active resolving agent. Split to obtain (Eliel, E. and WileN, S., Stereochemistry of Organic Compound, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C.H., J.Chromatogr., 113 (3): 283-302 (1975) ). The racemic mixtures of the chiral compounds of the present invention may be separated or isolated by any suitable method, including: (1) formation of nonionic diastereomeric salts with the chiral compounds and separation by fractional crystallization or other methods separation; (2) formation of diastereoisomeric compounds, separation of diastereomers and conversion to pure stereoisomers with chiral derivatizing reagents; and (3) direct separation under chiral conditions of substantially pure or enriched stereoisomers. See: Drug Stereochemistry, Analytical Methods and Pharmacology, edited by Irving W. Wainer, Marcel Dekker, Inc., New York (1993).

Diastereoisomeric salts can be obtained by combining enantiomerically pure chiral bases such as strychnine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), etc. Formed by the reaction of asymmetric compounds with acidic functional groups such as carboxylic and sulfonic acids. Diastereoisomeric salts may be introduced for separation by fractional crystallization or ion chromatography. For the separation of the optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid can lead to the formation of diastereoisomeric salts.

Alternatively, a diastereoisomeric pair is formed by reacting the substrate to be dissolved with one enantiomer of a chiral compound (Eliel, E. and Wilen, S., Stereochemistry of Organic Compound, John Wiley & Sons, Inc., New York, 1994, p. 322). Diastereoisomeric compounds can be obtained by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing reagent such as a menthyl derivative, followed by separation of the diastereomers and hydrolysis to obtain the pure or enriched Enantiomers are formed. Methods for determining optical purity involve the preparation of racemic mixtures of chiral esters such as menthyl esters such as (-) menthyl chloroformate or Mosher esters, acetic acid α-methoxy-α-(trifluoromethyl phenyl ester (Jacob, J. Org. Chem. 47:4165 (1982)) and analyze the NMR spectrum for the presence of two atropisomeric enantiomers or diastereomers. Appropriate diastereoisomers of atropisomeric compounds can be determined by normal and reverse phase chromatography followed by the method for separation of atropisomeric naphthyl-isoquinoline compounds (WO 96/15111) Separate and separate. By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography W.J. Lough, ed., Chapman and Hall, New York, (1989); Okamoto, J. of Chromatogr. 513:375-378 (1990)). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism. The absolute stereochemistry of chiral centers and enantiomers can be determined by X-ray crystallography.

Positional isomers such as E and Z forms of compounds of formula (I), (II) or (III) and intermediates used in their synthesis can be observed by characterization methods such as NMR and analytical HPLC. For certain compounds in which the exchange energy barrier is sufficiently high, the E and Z isomers can be separated, eg, by preparative HPLC.

Pharmaceutical composition and administration

The compounds of interest of the present invention are NIK kinase inhibitors and are useful in the treatment of various diseases such as cancer or inflammatory disorders.

The present invention also provides compositions and medicaments comprising compounds of formula (I), (II), (III) or any variant thereof detailed herein and at least one pharmaceutically acceptable carrier, diluent or excipient. Compositions of the invention are useful for inhibiting NF-kB signaling activity in a mammal (eg, a human patient), eg, by inhibiting NIK activity.

"Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II), (III) or any variant thereof as detailed herein and a pharmaceutically acceptable carrier, diluent or excipient (or potion). In another embodiment, the invention provides for the preparation of a composition (or medicament) comprising a compound of the invention. In another embodiment, the present invention provides the administration of a compound of formula (I), (II), (III) or any variant thereof as detailed herein and comprising Compositions of compounds of formula (I), (II), (III) or any variant thereof.

The compositions can be formulated, dosed and administered in a manner consistent with good medical practice. Factors considered herein include the particular disorder being treated, the particular mammal being treated, the individual patient's clinical condition, etiology, site of drug delivery, method of administration, administration regimen, and other factors known to the medical practitioner. The effective amount of the compound to be administered will be determined by such considerations as preventing or treating an undesired disease or disorder such as, for example, neurodegeneration, amyloidosis, neurofibrillary tangle formation, or undesired cell growth ( The minimum amount required for inhibition of NIK activity required for eg cancer cell growth). For example, the amount may be lower than that which is toxic to normal cells or to the mammal as a whole.

In one example, the therapeutically effective amount of a compound of the invention administered parenterally per day will be about 0.01-100 mg/kg patient body weight or about eg 0.1 to 20 mg/kg patient body weight, eg 0.3 to 15 mg per day /kg/day. The daily dose is administered in some embodiments as a single daily dose or in divided doses from two to six times a day, or in a sustained release form. For a 70 kg adult, the total daily dosage will generally be from about 7 mg to about 1,400 mg. The dosage regimen can be adjusted to provide the optimum therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

The compounds of the present invention can be administered in any conventional administration forms such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain conventional components in pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

The compounds of the present invention may be administered in any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, Intrathecal and epidural and intranasal administration, including intralesional administration if desired for local treatment. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

Compositions comprising compounds of formula (I), (II), (III) or any variant thereof detailed herein are generally formulated as pharmaceutical compositions in accordance with standard pharmaceutical practice. A typical formulation is prepared by mixing a compound of the invention with a diluent, carrier or excipient. Suitable diluents, carriers and excipients are known to those skilled in the art and are described in detail, for example, in Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids agents, coloring agents, sweeteners, flavoring agents, flavoring agents, diluents and other known additives to provide an elegant appearance to the drug (i.e. the compound of the present invention or its pharmaceutical composition) or to aid in the preparation of the drug product (i.e. ).

Suitable carriers, diluents or excipients are known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble or swelling polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. substance. The particular carrier, diluent or excipient used will depend on the manner and purpose for which the compound of the invention is being used. Solvents are generally selected based on solvents generally recognized as safe (GRAS) for administration to mammals by those skilled in the art. Generally, safe solvents are non-toxic aqueous solvents 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 (eg, PEG 400, PEG 300), and the like, and mixtures thereof. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids Additives, colorants, sweeteners, flavoring agents, flavoring agents and other known additives to provide an elegant appearance of the drug (ie, the compound of the present invention or its pharmaceutical composition) or to help prepare a drug product (ie, a medicament).

Acceptable diluents, carriers, excipients, and stabilizers that are nontoxic to recipients at the dosages and concentrations employed include buffers such as phosphates, citrates, and other organic acids; antioxidants, Including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; Alkyl parabens such as methyl or propyl parabens; catechol; m-diphenol; cyclohexanol; 3-pentanol; 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 dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexing substances (such as Zn-protein complexes); or non-ionic surfactants such as TWEEN ^™ , PLURONICS ^™ or polyethylene glycol (PEG). The active pharmaceutical ingredient of the present invention (such as the compound of formula (I), (II), (III) or any variant thereof as detailed herein) can also be encapsulated in prepared microcapsules (such as by coacervation technology or by interfacial Polymers, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules), colloidal drug delivery systems (such as liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules ) or coarse emulsion. Such techniques are disclosed in Remington: Science and Practice of Pharmacy: Remington Science and Practice of Pharmacy (2005) 21st Edition, Lippincott Williams & Wilkins, Philadelphia, PA.

Sustained release formulations of the compounds of the invention can be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers comprising a compound of formula (I), (II), (III) or any variant thereof as detailed herein, said matrix being in the form of a shaped article , such as membranes or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (such as poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (U.S. Patent No. 3,773,919), L-glutamic acid with - Copolymers of ethyl L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT ^TM (composed of lactic acid-glycolic acid copolymers and leuprolide acetate injection microspheres) and poly-D-(-)-3-hydroxybutyrate.

Formulations include those suitable for the routes of administration detailed 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 found in Remington: Science and Practice of Pharmacy: Remington Science and Practice of Pharmacy (2005) 21st Edition, Lippincott Williams & Wilkins, Philadelphia, PA. Such methods include bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.

In general, the formulations are prepared by uniformly and intimately admixing the active ingredient with liquid carriers, diluents or excipients or finely divided solid carriers, diluents or excipients or both, and then shaping the product if necessary. A typical formulation is prepared by mixing a compound of the invention and a carrier, diluent or excipient. Formulations can be prepared using conventional dissolution and mixing procedures. For example, a drug substance starting material (i.e. a compound of the invention or a stabilized form of a compound (e.g. complexed with a cyclodextrin derivative or other known complexing agent) is prepared in the presence of one or more excipients as described above. compound) in a suitable solvent. The compounds of the invention are generally prepared in pharmaceutical dosage forms to provide easy control of the dosage of the drug and to allow patient compliance with the prescribed regimen.

In one example, a compound of formula (I), (II) or (III) can be formulated by mixing with a physiologically acceptable carrier at ambient temperature, at an appropriate pH and at the desired purity. The pH of the formulation depends largely on the particular use and concentration of compound, but is generally about 3 to about 8. In one example, compounds of formula (I), (II), (III) or any variant thereof detailed herein are formulated in acetate buffer at pH 5. In additional embodiments, the compound of formula (I), (II) or (III) is sterile. Compounds can be stored as, for example, solid or amorphous compositions, lyophilized formulations or aqueous solutions.

Formulations of a compound of the invention suitable for oral administration can be prepared as discrete units such as pellets, capsules, cachets or tablets, each containing a predetermined amount of a compound of the invention.

Compressed tablets may be prepared by compressing, in a suitable tablet machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. preparation. Molded tablets may be made by molding in a suitable machine the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient.

Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules such as gelatin capsules, syrups or elixirs may be prepared for oral use. Formulations of compounds of the invention intended for oral use may be prepared by any method known in the art for the preparation of pharmaceutical compositions which may contain one or more substances, including sweetening agents, flavoring agents, , coloring and preservatives to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically 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 cornstarch or alginic acid; binders such as starch, gelatin or acacia; and lubricating agents. agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained release 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.

An example of a suitable oral administration form contains admixed with about 5-30 mg of anhydrous lactose, about 5-40 mg of croscarmellose sodium, about 5-30 mg of polyvinylpyrrolidone (PVP) K30 and about 1-10 mg of magnesium stearate. Tablets of about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg and 500 mg of a compound of the invention. Mix the powdered ingredients together first, then mix with the PVP solution. The resulting composition is dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving a compound of the invention, e.g. 5-400 mg of the compound, in a suitable buffer solution such as phosphate buffer and adding a tonicifier such as a salt such as sodium chloride if desired . The solution can be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

For the treatment of the eye or other external tissues such as mouth and skin, the formulation is preferably applied as a topical ointment or cream containing the active ingredient in an amount of eg 0.075 to 20% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include polyols, i.e. alcohols with two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerin and polyethylene glycols (including PEG 400) and mixtures thereof. Topical formulations may desirably include compounds that promote absorption or penetration of the active ingredient through the skin or other affected area. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.

The oily phase of the emulsions according to the invention can be constituted in a known manner from known ingredients. While the phase may contain only emulsifiers, it is also desirable to contain a mixture of at least one emulsifier with fat or oil or both. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier acting as a stabilizer. It is also preferred to include both oils and fats. Emulsifiers, with or without stabilizers, together constitute so-called emulsifying waxes, which together with oils and fats constitute so-called emulsifying ointment bases, which form the oily dispersed phase of cream preparations. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the invention include 60、 80. Cetearyl Alcohol, Benzyl Alcohol, Myristyl Alcohol, Glyceryl Monostearate and Sodium Lauryl Sulfate.

Aqueous suspensions of compounds of the invention contain the active materials 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, yellow Gum yarrow and acacia and dispersing or wetting agents such as naturally occurring phospholipids (e.g. lecithin), condensation products of alkylene oxides with fatty acids (e.g. polyoxyethylene stearate), ethylene oxides and long-chain fatty alcohols Condensation products of ethylene oxide (eg heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (eg 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 Sweeteners such as sucrose or saccharin.

The formulation of the compound of this invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known 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 nontoxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol, or prepared as a frozen Dry powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose any mixed fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are likewise employed in the preparation of injectables.

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

Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostats, and solutes to render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous nonaqueous Bacterial suspensions, which may contain suspending agents and thickeners.

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 active ingredient is preferably present in the formulation at a concentration of about 0.5 to 20% w/w, for example about 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges, which contain the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles, which contain an inert base such as gelatin and glycerin or sucrose. and the active ingredient in gum arabic; and a mouthwash comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as suppositories with a suitable base comprising, for example, cocoa butter or salicylic acid.

Formulations suitable for intrapulmonary or nasal administration have a particle size, for example, in the range of 0.1 to 500 microns (including particle sizes in the range of 0.1 to 500 microns in micron increments, such as 0.5, 1, 30 microns, 35 microns, etc.) Administration is performed by rapid inhalation through the nasal passages or by inhalation through the mouth 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 useful in the treatment of the disorders described below.

Formulations suitable for vaginal administration may be presented as vaginal rings, 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 can be packaged in unit-dose or multi-dose containers, such as hermetically sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, such as water for injection, just before use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing daily or sub-daily dosage units as herein above indicated, or an appropriate fraction thereof, of the active ingredient.

INDICATIONS AND TREATMENT

Compounds of formula (I), (II) or (III) inhibit NIK activity. Accordingly, in a further aspect of the invention, the compounds of the invention are useful in the treatment of diseases and disorders in mammalian, eg human patients, in which inhibition of NIK in the patient would be therapeutically effective. For example, compounds of the invention are useful in the treatment of diseases or disorders associated with overactive or undesired NF-kB signaling via, eg, NIK overactivation, in a mammal (eg, a human patient). In one embodiment, the compounds of the invention are used to inhibit NIK activity, for example by contacting NIK with a compound of formula (I), (II), (III) or any variant thereof as detailed herein, in an in vitro assay setting to proceed. For example, a compound of formula (I), (II) or (III) may be used as a control compound in an in vitro assay setting.

In further embodiments, the compounds of the invention are used to inhibit undesired NF-kB signaling, for example in cell proliferation assays, by introducing into cells the formula (I), (II), (III) as detailed herein ) compound or any variant thereof. In additional embodiments, the invention provides methods of treating a disease or disorder associated with overactive or undesired NF-kB signaling (e.g., cancer, inflammatory disease, etc.) in a mammal (e.g., a human patient) , the method comprising administering to a mammal (eg, a human patient) in need thereof a therapeutically effective amount of a compound of the invention.

Diseases and disorders treatable by the methods of the invention include cancer, inflammatory conditions, autoimmune diseases, and proliferation following medical procedures (e.g., arthritis, graft rejection, inflammatory bowel disease, cell proliferation following surgical angioplasty) Wait). In one embodiment, a mammal (e.g., a human patient) is treated with a compound of the present invention to inhibit inhibition of NIK, for example, but not limited to, and a pharmaceutically acceptable carrier, adjuvant or vehicle. An amount that inhibits NF-kB signaling is present.

In one embodiment, the compounds of the invention are useful in the treatment of cell proliferation disorders.

In one embodiment of the invention, the cancer which may be treated with the compounds of formula (I), (II) and (III) is selected from the group consisting of lung cancer (bronchial carcinoma (non-small cell lung cancer); gastrointestinal-rectal, colorectal and colon cancers of the genitourinary tract-kidney (papillary renal cell carcinoma); and skin-head and neck squamous cell carcinoma.

In one embodiment, compounds of formula (I), (II) and (III) are useful in the treatment of cancers selected from the group consisting of head and neck squamous cell carcinoma, histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, non- Small cell lung cancer, pancreatic cancer, papillary renal cell carcinoma, liver cancer, gastric cancer, colon cancer, leukemia, lymphoma, multiple myeloma, glioblastoma, and breast cancer.

In one embodiment, compounds of formula (I), (II) and (III) are useful in the treatment of cancers selected from the group consisting of histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, liver cancer, gastric cancer, colon cancer , leukemia, lymphoma, multiple myeloma, glioblastoma, and breast cancer.

In one embodiment, compounds of formula (I), (II) and (III) are useful in the treatment of a cancer selected from the group consisting of lymphoma, leukemia and multiple myeloma.

In one embodiment, the present invention provides the preparation of a medicament for the treatment of lymphoma, leukemia or multiple myeloma, said medicament comprising a compound of formula (I), (II), (III) or any variant thereof.

In one embodiment, the present invention provides the treatment of lymphoma, leukemia or multiple myeloma, the method comprises administering an effective amount of the compound of formula (I), (II), (III) or any of them detailed herein Variants.

In one embodiment, the compounds of the present invention are useful in the treatment of inflammatory diseases and disorders including, but not limited to, lupus (including systemic lupus erythematosus, extrarenal lupus and lupus nephritis), asthma, COPD, rhinitis, multiple sclerosis, IBD , arthritis, gastritis, rheumatoid arthritis, dermatitis, endometriosis, transplant rejection, myocardial infarction, Alzheimer's disease, type II diabetes, inflammatory bowel disease, sepsis, and atherosclerosis .

In one embodiment, the present invention provides the use of a compound of formula (I), (II), (III) or any variant thereof as detailed herein for the treatment of an inflammatory disorder.

In one embodiment, the present invention provides the use of a compound of formula (I), (II), (III) or any variant thereof as detailed herein for the manufacture of a medicament for the treatment of an inflammatory disorder.

In one embodiment, the present invention provides a compound of formula (I), (II), (III) or any variant thereof as detailed herein for use in the treatment of an inflammatory disorder.

In one embodiment, the present invention provides a method for treating an inflammatory disorder comprising administering to a patient in need thereof an effective amount of a compound of formula (I), (II), (III) or any variant thereof.

In one embodiment, the present invention provides a treatment for an inflammatory disorder selected from the group consisting of lupus (including systemic lupus erythematosus, extrarenal lupus and lupus nephritis), COPD, rhinitis, multiple sclerosis, IBD, Arthritis, rheumatoid arthritis, dermatitis, endometriosis, and transplant rejection, the method comprising administering an effective amount of a compound of formula (I), (II), (III) or any variant thereof as detailed herein .

combination

Compounds of formula (I), (II) and (III) may be used alone or in combination with other therapeutic agents for therapy. In one embodiment, the compounds of the invention may be used alone or in combination with chemotherapeutic agents. In one embodiment, the compounds of the invention may be used alone or in combination with anti-inflammatory agents. The compounds of the invention may be used in combination with one or more additional drugs that act by a different mechanism of action, such as anti-inflammatory compounds or anti-cancer compounds. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compounds of the invention so that they do not adversely affect each other. Such molecules are conveniently present in combination in amounts effective for the intended purpose. The compounds may be administered together in a single pharmaceutical composition or separately, and when administered separately this may occur simultaneously or sequentially in any order. The sequential administration may be close in time or distant in time.

In some embodiments, a compound of formula (I), (II), (III) or any variant thereof as detailed herein is combined as a combination therapy with a second therapeutic compound in a pharmaceutical combination formulation or dosing regimen, so Said second therapeutic compound has anti-inflammatory or anti-cancer properties or is useful in the treatment of inflammation, immune response disorder or hyperproliferative disorder (eg cancer). The second therapeutic agent can be an NSAID (non-steroidal anti-inflammatory drug) or other anti-inflammatory drug. The second therapeutic agent can be a chemotherapeutic agent. In one embodiment, the pharmaceutical composition of the present invention comprises a compound of formula (I), (II), (III) or any variant thereof as detailed herein in combination with a therapeutic agent such as an NSAID.

Example

While the invention has been described and explained with a certain degree of particularity, it will be understood that the disclosure has been made by way of example only and that various changes in combinations and arrangements of parts may be made by those skilled in the art without departing from what is claimed The spirit and scope of the invention are defined.

The chemical reactions in the examples can be readily adapted to prepare various other compounds of the invention, and alternative methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds of the invention may be successfully carried out by modifications apparent to those skilled in the art, such as by suitably protecting interfering groups, by utilizing other suitable compounds known in the art other than those described. reagents or by making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be deemed suitable for preparing other compounds of the invention.

General Method A : SNAr

To a solution of nitrogen-containing nucleophile (1 equiv) and cesium carbonate (3.0 equiv) in N,N-dimethylformamide (2 mL/mmol) was added 2-haloheterocycle (1.1 equiv). The reaction was heated to 100°C and stirred at this temperature for 2 hours. The reaction was then cooled to room temperature and acidified to pH=1 with 10% aqueous HCl if the product contained formic acid, or diluted with water if neutral. The solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was used directly in subsequent reactions or purified by flash chromatography.

General Method B : Amide Synthesis from Heterocyclic Carboxylic Acids

Aromatic or non-aromatic heterocyclic acid (1 eq) and HATU (1.2 eq) were weighed, transferred to a vial, and DMF and DIPEA (3-5 eq) were added sequentially to the vial. The amine (HNRR) was later added to the reaction mixture as free base or HCl salt and the reaction was stirred at room temperature or 50°C for 2-18 hours. The reaction conversion was monitored by LCMS. Upon completion, the reaction was cooled and the crude product was triturated via addition of water and collected by filtration or extracted with saturated ammonium chloride and DCM. Trituration or purification by chromatography affords the amide.

General Method C : Chan-Lam Cross-Coupling

Add nitrogen-containing nucleophile (1 equiv), arylboronic acid (1.5 equiv), copper(II) acetate in N,N-dimethylformamide (2 mL/mmol) and pyridine (3.0 equiv) to the vial Monohydrate (0.3 equiv). The reaction was stirred at 90°C for 6 hours under an oxygen atmosphere. The reaction was then cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and the aqueous phase was extracted 3 times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography.

General Procedure D : Hydrolysis of Nitriles to Primary Amides

To a solution of arylnitrile (1 eq) in ethanol (0.8 mL/mmol) and water (0.04 mL/mmol) was added hydrogenated (dimethylphosphinate-kp) [hydrobis(dimethylphosphino- kp)] platinum (II) (hydrido (dimethylphosphinousacid-kp) [hydrogenbis (dimethyl phosphinito-kp)] platinum (II)) (0.05 equivalent). The reaction was stirred at 90°C under air for 2 hours. The solution was then cooled to room temperature and extracted twice with ethyl acetate or dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was used directly in subsequent reactions or purified by flash chromatography.

General procedure for the cross-coupling of aryl-halides (ArX) to terminal alkynes:

General Procedure E : Weigh the aryl halide, transfer to a sealed tube, and bring up acetonitrile (3 mL/mmol) and triethylamine (3 mL/mmol). The solution was degassed with nitrogen and ketone iodide (I) (0.05 equiv) and bis(triphenylphosphine)palladium(II) chloride (0.1 equiv) were added. Then DMF (3 mL/mmol) was added, followed by the alkyne (2-3 eq.) dropwise. The reaction mixture was heated at 80°C for 3-18 hours, monitoring the consumption of starting material by LCMS. Upon completion, the reaction was cooled and the crude product was triturated with addition of water and collected by filtration or extracted with saturated ammonium chloride and DCM at which point the organic layer was dried, filtered and concentrated to dryness. The crude product was purified by reverse phase HPLC.

General Procedure F : Weigh aryl halide (where X = bromine) (1 eq), ketone iodide (I) (0.06 eq), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq) and dichloro Bis(phenylcyanide)palladium (0.1 equiv), transferred to a microwave tube. After addition of DMSO (3 mL/mmol), the reaction mixture was subsequently degassed, at which point a solution of the alkyne (3 equiv) in diisopropylamine (3 equiv) was added dropwise. The reaction mixture was capped and heated at 80 °C, monitoring the consumption of starting material by LCMS. Post-processing is the same as in operation E.

General Procedure G : Weigh the aryl halide (where X = bromine), transfer to a closed tube, and bring up DMSO or DMF (3 mL/mmol) and triethylamine (3 mL/mmol). The solution was degassed with nitrogen and bis(triphenylphosphine)palladium(II) chloride (0.2 equiv) and alkyne (2-3 equiv) were added ("copper free" condition). The reaction mixture was heated at 80°C for 2-18 hours, monitoring the consumption of starting material by LCMS. Post-processing is the same as in operation E above.

General procedure H : Conversion of esters to amides with sodium methoxide/formamide:

To a solution of the heterocyclic ester in N,N-dimethylformamide was added formamide (10 eq) followed by dropwise addition of sodium methoxide (3 eq). The mixture was stirred at room temperature or heated to 40 °C, monitored by LC-MS for completion. The crude reaction mixture was either triturated via addition of saturated ammonium chloride or extracted with dichloromethane where the product was not fragmented. In cases where this was an intermediate, the crude material was used directly in subsequent reactions.

General procedure I : Conversion of esters to amides with ammonium hydroxide in dioxane:

To a solution of the heterocyclic ester in dioxane (10 mL/mmol) was added ammonium hydroxide (25% substance) in water (50 equiv, 14 mmol). The reaction mixture was stirred at 40°C and monitored for completion by LC-MS. The crude reaction mixture was concentrated to dryness and purified by reverse phase HPLC to afford the product.

