Compounds and methods for kinase modulation, and indications therefor

Compounds and methods for kinase regulation and its indications

COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR

<b>Cross-reference of related applications</b>

This application claims the rights of U.S. Provisional Application 61/745,409 filed on December 21, 2012 and 35 USC §119(e) of 61/784,928 filed on March 14, 2013, both of which are referenced Way to incorporate.

The present invention relates to protein kinases and compounds that selectively modulate kinases and their uses. Specific examples cover the disease indications that can be withstood for treatment by modulating kinase activity with the compounds of the present invention.

Receptor protein tyrosine kinase (RPTK) regulates the key signal transduction cascade that controls cell growth and proliferation. Stem cell factor (SCF) receptor c-kit is a type III transmembrane RPTK, which includes five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a separate cytoplasm separated by a kinase insert segment Kinase domain. c-kit plays an important role in the development of melanocytes, mast cells, germ cells and hematopoietic cells.

Stem cell factor (SCF) is a protein encoded by the S1 locus, and according to the biological properties used to identify it, it is also called kit ligand (KL) and mast cell growth factor (MGF) (in Tsujimura,<i>Pathol Int</i> 1996,<b>46</b>: 933-938; Loveland et al.,<i>J. Endocrinol</i> 1997,<b>153</b>: 337-344; Vliagoftis et al.,<i>Clin Immunol</i> 1997,<b>100</b>: 435-440; Broudy,<i>Blood</i> 1997,<b>90</b>: 1345-1364; Pignon,<i>Hermatol </i><i>Cell Ther</i> 1997,<b>39</b>: 114-116; and Lyman et al.,<i>Blood</i> 1998,<b>91</b>: Review in 1101-1134. ). In this article, we use the abbreviation SCF to refer to the ligand for c-KitRTK (Receptor Tyrosine Kinase).

SCF is synthesized as a transmembrane protein with a molecular weight of 220 or 248 Daltons (Dalton) depending on the alternative splicing of mRNA encoding exon 6. Larger proteins can be broken down in a proteolytic manner to form non-covalently dimerized soluble glycosylated proteins. The soluble and membrane-bound form of SCF can bind to and activate c-Kit. For example, in the skin, SCF is mainly expressed by fibroblasts, keratinocytes, and endothelial cells, which regulate the activity of c-Kit by melanocytes and mast cells. In bone, bone marrow stromal cells express SCF and regulate hematopoiesis of c-Kit expressing stem cells. In the gastrointestinal tract, intestinal epithelial cells exhibit SCF and affect Cajal interstitial cells and intraepithelial lymphocytes. In the testicles, podocytes and granulosa cells exhibit SCF that regulates sperm production by interacting with c-Kit on germ cells.

Abnormal manifestations and/or activation of c-Kit and/or c-kit mutant forms have been involved in a variety of pathological conditions (Roskoski, 2005,<i>Biochemical and Biophysical Research Comm</i>.338: 1307-1315). For example, evidence that c-Kit is involved in neoplastic pathology includes its association with leukemia and mast cell tumors, small cell lung cancer, testicular cancer, and some cancers of the gastrointestinal tract and central nervous system. In addition, c-Kit has been involved in the following: it plays a role in the formation of female reproductive tract cancer, neuroectodermal-derived sarcoma, and Schwann cell tumors associated with multiple neurofibromas. It was found that mast cells are involved in improving the tumor microenvironment and enhancing tumor growth (Yang et al.,<i>J Clin Invest</i>.2003,<b>112</b>: 1851-1861; Viskochil,<i>J Clin Invest</i>.2003,<b>112</b>: 1791-1793). Therefore, compounds for regulating receptor protein kinases and methods of use are needed in this technology. The present invention meets this and other needs.

In one aspect, the present invention provides a compound of formula (I'),<chemistry general="n"><img he="318" wi="798" file="TWI617552B_D0001.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Or a pharmaceutically acceptable salt, solvate, tautomer, isomer or deuterated analog thereof, wherein: (i) R¹And R²Combined together to form an optionally substituted 5- or 6-membered fused ring with 0 to 3 heteroatoms selected from N, O or S as ring members, wherein one or two of the ring carbon atoms optionally undergo -C( =O)-replacement; or (ii) R¹Is H, halogen, C_1-4Alkyl, C_1-4Haloalkyl, C_1-4Haloalkoxy, cyclopropyl or lone electron pair and R²For -NH-L²-R⁶, Where R⁶Is H, optionally substituted aryl, optionally substituted aryl-C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C_1-4Alkyl, optionally substituted heterocycloalkyl, optionally substituted C_1-6Alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl-C_1-4Alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic group-C_1-4Alkyl; and where L²Department is selected from a key, -C(O)-, -C(O)N(R^f)-, -SO₂N(R^f)-, -SO₂-, -C(O)O-, -C(=NR^f)N(R^f)-, where each R^fIndependently H or C_1-4Alkyl; G is optionally substituted C_1-6Alkyl, optionally substituted aryl or optionally substituted 5- or 6-membered heteroaryl with one or more nitrogen atoms as ring members, wherein aryl or heteroaryl optionally has 0-2 The optionally substituted 5- to 8-membered ring fused with heteroatoms selected from O, N or S as ring members; L¹Selected from -CH(OH)-, -C(O)NR⁵-, -NR⁵C(O)-, -CH₂N(R⁵)-, -SO₂N(R⁵)-, -N(R⁵)C(O)N(R⁵)-, -N(R⁵)SO₂-, -N(R⁵)CH₂-, -OC_1-4Alkylene-, -C_1-4Alkylene-O-, -C(O)-, -NR⁵C(O)-, -SO₂-, -SON(R⁵)-, -N(R⁵)SO₂N(R⁵)-Or -S(O)-, where each R⁵Independently H or C_1-4Alkyl; Y¹Is N or C; Y²N or replaced as appropriate = C-; and Y³N or CH; its restriction condition is Y¹, Y²And Y³It is not N at the same time.

In another aspect, the present invention provides a composition. The composition includes any of formula (I'), (I'a), (I), (II), (III), (IV), (V) or (V') or as described herein The compound of any one of the formula and sub-formula, or a compound as listed in any one of the patent applications and described herein, or a pharmaceutically acceptable salt, solvate, tautomer or Isomers; and pharmaceutically acceptable excipients or carriers. The present invention also provides a composition, which includes a compound as listed in the scope of the patent application and described herein, a pharmaceutically acceptable excipient or carrier, and another therapeutic agent.

In another aspect, the present invention provides a method for preparing compounds of formula (IV), (V') and any sub-general formula.

In another aspect, the present invention provides a method of modulating protein kinase. The method includes administering any one of formula (I'), (I'a), (I), (II), (III), (IV), (V) or (V') to an individual in need Or a compound of any one of the formulae and sub-formulas described herein, or any one of the compounds listed in the scope of the patent application and the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof , Tautomers or isomers, or pharmaceutical compositions as described herein. In some embodiments, the protein kinase is c-kit protein kinase or mutant c-kit protein kinase.

In another aspect, the present invention provides a method of treating individuals suffering from or at risk of diseases or conditions mediated by protein kinases. The method includes administering to the individual an effective amount of any one of formula (I'), (I'a), (I), (II), (III), (IV), (V) or (V') Or a compound of any one of the sub-formulas, or a compound as listed in any one of the claims and described herein, or a pharmaceutically acceptable salt, solvate, tautomer or isomer thereof Body, or a composition comprising the following: formula (I'), (I'a), (I), (II), (III), (IV), (V) or (V') as described herein A compound of any one or any one of the sub-formulas, or a compound as listed in any one of the scope of the patent application or described herein, or a pharmaceutically acceptable salt, solvate, or tautomer Body or isomer.

<b>I. Definition</b>

Unless expressly indicated otherwise, the following definitions as used herein apply: It should be noted here that unless the context clearly dictates otherwise, the singular forms "one" and "the" used in this specification and the accompanying patent application are Including plural meanings.

"Halogen" or "halo" refers to all halogens, that is, chlorine (Cl), fluorine (F), bromine (Br) or iodine (I).

"Hydroxy" refers to the group -OH.

"Thiol" refers to the group -SH.

"Heteroatom" is meant to include oxygen (O), nitrogen (N), and sulfur (S).

Unless stated otherwise, the term "alkyl" by itself or as part of another substituent means a straight or branched chain hydrocarbon with the specified number of carbon atoms (ie C_1-6Means one to six carbons). Representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Other representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, but-2-enyl (e.g., -CH₂CH=CHCH₃), cis-2-buten-1-yl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. For each definition herein (e.g. alkyl, alkoxy, alkylamino, alkylthio, alkylene, haloalkyl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, For heteroarylalkyl), when the prefix indicates the number of carbon atoms in the alkyl moiety, the alkyl moiety or its part will have 12 or less carbon atoms in the main chain, or 8 or less Main chain carbon atoms or 6 or less main chain carbon atom. For example, C_1-6Alkyl refers to straight or branched chain hydrocarbons with 1, 2, 3, 4, 5 or 6 carbon atoms, and includes (but is not limited to) C_1-2Alkyl, C_1-4Alkyl, C_2-6Alkyl, C_2-4Alkyl, C_1-6Alkyl, C_2-8Alkyl, C_1-7Alkyl, C_2-7Alkyl and C_3-6alkyl. "Fluorine-substituted alkyl group" refers to an alkyl group substituted with one or more fluorine atoms, such as perfluoroalkyl groups. Among them, lower alkyl groups are preferably substituted with 1, 2, 3, 4, or 5 fluorine atoms. , 2 or 3 fluorine atoms. Although it should be understood that the substituent is attached at any available atom to produce a stable compound, when the optionally substituted alkyl group is such as -OR (e.g., alkoxy), -SR (e.g., thioalkyl), -NHR ( For example, when the R group is part of the alkylamino group), -C(O)NHR and the like, the substitution of the alkyl R group is any O, S or N bonded to the part (except where N is Heteroaryl ring atom) of the alkyl carbon substitution excludes any O, S, or N (except when N is a heteroaryl ring atom) of the substituent and any O, S, or N bonded to the moiety. Substitution of substituents combined with alkyl carbon. As used in this article, "Deuterated C_1-6"Alkyl" is intended to include partially deuterated or fully deuterated C_1-6alkyl. Non-limiting examples include -CD₃, CD₃CH₂-, CD₃CD₂-, -CD(CD₃)₂, -CD(CH₃)₂And similar groups.

The term "alkylene" by itself or as part of another substituent means a linear or branched saturated divalent hydrocarbon moiety derived from an alkane having the number of carbon atoms indicated in the prefix. For example, (that is, C_1-6Means one to six carbons; C_1-6Alkylene is intended to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, hexylene and the like). C_1-4Alkylene includes methylene-CH₂-, Ethylene-CH₂CH₂-, propylene-CH₂CH₂CH₂-And isopropyl-CH (CH₃)CH₂-, -CH₂CH(CH₃)-, -CH₂-(CH₂)₂CH₂-, -CH₂-CH(CH₃)CH₂-, -CH₂-C(CH₃)₂-, -CH₂-CH₂CH(CH₃)-. Typically, the alkyl group (or alkylene group) will have 1 to 24 carbon atoms, and in the present invention has 10 or less, 8 or less than 8, or 6 or less carbon atoms. The group is preferred. When the prefix is not included to indicate the number of carbon atoms in the alkylene moiety, the alkylene moiety or part thereof will have 12 or less main chain carbon atoms, or 8 or less main chain carbon atoms, 6 Or less than 6 main chain carbon atoms, or 4 or less main chain carbon atoms.

The term "alkenyl" refers to a straight chain monovalent hydrocarbon group or a branched chain monovalent hydrocarbon group having the number of carbon atoms indicated in the prefix and containing at least one double bond. For example, (C₂-C₆)Alkenyl is meant to include especially vinyl, propenyl, -CH=C(H)(CH₃), -CH=C(CH₃)₂, -C(CH₃)=C(H)₂, -C(CH₃)=C(H)(CH₃), -C(CH₂CH₃)=CH₂, Butadienyl (e.g. 2-(butadienyl)), pentadienyl (e.g. 2,4-pentadienyl and 3-(1,4-pentadienyl)) and hexadienyl and Its similar groups, and its high-carbon homologs and stereoisomers. Similarly, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon group containing at least one parametric bond and having the number of carbon atoms indicated in the prefix. Examples include (but are not limited to) especially ethynyl (e.g. -CC(H)), 1-propynyl (e.g. -CC(CH)₃)), -CC(CH₂CH₃), -C(H₂)CC(H), -C(H)₂CC(CH₃) And -C(H)₂CC(CH₂CH₃), and its high-carbon homologs and isomers. When the prefix is not included to indicate the number of carbon atoms in the alkenyl or alkynyl moiety, the alkenyl or alkynyl moiety or part thereof will have 12 or less main chain carbon atoms, or 8 or less main chain carbons Atoms, or 6 or less main chain carbon atoms, or 4 or less main chain carbon atoms.

The term "alkenylene" refers to a straight or branched chain divalent hydrocarbon moiety having the number of carbon atoms indicated in the prefix and containing at least one double bond. For example, that is, C_2-6Means two to six carbons; C_2-6Alkenylene is intended to include (but is not limited to) -CH=CH-, -CH₂-CH=CH-, -CH₂-CH=C(CH₃)-, -CH=CH-CH=CH- and similar groups. Similarly, the term "alkynylene" refers to a straight or branched chain divalent hydrocarbon moiety containing at least one parametric bond and having the number of carbon atoms indicated in the prefix. For example, that is, C_2-6Means two to six carbons; C_2-6Alkynylene is intended to include (but is not limited to) -CC-, -CCCH₂-, -CH₂-CCCH₂-, -CCCH(CH₃)-And similar groups. When the prefix is not included to indicate the number of carbon atoms in the alkenylene or alkynylene moiety, the alkenylene moiety or part thereof will have 12 or less main chain carbon atoms, or 8 or less main chain carbons Atoms, or 6 or less main chain carbon atoms, or 4 or less main chain carbon atoms.

"Cycloalkyl" or "carbocyclic ring" by itself or as part of another substituent means having The number of carbon atoms indicated in the prefix or (when not specified) a saturated or unsaturated non-aromatic monocyclic, bicyclic or tricyclic ring with 3-10, also 3-8, more preferably 3-6 ring members/ring Cyclic carbocyclic ring systems, such as cyclopropyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, adamantyl and similar groups, in which one or two ring carbon atoms may be replaced by carbonyl groups as appropriate. Cycloalkyl refers to a hydrocarbon ring with the indicated number of ring atoms (e.g. C_3-8Cycloalkyl means three to eight ring carbon atoms). "Cycloalkyl" or "carbocyclic ring" refers to a monobicyclic or polycyclic group, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and the like. When used in conjunction with cycloalkyl substituents, the term "polycyclic" refers herein to both fused and non-fused alkyl ring structures. "Cycloalkyl" or "carbocyclic ring" can form a bridged ring or a spiro ring. Cycloalkyl groups may have one or more double bonds or parametric bonds.

"Cycloalkylene" by itself or as part of another substituent refers to a divalent cycloalkyl group, wherein the cycloalkyl group as defined above has 3-10, also 3-8, more preferably 3-6 Ring members/rings. Exemplary cycloalkylene groups include, for example, 1,2-, 1,3- or 1,4-cis or trans-cyclohexylene, 2-methyl-1,4-cyclohexylene, 2,2-dimethyl -1,4-cyclohexylene and similar groups.

"Cycloalkylalkyl" refers to -(alkylene)-cycloalkyl, wherein the alkylene group as defined herein has the indicated number of carbon atoms or (when not specified) six or less, Preferably four or less main chain carbon atoms; and the cycloalkyl group as defined herein has the indicated number of carbon atoms or (when not specified) has 3-10, also 3-8, more preferably 3 -6 ring members/ring. C_3-8Cycloalkyl-C_1-2The alkyl group is intended to have 3 to 8 ring carbon atoms and 1 to 2 alkylene chain carbon atoms. Exemplary cycloalkylalkyl groups include, for example, cyclopropylmethylene, cyclobutylethylene, cyclobutylmethylene, and the like.

"Cycloalkylalkenyl" refers to -(alkenylene)-cycloalkyl, wherein the alkenylene group as defined herein has the indicated number of carbon atoms or (when not specified) six or less, Preferably four or less main chain carbon atoms; and the cycloalkyl group as defined herein has the indicated number of carbon atoms or (when not specified) has 3-10, also 3-8, more preferably 3 -6 ring members/ring. C_3-8Cycloalkyl-C_2-4Alkenyl is intended to have 3 to 8 ring carbon atoms and 2 to 4 alkenylene chain carbon atoms. Exemplary cycloalkylalkenyl groups include, for example, 2-cyclopropylvinyl, 2-cyclopentylethylene Group and similar groups.

"Cycloalkylalkynyl" refers to -(alkynylene)-cycloalkyl, wherein the alkynylene group as defined herein has the indicated number of carbon atoms or (when not specified) six or less, Preferably four or less main chain carbon atoms; and the cycloalkyl group as defined herein has the indicated number of carbon atoms or (when not specified) has 3-10, also 3-8, more preferably 3 -6 ring members/ring. C_3-8Cycloalkyl-C_2-4Alkynyl is intended to have 3 to 8 ring carbon atoms and 2 to 4 alkynylene chain carbon atoms. Exemplary cycloalkylalkynyl groups include, for example, 2-cyclopropylethynyl, 2-cyclobutylethynyl, 2-cyclopentylethynyl, and the like.

"Cycloalkenyl" by itself or as part of another substituent means having the number of carbon atoms indicated in the prefix or (when not specified) having 3-10, also 3-8, more preferably 3-6 rings A non-aromatic monocyclic, bicyclic or tricyclic carbocyclic ring system of members/rings containing at least one carbon-carbon double bond. Exemplary cycloalkenyl groups include, for example, 1-cyclohexenyl, 4-cyclohexenyl, 1-cyclopentenyl, 2-cyclopentenyl, and the like.

"Cycloalkenyl" by itself or as part of another substituent refers to a divalent cycloalkenyl group, wherein the cycloalkenyl group as defined herein has 3-10, also 3-8, more preferably 3-6 Ring members/rings. Exemplary cycloalkenylene groups include, for example, cyclohexene-1,4-diyl, 2-methyl-cyclohexene-1,4-diyl, 3-methyl-cyclohexene-1,4-diyl , 3,3-Dimethyl-cyclohexene-1,4-diyl, cyclohexene-1,2-diyl, cyclohexene-1,3-diyl and similar groups.

"Haloalkyl" is meant to include alkyl groups substituted with one to seven halogen atoms. Haloalkyl groups include monohaloalkyl groups and polyhaloalkyl groups. For example, the term "C_1-6"Haloalkyl" is intended to include trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.

"Haloalkoxy" refers to -O-haloalkyl, where haloalkyl is as defined herein, such as trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy and Its similar group.

"Alkoxy" refers to -O-alkyl, where alkyl is as defined herein. "Cycloalkoxy" refers to -O-cycloalkyl, where cycloalkyl is as defined herein. "Alkoxy substituted by fluorine "Group" refers to an alkoxy group in which an alkyl group is substituted with one or more fluorine atoms, wherein preferably the alkoxy group is substituted with 1, 2, 3, 4 or 5 fluorine atoms, and also 1, 2 or 3 fluorine atoms. Although it should be understood that the substituent on the alkoxy group is attached at any available atom to produce a stable compound, the substituent on the alkoxy group is such that O, S or N (except when N is a heteroaryl ring atom) does not bind To the alkyl carbon bound to the alkoxy O. In addition, when an alkoxy group is described as a substituent of another part, the alkoxy oxygen does not bond to a carbon atom or another part bonded to O, S or N of the other part (except when N is a heteroaryl ring atom) The alkene or alkyne carbon.

"Amino" or "amine" means the group -NH₂。

"Alkylamino" refers to -NH-alkyl, where alkyl is as defined herein. Exemplary alkylamine groups include CH₃NH-, ethylamino and similar groups.

"Dialkylamino" refers to -N(alkyl)(alkyl), where each alkyl group is independently as defined herein. Exemplary dialkylamino groups include dimethylamino, diethylamino, ethylmethylamino, and the like.

"Cycloalkylamino" means the group -NR^ddR^ee, Where R^ddAnd R^eeCombine with nitrogen to form a 5-7 membered heterocycloalkyl ring, wherein the heterocycloalkyl group may contain another heteroatom in the ring, such as O, N, or S, and may be further substituted with an alkyl group. Alternatively, "cycloalkylamino" refers to -NH-cycloalkyl, where cycloalkyl is as defined herein.

"Alkylthio" refers to -S-alkyl, where alkyl is as defined herein. Exemplary alkylthio groups include CH₃S-, ethylthio and similar groups.

"Aryl" by itself or as part of another substituent refers to a monocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbon group containing 6 to 14 ring carbon atoms, which may be a single ring or fused together or together Multi-ring (up to three rings) of valence linkage. Non-limiting examples of unsubstituted aryl groups include phenyl, 1-naphthyl, 2-naphthyl, and 4-biphenyl. Exemplary aryl groups (such as phenyl or naphthyl) may optionally be fused with cycloalkyl groups having preferably 5-7, more preferably 5-6 ring members.

"Arylene" by itself or as part of another substituent refers to a divalent aryl group, where the aryl group is as defined herein. Exemplary arylene groups include, for example, phenylene, biphenylene, and Similar groups.

"Aralkyl" refers to -(alkylene)-aryl, where alkylene is as defined herein and has the indicated number of carbon atoms or (when not specified) has six or less main chain carbons Atom, or four or less main chain carbon atoms; and aryl is as defined herein. Examples of arylalkyl groups include benzyl, phenethyl, 1-methylbenzyl and the like.

"Arylalkoxy" refers to -O-(alkylene)-aryl, where alkylene is as defined herein and has the number of carbon atoms indicated or (when not specified) six or six The following main chain carbon atoms, or four or fewer main chain carbon atoms; and the aryl group is as defined herein. Examples of arylalkoxy include benzyloxy, phenethoxy and the like.

"Aryloxy" refers to -O-aryl, where aryl is as defined herein. Exemplary aryloxy groups include, for example, phenoxy.

"Arylthio" refers to -S-aryl, where aryl is as defined herein. Exemplary arylthio groups include, for example, phenylthio.

"Heteroaryl" itself or as part of another substituent refers to a monocyclic aromatic group containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, which contains one or more, Preferably 1-4, more preferably 1-3, still more preferably 1-2 heteroatoms independently selected from the group consisting of O, S and N. Heteroaryl is also intended to include oxides of S or N, such as sulfinyl, sulfonyl, and N-oxides of the third ring nitrogen. The carbon or nitrogen atom is a heteroaryl ring structure which results in a point of attachment of a stable compound. Examples of heteroaryl groups include (but are not limited to) pyridyl, pyridazinyl, pyrazinyl, indolazinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl , Pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxthiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, Benzofuranyl, indolyl, triazinyl, quinolinyl,<img file="TWI617552B_D0002.tif" wi="55" he="60" img-format="tif" img-content="character" orientation="portrait" inline="no" />Linyl, phthalazinyl, benzotriazinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indole Azinyl, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzothienyl, quine Linyl, isoquinolinyl, indazolyl, pteridyl and thiadiazolyl. The "nitrogen-containing heteroaryl group" refers to a heteroaryl group in which any heteroatom is N. As used herein, "heterocyclic aromatic ring" means a heteroaryl ring.

"Heteroaryl" by itself or as part of another substituent refers to a divalent heteroaryl group, wherein the heteroaryl group is as defined herein. Exemplary heteroaryl groups include, for example, pyridine-2,5-diyl, pyrimidine-2,5-diyl, pyridazine-3,5-diyl, pyrazine-2,5-diyl and the like .

"Heteroarylalkyl" refers to -(alkylene)-heteroaryl, where alkylene is as defined herein and has the number of carbon atoms indicated or (when not specified) six or less Main chain carbon atoms, or four or less main chain carbon atoms; and heteroaryl groups are as defined herein. Non-limiting examples of heteroarylalkyl groups include 2-pyridylmethyl, 4-pyridylmethyl, 2-thiazolylethyl, and the like.

"Heterocyclyl", "heterocyclic" or "heterocyclic" refers to a saturated or unsaturated non-aromatic group containing at least one heteroatom independently selected from oxygen (O), nitrogen (N) or sulfur (S) Monocyclic or bicyclic group. Each heterocyclic ring can be attached at any available ring carbon or heteroatom. Each heterocyclic ring may have one or more rings. When multiple rings are present, they can be fused together or covalently linked. Each heterocyclic ring typically contains 1, 2, 3, 4, or 5 independently selected heteroatoms. Preferably, these groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, 0, 1, 2, 3, 4 or 5 nitrogen atoms, 0, 1, or 2 sulfur atoms, and 0, 1, or 2 oxygen atoms. More preferably, these groups contain 1, 2 or 3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Non-limiting examples of heterocyclic groups include morpholin-3-one, piperazine-2-one, piperazine-1-oxide, pyridin-2-one, piperidine, morpholine, piperazinyl, isoxazole Pyrrolidine, pyrazoline, imidazoline, pyrazol-5-one, pyrrolidine-2,5-dione, imidazolidine-2,4-dione, pyrrolidine, tetrahydroquinolinyl, decahydroquinolinyl , Tetrahydrobenzoxazepine, dihydrodibenzoxazone and similar groups.

"Heterocyclyl" by itself or as part of another substituent refers to a divalent heterocyclic group, wherein the heterocyclic group is as defined herein. Exemplary heterocyclic extension groups include, for example, piperazine-1,4-diyl, piperidine-1,4-diyl, 1,2,3,6-tetrahydropyridine-1,4-diyl, 3-nitrogen Heterobicyclic [3.2.1] symptom Alkane-3,8-diyl, 3,8-diazabicyclo[3.2.1]octane-3,8-diyl, 8-azabicyclo[3.2.1]octane-3,8-di Base, 2-azabicyclo[2.2.2]octane-2,5-diyl, 2,5-diazabicyclo[2.2.2]octane-2,5-diyl, 2,3,6 ,7-Tetrahydro-1H-aza-1,4-diyl, 2,3,6,7-tetrahydro-1H-aza-1,5-diyl, 2,5-dihydro-1H- Pyrrole-1,3-diyl and similar groups.

"Heterocyclylalkyl" refers to -(alkylene)-heterocyclyl, wherein alkylene is as defined herein and has the indicated number of carbon atoms or (when not specified) six or less Main chain carbon atoms, or four or less main chain carbon atoms; and the heterocyclic group is as defined herein. Exemplary heterocyclylalkyl groups include, for example, pyrrolidin-1-ylmethyl, 2-piperidinylmethyl, and the like.

"Heterocycloalkyl" refers to a saturated or unsaturated non-aromatic cycloalkyl group containing one to five heteroatoms selected from N, O, and S, in which nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally oxidized. Grade ammonium, the remaining ring atoms are C, and one or two of the C atoms can be replaced by carbonyl groups as appropriate. The heterocycloalkyl group can be a monocyclic, bicyclic or polycyclic ring system having 3 to 12, preferably 4 to 10 ring atoms, more preferably 5 to 8 ring atoms, wherein one to five ring atoms are selected from the following The heteroatoms: -N=, -N-, -O-, -S-, -S(O)- or -S(O)₂-, and in addition, one or two of the ring atoms are optionally replaced by a -C(O)- group. The heterocycloalkyl group may also be a heterocycloalkyl ring fused with a cycloalkyl, aryl or heteroaryl ring. Non-limiting examples of heterocycloalkyl groups include pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, butyrolactone moiety, valerolactone moiety, imidazolidone moiety, hydantoin, two Oxolane moiety, phthalimide moiety, piperidine, 1,4-dioxane moiety, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, sulfur Morpholinyl-S,S-oxide, piperazinyl, piperanyl, pyridine moiety, 3-pyrrolinyl, thiopiperanyl, pyrone moiety, tetrahydrofuranyl, tetrahydrothienyl,<img file="TWI617552B_D0003.tif" wi="60" he="55" img-format="tif" img-content="character" orientation="portrait" inline="no" />Pyridinyl and similar groups. The heterocycloalkyl group can be attached to the rest of the molecule via a ring carbon or heteroatom. As used herein, the term "heterocycloalkylene" by itself or as part of another substituent refers to a divalent heterocycloalkyl, wherein heterocycloalkyl is as defined herein. Non-limiting examples of heterocycloalkylene include piperidine-1,4-diyl, 1,2,3,6-tetrahydropyridine-1,4-diyl, 1,2,3,6-Tetrahydropyridine-1,5-diyl, 2,3,6,7-tetrahydro-1H-aza-1,4-diyl, 2,3,6,7- Tetrahydro-1H-aza-1,5-diyl, 2,5-dihydro-1H-pyrrole-1,3-diyl and similar groups.

"Heterocycloalkylalkyl" refers to -(alkylene)-heterocycloalkyl, wherein alkylene is as defined herein and has the indicated number of carbon atoms or (when not specified) six or six Or fewer carbon atoms in the main chain, or four or fewer carbon atoms in the main chain; and heterocycloalkyl is as defined herein. Non-limiting examples of heterocycloalkylalkyl groups include 2-pyridylmethyl, 2-thiazolylethyl, and the like.

Alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocyclyl, alkylene, alkenylene or Substituents of alkynylene include (but are not limited to) R', halogen, -OH, -NH₂, -NO₂, -CN, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OR', -SR', -OC(O)R', -OC(S)R', -C(O)R', -C(S)R', -C(O)OR',- C(S)OR', -S(O)R', -S(O)₂R', -C(O)NHR', -C(S)NHR', -C(O)NR'R', -C(S)NR'R", -S(O)₂NHR', -S(O)₂NR'R", -C(NH)NHR', -C(NH)NR'R", -NHC(O)R', -NHC(S)R', -NR"C(O)R',- NR'C(S)R", -NHS(O)₂R', -NR'S(O)₂R", -NHC(O)NHR', -NHC(S)NHR', -NR'C(O)NH₂, -NR'C(S)NH₂, -NR'C(O)NHR", -NR'C(S)NHR", -NHC(O)NR'R", -NHC(S)NR'R", -NR'C(O)NR" R''', -NR'''C(S)NR'R", -NHS(O)₂NHR', -NR'S(O)₂NH₂, -NR'S(O)₂NHR", -NHS(O)₂NR'R", -NR'S(O)₂The numbers of NR"R"', -NHR' and -NR'R" are in the range of zero to (2m'+1), where m'is the total number of carbon atoms in the group. R', R" and R''' each independently refer to hydrogen, C_1-8Alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryl substituted with 1-3 halogens, C₁-₈Alkoxy, haloalkyl, haloalkoxy or C₁-₈Thioalkoxy or unsubstituted aryl-C₁-₄alkyl. When R'and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6- or 7-membered ring. For example, -NR'R" is intended to include 1-pyrrole Ridinyl and 4-morpholinyl. R', R" and R''' may be further substituted with the following groups: R^a1, Halogen, -OH, -NH₂, -NO₂, -CN, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OR^a1, -SR^a1, -OC(O)R^a1, -OC(S)R^a1, -C(O)R^a1, -C(S)R^a1, -C(O)OR^a1, -C(S)OR^a1, -S(O)R^a1, -S(O)₂R^a1, -C(O)NHR^a1, -C(S)NHR^a1, -C(O)NR^a1R^a2, -C(S)NR^a1R^a2, -S(O)₂NHR^a1, -S(O)₂NR^a1R^a2, -C(NH)NHR^a1, -C(NH)NR^a1R^a2, -NHC(O)R^a1, -NHC(S)R^a1, -NR^a2C(O)R^a1, -NR^a1C(S)R^a2, -NHS(O)₂R^a1, -NR^a1S(O)₂R^a2, -NHC(O)NHR^a1, -NHC(S)NHR^a1, -NR^a1C(O)NH₂, -NR^a1C(S)NH₂, -NR^a1C(O)NHR^a2, -NR^a1C(S)NHR^a2, -NHC(O)NR^a1R^a2, -NHC(S)NR^a1R^a2, -NR^a1C(O)NR^a2R^a3, -NR^a3C(S)NR^a1R^a2, -NHS(O)₂NHR^a1, -NR^a1S(O)₂NH₂, -NR^a1S(O)₂NHR^a2, -NHS(O)₂NR^a1R^a2, -NR^a1S(O)₂NR^a2R^a3, -NHR^a1And -NR^a1R^a2, The number is in the range of zero to (2n'+1), where n'is the total number of carbon atoms in the group. R^a1, R^a2And R^a3Each independently refers to hydrogen, C_1-8Alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryl substituted with 1-3 halogens, C₁-₈Alkoxy, haloalkyl, haloalkoxy or C₁-₈Thioalkoxy or unsubstituted aryl-C₁-₄alkyl. R^a1, R^a2And R^a3Can be further substituted by the following groups: R^b1, Halogen, -OH, -NH₂, -NO₂, -CN, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OR^b1, -SR^b1, -OC(O)R^b1, -OC(S)R^b1, -C(O)R^b1, -C(S)R^b1, -C(O)OR^b1, -C(S)OR^b1, -S(O)R^b1, -S(O)₂R^b1, -C(O)NHR^b1, -C(S)NHR^b1, -C(O)NR^b1R^b2, -C(S)NR^b1R^b2, -S(O)₂NHR^b1, -S(O)₂NR^b1R^b2, -C(NH)NHR^b1, -C(NH)NR^b1R^b2, -NHC(O)R^b1, -NHC(S)R^b1, -NR^b2C(O)R^b1, -NR^b1C(S)R^b2, -NHS(O)₂R^b1, -NR^b1S(O)₂R^b2, -NHC(O)NHR^b1, -NHC(S)NHR^b1,- NR^b1C(O)NH₂, -NR^b1C(S)NH₂, -NR^b1C(O)NHR^b2, -NR^b1C(S)NHR^b2, -NHC(O)NR^b1R^b2, -NHC(S)NR^b1R^b2, -NR^b1C(O)NR^b2R^b3, -NR^b3C(S)NR^b1R^b2, -NHS(O)₂NHR^b1, -NR^b1S(O)₂NH₂, -NR^b1S(O)₂NHR^b2, -NHS(O)₂NR^b1R^b2, -NR^b1S(O)₂NR^b2R^b3, -NHR^b1And -NR^b1R^b2, The number is in the range of zero to (2p'+1), where p'is the total number of carbon atoms in the group. R^b1, R^b2And R^b3Each independently refers to hydrogen, C_1-8Alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryl substituted with 1-3 halogens, C₁-₈Alkoxy, haloalkyl, haloalkoxy or C₁-₈Thioalkoxy or unsubstituted aryl-C₁-₄alkyl.

Substituents of aryl and heteroaryl groups vary and are usually selected from: R', halogen, -OH, -NH₂, -NO₂, -CN, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OR', -SR', -OC(O)R', -OC(S)R', -C(O)R', -C(S)R', -C(O)OR',- C(S)OR', -S(O)R', -S(O)₂R', -C(O)NHR', -C(S)NHR', -C(O)NR'R", -C(S)NR'R", -S(O)₂NHR', -S(O)₂NR'R", -C(NH)NHR', -C(NH)NR'R", -NHC(O)R', -NHC(S)R', -NR"C(O)R',- NR'C(S)R", -NHS(O)₂R', -NR'S(O)₂R", -NHC(O)NHR', -NHC(S)NHR', -NR'C(O)NH₂, -NR'C(S)NH₂, -NR'C(O)NHR", -NR'C(S)NHR", -NHC(O)NR'R", -NHC(S)NR'R", -NR'C(O)NR" R''', -NR'''C(S)NR'R", -NHS(O)₂NHR', -NR'S(O)₂NH₂, -NR'S(O)₂NHR", -NHS(O)₂NR'R", -NR'S(O)₂NR"R''', -NHR', -NR'R", -N₃, Perfluorinated (C₁-C₄)Alkoxy and perfluoro(C₁-C₄) Alkyl, the number is in the range of zero to the total number of open valences on the aromatic ring system; and wherein R', R" and R"' are independently selected from hydrogen, haloalkyl, haloalkoxy, C_1-8Alkyl, C_3-6Cycloalkyl, cycloalkylalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryl-C_1-4Alkyl and aryloxy-C_1-4alkyl. Other suitable substituents include each of the above aryl substituents connected to ring atoms via an alkylene tether having 1 to 4 carbon atoms. R', R" and R''' can be further subjected to the following Group substitution: R^a1, Halogen, -OH, -NH₂, -NO₂, -CN, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OR^a1, -SR^a1, -OC(O)R^a1, -OC(S)R^a1, -C(O)R^a1, -C(S)R^a1, -C(O)OR^a1, -C(S)OR^a1, -S(O)R^a1, -S(O)₂R^a1, -C(O)NHR^a1, -C(S)NHR^a1, -C(O)NR^a1R^a2, -C(S)NR^a1R^a2, -S(O)₂NHR^a1, -S(O)₂NR^a1R^a2, -C(NH)NHR^a1, -C(NH)NR^a1R^a2, -NHC(O)R^a1, -NHC(S)R^a1, -NR^a2C(O)R^a1, -NR^a1C(S)R^a2, -NHS(O)₂R^a1, -NR^a1S(O)₂R^a2, -NHC(O)NHR^a1, -NHC(S)NHR^a1, -NR^a1C(O)NH₂, -NR^a1C(S)NH₂, -NR^a1C(O)NHR^a2, -NR^a1C(S)NHR^a2, -NHC(O)NR^a1R^a2, -NHC(S)NR^a1R^a2, -NR^a1C(O)NR^a2R^a3, -NR^a3C(S)NR^a1R^a2, -NHS(O)₂NHR^a1, -NR^a1S(O)₂NH₂, -NR^a1S(O)₂NHR^a2, -NHS(O)₂NR^a1R^a2, -NR^a1S(O)₂NR^a2R^a3, -NHR^a1,-NR^a1R^a2, -N₃, Perfluorinated (C₁-C₄)Alkoxy and perfluoro(C₁-C₄) Alkyl, the number is in the range of zero to the total number of open valences on the aromatic ring system; and where R^a1, R^a2And R^a3Each is independently selected from hydrogen, haloalkyl, haloalkoxy, C_1-8Alkyl, C_3-6Cycloalkyl, cycloalkylalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryl-C_1-4Alkyl or aryloxy-C_1-4alkyl. Other suitable substituents include each of the above aryl substituents connected to ring atoms via an alkylene tether having 1 to 4 carbon atoms.

When two substituents are present on the adjacent atoms of the substituted aryl or substituted heteroaryl ring, these substituents may be controlled by the formula -TC(O)-(CH₂)_qSubstituent replacement of -U-, where T and U are independently -NH-, -O-, -CH₂-Or a single bond, and q is an integer from 0 to 2. Alternatively, when two substituents are present on the adjacent atoms of the substituted aryl or substituted heteroaryl ring, these substituents may be represented by the formula -A-(CH₂)_rSubstituent replacement of -B-, where A and B are independently -CH₂-, -O-, -NH-, -S-, -S(O)-, -S(O)₂-, -S(O)₂NR'-or a single bond, and r is an integer from 1 to 3. Therefore, one of the single bonds of the new ring can be As the case may be replaced by a double bond. Alternatively, when two substituents are present on the adjacent atoms of the substituted aryl or substituted heteroaryl ring, these substituents may be controlled by the formula -(CH₂)_s-X-(CH₂)_tSubstituent replacement of -, wherein s and t are independently an integer from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)₂-Or-S(O)₂NR'-. -NR'- and -S(O)₂The substituent R'in NR'- is selected from hydrogen or unsubstituted C_1-6alkyl.

"Protecting group" refers to a group of atoms that shields, reduces or prevents the reactivity of a reactive group in a molecule when it is connected. Examples of protecting groups can be found in the following documents: TW Greene and PG Wuts, Protective Groups in Organic Chemistry (Wiley, 4th edition 2006); Beaucage and Iyer,<i>Tetrahedron</i> 48: 2223-2311 (1992); and Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vol. 1-8 (John Wiley and Sons. 1971-1996). Representative amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tertiary butoxycarbonyl (Boc), trimethylsilyl ( TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl, allyloxycarbonyl, 9-tylmethoxycarbonyl (FMOC) , Nitro-veratryloxycarbonyl (NVOC), triisopropylsilyl (TIPS), benzenesulfonyl and similar groups, carbamates, amides, N-sulfonyl derivatives , The group of formula -C(O)OR (where R is for example methyl, ethyl, tertiary butyl, benzyl, phenethyl, CH₂=CHCH₂-And similar groups), the group of formula -C(O)R' (wherein R'is, for example, methyl, phenyl, trifluoromethyl and the like), formula -SO₂The group of R" (wherein R" is, for example, tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethyl<img file="TWI617552B_D0004.tif" wi="60" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />Alkyl-6-yl, 2,3,6-trimethyl-4-methoxyphenyl and the like) and silyl-containing groups (such as 2-trimethylsilylethoxymethyl , Tert-butyldimethylsilyl, triisopropylsilyl and similar groups) (see also Boyle, AL (eds), Current Protocols in Nucleic Acid Chemistry, John Wiley and Sons, New York, No. 1 Volume, 2000).

As used throughout the manual, "optional" or "as the case may be" means that the event or situation described later may or may not occur, and the description includes the event or What happened and what didn't happen. For example, the phrase "an aromatic group substituted with one or two alkyl substituents as appropriate" means that an alkyl group may not necessarily be present, and the description includes the case where the aromatic group is substituted with an alkyl group and that the aromatic group is not When substituted by an alkyl group.

As used herein, the term "composition" refers to a formulation suitable for administration to a predetermined animal individual for therapeutic purposes, which contains at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient .

The term "pharmaceutically acceptable" means that the indicated substance does not have the properties that would cause a cautious medical practitioner to avoid administering the substance to the patient in consideration of the disease or condition being treated and the respective route of administration. For example, it is generally necessary for the substance to be sterile in nature, for example for injectables.

"Pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a patient (such as a mammal) (for example, a salt that has acceptable mammalian safety for a given dosage regimen). These salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids, depending on the specific substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired base (in pure form or in a suitable inert solvent). Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganite, potassium, and sodium salts , Zinc salts and similar salts. Salts derived from pharmaceutically acceptable organic bases include the salts of the following bases: primary, secondary, tertiary and quaternary amines, including substituted amines, cyclic amines, naturally occurring amines and their analogs, such as refined Amino acid, betaine, caffeine, choline, N,N'-benzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine Amine, N-ethylpiperidine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydrochloride, isopropylamine, lysine, methylglucamine, morpholine, piperidine Oxazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, N,N'-benzylethylenediamine Chloroprocaine (chloroprocaine), choline, diethanolamine, meglumine (N-methyl-reduced glucosamine) and the like. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired acid (in pure form or in a suitable inert solvent). Salts derived from pharmaceutically acceptable acids include the salts of the following acids: acetic acid, trifluoroacetic acid, propionic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid Acid, glycolic acid, gluconic acid, glucuronic acid, glutamine, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, methane Sulfonic acid, mucous acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, hydroiodic acid, carbonic acid, tartaric acid, p-toluenesulfonic acid, pyruvic acid, aspartame Acid, benzoic acid, anthranilic acid, methanesulfonic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, emboic acid (pamoic acid), ethanesulfonic acid, benzenesulfonic acid, 2-hydroxyethyl Sulfonic acid, p-aminobenzenesulfonic acid, stearic acid, cyclohexylaminosulfonic acid, alginic acid, hydroxybutyric acid, galacturonic acid, galacturonic acid and similar acids.

Also includes salts of amino acids, such as arginine and its analogs; and salts of organic acids (such as glucuronic acid or galacturonic acid and their analogs) (see, for example, Berge, SM et al., "Pharmaceutical Salts", J. Pharmaceutical Science, 1977, 66:1-19). Certain specific compounds of the present invention contain basic and acidic functional groups, which allow the compound to be converted into bases or acid addition salts.

The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent compound form differs from various salt forms in certain physical properties (such as solubility in polar solvents), but in other respects, for the purposes of the present invention, the salt is equivalent to the parent compound form.

In the context of the present invention, the term "therapeutically effective" or "effective amount" means that when administered, it is sufficient or effective to prevent, reduce or ameliorate one or more symptoms of the disease, disorder or medical condition being treated and/or prolong the treatment Surviving compound or compound quantity. The therapeutically effective amount will vary depending on the compound, disease, disorder or condition and its severity, and the age, weight, etc. of the mammal to be treated. Generally speaking, satisfactory results in an individual are indicated to be obtained at a daily dose of about 0.1 to about 10 g/kg of the individual's body weight. In some embodiments, the daily dose is in the following range: about 0.10 to 10.0 mg/kg body weight, about 1.0 to 3.0 mg/kg body weight, about 3 to 10 mg/kg body weight, about 3 to 150 mg/kg body weight, about 3 to 100 mg/kg body weight, about 10 to 100 mg/kg body weight, about 10 to 150 mg/kg body weight, or about 150 to 1000 mg/kg body weight. The dosage can be conveniently administered, for example, in divided doses up to four times a day or in sustained release.

The reference to specific amino acid residues in the human c-kit polypeptide is defined by the number corresponding to the Kit sequence in GenBank NP_000213 (SEQ ID NO: 1). The reference to a specific nucleotide position in the nucleotide sequence encoding all or a part of c-kit is defined by the number corresponding to the sequence provided in GenBank NM_000222 (SEQ ID NO: 2).

The terms "kit", "c-kit", and "c-Kit" mean enzymatically active kinases, which contain the largest alignment in terms of fragments of equal length and include full-length c-kit (such as human c-kit, For example, the amino acid residue of the ATP binding site of sequence NP_000213, SEQ ID NO: 1) has more than 90% amino acid sequence identity; or contains at least 200 consecutive amino acids with natural c-kit More than 90% of the amino acid sequence consistency part and maintain kinase activity. Preferably, the sequence identity is at least 95%, 97%, 98%, 99% or even 100%. Preferably, the predetermined level of sequence identity is at least 100-500, at least 200-400, or at least 300 consecutive amino acid residues long. Unless stated to the contrary, the term includes references to wild-type c-kit, allele variants, and mutant forms (e.g., with activating mutations).

In the context of the present invention, the term "synergistic effect" or "synergistic effect" means that two or more therapeutically effective compounds can provide an improved therapeutic effect when used in combination, and the improved therapeutic effect is greater than that based on each compound used alone The cumulative effect expected by the effect.

"Analysis" means creating experimental conditions and collecting data about specific results from exposure to specific experimental conditions. For example, enzymes can be analyzed based on their ability to act on detectable substrates. Compounds can be analyzed based on their ability to bind to specific target molecules.

As used herein, the terms "ligand" and "modulator" are equivalently used to refer to compounds that alter (ie increase or decrease) the activity of target biomolecules (eg enzymes such as kinases). Generally speaking, the ligand or modulator will be a small molecule, where "small molecule" refers to a molecular weight of 1500 Dalton or less than 1500 Dalton, or preferably 1000 Dalton or less than 1000 Dalton, 800 Daltons or compounds below 800 Daltons or 600 Daltons or below 600 Daltons. Therefore, "improved ligands" are ligands that have better pharmacological and/or pharmacokinetic properties compared to the reference compound. Among them, "better" can be used by those familiar with the relevant technology for specific biological systems or therapeutic applications. In terms of definition.

The term "binding" to the interaction between the target and the potential binding compound means that the potential binding compound associates with the target to a statistically significant degree compared to the general association with a protein (ie, non-specific binding). Therefore, the term "binding compound" refers to a compound that is statistically significantly associated with the target molecule. Preferably, the binding compound has a dissociation constant (K_D) Interact with the specified target.

When a compound binds to a target, the terms "greater affinity" and "selectivity" mean that the compound binds more tightly than the reference compound or the same compound under the reference conditions, that is, the dissociation constant is lower. In some embodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000 times greater affinity.

As used herein in connection with the compounds of the present invention, the term "synthesis" and similar terms mean chemical synthesis from one or more precursor substances. In addition, "analysis" means creating experimental conditions and collecting data on specific results of experimental conditions. For example, enzymes can be analyzed based on their ability to act on detectable substrates. Compounds or ligands can be based on their binding to specific The ability of the target molecule to analyze.

As used herein, the term "lone pair" or "lone electron pair" refers to a pair of electrons in the outermost layer of an atom, especially a nitrogen atom, which is not used in bonding.

As used herein, the term "modulation" refers to an effect that alters biological activity, especially the biological activity associated with specific biological molecules such as protein kinases. For example, agonists or antagonists of specific biomolecules regulate the activity of biomolecules (such as enzymes) by increasing (such as agonists, activators) or decreasing (such as antagonists, inhibitors) the activity of biomolecules such as enzymes. ) Of the activity. Typically with respect to (for example) the inhibitory concentration (IC₅₀) Or excitation concentration (EC₅₀) To illustrate the activity.

"Prodrug" means any compound that releases the active parent drug of Formula I in vivo when the prodrug is administered to a mammalian subject. The prodrug of the compound of formula I is prepared by modifying the functional groups present in the compound of formula I, in this way, the modified substance can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in compounds, and in this way, the modified substances can be cleaved into parent compounds by conventional operations or in vivo. Prodrugs include compounds of formula I in which the hydroxyl group, amine group, carboxyl group or sulfhydryl group in the compound of formula I are bonded to any group and can be cleaved in vivo to regenerate free hydroxyl, amine or sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, esters of hydroxyl functional groups in compounds of formula I (e.g. acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g. N,N-dimethylaminocarbonyl) and its analogs. The preparation, selection and use of prodrugs are discussed in the following documents: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Volume 14 of the ACS Symposium Series; "Design of Prodrugs", edited by H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is hereby incorporated by reference in its entirety.

"Tautomer" means that the proton of one atom of the molecule moves to another The compound produced by the phenomenon of sons. See Jerry March,<i>Advanced Organic Chemistry: Reactions, Mechanisms and Structures</i>, Fourth Edition, John Wiley &amp; Sons, pp. 69-74 (1992). Tautomers also refer to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomer form to another. Examples include keto-enol tautomers, such as acetone/propene-2-ol; imine-enamine tautomers and their analogs; ring-chain tautomers, such as glucose/2,3,4 ,5,6-pentahydroxy-hexanal and its analogues; tautomeric forms of heteroaryl groups containing -N=C(H)-NH- ring atoms, such as pyrazole, imidazole, benzimidazole, tri Azole and tetrazole. When the compound contains, for example, a ketone or oxime group or aromatic moiety, tautomeric isomerism ("tautomerism") may occur. The compounds described herein may have one or more tautomers and therefore include multiple isomers. The skilled person believes that other tautomeric ring atom arrangements may exist. All such isomeric forms of these compounds are expressly included in the present invention.

"Isomers" mean compounds that have the same molecular formula but differ in the bonding nature or order of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." "Stereoisomers" refer to compounds that have one or more asymmetric centers or double bonds with asymmetric substitutions, which exist in different stereoisomeric forms and can therefore produce individual stereoisomers or mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, there may be a pair of enantiomers. Enantiomers are characterized by the absolute configuration of their asymmetric centers and are described by the R-order rules and S-order rules of Cahn and Prelog, or by the way in which the molecules rotate around the plane of polarized light and are designated as right Rotary or levorotatory (that is, (+)-isomer or (-)-isomer, respectively). Opposite compounds can exist in the form of individual enantiomers or in the form of mixtures thereof. A mixture containing equal proportions of enantiomers The substance is called "racemic mixture". Unless otherwise stated, the description is intended to include individual stereoisomers as well as mixtures. The methods for determining the stereochemistry and separation of stereoisomers are well known in the art (see Chapter 4 of Advanced Organic Chemistry, 6th Edition J. March, John Wiley and Sons, New York, 2007 for discussion), but It is different in the contrast of one or more three-dimensional centers.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms (including hydrated forms). "Hydrate" refers to a complex formed by the combination of water molecules and solute molecules or ions. "Solvate" refers to a complex formed by the combination of solvent molecules and solute molecules or ions. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Solvates are meant to include hydrates. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. Generally speaking, the solvated form is equivalent to the unsolvated form, and is included in the scope of the present invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms. Generally speaking, all physical forms are equivalent for the purposes covered by the present invention and are intended to fall within the scope of the present invention.

In the context of the use, testing or screening of a compound that is or can be a modulator, the term "contact" means bringing the compound close enough to a specific molecule, complex, cell, tissue, organism, or other prescribed substance to allow the compound to interact with Potential binding interactions and/or chemical reactions may occur between other prescribed substances.

As used herein, the term "individual" refers to a living organism that is treated with a compound as described herein, including (but not limited to) any mammal, such as humans, other primates, competitive animals, and commercial interests. Animals (such as cows), farm animals (such as horses) or pets (such as cats).

The term "administration" refers to oral administration, administration in the form of suppositories, local contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or implantation of a slow release device, such as a small Osmotic pump. By including any parenteral and transmucosal (such as intrabuccal, sublingual, palate, gum, nasal, transvaginal, transrectal or transdermal) Ways to invest. Parenteral administration includes, for example, intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraperitoneal, and intracranial. Other delivery methods include (but are not limited to) the use of liposome formulations, intravenous infusion, transdermal patches, and the like.

"Solid form" refers to a solid preparation (that is, a preparation that is neither a gas nor a liquid) suitable for administering a pharmaceutically active compound for therapeutic purposes to a predetermined animal individual. The solid form includes any complex of the compound (such as a salt, co-crystal or amorphous complex) as well as any polymorph. The solid form may be a substantially crystalline, semi-crystalline, or substantially amorphous solid form. The solid form can be administered directly or can be used to prepare suitable compositions with improved medicinal properties. For example, the solid form can be used in formulations containing at least one pharmaceutically acceptable carrier or excipient.

As used herein, the term "prevention" language and method variations system refers to partially or completely delaying or eliminating the disease, disorder or condition, and / or one or more symptoms accompanying the onset or recurrence; or impede the individual then have to obtain or disorder or Condition; or a method to reduce the risk of an individual getting or reoccurring a disease or condition or one or more of its accompanying symptoms.

"Pain" or "pain condition" can be acute and/or chronic pain, including (not limited to) arachnoiditis; arthritis (such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout); back pain (Such as sciatica, intervertebral disc rupture, spondylolisthesis, nerve root disease); burning pain; cancer pain; dysmenorrhea; headache (such as migraine, aggregate headache, tension headache); head and facial pain (such as cranial neuralgia) , Trigeminal neuralgia); hyperalgesia; pathological pain; inflammatory pain (such as irritability, inflammatory bowel disease, ulcerative colitis, Crohn's disease, cystitis-related pain, caused by bacteria , Fungal or viral infections); keloid or scar tissue formation; labor pain or labor pain; muscle pain (such as polymyositis, dermatomyositis, inclusion body myositis, repetitive pressure injury (such as writing cramps, Carpal tunnel syndrome, tendinitis, tenosynovitis) caused by muscle pain); myofascial pain syndrome (such as muscle fiber pain); neuralgia (such as diabetic neuropathy, causalgia, entrapment neuropathy, brachial plexus) Nerve root avulsion, pillow Neuralgia, gout, reflex sympathetic dystrophy syndrome, phantom pain or pain after amputation, post-herpetic neuralgia, central pain syndrome, or caused by trauma (such as nerve damage), disease (such as diabetes, multiple sclerosis) , Guillan-Barre Syndrome, myasthenia gravis, neurodegenerative diseases (such as Parkinson's disease, Alzheimer's disease) disease), amyotrophic lateral sclerosis, or cancer treatment caused by nerve pain; pain related to skin diseases (such as herpes zoster, herpes simplex, skin tumors, cysts, neurofibromas); sports injuries (such as Incisions, sprains, strains, bruises, dislocations, fractures, spinal cords, head); spinal stenosis; surgical pain; tactile allodynia; temporomandibular disorders; vascular disease or injury (e.g., vasculitis, coronary artery disease, reperfusion) Injury (e.g. after ischemia, stroke or myocardial infarction); other specific organ or tissue pain (e.g. eye pain, corneal pain, bone pain, heart pain, visceral pain (e.g. kidney, gallbladder, gastrointestinal), joint pain, toothache , Pelvic sensitivity, pelvic pain, renal colic, urinary incontinence); pain related to other diseases (such as sickle cell anemia, AIDS, herpes zoster, psoriasis, endometriosis, asthma, chronic obstructive pulmonary disease (COPD) , Silicosis, pulmonary sarcoidosis, esophagitis, heartburn, gastroesophageal reflux disease, gastric and duodenal ulcers, functional dyspepsia, bone resorption diseases, osteoporosis, cerebral malaria, bacterial meningitis); or Pain caused by graft-versus-host rejection or allograft rejection.

"Unit dosage form" refers to a composition intended for single administration to treat an individual suffering from a disease or medical condition. Each unit dosage form typically contains each active ingredient of the present invention plus pharmaceutically acceptable excipients. Examples of unit dosage forms are individual lozenges, individual capsules, bulk powders, liquid solutions, ointments, creams, eye drops, suppositories, emulsions or suspensions. Treatment of diseases or conditions may require periodic administration of unit dosage forms, for example: a unit dosage form two or more times a day, one with each meal, one every four hours or other intervals, or only one per day. The expression "oral unit dosage form" means a unit dosage form designed for oral administration.

As used herein, the term c-kit-mediated disease or condition or kit-mediated disease or condition or KIT-mediated disease or condition refers to a disease or condition in which the biological function of c-kit and/or mutant c-kit affects the disease or The progression and/or course of a disease condition; and/or a disease or condition in which the regulation of c-kit and/or mutant c-kit changes the progression, course and/or symptoms. For example, mutations (such as W42, Wv, and W41 mutations) reported by Herbst et al. (J. Biol. Chem., 1992, 267: 13210-13216) in the c-kit gene confer severe, intermediate, and mild expressions, respectively. Type features. These mutations attenuate the intrinsic tyrosine kinase activity of the receptor to varying degrees, and are a model of the effect of modulating c-kit activity. C-kit-mediated diseases or conditions include diseases or conditions for which c-kit and/or mutant c-kit inhibition provides therapeutic benefits, for example, in which c-kit inhibitors (including the compounds described herein) are used to treat Individuals suffering from a disease or condition or at risk of the disease or condition provide therapeutic benefits. As used herein, the mutation c-kit, kit, or KIT includes kit with one or more mutations selected from the group consisting of D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del 550-558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C and T670I. In some cases, KIT mutations include D816F, D816H, D816N, D816Y, D816V, T670I, and V654A. In other cases, KIT mutations include D816V and/or V560G.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compounds. For example, the compound can be radiolabeled with a radioisotope such as tritium (³H), iodine-125 (¹²⁵I), carbon-14 (¹⁴C), carbon-11 (¹¹C) or fluorine-18 (¹⁸F). All isotopic variants of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

As used herein, the term "deuterated" alone or as part of a group means a substituted deuterium atom. When a specific location is designated as having deuterium (stated as "D" or "deuterium") At this time, it should be understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium of 0.015% (that is, at least 50.1% of deuterium is incorporated).

As used herein, the term "deuterated analog" alone or as part of a group means that a substituted deuterium atom replaces hydrogen. The deuterated analog of the present invention may be a derivative fully or partially substituted with deuterium. Preferably, the compound of the present invention substituted with deuterium has an alkyl group, an aryl group or a heteroaryl group fully or partially substituted with deuterium. In one embodiment, the compound of the invention substituted with deuterium has an alkyl group that is fully or partially substituted with deuterium, such as -CD₃, CD₂CD₃, -CD₂CD₂CD₃(N-Propyl-D7), -CD(CD₃)₂(Isopropyl-D7), -CD₂CD₂CD₂CD₃(N-butyl-D9), -CD₂-CD(CD₃)₂(Isobutyl-D9) and similar groups. In another embodiment, the compound of the invention substituted with deuterium has an aryl group that is fully or partially substituted with deuterium, such as a phenyl group, such as C₆D₅; Or a heteroaryl fully or partially substituted with deuterium, such as pyrazolyl-d₂Thiazolyl-d₂Pyridyl-d₃And similar groups.

As used herein in conjunction with an amino acid or nucleic acid sequence, the term "isolated" means that the sequence is separated from at least a portion of the amino acid and/or nucleic acid sequence with which it is normally associated.

In conjunction with amino acids or nucleic acid sequences, the term "purified" means that the target molecule constitutes a significantly greater proportion of biomolecules in the composition than that observed in existing compositions (for example, in cell culture). The larger ratio can be 2 times, 5 times, 10 times, or more than 10 times the ratio seen in existing compositions.

The present invention also includes isotopically labeled compounds of the present invention, which are the same as the compounds listed in this article, but the fact is that one or more atoms are replaced by an atom whose atomic mass or mass number is different from the atomic mass or mass number commonly seen in nature . Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as (but not limited to)²H (deuterium, D),³H (tritium),¹¹C,¹³C,¹⁴C,¹⁵N,¹⁸F.³¹P,³²P,³⁵S,³⁶Cl and¹²⁵I. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position is deemed to have hydrogen or its isotopes, such as deuterium (D) or tritium (³H). Certain isotopically labeled compounds of the present invention (e.g., by³H and¹⁴C labeled compound) is suitable for compound and/or substrate tissue distribution analysis. Tritiated (i.e.³H) and carbon-14 (i.e.¹⁴C) and fluorine-18 (¹⁸F) Isotopes are suitable due to their ease of preparation and detectability. In addition, after heavier isotopes (such as deuterium (that is,²H)) Substitution can obtain certain therapeutic advantages due to greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore may be better in some cases. The isotopically-labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the following procedures and examples, by substituting isotopically-labeled reagents for non-isotopically-labeled reagents.

<b>II. General</b>

The present invention relates to compounds of formula (I'), (I), (II), (III), (IV), (V) or (V') and all sub-general formulae, such as the compounds listed in the scope of the patent application , And compounds described herein as modulators of protein kinases, such as (but not limited to) compounds that are modulators of wild-type KIT and/or mutant forms of KIT protein kinase; and these compounds are used in the treatment of diseases or conditions The purpose.

