Cienopyridinone compound

Abstract

Provided are novel thienopyridinone compounds, pharmaceutical compositions containing the compounds, methods for preparing the compounds, and uses of the compounds as FGFR (fibroblast growth factor receptor) inhibitors and in the treatment of diseases such as cancer.

Description

Technical Field

[0001] The present invention relates to novel thienopyridinone compounds, pharmaceutical compositions containing said compounds, methods for preparing said compounds, and the use of said compounds as FGFR (fibroblast growth factor receptor) inhibitors, and the use of said compounds in the treatment of diseases such as cancer.

Background Art

[0002] The fibroblast growth factor (FGF) signaling pathway has been demonstrated to play an important role in processes from embryogenesis to wound healing, and also shows a strong connection with some characteristics of cancer. Genetic changes in FGFR family members are associated with tumor growth, metastasis, angiogenesis, and survival. Various FGFR inhibitors are in clinical trials and show clinical responses in patients with FGFR abnormalities. However, mutations that affect the amino acids of FGFR, such as FGFR1, 2, or 3, have been reported to cause resistance to FGFR inhibitors or reduce sensitivity to FGFR inhibitors. The occurrence of secondary FGFR kinase domain mutations during treatment with FGFR inhibitors is an important mechanism of acquired resistance to FGFR inhibition. In cancer, equivalent FGFR point mutations also newly exist. Gatekeeper mutations have been reported as one of the main mechanisms leading to resistance to tyrosine kinase inhibitors. Examples of gatekeeper mutations include FGFR3 V555L / V555M, FGFR1 V561M, FGFR2 V564F / V564I / V564M, and FGFR4 V550L. FGFR resistance mutations have been reported in clinical trials and in vitro cell lines. Therefore, new (second-generation) FGFR inhibitors are needed for more sustained activation in cancers with changes in the FGFR signaling pathway to overcome clinically acquired resistance to first-generation FGFR inhibitor therapies. Second-generation FGFR inhibitors are needed to maintain FGFR inhibitory activity by overcoming the reduced activity observed with first-generation FGFR inhibitors against FGFRs having the above gatekeeper mutations.

[0003] The compounds of the present invention have been found to be active against mutant FGFRs, particularly FGFRs having gatekeeper mutations, or mutant FGFR1 or mutant FGFR2 or mutant FGFR3, particularly against FGFR3 V555L, FGFR3 V555M, FGFR1 V561M, and FGFR2 V564I, and especially against FGFR3 V555L and FGFR3 V555M.

[0004] WO 2002 / 022598, WO 2003 / 087095, WO 2004 / 018419, WO 2004 / 043389, and WO 2005 / 046589 each disclose a series of quinolinone derivatives. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0005] The present invention relates to formula (I):

Chemical formula

[0006] In another aspect, there is provided a method for preventing or treating a condition or disorder mediated by FGFR kinase, the method comprising administering to a subject in need thereof a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

[0007] In a further aspect, there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the prevention or treatment of a condition or disorder mediated by FGFR kinase.

[0008] In a further aspect, there is provided the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the prevention or treatment of a condition or disorder mediated by FGFR kinase.

[0009] In another aspect, there is provided a method for preventing or treating (particularly treating) cancer, the method comprising administering to a subject in need thereof a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof. In particular, this cancer is a cancer mediated by FGFR kinase.

[0010] In a further aspect, provided is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the prevention or treatment (especially treatment) of cancer. In particular, this cancer is a cancer mediated by FGFR kinase.

[0011] In a further aspect, provided is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the prevention or treatment (especially treatment) of cancer. In particular, this cancer is a cancer mediated by FGFR kinase.

Mode for Carrying Out the Invention

[0012] Unless the context indicates otherwise, references to formula (I) in all parts of this document (including the uses, methods, and other aspects of the present invention) include references to all other sub-formulas (e.g., (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a)), sub-groups, preferences, embodiments, and examples as defined herein.

[0013] The prefix "C x~y "(wherein x and y are integers) when used herein refers to the number of carbon atoms in a given group. Thus, C 1~6 alkyl group contains 1 to 6 carbon atoms, C 3~6 cycloalkyl group contains 3 to 6 carbon atoms, C 1~4 alkoxy group contains 1 to 4 carbon atoms, and so on.

[0014] The term "halo" or "halogen" when used herein refers to a fluorine, chlorine, bromine, or iodine atom.

[0015] The term "C 1~4 alkyl" or "C 1~6"Alkyl", as used herein as a group or part of a group, refers to a straight-chain or branched-chain saturated hydrocarbon group containing 1 to 4 or 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl, and the like.

[0016] The term "C" 2~4 "alkenyl" or "C" 2~6 "alkenyl", as used herein as a group or part of a group, refers to a straight-chain or branched-chain hydrocarbon group containing 2 to 4 or 2 to 6 carbon atoms and containing a carbon-carbon double bond.

[0017] The term "C" 2~4 "alkynyl" or "C" 2~6 "alkynyl", as used herein as a group or part of a group, refers to a straight-chain or branched-chain hydrocarbon group having 2 to 4 or 2 to 6 carbon atoms and containing a carbon-carbon triple bond.

[0018] The term "C" 1~4 "alkoxy" or "C" 1~6 "alkoxy", as used herein as a group or part of a group, refers to -O-C 1~4 alkyl group or -O-C 1~6 alkyl group, where C 1~4 alkyl and C 1~6 alkyl are as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and the like.

[0019] The term "C" 3~6 "cycloalkyl", as used herein, refers to a saturated monocyclic hydrocarbon ring having 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0020] The term "hydroxy C" 1~4 alkyl" or "hydroxy C" 1~6"Alkyl", as used herein as a group or part of a group, refers to a C 1~4 alkyl or C 1~6 alkyl group as defined herein, in which one or more hydrogen atoms are replaced by a hydroxyl group. Thus, the terms "hydroxy C 1~4 alkyl" or "hydroxy C 1~6 alkyl" include monohydroxy C 1~4 alkyl, monohydroxy C 1~6 alkyl, polyhydroxy C 1~4 alkyl, and polyhydroxy C 1~6 alkyl. One, two, three, or more hydrogen atoms can be replaced by a hydroxyl group, so hydroxy C 1~4 alkyl or hydroxy C 1~6 alkyl can have one, two, three, or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.

[0021] The terms "halo C 1~4 alkyl" or "halo C 1~6 alkyl", as used herein as a group or part of a group, refer to a C 1~4 alkyl or C 1~6 alkyl group as defined herein, in which one or more hydrogen atoms are replaced by a halogen. Thus, the terms "halo C 1~4 alkyl" or "halo C 1~6 alkyl" include monohalo C 1~4 alkyl, monohalo C 1~6 alkyl, polyhalo C 1~4 alkyl, and polyhalo C 1~6 alkyl. One, two, three, or more hydrogen atoms can be replaced by a halogen, so halo C 1~4 alkyl or halo C 1~6 alkyl can have one, two, three, or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, trifluoromethyl, or trifluoroethyl, and the like.