General Procedure J : Ester Saponification:

To a solution of the heterocyclic ester in 1:1 tetrahydrofuran/water was added lithium hydroxide monohydrate (3-10 equivalents). The reaction was either stirred at room temperature or heated to 50 °C and monitored for completion by LC-MS. The tetrahydrofuran was then evaporated and the pH of the aqueous crude reaction mixture was adjusted to 3, at which point the product fractured and isolated, or the aqueous layer was extracted with dichloromethane or ethyl acetate if the product did not fracture. In cases where this was an intermediate, the crude material was used directly in subsequent reactions.

General Procedure K : Ketone/Aldehyde Reduction:

To a solution of the heterocyclic ketone/aldehyde in methanol was added sodium borohydride (1-3 equiv). The reaction was stirred at 0°C or room temperature until effervescence subsided, complete by LC-MS. The reaction mixture was extracted with dichloromethane and saturated ammonium chloride, at which point the organic layer was dried, filtered and concentrated to afford the crude heterocyclic alcohol intermediate, which was used directly in subsequent reactions.

General Method L : Fluorination Reaction

Add 4 equivalents of diethylaminosulfur trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride to a solution of alcohol, aldehyde or ketone in dichloromethane or dichloroethane (Deoxo-Fluor). The reaction was either stirred at room temperature or heated to 45°C and monitored for completion by LC-MS. The reaction mixture was concentrated to dryness and the crude intermediate was triturated via addition of water and used in subsequent reactions without further purification.

General Method M : Suzuki Coupling of Boronic Acids or Esters with Aryl Halides

Weigh the aryl halide, tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium(II) dichloride (0.05 equiv) and boronic acid or pinacol ester (1.2 equiv) into a microwave tube or airtight test tube middle. Acetonitrile (3 mL/mmol) and 1M aqueous sodium carbonate (3 equiv) were added. The vial was capped and heated at 100°C for 3-18 hours. Upon completion, the reaction was cooled and the crude product was triturated via addition of water and collected by filtration or extracted with saturated ammonium chloride and DCM. If the crude product was an intermediate, it was in most cases carried on to the next step with or without further purification, or if it was the final product it was purified by reverse phase HPLC.

General Procedure N : Reductive Amination of Aryl Aldehydes.

To a solution containing aryl aldehyde (1 eq) in 10% DMF solution of acetic acid (6 mL/mmol) was added molecular sieves (1 eq wt), amine (HNRR, 4 eq) and sodium cyanoborohydride (1.2 eq) . The reaction was heated at 45°C or stirred at room temperature. Upon completion, the reaction was extracted with DCM and saturated ammonium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated to give the crude product which was used in the next step without purification.

General Method O : Carbonyl Methanolysis of Aryl Halides

To a nitrogen flushed solution of the aryl iodide in TEA (3 mL/mmol), DMF (3 mL/mmol) and MeOH (3 mL/mmol) was added palladium(II) acetate (0.03 equiv) and Xantphos (0.06 equiv). The reaction mixture was flushed with carbon monoxide gas for several minutes, then sealed with an attached CO balloon and heated to 60 °C for 3 hours. Upon completion, the reaction was cooled to room temperature and the crude product was triturated by adding water and collected by filtration. The crude intermediate was used in the next step with or without further purification.

General Procedure P : Carbonylated Amidation with HMDS

To a non-exclusive nitrogen-degassed solution of aryl iodide (Ar-I) in DMF (170 equiv) was added bis(triphenylphosphine)palladium(II) dichloride (0.05 equiv) and hexamethyldisilazyl Amine (6 equiv). The reaction mixture was flushed with carbon monoxide gas for several minutes, then sealed with an attached CO balloon and heated to 70 °C for 18 hours. Upon completion, the reaction was cooled to room temperature and the crude product was triturated by adding water and collected by filtration. The crude intermediate was used in the next step with or without further purification.

General Procedure S : Conversion of Esters to Amides Using Ammonia in Methanol

A stirred solution of the ester (1 equiv) in methanol was treated with saturated ammonia (>20 equiv) in methanol. The mixture was stirred at room temperature or heated to 40 °C, and the reaction was monitored by LC-MS. The crude reaction mixture was concentrated and purified by reverse phase HPLC.

General Method T : SEM Deprotection with HCl

A 4.0M solution of the SEM-protected amine or alcohol and hydrogen chloride in dioxane (17.0 equiv) was combined in ethanol (4.0 mL/mmol) and stirred at 50°C for 2 hours. Samples were then concentrated in vacuo and used directly in subsequent reactions or purified by flash chromatography.

General procedure for Suzuki coupling with aryl trifluoroborates:

General Procedure U : A test tube containing a solution of aryl chloride/bromide (1 eq) and aryl trifluoroborate (1 eq) in ethanol is flushed with nitrogen, then Pd(OAc)2 (0.06 eq), Pd(OAc) ₂ (0.06 eq), RuPhos (0.12 equiv) and sodium carbonate (2 equiv). The tubes were sealed with disposable Teflon-lined lids and heated at 85°C for 12-20 hours. The reaction mixture was cooled to room temperature, filtered through celite, and used directly for reverse phase HPLC purification or extracted with dichloromethane and saturated ammonium chloride solution, then dried, evaporated, reverse phase purified or used without purification for subsequent A step of.

General Procedure V : Degas a solution of aryl chloride/bromide (1 eq) and aryl trifluoroborate (1 eq) in 20% aqueous dioxane (0.28 M), then add cesium carbonate (3 eq ) and tetrakis(triphenylphosphine)palladium(0) (0.05 equiv). The reaction mixture was heated at 100°C for 1 hour and then cooled to room temperature. Post-processing is the same as the general method U.

General Procedure W : Degas a solution of aryl chloride/bromide (1 eq) and aryl trifluoroborate (1 eq) in acetonitrile (0.25 M) followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.05 equiv) and a 1:1 mixture of 1M sodium carbonate (2 equiv) and 1M potassium acetate (2 equiv). Reactions were performed in 5 mL biotage microwave tubes, heated to 140°C for 20-40 minutes, then cooled to room temperature. Post-processing is the same as the general method U.

General Method X : Synthesis of SEM-Protected Tetrahydroindazoles

Step 1: A solution of diisopropylamine (1.7 equiv) in THF (4.6 mL/mmol) was cooled to -78°C, then a solution of n-butyllithium in hexane (1.6M, 1.5 equiv) was added dropwise . After stirring for 5 minutes, the mixture was added via cannula to a -78°C solution of ethyl diazoacetate (1.6 equiv) and cycloalkylketone (1.0 equiv) in THF (4.6 mL/mmol). The mixture was stirred at -78 °C for 1 h, then quenched by the addition of saturated aqueous _NH4Cl . The mixture was diluted with water and extracted with EtOAc (2x). The combined organic extracts were dried ( _MgSO4 ) and concentrated in vacuo. Purification by CombiFlash (heptane:EtOAc) provided the expected product.

Step 2: To a solution of the product from the previous step (1.0 eq) in pyridine (4.6 mL/mmol) was added _POCl3 (4.35 eq) and the mixture was allowed to stir at room temperature overnight. After concentration in vacuo, the mixture was poured onto ice, then extracted with EtOAc (3 times). The combined organic extracts were dried ( _MgSO4 ) and concentrated in vacuo. The residue was diluted with octane (2.1 mL/mmol) and heated at 110°C for 2 hours. After concentration in vacuo, purification by CombiFlash (heptane:EtOAc) provided the expected product.

Step 3: A solution of the product from the previous step (1.0 equiv) in THF (20 mL/mmol) was cooled to 0 °C, then sodium hydride (60%, 3.0 equiv) was added. After stirring for 1 h, SEMCl (1.2 equiv) was added and the mixture was allowed to warm to room temperature overnight. After quenching excess hydride by addition of 0 °C water, the mixture was extracted with EtOAc (3 times), the organic extracts were dried ( _MgSO4 ) and concentrated in vacuo. Purification by CombiFlash (heptane:EtOAc) provided the expected ester-containing product. The ester was diluted with THF (5.4 mL/mmol), acetonitrile (5.4 mL/mmol) and water (5.4 mL/mmol), lithium hydroxide monohydrate (7.0 equiv) was added, and the mixture was stirred overnight. The mixture was diluted with water, acidified to pH 3 with 1N HCl (aq), extracted with _Et2O (1x) and 10% MeOH/ _{CH2Cl2 (} 3x). The combined organic extracts were dried ( _MgSO4 ) and concentrated in vacuo to provide the expected carboxylic acid in sufficient purity for immediate use.

General Method Y: Alternative Synthesis of SEM-Protected Tetrahydroindazoles

Step 1: A solution of cycloalkyl ketone (1.0 equiv) in EtOH (0.5 mL/mmol) was cooled to 0 °C, then sodium ethoxide (21% wt solution in EtOH, 1.1 equiv) was added. To this mixture was added diethyl oxalate (1.0 eq) and the mixture was allowed to warm to room temperature overnight. Concentration in vacuo provided the expected product in sufficient purity for immediate use (yield assumed quantitative).

Step 2: A solution of the product from the previous step (1.0 equiv) in glacial acetic acid (0.5 mL/mmol) was cooled to 0°C, then hydrazine hydrate (1.1 equiv) was added. After warming to room temperature, the mixture was stirred for 1 h, then diluted with saturated aqueous NaHCO ₃ and extracted with 10% MeOH/CH ₂ Cl ₂ . The organic extracts were dried ( _MgSO4 ) and concentrated in vacuo. Purification by CombiFlash (heptane:EtOAc) afforded the expected tetrahydroindazole-3-carboxylate.

Step 3: Proceed in a similar manner to Step 3 of General Method X.

In some cases, stereoisomers were separated to give single enantiomers or diastereoisomers as individual unknown stereoisomers, which were arbitrarily drawn as single isomers. When appropriate, give information on the method of separation and the timing and sequence of elution.

Example 1

Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(1-methyl-1H-pyrrolidinyl) Azol-4-yl)thiazole-4-carboxamide

Step 1: Synthesis of ethyl 2-amino-5-chlorothiazole-4-carboxylate

Ethyl 2-amino-1,3-thiazole-4-carboxylate (3 g, 17.421 mmol, 1.00 equiv) and N-chlorosuccinimide (2.783 g, 20.841 mmol, 1.20 equiv) were dissolved in acetonitrile (50 mL) The solution was stirred at 80°C for 2 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (30:1) to give the title compound (2 g, 56%) as a pale yellow solid. LC-MS (ES, m/z): 207 [M+H] ⁺ .

Step 2: Synthesis of ethyl 2-bromo-5-chlorothiazole-4-carboxylate

2-Amino-5-chloro-1,3-thiazole-4-carboxylic acid ethyl ester (2.00g, 9.678mmol, 1.00 equivalent), tert-butylnitrile (1.20g, 11.637mmol, 1.20 equivalent), copper bromide (2.59 g, 11.596 mmol, 1.20 equiv) in acetonitrile (50 mL) was stirred at 80°C for 2 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (40:1) to afford the title compound (1.2 g, 46%) as a white solid. LC-MS (ES, m/z): 270 [M+H] ⁺ .

Step 3: Synthesis of (R)-5-chloro-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxylic acid ethyl ester

Similar to the procedure described in General Procedure U, ethyl 2-bromo-5-chlorothiazole-4-carboxylate was reacted with (R)-trifluoro(3-((3-hydroxy-1-methyl-2-oxo Substituting pyrrolidin-3-yl)ethynyl)phenyl)potassium borate to give the title compound (180 mg, 40%) as a pale yellow solid. LC-MS (ES, m/z): 376 [M+H] ⁺ .

Step 4: Synthesis of (R)-5-chloro-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-methanol Amide

Working analogously to that described in General Procedure S, (R)-5-Chloro-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)benzene Reaction of ethyl thiazole-4-carboxylate with ammonia afforded the title compound (150 mg, 90%) as a pale yellow solid. LC-MS (ES, m/z): 376 [M+H] ⁺ .

Step 5: Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(1-methyl- 1H-pyrazol-4-yl)thiazole-4-carboxamide

Working analogously to that described in General Procedure M, (R)-5-Chloro-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)benzene base) thiazole-4-carboxamide and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H - Pyrazole reaction afforded the title compound (33.1 mg, 27%) as a white solid. LC-MS(ES,m/z):422[M+H] ⁺ .1H NMR(400MHz,CD ₃ OD):δ8.38(s,1H),8.14(s,1H),8.03-8.00(m ,1H),7.89(s,1H),7.59-7.57(m,1H),7.52-7.49(m,1H),3.96(s,3H),3.53-3.47(m,2H),2.96(s,3H ), 2.65-2.59(m,1H), 2.38-2.31(m,1H).

Example 2

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(1-methyl-1H-pyrrolidinyl) Azol-5-ylamino)-1H-pyrazole-3-carboxamide

Step 1: Synthesis of 1-(3-methoxyphenyl)-4-[(1-methyl-1H-pyrazol-5-yl)amino]-1H-pyrazole-3-carboxylic acid

Under nitrogen, 4-bromo-1-(3-methoxyphenyl)-1H-pyrazole-3-carboxylic acid methyl ester (600mg, 1.928mmol, 1.00eq), 1-methyl-1H-pyrazole Azol-5-amine (563mg, 5.797mmol, 1.00 equivalent), t-BuXPhos (82mg, 0.193mmol, 0.10 equivalent), the third generation t-BuXPhos precatalyst (154mg, 0.194mmol, 0.10 equivalent), t-BuONa ( 279 mg, 2.903 mmol, 1.50 equiv) in 1,4-dioxane (12 mL) was irradiated with microwaves at 90° C. for 90 minutes. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (1:1) to give the title compound (425 mg, 70%) as a yellow solid. LC-MS (ES, m/z): 314 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-methoxyphenyl)-4-[(1-methyl-1H-pyrazol-5-yl)amino]-1H-pyrazole-3-carboxamide

1-(3-Methoxyphenyl)-4-[(1-methyl-1H-pyrazol-5-yl)amino]-1H-pyrazole-3 - Reaction of formic acid with ammonium chloride afforded the title compound (350 mg, 88%) as a yellow solid. LC-MS (ES, m/z): 313 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-hydroxyphenyl)-4-[(1-methyl-1H-pyrazol-5-yl)amino]-1H-pyrazole-3-carboxamide

To 1-(3-methoxyphenyl)-4-[(1-methyl-1H-pyrazol-5-yl)amino]-1H-pyrazole-3-carboxamide (340mg, 1.089mmol, 1.00 Equiv) in dichloromethane (20 mL) was added dropwise with stirring at 0°C tribromoborane (818 mg, 3.265 mmol, 3.00 equiv). The resulting solution was stirred at room temperature for 2 hours. The reaction was quenched by methanol. The resulting mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (3:1) to give the title compound (290 mg, 89%) as a yellow solid. LC-MS (ES, m/z): 299 [M+H] ⁺ .

Step 4: Synthesis

1-(3-hydroxyphenyl)-4-[(1-methyl-1H-pyrazol-5-yl)amino]-1H-pyrazole-3-carboxamide (280mg, 0.939mmol, 1.00 equivalents), 1,1,1-Trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (669 mg, 1.873 mmol, 2.00 equiv) and triethylamine (5 mL) in dichloromethane (50 mL) The solution was stirred at room temperature for 14 hours. The pH of the solution was adjusted to 8, and the mixture was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyldichloromethane/methanol (10:1) to give the title compound (350 mg, 87%) as a yellow solid. LC-MS (ES, m/z): 431 [M+H] ⁺ .

Step 5: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(1-methyl- 1H-pyrazol-5-ylamino)-1H-pyrazole-3-carboxamide

Similar to the procedure described in General Method G, 3-[3-carbamoyl-4-[(1-methyl-1H-pyrazol-5-yl)amino]-1H-pyrazole trifluoromethanesulfonate -1-yl]phenyl ester was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to afford the title compound (50.8 mg, 35%) as an off-white solid.

LC-MS (ES, m/z): 420 [M+H] ⁺ .

¹ H NMR(400MHz,CD ₃ OD):δ8.14(s,1H),8.04(s,1H),7.93-7.91(m,1H),7.53-7.49(m,1H),7.45-7.40(m ,2H),6.15(s,1H),3.78(s,3H),3.52-3.49(m,2H),2.96(s,3H),2.61-2.60(m,1H),2.38-2.32(m,1H ).

Example 3

Synthesis of 4-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidine -3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxamide

Step 1: Synthesis of 4-(1,3-Dimethyl-1H-pyrazol-4-yl)-1H-pyrazole-3-carboxylic acid methyl ester

Similar to the procedure described in general method M, methyl 4-bromo-1H-pyrazole-3-carboxylate was combined with 1,3-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)-1H-pyrazole was reacted to give the title compound (200 mg, 20%) as a yellow oil. LC-MS (ES, m/z): 221 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-bromophenyl)-4-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-pyrazole-3-carboxylic acid methyl ester

Similar to the procedure described in general method C, 4-(1,3-Dimethyl-1H-pyrazol-4-yl)-1H-pyrazole-3-carboxylic acid methyl ester and 3-bromophenylboronic acid The reaction gave the title compound (200 mg, 27%) as a yellow oil. LC-MS (ES, m/z): 375 [M+H] ⁺ .

Step 3: Synthesis of 4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Substituted pyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylic acid methyl ester

Similar to the procedure described in general method G, 1-(3-Bromophenyl)-4-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-pyrazole-3-carboxylic acid Reaction of the methyl ester with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one afforded the title compound (150 mg, 65%) as a yellow oil. LC-MS (ES, m/z): 434 [M+H] ⁺ .

Step 4: Synthesis of 4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Substituted pyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method S, 4-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-(3-[2-[(3R)-3-hydroxy-1 -Methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylic acid methyl ester was reacted with ammonia to give the title compound (20.4 mg, 14%) as white solid. LC-MS(ES,m/z):419[M+H] ⁺ .1H NMR(300MHz,CD ₃ OD):δ8.37(s,1H),8.06(s,1H),7.96-7.93(m ,1H),7.84(s,1H),7.55-7.45(m,2H),3.85(s,3H),3.55-3.48(m,2H),2.94(s,3H),2.65-2.57(m,1H ), 2.37-2.32(m,1H), 2.29(s,3H).

Example 4

Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-[(methylcarbamoyl )amino]-1H-pyrazole-3-carboxamide

Step 1: Synthesis of 4-amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxamide

A solution of 1-(3-bromophenyl)-4-acetamido-1H-pyrazole-3-carboxamide (200 mg, 0.619 mmol, 1.00 equiv) in methanol (10 mL) and hydrochloric acid (5 mL) was stirred at room temperature overnight. The pH of the solution was adjusted to 7 with aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1) to give the title compound (115 mg, 63%) as a white solid. LC-MS (ES, m/z): 281 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-bromophenyl)-4-[(methylcarbamoyl)amino]-1H-pyrazole-3-carboxamide

4-Amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxamide (130mg, 0.462mmol, 1.00eq), N-methylcarbamoyl chloride (129.5mg, 1.385mmol, 3.00eq ) and triethylamine (6 mL) in dichloromethane (12 mL) was stirred at room temperature for 2 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1) to give the title compound (140 mg, 89%) as a white solid. LC-MS (ES, m/z): 338 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-[(methyl Carbamoyl)amino]-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method G, 1-(3-bromophenyl)-4-[(methylcarbamoyl)amino]-1H-pyrazole-3-carboxamide with (R)-3- Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (23.4 mg, 13%) as a white solid. LC-MS(ES,m/z):397[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ8.42(s,1H),7.86-7.85(m,1H),7.74- 7.73(m,1H),7.41-7.30(m,2H),3.40-3.36(m,2H),2.83(s,3H),2.69(s,3H),2.53-2.46(m,1H),2.26- 2.17(m,1H).

Example 5

Synthesis of (R)-1'-ethyl-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4,4'- Bi(1H-pyrazole)-3-carboxamide

Step 1: Synthesis of ethyl 1'-ethyl-4,4'-bi(1H-pyrazole)-3-carboxylate

Similar to the procedure described in general method M, ethyl 4-iodo-1H-pyrazole-3-carboxylate was reacted with 1-ethyl-1H-pyrazol-4-ylboronic acid to afford the title compound (343 mg, 27 %), as a yellow oil. LC-MS (ES, m/z): 235 [M+H] ⁺ .

Step 2: Synthesis of ethyl 1-(3-bromophenyl)-1'-ethyl-4,4'-bi(1H-pyrazole)-3-carboxylate

Similar to the procedure described in General Method C, ethyl 1'-ethyl-4,4'-bi(1H-pyrazole)-3-carboxylate was reacted with 3-bromophenylboronic acid to afford the title compound (311 mg ,57%) as a white solid. LC-MS (ES, m/z): 389 [M+H] ⁺ .

Step 3: Synthesis of (R)-1'-ethyl-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4, 4'-bi(1H-pyrazole)-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-1'-ethyl-4,4'-bi(1H-pyrazole)-3-carboxylate was mixed with (R) -3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (215 mg, 62%) as a yellow oil. LC-MS (ES, m/z): 448 [M+H] ⁺ .

Step 4: Synthesis of (R)-1'-ethyl-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4, 4'-bi(1H-pyrazole)-3-carboxamide

Similar to the procedure described in General Method S, 1-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -Ethyl 4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (19.6 mg, 9%) as a white solid. LC-MS(ES,m/z):419[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ8.64(s,1H),8.24(s,1H),8.06(s, 1H),7.95-7.94(m,2H),7.62-7.45(m,2H),4.25-4.18(m,2H),3.55-3.47(m,2H),2.94(s,3H),2.65-2.57( m, 1H), 2.38-2.28 (m, 1H), 1.50 (t, J=7.2Hz, 3H).

Example 6

Synthesis of (R)-4-(ethylamino)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1H-pyrrolidinyl Azole-3-carboxamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-(N-ethylacetamido)-1H-pyrazole-3-carboxylate

1-(3-Bromophenyl)-4-acetylamino-1H-pyrazole-3-carboxylic acid ethyl ester (1 g, 2.839 mmol, 1.00 equiv), sodium hydride (340 mg, 14.168 mmol, 4.99 equiv) and iodine A solution of ethane (886 mg, 5.681 mmol, 2.001 equiv) in N,N-dimethylformamide (130 mL) was stirred at 0°C for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with dichloromethane/methanol (10:1) to afford the title compound (800 mg, 74%) as a red solid. LC-MS (ES, m/z): 380 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-bromophenyl)-4-(N-ethylacetamido)-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method S, ethyl 1-(3-bromophenyl)-4-(N-ethylacetamido)-1H-pyrazole-3-carboxylate was reacted with ammonia to afford the title compound (650 mg, 88%) as a yellow solid. LC-MS (ES, m/z): 351 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-bromophenyl)-4-(ethylamino)-1H-pyrazole-3-carboxamide

1-(3-Bromophenyl)-4-(N-ethylacetamido)-1H-pyrazole-3-carboxamide (650mg, 1.851mmol, 1.00eq) was dissolved in methanol (10mL) and hydrochloric acid (5mL) The solution in was stirred overnight at room temperature. Upon completion, the solution was adjusted to pH 7 with aqueous sodium hydroxide and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with dichloromethane/methanol (10:1) to give the title compound (150 mg, 26%) as a yellow solid. LC-MS (ES, m/z): 309 [M+H] ⁺ .

Step 4: Synthesis of 4-(ethylamino)-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl )-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method G, 1-(3-bromophenyl)-4-(ethylamino)-1H-pyrazole-3-carboxamide and (R)-3-ethynyl-3- Hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (52.5 mg, 32%) as a white solid. LC-MS(ES,m/z):368[M+H] ⁺ .1H NMR(300MHz,CD ₃ OD):δ7.85(s,1H),7.85-7.84(m,1H),7.73-7.69 (m,1H),7.38-7.29(m,1H),7.28-7.26(m,1H),3.40-3.37(m,2H),3.22-3.20(m,2H),3.06-2.98(m,3H) ,2.53-2.51(m,1H),2.46-2.45(m,1H),2.26-2.20(m,3H).

Example 7

Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(trifluoromethyl)thiazole-4 -Formamide

Step 1: Synthesis of ethyl 2-amino-5-iodothiazole-4-carboxylate

Ethyl 2-amino-1,3-thiazole-4-carboxylate (3 g, 17.421 mmol, 1.00 eq) and N-iodosuccinimide (4.689 g, 20.841 mmol, 1.20 eq) were dissolved in acetonitrile (50 mL) The solution was stirred at 80°C for 2 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (30:1) to give the title compound (3.5 g, 67%) as a pale yellow solid. LC-MS (ES, m/z): 299 [M+H] ⁺ .