<b>III. Compound</b>

In one aspect, the present invention provides a compound of formula (I'):<chemistry general="n"><img he="228" wi="713" file="TWI617552B_D0005.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Or its pharmaceutically acceptable salts, hydrates, solvates, tautomers and isomers; wherein the variables and substituents are as defined in the summary of the invention.

In some embodiments of the compound of formula (I), the molecular weight of the compound is less than 600. In some preferred embodiments, the molecular weight of the compound is less than 500. In other preferred embodiments, the molecular weight of the compound is less than 450. In other preferred embodiments, the molecular weight of the compound is less than 400. In other preferred embodiments, the molecular weight of the compound is less than 350. In other preferred embodiments, the molecular weight of the compound is less than 300.

In some embodiments of the compound of formula (I'), G is optionally substituted aryl or optionally substituted 5 or 6 membered heteroaryl having one to three nitrogen atoms as ring members, wherein aryl The radical or heteroaryl group is optionally fused with an optionally substituted 5- to 8-membered ring having 0-2 heteroatoms selected from O, N, or S as ring members. R¹And R²Combined together to form optionally substituted aryl or optionally substituted 5- or 6-membered fused heteroaryl ring with 0-3 heteroatoms selected from N, O or S as ring members, one of which is or Two ring carbon atoms are replaced by -C(=O)- as appropriate.

In some embodiments of compounds of formula (I'), the present invention provides compounds of formula (I):<chemistry general="n"><img he="424" wi="833" file="TWI617552B_D0006.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Or its pharmaceutically acceptable salts, hydrates, solvates, tautomers and isomers; wherein: (i) R¹And R²Combined together to form an optionally substituted 5- or 6-membered fused ring with 0 to 3 heteroatoms selected from N, O or S as ring members, wherein one or two of the ring carbon atoms optionally undergo -C( =O)-replacement; or (ii) R¹Is H, halogen, C_1-4Alkyl, C_1-4Haloalkyl, C_1-4Haloalkoxy, cyclopropyl or lone electron pair and R²For -NH-L²-R⁶, Where R⁶Is H, optionally substituted aryl, optionally substituted aryl-C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C_1-4Alkyl, optionally substituted heterocycloalkyl, optionally substituted C_1-6Alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl-C_1-4Alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic group-C_1-4Alkyl; and where L²Department is selected from a key, -C(O)-, -C(O)N(R^f)-, -SO₂N(R^f)-, -SO₂-, -C(O)O-, -C(=NR^f)N(R^f)-, where each R^f, Independently H or C_1-4Alkyl; R³And R⁴Each is independently selected from H, halogen, C_1-4Alkyl, C_1-4Haloalkyl, C_1-4Haloalkoxy, cyclopropyl, phenyl, CN, CN-CH₂-, C_1-4Alkoxy, R^gOr lone electron pair; Or R³And R⁴Combine with the atoms to which it is connected to form an optionally substituted 5- to 8-membered ring with 0-2 heteroatoms selected from O, N or S as ring members; wherein R^gAs -OH, -NH₂, -NO₂, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OR^h, -SR^h, -OC(O)R^h, -OC(S)R^h, -C(O)R^h, -C(S)R^h, -C(O)OR^h, -C(S)OR^h, -S(O)R^h, -S(O)₂R^h, -C(O)NHR^h, -C(S)NHR^h, -C(O)NR^hR^h, -C(S)NR^hR^h, -S(O)₂NHR^h, -S(O)₂NR^hR^h, -C(NH)NHR^h, -C(NH)NR^hR^h, -NHC(O)R^h, -NHC(S)R^h, -NR^hC(O)R^h, -NR^hC(S)R^h, -NHS(O)₂R^h, -NR^hS(O)₂R^h, -NHC(O)NHR^h, -NHC(S)NHR^h, -NR^hC(O)NH₂, -NR^hC(S)NH₂, -NR^hC(O)NHR^h, -NR^hC(S)NHR^h, -NHC(O)NR^hR^h, -NHC(S)NR^hR^h, -NR^hC(O)NR^hR^h, -NR^hC(S)NR^hR^h, -NHS(O)₂NHR^h, -NR^hS(O)₂NH₂, -NR^hS(O)₂NHR^h, -NHS(O)₂NR^hR^h, -NR^hS(O)₂NR^hR^h, -NHR^hOr -NR^hR^h, Where each R^hIndependently H or C_1-2Alkyl; in some cases, R³And R⁴Not hydrogen at the same time; L¹Selected from -C(O)NR⁵-, -CH₂N(R⁵)-, -SO₂N(R⁵)-, -N(R⁵)C(O)N(R⁵)-, -N(R⁵)SO₂-, -N(R⁵)CH₂-, -OC_1-4Alkylene-, -C_1-4Alkylene-O-, -C(O)-, -NR⁵C(O)-, -SO₂-, -SON(R⁵)-Or -S(O)-, where each R⁵Independently H or C_1-4Alkyl; Y¹Is N or C; Y²N or replaced as appropriate = C-; Y³N or CH; its restriction condition is Y¹, Y²And Y³N at the same time; Z¹Is N or CH; Z³Is N, C or CH; Z²And Z⁴Each independently is N or C, and its restriction is Z¹,Z²,Z³And Z⁴Not N at the same time; and<img file="TWI617552B_D0007.tif" wi="115" he="45" img-format="tif" img-content="character" orientation="portrait" inline="no" />It is a single bond or a double bond. In some embodiments of the compound of formula (I), Z²And Z³for C. In some cases, part of the compound of formula (I)<img file="TWI617552B_D0008.tif" wi="216" he="315" img-format="tif" img-content="character" orientation="portrait" inline="no" />Can exist in tautomeric forms exist:<img file="TWI617552B_D0009.tif" wi="258" he="261" img-format="tif" img-content="character" orientation="portrait" inline="no" />, Where the wavy line represents the connection point with the rest of the molecule.

In some embodiments of the compound of formula (I), Z¹Is N, Z²,Z³And Z⁴Is C. In other embodiments of the compound of formula (I), Z¹Is N, Z²For C, Z³And Z⁴Is N. In other embodiments of the compound of formula (I), Z¹Is N, Z²For C, Z³Is CH, and Z⁴Is N. In other embodiments of the compound of formula (I), Z¹Is N, Z²For C, Z³Is N, and Z⁴Is C. In other embodiments of the compound of formula (I), Z¹Is N, Z²Is N, Z³Is N, and Z⁴Is C. In other embodiments of the compound of formula (I), Z¹Is N, Z²Is N, Z³Is CH, and Z⁴Is N. In other embodiments of the compound of formula (I), Z¹Is N, Z²Is N, Z³And Z⁴Is C. In other embodiments of the compound of formula (I), Z¹For CH, Z²,Z³And Z⁴Is C. In other embodiments of the compound of formula (I), Z¹For CH, Z²For C, Z³Is N, and Z⁴Is C. In other embodiments of the compound of formula (I), Z¹For CH, Z²For C, Z³Is C, and Z⁴Is N. In other embodiments of the compound of formula (I), Z¹For CH, Z²For C, Z³And Z⁴Is N. In other embodiments of the compound of formula (I), Z¹For CH, Z²Is N, Z³Is C, and Z⁴Is C. In other embodiments of the compound of formula (I), Z¹For CH, Z²Is N, Z³Is N, and Z⁴Is C. In other embodiments of the compound of formula (I), Z¹For CH, Z²Is N, Z³Is CH, and Z⁴Is N. In other embodiments of the compound of formula (I), Z¹For CH, Z²,Z³And Z⁴Is N. All other variables and substituents Y¹, Y², Y³, R¹, R², L¹, R³And R⁴As defined in any sub-formula of formula (I) or in any embodiment of the compound of formula (I) as described herein.

In some embodiments of compounds of formula (I') or (I), the present invention provides compounds of formula (II):<chemistry general="n"><img he="414" wi="847" file="TWI617552B_D0010.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable Y¹, Y², Y³, R¹, R²,Z¹, L¹, R³And R⁴As defined in any embodiment of the compound of formula (I'), (I) or (IV) or in any sub-formula of formula (I'), (I), (II) or (IV). In one case, Z¹Is N. In another case, Z¹For CH. In some cases Below, part of the compound of formula (II)<img file="TWI617552B_D0011.tif" wi="185" he="273" img-format="tif" img-content="character" orientation="portrait" inline="no" />Exist in tautomeric form:<img file="TWI617552B_D0012.tif" wi="276" he="270" img-format="tif" img-content="character" orientation="portrait" inline="no" />,That The middle wavy line represents the connection point with the rest of the molecule.

In some embodiments of compounds of formula (I'), (I) or (II), L¹Selected from -C(O)NR⁵-, -CH₂N(R⁵)-, -SO₂N(R⁵)-, -N(R⁵)C(O)N(R⁵)-, -N(R⁵)SO₂-, -N(R⁵)CH₂-, -OC_1-4Alkylene-, -C_1-4Alkylene-O-, -C(O)-, -SO₂-, -SON(R⁵)-Or -S(O)-. In other embodiments, L¹Department is selected from -C(O)N(R⁵)-, -SO₂N(R⁵)-, -C(O)-, -SO₂-, -CH₂O-, -CH₂N(R⁵)-Or-SON(R⁵)-. In other embodiments, L¹Is C(O)N(R⁵)-. In other embodiments, L¹Is -C(O)NH- or -SO₂NH-. In one embodiment, L¹It is -C(O)NH-. In some cases, R⁵For H. In other cases, R⁵Is C_1-4alkyl. In other cases, R⁵H, C_1-4Alkyl or C_1-4Haloalkyl. In one case, R⁵For H, -CH₃, -CHF₂, -CH₂F or -CF₃. All other variables and substituents Y¹, Y², Y³, R¹, R²,Z¹,Z²,Z³,Z⁴, R³And R⁴As in any sub-formula of formula (I'), (I) or (II) or the compound of formula (I'), (I) or (II) is as defined in any of the embodiments described herein.

In some embodiments of compounds of formula (I'), (I) or (II), L¹For -NHSO₂-, -SO₂NH-, -NHC(O)NH-, -NHC(O)-, -CH₂O-, -OCH₂-, -C(O)NH-, -SO₂-, -C(O)O-, -C(O)-, -C(=NH)NH- or -NHC(=NH)-. In certain embodiments, L¹For -NHSO₂-, -SO₂NH-, -NHC(O)NH-, -NHC(O)-, -C(O)NH-,- SO₂-, -C(O)O-, -OC(O)-, -C(O)- or -C(=NH)NH-. In some cases, L¹For -NHSO₂-, -SO₂NH-, -NHC(O)NH- or -NHC(O)-. In other cases, L¹For -C(O)NH-, -SO₂-, -SO₂NH-, -C(O)O- or -C(O)-. In other cases, L¹For -NHSO₂-Or-SO₂NH-. In other cases, L¹For -C(O)NH-, -NHSO₂-, -SO₂NH- or -C(=NH)NH-. In other cases, L¹For -NHSO₂-, -SO₂NH-or-SO₂-. In other cases, L¹It is -NH-C(O)-. All other variables and substituents Y¹, Y², Y³, R¹, R²,Z¹,Z²,Z³,Z⁴, R³And R⁴As defined in any of the embodiments described herein.

In some embodiments of compounds of formula (I'), (I), (II), the present invention provides compounds of formula (III):<chemistry general="n"><img he="335" wi="749" file="TWI617552B_D0013.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable Y¹, Y², Y³, R¹, R², R³, R⁴And L¹As the compound of formula (I'), (I), (II) or (IV) in any of the embodiments described herein or formula (I'), (I), (II) or (IV) Defined in any sub-general formula. In some cases of the compound of formula (III), L¹For -C(O)NR⁵-, where L¹The carbonyl group is covalently bonded to the pyrazole ring, and L¹The nitrogen atom in is covalently bonded to the 6-membered aromatic ring in formula (III).

In some embodiments of compounds of formula (I'), (I), (II) or (III), R¹And R²Combine with the atoms to which it is connected to form an optionally substituted 5- or 6-membered fused heterocyclic aromatic ring with 1-3 heteroatoms selected from O, N or S as ring members; or optionally substituted Condensed benzene ring. In some cases, the substituent of the fused aromatic ring is as in the formula (I'), (I), (II), (III), (IV) compound as in any of the embodiments described herein or formula ( I'), (I), (II), (III) or (IV) as defined in any sub-general formula⁷Group.

In some embodiments of compounds of formula (I'), the present invention provides compounds of formula (I'a):<chemistry general="n"><img he="284" wi="847" file="TWI617552B_D0014.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Substituent G is as defined in any embodiment of the compound of formula (I'). R⁵H, C_1-4Alkyl or C_1-4Haloalkyl. Ring A is a 5- or 6-membered fused heterocyclic aromatic ring with 1-3 heteroatoms selected from O, N or S as ring members; or a fused benzene ring; each R⁷Independently selected from C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, -X¹-Aryl, aryl-C_1-4Alkyl-X¹-, Heteroaryl-X¹-, Heteroaryl-C_1-4Alkyl-X¹-, C_3-6Cycloalkyl-X¹-, C_3-6Cycloalkyl-C_1-4Alkyl-X¹-, C_3-6Cycloalkenyl-X¹-, CH₂=CH-X¹, C_3-6Cycloalkyl-C_2-4Alkenyl-X¹, C_3-6Cycloalkyl-C_2-4Alkynyl-X¹, Heterocyclyl-X¹-, heterocyclyl-C_1-4Alkyl-X¹-Or R⁸, Where R⁸Is selected from halogen, CN, -OH, -NH₂, -NO₂, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OR^a, -SR^a, -OC(O)R^a, -OC(S)R^a, -C(O)R^a, -C(S)R^a, -C(O)OR^a, -C(S)OR^a, -S(O)R^a, -S(O)₂R^a, -C(O)NHR^a, -C(S)NHR^a, -C(O)NR^aR^a, -C(S)NR^aR^a, -S(O)₂NHR^a, -S(O)₂NR^aR^a, -C(NH)NHR^a, -C(NH)NR^aR^a, -NHC(O)R^a, -NHC(S)R^a, -NR^aC(O)R^a, -NR^aC(S)R^a, -NHS(O)₂R^a, -NR^aS(O)₂R^a, -NHC(O)NHR^a, -NHC(S)NHR^a, -NR^aC(O)NH₂, -NR^aC(S)NH₂, -NR^aC(O)NHR^a, -NR^aC(S)NHR^a, -NHC(O)NR^aR^a, -NHC(S)NR^aR^a, -NR^aC(O)NR^aR^a, -NR^aC(S)NR^aR^a, -NHS(O)₂NHR^a, -NR^aS(O)₂NH₂, -NR^aS(O)₂NHR^a, -NHS(O)₂NR^aR^a, -NR^aS(O)₂NR^aR^a, -NHR^aOr -NR^aR^a, Where each R^aIndependently selected from C_1-6Alkyl, aryl, aryl-C_1-2Alkyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkyl, heteroaryl, heteroaryl-C_1-4Alkyl, heterocycloalkyl or heterocycloalkyl-C_1-4Alkyl, where each R^aDepending on the situation, further through 1-3 independently selected from the following R^bSubstituent substitution: C_1-6Alkyl, C_1-6Alkoxy, halogen, C_1-6Haloalkyl or C_1-6halogen Alkoxy; where X¹Is a key or -C(O)-, and where R⁷1-5 selected from the following R according to the situation⁹Member substitution: halogen, -CH=CH₂, CN, -OH, -NH₂, -NO₂, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OR^c, -SR^c, -OC(O)R^c, -OC(S)R^c, -P(=O)HR^c, -P(=O)R^cR^c, -PH(=O)OR^c, -P(=O)(OR^c)₂, -OP(=O)(OR^c)₂, -C(O)R^c, -C(S)R^c, -C(O)OR^c, -C(S)OR^c, -S(O)R^c, -S(O)₂R^c, -C(O)NHR^c, -C(S)NHR^c, -C(O)NR^cR^c, -C(S)NR^cR^c, -S(O)₂NHR^c, -S(O)₂NR^cR^c, -C(NH)NHR^c, -C(NH)NR^cR^c, -NHC(O)R^c, -NHC(S)R^c, -NR^cC(O)R^c, -NR^cC(S)R^c, -NHS(O)₂R^c, -NR^cS(O)₂R^c, -NHC(O)NHR^c, -NHC(S)NHR^c, -NR^cC(O)NH₂, -NR^cC(S)NH₂, -NR^cC(O)NHR^c, -NR^cC(S)NHR^c, -NHC(O)NR^cR^c, -NHC(S)NR^cR^c, -NR^cC(O)NR^cR^c, -NR^cC(S)NR^cR^c, -NHS(O)₂NHR^c, -NR^cS(O)₂NH₂, -NR^cS(O)₂NHR^c, -NHS(O)₂NR^cR^c, -NR^cS(O)₂NR^cR^c, -NHR^c, R^cOr -NR^cR^c, Where each R^cIndependently selected from C_1-6Alkyl, aryl, aryl-C_1-2Alkyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkyl, heteroaryl, heteroaryl-C_1-4Alkyl, heterocycloalkyl or heterocycloalkyl-C_1-4Alkyl, where each R^cDepending on the situation, further through 1-3 independently selected from the following R^dGroup substitution: CN, -OH, -N(R^e)(R^e), -NO₂, -C(O)OH, -P(=O)HR^e, -P(=O)R^eR^e, -PH(=O)OR^e, -P(=O)(OR^e)₂, -OP(=O)(OR^e)₂, -C(O)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -C(NH)NH₂, -OC(O)R^e, -OC(S)R^e, -C(O)R^e, -C(S)R^e, -C(O)OR^e, -S(O)₂R^e, -C(O)NHR^e, C_1-6Alkyl, C_1-6Alkoxy, halogen, C_1-6Haloalkyl or C_1-6Haloalkoxy, where each R^eIndependently for C_1-6Alkyl; or two adjacent R⁷The substituents and the atoms to which they are attached together form a 4-, 5- or 6-membered carbocyclic ring or a heterocyclic ring with 1-2 heteroatoms selected from O, N or S as ring members; Y²For CR¹⁰, Where R¹⁰H, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is subject to 1-5 R⁹Group or 1-5 R^cGroup or 1-5 R^dGroup or 1-5 R^eGroup substitution; where X²Is C_1-4Alkylene, -O-, -S- or -NH-; Y¹It is N or C; and the subscript m is 0, 1, or 2. In some embodiments, R¹⁰For H. In some embodiments, R¹⁰Is H, halogen, C_1-4Alkyl, C_1-2Alkoxy, CN, NH₂, C_1-2Alkyl NH, (C_1-2alkyl)₂N. In some embodiments, R¹⁰Is C_1-4Alkyl, halogen, -NH₂, -CN, -OCH₃, CF₃, CN, -OCF₃, -CHF₂, -CH₂F, -OCH₂F or -OCHF₂. In other embodiments, R¹⁰Is C_1-4alkyl. In other embodiments, R⁷Is C_1-4Alkyl, halogen, -CN, -OCH₃, CF₃, CN, -OCF₃, -CHF₂, -CH₂F, -OCH₂F or -OCHF₂. In other embodiments, R⁷Is C_1-4alkyl. In some embodiments, the subscript m is 0, 1, 2, or 3. In one embodiment, Y¹It is N or C. In another embodiment, Y³For CH.

In some embodiments, the variables and substituents G, Y¹, Y², Y³, A, R⁷And the subscript m is as defined in any sub-formula of (I'), (I'a) or (IV) or in any embodiment of the compound of formula (IV). In any embodiment of the compound of formula (I'a), the hydrogen atom in G has 1 to 12 or 1 to 8 or 1 to 6 or 1 to 3 or 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11 and 12 deuterium atoms replaced, with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99 for each deuterium %, 99.5% or 99.9% deuterium is incorporated. In certain embodiments, each hydrogen atom in G is replaced by a deuterium atom as appropriate, with each deuterium having at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99% , 99.5% or 99.9% deuterium incorporated.

In some embodiments of compounds of formula (I') or (I'a), G is optionally substituted C_1-6alkyl. In other embodiments, G is an optionally substituted aryl group or an optionally substituted 5- or 6-membered heteroaryl group having one or more nitrogen atoms as ring members, wherein the aryl group or the heteroaryl group is optionally combined with Have 0-2 heteroatoms selected from O, N or S as ring members as appropriate Instead, the 5- to 8-membered ring is fused. In some cases, the alkyl or aromatic part of G is subject to 1-3 R⁷; Or 1-3 R⁸; Or 1-3 R⁹; Or 1-3 R^a; Or 1-3 R^c; Or 1-3 R^d; Or 1-3 R^gSubstituents are substituted. In other cases, the alkyl or aromatic part of G is optionally selected from the following R²¹Group substitution: halogen, C_1-4Alkyl, C_1-4Haloalkyl, C_1-4Haloalkoxy, cyclopropyl, phenyl, CN, CN-CH₂-, C_1-4Alkoxy, -OH, -NH₂, -NO₂, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -ORⁱ, -SRⁱ, -OC(O)Rⁱ, -OC(S)Rⁱ, -C(O)Rⁱ, -C(S)Rⁱ, -C(O)ORⁱ, -C(S)ORⁱ, -S(O)Rⁱ, -S(O)₂Rⁱ, -C(O)NHRⁱ, -C(S)NHRⁱ, -C(O)NRⁱRⁱ, -C(S)NRⁱRⁱ, -S(O)₂NHRⁱ, -S(O)₂NRⁱRⁱ, -C(NH)NHRⁱ, -C(NH)NRⁱRⁱ, -NHC(O)Rⁱ, -NHC(S)Rⁱ, -NRⁱC(O)Rⁱ, -NRⁱC(S)Rⁱ, -NHS(O)₂Rⁱ, -NRⁱS(O)₂Rⁱ, -NHC(O)NHRⁱ, -NHC(S)NHRⁱ, -NRⁱC(O)NH₂, -NRⁱC(S)NH₂, -NRⁱC(O)NHRⁱ, -NRⁱC(S)NHRⁱ, -NHC(O)NRⁱRⁱ, -NHC(S)NRⁱRⁱ, -NRⁱC(O)NRⁱRⁱ, -NRⁱC(S)NRⁱRⁱ, -NHS(O)₂NHRⁱ, -NRⁱS(O)₂NH₂, -NRⁱS(O)₂NHRⁱ, -NHS(O)₂NRⁱRⁱ, -NRⁱS(O)₂NRⁱRⁱ, -NHRⁱOr -NRⁱRⁱ, Where RⁱIs C_1-2Alkyl or optionally substituted phenyl.

In some embodiments of compounds of formula (I') or (I'a), G is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 1H-1,2,4-triazol-5-yl, 1H-1, 2,4-triazol-3-yl, 1H-1,2,5-triazol-3-yl, 1H-5-pyrazolyl, 1H-4-pyrazolyl, 1H-3-pyrazolyl, 3-pyridazinyl, 4-pyridazinyl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indyl Azol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl,<img file="TWI617552B_D0015.tif" wi="193" he="191" img-format="tif" img-content="character" orientation="portrait" inline="no" />or<img file="TWI617552B_D0016.tif" wi="182" he="203" img-format="tif" img-content="character" orientation="portrait" inline="no" />, Each of them Depending on the situation, 1-3 independently selected from the following R²²Group substitution: halogen, C_1-4Alkyl, C_1-4Haloalkyl, C_1-4Haloalkoxy, cyclopropyl, phenyl, CN, CN-CH₂-, C_1-4Alkoxy Or R^g; Or after 1-3 R^gGroup substitution, where R²²The hydrogen atoms in it are replaced by 1-8 deuterium atoms as appropriate. In some embodiments, G is 2-pyridyl, 3-pyridyl, or 4-pyridyl, each of which is optionally selected from 1-3 independently from the following R²²Group substitution: halogen, C_1-4Alkyl, C_1-4Haloalkyl, C_1-4Haloalkoxy, cyclopropyl, phenyl, CN, CN-CH₂-, C_1-4Alkoxy or R^g; Or after 1-3 R^gGroup substitution. In other cases, G is 1H-5-pyrazolyl, 1H-4-pyrazolyl or 1H-3-pyrazolyl, each of which is independently selected from the following R by 1-3 as appropriate²²Group substitution: halogen, C_1-4Alkyl, C_1-4Haloalkyl, C_1-4Haloalkoxy, cyclopropyl, phenyl, CN, CN-CH₂-, C_1-4Alkoxy or R^g; Or after 1-3 R^gGroup substitution. In other cases, G is 1H-5-pyrazolyl, which may be independently selected from the following R via 1-3 as the case²²Group substitution: halogen, C_1-4Alkyl, C_1-4Haloalkyl, C_1-4Haloalkoxy, cyclopropyl, phenyl, CN, CN-CH₂-, C_1-4Alkoxy or R^g; Or after 1-3 R^gGroup substitution. In some cases, R²²For-CD₃, -C₆D₅, Partially Deuterated C_1-6Alkyl or per-deuterated C_1-6alkyl.

In some embodiments of compounds of formula (I'), (I'a), (I), (II) or (III), the present invention provides compounds of formula (IV):<chemistry general="n"><img he="313" wi="857" file="TWI617552B_D0017.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Ring A is a 5- or 6-membered fused heterocyclic aromatic ring with 1-3 heteroatoms selected from O, N or S as ring members; or a fused benzene ring; each R⁷Independently selected from C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, -X¹-Aryl, aryl-C_1-4Alkyl-X¹-, Heteroaryl-X¹-, Heteroaryl-C_1-4Alkyl-X¹-, C_3-6Cycloalkyl-X¹-, C_3-6Cycloalkyl-C_1-4Alkyl-X¹-, C_3-6Cycloalkenyl-X¹-, CH₂=CH-X¹, C_3-6Cycloalkyl-C_2-4Alkenyl-X¹, C_3-6Cycloalkyl-C_2-4Alkynyl-X¹, Heterocyclyl-X¹-, heterocyclyl-C_1-4Alkyl-X¹-Or R⁸, Where R⁸Is selected from halogen, CN, -OH, -NH₂, -NO₂, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂,- NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OR^a, -SR^a, -OC(O)R^a, -OC(S)R^a, -C(O)R^a, -C(S)R^a, -C(O)OR^a, -C(S)OR^a, -S(O)R^a, -S(O)₂R^a, -C(O)NHR^a, -C(S)NHR^a, -C(O)NR^aR^a, -C(S)NR^aR^a, -S(O)₂NHR^a, -S(O)₂NR^aR^a, -C(NH)NHR^a, -C(NH)NR^aR^a, -NHC(O)R^a, -NHC(S)R^a, -NR^aC(O)R^a, -NR^aC(S)R^a, -NHS(O)₂R^a, -NR^aS(O)₂R^a, -NHC(O)NHR^a, -NHC(S)NHR^a, -NR^aC(O)NH₂, -NR^aC(S)NH₂, -NR^aC(O)NHR^a, -NR^aC(S)NHR^a, -NHC(O)NR^aR^a, -NHC(S)NR^aR^a, -NR^aC(O)NR^aR^a, -NR^aC(S)NR^aR^a, -NHS(O)₂NHR^a, -NR^aS(O)₂NH₂, -NR^aS(O)₂NHR^a, -NHS(O)₂NR^aR^a, -NR^aS(O)₂NR^aR^a, -NHR^aOr -NR^aR^a, Where each R^aIndependently selected from C_1-6Alkyl, aryl, aryl-C_1-2Alkyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkyl, heteroaryl, heteroaryl-C_1-4Alkyl, heterocycloalkyl or heterocycloalkyl-C_1-4Alkyl, where each R^aDepending on the situation, further through 1-3 independently selected from the following R^bSubstituent substitution: C_1-6Alkyl, C_1-6Alkoxy, halogen, C_1-6Haloalkyl or C_1-6Haloalkoxy; where X¹Is a key or -C(O)-, and where R⁷1-5 selected from the following R according to the situation⁹Member substitution: halogen, -CH=CH₂, CN, -OH, -NH₂, -NO₂, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OR^c, -SR^c, -OC(O)R^c, -OC(S)R^c, -P(=O)HR^c, -P(=O)R^cR^c, -PH(=O)OR^c, -P(=O)(OR^c)₂, -OP(=O)(OR^c)₂, -C(O)R^c, -C(S)R^c, -C(O)OR^c, -C(S)OR^c, -S(O)R^c, -S(O)₂R^c, -C(O)NHR^c, -C(S)NHR^c, -C(O)NR^cR^c, -C(S)NR^cR^c, -S(O)₂NHR^c, -S(O)₂NR^cR^c, -C(NH)NHR^c, -C(NH)NR^cR^c, -NHC(O)R^c, -NHC(S)R^c, -NR^cC(O)R^c, -NR^cC(S)R^c, -NHS(O)₂R^c, -NR^cS(O)₂R^c, -NHC(O)NHR^c, -NHC(S)NHR^c, -NR^cC(O)NH₂, -NR^cC(S)NH₂, -NR^cC(O)NHR^c, -NR^cC(S)NHR^c, -NHC(O)NR^cR^c, -NHC(S)NR^cR^c,- NR^cC(O)NR^cR^c, -NR^cC(S)NR^cR^c, -NHS(O)₂NHR^c, -NR^cS(O)₂NH₂, -NR^cS(O)₂NHR^c, -NHS(O)₂NR^cR^c, -NR^cS(O)₂NR^cR^c, -NHR^c, R^cOr -NR^cR^c, Where each R^cIndependently selected from C_1-6Alkyl, aryl, aryl-C_1-2Alkyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkyl, heteroaryl, heteroaryl-C_1-4Alkyl, heterocycloalkyl or heterocycloalkyl-C_1-4Alkyl, where each R^cDepending on the situation, further through 1-3 independently selected from the following R^dGroup substitution: CN, -OH, -N(R^e)(R^e), -NO₂, -C(O)OH, -C(O)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -C(NH)NH₂, -P(=O)HR^e, -P(=O)R^eR^e, -PH(=O)OR^e, -P(=O)(OR^e)₂, -OP(=O)(OR^e)₂, -OC(O)R^e, -OC(S)R^e, -C(O)R^e, -C(S)R^e, -C(O)OR^e, -S(O)₂R^e, -C(O)NHR^e, C_1-6Alkyl, C_1-6Alkoxy, halogen, C_1-6Haloalkyl or C_1-6Haloalkoxy, where each R^eIndependently for C_1-6Alkyl; or two adjacent R⁷The substituents and the atoms to which they are attached together form a 4-, 5- or 6-membered carbocyclic ring or a heterocyclic ring with 1-2 heteroatoms selected from O, N or S as ring members; Y²For CR¹⁰, Where R¹⁰H, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is subject to 1-5 R⁹Group or 1-5 R^cGroup or 1-5 R^dGroup or 1-5 R^eGroup substitution; where X²Is C_1-4Alkylene, -O-, -S- or -NH-; Y¹It is N or C; and the subscript m is 0, 1, or 2. In some embodiments, R¹⁰For H. In other embodiments, R¹⁰Is H, halogen, C_1-4Alkyl, C_1-2Alkoxy, CN, NH₂, C_1-2Alkyl NH, (C_1-2alkyl)₂N. In other embodiments, R¹⁰Is C_1-4Alkyl, halogen, -CN, -NH₂, -OCH₃, CF₃, CN, -OCF₃, -CHF₂, -CH₂F, -OCH₂F or -OCHF₂. In other embodiments, R¹⁰Is C_1-4alkyl. In other embodiments, R⁷Is C_1-4Alkyl, halogen, -CN, -OCH₃, CF₃, CN, -OCF₃, -CHF₂, -CH₂F, -OCH₂F or -OCHF₂. In other embodiments, R⁷Is C_1-4alkyl. In one embodiment, Y¹Is C. In one embodiment, Y³for CH.

In some embodiments of compounds of formula (IV) or (I'a), the subscript m is 1 or 2, and all other substituents of formula (IV) are as defined in any of the embodiments described herein. In one case, the subscript m is 1. In another case, the subscript m is 2. In another case, the subscript m is 0. All other variables of formula (IV) Y¹, Y², Y³, R³, R⁴, R⁵And R⁷As defined in any of the embodiments described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Independently selected from C_1-6Alkyl, deuterated C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, -X¹-Aryl, aryl-C_1-4Alkyl-X¹-, Heteroaryl-X¹-, Heteroaryl-C_1-4Alkyl-X¹-, C_3-6Cycloalkyl-X¹-, C_3-6Cycloalkenyl-X¹-, C_3-6Cycloalkyl-C_1-4Alkyl-X¹-, heterocyclyl-X¹-, heterocyclyl-C_1-4Alkyl-X¹-, CH₂=CH-X¹, C_3-6Cycloalkyl-C_2-4Alkenyl-X¹, C_3-6Cycloalkyl-C_2-4Alkynyl-X¹, Halogen, CN, -OH, -NH₂, -NO₂, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OR^a, -SR^a, -OC(O)R^a, -OC(S)R^a, -C(O)R^a, -C(S)R^a, -C(O)OR^a, -C(S)OR^a, -S(O)R^a, -S(O)₂R^a, -C(O)NHR^a, -C(S)NHR^a, -C(O)NR^aR^a, -C(S)NR^aR^a, -S(O)₂NHR^a, -S(O)₂NR^aR^a, -C(NH)NHR^a, -C(NH)NR^aR^a, -NHC(O)R^a, -NHC(S)R^a, -NR^aC(O)R^a, -NR^aC(S)R^a, -NHS(O)₂R^a, -NR^aS(O)₂R^a, -NHC(O)NHR^a, -NHC(S)NHR^a, -NR^aC(O)NH₂, -NR^aC(S)NH₂, -NR^aC(O)NHR^a, -NR^aC(S)NHR^a, -NHC(O)NR^aR^a, -NHC(S)NR^aR^a, -NR^aC(O)NR^aR^a, -NR^aC(S)NR^aR^a, -NHS(O)₂NHR^a, -NR^aS(O)₂NH₂, -NR^aS(O)₂NHR^a, -NHS(O)₂NR^aR^a, -NR^aS(O)₂NR^aR^a, -NHR^aOr -NR^aR^a, Where each R^aIndependently for C_1-6Alkyl, aryl, aryl-C_1-2Alkyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkyl, heteroaryl, heteroaryl-C_1-4Alkyl, heterocycloalkyl or heterocycloalkyl-C_1-4Alkyl, where each R^aDepending on the situation, further through 1-3 independently selected from the following R^bSubstituent substitution: C_1-6Alkyl, -OCH₃, -OCH₂CH₃, -O-CH(CH₃)₂, -Cl,- F, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂Or -OCH₂F; where X¹Is a key or -C(O)-, and where R⁷The aliphatic or aromatic part of 1-5 is selected from the following R⁹Member substitution: halogen, CN, -OH, -NH₂, -NO₂, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OR^c, -SR^c, -P(=O)HR^c, -P(=O)R^cR^c, -PH(=O)OR^c, -P(=O)(OR^c)₂, -OP(=O)(OR^c)₂, -OC(O)R^c, -OC(S)R^c, -C(O)R^c, -C(S)R^c, -C(O)OR^c, -C(S)OR^c, -S(O)R^c, -S(O)₂R^c, -C(O)NHR^c, -C(S)NHR^c, -C(O)NR^cR^c, -C(S)NR^cR^c, -S(O)₂NHR^c, -S(O)₂NR^cR^c, -C(NH)NHR^c, -C(NH)NR^cR^c, -NHC(O)R^c, -NHC(S)R^c, -NR^cC(O)R^c, -NR^cC(S)R^c, -NHS(O)₂R^c, -NR^cS(O)₂R^c, -NHC(O)NHR^c, -NHC(S)NHR^c, -NR^cC(O)NH₂, -NR^cC(S)NH₂, -NR^cC(O)NHR^c, -NR^cC(S)NHR^c, -NHC(O)NR^cR^c, -NHC(S)NR^cR^c, -NR^cC(O)NR^cR^c, -NR^cC(S)NR^cR^c, -NHS(O)₂NHR^c, -NR^cS(O)₂NH₂, -NR^cS(O)₂NHR^c, -NHS(O)₂NR^cR^c, -NR^cS(O)₂NR^cR^c, -NHR^c, R^cOr -NR^cR^c, Where each R^cIndependently for C_1-6Alkyl, aryl, aryl-C_1-2Alkyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkyl, heteroaryl, heteroaryl-C_1-4Alkyl, heterocycloalkyl or heterocycloalkyl-C_1-4Alkyl, where each R^cDepending on the situation, further through 1-3 independently selected from the following R^dGroup substitution: CN, -OH, -N(R^e)(R^e), -NO₂, -C(O)OH, -C(O)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -C(NH)NH₂, -P(=O)HR^e, -P(=O)R^eR^e, -PH(=O)OR^e, -P(=O)(OR^e)₂, -OP(=O)(OR^e)₂, -OC(O)R^e, -OC(S)R^e, -C(O)R^e, -C(S)R^e, -C(O)OR^e, -S(O)₂R^e, -C(O)NHR^e, C_1-6Alkyl, C_1-6Alkoxy, halogen, C_1-6Haloalkyl or C_1-6Haloalkoxy, where R^eIs C_1-6Alkyl; or two adjacent R⁷The substituent and the atom to which it is attached together form a 4, 5 or 6-membered carbocyclic or heterocyclic ring with 1-2 heteroatoms selected from O, N or S as ring members; and the subscript m is 0, 1 or 2 . In some cases, X¹It's a key. In other cases, X¹It is -C(O)-. In some cases, R⁹For CN, -CH₃, -OCH₃, -OCH₂CH₃, -O-CH(CH₃)₂, -Cl, -F,- CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂Or -OCH₂F, -P(=O)CH₃, -P(=O)(CH₃)₂, -PH(=O)O(C_1-4Alkyl), -P(=O)(OC_1-4alkyl)₂, -OP(=O)(OC_1-4alkyl)₂, C_1-6Alkyl, phenyl, per-deuterated phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl Group, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyrimidinyl, 4 -Pyrimidinyl, 5-pyrimidinyl, 2-oxazolyl, 5-oxazolyl, 4-oxazolyl, 2-thienyl, 3-thienyl, 1-piperidinyl, 4-piperidinyl or 4 -Morpholinyl, 4-morpholinylcarbonyl, cyclopropylcarbonyl, 1-piperazinyl, 4-methyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperazinylcarbonyl, 1-piperazine Pyridinylcarbonyl, 1-pyrrolidinylcarbonyl, dimethylamino, 2-(4-morpholinyl)ethoxy, 3-methoxypropoxy, dimethylaminomethanyl, acetamide Group, propyl group, thioN-morpholinyl group, methylsulfonylamino group, methylsulfonyl group, propylamino group, 1-cyclopentenyl, 1-cyclohexenyl, 1,2, 3,6-Tetrahydropyridin-4-yl, 1,2,3,6-tetrahydropyridin-5-yl, 2,5-dihydro-1H-pyrrol-3-yl, 2,5-dihydro- Pyrrol-1-yl, each of which is independently selected from the following R by 1-3 as the case may be^jGroup substitution: OH, NH₂, CN, -CH₃, -OCH₃, -OCH₂CH₃, -O-CH(CH₃)₂, -Cl, -F, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, C_1-6Alkyl, 4-morpholinyl, 4-morpholinylcarbonyl, cyclopropyl, cyclopropylmethyl, cyclopropylcarbonyl, 1-piperazinyl, 4-methyl-1-piperazinyl, 1- Pyrrolidinyl, 1-piperazinylcarbonyl, 1-piperidinylcarbonyl, 1-pyrrolidinylcarbonyl, dimethylamino, 2-(4-morpholinyl)ethoxy, 3-methoxypropyl An oxy group, an acetamido group, a propionyl group, a methylsulfonylamino group, a methylsulfonylamino group, a propionylamino group, a dimethylaminomethanyl group, or an ethoxycarbonylamino group. In other cases, R^aIs C_1-6Alkyl, phenyl, per-deuterated phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl Group, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyrimidinyl, 4 -Pyrimidinyl, 5-pyrimidinyl, 2-oxazolyl, 5-oxazolyl, 4-oxazolyl, 2-thienyl, 3-thienyl, 1-piperidinyl, 4-piperidinyl or 4 -Morpholine Group, 4-morpholinylcarbonyl, cyclopropylcarbonyl, 1-piperazinyl, 4-methyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperazinylcarbonyl, 1-piperidinylcarbonyl , 1-pyrrolidinylcarbonyl, dimethylamino, 2-(4-morpholinyl)ethoxy, 3-methoxypropoxy, dimethylaminomethanyl, acetamido, propyl Amino, thioN-morpholinyl, 1-pyrrolidinyl, methylsulfonylamino, methylsulfonyl, propionylamino, 1-cyclopentenyl, 1-cyclohexenyl, 1 ,2,3,6-Tetrahydropyridin-4-yl, 1,2,3,6-tetrahydropyridin-5-yl, 2,5-dihydro-1H-pyrrol-3-yl, 2,5- Dihydro-pyrrol-1-yl, each of which is subject to 1-3 R^jGroup substitution. In other cases, R^a, R^cOr R⁹Each independently C_1-6Alkyl or C_1-4Alkoxy, each of which is optionally substituted by a member selected from: C_1-6Alkyl, methoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-oxazolyl, 5-oxazolyl, 4-oxazolyl, 2-thienyl, 3-thienyl, 1-piperidinyl, 4-piperidinyl, or 4-morpholinyl. In other cases, R^dDepartment is selected from C_1-6Alkyl, -CN, -OCH₃, -OCH₂CH₃, -O-CH(CH₃)₂, -Cl, -F, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, -NH-C_1-6Alkyl, -N(C_1-6Alkyl) (C_1-6alkyl). All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Is selected from halogen, -CN, vinyl-X¹, C_1-6Alkyl-X¹, C_1-6Alkoxy-X¹, C_2-6Alkynyl-X¹, C_3-6Cycloalkyl-X¹, C_3-6Cycloalkenyl-X¹-, C_3-6Cycloalkyl-C_1-4Alkyl-X¹, C_3-6Cycloalkyl-C_2-4Alkynyl-X¹, Aryl-X¹, Aryl-C_1-4Alkyl-X¹, Heteroaryl-X¹, Heteroaryl-C_1-4Alkyl-X¹, Heterocyclyl-X¹, Heterocyclyl-C_1-4Alkyl, -C(O)-R^a, -C(O)NHR^a, -C(O)NR^aR^a, -NHC(O)R^a, -NHC(O)OR^a, -NHC(O)NHR^a, -NHC(O)NR^aR^a, -NR^aR^a, -NHR^a, -C(O)OR^a, -OC(O)R^a, -SO₂R^a, -NHSO₂R^a, -NHSO₂NHR^a, -NHSO₂NR^aR^a, -SO₂NHR^aOr -SO₂NR^aR^a, Where at each occurrence, R⁷1-4 Rs depending on the situation⁹Member replacement. In some cases, each R⁹Select independently From halogen, -CN, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkyl, aryl, aryl-C_1-4Alkyl, heteroaryl, heteroaryl-C_1-4Alkyl, heterocyclyl or heterocyclyl-C_1-4Alkyl or R⁸. In one case, R⁷For H. In other cases, the two adjacent R on the aromatic ring⁹The substituents are joined together to form a 5- or 6-membered ring with 0-2 heteroatoms selected from O, N, or S. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Is selected from halogen, CN, vinyl, C₁-₆Alkyl, C_1-6Alkoxy, C_2-6Alkynyl, C_3-6Cycloalkyl, C_3-6Cycloalkenyl, C_3-6Cycloalkyl-C_1-4Alkyl, C_3-6Cycloalkyl-C_2-4Alkynyl, aryl, aryl-C_1-4Alkyl, heteroaryl, heteroaryl-C_1-4Alkyl, heterocycloalkyl, heterocycloalkyl-C_1-4Alkyl, -C(O)-R^a, -C(O)NHR^a, -C(O)NR^aR^a, -NHC(O)R^a, -NHC(O)OR^a, -NHC(O)NHR^a, -NHC(O)NR^aR^a, -NR^aR^a, -NHR^a, -C(O)OR^a, -OC(O)R^a, -SO₂R^a, -NHSO₂R^a, -NHSO₂NHR^a, -NHSO₂NR^aR^a, -SO₂NHR^aOr -SO₂NR^aR^a, Each of them independently undergoes 1-4 Rs depending on the situation⁹Substituents; or independently by 1-4 Rs as appropriate^cSubstituents; or independently by 1-4 Rs as appropriate^dSubstituent substitution; or optionally by 1-4 R selected from the following¹⁵Substituent substitution: halogen, -CN, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkyl, heterocycloalkyl-C_1-4Alkyl, -C(O)-R^c, -C(O)NHR^c, -C(O)NR^cR^c, -NHC(O)R^c, -P(=O)HR^c, -P(=O)R^cR^c, -PH(=O)OR^c, -P(=O)(OR^c)₂, -OP(=O)(OR^c)₂, -NHC(O)OR^c, -NHC(O)NHR^c, -NR^cR^c, -NHR^c, -C(O)OR^c, -OC(O)R^c, -OC(O)NHR^c, -SO₂R^c, -NHSO₂R^c, -SO₂NHR^cOr -SO₂NR^cR^c; Or independently through 1-4 R selected from the following as the case may be¹⁶Substituent substitution: C_1-6Alkyl, -OH, -CN, -NO₂, -NH₂, -NHCH₃, -N(CH₃)₂, -OCH₃, -OCH₂CH₃, -O-CH(CH₃)₂, -Cl, -F, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂,- OCH₂F, 4-morpholinyl, cyclopropyl, cyclopropoxy, cyclopropylmethyl, 1-pyrrolidinyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, acetyl, methoxy A carbonyl group, an acetamido group, a dimethyl carbamate group, a methyl carbamate group, a methanesulfonate group, or a methylsulfonamide group. In some cases, R^cIs C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkyl, heterocycloalkyl or heterocycloalkyl-C_1-4alkyl. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Is selected from aryl, heteroaryl, C_2-6Alkynyl, C_3-6Cycloalkenyl, heterocycloalkyl, -C(O)-R^a, -C(O)NHR^a, -C(O)NR^aR^a, -C(O)OR^a, -SO₂NHR^aOr -SO₂NR^aR^a, Each of which is optionally substituted by the following substituents: (i) 1-4 R⁹Substituent; or (ii) 1-4 R^cSubstituent; or (iii) 1-4 R^dSubstituents; or (iv) 1-4 R selected from the following¹⁵Substituents: halogen-CN, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkyl, heterocycloalkyl-C_1-4Alkyl, -C(O)-R^c, -C(O)NHR^c, -C(O)NR^cR^c, -NHC(O)R^c, -NHC(O)OR^c, -NHC(O)NHR^c, -NR^cR^c, -NHR^c, -C(O)OR^c, -P(=O)HR^c, -P(=O)R^cR^c, -PH(=O)OR^c, -P(=O)(OR^c)₂, -OP(=O)(OR^c)₂, -OC(O)R^c, -OC(O)NHR^c, -SO₂R^c, -NHSO₂R^c, -SO₂NHR^cOr -SO₂NR^cR^c; Or (v)1-4 R¹⁶Group; or (vi) 1-4 independently selected from the following R¹⁷Substituent: C_1-6Alkyl, -OH, -CN, -NO₂, -NH₂, -NHCH₃, -N(CH₃)₂, -OCH₃, -OCH₂CH₃, -O-CH(CH₃)₂, -Cl, -F, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, 4-morpholinyl, thioN-morpholinyl, 1-piperidinyl, cyclopropyl, 1-cyanocyclopropyl, cyclopropoxy, cyclopropylmethyl, 1-pyrrolidinyl , 1-piperazinyl, 1-piperazinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, acetyl, methoxycarbonyl, acetamido, dimethylaminomethanoyl, Methyl carbamate, methylsulfonate, methylsulfonate, -C_1-2Alkyl-R^k, -C(O)-R^k, -C(O)NHR^k, -C(O)NR^kR^k, -NHC(O)R^k, -P(=O)HR^k, -P(=O)R^kR^k, -PH(=O)OR^k, -P(=O)(OR^k)₂, -OP(=O)(OR^k)₂, -C(O)OR^k, -OC(O)R^k, -SO₂R^k, -NHSO₂R^k, -SO₂NHR^k, -SO₂NR^kR^k, Where each R^kIndependently for C_1-6Alkyl, C_3-6Cycloalkyl, phenyl or heterocycloalkyl, where R^kDepending on the situation, further pass 1-3 R^d, R^eOr R^jGroup substitution; or (vii) 1-4 R selected from the following¹⁸Substituents: F, Cl, I, -CH₃, -OCH₃, OCH₂CH₃, -O-CH(CH₃)₂, -OH, -CN, -NO₂, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, cyclopropyl, cyclopropylmethyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -PH(=O)-C_1-6Alkyl, -P(=O)(C_1-6alkyl)₂, -PH(=O)O(C_1-6Alkyl), -P(=O)(OC_1-6alkyl)₂, -OP(=O)(OC_1-6alkyl)₂, -NHSO₂-C_1-6Alkyl, -SO₂NH-C_1-6Alkyl, -NHC(O)-C_1-6Alkyl, -C(O)NH-C_1-6Alkyl, -NHC(O)NH-C_1-6Alkyl, NHC(O)OC_1-6Alkyl, -C(O)-C_1-6Alkyl, -C(O)OC_1-6Alkyl, -OC(O)-C_1-6Alkyl, -NHSO₂CH₃, NH₂C(O)-, CH₃NHC(O)-, NH₂SO₂-, CH₃SO₂-, (CH₃)₂NC(O)-, CH₃C(O)NH-, CH₃SO₂NH-, benzyl, benzyl-C(O), (C_1-4Alkyl)OC(O)-, cyclopropyl-C(O)-, cyclopropylethyl-C(O)-, cyclobutyl-C(O)-, cyclobutylmethyl-C(O)- , Ph-NH-C(O)-, 4-morpholinyl, 4-morpholinylmethyl, 4-morpholinylethyl, thioN-morpholinyl, 4-thiomorpholinyl-C (O)-, 4-morpholinyl-C(O)-, 1-piperidinyl, 1-piperidinyl-C(O)-, p-CH₃-Ph-SO₂NH-, Ph-SO₂NH-, propyl-SO₂NH-, cyclopropyl-SO₂NH-, cyclobutyl-SO₂NH-, butyl SO₂NH-, ethoxycarbonyl-NH-, methoxycarbonyl-NH-, cyclopropoxy, cyclopropylmethyl, 1-pyrrolidinyl, 1-piperazinyl, 1-piperazinylcarbonyl, 4 -Methyl-1-piperazinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, acetyl, methoxycarbonyl, acetamido, dimethylaminomethanoyl, methylamine Formyl, ethoxycarbonylamino, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl , 1-morpholinoethyl, 3-methoxypropoxy, 2-(4-morpholinyl)ethoxy, 4-morpholinylmethylcarbonyl or 4-morpholinylethylcarbonyl, wherein In each occurrence, R¹⁸Optionally further substituted with 1-3 substituents independently selected from the following: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azacyclobutyl, 2-azacyclobutyl, 3-azacyclobutyl Butyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in the compound of formula (I'a) or (IV) as defined in any of the embodiments described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Is selected from aryl, heteroaryl, C_2-6Alkynyl, C_3-6Cycloalkenyl or heterocycloalkyl, each of which is optionally substituted with the following substituents: (i) 1-4 R⁹Substituent; or (ii) 1-4 R^cSubstituent; or (iii) 1-4 R^dSubstituent; or (iv) 1-4 R¹⁵Substituent; or (v)1-4 R¹⁶Group; or (vi) 1-4 independently selected from the following R¹⁷Substituent: C_1-6Alkyl, -OH, -CN, -NO₂, -NH₂, -NHCH₃, -N(CH₃)₂, -OCH₃, -OCH₂CH₃, -O-CH(CH₃)₂, -Cl, -F, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, 4-morpholinyl, 1-piperidinyl, cyclopropyl, 1-cyanocyclopropyl, cyclopropoxy, cyclopropylmethyl, 1-pyrrolidinyl, 1-piperazinyl, 1 -Piperazinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, acetyl, methoxycarbonyl, acetamido, dimethylaminomethanyl, methylaminomethanyl, methyl Sulfonyl, methylsulfonamide, -C_1-2Alkyl-R^k, -C(O)-R^k, -P(=O)HR^k, -P(=O)R^kR^k, -PH(=O)OR^k, -P(=O)(OR^k)₂, -OP(=O)(OR^k)₂, -C(O)NHR^k, -C(O)NR^kR^k, -NHC(O)R^k, -C(O)OR^k, -OC(O)R^k, -SO₂R^k, -NHSO₂R^k, -SO₂NHR^k, -SO₂NR^kR^k, Where each R^kIndependently for C_1-6Alkyl, C_3-6Cycloalkyl, phenyl or heterocycloalkyl, where R^kDepending on the situation, further pass 1-3 R^d, R^eOr R^jGroup substitution; or (vii) 1-4 R selected from the following¹⁸Substituents: F, Cl, I, -CH₃, -OCH₃, OCH₂CH₃, -O-CH(CH₃)₂, -OH, -CN, -NO₂, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NHSO₂CH₃, NH₂C(O)-, CH₃NHC(O)-, NH₂SO₂-, CH₃SO₂-,- PH(=O)-C_1-6Alkyl, -P(=O)(C_1-6alkyl)₂, -PH(=O)(OC_1-6Alkyl), -P(=O)(OC_1-6alkyl)₂, -OP(=O)(OC_1-6alkyl)₂, (CH₃)₂NC(O)-, CH₃C(O)NH-, CH₃SO₂NH-, benzyl, benzyl-C(O), (C_1-4Alkyl)OC(O)-, cyclopropyl-C(O)-, cyclopropylethyl-C(O)-, cyclobutyl-C(O)-, cyclobutylmethyl-C(O)- , Ph-NH-C(O)-, 4-morpholinyl, 4-morpholinylmethyl, 4-morpholinylethyl, 4-morpholinyl-C(O)-, 1-piperidinyl , 1-piperidinyl-C(O)-, p-CH₃-Ph-SO₂NH-, Ph-SO₂NH-, propyl-SO₂NH-, cyclopropyl-SO₂NH-, cyclobutyl-SO₂NH-, butyl SO₂NH-, ethoxycarbonyl-NH-, methoxycarbonyl-NH-, cyclopropoxy, cyclopropylmethyl, 1-pyrrolidinyl, 1-piperazinyl, 1-piperazinylcarbonyl, 4 -Methyl-1-piperazinylcarbonyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl , 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, acetyl, methoxycarbonyl, acetamido, dimethylaminomethanoyl, methylaminomethanoyl, ethoxycarbonylamino , 1-morpholinoethyl, 3-methoxypropoxy, 2-(4-morpholinyl)ethoxy, 4-morpholinylmethylcarbonyl or 4-morpholinylethylcarbonyl, wherein In each occurrence, R¹⁸Optionally further substituted with 1-3 substituents independently selected from the following: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in the compound of formula (I'a) or (IV) as defined in any of the embodiments described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Is selected from halogen, -CN, C_1-6Alkyl, C_1-6Alkoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, per-deuterated pyridyl, phenyl, per-deuterated phenyl, 1-pyrazolyl, 3-1H-pyrazolyl, 4- 1H-pyrazolyl, vinyl, ethynyl, propynyl, 3-fluoropropynyl, cyclopropyl-ethynyl, cyclobutyl-acetylene Cyclopentyl-ethynyl, cyclohexyl-ethynyl, 1-cyclopentenyl-ethynyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, cyclopropyl, cyclobutyl, cyclopentyl Cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-piperazinyl, 1-piperidinyl, morpholinyl, 1,2,5,6- Tetrahydropyridin-4-yl, 1,2,5,6-tetrahydropyridin-3-yl, 2,3-dihydro-1,4-benzodioxen-5-yl, 1, 3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, indanyl, 1,2-benzoxazolyl, 1, 3-benzoxazolyl, 1-cyclohexenyl, 1-cyclopentenyl, 1-cyclooctenyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl, 5,6-dihydro-2H-piperan-4-yl, 5,6-dihydro-2H-piperan-3-yl, 1-pyrrolyl, 2 -Pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 2-pyrazolyl, 3-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5 -Oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,2,3- Triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-4-yl, 1,2, 3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl, 1,2,4-triazol-3-yl, 1, 2,4-triazol-4-yl, 1,2,4-triazol-5-yl, 1-oxa-2,3-diazol-4-yl, 1-oxa-2,3-diazole- 5-yl, 1-oxa-2,4-diazol-3-yl, 1-oxa-2,4-diazol-5-yl, 1-oxa-2,5-diazol-3-yl, 1 -Oxa-2,5-diazol-4-yl, 1-thio-2,3-diazol-4-yl, 1-thio-2,3-diazol-5-yl, 1-thio-2, 4-thiazol-3-yl, 1-thia-2,4-diazol-5-yl, 1-thia-2,5-diazol-3-yl, 1-thia-2,5-diazole- 4-yl, 1-tetrazolyl, 3-tetrazolyl, 1H-5-tetrazolyl, 3H-5-tetrazolyl, 2-furyl, 3-furyl, 2-thienyl or 3-thiophene Group, each of which is optionally substituted with the following substituents: (i) 1-4 R⁹Substituent; or (ii) 1-4 R^cSubstituent; or (iii) 1-4 R^dSubstituents; or (iv) 1-4 R selected from the following¹⁵Substituents: halogen-CN, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkyl, heterocycloalkyl-C_1-4Alkyl, -C(O)-R^c, -C(O)NHR^c, -C(O)NR^cR^c, -NHC(O)R^c, -NHC(O)OR^c, -NHC(O)NHR^c, -NR^cR^c, -NHR^c, -C(O)OR^c, -OC(O)R^c, -OC(O)NHR^c, -SO₂R^c, -NHSO₂R^c, -SO₂NHR^cOr -SO₂NR^cR^c; Or (v)1-4 R¹⁶Group; or (vi) 1-4 independently selected from the following R¹⁷Substituent: C_1-6Alkyl, -OH, -CN, -NO₂, -NH₂, -NHCH₃, -N(CH₃)₂, -OCH₃, -OCH₂CH₃, -O-CH(CH₃)₂, -Cl, -F, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, 4-morpholinyl, thioN-morpholinyl, 1-piperidinyl, cyclopropyl, 1-cyanocyclopropyl, cyclopropoxy, cyclopropylmethyl, 1-pyrrolidinyl , 1-piperazinyl, 1-piperazinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, acetyl, methoxycarbonyl, acetamido, dimethylaminomethanoyl, Methyl carbamate, methylsulfonate, methylsulfonate, -C_1-2Alkyl-R^k, -C(O)-R^k, -C(O)NHR^k, -C(O)NR^kR^k, -NHC(O)R^k, -C(O)OR^k, -PH(=O)R^k, -P(=O)R^kR^k, -PH(=O)OR^k, -P(=O)(OR^k)₂, -OP(=O)(OR^k)₂, -OC(O)R^k, -SO₂R^k, -NHSO₂R^k, -SO₂NHR^k, -SO₂NR^kR^k, Where each R^kIndependently for C_1-6Alkyl, C_3-6Cycloalkyl, phenyl or heterocycloalkyl, where R^kDepending on the situation, further pass 1-3 R^d, R^eOr R^jGroup substitution; or (vii) 1-4 R selected from the following¹⁸Substituents: F, Cl, I, -CH₃, -OCH₃, OCH₂CH₃, -O-CH(CH₃)₂, -OH, -CN, -NO₂, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NHSO₂CH₃, NH₂C(O)-, CH₃NHC(O)-, NH₂SO₂-, CH₃SO₂-, (CH₃)₂NC(O)-, CH₃C(O)NH-, CH₃SO₂NH-, benzyl, benzyl-C(O), (C_1-4Alkyl)OC(O)-, cyclopropyl-C(O)-, cyclopropylethyl-C(O)-, cyclobutyl-C(O)-, cyclobutylmethyl-C(O)- , Ph-NH-C(O)-, thioN-morpholinyl, 4-thiomorpholinyl-C(O)-, -PH(=O)-C_1-6Alkyl, -P(=O)(C_1-6alkyl)₂, -PH(=O)(OC_1-6Alkyl), -P(=O)(OC_1-6alkyl)₂, -OP(=O)(OC_1-6alkyl)₂, 4-morpholinyl, 4-morpholinylmethyl, 4-morpholinylethyl, 4-morpholinyl-C(O)-, 1-piperidinyl, 1-piperidinyl-C(O )-, p-CH₃-Ph-SO₂NH-, Ph-SO₂NH-, propyl-SO₂NH-, cyclopropyl-SO₂NH-, cyclobutyl-SO₂NH-, butyl SO₂NH-, ethoxycarbonyl-NH-, methoxycarbonyl-NH-, cyclopropoxy, cyclopropylmethyl, 1-pyrrolidinyl, 1-piperazinyl, 1-piperazinylcarbonyl, 4 -Methyl-1-piperazinylcarbonyl, 1-azetidinyl, 2-azetidinyl, 3- Azetidinyl, 2-oxetanyl, 3-oxetanyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, acetyl, methoxycarbonyl, acetylamino, Dimethylaminoformyl, methylaminoformyl, ethoxycarbonylamino, 1-morpholinoethyl, 3-methoxypropoxy, 2-(4-morpholinyl)ethoxy Group, 4-morpholinylmethylcarbonyl or 4-morpholinylethylcarbonyl, where in each occurrence, R¹⁸Optionally further substituted with 1-3 substituents independently selected from the following: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. In certain embodiments, R⁷The hydrogen atoms in it may be 1 to 12 or 1 to 8 or 1 to 6 or 1 to 3 or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 depending on the situation. Deuterium atom replacement, with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5%, or 99.9% deuterium incorporation for each deuterium. In certain embodiments, R⁷Each hydrogen atom in it is replaced by a deuterium atom as appropriate, and for each deuterium it has at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium and enter. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in the compound of formula (I'a) or (IV) as defined in any of the embodiments described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Is selected from halogen, -CN, C_1-6Alkyl, C_1-6Alkoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methoxy-4-pyridyl, phenyl, 1-pyrazolyl, 3-1H-pyrazolyl, 4-1H -Pyrazolyl, 1-methyl-4-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, vinyl, ethynyl, propynyl, 3-fluoropropynyl, cyclopropyl -Ethynyl, cyclobutyl-ethynyl, cyclopentyl-ethynyl, cyclohexyl-ethynyl, 1-cyclopentenyl-ethynyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl , 1-methyl-1-cyclopropyl, 1-ring Propylethyl, 1-methyl-1-cyclobutyl, 1-cyclobutylethyl, methoxymethoxy, 4-morpholinylmethoxy, 1-piperidinylmethoxy, 4 ,4-Difluoropiperidinyl, 4-ethoxycarbonyl-1-piperazinyl, 1-piperazinyl, 1-piperidinyl, 4-morpholinyl, 1,2,3,6-tetrahydro Pyridin-4-yl, 1,2,3,6-tetrahydropyridin-5-yl, 1-cyclopropylcarbonyl-2,3,6-trihydropyridin-4-yl, 2,2,6,6 -Tetramethyl-1,5-dihydropyridin-4-yl, 2,2,6,6-tetramethyl-1,5-dihydropyridin-3-yl, 1-cyclopropylcarbonyl-2, 3,6-Trihydropyridin-5-yl, 1-methylsulfonyl-2,3,6-trihydropyridin-4-yl, 1-methylsulfonyl-2,3,6-trihydropyridine- 5-yl, 1-(4-morpholinylcarbonyl)-2,3,6-trihydropyridin-4-yl, 1-(4-morpholinylcarbonyl)-2,3,6-trihydropyridine- 5-yl, 1-tertiary butoxycarbonyl-2,3,6-trihydropyridin-4-yl, 1-tertiary butoxycarbonyl-2,3,6-trihydropyridin-5-yl, 2,3-Dihydro-1,4-benzodioxol-5-yl, 1,3-benzodioxol-4-yl, 1,3-benzodioxol Oxol-5-yl, indanyl, 1,2-benzoxazolyl, 1,3-benzoxazolyl, 1-cyclohexenyl, 1-cyclopentenyl, 1- Cyclooctenyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-cyclopropyl-5-pyrimidinyl, 2-cyclopropyl-pyrimidin-5-yl, 2-pyrazinyl, 3 -Pyridazinyl, 4-pyridazinyl, 5,6-dihydro-2H-piperan-4-yl, 5,6-dihydro-2H-piperan-3-yl, 1-pyrrolyl, 2- Pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 2-pyrazolyl, 3-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5- Oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,2,3-tri Azol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-4-yl, 1,2,3 -Triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl, 1,2,4-triazol-3-yl, 1,2 ,4-triazol-4-yl, 1,2,4-triazol-5-yl, 1-oxa-2,3-diazol-4-yl, 1-oxa-2,3-diazole-5 -Base, 1-oxa-2,4-diazol-3-yl, 1-oxa-2,4-diazol-5-yl, 1-oxa-2,5-diazol-3-yl, 1-oxa-2,5-diazol-4-yl, 1-thio-2,3-diazole- 4-yl, 1-thia-2,3-diazol-5-yl, 1-thia-2,4-diazol-3-yl, 1-thia-2,4-diazol-5-yl, 1 -Thia-2,5-diazol-3-yl, 1-thia-2,5-diazol-4-yl, 1-tetrazolyl, 3-tetrazolyl, 1H-5-tetrazolyl, 3H -5-tetrazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-chloro-5-thienyl or 1-cyclopropylcarbonyl-piperidin-4-yl, Each of them is subject to 1-4 Rs depending on the situation¹⁶Or R¹⁷Substituents; or 1-4 R¹⁸Substituent substitution, where in each occurrence, R¹⁸Depending on the situation, further through 1-3 R selected from the following¹⁹Substituent substitution: CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂-. In some cases, R^kIs C_1-6Alkyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-2Alkyl, 4-morpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl , 2-oxetanyl, 3-oxetanyl, 2-oxo-1-pyrrolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4 -Piperidinyl, piperazinyl, phenyl or benzyl, each of which is optionally substituted with 1-3 substituents selected from the following: -CH₃, -OCH₃, F, Cl, CN, CF₃, CHF₂, CH₂F, -OCF₃, -N(CH₃)₂, -NHCH₃. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷System is selected from 3-fluoropropynyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methoxy-4-pyridyl, phenyl, 1-pyrazolyl, 3-1H-pyridyl Azolyl, 4-1H-pyrazolyl, 1-methyl-4-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, 4-morpholinyl, 3-isoxazolyl, 4 -Isoxazolyl, 5-isoxazolyl, 2,5-dimethyl-4-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-methyl-5- Thiazolyl, 1-isopropyl-pyrazol-4-yl, 1-cyclohexenyl, 1-cyclopentenyl, 1-cyclooctenyl, 1,2,3,6-tetrahydropyridine-4 -Yl, 1,2,3,6-tetrahydropyridin-5-yl, cyclopropyl, 2,5-dihydro-1H-pyrrol-3-yl, 2,5-dihydro-1H-pyrrole-2 -Group or 2,5-dihydropyrrol-1-yl, each of which is subject to 1-4 R¹⁶Or R¹⁷Substituent; or 1-4 R¹⁸Substituent substitution, where in each occurrence, R¹⁸Depending on the situation, further through 1-3 R selected from the following¹⁹Substituent substitution: CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂,- NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂-. In some cases, R^kIs C_1-6Alkyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-2Alkyl, 4-morpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 1-piperidinyl, 2-piperidinyl , 3-piperidinyl, 4-piperidinyl, piperazinyl, phenyl or benzyl, each of which is optionally substituted with 1-3 substituents selected from the following: -CH₃, -OCH₃, F, Cl, CN, CF₃, CHF₂, CH₂F, -OCF₃, -N(CH₃)₂, -NHCH₃. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷For H, CN, vinyl, C_1-6Alkyl, deuterated C_1-6Alkyl, per-deuterated C_1-6Alkyl, halogen, C_1-6Alkoxy, 2-cyclopropylethynyl, pyridyl, phenyl, benzyl, pyrazolyl, oxazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopropyl, cyclopropyl Cyclomethyl, cyclopropylcarbonyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, benzyl, anilinomethanyl, piperidinyl, piper Azinyl, morpholinyl, cyclopentenyl, cyclohexenyl, 1,2,3,6-tetrahydropyridin-4-yl, 2,3-dihydro-1,4-benzodioxane Hexen-5-yl, 1,3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, indanyl, 1,2 -Benzoxazolyl, 1,3-benzoxazolyl, each of which is optionally substituted with 1-4 members independently selected from the following: halogen, -CH₃, CD₃, -OCH₃, CN, CF₃, CF₃O-, -CF₂H, CHF₂O-, -N(CH₃)₂, -NHCH₃, CH₃CONH-, NH₂C(O)-, CH₃NHC(O)-, (CH₃)₂NC(O)-, cyclopropyl, 1-cyanocyclopropyl, CH₃SO₂NH-, cyclopropyl-SO₂NH-, butyl-SO₂NH-, p-CH₃C₆H₄SO₂NH-, NH₂SO₂-, CH₃NHSO₂-, (CH₃)₂NSO₂-, 4-morpholinyl, piperidinyl, 4-methyl-1-piperazinyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 4-morpholinylcarbonyl, piper Pyridinylcarbonyl, piperazinylcarbonyl, tertiary butoxycarbonyl or 2-(4-morpholine base)-ethyl. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷It is selected from Cl, Br, phenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-cyclopropylcarbonyl- 1,2,3,6-Tetrahydropyridin-4-yl, 1-N-morpholinylcarbonyl, 1,2,3,6-tetrahydropyridin-4-yl, 1,2,3,6-tetra Hydropyridin-5-yl, 1,3-dimethyl-pyrazol-4-yl or 1-(4-piperidinyl)pyrazol-4-yl, 3,4-dimethyl-1H-pyrazole -5-yl, 1-(cyclopropylcarbonyl)-2,5-dihydro-pyrrol-3-yl, 3-fluoro-propynyl, 3,5-dimethyl-isoxazol-4-yl , 5-thiazolyl, each of which is independently selected from the following R by 1-3 as the case may be¹⁴Substituent substitution: F, Cl, -CH₃, -Et, propyl, isopropyl, 2-methylpropyl, CD₃, -OCH₃, CN, CH₂F, -CF₂H, CF₃, CF₃O-, CHF₂O-, CH₂FO-, NH₂, -N(CH₃)₂, -NHCH₃, CH₃CONH-, NH₂C(O)-, CH₃NHC(O)-, (CH₃)₂NC(O)-, -PH(=O)(C_1-4Alkyl), -P(=O)(C_1-4alkyl)₂, -PH=O)CH₃, -P(=O)(CH₃)₂, Cyclopropyl, 1-cyanocyclopropyl, 4-morpholinyl, 4-morpholinylmethyl, 4-thiomorpholinyl, 4-morpholinylcarbonyl, 4-thiomorpholinylcarbonyl , 4-morpholinylmethylcarbonyl, 4-thiomorpholinylmethylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 4-piperidinyl, 4-piperidine Carbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, tertiary butoxycarbonyl, 2-(4-morpholinyl)-ethyl, 2-(4-morpholinyl)-ethoxy , 1,2-Dihydroxyethylcarbonyl, 3-methoxypropoxy, 1-pyrrolidinyl, PhSO₂NH-, C_1-4Alkyl-SO₂NH-, cyclopropyl-SO₂NH-, p-CH₃C₆H₄SO₂NH-, NH₂SO₂-, C_1-4Alkyl-NHSO₂-, (C_1-4alkyl)₂NSO₂-, C_1-4Alkyl -NHC(O)-, C_1-4Alkyl-C(O)-, C_1-4Alkyl-SO₂-, 4-morpholinyl-C_1-4Alkoxy or 1-pyrrolidinyl carbonyl, each of which is subject to 1-2 C_1-4Alkyl substitution. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Is an aryl group optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or R⁷Two adjacent R on⁹Substituents and The connected atoms together form a 5- or 6-membered ring with 0-2 other heteroatoms selected from O, N or S, and optionally through 1-3 R^dSubstituent substitution; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Or R¹⁷Substituent; or (vi) 1-3 R¹⁸Substituents, where R⁷, R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. In some cases, R⁷Is phenyl or per-deuterated phenyl (C₆D₅), each of which is subject to 1-3 Rs depending on the situation¹⁶Or R¹⁷Substituent; or 1-3 R¹⁸Substituent substitution, where R¹⁶, R¹⁷And R¹⁸Depending on the situation, each further passes 1-3 R¹⁹Group substitution. In other cases, R⁷Optionally, phenyl substituted with 1-3 substituents independently selected from the following: F, Cl, CH₃, -OCH₃, CF₃, CF₃O-, -CFH₂, -CF₂H, CHF₂O-, CH₂FO-, -NHCH₃, -N(CH₃)₂, -CN, 4-morpholinyl, 4-morpholinylmethyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 1-pyrrolidinyl, 1-pyrrolidinylcarbonyl, 4- Morpholinylcarbonyl, 1-piperidinylcarbonyl, 4-methyl-1-piperazinylcarbonyl, 1-pyrrolidinylcarbonyl, cyclopropyl, cyclopropylcarbonyl, 4-morpholinylethyl, CH₃SO₂, CH₃SO₂NH-, CH₃C(O)-, 4-morpholinylmethylcarbonyl, 1,2-dihydroxypropanyl, (CH₃)₂NC(O)- or methoxycarbonylamino group, each of which is optionally substituted with 1-2 groups independently selected from the following: C_1-6Alkyl, C_1-4Alkoxy, 4-morpholinyl or 4-morpholinylmethyl. In other cases, R⁷Is 1-naphthyl or 2-naphthyl, each of which is subject to 1-3 R¹⁶Or R¹⁷Substituent; or 1-3 R¹⁸Substituent substitution, where R¹⁶, R¹⁷And R¹⁸Depending on the situation, each further passes 1-3 R¹⁹Group substitution. In certain embodiments, R⁷The hydrogen atoms in it may be 1 to 12 or 1 to 8 or 1 to 6 or 1 to 3 or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 depending on the situation. Replacement of deuterium atoms, with respect to each deuterium At least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium is incorporated. In certain embodiments, R⁷Each hydrogen atom in it is replaced by a deuterium atom as appropriate, and for each deuterium it has at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium and enter. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷For 1H-4-benzotriazolyl, 1H-5-benzotriazolyl, 1H-4-benzimidazolyl, 1H-5-benzimidazolyl, 1H-4-indazolyl, 1H-5 -Indazolyl, 1H-6-indazolyl, 1H-7-indazolyl, 1H-4-indolyl, 1H-5-indolyl, 1H-6-indolyl, 1H-7-indole Dolyl, 2-side oxy-6-indolinyl, 2-side oxy-4-indolinyl, 2-side oxy-5-indolinyl, 2-side oxy-7- Indolinyl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl, 1,2-benzo Oxazol-7-yl, 1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3- Benzoxazol-7-yl, 1,2-benzothiazol-4-yl, 1,2-benzothiazol-5-yl, 1,2-benzothiazol-6-yl, 1,2-benzene Thiazol-7-yl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl Group, 8-isoquinolinyl, 5-<img file="TWI617552B_D0018.tif" wi="57" he="60" img-format="tif" img-content="character" orientation="portrait" inline="no" />Linyl, 6-<img file="TWI617552B_D0019.tif" wi="57" he="60" img-format="tif" img-content="character" orientation="portrait" inline="no" />Linyl, 7-<img file="TWI617552B_D0020.tif" wi="60" he="60" img-format="tif" img-content="character" orientation="portrait" inline="no" />Linyl, 8-<img file="TWI617552B_D0021.tif" wi="60" he="60" img-format="tif" img-content="character" orientation="portrait" inline="no" />Linyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl Group, 8-quinolinyl, 4-indanyl, 5-indanyl, 5-tetralinyl, 6-tetralinyl, 1,3-dihydroisobenzofuran-4-yl, 1, 3-Dihydroisobenzofuran-5-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran -6-yl, 2,3-dihydrobenzofuran-7-yl, 1,3-dihydroisobenzothiophen-4-yl, 1,3-dihydroisobenzothiophen-5-yl, 2 ,3-Dihydrobenzothiophen-4-yl, 2,3-dihydrobenzothiophen-5-yl, 2,3-dihydrobenzothiophen-6-yl, 2,3-dihydrobenzothiophene -7-yl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, 5-iso<img file="TWI617552B_D0022.tif" wi="60" he="57" img-format="tif" img-content="character" orientation="portrait" inline="no" />Alkyl, 6-iso<img file="TWI617552B_D0023.tif" wi="57" he="57" img-format="tif" img-content="character" orientation="portrait" inline="no" />Alkyl, 7-iso<img file="TWI617552B_D0024.tif" wi="60" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />Alkyl, 8-iso<img file="TWI617552B_D0025.tif" wi="57" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />Alkyl, 5-<img file="TWI617552B_D0026.tif" wi="60" he="60" img-format="tif" img-content="character" orientation="portrait" inline="no" />Alkyl, 6-<img file="TWI617552B_D0027.tif" wi="57" he="60" img-format="tif" img-content="character" orientation="portrait" inline="no" />Alkyl, 7-<img file="TWI617552B_D0028.tif" wi="57" he="57" img-format="tif" img-content="character" orientation="portrait" inline="no" />Alkyl, 8-<img file="TWI617552B_D0029.tif" wi="60" he="60" img-format="tif" img-content="character" orientation="portrait" inline="no" />Alkyl, 2,3-dihydro-1,3-benzothio Azol-4-yl, 2,3-dihydro-1,3-benzothiazol-5-yl, 2,3-dihydro-1,3-benzothiazol-6-yl, 2,3-dihydro -1,3-Benzothiazol-7-yl, 2,3-dihydro-1,2-benzothiazol-4-yl, 2,3-dihydro-1,2-benzothiazol-5-yl , 2,3-Dihydro-1,2-benzothiazol-6-yl, 2,3-dihydro-1,2-benzothiazol-7-yl, 2,3-dihydro-1,3- Benzoxazol-4-yl, 2,3-dihydro-1,3-benzoxazol-5-yl, 2,3-dihydro-1,3-benzoxazol-6-yl, 2 ,3-Dihydro-1,3-benzoxazol-7-yl, 2,3-dihydro-1,2-benzoxazol-4-yl, 2,3-dihydro-1,2- Benzoxazol-5-yl, 2,3-dihydro-1,2-benzoxazol-6-yl, 2,3-dihydro-1,2-benzoxazol-7-yl, 4 -Benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzene And [b]thienyl, 7-benzo[b]thienyl, 4-benzo[c]thienyl, 5-benzo[c]thienyl 2,3-dihydro-1,4-benzodi Oxepan-5-yl, 1,3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, indanyl, 1,2-Benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl, 1,2-benzoxazole-7- Yl, 1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl or 1,3-benzoxazole- 7-group, each of which is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -PH(=O)CH₃, -P(=O)(CH₃)₂, -PH(=O)OCH₃, -P(=O)(OCH₃)₂, -OP(=O)(OCH₃)₂, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷It is a heteroaryl group optionally substituted by the following substituents: (i) 1-3 R⁹Substituent; or R⁷Two adjacent R on⁹The substituents and the atoms to which they are attached together form a 5- or 6-membered ring with 0-2 other heteroatoms selected from O, N or S, and optionally through 1-3 R^dSubstituent substitution; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -PH(=O)CH₃, -P(=O)(CH₃)₂, -PH(=O)OCH₃, -P(=O)(OCH₃)₂, -OP(=O)(OCH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. In some cases, R⁷It is optionally substituted 5- or 6-membered heteroaryl. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷For 5-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 2-pyridazinyl, 3-pyridazinyl, 1 -Pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 2-pyrazolyl, 3-pyrazolyl, 2-oxazolyl, 4- Oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazole Group, 4-isothiazolyl, 5-isothiazolyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazole-3 -Yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazole -2-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl, 1-oxa-2, 3-diazol-4-yl, 1-oxa-2,3-diazol-5-yl, 1-oxa-2,4-diazol-3-yl, 1-oxa-2,4-diazol-5-yl, 1-oxa-2,5-diazol-3-yl, 1-ox-2 ,5-Diazol-4-yl, 1-thia-2,3-diazol-4-yl, 1-thia-2,3-diazol-5-yl, 1-thia-2,4-diazole -3-yl, 1-thio-2,4-diazol-5-yl, 1-thio-2,5-diazol-3-yl, 1-thio-2,5-diazol-4-yl, 1-tetrazolyl, 3-tetrazolyl, 1H-5-tetrazolyl, 3H-5-tetrazolyl, 2-furyl, 3-furyl, 2-thienyl or 3-thienyl, each One is optionally substituted by the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -PH(=O)CH₃, -P(=O)(CH₃)₂, -PH(=O)OCH₃, -P(=O)(OCH₃)₂, -OP(=O)(OCH₃)₂, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷It is selected from 1-benzotriazolyl, 1-benzimidazolyl, 1H-2-benzimidazolyl, 1-indazolyl, 1H-3-indazolyl, 1-indolyl, 1H-2 -Indolyl, 1H-3-indolyl, 1,2-benzoxazol-3-yl, 1,3-benzoxazol-2-yl, 1,2-benzothiazol-3-yl , 1,3-Benzothiazol-2-yl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl Base, 3-<img file="TWI617552B_D0030.tif" wi="52" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />Linyl, 4-<img file="TWI617552B_D0031.tif" wi="57" he="57" img-format="tif" img-content="character" orientation="portrait" inline="no" />Linyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinazolinyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzo[b]thienyl, 3- Each of benzo[b]thienyl or 1-benzo[c]thienyl is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents may be further subjected to 1-3 R¹⁹Substituents are substituted. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Department selected from:<chemistry general="n"><img he="542" wi="2100" file="TWI617552B_D0032.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>or<img file="TWI617552B_D0033.tif" wi="221" he="195" img-format="tif" img-content="character" orientation="portrait" inline="no" />, Each of which is optionally substituted by the following substituents: (i) 1-3 R⁹Substituents; Or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -PH(=O)CH₃, -P(=O)(CH₃)₂, -PH(=O)(OC_1-6Alkyl), -P(=O)(OC_1-6alkyl)₂, -OP(=O)(OC_1-6alkyl)₂, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂, Where the wavy line represents the connection point with the rest of the molecule. symbol<img file="TWI617552B_D0034.tif" wi="82" he="79" img-format="tif" img-content="character" orientation="portrait" inline="no" />Means R⁷R which can be explained above⁷Any available position of the group and the molecule The rest is connected. For example<img file="TWI617552B_D0035.tif" wi="310" he="226" img-format="tif" img-content="character" orientation="portrait" inline="no" />Intended to include 1-indolazinyl, 2-indolazine Group, 3-indolazinyl, 4-indolazinyl, 5-indolazinyl, 6-indolazinyl, 7-indolazinyl and 8-indolazinyl (that is, the substitution can be The 1, 2, 3, 5, 6, 7 or 8 positions of the dolazine ring).