[0022] The term "haloC 1~4 alkoxy" or "haloC 1~6 alkoxy", when used herein as a group or part of a group, refers to -O-C 1~4 alkyl or -O-C 1~6 alkyl as defined herein, in which one or more hydrogen atoms are replaced by halogen. Thus, the term "haloC 1~4 alkoxy" or "haloC 1~6 alkoxy" includes monohaloC 1~4 alkoxy, dihaloC 1~6 alkoxy, and includes polyhaloC 1~4 alkoxy and polyhaloC 1~6 alkoxy. One, two, three, or more hydrogen atoms may be replaced by halogen, and thus haloC 1~4 alkoxy or haloC 1~6 alkoxy may have one, two, three, or more halogens. Examples of such groups include fluoroethyloxy, difluoromethoxy, or trifluoromethoxy, and the like.

[0023] The term cyanoC 1~4 alkyl or cyanoC 1~6 alkyl, when used herein, refers to C 1~4 alkyl or C 1~6 alkyl as defined herein, which is substituted with one or two cyano groups (especially one cyano group).

[0024] As used herein, the term "heterocyclyl" should include both aromatic and non-aromatic ring systems unless the context indicates otherwise. Thus, for example, the term "heterocyclyl" includes within its scope aromatic, non-aromatic, unsaturated, partially saturated, and fully saturated heterocyclyl ring systems. Generally, unless the context indicates otherwise, such ring systems may be monocyclic, bicyclic, or bridged, and may include, for example, 3 to 12 ring members, or 4 to 10 ring members, or more generally 5 to 10 ring members. Reference to 4 to 7 ring members includes rings containing 4, 5, 6, or 7 atoms within the ring, reference to 3 to 6 ring members includes rings containing 3, 4, 5, or 6 atoms within the ring, and reference to 4 to 6 ring members includes rings containing 4, 5, or 6 atoms within the ring. Examples of monocyclic heterocyclyl ring systems are ring systems containing 3, 4, 5, 6, 7, or 8 ring members, more generally 3 to 7 ring members, preferably 4, 5, 6, or 7 ring members, and more preferably 5 or 6 ring members. Examples of bicyclic heterocyclyl ring systems are those containing 8, 9, 10, 11, or 12 ring members, more generally 9 or 10 ring members. Heterocyclyl ring systems typically contain at least 1 heteroatom selected from nitrogen, oxygen, or sulfur, particularly up to 5, up to 4, up to 3, up to 2, or a single heteroatom. When reference is made herein to a heterocyclyl ring system, the heterocyclyl ring may be optionally substituted with one or more substituents as discussed herein unless the context indicates otherwise (i.e., it may be unsubstituted or substituted).

[0025] A heterocyclyl ring system can be a heteroaryl ring system having 5 to 12 ring members, more generally 5 to 10 ring members. The term "heteroaryl" is used herein to denote a heterocyclyl ring system having aromatic character. The term "heteroaryl" encompasses polycyclic (e.g., bicyclic) ring systems where one or more rings may be non-aromatic provided that at least one ring is aromatic. In such polycyclic systems, the ring system may be attached to the remainder of the compound by an aromatic or non-aromatic ring.

[0026] Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more generally 5 to 10 ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or bicyclic structure formed from fused 5- and 6-membered rings, or two fused 6-membered rings, or two fused 5-membered rings. The heteroaryl ring system can typically contain up to about 5 heteroatoms selected from nitrogen, oxygen, and sulfur. Typically, the heteroaryl ring contains up to 4 heteroatoms, more typically up to 3 heteroatoms, more generally up to 2, for example, a single heteroatom. In one embodiment, the heteroaryl ring contains at least 1 ring nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic in the case of imidazole or pyridine, or essentially non-basic in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group, including any ring amino group substituents, is less than 5.

[0027] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, oxadiazolyl, oxatriazole, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups. In particular, examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, and triazolyl groups.

[0028] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0029] The bicyclic heteroaryl group can be, for example, a group selected from the following: a) A benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; b) A pyridine ring fused to a 5- or 6-membered ring containing 0, 1, 2, or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing 0, 1, 2, or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms; g) an oxazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms; h) an isoxazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms; i) a thiazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms; j) an isothiazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms; k) a thiophene ring fused to a 5- or 6-membered ring containing 0, 1, 2, or 3 ring heteroatoms; l) a furan ring fused to a 5- or 6-membered ring containing 0, 1, 2, or 3 ring heteroatoms; m) a cyclohexyl ring fused to a 5- or 6-membered aromatic ring containing 1, 2, or 3 ring heteroatoms; and n) a cyclopentyl ring fused to a 5- or 6-membered aromatic ring containing 1, 2, or 3 ring heteroatoms.

[0030] Specific examples of bicyclic heteroaryl groups containing a 5-membered ring fused to another 5-membered ring include, but are not limited to, imidazothiazolyl (e.g., imidazo[2,1-b]thiazole) and imidazoimidazolyl (e.g., imidazo[1,2-a]imidazole).

[0031] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl, indazolyl, pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidine), triazolopyrimidinyl (e.g., [1,2,4]triazolo[1,5-a]pyrimidine), benzodioxolyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridinyl, and pyrazolopyridinyl (e.g., pyrazolo[1,5-a]pyridine) groups.

[0032] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, indazolyl, pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidine), triazolopyrimidinyl (e.g., [1,2,4]triazolo[1,5-a]pyrimidine), imidazopyrazinyl, imidazopyridazinyl, imidazopyridinyl, and pyrazolopyridinyl (e.g., pyrazolo[1,5-a]pyridine) groups.

[0033] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, indolyl, isoindolyl, indolizinyl, indolinyl groups.

[0034] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolidinyl, quinolinyl, isoquinolinyl, cinnolinyl, chromanyl, isochromanyl, thiochromanyl, benzopyranyl, benzodioxanyl, benzoxazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0035] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolidinyl, quinolinyl, isoquinolinyl, benzopyranyl, benzodioxanyl, benzoxazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0036] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0037] Examples of polycyclic heteroaryl groups containing aromatic and non-aromatic rings include tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 4,5,6,7-tetrahydrobenzofuranyl, tetrahydrotriazolopyrazinyl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl), and indolinyl.

[0038] The nitrogen-containing heteroaryl ring must contain at least one ring nitrogen atom. In addition, each ring may typically contain up to about 4 other heteroatoms selected from nitrogen, sulfur, and oxygen. Typically, the heteroaryl ring contains up to 3 heteroatoms, e.g., 1, 2, or 3, more generally, up to 2 nitrogens, e.g., a single nitrogen. The nitrogen atoms in the heteroaryl ring can be basic in the case of imidazole or pyridine, or essentially non-basic in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any ring amino group substituents, is less than 5.

[0039] Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl and benzoisothiazole, indolyl, 3H-indolyl, isoindolyl, indolizinyl, isoindolinyl, purinyl, indazolyl, quinolidinyl, benzoxazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl.

[0040] Examples of nitrogen-containing polycyclic heteroaryl groups containing aromatic and non-aromatic rings include tetrahydroisoquinolinyl, tetrahydroquinolinyl, and indolinyl.