Step 2: Synthesis of ethyl 2-chloro-5-iodothiazole-4-carboxylate

2-Amino-5-iodothiazole-4-carboxylic acid ethyl ester (3g, 10.067mmol, 1.00 equivalent), tert-butylnitrile (1.24g, 12.080mmol, 1.20 equivalent), cuprous chloride (1.19g, 12.080 A solution of mmol, 1.20 equiv) in acetonitrile (50 mL) was stirred at 80°C for 2 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (40:1) to afford the title compound (1.8 g, 56%) as a white solid. LC-MS (ES, m/z): 318 [M+H] ⁺ .

Step 3: Synthesis of ethyl 2-chloro-5-(trifluoromethyl)thiazole-4-carboxylate

Ethyl 2-chloro-5-iodothiazole-4-carboxylate (1.05g, 3.295mmol, 1.00eq), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (948.21mg, 4.936 A solution of mmol, 1.50 equiv), cuprous iodide (938.74 mg, 4.929 mmol, 1.50 equiv) in N,N-dimethylformamide (20 mL) was stirred at 70°C for 12 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:10) to give the title compound (260 mg, 32%) as a colorless oil. LC-MS (ES, m/z): 260 [M+H] ⁺ .

Step 4: Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(trifluoromethyl) Thiazole-4-carboxylic acid ethyl ester

Similar to the procedure described in General Procedure U, ethyl 2-chloro-5-(trifluoromethyl)thiazole-4-carboxylate was mixed with (R)-trifluoro(3-((3-hydroxy-1-methyl 2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate potassium to give the title compound (300 mg, 72%) as a yellow solid. LC-MS (ES, m/z): 439 [M+H] ⁺ .

Step 5: Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(trifluoromethyl) Thiazole-4-carboxamide

Similar to the procedure described in general method S, (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5 -Ethyl (trifluoromethyl)thiazole-4-carboxylate was reacted with ammonia to give the title compound (180 mg, 67%) as a white solid. LC-MS(ES,m/z):410[M+H] ⁺ .1HNMR(300MHz,CD ₃ OD):δ8.24(s,1H),8.11-8.08(m,1H),7.68-7.65( m, 1H), 7.58-7.54(m, 1H), 3.55-3.47(m, 2H), 2.96-2.94(s, 3H), 2.65-2.50(m, 1H), 2.38-2.32(m, 1H).

Example 8

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(trifluoromethyl)-1H- Pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-iodo-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method C, ethyl 4-iodo-lH-pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to afford the title compound (1.6 g, 83%) as a white solid. LC-MS (ES, m/z): 421 [M+H] ⁺ .

Step 2: Synthesis of ethyl 1-(3-bromophenyl)-4-(trifluoromethyl)-1H-pyrazole-3-carboxylate

1-(3-Bromophenyl)-4-iodo-1H-pyrazole-3-carboxylic acid ethyl ester (500mg, 1.188mmol, 1.00eq), cuprous iodide (45mg, 0.236mmol, 0.20eq), A solution of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (342 mg, 1.782 mmol, 1.50 equiv) in N,N-dimethylformamide (12 mL) was stirred at 80° C. for 14 hours. The reactant solution was diluted with water, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:4) to give the title compound (300 mg, 70%) as a yellow solid. LC-MS (ES, m/z): 363 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(trifluoromethyl Base)-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-(trifluoromethyl)-1H-pyrazole-3-carboxylate and (R)-3-ethynyl -3-Hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (180 mg, 78%) as a yellow solid. LC-MS (ES, m/z): 422 [M+H] ⁺ .

Step 4: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(trifluoromethyl) -1H-pyrazole-3-carboxamide

Similar to the procedure described in General Method S, 1-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -4-(Trifluoromethyl)-1H-pyrazole-3-carboxylic acid ethyl ester was reacted with ammonia to give the title compound (53.7 mg, 32%) as a yellow solid. LC-MS(ES,m/z):393[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ8.88(s,1H),8.07-8.06(m,1H),7.95- 7.92 (m, 1H), 7.57-7.50 (m, 2H), 3.51-3.47 (m, 2H), 2.94 (s, 3H), 2.64-2.56 (m, 1H), 2.37-2.28 (m, 1H).

Example 9

Synthesis of 4-(1,5-Dimethyl-1H-pyrazol-4-yl)-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidine -3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxamide

Step 1: Synthesis of 4-(1,5-Dimethyl-1H-pyrazol-4-yl)-1H-pyrazole-3-carboxylic acid methyl ester

Similar to the procedure described in general method M, methyl 4-bromo-1H-pyrazole-3-carboxylate was combined with 1,5-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)-1H-pyrazole was reacted to give the title compound (440 mg, 50%) as a yellow oil. LC-MS (ES, m/z): 221 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-bromophenyl)-4-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazole-3-carboxylic acid methyl ester

Similar to the procedure described in general method C, 4-(1,5-Dimethyl-1H-pyrazol-4-yl)-1H-pyrazole-3-carboxylic acid methyl ester and 3-bromophenylboronic acid The reaction gave the title compound (300 mg, 40%) as a pale yellow oil. LC-MS (ES, m/z): 375 [M+H] ⁺ .

Step 3: Synthesis of 4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Substituted pyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylic acid methyl ester

Similar to the procedure described in general method G, 1-(3-Bromophenyl)-4-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazole-3-carboxylic acid Reaction of the methyl ester with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one afforded the title compound (240 mg, 69%) as a yellow oil. LC-MS (ES, m/z): 434 [M+H] ⁺ .

Step 4: Synthesis of 4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Substituted pyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method S, 4-(1,5-Dimethyl-1H-pyrazol-4-yl)-1-(3-[2-[(3R)-3-hydroxy-1 -Methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylic acid methyl ester was reacted with ammonia to give the title compound (10.8 mg, 5%) as white solid. LC-MS (ES, m/z): 419[M+H] ⁺ . ¹ H NMR (300MHz, CD ₃ OD): δ8.34(s, 1H), 8.06(m, 1H), 7.96-7.92( m,1H),7.58(s,1H),7.55-7.44(m,2H),3.83(s,3H),3.52-3.45(m,2H),2.94(s,3H),2.64-2.57(m, 1H), 2.35-2.29 (m, 1H), 2.28 (s, 3H).

Example 10

Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(1-methyl-1H-pyrrolidinyl) Azol-4-ylamino)thiazole-4-carboxamide

Step 1: Synthesis of 2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-[(1- Methyl-1H-pyrazol-4-yl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester

Under nitrogen, 5-chloro-2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1 , ethyl 3-thiazole-4-carboxylate (207mg, 0.512mmol, 1.00 equivalent), 1-methyl-1H-pyrazol-4-amine (240mg, 2.471mmol, 4.829 equivalent), the second generation RuPhos Pd Catalyst (58mg, 0.075mmol, 0.146eq), RuPhos (69mg, 0.148mmol, 0.289eq), cesium carbonate (160mg, 0.491mmol, 0.960eq) in 1,4-dioxane (10mL) at 80°C Stir for 1 hour. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (30:1) to give the title compound (190 mg, 82%) as a brown solid. LC-MS (ES, m/z): 466 [M+H] ⁺ .

Step 2: Synthesis of 2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-[(1- Methyl-1H-pyrazol-4-yl)amino]-1,3-thiazole-4-carboxylic acid

Similar to the procedure described in General Method J, 2-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -5-[(1-Methyl-1H-pyrazol-4-yl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester was reacted with potassium hydroxide to give the title compound (150 mg, 86%), For light brown oil. LC-MS (ES, m/z): 438 [M+H] ⁺ .

Step 3: Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(1-methyl- 1H-pyrazol-4-ylamino)thiazole-4-carboxamide

Similar to the procedure described in general method B, 2-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -5-[(1-Methyl-1H-pyrazol-4-yl)amino]-1,3-thiazole-4-carboxylic acid was reacted with ammonium chloride to give the title compound (8.3 mg, 10%) as shallow yellow solid. LC-MS(ES,m/z):437[M+H] ⁺ . ¹ H NMR(400MHz,CD ₃ OD,ppm):δ7.95(s,1H),7.83-7.81(m,2H), 7.59(s,1H),7.48-7.40(m,2H),3.92(s,3H),3.52-3.46(m,2H),2.95(s,3H),2.64-2.58(m,2H),2.37- 2.30(m,1H).

Example 11

Synthesis of (R)-5-(2-fluoro-5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1,2,4-thia Oxadiazole-3-carboxamide

Step 1: Synthesis of (3R)-3-[2-[3-(3-bromo-1,2,4-thiadiazol-5-yl)-4-fluorophenyl]ethynyl]-3-hydroxy- 1-Methylpyrrolidin-2-one

Similar to the procedure described in general method X, 3-bromo-5-chloro-1,2,4-thiadiazole was mixed with (R)-trifluoro(2-fluoro-5-((3-hydroxy-1- Methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)potassium borate was reacted to give the title compound (300 mg, 15%) as a yellow solid. LC-MS (ES, m/z): 396 [M+H] ⁺ . Step 2: Synthesis of 5-(2-fluoro-5-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1, 2,4-Thiadiazole-3-carbonitrile

Under nitrogen, (3R)-3-[2-[3-(3-bromo-1,2,4-thiadiazol-5-yl)-4-fluorophenyl]ethynyl]-3-hydroxyl- A solution of 1-methylpyrrolidin-2-one (300 mg, 0.757 mmol, 1.00 equiv) and CuCN (135 mg, 1.507 mmol, 1.99 equiv) in NMP (10 mL) was heated at 150° C. for 1 hour under microwave irradiation. After cooling, the mixture was diluted with dichloromethane, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1) to give the title compound (160 mg, 62%) as a brown oil. LC-MS (ES, m/z): 343 [M+H] ⁺ .

Step 3: Synthesis of (R)-5-(2-fluoro-5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1,2, 4-Thiadiazole-3-carboxamide

Similar to the procedure described in general method D, 5-(2-fluoro-5-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl ]phenyl)-1,2,4-thiadiazole-3-carbonitrile reacts with hydrogenated (dimethylphosphinic acid-kp)[hydrogenbis(dimethylphosphino-kp)]platinum(II), The title compound (15.7 mg, 9%) was obtained as a white solid. LC-MS(ES,m/z):361[M+H] ⁺ . ¹ H NMR(400MHz,CD ₃ OD):δ8.50-8.48(m,1H),7.65-7.62(m,1H), 7.37-7.32 (m, 1H), 3.41-3.35 (m, 2H), 2.84 (s, 3H), 2.53-2.47 (m, 1H), 2.25-2.20 (m, 1H).

Example 12

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(1-methyl-1H-pyrrolidinyl) Azol-4-ylamino)-1H-pyrazole-3-carboxamide

Step 1: Synthesis of 4-bromo-1-(3-methoxyphenyl)-1H-pyrazole-3-carboxylic acid methyl ester

Similar to the procedure described in general method C, 4-bromo-lH-pyrazole-3-carboxylic acid methyl ester was reacted with 3-bromophenylboronic acid to afford the title compound (2.1 g, 46%) as a white solid. LC-MS (ES, m/z): 311 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-methoxyphenyl)-4-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-pyrazole-3-carboxylic acid

Under nitrogen, ethyl 4-iodo-1-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate (200mg, 0.537mmol, 1.00eq), 1-methyl-1H-pyrazole -4-amine (160mg, 1.647mmol, 1.00eq), t-BuXPhos (20mg, 0.047mmol, 0.10eq), the third generation t-BuXPhos precatalyst (40mg, 0.050mmol, 0.10eq), t-BuONa (80mg , 0.832 mmol, 1.50 eq) in 1,4-dioxane (12 mL) was irradiated with microwaves at 90° C. for 60 min. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1) to give the title compound (120 mg, 71%) as a red oil. LC-MS (ES, m/z): 314 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-methoxyphenyl)-4-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-pyrazole-3-carboxamide

1-(3-Methoxyphenyl)-4-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-pyrazole-3 - Reaction of formic acid with ammonium chloride afforded the title compound (400 mg, 89%) as a yellow solid. LC-MS (ES, m/z): 313 [M+H] ⁺ .

Step 4: Synthesis of 1-(3-hydroxyphenyl)-4-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-pyrazole-3-carboxamide

1-(3-methoxyphenyl)-4-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-pyrazole-3-carboxamide ( To a solution of 400 mg, 1.281 mmol, 1.00 equiv) in dichloromethane (30 mL) was added tribromoborane (962 mg, 3.840 mmol, 3.00 equiv) dropwise. The resulting solution was stirred at room temperature for 2 hours. The reaction was quenched by methanol and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1) to give the title compound (310 mg, 81%) as a yellow solid. LC-MS (ES, m/z): 299 [M+H] ⁺ .

Step 5: Synthesis of 3-[3-carbamoyl-4-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-pyrazol-1-yl]phenyl trifluoromethanesulfonate ester

1-(3-Hydroxyphenyl)-4-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-pyrazole-3-carboxamide (310mg, 1.039mmol, 1.00eq) , 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (740mg, 2.071mmol, 2.00eq) and triethylamine (3mL) in dichloromethane (30mL) The solution in was stirred at room temperature for 14 hours. The pH of the solution was adjusted to 8, and the mixture was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (5:1) to obtain the title compound (280 mg, 63%) as a pale yellow solid. LC-MS (ES, m/z): 431 [M+H] ⁺ .

Step 6: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(1-methyl- 1H-pyrazol-4-ylamino)-1H-pyrazole-3-carboxamide

Similar to the procedure described in General Method G, 3-[3-carbamoyl-4-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-pyrazole trifluoromethanesulfonate -1-yl]phenyl ester was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give the title compound (44.5 mg, 30%) as a pale yellow solid.

LC-MS (ES, m/z): 420 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD): δ7.91-7.90(m,1H),7.87(s,1H),7.81-7.78(m,1H),7.56(s,1H),7.39-7.29(m ,3H), 3.77(s,3H), 3.40-3.35(m,2H), 2.84(s,3H), 2.53-2.47(m,1H), 2.26-2.19(m,1H).

Example 13

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(pyridin-2-yl)-1H -pyrazole-3-carboxamide

Step 1: Synthesis of 1-(3-methoxyphenyl)-4-(pyridin-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester

Reaction of 4-bromo-1-(3-methoxyphenyl)-1H-pyrazole-3-carboxylic acid methyl ester with 2-(tributylstannyl)pyridine similar to the procedure described in general method Q , to obtain the title compound (500 mg, 72%) as a pale yellow solid. LC-MS (ES, m/z): 310 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-methoxyphenyl)-4-(pyridin-2-yl)-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method S, reaction of 1-(3-methoxyphenyl)-4-(pyridin-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester with ammonia afforded the title Compound (480 mg, 95%), as light yellow solid. LC-MS (ES, m/z): 295 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-hydroxyphenyl)-4-(pyridin-2-yl)-1H-pyrazole-3-carboxamide

1-(3-Methoxyphenyl)-4-(pyridin-2-yl)-1H-pyrazole-3-carboxamide (460mg, 1.563mmol, 1.00eq) was dissolved in dichloro To a solution in methane (50 mL) was added boron tribromide (1.2 g, 4.790 mmol, 3.00 equiv) dropwise. The resulting mixture was stirred at 0 °C for 2 hours and the reaction was quenched by methanol. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (5:1) to give the title compound (430 mg, 98%) as a pale yellow solid. LC-MS (ES, m/z): 281 [M+H] ⁺ .

Step 4: Synthesis of 3-[3-carbamoyl-4-(pyridin-2-yl)-1H-pyrazol-1-yl]phenyl trifluoromethanesulfonate

1-(3-hydroxyphenyl)-4-(pyridin-2-yl)-1H-pyrazole-3-carboxamide (420mg, 1.498mmol, 1.00 equivalent), 1,1,1-trifluoro-N A solution of -phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (1.067 g, 2.987 mmol, 2.00 equiv) and triethylamine (5 mL) in dichloromethane (50 mL) was stirred at room temperature for 14 hours. The pH of the reaction solution was adjusted to 8, and the mixture was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1) to give the title compound (580 mg, 94%) as a pale yellow solid. LC-MS (ES, m/z): 413 [M+H] ⁺ .

Step 5: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(pyridin-2-yl )-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method G, 3-[3-carbamoyl-4-(pyridin-2-yl)-1H-pyrazol-1-yl]phenyl trifluoromethanesulfonate was combined with (R )-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (44.2 mg, 30%) as a white solid. LC-MS(ES,m/z):402[M+H] ⁺ . ¹ H NMR(400MHz,CD ₃ OD):δ8.86(s,1H),8.61-8.59(m,1H),8.13- 8.12(m,1H),8.01-7.99(m,2H),7.92-7.88(m,1H),7.58-7.50(m,2H),7.40-7.37(m,1H),3.53-3.49(m,2H ), 2.96(s,3H), 2.62-2.61(m,1H), 2.38-2.33(m,1H).

Example 14

Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(oxetane-3- Amino)thiazole-4-carboxamide

Step 1: Synthesis of 2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-[(oxa Ethyl cyclobutan-3-yl)amino]-1,3-thiazole-4-carboxylate

Under nitrogen, 5-chloro-2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1, Ethyl 3-thiazole-4-carboxylate (207mg, 0.512mmol, 1.00eq), oxetane-3-amine (187mg, 2.558mmol, 5.00eq), RuPhos (24mg, 0.051mmol, 0.101eq), A solution of RuPhos-PdCl-2nd G (40 mg, 0.051 mmol, 0.101 equiv), cesium carbonate (166 mg, 0.511 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) was stirred at 80°C for 1 hour. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluting with dichloromethane/methanol (20:1) to afford the title compound (150 mg, 69%) as an off-white solid. LC-MS (ES, m/z): 442 [M+H] ⁺ .

Step 2: Synthesis of 2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-[(oxa Cyclobutan-3-yl)amino]-1,3-thiazole-4-carboxylic acid

Similar to the procedure described in General Method J, 2-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) - Reaction of ethyl 5-[(oxetan-3-yl)amino]-1,3-thiazole-4-carboxylate with potassium hydroxide afforded the title compound (90 mg, 78%) as a light brown oil . LC-MS (ES, m/z): 414 [M+H] ⁺ .

Step 3: Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(oxetane -3-ylamino)thiazole-4-carboxamide

Similar to the procedure described in general method B, 2-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) - 5-[(Oxetan-3-yl)amino]-1,3-thiazole-4-carboxylic acid was reacted with ammonium chloride to give the title compound (16.0 mg, 18%) as an off-white solid. LC-MS(ES,m/z):413[M+H] ⁺ . ¹ H NMR(400MHz,CD ₃ OD):δ7.95(s,1H),7.84-7.82(m,1H),7.47- 7.43(m,2H),5.08-4.98(m,2H),4.73-4.68(m,3H),3.50-3.34(m,2H),2.96(s,3H),2.65-2.58(m,1H), 2.38-2.29(m,1H).

Example 15

Synthesis of (R)-5-ethyl-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide

Step 1: Synthesis of (R)-5-ethyl-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4- ethyl formate

2-Bromo-5-ethyl-thiazole-4-carboxylic acid methyl ester (200.0 mg, 0.80 mmol), (3R)-3-hydroxy-1-methyl-3-[2-[ 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethynyl]pyrrolidin-2-one (355.0mg, 1.04mmol), potassium acetate (141mg, 1.44mmol), sodium carbonate (144mg, 1.36mmol) and 1,1'-bi(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (53 mg, 0.064 mmol). Degassed ACN (8 mL) and water (2 mL) were added. The vial was capped and the reaction mixture was stirred under microwave conditions at 110°C for 30 minutes. The reaction mixture was poured into ethyl acetate and water and filtered through a pad of celite. The organic layer was washed with water and brine, dried _{over Na2SO4} , filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with heptane/ethyl acetate to obtain 183.3 mg (59.6%) as the expected product. LC-MS (ES, m/z): 385 [M+H] ⁺ .

Step 2: Synthesis of the title compound

Similar to the procedure described in general method S, (R)-5-ethyl-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl) Ethyl phenyl)thiazole-4-carboxylate was treated with a saturated solution of ammonia in methanol to afford the title compound (52.5 mg, 52.4%) as a solid. LC-MS(ES,m/z):370[M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.07–8.05(m,1H),8.00–7.94(m,1H), 7.92(s,1H),7.55–7.49(m,3H),6.49(s,1H),3.37–3.34(m,3H),3.30–3.29(m,1H),2.80(s,3H),2.48– 2.42 (m, 1H), 2.24–2.15 (m, 1H), 1.27 (t, J=7.5Hz, 3H).

Example 16

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-6,8-dihydro-5H-imidazo [5,1-c][1,4]oxazine-3-carboxamide

Step 1: Synthesis of tert-butyl 3-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate

Similar to the procedure described in general method B, 4-[(tert-butoxy)carbonyl]morpholine-3-carboxylic acid was reacted with methoxy(methyl)amine hydrochloride to afford the title compound (3.5 g, 59 %), as a white solid. LC-MS (ES, m/z): 275 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl 3-[(3-bromophenyl)carbonyl]morpholine-4-carboxylate

To a solution of 1,3-dibromobenzene (3.44 g, 14.58 mmol, 1.00 equiv) in THF (200 mL) was added dropwise n-butyllithium (8 mL, 2M solution in THF, 1.10 equiv) under nitrogen . The resulting solution was stirred at -78°C for 2 hours, and tert-butyl 3-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate (4.00 g , 14.58mmol, 1.00 equivalent). The resulting solution was stirred at -78°C for an additional 3 hours. The reaction was quenched by adding a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:3) to give the title compound (2.0 g, 37%) as a white solid. LC-MS (ES, m/z): 370 [M+H] ⁺ .

Step 3: Synthesis of 3-(3-bromophenyl)-4H,6H,7H-imidazo[4,3-c][1,4]oxazine

A solution of tert-butyl 3-[(3-bromophenyl)carbonyl]morpholine-4-carboxylate (2 g, 5.40 mmol, 1.00 equiv) in formamide (20 mL) and acetic acid (2 mL) was added under nitrogen Irradiation with microwave irradiation was performed at 170° C. for 25 minutes. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:10) to give the title compound (720 mg, 48%) as a yellow solid. LC-MS (ES, m/z): 279 [M+H] ⁺ .

Step 4: Synthesis of 3-(3-bromophenyl)-1-iodo-4H,6H,7H-imidazo[4,3-c][1,4]oxazine

Under nitrogen, 3-(3-bromophenyl)-4H,6H,7H-imidazo[4,3-c][1,4]oxazine (500mg, 1.79mmol, 1.00eq) in tetrahydrofuran (20mL ) was added lithium diisopropylamide (0.9 mL, 2M in THF, 1.00 equivalents). The resulting solution was stirred at -78°C for 2 hours and iodine (454 mg, 1.79 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) was added. The resulting solution was stirred at -78°C for an additional 1 hour. The reaction was quenched by adding saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:10) to obtain the title compound (500 mg, 69%) as a pale yellow solid. LC-MS (ES, m/z): 405 [M+H] ⁺ .

Step 5: Synthesis of methyl 3-(3-bromophenyl)-4H,6H,7H-imidazo[4,3-c][1,4]oxazine-1-carboxylate

3-(3-Bromophenyl)-1-iodo-4H,6H,7H-imidazo[4,3-c][1,4]oxazine was reacted with carbon monoxide similarly to the procedure described in General Method O , to obtain the title compound (210 mg, 56%) as a yellow solid. LC-MS (ES, m/z): 337 [M+H] ⁺ .

Step 6: Synthesis of 3-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4H,6H,7H- Methyl imidazo[4,3-c][1,4]oxazine-1-carboxylate

Similar to the procedure described in general method G, methyl 3-(3-bromophenyl)-4H,6H,7H-imidazo[4,3-c][1,4]oxazine-1-carboxylate Reaction with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one afforded the title compound (90 mg, 38%) as a yellow solid. LC-MS (ES, m/z): 396 [M+H] ⁺ .

Step 7: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-6,8-dihydro-5H -imidazo[5,1-c][1,4]oxazine-3-carboxamide

Similar to the procedure described in General Method S, 3-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -4H,6H,7H-Imidazolo[4,3-c][1,4]oxazine-1-carboxylic acid methyl ester was reacted with ammonia to afford the title compound (38.4 mg, 50%) as an off-white solid. LC-MS(ES,m/z):381[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ7.69(s,1H),7.54(d,J＝7.5Hz,1H) ,7.41-7.33(m,2H),5.06(s,2H),4.49(t,J=5.4Hz,2H),4.04(t,J=5.1Hz,2H),3.48-3.44(m,2H), 2.92 (s, 3H), 2.61-2.53 (m, 1H), 2.34-2.25 (m, 1H).

Example 17

Synthesis of (R)-4-(cyclopropanecarboxamido)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1H -pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-cyclopropaneamido-1H-pyrazole-3-carboxylate

Add 4-amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (500mg, 1.612mmol, 1.00eq), triethylamine (323mg, 3.192mmol, 1.98eq) at room temperature To a stirred solution in dichloromethane (20 mL, 314.601 mmol, 195.15 equiv) was added cyclopropanecarbonyl chloride (254 mg, 2.430 mmol, 1.507 equiv) dropwise. The mixture was stirred at room temperature for 2 hours. After completion, the resulting solution was concentrated in vacuo, and the residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). Yield the title compound (470 mg, 77%) as an off-white solid. LC-MS (ES, m/z): 378 [M+H] ⁺ .