In some embodiments of the compound of formula (IV) or (I'a), R⁷Department selected from:<chemistry general="n"><img he="558" wi="2073" file="TWI617552B_D0036.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry><img file="TWI617552B_D0037.tif" wi="632" he="188" img-format="tif" img-content="character" orientation="portrait" inline="no" />or<img file="TWI617552B_D0038.tif" wi="276" he="176" img-format="tif" img-content="character" orientation="portrait" inline="no" />, Each of which is selected by the following substituents as appropriate Generation: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, -PH(=O)CH₃, -P(=O)(CH₃)₂, -PH(=O)(OC_1-6Alkyl), -P(=O)(OC_1-6alkyl)₂, -OP(=O)(OC_1-6alkyl)₂, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂, Where the wavy line represents the connection point with the rest of the molecule. symbol<img file="TWI617552B_D0039.tif" wi="81" he="81" img-format="tif" img-content="character" orientation="portrait" inline="no" />Means R⁷R which can be explained above⁷The group is connected to the rest of the molecule at any available position. For example,<img file="TWI617552B_D0040.tif" wi="274" he="237" img-format="tif" img-content="character" orientation="portrait" inline="no" />meaning Want to include 1H-pyrrolo[3,2-b]pyridin-1-yl, 1H-pyrrolo[3,2-b]pyridin-2-yl, 1H- Pyrrolo[3,2-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl and 1H -Pyrrolo[3,2-b]pyridin-7-yl (that is, the substitution can be at the 1, 2, 3, 5, 6 or 7 positions of the pyrrolo[3,2-b]pyridine ring). All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Department selected from:<chemistry general="n"><img he="566" wi="2112" file="TWI617552B_D0041.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry><img file="TWI617552B_D0042.tif" wi="642" he="182" img-format="tif" img-content="character" orientation="portrait" inline="no" />or<img file="TWI617552B_D0043.tif" wi="283" he="173" img-format="tif" img-content="character" orientation="portrait" inline="no" />, Each of which is selected by the following substituents as appropriate Generation: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -PH( =O)CH₃, -P(=O)(CH₃)₂, -PH(=O)(OC_1-6Alkyl), -P(=O)(OC_1-6alkyl)₂, -OP(=O)(OC_1-6alkyl)₂, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂, Where the wavy line represents the connection point with the rest of the molecule. symbol<img file="TWI617552B_D0044.tif" wi="82" he="77" img-format="tif" img-content="character" orientation="portrait" inline="no" />Means R⁷R which can be explained above⁷The group is connected to the rest of the molecule at any available position. For example,<img file="TWI617552B_D0045.tif" wi="350" he="257" img-format="tif" img-content="character" orientation="portrait" inline="no" />It is intended to include 5H-pyrrolo[3,2-c]pyridazin-3-yl, 5H-pyrrolo[3,2-c]pyridazin-4-yl, 5H-pyrrolo[3,2-c]pyridazin-4-yl Azin-5-yl, 5H-pyrrolo[3,2-c]pyridazin-6-yl, 5H-pyrrolo[3,2-c]pyridazin-7-yl (that is, the substitution can be in 5H-pyrrole And [3,2-c]pyridazine ring at position 3, 4, 5, 6 or 7). All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Department selected from:<chemistry general="n"><img he="558" wi="2006" file="TWI617552B_D0046.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry><img file="TWI617552B_D0047.tif" wi="997" he="190" img-format="tif" img-content="character" orientation="portrait" inline="no" />, Each of which is selected by the following substituents as appropriate Generation: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-,-PH(=O)CH₃, -P(=O)(CH₃)₂, -PH(=O)(OC_1-6Alkyl), -P(=O)(OC_1-6alkyl)₂, -OP(=O)(OC_1-6alkyl)₂, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂, Where the waveform The line represents the connection point with the rest of the molecule. symbol<img file="TWI617552B_D0048.tif" wi="84" he="82" img-format="tif" img-content="character" orientation="portrait" inline="no" />Means R⁷R which can be explained above⁷The group is connected to the rest of the molecule at any available position. For example,<img file="TWI617552B_D0049.tif" wi="313" he="231" img-format="tif" img-content="character" orientation="portrait" inline="no" />It is intended to include 5H-pyrrolo[3,2-c]pyrimidin-2-yl, 5H-pyrrolo[3,2-c]pyrimidin-4-yl, 5H-pyrrolo[3,2-c]pyrimidine-5 -Group, 5H-pyrrolo[3,2-c]pyrimidin-6-yl and 5H-pyrrolo[3,2-c]pyrimidin-7-yl (that is, the substitution can be in 5H-pyrrolo[3,2 -c] 2, 4, 5, 6 or 7 positions of the pyrimidine ring). All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Department selected from:<chemistry general="n"><img he="383" wi="2081" file="TWI617552B_D0050.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry><img file="TWI617552B_D0051.tif" wi="654" he="208" img-format="tif" img-content="character" orientation="portrait" inline="no" />or<img file="TWI617552B_D0052.tif" wi="279" he="200" img-format="tif" img-content="character" orientation="portrait" inline="no" />, Each of which is selected by the following substituents as appropriate Generation: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, -PH(=O)CH₃, -P(=O)(CH₃)₂, -PH(=O)(OC_1-6Alkyl), -P(=O)(OC_1-6alkyl)₂, -OP(=O)(OC_1-6alkyl)₂, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂, Where the wavy line represents the connection point with the rest of the molecule. symbol<img file="TWI617552B_D0053.tif" wi="82" he="84" img-format="tif" img-content="character" orientation="portrait" inline="no" />Means R⁷R which can be explained above⁷The group is connected to the rest of the molecule at any available position. For example,<img file="TWI617552B_D0054.tif" wi="335" he="235" img-format="tif" img-content="character" orientation="portrait" inline="no" />It is intended to include 5H-pyrrolo[2,3-b]pyrazin-2-yl, 5H-pyrrolo[2,3-b]pyrazin-3-yl, 5H-pyrrolo[2,3-b]pyrazine Azin-5-yl, 5H-pyrrolo[2,3-b]pyrazine-6-yl, 5H-pyrrolo[2,3-b]pyrazine-7-yl (that is, the substitution can be in 5H-pyrrole And [2,3-b] pyrazine ring at positions 2, 3, 5, 6 or 7). All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Is cycloalkyl or cycloalkenyl, each of which is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents may be further subjected to 1-3 R¹⁹Substituents are substituted. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-cyclopentenyl, 3-cyclopentenyl, 4-cyclopentenyl, 1-cyclohexene Group, 3-cyclohexenyl, 4-cyclohexenyl, 1-cyclohexenyl, 1-octenyl, 1,4-cyclohexadienyl, 1,4-cyclohexadiene-3- Or cyclooctatetraene, each of which is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents may be further subjected to 1-3 R¹⁹Substituents are substituted. In some cases, R⁷Cyclopentenyl, cyclohexenyl or cyclopropyl, each of which is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent ; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸, Where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents may be further subjected to 1-3 R¹⁹Substituents are substituted. All other variables of formula (IV) Y¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Optionally substituted with the following substituents heterocycloalkyl: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸, Where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents may be further subjected to 1-3 R¹⁹Substituents are substituted. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷It is 1-aziridinyl, 2-aziridinyl, 1-1-azetidinyl, 2-azetidinyl, 3-azetidinyl, 1-pyrrolidinyl, 2-pyrrole Pyridinyl, 3-pyrrolidinyl, 2,3-dihydro-1H-pyrrol-1-yl, 2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrole- 3-yl, 2,3-dihydro-1H-pyrrol-4-yl, 2,3-dihydro-1H-pyrrol-5-yl, 2,5-dihydro-1H-pyrrol-1-yl, 2 ,5-Dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-3-yl, 2,3-dihydro-1H-imidazol-1-yl, 2,3-dihydro -1H-imidazol-2-yl, 2,3-dihydro-1H-imidazol-4-yl, 2,3-dihydrothiazol-2-yl, 2,3-dihydrothiazol-4-yl, 2, 3-Dihydrothiazol-5-yl, 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,3-dihydrofuran-4-yl, 2,3- Dihydrofuran-5-yl, 2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,3-dihydropiperan-2-yl, 2,3-di Hydropiperan-3-yl, 2,3-dihydropiperan-4-yl, 2,3-dihydropiperan-5-yl, 2,3-dihydropiperan-6-yl, 3,6 -Dihydro-2H-piperan-2-yl, 3,6-dihydro-2H-piperan-3-yl, 3,6-dihydro-2H-piperan-4-yl, 3,6-di Hydro-2H-piperan-5-yl, 3,6-dihydro-2H-piperan-6-yl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl , 1-piperazinyl, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1,2,3,6-tetrahydropyridin-1-yl, 1,2 ,3,6-Tetrahydropyridin-1-yl, 1,2,3,6-tetrahydropyridin-2-yl, 1,2,3,6-tetrahydropyridin-3-yl, 1,2,3 ,6-Tetrahydropyridine-4-yl, 1,2,3,6-tetrahydropyridine -5-yl or 1,2,3,6-tetrahydropyridin-6-yl, each of which is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸, Where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents may be further subjected to 1-3 R¹⁹Substituents are substituted. In some cases, R⁷For 1-aziridinyl, 2-aziridinyl, 2,3-dihydro-1H-pyrrol-5-yl, 2,5-dihydro-1H-pyrrol-3-yl, 2,3-dihydro Hydrogen-1H-imidazol-4-yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,3-dihydrofuran-4-yl, 2,3- Dihydrofuran-5-yl, 2,5-dihydrofuran-3-yl, 2,3-dihydropiperan-5-yl, 2,3-dihydropiperan-6-yl, 3,6- Dihydro-2H-piperan-4-yl, 3,6-dihydro-2H-piperan-5-yl, 1,2,3,6-tetrahydropyridin-4-yl or 1,2,3, 6-Tetrahydropyridin-5-yl, each of which is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸, Where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents may be further subjected to 1-3 R¹⁹Substituents are substituted. In other cases, R⁷Is 1,2,3,6-tetrahydropyridin-4-yl or 1,2,3,6-tetrahydropyridin-5-yl, 2,5-dihydro-1H-pyrrol-1-yl, 2, 5-dihydro-1H-pyrrol-2-yl or 2,5-dihydro-1H-pyrrol-3-yl, each of which is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸, Where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents may be further subjected to 1-3 R¹⁹Substituents are substituted. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Is C_2-4Alkenyl or C_2-4Alkynyl, each of which is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v) 1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸, Where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents may be further subjected to 1-3 R¹⁹Substituents are substituted. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Is vinyl, ethynyl, 1-propynyl, 3-fluoro-propynyl or cyclopropylethynyl, each of which is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸, Where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents may be further subjected to 1-3 R¹⁹Substituents are substituted. In some cases, R⁷Is ethynyl, 1-propynyl, 3-fluoro-propynyl or cyclopropylethynyl, each of which is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸, Where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents may be further subjected to 1-3 R¹⁹Substituents are substituted. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), R⁷Is halogen, C_1-6Alkyl, CN, -C_1-2Alkyl-R^k, -C(O)-R^k, -C(O)NHR^k, -C(O)NR^kR^k, -NHC(O)R^k, -C(O)OR^k, -OC(O)R^k, -SO₂R^k, -NHSO₂R^k, -SO₂NHR^k, -SO₂NR^kR^k, Where each R^kIndependently for C_1-6Alkyl, C_3-6Cycloalkyl, phenyl or heterocycloalkyl, where R^kDepending on the situation, further pass 1-3 R^dGroup substitution. In some cases, R^kIs C_1-6Alkyl, C_3-6Cycloalkyl, phenyl, 4-morpholinyl, 1-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl or 2-piperazinyl, where R^kDepending on the situation, further pass 1-3 R^dGroup substitution. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), two adjacent R⁷The substituents and the atoms to which they are attached together form a 5- or 6-membered ring with 0-2 heteroatoms selected from N, O or S, wherein the ring is optionally substituted by the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸, Where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents may be further subjected to 1-3 R¹⁹Substituents are substituted. In certain embodiments, the 5- or 6-membered ring system is selected from cyclopentane, cyclohexane, pyrrolidine, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, tetrahydrofuran, tetrahydropiperidine Pyran, 1,4-dioxane, pyridine, pyrazine, piperidine, piperazine, pyrimidine or pyridazine ring system, each of which is subject to 1-3 R¹⁶; Or 1-3 R¹⁷; Or 1-3 R¹⁸Substituent substitution, where R¹⁶, R¹⁷Or R¹⁸Substituents may further undergo 1-3 R¹⁹Substituents are substituted. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵And the subscript m is as defined in any embodiment described herein.

In some embodiments of the compound of formula (IV) or (I'a), ring A is an optionally substituted 5-membered fused heterocycle having 1-3 heteroatoms selected from O, N, or S as ring members. Cyclic aromatic ring; or optionally substituted fused benzene ring; or when ring A is substituted by two or more substituents, two such substituents together with the atoms to which they are connected form 5 or 6 members as appropriate ring. All other variables Y of formula (I'a) or (IV)¹, Y², Y³, R³, R⁴, R⁵As defined in any of the embodiments described herein.

In any embodiment of the compound of formula (I'a) or (IV), R⁷The hydrogen atoms in it may be 1 to 12 or 1 to 8 or 1 to 6 or 1 to 3 or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 depending on the situation. Deuterium atom replacement, with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5%, or 99.9% deuterium incorporation for each deuterium. In certain embodiments, R⁷Each hydrogen atom in it is replaced by a deuterium atom as appropriate, and for each deuterium it has at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium and enter.

In some embodiments of the compound of formula (I'a) or (IV), ring A is a 5-membered fused heterocyclic aromatic ring having 1-3 heteroatoms selected from O, N or S as ring members; or Condensed benzene ring. All other variables of formula (IV) Y¹, Y², Y³, R³, R⁴, R⁵As defined in any of the embodiments described herein. In some cases, ring A is a fused pyrrole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, imidazole, thiophene, or benzene ring.

In certain embodiments of the compound of formula (IV), part:<img file="TWI617552B_D0055.tif" wi="295" he="187" img-format="tif" img-content="character" orientation="portrait" inline="no" />Selected from<img file="TWI617552B_D0056.tif" wi="1316" he="197" img-format="tif" img-content="character" orientation="portrait" inline="no" /><chemistry general="n"><img he="205" wi="2081" file="TWI617552B_D0057.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry><img file="TWI617552B_D0058.tif" wi="986" he="207" img-format="tif" img-content="character" orientation="portrait" inline="no" />or<img file="TWI617552B_D0059.tif" wi="271" he="171" img-format="tif" img-content="character" orientation="portrait" inline="no" />, Each of which is subject to 1-2 R⁷The group is substituted, and the wavy line indicates the point of attachment to the rest of the molecule. In some implementation In the example,<img file="TWI617552B_D0060.tif" wi="250" he="152" img-format="tif" img-content="character" orientation="portrait" inline="no" />After 1-2 R⁷Group substitution. In one embodiment,<img file="TWI617552B_D0061.tif" wi="240" he="155" img-format="tif" img-content="character" orientation="portrait" inline="no" />for<img file="TWI617552B_D0062.tif" wi="255" he="190" img-format="tif" img-content="character" orientation="portrait" inline="no" />(Pyrrolo[2,3-b]pyridine moiety), which is subject to 1-2 R⁷Group substitution. exist In other embodiments,<img file="TWI617552B_D0063.tif" wi="251" he="170" img-format="tif" img-content="character" orientation="portrait" inline="no" />for<img file="TWI617552B_D0064.tif" wi="253" he="163" img-format="tif" img-content="character" orientation="portrait" inline="no" />(Pyrazolo[1,5-a]pyrimidine part), depending on the situation Condition by 1-2 R⁷Group substitution. In other embodiments,<img file="TWI617552B_D0065.tif" wi="250" he="169" img-format="tif" img-content="character" orientation="portrait" inline="no" />for<img file="TWI617552B_D0066.tif" wi="240" he="153" img-format="tif" img-content="character" orientation="portrait" inline="no" />(Thieno [2,3-b]pyridine moiety), which is subject to 1-2 R⁷Group substitution. In other embodiments,<img file="TWI617552B_D0067.tif" wi="261" he="173" img-format="tif" img-content="character" orientation="portrait" inline="no" />for<img file="TWI617552B_D0068.tif" wi="199" he="230" img-format="tif" img-content="character" orientation="portrait" inline="no" />(Pyrazolo[3,4-b]pyridine moiety), which is optionally taken by R7 group generation. In other embodiments,<img file="TWI617552B_D0069.tif" wi="249" he="171" img-format="tif" img-content="character" orientation="portrait" inline="no" />for<img file="TWI617552B_D0070.tif" wi="254" he="166" img-format="tif" img-content="character" orientation="portrait" inline="no" />(Quinoline part), which may be subject to 1- 2 R⁷Group substitution. All other variables of formula (IV) R³, R⁴And R⁵As described in this article As defined in any embodiment. In some embodiments,<img file="TWI617552B_D0071.tif" wi="257" he="166" img-format="tif" img-content="character" orientation="portrait" inline="no" />The hydrogen atom depends on the situation After 1 to 6 deuterium replacements, there is at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5%, or 99.9% deuterium incorporation for each deuterium. In some embodiments,<img file="TWI617552B_D0072.tif" wi="255" he="183" img-format="tif" img-content="character" orientation="portrait" inline="no" />Each hydrogen atom is replaced by a deuterium atom as the case may be. For each deuterium, it has at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium is incorporated.

In certain embodiments of the compound of formula (IV), part:<img file="TWI617552B_D0073.tif" wi="316" he="200" img-format="tif" img-content="character" orientation="portrait" inline="no" />Selected from<img file="TWI617552B_D0074.tif" wi="1405" he="260" img-format="tif" img-content="character" orientation="portrait" inline="no" /><chemistry general="n"><img he="280" wi="2023" file="TWI617552B_D0075.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry><img file="TWI617552B_D0076.tif" wi="1166" he="316" img-format="tif" img-content="character" orientation="portrait" inline="no" />or<img file="TWI617552B_D0077.tif" wi="346" he="290" img-format="tif" img-content="character" orientation="portrait" inline="no" />, Each of them depends on the situation Condition by 1-2 R⁷The group is substituted, and the wavy line indicates the point of attachment to the rest of the molecule.

In some embodiments of compounds of formula (I'), (I'a), (I), (II) or (III), the present invention provides compounds of formula (V):<chemistry general="n"><img he="348" wi="839" file="TWI617552B_D0078.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

In certain embodiments, R¹Is H, halogen, C_1-4Alkyl, C_1-4Haloalkyl, C_1-4Haloalkoxy, cyclopropyl or lone electron pair; L²One key, -CH₂-, -C(O)-or -SO₂; R⁶Is an alkyl group, an aryl group or a heteroaryl group, each of which is independently selected from the following R through 1-3 as the case may be⁹Member substitution: C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, -X¹-Aryl, aryl-C_1-4Alkyl-X¹-, Heteroaryl-X¹-, Heteroaryl-C_1-4Alkyl-X¹-, C_3-6Cycloalkyl-X¹-, C_3-6Cycloalkyl-C_1-4Alkyl-X¹-, C_3-6Cycloalkenyl-X¹-, CH₂=CH-X¹-, C_3-6Cycloalkyl- C_2-4Alkenyl-X¹-, C_3-6Cycloalkyl-C_2-4Alkynyl-X¹-, heterocyclyl-X¹-, heterocyclyl-C_1-4Alkyl-X¹-Or R⁸; Or two adjacent R⁹The members together with the atoms to which they are connected form a 5- or 6-membered fused ring with 0-2 heteroatoms selected from O, N or S as ring members. In some cases, R¹It is H or a lone electron pair. In one case, R¹For H. In other cases, Y¹Is N, and R¹It is a lone electron pair. Other variables of formula (V) Y¹, Y², Y³, R³, R⁴, L¹And L²As defined in any of the embodiments described herein. In some embodiments of the compound of formula (V), L¹For -C(O)NR⁵-, where L¹The carbonyl group is covalently bonded to the pyrazole ring, and L¹The nitrogen atom in is covalently bonded to the 6-membered aromatic ring in formula (V).

In some embodiments of compounds of formula (I'), (I'a), (I), (II), (III) or (V), the present invention provides compounds of formula (V'):<chemistry general="n"><img he="359" wi="931" file="TWI617552B_D0079.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

In certain embodiments, R¹Is H, halogen, C_1-4Alkyl, C_1-4Haloalkyl, C_1-4Haloalkoxy, cyclopropyl or lone electron pair; L²One key, -CH₂-, -C(O)-or -SO₂; R⁶Is an alkyl group, an aryl group or a heteroaryl group, each of which is independently selected from the following R through 1-3 as the case may be⁹Member substitution: C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, -X¹-Aryl, aryl-C_1-4Alkyl-X¹-, Heteroaryl-X¹-, Heteroaryl-C_1-4Alkyl-X¹-, C_3-6Cycloalkyl-X¹-, C_3-6Cycloalkyl-C_1-4Alkyl-X¹-, C_3-6Cycloalkenyl-X¹-, CH₂=CH-X¹-, C_3-6Cycloalkyl-C_2-4Alkenyl-X¹-, C_3-6Cycloalkyl-C_2-4Alkynyl-X¹-, heterocyclyl-X¹-, heterocyclyl-C_1-4Alkyl-X¹-Or R⁸; Or two adjacent R⁹The members together with the atoms to which they are connected form a 5- or 6-membered fused ring with 0-2 heteroatoms selected from O, N or S as ring members. In some cases, R¹It is H or a lone electron pair. In one case, R¹For H. In other cases, Y¹Is N, and R¹It is a lone electron pair. Other variables of formula (V') Y¹, Y², Y³, R³, R⁴And L²As defined in any of the embodiments described herein.

In some embodiments of the compound of formula (V) or (V'), R⁶Is an aryl group or a heteroaryl group, which Each one is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. In some cases, R⁶Is phenyl, 1-naphthyl or 2-naphthyl, each of which is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. In some cases, R⁶It is a heteroaryl group having 1-3 heteroatoms selected from O, N or S as ring members. In other cases, R⁶It is a heteroaryl group having 1-2 heteroatoms selected from N as ring members. Other variables of formula (V) Y¹, Y², Y³, R¹, R³, R⁴, R⁵And L²As defined in any of the embodiments described herein.

In some embodiments of the compound of formula (V) or (V'), R⁶Is a phenyl group, optionally substituted by the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituent; or (viii) 1-3 R¹⁹Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. Other variables of formula (V) Y¹, Y², Y³, R¹, R³, R⁴, R⁵And L²As defined in any of the embodiments described herein.

In some embodiments of the compound of formula (V) or (V'), R⁶Is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl or 4-pyridazinyl, which Each one is optionally substituted with the following substituents: (i) 1-3 R⁹Substituent; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituent; or (viii) 1-3 R¹⁹Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. Other variables of formula (V) or (V') Y¹, Y², Y³, R¹, R³, R⁴, R⁵And L²As defined in any of the embodiments described herein.

In the compound of formula (I), (II), (III), (IV), (V) or (V') and any sub-formula In some embodiments, R³And R⁴Each is independently selected from H, halogen, C_1-4Alkyl, C_1-4Haloalkyl, C_1-4Haloalkoxy, cyclopropyl, phenyl, CN, CN-CH₂-, C_1-4Alkoxy, R^gOr lone electron pair; or R³And R⁴Combine with the atoms to which it is connected to form an optionally substituted 5- to 8-membered ring with 0-2 heteroatoms selected from O, N or S as ring members; wherein R^gAs -OH, -NH₂, -NO₂, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OR^h, -SR^h, -OC(O)R^h, -OC(S)R^h, -C(O)R^h, -C(S)R^h, -C(O)OR^h, -C(S)OR^h, -S(O)R^h, -S(O)₂R^h, -C(O)NHR^h, -C(S)NHR^h, -C(O)NR^hR^h, -C(S)NR^hR^h, -S(O)₂NHR^h, -S(O)₂NR^hR^h, -C(NH)NHR^h, -C(NH)NR^hR^h, -NHC(O)R^h, -NHC(S)R^h, -NR^hC(O)R^h, -NR^hC(S)R^h, -NHS(O)₂R^h, -NR^hS(O)₂R^h, -NHC(O)NHR^h, -NHC(S)NHR^h, -NR^hC(O)NH₂, -NR^hC(S)NH₂, -NR^hC(O)NHR^h, -NR^hC(S)NHR^h, -NHC(O)NR^hR^h, -NHC(S)NR^hR^h, -NR^hC(O)NR^hR^h, -NR^hC(S)NR^hR^h, -NHS(O)₂NHR^h, -NR^hS(O)₂NH₂, -NR^hS(O)₂NHR^h, -NHS(O)₂NR^hR^h, -NR^hS(O)₂NR^hR^h, -NHR^hOr -NR^hR^h, Where each R^hIndependently H or C_1-2alkyl. In certain embodiments, R³And R⁴It is not hydrogen at the same time. In some cases, R³And R⁴Each independently selected from H, C_1-6Alkyl, halogen, CN, cyclopropyl, CN-CH₂-, phenyl, cyclopropylmethyl, C_1-6Alkoxy, C_1-6Haloalkyl, C_1-6Haloalkoxy or R^g. In some embodiments, R³And R⁴Each independently halogen, C_1-6Alkyl, C_1-6Alkoxy, cyclopropyl, -CN, C_1-4Haloalkyl or C_1-4Haloalkoxy. In other embodiments, R³And R⁴Each is independently selected from Br, Cl, methyl, ethyl, cyclopropyl, -CN, CF₃, CHF₂, CH₂F, -OCH₃, -OCF₃, -OCHF₂Or -OCH₂F, CNC₂-, NH₂C(O)-, CH₃NHCO- or CH₃C(O)NH-. In other cases, R³And R⁴Each is independently selected from H, -CH₃, -CD₃, -C₆D₅, -CF₃, -CHF₂, -CH₂F, -OCF₃, -OCHF₂, -OCH₂F, halogen, CN, cyclopropyl, CN-CH₂-, phenyl, cyclopropylmethyl or -OCH₃. In other cases, R³And R⁴Each independently is H, F, Cl, Br, NH₂C(O)-, CH₃, CD₃, Et, cyclopropyl, CN, CH₂CH₂-Or CH₃C(O)NH-. In other cases, R³And R⁴Each is independently selected from H, -OH, -NH₂, -NO₂, -C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, -C(NH)NH₂, -OC(O)R^h, -C(O)R^h, -C(O)OR^h, -S(O)R^h, -S(O)₂R^h, -C(O)NHR^h, -C(O)NR^hR^h, -C(S)NR^hR^h, -S(O)₂NHR^h, -S(O)₂NR^hR^h, -C(NH)NHR^h, -C(NH)NR^hR^h, -NHC(O)R^h, -NHC(S)R^h, -NR^hC(O)R^h, -NHC(O)NHR^h, -NHC(S)NHR^h, -NR^hC(O)NH₂, -NR^hC(O)NHR^h, -NHC(O)NR^hR^h, -NR^hC(O)NR^hR^h, -NHS(O)₂NHR^h, -NR^hS(O)₂NH₂, -NR^hS(O)₂NHR^h, -NHS(O)₂NR^hR^h, -NR^hS(O)₂NR^hR^h, -NHR^hOr -NR^hR^h, Where R^hIs H or C_1-6alkyl. In some embodiments, R³And R⁴For H. In other embodiments, R³Is H, and R⁴Is a substituent other than hydrogen as described herein. In other embodiments, R⁴Is H, and R³Is a substituent other than hydrogen as described herein. In other embodiments, R³And R⁴All are substituents other than hydrogen as described herein. Other variables and substituents are as defined in any of the embodiments described herein.

Some embodiments of compounds of formula (I'), (I'a), (I), (II), (III), (IV), (V) or (V') or any of its sub-general formulas Medium, Y¹C, Y²For CR¹⁰, And Y³For CH. In other embodiments, Y¹Is C, and Y²And Y³Is N. In other embodiments, Y¹C, Y²Is N, and Y³For CH. In other embodiments, Y¹C, Y²For CR¹⁰, And Y³Is N. In other embodiments, Y¹Is N, Y²Is N, and Y³Is N. In other embodiments, Y¹Is N, Y²For CR¹⁰, And Y³. In other embodiments, Y¹Is N, Y²For CR¹⁰, And Y³Is N. In other embodiments, Y¹Is N, Y²For CR¹⁰, And Y³For CH. In other embodiments, Y¹Is N, Y²Is N, and Y³For CH. In some cases, R¹⁰For H, CN, C_1-4Alkyl, halogen, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_1-4Alkoxy. In one embodiment, R¹⁰For H. All other variables R¹, R²,Z¹,Z²,Z³,Z⁴, R³, R⁴, R⁵, L¹Or L²As defined in any of the embodiments described herein.

In certain embodiments of compounds of formula (I'), (I'a), (I), (II), (III), (IV), (V) or (V') or any sub-formula thereof Medium, Y¹C, Y³Is CH, and Y²H, C_1-6Alkyl, C_1-6Alkoxy, vinyl, ethynyl, phenyl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is subject to 1-5 R⁹Group or 1-5 R^cGroup or 1-5 R^dGroup or 1-5 R^eGroup substitution. All other variables R¹, R²,Z¹,Z²,Z³,Z⁴, R³, R⁴, R⁵, L¹Or L²As defined in any of the embodiments described herein.

In certain embodiments of compounds of formula (IV), (V), (V') or any of its sub-general formulae, or compounds of formula (IV), (V), (V') are as described herein In any embodiment, or as an example In any of the compounds described in, part of<img file="TWI617552B_D0080.tif" wi="145" he="227" img-format="tif" img-content="character" orientation="portrait" inline="no" />Can exist in tautomeric forms:<img file="TWI617552B_D0081.tif" wi="217" he="192" img-format="tif" img-content="character" orientation="portrait" inline="no" />The wavy line represents the connection point with the rest of the molecule.

<i>Sub-formula of formula (I'), (I'a), (I), (II), (III), (IV), (V) or (V')</i>

In a group of embodiments of the present invention, the compound of formula (I'), (I), (II) or (III) has sub-formula (IIIa), (IIIb), (IIIc), (IIId) or (IIIe):<chemistry general="n"><img he="1065" wi="2033" file="TWI617552B_D0082.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variables and substituents R in sub-formulas (IIIa), (IIIb), (IIIc), (IIId) or (IIIe)³, R⁴, R⁷, L¹, Y²And Y³As defined in any embodiment of the compound of formula (I'), (I'a), (I), (II) or (III) and as in any embodiment disclosed herein. In some embodiments, R⁷The compound of formula (IV) is as defined in any of the examples described herein. In some embodiments, L¹The compound of formula (I'), (I'a), (I) or (II) is as defined in the examples disclosed herein. In some embodiments, R⁵For H. In some cases, L¹For -NHSO₂-, -SO₂NH-, -NHC(O)NH-, -NHC(O)-, -CH₂O-, -OCH₂-, -C(O)NH-, -SO₂-, -C(O)O-, -C(O)-, -C(=NH)NH- or -NHC(=NH)-. In some cases, L¹For-SO₂NH-, -CH₂O-, -OCH₂-Or -C(O)NH-. In other cases, L¹It is -C(O)NH-. In one embodiment, the present invention provides a compound of formula (IIIa). In another embodiment, the present invention provides a compound of formula (IIIb). In another embodiment, the present invention provides a compound of formula (IIIc). In another embodiment, the present invention provides a compound of formula (IIId). In another embodiment, the present invention provides a compound of formula (IIIe). In some embodiments of compounds of formula (IIIa), (IIIb), (IIIc), (IIId) or (IIIe), Y²And Y³For CH. In other embodiments of compounds of formula (IIIa), (IIIb), (IIIc), (IIId) or (IIIe), Y²Is N, and Y³For CH. In other embodiments of compounds of formula (IIIa), (IIIb), (IIIc), (IIId) or (IIIe), Y²For CR¹⁰, Where R¹⁰It is a substitution other than hydrogen as described herein with respect to compounds of formula (I'), (I'a), (I), (II), (III), (IV), (V) or (V') Base, and Y³For CH.

In the second group of embodiments of the present invention, compounds of formula (I'), (I), (II), (III) or (IIIa) have sub-formulas (IIIa-1), (IIIa-2), (IIIa) -3), (IIIa-4), (IIIa-5), (IIIa-6), (IIIa-7) or (IIIa-8):<chemistry general="n"><img he="948" wi="1955" file="TWI617552B_D0083.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, L¹, R¹⁰And R⁷As defined in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III) or (IIIa). In some embodiments, R⁷The compound of formula (IV) is as defined in any of the examples described herein. In some embodiments, R¹⁰Department is selected from C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is subject to 1-5 R⁹Group substitution; where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In other embodiments, R¹⁰For CN, C_1-4Alkyl, halogen, C_1-4Haloalkyl, C_1-4Haloalkoxy or C_1-4Alkoxy. In some embodiments of compounds of formula (IIIa-1) to (IIIa-8), L¹For -C(O)NH-, -SO₂NH-, -NHSO₂-, -CH₂O-or-OCH₂-. In certain embodiments of compounds of formula (IIIa-1) to (IIIa-8), L¹It is -C(O)NH-. In one embodiment, the present invention provides a compound of formula (IIIa-1). In another embodiment, the present invention provides a compound of formula (IIIa-2). In another embodiment, the present invention provides a compound of formula (IIIa-3). In another embodiment, the present invention provides a compound of formula (IIIa-4). In another embodiment, the present invention provides a compound of formula (IIIa-5). In another embodiment, the present invention provides a compound of formula (IIIa-6). In another embodiment, the present invention provides a compound of formula (IIIa-7). In another embodiment, the present invention provides a compound of formula (IIIa-8).

In the third group of embodiments of the present invention, the formula (I'), (I), (II), (III) or (IIIb) is combined The substance has the sub-formula (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5):<chemistry general="n"><img he="969" wi="1981" file="TWI617552B_D0084.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R¹⁰, L¹And R⁷As defined in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III) or (IIIb). In some embodiments, R⁷The compound of formula (IV) is as defined in any of the examples described herein. In some embodiments, R¹⁰Department is selected from C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is subject to 1-5 R⁹Group substitution; where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In other embodiments, R¹⁰For CN, C_1-4Alkyl, halogen, C_1-4Haloalkyl, C_1-4Haloalkoxy or C_1-4Alkoxy. In some embodiments of compounds of formula (IIIb-1) to (IIIb-5), L¹For -C(O)NH-, -SO₂NH-, -NHSO₂-, -CH₂O-or-OCH₂-. In certain embodiments of compounds of formula (IIIb-1) to (IIIb-5), L¹It is -C(O)NH-. In one embodiment, the present invention provides a compound of formula (IIIb-1). In another embodiment, the present invention provides a compound of formula (IIIb-2). In another embodiment, the present invention provides a compound of formula (IIIb-3). In another embodiment, the present invention provides a compound of formula (IIIb-4). In another embodiment, the present invention provides a compound of formula (IIIb-5).

In the fourth group of embodiments of the present invention, compounds of formula (I'), (I), (II), (III) or (IIIc) have sub-formulas (IIIc-1), (IIIc-2), (IIIc) -3), (IIIc-4) or (IIIc-5):<chemistry general="n"><img he="1002" wi="1878" file="TWI617552B_D0085.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R¹⁰, L¹And R⁷As defined in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III) or (IIIc). In some embodiments, R⁷The compound of formula (IV) is as defined in any of the examples described herein. In some embodiments, R¹⁰Department is selected from C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is subject to 1-5 R⁹Group substitution; where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In other embodiments, R¹⁰For CN, C_1-4Alkyl, halogen, C_1-4Haloalkyl, C_1-4Haloalkoxy or C_1-4Alkoxy. In some embodiments of compounds of formula (IIIc-1) to (IIIc-5), L¹For -C(O)NH-, -SO₂NH-, -NHSO₂-, -CH₂O-or-OCH₂-. In certain embodiments of compounds of formula (IIIc-1) to (IIIc-5), L¹It is -C(O)NH-. In one embodiment, the present invention provides a compound of formula (IIIc-1). In another embodiment, the present invention provides a compound of formula (IIIc-2). In another embodiment, the present invention provides a compound of formula (IIIc-3). In another embodiment, the present invention provides a compound of formula (IIIc-4). In another embodiment, the present invention provides a compound of formula (IIIc-5).

In the fifth group of embodiments of the present invention, compounds of formula (I'), (I), (II), (III) or (IIId) have sub-formulas (IIId-1), (IIId-2), (IIId) -3), (IIId-4) or (IIId-5):<chemistry general="n"><img he="1054" wi="1735" file="TWI617552B_D0086.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R¹⁰And L¹As defined in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III) or (IIId). In some embodiments, R¹⁰Department is selected from C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is subject to 1-5 R⁹Group substitution; where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In other embodiments, R¹⁰For CN, C_1-4Alkyl, halogen, C_1-4Haloalkyl, C_1-4Haloalkoxy or C_1-4Alkoxy. In some embodiments of compounds of formula (IIId-1) to (IIId-5), L¹For -C(O)NH-, -SO₂NH-, -NHSO₂-, -CH₂O-or-OCH₂-. In certain embodiments of compounds of formula (IIId-1) to (IIId-5), L¹It is -C(O)NH-. In one embodiment, the present invention provides a compound of formula (IIId-1). In another embodiment, the present invention provides a compound of formula (IIId-2). In another embodiment, the present invention provides a compound of formula (IIId-3). In another embodiment, the present invention provides a compound of formula (IIId-4). In another embodiment, the present invention provides a compound of formula (IIId-5).

In the sixth group of embodiments of the present invention, compounds of formula (I'), (I), (II), (III) or (IIIe) have sub-formulas (IIIe-1), (IIIe-2), (IIIe) -3), (IIIe-4) or (IIIe-5):<chemistry general="n"><img he="1059" wi="1917" file="TWI617552B_D0087.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R¹⁰, R⁷And L¹As defined in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III) or (IIIe). In some embodiments, R⁷The compound of formula (IV) is as defined in any of the examples described herein. In some embodiments, R¹⁰Department is selected from C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is subject to 1-5 R⁹Group substitution; where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In other embodiments, R¹⁰For CN, C_1-4Alkyl, halogen, C_1-4Haloalkyl, C_1-4Haloalkoxy or C_1-4Alkoxy. In some embodiments of compounds of formula (IIIe-1) to (IIIe-5), L¹For -C(O)NH-, -SO₂NH-, -NHSO₂-, -CH₂O-or-OCH₂-. In certain embodiments of compounds of formula (IIIe-1) to (IIIe-5), L¹It is -C(O)NH-. In one embodiment, the present invention provides a compound of formula (IIIe-1). In another embodiment, the present invention provides a compound of formula (IIIe-2). In another embodiment, the present invention provides a compound of formula (IIIe-3). In another embodiment, the present invention provides a compound of formula (IIIe-4). In another embodiment, the present invention provides a compound of formula (IIIe-5).

In the seventh group of embodiments of the present invention, the compounds of formula (I'), (I'a), (I), (II), (III), (IIIa), (IV) have sub-formula (IVa):<chemistry general="n"><img he="414" wi="923" file="TWI617552B_D0088.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R⁵, R⁷, M, Y²And Y³As in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III), (IIIa) or (IV) or in any embodiment as disclosed herein Defined. In one embodiment, R⁵Is H or C_1-4alkyl. In another embodiment, R⁵For H. In some embodiments, Y²N or CR¹⁰, And Y³Is N or CH, where R¹⁰H, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is optionally substituted by the following substituents: (i) 1-5 R⁹Group; or (ii) 1-5 R^cSubstituent; or (iii) 1-5 R^dSubstituent; or (iv) 1-5 R¹⁵Substituent; or (v)1-5 R¹⁶Substituent; or (vi) 1-5 R¹⁷Substituent; or (vii) 1-5 R¹⁸Substituent; or (viii) 1-5 R¹⁹Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂, Where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In some embodiments of the compound of formula (IVa), Y²And Y³For CH. In other embodiments, Y²Is N, and Y³For CH. In other embodiments, Y²For CR¹⁰, Where R¹⁰Is a substituent other than hydrogen as described herein, and Y³For CH. In certain embodiments of compounds of formula (IVa), the subscript m is zero. In other embodiments of the compound of formula (IVa), the subscript m is 1. In other embodiments of the compound of formula (IVa), the subscript m is 2.