[0041] The term "non-aromatic group", unless the context indicates otherwise, includes unsaturated, partially saturated, and fully saturated heterocyclic ring systems that do not contain aromatic characteristics. The terms "unsaturated" and "partially saturated" refer to a ring structure that contains atoms sharing multiple valence bonds, i.e., a ring containing at least one multiple bond (e.g., including C=C, C≡C, or N=C bonds). The term "fully saturated" refers to a ring in which no multiple bonds exist between ring atoms. Examples of saturated heterocyclic groups include piperidine, morpholine, thiomorpholine, and piperazine. Examples of partially saturated heterocyclic groups include pyrazoline (e.g., 2-pyrazoline and 3-pyrazoline).

[0042] Examples of non-aromatic heterocyclic groups are groups having 3 to 12 ring members, more generally 5 to 10 ring members. Such groups can be monocyclic or bicyclic and can typically have, usually, 1 to 5 heteroatom ring members (more generally, 1, 2, 3, or 4 heteroatom ring members) selected from nitrogen, oxygen, and sulfur. The heterocyclic group can include, for example, cyclic ether moieties (e.g., in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g., in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g., in pyrrolidine), and combinations thereof (e.g., thiomorpholine).

[0043] As specific examples, morpholinyl, thiomorpholinyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), azetidinyl, pyranyl (2H-pyranyl or 4H-pyranyl), dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxanyl, dioxolanyl, tetrahydropyranyl, imidazolinyl, oxazolinyl, oxazolidinyl, oxetanyl, thiazolinyl, 2-pyrazolinyl, pyrazolidinyl, and piperazinyl can be mentioned. Generally, preferred non-aromatic heterocyclyl groups include saturated groups such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, and piperazinyl.

[0044] As specific examples, morpholinyl, thiomorpholinyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), pyranyl (2H-pyranyl or 4H-pyranyl), dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxanyl, tetrahydropyranyl, imidazolinyl, oxazolinyl, oxazolidinyl, 2-pyrazolinyl, pyrazolidinyl, and piperazinyl can be mentioned. Generally, preferred non-aromatic heterocyclyl groups include saturated groups such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, and piperazinyl.

[0045] In a nitrogen-containing non-aromatic heterocyclic ring, the ring must contain at least one ring nitrogen atom.

[0046] Specific examples of the nitrogen-containing non-aromatic heterocyclyl group include aziridinyl, morpholinyl, thiomorpholinyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), dihydrothiazolyl, imidazolinyl, oxazolinyl, thiazolinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl, and piperazinyl.

[0047] Specific examples of the 3- to 6-membered monocyclic saturated heterocyclyl include morpholinyl, thiomorpholinyl, dioxanyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), piperazinyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), dithianyl, trioxanyl, trithianyl, aziridinyl, oxiranyl, thietanyl, diaziridinyl, dioxarinyl, oxetanyl, azetidinyl, thietanyl, dioxetanyl ring systems.

[0048] Specific examples of the 3- to 6-membered monocyclic saturated heterocyclyl include morpholinyl, thiomorpholinyl, dioxanyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), piperazinyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), oxiranyl, azetidinyl ring systems.

[0049] Specific examples of 3- to 6-membered monocyclic saturated heterocyclyls include morpholinyl, thiomorpholinyl, dioxanyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), piperazinyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), imidazolidinyl, pyrazolidinyl, dioxolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl) ring systems.

[0050] Specific examples of 3- to 6-membered monocyclic heterocyclyls include morpholinyl, thiomorpholinyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxanyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), dithianyl, trioxanyl, trithianyl, aziridinyl, oxiranyl, thietanyl, diaziridinyl, dioxalinyl, oxetanyl, azetidinyl, thietanyl, dioxetanyl, azirinyl, azetyl, 1,2-dithietyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, dithiazolyl, pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, thiadiazinyl, oxazinyl, triazinyl ring systems.

[0051] Specific examples of monocyclic heterocyclyls having 3 to 6 members include morpholinyl, thiomorpholinyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxanyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), oxiranyl, oxetanyl, azetidinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, dithiazolyl, pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, thiadiazinyl, oxadiazinyl, triazinyl ring systems.

[0052] As specific examples of complex rings of 3 to 12 members, morpholinyl, thiomorpholinyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxanyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), dithianyl, trioxanyl, trithianyl, aziridinyl, oxiranyl, thietanyl, diaziridinyl, dioxalinyl, oxetanyl, azetidinyl, thietanyl, dioxetanyl, azirinyl, azetyl, 1,2-dithietyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, dithiazolyl, pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, thiadiazinyl, oxadiazinyl, triazinyl, azepanyl, oxepanyl, thiepanyl, 1,2-diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, azocanyl, azocinyl, imidazothiazolyl (e.g., imidazo[2,1-b]thiazolyl), imidazoimidazolyl (e.g., imidazo[1,2-a]imidazolyl), benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl, indazolyl, pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidinyl), triazolopyrimidinyl (e.g., [1,2,4]triazolo[1,5-a]pyrimidinyl), benzodioxolyl, imidazopyridinyl, and pyrazolopyridinyl (e.g., pyrazolo[1,5-a] pyridinyl), quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 4,5,6,7-tetrahydrobenzofuranyl, tetrahydrotriazolopyrazinyl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl), 8-oxa-3-azabicyclo[3.2.1]octanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl ring systems.

[0053] As specific examples of complex rings of 3 to 12 members, morpholinyl, thiomorpholinyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxanyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), oxiranyl, oxetanyl, azetidinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, dithiazolyl, pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, thiazinyl, oxazinyl, triazinyl, imidazothiazolyl (e.g., imidazo[2,1-b]thiazolyl), imidazoimidazolyl (e.g., imidazo[1,2-a]imidazolyl), benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, indazolyl, pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidinyl), triazolopyrimidinyl (e.g., [1,2,4]triazolo[1,5-a]pyrimidinyl), benzodioxolyl, imidazopyridinyl and pyrazolopyridinyl (e.g., pyrazolo[1,5-a]pyridinyl), quinolinyl, isoquinolinyl, benzodioxanyl, quinolidinyl, benzoxazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 4,5,6,7-tetrahydrobenzofuranyl, tetrahydrotriazolopyrazinyl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,Examples of the (3-a) pyrazinyl ring system include.,

[0054] Specific examples of the 5- to 6-membered aromatic heterocyclic rings include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl ring systems.

[0055] Examples of the heterocyclyl and carbocyclyl rings representing the B or D substituents include bridged ring systems such as bridged cycloalkanes like norbornane (1,4-endo-methylenecyclohexane), adamantane, oxa-adamantane, etc.; bridged morpholine rings such as 8-oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane, etc.; bridged piperazine rings such as 3,6-diazabicyclo[3.1.1]heptane, etc.; and bridged piperidine rings such as 1,4-ethylenepiperidine, etc. For an explanation of the difference between fused and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131 - 133, 1992.