Step 2: Synthesis of 4-cyclopropaneamido-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -1H-Pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-cyclopropaneamido-1H-pyrazole-3-carboxylate was reacted with (R)-3-ethynyl-3 -Hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (185 mg, 80%) as an off-white solid. LC-MS (ES, m/z): 437 [M+H] ⁺ . Step 3: Synthesis of (R)-4-(cyclopropanecarboxamido)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl )-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method S, 4-cyclopropaneamido-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl ]ethynyl]phenyl)-lH-pyrazole-3-carboxylic acid ethyl ester was reacted with ammonia to afford the title compound (77.2 mg, 49%) as a white solid. LC-MS(ES,m/z):408[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ8.70(s,1H),7.96(s,1H),7.83(d, J＝8.1Hz,1H),7.51-7.41(m,2H),3.49-3.44(m,2H),2.92(s,3H),2.59-2.49(m,1H),2.39-2.22(m,1H) ,1.85-1.75(m,1H),0.99-0.91(m,4H).

Example 18

Synthesis of (R)-4-acetylamino-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1H-pyrazole-3 -Formamide

Step 1: Synthesis of ethyl 4-acetylamino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylate

4-Amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (500mg, 1.612mmol, 1.00eq) and triethylamine (329mg, 3.251mmol, 2.017eq) in di The solution in methyl chloride (20 mL) was stirred at room temperature for 12 hours. The resulting reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:3). The title compound (450 mg, 79%) was produced as an off-white solid. LC-MS (ES, m/z): 352 [M+H] ⁺ .

Step 2: Synthesis of (R)-4-acetylamino-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1H-pyrrolidinyl Ethyl azole-3-carboxylate

Similar to the procedure described in general method G, ethyl 4-acetamido-1-(3-bromophenyl)-1H-pyrazole-3-carboxylate was combined with (R)-3-ethynyl-3-hydroxy -1-Methylpyrrolidin-2-one was reacted to give the title compound (170 mg, 73%) as an off-white solid. LC-MS (ES, m/z): 411 [M+H] ⁺ .

Step 3: Synthesis of (R)-4-acetylamino-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1H-pyridine Azole-3-carboxamide

Similar to the procedure described in General Procedure S, (R)-4-Acetamido-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl) Ethyl phenyl)-1H-pyrazole-3-carboxylate was reacted with ammonia to afford the title compound (93.7 mg, 59%) as a white solid. LC-MS (ES, m/z): 382[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ8.77(s, 1H), 7.99(s, 1H), 7.88-7.86( m,1H),7.54-7.45(m,2H),3.55-3.46(m,2H),2.95(s,3H),2.65-2.59(m,1H),2.37-2.30(m,1H),2.27( s, 3H).

Example 19

Synthesis of (R)-4-amino-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1H-pyrazole-3- Formamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-nitro-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method C, ethyl 4-nitro-lH-pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to afford the title compound (11 g, 60%) as an off-white solid. LC-MS (ES, m/z): 340 [M+H] ⁺ .

Step 2: Synthesis of ethyl 4-amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylate

Add 1-(3-bromophenyl)-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (6.800g, 19.992mmol, 1.00eq) and Raney nickel (3.0g) under stirring at room temperature Hydrazine hydrate (2.16 g, 43.148 mmol, 2.00 equiv) was added dropwise to the reaction mixture in ethanol (50 mL) for 1 hour. The resulting reaction mixture was diluted with 200 mL ethanol and 200 mL dichloromethane. The solid was filtered off and the resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1:1) to give ethyl 4-amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylate (5.5 g, 89%) as an off-white solid. LC-MS (ES, m/z): 310 [M+H] ⁺ .

Step 3: Synthesis of 4-amino-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1H- Ethyl pyrazole-3-carboxylate

Similar to the procedure described in general method G, ethyl 4-amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylate was combined with (R)-3-ethynyl-3-hydroxy- 1-Methylpyrrolidin-2-one was reacted to give the title compound (185 mg, 78%) as an off-white solid. LC-MS (ES, m/z): 369 [M+H] ⁺ .

Step 4: Synthesis of 4-amino-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1H- Pyrazole-3-carboxamide

Similar to the procedure described in general method S, 4-amino-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl ]Phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester was reacted with ammonia to afford the title compound (52.8 mg, 31%) as an off-white solid. LC-MS(ES,m/z):340[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ7.91(s,1H),7.80-7.77(m,2H),7.48- 7.37 (m, 2H), 3.51-3.46 (m, 2H), 2.94 (s, 3H), 2.64-2.56 (m, 1H), 2.37-2.27 (m, 1H).

Examples 20 and 21

Synthesis of 4-((1S,2R)-2-fluorocyclopropanecarboxamido)-1-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl )ethynyl)phenyl)-1H-pyrazole-3-carboxamide and 4-((1R,2S)-2-fluorocyclopropanecarboxamido)-1-(3-(((R)-3- Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1H-pyrazole-3-carboxamide

(isolated as individual unknown stereoisomers and arbitrarily assigned as (S,R) or (R,S))

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-[(2-fluorocyclopropane)amido]-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method B, ethyl 4-amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylate was mixed with (trans)-2-fluorocyclopropane-1- Reaction with formic acid afforded the title compound (678 mg, 88%) as a yellow oil. LC-MS (ES, m/z): 396 [M+H] ⁺ .

Step 2: Synthesis of 4-[(trans-2-fluorocyclopropane)amido]-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidine-3 -yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-[(2-fluorocyclopropane)amido]-1H-pyrazole-3-carboxylate was mixed with (R) -3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (530 mg, 68%) as an off-white solid. LC-MS (ES, m/z): 455 [M+H] ⁺ .

Step 3: Synthesis of 4-((1S,2R)-2-fluorocyclopropanecarboxamido)-1-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidine- 3-yl)ethynyl)phenyl)-1H-pyrazole-3-carboxamide and 4-((1R,2S)-2-fluorocyclopropanecarboxamido)-1-(3-(((R) -3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method S, 4-[(2-fluorocyclopropane)amido]-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Reaction of ethyl pyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylate with ammonia gave 91.0 mg (18%) of the first eluting (herein referred to as 1S,2R-isomer) isomer and 91.4 mg (18%) of the second eluting (referred to here as 1R,2S-isomer) isomer as a white solid. The stereochemistry of the two isomers was assigned arbitrarily. The first eluting isomer: t _R =9.57min (Chiralcel OJ-H, 0.46*25cm, Hex:IPA=50:50, 1ml/min); the second eluting isomer: t _R =13.89 min(Chiralcel OJ-H, 0.46*25cm, Hex:IPA=50:50, 1 ml/min); the two isomers showed the same LC-MS and ¹ HNMR as shown below.

LC-MS (ES, m/z): 426[M+H] ⁺ . ¹ H NMR (300MHz, CD ₃ OD): δ8.85(s, 1H), 7.96(s, 1H), 7.85-7.81( m,1H),7.52-7.42(m,2H),4.97-4.75(m,1H),3.51-3.47(m,2H),2.94(s,3H),2.64-2.56(m,1H),2.40- 2.30 (m, 2H), 1.62-1.47 (m, 1H), 1.42-1.31 (m, 1H).

Example 22

Synthesis of 4-((1R,2R)-2-fluorocyclopropanecarboxamido)-1-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl )ethynyl)phenyl)-1H-pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-[[(1R,2R)-2-fluorocyclopropane]amido]-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method B, ethyl 4-amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylate was reacted with (1R,2R)-2-fluorocyclopropane-1 - Reaction with formic acid afforded the title compound (350 mg, 91%) as a yellow oil. LC-MS (ES, m/z): 396 [M+H] ⁺ .

Step 2: Synthesis of 4-[[(1R,2R)-2-fluorocyclopropane]amido]-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Pyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-[[(1R,2R)-2-fluorocyclopropane]amido]-1H-pyrazole-3-carboxylate Reaction of the yl ester with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one afforded the title compound (273 mg, 68%) as a yellow oil. LC-MS (ES, m/z): 455 [M+H] ⁺ .

Step 3: Synthesis of 4-((1R,2R)-2-fluorocyclopropanecarboxamido)-1-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidine- 3-yl)ethynyl)phenyl)-1H-pyrazole-3-carboxamide

Similar to the procedure described in General Method S, 4-[[(1R,2R)-2-fluorocyclopropane]amido]-1-(3-[2-[(3R)-3-hydroxy-1- Reaction of ethyl methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylate with ammonia afforded the title compound (107.6 mg, 42%) as a white solid . LC-MS(ES,m/z):426[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ8.79(s,1H),8.00(s,1H),7.88(d, J＝7.5Hz,1H),7.54-7.43(m,2H),5.01-4.78(m,1H),3.52-3.47(m,2H),2.94(s,3H),2.64-2.57(m,1H) ,2.37-2.28(m,1H),2.10-2.04(m,1H),1.79-1.70(m,1H),1.30-1.23(m,1H).

Example 23

Synthesis of 4-((1S,2S)-2-fluorocyclopropanecarboxamido)-1-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl )ethynyl)phenyl)-1H-pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-[[(1S,2S)-2-fluorocyclopropane]amido]-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method B, ethyl 4-amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylate was mixed with (1S,2S)-2-fluorocyclopropane-1 - Reaction with formic acid afforded the title compound (334 mg, 87%) as a yellow oil. LC-MS (ES, m/z): 396 [M+H] ⁺ .

Step 2: Synthesis of 4-[[(1S,2S)-2-fluorocyclopropane]amido]-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Pyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-[[(1S,2S)-2-fluorocyclopropane]amido]-1H-pyrazole-3-carboxylate Reaction of the yl ester with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one afforded the title compound (239 mg, 62%) as a yellow oil. LC-MS (ES, m/z): 455 [M+H] ⁺ .

Step 3: Synthesis of 4-((1S,2S)-2-fluorocyclopropanecarboxamido)-1-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidine- 3-yl)ethynyl)phenyl)-1H-pyrazole-3-carboxamide

Similar to the procedure described in General Method S, 4-[[(1S,2S)-2-fluorocyclopropane]amido]-1-(3-[2-[(3R)-3-hydroxy-1- Reaction of ethyl methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylate with ammonia afforded the title compound (39.3 mg, 18%) as a white solid . LC-MS(ES,m/z):426[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ8.79(s,1H),8.00(s,1H),7.88(d, J＝7.5Hz,1H),7.54-7.44(m,2H),5.03-4.78(m,1H),3.52-3.47(m,2H),2.84(s,3H),2.64-2.57(m,1H) ,2.37-2.28(m,1H),2.10-2.05(m,1H),1.85-1.71(m,1H),1.30-1.23(m,1H).

Example 24

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-propionylamino-1H-pyrazole- 3-formamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-propionylamino-1H-pyrazole-3-carboxylate

4-Amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (200mg, 0.645mmol, 1.00eq), propionyl chloride (0.06mL, 0.648mmol, 3.35eq) and triethyl A solution of the amine (0.06 mL, 0.432 mmol, 2.23 equiv) in dichloromethane (5 mL) was stirred at room temperature for 30 minutes. The resulting mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with dichloromethane/methanol (10:1) to afford the title compound (200 mg, 85%) as a white solid. LC-MS (ES, m/z): 366 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-propionylamino- 1H-Pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-propionylamino-1H-pyrazole-3-carboxylate was combined with (R)-3-ethynyl-3- Hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (160 mg, 69%) as a brown solid. LC-MS (ES, m/z): 425 [M+H] ⁺ .

Step 3: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-propionylamino-1H- Pyrazole-3-carboxamide

Similar to the procedure described in General Method S, 1-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) - Reaction of ethyl 4-propionylamino-1H-pyrazole-3-carboxylate with ammonia afforded the title compound (51.6 mg, 37%) as an off-white solid. LC-MS(ES,m/z):396[M+H] ⁺ . ¹ H NMR(400MHz,CD ₃ OD):δ8.78-7.79(m,1H),8.00(s,1H),7.86- 7.88(m,1H),7.45-7.54(m,2H),3.47-3.53(m,2H),2.95(s,3H),2.64-2.59(m,1H),2.51-2.47(m,2H), 2.37-2.30(m,1H),2.31(m,3H).

Examples 25 and 26

Synthesis of 4-((R)-2,2-difluorocyclopropanecarboxamido)-1-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidine-3- yl)ethynyl)phenyl)-1H-pyrazole-3-carboxamide and 4-((S)-2,2-difluorocyclopropanecarboxamido)-1-(3-(((R)- 3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1H-pyrazole-3-carboxamide

(isolated as individual unknown stereoisomers and arbitrarily assigned as (R) or (R))

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-[(2,2-difluorocyclopropane)amido]-1H-pyrazole-3-carboxylate

4-Amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester was reacted with 2,2-difluorocyclopropane-1-carboxylic acid analogously to the procedure described in general method B , to obtain the title compound (650 mg, 79%) as an off-white solid. LC-MS (ES, m/z): 414 [M+H] ⁺ .

Step 2: Synthesis of racemic 4-[(2,2-difluorocyclopropane)amido]-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Pyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-[(2,2-difluorocyclopropane)amido]-1H-pyrazole-3-carboxylate was combined with (R)-3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (400 mg, 85%) as an off-white solid. LC-MS (ES, m/z): 473 [M+H] ⁺ .

Step 3: Synthesis of 4-((R)-2,2-difluorocyclopropanecarboxamido)-1-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidine -3-yl)ethynyl)phenyl)-1H-pyrazole-3-carboxamide and 4-((S)-2,2-difluorocyclopropanecarboxamido)-1-(3-((( R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method S, 4-[(2,2-difluorocyclopropane)amido]-1-(3-[2-[(3R)-3-hydroxy-1-methyl- Reaction of ethyl 2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylate with ammonia afforded 54.1 mg (29%) of the first eluate as a white solid (referred to here as the (1R)-isomer) and 39.3 mg (21%) of the second eluate (referred to herein as the (1S)-isomer) as a white solid. The stereochemistry of the two isomers was assigned arbitrarily.

The first elution isomer: t _R =16.40min ((R,R)WHELK-O1, 0.45*25cm, Hex (0.2%IPA):EtOH=65:35,1ml/min); the second elution Deisomerization: _tR = 18.55min ((R,R)WHELK-O1, 0.45*25cm, Hex(0.2%IPA):EtOH = 65:35, 1ml/min); both isomers showed equivalent LC-MS and ¹ H NMR are shown below.

LC-MS (ES, m/z): 444[M+H] ⁺ . ¹ H NMR (300MHz, CD ₃ OD): δ8.76(s, 1H), 7.97(s, 1H), 7.85-7.82( d,J＝8.7Hz,1H),7.51-7.41(m,2H),3.53-3.41(m,2H),2.94(s,3H),2.90-2.87(m,1H),2.62-2.54(m, 1H), 2.35-2.26(m, 1H), 2.16-2.04(m, 1H), 1.94-1.84(m, 1H).

Example 27

Synthesis of (R)-4-(1-fluorocyclopropanecarboxamido)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl )-1H-pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-[(1-fluorocyclopropane)amido]-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method B, 4-amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester was reacted with 1-fluorocyclopropane-1-carboxylic acid to afford the title Compound (390 mg, 82%), as a white solid. LC-MS (ES, m/z): 396 [M+H] ⁺ .

Step 2: Synthesis of (R)-4-(1-fluorocyclopropanecarboxamido)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl )phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-[(1-fluorocyclopropane)amido]-1H-pyrazole-3-carboxylate was mixed with (R) -3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (408 mg, 91%) as a beige solid. LC-MS (ES, m/z): 455 [M+H] ⁺ .

Step 3: Synthesis of (R)-4-(1-fluorocyclopropanecarboxamido)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl )phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method S, 4-[(1-fluorocyclopropane)amido]-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Reaction of ethyl pyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylate with ammonia afforded the title compound (56 mg, 16%) as a white solid. LC-MS(ES,m/z):426[M+H] ⁺ . ¹ H NMR(400MHz,CD ₃ OD):δ8.83(s,1H),8.02(s,1H),7.90(d, J＝1.2Hz,1H),7.89-7.51(m,1H),7.47(m,1H),3.53-3.47(m,2H),2.95(s,3H),2.65-2.59(m,1H),2.37 -2.30(m,1H),1.53-1.51(m,1H),1.49-1.42(m,3H).

Example 28

Synthesis of (R)-4-(3,3-dimethylureido)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)benzene base)-1H-pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-[(dimethylcarbamoyl)amino]-1H-pyrazole-3-carboxylate

4-Amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (200mg, 0.645mmol, 1.00 equivalent), N,N-dimethylcarbamoyl chloride (84mg, 0.781mmol , 1.20 equiv) and triethylamine (131 mg, 1.295 mmol, 2.00 equiv) in dichloromethane (10 mL) was stirred at room temperature for 2 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with dichloromethane/methanol (10:1) to give the title compound (180 mg, 62%) as a yellow solid. LC-MS (ES, m/z): 381 [M+H] ⁺ .

Step 2: Synthesis of 4-[(dimethylcarbamoyl)amino]-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl ]ethynyl]phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-[(dimethylcarbamoyl)amino]-1H-pyrazole-3-carboxylate was mixed with (R) -3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (90 mg, 62%) as a yellow solid. LC-MS (ES, m/z): 440 [M+H] ⁺ .

Step 3: Synthesis of (R)-4-(3,3-dimethylureido)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)acetylene Base) phenyl) -1H-pyrazole-3-carboxamide

Similar to the procedure described in general method S, 4-[(dimethylcarbamoyl)amino]-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Reaction of ethyl pyrrolidin-3-yl]ethynyl]phenyl)-1H-pyrazole-3-carboxylate with ammonia afforded the title compound (42.8 mg, 50%) as a yellow solid. LC-MS(ES,m/z):411[M+H] ⁺ . ¹ H NMR(300MHz,DMSO-d ₆ ):δ9.27(s,1H),8.62(s,1H),8.06(s ,1H),8.00(s,1H),7.94-7.91(m,1H),7.67(s,1H),7.54-7.49(m,1H),7.39-7.36(d,J＝7.8Hz,1H), 6.513 (s, 1H), 3.38-3.32 (m, 2H), 2.94 (s, 6H), 2.80 (s, 3H), 2.45-2.41 (m, 1H), 2.23-2.14 (m, 1H).

Example 29

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(2-methoxyacetamido) -1H-pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-(2-methoxyacetamido)-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method B, ethyl 4-amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylate was reacted with 2-methoxyacetic acid to afford the title compound (200 mg ,46%) as a yellow solid. LC-MS (ES, m/z): 382 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(2-methyl Oxyacetylamino)-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-(2-methoxyacetamido)-1H-pyrazole-3-carboxylate was mixed with (R)-3 -Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (200 mg, 52%) as a yellow solid. LC-MS (ES, m/z): 441 [M+H] ⁺ .

Step 3: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(2-methoxy Acetylamino)-1H-pyrazole-3-carboxamide

Similar to the procedure described in General Method S, 1-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) - Reaction of ethyl 4-(2-methoxyacetylamino)-1H-pyrazole-3-carboxylate with ammonia gave the title compound (54.1 mg, 28%) as a pale yellow solid. LC-MS(ES,m/z):412[M+H] ⁺ . ¹ H NMR(300MHz,DMSO-d ₆ ):δ10.37(s,1H),8.90(s,1H),8.10(s ,1H),8.04(s,1H),8.00-7.96(m,1H),7.69(s,1H),7.56-7.50(m,1H),7.41-7.39(d,J＝7.5Hz,1H), 6.51(s,1H),4.06(s,2H),3.43(s,3H),3.38-3.30(m,2H),2.80(s,3H),2.45-2.41(m,1H),2.24-2.15( m, 1H).

Example 30

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-isobutyrylamino-1H-pyrazole -3-Carboxamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-(2-methylpropionylamino)-1H-pyrazole-3-carboxylate

4-Amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (200mg, 0.645mmol, 1.00eq), isobutyryl chloride (83mg, 0.779mmol, 1.21eq) and tris A solution of ethylamine (130 mg, 1.285 mmol, 1.99 equiv) in dichloromethane (15 mL) was stirred at room temperature for 30 minutes. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:10). The title compound (120 mg, 49%) was produced as a yellow solid. LC-MS (ES, m/z): 380 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(2-methyl Ethyl propionylamino)-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-(2-methylpropionylamino)-1H-pyrazole-3-carboxylate was mixed with (R)-3 -Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (120 mg, 87%) as a yellow oil. LC-MS (ES, m/z): 439 [M+H] ⁺ .

Step 3: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-isobutyrylamino-1H -pyrazole-3-carboxamide

Similar to the procedure described in General Method S, 1-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) - Reaction of ethyl 4-(2-methylpropionylamino)-1H-pyrazole-3-carboxylate with ammonia gave the title compound (57.5 mg, 62%) as a white solid. LC-MS (ES, m/z): 410[M+H] ⁺ . ¹ H NMR (300MHz, CD ₃ OD): δ8.77(s, 1H), 7.99(s, 1H), 7.88-7.85( m,1H),7.54-7.43(m,2H),3.55-3.47(m,2H),2.73(s,3H),2.73-2.56(m,2H),2.37-2.28(m,1H),1.25( s, 6H).

Example 31

Synthesis of (R)-4-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1-methyl-1H-imidazole-2- Formamide

Step 1: Synthesis of (R)-4-(3-((3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1-methyl-1H-imidazole -2-Methyl carboxylate

(3R)-3-Hydroxy-1-methyl-3-[2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)phenyl]ethynyl]pyrrolidin-2-one (73mg., 0.21mmol), 4-bromo-1-methyl-1h-imidazole-2-carboxylic acid methyl ester (40mg, 0.18mmol), A solution of cesium fluoride (54 mg, 0.36 mmol) and bis(triphenylphosphine)palladium(II) dichloride (12.5 mg, 0.018 mmol) in ethanol (1.5 mL) and water (1.0 mL) was degassed. The reaction mixture was heated in the microwave at 100 °C for 45 minutes. The reactant was filtered through celite. The crude product was purified by flash chromatography (MeOH/DCM) followed by rHPLC to give the product (27 mg, 42.7%). LC-MS (ES, m/z): 354 [M+H] ⁺ .

Step 2: Synthesis of (R)-4-(3-((3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1-methyl-1H-imidazole -2-Methyl carboxylate

Similar to the procedure described in general method S, (R)-4-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1 -Methyl-1H-imidazole-2-carboxylic acid methyl ester was reacted with ammonia to give the title compound (13.4 mg, 42.5%).

LC-MS (ES, m/z): 339 [M+H] ⁺ . 1H NMR (400MHz, DMSO) δ7.94–7.88(m,2H),7.85–7.76(m,2H),7.58–7.46(m,1H),7.43–7.37(m,1H),7.32–7.26(m ,1H),6.52–6.39(s,1H),3.98–3.96(s,3H),3.38–3.33(m,2H),2.82–2.78(s,3H),2.47–2.39(m,1H),2.23 –2.14(m,1H).

Example 32

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(methylamino)-1H-pyrrolidinyl Azole-3-carboxamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-(N-methylacetamido)-1H-pyrazole-3-carboxylate

1-(3-Bromophenyl)-4-acetylamino-1H-pyrazole-3-carboxylic acid ethyl ester (300mg, 0.852mmol, 1.00eq), methyl iodide (142mg, 1.00mmol, 1.17eq) and A solution of sodium hydride (61 mg, 2.542 mmol, 2.984 equiv) in N,N-dimethylformamide (10 mL) was stirred at 0 °C for 2 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:10) to give the title compound (270 mg, 87%) as a yellow solid. LC-MS (ES, m/z): 366 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-bromophenyl)-4-(N-methylacetamido)-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method S, ethyl 1-(3-bromophenyl)-4-(N-methylacetamido)-1H-pyrazole-3-carboxylate was reacted with ammonia to afford the title compound (200mg, 87%) as a yellow solid. LC-MS (ES, m/z): 337 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-bromophenyl)-4-(methylamino)-1H-pyrazole-3-carboxamide

1-(3-Bromophenyl)-4-(N-methylacetamido)-1H-pyrazole-3-carboxamide (200mg, 0.593mmol, 1.00eq) was dissolved in methanol (10mL) and hydrochloric acid (5mL) The solution in was stirred overnight at room temperature. After completion, the pH of the solution was adjusted to 7 with aqueous sodium hydroxide solution, followed by extraction with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with dichloromethane/methanol (10:1) to afford the title compound (100 mg, 57%) as a white solid. LC-MS (ES, m/z): 295 [M+H] ⁺ .