In the eighth group of embodiments of the present invention, the compound of formula (I'), (I'a), (I), (II), (III), (IIIa), (IV) or (IVa) has the sub-formula (IVa-1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa -9), (IVa-10):<chemistry general="n"><img he="1447" wi="1940" file="TWI617552B_D0089.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R⁵, R⁷And R¹⁰As in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III), (IIIa) or (IV) and in any embodiment as disclosed herein Defined. In one embodiment, R⁵Is H or C_1-4alkyl. In another embodiment, R⁵For H. In another embodiment, R⁵Is C_1-4alkyl. In some embodiments, R¹⁰Department is selected from C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is subject to 1-5 R⁹Group substitution; where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In other embodiments, R¹⁰For CN, C_1-4Alkyl, halogen, C_1-4Haloalkyl, C_1-4Haloalkoxy or C_1-4Alkoxy. In other embodiments, R¹⁰For CN, CH₃, Et, Cl, Br, F, CF₃, CF₂H-, CFH₂-, CH₃O-, CF₃O-, CF₂HO- or CFH₂O-.

In the ninth group of embodiments of the present invention, formulas (I'), (I'a), (I), (II), (III), (IIIa), (IV), (IVa), (IVa- 1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9) Or (IVa-10) compound has sub-formula (IVa-Ia), (IVa-2a), (IVa-3a), (IVa-4a), (IVa-5a), (IVa-6a), (IVa-7a) ), (IVa-8a), (IVa-9a) or (IVa-10a):<chemistry general="n"><img he="1415" wi="1929" file="TWI617552B_D0090.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R⁷And R¹⁰Such as formula (I'), (I'a), (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), ( Any one of IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9) or (IVa-10) compounds As defined in the examples or as in any of the examples disclosed herein.

In the tenth group of embodiments of the present invention, formulas (I'), (I'a), (I), (II), (III), (IIIa), (IV), (IVa), (IVa- 1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9) , (IVa-10), (IVa-1a), (IVa-2a), The compound of (IVa-5a) or (IVa-8a) has the sub-formula (IVa-1b), (IVa-2b), (IVa-5b) or (IVa-6b):<chemistry general="n"><img he="968" wi="1832" file="TWI617552B_D0091.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴And R⁷Such as formula (I'), (I'a), (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), ( Any one of IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9) or (IVa-10) compounds As defined in the examples or as in any of the examples disclosed herein. In one embodiment, the compound has sub-formula (IVa-2b).

In the 11th group of embodiments of the present invention, the compound of formula (I'), (I'a), (I), (II), (III) or (IV) has sub-formula (IVb):<chemistry general="n"><img he="306" wi="929" file="TWI617552B_D0092.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R⁵, R⁷, M, Y²And Y³As defined in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III) or (IV) and in any embodiment disclosed herein. In one embodiment, R⁵Is H or C_1-4alkyl. In another embodiment, R⁵For H. In some embodiments of the compound of formula (IVb), Y²For CR¹⁰, And Y³Is CH, where R¹⁰H, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4alkyl-, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is optionally substituted by the following substituents: (i) 1-5 R⁹Group; or (ii) 1-5 R^cSubstituent; or (iii) 1-5 R^dSubstituent; or (iv) 1-5 R¹⁵Substituent; or (v)1-5 R¹⁶Substituent; or (vi) 1-5 R¹⁷Substituent; or (vii) 1-5 R¹⁸Substituent; or (viii) 1-5 R¹⁹Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂, Where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In other embodiments of the compound of formula (IVb), Y²And Y³For CH. In other embodiments, Y²Is N, and Y³For CH. In other embodiments, Y²For CR¹⁰, Where R¹⁰Is a substituent other than hydrogen as disclosed herein, and Y³For CH. In certain embodiments of compounds of formula (IVb), the subscript m is zero. In other embodiments of the compound of formula (IVb), the subscript m is 1. In other embodiments of the compound of formula (IVb), the subscript m is 2.

In the twelfth group of embodiments of the present invention, the compound of formula (I'), (I'a), (I), (II), (III), (IV) or (IVb) has sub-formula (IVb-1) ), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7) or (IVb-8):<chemistry general="n"><img he="1626" wi="1924" file="TWI617552B_D0093.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R⁵, R⁷, M and R¹⁰As in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III), (IV) or (IVb) or in any embodiment as disclosed herein Defined. In some embodiments, m is zero. In formula (IVb-7) or (IVb-8), each R⁷Is an independently selected member. In formula (IVb-1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7) or (IVb-8) compounds In one embodiment, R⁵Is H or C_1-4alkyl. In formula (IVb-1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7) or (IVb-8) compounds In another embodiment, R⁵For H. In another embodiment, R⁵Is C_1-4alkyl. In formula (IVb-1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7) or (IVb-8) compounds In some embodiments, R¹⁰Department is selected from C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is subject to 1-5 R⁹Group substitution; where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In formula (IVb-1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7) or (IVb-8) compounds In other embodiments, R¹⁰For CN, C_1-4Alkyl, halogen, C_1-4Haloalkyl, C_1-4Haloalkoxy or C_1-4Alkoxy. In formula (IVb-1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7) or (IVb-8) compounds In other embodiments, R¹⁰For CN, CH₃, Et, Cl, Br, F, CF₃, CF₂H-, CFH₂-, CH₃O-, CF₃O-, CF₂HO- or CFH₂O-.

In the 13th group of embodiments of the present invention, the compound of formula (I'), (I'a), (I), (II), (III) or (IV) has sub-formula (IVc):<chemistry general="n"><img he="312" wi="911" file="TWI617552B_D0094.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R⁵, R⁷, M, Y²And Y³As defined in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III) or (IV) or as in any embodiment disclosed herein. In one embodiment, R⁵Is H or C_1-4alkyl. In another embodiment of the compound of formula (IVc), R⁵For H. In some embodiments of the compound of formula (IVc), Y²N or CR¹⁰, And Y³Is N or CH, where R¹⁰H, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is optionally substituted by the following substituents: (i) 1-5 R⁹Group; or (ii) 1-5 R^cSubstituent; or (iii) 1-5 R^dSubstituent; or (iv) 1-5 R¹⁵Substituent; or (v)1-5 R¹⁶Substituent; or (vi) 1-5 R¹⁷Substituent; or (vii) 1-5 R¹⁸Substituent; or (viii) 1-5 R¹⁹Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azacyclobutyl, 2-azacyclobutyl, 3-azacyclobutyl Butyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂, Where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In other embodiments of the compound of formula (IVc), Y²And Y³For CH. In other embodiments, Y²Is N, and Y³For CH. In other embodiments, Y²For CR¹⁰, Where R¹⁰Is a substituent other than hydrogen as disclosed herein, and Y³For CH. In certain embodiments of compounds of formula (IVc), the subscript m is zero. In other embodiments of the compound of formula (IVc), the subscript m is 1. In other embodiments of the compound of formula (IVc), the subscript m is 2.

In the 14th group of embodiments of the present invention, the compound of formula (I'), (I'a), (I), (II), (III), (IV) or (IVc) has the sub-formula (IVc-1) ), (IVc-2), (IVc-3), (IVc-4) or (IVc-5):<chemistry general="n"><img he="933" wi="1943" file="TWI617552B_D0095.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

The variable R in formula (IVc-1), (IVc-2), (IVc-3), (IVc-4) or (IVc-5)³, R⁴, R⁵, R⁷, M and R¹⁰As in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III), (IV) or (IVc) or in any embodiment as disclosed herein Defined. In one embodiment, m is zero. In another embodiment, m is 1. In another embodiment, m is 2, and each R⁷Is an independently selected member. In formulas (IVc-1), (IVc-2), (IVc-3), In an embodiment of (IVc-4) or (IVc-5) compound, R⁵Is H or C_1-4alkyl. In another embodiment of the compound of formula (IVc-1), (IVc-2), (IVc-3), (IVc-4) or (IVc-5), R⁵For H. In another embodiment, R⁵Is C_1-4alkyl. In some embodiments of compounds of formula (IVc-1), (IVc-2), (IVc-3), (IVc-4) or (IVc-5), R¹⁰Department is selected from C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is subject to 1-5 R⁹Group substitution; where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In other embodiments of compounds of formula (IVc-1), (IVc-2), (IVc-3), (IVc-4) or (IVc-5), R¹⁰For CN, C_1-4Alkyl, halogen, C_1-4Haloalkyl, C_1-4Haloalkoxy or C_1-4Alkoxy. In other embodiments of compounds of formula (IVc-1), (IVc-2), (IVc-3), (IVc-4) or (IVc-5), R¹⁰For CN, CH₃, Et, Cl, Br, F, CF₃, CF₂H-, CFH₂-, CH₃O-, CF₃O-, CF₂HO- or CFH₂O-.

In the fifteenth group of embodiments of the present invention, the compound of formula (I'), (I'a), (I), (II), (III) or (IV) has sub-formula (IVd):<chemistry general="n"><img he="365" wi="1133" file="TWI617552B_D0096.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

The variable R in formula (IVd)³, R⁴, R⁵, R⁷, P, Y²And Y³As defined in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III) or (IV) or as in any embodiment disclosed herein. In one embodiment, R⁵Is H or C_1-4alkyl. In another embodiment of the compound of formula (IVd), R⁵For H. In some embodiments of the compound of formula (IVd), Y²N or CR¹⁰, And Y³Is N or CH, where R¹⁰H, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is optionally substituted by the following substituents: (i) 1-5 R⁹Group; or (ii) 1-5 R^cSubstituent; or (iii) 1-5 R^dSubstituent; or (iv) 1-5 R¹⁵Substituent; or (v)1-5 R¹⁶Substituent; or (vi) 1-5 R¹⁷Substituent; or (vii) 1-5 R¹⁸Substituent; or (viii) 1-5 R¹⁹Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂, Where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In other embodiments of the compound of formula (IVd), Y²And Y³For CH. In other embodiments, Y²Is N, and Y³For CH. In other embodiments, Y²For CR¹⁰, Where R¹⁰Is a substituent other than hydrogen as disclosed herein , and Y³For CH. The subscript p is 0, 1, 2, or 3. In certain embodiments of compounds of formula (IVd), the subscript p is zero. In other embodiments of the compound of formula (IVd), the subscript p is 1. In other embodiments of the compound of formula (IVd), the subscript p is 2. In other embodiments of the compound of formula (IVd), the subscript p is 3.

In the sixteenth group of embodiments of the present invention, the compound of formula (I'), (I'a), (I), (II), (III), (IV) or (IVd) has sub-formula (IVd-1) ), (IVd-2), (IVd-3), (IVd-4) or (IVd-5):<chemistry general="n"><img he="924" wi="1917" file="TWI617552B_D0097.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

The variable R in formula (IVd-1), (IVd-2), (IVd-3), (IVd-4) or (IVd-5)³, R⁴, R⁵, R⁷, M and R¹⁰As in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III), (IV) or (IVd) or in any embodiment as disclosed herein Defined. In one embodiment, p is zero. In another embodiment, p is 1. In another embodiment, p is 2, and each R⁷Is an independently selected member. In one embodiment of the compound of formula (IVd-1), (IVd-2), (IVd-3), (IVd-4) or (IVd-5), R⁵Is H or C_1-4alkyl. In another embodiment of the compound of formula (IVd-1), (IVd-2), (IVd-3), (IVd-4) or (IVd-5), R⁵For H. In another embodiment, R⁵Is C_1-4alkyl. In some embodiments of compounds of formula (IVd-1), (IVd-2), (IVd-3), (IVd-4) or (IVd-5), R¹⁰Department is selected from C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is subject to 1-5 R⁹Group substitution; where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In other embodiments of compounds of formula (IVd-1), (IVd-2), (IVd-3), (IVd-4) or (IVd-5), R¹⁰For CN, C_1-4Alkyl, halogen, C_1-4Haloalkyl, C_1-4Haloalkoxy or C_1-4Alkoxy. In other embodiments of compounds of formula (IVd-1), (IVd-2), (IVd-3), (IVd-4) or (IVd-5), R¹⁰For CN, CH₃, Et, Cl, Br, F, CF₃, CF₂H-, CFH₂-, CH₃O-, CF₃O-, CF₂HO- or CFH₂O-.

In the seventeenth group of embodiments of the present invention, the compound of formula (I'), (I'a), (I), (II), (III) or (IV) has sub-formula (IVe):<chemistry general="n"><img he="337" wi="793" file="TWI617552B_D0098.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R⁵, R⁷, M, Y²And Y³As defined in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III) or (IV) or as in any embodiment disclosed herein. In one embodiment, R⁵Is H or C_1-4alkyl. In another embodiment of the compound of formula (IVe), R⁵For H. In some embodiments of the compound of formula (IVe), Y²N or CR¹⁰, And Y³Is N or CH, where R¹⁰H, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is optionally substituted by the following substituents: (i) 1-5 R⁹Group; or (ii) 1-5 R^cSubstituent; or (iii) 1-5 R^dSubstituent; or (iv) 1-5 R¹⁵Substituent; or (v)1-5 R¹⁶Substituent; or (vi) 1-5 R¹⁷Substituent; or (vii) 1-5 R¹⁸Substituent; or (viii) 1-5 R¹⁹Substituents, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷Or R¹⁸Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂, Where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In other embodiments of the compound of formula (IVe), Y²And Y³For CH. In other embodiments, Y²Is N, and Y³For CH. In other embodiments, Y²For CR¹⁰, Where R¹⁰Is a substituent other than hydrogen as disclosed herein, and Y³For CH.

In the eighteenth group of embodiments of the present invention, the compound of formula (I'), (I'a), (I), (II), (III), (IV) or (IVe) has sub-formula (IVe-1) ), (IVe-2), (IVe-3), (IVe-4) or (IVe-5):<chemistry general="n"><img he="1027" wi="1735" file="TWI617552B_D0099.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

The variable R in formula (IVe-1), (IVe-2), (IVe-3), (IVe-4) or (IVe-5)³, R⁴, R⁵, R⁷, M and R¹⁰As in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III), (IV) or (IVe) or in any embodiment as disclosed herein Defined. In one embodiment of the compound of formula (IVe-1), (IVe-2), (IVe-3), (IVe-4) or (IVe-5), R⁵Is H or C₁-₄alkyl. In another embodiment of the compound of formula (IVe-1), (IVe-2), (IVe-3), (IVe-4) or (IVe-5), R⁵For H. In another embodiment, R⁵Is C_1-4alkyl. In some embodiments of compounds of formula (IVe-1), (IVe-2), (IVe-3), (IVe-4) or (IVe-5), R¹⁰Department is selected from C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, aryl-C_1-4Alkyl-, heteroaryl-C_1-4Alkyl -, C_3-6Cycloalkyl-C_1-4Alkyl -, C_3-6Cycloalkenyl-C_1-4Alkyl -, CH₂=CH-X²-, C_3-6Cycloalkyl-C_2-4Alkenyl-X²-, C_3-6Cycloalkyl-C_2-4Alkynyl-X²-, heterocyclyl-C_1-4Alkyl-or R⁸, Each of which is subject to 1-5 R⁹Group substitution; where X²Is C_1-4Alkylene, -O-, -S- or -NH-. In other embodiments of compounds of formula (IVe-1), (IVe-2), (IVe-3), (IVe-4) or (IVe-5), R¹⁰For CN, C_1-4Alkyl, halogen, C_1-4Haloalkyl, C_1-4Haloalkoxy or C_1-4Alkoxy. In other embodiments of compounds of formula (IVe-1), (IVe-2), (IVe-3), (IVe-4) or (IVe-5), R¹⁰For CN, CH₃, Et, Cl, Br, F, CF₃, CF₂H-, CFH₂-, CH₃O-, CF₃O-, CF₂HO- or CFH₂O-.

In the nineteenth group of embodiments of the present invention, the compound of formula (I'), (I), (II), (III), (V) or (V') has the sub-formula (Va):<chemistry general="n"><img he="413" wi="1055" file="TWI617552B_D0100.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Y⁴, Y⁵, Y⁶, Y⁷And Y⁸Each of the substituents is independently selected from CH, CR⁹Or N, where in each occurrence, Y⁴, Y⁵, Y⁶, Y⁷And Y⁸At least two of the substituents are independently selected from CH or CR⁹, Where R⁹The compound of formula (I'), (I), (II), (III), (V) or (V') is as defined in any of the embodiments described herein. In certain embodiments, R⁹For R^cOr R^dOr R^eSubstituents. In some embodiments, L²One key, -CH₂-, -C(O)-or -SO₂-. In one case, L²It's a key. In another case, L²For -CH₂-, -C(O)-or -SO₂-. In some embodiments of the compound of formula (Va), Y⁴, Y⁵, Y⁶, Y⁷And Y⁸Each independently is CH or CR⁹. In other embodiments, Y⁴Is N, and Y⁵, Y⁶, Y⁷And Y⁸Each independently is CH or CR⁹. In other embodiments, Y⁴Is N, Y⁵Is N, and Y⁶, Y⁷And Y⁸Each independently is CH or CR⁹. In other embodiments, Y⁴Is N, Y⁶Is N, and Y⁵, Y⁷And Y⁸Each independently is CH or CR⁹. Y⁴Is N, Y⁷Is N, and Y⁵, Y⁶And Y⁸Each independently is CH or CR⁹. Y⁴Is N, Y⁸Is N, and Y⁵, Y⁶And Y⁷Each independently is CH or CR⁹. Y⁵Is N, and Y⁴, Y⁶, Y⁷And Y⁸Each independently is CH or CR⁹. Y⁶Is N, and Y⁴, Y⁵, Y⁷And Y⁸Each independently is CH or CR⁹. In certain embodiments of the compound of formula (Va), containing Y⁴, Y⁵, Y⁶, Y⁷And Y⁸The aromatic ring of is optionally substituted by the following substituents: (i) 1-3 R⁹Group; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituents; or (vii) 1-3 R¹⁸Substituents; (viii) 1-3 R¹⁹Substituents; or (ix) 1-3 independently selected from the following R²⁰Substituents: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, -PH(=O)CH₃, -P(=O)(CH₃)₂, -PH(=O)(OC_1-6Alkyl), -P(=O)(OC_1-6alkyl)₂, -OP(=O)(OC_1-6alkyl)₂, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH-, EtNHSO₂-, PhNHSO₂-, CH₃SO₂NH-, EtSO₂NH-, PhSO₂NH-, CH₃SO₂, EtSO₂, PhSO₂-, 4-morpholinyl, EtOC(O)NH-, CH₃OC(O)NH-, EtNHC(O)NH-, CH₃NHC(O)NH-, EtOC(O)O- or CH₃OC(O)O-, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹Or R²⁰Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. In one embodiment, R⁵For H. In some embodiments, Y¹Is N, and R¹It is a lone electron pair. In certain embodiments, Y¹C and R¹Is H, halogen, C_1-4Alkyl, C_1-4Haloalkoxy or cyclopropyl. In one embodiment, Y¹C and R¹For H. Variable R¹, R³, R⁴, R⁵, Y¹, Y², Y³And L²As in any embodiment of the compound of formula (I'), (I'a), (I), (II), (III), (IIIa) or (IV) and in any embodiment as disclosed herein Defined.

In the twentieth group of embodiments of the present invention, the compound of formula (I'), (I), (II), (III), (V), (V') or (Va) has the sub-formula (Va-1) , (Va-2) or (Va-3):<chemistry general="n"><img he="1105" wi="1796" file="TWI617552B_D0101.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

The variable R in formula (Va-1), (Va-2) or (Va-3)³, R⁴, R⁵, R¹⁰, R¹, L², Y⁴, Y⁵, Y⁶, Y⁷Or Y⁸As defined in any embodiment of the compound of formula (I'), (I), (II), (III), (V), (V') or (Va). In some cases of compounds of formula (Va-1), (Va-2) or (Va-3), R⁵For H. In other cases of compounds of formula (Va-1), (Va-2) or (Va-3), R¹For H. In other cases of compounds of formula (Va-1), (Va-2) or (Va-3), L²It's a key. In other cases of compounds of formula (Va-1), (Va-2) or (Va-3), R¹⁰For H. In one embodiment of the compound of formula (Va-1), (Va-2) or (Va-3), R¹, R⁵And R¹⁰Is H, and L²It's a key.

In the 21st group of embodiments of the present invention, the formulas (I'), (I), (II), (III), (V), (V'), (Va), (Va-1), (Va -2) or (Va-3) compound has the sub-formula (Va-1a), (Va-1a-1), (Va-2a), (Va-2a-1) or (Va-3a):<chemistry general="n"><img he="1723" wi="1685" file="TWI617552B_D0102.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

The variable R in formula (Va-1a), (Va-1a-1), (Va-2a), (Va-2a-1) or (Va-3a)³, R⁴, R¹⁰, R¹, L², Y⁴, Y⁵, Y⁶, Y⁷Or Y⁸Such as formula (I'), (I), (II), (III), (V), (V'), (Va), (Va-1), (Va-2) or (Va-3) compound As defined in any of the embodiments.

In the 22nd group of embodiments of the present invention, the formulas (I'), (I), (II), (III), (V), (V'), (Va), (Va-1), (Va -2), (Va-3), (Va-1a), (Va-1a-1), (Va-2a), (Va-2a-1) or (Va-3a) compounds have sub-formula (Va- 1b), (Va-1b-1), (Va-2b), (Va-2b-1) or (Va-3b):<chemistry general="n"><img he="1065" wi="2009" file="TWI617552B_D0103.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

The variable R in formula (Va-1b), (Va-1b-1), (Va-2b), (Va-2b-1) or (Va-3b)³, R⁴, R¹, Y⁴, Y⁵, Y⁶, Y⁷Or Y⁸Such as formula (I'), (I), (II), (III), (V), (V'), (Va), (Va-1), (Va-2), (Va-3), (Va-1a), (Va-1a-1), (Va-2a) or (Va-2a-1) compound as defined in any of the examples.

In the 23rd group of embodiments of the present invention, the compound of formula (I'), (I), (II), (III), (V), (V') or (Va) has the sub-formula (Va-4) :<chemistry general="n"><img he="414" wi="1196" file="TWI617552B_D0104.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

The variable R in formula (Va-4)³, R⁴, L¹, Y², Y³, R¹, L²And R⁹As defined in any embodiment of the compound of formula (I'), (I), (II), (III), (V), (V') or (Va). The subscript n is 0, 1, 2 or 3. In some embodiments of the compound of formula (Va-4), L¹Is -C(O)N(R⁵)-, where R⁵Is H or C_1-4alkyl. In some embodiments of the compound of formula (Va-4), L²It's a key. In some embodiments of the compound of formula (Va-4), Y³Is N, and Y²For CR¹⁰. In other embodiments of the compound of formula (Va-4), Y³Is N, and Y²For CH. In other embodiments of the compound of formula (Va-4), Y³And Y²For CH. In other embodiments of the compound of formula (Va-4), Y³Is CH, and Y²Is N. Some examples of compounds of formula (Va-4) Medium, R⁹For R^c; Or R^d; Or R^e; Or R¹⁵; Or R¹⁶; Or R¹⁷; Or R¹⁹; Or R²⁰Group.

In the twenty-fourth group of embodiments of the present invention, the compound of formula (I'), (I), (II), (III), (V), (V'), (Va) or (Va-4) Formula (Va-4a):<chemistry general="n"><img he="422" wi="1190" file="TWI617552B_D0105.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R⁵, Y², Y³, R¹, L²And R⁹As defined in any embodiment of the compound of formula (I'), (I), (II), (III), (V), (V'), (Va) or (Va-4a). The subscript n is 0, 1, 2 or 3. In some embodiments of the compound of formula (Va-4a), R⁵For H. In other embodiments of the compound of formula (Va-4a), R⁵Is C_1-4alkyl. In some embodiments of the compound of formula (Va-4a), L²One key, -CH₂-, -C(O)-or -SO₂. In some embodiments of the compound of formula (Va-4a), L²It's a key. In some embodiments of the compound of formula (Va-4a), Y³Is N, and Y²For CR¹⁰. In other embodiments of the compound of formula (Va-4a), Y³Is N, and Y²For CH. In other embodiments of the compound of formula (Va-4a), Y³And Y²For CH. In other embodiments of the compound of formula (Va-4a), Y³For CH and Y²Is N. In some embodiments of the compound of formula (Va-4a), R⁹For R^c; Or R^d; Or R^e; Or R¹⁵; Or R¹⁶; Or R¹⁷; Or R¹⁹; Or R²⁰Group.

In the 25th group of embodiments of the present invention, formulas (I'), (I), (II), (III), (V), (V'), (Va), (Va-4) or (Va -4a) The compound has the sub-formula (Va-4a-1):<chemistry general="n"><img he="414" wi="1254" file="TWI617552B_D0106.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R⁵, Y², Y³, R¹, L², R⁹And subscript n such as any of the compounds of formula (I'), (I), (II), (III), (V), (V'), (Va), (Va-4) or (Va-4a) In one embodiment Defined. In some embodiments of the compound of formula (Va-4a-1), L²One key, -CH₂-, -C(O)-or -SO₂。

In the 26th group of embodiments of the present invention, the formulas (I'), (I), (II), (III), (V), (V'), (Va), (Va-4), (Va -4a) or (Va-4a-1) compound has the sub-formula (Va-4a-Ia):<chemistry general="n"><img he="387" wi="1222" file="TWI617552B_D0107.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, R⁵, Y², Y³, R¹, R⁹And subscript n such as formula (I'), (I), (II), (III), (V), (V'), (Va), (Va-4), (Va-4a) or (Va -4a-1) As defined in any of the examples of the compound. In some embodiments of the compound of formula (Va-4a-1), Y³Is N, and Y²For CR¹⁰. In other embodiments of the compound of formula (Va-4a-1), Y³Is N, and Y²For CH. In other embodiments of the compound of formula (Va-4a-1), Y³And Y²For CH. In other embodiments of the compound of formula (Va-4a-1), Y³Is CH, and Y²Is N.

In the 27th group of embodiments of the present invention, the compound of formula (I'), (I), (II), (III), (V), (V') or (Va) has the sub-formula (Va-5a) , (Va-5b) or (Va-5c):<chemistry general="n"><img he="535" wi="1928" file="TWI617552B_D0108.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Variable R³, R⁴, L¹, Y², Y³, R¹, L²And R⁹As defined in any embodiment of the compound of formula (I'), (I), (II), (III), (V), (V') or (Va). The subscript n is 0, 1, 2 or 3. In some embodiments of compounds of formula (Va-5a), (Va-5b) or (Va-5c), L¹Is -C(O)N(R⁵)-, where R⁵Is H or C_1-4alkyl. In some embodiments of the compound of formula (Vb), L²It's a key. In some embodiments of compounds of formula (Va-5a), (Va-5b) or (Va-5c), Y³Is N, and Y²For CR¹⁰. Among the compounds of formula (Va-5a), (Va-5b) or (Va-5c) In other examples, Y³Is N, and Y²For CH. In other embodiments of compounds of formula (Va-5a), (Va-5b) or (Va-5c), Y³And Y²For CH. In other embodiments of compounds of formula (Va-5a), (Va-5b) or (Va-5c), Y²Is CH, and Y²Is N. In some embodiments of compounds of formula (Va-5a), (Va-5b) or (Va-5c), R⁹For R^c; Or R^d; Or R^e; Or R¹⁵; Or R¹⁶; Or R¹⁷; Or R¹⁹; Or R²⁰Group.

In the 28th group of embodiments of the present invention, the compound of formula (I'), (I), (II), (III), (V), (V') or (Va) has the sub-formula (Va-6) :<chemistry general="n"><img he="402" wi="1124" file="TWI617552B_D0109.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

The variable R in formula (Va-6)³, R⁴, R⁵, R¹⁰, L², Y⁴, Y⁵, Y⁶, Y⁷Or Y⁸As defined in any embodiment of the compound of formula (I'), (I), (II), (III), (V), (V') or (Va). In some cases of the compound of formula (Va-6), R⁵For H. In other cases of the compound of formula (Va-6), R¹For H. In other cases of the compound of formula (Va-6), L²It's a key. In other cases of the compound of formula (Va-6), R¹⁰For H. In other cases of the compound of formula (Va-6), Y⁴, Y⁵, Y⁶, Y⁷And Y⁸Is CH, each of which is optionally substituted by the following substituents: (i) R⁹Group; or (ii) R^cSubstituent; or (iii) R^dSubstituent; or (iv) R¹⁵Substituent; or (v) R¹⁶Substituent; or (vi) R¹⁷Substituent; or (vii) R¹⁸Substituent; (viii) R¹⁹Substituent; or (ix) R²⁰Substituents, which are selected from -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH-, EtNHSO₂-, PhNHSO₂-, CH₃SO₂NH-, EtSO₂NH-, PhSO₂NH-, CH₃SO₂, EtSO₂, PhSO₂-, 4-morpholinyl, EtOC(O)NH-, CH₃OC(O)NH-, EtNHC(O)NH-, CH₃NHC(O)NH-, EtOC(O)O- or CH₃OC(O)O-, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹Or R²⁰Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. In some embodiments of compounds of formula (Va-1), (Va-2) or (Va-3), R¹, R⁵And R¹⁰Is H; L²Is a key; and Y⁴, Y⁵, Y⁶, Y⁷And Y⁸Is CH, each of which is optionally substituted by the following substituents: (i) R⁹Group; or (ii) R^cSubstituent; or (iii) R^dSubstituent; or (iv) R¹⁵Substituent; or (v) R¹⁶Substituent; or (vi) R¹⁷Substituent; or (vii) R¹⁸Substituent; (viii) R¹⁹Substituent; or (ix) R²⁰Substituents, which are selected from -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH-, EtNHSO₂-, PhNHSO₂-, CH₃SO₂NH-, EtSO₂NH-, PhSO₂NH-, CH₃SO₂, EtSO₂, PhSO₂-, 4-morpholinyl, EtOC(O)NH-, CH₃OC(O)NH-, EtNHC(O)NH-, CH₃NHC(O)NH-, EtOC(O)O- or CH₃OC(O)O-, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹Or R²⁰Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂。

In the 29th group of embodiments of the present invention, the compound of formula (I'), (I), (II), (III), (V), (V'), (Va) or (Va-6) Formula (Va-6a), (Va-6b), (Va-6c) or (Va-6d):<chemistry general="n"><img he="1095" wi="1730" file="TWI617552B_D0110.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

The variable R in formula (Va-6a), (Va-6b), (Va-6c) or (Va-6d)³, R⁴And R⁹As defined in any embodiment of the compound of formula (I'), (I), (II), (III), (V), (V'), (Va) or (Va-6). The subscript p is 0, 1, 2, or 3. In some embodiments of compounds of formula (Va-6a), (Va-6b), (Va-6c) or (Va-6d), R⁹For R²⁰。

In any formula (Va), (Va-1), (Va-2), (Va-3), (Va-1a), (Va-2a), (Va-3a), (Va-1a-1), (Va-2a-1), (Va-1b), (Va-2b), (Va-3b), (Va-1b-1), (Va-2b-1), (Va-6), (Va -6a), (Va-6b), (Va-6c) or (Va-6d) compounds in some embodiments, which contain Y⁴, Y⁵, Y⁶, Y⁷And Y⁸The aromatic ring of is optionally substituted by the following substituents: (i) 1-3 R⁹Group; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituent; or (vii) 1-3 R¹⁸Substituents; (viii) 1-3 R¹⁹Substituents; or (ix)1-3 Independently selected from the following R²⁰Substituents: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 1-azetanyl, 2-azetanyl, 3-azetanyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH-, EtNHSO₂-, PhNHSO₂-, CH₃SO₂NH-, EtSO₂NH-, PhSO₂NH-, CH₃SO₂, EtSO₂, PhSO₂-, 4-morpholinyl, EtOC(O)NH-, CH₃OC(O)NH-, EtNHC(O)NH-, CH₃NHC(O)NH-, EtOC(O)O- or CH₃OC(O)O-, where R⁹, R^c, R^d, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹Or R²⁰Each of the substituents is optionally further selected from the following R by 1-3 independently¹⁹Substituent substitution: -CN, F, Cl, I, -OCH₃, C_1-6Alkyl, cyclopropyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH₂, -NHCH₃, -N(CH₃)₂, -CH₂F, -CHF₂, CF₃, -OCF₃, -OCHF₂, -OCH₂F, CH₃C(O)-, CH₃C(O)O-, CH₃OC(O)-, CH₃NHC(O)-, CH₃C(O)NH-, (CH₃)₂NC(O)-, (CH₃)₂NS(O)₂-, (CH₃)₂S(O)₂NH- or CH₃SO₂. In some cases, contains Y⁴, Y⁵, Y⁶, Y⁷And Y⁸The aromatic ring is optionally substituted benzene ring. In other cases, contains Y⁴, Y⁵, Y⁶, Y⁷And Y⁸The aromatic ring is optionally substituted pyridine ring, where Y⁴Is N; or Y⁵Is N or Y⁶Is N. In other cases, contains Y⁴, Y⁵, Y⁶, Y⁷And Y⁸The aromatic ring is optionally substituted pyrimidine ring, where Y⁴And Y⁶Is N; or Y⁴And Y⁸Is N; or Y⁵And Y⁷Is N. In other cases, contains Y⁴, Y⁵, Y⁶, Y⁷And Y⁸The aromatic ring is optionally substituted pyrazine ring, where Y⁴And Y⁷Is N. In other cases, contains Y⁴, Y⁵, Y⁶, Y⁷And Y⁸The aromatic ring is optionally substituted pyridazine ring, where Y⁴And Y⁵Is N; or Y⁵And Y⁶Is N. In some embodiments, the optional substituents of the benzene, pyridine, pyrimidine, pyrazine or pyridazine ring are (i) 1-3 R⁹Group; or (ii) 1-3 R^cSubstituent; or (iii) 1-3 R^dSubstituent; or (iv) 1-3 R¹⁵Substituent; or (v)1-3 R¹⁶Substituent; or (vi) 1-3 R¹⁷Substituents; or (vii) 1-3 R¹⁸Substituents; (viii) 1-3 R¹⁹Substituent; or (ix)1-3 R²⁰Substituents.

In any formula (IIIa), (IIIb), (IIIc), (IIId), (IIId), (IIIe), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIa-6), (IIIa-7), (IIIa-8), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4), (IIIb -5), (IIIc-1), (IIIc-2), (IIIc-3), (IIIc-4), (IIIc-5), (IIId-1), (IIId-2), (IIId-3 ), (IIId-4), (IIId-5), (IIIe-1), (IIIe-2), (IIIe-3), (IIIe-4), (IIIe-5), (IVa), (IVa -1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9 ), (IVa-10), (IVa-1a), (IVa-2a), (IVa-3a), (IVa-4a), (IVa-5a), (IVa-6a), (IVa-7a), (IVa-8a), (IVa-9a), (IVa-10a), (IVa-1b), (IVa-2b), (IVa-5b), (IVa-6b), (IVb), (IVb-1 ), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7), (IVb-8), (IVc), (IVc -1), (IVc-2), (IVc-3), (IVc-4), (IVc-5), (IVd), (IVd-1), (IVd-2), (IVd-3), (IVd-4), (IVd-5), (IVe), (IVe-1), (IVe-2), (IVe-3), (IVe-4), (IVe-5), (V), (V'), (Va), (Va-1), (Va-2), (Va-3), (Va-1a), (Va-2a), (Va-3a), (Va-1a-1), (Va-2a-1), (Va-1b), (Va-2b), (Va-3b), (Va-1b-1), (Va-2b-1), (Va-6), (Va -6a), (Va-6b), (Va-6c) or (Va-6d) compounds in some embodiments, R³And R⁴Each independently selected from H, C_1-6Alkyl, halogen, CN, cyclopropyl, CN-CH₂-, phenyl, cyclopropylmethyl, C_1-6Alkoxy, C_1-6Haloalkyl, C_1-6Haloalkoxy or R^g. In other cases, R³And R⁴Each is independently selected from H, -CH₃, -CD₃, -C₆D₅, -CF₃, -CHF₂, -CH₂F, -OCF₃, -OCHF₂, -OCH₂F, halogen, CN, cyclopropyl, CN-CH₂-, phenyl, cyclopropylmethyl or -OCH₃. In other cases, R³And R⁴Each independently is H, F, Cl, Br, NH₂C(O)-, CH₃, CD₃, Et, cyclopropyl, CN, CH₂CH₂-Or CH₃C(O)NH-. In other cases, R³And R⁴For D. In other cases, R³And R⁴Is C_1-6alkyl. In other cases, R³And R⁴Is C_1-4Alkoxy.

In some embodiments, the present invention provides any compound set forth in Table 1, or its medical Pharmaceutically acceptable salts, hydrates, solvates, tautomers or isomers. In certain embodiments, the present invention provides the above selected compounds and pharmaceutically acceptable salts thereof. In certain embodiments, the present invention provides any one of compounds P-2001 to P-2273 and P-2274 to P-2307 as described herein, or a pharmaceutically acceptable salt, hydrate, Solvates, tautomers or isomers. In certain embodiments, the present invention provides any of formula (I'), (I'a), (I), (II), (III), (IV) or any sub-formula as described herein A compound, any compound described in the examples, and any compound described herein, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, or isomer thereof.

In some embodiments, the present invention provides a compound selected from: (2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanol (P-2001 ), (2-Phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanone (P-2002), N-(3-aminomethanylbenzene Yl)-2-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (P-2003), 2-phenyl-N-(1H-pyrazol-3-yl)- 1H-pyrrolo[2,3-b]pyridine-5-carboxamide (P-2004), 4-bromo-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridine-5 -Yl)-1H-pyrazole-5-carboxamide (P-2005), 3-[(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carboxamide Amino] ethyl propionate (P-2006), 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyridine Azol-5-carboxamide (P-2007), 4-methyl-3-phenyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H -Pyrazole-5-carboxamide (P-2008), 3-cyclopropyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyridine Azole-5-carboxamide (P-2009), 5-fluoro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-indazole-3- Formamide (P-2010), N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-4-carboxamide (P-2011), 3-fluoro-N- (2-Phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxamide (P-2012), 3,5-dimethyl-N-(2-benzene Yl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole-4-carboxamide (P-2013), N-(2-phenyl-1H-pyrrolo[2,3 -b]pyridin-5-yl)pyridazine-3-carboxamide (P-2014), N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2H -Triazole-4-carboxamide (P-2015), 3-methyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-methyl Amide (P-2016), 4,5-Dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole-3-methanamide (P-2017), N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-4-sulfonamide (P-2018), N- [2-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3-methyl-1H-pyrazole-5-carboxamide (P-2019), N3-[2-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]benzene-1,3-dimethylamide (P-2020), 3-(cyano Methyl)-N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]benzamide (P-2021), 2-chloro-N -[2-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6-methyl-benzamide (P-2022), 4-chloro-N -[2-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3-methyl-1H-pyrazole-5-carboxamide (P-2023) , N-[2-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyridine Azole-5-carboxamide (P-2024), 3-cyano-N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]benzyl Amide (P-2025), 3-acetamido-N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]benzamide ( P-2026), N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2H-indazole-4-carboxamide (P-2027 ), 3-ethyl-N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methyl-1H-pyrazole-5- Formamide (P-2028), N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methyl-1H-pyrazole- 3-formamide (P-2029), 2-ethyl-N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]pyrazole-3 -Sulfonamide (P-2030), 5-methyl-N-[2-[1-(morpholin-4-carbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H- Pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-3-carboxamide (P-2031), 3,4-dimethyl-N-(1H-pyrrolo[2, 3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P-2032), N-[1-(phenylsulfonyl)-2-[1-(morpholine-4- Carbonyl)-3,6-dihydro-2H-pyridin-4-yl]pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-methyl Amide (P-2033), 3,4-Dimethyl-N-[2-[1-(morpholin-4-carbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H -Pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2034), N-[2-(4-fluorophenyl)-1H-pyrrolo [2,3-b]pyridin-5-yl]-1H-1,2,4-triazole-5-carboxamide (P-2035), 4-chloro-3-methyl-N-[2- [1-(morpholine-4-carbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole -5-methylamide (P-2036), N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5-methyl-2H- Triazole-4- Formamide (P-2037), N-[2-(1,3-dimethylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3, 4-Dimethyl-1H-pyrazole-5-carboxamide (P-2038), 4-chloro-N-[2-[1-(cyclopropylcarbonyl)-3,6-dihydro-2H-pyridine -4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-5-methyl-1H-pyrazole-3-carboxamide (P-2039), 3,4-bis Methyl-N-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P-2040), N-[3 -(4-Fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2041 ), N-[2-[1-(cyclopropylcarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]- 5-methyl-1H-pyrazole-3-carboxamide (P-2042), N-[2-[1-(cyclopropylcarbonyl)-3,6-dihydro-2H-pyridin-4-yl] -1H-pyrrolo[2,3-b]pyridin-5-yl]-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2043), N-(2-anilino Pyrimidine-5-yl)-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2044), N-(6-anilino-3-pyridyl)-3,4-bis Methyl-1H-pyrazole-5-carboxamide (P-2045), N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]- 1H-indazole-3-carboxamide (P-2046), N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4,5 ,6,7-Tetrahydro-1H-indazole-3-carboxamide (P-2047), 3,4-dimethyl-N-[2-[1-(4-piperidinyl)pyrazole- 4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2048), N-(2-chloro-1H-pyrrolo [2,3-b]pyridin-5-yl)-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2049), N-[2-[3-(ethylamine Sulfonyl)anilino)pyrimidin-5-yl)-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2050), 3,4-Dimethyl-N-[2-(3-N-morpholinoanilino)pyrimidin-5-yl]-1H-pyrazole-5-methan Amine (P-2051), 3,4-dimethyl-N-[2-[3-(propanesulfonylamino)anilino]pyrimidin-5-yl]-1H-pyrazole-5-carboxamide (P-2052), N-[2-[3-(Benzenesulfonamido)anilino]pyrimidin-5-yl)-3,4-dimethyl-1H-pyrazole-5-methanamide ( P-2053), 3,4-dimethyl-N-[2-[3-(methylaminomethanyl)anilino]pyrimidin-5-yl]-1H-pyrazole-5-methanamide ( P-2054), N-[3-[[5-[(3,4-Dimethyl-1H-pyrazole-5-carbonyl)amino]pyrimidin-2-yl]amino]phenyl]amino Ethyl formate (P-2055), N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1,4,5,6-tetrahydro Cyclopentan[c]pyrazole-3-carboxamide (P-2056), 4-chloro-3-methyl-N-[2-(1-methylsulfonyl-3,6-dihydro-2H- (Pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2057), 3-methyl-N-(2 -N-morpholinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P-2058), 4,5-dimethyl-N -[2-(4-N-morpholinylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-3-carboxamide (P-2059), 4-chloro-N-[2-[1-(cyclopropylcarbonyl)-2,5-dihydropyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3 -Methyl-1H-pyrazole-5-carboxamide (P-2060), N-[2-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-1H- Pyrrolo[2,3-b]pyridin-5-yl]-4-chloro-3-methyl-1H-pyrazole-5-carboxamide (P-2061), 4-chloro-3-methyl- N-[2-[1-(morpholine-4-carbonyl)-2,5-dihydropyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H- Pyrazol-5-carboxamide (P-2062), N-[2-(3-fluoroprop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3 ,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2063), N-[2-[3-(dimethylamino)phenyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]-3,4-dimethyl -1H-pyrazole-5-carboxamide (P-2064), N-[2-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b] Pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2065), 3,4-dimethyl-N-[2-[3-(2- N-morpholinoethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2066), 3,4 -Dimethyl-N-[2-[4-(methylaminocarboxyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5- Formamide (P-2067), N-[2-(3-fluoroprop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3-methyl-1H -Pyrazole-5-carboxamide (P-2068), 4,5-dimethyl-N-[2-[2-(4-methylpiperazin-1-yl)-4-pyridyl]- 1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-3-carboxamide (P-2069), 4,5-dimethyl-N-[2-(3- N-morpholinylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-3-carboxamide (P-2070), N-(4,5- Dimethyl-1H-pyrazol-3-yl)-2-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (P-2071), N-[2-(4 -Fluorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl]-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2072), 3,4- Dimethyl-N-[2-[1-(2-N-morpholinoacetyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-pyrrolo[2,3- b]Pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2073), N-[2-[1-(2,3-dihydroxypropionyl)-3,6-di Hydrogen-2H-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P- 2074), N-[2-(2-chloro-4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H -Pyrazole-5-carboxamide (P-2075), N-[2-(2-fluoro-4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-5- Base] -3,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2076), N-[2-(2-chloro-5-methoxy-phenyl)-1H-pyrrolo[2,3 -b]pyridin-5-yl]-3,4-dimethyl -1H-pyrazole-5-carboxamide (P-2077), N-[2-(3-fluoro-5-N-morpholinyl-phenyl)-1H-pyrrolo[2,3-b ]Pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2078), 3,4-dimethyl-N-[2-(3-pyrrolidine -1-ylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2079), N-[2-(4- Aminocyclohexen-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P- 2080), N-[2-(4-cyano-3-N-morpholinyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl Group-1H-pyrazole-5-carboxamide (P-2081), N-[2-(3-fluoro-2-N-morpholinyl-4-pyridyl)-1H-pyrrolo[2,3 -b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2082), N-[2-(1-isobutylpyrazole-4- Yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2083), N-[2- (1,5-Dimethylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-methyl Amide (P-2084), N-[2-[4-(dimethylaminomethanyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4 -Dimethyl-1H-pyrazole-5-carboxamide (P-2085), 3,4-dimethyl-N-[2-[3-(trifluoromethoxy)phenyl]-1H- Pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2086), N-[2-[3-(dimethylaminocarboxyl)benzene Yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2087), 3,4-bis Methyl-N-[2-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2088), 3 ,4-Dimethyl-N-[2-(6-N-morpholin-3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2089), N-[2-(6-methoxy-3-pyridyl)-1H-pyrrolo[ 2,3-b]pyridin-5-yl]-3,4-dimethyl Base-1H-pyrazole-5-carboxamide (P-2090), 3,4-dimethyl-N-[2-(2-methylthiazol-5-yl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2091), N-[2-(4-cyanophenyl)-1H-pyrrolo[2,3- b]Pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2092), N-[2-(2-fluorophenyl)-1H-pyrrolo [2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2093), N-[2-(3-fluorophenyl) -1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2094), N-[2-(3 -Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2095), N- [2-(2-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P- 2096), 3,4-Dimethyl-N-[2-(o-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2097), N-[2-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyridine Azole-5-carboxamide (P-2098), N-[2-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4- Dimethyl-1H-pyrazole-5-carboxamide (P-2099), N-[2-(3-acetamidophenyl)-1H-pyrrolo[2,3-b]pyridine-5 -Yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2100), 3,4-dimethyl-N-[2-[4-(pyrrolidine-1- Carbonyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2101), N-[2-[4-(3 -Methoxypropoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P -2102), 3,4-dimethyl-N-[2-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine Pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2104), 3,4-dimethyl-N-[2-[4-(thiomorpholine-4-carbonyl)benzene Yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2105), 3,4-dimethyl-N-[2- [3-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2106), 3 ,4-Dimethyl-N-[2-[3-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole- 5-formamide (P-2107), N-[2-(2-cyclopropyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4 -Dimethyl-1H-pyrazole-5-carboxamide (P-2108), N-[2-(2-methoxy-4-pyridyl)-1H-pyrrolo[2,3-b] Pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2109), 3,4-dimethyl-N-[2-(2-N-? Linyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2110), N-[2-[4 -(Methanesulfonylamino)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P -2111), 3,4-dimethyl-N-(2-pyrazole-1-yl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-methyl Amide (P-2112), N-[2-[2-chloro-5-(trifluoromethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3 ,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2113), 4,5-dimethyl-N-(2-methylpyrazolo[1,5-a]pyrimidine- 6-yl)-1H-pyrazole-3-carboxamide (P-2114), 3,4-dimethyl-N-(2-pyrrolidin-1-yl-1H-pyrrolo[2,3- b]Pyridin-5-yl)-1H-pyrazole-5-carboxamide (P-2115) or 3-methyl-N-(2-pyrazole-1-yl-1H-pyrrolo[2,3 -b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P-2116), N-[2-[4-(methylsulfonamide)phenyl]-1H-pyrrolo[ 2,3-b]pyridin-5-yl]-3,4-dimethyl -1H-pyrazole-5-carboxamide (P-2117), N-[2-[3-[4-(cyclopropylcarbonyl)piperazin-1-yl]phenyl]-1H-pyrrolo[ 2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2118), N-[2-(4-fluorophenyl)- 1H-pyrrolo[2,3-b]pyridin-5-yl]-1,5-dimethyl-pyrazole-3-carboxamide (P-2119), N-[2-(4-cyano -3-pyrrolidin-1-yl-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2120), 3,4-Dimethyl-N-[2-[3-(Methylsulfasulfonyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ]-1H-pyrazole-5-carboxamide (P-2121), N-[2-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3 ,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2122), 3,4-Dimethyl-N-[2-(6-methyl-3-pyridyl)-1H- Pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2123), 3,4-dimethyl-N-[2-(4-pyridyl )-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2124), 3,4-dimethyl-N-[2-( 4-pyrrolidin-1-ylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2125), 3,4- Dimethyl-N-[2-[3-(propanesulfonamido)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-methyl Amine (P-2126), N-[2-(4-dimethylphosphorylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl -1H-pyrazole-5-carboxamide (P-2127), N-[2-(3-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3 ,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2128), N-[2-(2-fluoro-3-methoxy-phenyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2129), 3,4-dimethyl-N-[2-(between Tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyridine Azol-5-carboxamide (P-2130), N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3-methyl-1H -1,2,4-Triazole-5-carboxamide (P-2131), N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl ]-3-Propyl-1H-pyrazole-5-carboxamide (P-2132), N-[2-(6-acetamido-3-pyridyl)-1H-pyrrolo[2,3 -b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2133), N-[2-[3-(butylamine carboxamide Yl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2134), N- [2-(2-Methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide( P-2135), 3,4-dimethyl-N-[2-(2-methyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H- Pyrazol-5-carboxamide (P-2136), N-[2-(4-acetamidophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3, 4-Dimethyl-1H-pyrazole-5-carboxamide (P-2137), 3,4-dimethyl-N-[2-[4-(morpholin-4-carbonyl)phenyl]- 1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2138), N-[2-(2,4-dimethylthiazole-5 -Yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2139), N-[2 -[1-(Difluoromethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5 -Formamide (P-2140), N-[(4-chloro-3-methyl-1H-pyrazol-5-yl)methyl]-2-(4-fluorophenyl)-1H-pyrrolo [2,3-b]pyridine-5-amine (P-2141), 2-(4-fluorophenyl)-N-[(3-methyl-1H-pyrazol-5-yl)methyl]- 1H-pyrrolo[2,3-b]pyridine-5-amine (P-2142), N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-5- Yl]-1H-pyrazole-5-carboxamide (P-2143), 3,4-dimethyl-N-(2-phenylthiazolo[5,4-b]pyridin-6-yl)-1H-pyrazole-5-carboxamide (P- 2144), 3,4-dimethyl-N-(2-phenyl-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazole-5-carboxamide (P- 2145), N-[2-(3-Fluoro-2-methyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H- Pyrazol-5-carboxamide (P-2146), N-[2-(3-chloro-2-methyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl] -3,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2147), N-[2-[4-(cyclopropylaminocarboxyl)phenyl]-1H-pyrrolo [2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2148), 3,4-dimethyl-N-[2 -[4-[(3-Methyloxetan-3-yl)methoxy]phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole- 5-formamide (P-2149), 4-chloro-3-methyl-N-(2-phenyl-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazole -5-methylamide (P-2150), 3-methyl-N-(2-phenyl-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazole-5- Formamide (P-2151), N-[2-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl]-3,4-dimethyl-1H- Pyrazole-5-carboxamide (P-2152), N-[2-(2-ethoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]- 3,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2153), N-[2-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3 -b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2154), N-[2-(2-cyclopropylpyrimidin-5-yl )-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2155), N-[2-( 4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(trifluoromethyl)-1H-pyridine Azol-5-carboxamide (P-2156), N-[2-[2-(cyclopropylamino)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl] -3,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2157), 3,4-dimethyl-N-[2-(2-N-morpholinopyrimidine-5- Yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2158), 3-ethyl-N-[2-(4- Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2159), 3,4-dimethyl-N-[ 2-[2-(4-Methylpiperazin-1-yl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-methyl Amide (P-2160), N-[2-(4-cyano-2-methyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4- Dimethyl-1H-pyrazole-5-carboxamide (P-2161), 4-[3-[5-[(3,4-dimethyl-1H-pyrazole-5-carbonyl)amino] -1H-pyrazolo[3,4-b]pyridin-3-yl]phenyl]piperazine-1-carboxylic acid tert-butyl ester (P-2162), N-[2-(2-isopropyl- 4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2163), 3, 4-Dimethyl-N-[2-(2,3,4,5,6-pentadeuterophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole -5-methylamide (P-2164), 3,4-dimethyl-N-[2-(1,3,5-trimethylpyrazol-4-yl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2165), 3,4-dimethyl-N-[3-(3-piperazin-1-ylbenzene Yl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2166), N-[2-(3,5-dimethyl -1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P -2167), 3,4-dimethyl-N-[2-[3-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2168), N-[2-(6-methoxy-2-methyl-3-pyridyl)- 1H-pyrrolo[2,3-b]pyridin-5-yl]- 3,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2169), N-[2-(2-methoxy-6-methyl-3-pyridyl)-1H-pyrrole And [2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2170), N-[2-(3-chloro-2 -Methoxy-4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P- 2171), 3-(difluoromethyl)-N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5- Formamide (P-2172), 4-chloro-3-ethyl-N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H -Pyrazol-5-carboxamide (P-2173), N-[2-[4-Fluoro-3-(2H-tetrazol-5-yl)phenyl]-1H-pyrrolo[2,3- b]Pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2174), N-cyclopropyl-4-[5-[(3,4- Dimethyl-1H-pyrazole-5-carbonyl)amino]-1H-pyrrolo[2,3-b]pyridin-2-yl]pyridine-2-carboxamide (P-2175), 3,4 -Dimethyl-N-[2-[2-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5 -Formamide (P-2176), N-[2-(2-ethyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-di Methyl-1H-pyrazole-5-carboxamide (P-2177), N-[2-(6-ethyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-5 -Yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2178), N-[2-(2,3-dihydro-[1,4]dioxane Hexeno[2,3-b]pyridin-8-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5- Formamide (P-2179), 3,4-dimethyl-N-[2-[2-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-5- Group]-1H-pyrazole-5-carboxamide (P-2180), N-[2-(2,4-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-5 -Base]-3,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2181), 3,4-Dimethyl-N-[2-[2-(trifluoromethoxy)phenyl]-1H -Pyrrolo[2,3-b]pyridine-5- Group]-1H-pyrazole-5-carboxamide (P-2182), N-[2-(5-methoxy-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine- 5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2183), 3,4-dimethyl-N-[2-(5-methyl-3- Pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2184), N-[2-(4-methoxy- 3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2185), 3, 4-Dimethyl-N-[2-[2-(4-Methanesulfonylpiperazin-1-yl)-4-pyridyl]-1H-pyrrolo[2,3-b]pyridine-5- Yl]-1H-pyrazole-5-carboxamide (P-2186), N-[2-[2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-4-pyridinyl]-1H -Pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2187), N-(2-iodo-1H- Pyrrolo[2,3-b]pyridin-5-yl)-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2188), N-[2-[2-[4 -(2-Cyanoacetoxy)piperazin-1-yl]-4-pyridyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl- 1H-pyrazole-5-carboxamide (P-2189), 4,5-dimethyl-N-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrrole And [2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2190), 4,5-dimethyl-N-(3-(6-(piperazine -1-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2191), 4,5- Dimethyl-N-(3-(6-N-morpholinylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-methyl Amide (P-2192), 4,5-dimethyl-N-(3-(2-N-morpholinylpyridin-4-yl)-1H-pyrrolo[2,3-b)pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2193), N-(2-(1-(1-acetylazetidin-3-yl) -3-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-methyl Amide (P-2194), N-(2-(1-(azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3 -b] Pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2195), 4,5-dimethyl-N-(2-(5-methyl- 1-(oxetan-3-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-methan Amine (P-2196), N-(2-(1-(azetidin-3-yl)-5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b)Pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2197), 4,5-dimethyl-N-(2-(5-methyl Base-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-methan Amine (P-2198), N-(2-(1-(1-Acetylpiperidin-4-yl)-5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2 ,3-b)pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2199), N-(2-(1-(1-(cyclopropyl) (Carbonyl)piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl -1H-pyrazole-3-carboxamide (P-2200), 4,5-dimethyl-N-(2-(3-methyl-1-(piperidin-4-yl)-1H-pyridine (Azol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2201), N-(2-(1-( 1-Acetylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5- Dimethyl-1H-pyrazole-3-carboxamide (P-2202), N-(2-(1-(1-(cyclopropylcarbonyl)piperidin-4-yl)-3-methyl-1H -Pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2203) , N-(2-(2-(Cyclopropylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyridine Azol-3-carboxamide (P-2204), N-(2-(3-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-pyrrolo[2,3-b ]Pyridin-5-yl)-4,5-Dimethyl-1H-pyrazole-3-carboxamide (P-2205), N-(2-(2-(cyclopropanecarboxamide)pyridin-4-yl)-1H-pyrrolo[ 2,3-b)pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2206), N-(2-(2-(1-(cyclic Propylcarbonyl)piperidin-4-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3- Formamide (P-2207), 4,5-dimethyl-N-(2-(2-(pyrrolidin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b ]Pyridine (Pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2208), 4,5-dimethyl-N-(2-(2-(piperidin-1-yl)pyridine-4 -Yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2209), 4,5-dimethyl-N-(2 -(2-(4-Methylpiperidin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-methan Amine (P-2210), 4,5-dimethyl-N-(2-(2-(piperidin-4-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine -5-yl)-1H-pyrazole-3-carboxamide (P-2211), N-(2-(2-(4-hydroxypiperidin-1-yl)pyridin-4-yl)-1H- Pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2212), N-(2-(2-(3 -Hydroxypiperidin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-methyl Amide (P-2213), N-(2-(2-(4-acetylpiperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5 -Yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2214), 4,5-dimethyl-N-(2-(2-(4-(3- (Methylbut-2-enyl)piperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-methan Amide (P-2215), 4,5-Dimethyl-N-(2-(2-(morpholin-4-carbonyl)pyridin-4-yl)-1H-pyrrolo[2,3-b] Pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2216), 4,5-dimethyl-N-(2-(2-(4-methylpiperazine-1-carbonyl) )Pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2217), 4,5-dimethyl- N-(2-(2-(pyrrolidine-1-carbonyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-methan Amine (P-2218), 4,5-dimethyl-N-(2-(2-(thiomorpholine-4-carbonyl)pyridin-4-yl)-1H-pyrrolo[2,3-b)pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2219), 4-(5-(4,5-dimethyl-1H-pyrazole-3-methylamide) Amino)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-methoxyethyl)picolinamide (P-2220), 4-(5-(4 ,5-Dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridine-2- Yl)-N-(2-(dimethylamino)ethyl)picolinamide (P-2221), 4-(5-(4,5-dimethyl-1H-pyrazole-3-methyl) Amino)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-methoxyethyl)picolinamide (P-2222), 4-(5-(4 ,5-Dimethyl-1H-pyrazole-3-carboxamide)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-methoxypyridinecarboxamide (P- 2223), 4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N, N-dimethylpyridine carboxamide (P-2224), 4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3 -b)pyridin-2-yl)-N-(2-N-morpholinoethyl)picolinamide (P-2225), 4-(5-(4,5-dimethyl-1H-pyridine) Oxazole-3-carboxamide)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)picolinate Amide (P-2226), N-(2-cyanoethyl)-4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo [2,3-b]pyridin-2-yl)picolinamide (P-2227), 4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)- 1H-pyrrolo[2,3-b]pyridin-2-yl)-N-isobutylpyridinecarboxamide (P-2228), 4-(5-(4,5-dimethyl-1H-pyridine Oxazole-3-carboxamide)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-isopropylpyridinecarboxamide (P-2229), 4-(5-(4 ,5-Dimethyl-1H-pyrazole-3-carboxamide)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N,N-diethylpicolinamide ( P-2230), 4-methyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole- 3-formamide (P-2231), 4-chloro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-3-carboxamide (P-2232), 5-chloro-N-(2-phenyl-1H-pyrrolo[2,3-b)pyridin-5-yl)-4-(trifluoromethyl)-1H-pyrazole-3-carboxamide (P-2233), 5-(difluoromethyl)-4-methyl- N-(2-Phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H- Pyrazole-3-carboxamide (P-2234), 4-(difluoromethyl)-5-methyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridine-5 -Yl)-1H-pyrazole-3-carboxamide (P-2235), 5-chloro-4-(difluoromethyl)-N-(2-phenyl-1H-pyrrolo[2,3- b)Pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2236), 4-chloro-5-(difluoromethyl)-N-(2-phenyl-1H-pyrrolo [2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2237), N-(2-(2-methoxypyridin-3-yl)-1H- Pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2238), N-(2-(2-ethoxy Pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2239), N-(2-(2-(Difluoromethoxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H- Pyrazol-3-carboxamide (P-2240), 4,5-dimethyl-N-(2-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrrolo[2, 3-b)pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2241), N-(2-(2,6-dimethoxypyridin-3-yl)-1H- Pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2242), N-(2-(5-cyclopropyl) Pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2243), N-(2-(5,6-dimethylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole -3-formamide (P-2244), N-(2-(2-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5- Dimethyl-1H-pyrazole-3-carboxamide (P-2245), 4,5-dimethyl-N-(2-(2-methylpyridin-4-yl)-1H-pyrrolo[ 2,3-b)pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2246), N-(2-(2-ethoxypyridin-4-yl)-1H-pyrrole And [2,3-b)pyridin-5-yl)-4,5-dimethyl Group-1H-pyrazole-3-carboxamide (P-2247), N-(2-(2-isopropoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine- 5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2248), N-(2-(3-chloro-2-methoxypyridin-4-yl) -1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2249), N-(2-(3 -Chloropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2250) , 4,5-Dimethyl-N-(2-(3-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3 -Formamide (P-2251), 4,5-dimethyl-N-(2-(2-(pyrrolidin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3- b]Pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2252), N-(2-(5-fluoropyridin-3-yl)-1H-pyrrolo[2,3- b)Pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2253), 4,5-dimethyl-N-(2-(5-( (Trifluoromethyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2254), N-(2 -(6-Cyclopropylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2255), N-(2-(5-ethylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H -Pyrazole-3-carboxamide (P-2256), N-(2-(2-(difluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl) -4,5-Dimethyl-1H-pyrazole-3-carboxamide (P-2257), N-(2-(4-chloro-2-methylphenyl)-1H-pyrrolo[2, 3-b)pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2258), N-(2-(4-fluoro-2-methylbenzene) Yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2259), N-(2- (2,4-Difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H- Pyrazol-3-carboxamide (P-2260), N-(2-(3-cyano-2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine-5- Yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2261), N-(2-(4-fluoro-2,3-dimethylphenyl)-1H- Pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2262), N-(2-(2-(two(Fluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2263) , N-(2-(2-(Difluoromethoxy)-3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl- 1H-pyrazole-3-carboxamide (P-2264), N-(2-(3,6-dihydro-2H-piperan-4-yl)-1H-pyrrolo[2,3-b] Pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2265), 4,5-dimethyl-N-(2-(2,2,6 ,6-Tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-methan Amide (P-2266), N-(2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1H-pyrrolo[2, 3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2267), N-[2-[2-(difluoromethoxy) -4-Fluoro-phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2268) , N-[2-(6-Fluoro-3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5- Formamide (P-2269), N-[2-(5-cyano-3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl Group-1H-pyrazole-5-carboxamide (P-2270), N-[2-(3,6-dihydro-2H-piperan-4-yl)-1H-pyrrolo[2,3- b]Pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2271), 3-[5-[(3,4-dimethyl-1H- Pyrazol-5-carbonyl)amino]-1H-pyrrolo[2,3-b]pyridin-2-yl]pyridine-4-carboxamide (P-2272), N-[2-(2,3-dihydrobenzofuran-7-yl)-1H-pyrrolo[2 ,3-b]pyridin-5-yl]-3,4- Dimethyl-1H-pyrazole-5-carboxamide (P-2273), 3,4-dimethyl-N-[2-(3-piperazin-1-ylphenyl)-1H-pyrrolo [2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2274), 4-fluoro-N-[2-(4-fluorophenyl)-1H-pyrrole And [2,3-b]pyridin-5-yl]-3-methyl-1H-pyrazole-5-carboxamide (P-2275), N-[2-[3-(isobutylaminomethyl (Phenyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2276), N -[2-(4-Chloro-2-methyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5 -Formamide (P-2277), N-[2-(3-chloro-4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl Group-1H-pyrazole-5-carboxamide (P-2278), N-[2-(4-fluoro-2,3-dimethyl-phenyl)-1H-pyrrolo[2,3-b ]Pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2279), N-[2-(2,6-difluoro-3-pyridyl) -1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2280), N-[2-(2 ,2-Difluoro-1,3-benzodioxol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl -1H-pyrazole-5-carboxamide (P-2281), N-[2-(5,6-dimethyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine- 5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2282), N-[2-(6-fluoro-2-methyl-3-pyridyl)- 1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2283), N-[2-(4- Methoxy-2,3-dimethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-methyl Amide (P-2284), 3-[4-[5-[(3,4-Dimethyl-1H-pyrazole-5-carbonyl)amino]-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methyl-pyrazol-1-yl]azetidine-1-carboxylate (P-2285), N-[2-[1- (Azetidin-3-yl)-3-methyl-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine Pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2286), 3-(difluoromethyl)-N-[2-(4-fluorobenzene Yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methyl-1H-pyrazole-5-carboxamide (P-2287), N-(2-iodo-1H -Pyrrolo[2,3-b]pyridin-5-yl)-2H-indazole-4-carboxamide (P-2288), N-(2-phenyl-1H-pyrrolo[2,3- b]Pyridin-5-yl)-2H-indazole-4-carboxamide (P-2289), 3-[(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl )Carboxamide]methyl benzoate (P-2290), 3-[(2-Phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carboxamide] Benzoic acid (P-2291), 4-[5-[(3,4-Dimethyl-1H-pyrazole-5-carbonyl)amino]-1H-pyrrolo[2,3-b]pyridine- 2-yl]-2-fluoro-benzoic acid (P-2292), 2-[3-[5-[(3,4-dimethyl-1H-pyrazole-5-carbonyl)amino]-1H- Pyrrolo[2,3-b]pyridin-2-yl]phenyl]acetic acid (P-2293), 1-[4-[5-[(3,4-dimethyl-1H-pyrazole-5- Carbonyl)amino]-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl]cyclopropanecarboxylic acid (P-2294), 2-[4-[5-[(3,4-twoMethyl-1H-pyrazole-5-carbonyl)amino]-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl]acetic acid (P-2295), 4-[5-[( 3,4-Dimethyl-1H-pyrazole-5-carbonyl)amino]-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-methyl-benzoic acid (P-2296 ), 3-[5-[(3,4-Dimethyl-1H-pyrazole-5-carbonyl)amino]-1H-pyrrolo[2,3-b]pyridin-2-yl]-2- Methyl-benzoic acid (P-2297), 1-methyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)indazole-4-carboxamide ( P-2298), N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-indole-4-carboxamide (P-2299), N-( 2-Phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-benzimidazole-4-carboxamide (P- 2300), N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2H-indazole-4-carboxamide (P-2301), 3,4-di Methyl-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P-2302), 4-[(2 -Phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)aminomethanyl]benzoic acid (P-2303), N,3,4-trimethyl-N-(2-benzene Group-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P-2304), N-[2-(2,3-dihydro-1 ,4-benzodioxen-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5- Formamide (P-2305), 4-[4-[5-[(3,4-dimethyl-1H-pyrazole-5-carbonyl)amino]-1H-pyrrolo[2,3-b ]Pyridin-2-yl]pyrazol-1-yl]piperidine-1-carboxylate (P-2306) or N-[2-(cyclohexen-1-yl)-1H-pyrrolo [2,3-b]Pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2307), or its pharmaceutically acceptable salts and hydrates , Solvates, tautomers or isomers. In certain embodiments, compounds P-2001 to P-2273 and P-2274 to P-2307 The pyrazole ring part in any one of:<img file="TWI617552B_D0111.tif" wi="149" he="183" img-format="tif" img-content="character" orientation="portrait" inline="no" />Can exist in tautomeric forms:<img file="TWI617552B_D0112.tif" wi="176" he="139" img-format="tif" img-content="character" orientation="portrait" inline="no" />,That The middle wavy line represents the connection point with the rest of the molecule.