[0056] As used herein, the term "carbocyclic" should include both aromatic and non-aromatic carbocyclic systems, unless the context indicates otherwise. Thus, for example, the term "carbocyclic" includes within its scope aromatic, non-aromatic, unsaturated, partially saturated, and fully saturated carbocyclic ring systems. In general, unless the context indicates otherwise, such ring systems may be monocyclic, bicyclic, or bridged, and may contain, for example, 3 to 12 ring members, or 4 to 10 ring members, or more generally 5 to 10 ring members. Reference to 4 to 7 ring members includes rings containing 4, 5, 6, or 7 atoms within the ring, and reference to 4 to 6 ring members includes rings containing 4, 5, or 6 atoms within the ring. Examples of monocyclic carbocyclic ring systems are rings containing 3, 4, 5, 6, 7, and 8 ring members, more generally 3 to 7 ring members, preferably 4, 5, 6, or 7 ring members, and more preferably 5 or 6 ring members. Examples of bicyclic carbocyclic ring systems are those containing 8, 9, 10, 11, and 12 ring members, more generally 9 or 10 ring members. When reference is made herein to a carbocyclic ring system, the carbocyclic ring may be optionally substituted with one or more substituents as discussed herein (i.e., it may be unsubstituted or substituted), unless the context indicates otherwise.

[0057] A carbocyclic ring system can be an aryl ring system. As used herein, the term "aryl" refers to a carbocyclic aromatic group and includes polycyclic (e.g., bicyclic) ring systems where one or more rings may be non-aromatic as long as at least one ring is aromatic. In such polycyclic systems, the ring system may be attached to the remainder of the compound by an aromatic or non-aromatic ring. The term "aryl" includes phenyl, naphthyl, indenyl, and tetrahydronaphthyl groups.

[0058] Specific examples of 3- to 12-membered carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, naphthyl, indenyl, tetrahydronaphthyl, azulenyl, norbornane (1,4-endo-methylene-cyclohexane), and adamantane ring systems.

[0059] The lines drawn within the ring system indicate that the bond can be attached to any of the suitable and available ring atoms.

[0060] In embodiments containing two or more heteroatoms, these heteroatoms may be the same, or some or all of the two or more heteroatoms may be different.

[0061] The term "optional" or "optionally" means that the event described subsequently may or may not occur. This term encompasses the cases where this event may or may not occur.

[0062] As used herein, the expression "one or more", where possible and depending on the context, refers to at least 1, for example, 1, 2, 3, 4, 5, or more.

[0063] In the compound of formula (I), the carbon atom indicated by the following formula together with " * " is a chiral center. The present invention provides a compound of formula (I) in which the chiral center represents a specific stereochemistry (S or R), particularly a compound of formula (I) in which the chiral center has S-stereochemistry. A compound of formula (I) having S-stereochemistry at the chiral center * or any subgroup thereof exhibits high GFGR inhibitory activity.

Chemical formula

[0064] Therefore, the present invention provides a compound of formula (I-a)

Chemical formula

[0065] The present invention relates to formula (I-A)

Chemical formula

[0066] The present invention relates to the following formula (I-A-a):

Chemical formula

[0067] The present invention relates to formula (I-B)

Chemical formula

[0068] The present invention relates to the following formula (I-B-a):

Chemical formula

[0069] The present invention relates to formula (I-C)

Chemical formula

[0070] The present invention relates to the following formula (I-C-a):

Chemical formula

[0071] The present invention relates to formula (I-D):

Chemical formula

[0072] The present invention relates to the following formula (I-D-a):

Chemical formula

[0073] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), A 1 , A 2 , and A 3 represent CH or CR a .

[0074] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), A 1 , A 2 , and A 3 represents CH.

[0075] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), A 1 , A 2 , and A 3 one of represents CR a .

[0076] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), A 1 , A 2 , and A 3 at least one of represents CR a .

[0077] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), A 1 represents CR a , A 2 and A 3 represent CH.

[0078] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), A 2 represents CR a , A 1 , and A 3 represent CH.

[0079] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), A 1 , A 2 , and A 3 represent N or CH.

[0080] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), A 1 , A 2 , and A 3 of which one represents CR a , R a represents C 1~6 alkyl, especially C 1~4 alkyl, such as methyl; halo C 1~6 alkyl, such as trifluoromethyl; or halo, such as fluoro.

[0081] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), A 1 , A 2 , and A 3 of which one represents CR a , R a represents C 1~6 alkyl, especially C 1~4 alkyl, such as methyl; halo C 1~6 alkyl (such as trifluoromethyl); halo, such as fluoro; or C 1~6 alkoxy, especially C 1~4 alkoxy, such as methoxy.

[0082] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), one of A1, A2, and A3 represents N, and the remaining A substituents represent CH or CRa.

[0083] In one embodiment, in the compound of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), A 2 represents N, and A 1 and A 3 represent CH or CR a In particular, A 2 represents N, and A 1 and A 3 represent CH.

[0084] In one embodiment, in the compound of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), A 3 represents N, and A 1 and A 2 represent CH or CR a In particular, A 3 represents N, and A 1 and A 2 represent CH.

[0085] In one embodiment, in the compound of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), A 1 , A 2 , and A 3 Two of the substituents represent N, and the remaining A represents CH or CR a .

[0086] In one embodiment, in the compound of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), or (I-C-a), Y is a direct bond.

[0087] In one embodiment, in the compound of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), or (I-C-a), Y is -O-, C(=O), NR y , S(=O) 2、 or C 1~4 is alkyl.

[0088] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), or (I-C-a), Y is a direct bond, C(=O), or NR y , for example NCH 3 .

[0089] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), or (I-C-a), Y is a direct bond, -O-, or C(=O).

[0090] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), or (I-C-a), Y is -O- or C(=O).

[0091] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), C 1 is hydrogen.

[0092] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), C 2 is hydrogen.

[0093] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), C 1 is hydrogen, and C 2 is C 1~4 alkyl.

[0094] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), C 1 and C 2 are both hydrogen.

[0095] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), C 1 is hydrogen and C 2 is hydroxyl.

[0096] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), C 1 is hydrogen and C 2 is C 1~4 alkoxy.

[0097] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), C 1 and C 2 are both C 1~4 alkyl.

[0098] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), C 1 and C 2 together with the carbon atom to which they are attached form C 3~6 cycloalkyl, especially cyclopropyl.

[0099] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), [Chemical formula] represents -CH 3 .

[0100] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), [Chemical formula] represents -CH 2 (C 1~4 alkyl) (in particular -CH 2 CH 3 or -CH 2 CH 2 CH 3 ).

[0101] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), [Chemical formula] represents -CH(C 1~4 alkyl) 2 (in particular -CH(CH 3 )) 2 ).

[0102] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), [Chemical formula] represents -CH 2 -(C 1~4 alkoxy) (especially -CH 2 -OCH 3 ).

[0103] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a),

Chemical formula

[0104] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), or (I-C-a), R y is hydrogen.

[0105] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), or (I-C-a), R y is C 1~4 alkyl (especially methyl).

[0106] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), each R b is hydrogen.

[0107] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), each R b is independently C 1~6 alkyl, halo C 1~6 alkyl, C 1~6 alkoxy, C 1~6 alkyloxycarbonyl, C 2~6 alkenyl, C2~6 Alkynyl, cyano C 1~6 Alkyl, hydroxy C 1~6 Alkyl, -C(=O)-NH 2 , -C(=O)-NH(C 1~4 Alkyl), -C(=O)-N(C 1~4 Alkyl) 2 , C 3~6 Cycloalkyl, phenyl, N, O, or at least 1 heteroatom selected from S, a 3- to 6-membered monocyclic heterocyclyl, or C 3~6 Cycloalkyl or phenyl or a 3- to 6-membered monocyclic heterocyclyl containing at least 1 heteroatom selected from N, O, or S, substituted C 1~6 Alkyl.