Step 4: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(methylamino)- 1H-pyrazole-3-carboxamide

Similar to the procedure described in general method G, 1-(3-bromophenyl)-4-(methylamino)-1H-pyrazole-3-carboxamide and (R)-3-ethynyl-3- Hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (46.7 mg, 44%) as a white solid. LC-MS(ES,m/z):354[M+H] ⁺ .1H NMR(300MHz,CD ₃ OD):δ7.96-7.95(s,1H),7.86-7.82(m,1H),7.77 (s,1H),7.49-7.43(m,1H),7.39-7.36(m,1H),3.51-3.46(m,2H),2.94(s,3H),2.83(s,3H),2.63-2.36 (m,1H),2.34-2.27(m,1H).

Example 33

Synthesis of (R)-5-acetylamino-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide

Step 1: Synthesis of (R)-5-acetylamino-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4- Formamide

5-amino-2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1,3-thiazole -4-formamide (100mg, 0.281mmol, 1.00 equivalent), acetyl acetate (0.04mL, 0.426mmol, 1.52 equivalent), triethylamine (0.04mL, 0.288mmol, 1.03 equivalent) in acetonitrile (10mL) The solution was stirred at 25°C for 12 hours. The resulting solution was concentrated in vacuo, and the residue was purified by column chromatography on silica gel and eluted with dichloromethane/methanol (20:1). The title compound (14.6 mg, 13%) was produced as a white solid. LC-MS(ES,m/z):399[M+H] ⁺ .1H NMR(400MHz,CD ₃ OD):δ8.10(s,1H),7.98-7.96(d,J＝8.0Hz,1H ),7.55-7.46(m,2H),3.55-3.46(m,2H),2.96(s,3H),2.65-2.59(m,1H),2.37-2.28(m,1H),2.30(s,3H ).

Example 34

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-2'-methyl-4,4'- Bi(1H-pyrazole)-3-carboxamide

Step 1: Synthesis of ethyl 4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method M, ethyl 4-iodo-1H-pyrazole-3-carboxylate was mixed with 1-methyl-4-(4,4,5,5-tetramethyl-1,3 ,2-Dioxaborolan-2-yl)-1H-pyrazole was reacted to give the title compound (352 mg, 18%) as a yellow solid. LCMS determined by LC-MS (ES, m/z): 221 [M+H] ⁺ .

Step 2: Synthesis of ethyl 1-(2-bromophenyl)-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazole-3-carboxylate

Similar to the procedure described in general procedure C, 4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxylic acid ethyl ester was reacted with 3-bromophenylboronic acid to afford the title Compound (239 mg, 40%), as a yellow oil. LC-MS (ES, m/z): 375 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(1-methyl Base-1H-pyrazol-3-yl)-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazole-3-carboxylate Reaction with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one afforded the title compound (130 mg, 80%) as a yellow oil. LC-MS (ES, m/z): 434 [M+H] ⁺ .

Step 4: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-2'-methyl-4, 4'-bi(1H-pyrazole)-3-carboxamide

Similar to the procedure described in General Method S, 1-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -Ethyl 4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (10.3 mg, 7%) as a white solid. LC-MS(ES,m/z):405[M+H] ⁺ . ¹ H NMR(400MHz,CD ₃ OD):δ8.64(s,1H),8.20(s,1H),8.07(s, 1H),7.96-7.93(m,2H),7.54-7.52(m 1H),7.48-7.47(m,1H),3.94(s,3H),3.51(m,2H),2.96(s,3H), 2.65-2.61(m,1H),2.39-2.31(m,1H).

Example 35

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(pyridin-2-ylamino)- 1H-pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-[(pyridin-2-yl)amino]-1H-pyrazole-3-carboxylate

Under nitrogen, ethyl 4-amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylate (300mg, 0.967mmol, 1.00eq), 2-iodopyridine (238mg, 1.161mmol, 1.20 equiv), RuPhos (90 mg, 0.193 mmol, 0.20 equiv), RuPhos-PdCl-2nd G (150 mg, 0.193 mmol, 0.20 equiv), and cesium carbonate (473 mg, 1.452 mmol, 1.50 equiv) in dimethylsulfoxide (30 mL) The solution in was stirred overnight at 100°C. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:50) to give the title compound (50 mg, 13%) as a white solid. LC-MS (ES, m/z): 387 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-[(pyridine- 2-yl)amino]-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-[(pyridin-2-yl)amino]-1H-pyrazole-3-carboxylate was combined with (R)- 3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (40 mg, 70%) as a yellow solid. LC-MS (ES, m/z): 466 [M+H] ⁺ .

Step 3: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(pyridin-2-yl Amino)-1H-pyrazole-3-carboxamide

Similar to the procedure described in General Method S, 1-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) Ethyl 4-[(pyridin-2-yl)amino]-1H-pyrazole-3-carboxylate was reacted with ammonia to afford the title compound (15.6 mg, 42%) as a white solid. LC-MS (ES, m/z): 417[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ8.96 (s, 1H), 8.30-8.29 (m, 1H), 8.014 ( s,1H),7.92-7.90(m,1H),7.62-7.58(m,1H),7.54-7.50(m,1H),7.44-7.43(d,J＝7.6Hz,1H),6.88-6.86( d,J＝8.4Hz,1H),6.81-6.78(m,1H),3.56-3.47(m,2H),2.96(s,3H),2.66-2.56(m,1H),2.38-2.31(m, 1H).

Example 36

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(1-methyl-1H-pyrrolidinyl) Azol-3-ylamino)-1H-pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 4-iodo-1-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method C, ethyl 4-iodo-1H-pyrazole-3-carboxylate was reacted with 3-methoxyphenylboronic acid to afford the title compound (1.6 g, crude) as a red oil . LC-MS (ES, m/z): 373 [M+H] ⁺ .

Step 2: Synthesis of ethyl 1-(3-methoxyphenyl)-4-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazole-3-carboxylate

Under nitrogen, 4-iodo-1-(3-methoxyphenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (1.2g, 3.224mmol, 1.00 equiv), 1-N, 2-N -Dimethylcyclohexane-1,2-diamine (464mg, 3.262mmol, 1.00 equivalent), 1-methyl-1H-pyrazol-3-amine (1.6g, 16.475mmol, 1.00 equivalent), potassium phosphate (876mg, 4.127mmol, 2.00eq), a solution of copper(I) iodide (265mg, 1.391mmol, 0.500eq) in dimethylsulfoxide (14mL) was stirred at 80°C for 12 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:4) to give the title compound (580 mg, 53%) as a pale yellow solid. LC-MS (ES, m/z): 342 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-methoxyphenyl)-4-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method S, 1-(3-Methoxyphenyl)-4-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazole-3 - Reaction of ethyl formate with ammonia to give 1-(3-methoxyphenyl)-4-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazole-3- The title compound in formamide (500 mg, 94%) as a pale yellow oil. LC-MS (ES, m/z): 313 [M+H] ⁺ .

Step 4: Synthesis of 1-(3-hydroxyphenyl)-4-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazole-3-carboxamide

1-(3-methoxyphenyl)-4-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazole-3-carboxamide ( To a solution of 500 mg, 1.60 mmol, 1.00 equiv) in dichloromethane (20 mL) was added tribromoborane (1.98 g, 7.90 mmol, 1.00 equiv) dropwise. The resulting solution was stirred at room temperature for 2 hours. The reaction was quenched with methanol. The resulting mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with dichloromethane/methanol (10:1) to afford the title compound (400 mg, 84%) as a yellow solid. LC-MS (ES, m/z): 299 [M+H] ⁺ .

Step 5: Synthesis of 3-[3-carbamoyl-4-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazol-1-yl]phenyl trifluoromethanesulfonate ester

Add 1-(3-hydroxyphenyl)-4-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazole-3-carboxamide (180 mg, 0.603mmol, 1.00eq) in dichloromethane (30mL) was added dropwise diisopropylethylamine (234mg, 1.811mmol, 3.00eq), and then trifluoromethanesulfonic anhydride was added dropwise under stirring at 0°C (169mg, 0.599mmol, 1.50 equiv). The resulting solution was stirred at 0°C for 2 hours. The solution was adjusted to pH 8 and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:1) to give the title compound 130 mg (50%) as a pale yellow solid. LC-MS (ES, m/z): 431 [M+H] ⁺ .

Step 6: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(1-methyl- 1H-pyrazol-3-ylamino)-1H-pyrazole-3-carboxamide

Similar to the procedure described in General Method G, 3-[3-carbamoyl-4-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazole trifluoromethanesulfonate -1-yl]phenyl ester was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to afford the title compound (20.8 mg, 12%) as an off-white solid. LC-MS(ES,m/z):420[M+H] ⁺ .1H NMR(300MHz,CD ₃ OD):δ8.45(s,1H),8.00(s,1H),7.99-7.88(m ,1H),7.53-7.49(t,J=8Hz,1H),7.44-7.41(m,2H),5.90(s,1H),3.83(s,3H),3.55-3.46(m,2H),3.15( s,3H), 2.65-2.60(m,1H), 2.38-2.31(m,1H).

Example 37

Synthesis of (R)-5-(3,3-dimethylureido)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)benzene base) thiazole-4-carboxamide

Step 1: Synthesis of ethyl 5-[(dimethylcarbamoyl)amino]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylate

5-Amino-2-(3-iodophenyl)-1,3-thiazole-4-carboxylic acid ethyl ester (400mg, 1.069mmol, 1.00eq), triethylamine (6mL, 43.166mmol, 40.38eq), A solution of N,N-dimethylcarbamoyl chloride (137 mg, 1.274 mmol, 1.19 equiv) in dichloromethane (70 mL) was stirred at 40°C for 2 days. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:5). The title compound (300 mg, 63%) was produced as a yellow solid. LC-MS (ES, m/z): 446 [M+H] ⁺ .

Step 2: Synthesis of 5-[(dimethylcarbamoyl)amino]-2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl ]ethynyl]phenyl)-1,3-thiazole-4-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 5-[(dimethylcarbamoyl)amino]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylate was combined with (R )-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give the title compound (100 mg, 65%) as a yellow oil. LC-MS (ES, m/z): 457 [M+H] ⁺ .

Step 3: Synthesis of (R)-5-(3,3-dimethylureido)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)acetylene Base) phenyl) thiazole-4-carboxamide

Similar to the procedure described in general method S, 5-[(dimethylcarbamoyl)amino]-2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Reaction of ethyl pyrrolidin-3-yl]ethynyl]phenyl)-1,3-thiazole-4-carboxylate with ammonia afforded the title compound (55.8 mg, 60%) as a pale yellow solid. LC-MS(ES,m/z):428[M+H] ⁺ . ¹ H NMR(300MHz,DMSO-d ₆ ):δ11.45(s,1H),8.03-8.00(m,2H),7.93 -7.89(m,1H),7.75(s,1H),7.53-7.45(m,2H),6.49(s,1H),3.38-3.31(m,2H),3.00(s,6H),2.81(s ,3H), 2.46-2.42(m,1H), 2.27-2.17(m,1H).

Example 38

Synthesis of 5-((1R,2R)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl )ethynyl)phenyl)thiazole-4-carboxamide

Step 1: Synthesis of ethyl 5-[[(1R,2R)-2-fluorocyclopropane]amido]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylate

Similar to the procedure described in general method B, ethyl 5-amino-2-(3-iodophenyl)-1,3-thiazole-4-carboxylate was mixed with (1R,2R)-2-fluorocyclopropane- 1-Formic acid was reacted to give the title compound (390 mg, 63%) as a white solid. LC-MS (ES, m/z): 461 [M+H] ⁺ .

Step 2: Synthesis of 5-[[(1R,2R)-2-fluorocyclopropane]amido]-2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Pyrrolidin-3-yl]ethynyl]phenyl)-1,3-thiazole-4-carboxylic acid ethyl ester

Similar to the procedure described in general method G, 5-[[(1R,2R)-2-fluorocyclopropane]amido]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylic acid The ethyl ester was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to afford the title compound (180 mg, 88%) as a red solid. LC-MS (ES, m/z): 472 [M+H] ⁺ .

Step 3: Synthesis of 5-((1R,2R)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidine- 3-yl)ethynyl)phenyl)thiazole-4-carboxamide

Similar to the procedure described in General Method S, 5-[[(1R,2R)-2-fluorocyclopropane]amido]-2-(3-[2-[(3R)-3-hydroxy-1- Reaction of ethyl methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1,3-thiazole-4-carboxylate with ammonia gave the title compound (59.7 mg, 35%) as white solid. LC-MS(ES,m/z):443[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ8.11(s,1H),7.99-7.96(m,1H),7.56- 7.46(m,2H),5.10-5.06(m,1H),3.54-3.47(m,2H),2.96(s,3H),2.67-2.59(m,1H),2.39-2.30(m,1H), 2.22-2.17(m,1H),1.90-1.80(m,1H),1.41-1.32(m,1H).

Example 39

Synthesis of 5-((1S,2S)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl )ethynyl)phenyl)thiazole-4-carboxamide

Step 1: Synthesis of ethyl 5-[[(1S,2S)-2-fluorocyclopropane]amido]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylate

Similar to the procedure described in general method B, ethyl 5-amino-2-(3-iodophenyl)-1,3-thiazole-4-carboxylate was mixed with (1S,2S)-2-fluorocyclopropane- 1-Formic acid was reacted to give the title compound (450 mg, 73%) as a white solid. LC-MS (ES, m/z): 461 [M+H] ⁺ .

Step 2: Synthesis of 5-[[(1S,2S)-2-fluorocyclopropane]amido]-2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Pyrrolidin-3-yl]ethynyl]phenyl)-1,3-thiazole-4-carboxylic acid ethyl ester

Similar to the procedure described in general method G, 5-[[(1S,2S)-2-fluorocyclopropane]amido]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylic acid The ethyl ester was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to afford the title compound (180 mg, 88%) as a white solid. LC-MS (ES, m/z): 472 [M+H] ⁺ .

Step 3: Synthesis of 5-((1S,2S)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidine- 3-yl)ethynyl)phenyl)thiazole-4-carboxamide

Similar to the procedure described in General Method S, 5-[[(1S,2S)-2-fluorocyclopropane]amido]-2-(3-[2-[(3R)-3-hydroxy-1- Reaction of ethyl methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1,3-thiazole-4-carboxylate with ammonia afforded the title compound (41.5 mg, 22%) as white solid. LC-MS(ES,m/z):443[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ7.92(s,1H),7.81-7.78(m,1H),7.38- 7.28(m,2H),4.92-4.89(s,1H),3.55-3.31(m,2H),2.78(s,3H),2.48-2.41(m,1H),2.21-2.14(m,1H), 2.11-1.99 (m, 1H), 1.70-1.61 (m, 1H), 1.24-1.14 (m, 1H).

Example 40

Synthesis of (R)-5-amino-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)oxazole-4-carboxamide

Step 1: Synthesis of ethyl 2-(3-bromobenzamido)-2-cyanoacetate

To a solution of ethyl 2-amino-2-cyanoacetate 4-methylbenzenesulfonate (730 mg, 2.31 mmol) in dichloromethane (9.0 mL) was added pyridine (0.47 mL, 5.77 mmol) at 0°C ), followed by the addition of 3-bromobenzoyl chloride (0.45 mL, 3.46 mmol). The reaction mixture was stirred at 0°C for 2 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane, eluting at 40% EtOAc) to afford the product (653 mg, 90%). LC-MS (ES, m/z): 311 [M+H] ⁺ .

Step 2: Synthesis of ethyl 5-amino-2-(3-bromophenyl)oxazole-4-carboxylate

2-[(3-Bromobenzoyl)amino]-2-cyano-acetic acid ethyl ester (100mg, 0.32mmol) in 1,4-dioxane (1.60mL, 6.4 mmol) solution was stirred at 100°C for 4 hours. The reaction was concentrated to give crude product (100 mg, 100%).

LC-MS (ES, m/z): 311. [M+H] ⁺ .

Step 3: Synthesis of ethyl 2-(3-bromophenyl)-5-((tert-butoxycarbonyl)amino)oxazole-4-carboxylate

To a solution of ethyl 5-amino-2-(3-bromophenyl)oxazole-4-carboxylate (110 mg, 0.35 mmol) in acetonitrile (3.5 mL) was added N,N-diisopropylethyl Amine (0.30 mL, 1.8 mmol), 4-dimethylaminopyridine (4.3 mg, 0.035 mmol) and di-tert-butyl dicarbonate (233 mg, 1.06 mmol). The reaction mixture was stirred at RT for 18 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated by rotovap. The crude product was purified by flash chromatography (EtOAc/heptane) to afford the product (105 mg, 72%).

LC-MS (ES, m/z): 411 [M+H] ⁺ .

Step 4: Synthesis of (R)-5-((tert-butoxycarbonyl)amino)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl ) phenyl) oxazole-4-carboxylic acid ethyl ester

2-(3-Bromophenyl)-5-(tert-butoxycarbonylamino)oxazole-4-carboxylic acid ethyl ester (90.0mg, 0.22mmol), (3R)-3-ethynyl-3-hydroxy - 1-methylpyrrolidin-2-one (36.5mg, 0.26mmol), Pd(PPh ₃ ) ₂ Cl ₂ (15mg, 0.022mmol) and TEA (0.75mL) in dimethylsulfoxide (4.4mL) The solution was heated in the microwave at 100°C for 40 minutes. The reaction was quenched with water and quenched with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (MeOH/DCM) to give (90 mg, 87.6%).

LC-MS (ES, m/z): 470 [M+H] ⁺ .

Step 5: Synthesis of (R)-5-amino-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)oxazole-4- Formamide

Bubble ammonia gas into 5-(tert-butoxycarbonylamino)-2-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl] A solution of ethyl ethynyl]phenyl]oxazole-4-carboxylate (90 mg, 0.19 mmol) in methanol (4.0 mL) for 5 min. The reaction mixture was stirred at 50°C for 24 hours. The crude product was concentrated and purified by flash chromatography (MeOH/DCM) to give -N-[4-carbamoyl-2-[3-[2-[(3R)-3-hydroxy-1-methyl-2- Oxo-pyrrolidin-3-yl]ethynyl]phenyl]oxazol-5-yl]tert-butyl carbamate.

N-[4-carbamoyl-2-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo in 1,4-dioxane (1.0 mL) -pyrrolidin-3-yl]ethynyl]phenyl]oxazol-5-yl]carbamate tert-butyl ester (84mg, 0.19mmol) and in 1,4-dioxane (0.95mL, 3.8mmol) A solution of hydrochloric acid (4mol/L) was stirred at RT for 18 hours. The reaction was concentrated, and the residue was subjected to rHPLC to obtain the product (12.8 mg, 18%). LC-MS (ES, m/z): 341 [M+H] ⁺ .

1H NMR (400MHz, DMSO) δ7.85–7.81(m,1H),7.79–7.73(m,1H),7.54–7.48(m,1H),7.48–7.43(m,1H),7.12–6.88(m ,4H), 6.53–6.48(s,1H), 3.38–3.34(m,2H), 2.83–2.78(s,3H), 2.47–2.40(m,1H), 2.23–2.15(m,1H).

Examples 41 and 42

Synthesis of 5-((1R,2S)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl )ethynyl)phenyl)thiazole-4-carboxamide and 5-((1S,2R)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxyl-1- Methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide

(isolated as individual unknown stereoisomers and arbitrarily assigned as (S,R) or (R,S))

Step 1: Synthesis of ethyl 5-[(2-fluorocyclopropane)amido]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylate

Similar to the procedure described in general method B, ethyl 5-amino-2-(3-iodophenyl)-1,3-thiazole-4-carboxylate was mixed with (trans)-2-fluorocyclopropane-1 - Reaction with formic acid afforded the title compound (850 mg, 69%) as a white solid. LC-MS (ES, m/z): 461 [M+H] ⁺ .

Step 2: Synthesis of 5-[trans-(2-fluorocyclopropane)amido]-2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidine- 3-yl]ethynyl]phenyl)-1,3-thiazole-4-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 5-[(2-fluorocyclopropane)amido]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylate was combined with (R )-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (450 mg, 88%) as a pale yellow solid. LC-MS (ES, m/z): 472 [M+H] ⁺ .

Step 3: Synthesis of 5-((1R,2S)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidine- 3-yl)ethynyl)phenyl)thiazole-4-carboxamide and 5-((1S,2R)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy -1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide

Similar to the procedure described in general method S, 5-[(2-fluorocyclopropane)amido]-2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxo Reaction of ethyl pyrrolidin-3-yl]ethynyl]phenyl)-1,3-thiazole-4-carboxylate with ammonia gave 25.6 mg (6%) of the first elution as a white solid (here 1R,2S-isomer) and 21.8 mg (5%) of the second eluting (herein 1S,2R-isomer) isomer as a white solid.

The stereochemistry of the two isomers was assigned arbitrarily (single isomer for which the absolute stereochemistry is unknown). The first elution isomer: t _R = 12.26min (Chiralcel OJ-3, 0.46*15cm, Hex (0,1% DEA): IPA = 50:50, 1ml/min); the second elution isomer Isomer: t _R = 19.00min (Chiralcel OJ-3, 0.46*15cm, Hex(0,1%DEA): IPA = 50:50, 1ml/min); both isomers showed equivalent LC-MS and ¹ H NMR, as shown below.

LC-MS(ES,m/z):443[M+H] ⁺ . ¹ H NMR(300MHz,DMSO-d ₆ ):δ11.86(s,1H),8.10(s,1H),8.06(s ,1H),7.96-7.92(m,1H),7.84(s,1H),7.51-7.50(m,2H),6.49(s,1H),4.95(d,J＝60Hz,1H),3.38-3.32 (m,2H),2.90-2.81(m,1H),2.81(s,3H),2.45-2.43(m,1H),2.21-2.17(m,1H),1.68-1.55(m,1H),1.37 -1.30(m,1H).

Example 43

Synthesis of (R)-3-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1,2,4-thiadiazole-5 -Formamide

Step 1: Synthesis of 3-bromo-5-(1-ethoxyethynyl)-1,2,4-thiadiazole

Similar to the procedure described in General Method Q, 3-bromo-5-chloro-1,2,4-thiadiazole was reacted with tributyl(1-ethoxyethynyl)stannane to afford the title compound (1.5 g, 64%), as a yellow solid. LC-MS (ES, m/z): 235 [M+H] ⁺ .

Step 2: Synthesis of ethyl 3-bromo-1,2,4-thiadiazole-5-carboxylate

Similar to the procedure described in General Procedure R, 3-bromo-5-(1-ethoxyethynyl)-1,2,4-thiadiazole was reacted with sodium periodate and potassium permanganate to afford the title Compound (650 mg, 43%), a colorless oil. LC-MS (ES, m/z): 237 [M+H] ⁺ .

Step 3: Synthesis of 3-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1,2,4- Thiadiazole-5-carboxylic acid

Similar to the procedure described in General Procedure U, ethyl 3-bromo-1,2,4-thiadiazole-5-carboxylate was mixed with (R)-trifluoro(3-((3-hydroxy-1-methyl 2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate potassium to give the title compound (90 mg, 27%) as a brown solid. LC-MS (ES, m/z): 344 [M+H] ⁺ .

Step 4: Synthesis of 3-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1,2,4- Thiadiazole-5-carboxamide

Similar to the procedure described in general method B, 3-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -1,2,4-Thiadiazole-5-carboxylic acid was reacted with ammonium chloride to give the title compound (12.1 mg, 15%) as a white solid. LC-MS(ES,m/z):343[M+H] ⁺ .1HNMR(300MHz,CD ₃ OD):δ8.43(s,1H),8.34-8.31(m,1H),8.60-8.53( m, 1H), 8.50-8.48(m, 1H), 3.49-3.45(m, 2H), 2.92(s, 3H), 2.63-2.55(m, 1H), 2.36-2.26(m, 1H).

Example 44

Synthesis of (R)-5-(difluoromethyl)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4 -Formamide

Step 1: Synthesis of (R)-5-(difluoromethyl)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl) Thiazole-4-carboxamide

Similar to the procedure described in General Procedure U, 2-bromo-5-(difluoromethyl)-1,3-thiazole-4-carboxamide and (R)-trifluoro(3-((3-hydroxy- 1-Methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)potassium borate was reacted to give the title compound (43.2 mg, 14%) as a white solid. LC-MS(ES,m/z):392[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ8.22(s,1H),8.10-8.04(m,1H),7.86( s,1H),7.68-7.63(m,1H),7.56-7.51(m,1H),3.55-3.48(m,2H),2.95(s,3H),2.66-2.58(m,1H),2.38- 2.29(m,1H).