In some embodiments, the present invention provides any of formulas (I'), (I'a), (I), (II), (III), (IV), (V), (V')(IIIa), (IIIb), (IIIc), (IIId), (IIId), (IIIe), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIa-6), (IIIa-7), (IIIa-8), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4), (IIIb-5), (IIIc -1), (IIIc-2), (IIIc-3), (IIIc-4), (IIIc-5), (IIId-1), (IIId-2), (IIId-3), (IIId-4) ), (IIId-5), (IIIe-1), (IIIe-2), (IIIe-3), (IIIe-4), (IIIe-5), (IVa), (IVa-1), (IVa -2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa- 7), (IVa-8), (IVa-9), (IVa-10), (IVa-1a), (IVa-2a), (IVa-3a), (IVa-4a), (IVa-5a) , (IVa-6a), (IVa-7a), (IVa-8a), (IVa-9a), (IVa-10a), (IVa-1b), (IVa-2b), (IVa-5b), ( IVa-6b), (IVb), (IVb-1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7) , (IVb-8), (IVc), (IVc-1), (IVc-2), (IVc-3), (IVc-4), (IVc-5), (IVd), (IVd-1) , (IVd-2), (IVd-3), (IVd-4), (IVd-5), (IVe), (IVe-1), (IVe-2), (IVe-3), (IVe- 4), (IVe-5), (Va), (Va-1), (Va-2), (Va-3), (Va-1a), (Va-2a), (Va-3a), ( Va-1a-1), (Va-2a-1), (Va-1b), (Va-2b), (Va-3b), (Va-1b-1), (Va-2b-1), ( Va-6), (Va-6a), (Va-6b), (Va-6c) or (Va-6d) compounds, or their pharmaceutically acceptable salts, hydrates, solvates, and mutual mutations Constructs or isomers.

In some embodiments, the present invention provides any compound selected from the group consisting of P-2001 to P-2102, P-2104 to P-2273, and P-2274 to P-2307, such as compounds P-2001, P-2002 , P-2003, P-2004, P-2005, P-2006, P-2007, P-2008, P-2009, P-2010, P-2011, P-2012, P-2013, P-2014, P -2015, P-2016, P-2017, P-2018, P-2019, P-2020, P-2021, P-2022, P-2023, P-2024, P-2025, P-2026, P-2027 , P-2028, P-2029, P-2030, P-2031, P-2032, P-2033, P-2034, P-2035, P-2036, P-2037, P-2038, P-2039, P -2040, P-2041, P-2042, P-2043, P-2044, P-2045, P-2046, P-2047, P-2048, P-2049, P-2050, P-2051, P-2052 , P-2053, P-2054, P-2055, P-2056, P-2057, P-2058, P-2059, P-2060, P-2061, P-2062, P-2063, P-2064, P -2065, P-2066, P-2067, P-2068, P-2069, P-2070, P-2071, P-2072, P-2073, P-2074, P-2075, P-2076, P-2077 , P-2078, P-2079, P-2080, P-2081, P-2082, P-2083, P-2084, P-2085, P-2086, P-2087, P-2088, P-2089, P -2090, P-2091, P-2092, P-2093, P-2094, P-2095, P-2096, P-2097, P-2098, P-2099, P- 2100, P-2101, P-2102, P-2104, P-2105, P-2106, P-2107, P-2108, P-2109, P-2110, P-2111, P-2112, P-2113, P-2114, P-2115, P-2116, P-2117, P-2118, P-2119, P-2120, P-2121, P-2122, P-2123, P-2124, P-2125, P- 2126, P-2127, P-2128, P-2129, P-2130, P-2131, P-2132, P-2133, P-2134, P-2135, P-2136, P-2137, P-2138, P-2139, P-2140, P-2141, P-2142, P-2143, P-2144, P-2145, P-2146, P-2147, P-2148, P-2149, P-2150, P- 2151, P-2152, P-2153, P-2154, P-2155, P-2156, P-2157, P-2158, P-2159, P-2160, P-2161, P-2162, P-2163, P-2164, P-2165, P-2166, P-2167, P-2168, P-2169, P-2170, P-2171, P-2172, P-2173, P-2174, P-2175, P- 2176, P-2177, P-2178, P-2179, P-2180, P-2181, P-2182, P-2183, P-2184, P-2185, P-2186, P-2187, P-2188, P-2189, P-2190, P-2191, P-2192, P-2193, P-2194, P-2195, P-2196, P-2197, P-2198, P-2199, P-2200, P- 2201, P-2202, P-2203, P-2204, P-2205, P-2206, P-2207, P-2208, P-2209, P-2210, P-2211, P-2212, P-2213, P-2214, P-2215, P-2216, P-2217, P-2218, P-2219, P-2220, P-2221, P-2222, P-2223,P-2224, P-2225, P-2226, P-2227, P-2228, P-2229, P-2230, P-2231, P-2232, P-2233, P-2234, P-2235, P- 2236, P-2237, P-2238, P-2239, P-2240, P-2241, P-2242, P-2243, P-2244, P-2245, P-2246, P-2247, P-2248, P-2249, P-2250, P-2251, P-2252, P-2253, P-2254, P-2255, P-2256, P-2257, P-2258, P-2259, P-2260, P- 2261, P-2262, P-2263, P-2264, P-2265, P-2266, P-2267, P-2268, P-2269, P-2270, P-2271, P-2272, P-2273, P-2274, P-2275, P-2276, P-2277, P-2278, P-2279, P-2280, P-2281, P-2282, P-2283, P- 2284, P-2285, P-2286, P-2287, P-2288, P-2289, P-2290, P-2291, P-2292, P-2293, P-2294, P-2295, P-2296, P-2297, P-2298, P-2299, P-2300, P-2301, P-2302, P-2303, P-2304, P-2305, P-2306 or P-2307, or their pharmaceutically acceptable Accepted salts, hydrates, solvates, tautomers or isomers.

<i>Preparation</i>

In another aspect, the present invention provides a method of preparing a compound of formula (IV) or any sub-formula as described herein. The method includes making a compound of formula (VI) or any of its sub-formulas:<chemistry general="n"><img he="205" wi="573" file="TWI617552B_D0113.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

With reagents of the following formula:<chemistry general="n"><img he="296" wi="516" file="TWI617552B_D0114.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Contact under conditions sufficient to form a compound of formula (VIII):<chemistry general="n"><img he="307" wi="904" file="TWI617552B_D0115.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

And make the compound of formula VIII and have the following formula: G²-(R⁷)_mThe reagent is reacted under conditions sufficient to form the compound of formula (IV), where J¹For-NR⁵, -NH₂, P¹NH-, P¹NR⁵-, -COOH or -C(O)Q¹; G¹For -NH₂, -COOH or -C(O)Q²; And J²It is halogen, tosylate, mesylate or trifluoromethanesulfonate. P¹It is an amine protecting group. Q¹And Q²Each independently is -OH, halogen, C_1-4Alkoxy or phenoxy. G²For NH₂, -B(OR⁵⁰)₂Or -Sn(Bu)₃, Where R⁵⁰Is -OH, alkyl or two -OR⁵⁰The substituent and the boron atom to which it is attached together form a 5- or 6-membered ring which is optionally substituted. In one case, -B(OR⁵⁰)₂4,4,5,5-tetramethyl-1,3,2-dioxoboron<img file="TWI617552B_D0116.tif" wi="55" he="60" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-base. Variable R³, R⁴, R⁵, Y¹, Y², Y³And A is as defined in the formula and sub-formula in any of the embodiments disclosed herein. In some embodiments, A is a fused pyrrole ring, which forms a pyrrolo[2,3-b]pyridine together with the aromatic ring to which it is fused. In other embodiments, A is a fused thiophene ring, which together with the fused aromatic ring forms a thieno[3,2-b]pyridine moiety. In other embodiments, A is a fused pyrazole ring, which together with the fused aromatic ring forms a pyrazolo[3,4-b]pyridine moiety. In other embodiments, A is a fused benzene ring, which together with the fused aromatic ring forms a quinoline moiety. In one embodiment, J²Is I, Cl or Br, and J¹For NH₂Or NHP¹. In another embodiment, G²4,4,5,5-tetramethyl-1,3,2-dioxoboron<img file="TWI617552B_D0117.tif" wi="52" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-base. In another embodiment, G¹For -COOH. In another embodiment, G¹For -NH₂. In some cases, the reaction between the compound of formula (VI) and the reagent of formula (VII) can be carried out in the presence of a coupling agent. Exemplary coupling agents include (but are not limited to) benzotriazol-1-yl-oxytripyrrolidine phosphonium hexafluorophosphate (PyBOP), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide (EDC) and hexafluorophosphate O-benzotriazole-N,N,N',N'-tetramethyl<img file="TWI617552B_D0118.tif" wi="62" he="55" img-format="tif" img-content="character" orientation="portrait" inline="no" />(HBTU). In some embodiments, R⁵⁰For H. In some embodiments, G²-(R⁷)_mReact with the compound of formula (VIII) in the presence of a palladium complex. In some cases, palladium complexes include (but are not limited to) Pd(PPh₃)₄, Palladium acetate, bis(diphenylphosphino)ferrocene]dichloropalladium, ginseng (dibenzylideneacetone)dipalladium(0), bis(triphenylphosphine)palladium(II) dichloride and analog. In certain embodiments, the compound of formula VI has the sub-formula (VI-1), (VI-2), (VI-3), (VI-4) or (VI-5):<chemistry general="n"><img he="372" wi="1905" file="TWI617552B_D0119.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Where P²Is H or amine protecting group; J¹And J²As defined in any of the embodiments and formulas disclosed herein, and Y²And Y³As defined in any of the embodiments and formulas disclosed herein. In certain embodiments, P¹And P²Each is independently selected from the group consisting of 9-thylmethoxycarbonyl, tertiary butoxycarbonyl, trimethylsilyl, tertiary butyldiphenylsilyl, benzenesulfonyl, 4-methylbenzenesulfonyl or 2,6-dichlorophenylcarbonyl.

In some embodiments, the method for preparing the compound of formula (IV) includes combining the compound of formula VI with reagent G²-(R⁷)_mContact under conditions sufficient to form a compound of formula (IX):<chemistry general="n"><img he="197" wi="698" file="TWI617552B_D0120.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

And then make the compound of formula (IX) have the following formula:<img file="TWI617552B_D0121.tif" wi="185" he="235" img-format="tif" img-content="character" orientation="portrait" inline="no" />The reagent is sufficient to form the formula Reaction under the conditions of IV compound. In some cases, the compound of formula (IX) and the reagent<img file="TWI617552B_D0122.tif" wi="208" he="246" img-format="tif" img-content="character" orientation="portrait" inline="no" />The reaction between can be carried out in the presence of a coupling agent. Exemplary coupling agents include (but are not limited to) benzotriazol-1-yl-oxytripyrrolidine phosphonium hexafluorophosphate (PyBOP), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide (EDC) and hexafluorophosphate O-benzotriazole-N,N,N',N'-tetramethyl<img file="TWI617552B_D0123.tif" wi="62" he="52" img-format="tif" img-content="character" orientation="portrait" inline="no" />(HBTU). In some cases, reagent G²-(R⁷)_mReact with the compound of formula (VI) under basic conditions (for example, in the presence of triethylamine) or at a temperature above 100°C.

In some embodiments, the present invention provides methods for preparing compounds of formula (IVa), (IVb), (IVc), (IVd) or (IVe). The method includes (i) making any formula (VI-1), (VI-2), (VI- 2), (VI-3), (VI-4) or (VI-5) compounds with the following formula:<img file="TWI617552B_D0124.tif" wi="171" he="253" img-format="tif" img-content="character" orientation="portrait" inline="no" />The reagent is sufficient Contact under the conditions to form a compound of formula (VI-1a), (VI-2a), (VI-3a), (VI-4a) or (VI-5a):<chemistry general="n"><img he="1076" wi="1909" file="TWI617552B_D0125.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

(ii) Respectively make any compound of formula (VI-1a), (VI-2a), (VI-3a), (VI-4a) or (VI-5a) and have the following formula: G²-(R⁷)_mThe reagent is reacted under conditions sufficient to form a compound of formula (VI-1b), (IVb), (IVc), (IVd) or (VI-5b):<chemistry general="n"><img he="468" wi="1321" file="TWI617552B_D0126.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

For compounds of formula (VI-1b) or (VI-5b), the method includes another step: removing formula (VI-1b) or (VI-1b) or (VI-1b) or ( VI-5b) Protecting group P in the compound². In one embodiment, the protecting group P is removed²It is carried out under alkaline conditions (for example in the presence of KOH). In some cases, the method also includes preparing the compound of formula (IVa), (IVb), (IVc), (IVd) or (IVe) by the following method: performing the above steps (i) and (ii) in reverse order For example, first make any compound of formula (VI-1), (VI-2), (VI-2), (VI-3), (VI-4) or (VI-5) and G²-(R⁷)_mReaction, and then with the compound of the following formula:<img file="TWI617552B_D0127.tif" wi="200" he="242" img-format="tif" img-content="character" orientation="portrait" inline="no" />reaction. Sub-formulas (VI-1a), (VI-2a), (VI-3a), (VI-4a), (VI-5a), (VI- Variable R in 1b) and (VI-5b)³, R⁴, R⁵, Y², Y³, M, R⁷And P²Ru Form and Sub Form As defined in any of the embodiments disclosed herein. In one case, m is 1.

In one embodiment, G²For -B(OH)₂. In another embodiment, G²It is 2-hydroxy-1,3,2-benzodioxaborole or 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-benzo-dioxaborole<img file="TWI617552B_D0128.tif" wi="55" he="60" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-base. In another embodiment, G²For -Sn(Bu)₃。

In another aspect, the present invention provides a method for preparing a compound of formula (V'):<chemistry general="n"><img he="354" wi="932" file="TWI617552B_D0129.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

The method involves making a compound of formula (X):<chemistry general="n"><img he="314" wi="731" file="TWI617552B_D0130.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Compound with formula (XI): NH₂-L²-R⁶Contact under conditions sufficient to form a compound of formula (V'), where J²Is halogen, tosylate, mesylate or trifluoromethanesulfonate, and the variable R³, R⁴, R⁵, Y¹, Y², Y³And R¹The compound of formula (I'), (I'a), (I), (II), (III), (IV), (V) or (V') is as described in any of the embodiments described herein definition. In some embodiments, the reaction is carried out under acidic conditions at a temperature above 100°C. In one embodiment, the reaction can be carried out in the presence of an aqueous hydrochloric acid solution. In some cases, J²It is Cl or Br. In some embodiments, Y¹Is N, and R¹It is a lone electron pair. In some cases, L²It's a key. In other cases, R⁶Is an aryl group or a heteroaryl group, each of which is optionally substituted with the following substituents: 1-3 R⁹; Or 1-3 R^c; Or 1-3 R^d; Or 1-3 R^e; Or 1-3 R¹⁵; Or 1-3 R¹⁶; Or 1-3 R¹⁷; Or 1-3 R¹⁹; Or 1-3 R²⁰Group.

In other embodiments, the present invention provides a synthetic intermediate having formula (XII):<chemistry general="n"><img he="219" wi="674" file="TWI617552B_D0131.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>Where J¹For-NR⁵, -NH₂, P¹NH-, (P¹)₂N- or P¹NR⁵, Where P¹Amine-based protection Protective base; J³For -B(OR⁵⁰)₂, Where R⁵⁰Is -OH, alkyl or two -OR⁵⁰The substituent and the boron atom to which it is attached together form a 5- or 6-membered ring which is optionally substituted. In some cases, with two -OR⁵⁰Group formation of 5 or 6 members, depending on the situation, 1-3 independently selected C_1-6Alkyl substitution. In one case, -B(OR⁵⁰)₂4,4,5,5-tetramethyl-1,3,2-dioxoboron<img file="TWI617552B_D0132.tif" wi="52" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl, 5,5-dimethyl-1,3,2-dioxoboron<img file="TWI617552B_D0133.tif" wi="55" he="55" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl or 4,4,6-trimethyl-1,3,2-dioxoboron<img file="TWI617552B_D0134.tif" wi="57" he="55" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-base. In another case, -B(OR⁵⁰)₂4,4,5,5-tetramethyl-1,3,2-dioxoboron<img file="TWI617552B_D0135.tif" wi="50" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-base. In another case, R⁵⁰For H. Variable R⁵, Y¹, Y², Y³And A is as defined in the formula and sub-formula in any of the embodiments disclosed herein. The intermediate is suitable for preparing compounds of formula (I'a) or (IV) or any sub-formulas thereof. In some embodiments, A is a fused pyrrole ring, which forms a pyrrolo[2,3-b]pyridine together with the aromatic ring to which it is fused. In other embodiments, A is a fused thiophene ring, which together with the fused aromatic ring forms a thieno[3,2-b]pyridine moiety. In other embodiments, A is a fused pyrazole ring, which together with the fused aromatic ring forms a pyrazolo[3,4-b]pyridine moiety. In other embodiments, A is a fused benzene ring, which together with the fused aromatic ring forms a quinoline moiety. In certain embodiments, the compound of formula (XII) has the sub-formula (XII-1), (XII-2), (XII-3), (XII-4) or (XII-5):<chemistry general="n"><img he="430" wi="1875" file="TWI617552B_D0136.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Where P²It is H or an amino acid protecting group. In one embodiment, P²For H. In some embodiments, the compound of formula (XII) has a general formula selected from the group consisting of: formula (XII-6), (XII-7), (XII-8), (XII-9), (XII-10), (XII-11), (XII-12), (XII-13), (XII-14), (XII-15), (XII-16) or (XII-17):<chemistry general="n"><img he="1339" wi="1939" file="TWI617552B_D0137.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

Where P²It is H or an amino acid protecting group. In one embodiment, P²For H.

In some embodiments of compounds of formula (XII) or sub-formulas (XII-1) to (XII-17), Y²For CR¹⁰, And Y³For CH. In some cases, R¹⁰For H. In some embodiments, Y²Is N, and Y³For CH. In other embodiments, Y²For CR¹⁰, And Y³Is N. In some embodiments, Y²And Y³For CH. In some embodiments where the compound of formula (XII) or any one of sub-formulas (XII-1) to (XII-17) is as described herein, J¹For NH². In some embodiments where the compound of formula (XII) or any one of sub-formulas (XII-1) to (XII-17) is as described herein, J³For -B(OR⁵⁰)₂, Where R⁵⁰Is -OH, alkyl or two -OR⁵⁰The substituent and the boron atom to which it is attached together form a 5- or 6-membered ring which is optionally substituted. In some embodiments where the compound of formula (XII) or any one of sub-formulas (XII-1) to (XII-17) is as described herein, J³4,4,5,5-tetramethyl-1,3,2-dioxoboron<img file="TWI617552B_D0138.tif" wi="55" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-base. In some embodiments where the compound of formula (XII) or any one of sub-formulas (XII-1) to (XII-17) is as described herein, P²For H. In one embodiment, J¹For NH₂, J³For -B(OR⁵⁰)₂, Where R⁵⁰Is -OH, alkyl or two -OR⁵⁰The substituent and the boron atom to which it is attached together form a substituted 5 or 6 member as appropriate ring. In the case where the compound of formula (XII) or any one of sub-formulas (XII-1) to (XII-17) is as described herein, J¹For NH₂, And J³4,4,5,5-tetramethyl-1,3,2-dioxoboron<img file="TWI617552B_D0139.tif" wi="52" he="65" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-base.

<i>Organic Synthesis Technology</i>

There are a variety of organic synthesis techniques in this technology to help construct potential regulators. Many of these organic synthesis methods are described in detail in standard reference sources used by those skilled in the art. An example of such a reference is March 1994, Advanced Organic Chemistry; Reactions, Mechanisms and Structure, New York, McGraw Hill. Therefore, the technology suitable for the synthesis of potential modulators of kinase function can be easily used by those who are familiar with organic chemical synthesis.

<i>Alternative compound form or derivative</i>

The compounds covered herein are described with reference to the general formula and specific compounds. In addition, it is disclosed that the compound can exist in many different forms or derivatives, all of which fall within the scope of the present invention. Alternative forms or derivatives include, for example, (a) prodrugs and active metabolites; (b) tautomers, isomers (including stereoisomers and regional isomers) and racemic mixtures; (c) pharmaceuticals Academically acceptable salts; and (d) solid forms, including different crystal forms, polycrystalline or amorphous solids, including their hydrates and solvates, and other forms.

(a)<i>Prodrugs and metabolites</i>

In addition to the formulas and compounds of the present invention described herein, the present invention also includes prodrugs (usually pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites) and pharmaceutically acceptable salts thereof .

A prodrug is a compound or a pharmaceutically acceptable salt thereof that produces the desired active compound when metabolized under physiological conditions or when converted by solvolysis. Prodrugs include, but are not limited to, esters, amides, urethanes, carbonates, ureas, solvates or hydrates of the active compound. Typically, prodrugs are inactive or less active than the active compound, but can provide one or more advantageous handling, administration, and/or metabolic properties. For example, some former Drugs are esters of active compounds; during metabolism, the ester groups are cleaved to produce active drugs. Esters include, for example, esters of carboxylic acid groups, or S-acyl or O-acyl derivatives of thiol, alcohol, or phenol groups. In this case, common examples are alkyl esters of carboxylic acids. Prodrugs may also include variants in which the -NH group of the compound is acylated, such as the 1H-pyrrolo[2,3-b]pyridine ring of the compound as described herein or the nitrogen of the sulfonamide group , Where the acyl group is cleaved to obtain the free -NH group of the active drug. Some prodrugs can be activated enzymatically to obtain the active compound, or the compound can undergo other chemical reactions to obtain the active compound. A prodrug may change from a prodrug form to an active form in a single step, or may have one or more intermediate forms that may or may not be active themselves.

like<i>The Practice of Medicinal Chemistry</i>, As described in Chapters 31-32 (Edited by Wermuth, Academic Press, San Diego, CA, 2001), prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs . Generally speaking, a bioprecursor prodrug is a compound that is inactive or has an activity lower than that of the corresponding active pharmaceutical compound, which contains one or more protecting groups and is converted into an active form by metabolism or solvolysis. The active drug form and any released metabolites should have acceptable low toxicity. Typically, the formation of active pharmaceutical compounds involves a metabolic process or reaction having one of the following types: Oxidation reaction: Oxidation reaction is exemplified by (but not limited to) reactions such as: oxidation of alcohol, carbonyl and acid functional groups, aliphatic carbon Hydroxylation, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic and sulfur, oxidative N-dealkylation Oxidative, oxidative O-dealkylation and S-dealkylation, oxidative deamine and other oxidation reactions.

Reduction reaction: The reduction reaction is exemplified by (but not limited to) such as the following reactions: reduction of carbonyl functional groups, reduction of alcohol functional groups and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions.

Reactions with unchanged oxidation state: Reactions with unchanged oxidation state are exemplified by reactions such as the following (But not limited to): hydrolysis of esters and ethers, hydrolysis and cleavage of carbon-nitrogen single bonds, hydrolysis and cleavage of non-aromatic heterocycles, hydration and dehydration of multiple bonds, new atom linkages generated by dehydration reactions, hydrolysis and dehalogenation , Removal of hydrogen halide molecules and other such reactions.

A carrier prodrug is a compound that contains a transport moiety (for example, one that improves uptake and/or local delivery to the site of action). For this kind of carrier prodrug, it is hoped that the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and the prodrug and any release transport moiety are acceptable It is non-toxic. For drugs where it is desired that the transport moiety enhance uptake of the drug, the release of the transport moiety should typically be rapid. In other cases, it is necessary to use parts that provide slow release (for example, certain polymers or other parts, such as cyclodextrin). (See, for example, Cheng et al., U.S. Patent Publication No. 20040077595, Application No. 10/656,838, which are incorporated herein by reference). Such carrier prodrugs are generally advantageous for oral administration of the drug. In some cases, the transport portion provides targeted delivery of the drug, for example, the drug can be bound to an antibody or antibody fragment. The carrier prodrug can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site specificity, decreased toxicity and adverse reactions, and/or drug formulation The improvement of substances (such as stability, water solubility, inhibition of undesirable sensory or biochemical properties). For example, the lipophilicity can be increased by esterifying the hydroxyl group with a lipophilic carboxylic acid or esterifying the carboxylic acid group with an alcohol (e.g., aliphatic alcohol). Wermuth,<b>Ibid.</b>。

The metabolite (e.g., active metabolite) is consistent with the prodrug (e.g., bioprecursor prodrug) as described above. Therefore, these metabolites are pharmacologically active compounds or compounds that can be further metabolized into pharmacologically active compounds (which are derivatives produced by metabolic processes) in the individual's body. Among them, the active metabolites are these pharmacologically active derivative compounds. For prodrugs, the prodrug compound is generally inactive or has an activity lower than that of the metabolite. For active metabolites, the parent compound may be the active compound or may be an inactive prodrug. For example, in some compounds, one or more alkoxy groups can be metabolized into hydroxyl groups at the same time The pharmacological activity is retained, and/or the carboxyl group can be esterified, such as glucuronidation. In some cases, there may be more than one metabolite, where the intermediate metabolite is further metabolized to provide the active metabolite. For example, in some cases, derivative compounds produced by metabolic glucuronidation may be inactive or have low activity, and may be further metabolized to provide active metabolites.

The metabolites of compounds can be identified using conventional techniques known in the art and their activity can be determined using tests such as those described herein. See, for example, Bertolini et al., 1997,<i>J.Med.Chem</i>., 40: 2011-2016; Shan et al., 1997,<i>J Pharm Sci</i> 86(7): 756-757; Bagshawe, 1995,<i>Drug Dev.Res</i>.,34: 220-230; Wermuth,<b>Ibid.</b>。

(b)<i>Tautomers, stereoisomers and regional isomers</i>

It should be understood that some compounds may exhibit the phenomenon of tautomerism. In these cases, the formulas provided herein only clearly describe one possible tautomeric form. Therefore, it should be understood that the formula provided herein is intended to represent any tautomeric form of the described compound, and is not limited to the specific tautomeric form described by the scheme of the formula.

Likewise, some of the compounds of the present invention may exist in stereoisomeric forms, meaning that they have the same atoms connected by covalently bonded atoms, but the spatial orientation of the atoms is different. For example, the compound may be an optical stereoisomer, which contains one or more opposing centers, and therefore it may be in two or more stereoisomeric forms (e.g., enantiomers or diastereomers). Construct) exists. Therefore, these compounds can exist in the form of single stereoisomers (that is, substantially no other stereoisomers), racemates and/or enantiomers and/or mixtures of diastereomers . As another example, stereoisomers include geometric isomers, such as the cis-or anti-orientation of substituents on adjacent carbons of a double bond. It is hoped that all such single stereoisomers, racemates and mixtures thereof are within the scope of the present invention. Unless stated to the contrary, all such stereoisomeric forms are included in the formulas provided herein.

In some embodiments, the opposing compound of the present invention contains at least 80% single Conformer (60% enantiomeric excess ("ee") or diastereomeric excess ("de")) or at least 85% (70% ee or de) single isomer, 90% (80% ee) Or de) single isomer, 95% (90% ee or de) single isomer, 97.5% (95% ee or de) single isomer or 99% (98% ee or de) single isomer form. Those familiar with the technology should generally understand that an optically pure compound with a center of antipodalism is a compound that consists essentially of one of two possible enantiomers (that is, enantiomerically pure), and has Optically pure compounds with more than one antipodal center are both diastereomerically pure and enantiomerically pure compounds. In some embodiments, the compound exists in an optically pure form, which is obtained by methods known in the art (e.g., by recrystallization technology, palmar synthesis technology (including synthesis from optically pure starting materials), and Use the chromatographic separation of the palm-shaped column) to prepare and/or separate.

(c)<i>Pharmaceutically acceptable salt</i>

Unless stated to the contrary, the description of a compound herein includes a pharmaceutically acceptable salt of the compound. Therefore, the compounds described herein and listed in any one of the patent applications may be in the form of pharmaceutically acceptable salts, or may be formulated in the form of pharmaceutically acceptable salts. The pharmaceutically acceptable salt forms covered include, but are not limited to, mono-salts, double-salts, ginseng-salts, four-salts, and the like. The pharmaceutically acceptable salt is non-toxic at its dosage and concentration. By changing the physiological characteristics of the compounds without preventing them from exerting their physiological effects, the preparation of these salts can be beneficial for pharmacological uses. Applicable physical property changes include lowering the melting point to facilitate transmucosal administration, and increasing solubility to facilitate the administration of higher concentrations of drugs. The compound of the present invention can have a sufficiently acidic functional group, a sufficiently basic functional group, or two functional groups, and therefore can react with a variety of inorganic bases or organic bases and any one of inorganic and organic acids to form a pharmaceutically acceptable Of salt.

Pharmaceutically acceptable salts include acid addition salts, such as salts containing the following: chloride, bromide, iodide, hydrochloride, acetate, phenylacetate, acrylate, ascorbate, aspartate , Benzoate, 2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methyl Benzene Formate, bicarbonate, butyne-1,4-dioate, hexyne-1,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate, citrate , Decanoate, formate, fumarate, glycolate, gluconate, glucarate, glucuronate, glucose-6-phosphate, glutamate, heptamine Acid salt, caproate, isethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate, lactate, malate, maleate, hydroxymaleate Diacid salt, methyl maleate, malonate, mandelic acid, nicotinate, nitrate, isonicotinate, caprylate, oleate, oxalate, dihydroxynaphthalene Acid salt, phosphate, monohydrogen phosphate, dihydrogen phosphate, orthophosphate, metaphosphate, pyrophosphate, 2-phosphoglycerate, 3-phosphoglycerate, phthalate, propylene Salt, phenylpropionate, propiolate, pyruvate, quinate, salicylate, 4-aminosalicylate, sebacate, stearate, suberic acid Salt, succinate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, sulfamate, sulfonate, benzenesulfonate (also known as benzenesulfonate) (besylate)), ethane sulfonate (i.e. ethanesulfonate), ethane-1,2-disulfonate, 2-hydroxyethane sulfonate (i.e. isethionate), methane Sulfonate (i.e. methanesulfonate), naphthalene-1-sulfonate, naphthalene-2-sulfonate (i.e. naphthalenesulfonate), propane sulfonate, p-toluenesulfonate (i.e. toluene) Sulfonate), xylene sulfonate, cyclohexyl amine sulfonate, tartrate and trifluoroacetate. These pharmaceutically acceptable acid addition salts can be prepared using appropriate corresponding acids.

When acidic functional groups such as carboxylic acids or phenols are present, pharmaceutically acceptable salts also include base addition salts, such as salts containing the following: benzathine penicillin, chloroprocaine, choline, ethanolamine, diethanolamine , Triethanolamine, tertiary butylamine, dicyclohexylamine, ethylenediamine, N,N'-benzylethylenediamine, meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine, Procaine, aluminum, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, ammonium and monoalkylamine, dialkylamine or trialkylamine (such as diethylamine), or derivatives From the salts of amino acids such as L-histidine, L-glycine, L-lysine and L-arginine. For example, see<i>Remington's Pharmaceutical Sciences</i>, 19th edition, Mack Publishing Co., Easton, PA, Volume 2, Page 1457, 1995. These pharmaceutically acceptable base addition salts can be prepared using appropriate corresponding bases.

Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound can be dissolved in a suitable solvent such as an aqueous solution containing a suitable acid or a water-alcohol solution, and then separated by evaporating the solution. In another example, the salt can be prepared by reacting the free base with an acid in an organic solvent. If the specific compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, such as treating the free acid with a suitable inorganic or organic base.

(d)<i>Other compound forms</i>

In the case of solid reagents, those skilled in the art should understand that compounds and salts can exist in different crystal or polymorphic forms, or can be formulated into co-crystals, or can be in amorphous form, or can be any of them. Combinations (e.g., mixtures of partially crystalline, partially amorphous, or polymorphs), all of which are intended to be within the scope of the present invention and specified formulas. However, the salt system is formed by acid/base addition, that is, the free base or free acid of the related compound reacts with the corresponding addition base or acid to form an acid/base reaction to generate ionic charge interaction. The co-crystal is a neutral compound A new type of chemical substance formed between the compound makes the compound and another molecular substance in the same crystal structure.

In some cases, the compounds of the present invention are complexed with acids or bases, including base addition salts, such as salts of ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, tertiary butylamine, piperazine, and meglumine; Acid addition salts, such as acetate, acetylsalicylate, benzenesulfonate, camphorsulfonate, citrate, formate, fumarate, glutarate, hydrochloride, Maleate, methanesulfonate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate and tosylate; and amino acids such as propylamine Acid, arginine, aspartame, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine , Methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine. In the compound of the present invention In combination with an acid or base, it is preferable to form an amorphous complex and a non-crystalline substance, such as a typical salt or co-crystal. In some cases, the amorphous form of the complex is facilitated by additional processing, such as by spray drying, mechanochemical methods (such as roller compaction), or microwave irradiation of the parent compound mixed with acids or bases. These methods may also include the addition of ionic and/or non-ionic polymer systems, including (but not limited to) hydroxypropyl methylcellulose acetate succinate (HPMCAS) and methacrylic acid copolymers (such as Eudragit® L100-55) ), which further stabilizes the amorphous nature of the composite. These amorphous composites provide several advantages. For example, lowering the melting temperature relative to the free base can facilitate additional processing (such as hot melt extrusion) to further improve the biomedical properties of the compound. In addition, amorphous composites are easy to pulverize, which provides improved compression to load solids in capsule or lozenge form.

In addition, the equations are intended to cover hydrates or solvates as well as non-hydrated or non-solvated forms of the identified structures. For example, the compounds shown include hydrated and non-hydrated forms. Other examples of solvates include structures in combination with suitable solvents such as isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, or ethanolamine.

<b>IV. Formulations and administration</b>

In another aspect, the present invention provides a pharmaceutical composition comprising/including a pharmaceutically acceptable carrier, excipient and/or diluent, and the compound of the present invention described herein or its pharmaceutically Acceptable salt or solvate. In an exemplary embodiment, the present invention provides a pharmaceutical formulation comprising/comprising a compound as described herein. In some embodiments, the present invention provides a pharmaceutical composition comprising/including any of the formulas (I'), (I'a), (I), (II), (III), ( IV), (V), (V') and any sub-general formula, for example, a compound of any of the following formulas: (I'), (I'a), (I), (II), (III), (IV ), (IIIa), (IIIb), (IIIc), (IIId), (IIId), (IIIe), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIa-6), (IIIa-7), (IIIa-8), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4), (IIIb -5), (IIIc-1), (IIIc-2), (IIIc-3), (IIIc-4), (IIIc-5), (IIId-1), (IIId-2), (IIId-3 ), (IIId-4), (IIId-5), (IIIe-1), (IIIe-2), (IIIe-3), (IIIe-4), (IIIe-5), (IVa), (IVa-1), (IVa-2), (IVa-3), (IVa-4 ), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9), (IVa-10), (IVa-1a), (IVa-2a), (IVa-3a), (IVa-4a), (IVa-5a), (IVa-6a), (IVa-7a), (IVa-8a), (IVa-9a), (IVa-10a), (IVa -1b), (IVa-2b), (IVa-5b), (IVa-6b), (IVb), (IVb-1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7), (IVb-8), (IVc), (IVc-1), (IVc-2), (IVc-3), (IVc-4 ), (IVc-5), (IVd), (IVd-1), (IVd-2), (IVd-3), (IVd-4), (IVd-5), (IVe), (IVe-1 ), (IVe-2), (IVe-3), (IVe-4), (IVe-5), (Va), (Va-1), (Va-2), (Va-3), (Va -1a), (Va-2a), (Va-3a), (Va-1a-1), (Va-2a-1), (Va-1b), (Va-2b), (Va-3b), (Va-1b-1), (Va-2b-1), (Va-6), (Va-6a), (Va-6b), (Va-6c) or (Va-6d), and medicine Acceptable carriers, excipients and/or diluents.

These methods and compounds will typically be used to treat human subjects. However, it can also be used to treat similar or identical indications in other animal individuals. The compounds described herein can be administered by different routes, including injection (ie parenteral, including intravenous, intraperitoneal, subcutaneous and intramuscular), oral, transdermal, transmucosal, transrectal or inhalation administration. These dosage forms should allow the compound to reach the target cells. Other factors are well known in the art and include considerations such as toxicity and dosage forms that delay the compound or composition from exerting its effects. Technologies and formulations can generally be found in Remington:<i>The Science and Practice of Pharmacy</i>, 21st edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (hereby incorporated by reference).

In some embodiments, the composition will include pharmaceutically acceptable carriers or excipients, such as fillers, binders, disintegrants, slip agents, lubricants, complexing agents, solubilizers, and surfactants, It can be selected to facilitate the administration of the compound by a specific route. Examples of carriers include calcium carbonate, calcium phosphate, various sugars (such as lactose, glucose or sucrose), various types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles and their classes Like things. Carriers also include physiologically compatible liquids as solvents or suspensions, including, for example, sterile solutions of water for injection (WFI), physiological saline solution, dextrose solution, Hank's solution, Lin Ringer's solution, vegetable oil, mineral oil, animal oil, polyethylene glycol, liquid paraffin and the like. Excipients may also include, for example, colloidal silica, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, coarse crystalline cellulose, carboxymethyl cellulose , Croscarmellose sodium, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, stearin Sodium, syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitate, hydrogenated vegetable oil, hydrogenated cottonseed oil, castor seed Mineral oil, polyethylene glycol (e.g. PEG 4000-8000), polyoxyethylene glycol, poloxamer, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, two methacrylic acid Vinylbenzene copolymer, sodium docusate, cyclodextrin (e.g. 2-hydroxypropyl-delta-cyclodextrin), polysorbate (e.g. polysorbate 80), cetyltrimethylammonium bromide (cetrimide), TPGS (d-α-tocopherol polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ether, two fatty acid esters of polyethylene glycol, or Polyoxyalkylene sorbitan fatty acid ester (e.g. polyoxyethylene sorbitan ester Tween^®), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters (for example, sorbitan fatty acid esters from fatty acids such as oleic acid, stearic acid or palmitic acid), mannitol, wood Sugar alcohol, sorbitol, maltose, lactose, lactose monohydrate or spray-dried lactose, sucrose, fructose, calcium phosphate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, glucose binder (dextrate), polydextrose (dextran) , Dextrin, dextrose, cellulose acetate, maltodextrin, polydimethylsiloxane, polydextrose, chitosan, gelatin, HPMC (hydroxypropyl methylcellulose), HPC ( Hydroxypropyl cellulose), hydroxyethyl cellulose and the like.

The pharmaceutical formulation may contain a unit dose of a predetermined amount of active ingredient per unit dose Form submission. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of the compound of the present invention (in any form of free base, solvent, depending on the condition being treated, the route of administration, and the age, weight and condition of the patient). Hydrates (including hydrates or salt forms). A preferred unit dose formulation is a formulation containing a daily dose, a weekly dose, a monthly dose, a sub-dose or an appropriate part of the active ingredient. In addition, the pharmaceutical formulations can be prepared by any method well known in the pharmaceutical technology.

The pharmaceutical formulation may be suitable for administration by any appropriate route, such as by oral administration (including capsules, lozenges, liquid-filled capsules, disintegrating lozenges, immediate, delayed and controlled release lozenges, oral sticks, Solution, syrup, intrabuccal and sublingual), rectal, nasal, inhalation, topical (including transdermal), transvaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. These formulations can be prepared by any method known in the pharmaceutical technology (for example, by associating the active ingredient with a carrier, excipient, or diluent). Generally speaking, the carrier, excipient or diluent used in the pharmaceutical formulation is "non-toxic" means that it is considered safe for consumption in the amount delivered in the pharmaceutical composition, and "inert" means It does not appreciably react with the active ingredient or produce undesirable effects on the therapeutic activity of the active ingredient.

In some embodiments, oral administration may be used. Pharmaceutical preparations for oral use can be formulated into conventional oral dosage forms such as discrete unit capsules, lozenges and liquid preparations such as syrups, elixirs and concentrated drops. The compounds described herein can be combined with solid excipients, and the resulting mixture can be ground as appropriate, and if necessary, the mixture of particles can be processed after adding suitable auxiliaries to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, and solutions. (For example, aqueous solution, alcohol solution or oily solution) and the like. Suitable excipients are especially fillers, such as sugars, including lactose, glucose, sucrose, mannitol or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, Methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose (CMC) and/or polyvinylpyrrolidone (PVP: povidone); oily excipients, including vegetable oils and animal oils, such as Sunflower oil, olive oil or cod liver oil. Oral dosage formulations may also contain disintegrants, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (such as sodium alginate); lubricants, such as talc or magnesium stearate; plasticizers, such as Glycerin or sorbitol; sweeteners, such as sucrose, fructose, lactose or aspartame; natural or synthetic flavors, such as peppermint, wintergreen oil or cherry flavors; or dyes or pigments, which can be used for identification or Characterize different doses or combinations, such as unit doses. Sugar-coated pill core with suitable coating is also provided. For this purpose, a concentrated sugar solution can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solution, and Suitable for organic solvents or solvent mixtures. Oral liquids such as solutions, syrups, and elixirs can be prepared in a unit dosage form so as to contain a predetermined amount of the compound in a predetermined amount.

Pharmaceutical preparations that can be used orally include insertable capsules made of gelatin ("capsules"), and soft and sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The inserted capsules may contain active ingredients mixed with fillers such as lactose, binders such as starch, and/or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.

In some embodiments, injection (parenteral administration) may be used, such as intramuscular, intravenous, intraperitoneal, and/or subcutaneous injection. The compound for injection described herein can be formulated in a sterile liquid solution, preferably in a physiologically compatible buffer or solution, such as physiological saline solution, Hank's solution or Ringer's solution. Dispersions can also be prepared in non-aqueous solutions such as glycerin, propylene glycol, ethanol, liquid polyethylene glycol, triacetin and vegetable oils. The solution may also contain preservatives such as methyl paraben, propyl paraben, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In addition, the compound can be formulated into a solid form, including, for example, a lyophilized form, and redissolved or suspended immediately before use. The formulation can be presented in unit-dose or multi-dose containers (such as sealed ampoules and vials), and can be stored under freeze-drying (lyophilization) conditions, just before use A sterile liquid carrier (e.g. water for injection) is added immediately.

In some embodiments, transmucosal, topical, or transdermal administration may be used. In the compound formulations described herein, penetrants suitable for the barrier to be penetrated are used. Such penetrants are generally known in the art, and for transmucosal administration, include, for example, bile salts and fusidic acid derivatives. In addition, detergents can be used to promote penetration. For example, transmucosal administration can be via a nasal spray or suppository (rectal or vaginal). The composition described herein for topical administration of the compound can be formulated into oils, creams, lotions, ointments, and the like by selecting appropriate carriers known in the art. Suitable carriers include vegetable oil or mineral oil, white petrolatum (white soft paraffin), branched chain fat or oil, animal fat and high molecular weight alcohol (C₁₂above). In some embodiments, the carrier is selected so that the active ingredient is soluble. It may also include emulsifiers, stabilizers, moisturizers, and antioxidants, and, if necessary, agents that impart color or fragrance. Creams for topical application are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water, in which the active ingredients dissolved in a small amount of solvent (such as oil) are mixed. In addition, administration by a transdermal method may include a transdermal patch or dressing, such as a bandage impregnated with active ingredients and optionally one or more carriers or diluents known in the art. To be administered in the form of a transdermal delivery system, the dosage administration will be continuous rather than intermittent during the entire dosing regimen.

In some embodiments, the compound is administered as an inhalant. The compounds described herein can be formulated into dry powders or suitable solutions, suspensions or aerosols. Powders and solutions can be formulated with suitable additives known in the art. For example, the powder may include a suitable powder base (such as lactose or starch) and the solution may include propylene glycol, sterile water, ethanol, sodium chloride, and other additives (such as acids, bases, and buffer salts). These solutions or suspensions can be administered by inhalation through sprays, pumps, atomizers or nebulizers and the like. The compounds described herein can also be used in combination with other inhalation therapies, such as corticosteroids, such as fluticasone proprionate, beclomethasone dipropionate, triamcinolone acetonide (triamcinolone acetonide), budesonide and mometasone furoate; beta agonists such as albuterol, salmeterol and formoterol; anti Cholinergic agents such as ipratroprium bromide or tiotropium; vasodilators such as treprostinal and iloprost; enzymes such as DNase; therapeutic Proteins; immunoglobulin antibodies; oligonucleotides, such as single- or double-stranded DNA or RNA, siRNA; antibiotics, such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cells Hormone antagonists; protease inhibitors; cromolyn sodium; nedocril sodium; and sodium cromoglycate.

The amount of various compounds to be administered can be determined by standard procedures, taking into account factors such as the following: compound activity (in vitro, for example, the IC of the compound against the target₅₀, Or in vivo activity in an animal efficacy model), pharmacokinetic results in an animal model (such as biological half-life or bioavailability), the age, size and weight of the individual, and the disease associated with the individual. The importance of these and other factors is well known to those skilled in the art. Generally, the dosage will be in the range of about 0.01 to 50 mg/kg, and also about 0.1 to 20 mg/kg of the individual being treated. Multiple doses can be used.

The compounds described herein can also be used in combination with other therapies used to treat the same diseases. The combined use includes administering the compound and one or more other therapeutic agents at different times, or co-administering the compound and one or more other therapies. In some embodiments, the dosage of one or more of the compounds of the present invention or other therapeutic agents used in the combination can be modified by methods well known to those skilled in the art, such as reducing the dosage relative to the compound or therapy alone.

It should be understood that combined use includes use with other therapies, drugs, medical procedures, etc., wherein another therapy or procedure can be compared to the compound described herein at a different time (for example, in a short period of time, such as in a few hours). (E.g. 1, 2, 3, 4-24 hours), or Administer over a longer period of time (e.g., 1-2 days, 2-4 days, 4-7 days, 1-4 weeks), or at the same time as the compounds described herein. Combination use also includes use with one-time or occasional administration of therapies or medical procedures (such as surgery) in which the compounds described herein are administered for a short or longer time before or after another therapy or procedure. In some embodiments, the present invention provides the delivery of the compounds described herein and one or more other pharmaceutical therapeutics by different routes of administration or by the same route of administration. The combined use for any route of administration includes the delivery of the compound described herein and one or more other pharmaceutical therapeutics together in any formulation by the same route of administration, the formulation including the two compounds to maintain at the time of administration Its therapeutic activity is a chemically linked formulation. In one aspect, another drug therapy can be co-administered with the compounds described herein. Co-formulations or formulations of chemically bonded compounds are used in combination by co-administration, or separately formulated within a short period of time (for example, within 1 hour, 2 hours, 3 hours, or at most 24 hours) of each other The substance is administered with two or more compounds, and these compounds are administered by the same or different routes. Co-administration of individual formulations includes co-administration by delivery via one device (for example, the same inhalation device, the same syringe, etc.), or administration from separate devices within a short period of time. Co-formulations of the compounds described herein and one or more other drug therapies delivered by the same route include preparations of substances in common so that they can be administered by a device, including individual compounds combined into a formulation, Or a compound that has been modified to chemically bond but still retains biological activity. The chemically joined compounds may have a linkage that is substantially maintained in the living body, or the linkage may be broken down in the living body to separate the two active components.

<b>V. Disease indications and regulation of c-kit kinase</b>

<i>Exemplary diseases related to c-Kit or mutant forms of c-Kit</i>

Compounds of formula (I'), (I'a), (I), (II), (III), (IV), (V), (V') or any sub-formula and as described herein The compounds are suitable for the treatment of c-kit-related diseases, such as diseases related to unregulated kinase signal transduction, especially including cell proliferation disorders, fibrotic disorders and metabolic disorders. Lipson, as below and incorporated in this article by reference in its entirety As described in more detail in US20040002534 (US application 10/600,868 filed on June 23, 2003), cell proliferation disorders that can be treated by the present invention include cancer and mast cell proliferation disorders.

As described below, the presence of c-kit or mutant c-kit is also associated with many different types of cancers, diseases and conditions. In addition, the correlation between c-kit abnormalities and diseases is not limited to cancer. Therefore, c-kit is related to the following: malignant diseases, including mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GIST), metastatic GIST, glioblastoma, astrocytoma, neuroblastoma , Female reproductive tract cancer, neuroectodermal sarcoma, colorectal cancer, carcinoma in situ, Schwann cell tumor formation associated with neurofibromatosis, acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic bone marrow Leukemia, mastocytosis, melanoma and canine mast cell tumors; and inflammatory diseases, including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel disease, transplant rejection, eosinophilia Red blood cells, pigmented urticaria (UP), persistent eruptive patchy telangiectasia (telangiectasia macularis eruptiva) perstans, TMEP), systemic mastocytosis, indolent systemic mastocytosis, mild systemic mastocytosis, aggressive systemic mastocytosis, mast cell leukemia and mast cell sarcoma. The existence of mutant forms of c-kit is associated with diseases or conditions such as gastrointestinal stromal tumors (GIST), mast cell leukemia, germ cell tumors, t-cell lymphomas, mastocytosis, acute lymphocytic leukemia, and spermatozoa Cell tumor.

<i>Exemplary malignant diseases related to c-kit</i>

Abnormal manifestations and/or activation of c-kit and/or c-kit mutant forms have been implicated in a variety of cancers (Roskoski, 2005, Biochemical and biophysical Research Comm. 338: 1307-1315). Evidence that c-kit is involved in neoplastic pathology includes its association with leukemia and mast cell tumors, small cell lung cancer, testicular cancer, and some cancers of the gastrointestinal tract and central nervous system. In addition, c-kit has been involved in the following: in female reproductive tract carcinogenesis (Inoue et al., 1994, Cancer Res. 54(11): 3049-3053), sarcoma of neuroectodermal origin (Ricotti et al., 1998, Blood 91: 2397-2405) and Schwann cell tumor formation associated with neurofibromas (Ryan et al., 1994, J. Neuro. Res. 37: 415-432). It was found that mast cells are involved in improving the tumor microenvironment and enhancing tumor growth (Yang et al., 2003, J Clin Invest. 112: 1851-1861; Viskochil, 2003, J Clin Invest. 112: 1791-1793). Therefore, c-kit is an applicable target for the treatment of neurofibromas and malignant tumors.

Small cell lung cancer: The c-kit kinase receptor has been found to be abnormally expressed in many cases of small cell lung cancer (SCLC) cells (Hibi et al., 1991, Oncogene 6:2291-2296). Therefore, as an example, inhibition of c-kit kinase can be beneficial in the treatment of SCLC, such as improving the long-term survival of patients with SCLC.

Leukemia: SCF binds to c-kit to protect hematopoietic stem and progenitor cells from apoptosis (Lee et al., 1997, J. Immunol. 159: 3211-3219), thereby promoting colony formation and hematopoiesis. The performance of c-kit is often observed in acute myeloid leukemia (AML) and in some cases of acute lymphocytic leukemia (ALL) (for a review, see Sperling et al., 1997, Haemat 82: 617-621; Escribano et al., 1998, Leuk. Lymph. 30:459-466). Although c-kit is present in most AML cells, its performance does not appear to be a prognosis of disease progression (Sperling et al., 1997, Haemat 82:617-621). However, SCF protects AML cells from apoptosis induced by chemotherapeutics (Hassan et al., 1996, Acta. Hem. 95:257-262). The inhibition of c-kit by the present invention will enhance the efficacy of these agents and induce apoptosis of AML cells.

Discovery of cells from patients suffering from myelodysplastic syndrome (Sawada et al., 1996, Blood 88: 319-327) or chronic myelogenous leukemia (CML) (Sawai et al., 1996, Exp. Hem. 2: 116-122) The pure line growth is significantly enhanced by the combination of SCF and other cytokines. CML is characterized by the expansion of Philadelphia chromosome positive cells in the bone marrow (Verfaillie et al., Leuk. 1998, 12: 136-138), which seems to be mainly produced by the inhibition of apoptosis and death (Jones, Curr. Opin) .Onc. 1997, 9: 3-7). P210, a product of the Philadelphia chromosome, has been reported^BCR-ABLCan mediate the inhibition of apoptosis (Bedi et al., Blood 1995, 86: 1148-1158). Because of p210^BCR-ABLAnd c-kit both inhibit cell apoptosis and p62 has been suggested^dokAs a substrate (Carpino et al., Cell 1997, 88: 197-204), the clonal amplification mediated by such kinases can occur through common signal transduction pathways. However, it has also been reported that c-kit and p210^BCR-ABLDirect interaction (Hallek et al., Brit. J Haem. 1996, 94: 5-16), which indicates that c-kit has a causally greater role in CML pathology. Therefore, the inhibition of c-kit will be suitable for the treatment of the above diseases.

Gastrointestinal cancer: normal colorectal mucosa does not show c-kit (Bellone et al., 1997, J. Cell Physiol. 172:1-11). However, c-kit is often expressed in colorectal cancer (Bellone et al., 1997, J. Cell Physiol. 172:1-11), and the autocrine loops of SCF and c-kit have been observed in several colon cancer cell lines To (Toyota et al., 1993, Turn Biol 14: 295-302; Lahm et al., 1995, Cell Growth &amp; Differ 6: 1111-1118; Bellone et al., 1997, J. Cell Physiol. 172: 1-11). In addition, the use of neutralizing antibodies (Lahm et al., 1995, Cell Growth &amp; Differ. 6: 1111-1118) and down-regulation of c-kit and/or SCF to disrupt the autocrine loop significantly inhibited cell proliferation (Lahm et al., 1995 , Cell Growth &amp; Differ 6: 1111-1118; Bellone et al., 1997, J. Cell Physiol. 172: 1-11).

The SCF/c-kit autocrine loop has been observed in gastric cancer cell lines (Turner et al., 1992, Blood 80: 374-381; Hassan et al., 1998, Digest. Dis. Science 43: 8-14), and it consists of Sexual c-kit activation also appears to be important for gastrointestinal stromal tumors (GIST). GIST is the most common mesenchymal tumor of the digestive system. More than 90% of GISTs express c-kit, which is consistent with the presumed source that these tumor cells are derived from Cajal interstitial cells (ICC) (Hirota et al., 1998, Science 279:577-580). It is believed that ICC regulates the contraction of the gastrointestinal tract, and patients who lack c-kit in their ICC exhibit chronic idiopathic intestinal pseudo-obstruction in the form of myopathy (Isozaki et al., 1997, Amer. J. of Gast. 9 332-334 ). It has been observed that c-kit, which is present in GIST in several different patients, has mutations in the intracellular membrane domain, leading to constitutive activation of c-kit (Hirota et al., 1998, Science 279:577-580). Therefore, inhibition of c-kit kinase will be an effective method for the treatment of these cancers.