[0108] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), each R b is independently C 1~6 Alkyl, halo C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyloxycarbonyl, C 2~6 Alkenyl, C 2~6 Alkynyl, cyano C 1~6 Alkyl, hydroxy C 1~6 Alkyl, -C(=O)-NH 2 , -C(=O)-NH(C 1~4 Alkyl), or C(=O)-N(C 1~4 Alkyl) 2 is.

[0109] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), each R b is independently C 1~4 Alkyl (especially methyl or ethyl).

[0110] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), D, D 1 , D 2 , or D 3 is unsubstituted.

[0111] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), D, D 1 , D 2 , or D 3 is substituted with one, two, three, or four R c substituents.

[0112] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), D, D 1 , D 2 , or D 3 is substituted with two R c substituents.

[0113] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), D, D 1 , D 2 , or D 3 is substituted with one or two R c substituents.

[0114] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), D, D 1 , D 2 , or D 3 is substituted with one or two R c substituents, and each R cis, independently, oxo; halo, for example fluoro; C 1~6 alkyl, especially C 1~4 alkyl, for example methyl; C 1~6 alkyloxy, especially C 1~4 alkyloxy, for example methoxy; halo C 1~6 alkyl, for example, trifluoromethyl or trifluoroethyl; halo C 1~6 alkyloxy, for example trifluoromethoxy; HOOC-C 1~6 alkyl-, for example -CH 2 -COOH; carboxyl-C(=O)-O-C 1~6 C substituted with alkyl 1~6 alkyl, for example, -CH 2 -C(=O)-O-CH 2 -CH 3 ; C 1~6 alkyloxy-O-C(=O)-, for example -C(=O)-O-CH 3 selected from the following.

[0115] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), D, D 1 , D 2 , or D 3 is substituted with one or two R c substituents, and each R c is, independently, oxo; halo, for example fluoro; C 1~6 alkyl, especially C 1~4 alkyl, for example methyl; C 1~6 alkyloxy, especially C 1~4 alkyloxy, for example methoxy; or halo C 1~6 selected from alkyl, for example trifluoromethyl or trifluoroethyl.

[0116] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), D, D 1 , D2 or D 3 is substituted with two Rs c substituent, and each R c substituent is independently C 1~6 alkyl, especially C 1~4 alkyl, for example, represents methyl.

[0117] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), D, D 1 , D 2 or D 3 is substituted with four Rs c substituent, and each R c substituent is independently C 1~6 alkyl, especially C 1~4 alkyl, for example, represents methyl.

[0118] In one embodiment, in the compounds of formula (I), (I-C), (I-C-a), (I-D), or (I-D-a), D or D 3 is a bridged heterocyclyl, for example, 8-oxa-3-azabicyclo[3.2.1]octane.

[0119] In one embodiment, in the compounds of formula (I), (I-a), (I-C), (I-C-a), (I-D), or (I-D-a), D or D3 is a bridged heterocyclyl, where this bridge is, for example, in -CH 2 -, -CH 2 -CH 2 -, or -CH 2 -CH 2 -CH 2 -, especially -CH 2 -CH 2 -.

[0120] In one embodiment, in the compounds of formula (I-C) or (I-C-a), D 3is a 4-, 5-, 6-, or 7-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O, or S, and said heterocyclyl is optionally substituted with 1 to 5 R c substituents or 1 to 4 R c substituents, 1 to 3 R c substituents or 1 or 2 R c substituents or 1 R c substituent.

[0121] In one embodiment, in the compound of formula (I-C) or (I-C-a), D 3 is a 4-, 5-, 6-, or 7-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O, or S, and said heterocyclyl is unsubstituted.

[0122] In one embodiment, in the compound of formula (I-C) or (I-C-a), D 3 is a 5- or 6-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, or S, and said heterocyclyl is optionally substituted with 1 to 5 R c substituents, particularly a 6-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O, or S, and said heterocyclyl is optionally substituted with 1 to 5 R c substituents, 1 to 4 R c substituents, 1 to 3 R c substituents, 1 or 2 R c substituents, or 1 R c substituent.

[0123] In one embodiment, in the compound of formula (I-C) or (I-C-a), D 3 is a 5- or 6-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O, or S, and said heterocyclyl is optionally substituted with 1 to 5 R c substituents, 1 to 4 R c substituents, 1 to 3 R c substituents, 1 or 2 Rc by a substituent, or one R c is substituted by a substituent. In one embodiment, this heterocyclyl is unsubstituted. In one embodiment, D 3 is optionally substituted piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or tetrahydropyranyl. In one embodiment, D 3 is unsubstituted piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or tetrahydropyranyl. In one embodiment, D 3 is unsubstituted piperazinyl; piperazinyl substituted by one C 1~4 alkyl, for example methyl; unsubstituted morpholinyl; or morpholinyl substituted by one or two C 1~4 alkyl, especially two C 1~4 alkyl, for example methyl.

[0124] In one embodiment, in the compound of formula (I-C) or (I-C-a), D 3 is a 4-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O, or S, and said heterocyclyl is optionally substituted by 1 to 5 R c substituents, 1 to 4 R c substituents, 1 to 3 R c substituents, 1 or 2 R c substituents, or one R c substituent. In one embodiment, this heterocyclyl is unsubstituted. In one embodiment, D 3 is unsubstituted azetidinyl.

[0125] In one embodiment, in the compound of formula (I-C) or (I-C-a), D 3 is a 5- or 6-membered aromatic monocyclic heterocyclyl containing at least one heteroatom selected from N, O, or S, and said heterocyclyl is optionally substituted by 1 to 5 R cIt is substituted with a substituent and is, in particular, a 5-membered aromatic monocyclic heterocyclyl containing at least 1 heteroatom selected from N, O, or S, and the heterocyclyl is optionally substituted with 1 to 5 R c substituents and 1 to 4 R c substituents and 1 to 3 R c substituents and 1 or 2 R c substituents or 1 R c It is substituted with a substituent and is, for example, optionally substituted pyrazole.

[0126] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), each R c is independently oxo, C 1~6 alkyl, hydroxy C 1~6 alkyl, halo C 1~6 alkyl, halo C 1~6 alkyloxy, carboxyl, HOOC-C 1~6 alkyl-, cyano, cyano C 1~6 alkyl, C 1~6 alkyl-C(=O)-, -SO 2 -C 1~6 alkyl, C 3~6 cycloalkyl, phenyl, a 3- to 6-membered monocyclic saturated heterocyclyl containing at least 1 heteroatom selected from N, O, or S, or a 5- or 6-membered monocyclic aromatic heterocyclyl containing at least 1 heteroatom selected from N, O, or S.

[0127] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), each R c is independently oxo, halo, C 1~6 alkyl, C 1~6 alkoxy, or halo C 1~6 alkyl, particularly C 1~6 alkyl, for example, methyl.