Example 45

Synthesis of (R)-5-amino-2-(2-fluoro-5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4- Formamide

Step 1: Synthesis of ethyl 2-[(5-bromo-2-fluorophenyl)carboxamido]-2-cyanoacetate

To 1-cyano-2-ethoxy-2-oxoethane-1-ammonium 4-methylbenzene-1-sulfonate (5.00g, 16.648mmol, 1.00 equivalent) in dichloromethane (150mL) To the solution in was added pyridine (2.68 mL, 33.295 mmol, 2.00 equiv). Then 5-bromo-2-fluorobenzoyl chloride (4.00 g, 16.845 mmol, 1.01 equiv) was added dropwise with stirring at 0°C. After stirring at 0 °C for 30 minutes, the reaction mixture was diluted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1:2) to afford the title compound (4.0 g, 73%) as a white solid. LC-MS (ES, m/z): 329 [M+H] ⁺ .

Step 2: Synthesis of ethyl 5-amino-2-(5-bromo-2-fluorophenyl)-1,3-thiazole-4-carboxylate

Under nitrogen, ethyl 2-[(5-bromo-2-fluorophenyl)carboxamido]-2-cyanoacetate (3.80 g, 11.546 mmol, 1.00 equiv), Lawesson's reagent (5.14 g, 12.708 A suspension of mmol, 1.10 equiv) in toluene (100 mL) was stirred at 90°C for 12 hours. The resulting solution was diluted with ethyl acetate. The pH of the solution was adjusted to 3 with 1N hydrochloric acid, and then to pH 8 with aqueous sodium bicarbonate. The resulting mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column and eluted with dichloromethane/petroleum ether (1:3) to afford the title compound (2 g, crude) as a yellow solid. LC-MS (ES, m/z): 345 [M+H] ⁺ .

Step 3: Synthesis of ethyl 5-[bis[(tert-butoxy)carbonyl]amino]-2-(5-bromo-2-fluorophenyl)-1,3-thiazole-4-carboxylate

5-Amino-2-(5-bromo-2-fluorophenyl)-1,3-thiazole-4-carboxylic acid ethyl ester (2.0 g, 5.794 mmol, 1.00 equiv), 4-dimethylaminopyridine ( A solution of 530 mg, 4.338 mmol, 0.75 eq) and di-tert-butyl pyrocarbonate (2.58 g, 11.821 mmol, 2.04 eq) in acetonitrile (50 mL) was stirred at 60°C for 3 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:5). The title compound (500 mg, 16%) was produced as a yellow solid. LC-MS (ES, m/z): 545 [M+H] ⁺ .

Step 4: Synthesis of N-[2-(5-bromo-2-fluorophenyl)-4-carbamoyl-1,3-thiazol-5-yl]-N-[(tert-butoxy)carbonyl]ammonia tert-butyl formate

Similar to the procedure described in general method S, 5-[bis[(tert-butoxy)carbonyl]amino]-2-(5-bromo-2-fluorophenyl)-1,3-thiazole-4-carboxylic acid The ethyl ester was reacted with ammonia to give the title compound (450 mg, crude) as a yellow solid. LC-MS (ES, m/z): 546 [M+H] ⁺ .

Step 5: Synthesis of 5-amino-2-(5-bromo-2-fluorophenyl)-1,3-thiazole-4-carboxamide

N-[2-(5-bromo-2-fluorophenyl)-4-carbamoyl-1,3-thiazol-5-yl]-N-[(tert-butoxy)carbonyl]carbamate tert-butyl A solution of the phenyl ester (450 mg, 0.871 mmol, 1.00 equiv) in 1,4-dioxane (10 mL, saturated with hydrogen chloride) was stirred at room temperature overnight. After completion, the solution was adjusted to pH 7 with aqueous sodium hydroxide solution, and then extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with dichloromethane/methanol (10:1) to give the title compound (200 mg, 73%) as a yellow oil. LC-MS (ES, m/z): 316 [M+H] ⁺ .

Step 6: Synthesis of 5-amino-2-(2-fluoro-5-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl )-13-thiazole-4-carboxamide

Similar to the procedure described in general method G, 5-amino-2-(5-bromo-2-fluorophenyl)-1,3-thiazole-4-carboxamide and (R)-3-ethynyl-3 -Hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (14 mg, 6%) as an off-white solid. LC-MS (ES, m/z): 375[M+H] ⁺ .1H NMR (400MHz, DMSO-d ₆ ): δ8.30 (dd, J=7.2, 5.1Hz, 1H), 7.57(s, 1H),7.45-7.32(m,4H),7.09(s,1H),6.45(s,1H),3.37-3.33(m,2H),2.80(s,3H),2.44-2.40(m,1H) ,2.23-2.14(m,1H).

Example 46

Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(methylamino)thiazole-4- Formamide

Step 1: Synthesis of ethyl 5-[[(tert-butoxy)carbonyl](methyl)amino]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylate

5-[[(tert-butoxy)carbonyl]amino]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylic acid ethyl ester (500.00mg, 1.054mmol, 1.00 equivalents), carbonic acid A solution of cesium (685.56 mg, 2.104 mmol, 2.00 equiv), methyl iodide (298.05 mg, 2.100 mmol, 1.99 equiv) in dimethylsulfoxide (30 mL) was stirred at 45°C for 1 hour. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:10) to give the title compound (500 mg, 97%) as a pale yellow oil. LC-MS (ES, m/z): 489 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl N-[4-carbamoyl-2-(3-iodophenyl)-1,3-thiazol-5-yl]-N-methylcarbamate

Similar to the procedure described in general method S, ethyl 5-[[(tert-butoxy)carbonyl]amino]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylate and ammonia The reaction gave the title compound (200 mg, 40%) as a yellow solid. LC-MS (ES, m/z): 460 [M+H] ⁺ .

Step 3: Synthesis

N-[4-carbamoyl-2-(3-iodophenyl)-1,3-thiazol-5-yl]-N-methylcarbamate tert-butyl ester (190.00mg, 0.414mmol, 1.00eq ) in 1,4-dioxane (10 mL, saturated with hydrogen chloride) was stirred overnight at room temperature. After completion, the pH of the solution was adjusted to 7 with aqueous sodium hydroxide solution, followed by extraction with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with dichloromethane/methanol (10:1) to give the title compound (130 mg, 87%) as a pale yellow solid. LC-MS (ES, m/z): 360 [M+H] ⁺ .

Step 4: Synthesis of (R)-2-(3-((3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(methylamino)thiazole -4-formamide

Similar to the procedure described in general method G, 2-(3-iodophenyl)-5-(methylamino)-1,3-thiazole-4-carboxamide and (R)-3-ethynyl-3 -Hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (42.3 mg, 41%) as a white solid. LC-MS(ES,m/z):371[M+H] ⁺ .1H NMR(400MHz,CD ₃ OD):δ7.94(s,1H),7.83-7.08(m,1H),7.46-7.40 (m,2H), 3.54-3.47(m,2H), 3.09(s,3H), 2.95(s,3H), 2.64-2.58(m,1H), 2.37-2.30(m,1H).

Example 47

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(pyridin-3-yl)-1H -pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 4-(pyridin-3-yl)-1H-pyrazole-3-carboxylate

Proceeding similarly to that described in general method M, ethyl 4-iodo-lH-pyrazole-3-carboxylate was reacted with pyridin-3-ylboronic acid to afford the title compound (390 mg, 18%) as a yellow oil. LC-MS (ES, m/z): 218 [M+H] ⁺ .

Step 2: Synthesis of ethyl 1-(3-bromophenyl)-4-(pyridin-3-yl)-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method C, ethyl 4-(pyridin-3-yl)-1H-pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to afford the title compound (210 mg, 36%) , as a yellow oil. LC-MS (ES, m/z): 372 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(pyridine-3 -yl)-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-(pyridin-3-yl)-1H-pyrazole-3-carboxylate and (R)-3-acetylene 1-3-hydroxy-1-methylpyrrolidin-2-one to give the title compound (150 mg, 65%) as a yellow solid. LC-MS (ES, m/z): 431 [M+H] ⁺ .

Step 4: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(pyridin-3-yl )-1H-pyrazole-3-carboxamide

Similar to the procedure described in General Method S, 1-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) Ethyl 4-(pyridin-3-yl)-1H-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (28.8 mg, 28%) as a white solid. LC-MS (ES, m/z): 402[M+H] ⁺ . ¹ H NMR (300MHz, CD ₃ OD): δ8.82(s, 1H), 8.66(s, 1H), 8.48-8.47( m,1H),8.17-8.10(m,2H),7.99-7.95(m,1H),7.57-7.45(m,3H),3.55-3.45(m,2H),2.94(s,3H),2.65- 2.57(m,1H),2.38-2.31(m,1H).

Example 48

Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(1-methyl-1H -pyrazol-5-yl)-1H-pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method M, ethyl 4-iodo-1H-pyrazole-3-carboxylate was reacted with 1-methyl-1H-pyrazol-5-ylboronic acid to afford the title compound (500 mg, 45 %), as a yellow oil. LC-MS (ES, m/z): 221 [M+H] ⁺ .

Step 2: Synthesis of ethyl 1-(3-bromophenyl)-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method C, ethyl 4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to give The title compound (410 mg, 48%) as a tan solid. LC-MS (ES, m/z): 375 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(1-methyl Ethyl-1H-pyrazol-5-yl)-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazole-3-carboxylate Reaction with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one gave the title compound (350 mg, 76%) as a yellow solid. LC-MS (ES, m/z): 434 [M+H] ⁺ .

Step 4: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(1-methyl Base-1H-pyrazol-5-yl)-1H-pyrazole-3-carboxamide

Similar to the procedure described in General Method S, 1-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) - Reaction of ethyl 4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazole-3-carboxylate with ammonia gave the title compound (27.6 mg, 7.6%) as a white solid. LC-MS(ES,m/z):405[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ8.55(s,1H),8.09(d,J＝1.5Hz,1H) ,7.99-7.95(m,1H),7.58-7.49(m,3H),6.39(d,J=2.1Hz,1H),3.79(s,3H),3.56-3.34(m,2H),2.94(s ,3H), 2.65-2.57(m,1H), 2.38-2.29(m,1H).

Example 49

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(pyridin-4-yl)-1H -pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 4-(pyridin-4-yl)-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method M, ethyl 4-iodo-lH-pyrazole-3-carboxylate was reacted with pyridin-4-ylboronic acid to afford the title compound (596 mg, 36%) as a yellow solid. LC-MS (ES, m/z): 218 [M+H] ⁺ .

Step 2: Synthesis of ethyl 1-(3-bromophenyl)-4-(pyridin-4-yl)-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method C, ethyl 4-(pyridin-4-yl)-1H-pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to afford the title compound (572 mg, 56%) , as a white solid. LC-MS (ES, m/z): 372 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(pyridine-4 -yl)-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-(pyridin-4-yl)-1H-pyrazole-3-carboxylate and (R)-3-acetylene 1-3-hydroxy-1-methylpyrrolidin-2-one to give the title compound (290 mg, 46%) as a yellow solid. Confirmed by LCMS. LC-MS (ES, m/z): 431 [M+H] ⁺ .

Step 4: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(pyridin-4-yl )-1H-pyrazole-3-carboxamide

Similar to the procedure described in General Method S, 1-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) Ethyl 4-(pyridin-4-yl)-1H-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (39.6 mg, 15%) as a white solid. LC-MS(ES,m/z):402[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ8.80(s,1H),8.55(d,J＝6.3Hz,2H) ,8.10(d,J＝1.8Hz,1H),8.00-7.96(m,1H),7.84-7.81(m,2H),7.59-7.49(m,2H),3.56-3.48(m,2H),2.95 (s, 3H), 2.65-2.58 (m, 1H), 2.39-2.29 (m, 1H).

Example 50

Synthesis of (R)-3-(2-fluoro-5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1,2,4-thia Oxadiazole-5-carboxamide

Step 1: Synthesis of 3-(2-fluoro-5-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1, 2,4-Thiadiazole-5-carboxylic acid

Similar to the procedure described in General Procedure U, ethyl 3-bromo-1,2,4-thiadiazole-5-carboxylate was mixed with (R)-trifluoro(2-fluoro-5-((3-hydroxy -1-Methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)potassium borate was reacted to give the title compound (120 mg, 33%) as a red solid. LC-MS (ES, m/z): 362 [M+H] ⁺ .

Step 2: Synthesis of (R)-3-(2-fluoro-5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1,2, 4-Thiadiazole-5-carboxamide

Similar to the procedure described in general method B, 3-(2-fluoro-5-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl] Ethynyl]phenyl)-1,2,4-thiadiazole-5-carboxylic acid was reacted with ammonium chloride to give the title compound (15.6 mg, 13%) as a white solid. LC-MS(ES,m/z):361[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ8.39-8.36(m,1H),7.65-7.60(m,1H), 7.32-7.26 (m, 1H), 3.49-3.30 (m, 2H), 2.92 (s, 3H), 2.62-2.53 (m, 1H), 2.35-2.25 (m, 1H).

Example 51

Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(methylsulfonylamino)thiazole- 4-Formamide

Step 1: Synthesis of 2-(3-iodophenyl)-5-methanesulfonylamino-1,3-thiazole-4-carboxamide

5-Amino-2-(3-iodophenyl)-1,3-thiazole-4-carboxamide (300mg, 0.869mmol, 1.00eq), triethylamine (101mg, 0.998mmol, 1.15eq) and methanesulfonate A solution of the acid methanesulfonyl ester (227 mg, 1.303 mmol, 1.50 equiv) in dichloromethane (20 mL) was stirred at room temperature for 5 hours. The resulting solution was concentrated in vacuo. The crude product was purified by reverse phase chromatography to afford the title compound (195 mg, 53%) as an off-white solid. LC-MS (ES, m/z): 424 [M+H] ⁺ .

Step 2: Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(methylsulfonylamino ) Thiazole-4-carboxamide

Similar to the procedure described in general method G, 2-(3-iodophenyl)-5-methanesulfonylamino-1,3-thiazole-4-carboxamide and (R)-3-ethynyl-3- Hydroxy-1-methylpyrrolidin-2-one was reacted to afford the title compound (65.7 mg, 43%) as an off-white solid. LC-MS(ES,m/z):435[M+H] ⁺ .1HNMR(400MHz,CD ₃ OD):δ8.01(s,1H),7.92-7.90(d,J＝7.2Hz,1H) ,7.45-7.39(m,2H),3.55-3.42(m,2H),2.99(s,3H),2.95(s,3H),2.64-2.59(m,1H),2.36-2.29(m,1H) .

Example 52

Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(2,2,2-trifluoro Ethylamino)thiazole-4-carboxamide

Step 1: Synthesis of 5-[[(tert-butoxy)carbonyl](2,2,2-trifluoroethyl)amino]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylic acid ethyl ester

5-[[(tert-butoxy)carbonyl]amino]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylic acid ethyl ester (500.00mg, 1.054mmol, 1.00 equivalent), three A solution of 2,2,2-trifluoroethyl fluoromethanesulfonate (489.34mg, 2.108mmol, 2.00eq), cesium carbonate (686.93mg, 2.108mmol, 2.00eq) in dimethylsulfoxide (20mL) was Stir at 55°C for 12 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:10) to give the title compound (400 mg, 68%) as a yellow oil. LC-MS (ES, m/z): 557 [M+H] ⁺ .

Step 2: Synthesis of N-[4-carbamoyl-2-(3-iodophenyl)-1,3-thiazol-5-yl]-N-(2,2,2-trifluoroethyl)carbamate tert-butyl ester

Similar to the procedure described in general method S, 5-[[(tert-butoxy)carbonyl](2,2,2-trifluoroethyl)amino]-2-(3-iodophenyl)-1, Ethyl 3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (180 mg, 47%) as a yellow oil. LC-MS (ES, m/z): 528 [M+H] ⁺ .

Step 3: Synthesis of 2-(3-iodophenyl)-5-[(2,2,2-trifluoroethyl)amino]-1,3-thiazole-4-carboxamide

N-[4-carbamoyl-2-(3-iodophenyl)-1,3-thiazol-5-yl]-N-(2,2,2-trifluoroethyl)carbamate tert-butyl A solution of the ester (180 mg, 0.341 mmol, 1.00 equiv) in 1,4-dioxane (10 mL, saturated with hydrogen chloride) was stirred at room temperature overnight. After completion, the pH of the solution was adjusted to 7 with aqueous sodium hydroxide solution, followed by extraction with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with dichloromethane/methanol (10:1) to give the title compound (140 mg, 96%) as a yellow solid. LC-MS (ES, m/z): 428 [M+H] ⁺ .

Step 4: Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(2,2,2 -Trifluoroethylamino)thiazole-4-carboxamide

Similar to the procedure described in general method G, 2-(3-iodophenyl)-5-[(2,2,2-trifluoroethyl)amino]-1,3-thiazole-4-carboxamide was combined with (R)-3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (63.4 mg, 44%) as a white solid. LC-MS (ES, m/z): 439[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ7.98 (s, 1H), 7.86-7.84 (d, J=7.6Hz, 1H),7.50-7.42(m,2H),4.13-4.06(m,2H),3.54-3.47(m,2H),2.95(s,3H),2.64-2.58(m,1H),2.37-2.30( m, 1H).

Example 53

Synthesis of (R)-5-(ethylamino)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4- Formamide

Step 1: Synthesis of ethyl 5-[[(tert-butoxy)carbonyl](ethyl)amino]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylate

5-[[(tert-butoxy)carbonyl]amino]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylic acid ethyl ester (500.00mg, 1.054mmol, 1.00 equivalent), iodine A solution of ethane (197.29 mg, 1.265 mmol, 1.20 equiv), cesium carbonate (686.93 mg, 2.108 mmol, 2.00 equiv) in dimethylsulfoxide (30 mL) was stirred at 40°C for 4 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:10) to obtain 490 mg (93%) of the title compound as a pale yellow oil. LC-MS (ES, m/z): 503 [M+H] ⁺ .

Step 2: Synthesis of N-[4-carbamoyl-2-(3-iodophenyl)-1,3-thiazol-5-yl]-N-(2,2,2-trifluoroethyl)carbamate tert-butyl ester

Similar to the procedure described in general method S, 5-[[(tert-butoxy)carbonyl](2,2,2-trifluoroethyl)amino]-2-(3-iodophenyl)-1, Ethyl 3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (180 mg, 93%) as a yellow oil. LC-MS (ES, m/z): 474 [M+H] ⁺ .

Step 3: Synthesis of 5-(ethylamino)-2-(3-iodophenyl)-1,3-thiazole-4-carboxamide

5-[[(tert-butoxy)carbonyl](ethyl)amino]-2-(3-iodophenyl)-1,3-thiazole-4-carboxylic acid ethyl ester (180mg, 0.358mmol, 1.00eq ) in 1,4-dioxane (10 mL, saturated with hydrogen chloride) was stirred overnight at room temperature. After completion, the pH of the solution was adjusted to 7 with aqueous sodium hydroxide solution, followed by extraction with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with dichloromethane/methanol (10:1) to give the title compound (130 mg, 97%) as a pale yellow solid. LC-MS (ES, m/z): 374 [M+H] ⁺ .

Step 4: Synthesis of (R)-5-(ethylamino)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole -4-formamide

Similar to the procedure described in general method G, 5-(ethylamino)-2-(3-iodophenyl)-1,3-thiazole-4-carboxamide and (R)-3-ethynyl-3 -Hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (31.2 mg, 23%) as a white solid. LC-MS(ES,m/z):385[M+H] ⁺ .1H NMR(400MHz,CD ₃ OD):δ7.94(s,1H),7.81(d,J=7.2Hz,1H), 7.46-7.40(m,2H),3.54-3.49(m,2H),3.39-3.36(m,2H),2.95(s,3H),2.64-2.58(m,1H),2.37-2.30(m,1H ), 1.35 (t, J=7.2Hz, 3H).

Example 54

Synthesis of (R)-2-(5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-2-methylphenyl)thiazole-4-carboxamide

Step 1: Synthesis of ethyl 2-(5-hydroxy-2-methylphenyl)-1,3-thiazole-4-carboxylate

Similar to the procedure described in general method M, ethyl 2-bromo-1,3-thiazole-4-carboxylate was mixed with 4-methyl-3-(tetramethyl-1,3,2-dioxaborin Reaction of heterocyclopentan-2-yl)phenol gave the title compound (4.48 g, 96%) as a yellow oil. LC-MS (ES, m/z): 264 [M+H] ⁺ .

Step 2: Synthesis of ethyl 2-[2-methyl-5-[(trifluoromethane)sulfonyloxy]phenyl]-1,3-thiazole-4-carboxylate

2-(5-Hydroxy-2-methylphenyl)-1,3-thiazole-4-carboxylic acid ethyl ester (4.48g, 17.014mmol, 1.00 equivalent), 1,1,1-trifluoro-N- A solution of phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (9.1 g, 25.472 mmol, 1.50 equiv) and triethylamine (8 mL) in dichloromethane (50 mL) was stirred at room temperature for 12 hours. The pH of the solution was adjusted to 8, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:1) to give the title compound (3.85 g, 57%) as a white solid. LC-MS (ES, m/z): 396 [M+H] ⁺ .

Step 3: Synthesis of 2-(5-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-2-methylphenyl)-1 , Ethyl 3-thiazole-4-carboxylate

Similar to the procedure described in general method G, ethyl 2-[2-methyl-5-[(trifluoromethane)sulfonyloxy]phenyl]-1,3-thiazole-4-carboxylate was combined with ( R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (111 mg, 57%) as a white solid. LC-MS (ES, m/z): 385 [M+H] ⁺ .

Step 4: Synthesis of (R)-2-(5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-2-methylphenyl)thiazole-4- Formamide

Similar to the procedure described in general method S, 2-(5-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-2- Ethyl (methylphenyl)-1,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (18 mg, 18%) as a white solid. LC-MS(ES,m/z):356[M+H] ⁺ .1HNMR(300MHz,CD ₃ OD):δ8.33(s,1H),7.90(d,J＝1.5Hz,1H),7.48 (dd,J=7.8Hz,1.5Hz,1H),7.38(d,J=8.1Hz,1H),3.51-3.45(m,2H),2.94(m,3H),2.63(s,3H),2.60 -2.55(m,1H),2.36-2.27(m,1H).

Example 55

Synthesis of 1-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-3a,4,6,6a-tetrahydro- 1H-Furo[3,4-c]pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 1-(3-iodophenyl)-1H,3aH,4H,6H,6aH-furo[3,4-c]pyrazole-3-carboxylate

Add ethyl 2-chloro-2-[(E)-2-(3-iodophenyl)diazen-1-yl]acetate (3.6g, 10.21mmol, 1.00eq) under stirring at -15°C To a solution in 2,5-dihydrofuran (10 mL) was added triethylamine (1.03 g, 10.18 mmol, 1.00 equiv) dropwise. The resulting solution was stirred overnight at room temperature, diluted with water, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:10). The title compound (300 mg, 7%) was produced as a yellow solid. LC-MS (ES, m/z): 387 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-1H,3aH,4H, 6H,6aH-Furo[3,4-c]pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-iodophenyl)-1H,3aH,4H,6H,6aH-furo[3,4-c]pyrazole-3-carboxylate was mixed with (R)-3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (170 mg, 64%) as a yellow oil. LC-MS (ES, m/z): 398 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-3a,4,6,6a- Tetrahydro-1H-furo[3,4-c]pyrazole-3-carboxamide

Similar to the procedure described in General Method S, 1-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -1H,3aH,4H,6H,6aH-furo[3,4-c]pyrazole-3-carboxylic acid ethyl ester was reacted with ammonia to give the title compound (72.6 mg, 37%) as stereoisomers mixture. LC-MS(ES,m/z):369[M+H] ⁺ . ¹ H NMR(300MHz,DMSO-d ₆ ):δ7.72(s,1H),7.31-7.13(m,3H),7.10 -7.10(m,1H),6.93-6.91(m,1H),6.42(s,1H),5.06-5.01(m,1H),4.15-3.97(m,3H),3.80-3.75(m,2H) ,3.38-3.31(m,2H),2.79(s,3H),2.50-2.37(m,1H),2.22-2.15(m,1H).

Example 56

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-6,7-dihydro-5H-pyrrolo [1,2-e]imidazole-3-carboxamide

Step 1: Synthesis of Pent-4-ynyl Methanesulfonate

To a solution of pent-4-ynyl-alcohol (3 g, 35.66 mmol, 1.00 equiv), triethylamine (5.77 g, 57.02 mmol, 1.60 equiv) in dichloromethane (20 mL) was dropped under stirring at 0°C Add methanesulfonyl chloride (4.9 g, 42.78 mmol, 1.20 equiv). Upon completion, the resulting solution was diluted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (3.1 g, 54%) as an off-white solid. LC-MS (ES, m/z): 163 [M+H] ⁺ .

Step 2: Synthesis of 5-azidopent-1-yne

To a solution of pent-4-ynyl methanesulfonate (3 g, 18.495 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) was added sodium azide (2.4 g, 36.917 equivalent). The resulting solution was stirred at room temperature for 2 hours, diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The title compound (2.5 g, crude) was produced as a tan solid. LC-MS (ES, m/z): 110 [M+H] ⁺ .