Overexpression or constitutive activation of Kit mutations has been involved in gastrointestinal stromal tumors (GIST), and most GISTs contain oncogenic KIT receptor or PDGFRA receptor tyrosine kinase mutations (Miettinen et al., 2006, Arch Pathol Lab Med, 130: 14661478; Fletcher et al., 2007, Current Opinion in Genetics &amp; Development, 17: 3-7; and Frost et al. 2002, Molecular Cancer Therapeutics, 1: 1115-1124). Frost et al., 2002 have shown that the D816V KIT mutation is resistant to imatinib, making other types of c-kit inhibitors applicable. Many GISTs have activating mutations in the proximal membrane region of KIT (Lux et al., 2000, American Journal Pathology, 156:795). The constitutive activation of Kit receptor tyrosine kinase is the central pathological event in most GISTs and is generally produced by oncogenic point mutations (Heinrich et al. 2002, Human Pathology, 33: 484-495). Inhibition of wild-type KIT and/or certain mutant KIT isoforms with small molecule tyrosine kinase inhibitors has become the standard of care for patients with metastatic GIST (Schittenhelm et al. 2006, Cancer Res., 66:473 -481). Therefore, inhibition of c-kit kinase and/or mutant c-kit kinase will be an effective method for the treatment of GIST.

Testicular cancer: Male germ cell tumors have been histologically classified as seminoma, which maintains germ cell characteristics; and non-seminoma, which shows embryonic differentiation characteristics. It is believed that both seminoma and non-seminoma start from the pre-spreading stage named as carcinoma in situ (CIS) (Murty et al., 1998, Sem. Oncol. 25: 133-144). Both c-kit and SCF have been reported to be essential for normal gonadal development during embryogenesis (Loveland et al., 1997, J. Endocrinol 153:337-344). The loss of either receptor or ligand results in the animal without germ cells. In postnatal testes, c-kit has been found to be expressed in Leydig cells and spermatogonia, while SCF is expressed in podocytes (Loveland et al., 1997, J. Endocrinol 153:337-344). Testicular tumors are often produced by Leyte cells in transgenic mice expressing human papillomavirus 16 (HPV16) E6 and E7 oncogenes (Kondoh et al., 1991, J. Virol. 65: 3335-3339; Kondoh et al. Human, 1994, J. Urol. 152: 2151-2154). These tumors express both c-kit and SCF, and the autocrine loop can promote and function p53 cells Loss of related tumor formation (Kondoh et al., 1995, Oncogene 10:341-347) and retinoblastoma gene products obtained by association with E6 and E7 (Dyson et al., 1989, Science 243:934-937; Werness et al., 1990, Science 248: 76-79; Scheffner et al., 1990, Cell 63: 1129-1136). SCF (Kondoh et al., 1995, Oncogene 10:341-347) or c-kit (Li et al., 1996, Canc. The formation of testicular tumors in rats. The activation of c-kit kinase will be critical for tumor formation in these animals, and therefore modulation of the c-kit kinase pathway by the present invention will prevent or treat these disorders.

The expression of c-kit in germ cell tumors shows that the receptor is expressed by most carcinomas in situ and seminoma, but c-kit is only expressed in a few non-seminomas (Strohmeyer et al., 1991, Canc. Res. 51: 1811-1816; Rajpert-de Meyts et al., 1994, Int. J. Androl. 17: 85-92; Izquierdo et al., 1995, J. Pathol. 177: 253-258; Strohmeyer et al., 1995 , J. Urol. 153: 511-515; Bokenmeyer et al., 1996, J. Cancer Res. Clin. Oncol. 122: 301-306; Sandlow et al., 1996, J. Androl. 17: 403-408). Therefore, inhibition of c-kit kinase provides a way to treat these conditions.

CNS cancer: SCF and c-kit are expressed throughout the CNS of developing rodents, and the expression pattern indicates their role in the growth, migration and differentiation of neuroectodermal cells. The performance of receptors and ligands have also been reported in the adult brain (Hamel et al., 1997, J. Neuro-Onc. 35:327-333). The performance of c-kit has also been observed in normal human brain tissue (Tada et al., 1994, J. Neuro 80: 1063-1073). Glioblastoma and astrocytoma, which define most intracranial tumors, arise from the neoplastic transformation of astrocytes (Levin et al., 1997, Principles &amp; Practice of Oncology: 2022-2082). The performance of c-kit has been observed in glioblastoma cell lines and tissues (Berdel et al., 1992, Canc. Res. 52: 3498-3502; Tada et al., 1994, J. Neuro 80: 1063-1073 ; Stanulla et al., 1995, Act Neuropath 89:158-165).

Cohen et al., 1994, Blood 84: 3465-3472 reported that all 14 neuroblastoma cell lines examined contained the c-kit/SCF autocrine loop, and the performance of receptors and ligands were all in the examined ones. Observed in 45% of tumor samples. In both cell lines, anti-c-kit antibodies inhibited cell proliferation, indicating that the SCF/c-kit autocrine loop promotes growth (will Cohen et al., 1994, Blood 84: 3465-3472). Therefore, c-kit kinase inhibitors can be used to treat these cancers.

<i>Exemplary mast cell disease involving c-kit</i>

Excessive activation of c-kit is also related to diseases caused by excessive mast cells. Mastocytosis is a term used to describe a heterogeneous population of disorders characterized by excessive mast cell proliferation (Metcalfe, 1991, J. Invest. Derm 93: 2S-4S; Golkar et al., 1997, Lancet 349: 1379-1385) . Increased c-kit performance has been reported on mast cells of patients with aggressive mastocytosis (Nagata et al., 1998, Leukemia 12: 175-181).

In addition, mast cells and eosinophils represent key cells involved in allergy, inflammation and asthma (Thomas et al., 1996, Gen. Pharmacol 27:593-597; Metcalfe et al., 1997, Physiol Rev 77:1033-1079 ; Naclerio et al., 1997, JAMA 278:1842-1848; Costa et al., 1997, JAMA 278:1815-1822). SCF and thus c-kit directly and indirectly regulate the activation of both mast cells and eosinophils, thereby affecting the primary cells involved in allergies and asthma through a variety of mechanisms. Because of the mutual regulation of mast cell and eosinophil function and the role that SCF can play in this regulation, the inhibition of c-kit can be used to treat chronic rhinitis, inflammation, and asthma related to allergies.

Mastocytosis: It has been reported that c-kit's SCF (also known as mast cell growth factor) stimulation is essential for the growth and development of mast cells (Hamel et al., 1997, J. Neuro-Onc. 35:327-333 ; Kitamura et al., 1995, Int. Arch. Aller. Immunol. 107: 54-56). Mice with c-kit mutations that attenuate their signal transduction activity exhibit significantly fewer mast cells in their skin (Tsujimura, 1996, Pathol Int 46:933-938). Excessive activation of c-kit may be related to diseases caused by excessive mast cells.

Mastocytosis is limited to the skin of most patients, but other organs can be involved in 15-20% of patients (Valent, 1996, Wein/Klin Wochenschr 108: 385-397; Golkar et al., 1997, Lancet 349: 1379- 1385). Even in patients with systemic mastocytosis, the disease can range from relatively benign prognosis to aggressive mastocytosis and mast cell leukemia. (Valent, 1996, Wein/Klin Wochenschr 108: 385-397; Golkar et al., 1997, Lancet 349: 1379-1385). c-kit has been found on malignant mast cells derived from canine mast cell tumors (London et al., 1996, J. Compar. Pathol. 115: 399-414) and in patients with aggressive systemic mastocytosis Observed on mast cells (Baghestanian et al., 1996, Leuk.: 116-122; Castells et al., 1996, J. Aller. Clin. Immunol. 98: 831-840).

SCF has been shown to be expressed on stromal cells in the form of membrane-bound proteins, and its expression can be induced by fibrogenic growth factors such as PDGF. It has also been shown to be expressed on keratinocytes of normal skin in the form of membrane-bound protein. However, in the skin of patients with mastocytosis, increased amounts of soluble SCF have been observed (Longley et al., 1993, New Engl. J. Med. 328: 1302-1307).

It has been reported that mast cell chymosin can cleave membrane-associated SCF into a soluble and biologically active form. This mast cell-mediated process can generate a feedback loop to enhance the proliferation and function of mast cells (Longley et al., 1997, Proc. Natl. Acad. Sci. 94: 9017-9021), and it is also related to the etiology of mastocytosis. Words can be important. Transgenic mice that overexpress the form of SCF that cannot be proteolytically released from keratinocytes do not suffer from mastocytosis, while similar animals that exhibit normal SCF in keratinocytes exhibit a form similar to human skin mastocytosis Phenotype (Kunisada et al., 1998, J. Exp. Med. 187: 1565-1573). The formation of large amounts of soluble SCF can promote pathologies associated with mastocytosis in some patients, and the present invention can treat or prevent these conditions by regulating the interaction between SCF and c-kit kinase. Several different mutations of c-kit that produce constitutive kinase activity have been found in human and rodent mast cell tumor cell lines (Furitsu et al., 1993, J. Clin. Invest. 92: 1736-1744; Tsujimura et al., 1994, Blood 9: 2619-2626; Tsujimura et al., 1995, Int. Arch. Aller. Immunol 106: 377-385; Tsujimura, 1996, Pathol Int 46: 933- 938). In addition, activating mutations of the c-kit gene have been found in peripheral monocytes isolated from patients with mastocytosis and related hematological disorders (Nagata et al., 1998, Mastocytosis Leuk 12: 175-181) and from Observed in mast cells of patients with pigmented urticaria and aggressive mastocytosis (Longley et al., 1996, Nat. Gen, 12:312-314). Therefore, inhibition of c-kit kinase will prove to have an excellent therapeutic effect for the treatment of these diseases.

In some patients, activating mutations of c-kit can cause the pathogen of the disease, and the interaction between SCF and c-kit kinase can be adjusted to treat these patients or prevent their diseases. SCF activation of c-kit has been shown to prevent mast cell apoptosis, which may be critical for maintaining skin mast cell stability (Iemura et al., 1994, Amer. J. Pathol 144:321-328; Yee et al., 1994, J. Exp. Med. 179: 1777-1787; Mekori et al., 1994, J. Immunol 153: 2194-2203; Mekori et al., 1995, Int. Arch. Allergy Immunol. 107: 137-138). Inhibition of mast cell apoptosis can lead to the accumulation of mast cells associated with mastocytosis. Therefore, observations of c-kit activation caused by overexpression of the receptor, over-formation of soluble SCF, or mutations in the c-kit gene that constitutively activate its kinase provide the following basic principles. Inhibiting the kinase activity of c-kit will reduce mast cells Number and provide benefits to patients with mastocytosis.

For cells with activating c-kit mutations, inhibitors of c-kit have been found to inhibit or even lethal cells (Ma et al., 2000, J Invest Dermatol. 114:392-394), especially with regard to mutations in regulatory regions This is the case (Ma et al., 2002, Blood 99: 1741-1744). Ma et al., 2002 also showed that in terms of mutations in the catalytic region, inhibitors STI571 (Gleevec) and SU9529 do not inhibit cells, making other types of c-kit inhibitors applicable. Therefore, c-kit inhibitors against both wild-type c-kit and c-kit with mutations, such as activating mutations, in the regulatory region and/or the catalytic region can be used.

It has been shown that mastocytosis is characterized by a pathological increase of mast cells in tissues associated with KIT mutations (Metcalfe, 2008, Blood, 112:946-956; and Ma et al., 2002). The D816 mutation of c-kit has been detected in patients with mastocytosis (Taylor et al., 2001, Blood, 98: 1195-1199; and Longley et al. 1999, Proc. Natl. Acad. Sci. 96: 1609-14). Inhibition of KIT oncogenic protein KIT with small molecule tyrosine kinase inhibitor^D816VIt can treat patients suffering from systemic mastocytosis (Shah et al., 2006, Blood, 108:286-291). Therefore, c-kit inhibitors can be used to treat patients with mastocytosis.

Asthma and allergies: Mast cells and eosinophils represent key cells in parasitic infections, allergies, inflammation and asthma (Thomas et al., 1996, Gen. Pharmacol 27:593-597; Metcalfe et al., 1997, Physiol Rev 77: 1033-1079; Holgate, 1997, CIBA Found. Symp.; Naclerio et al., 1997, JAMA 278: 1842-1848; Costa et al., 1997, JAMA 778: 1815-1822). SCF has been shown to be essential for mast cell development, survival and growth (Kitamura et al., 1995, Int. Arch. Aller. Immunol. 107: 54-56; Metcalfe et al., 1997, Physiol Rev 77: 1033-1079). In addition, SCF cooperates with the eosinophil-specific regulator IL-5 to increase the development of eosinophil progenitor cells (Metcalf et al., 1998, Proc. Natl. Acad. Sci., USA 95: 6408-6412). It has also been reported that SCF can induce the secretion of factors from mast cells (Okayama et al., 1997, Int.Arch.Aller.Immunol.114:75-77; Okayama et al., 1998, Eur.J.Immunol.28:708-715), It promotes the survival of eosinophils (Kay et al., 1997, Int. Arch. Aller. Immunol. 113: 196-199), and it promotes chronic eosinophil-mediated inflammation (Okayama et al., 1997, Int. Arch. Aller. Immunol. 114: 75-77; Okayama et al., 1998, Eur. J. Immunol. 28: 708-715). In this regard, SCF directly and indirectly regulates the activation of both mast cells and eosinophils.

SCF induces the release of mediators from mast cells, and activates IgE-induced degranulation of these cells (Columbo et al., 1992, J. Immunol 149:599-602) and sensitizes them to eosinophils The granule derived from sex granulocytes mainly reacts with basic proteins (Furuta et al., 1998, Blood 92: 1055-1061). Among the factors released by activated mast cells are IL-5, GM-CSF and TNF-α, which affect eosinophil protein secretion (Okayama et al., 1997, Int.Arch.Aller.Immunol.114:75- 77; Okayama et al., 1998, Eur. J. Immunol. 28:708-715). In addition to inducing the release of histamine from mast cells (Luckacs et al., 1996, J. Immunol. 156: 3945-3951; Hogaboam et al., 1998, J. Immunol. 160: 6166-6171), SCF promotes eosinophils Mast cell production of eosinophil chemotactic factor (eosinophil chemotactic factor, eotaxin) (Hogaboam et al., 1998, J. Immunol. 160: 6166-6171) and eosinophil infiltration (Luckacs et al., 1996, J. Immunol. 156) : 3945-3951).

SCF also directly affects mast cells (Dastych et al., 1994, J. Immunol. 152:213-219; Kinashi et al., 1994, Blood 83:1033-1038) and eosinophils (Yuan et al., 1997, J. Exp. Med. 186: 313-323) the adhesion between the two, which in turn regulates tissue infiltration. Therefore, SCF can affect the primary cells involved in allergies and asthma through a variety of mechanisms. Currently, corticosteroids are the most effective treatment for chronic rhinitis and inflammation associated with allergies (Naclerio et al., 1997, JAMA 278: 1842-1848; Meltzer, 1997, Aller. 52: 33-40). These agents act through a variety of mechanisms, including reducing circulation and infiltration of mast cells and eosinophils, and impairing the survival of eosinophils associated with the inhibition of cytokine production (Meltzer, 1997, Aller. 52: 33-40 ). It has also been reported that steroids can inhibit the performance of SCF by fibroblasts and resident connective tissue cells, which leads to impaired survival of mast cells (Finotto et al., 1997, J. Clin. Invest. 99 1721-1728). Due to the mutual regulation of mast cell and eosinophil function and the role that SCF can play in this regulation, the inhibition of c-kit kinase will provide a method for the treatment of chronic rhinitis, inflammation and asthma associated with allergies.

Inflammatory arthritis (such as rheumatoid arthritis): Since mast cells are related to the arthritis process (Lee et al., 2002, Science 297:1689-1692), c-kit provides prevention, Suitable targets for delaying and/or treating inflammatory arthritis (such as rheumatoid arthritis).

Multiple sclerosis: As demonstrated in mouse models of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), it has been shown that mast cells play a broad role in autoimmune diseases. Indicating mast cells are needed for the full manifestation of the disease. Secor et al., 2000, J Exp Med 191:813-821. Therefore, c-kit also provides suitable targets for the prevention, delay and/or treatment of multiple sclerosis.

<i>Kinase activity analysis</i>

Many different kinase activity assays can be used to analyze activity modifiers and/or determine the specificity of modulators for a particular kinase or group of kinases. In addition to the analysis mentioned in the examples below, the average technician will understand other analyses that can be used and can modify the analysis for specific applications. For example, many papers on kinases describe the analysis that can be used.

In certain embodiments, the compound of formula (I'), (I'a), (I), (II), (III), (IV), (V) or (V') or any sub-formula Or the compound as disclosed herein is active in the assay to measure the activity of c-kit and/or mutant c-kit protein kinase. In some embodiments, as determined in the generally recognized c-kit and/or mutant c-kit kinase activity analysis, the compound of formula (I), (II) or any sub-formula or as described herein Compound IC₅₀Less than 10,000nM, 1,000nM, less than 500nM, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM, or less than 1nM. In some embodiments, as in generally recognized mutant c-kit kinases (such as D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del 550 -558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C And T670I) as determined in the activity analysis, as the IC of the compound described herein₅₀Less than 10,000nM, 1,000nM, less than 500nM, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM, or less than 1nM. In some embodiments, it is used to measure c-kit excitation Enzyme activity and/or mutant c-kit kinase (such as D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del 550-558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C and T670I) activity analysis Including analyses such as those described in Example 17 (e.g., biochemical or cell-based analysis) or analyses similar to those described in Example 17 well known in the art.

In some embodiments, the formula (I'), (I'a), (I), (II), (III), (IV), (V) or (V') or any of the formulae as described herein A compound of a sub-formula or a compound as described herein is active in an assay to measure the activity of c-kit protein kinase and/or an assay to measure mutant c-kit (such as D816V and/or V560G). In some embodiments, as determined in a generally accepted c-kit kinase activity analysis (including mutant c-kit kinase activity analysis), the IC of the compound described herein₅₀Less than 10,000nM, 1,000nM, less than 500nM, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM, or less than 1nM. In some embodiments, in the D816V and/or V560G mutant c-kit activity analysis, the IC of the compound described herein is₅₀Less than 100nM, less than 10nM or less than 1nM.

<i>Regulate c-kit kinase</i>

In another aspect, the present invention provides a method for modulating or inhibiting c-kit and/or mutant c-kit kinase. The method includes administering to the individual an effective amount of any of the formulas (I'), (I'a), (I), (II), (III), (IV), (V), ( V') and any sub-general formula, for example, any compound of the following formula: (I'), (I'a), (I), (II), (III), (IV), (V0, (V') ), (IIIa), (IIIb), (IIIc), (IIId), (IIId), (IIIe), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIa-6), (IIIa-7), (IIIa-8), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4), (IIIb -5), (IIIc-1), (IIIc-2), (IIIc-3), (IIIc-4), (IIIc-5), (IIId-1), (IIId-2), (IIId-3 ), (IIId-4), (IIId-5), (IIIe- 1), (IIIe-2), (IIIe-3), (IIIe-4), (IIIe-5), (IVa), (IVa-1), (IVa-2), (IVa-3), ( IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9), (IVa-10), (IVa-1a), (IVa- 2a), (IVa-3a), (IVa-4a), (IVa-5a), (IVa-6a), (IVa-7a), (IVa-8a), (IVa-9a), (IVa-10a) , (IVa-1b), (IVa-2b), (IVa-5b), (IVa-6b), (IVb), (IVb-1), (IVb-2), (IVb-3), (IVb- 4), (IVb-5), (IVb-6), (IVb-7), (IVb-8), (IVc), (IVc-1), (IVc-2), (IVc-3), ( IVc-4), (IVc-5), (IVd), (IVd-1), (IVd-2), (IVd-3), (IVd-4), (IVd-5), (IVe), ( IVe-1), (IVe-2), (IVe-3), (IVe-4), (IVe-5), (Va), (Va-1), (Va-2), (Va-3) , (Va-1a), (Va-2a), (Va-3a), (Va-1a-1), (Va-2a-1), (Va-1b), (Va-2b), (Va- 3b), (Va-1b-1), (Va-2b-1), (Va-6), (Va-6a), (Va-6b), (Va-6c) or (Va-6d), or The compounds described in Table 1, Table 2 or Table 3, or P-2001 to P-2273 and P-2274 to P-2307, or the compound as described herein, or a pharmaceutically acceptable salt thereof , Hydrate, solvate, tautomer or isomer, or a composition comprising a compound of any formula as described herein, thereby modulating or inhibiting c-kit and/or mutant c-kit kinase. In some embodiments, c-kit is wild-type kit kinase. In other embodiments, the c-kit kinase is a mutant kit kinase with a mutation selected from: D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del 550-558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C and T670I. In one embodiment, the mutant c-kit has an activating D816V and/or V560G mutation. In some embodiments, the method includes combining the cells with the formula (I'), (I'a), (I), (II), (III), (IV) as described herein in vivo or in vitro , (V), (V') or a compound of any sub-formula, or a compound as disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer or isomer thereof , Or include any formula as described in this article Contact with the composition of the compound. In other embodiments, the method includes combining the mutant c-kit kinase with the formula (I'), (I'a), (I), (II), (III) as described herein, in vivo or in vitro , (IV), (V), (V') or a compound of any sub-formula, or a compound as disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer Or isomers, or contact with a composition comprising a compound of any formula as described herein.

<b>VI. Methods for the treatment of conditions mediated by c-Kit kinase</b>

In another aspect, the present invention provides a treatment for suffering from a disease or condition mediated by c-kit and or mutant c-kit protein kinase or at risk of a disease or condition mediated by c-kit and or mutant c-kit protein kinase The method of the individual. The method includes administering to the individual an effective amount of a compound of any of the following formulae: (I'), (I'a), (I), (II), (III), (IV), (V), (V' A compound as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer or isomer thereof, or a composition comprising a compound of any formula as described herein. In some embodiments, the mutant c-kit kinase has a mutation selected from: D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del 550 -558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C Or T670I or a combination thereof. In one embodiment, the mutant c-kit has an activating D816 mutation. In one embodiment, the mutant c-kit has an activating D816V mutation. In another embodiment, the mutant c-kit has a V560G mutation. In another embodiment, the mutant c-kit has activating D816V and V560G mutations. In certain embodiments, the method includes administering to the individual an effective amount of any one or more of the compounds as described herein in combination with one or more other therapies for the disease or condition.

In some embodiments, the present invention provides a method for inhibiting the undesired proliferation of tumor cells that exhibit D816 (such as D816F, D816H, D816N, D816Y, or D816V) and/or V560G mutant c-kit protein kinase. The method comprises making tumor cells expressing D816 (such as D816F, D816H, D816N, D816Y or D816V) and/or V560G mutant c-kit protein kinase and an effective amount of any of the formulas (I'), (I') as described herein 'a) (I), (II), (III), (IV), (V), (V') or a compound of any sub-formula, or any compound as described herein, or a medicine thereof Contact with an academically acceptable salt, hydrate, solvate, tautomer or isomer, or a composition containing a compound as described herein. In some cases, tumor cells exhibit D816V and/or V560G mutant c-kit kinase.

In certain embodiments, the present invention provides a method of treating c-kit protein kinase D816 (such as D816F, D816H, D816N, D816Y, or D816V) and/or V560G mutation-positive patients. The method includes administering to a patient in need an effective amount of any of those described herein A compound of formula (I'), (I'a), (I), (II), (III), (IV), (V), (V') or any sub-formula, or as described herein Any compound, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer or isomer thereof, or a composition comprising a compound as described herein. In some embodiments, the patient is positive for the D816V mutation. In other embodiments, the patient is positive for the V560G mutation. In some embodiments, the patient is positive for the D816V and V560G mutations. In some cases, patients suffer from gastrointestinal stromal tumors (GIST) and/or mastocytosis.

In some embodiments, the diseases or conditions that can be treated with the compounds of the present invention include, but are not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, epileptic seizures, and Epilepsy; neoplastic diseases, including (but not limited to) melanoma, glioma, glioblastoma multiforme, fibrous astrocytoma, sarcoma, cancer (e.g. gastrointestinal, liver, biliary tract, bile duct (cholangiocarcinoma) ), colorectal, lung, gallbladder, breast, pancreas, thyroid, kidney, ovary, adrenal cortex, prostate), lymphoma (e.g. histiocytic lymphoma) neurofibroma, gastrointestinal stromal tumor, acute myeloid leukemia, myelodysplasia Syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors (such as medullary thyroid cancer), carcinoid tumors, small cell lung cancer, Kaposi's sarcoma sarcoma) and pheochromocytoma; pain of neuropathic or inflammatory origin, including (but not limited to) acute pain, chronic pain, cancer-related pain and migraine; cardiovascular disease, including (but not limited to) heart failure, deficiency Blood stroke, cardiac hypertrophy, thrombosis (such as thrombosis microvascular disease syndrome), atherosclerosis and reperfusion injury; inflammation and/or proliferation, including (but not limited to) psoriasis, eczema, arthritis and autoimmunity Diseases and conditions, osteoarthritis, endometriosis, scars, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, including (but not limited to) organ transplants Rejection, graft-versus-host disease, and HIV-related Kaposis sarcoma; kidney, cyst or prostate diseases, including (but not limited to) diabetic nephropathy, polycystic kidney disease, nephrosclerosis, fibroids nephritis, prostatic hyperplasia, Hepatic polycystic disease, tuberous sclerosis, Heber -Von Hippel Lindau disease, medullary cystic kidney disease, renal wasting disease and cystic fibrosis; metabolic disorders, including (but not limited to) obesity; infections, including (but not limited to) Helicobacter pylori (<i>Helicobacter pylori</i>),hepatitis(<i>Hepatitis</i>) And influenza (<i>Influenza</i>) Viruses, fever, HIV and sepsis; lung diseases, including (but not limited to) chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases, including (but not limited to) Noonan's syndrome ), Costello syndrome (facial skin skeletal syndrome), leopard syndrome (LEOPARD syndrome), cardio-faciocutaneous syndrome (cardio-faciocutaneous syndrome) syndrome, CFC) and neurospine syndrome abnormalities that cause cardiovascular, bone, intestinal, skin, hair, and endocrine diseases; and diseases related to muscle regeneration or degeneration, including (but not limited to), sarcopenia, muscular dystrophy ( Including (but not limited to) Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Muscle Myotonic, Oculopharyngeal, distal and congenital muscular dystrophy), motor neuron diseases (including but not limited to) amyotrophic lateral sclerosis, infantile spinal progressive muscular atrophy, Moderate spinal muscular atrophy, youth spinal muscular atrophy, spine bulbar muscular atrophy and adult spinal muscular atrophy), inflammatory myopathy (including but not limited to dermatomyositis, polymyositis and inclusion body myositis) ), neuromuscular junction diseases (including (but not limited to) myasthenia gravis, Lambert-Eaton syndrome and congenital myasthenia syndrome), myopathy caused by endocrine abnormalities (including (but not limited to) ) Hyperthyroid myopathy and hypothyroid myopathy), peripheral neurological diseases (including (but not limited to) Charcot-Marie-Tooth disease) disease), Dejerine-Sottas disease and Friedreich's ataxia), other myopathy (including (but not limited to) congenital myotonia, congenital accessory myotonia) , Central core disease (central core disease, rod-shaped myopathy, myotubular myopathy and periodic paralysis) and muscle metabolic diseases (including but not limited to phosphorylase deficiency, acid maltase deficiency, Phosphofructokinase deficiency, debranching enzyme deficiency, thread Myopathy, carnitine deficiency, carnitine lipotransferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate dismutase deficiency, lactate dehydrogenase deficiency, and inosine deaminase deficiency disease). In one embodiment, the disease or condition is selected from the group consisting of melanoma, glioma, glioblastoma multiforme, fibrous astrocytoma, sarcoma, liver cancer, biliary tract cancer, cholangiocarcinoma, Colorectal cancer, lung cancer, gallbladder cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, adrenal cortex cancer, prostate cancer, histiocyte lymphoma, neurofibroma, gastrointestinal stromal tumor, acute myeloid leukemia, bone marrow development Adverse syndromes, leukemia, tumor angiogenesis, medullary thyroid cancer, carcinoid tumors, small cell lung cancer, Kaposi's sarcoma, pheochromocytoma, acute pain, chronic pain and polycystic kidney disease. In a preferred embodiment, the disease or condition is selected from the group consisting of melanoma, glioma, glioblastoma multiforme, fibrous astrocytoma, colorectal cancer, thyroid cancer, lung cancer, Ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumors, bile duct cancer, cholangiocarcinoma, acute pain, chronic pain and polycystic kidney disease.

In other embodiments, the diseases or conditions that can be treated with the compounds of the present invention include (but are not limited to) ischemic stroke, cerebrovascular ischemia, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia, senile chorea, Huntington's disease, neoplastic diseases, and complications of neoplastic diseases, hypoxia induced by chemotherapy, gastrointestinal stromal tumors, Prostate tumor, mast cell tumor, large mast cell tumor, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, glioma, neuroglioma Blastoma, astrocytoma, neuroblastoma, sarcoma, sarcoma of neuroectodermal origin, leiomyosarcoma, lung cancer, breast cancer, pancreatic cancer, colon cancer, hepatocellular carcinoma, kidney cancer, female reproductive tract cancer, squamous cell carcinoma Adenocarcinoma, carcinoma in situ, lymphoma, histiocytic lymphoma, non-Hodgkin's lymphoma, MEN2 syndrome, neurofibromas, Schwann cell tumor formation, myelodysplastic syndrome, leukemia, Tumor angiogenesis, thyroid Cancer, liver cancer, bone cancer, skin cancer, brain cancer, central nervous system cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, colon cancer, bladder cancer, prostate cancer, gastrointestinal cancer, intrauterine cancer Membrane cancer, fallopian tube cancer, testicular cancer, ovarian cancer, neuropathic pain, inflammatory pain, acute pain, chronic pain, migraine, cardiovascular disease, heart failure, cardiac hypertrophy, thrombosis, thrombotic microangiopathy Syndrome, atherosclerosis, reperfusion injury, ischemia, cerebrovascular ischemia, liver ischemia, inflammation, polycystic kidney disease, age-related macular degeneration, rheumatoid arthritis, allergic rhinitis, Inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, Sjogren's Syndrome, Wegener's granulomatosis, psoriasis, scleroderma, chronic thyroid Inflammation, Grave's disease disease), myasthenia gravis, multiple sclerosis, osteoarthritis, endometriosis, epidermal scars, tissue scars, vascular restenosis, fibrotic disorders, eosinophilia, CNS inflammation, pancreatitis, nephritis, Atopic dermatitis, hepatitis, immunodeficiency disease, severe combined immunodeficiency, organ transplant rejection, graft-versus-host disease, nephropathy, prostatopathy, diabetic nephropathy, nephrosclerosis, fibrosial nephritis, interstitial nephritis, lupus Nephritis, prostatic hyperplasia, chronic renal failure, renal tubular necrosis, diabetes-related renal complications, related renal hypertrophy, type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, hepatic steatosis, insulin resistance, hyperglycemia, lipid Relieve obesity, infection, Helicobacter pylori infection, influenza virus infection, fever, sepsis, lung disease, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, allergies, bronchitis, emphysema, pulmonary fibrosis, genetic developmental diseases, Noonan syndrome, Crouzon syndrome, acrocephalo-syndactyly type I (acrocephalo-syndactyly type I), Pfeiffer's syndrome, Jackson-Wells syndrome (Jackson-Wells syndrome) Weiss syndrome), Kerstiros syndrome, facial skin skeletal syndrome, leopard syndrome, heart-facial skin syndrome, abnormal neurospine syndrome that causes cardiovascular, bone, intestine, skin, hair or endocrine diseases, bone structural disorders or mineralization , Osteoporosis, increased fracture Risks, hypercalcemia, bone metastases, Graves' disease, Hirschsprung's disease, lymphedema, insufficient selective T cells, X-linked agammaglobulinemia , Diabetic retinopathy, hair loss, erectile dysfunction and tuberous sclerosis.

In some embodiments, the disease is selected from the group consisting of: mast cell tumor, small cell lung cancer, testicular cancer, gastrointestinal stromal tumor (GIST), metastatic GIST, glioblastoma, astrocytoma, neuroblastoma Cell tumor, female reproductive tract cancer, sarcoma of neuroectodermal origin, colorectal cancer, carcinoma in situ, Schwann cell tumor formation associated with neurofibroma, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous Leukemia, mastocytosis, pigmented urticaria (UP), persistent eruptive plaque telangiectasia (TMEP), systemic mastocytosis, indolent systemic mastocytosis, mild systemic mast cells Hyperplasia, aggressive systemic mastocytosis, mast cell leukemia, mast cell sarcoma melanoma and large mast cell tumors, and inflammatory diseases, including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, Inflammatory bowel disease, transplant rejection, and eosinophilia. In some cases, the disease is c-kit and/or c-kit mutants (such as D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H , Del 550-558+V654A, Del 557-561+V654A, Ins503AY, V56OG, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C or T670I mutant) Lead the disease. In one embodiment, the disease is a disease mediated by a D816 (such as D816F, D816H, D816N, D816Y, or D816V) mutant. In another embodiment, the disease is a disease mediated by the D816V mutation. In another embodiment, the disease is a disease mediated by a V560G mutation. In another embodiment, the disease is a disease mediated by D816V and V560G mutations. In one embodiment, the disease is a cancer preferably selected from the group consisting of: melanoma, glioma, glioma pleomorphic Blastoma, fibrous astrocytoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumors, biliary tract cancer and cholangiocarcinoma. In one embodiment, the cancer is melanoma, colorectal cancer, thyroid cancer, or lung cancer.

In some embodiments, the present invention provides a method of treating diseases or conditions selected from the group consisting of: pigmented urticaria (UP), persistent eruptive plaque telangiectasia (TMEP), systemic mastocytosis, Indolent systemic mastocytosis, mild systemic mastocytosis, aggressive systemic mastocytosis, mast cell leukemia, mast cell sarcoma, GIST and metastatic GIST. The method includes administering to an individual in need an effective amount of any one or more of the compounds as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer or isomer thereof , Or a composition as described herein.

In some embodiments, the present invention provides a method of treating any c-kit protein kinase-mediated disease or condition, including any c-kit mutant kinase-mediated disease or condition, in an animal individual in need thereof, wherein The method includes administering to the individual an effective amount of any one or more of the compounds as described herein. In certain embodiments, the method includes administering to the individual an effective amount of any one or more of the compounds as described herein in combination with one or more other therapies for the disease or condition.

In some embodiments, the present invention provides the treatment of any c-kit D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del 550-558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H , Y823D, Y823C, or T670I mutant protein kinase-mediated disease or condition method, wherein the method comprises administering to the individual an effective amount of any one or more of the compounds as described herein. In certain embodiments, the method includes administering to the individual effective in combination with one or more other therapies for the disease or condition Any amount of any one or more of the compounds as described herein. In some embodiments, the c-kit mutant protein kinase is a c-kit D816 (such as D816F, D816H, D816N, D816Y, or D816V) mutant kinase. In one embodiment, the c-kit mutant protein kinase is c-kit D816V mutant. In another embodiment, the c-kit mutant protein kinase is a c-kit V560G mutant. In another embodiment, the c-kit mutant protein kinase is c-kit D816V/V560G mutant.

In some embodiments, any of the formulas (I'), (I'a), (I), (II), (III), (IV), (V), (V') or A compound of any sub-formula, or a compound as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer or isomer thereof, or a compound as described herein The composition of the compound is a c-kit and/or mutant c-kit kinase inhibitor, and as determined in the generally accepted analysis of c-kit kinase activity, IC₅₀Less than 500nM, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM, or less than 1nM. In some embodiments, with respect to c-kit, c-kit D816V mutation, c-kit V560G mutation, or D816V/V560G mutation, the IC of the compound described herein is₅₀Will be less than 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM. In some embodiments, a compound as described herein will selectively inhibit one or more mutant c-kit kinases relative to one or more other mutant c-kit kinases.

In some embodiments, the present invention provides a method of inhibiting c-kit mutant protein kinase (such as D816V, V560G or D816V/V560G mutant protein kinase). The method includes making any compound of formula (I), (II) or any sub-formula as described herein, or a compound as described herein, or a composition comprising a compound as described herein, or Its pharmaceutically acceptable salts, hydrates, solvates, tautomers or isomers are contacted with cells or c-kit mutant protein kinase in vitro or in vivo.

In certain embodiments, the present invention provides any of formulas (I'), (I'a), (I), (II), (III), (IV), (V), ( V') or a compound of any sub-formula, or as this Use of the compound described herein, or a composition comprising the compound described herein, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer or isomer thereof, for To manufacture medicaments for the treatment of diseases or conditions as described herein. In other embodiments, the present invention provides a compound of any formula (I), (II) or any sub-formula as described herein, or a compound as described herein, or a compound as described herein The composition of, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer or isomer thereof, for the treatment of diseases or conditions as described herein.

<i>Combination therapy</i>

Protein kinase modulators can be usefully combined with another pharmacologically active compound or with two or more other pharmacologically active compounds, especially for the treatment of cancer. In one embodiment, the composition includes any one or more of the compounds described herein and one or more compounds that are therapeutically effective for the same disease indication, wherein the compounds have a synergistic effect on the disease indication. In one embodiment, the composition includes any one or more of the compounds described herein that are effective in treating cancer and one or more other compounds that are effective in treating the same cancer, and in addition, the compounds are synergistically effective in treating the cancer.

In some embodiments, the present invention provides a method of treating a disease or condition mediated by c-kit and/or mutant c-kit protein kinase in an animal subject in need thereof, wherein the method comprises combining with one or more of the diseases as described herein The combination of the other therapeutic agents described above administers to the individual an effective amount of any one or more of the compounds described herein, or one or more of any of the formulas (I'), (I'a) (I), as described herein , (II), (III), (IV), (V), (V') or a compound of any sub-formula, or a pharmaceutically acceptable salt, solvate, tautomer or isomer Body, or a composition comprising a compound as described herein. In certain embodiments, the present invention provides a method of treating a disease or condition mediated by c-kit and/or mutant c-kit protein kinase in an animal subject in need thereof, wherein the method includes combining with one or more diseases used for the disease Or other therapeutic combinations of the condition administer to the individual an effective amount of any one or more of the compounds as described herein, or one or more of any of the formulas (I'), (I'a), (I'), (I'a), (I'), (I'a), (I ), (II), (III), (IV), (V), (V') or A compound of any sub-formula, or a pharmaceutically acceptable salt, solvate, tautomer or isomer thereof, or a composition comprising a compound as described herein.

), (Va), (Va-1), (Va-2), (Va-3), (Va-1a), (Va-2a), (Va-3a), (Va-1a-1), (Va-2a-1), (Va-1b), (Va-2b), (Va-3b), (Va-1b-1), (Va-2b-1), (Va-6), (Va -6a), (Va-6b), (Va-6c) or (Va-6d), or the compounds disclosed in the examples, the compounds described in Table 1, Table 2 or Table 3, or P-2001 to P2002 and P -Compounds from 2004 to P-2307, or compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, tautomers or isomers thereof, and one or more other treatments Agent. In some embodiments, one or more other therapeutic agents are selected from: alkylating agents, including (but not limited to) adozelesin, altretamine, bendamustine , Bizelesin, busulfan, carboplatin, carboquone, carmofur (carmofur), carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, Etoglucid, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomo Lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine, austin Oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine, satraplatin, semustine (semustine), streptozocin, temozolomide, thiotepa, treosulfan, triaziquone, triethylene melamine, trimolybdenum tetranitrate, triturate Trofosphamide and uramustine; antibiotics, including (but not limited to) aclarubicin, amrubicin, bleomycin, actinomycin (dactinomycin), daunorubicin, cranberry (doxorubicin), elsamitrucin, epirubicin, idarubicin, menogaril , Mitomycin, neocarzinostatin, pentostatin, pirarubicin (pirarubicin, plicamycin, valrubicin, and zorubicin; antimetabolites, including (but not limited to) aminopterin, azacitidine ( azacitidine, azathioprine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, fluorourea Floxuridine, fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed (pemetrexed), raltitrexed, flupyridine- Uracil, thioguanine, trimethoprim, trimetrexate, and vidarabine; immunotherapy, antibody therapy, including (but not limited to) alemtuzumab, Bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab, pertuzumab ), rituximab, brentuximab, tositumomab, trastuzumab, 90 Yibritumomab tiuxetan ), ipilimumab, tremelimumab and anti-CTLA-4 antibodies; hormones or hormone antagonists, including (but not limited to) anastrozole, androgen, cloth Serrelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene , Letrozole, leuprolide, magestrol, raloxifene, tamoxifen and toremifene; yew Alkanes, including (but not limited to) DJ-927, docetaxel, TPI287, larotaxel, ortataxel, paclitaxel, DHA-paclitaxel and tesetaxel; retinoids, including (but not limited to) alitre Alitretinoin, bexarotene, fenretinide, isotretinoin and tretinoin; alkaloids, including (but not limited to) colchicine (demecolcine) , Homoharringtonine (homoharringtonine), vinblastine (vinblastine), vincristine (Vincristine), vindesine (vindesine), vinflunine (vinflunine) and vinorelbine (vinorelbine); anti-angiogenesis agents, including (But not limited to) AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide and thalidomide; topological heterogeneity Inhibitors of constitutive enzymes, including (but not limited to) amsacrine, belotecan, edotecarin, etoposide, etoposide phosphate, esotecan (exatecan), irinotecan (also active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin)), Lucanthone, Mitoxantrone, Pick Pixantrone, rubitecan, teniposide, topotecan and 9-aminocamptothecin; kinase inhibitors, including (but not limited to) axitin Ni (axitinib, AG 013736), dasatinib (dasatinib, BMS 354825), erlotinib, gefitinib, flavopiridol, imatinib mesylate mesylate, lapatinib, motesanib diphosphate (AMG 706), nilotinib (AMN107), seliciclib, sorafenib, Sunitinib malate, AEE-788, BMS-599626, UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, PLX3397, Division Selumetinib and vatalanib; targeted signal transduction inhibitors, including (but not limited to) bortezomib, geldanamycin and rapamycin ( rapamycin); biological response modifiers, including (but not limited to) imiquimod, interferon-α and interleukin-2; and other chemotherapeutic agents, including (but not limited to) 3-AP(3 -Amino-2-formaldehyde thiourea), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1 (bryostatin) -1), cilengitide, elesclomol, eribulin mesylate (eribulinmesylate, E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac , Testolactone, tiazofurin, mTOR inhibitors (e.g. sirolimus, temsirolimus, everolimus, desfolimus ( deforolimus)), PI3K inhibitors (e.g. BEZ235, GDC-0941, XL147, XL765), Cdk4 inhibitors (e.g. PD-332991), Akt inhibitors, Hsp90 inhibitors (e.g. geldanamycin, radicanin (radicicol), tanespimycin (tanespimycin)), Farnesyltransferase inhibitors (such as tipifarnib) and aromatase inhibitors (anastrozole, letrozole, exemestane). In one embodiment, the method of treating cancer comprises administering to an individual an effective amount of a chemotherapeutic agent selected from the group consisting of any one or more of the formula (I), (II) or any one of the subtypes described herein. A compound of formula or a combination of compounds as described herein: capecitabine, 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide , Vinblastine, Bevacizumab, Cetuximab, Interferon-α, Interleukin-2 or Erlotinib. In another embodiment, the chemotherapeutic agent is a Mek inhibitor. Exemplary Mek inhibitors include (but are not limited to) AS703026, AZD6244 (sumetinib), AZD8330, BIX 02188, CI-1040 (PD184352), GSK1120212 (JTP-74057), PD0325901, PD318088, PD98059, RDEA119 (BAY 869766) ), TAK-733 and U0126-EtOH. In another embodiment, the chemotherapeutic agent is a tyrosine kinase inhibitor. Exemplary tyrosine kinase inhibitors include (but are not limited to) AEE788, AG-1478 (Tyrphostin AG-1478), AG-490, Apatinib (Apatinib, YN968D1), AV-412, AV -951 (Tivozanib), Axitinib, AZD8931, BIBF1120 (Vargatef), BIBW2992 (afatinib), BMS794833, BMS-599626, Brini Cloth (Brivanib, BMS-540215), Brivanib alaninate (BMS-582664), Cediranib (Cediranib, AZD2171), Chrysophanic acid (Chrysophanol) , Clenlanib (Crenolanib, CP-868569), CUDC-101, CYC116, Dovitinib dilactate (Dovitinib siRNA, antidiabetic agents, such as metformin (metformin), PPAR agonists (rosiglitazone, pioglitazone, bezafibrate, ciprofibrate, clofibrate (clofibrate), gemfibrozil, fenofibrate, indeglitazar) and DPP4 inhibitors (sitagliptin, vildagliptin), Saxagliptin, dutogliptin, gemigliptin, alogliptin). In another embodiment, the agent is an EGFR inhibitor. Exemplary EGFR inhibitors include (but are not limited to) AEE-788, AP-26113, BIBW-2992 (Tovok), CI-1033, GW-572016, Iressa, LY2874455, RO-5323441, Texa Watt (erlotinib, OSI-774), CUDC-101 and WZ4002. In one embodiment, the method of treating cancer comprises administering to the individual an effective amount of a composition comprising any one or more of the compounds described herein in combination with a chemotherapeutic agent selected from the group consisting of: capecitabine, 5- Fluorouracil, Carboplatin, Dacarbazine, Gefitinib, Oxaliplatin, Taiping Paclitaxel, SN-38, Temozolomide, Vinblastine, Bevacizumab, Cetuximab, Interferon-α, Interleukin-2 or Erlotinib. In some embodiments, the kit protein kinase modulator can be administered simultaneously, sequentially or separately in combination with one or more agents as described above, especially any of the formulas (I'), (I') described herein 'a), (I), (II), (III), (IV), (V) or a compound of any sub-formula, or a compound described herein, or a pharmaceutically acceptable salt or solvent thereof Compounds, tautomers or isomers.

In some embodiments, the present invention provides treatment by c-kit and/or by administering to an individual an effective amount of a composition as described herein in combination with one or more other therapeutic agents as described herein A method for a disease or condition mediated by a mutant c-kit kinase (including any mutation thereof), the composition comprising any one or more compounds as described herein. In other embodiments, the present invention provides treatment by administering to an individual an effective amount of the composition as described herein in combination with one or more other suitable therapies for the treatment of diseases or conditions. Or a method for a disease or condition mediated by a mutant c-kit kinase (including any mutation thereof), the composition includes any one or more of the compounds as described herein.

In some embodiments, a composition is provided, which includes a therapeutically effective amount of any one or more of the compounds as described herein and at least one pharmaceutically acceptable carrier, excipient and/or diluent, including any A combination of two or more compounds as described herein. The composition may further include a plurality of different pharmacologically active compounds, which may include a plurality of compounds as described herein. In certain embodiments, the composition may include any one or more of the compounds described herein and one or more compounds that are therapeutically effective for the same disease indication. In one aspect, the composition includes any one or more compounds as described herein and one or more compounds effective in treating the same disease indication, wherein the compounds have a synergistic effect on the disease indication. In one embodiment, the composition includes any one or more of the compounds described herein that are effective in treating cancer and one or more other compounds that are effective in treating the same cancer, and in addition, the compounds are synergistically effective in treating the cancer. The compounds can be administered simultaneously or sequentially.

In one embodiment, the present invention provides for the treatment of c-kit mutant kinase ( Such as D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del 550-558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP , Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C or T670I mutant kinase) mediated diseases or conditions, the The composition includes any one or more compounds as described herein. In one embodiment, the present invention provides for the treatment of c-kit mutant kinases (such as D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558) by administering an effective amount of the composition to the individual. , Del 557-561, N822K, V654A, N822H, Del 550-558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C or T670I mutant) mediated cancer method, the composition includes any one or more of the compounds as described herein. In one embodiment, the present invention provides treatment by administering to an individual an effective amount of a composition in combination with one or more suitable anti-cancer therapies as described herein (such as one or more chemotherapeutic drugs or agents). c-kit mutant kinases (such as D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del 550-558+V654A, Del 557-561+ V654A, Ins503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C or T670I mutant) mediated cancer method, the composition includes any one or more of the compounds as described herein. In one case, the c-kit mutant kinase is D816V mutant kinase. In another case, c- The kit mutant kinase is a V560G mutant kinase. In another case, the c-kit mutant kinase has both D816V and V560G mutations.

In some embodiments, the present invention provides for administering to an individual an effective amount of a compound as described herein or a composition comprising any one or more of the compounds by combining with one or more other therapies or medical procedures effective in the treatment of cancer, A method of treating cancer as described herein in an individual in need. Other therapies or medical procedures include suitable anti-cancer therapies (e.g., drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedures (e.g., surgery, radiation therapy, hyperthermia, bone marrow or stem cell transplantation). In one embodiment, one or more suitable anti-cancer therapies or medical procedures are selected from treatment with chemotherapeutics (e.g. chemotherapeutic drugs), radiation therapy (e.g. x-rays, gamma rays or electrons, protons, neutrons or alpha Particle beam), high temperature heating (e.g. microwave, ultrasound, radiofrequency resection), vaccine therapy (e.g. AFP gene hepatocellular carcinoma vaccine, AFP adenovirus vector vaccine, AG-858, allogeneic GM-CSF secreted breast cancer vaccine, tree Dendritic cell peptide vaccine), gene therapy (e.g. Ad5CMV-p53 vector, adenovirus encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (e.g., aminoacetoxypropionic acid, motexafin motexafin lutetium)), oncolytic cell virus or bacterial therapy, surgery or bone marrow and stem cell transplantation. In certain embodiments, the present invention provides for the treatment of cancer in an individual in need by administering to an individual an effective amount of a compound as described herein and separately or simultaneously applying radiation therapy as described herein. Methods. In one embodiment, the present invention provides by administering to an individual an effective amount of a compound as described herein followed by radiation therapy (e.g. x-rays, gamma rays or electrons, protons, neutrons or alpha particle beams). Methods of treating cancer in individuals in need. In another embodiment, the present invention provides by applying radiation therapy (e.g. x-rays, gamma rays or electrons, protons, neutrons or alpha particle beams) to the individual followed by administering to the individual an effective amount of as described herein Compounds, methods of treating cancer in individuals in need. In another embodiment, the present invention provides by simultaneously administering a compound as described herein to an individual and performing radiation therapy (such as x-rays, gamma rays or electrons, protons, neutrons or alpha particle beams). One you need Methods of treating cancer in the body.

In another aspect, the present invention provides a kit or container, which includes any of the formulas (I'), (I'a), (I), (II), (III), (IV) as described herein ), (V), (V') or a compound of any sub-formula, or a pharmaceutically acceptable salt thereof, a compound as described herein, or a composition as described herein. In some embodiments, the compound or composition is packaged in, for example, a vial, bottle, or flask, which can be further packaged in, for example, a box, envelope, or bag; the compound or composition is approved by the US Food and Drug Administration (US Food and Drug Administration). Administration) or similar regulatory agencies approved for administration to mammals (such as humans); compounds or compositions are approved for administration to mammals (such as humans) for protein kinase-mediated diseases or conditions; this The kits or containers of the invention may include other indications for use and/or compounds or compositions suitable or approved for administration to mammals (e.g., humans) for c-kit protein kinase-mediated diseases or conditions Written instructions; and the compound or composition can be packaged in unit dose or single dose form (for example, single dose pills, capsules or the like).

<b>VII. Examples</b>

The following examples are provided to illustrate but not limit the claimed invention.

Compounds falling within the scope of the present invention can be synthesized using a variety of reactions known to those skilled in the art as described below. Those familiar with this technology will also realize that alternative methods can be used to synthesize the target compounds of the present invention, and the methods described in the main body of this document are not exhaustive, but do provide a broadly applicable and practical approach to related compounds . In some examples, the mass spectrum result of the indicated compound may have more than one value, which is due to the isotopic distribution of atoms in the molecule, such as compounds with bromine or chlorine substituents.

Certain molecules claimed in this patent can exist in different enantiomeric and diastereomeric forms, or one or more of the hydrogen atoms of the molecule can be replaced by one or more deuterium atoms, including per-deuterated analogs. All such variants of these compounds. In addition, it should be noted that the term "deuterated analog" refers to a compound in which at least one hydrogen atom has been replaced by a deuterium atom.

Those familiar with this technology will also recognize that acids and bases are often used during standard processing procedures in organic chemistry. During the experimental procedures described in this patent, a salt of the parent compound is sometimes produced (when it has the necessary inherent acidity or alkalinity).

<b>Example 1: Preparation of N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5- Formamide (P-2024)</b>

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<b>Step 1-Synthesis of 3-((4-fluorophenyl)ethynyl)-5-nitropyridin-2-amine (3):</b>To contain 3-bromo-5-nitro-pyridin-2-amine (<b>1</b>) (62.63g, 287mmol) of tetrahydrofuran (400mL) and triethylamine (120mL, 861mmol) in the suspension was added 1-ethynyl-4-fluorobenzene 2 (38.0g, 316mmol), copper iodide (I) (378mg, 1.98mmol) and bis(triphenylphosphine)palladium(II) dichloride (1.39g, 1.98mmol). The reaction mixture was purged with nitrogen at room temperature for 5 minutes, and heated in a sealed container at 50°C overnight. The reaction mixture was cooled and filtered. The obtained solid was washed with 3:1 heptane: ethyl acetate (1.6 L), water (500 mL), heptane (1 L), and dried in a vacuum oven at 50° C. to obtain crude 3- ((4-Fluorophenyl)ethynyl)-5-nitropyridin-2-amine 3 (59.27g). From¹The data of H NMR spectrum is consistent with the structure of the compound, and the solid can be used in the next step without further purification.

<b>Step 2-Synthesis of 3-((4-fluorophenyl)ethynyl)pyridine-2,5-diamine (4):</b>It took 90 minutes to add 3-((4-fluorophenyl)ethynyl)-5-nitropyridin-2-amine<b>3</b>(59.27g) of tetrahydrofuran (800mL) and ethyl acetate (800mL) was added tin(II) chloride (208g, 0.952mol), At the same time, the reactants were heated to 60°C. After the addition was complete, the reaction was stirred at 60°C for 2 hours. The reaction mixture was cooled and filtered through Celite (550 g). The diatomaceous earth was washed with ethyl acetate (3L) followed by tetrahydrofuran (5L) to give the compound<b>4</b>(55.22g). From¹The data of the H NMR spectrum is consistent with the structure of the compound, and the compound can be used in the next step without further purification.

<b>Step 3-Synthesis of 2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (5):</b>Potassium tertiary butoxide (55g) and crude 3-((4-fluorophenyl)ethynyl)pyridine-containing crude 3-((4-fluorophenyl)ethynyl)pyridine- 2,5-diamine<b>4</b>(55.22g) of N-methyl-2-pyrrolidone (750 mL). After 2 hours, the reaction mixture was cooled to room temperature (about 22°C), and water (5.5 L) was added. The aqueous layer was extracted with dichloromethane (about 8L). The organic layers were combined and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel (1.5kg) column chromatography with 0-5% methanol/dichloromethane elution to obtain 2-(4-fluorophenyl)-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-amine<b>5</b>(4.5g).¹The HNMR and MS spectroscopy data are consistent with the desired product.

<b>Step 4-Synthesis of N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5- Formamide (P-2024):</b>3,4-Dimethyl-1H-pyrazole-5-carboxylic acid<b>6</b>(0.11 g, 0.78 mmol) and a mixture of benzotriazol-1-yl-oxytripyrrolidine phosphonium hexafluorophosphate (0.5 g, 0.96 mmol) in dimethylacetamide (4 mL) was stirred for 30 minutes. Sequentially add 2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine to the mixture<b>5</b>(0.12g, 0.53mmol) and N,N-diisopropylethylamine (0.1mL). The reaction was stirred at room temperature overnight. Acetonitrile and water were added to the reaction mixture, and the precipitate was collected, washed with ethyl acetate and methanol. It was dried under vacuum to obtain the compound (<b>P-2024</b>) (85mg, 46%). MS ESI [M+H+]+=350.1. From¹The data of H NMR spectrum is consistent with the structure of the compound.

Exemplary compound N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3-methyl-1H-pyrazole-5-carboxamide ( P-2019); N3-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine 5-Dimethyl-pyrazole-3-carboxamide (P-2119); N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl] -3-Methyl-1H-1,2,4-triazole-5-carboxamide (P-2131); N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3- b]Pyridin-5-yl]-3-propyl-1H-pyrazole-5-carboxamide (P-2132); 3-ethyl-N-[2-(4-fluorophenyl)-1H- Pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2159); 3-(difluoromethyl)-N-[2-(4-fluoro (Phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2172); and 4-chloro-3-ethyl-N- [2-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2173) is based on scheme 1 and examples Prepared according to the synthetic scheme described in 1. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound.

<b>Example 2: Preparation of 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyridine</b><b>Azole-5-carboxamide (P-2007).</b>

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<b>Step 1-Synthesis of 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (10):</b>5-bromo-1H-pyrrolo[2,3-b]pyridine<b>8</b>A solution of (196g, 994mmol) in dry tetrahydrofuran (2L) was cooled to 0°C and treated with sodium hydride (60% in mineral oil, 49.3g 1233mmol) over 30 minutes. After two hours, add benzenesulfonyl chloride dropwise<b>9</b>(153 mL, 1193 mmol), and the reaction was stirred at room temperature overnight. The reaction was quenched with brine (1 L). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2×500 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Wet-grind the product and methyl tert-butyl ether together to obtain a brown solid compound<b>10</b>(319g, 95%). From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 2-Synthesis of tertiary butyl (1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbamate (11):</b>Put 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[<i>2,3-b</i>Pyridine(<b>10</b>) (200g, 594mmol), tertiary butyl carbamate (118g, 1009mmol), cesium carbonate (368g, 1128mmol), Xantphos (32g, 65mmol) and palladium (II) acetate (10.7g, 47.5mmol) in 1, The suspension in 4-dioxane (3L) was degassed with nitrogen for 10 minutes and then heated under reflux overnight. LC/MS and TLC indicated that the reaction was complete. The reaction was diluted with ethyl acetate/tetrahydrofuran (1:1, 1 L) and filtered through Celite. The filtrate was extracted with water (1 L). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2×500 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Wet-grind the product and methyl tert-butyl ether together to obtain a brown solid compound<b>11</b>(125g, 57%). From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 3-Synthesis of (2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbamate (12):</b>To N-[1-(phenylsulfonyl)pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]carbamic acid tert-butyl ester (0.5 g, 1.34 mmol) in anhydrous tetrahydrofuran (10 mL) was added tert-butyl lithium (1.7 mL, 1.7 M). The resulting mixture was warmed to -20°C, and then cooled to -78°C. Anhydrous tetrahydrofuran (2 mL) containing iodine (0.4 g, 1.58 mmol) was added, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched with aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was collected, washed with aqueous sodium thiosulfate solution (10%), brine, and dried under sodium sulfate. After removing the desiccant and solvent, the residue was purified by column chromatography to obtain the compound as an off-white solid (<b>12</b>) (0.38g, 56%). MS(ESI)[M+H+]+=500.15. From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 4-Synthesis of (2-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl) carbamate (13):</b>To (2-iodo-1-(phenyl)sulfonyl)-1H-pyrrolo[<i>2,3-b</i>)Pyridin-5-yl)carbamic acid tert-butyl ester (<b>12</b>) (45g, 73mmol) in tetrahydrofuran (600mL) was added tetrabutylammonium fluoride trihydrate (126g, 400mmol). The solution was stirred at room temperature overnight. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Wet-grind the crude material with dichloromethane to obtain the compound as an off-white solid (<b>13</b>) (15g, 59%). From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 5-Synthesis of tertiary butyl (2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbamate (15):</b>(2-Iodine-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl)aminocarbamate<b>13</b>(8.3g, 23mmol), phenyl<img file="TWI617552B_D0142.tif" wi="62" he="59" img-format="tif" img-content="character" orientation="portrait" inline="no" />acid<b>14</b>(3.0g, 25mmol), potassium carbonate (9.6g, 69mmol) in 1,4-dioxane/water (10:1, 165mL) suspension was degassed with nitrogen for 10 minutes, followed by the addition of four (triphenyl) Phosphine) Palladium(0) (1.6 g, 1.4 mmol, 0.06 equivalents). The reaction mixture was heated under reflux overnight. LC/MS indicated that the reaction was complete. The reaction mixture was diluted with tetrahydrofuran (50 mL) and filtered through Celite. The filtrate with brine (100mL) extraction. The layers were separated, and the aqueous phase was extracted with ethyl acetate (2×100 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was wet-milled with dichloromethane to obtain a brown solid compound (<b>15</b>) (5.3g, 74%). From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 6-Synthesis of 2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-amine (16):</b>To (2-phenyl-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl)aminocarbamate<b>15</b>(5.3 g, 17 mmol) trifluoroacetic acid (12 mL) was added to a suspension in dichloromethane (60 mL). The solution was stirred at room temperature for two hours, at which time LC/MS indicated that the reaction was complete. The reaction was concentrated under reduced pressure. The crude material was suspended in a 10% aqueous sodium carbonate solution (100 mL), and stirred at room temperature for 1 hour. The solid was filtered, washed with water (50 mL), methyl tert-butyl ether (50 mL) and dichloromethane (50 mL), and dried in vacuum at 50°C. Obtain a brown solid compound<b>16</b>(3.2g, 89%). From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 7- Synthesis of 3,4-Dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P -2007):</b>Compound<b>6</b>(0.09g, 0.67mmol) and benzotriazol-1-yl-oxytripyrrolidine phosphonium hexafluorophosphate (0.35g, 0.67mmol) in dimethylacetamide (4mL) at room temperature Stir for 30 minutes. To this mixture was added 2-phenyl-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-amine(<b>16</b>) (0.08g, 0.38mmol) and diisopropylethylamine (0.1mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was added dropwise to water, and the suspension was stirred for 1 hour. The solid was filtered and purified by preparative HPLC to obtain the compound as a white solid (<b>P-2007</b>) (46mg, 36%). MS ESI [M+H+]+=332.2.¹The H NMR spectrum is consistent with the structure of the compound.