[0128] In one embodiment, in the compound of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), B is a 5- or 6-membered carbocyclic or heterocyclic ring containing at least one heteroatom selected from N, O, or S, and each of the carbocyclic and heterocyclic rings is optionally substituted with 1 to 5, particularly 1 to 4, or 1 to 3, or 1 or 2, or 1 R substituent. In one embodiment, B is unsubstituted.

[0129] In one embodiment, in the compound of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), B is phenyl or a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, or S, and each of the phenyl and heterocyclic rings is optionally substituted with 1 to 5, particularly 1 to 4, or 1 to 3, or 1 or 2, or 1 R substituent. In one embodiment, B is unsubstituted.

[0130] In one embodiment, in the compound of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), B is a 3- to 6-membered monocyclic carbocyclic or heterocyclic ring containing at least one heteroatom selected from N, O, or S, and each of the carbocyclic and heterocyclic rings is optionally substituted with 1 to 5, particularly 1 to 4, or 1 to 3, or 1 or 2, or 1 R substituent. In one embodiment, B is unsubstituted.

[0131] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), B is a 3- to 6-membered monocyclic non-aromatic carbocyclic or heterocyclic ring containing at least one heteroatom selected from N, O, or S, and each of said carbocyclic and heterocyclic rings is optionally substituted with 1 to 5, particularly 1 to 4, or 1 to 3, or 1 or 2, or 1 R substituent. In one embodiment, B is unsubstituted.

[0132] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), B is a 6-membered aromatic monocyclic heterocyclic ring containing at least one heteroatom selected from N, O, or S, and said heterocyclic ring is optionally substituted with 1 to 4, particularly 1 to 3, or 1 or 2, or 1 R substituent. For example, B is optionally substituted pyridyl, pyrimidinyl, or pyrazinyl, and particularly, B is optionally substituted pyridyl or pyrimidinyl. In one embodiment, B is unsubstituted. In one embodiment, B is substituted with 1 R substituent. In one embodiment, the R substituent is C 1~6 alkyl, C 1~6 alkoxy, and C 3~6 selected from cycloalkyl. In one embodiment, the R substituent is halo C 1~6 alkyl. In one embodiment, B is optionally substituted pyrimidinyl. In one embodiment, B is unsubstituted pyrimidinyl.

[0133] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), B is a 5-membered aromatic monocyclic heterocyclyl containing at least 1 heteroatom selected from N, O, or S, and said heterocyclyl is optionally substituted with 1 to 3, particularly 1 or 2, or 1 R substituents. For example, B is optionally substituted pyrazolyl, oxazolyl, or thiazolyl, and particularly, B is optionally substituted oxazolyl or thiazolyl. In one embodiment, B is unsubstituted. In one embodiment, B is substituted with 1 R substituent. In one embodiment, the R substituent is C 1~6 alkyl, C 1~6 alkoxy, and C 3~6 selected from cycloalkyl. In one embodiment, the R substituent is halo C 1~6 alkyl.

[0134] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), B is a 9- to 12-membered bicyclic carbocyclyl or heterocyclyl containing at least 1 heteroatom selected from N, O, or S, and said carbocyclyl and heterocyclyl are each optionally substituted with 1 to 5, particularly 1 to 4, or 1 to 3, or 1 or 2, or 1 R substituents. In one embodiment, B is unsubstituted.

[0135] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), B is pyrimidinyl optionally substituted with 1 to 3, particularly 1 or 2, or 1 R substituents; particularly, B is unsubstituted pyrimidinyl.

[0136] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), each R is independently C 1~6 alkyl, cyano, halo, C 1~6 alkoxy, haloC 1~6 alkoxy, hydroxyl, hydroxyC 1~6 alkyl, haloC 1~6 alkyl, oxo, -SO 2 -NH 2 、SO 2 -NH(C 1~4 alkyl), -SO 2 -N(C 1~4 alkyl) 2 、-NH-C(=O)-C 2~6 alkenyl, -C(=O)-C 1~6 alkyl, -C(=O)-C 2~6 alkenyl, or C 1~6 alkyl-O-C(=O)-.

[0137] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), each R is independently C 1~6 alkyl, cyano, halo, C 1~6 alkoxy, haloC 1~6 alkoxy, hydroxyl, hydroxyC 1~6 alkyl, haloC 1~6 alkyl, oxo, -SO 2 -NH 2 、SO 2 -NH(C 1~4 alkyl), -SO 2 -N(C 1~4 alkyl) 2 、-NH-C(=O)-C 2~6 alkenyl, -C(=O)-C 1~6 alkyl, -C(=O)-C 2~6 alkenyl, C 3~6It is a 3- to 6-membered monocyclic heterocyclyl containing at least one heteroatom selected from cycloalkyl, phenyl, or N, O, or S.

[0138] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), there is one R substituent, and said R is halo C 1~6 is alkyl.

[0139] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), B is unsubstituted.

[0140] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), B is substituted with 1 to 5 R substituents, particularly 1 to 4 R substituents, or 1 to 3 R substituents, or 1 or 2 R substituents, or 1 R substituent.

[0141] In one embodiment, in the compounds of formula (I), (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a), one or more of the following conditions, particularly all if possible, apply: A 1 、A 2 、and A 3 each represent CH; or A 1 and A 3 represent CH, and A 2 represents N; or A 1 、A 2 、and A 3 at least one of represents CR a ; or A 1 represents CR a 、A 2 and A 3represents CH; or A 2 represents CR a and A 1 and A 3 represents CH; or A 3 represents N, and A 1 and A 2 represents CH; in particular, A 1 and A 3 represents CH, and A 2 represents N, or A 3 represents N, and A 1 and A 2 represents CH; C1 is hydrogen or C 1~4 alkyl, in particular, hydrogen or methyl; C2 is hydrogen, or C 1~4 alkyl, or C 1~4 alkoxy, in particular, hydrogen, methyl, or methoxy; Y is a direct bond, -O-, or C(=O); in particular, Y is a direct bond; each R a is independently C 1~6 alkyl, such as methyl, halo C 1~6 alkyl, such as trifluoromethyl, halo, such as fluoro, or C 1~6 alkoxy, such as methoxy; each R b is independently hydrogen or C 1~6 alkyl, in particular, C 1~4 alkyl, such as methyl or ethyl; in particular, each R b is hydrogen; D is a 4-, 5-, or 6-membered monocyclic saturated heterocyclyl containing at least one heteroatom selected from N, O, or S, and the heterocyclyl is optionally substituted with one or two R c substituents; in particular, D is piperazinyl, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, or azetidinyl, where the ring system is optionally substituted with one or two R c substituents; in particular, D is piperazinyl or morpholinyl, where the ring system is optionally substituted with one or two Rc is substituted with a substituent, in particular, R c is C 1~4 alkyl, such as methyl; each R c is independently oxo; C 1~6 alkyl, such as methyl; halo, such as fluoro; C 1~6 alkoxy, such as methoxy; or haloC 1~6 alkyl, such as trifluoromethyl or trifluoroethyl; B is a 5- or 6-membered aromatic monocyclic heterocyclyl containing at least 1 heteroatom selected from N, O, or S, and the heterocyclyl is optionally substituted with 1 R substituent; in particular, B is pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl; in particular, B is pyrimidinyl; each R is independently C 1~6 alkyl, such as methyl or isopropyl, C 1~6 alkoxy, such as methoxy, or C 3~6 cycloalkyl, such as cyclopropyl.