Step 3: Synthesis of ethyl 5H,6H,7H-pyrrolo[1,2-c]imidazole-3-carboxylate

5-Azidopent-1-yne (1.0 g, 9.16 mmol, 1.00 equiv), 2-ethoxy-2-oxoacetonitrile (5 mL, 50.46 mmol, 5.50 equiv), gold(iii) chloride (139mg, 0.46mmol, 0.05eq) and methanesulfonic acid (969mg, 10.08mmol, 1.10eq) in methyl cyanoformate (5mL) was stirred at room temperature for 12 hours. The resulting solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, then washed with aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1) to give the title compound (350 mg, crude) as a pale yellow solid. LC-MS (ES, m/z): 167 [M+H] ⁺ .

Step 4: Synthesis of ethyl 1-iodo-5H,6H,7H-pyrrolo[1,2-c]imidazole-3-carboxylate

5H, 6H, 7H-pyrrolo[1,2-c]imidazole-3-carboxylic acid ethyl ester (350.00mg, 1.94mmol, 1.00 equivalent), N-iodosuccinimide (436.98mg, 1.94mmol, 1.00 eq) in acetonitrile (5 mL) was stirred at 70°C for 6 hours. The reaction was quenched with aqueous sodium thiosulfate and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:1). The title compound (70 mg, 12%) was produced as a pale yellow solid. LC-MS (ES, m/z): 293 [M+H] ⁺ .

Step 5: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5H,6H,7H- Ethyl pyrrolo[1,2-c]imidazole-3-carboxylate

Similar to the procedure described in General Procedure U, ethyl 1-iodo-5H,6H,7H-pyrrolo[1,2-c]imidazole-3-carboxylate was mixed with (R)-trifluoro(3-(( Potassium 3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate was reacted to give the title compound (20 mg, 52%) as a white solid. LC-MS (ES, m/z): 380 [M+H] ⁺ .

Step 6: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-6,7-dihydro-5H -Pyrrolo[1,2-e]imidazole-3-carboxamide

Similar to the procedure described in General Method S, 1-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -5H,6H,7H-Pyrrolo[1,2-c]imidazole-3-carboxylic acid ethyl ester was reacted with ammonia to give the title compound (5.8 mg, 25%) as a white solid. LC-MS(ES,m/z):365[M+H] ⁺ .1H NMR(300MHz,CD ₃ OD):δ7.84(s,1H),7.77-7.70(m,1H),7.41-7.31 (m,2H),4.38-4.33(m,2H),3.54-3.46(m,2H),3.15-3.10(m,2H),2.94(s,3H),2.80-2.73(m,2H),2.63 -2.55(m,1H),2.36-2.26(m,1H).

Example 57

Synthesis of (R)-5-((1H-pyrazol-1-yl)methyl)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)acetylene Base) phenyl) thiazole-4-carboxamide

Step 1: Synthesis of 2-bromo-5-(bromomethyl)-1,3-thiazole-4-carboxylic acid methyl ester

2-Bromo-5-methyl-1,3-thiazole-4-carboxylic acid methyl ester (500.00mg, 2.118mmol, 1.00eq), N-bromosuccinimide (570mg, 3.203mmol, 1.51eq) and A solution of benzoyl peroxide (217.08mg, 0.847mmol, 0.40eq) in carbon tetrachloride (80mL) was stirred at 80°C for 14 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:30). Yield 650 mg (97%) of the title compound as a yellow oil. LC-MS (ES, m/z): 314 [M+H] ⁺ .

Step 2: Synthesis of 2-bromo-5-(1H-pyrazol-1-ylmethyl)-1,3-thiazole-4-carboxylic acid methyl ester

2-Bromo-5-(bromomethyl)-1,3-thiazole-4-carboxylic acid methyl ester (600.00mg, 1.905mmol, 1.00eq), cesium carbonate (1861.93mg, 5.715mmol, 3.00eq) and 1H - A solution of pyrazole (389.04 mg, 5.715 mmol, 3.00 equiv) in acetonitrile (50 mL) was stirred at room temperature for 3 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:5). The title compound (85 mg, 15%) was produced as a yellow solid. LC-MS (ES, m/z): 302 [M+H] ⁺ .

Step 3: Synthesis of 2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-(1H-pyrrolidinyl) Azol-1-ylmethyl)-1,3-thiazole-4-carboxylic acid methyl ester

Similar to the procedure described in General Procedure U, 2-bromo-5-(1H-pyrazol-1-ylmethyl)-1,3-thiazole-4-carboxylic acid methyl ester was combined with (R)-trifluoro( Potassium 3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate was reacted to give the title compound (70 mg, 61%) as a red solid. LC-MS (ES, m/z): 437 [M+H] ⁺ .

Step 4: Synthesis of (R)-5-((1H-pyrazol-1-yl)methyl)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3- Base) ethynyl) phenyl) thiazole-4-carboxamide

Similar to the procedure described in General Method S, 2-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) - Reaction of methyl 5-(1H-pyrazol-1-ylmethyl)-1,3-thiazole-4-carboxylate with ammonia afforded the title compound (8.9 mg, 13%) as a white solid. LC-MS (ES, m/z): 422[M+H] ⁺ . ¹ H NMR (300MHz, CD ₃ OD): δ8.07 (t, J=1.2Hz, 1H), 7.96-7.90 (m, 1H),7.85(s,1H),7.58-7.54(m,2H),7.46(t,J=7.5Hz,1H),6.36(t,J=2.1Hz,1H),6.07(s,2H), 3.48-3.46 (m, 2H), 2.93 (s, 3H), 2.65-2.55 (m, 1H), 2.35-2.25 (m, 1H).

Example 58

Synthesis of (R)-2-(2,4-difluoro-5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-methyl Thiazole-4-carboxamide

Step 1: Synthesis of ethyl 2-(5-bromo-2,4-difluorophenyl)-5-methylthiazole-4-carboxylate

Similar to the procedure described in general method M, ethyl 2-bromo-5-methylthiazole-4-carboxylate was reacted with 2-(5-bromo-2,4-difluorophenyl)-4,4,5 , 5-Tetramethyl-1,3,2-dioxaborolane was reacted to give the title compound (510 mg, 69%) as a white solid. LC-MS (ES, m/z): 362 [M+H] ⁺ .

Step 2: Synthesis of (R)-2-(2,4-difluoro-5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5 -Ethyl methylthiazole-4-carboxylate

Similar to the procedure described in general method G, ethyl 2-(5-bromo-2,4-difluorophenyl)-5-methylthiazole-4-carboxylate was combined with (R)-3-ethynyl- 3-Hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (200 mg, 86%) as a white solid. LC-MS (ES, m/z): 421 [M+H] ⁺ .

Step 3: Synthesis of (R)-2-(2,4-difluoro-5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5 -Methylthiazole-4-carboxamide

Similar to the procedure described in general method S, (R)-2-(2,4-difluoro-5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)acetylene Ethyl)phenyl)-5-methylthiazole-4-carboxylate was reacted with ammonia to give the title compound (55.5 mg, 29%) as a white solid. LC-MS(ES,m/z):392[M+H] ⁺ . ¹ H NMR(300MHz,DMSO-d6):δ8.61-8.57(m,1H),8.15(s,1H),7.70- 7.65(m,1H),7.53(s,1H),6.58(s,1H),3.38-3.32(m,2H),2.80(s,3H),2.78(s,3H),2.49-2.44(m, 1H), 2.25-2.20 (m, 1H).

Example 59

Synthesis of (R)-5-(difluoromethyl)-2-(2-fluoro-5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl ) Thiazole-4-carboxamide

Step 1: Synthesis of methyl 2-bromo-5-(dibromomethyl)-1,3-thiazole-4-carboxylate

To 2-bromo-5-methyl-1,3-thiazole-4-carboxylic acid methyl ester (350.00mg, 1.483mmol, 1.00eq) and N-bromosuccinimide (790mg, 4.439mmol, 2.99eq) in To a solution in carbon tetrachloride (20 mL) was added benzoyl peroxide (73 mg, 0.285 mmol, 0.19 equiv). The resulting solution was stirred at 80°C for 3 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:10). The title compound (760 mg, crude) was produced as a colorless oil. LC-MS (ES, m/z): 394 [M+H] ⁺ .

Step 2: Synthesis of 2-bromo-5-formyl-1,3-thiazole-4-carboxylic acid methyl ester

2-Bromo-5-(dibromomethyl)-1,3-thiazole-4-carboxylic acid methyl ester (700.00mg, 1.777mmol, 1.00eq) and silver nitrate (610mg, 3.591mmol, 2.02eq) were dissolved in ethanol (20 mL)/water (2 mL) was stirred at 80°C for 3 hours. The precipitate was filtered off and the filtrate was concentrated in vacuo to afford the title compound (560 mg, crude) as a yellow solid. LC-MS (ES, m/z): 250 [M+H] ⁺ .

Step 3: Synthesis of 2-bromo-5-(difluoromethyl)-1,3-thiazole-4-carboxylic acid methyl ester

Similar to the procedure described in General Procedure L, 2-bromo-5-formyl-1,3-thiazole-4-carboxylic acid methyl ester was reacted with bis(2-methoxyethyl)aminosulfur trifluoride, The title compound (270 mg, 44%) was obtained as a yellow solid. LC-MS (ES, m/z): 272 [M+H] ⁺ .

Step 4: Synthesis of 2-bromo-5-(difluoromethyl)-1,3-thiazole-4-carboxamide

Similar to the procedure described in general method S, 2-bromo-5-(difluoromethyl)-1,3-thiazole-4-carboxylic acid methyl ester was reacted with ammonia to afford the title compound (250 mg, 95%), It is a yellow solid. LC-MS (ES, m/z): 257 [M+H] ⁺ .

Step 5: Synthesis of (R)-5-(difluoromethyl)-2-(2-fluoro-5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl )phenyl)thiazole-4-carboxamide

Similar to the procedure described in General Procedure U, 2-bromo-5-(difluoromethyl)-1,3-thiazole-4-carboxamide and (R)-trifluoro(2-fluoro-5-(( 3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)potassium borate was reacted to give the title compound (52.0 mg, 14%) as a pink solid. LC-MS(ES,m/z):410[M+H] ⁺ . ¹ H NMR(300MHz,DMSO-d ₆ ):δ8.60-8.57(m,1H),8.52(s,1H),8.03 (s,1H),7.93(t,J＝47.2Hz,1H),7.70-7.65(m,1H),7.58-7.51(m,1H),3.38-3.30(m,2H),2.81(s,3H ), 2.50-2.42(m,1H), 2.27-2.18(m,1H).

Example 60

Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-methyloxazole-4-carboxamide

Step 1: Synthesis of 2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-methyl-1 ,3-oxazole-4-carboxylate

Similar to the procedure described in General Procedure U, ethyl 2-bromo-5-methyl-1,3-oxazole-4-carboxylate was mixed with (R)-trifluoro(3-((3-hydroxy-1 -Methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)potassium borate was reacted to give the title compound (403 mg, 55%) as a pale yellow solid. LC-MS (ES, m/z): 369 [M+H] ⁺ .

Step 2: Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-methyloxazole-4 -Formamide

Similar to the procedure described in General Method S, 2-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -5-Methyl-1,3-oxazole-4-carboxylic acid ethyl ester was reacted with ammonia to give the title compound (51 mg, 16%) as a white solid. LC-MS(ES,m/z):340[M+H] ⁺ .1HNMR(300MHz,DMSO-d ₆ ):δ8.02-7.95(m,2H),7.63-7.57(m,3H),7.48 (s,1H),6.53(s,1H),3.38-3.31(m,2H),2.81(s,3H),2.65(s,3H),2.47-2.43(m,1H),2.28-2.12(m ,1H).

Example 61

Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-methoxy-1H-pyrazole- 3-formamide

Step 1: Synthesis of 1-(3-bromophenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid methyl ester

(3-Bromophenyl)hydrazine hydrochloride (11g, 49.217mmol, 1.00eq), but-2-ynedioic acid dimethyl ester (7.1g, 49.952mmol, 1.02eq) and triethylamine (10g, 98.824 mmol, 2.01 equiv) in ethanol (100 mL) was heated at reflux for 5 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:2) to afford the title compound (8.5 g, 58%) as an off-white solid. LC-MS (ES, m/z): 297 [M+H] ⁺ .

Step 2: Synthesis of 1-(3-bromophenyl)-5-methoxy-1H-pyrazole-3-carboxylic acid methyl ester

1-(3-Bromophenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid methyl ester (4.00g, 12.86mmol, 1.00eq), methyl iodide (2.74g, 19.30mmol, 1.50eq) . A solution of cesium carbonate (6.28 g, 19.27 mmol, 1.50 equiv) in N,N-dimethylformamide (60 mL) was stirred at room temperature for 3 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:20) to obtain the title compound (2.3 g, 55%) as a pale yellow oil. LC-MS (ES, m/z): 311 [M+H] ⁺ .

Step 3: Synthesis of 1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-methoxy- 1H-Pyrazole-3-carboxylic acid methyl ester

Similar to the procedure described in general method G, 1-(3-bromophenyl)-5-methoxy-1H-pyrazole-3-carboxylic acid methyl ester was combined with (R)-3-ethynyl-3- Hydroxy-1-ethylpyrrolidin-2-one was reacted to give the title compound (200 mg, 84%) as a red oil. LC-MS (ES, m/z): 384 [M+H] ⁺ .

Step 4: Synthesis of (R)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-methoxy-1H- Pyrazole-3-carboxamide

Similar to the procedure described in General Method S, 1-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -5-Methoxy-1H-pyrazole-3-carboxylic acid methyl ester was reacted with ammonia to give the title compound (40.6 mg, 21%) as a white solid. LC-MS(ES,m/z):355[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ7.78(s,1H),7.72-7.68(m,1H),7.40- 7.33(m,2H),6.18(s,1H),3.94(s,3H),3.94-3.33(m,2H),2.84(s,3H),2.53-2.46(m,1H),2.27-2.17( m, 1H).

Example 62

Synthesis of (R)-4-(cyclobutanecarboxamido)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)- 1H-pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-cyclobutaneamido-1H-pyrazole-3-carboxylate

4-Amino-1-(3-bromophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (300mg, 0.967mmol, 1.00eq), cyclobutanecarbonyl chloride (138mg, 1.164mmol, 1.20eq) and a solution of triethylamine (1.5 mL, 10.792 mmol, 11.16 equiv) in dichloromethane (8 mL) was stirred at room temperature for 30 minutes. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:10). The title compound (320 mg, 84%) was produced as a yellow solid. LC-MS (ES, m/z): 392 [M+H] ⁺ .

Step 2: Synthesis of 4-cyclobutaneamido-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl )-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 1-(3-bromophenyl)-4-cyclobutaneamido-1H-pyrazole-3-carboxylate was combined with (R)-3-ethynyl- 3-Hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (200 mg, 87%) as a yellow oil. LC-MS (ES, m/z): 451 [M+H] ⁺ .

Step 3: Synthesis of (R)-4-(cyclobutanecarboxamido)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)benzene base)-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method S, 4-cyclobutaneamido-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidine-3- Reaction of ethyl]ethynyl]phenyl)-1H-pyrazole-3-carboxylate with ammonia gave the title compound (80.7 mg, 43%) as a white solid. LC-MS (ES, m/z): 422[M+H] ⁺ . ¹ H NMR (300MHz, CD ₃ OD): δ8.79(s, 1H), 7.99(s, 1H), 7.88-7.86( m,1H),7.55-7.44(m,2H),3.53-3.47(m,2H),3.42-3.31(m,1H),2.66(s,3H),2.65-2.58(m,1H),2.43- 2.32 (m, 5H), 2.31-2.26 (m, 1H), 2.17-2.15 (m, 1H).

Example 63

Synthesis of (R)-5-(cyclopropanecarboxamido)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole- 4-Formamide

Step 1: Synthesis of ethyl 2-(3-bromophenyl)-5-cyclopropaneamido-1,3-thiazole-4-carboxylate

5-Amino-2-(3-bromophenyl)-1,3-thiazole-4-carboxylic acid ethyl ester (100mg, 0.306mmol, 1.00eq), cyclopropanecarbonyl chloride (30mg, 0.287mmol, 0.94eq) . A solution of triethylamine (0.1 mL, 0.719 mmol, 2.35 equiv) in dichloromethane (5 mL) was stirred at room temperature for 30 minutes. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:10). The title compound (100 mg, 83%) was produced as a yellow solid. LC-MS (ES, m/z): 381 [M+H] ⁺ .

Step 2: Synthesis of 5-cyclopropaneamido-2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -1,3-Thiazole-4-carboxylic acid ethyl ester

Similar to the procedure described in general method G, ethyl 2-(3-bromophenyl)-5-cyclopropaneamido-1,3-thiazole-4-carboxylate was combined with (R)-3-ethynyl- 3-Hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (100 mg, 87%) as a white solid. LC-MS (ES, m/z): 440 [M+H] ⁺ . Step 3: Synthesis of (R)-5-(cyclopropanecarboxamido)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl ) Thiazole-4-carboxamide

Similar to the procedure described in general method S, 5-cyclopropaneamido-2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl Ethyl]ethynyl]phenyl)-1,3-thiazole-4-carboxylate was reacted with ammonia to afford the title compound (35.4 mg, 25%) as a white solid. LC-MS(ES,m/z):425[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ7.98(s,1H),7.85(d,J＝7.5Hz,1H) ,7.43-7.33(m,2H),3.44-3.38(m,2H),2.98(s,3H),2.60-2.46(m,1H),2.26-2.17(m,1H),1.90-1.78(m, 1H), 0.98-0.89 (m, 4H).

Example 64

Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(methoxymethyl)thiazole- 4-Formamide

Step 1: Synthesis of 2-bromo-5-(hydroxymethyl)-1,3-thiazole-4-carboxylic acid methyl ester

Similar to the procedure described in general method K, 2-bromo-5-formyl-1,3-thiazole-4-carboxylic acid methyl ester was reacted with sodium borohydride to afford the title compound (2.2 g, 73%) as white solid. LC-MS (ES, m/z): 252 [M+H] ⁺ .

Step 2: Synthesis of 2-bromo-5-(methoxymethyl)-1,3-thiazole-4-carboxylic acid methyl ester

Methyl 2-bromo-5-(hydroxymethyl)-1,3-thiazole-4-carboxylate (1 g, 3.967 mmol, 1.00 eq), sodium hydride (320 mg, 8.001 mmol, 2.02 eq, 60%), A solution of methyl iodide (0.3 mL, 4.82 mmol, 1.215 equiv) in N,N-dimethylformamide (40 mL) was stirred at 0 °C for 2 minutes. The reaction was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with ethyl acetate/petroleum ether (1:10) to give the title compound (0.2 g, 19%) as a yellow oil. LC-MS (ES, m/z): 266 [M+H] ⁺ .

Step 3: Synthesis of 2-bromo-5-(methoxymethyl)-1,3-thiazole-4-carboxamide

Similar to the procedure described in general method S, 2-bromo-5-(methoxymethyl)-1,3-thiazole-4-carboxylic acid methyl ester was reacted with ammonia to afford the title compound (0.19 g, 95% ), as a white solid. LC-MS (ES, m/z): 251 [M+H] ⁺ .

Step 4: Synthesis of (R)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(methoxymethyl ) Thiazole-4-carboxamide

Similar to the procedure described in General Procedure U, 2-bromo-5-(methoxymethyl)-1,3-thiazole-4-carboxamide and (R)-trifluoro(3-((3-hydroxy -1-Methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)potassium borate was reacted to give the title compound (73.9 mg, 25%) as a white solid. LC-MS(ES,m/z):386[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ8.12(s,1H),8.00-7.97(m,1H),7.58- 7.46 (m, 2H), 5.08 (s, 2H), 3.51-3.47 (m, 5H), 2.94 (s, 3H), 2.63-2.57 (m, 1H), 2.37-2.31 (m, 1H).

Example 65

Synthesis of (R)-4-(2-fluoro-5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-2-carboxamide

Step 1: Synthesis of methyl 4-bromo-1,3-thiazole-2-carboxylate

2,4-Dibromo-1,3-thiazole was reacted with carbon monoxide similarly to the procedure described in general method O to afford the title compound (1.2 g, 13%) as a pale yellow solid. LC-MS (ES, m/z): 222 [M+H] ⁺ .

Step 2: Synthesis of 4-bromo-1,3-thiazole-2-carboxamide

Similar to the procedure described in general method S, 4-bromo-1,3-thiazole-2-carboxylic acid methyl ester was reacted with ammonia to afford the title compound (410 mg, 88%) as a pale yellow solid. LC-MS (ES, m/z): 207 [M+H] ⁺ .

Step 3: Synthesis of (R)-4-(2-fluoro-5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-2-methanol Amide

Similar to the procedure described in General Procedure U, 4-bromo-1,3-thiazole-2-carboxamide was reacted with (R)-trifluoro(2-fluoro-5-((3-hydroxy-1-methyl- 2-Oxopyrrolidin-3-yl)ethynyl)phenyl)potassium borate was reacted to give the title compound (46.1 mg, 19%) as a white solid. LC-MS(ES,m/z):361[M+H] ⁺ . ¹ H NMR(300MHz,CDCl ₃ ):δ8.46-8.43(m,1H),8.18(s,1H),7.52-7.48 (m,1H), 7.28-7.22(m,1H), 3.48-3.45(m,2H), 2.94(s,3H), 2.63-2.53(m,1H), 2.36-2.29(m,1H).

Example 66

Synthesis of (R)-4-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-methoxythiazole-2-carboxamide

Step 1: Synthesis of ethyl [(2-methoxy-2-oxoethyl)carbamoyl]formate

Ethyl 2-chloro-2-oxoacetate (20.1g, 147.216mmol, 1.00 equivalent), methyl 2-aminoacetate hydrochloride (12.6g, 100.355mmol, 0.68 equivalent), triethylamine (30.3 g, 299.437 mmol, 2.03 equiv) in dichloromethane (800 mL) was stirred at 25°C for 4 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with ethyl acetate/petroleum ether (1:4). The title compound (17.5 g, 63%) was produced as a yellow oil. LC-MS (ES, m/z): 190 [M+H] ⁺ .

Step 2: Synthesis of ethyl 5-methoxy-1,3-thiazole-2-carboxylate

2-(2-Methoxy-2-oxoacetylamino) ethyl acetate (5g, 26.432mmol, 1.00eq), phosphorus pentasulfide (6.45g, 29.018mmol, 1.10eq) in 1,4-dioxane (150 mL) was stirred at 110°C for 12 hours. The solids were removed and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:4) to give the title compound (0.24 g, 5%) as a brown oil. LC-MS (ES, m/z): 188 [M+H] ⁺ .

Step 3: Synthesis of ethyl 4-bromo-5-methoxy-1,3-thiazole-2-carboxylate

5-Methoxy-1,3-thiazole-2-carboxylic acid ethyl ester (188mg, 1.004mmol, 1.00eq), N-bromosuccinimide (356mg, 2.00mmol, 1.99eq) in acetonitrile (20mL) The solution in was stirred at 20°C for 4 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:3). The title compound (200 mg, 75%) was produced as a yellow solid. LC-MS (ES, m/z): 266 [M+H] ⁺ .

Step 4: Synthesis of 4-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-methoxy- Ethyl 1,3-thiazole-2-carboxylate

Similar to the procedure described in General Procedure U, ethyl 4-bromo-5-methoxy-1,3-thiazole-2-carboxylate was mixed with (R)-trifluoro(3-((3-hydroxy-1 -Methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)potassium borate was reacted to give the title compound (84 mg, 28%) as a yellow solid. LC-MS (ES, m/z): 401 [M+H] ⁺ .

Step 5: Synthesis of 4-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-methoxy- 1,3-Thiazole-2-carboxamide

Similar to the procedure described in General Method S, 4-(3-[2-[(3R)-3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl) -Ethyl 5-methoxy-1,3-thiazole-2-carboxylate was reacted with ammonia to give the title compound (28.3 mg, 36%) as a white solid. LC-MS (ES, m/z): 372[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ8.17 (s, 1H), 8.09-8.08 (d, J=7.2Hz, 1H),7.44-7.38(m,2H),4.20(s,3H),3.54-3.47(m,2H),2.95(s,3H),2.64-2.58(m,1H),2.37-2.30(m, 1H).

Example 67

Synthesis of (R)-4-(difluoromethyl)-1-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-1H- Pyrazole-3-carboxamide

Step 1: Synthesis of ethyl 1-(3-bromophenyl)-4-methyl-1H-pyrazole-3-carboxylate

Similar to the procedure described in general method C, ethyl 4-methyl-1H-pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to afford the title compound (6.24 g, 67%) as a white solid . LC-MS (ES, m/z): 309 [M+H] ⁺ .