Exemplary compound 4-bromo-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P-2005); 4 -Methyl-3-phenyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P-2008) ; 3-Cyclopropyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P-2009); 5 -Fluoro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-indazole-3-carboxamide (P-2010); N-(2- Phenyl-1H-pyridine Rolo[2,3-b]pyridin-5-yl)pyrimidine-4-carboxamide (P-2011); 3-fluoro-N-(2-phenyl-1H-pyrrolo[2,3-b ]Pyridin-5-yl)pyridine-2-carboxamide (P-2012); 3,5-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridine-5 -Yl)isoxazole-4-carboxamide (P-2013); N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridazine-3-carboxamide Amine (P-2014); N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2H-triazole-4-methamide (P-2015); 3 -Methyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxamide (P-2016); and 4,5-dimethyl -N-(2-Phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole-3-carboxamide (P-2017) is described in process 2 and example 2 Synthesis scheme and preparation. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound.

<b>Example 3: Preparation of (2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanol (P-2001) and (2-phenyl-1H-pyrrole) And [2,3-b]pyridin-5-yl)-(3-pyridyl)methanone (P-2002)</b>

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<b>Step 1-Preparation of (2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanol (P-2001):</b>Add 5-bromo-2-phenyl-1H-pyrrolo[<i>2,3-b</i>Pyridine(<b>18</b>) (56mg, 0.21mmol) of tetrahydrofuran (6mL) was slowly added with n-butyllithium-containing tetrahydrofuran (0.21ml, 2.5M). After one hour, add 3-pyridine carboxaldehyde (<b>19</b>) (0.02ml, 0.19mmol) of tetrahydrofuran (5mL) into the reaction mixture. The reaction mixture was warmed to room temperature (about 22°C), and poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography by eluting with 20% to 100% ethyl acetate in hexane to obtain the compound (<b>P-2001</b>) (40mg, 64.7%). MS(EI) [M+H+]+=301.85. From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 2-Preparation of (2-Phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methan</b><b>Ketone (P-2002):</b>The compound (<b>P-2001</b>) Oxidize with a mixture of tetrahydrofuran and dichloromethane containing 2-iodobenzoic acid (IBX). The reaction mixture was stirred at room temperature for 48 hours and quenched with water. After the aqueous treatment, the product was purified by silica gel chromatography with a gradient of dichloromethane and methanol (2-20%) to obtain the compound (<b>P-2002</b>) (17mg, 68%). MS ESI[M+H+]+=299.85. From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Example 4: Preparation of (2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanone (P-2006) and (2-phenyl-1H- Pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanone (P-2018)</b>

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<b>Step 1-Preparation of (2-Phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanone P-2006:</b>To 2-phenyl-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-amine<b>16</b>(50mg, 0.24mmol) and ethyl 3-isocyanatopropionate<b>22</b>(50mg, 0.35mmol) To a mixture of dimethylformamide (3ml) was added N,N-diisopropylethylamine (0.1mL). The reaction mixture was stirred at room temperature for 3 hours. The formed precipitate was filtered and washed with a mixture of ethyl acetate and hexane to obtain compound (<b>P-2006</b>) (22mg, 26%). MS ESI[M+H+]+=352.85. From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 2-Preparation of (2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanone (P-2018):</b>To contain 2-phenyl-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-amine<b>16</b>(15mg, 0.07mmol) of pyridine (3mL) was added 1H-pyrazole-4-sulfonyl chloride<b>24</b>(30mg, 0.18mmol). The reaction mixture was stirred at room temperature for 2 hours, and concentrated. The residue was purified by column chromatography with a gradient of dichloromethane and methanol (0-15%) to obtain compound (<b>P-2018</b>) (9mg, 37%). MS ESI [M+H+]+=340.1. From¹The data of H NMR spectrum is consistent with the structure of the compound.

Exemplary compound 2-ethyl-N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]pyrazole-3-sulfonamide (P-2030 ) Is based on the synthesis scheme described in Flow 4 and Example 4 preparation. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound.

<b>Example 5: Preparation of (2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanone (P-2071)</b>

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<b>Step 1-Synthesis of 6-amino-5-(phenylethynyl)nicotinic acid (28):</b>To 6-amino-5-bromo-nicotinic acid ethyl ester<b>26</b>(5.04g, 20.6mmol) in tetrahydrofuran (30mL) was added triethylamine (8.6mL, 61.7mmol, 3.0 equivalents), copper (I) iodide (23.4mg, 0.28mmol), bis(triphenyl) Phosphine) Palladium(II) dichloride (190mg, 0.28mmol) and phenylacetylene<b>27</b>(4.1 mL, 37.6 mmol). The reaction mixture was purged with nitrogen and then heated to reflux in a sealed tube. When LCMS indicated complete reaction, the reaction was cooled, poured into water, and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was wet-milled with 3:1 heptane:ethyl acetate to obtain the compound (<b>28</b>) (3.05g). The filtrate was allowed to stand overnight at room temperature, and after washing with heptane, another compound was obtained as a beige solid (<b>28</b>) (1.67g). Total yield: 4.72 g (86% yield). From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 2-Synthesis of 2-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (29):</b>To contain compounds (<b>28</b>) (40 mg, 0.15 mmol) of N-methylpyrrolidine (1.6 mL) was added potassium tert-butoxide (35 mg, 0.32 mmol, 3.2 equivalents). The reaction mixture was heated at 80°C overnight, cooled to room temperature, hydrochloric acid (1N, 3 mL) was added and poured into water (250 mL). Use 1 The N hydrochloric acid aqueous solution adjusts the pH value of the resulting solution to produce a precipitate. The precipitate was filtered, washed with water and ether to obtain the orange-brown solid compound (<b>29</b>) (30 mg, 71% yield). From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 3-Synthesis of (2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanone (P-2071):</b>To contain 2-phenyl-1H-pyrrolo[<i>2,3-b</i>]Pyridine-5-carboxylic acid<b>29</b>(50mg, 0.21mmol) of tetrahydrofuran (3mL) was added hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidine phosphonium (0.12g, 0.23mmol) and N,N-diisopropylethylamine ( 0.2ml, 1.16mmol). The suspension was stirred at room temperature for 30 minutes, and 3,4-dimethyl-1H-pyrazol-5-amine (<b>30</b>) (28 mg, 0.25 mmol) of N,N-dimethylformamide (1 mL). The reaction mixture was stirred at room temperature overnight, and the reaction was quenched with water. The precipitate was collected, washed with ethyl acetate, and purified by silica gel column chromatography to obtain the compound (<b>P-2071</b>) (18mg, 25%). MS ESI[M+H+]+=331.85. From¹The data of H NMR spectrum is consistent with the structure of the compound.

Exemplary compound N-(3-aminocarboxylphenyl)-2-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (P-2003); and 2-phenyl -N-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (P-2004) is based on the synthesis scheme described in Scheme 5 and Example 5 preparation. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound.

<b>Example 6: Preparation of N-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl]-4,5-dimethyl-1H-pyrazole-3-methan Amine (P-2072) and N-(3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3,4-dimethyl-1H-pyridine Azole-5-carboxamide (P-2041)</b>

<b>Process 6.</b><chemistry general="n"><img he="898" wi="2007" file="TWI617552B_D0146.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of 6-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine (34):</b>To contain 3-(4-fluorophenyl)-1H-pyrazol-5-amine<b>32</b>(75g, 423mmol) and bromomalonaldehyde<b>33</b>(63.9 g, 423 mmol) of ethanol (652 mL) was added p-toluenesulfonic acid monohydrate (8.05 g, 42.3 mmol). The reaction mixture was heated to reflux overnight. After cooling, the reaction mixture was concentrated under reduced pressure to obtain a crude residue. The residue was dissolved in dichloromethane and purified by silica gel column chromatography with 0-100% ethyl acetate/heptane to obtain the compound as a pale yellow solid<b>34</b>(3.6g, 12.32mmol, 2.9% yield). From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 2-Synthesis of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-6-amine (35):</b>To 6-bromo-2-(4-fluorophenyl)pyrazolo[<i>1,5-a</i>]Pyrimidine(<b>34</b>) (4g, 13.69mmol), sodium tert-butoxide (1.842g, 19.17mmol) and benzophenone imine (2.76mL, 16.43mmol) in the mixture of degassed toluene (45.6mL), add 2,2 '-Bis(diphenylphosphino)-1,1'-binaphthyl (0.294g, 1.027mmol) and ginseng (dibenzylideneacetone)dipalladium(0) (0.313g, 0.342mmol). The reaction mixture was heated at 100°C overnight and concentrated under reduced pressure to obtain a crude residue, which was dissolved in tetrahydrofuran (150 mL) and 2N aqueous hydrochloric acid (150 mL), and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the aqueous layer was separated, basified with saturated aqueous potassium carbonate solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a crude residue. Dissolve the residue in dichloromethane and apply silica gel Purification by column chromatography with 0-10% methanol/dichloromethane elution, and wet milling with methyl tert-butyl ether/heptane to obtain a brown solid compound (<b>35</b>) (0.05 g, 0.219 mmol, 1.6% yield). From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 3-Synthesis of N-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl]-4,5-dimethyl-1H-pyrazole-3-methan Amine (P-2072):</b>To contain 3,4-dimethyl-1H-pyrazole-5-carboxylic acid<b>6</b>(35mg, 0.25mmol) of dimethylacetamide (4mL) was added hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidine phosphonium (0.12g, 0.23mmol) and N,N-di Isopropylethylamine (0.2ml, 1.16mmol). The suspension was stirred at room temperature for 30 minutes. Add 2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-6-amine (<b>35</b>) (22 mg, 0.1 mmol, brown solid). The reaction mixture was stirred at room temperature overnight and poured into water. The precipitate was collected and purified by column chromatography to obtain the compound as a pale yellow solid (<b>P-2072</b>) (5mg, 15%). MS ESI [M+H+]+=351.95. From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 4-Synthesis of 3-(4-fluorophenyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (38):</b>3-(4-fluorophenyl)-1H-pyrazol-5-amine<b>32</b>(10g, 56.4mmol) and internally prepared sodium nitromalonaldehyde monohydrate<b>37</b>A yellow suspension (9.31 g, 59.3 mmol) in acetic acid (202 mL) was heated at 50°C overnight. The reaction mixture was diluted with water (10 volumes), and the resulting solid was filtered and washed with more water to obtain the compound<b>38</b>, Which is used directly in the next step. From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 5-Synthesis of 3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-5-amine 39:</b>To contain 3-(4-fluorophenyl)-5-nitro-1H-pyrazolo[<i>3,4-b</i>]Pyridine<b>38</b>(14.57 g, 56.4 mmol) in a mixture of ethanol (500 mL) and tetrahydrofuran (500 mL) was added to the reaction vessel with hydrogen under a pressure of 40 psi. After the hydrogen consumption ceases, the reaction is terminated. The reaction mixture was filtered through a bed of Celite, and the residue was washed with additional tetrahydrofuran. The filtrate was concentrated under reduced pressure to obtain a solid compound<b>39</b>(11.4 g, 50.0 mmol, 89% yield, over 2 steps). From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 6-Synthesis of N-(3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3,4-dimethyl-1H-pyrazole-5 -Formamide (P-2041):</b>To 3-(4-fluorophenyl)-1H-pyrazolo[<i>3,4-b</i>]Pyridin-5-amine<b>39</b>(0.150g, 0.657mmol) Add triethylamine (0.102mL, 0.723mmol), 3,4-dimethyl-1H-pyrazole to a solution of N,N-dimethylformamide (3.87mL) -5-carboxylic acid (0.101g, 0.723mmol) and hexafluorophosphate O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl chloride (0.250g, 0.657 mmol) and stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with acetate. The organic layer was separated and concentrated under reduced pressure, and the resulting residue was dissolved in a minimum amount of dichloromethane, and purified by chromatography with 0-10% methanol/dichloromethane elution, and combined with methyl The tertiary butyl ether/heptane was wet-milled together to obtain the compound as a pale yellow solid (<b>P-2041</b>) (0.100 g, 0.285 mmol, 43.4% yield). MS ESI [M+H+]+=351.3. From¹The data of H NMR spectrum is consistent with the structure of the compound.

Exemplary compound 3,4-dimethyl-N-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P -2040) and 4,5-dimethyl-N-(2-methylpyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazole-3-carbamide (P-2114 ) Was prepared according to the synthetic scheme set forth in Scheme 6 and Example 6. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound.

<b>Example 7: Preparation of N-[2-(3-fluoroprop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyridine Azole-5-carboxamide (P-2063)</b>

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<b>Step 1-Synthesis of N-[1-(phenylsulfonyl)-2-bromo-pyrrolo[2,3-b]pyridin-5-yl]amino</b><b>Tertiary butyl formate 41:</b>To N-[1-(phenylsulfonyl)pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]carbamic acid tert-butyl ester<b>11</b>(0.5 g, 1.34 mmol) of dry tetrahydrofuran (10 mL) was added tertiary butyl lithium (1.6 mL, 1.7M). The resulting mixture was warmed to -20°C, and then cooled to -78°C. Anhydrous tetrahydrofuran (3 mL) containing 1,2-dibromo-1,1,2,2-tetrachloroethane (0.22 g, 0.676 mmol) was slowly added to the mixture, and the reaction mixture was allowed to reach room temperature overnight. The reaction mixture was quenched with aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried under sodium sulfate. The desiccant and solvent are removed, and the residue is purified by column chromatography to obtain a viscous oily compound<b>41</b>, It solidified into a light yellow solid (0.24g, 39%). MS(ESI)[M+H+]+=453.8. From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 2-Synthesis of tertiary N-[1-(phenylsulfonyl)-2-(3-hydroxyprop-1-ynyl)pyrrolo[2,3-b]pyridin-5-yl]carbamate Ester 43:</b>To N-[1-(phenylsulfonyl)-2-bromo-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]carbamic acid tert-butyl ester<b>41</b>(250mg, 0.55mmol), copper(I) iodide (20mg, 0.11mmol), palladium(II) acetate (20mg, 0.09mmol) and triphenylphosphine (40mg, 0.15mmol) in diethylamine (5mL) Propargyl alcohol<b>42</b>(0.25ml, 4.23mmol). The reaction mixture was stirred at room temperature for 4.5 hours, and filtered through Celite, and concentrated. The residue was mixed with water, and extracted with ethyl acetate. The organic layer was collected, washed with water and brine, and then dried over sodium sulfate. The solvent was removed, and the residue was purified by silica gel chromatography with a gradient of ethyl acetate and hexane (10-100%) to obtain the compound<b>43</b>(100mg, 34%). MS ESI [M+H+]+=427.9. From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 3-Synthesis of tertiary N-[1-(phenylsulfonyl)-2-(3-fluoroprop-1-ynyl)pyrrolo[2,3-b]pyridin-5-yl]aminocarboxylic acid Ester 44:</b>To N-[1-(phenylsulfonyl)-2-(3-hydroxyprop-1-ynyl)pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]carbamic acid tert-butyl ester<b>43</b>(100mg, 0.23mmol) of dichloromethane (10ml) was added bis(2-methoxyethyl)aminosulfur trifluoride (0.08ml, 0.43mmol). The reaction mixture was stirred between -10°C and 0°C for 10 Minutes, and allowed to warm to room temperature. The reaction was quenched with water. The organic layer was collected, washed with water and brine, and dried over sodium sulfate. The solvent was removed, and the residue was purified by chromatography with ethyl acetate and hexane (20-100%) to obtain the compound<b>44</b>. MS ESI [M+H+]+=430.1. From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 4-Synthesis of 2-(3-fluoroprop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (45):</b>To N-[1-(phenylsulfonyl)-2-(3-fluoroprop-1-ynyl)pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]carbamic acid tert-butyl ester<b>44</b>(50mg, 0.12mmol) was added methanol (4ml, 1M) containing potassium hydroxide. The reaction was stirred at room temperature for 30 minutes. Dioxane (6 mL, 4M) containing hydrochloric acid was added to the reaction mixture, and the reaction was stirred at room temperature for three hours. The reaction mixture was concentrated twice from toluene and dried under vacuum to obtain the compound (<b>45</b>) (30mg). MS ESI [M+H+]+=190.1. The compound can be used in subsequent reactions without further purification.

<b>Step 5-Synthesis of N-[2-(3-fluoroprop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyridine Azol-5-carboxamide (P-2063):</b>To contain 3,4-dimethyl-1H-pyrazole-5-carboxylic acid<b>6</b>(50 mg, 0.36 mmol) of dimethylacetamide (3 mL) was added benzotriazol-1-yl-oxytripyrrolidine phosphonium hexafluorophosphate (200 mg, 0.38 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and 2-(3-fluoroprop-1-ynyl)-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-amine hydrochloride<b>45</b>(12 mg, 0.05 mmol) and N,N-diisopropylethylamine (1 mL), and further stirred at room temperature for three hours. Then the reaction mixture was purified by chromatography with a gradient of ethyl acetate and hexane to obtain the compound (<b>P-2063</b>) (2.2mg, 13%). MS ESI [M+H+]+=312.1. From¹The data of H NMR spectrum is consistent with the structure of the compound.

Exemplary compound N-[2-(3-fluoroprop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3-methyl-1H-pyrazole-5- Formamide (P-2068) was prepared according to the synthetic scheme set forth in Scheme 7 and Example 7. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound.

<b>Example 8: Preparation of N-[2-[3-(phenylsulfonamido)anilino]pyrimidin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carbamide (P- 2053)</b>

<chemistry general="n"><img he="490" wi="2042" file="TWI617552B_D0148.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of N-(2-chloropyrimidin-5-yl)-3,4-dimethyl-1H-pyrazole-5-carboxamide (48):</b>Add 3,4-dimethyl-1H-pyrazole-5-carboxylic acid to a 20mL scintillation vial<b>6</b>(0.6 g, 4.28 mmol) and benzotriazol-1-yl-oxytripyrrolidine phosphonium hexafluorophosphate (2.4 g, 4.61 mmol) in dimethylacetamide (4 mL) to form a reaction mixture. The reaction mixture was stirred at room temperature for 30 minutes, and solution A was obtained. Add 2-chloropyrimidin-5-amine to another 20mL scintillation vial<b>47</b>(0.75 g, 5.79 mmol) and N,N-diisopropylethylamine (0.1 mL) to form a mixture. The mixture was heated at 60°C to form solution B. The active acid (solution A) was then added to the amine (solution B). The reaction mixture was stirred at 60°C overnight, and cooled to room temperature. Add water to the reaction mixture to form a precipitate, which is collected to obtain the compound<b>48</b>(323mg, 30%). MS ESI [M+H+]+=251.8.

<b>Step 2-Preparation of N-[2-[3-(phenylsulfonamido)anilino]pyrimidin-5-yl]-3,4-dimethyl-1H-pyrazole-5-methamide (P- 2053):</b>Add N-(2-chloropyrimidin-5-yl)-3,4-dimethyl-1H-pyrazole-5-carboxamide to the microwave reaction vessel<b>48</b>(50mg, 0.2mmol), isopropanol (3mL), N-(3-aminophenyl)benzenesulfonamide<b>49</b>(113.64 mg, 0.46 mmol) and aqueous hydrochloric acid (0.1 mL, 37%). The reaction mixture was heated in a microwave reactor at 160°C for 120 minutes. The reaction mixture was purified by silica gel chromatography with a gradient of dichloromethane and methanol (0-15%). Combine the dissociated fractions to obtain the compound (<b>P-2053</b>): (41mg, 45%). MS ESI [M+H+]+=464.3.

Exemplary compound N-(2-anilinopyrimidin-5-yl)-3,4-dimethyl-1H-pyrazole-5-methan Amine (P-2044); N-(6-anilino-3-pyridyl)-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2045); N-[2- [3-(Ethylsulfonyl)anilino]pyrimidin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2050); 3,4-di Methyl-N-[2-(3-N-morpholinoanilino)pyrimidin-5-yl]-1H-pyrazole-5-carboxamide (P-2051); 3,4-dimethyl- N-[2-[3-(Propansulfonyl)anilino]pyrimidin-5-yl]-1H-pyrazole-5-carboxamide (P-2052); 3,4-Dimethyl-N -[2-[3-(Methylaminomethanoyl)anilino]pyrimidin-5-yl]-1H-pyrazole-5-carboxamide (P-2054); and N-[3-[[5 -[(3,4-Dimethyl-1H-pyrazole-5-carbonyl)amino]pyrimidin-2-yl]amino]phenyl]carbamate (P-2055) is based on process 8 and Prepared according to the synthetic scheme set forth in Example 8. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound.

<b>Example 9: Preparation of N-[2-[1-(cyclopropylcarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ]-4,5-Dimethyl-1H-pyrazole-3-carboxamide (P-2043)</b>

<chemistry general="n"><img he="726" wi="2015" file="TWI617552B_D0149.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of N-[2-chloropyrimidin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide 52:</b>Containing 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron<img file="TWI617552B_D0150.tif" wi="64" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester<b>51</b>(3g, 9.7mmol) of dichloromethane (5mL) was added 1,4-dioxane (4N, 5mL) containing hydrochloric acid. The reaction was stirred at room temperature overnight and then concentrated from toluene twice. The residue was washed with ethyl acetate and dried under vacuum to obtain the compound in the form of the hydrochloride salt<b>52</b>(2.3g, 96%). From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 2-Synthesis of cyclopropyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron</b><img file="TWI617552B_D0151.tif" wi="69" he="69" img-format="tif" img-content="character" orientation="portrait" inline="no" /><b>-2-base)-</b><b>3,6-Dihydro-2H-pyridin-1-yl]methanone 54:</b>Containing 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron<img file="TWI617552B_D0152.tif" wi="59" he="59" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride<b>52</b>(0.7g, 2.85mmol) of acetonitrile (15mL) was added cyclopropanecarbonyl chloride successively<b>53</b>(0.3g, 2.87mmol) and N,N-diisopropylethylamine (0.8mL). The reaction mixture was stirred at room temperature for 3 hours, and then passed through a silica gel column (dissolved with ethyl acetate and hexane) to obtain the crude product in the light-colored dissociated fraction. The fractions were combined and concentrated. The residue was wet triturated with a mixture of ethyl acetate and hexane. The mother liquor is collected and concentrated to obtain an orange gel-like compound<b>54</b>. Compound<b>54</b>It can be used in subsequent reactions without further purification.

<b>Step 3-Synthesis of N-[2-[1-(cyclopropylcarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ] Tertiary butyl carbamate 55:</b>Feed the microwave reaction vessel containing N-(2-iodo-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl)aminocarbamate<b>13</b>(400mg, 1.11mmol), cyclopropyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron<img file="TWI617552B_D0153.tif" wi="59" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)-3,6-dihydro-2H-pyridin-1-yl)methanone<b>54</b>(340mg, 1.23mmol), dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(ii) acetone adduct (68.41mg, 0.09mmol) in acetonitrile (6mL) and potassium carbonate (1N , 3.3mL). The mixture was irradiated with microwaves at 100°C for 30 minutes. The reaction was quenched with water, neutralized with aqueous hydrochloric acid (5N), extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removing the solvent and filtering the salt, the residue was purified by silica gel chromatography with ethyl acetate and hexane to obtain the compound<b>55</b>(102mg, 24%). From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 4-Synthesis of [4-(5-amino-1H-pyrrolo[2,3-b]pyridin-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-cyclopropyl -Methone 56:</b>To contain N-[2-[1-(cyclopropylcarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]carbamic acid tert-butyl ester<b>55</b>Add 1,4-dioxane (4M, 0.7 mL) containing hydrochloric acid to dichloromethane (102 mg, 0.27 mmol). The reaction mixture was stirred at room temperature overnight. After removing the solvent, the residue was dried under vacuum to obtain the compound as a yellow solid<b>56</b>(85mg, 100%). MS ESI [M+H+]+=282. It can be used as is without purification.

step<b>Step 5-Synthesis of N-[2-[1-(cyclopropylcarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ]-4,5-Dimethyl-1H-pyrazole-3-carboxamide (P-2043):</b>To contain 4,5-dimethyl-1H-pyrazole-3-carboxylic acid<b>6</b>(0.02 g, 0.17 mmol) of acetonitrile (3 mL) was added hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidine phosphonium (0.1 g, 0.19 mmol). The reaction mixture was stirred at room temperature for one hour, and then [4-(5-amino-1H-pyrrolo[<i>2,3-b</i>]Pyridin-2-yl)-3,6-dihydro-2H-pyridin-1-yl)-cyclopropyl-methanone hydrochloride<b>56</b>(0.05g, 0.16mmol) and triethylamine (0.03ml, 0.19mmol), and stirred overnight at room temperature. The reaction was quenched with water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removing the solvent, the residue was wet-milled with ethyl acetate. Collect the solid and wash with methanol and water to obtain the compound as a white solid<b>57</b>(5mg, 7%). MS ESI [M+H]+=404.9. From¹The data of H NMR spectrum is consistent with the structure of the compound.

Exemplary compound 5-methyl-N-[2-[1-(morpholin-4-carbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-pyrrolo[2,3- b]Pyridin-5-yl]-1H-pyrazole-3-carboxamide (P-2031); N-[1-(phenylsulfonyl)-2-[1-(morpholin-4-carbonyl) -3,6-Dihydro-2H-pyridin-4-yl]pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2033); 3,4-Dimethyl-N-[2-[1-(morpholin-4-carbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-pyrrole And [2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2034); 4-chloro-3-methyl-N-[2-[1-(? (Pholin-4-carbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-methan Amine (P-2036); 4-chloro-N-[2-[1-(cyclopropylcarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-pyrrolo[2,3- b]Pyridin-5-yl]-5-methyl-1H-pyrazole-3-carboxamide (P-2039); and N-[2-[1-(cyclopropylcarbonyl)-3,6-di Hydrogen-2H-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-5-methyl-1H-pyrazole-3-carboxamide (P-2042) series Prepared according to the synthetic scheme set forth in Scheme 9 and Example 9. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound.

<b>Example 10: Preparation of 3,4-Dimethyl-N-[2-[1-(2-N-morpholinylacetinyl)-3,6-dihydro-2H-pyridin-4-yl]-1H -Pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2073)</b>

<chemistry general="n"><img he="706" wi="2061" file="TWI617552B_D0154.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of 2-iodo-1H-pyrrolo[2,3-b]pyridine-5-amine hydrochloride 58:</b>To contain 2-iodo-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]carbamic acid tert-butyl ester<b>13</b>(0.25 g, 0.7 mmol) of dichloromethane (5 mL) was added 1,4-dioxane (3 mL, 4M) containing hydrochloric acid. The suspension was stirred at room temperature for three hours. The reaction mixture was concentrated and dried under vacuum to obtain the compound in the form of the hydrochloride salt<b>58</b>(0.26g). MS ESI [M+H+]+=260.0. Compound<b>58</b>It can be used in subsequent reactions without purification.

<b>Step 2-Synthesis of N-(2-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dimethyl-1H-pyrazole-5-carboxamide 59:</b>3,4-Dimethyl-1H-pyrazole-5-carboxylic acid<b>6</b>(0.81g, 5.79mmol) and benzotriazol-1-yl-oxytripyrrolidine phosphonium hexafluorophosphate (3.01g, 5.79mmol) in dimethylacetamide (20ml) at room temperature Stir for one hour. Sequentially add 2-iodo-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-amine<b>58</b>(0.5g, 1.93mmol) and N,N-diisopropylethylamine (0.67ml, 3.86mmol). The reaction mixture was stirred at room temperature for 3 hours, and then added dropwise to ice water (200 mL). The resulting suspension was stirred overnight. The solid was collected by filtration, washed with water, and wet-milled with methanol to obtain the compound<b>59</b>(1.4g, 96%). MS ESI [M+H+]+=382.05. The compound can be used in subsequent reactions without purification.

<b>Step 3-Preparation of 3,4-Dimethyl-N-[2-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-base]-1H-pyrazole-5-carboxamide 60:</b>To contain N-(2-iodo-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl)-3,4-dimethyl-1H-pyrazole-5-carboxamide<b>59</b>(0.15g, 0.39mmol) of 1,4-dioxane (3ml) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron)<img file="TWI617552B_D0155.tif" wi="64" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2- Yl)-1,2,3,6-tetrahydropyridine hydrochloride<b>52</b>(0.19g, 0.79mmol), dichloro(1,1-bis(diphenylphosphino)ferrocene) palladium(ii) acetone adduct (0.02g, 0.03mmol) and potassium carbonate aqueous solution (1.2mL, 1M ). The reaction mixture was heated in a microwave reactor at 130°C for 20 minutes. The reaction mixture was poured into ice water, and the precipitate was collected by filtration, and then wet-milled with ethyl acetate to obtain a compound<b>60</b>(73mg, 55%). The compound can be used in subsequent reactions without further purification.

<b>Step 4-Preparation of 3,4-Dimethyl-N-[2-[1-(2-N-morpholinylacetyl)-3,6-dihydro-2H-pyridin-4-yl]-1H -Pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2073):</b>To 2-N-morpholinoacetic acid hydrochloride<b>61</b>(0.02g, 0.11mmol) in dimethylacetamide (2ml) was added benzotriazol-1-yl-oxytripyrrolidine phosphonium hexafluorophosphate (55.69mg, 0.11mmol). The mixture was stirred at room temperature for 40 minutes, and then 3,4-dimethyl-N-[2-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]-1H-pyrazole-5-carboxamide<b>60</b>(0.02g, 0.07mmol) and N,N-diisopropylethylamine (0.02ml, 0.14mmol). The reaction mixture was stirred at room temperature for two hours. After the completion of the reaction was proved as by LCMS, the reaction mixture was filtered and purified by preparative HPLC to obtain compound (<b>P-2073</b>) (5mg, 15%). MS(ESI)[M+H]+=464.6. From¹The data of H NMR spectrum is consistent with the structure of the compound.

Exemplary compound N-[2-[1-(2,3-dihydroxypropanyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-pyrrolo[2,3-b] Pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2074) was prepared according to the synthetic scheme set forth in Scheme 10 and Example 10. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound.

<b>Example 11: Preparation of 3-methyl-N-(2-N-morpholinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P -2058)</b>

<b>Process 11.</b><chemistry general="n"><img he="322" wi="1970" file="TWI617552B_D0156.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of N-(2-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methyl-1H-pyrazole-5-carboxamide 64:</b>3-methyl-1H-pyrazole-5-carboxylic acid<b>63</b>(0.15g, 1.19mmol) and benzotriazol-1-yl-oxytripyrrolidine phosphonium hexafluorophosphate (0.66g, 1.27mmol) in dimethylacetamide (2mL) at room temperature Stir for 30 minutes. To this reaction mixture was added 2-iodo-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-amine hydrochloride<b>58</b>(0.15g, 0.51mmol) and N,N-diisopropylethylamine. The reaction mixture was stirred at room temperature for three hours, and then purified by silica gel column chromatography with a gradient of dichloromethane in methanol (5-20%) to obtain the compound<b>64</b>(0.1g, 64%). MS ESI [M+H+]-=368.0. From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 2-Synthesis of 3-methyl-N-(2-N-morpholinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P -2058):</b>The N-(2-iodo-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl)-3-methyl-1H-pyrazole-5-carboxamide<b>64</b>(0.05g, 0.14mmol) and morpholine<b>65</b>(4 mL) of the mixture was heated in a microwave reactor at 160°C for 60 minutes. The reaction mixture was purified by preparative HPLC to obtain compound (<b>P-2058</b>) (18mg, 40%). MS ESI [M+H+]+=327.3. From¹The data of H NMR spectrum is consistent with the structure of the compound.

Exemplary compound 3,4-Dimethyl-N-(2-pyrrolidin-1-yl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-methan The amine (P-2115) was prepared according to the synthetic scheme set forth in Scheme 11 and Example 11. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound.

<b>Example 12: Preparation of N-[2-(1,3-dimethylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4,5-dimethyl -1H-pyrazole-3-carboxamide (P-2038)</b>

<b>Process 12</b><chemistry general="n"><img he="752" wi="1988" file="TWI617552B_D0157.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of 1-(phenylsulfonyl)-2-iodo-pyrrolo[2,3-b]pyridine-5-amine 67:</b>To N-[1-(phenylsulfonyl)-2-iodo-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]carbamic acid tert-butyl ester<b>12</b>(0.5g, 1mmol) in acetonitrile (5ml) was added with dioxane (10mL, 4M) containing hydrochloric acid. The reaction mixture was stirred at room temperature for four hours. The reaction mixture was concentrated and dried under vacuum to obtain the compound in the form of the hydrochloride salt<b>67</b>(0.6g). The compound can be used in subsequent reactions without purification.

<b>Step 2-Synthesis of N-[1-(phenylsulfonyl)-2-iodo-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]-4,5-dimethyl-1H-pyrazole-3-carboxamide 68:</b>To contain 3,4-dimethyl-1H-pyrazole-5-carboxylic acid<b>6</b>(0.2g, 1.43mmol) of acetonitrile (20mL) was successively added hexafluorophosphate O-benzotriazole-N,N,N',N'-tetramethyl-<img file="TWI617552B_D0158.tif" wi="64" he="59" img-format="tif" img-content="character" orientation="portrait" inline="no" />(0.55g, 1.45mmol) and N,N-diisopropylethylamine (0.5ml, 2.89mmol). The suspension was stirred at room temperature for 2 hours to obtain a clear solution. Add 1-(phenylsulfonyl)-2-iodo-pyrrolo[<i>2,3-b</i>]Pyridin-5-amine hydrochloride<b>67</b>(0.4 g, 0.92 mmol) of tetrahydrofuran (1 mL). The reaction mixture was stirred at 40°C overnight. The reaction mixture was concentrated, and the residue was partitioned with ethyl acetate, washed with brine, and dried over sodium sulfate. The solvent was removed, and the residue was purified by flash chromatography on silica gel to obtain the product as a pale yellow solid<b>68</b>(0.1g, 21%). MS(ESI)[M+H+]+=522.0. From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 3-Synthesis of N-[1-(phenylsulfonyl)-2-(1,3-dimethylpyrazol-4-yl)pyrrolo[2,3-b]pyridin-5-yl]-4 ,5-Dimethyl-1H-pyrazole-3-carboxamide 70:</b>To contain N-[1-(phenylsulfonyl)-2-iodo-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]-4,5-dimethyl-1H-pyrazole-3-carboxamide<b>68</b>Add 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) to acetonitrile (3ml) (52mg, 0.1mmol)<img file="TWI617552B_D0159.tif" wi="60" he="57" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)pyrazole<b>69</b>(26mg, 0.12mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (14mg, 0.02mmol) and potassium carbonate aqueous solution (1ml, 1M). The reaction mixture was irradiated with microwaves at 100°C for 15 minutes. The reaction mixture was partitioned with ethyl acetate, washed with brine, and dried over sodium sulfate. The desiccant and solvent are removed, and the residue is purified by column chromatography to obtain an off-white solid product<b>70</b>(0.02g, 36%). MS(ESI)[M+H+]+=490.0. From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 4-Synthesis of N-[2-(1,3-dimethylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4,5-dimethyl -1H-pyrazole-3-carboxamide (P-2038):</b>To contain N-[1-(phenylsulfonyl)-2-(1,3-dimethylpyrazol-4-yl)pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]-4,5-dimethyl-1H-pyrazole-3-carboxamide<b>70</b>Tetrabutylammonium fluoride (0.23ml, 0.76mmol) was added to acetonitrile (2mL) (0.02g, 0.04mmol). The reaction mixture was stirred at 80°C for six hours, then partitioned with ethyl acetate, washed with brine, and dried over sodium sulfate. The desiccant and solvent were removed, and the residue was purified by silica gel column chromatography followed by preparative HPLC to obtain the compound (<b>P-2038</b>) (5mg, 35%). MS(ESI)[M+H+]+=349.9. From¹The data of H NMR spectrum is consistent with the structure of the compound.

Exemplary compound N-[1-(phenylsulfonyl)-2-[1-(morpholin-4-carbonyl)-3,6-dihydro-2H-pyridin-4-yl]pyrrolo[2,3 -b]Pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2033) was prepared according to the synthetic scheme described in Scheme 12 and Example 12. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound.

<b>Example 13: Preparation of 3,4-Dimethyl-N-(2-pyrazol-1-yl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-methyl Amide (P-2112)</b>

<b>Process 13.</b><chemistry general="n"><img he="703" wi="1977" file="TWI617552B_D0160.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of N-[1-(phenylsulfonyl)-2-bromo-pyrrolo[2,3-b]pyridin-5-yl]-N-tertiary butoxycarbonyl-aminocarboxylic acid third Butyl 72:</b>Add N-[1-(phenylsulfonyl)-2-bromo-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]carbamic acid tert-butyl ester<b>41</b>(1.2g, 2.65mmol), tetrahydrofuran (10mL), di-tertiary butyl dicarbonate (1.32g, 6.07mmol), 4-dimethylaminopyridine (0.01g, 0.08mmol) and N,N-dicarbonate Isopropylethylamine (1.5ml). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was partitioned between water and ethyl acetate. The organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate. The solvent is removed, and the residue is dried under vacuum to give the compound<b>72</b>. MS ESI [M+H+]+=554.2. The compound can be used in subsequent reactions without further purification.

<b>Step 2-Synthesis of tertiary butyl N-(2-pyrazole-1-yl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbamate 74:</b>Add N-[1-(phenylsulfonyl)-2-bromo-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl]-N-tertiary butoxycarbonyl-carbamic acid tert-butyl ester<b>72</b>(0.4g, 0.72mmol), 1H-pyrazole<b>73</b>(0.5g, 7.34mmol), ginseng (benzylideneacetone) two palladium (0) (0.05g, 0.05mmol) and racemic 2,2'-bis(diphenylphosphino)-1,1 '-Binaphthyl (0.050g, 0.08mmol) and toluene (5mL). The mixture was stirred at room temperature for 5 minutes, then potassium tert-butoxide (0.7 g, 6.24 mmol) and another 2 mL of toluene were added successively. The mixture was irradiated with microwaves at 145°C for 15 minutes. The mixture was poured into brine, and extracted with ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography with a gradient of methanol and dichloromethane (0-20%) to obtain the compound<b>74</b>(0.12g, 55%). MS ESI [M+H+]+=300.1. From¹H NMR spectroscopy The data is consistent with the structure of the compound.

<b>Step 3-Synthesis of 2-pyrazole-1-yl-1H-pyrrolo[2,3-b]pyridine-5-amine hydrochloride 75:</b>To contain N-(2-pyrazole-1-yl-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl)aminocarbamate<b>74</b>(0.12g, 0mol) of dichloromethane (4mL) was added 1,4-dioxane (5mL, 4N) containing hydrochloric acid. The reaction mixture was stirred for 30 minutes and concentrated. The residue was dried under vacuum to obtain the compound<b>75</b>(0.13g, 96%). MS ESI [M+H+]+=199.85. The compound can be used in subsequent reactions without purification.

<b>Step 4-Synthesis of 3,4-Dimethyl-N-(2-pyrazol-1-yl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-methyl Amide (P-2112):</b>Add 3,4-dimethyl-1H-pyrazole-5-carboxylic acid to a 20mL scintillation vial<b>6</b>(0.1g, 0.71mmol), benzotriazol-1-yl-oxytripyrrolidine phosphonium hexafluorophosphate (0.36g, 0.7mmol) and dimethylacetamide (2mL). The reaction mixture was stirred at room temperature for one hour. Sequentially add 2-pyrazol-1-yl-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-amine hydrochloride<b>75</b>(0.13g, 0.39mmol) and N,N-diisopropylethylamine (1.5ml, 8.67mmol) in dimethylacetamide (1mL). The reaction mixture was stirred at room temperature for two hours, and concentrated. The residue was purified by silica gel column chromatography with a gradient of methanol and dichloromethane to obtain the product, which was further titrated with a mixture of ethyl acetate and hexane to obtain the compound<b>76</b>(5mg, 4%). MS ESI [M+H+]+=322.3. From¹The data of H NMR spectrum is consistent with the structure of the compound.

Exemplary compound 3-methyl-N-(2-pyrazol-1-yl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P -2116) was prepared according to the synthetic scheme set forth in Scheme 13 and Example 13. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound.

<b>Example 14: Preparation of N-[2-[2-chloro-5-(trifluoromethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-di Methyl-1H-pyrazole-5-carboxamide (P-2113)</b>

<b>Process 14.</b><chemistry general="n"><img he="426" wi="1898" file="TWI617552B_D0161.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

To N-(2-iodo-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl)-3,4-dimethyl-1H-pyrazole-5-carboxamide<b>59</b>(0.05g, 0.13mmol), [2-chloro-5-(trifluoromethoxy)phenyl]<img file="TWI617552B_D0162.tif" wi="64" he="64" img-format="tif" img-content="character" orientation="portrait" inline="no" />acid<b>77</b>(37.84mg, 0.16mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(ii) acetone adduct (7.05mg, 0.01mmol) in 1,4-dioxane ( Add potassium carbonate aqueous solution (0.4mL, 1M) to the solution in 3ml). The reaction mixture was irradiated with microwaves at 120°C for 20 minutes. The reaction was quenched with water, neutralized with 1M aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness. The residue was adsorbed onto a silica gel pad and purified via flash column chromatography (0-10% methanol/dichloromethane). The desired fraction was concentrated to dryness, and then wet-milled with ethyl acetate to obtain the compound as an off-white solid (<b>P-2113</b>) (30mg, 51%). MS ESI [M+H+]+=450.2. From¹The data of H NMR spectrum is consistent with the structure of the compound.

Exemplary compound 4,5-dimethyl-N-[2-(4-N-morpholinylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole -3-formamide (P-2059); N-[2-[3-(dimethylamino)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3, 4-Dimethyl-1H-pyrazole-5-carboxamide (P-2064); N-[2-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2 ,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2065); 3,4-dimethyl-N-[2-[ 3-(2-N-morpholinylethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2066 ); 3,4-Dimethyl-N-[2-[4-(methylaminomethanyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H- Pyrazole-5-carboxamide (P-2067); 4,5-dimethyl-N-[2-[2-(4-methylpiperazin-1-yl)-4-pyridyl]-1H -Pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-3-carboxamide (P-2069); 4,5-dimethyl-N-[2-(3-N -Morpholinylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-3-carboxamide (P-2070); N-[2-(2- Chloro-4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P -2075); N-[2-(2-Fluoro-4-methoxy-benzene Yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide; (P-2076); N-[2 -(2-Chloro-5-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-methyl Amide (P-2077); N-[2-(3-Fluoro-5-N-morpholinyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3, 4-Dimethyl-1H-pyrazole-5-carboxamide (P-2078); 3,4-Dimethyl-N-[2-(3-pyrrolidin-1-ylphenyl)-1H- Pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2079); N-[2-(4-aminocyclohexen-1-yl) -1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2080); N-[2-(4 -Cyano-3-N-morpholinyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-methyl Amide (P-2081); N-[2-(3-Fluoro-2-N-morpholinyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]- 3,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2082); N-[2-(1-isobutylpyrazol-4-yl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2083); N-[2-(1,5-dimethylpyrazole -4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2084); N- [2-[4-(Dimethylaminocarboxyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole- 5-formamide (P-2085); 3,4-dimethyl-N-[2-[3-(trifluoromethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridine -5-yl]-1H-pyrazole-5-carboxamide (P-2086); N-[2-[3-(dimethylaminocarboxyl)phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2087); 3,4-dimethyl-N-[2-(3 -Pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2088); 3,4-dimethyl-N-[2-(6-N-morpholino-3 -Pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2089); N-[2-(6-methoxy -3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2090); 3 ,4-Dimethyl-N-[2-(2-Methylthiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-methyl Amide (P-2091); N-[2-(4-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H- Pyrazol-5-carboxamide (P-2092); N-[2-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-di Methyl-1H-pyrazole-5-carboxamide (P-2093); N-[2-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]- 3,4-Dimethyl-1H-pyrazole-5-carboxamide (P- 2094); N-[2-(3-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-methyl Amide (P-2095); N-[2-(2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyridine Azole-5-carboxamide (P-2096); 3,4-dimethyl-N-[2-(o-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]- 1H-pyrazole-5-carboxamide (P-2097); N-[2-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3 ,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2098); N-[2-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine -5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2099); N-[2-(3-acetamidophenyl)-1H-pyrrolo [2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2100); 3,4-dimethyl-N-[2 -[4-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2101); N-[2-[4-(3-Methoxypropoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H- Pyrazole-5-carboxamide (P-2102); 3,4-Dimethyl-N-[2-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo [2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2104); 3,4-dimethyl-N-[2-[4-(thio? (Pholin-4-carbonyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2105); 3,4-dimethyl -N-[2-[3-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2106); 3,4-Dimethyl-N-[2-[3-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ]-1H-pyrazole-5-carboxamide (P-2107); N-[2-(2-cyclopropyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-5 -Base]-3,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2108); N-[2-(2-methoxy-4-pyridyl)-1H-pyrrolo[2,3-b ]Pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2109); 3,4-dimethyl-N-[2-(2-N- Morpholinyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2110); N-[2-[ 4-(Methanesulfonamido)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carbamide ( P-2111); N-[2-[3-[4-(cyclopropylcarbonyl)piperazin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]- 3,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2118); N-[2-(4-cyano-3-pyrrolidin-1-yl-phenyl)-1H- Pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2120); 3,4-dimethyl-N- [2-[3-(Methylsulfonyl)phenyl]-1H-pyrrole And [2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2121); N-[2-(4-chlorophenyl)-1H-pyrrolo[2 ,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2122); 3,4-dimethyl-N-[2-( 6-Methyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2123); 3,4-bis Methyl-N-[2-(4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (2124); 3,4 -Dimethyl-N-[2-(4-pyrrolidin-1-ylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-methan Amine (P-2125); 3,4-Dimethyl-N-[2-[3-(propanesulfonamido)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ]-1H-pyrazole-5-carboxamide (P-2126); N-[2-(3-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]- 3,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2128); N-[2-(2-fluoro-3-methoxy-phenyl)-1H-pyrrolo[2 ,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2129); 3,4-dimethyl-N-[2-( M-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2130); N-[2-(6-acetamide 3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2133); N-[2-[3-(Butylaminomethylamino)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H- Pyrazol-5-carboxamide (P-2134); N-[2-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4 -Dimethyl-1H-pyrazole-5-carboxamide (P-2135); 3,4-dimethyl-N-[2-(2-methyl-3-pyridyl)-1H-pyrrolo [2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2136); N-[2-(4-acetamidophenyl)-1H-pyrrolo [2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2137); 3,4-dimethyl-N-[2-[4 -(Morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2138); N-[ 2-(2,4-Dimethylthiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5- Formamide (P-2139); N-[2-[1-(Difluoromethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3 ,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2140); 3,4-Dimethyl-N-[2-[2-(trifluoromethyl)-3-pyridyl ]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2176); N-[2-(2-ethyl-4-pyridine Yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2177); N-[2- (6-Ethyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)- 3,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2178); N-[2-(2,3-dihydro-[1,4]dioxeino[ 2,3-b]pyridin-8-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide ( P-2179); 3,4-Dimethyl-N-[2-[2-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H -Pyrazole-5-carboxamide (P-2180); N-[2-(2,4-Dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]- 3,4-Dimethyl-1H-pyrazole-5-carboxamide (P-2181); 3,4-Dimethyl-N-[2-[2-(trifluoromethoxy)phenyl] -1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2182); N-[2-(5-methoxy-3-pyridine Yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (p-2183); 3,4-di Methyl-N-[2-(5-methyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P -2184); N-[2-(4-methoxy-3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H- Pyrazol-5-carboxamide (P-2185); and compounds P-2144, P-2146, P-2147, P-2148, P-2149, P-2153, P-2154, p-2155, P- 2156, P-2157, P-2158, P-2160, P-2161, P-2163, P-2164, P-2166, P-2167, P-2168, P-2169, P-2170, P-2171 and P-2174 was prepared according to the synthetic scheme set forth in Scheme 14 and Example 14. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound. In addition, compounds P-2238, P-2239, P-2240, P-2241, P-2242, P-2243, P-2244, P-2245, P-2246, P-2247, P-2248, P-2249 , P-2250, P-2251, P-2252, P-2253, P-2254, P-2255, P-2256, P-2257, P-2258, P-2259, P-2260, P-2261, P -2262, P-2263, P-2264, P-2265, P-2266, and P-2267 can be prepared according to the synthetic route described in Example 14 and Scheme 14.

<b>Example 15: Preparation of N-[2-(4-dimethylphosphorylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H- Pyrazol-5-carboxamide (P-2127)</b>

<b>Process 15.</b><chemistry general="n"><img he="879" wi="1949" file="TWI617552B_D0163.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of methyl phosphinyl methane (80):</b>In a round bottom flask, tetrahydrofuran (20ml, 3M) containing methylmagnesium chloride was cooled with an ice water bath. Add 1-ethoxyphosphinyloxyethane dropwise<b>79</b>(2.58ml, 20mmol) of tetrahydrofuran (5ml). The reaction mixture was stirred from 0°C to room temperature for 5 hours. Saturated sodium bicarbonate (20 mL) and methanol (20 mL) were slowly added to the reaction mixture in succession. A precipitate formed, and the reaction mixture was allowed to stir at room temperature overnight. The formed salt was filtered, and the filtrate was concentrated under reduced pressure. The reaction mixture was dried under vacuum to obtain a clear semi-solid/oil (<b>80</b>)。¹H NMR[D₂O] The spectrum is consistent with the desired product.

<b>Step 2-Synthesis of 1-bromo-4-dimethylphosphoryl-benzene (82):</b>In a pressure vessel, put 1,4-dibromobenzene<b>81</b>(4g, 16.96mmol), methylphosphoranyl methane (<b>80</b>) (5.5g, 70.67mmol), Si(triphenylphosphine)palladium(0) (0.98g, 0.85mmol) and triethylamine (9.45ml, 67.82mmol) were dissolved in acetonitrile (40ml). The reaction was stirred at 90°C overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was loaded on silica gel and purified by silica gel chromatography to obtain the crude compound as a yellowish solid<b>82</b>(2.1g). The solid can be used in subsequent reactions without further purification. MS(ESI)[M+H+]+=232.7/234.7.¹The H NMR spectrum is consistent with the structure of the compound.

<b>Step 3-Synthesis of 2-(4-dimethylphosphorylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron</b><img file="TWI617552B_D0164.tif" wi="64" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" /><b>83：</b>Add 1-bromo-4-dimethylphosphoryl-benzene to the pressure vessel<b>82</b>(2.1g, 9.01mmol) Add 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-bis Oxyboron<img file="TWI617552B_D0165.tif" wi="59" he="59" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)-1,3,2-dioxoboron<img file="TWI617552B_D0166.tif" wi="62" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />(4.58g, 18.02mmol), potassium acetate (2.99ml, 47.76mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (ii) dichloromethane complex (0.99ml, 1.17mmol). The mixture was stirred at 90°C for four hours. The reaction mixture was cooled and filtered through Celite. The filtrate was concentrated to dryness. Load one third of the material on silica gel and purify it by silica gel chromatography to obtain the compound<b>83</b>(350mg). MS(ESI)[M+H+]+=280.80. Compound<b>83</b>It can be used in subsequent reactions without further purification.

<b>Step 4: Synthesis of N-[2-(4-dimethylphosphorylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H- Pyrazol-5-carboxamide (P-2127):</b>To 2-(4-dimethylphosphorylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron<img file="TWI617552B_D0167.tif" wi="64" he="67" img-format="tif" img-content="character" orientation="portrait" inline="no" /><b>83</b>(60mg, 0.21mmol) was added N-(2-iodo-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-yl)-3,4-dimethyl-1H-pyrazole-5-carboxamide<b>59</b>(163.3mg, 0.43mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (ii) dichloromethane complex (0.01g, 0.01mmol) and potassium carbonate aqueous solution (0.64ml) , 1M). The reaction mixture was irradiated with microwaves at 110°C for 20 minutes. The reaction mixture was filtered, and the precipitate was collected and wet-milled with a mixture of methanol and acetonitrile to obtain the product as an off-white solid (<b>P-2127</b>) (33mg, 37.8%). MS(ESI)[M+H+]+=408.30.¹The H NMR spectrum and mass spectrum data are consistent with the structure of the compound.

<b>Example 16: Preparation of N-[(4-chloro-5-methyl-1H-pyrazol-3-yl)methyl]-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b ]Pyridin-5-amine (P-2141) and the preparation of 2-(4-fluorophenyl)-N-[(5-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrrolo[ 2,3-b)pyridine-5-amine (P-2142)</b>

<chemistry general="n"><img he="448" wi="2060" file="TWI617552B_D0168.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Preparation of N-[(4-chloro-5-methyl-1H-pyrazol-3-yl)methyl]-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b ]Pyridin-5-amine (P-2141):</b>Add 2-(4-fluorophenyl)-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-amine<b>5</b>(0.4g, crude) and sodium borohydride (84mg, 1.34mmol). The reaction mixture was stirred at room temperature for three days. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried under sodium sulfate. The desiccant and solvent were removed, and the residue was successively purified by silica gel column chromatography and preparative HPLC to obtain the product as a yellow solid (<b>P-2141</b>) (48mg, 12%). MS(ESI)[M+H+]+=355.95.¹The HNMR spectrum and mass spectrum data are consistent with the structure of the compound.

<b>Step 2-Preparation of 2-(4-fluorophenyl)-N-[(5-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5 -Amine (P-2142):</b>To 2-(4-fluorophenyl)-1H-pyrrolo[<i>2,3-b</i>]Pyridin-5-amine<b>5</b>(46mg, 0.2mmol) and 5-methyl-1H-pyrazole-3-carbaldehyde<b>87</b>To a mixture of (58mg, 0.53mmol) in acetonitrile (3mL) were added trifluoroacetic acid (0.1ml, 1.3mmol) and triethylsilane (0.1ml, 0.63mmol) successively. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was dissolved in a mixture of water and saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried under sodium sulfate. After removing the desiccant and solvent, the residue was purified by column chromatography to obtain a brown solid compound (<b>P-2142</b>) (28mg, 43%). MS(ESI)[M+H+]+=453.75.¹The H NMR spectrum and mass spectrum data are consistent with the structure of the compound.

<b>Example 17: Preparation of 3,4-dimethyl-N-(2-phenylthiazolo[5,4-b]pyridin-6-yl)-1H-pyrazole-5-carboxamide (P-2144)</b>

<b>Process 17.</b><chemistry general="n"><img he="750" wi="1922" file="TWI617552B_D0169.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of 6-nitro-2-phenyl-thiazolo[5,4-b]pyridine (103):</b>In a pressure vessel, the 2-chloro-3,5-dinitro-pyridine<b>101</b>(2.5g, 12.04mmol) and phenylthiocarbamide<b>102</b>(6.6g, 48.18mmol) was dissolved in cyclobutane (20ml, 209.87mmol). The mixture was heated to 100°C and stirred overnight. The reaction mixture was cooled to room temperature, quenched with brine, extracted with ethyl acetate, and washed with brine. The organic layer was dried with sodium sulfate. After removing the solvent, the residue was wet-milled with methanol, filtered, and the filter cake was washed with hexane. Wet-grind the solid with methanol again to obtain a brown solid product<b>103</b>(0.46g, 14.7%).

<b>Step 2-Synthesis of 2-phenylthiazolo[5,4-b]pyridine-6-amine 104:</b>To contain 6-nitro-2-phenyl-thiazolo[5,4-b]pyridine<b>103</b>Iron (30 mg) was added to a round-bottomed flask of aqueous hydrochloric acid (12N, 1 mL) (30 mg, 0.116 mmol) and methanol (1 mL). The reaction mixture was stirred at 80°C for 2 hours, cooled to room temperature, filtered through Celite, and washed with methanol and dichloromethane. The filtrate was concentrated to half volume, filtered with water, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. After removing the solvent, the residue was dried under vacuum to obtain 2-phenylthiazolo[5,4-b]pyridine-6-amine as a yellowish solid<b>104</b>(93mg, 98%).

<b>Step 3-Synthesis of 3,4-dimethyl-N-(2-phenylthiazolo[5,4-b]pyridin-6-yl)-1H-pyrazole-5-carboxamide 105:</b>Add 3,4-dimethyl-1H-pyrazole-5-carboxylic acid to the scintillation vial<b>6</b>(0.03g, 0.21mmol) and (hexafluorophosphate O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl<img file="TWI617552B_D0170.tif" wi="59" he="57" img-format="tif" img-content="character" orientation="portrait" inline="no" />) (0.1g, 0.26mmol) of dimethylacetamide (3ml). Place the reaction mixture in the chamber Stir at low temperature for one hour. Then add 2-phenylthiazolo[5,4-b]pyridine-6-amine to this mixture<b>104</b>(30mg, 0.13mmol) and triethylamine (0.04ml, 0.26mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with ethyl acetate, and washed with brine. The organic layer was dried with sodium sulfate. After removing the solvent, the residue was purified by reverse phase column chromatography to obtain a fluffy white solid compound (<b>P-2144</b>) (6.3mg, 13.7%). MS(ESI)[M+H+]+=349.85.¹The H NMR and mass spectrum data are consistent with the desired product.

<b>Example 18: Preparation of N-[2-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl]-3,4-dimethyl-1H-pyrazole-5- Formamide (P-2152)</b>

<chemistry general="n"><img he="783" wi="2045" file="TWI617552B_D0171.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of 2-(2-fluorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (108):</b>To contain 5-nitropyridine-2,3-diamine<b>106</b>(125mg, 0.8mmol) and 2-fluorobenzoic acid<b>107</b>Eaton's reagent (2ml, 12.73mmol) was added to the pressure vessel (112.17mg, 0.8mmol). The reaction mixture was stirred at 150°C. The mixture was cooled to room temperature and quenched with water. The precipitate was collected and dried under vacuum to obtain the compound<b>108</b>. The compound can be used in subsequent reactions without purification.

<b>Step 2-Synthesis of 2-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridine-6-amine (109):</b>To 2-(2-fluorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine<b>108</b>(100mg, 0.38mmol), aqueous hydrochloric acid (12N, 3mL) and methanol (3mL) into the pressure vessel was charged with iron (22mg). The reaction mixture was stirred at 80°C for two hours, cooled to room temperature, and Filter through Celite and wash with methanol and dichloromethane. The filtrate was concentrated to half volume, filtered with water, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. After removing the solvent, the residue was dried under vacuum to obtain the compound as a yellow solid<b>109</b>(60mg, 68.4%). The compound can be used in subsequent reactions without purification.

<b>Step 3-Synthesis of N-[2-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl]-3,4-dimethyl-1H-pyrazole-5- Formamide (P-2152):</b>Add 3,4-dimethyl-1H-pyrazole-5-carboxylic acid to the scintillation vial<b>6</b>(44mg, 0.32mmol) and (hexafluorophosphate O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl<img file="TWI617552B_D0172.tif" wi="67" he="59" img-format="tif" img-content="character" orientation="portrait" inline="no" />) (0.15g, 0.39mmol) of dimethylacetamide (3ml). The reaction mixture was stirred at room temperature for one hour, and then 2-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridine-6-amine was added<b>109</b>(45mg, 0.2mmol) and N,N-diisopropylethylamine (0.07ml, 0.39mmol). The mixture was stirred at room temperature overnight, quenched with water, extracted with ethyl acetate, and washed with brine. The organic layer was collected and dried with sodium sulfate. After removing the solvent, the residue was purified by column chromatography and further wet-milled with methanol to obtain the compound as an off-white solid (<b>P-2152</b>) (22mg, 30%). MS(ESI)[M+H+]+=351.1.¹The H NMR and mass spectrum data are consistent with the desired product.

Exemplary compound 3,4-dimethyl-N-(2-phenyl-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazole-5-carboxamide (P- 2145), 4-chloro-3-methyl-N-(2-phenyl-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazole-5-carboxamide (P -2150) and 3-methyl-N-(2-phenyl-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazole-5-carboxamide (P-2151) It was prepared according to the synthetic scheme set forth in Scheme 18 and Example 18. From¹The data of H NMR spectrum and the observed molecular weight (Table 1) are consistent with the structure of the compound.

<b>Example 19: Preparation of 4-[3-[5-[(3,4-Dimethyl-1H-pyrazole-5-carbonyl)amino]-1H-pyrazolo[3,4-b]pyridine-3 -Yl]phenyl]tert-butyl piperazine-1-carboxylate (P-2162) and 3,4-dimethyl-N-[3-(3-piperazin-1-ylphenyl)-1H- Pyrazolo[3,4-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2165)</b>

<chemistry general="n"><img he="1104" wi="2045" file="TWI617552B_D0173.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of tert-butyl 4-[3-(5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl]piperazine-1-carboxylate (113):</b>To contain 3-bromo-5-nitro-1H-pyrazolo[3,4-b]pyridine<b>111</b>(0.1g, 0.41mmol) of acetonitrile (3ml) was added 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxboron<img file="TWI617552B_D0174.tif" wi="59" he="64" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester<b>112</b>(0.2g, 0.52mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (12mg, 0.016mmol) and potassium carbonate aqueous solution (1ml, 1M). The reaction mixture was irradiated in a microwave at 120°C for 20 minutes and at 150°C for 170 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried under sodium sulfate. After removing the desiccant and solvent, the residue was purified by silica gel column chromatography to obtain the compound as a brown solid<b>113</b>(58mg, 23%). MS(ESI)[MH-]-=423.20.

<b>Step 2-Synthesis of tertiary butyl 4-[3-(5-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl]piperazine-1-carboxylate (114):</b>Containing 4-[3-(5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl]piperazine-1-carboxylic acid tert-butyl ester<b>113</b>(58mg, 0.14mmol) of methanol (2ml) and dichloromethane (2ml) was added with palladium on carbon (5mg, 10%, wet). The reaction mixture was stirred at room temperature under a hydrogen balloon overnight. After removing the catalyst and solvent, the residue was dried under vacuum to obtain the compound as a brown solid<b>114</b>(46mg, 85%). MS(ESI)[M-H+]-=395.25. The compound can be used in subsequent reactions without purification.