[0142] In one embodiment, the compound is a compound of formula (I-C), (I-C-a), (I-D), or (I-D-a), where one or more, in particular all if possible, of the following conditions apply: A 1 、A 2 、and A 3 each represents CH independently; or A 1 and A 3 represent CH, and A 2 represents N; or A 1 、A 2 、and A 3 at least one of represents CR a ; or A 1 represents CR a ,and A 2 and A 3 represent CH; or A 2 represents CR a ,and A 1 and A3 represents CH; or A 3 represents N, and A 1 and A 2 represents CH; in particular, A 1 and A 3 represents CH, A 2 represents N, or A 3 represents N, A 1 and A 2 represents CH; C1 is hydrogen or C 1~4 alkyl, in particular, hydrogen or methyl; C2 is hydrogen, or C 1~4 alkyl, or C 1~4 alkoxy, for example, hydrogen, methyl, or methoxy; in particular, hydrogen or C 1~4 alkyl, for example, hydrogen or methyl; Y is a direct bond, -O-, or C(=O); in particular, a direct bond or C(=O); more specifically, a direct bond, each R a is independently C 1~6 alkyl, for example, methyl, halo C 1~6 alkyl, for example, trifluoromethyl, halo, for example, fluoro, or C 1~6 alkoxy, for example, methoxy; in particular, hydrogen, halogen, halo, or C 1~6 alkyl; each R b is hydrogen; D or D 3 is a 4-, 5-, or 6-membered monocyclic saturated heterocyclyl containing at least one heteroatom selected from N, O, or S, and the heterocyclyl is optionally substituted with one or two R c substituents; in particular, D is piperazinyl, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, or azetidinyl, where the ring system is optionally substituted with one or two R c substituents; in particular, D is optionally substituted piperazinyl, morpholinyl, or pyrrolidinyl, in particular, D is optionally substituted piperazinyl or morpholinyl; Each R c is, independently, oxo; C 1~6 alkyl, such as methyl, halo, such as fluoro, C 1~6 alkoxy, such as methoxy; or haloC 1~6 alkyl, such as trifluoromethyl or trifluoroethyl; in particular, C 1~6 alkyl, such as methyl; B is a 5- or 6-membered aromatic monocyclic heterocyclyl containing at least 1 heteroatom selected from N, O, or S, said heterocyclyl being optionally substituted with 1 R substituent; in particular, B is pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl; in particular, B is substituted pyrimidinyl; Each R is, independently, C 1~6 alkyl, such as, methyl or isopropyl, C 1~6 alkoxy, such as methoxy, or C 3~6 cycloalkyl, such as cyclopropyl.

[0143] In one embodiment, the compound is a compound of formula (I-D) or (I-D-a), where one or more, particularly all if possible, of the following conditions apply: A 1 and A 3 represents CH, A 2 represents N, or A 3 represents N, A 1 and A 2 represents CH; C1 is hydrogen or C 1~4 alkyl, in particular, hydrogen or methyl; C2 is hydrogen, or C 1~4 alkyl, or C 1~4 alkoxy, in particular, hydrogen, methyl, or methoxy; Y is a direct bond; Each R b is hydrogen; D is a 6-membered monocyclic saturated heterocyclyl containing at least 1 heteroatom selected from N or O, said heterocyclyl being optionally substituted with 1 or 2 Rc substituted with a substituent; in particular, D is piperazinyl or morpholinyl, and said ring system is optionally substituted with one or two R c substituted with a substituent; in particular, D is optionally substituted piperazinyl or optionally substituted morpholinyl, and said ring system is optionally substituted with one or two R c substituents, for example one or two C 1~4 alkyl, for example substituted with one or two methyl groups; B is a 6-membered aromatic monocyclic heterocyclyl containing one or two N heteroatoms; in particular, B is pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl; in particular, B is unsubstituted pyrimidinyl.

[0144] In one embodiment, the compound of the present invention is

Chemical formula

[0145] In one embodiment, the compound of the present invention is

Chemical formula

[0146] In one embodiment, the compound of the present invention is

Chemical formula

[0147] In one embodiment, the compound of the present invention is

Chemical formula

[0148] In one embodiment, the compound of the present invention is

Chemical formula

[0149] In one embodiment, the compound of the present invention is

Chemical formula

[0150] To avoid misunderstanding, it should be understood that each general and specific selection, embodiment, and example of one substituent can, if chemically possible, be combined with each general and specific selection, embodiment, and example of one or more other substituents defined herein, and that all such embodiments are included in the present application.

[0151] Method for preparing the compound of formula (I) In this section, as in all other sections of this application, unless the context otherwise indicates, references to formula (I) also include all other subgroups and examples defined herein (e.g., (I-a), (I-A), (I-A-a), (I-B), (I-B-a), (I-C), (I-C-a), (I-D), or (I-D-a)).

[0152] Generally, the compound of formula (I) can be prepared according to the following Reaction Scheme 1. In Scheme 1, W 1 and W 2 represent suitable leaving groups (e.g., halo such as chloro), and P represents a suitable protecting group (e.g., 4-methoxybenzyl). All other variable elements of Scheme 1 are defined according to the present invention. [Chemical]

[0153] In Scheme 1, the following reaction conditions are applied: 1: In the presence of a suitable protecting reagent H-P (e.g., 4-methoxybenzaldehyde), a suitable reducing agent (e.g., NaBH 4 ), a suitable acid (e.g., trifluoroacetic acid), and a suitable solvent (e.g., ethyl acetate) at a suitable temperature (e.g., room temperature); 2: a) In the presence of methylmalonyl chloride, a suitable reducing agent (e.g., sodium hydride), and a suitable solvent (e.g., N,N-dimethylformamide) at a suitable temperature (e.g., room temperature); and b) in the presence of sodium methoxide at a suitable temperature (e.g., 110 °C); 3: In the presence of a suitable leaving group introducing agent (e.g., oxalyl chloride or phosphoryl chloride) and a suitable solvent (e.g., N,N-dimethylformamide and dichloromethane) at a suitable temperature (e.g., room temperature or 15 °C); 4: In the presence of a suitable reducing agent (e.g., diisobutylaluminum hydride) and a suitable solvent (e.g., tetrahydrofuran or dichloromethane) at a suitable temperature (e.g., -78 °C); 5: In the presence of phenylmethanamine, a suitable base (e.g., diisopropylethylamine), and a suitable solvent (e.g., acetonitrile) at a suitable temperature (e.g., 70 °C); 6: In the presence of a suitable reducing agent (e.g., H 2 ) and a suitable catalyst (e.g., palladium on carbon) in a suitable solvent (e.g., alcohol, e.g., methanol) at a suitable temperature (e.g., 50 °C); 7: In the presence of a suitable oxidizing agent (e.g., FeCl 3 ) and a suitable solvent (e.g., 1,4-dioxane) at a suitable temperature (e.g., 20 °C or 25 °C); 8: In the presence of a suitable deprotecting agent (e.g., trifluoromethanesulfonic acid) and a suitable solvent (e.g., trifluoroacetic acid) at a suitable temperature (e.g., 20 °C, 60 °C, 80 °C, or 85 °C); In the presence of a suitable base (e.g., N,N - diisopropylethylamine, potassium bicarbonate, or sodium bicarbonate), a suitable phase transfer catalyst (e.g., tetrabutylammonium iodide, or 18 - crown - 6), and a suitable solvent (e.g., dichloromethane, chloroform, N,N - dimethylacetamide, or an alcohol such as ethanol) at a suitable temperature (e.g., 35 °C, 40 °C, 60 °C, 85 °C, or 110 °C).