Step 2: Synthesis of ethyl 1-(3-bromophenyl)-4-(dibromomethyl)-1H-pyrazole-3-carboxylate

1-(3-Bromophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.236g, 3.998mmol, 1.00eq), AIBN (262.7mg, 1.60mmol, 0.40eq) and A solution of N-bromosuccinimide (2.136 g, 12.00 mmol, 3.00 equiv) in carbon tetrachloride (100 mL) was stirred at 80° C. for 12 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:10) to give the title compound (1.99 g, crude) as a pale yellow solid. LC-MS (ES, m/z): 465 [M+H] ⁺ .

Step 3: Synthesis of ethyl 1-(3-bromophenyl)-4-formyl-1H-pyrazole-3-carboxylate

1-(3-Bromophenyl)-4-(dibromomethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (1.167 g, 2.499 mmol, 1.00 equiv) in 1,4-dioxane ( 10 mL) was added a solution of silver nitrate (1.062 g, 6.252 mmol, 1.00 equiv) in water (4 mL). The resulting solution was stirred at 70°C for 12 hours, then diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with ethyl acetate/petroleum ether (1:10). The title compound (613 mg, 76%) was produced as a pale yellow solid. LC-MS (ES, m/z): 323 [M+H] ⁺ .

Step 4: Synthesis of ethyl 1-(3-bromophenyl)-4-(difluoromethyl)-1H-pyrazole-3-carboxylate

Similar to the procedure described in General Procedure L, 1-(3-bromophenyl)-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester and bis(2-methoxyethyl)aminotris Reaction with sulfur fluoride gave the title compound (539 mg, 82%) as a white solid. LC-MS (ES, m/z): 345 [M+H] ⁺ .

Step 5: Synthesis of 1-(3-bromophenyl)-4-(difluoromethyl)-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method S, ethyl 1-(3-bromophenyl)-4-(difluoromethyl)-1H-pyrazole-3-carboxylate was reacted with ammonia to afford the title compound (493 mg ,75%) as a white solid. LC-MS (ES, m/z): 316 [M+H] ⁺ .

Step 6: Synthesis of 4-(difluoromethyl)-1-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]benzene base)-1H-pyrazole-3-carboxamide

Similar to the procedure described in general method G, 1-(3-bromophenyl)-4-(difluoromethyl)-1H-pyrazole-3-carboxamide and (R)-3-ethynyl-3 -Hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (89.1 mg, 18%) as a white solid. LC-MS(ES,m/z):375[M+H] ⁺ .1H NMR(300MHz,CD ₃ OD):δ8.73-8.72(m,1H),8.09-8.08(m,1H),7.97 -7.93(m,1H),7.58-7.14(m,3H),3.54-3.50(m,2H),2.96(s,3H),2.66-2.58(m,1H),2.39-2.30(m,1H) .

Example 68

Synthesis of (R)-2-(5-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-2-methoxyphenyl)thiazole-4-carboxamide

Step 1: Synthesis of ethyl 2-(5-bromo-2-methoxyphenyl)-1,3-thiazole-4-carboxylate

Similar to the procedure described in general method M, ethyl 2-bromo-1,3-thiazole-4-carboxylate was reacted with 5-bromo-2-methoxyphenylboronic acid to afford the title compound (381 mg, 33% ), a white solid. LC-MS (ES, m/z): 342 [M+H] ⁺ .

Step 2: Synthesis of 2-(5-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-2-methoxyphenyl)- Ethyl 1,3-thiazole-4-carboxylate

Similar to the procedure described in general method G, ethyl 2-(5-bromo-2-methoxyphenyl)-1,3-thiazole-4-carboxylate was reacted with (R)-3-ethynyl-3 -Hydroxy-1-methylpyrrolidin-2-one was reacted to give the title compound (279 mg, 66%) as a yellow oil. LC-MS (ES, m/z): 401 [M+H] ⁺ .

Step 3: Synthesis of (R)-2-(5-((3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-2-methoxyphenyl)thiazole-4 -Formamide

Similar to the procedure described in general method S, 2-(5-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-2- Ethyl (methoxyphenyl)-1,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (35.8 mg, 13%) as a white solid. LC-MS (ES, m/z): 372[M+H] ⁺ . ¹ H NMR (300MHz, CD ₃ OD): δ8.61(s, 1H), 8.27(s, 1H), 7.60-7.56( m,1H),7.23(d,J＝8.7Hz,1H),4.11(s,3H),3.57-3.45(m,2H),2.95(s,3H),2.65-2.57(m,1H),2.37 -2.28(m,1H).

Example 69

Synthesis of (R)-5-(3,3-difluorocyclobutanecarboxamido)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)acetylene Base) phenyl) thiazole-4-carboxamide

Step 1: Synthesis of (R)-5-(3,3-difluorocyclobutanecarboxamido)-2-(3-((3-hydroxy-1-methyl-2-oxopyrrolidine-3- Base) ethynyl) phenyl) thiazole-4-carboxamide

Similar to the procedure described in general method B, 5-amino-2-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl ]Phenyl)-1,3-thiazole-4-carboxamide was reacted with 3,3-difluorocyclobutane-1-carboxylic acid to afford the title compound (45 mg, 17%) as an off-white solid. LC-MS(ES,m/z):475[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD):δ8.12(s,1H),7.99-7.96(m,1H),7.57- 7.46(m,2H),3.55-3.47(m,2H),3.37-3.34(m,1H),2.98(s,3H),2.94-2.87(m,4H),2.66-2.61(m,1H), 2.60-2.34(m,1H).

biological example

NIK enzyme inhibition assay : Nuclear factor-κB (NF-kB)-inducible kinase (NIK) catalyzed adenosine-5′-triphosphate (ATP ) ability to hydrolyze. The purified NIK (0.5nM) derived from the baculovirus-infected insect cell expression system was mixed with the test compound in 50mM 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid buffer (pH 7.2 ) containing 10 mM MgCl ₂ , 2 mM dithiothreitol, 10 μM ATP, 0.01% Triton X-100, 0.1% γ-globulin from bovine blood, 1% dimethyl Sulfoxide (DMSO), 7 μg/mL ADP antibody and 5 nM ADP-MR121633 tracer. The reaction was quenched by adding 20 mM 2,2',2",2"'-(ethane-1,2-diyldiazepine)tetraacetic acid and 0.01% Brij 35. Displacing the antibody-bound tracer with ADP produced during the NIK reaction caused a decrease in fluorescence polarization, which was measured by laser excitation at 633 nm with a Fluorescence CorrelationSpectroscopy Plus reader (Evotec AG). Equilibrium dissociation constant (K _i ) values for NIK inhibitors were calculated from the activity vs. inhibitor concentration curves using Morrison's quadratic equation, which accounts for tight binding potential, and also by applying relative to their Michaelis constant ( Conversion factor for _Km ), which accounts for competitive inhibition and the substrate concentration used in the assay. For the NIKs described in Table 2 below, the compounds listed in Table 1 have the corresponding inhibition values (NIK ADP-FP, K _i in micromoles).

Cellular Assays : Several assays were developed to characterize the cellular activity of NIK inhibitors.

(1) The first assay available to delineate whether a test compound can inhibit NF-kB signaling via NIK inhibition without affecting cell survival. In this assay, human embryonic kidney 293 cells were stably transfected with a tetracycline-inducible NIK DNA construct containing the cytomegalovirus promoter plus two reporter DNA constructs. One reporter encodes firefly luciferase under the control of three repeats of the NF-kB response element from the ELAM-1 gene, reflecting the level of NIK activity in the cell, while other reporter genes are activated in the herpes simplex virus thymidine kinase Renilla luciferase was constitutively expressed under the control of the gene and used as a general measure of cell survival. Cells were incubated for 24 h with various concentrations of compounds (final 0.2% DMSO) in medium containing 1 μg/mL doxycycline and 10% tet-approved fetal bovine serum (Clontech), followed by Dual Glo fluorescein Enzyme Detection System (Promega), reporter signal was detected according to the vendor's protocol.

(2) A second set of cellular assays was used to define the selectivity of NIK inhibitors for inhibition of canonical vs. Nuclear translocation of A(p65) was quantified. For p52 (non-canonical NF-kB signaling) nuclear translocation analysis, HeLa cells were treated with different concentrations of compounds (finally 0.2% DMSO) in medium containing 10% fetal bovine serum, followed by 100 ng/mL anti- Stimulation with lymphotoxin beta receptor antibody (R&D Systems) for 5 hours. In the REL-A nuclear translocation assay, HeLa cells were cultured with compounds (final 0.2% DMSO) in media containing 10% fetal bovine serum for 4.5 hours, and then they were treated with 10 ng/mL tumor necrosis factor (TNF) - Alpha (R&D Systems) stimulation for 30 minutes. Cells were fixed with 4% paraformaldehyde, permeabilized by addition of 0.1% Triton X-100 in phosphate buffered saline, and then treated with 2ug/mL anti-p52 antibody (Millipore) or 400ng/Ml anti-REL- A(p65) antibody (Santa Cruz Biotechnology) was incubated together. Finally, cells were incubated with Alexa488-labeled secondary antibody (Invitrogen) and DRAQ5 Southern blot (Biostatus). Imaging was performed using Opera reader (Perkin Elmer), and the data were analyzed with the aid of Acapella software (Perkin Elmer). Translocation of p52 or REL-A into the nucleus was quantified by the ratio of nuclear to cytoplasmic signal intensity. Inhibitor concentrations required for 50% inhibition ( _IC50 values) in these cellular assays were deduced from signal vs. inhibitor concentration curves. Compounds listed in Tables 1A and 1B had corresponding inhibition values ( _IC50 in micromolar) as given in Table 2 for the NIK p52 translocation assay.

Table 2

Claims (33)

1. formula (I) compound or its stereoisomer, dynamic isomer, solvate, prodrug or salt:

Wherein：

Ring A is monocyclic or condensed-bicyclic；

Q is N or C, wherein when Q is N, then A₁Key between Q is not double bond and Q and A₄Between key be not double bond；

A₁It is NR¹、N、S、CR¹Or CHR¹；

A₂It is NR²、N、O、S、CR²Or CHR²；

A₃It is N or C；

A₄It is N；And

A₁-A₄In one, two or three be N, wherein:

R¹It is each independently selected from H, halogen, NR^aR^b、NHC(O)NR^aR^b、NHS(O)₂CH₃、C₁-C₃Alkyl, C₃-C₇Cycloalkyl, C₁- C₃Alkoxy and 3-11 circle heterocycles bases, wherein R¹Alkyl optionally by F, OH, CN, SH, C₁-C₃Alkoxy or 3-11 circle heterocycles bases Substitution；R¹Cycloalkyl optionally by F, OH, CN, SH, CH₃Or CF₃Substitution；R¹Alkoxy optionally substituted by F, OH, CN or SH； And R¹Heterocyclic radical optionally by F, OH, CN, SH, CF₃Or C₁-C₃Alkyl substitutes,

R²It is each independently selected from H, NR^aR^b、C₁-C₆Alkyl, C₃-C₇Cycloalkyl, C₁-C₆Alkoxy, phenyl and 3-11 circle heterocycles Base, wherein R²Optionally by R^cSubstitution；Or

R¹And R²The atom connected together with them is formed selected from C₃-C₇The ring-type of cycloalkyl, phenyl and 3-11 circle heterocycles bases Group, wherein the cyclic group is optionally by R^dSubstitution；

R⁴Selected from H, C₁-C₆Alkyl, CH₂F and CH₂OH；

R⁵It is 3-11 circle heterocycles bases, optionally by R^eOr-C (=O) N (C₁-C₆Alkyl)₂Substitution；Or

R⁴And R⁵Formed together optionally by R^eSubstituted C₃-C₁₁Cycloalkyl or optionally by R^eSubstituted 3-11 circle heterocycles bases；

A₅-A₈One of be N and remaining be CR⁶Or all CR⁶；

R⁶At each occurrence independently selected from H, F, Cl, NH₂、NHCH₃、N(CH₃)₂、OH、OCH₃、OCHF₂、OCH₂F、OCF₃、 SH、SCH₃、SCHF₂、SCH₂F、CN、CH₃、CHF₂、CH₂F、CH₂OH、CF₃、NO₂And N₃；

R^aSelected from H and optionally by C₁-C₃Alkoxy, F, OH, CN, SH, CH₃Or CF₃Substituted C₁-C₆Alkyl；

R^bSelected from H, C₁-C₆Alkyl, C₁-C₆Alkoxy, C₃-C₆Cycloalkyl, C (O) R^g, phenyl and 3-11 circle heterocycles bases, wherein R^bCan With optionally by C₁-C₃Alkoxy, F, OH, CN, SH, CH₃Or CF₃Substitution；

R^cAnd R^dIt is each independently selected from halogen ,-(X¹)_0-1-CN、-(X¹)_0-1-NO₂、-(X¹)_0-1-SF₅、-(X¹)_0-1-OH、- (X¹)_0-1-NH₂、-(X¹)_0-1-N(H)(R^1a)、-(X¹)_0-1-N(R^1b)(R^1a)、-(X¹)_0-1-CF₃、C_1-C₆Alkyl, C_1-C₆Alkyl halide Base, C_1-C₆Miscellaneous alkyl, C_1-C₆Alkoxy, C_1-C₆Alkyl sulfenyl, oxo base ,-(X¹)_0-1-C_1-C₆Alkyl ,-(X¹)_0-1-C_3-C₁₀Ring Alkyl ,-O-C_3-C₁₀Cycloalkyl ,-(X¹)_0-1- 3-11 circle heterocycles base ,-(X¹)_0-1-C₆-C₁₀Aryl ,-C (=O) (X¹)₁-C_3-C₁₀Ring Alkyl ,-C (=O) (X¹)₁- 3-11 circle heterocycles base ,-(X¹)_0-1- C (=Y¹)N(H)(R^1a)、-(X¹)_0-1- C (=Y¹)NH₂、- (X¹)_0-1- C (=Y¹)N(R^1a)(R^1b)、-(X¹)_0-1- C (=Y¹)OR^1a、-(X¹)_0-1- C (=Y¹)OH、-(X¹)_0-1- N (H) C (= Y¹)(R^1a)、-(X¹)_0-1-N(R^1b) C (=Y¹)(R^1a)、-(X¹)_0-1-N(R^1b) C (=Y¹)(H)、-(X¹)_0-1- N (H) C (=Y¹) OR^1a、-(X¹)_0-1-N(R^1b) C (=Y¹)OR^1a、-(X¹)_0-1-S(O)_1-2R^1a、-(X¹)_0-1-N(H)S(O)_1-2R^1a、-(X¹)_0-1-N (R^1b)S(O)_1-2R^1a、-(X¹)_0-1-S(O)_0-1N(H)(R^1a)、-(X¹)_0-1-S(O)_0-1N(R^1b)(R^1a)、-(X¹)_0-1-S(O)_{0- 1}NH₂、-(X¹)_0-1- S (=O) (=NR^1b)R^1a、-(X¹)_0-1- C (=Y¹)R^1a、-(X¹)_0-1- C (=Y¹)H、-(X¹)_0-1- C (= NOH)R^1a、-(X¹)_0-1- C (=NOR^1b)R^1a、-(X¹)_0-1- NHC (=Y¹)N(H)(R^1a)、-(X¹)_0-1- NHC (=Y¹)NH₂、- (X¹)_0-1- NHC (=Y¹)N(R^1b)(R^1a)、-(X¹)_0-1-N(R^1a) C (=Y¹)N(H)(R^1a)、-(X¹)_0-1-N(R^1a) C (=Y¹)N (R^1a)(R^1b)、-(X¹)_0-1-N(R^1a) C (=Y¹)NH₂、-(X¹)_0-1- OC (=Y¹)R^1a、-(X¹)_0-1- OC (=Y¹)H、-(X¹)_0-1- OC (=Y¹)OR^1a、-(X¹)_0-1- OP (=Y¹)(OR^1a)(OR^1b)、-(X¹)-SC (=Y¹)OR^1aWith-(X¹)-SC (=Y¹)N(R^1a) (R^1b), wherein X¹Selected from C_1-C₆Alkylidene, C_1-C₆Sub- miscellaneous alkyl, C_2-C₆Alkenylene, C_2-C₆Alkynylene, C_1-C₆Alkylidene epoxide, C_3-C₇Cycloalkylidene, the sub- heterocyclic radical of 3-11 members and phenylene；R^1aAnd R^1bIt is each independently selected from C_1-C₆Alkyl, C_1-C₆Alkyl halide Base, C_1-C₆Miscellaneous alkyl, C_3-C₇Cycloalkyl, (C_3-C₇Cycloalkylidene) C_1-C₆Alkyl, 3-11 circle heterocycles base, (the sub- heterocyclic radical of 3-11 members) C_1-C₆Alkyl, C₆Aryl and (C₆-C₁₀Arlydene) C_1-C₆Alkyl, or R^1aAnd R^1bOptionally combined when being connected with identical nitrogen-atoms Formed comprising the 0-3 other heteroatomic 3-11 circle heterocycles bases selected from N, O and S；Y¹It is O, NR^1cOr S, wherein R^1cBe H or C_1-C₆Alkyl；Wherein R^cOr R^dThe arbitrary portion including R of substituent^1a、R^1bAnd R^1cIt is further independently of one another at each occurrence By 0 to 4 R^fSubstituent substitutes, described R^fSubstituent is selected from halogen, CN, NO₂、SF₅、OH、NH₂、-N(C_1-C₆Alkyl)₂、-NH (C_1-C₆Alkyl), oxo base, C_1-C₆Alkyl ,-(C₂-C₆Alkynylene)-(3-11 circle heterocycles bases, wherein the heterocyclic radical is optionally by R^e Substitution), C_1-C₆Hydroxy alkyl, C_1-C₆Miscellaneous alkyl, C_1-C₆Alkoxy, C_1-C₆Alkyl sulfenyl, C_3-C₇Cycloalkyl, 3-11 circle heterocycles Base ,-C (=O) N (H) (C_1-C₆Alkyl) ,-C (=O) N (C_1-C₆Alkyl)₂,-C (=O) NH₂,-C (=O) OC_1-C₆Alkyl ,-C (= O) OH ,-N (H) C (=O) (C_1-C₆Alkyl) ,-N (C_1-C₆Alkyl) C (=O) (C_1-C₆Alkyl) ,-N (H) C (=O) OC_1-C₆Alkane Base ,-N (C_1-C₆Alkyl) C (=O) OC_1-C₆(halo) alkyl ,-S (O)_1-2C_1-C₆Alkyl ,-N (H) S (O)_1-2C_1-C₆Alkyl ,-N (C_1-C₆Alkyl) S (O)_1-2C_1-C₆Alkyl ,-S (O)_0-1N(H)(C_1-C₆Alkyl) ,-S (O)_0-1N(C_1-C₆Alkyl)₂、-S(O)_{0- 1}NH₂,-C (=O) C_1-C₆Alkyl ,-C (=O) C_3-C₇Cycloalkyl ,-C (=NOH) C_1-C₆Alkyl ,-C (=NOC_1-C₆Alkyl) C_1-C₆ Alkyl ,-NHC (=O) N (H) (C_1-C₆Alkyl) ,-NHC (=O) N (C_1-C₆Alkyl)₂,-NHC (=O) NH₂、-N(C_1-C₆Alkyl) C (=O) N (H) (C_1-C₆Alkyl) ,-N (C_1-C₆Alkyl) C (=O) NH₂,-OC (=O) C_1-C₆Alkyl ,-OC (=O) OC_1-C₆Alkane Base ,-OP (=O) (OC_1-C₆Alkyl)₂,-SC (=O) OC_1-C₆Alkyl and-SC (=O) N (C_1-C₆Alkyl)₂, wherein R^fAny alkane Base section is optionally optionally substituted by halogen；

R^eSelected from halogen, OH, C₁-C₆Alkyl and oxo base；And

R^gSelected from C₁-C₆Alkyl and C₃-C₆Cycloalkyl, wherein R^gCan be optionally by C₁-C₃Alkoxy, F, OH, CN, SH, CH₃Or CF₃ Substitution；

Condition is that the compound is not the compound selected from compound 1x -199x.

2. the compound of claim 1 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein Q are C, And the compound has formula (II):

Its middle ring A, A₁、A₂、A₃、A₄、A₅、A₆、A₇、A₈、R⁴And R⁵As defined in claim 1.

3. the compound of claim 1 or claim 2 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, its middle ring A is monocyclic.

4. the compound of claim 1 or claim 2 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein A₁It is N or CHR¹。

5. the compound of claim 4 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A₁Be N, A₂It is S and A₃It is C.

6. the compound of claim 1 or claim 2 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein A₂It is N, O or CHR²。

7. the compound or stereoisomer of claim 6, dynamic isomer, solvate, prodrug or salt, wherein A₁It is S, A₂ It is N and A₃It is C.

8. the compound of claim 1 or claim 2 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein A₂It is O.

9. the compound of claim 8 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A₁It is CR¹、A₂It is O and A₃It is C.

10. the compound of claim 1 or claim 2 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein A₁It is NR¹, S or CR¹；And A₂It is NR², S or CR²。

11. the compound of claim 10 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, its middle ring A It is monocyclic.

12. the compound of claim 11 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A₁It is NR¹。

13. the compound of claim 12 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A₂It is CR²And A₃It is C.

14. the compound of claim 11 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A₁It is CR¹。

15. the compound of claim 14 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A₂It is CR²And A₃It is N.

16. the compound of claim 10 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A₁It is S。

17. the compound of claim 11 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A₂It is CR²And A₃It is C.

18. the compound of any one of claim 1 to 17 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein A⁵、A⁶、A⁷And A⁸It is CR independently of one another⁶, wherein R⁶At each occurrence independently selected from H, F, OCH₃And CH₃, and n It is 0.

19. the compound of any one of claim 1 to 17 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, its middle ring B is substituted phenyl and Q is C；And the compound has formula (III):

Wherein n is 0,1 or 2, R⁶It is each independently selected from F, Cl, OCH₃、CH₃And CF₃。

20. the compound of any one of claim 1 to 19 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein R⁴And R⁵Formed optionally by R together with the carbon connected with them^eSubstituted C₈-C₁₀Cycloalkyl.

21. the compound of any one of claim 1 to 19 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein R⁴And R⁵Formed optionally by R together with the carbon connected with them^eSubstituted 4-9 circle heterocycles bases.

22. the compound of any one of claim 1 to 19 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein following part:

It is defined as

Wherein:

A₉It is O, NR¹¹Or CR¹¹R¹², wherein R¹¹And R¹²It is each independently selected from H, halogen, OH and C₁-C₃Alkyl；

R⁷And R⁸It is each independently selected from halogen, OH, C₁-C₆Alkyl, or R⁷And R⁸Formation=O together, and

R⁹And R¹⁰It is each independently selected from H and R^e, or R⁹And R¹⁰The atom connected together with them is formed optionally by R^eSubstitution C₅-C₆Cycloalkyl or optionally by R^eSubstituted 5-6 circle heterocycles bases.

23. the compound of claim 22 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein R⁷With R⁸Formation=O together；R⁹And R¹⁰Individually H；And A₉It is NR¹¹, wherein R¹¹It is C₁-C₃Alkyl.

24. the compound of claim 22 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein described PartIt is

25. the compound of claim 1 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein described Compound is selected from：

It is compound or its stereoisomer, dynamic isomer comprising any one of claim 1 to 25, molten 26. pharmaceutical composition Agent compound or prodrug or its officinal salt and pharmaceutical acceptable carrier, diluent or excipient.

27. used in therapy such as the compound or pharmaceutical composition of any one of claim 1 to 26.

28. such as purposes of the compound or pharmaceutical composition of any one of claim 1 to 26 in inflammatory conditions are treated.

29. the compound or pharmaceutical composition such as any one of claim 1 to 26 are preparing the medicament for being used for treating inflammatory conditions In purposes.

30. the purposes of claim 28 or 29, wherein the inflammatory conditions are selected from lupus, systemic loupus erythematosus, COPD, nose Inflammation, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and graft rejection.

31. treating the method for inflammatory conditions in patients, this method is included to patient using effective dose such as claim 1 to 26 The compound or pharmaceutical composition of any one.

32. the method for claim 31, wherein the inflammatory conditions are selected from lupus, systemic loupus erythematosus, COPD, rhinitis, more Hair property hardening, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and graft rejection.

33. the preparation method of formula (I) compound of claim 1,

Wherein Q, A₁-A₈、R⁴And R⁵As defined in any one of claim 1 to 25, this method includes：

Make in the presence of (a) (i) palladium (0) catalyst or (a) (ii) copper catalyst and (b) alkali, under Suzuki reaction conditions Formula (A) compound：

Wherein X is Cl, Br or I,

Contacted with formula (B) compound,

Wherein [M] is boric acid, borate or trifluoroborate,

Obtain formula (I) compound.