<b>Step 3-Synthesis of 4-[3-[5-[(3,4-Dimethyl-1H-pyrazole-5-carbonyl)amino]-1H-pyrazolo[3,4-b]pyridine-3 -Yl]phenyl]piperazine-1-carboxylate (P-2162):</b>To contain 4,5-dimethyl-1H-pyrazole-3-carboxylic acid<b>6</b>(30mg, 0.21mmol) of N,N-dimethylamide (4mL) was successively added hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidine phosphonium (0.115g, 0.22mmol) and N,N -Diisopropylethylamine (0.1ml, 0.58mmol). The suspension was stirred at room temperature for 60 minutes. To this suspension was added tert-butyl 4-[3-(5-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl]piperazine-1-carboxylate<b>114</b>(46 mg, 0.12 mmol) of N,N-dimethylamide (1 mL). The reaction mixture was stirred at room temperature for two days, then quenched with water, and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried under sodium sulfate. After removing the desiccant and solvent, the residue was purified by column chromatography and preparative HPLC to obtain the compound as a white solid<b>115</b>(12mg, 10%). MS(ESI)[M+H+]+=517.4. From¹The data of H NMR spectrum is consistent with the structure of the compound.

<b>Step 4-Preparation of 3,4-Dimethyl-N-[3-(3-piperazin-1-ylphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1H -Pyrazole-5-carboxamide (P-2165):</b>To contain 4-[3-[5-[(3,4-dimethyl-1H-pyrazole-5-carbonyl)amino]-1H-pyrazolo[3,4-b]pyridin-3-yl ]Phenyl]piperazine-1-carboxylic acid tert-butyl ester<b>115</b>(8mg, 0.02mmol) of tetrahydrofuran (1mL) was added with dioxane (0.4ml, 4M) containing hydrochloric acid. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried under sodium sulfate. After removing the desiccant and solvent, the residue was purified by preparative HPLC to obtain the compound as a white solid<b>116</b>(2mg, 28%). MS(ESI)[M+H+]+=417.15.¹H NMR and MS are consistent with the desired product.

Exemplary compound 4,5-dimethyl-N-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl )-1H-pyrazole-3-carboxamide (P-2190); 4,5-dimethyl-N-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H -Pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2191); 4,5-dimethyl-N-(3-(6-N -Morpholin-2-yl)-1H-pyrrolo[2,3-b] Pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2192); and 4,5-dimethyl-N-(3-(2-N-morpholinylpyridin-4-yl) )-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2193) can be prepared according to the synthetic scheme described in Scheme 19 and Example 19.

<b>Example 20: Preparation of 3,4-dimethyl-N-[2-[3-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-1H-pyrrolo[2, 3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (P-2168)</b>

<chemistry general="n"><img he="421" wi="2048" file="TWI617552B_D0175.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of 3-methyl-1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron</b><img file="TWI617552B_D0176.tif" wi="66" he="66" img-format="tif" img-content="character" orientation="portrait" inline="no" /><b>-2-yl)pyrazole (119):</b>Place 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) into the round bottom flask<img file="TWI617552B_D0177.tif" wi="59" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)-1H-pyrazole<b>117</b>(0.7g, 3.36mmol) of dimethylformamide (10ml) and cooled in an ice water bath. Sodium hydride (60% in mineral oil, 0.34 g, 8.41 mmol) was added, and the mixture was stirred for 60 minutes. Add 3-iodooxetane dropwise to this mixture under nitrogen<b>118</b>(0.3ml, 3.49mmol). The reaction was warmed to room temperature and stirred overnight. The reaction was quenched with methanol and concentrated to dryness. The resulting liquid crude product solidified into a medium brown viscous substance<b>119</b>. This material can be used in subsequent reactions without purification. MS ESI [M+H+]+=264.8.

<b>Step 2-Synthesis of 3,4-dimethyl-N-[2-[3-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-1H-pyrrolo[2, 3-b]pyridin-5-yl]-1H-pyrazole-5-carboxamide (2168):</b>Put N-(2-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dimethyl-1H-pyrazole-5-carboxamide into the microwave container<b>59</b>(0.05g, 0.13mmol) and 3-methyl-1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxboron<img file="TWI617552B_D0178.tif" wi="62" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)pyrazole<b>119</b>(0.18g, crude), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.01g, 0.02mmol) and 1,4-dioxane (3mL). To this mixture was added potassium carbonate (1M aqueous solution, 0.8 ml), and the reactant was irradiated at 110°C for 20 minutes. After filtration, the mixture was subjected to preparative HPLC with acetonitrile: water and 0.1% formazan The acid gradient dissociation is used to purify to obtain the compound in the form of the main product (<b>P-2168</b>). MS(ESI)[M+H+]+=392.2.¹H NMR and mass spectrum are consistent with the desired product.

Exemplary compound N-(2-(1-(1-acetylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3 -b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2194), N-(2-(1-(azetidin-3- Yl)-3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3 -Formamide (P-2195); 4,5-dimethyl-N-(2-(5-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl )-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2196); N-(2-(1-(azetidin- 3-yl)-5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole -3-methanamide (P-2197); 4,5-dimethyl-N-(2-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl )-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2198); N-(2-(1-(1-acetyl Piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H -Pyrazole-3-carboxamide (P-2199); N-(2-(1-(1-(cyclopropylcarbonyl)piperidin-4-yl)-5-methyl-1H-pyrazole-4 -Yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2200); 4,5- Dimethyl-N-(2-(3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-5 -Yl)-1H-pyrazole-3-carboxamide (P-2201); N-(2-(1-(1-acetylpiperidin-4-yl)-3-methyl-1H-pyridine (Azol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2202); and N-(2-(1-(1-(Cyclopropanyl)piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b] (Pyridin-5-yl)-4,5-Dimethyl-1H-pyrazole-3-carboxamide (P-2203) can be prepared according to the synthetic scheme set forth in Scheme 20 and Example 20.

<b>Example 21: Preparation of N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5- Formamide (P-2024)</b>

<b>Process 21.</b><chemistry general="n"><img he="948" wi="1976" file="TWI617552B_D0179.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Preparation of 5-[bis(tertiary butoxycarbonyl)amino]pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester 122:</b>Put 1H-pyrrolo[2,3-b]pyridine-5-amine into the round bottom flask<b>121</b>(1g, 7.51mmol), di-tert-butyl dicarbonate (6.5g, 29.78mmol), 4-dimethylaminopyridine (0.03g, 0.23mmol) and N,N-diisopropylethylamine ( 5ml, 28.71mmol) of tetrahydrofuran (20mL). The reaction was stirred at room temperature overnight and then concentrated. The residue was mixed with water and brine, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and evaporated to dryness. The obtained solid was purified by silica gel chromatography to obtain the compound<b>122</b>(0.73g, 22%). MS ESI [M+H+]+=434.3.¹The H NMR and mass spectrum data are consistent with the desired product.

<b>Step 2-Preparation of [5-(3rd butoxycarbonylamino)-1H-pyrrolo[2,3-b]pyridin-2-yl]</b><img file="TWI617552B_D0180.tif" wi="64" he="57" img-format="tif" img-content="character" orientation="portrait" inline="no" /><b>Acid 124:</b>Under nitrogen atmosphere to 5-[bis(tertiary butoxycarbonyl)amino]pyrrolo[2,3-b]pyridine-1-carboxylate<b>122</b>(0.38g, 0.88mmol) and triisopropyl borate<b>123</b>(2ml, 8.67mmol) To an ice-cold solution in tetrahydrofuran (5mL) was added a 2M solution of lithium diisopropylamide (3.6ml). The reaction mixture was stirred at 0°C for one hour, and then the reaction was allowed to stir at room temperature for another hour. The mixture was quenched with 2N HCl, placed on silica, and concentrated to dryness. The crude material was purified by silica gel chromatography with a gradient of methanol: dichloromethane (0-30%) to obtain the compound<b>124</b>(0.1g, 41%). The analysis data is consistent with the desired product.

<b>Step 3-Preparation of tertiary butyl N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]carbamate (126):</b>Put [5-(tertiary butoxycarbonylamino)-1H-pyrrolo[2,3-b]pyridin-2-yl] into the microwave container<img file="TWI617552B_D0181.tif" wi="67" he="59" img-format="tif" img-content="character" orientation="portrait" inline="no" />acid<b>124</b>(0.1g, 0.36mmol), 1-fluoro-4-iodo-benzene (0.09g, 0.4mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50mg , 0.06mmol) and 1,4-dioxane (4mL). Potassium carbonate (1M aqueous solution, 1 mL) was added, and the reaction was irradiated at 80°C for 10 minutes. The mixture was placed on silica and purified by silica gel chromatography with ethyl acetate:hexane gradient (20-100%) to obtain the compound<b>126</b>(0.02g, 17%). MS ESI [M+H+]+=327.8. The analysis data is consistent with the desired product.

<b>Step 4-Preparation of 2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine 5:</b>Containing N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]carbamic acid tert-butyl ester<b>125</b>(0.02 g, 0.06 mmol) of dichloromethane (2 mL) was added 1,4-dioxane containing hydrochloric acid (4 mL, 4N) and aqueous hydrochloric acid solution (50 μL, 12N). The reaction was stirred at room temperature for two hours and concentrated. The residue was dried under vacuum to obtain the crude compound<b>5</b>, It can be used without purification. MS ESI [M+H+]+=227.7. The analysis data is consistent with the desired product.

<b>Step 5-Preparation of N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4,5-dimethyl-1H-pyrazole-3- Formamide (P2034):</b>To a solution of 3,4-dimethyl-1H-pyrazole-5-carboxylic acid 6 (0.03g, 0.21mmol) in dimethylacetamide (2mL) was added hexafluorophosphate benzotriazole-1- Yl-oxytripyrrolidine phosphonium (0.11 g, 0.21 mmol), and the mixture was stirred at room temperature for 30 minutes. Sequentially add 2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-5-amine hydrochloride<b>5</b>(16mg, 0.06mmol) and N,N-diisopropylethylamine (0.5ml, 2.89mmol). The reaction mixture was stirred at room temperature for one hour, and purified by preparative HPLC to obtain compound (<b>P-2034</b>) (5mg, 21%). MS ESI[M+H+]+=350.15.¹The H NMR and mass spectrum data are consistent with the desired product.

<b>Step 6-Preparation of 5-[(4,5-Dimethyl-1H-pyrazole-3-carbonyl)amino]-2-(4-fluorophenyl)pyrrolo[2,3-b]pyridine-1 -Isopropyl formate (128):</b>Add 4,5-dimethyl-1H-pyrazole-3-carboxylic acid at -20°C<b>6</b>(69.3mg, 0.49mmol) of N-methylmorpholine (2mL) was added dropwise Isopropyl Chloroformate<b>127</b>(0.5ml, 1.0M in toluene, 0.5mmol). The mixture was stirred at -20°C for 10 minutes. Then add 2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-5amine to this mixture<b>5</b>(105 mg, 0.46 mmol), N-methylmorpholine (2 mL). The reaction mixture was stirred at -20°C for 20 minutes and allowed to warm to room temperature. It was then stirred at room temperature overnight. The solvent was removed, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was collected, washed with brine, and dried under sodium sulfate. After removing the desiccant and solvent, the residue is purified by column chromatography to obtain the compound<b>128</b>(32mg, 15.9%). MS ESI [M+H+]+=435.90.¹H NMR and MS are consistent with the desired product.

<b>Step 7-Preparation of N-[2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4,5-dimethyl-1H-pyrazole-3- Formamide (P-2034):</b>Containing 5-[(4,5-dimethyl-1H-pyrazole-3-carbonyl)amino]-2-(4-fluorophenyl)pyrrolo[2,3-b]pyridine-1-carboxylic acid Isopropyl ester<b>128</b>(20mg, 0.046mmol) of methanol (2mL) was added potassium hydroxide (8mg, 0.14mmol). The reaction mixture was stirred at room temperature overnight, concentrated, placed in water and brine, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After removing the desiccant and solvent, the residue was purified by silica gel chromatography to obtain compound (<b>P-2034</b>) (12mg, 74%). MS ESI [M+H+]+=350.1.

<b>Example 22: Preparation of N-[2-(2-cyclopropyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4,5-dimethyl-1H- Pyrazol-3-carboxamide (P-2108)</b>

<b>Process 22.</b><chemistry general="n"><img he="1273" wi="1941" file="TWI617552B_D0182.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of 5-[bis(tertiary butoxycarbonyl)amino]-2-iodo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (127):</b>Put 1H-pyrrolo[2,3-b]pyridine-5-amine into the round bottom flask<b>126</b>(1g, 7.51mmol), di-tert-butyl dicarbonate (6.5g, 29.78mmol), 4-dimethylaminopyridine (0.03g, 0.23mmol) and N,N-diisopropylethylamine ( 5ml, 28.71mmol) of tetrahydrofuran (20mL). The reaction mixture was stirred at room temperature overnight, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was collected, washed with brine, and dried over sodium sulfate. After removing the desiccant and solvent, the residue was purified by column chromatography on silica gel with a gradient of ethyl acetate: hexane to obtain the compound<b>127</b>(0.73g, 22%). MS(ESI)[M+H+]+=434.3.¹The H NMR and mass spectrum data are consistent with the desired product.

<b>Step 2-Synthesis of 5-[bis(tertiary butoxycarbonyl)amino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron</b><img file="TWI617552B_D0183.tif" wi="62" he="67" img-format="tif" img-content="character" orientation="portrait" inline="no" /><b>-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (131a):</b>To ice-cold 5-[bis(tertiary butoxycarbonyl)amino]-2-iodo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester<b>127</b>(0.1g, 0.23mmol) and isopropoxy-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)borane (0.091g, 0.49mmol) in tetrahydrofuran (3ml) add diisopropylamino group Lithium (2M, 0.23ml, 0.46mmol). The mixture was stirred at 0°C for one hour. The reaction was quenched with aqueous hydrochloric acid. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with brine, and dried over sodium sulfate. After removing the solvent, the residue was purified by silica gel column chromatography to obtain the compound<b>131a</b>. MS(ESI)[M+H+]+=559.80. The analysis data is consistent with the desired product.

<b>Step 3-Synthesis of 2-(4,4,5,5-tetramethyl-1,3,2-dioxboron</b><img file="TWI617552B_D0184.tif" wi="66" he="64" img-format="tif" img-content="character" orientation="portrait" inline="no" /><b>-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-amine (132):</b>To contain 5-[bis(tertiary butoxycarbonyl)amino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron<img file="TWI617552B_D0185.tif" wi="62" he="64" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester<b>131a</b>(1 equivalent) of tetrahydrofuran (THF) is added hydrochloric acid (1 to 10 equivalents). The reaction mixture was stirred at room temperature overnight. The solvent was removed, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, and dried over sodium sulfate. After removing the solvent, the residue was dried under vacuum to obtain the compound<b>132</b>。

<b>Step 4-Synthesis of 5-[bis(tert-butoxycarbonyl)amino]-2-iodo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (129):</b>Place tertiary butyl N-(2-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)carbamate into the round bottom flask<b>128</b>(0.8g, 2.23mmol), di-tert-butyl dicarbonate (1g, 4.58mmol), 4-dimethylaminopyridine (0.01g, 0.08mmol) and N,N-diisopropylethylamine ( 1ml, 5.74mmol) of tetrahydrofuran (20mL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was collected, washed with brine, and dried under sodium sulfate. After removing the desiccant and solvent, the residue is dried under vacuum to obtain the compound<b>129</b>, It can be used in subsequent reactions without purification. MS(ESI)[M+H+]+=560.25.

<b>Step 5-Synthesis of N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron</b><img file="TWI617552B_D0186.tif" wi="66" he="64" img-format="tif" img-content="character" orientation="portrait" inline="no" /><b>-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]carbamic acid tert-butyl ester (131b):</b>Containing 5-[bis(tertiary butoxycarbonyl)amino]-2-iodo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester<b>129</b>Add butyl lithium (1.6M, 0.6ml, 0.9mmol) to tetrahydrofuran (3ml) (0.1g, 0.23mmol). The mixture was stirred at room temperature for 20 minutes. Slowly add isopropoxy-containing to this mixture (4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)borane<b>130</b>(0.1g, 0.53mmol) of tetrahydrofuran (2ml). The resulting mixture was stirred at room temperature for three hours and then overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After removing the solvent, the residue was purified by silica gel column chromatography to obtain the compound as an off-white solid<b>131</b>(16mg, 16%). MS(ESI)[M+H+]+=359.9.

<b>Step 6-Synthesis of 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron</b><img file="TWI617552B_D0187.tif" wi="59" he="64" img-format="tif" img-content="character" orientation="portrait" inline="no" /><b>-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-amine (132):</b>To contain N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron<img file="TWI617552B_D0188.tif" wi="62" he="64" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]carbamic acid tert-butyl ester<b>131</b>(14mg, 0.04mmol) of tetrahydrofuran (1ml) was added with dioxane (0.5mL, 4M) containing hydrochloric acid. The reaction mixture was stirred at room temperature overnight. The solvent was removed, and the residue was partitioned between an appropriate solvent (ethyl acetate or dichloromethane), water and saturated sodium bicarbonate. The organic layer was collected and dried over sodium sulfate. After removing the solvent, the residue was dried under vacuum to obtain the crude compound as a brown solid<b>132</b>(8mg, 67%), it can be used in subsequent reactions without purification. MS(ESI)[M+H+]+=259.8.

<b>Step 7- Synthesis of 4,5-dimethyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron</b><img file="TWI617552B_D0189.tif" wi="64" he="64" img-format="tif" img-content="character" orientation="portrait" inline="no" /><b>-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-3-carboxamide (133):</b>To 3,4-dimethyl-1H-pyrazole-5-carboxylic acid in an appropriate amount of solvent (such as dimethylacetamide, tetrahydrofuran, acetonitrile or N,N-dimethylformamide)<b>6</b>(1 equivalent) successively add hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidine phosphonium (1 equivalent) or hexafluorophosphate O-benzotriazole-N,N,N',N'- Tetramethyl-<img file="TWI617552B_D0190.tif" wi="67" he="59" img-format="tif" img-content="character" orientation="portrait" inline="no" />(1 equivalent) and N-hydroxybenzotriazole (1 equivalent) and N,N-diisopropylethylamine (1 equivalent) or triethylamine (1 equivalent). The mixture is stirred at room temperature for 30 minutes to several hours. Add 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron to this mixture<img file="TWI617552B_D0191.tif" wi="62" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-amine<b>132</b>(1 equivalent) and N,N-diisopropylethylamine (1 equivalent) or triethylamine (1 equivalent). The reaction mixture is stirred at room temperature for one hour to 2-3 days. Heating can be used when needed. Partition the reaction mixture in organic solvents (including but not limited to) hexane, benzene, ethyl acetate and dichloro Between methane) and water. The organic layer was collected and dried over sodium sulfate. After removing the desiccant and solvent, the residue is purified by chromatography to obtain the compound<b>133</b>。

<b>Step 8-Synthesis of N-[2-(2-cyclopropyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4,5-dimethyl-1H- Pyrazole-3-carboxamide (P-2108):</b>To 4,5-dimethyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxyl boron<img file="TWI617552B_D0192.tif" wi="62" he="64" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazole-3-carboxamide<b>133</b>(1 equivalent), 4-bromo-2-cyclopropyl-pyridine<b>134</b>(1 equivalent), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) or 4(triphenylphosphine)palladium(0)(0.1 equivalent) in an appropriate amount of solvent (e.g. acetonitrile) Or add an appropriate amount of potassium carbonate aqueous solution (1M) to the mixture in tetrahydrofuran or dioxane). The reaction mixture is irradiated in a microwave at a temperature in the range of 90°C to 180°C for about 10 minutes to 2-3 hours. The reaction mixture was partitioned between water and organic solvents (including but not limited to hexane, ethyl acetate, and dichloromethane). The organic layer was collected, washed with brine, and dried under sodium sulfate. After removing the desiccant and solvent, the residue is purified by chromatography to obtain the compound<b>135</b>。

<b>Step 9- Synthesis of 5-[tertiary butoxycarbonyl-(1-tertiary butoxycarbonyl-4,5-dimethyl-pyrazole-3-carbonyl)amino]-2-iodo-pyrrolo[ 2,3-b] tertiary butyl pyridine-1-carboxylate (136):</b>Put N-(2-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dimethyl-1H-pyrazole-5-methan into the round bottom flask amine<b>59</b>(0.5g, 1.31mmol), di-tert-butyl dicarbonate (1.15g, 5.25mmol) and 4-dimethylaminopyridine (0.02g, 0.13mmol) in tetrahydrofuran (18ml). N,N-Diisopropylethylamine (0.8 ml, 4.59 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried under sodium sulfate. After removing the desiccant and solvent, the residue was purified by silica gel column chromatography (0-10% methanol/dichloromethane, 12 G) to obtain a white, brittle foamy compound<b>136</b>(700mg. 78.3%). MS(ESI)[M+H+]+=682.4.¹The H NMR and mass spectrum data are consistent with the structure of the desired product.

<b>Step 10-Synthesis of 5-[Third-butoxycarbonyl-(1-Third-butoxycarbonyl-4,5-dimethyl-pyrazole-3-carbonyl)amino]-2-(4,4, 5,5-Tetramethyl-1,3,2-Dioxyboron</b><img file="TWI617552B_D0193.tif" wi="69" he="66" img-format="tif" img-content="character" orientation="portrait" inline="no" /><b>-2-yl)pyrrolo</b><b>[2,3-b] tertiary butyl pyridine-1-carboxylate (137):</b>At -20°C, it contains 5-[tertiary butoxycarbonyl-(1-tertiary butoxycarbonyl-4,5-dimethyl-pyrazole-3-carbonyl)amino]-2-iodo- Pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester<b>136</b>(50mg, 0.073mmol) and isopropoxy-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)borane<b>130</b>(0.03g, 0.15mmol) of tetrahydrofuran (3ml) was added with tetrahydrofuran (1ml) containing lithium diisopropylamide (2M, 0.15ml, 0.3mmol). The mixture was slowly warmed to room temperature and stirred at room temperature overnight. The reaction was quenched with aqueous hydrochloric acid. The mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. After removing the solvent, the residue was purified by silica gel column chromatography to obtain the compound<b>137</b>. MS(ESI)[M+H+]+=682.5.

<b>Step 11-Synthesis of 3-[[2-(2-cyclopropyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]aminomethanyl]-4,5- Tertiary butyl dimethyl-pyrazole-1-carboxylate (138):</b>To 5-[third butoxycarbonyl-(1-third butoxycarbonyl-4,5-dimethyl-pyrazole-3-carbonyl)amino]-2-(4,4,5,5 -Tetramethyl-1,3,2-dioxboron<img file="TWI617552B_D0194.tif" wi="59" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester<b>137</b>(1 equivalent), 4-bromo-2-cyclopropyl-pyridine<b>134</b>(1 equivalent), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) or 4(triphenylphosphine)palladium(0)(0.1 equivalent) in an appropriate amount of solvent (e.g. acetonitrile) Or add an appropriate amount of potassium carbonate aqueous solution (1M) to the mixture in tetrahydrofuran or dioxane). The reaction mixture is irradiated in a microwave at a temperature in the range of 90 to 180°C for 10 minutes to 2-3 hours. The reaction mixture was partitioned between water and an appropriate solvent (ethyl acetate or dichloromethane). The organic layer was collected, washed with brine, and dried under sodium sulfate. After removing the desiccant and solvent, the residue is purified by chromatography to obtain the compound<b>138</b>。

<b>Step 12- Synthesis of N-[2-(2-cyclopropyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4,5-dimethyl-1H- Pyrazole-3-carboxamide (P-2108):</b>To 3-[[2-(2-cyclopropyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]aminomethanyl]-4 in an appropriate amount of tetrahydrofuran, Tert-butyl 5-dimethyl-pyrazole-1-carboxylate<b>138</b>(1 equivalent) hydrochloric acid (1 to 10 equivalents) is added. The reaction mixture was stirred at room temperature overnight. The solvent was removed, and the residue was partitioned between an appropriate solvent (ethyl acetate or dichloromethane), water and saturated sodium bicarbonate. Collect the organic layer Collect, wash with brine, and dry over sodium sulfate. After removing the desiccant and solvent, the residue is purified by chromatography to obtain the compound<b>135</b>。

Exemplary compound N-(2-(2-(cyclopropylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H -Pyrazole-3-carboxamide (P-2204); N-(2-(3-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-pyrrolo[2,3 -b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2205); N-(2-(2-(cyclopropanecarboxamide) (Pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P-2206); N -(2-(2-(1-(Cyclopropylcarbonyl)piperidin-4-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5 -Dimethyl-1H-pyrazole-3-carboxamide (P-2207); 4,5-dimethyl-N-(2-(2-(pyrrolidin-1-yl)pyridin-4-yl )-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2208); 4,5-dimethyl-N-(2-( 2-(piperidin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2209) ; 4,5-Dimethyl-N-(2-(2-(4-methylpiperidin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5 -Yl)-1H-pyrazole-3-carboxamide (P-2210); 4,5-dimethyl-N-(2-(2-(piperidin-4-yl)pyridin-4-yl) -1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2211); N-(2-(2-(4-hydroxypiperidine- 1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (P- 2212); and N-(2-(2-(3-hydroxypiperidin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4, 5-Dimethyl-1H-pyrazole-3-carboxamide (P-2213) can be prepared according to the synthesis scheme described in Example 22 and Scheme 22.

<b>Example 23: Preparation of 4,5-dimethyl-N-[2-[2-(4-methylsulfonylpiperazin-1-yl)-4-pyridyl]-1H-pyrrolo[2,3- b]Pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2189)</b>

<chemistry general="n"><img he="455" wi="2076" file="TWI617552B_D0195.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Synthesis of 3-Pendoxy-3-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron</b><img file="TWI617552B_D0196.tif" wi="62" he="64" img-format="tif" img-content="character" orientation="portrait" inline="no" /><b>-2-</b><b>(Yl)-2-pyridyl]piperazin-1-yl]propionitrile (141):</b>2-cyanoacetic acid<b>140</b>(0.1g, 1.18mmol) of tetrahydrofuran (3ml) was added hexafluorophosphate O-benzotriazole-N,N,N',N'-tetramethyl-<img file="TWI617552B_D0197.tif" wi="64" he="59" img-format="tif" img-content="character" orientation="portrait" inline="no" />(0.48ml, 1.32mmol) and N,N-diisopropylethylamine (0.4ml, 2.31mmol). The reaction mixture was stirred at room temperature for 30 minutes. Add 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxboron to the mixture<img file="TWI617552B_D0198.tif" wi="59" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)-2-pyridyl)piperazine<b>139</b>(0.2g, 0.69mmol) of tetrahydrofuran (1ml). The reaction mixture was stirred at room temperature overnight, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was collected, washed with brine, and dried under sodium sulfate. After removing the desiccant and solvent, the residue was dried under vacuum to obtain the crude compound<b>141</b>(0.35g), which can be used in subsequent reactions without purification.

<b>Step 2-Synthesis of 4,5-Dimethyl-N-[2-[2-(4-Methanesulfonylpiperazin-1-yl)-4-pyridyl]-1H-pyrrolo[2,3- b]Pyridin-5-yl]-1H-pyrazole-3-carboxamide (P-2189):</b>To contain N-(2-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dimethyl-1H-pyrazole-5-carboxamide<b>59</b>(0.1g, 0.26mmol) of acetonitrile (3ml) was added 3-side oxo-3-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron<img file="TWI617552B_D0199.tif" wi="59" he="59" img-format="tif" img-content="character" orientation="portrait" inline="no" />-2-yl)-2-pyridyl)piperazin-1-yl)propionitrile<b>141</b>(0.2g, crude), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (15mg, 0.019mmol) and potassium carbonate aqueous solution (1ml, 1M). The reaction mixture was irradiated in a microwave at 130°C for 30 minutes. The residue was partitioned between ethyl acetate and water. The organic layer was collected, washed with brine, and dried under sodium sulfate. After removing the desiccant and solvent, the residue was purified by preparative HPLC to obtain the compound as a yellow solid (<b>P-2189</b>) (35mg, 25%). MS(ESI)[M+H+]-+=484.30.¹The H NMR and mass spectrum data are consistent with the desired product.

Exemplary compound 3,4-dimethyl-N-[2-[2-(4-methylsulfonylpiperazin-1-yl)-4-pyridyl]-1H-pyrrolo[2,3-b ]Pyridin-5-yl]-1H-pyrazole-5-carboxamide (P-2186) and N-[2-[2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-4- Pyridyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dimethyl-1H-pyrazole-5-carboxamide (P-2187) is based on Example 23 and Prepared according to the synthetic scheme set forth in Scheme 23.¹The HNMR and mass spectrum data are consistent with the structure of the compound. Compound N-(2-(2-(4-Acetylpiperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5 - Dimethyl-1H-pyrazole-3-carboxamide (P-2214) and 4,5-dimethyl-N-(2-(2-(4-(3-methylbut-2-ene (Yl)piperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2215) also It can be prepared via the synthetic routes outlined in Example 23 and Scheme 23.

<b>Example 24: Preparation of N-cyclopropyl-4-[5-[(3,4-dimethyl-1H-pyrazole-5-carbonyl)amino]-1H-pyrrolo[2,3-b]pyridine -2-yl)pyridine-2-carboxamide (P-2175)</b>

<chemistry general="n"><img he="485" wi="2049" file="TWI617552B_D0200.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Preparation [2-(Cyclopropylaminomethanyl)-4-pyridyl]</b><img file="TWI617552B_D0201.tif" wi="66" he="59" img-format="tif" img-content="character" orientation="portrait" inline="no" /><b>Acid (141):</b>Add 4-dihydroxyboropyridine-2-carboxylic acid to the round bottom flask<b>139</b>(120mg, 0.72mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.28g, 1.44mmol) and 1-hydroxybenzotriazole (0.19g , 1.44 mmol) dimethylacetamide (3ml). The mixture was stirred at room temperature for 40 minutes, and then cyclopropylamine (0.06ml, 1.44mmol) and N,N-diisopropylethylamine (0.25ml, 1.44mmol) were added successively. The reaction mixture was stirred at room temperature for three hours, poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried under sodium sulfate. After removing the desiccant and solvent, the residue is dried under vacuum to obtain the compound<b>141</b>(60mg, 40.5%). The compound can be used in subsequent reactions without purification.

<b>Step 2-Preparation of N-cyclopropyl-4-[5-[(3,4-dimethyl-1H-pyrazole-5-carbonyl)amino]-1H-pyrrolo[2,3-b]pyridine -2-yl]pyridine-2-carboxamide (P-2175):</b>Put N-(2-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dimethyl-1H-pyrazole-5-carboxamide into the microwave container<b>59</b>(60mg, 0.16mmol), [2-(cyclopropylaminomethanyl)-4-pyridyl]<img file="TWI617552B_D0202.tif" wi="69" he="62" img-format="tif" img-content="character" orientation="portrait" inline="no" />acid<b>141</b>(0.06g, 0.31mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (0.01g, 0.01 mmol) and 1,4 dioxane (3 mL). To the mixture was further added an aqueous potassium carbonate solution (0.47 ml, 1 M), and the reactant was irradiated in a microwave at 130° C. for 30 minutes. Add another equivalent of [2-(cyclopropylaminomethanyl)-4-pyridyl]<img file="TWI617552B_D0203.tif" wi="67" he="59" img-format="tif" img-content="character" orientation="portrait" inline="no" />Acid, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and potassium carbonate aqueous solution (0.47ml, 1M), and the reaction mixture was irradiated in microwave at 135°C for another 30 minute. The reaction mixture was neutralized with 1N aqueous hydrochloric acid, poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried under sodium sulfate. After removing the desiccant and solvent, the residue was purified by silica gel column chromatography and wet-milled with methanol to obtain a white solid compound (<b>P-2175</b>) (5.5mg, 8.4%). MS(ESI)[M+H+]+=415.85.¹The H NMR and mass spectrum data are consistent with the structure of the compound.

Exemplary compound 4,5-dimethyl-N-(2-(2-(morpholin-4-carbonyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl )-1H-pyrazole-3-carboxamide (P-2216); 4,5-dimethyl-N-(2-(2-(4-methylpiperazine-1-carbonyl)pyridine-4- Yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2217); 4,5-dimethyl-N-(2- (2-(Pyrrolidine-1-carbonyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carbamide (P-2218 ); 4,5-Dimethyl-N-(2-(2-(thiomorpholine-4-carbonyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5- Group)-1H-pyrazole-3-carboxamide (P-2219); 4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamide)-1H-pyrrolo [2,3-b]pyridin-2-yl)-N-(2-methoxyethyl)picolinamide (P-2220); 4-(5-(4,5-dimethyl-1H -Pyrazole-3-carboxamide)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-(dimethylamino)ethyl)picolinamide (P -2221); 4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N -(2-Methoxyethyl)picolinamide (P-2222); 4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrole And [2,3-b]pyridin-2-yl)-N-methoxypyridinecarboxamide (P-2223); 4-(5-(4,5-dimethyl-1H-pyrazole-3 -Carboxamide)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N,N-dimethylpyridinecarboxamide (P-2224); 4-(5-(4, 5-Dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-N-morpholinoethyl) Picolinamide (P-2225); 4-(5-(4,5-dimethyl-1H- Pyrazol-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)pyridine Formamide (P-2226); N-(2-cyanoethyl)-4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrole And [2,3-b]pyridin-2-yl)pyridinecarboxamide (P-2227); 4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamide) -1H-pyrrolo[2,3-b]pyridin-2-yl)-N-isobutylpyridinecarboxamide (P-2228); 4-(5-(4,5-dimethyl-1H- Pyrazole-3-carboxamide)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-isopropylpyridinecarboxamide (P-2229); and 4-(5- (4,5-Dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N,N-diethylpicolinate Amine (P-2230) can be prepared according to the synthetic scheme set forth in Example 24 and Scheme 24.

<b>Example 25: Preparation of 5-methyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(trifluoromethyl)-1H-pyrazole-3 -Formamide (P-2190)</b>

<chemistry general="n"><img he="412" wi="2064" file="TWI617552B_D0204.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></chemistry>

<b>Step 1-Preparation of 5-methyl-4-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (145):</b>To bis(trifluoromethanesulfonyl) zinc (0.15g, 0.45mmol) and 5-methyl-1H-pyrazole-3-carboxylic acid<b>143</b>To a mixture of (0.05 g, 0.4 mmol) in dichloromethane (2 mL) were added water (0.5 mL) and tertiary butyl hydroperoxide (0.3 mL, 70% aqueous solution, 2 mmol) successively. The reaction mixture was warmed to room temperature and stirred for two hours, and then overnight. The reaction mixture was stirred at 50°C for three days. The reaction mixture was partitioned between dichloromethane and water. The organic layer was collected and dried over sodium sulfate. After removing the desiccant and solvent, the residue was purified by preparative HPLC to obtain the compound as a white solid<b>145</b>(5mg, 6.5%). MS(ESI)[M+H+]+=194.70.¹The H NMR and mass spectrum data are consistent with the structure of the compound.

<b>Step 2-Preparation of 5-methyl-4-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (P-2190):</b>Favor a suitable amount of solvents (such as dimethylacetamide, tetrahydrofuran, acetonitrile or N,N-dimethylformamide) Amine) in 5-methyl-4-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (1 equivalent)<b>145</b>Sequentially add hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidine phosphonium (1 equivalent) or hexafluorophosphate O-benzotriazole-N,N,N',N'-tetramethyl-<img file="TWI617552B_D0205.tif" wi="62" he="57" img-format="tif" img-content="character" orientation="portrait" inline="no" />(1 equivalent) and N-hydroxybenzotriazole (1 equivalent) and N,N-diisopropylethylamine (1 equivalent) or triethylamine (1 equivalent). The mixture is stirred at room temperature for 30 minutes to several hours. Add 2-(4-phenyl)-1H-pyrrolo[2,3-b]pyridine-5-amine hydrochloride to this mixture<b>16</b>(1 equivalent) and N,N-diisopropylethylamine (1 equivalent) or triethylamine (1 equivalent). The reaction mixture is stirred at room temperature for one hour to 2-3 days. Heating can be used when needed. The reaction mixture was partitioned between an organic solvent (ethyl acetate, dichloromethane, etc.) and water. The organic layer was collected and dried over sodium sulfate. After removing the desiccant and solvent, the residue is purified by chromatography or/and preparative HPLC to obtain the compound<b>P-2190</b>。

Exemplary compound 4-methyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-3- Formamide (P-2231); 4-chloro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)-1H- Pyrazol-3-carboxamide (P-2232); 5-chloro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(trifluoromethyl Yl)-1H-pyrazole-3-carboxamide (P-2233); 5-(difluoromethyl)-4-methyl-N-(2-phenyl-1H-pyrrolo[2,3- b]Pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2234); 4-(difluoromethyl)-5-methyl-N-(2-phenyl-1H-pyrrole And [2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2235); 5-chloro-4-(difluoromethyl)-N-(2-benzene Group-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2236); and 4-chloro-5-(difluoromethyl)- N-(2-Phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide (P-2237) can be described according to Example 25 and Scheme 25 The synthesis scheme is prepared.

The compounds listed in Table 1 below (for example, compounds P-2001 to P-2189) were prepared according to the schemes illustrated in Examples 1-25 and Schemes 1-25. The¹The H NMR and mass spectrum data are consistent with the structure of the compound.

<tables><img he="2934" wi="2080" file="twi617552b_d0206.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3140" wi="2133" file="twi617552b_d0207.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3175" wi="2061" file="twi617552b_d0208.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3089" wi="2064" file="twi617552b_d0209.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3089" wi="2068" file="twi617552b_d0210.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3186" wi="2064" file="twi617552b_d0211.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3179" wi="2073" file="twi617552b_d0212.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3159" wi="2046" file="twi617552b_d0213.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3045" wi="2050" file="twi617552b_d0214.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3094" wi="2096" file="twi617552b_d0215.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3028" wi="2071" file="twi617552b_d0216.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3160" wi="2065" file="twi617552b_d0217.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3121" wi="2099" file="twi617552b_d0218.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3146" wi="2083" file="twi617552b_d0219.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="2323" wi="2092" file="twi617552b_d0220.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables>

Exemplary compounds of the invention as set forth in Table 2, for example, compounds P-2190 to P-2273 were prepared according to the schemes set forth in Examples 1-25 and Schemes 1-25.¹The H NMR and mass spectrum data are consistent with the structure of the compound.

<tables><img he="3084" wi="2151" file="twi617552b_d0221.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3074" wi="2083" file="twi617552b_d0222.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3197" wi="2117" file="twi617552b_d0223.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3000" wi="2052" file="twi617552b_d0224.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3000" wi="2072" file="twi617552b_d0225.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3088" wi="2085" file="twi617552b_d0226.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="2614" wi="2059" file="twi617552b_d0227.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables>

Exemplary compounds of the invention as set forth in Table 3, for example, compounds P-2274 to P-2307 were prepared according to the schemes set forth in Examples 1-25 and Schemes 1-25.¹The H NMR and mass spectrum data are consistent with the structure of the compound.

<tables><img he="3078" wi="2079" file="twi617552b_d0228.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3057" wi="2078" file="twi617552b_d0229.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="2634" wi="2086" file="twi617552b_d0230.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables>

<b>Example 26: Compound properties</b>

Although the inhibitory activity of the compound against any c-kit kinase and its mutants is important for its activity in the treatment of diseases, the compounds described herein exhibit advantageous properties that also provide advantages as drugs.

The compounds described herein are suitable for the treatment of diseases related to c-kit and its mutants, such as diseases related to unregulated kinase signal transduction, especially including cell proliferation disorders, fibrotic disorders and metabolic disorders. As described in more detail in Lipson et al., US2004/0002534 (US application 10/600,868 filed on June 23, 2003), which can be treated by the present invention, as described below and in Lipson et al., which is incorporated herein by reference in its entirety, Including cancer and mast cell proliferation disorders.

The existence of c-kit or c-kit mutants is also related to many different types of cancers. In addition, the correlation between c-kit abnormalities and diseases is not limited to cancer. Therefore, c-kit is related to the following: malignant diseases, including mast cell tumor, small cell lung cancer, testicular cancer, gastrointestinal stromal tumor (GIST), glioblastoma, astrocytoma, neuroblastoma, female reproductive tract Carcinoma, sarcoma of neuroectodermal origin, colorectal cancer, carcinoma in situ, Schwann cell tumor formation associated with neurofibromas, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis , Melanoma and canine mast cell tumors; and inflammatory diseases, including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel disease, transplant rejection and eosinophilia.

<i>Exemplary c-kit biochemical analysis</i>

The analysis of c-kit kinase based on biochemical cell activity is known in the art, for example, as described in US Pat. Way to incorporate. c-kit (or its kinase domain) is the active kinase in AlphaScreen. Determination of IC against c-Kit kinase activity inhibition₅₀Value, where the phosphorylation inhibition of the peptide is measured as a function of compound concentration. The compound to be tested is dissolved in DMSO to a concentration of 20 mM. It was diluted from 30 μl to 120 μl DMSO (4 mM), and 1 μl was added to the analysis plate. Subsequently, it was serially diluted 1:3 (50 μl to 100 μl DMSO) for a total of 8 points. Prepare each plate so that each kinase reactant is in 1× kinase buffer (50mM HEPES (pH 7.2), 5mM MgCl₂, 5mM MnCl₂, 0.01% NP-40, 0.2% BSA), 20μl reaction in 5% DMSO and 10μM ATP Things. The substrate is 100 nM biotin-(E4Y)3 (Open Source Biotech, Inc.). The concentration of c-kit kinase is 0.1 ng per sample. After incubating the kinase reaction at room temperature for 1 hour, add 5 μl of donor beads (streptavidin-coated beads (Perkin Elmer Life Science) in stop buffer (50 mM EDTA in 1× kinase buffer) ), the final concentration is 1μg/ml), the samples are mixed and incubated at room temperature for 20 minutes, and then 5μl of acceptor beads (PY20 coated beads (Perkin Elmer Life Science) in the stop buffer (Perkin Elmer Life Science) are added, the final concentration 1μg/ml). The samples were incubated at room temperature for 60 minutes, and the signal of each well was read on an AlphaQuest reader. Phosphorylation of the substrate causes the PY20 antibody to bind and the donor and acceptor beads to associate, so the signal is related to kinase activity. Use signal to determine IC of compound concentration₅₀。

A similar analytical test compound with a 10-fold higher ATP concentration was also used. For these samples, the compound to be tested was dissolved in DMSO to a concentration of 20 mM. It was diluted from 30 μl to 120 μl DMSO (4 mM), and 1 μl was added to the analysis plate. Subsequently, it was serially diluted 1:3 (50 μl to 100 μl DMSO) for a total of 8 points. Prepare each plate so that each kinase reactant is in 1× kinase buffer (25mM HEPES (pH 7.5), 2mM MgCl₂, 2mM MnCl₂, 0.01% Tween-20, 1mM DTT and 0.001% BSA), 5% DMSO and 100μM ATP in 20μl reaction. The substrate was 30 nM biotin-(E4Y)10 (Upstate Biotech, catalog number 12-440). The concentration of c-kit kinase is 1 ng per sample. After incubating the kinase reaction at room temperature for 1 hour, add 5 μl of donor beads (streptavidin-coated beads (Perkin Elmer) in stop buffer (25mM HEPES pH 7.5, 100mM EDTA, 0.3% BSA) Life Science), final concentration 10μg/ml), mix the samples, and incubate at room temperature for 20 minutes, then add 5μl of acceptor beads (PY20 coated beads (Perkin Elmer Life Science) in stop buffer), The final concentration is 10μg/ml). The samples were incubated at room temperature for 60 minutes, and the signal of each well was read on an AlphaQuest or Envision reader (Perkin Elmer Life Science). Phosphorylation of the substrate causes the PY20 antibody to bind and the donor and acceptor beads to associate, so The signal is related to kinase activity. Use signal to determine IC of compound concentration₅₀。

The c-kit enzyme used in the above analysis was obtained from Cell Signaling Technology (Cat. No. 7754) or prepared as follows: Use common polymerase chain reaction (PCR) methods to engineer plastid coding kit (the DNA and the encoded protein sequence shown below) ). Complementary DNA selected from various human tissues was purchased from Invitrogen and used as a substrate for PCR reactions. Specific custom synthetic oligonucleotide primers are designed to prime PCR products and provide appropriate restriction enzyme cleavage sites for the engagement with plastids. The complete sequence encoding the enzyme was prepared through a gene synthesis program using custom synthetic oligonucleotides (Invitrogen, see below) covering the complete coding sequence.

The plastid used to mate with the kinase-encoded insert is a derivative of pET (Novagen) expressed in E. coli. The Kit kinase was engineered to include a histidine tag for purification using metal affinity chromatography. The kinase-encoding plastids are engineered into bicistronic mRNA to jointly express a second protein that modifies the kinase protein during its expression in the host cell. Together they show the phosphotyrosine dephosphorylation of protein tyrosine phosphatase 1B (PTP).

In terms of protein expression, the plastids containing the Kit gene were transferred to E. coli strain BL21(DE3)RIL and selected for growth on LB agar plates containing appropriate antibiotics. A single colony was grown in 200 mL TB (Terrific broth) medium at 37°C overnight. 16×1L of fresh TB medium in a 2.8L flask was inoculated with 10 mL of overnight medium, and grown at 37°C under constant shaking. Once the medium reaches an absorbance of 1.0 at 600nm, IPTG is added, and the medium is grown for another 12 to 18 hours at a temperature in the range of 12-30°C. The cells were collected by centrifugation, and the aggregated pellets were frozen at -80°C until ready to dissolve.

For protein purification; the frozen E. coli cell aggregate pellet is resuspended in lysis buffer and lysed using standard mechanical methods. IMAC purified protein is purified using immobilized metal affinity via a polyhistidine tag. Purify Kit kinase using the following three-step purification method: IMAC, size exclusion chromatography, and ion exchange chromatography. Thrombin (Thrombin, Calbiochem) was used to remove the polyhistidine tag.

Analyze compounds using an analysis similar to the above analysis, using a final reaction volume of 25μl of the following substances: c-Kit(h) (5-10mU) at 8mM MOPS pH 7.0, 0.2mM EDTA, 10mM MnCl₂, 0.1mg/ml more (Glu, Tyr) 4: 1, 10mM magnesium acetate and γ-³³P-ATP (about 500cpm/pmol), a compound with appropriate concentration. Incubate for 40 minutes at room temperature and stop by adding 5 μl of 3% phosphoric acid. 10 μl of each sample was spotted on Filtermat A and washed 3 times with 75 mM phosphoric acid (once with methanol), dried, and measured on a scintillation counter (at Upstate USA, Charlottesville, VA).

<i>Exemplary c-kit mutant biochemical analysis</i>

The c-kit mutant D816V (or its kinase domain) is the active kinase in AlphaScreen. Determination of the IC against the inhibition of c-Kit mutant D816V kinase activity₅₀Value, where the phosphorylation inhibition of the peptide substrate is measured as a function of compound concentration. The compound to be tested is dissolved in DMSO to a concentration of 20 mM. It was diluted from 30 μl to 120 μl DMSO (4 mM), and 1 μl was added to the analysis plate. Subsequently, it was serially diluted 1:3 (50 μl to 100 μl DMSO) for a total of 8 points. Prepare each plate so that each kinase reactant is in 1× kinase buffer (25mM HEPES (pH 7.2), 8mM MgCl₂, 2mM MnCl₂, 50mM NaCl, 0.01% Brij, 1mM DTT, 0.01% BSA), 5% DMSO and 20μM ATP in 20μl reaction. The substrate was 30 nM biotin-(E4Y)10 (EMD Millipore, catalog number 12-440). The concentration of c-kit mutant D816V kinase is 0.75 ng per sample. After incubating the kinase reaction at room temperature for 30 minutes, add 5 μl of donor beads (streptavidin-coated beads (Perkin Elmer) in stop buffer (25mM Hepes pH 7.5, 100mM EDTA, 0.01% BSA) Life Science), final concentration 7.5μg/ml), mix the samples and incubate at room temperature for 20 minutes, then add 5μl of acceptor beads in stop buffer (PY20 coated beads (Perkin Elmer Life Science) , The final concentration is 7.5μg/ml). The samples were incubated at room temperature for 60 minutes, and the signal of each well was read on the EnVision reader. Phosphorylation of the substrate causes the PY20 antibody to bind and the donor and acceptor beads to associate, so the signal is related to kinase activity. Use signal to determine IC of compound concentration₅₀。

<i>Protein expression and purification</i>

The recombinant c-kit mutant D816V (residues 551-934, residues 694-753 of the kinase insertion domain deleted) with a 6x histidine N-terminal tag was expressed in E. coli Arctic Express (DE3) RIL (Stratagene). Grow the cells in the best broth (TB) medium at 37°C to an OD of 0.6₆₀₀At this time, the temperature was lowered to 10°C, the protein was induced with 1.0mM IPTG for 18 hours, and collected by centrifugation at 8000×g for 20 minutes. Resuspend cells in 0.1M KPO₄ pH 8.0, 250mM NaCl, 10% glycerol, 0.75% NP-40, 25mM imidazole, 5mM BME (with 0.2mg/ml lysozyme), 2.0mM PMSF, 25μg/ml DNase I, incubate in ice for 30 minutes, And use cell disrupting agent (MicroFluidics) to dissolve. The lysate was clarified by centrifugation at 20,000×g for 2 hours. The protein was captured with Talon resin (Clontech). Use 25mM Tris-HCl pH 8.3, 250mM NaCl, 15% glycerol, 1% Triton X-100 to wash away the contaminating protein, and use 100mM EDTA to dissolve the protein. The protein was further purified using gel filtration column 26/600 Superdex 200 (GE) in 50 mM Tris-HCl, pH 8.0, 250 mM NaCl, 15% glycerol, and 5 mM BME. The protein was aliquoted and flash frozen in liquid nitrogen.

<i>Exemplary cell-based analysis of c-kit mutant kinase activity</i>

The engineered BaF3-FL KIT D816V or BaF3-FL KIT V560G/D816V cell line was used to evaluate the c-Kit mutant D816V inhibitor. The BaF3-FL KIT D816V cell line was generated by introducing the KIT mutant (D816V) full-length constructs, which made the cells grow dependent on the introduced kinase. The inhibitor of c-Kit mutant D816V kinase reduces or eliminates the mediated activation of c-kit mutant D816V kinase, resulting in a decrease in the cell proliferation of BaF3-FL Kit mutant D816V cells. Measure the inhibition by the effect of compound concentration on cell growth to evaluate IC₅₀value. Divide BaF3-FL KIT D816V cells into 1×10 per well of a 96-well cell culture plate⁴Cells were seeded in 50 μl supplemented with 10% FBS (Invitrogen code 10438), 1% non-essential amino acid (Invitrogen code 11140), 1% penicillin streptomycin (Invitrogen code 15140), 1% L-glutamic acid ( Invitrogen number 25030-081) RPMI medium 1× (Invitrogen No. 11875-093) cell culture medium. The compound was dissolved in DMSO at a concentration of 5 mM, and a total of eight points were serially diluted 1:3, and added to the cells at a final maximum concentration of 10 μM in 100 μl cell culture medium (final concentration 0.2% DMSO). The cells were also treated with dasatinib as a positive control. Place the cells at 37°C, 5% CO₂Cultivate for three days. Equilibrate the ATPlite buffer (Perkin Elmer No. 6016739) and the substrate to room temperature, and restore the enzyme/substrate recombinant firefly luciferase/D-luciferin. Allow the cell plate to equilibrate to room temperature for 30 minutes, and then dissolve it by adding 25 μL of ATPlite reagent per well. Mix the plate on a plate shaker for 5 minutes to lyse the cells. Use the improved luminescence scheme to read 0.1s per well to read the plate on the Tecan Safire. Luminescence reading assesses ATP content, which is directly related to cell number, so that the reading is used as a function of compound concentration to determine IC₅₀value.

The plastids P75635 and P75565 are engineered for mammalian cell performance. Of the two plastids, the full-length human v-kit Hardy-Zuckerman 4 cat sarcoma virus oncogene homolog gene (NCBI deposit NM_000222, KIT, residues M1-V976) was subpopulated into pCI-Neo vector (Promega E1841). )middle. The plastid P75635 contains a mutation from residue 816 of aspartic acid to valine. The plastid P75565 contains a double mutation of residues valine 560 to glycine and aspartic acid 816 to valine. The pCI-neo mammalian expression vector carries human cytomegalovirus (CMV), the early enhancer/promoter region to promote the constitutive expression of KIT, and contains the neomycin phosphotransferase gene (a selectable marker).

It should be understood that the results of these analyses may vary with the analysis conditions. The level of inhibition determined under the conditions described herein represents the relative activity of the compound tested under the specific conditions used. Cell-based analysis may exhibit variability due to the complexity of the system and its sensitivity to any changes in the analysis conditions. Therefore, a certain level of inhibition in a cell-based analysis indicates that the compound has a certain inhibitory activity on their cells, and the lack of inhibitory effect below the threshold value of the highest concentration tested does not necessarily indicate that the compound has no inhibitory activity on cells. It only indicates that no inhibition is observed under the conditions tested. In some love In this case, the compound is not tested in all analyses, or the analytical results are not valid.

The following table provides data representing the biochemical inhibitory activity of c-kit and c-kitD816V of exemplary compounds as described herein. In the table below, the activity of kit and kit mutant analysis is provided as follows: +++=0.0001&lt;IC₅₀&lt;1μM; ++=1μM&lt;IC₅₀&lt;10μM; +=10μM&lt;IC₅₀&lt;200μM.<tables><img he="2475" wi="1505" file="twi617552b_d0231.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3149" wi="1523" file="twi617552b_d0232.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="3180" wi="1548" file="twi617552b_d0233.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables><tables><img he="1132" wi="1513" file="twi617552b_d0234.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /></tables>

Compounds P-2001 to P-2102, P-2104 to P-2116, and P-2118 to P-2189, such as compounds P-2001, P-2002, P-2004, P-2005, P-2006, P-2007 , P-2008, P-2012, P-2013, P-2014, P-2015, P-2016, P-2019, P-2020, P-2022, P-2023, P-2024, P-2026, P -2027, P-2028, P-2029, P-2030, P-2031, P-2032, P-2033, P-2034, P-2035, P-2036, P-2037, P-2038, P-2039 , P-2040, P-2041, P-2042, P-2043, P-2044, P-2045, P-2046, P-2047, P-2048, P-2049, P-2050, P-2051, P -2052, P-2053, P-2054, P-2055, P-2056, P-2057, P-2058, P-2059, P-2060, P-2061, P-2062, P-2063, P-2064 , P-2065, P-2066, P-2067, P-2068, P-2069, P-2070, P-2072, P-2073, P-2074, P-2075, P-2076, P-2077, P -2078, P-2079, P-2080, P-2081, P-2082, P-2083, P-2084, P-2085, P-2086, P-2087, P-2088, P-2089, P-2090 , P-2091, P-2092, P-2093, P-2094, P-2095, P-2096, P-2097, P-2098, P-2099, P-2100, P-2101, P-2102, P -2104, P-2105, P-2106, P-2107, P-2108, P-2109, P-2110, P-2111, P-2112, P-2113, P-2114, P-2115, P-2116 , P-2117, P-2118, P-2119, P-2120, P-2121, P-2122, P- 2123, P-2124, P-2125, P-2126, P-2127, P-2128, P-2129, P-2130, P-2131, P-2132, P-2133, P-2134, P-2135, P-2136, P-2137, P-2138, P-2139, P-2140, P-2141, P-2142, P-2144, P-2145, P-2146, P-2147, P-2148, P- 2149, P-2150, P-2151, P-2152, P-2153, P-2154, P-2155, P-2156, P-2157, P-2158, P-2159, P-2160, P-2161, P-2162, P-2163, P-2164, P-2165, P-2166, P-2167, P-2168, P-2169, P-2170, P-2171, P-2172, P-2173, P- 2174, P-2175, P-2176, P-2177, P-2178, P-2179, P-2180, P-2181, P-2182, P-2183, P-2184, P-2185, P-2186, The IC of P-2187, P-2188 and P-2189 in at least one c-kit cell analysis described in Example 26 above₅₀Less than 10μM.

Compounds P-2190 to P-2267, such as compounds P-2190, P-2191, P-2192, P-2193, P-2194, P-2195, P-2196, P-2197, P-2198, P-2199 , P-2200, P-2201, P-2202, P-2203, P-2204, P-2205, P-2206, P-2207, P-2208, P-2209, P-2210, P-2211, P -2212, P-2213, P-2214, P-2215, P-2216, P-2217, P-2218, P-2219, P-2220, P-2221, P-2222, P-2223, P-2224 , P-2225, P-2226, P-2227, P-2228, P-2229, P-2230, P-2231, P-2232, P-2233, P-2234, P-2235, P-2236, P -2237, P-2238, P-2239, P-2240, P-2241, P-2242, P-2243, P-2244, P-2245, P-2246, P-2247, P-2248, P-2249 , P-2250, P-2251, P-2252, P-2253, P-2254, P-2255, P-2256, P-2257, P-2258, P-2259, P-2260, P-2261, P -2262, P-2263, P-2264, P-2265, P-2266 and P-2267 in the IC of at least one c-kit cell analysis described in Example 26 above₅₀Less than 10μM.

Compounds P-2268 to P-2307, such as compounds P-2268, P-2269, P-2270, P-2271, P-2272, P-2273, P-2274, P-2275, P-2276, P-2277 , P- 2278, P-2279, P-2280, P-2281, P-2282, P-2283, P-2284, P-2285, P-2286, P-2287, P-2288, P-2289, P-2290, P-2291, P-2292, P-2293, P-2294, P-2295, P-2296, P-2297, P-2298, P-2299, P-2300, P-2301, P-2302, P- IC of 2303, P-2304, P-2305, P-2306 and P-2307 in at least one c-kit cell analysis described in Example 26 above₅₀Less than 10μM.

In male Sprague Dawley rat (Sprague Dawley rat) or male Migru dog (Beagle dog) in the evaluation of compounds as described herein (including any solid forms or formulations thereof) (e.g. compounds P-2001, P-2002, P-2004 to P-2273 and P-2274 to P-2307) Kinetic properties. Compounds were administered to rats daily by intravenous (IV) injections via surgically implanted jugular vein catheters or via oral gavage (PO). Each compound was prepared as a 20 mg/mL stock solution in dimethylsulfoxide, which was further diluted to provide a dosing stock solution of the desired concentration for the IV or PO formulation. For IV administration, the dosing stock solution is diluted in a 1:1:8 mixture of Solutol®:ethanol:water. For PO administration, the dosing stock solution is diluted in 1% methylcellulose. Dilute the compounds to 0.5 mg/mL (for IV administration) and 0.4 mg/mL (for PO administration) in a cassette format (or each compound, its solid form or its formulations are carried out individually), And they were administered at 1 mg/kg (2 mL/kg) or 2 mg/kg (5 mL/kg). For IV-administered animals, collect tail vein blood with lithium heparin anticoagulant at the 5th, 15th, 30th and 60th minute, 4th, 8th and 24th hour after administration every day sample. For PO-administered animals, blood samples from the tail vein were collected with lithium heparin anticoagulant every day at 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration. Oral capsules are used daily to administer 50 mg/mL of a suitable formulation. Every day at the 30th minute, 1st hour, 2nd hour, 4th hour, 8th hour and 24th hour after administration, blood samples from the cephalic vein were collected with lithium heparin anticoagulant. All samples were processed into plasma and frozen for subsequent analysis of each compound by LC/MS/MS. Plot the plasma level as a function of time to assess AUC (ng*hr/mL). The compound of the present invention preferably exhibits improved pharmacokinetic properties relative to the previously described compound, that is, the value of one or more of the AUC, Cmax and half-life of the compound of the present invention is substantially higher than that of the previously described compound .

All patents, patent applications and other references cited in the specification represent the technical level of those who are familiar with the technology to which the present invention belongs, and are incorporated in the form of full citation including any tables and figures, and the degree of citation is as if Each reference has been individually incorporated into the general by citation in its entirety.

Those who are familiar with the technology can easily understand that the present invention is very suitable for obtaining the goals and advantages, as well as their inherent goals and advantages. The methods, variations, and compositions described herein that currently represent preferred embodiments are exemplary and are not intended to limit the scope of the present invention. The changes and other uses should be thought of by those who are familiar with the technology, and they are included in the spirit of the present invention and defined by the scope of the patent application.

Although the present invention has been disclosed with reference to specific embodiments, it is obvious that other embodiments and variations of the present invention can be designed by those skilled in the art without departing from the true spirit and scope of the present invention.

In addition, when describing the features or aspects of the present invention based on the Markush group or other alternative groupings, those familiar with the art should understand that the present invention is therefore based on any individual member of the Markush group or other group Or subgroup members can be described.

Likewise, unless indicated to the contrary, when various numerical values are provided in the embodiments, other embodiments are described by using any two values other than the end of the range. These ranges also belong to the scope of the disclosure content.

SEQ ID NO：1序列NP_000213 <img he="2786" wi="1913" file="TWI617552B_D0235.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /><img he="1656" wi="1873" file="TWI617552B_D0236.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" />

SEQ ID NO：2序列NM_000222 <img he="1176" wi="1924" file="TWI617552B_D0237.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /><img he="2986" wi="1941" file="TWI617552B_D0238.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" /><img he="2300" wi="1930" file="TWI617552B_D0239.tif" img-content="drawing" img-format="tif" orientation="portrait" inline="no" />