[0154] In Scheme 1, the intermediate of formula (XII) can be a specific stereoisomer, e.g., the S - enantiomer that gives a specific stereoisomer, e.g., the S - enantiomer of formula (I) as shown in Scheme 1a below for the preparation of a compound of formula (I - a).

Chemical formula

[0155] The intermediate of formula (IX) (wherein Y represents NR y and the intermediate is represented by formula (IX - a)) can also be prepared according to the following Reaction Scheme 2. In Scheme 2, W 3 represents a suitable leaving group (e.g., halo such as bromo). All other variable elements of Scheme 2 are defined according to the present invention.

Chemical formula

[0156] In Scheme 2, the following reaction conditions are applicable: 1: In the presence of a suitable catalyst (e.g., tris(dibenzylideneacetone) - dipalladium(0)), a suitable ligand (e.g., (2 - biphenyl)di - tert - butylphosphine), and a suitable base (e.g., sodium - tert - butoxide) in a suitable solvent (e.g., tetrahydrofuran) at a suitable temperature (e.g., 60 °C); 2: In the presence of a suitable reducing agent (e.g., H 2 ) and a suitable catalyst (e.g., Raney nickel) in a suitable solvent (e.g., dioxane) at a suitable temperature (e.g., room temperature).

[0157] The intermediate of formula (IX) (wherein Y represents a bond and the intermediate is represented by formula (IX-b)) can also be prepared according to the following reaction scheme 2a. In Scheme 2a, W 3 represents a suitable leaving group (e.g., halo such as bromo or chloro). All other variable elements in Scheme 2a are defined according to the present invention.

Chemical formula

[0158] In Scheme 2a, the following reaction conditions are applied: 1: In the presence of a suitable base (e.g., N,N-diisopropylethylamine) and a suitable solvent (e.g., an alcohol such as n-butanol) at a suitable temperature (e.g., 110 °C); 2: In the presence of a suitable reducing agent (e.g., H 2 ), a suitable catalyst (e.g., palladium on carbon), and a suitable temperature (e.g., 30 °C) in a suitable solvent (e.g., an alcohol such as methanol).

[0159] The intermediate of formula (XIV) (wherein Y represents -C(=O)- and the intermediate is represented by formula (XIV-a)) can also be prepared according to the following reaction scheme 3. In Scheme 3, the variable elements are defined according to the present invention.

Chemical formula

[0160] The compound of formula (I) (wherein Y represents NR y and the compound is represented by formula (I-1)) can also be prepared according to the following reaction scheme 4. In Scheme 4, W 4 represents a suitable leaving group (e.g., halo such as bromo). All other variable elements in Scheme 4 are defined according to the present invention.

Chemical formula

[0161] The reaction of Scheme 4 is carried out in the presence of a suitable catalyst (e.g., a palladium catalyst such as Pd 2 (dba) 3 etc.), a suitable ligand (e.g., davephos (2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl)), a suitable base (e.g., LiHMDS (lithium bis(trimethylsilyl)amide)), and a suitable solvent (e.g., tetrahydrofuran).

[0162] In Scheme 4, the intermediate of formula (XVI) can be the S enantiomer of formula (I) as shown in the following Scheme 4a for the preparation of a specific stereoisomer, e.g., the S enantiomer that gives a specific stereoisomer, e.g., the compound of formula (I-1-a).

Chemical formula

[0163] The compound of formula (I) (wherein Y represents a direct bond and the compound is represented by formula (I-D)) can also be prepared according to the following reaction Scheme 5. In Scheme 5, W 4 represents a suitable leaving group (e.g., halo such as bromo). All other variable elements of Scheme 5 are defined according to the present invention.

Chemical formula

[0164] In Scheme 5, the intermediate of formula (XVI) can be a specific stereoisomer, for example, the S enantiomer that gives a specific stereoisomer, for example, the S enantiomer of formula (I-D) as shown in Scheme 5a below for the preparation of a compound of formula (I-D-a).

Chemical formula

[0165] The intermediate of formula (XVI) can be prepared according to the following Reaction Scheme 6. In Scheme 6, W 1 represents a suitable leaving group (for example, halo such as chloro), and W 4 represents a suitable leaving group (for example, halo such as bromo). All other variable elements of Scheme 6 are defined according to the present invention.

Chemical formula

[0166] In Scheme 6, the following reaction conditions apply: 1: In the presence of a suitable solvent (for example, an alcohol such as ethanol) at a suitable temperature (for example, 70 °C); 2: In the presence of a suitable base (for example, NaHCO 3 ) and a suitable solvent (for example, dimethylformamide) at a suitable temperature (for example, 80 °C).

[0167] The intermediate of formula (XVIII) (wherein W 1 represents chloro and the intermediate is represented by formula (XVIII-a)), and the intermediate of formula (XI) (wherein W 1 represents chloro and the intermediate is represented by formula (XI-a)) can be prepared according to the following Reaction Scheme 7. In Scheme 7, the variable elements are defined according to the present invention.

Chemical formula

[0168] In Scheme 7, the following reaction conditions apply: 1: In the presence of aniline, a suitable protecting group introducing agent (e.g., trimethoxymethane), and a suitable solvent (e.g., ethylene glycol) at a suitable temperature (e.g., 135 °C); 2: In the presence of a suitable chloro introducing agent (e.g., phosphoryl trichloride) and a suitable solvent (e.g., N,N-dimethylformamide) at a suitable temperature (e.g., 60 °C); 3: In the presence of a suitable oxidizing agent (e.g., FeCl 3 ) and a suitable solvent (e.g., 1,4-dioxane) at a suitable temperature (e.g., 110 °C).

[0169] The compounds of formula (I) can also be converted into each other via reactions or functional group transformations known in the art.

[0170] For example, a compound of formula (I) [wherein R c represents -C(=O)-O-C 1~6 alkyl-substituted C 1~6 alkyl, or C 1~6 alkyl-O-C(=O)-] can be converted into a compound of formula (I) [wherein R c represents HOOC-C1-6 alkyl or carboxyl] in the presence of lithium hydroxide and a suitable solvent such as tetrahydrofuran or alcohol (e.g., methanol).

[0171] The compounds of the present invention prepared by the methods described herein can be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, and these mixtures can be separated from each other according to resolution procedures known in the art. The racemic compounds of formula (I) containing a basic nitrogen atom can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, from which the enantiomers are liberated with an alkali. Alternative separation methods for the enantiomeric forms of the compounds of formula (I), as well as their pharmaceutically acceptable addition salts and solvates, include liquid chromatography using a chiral stationary phase, for example, over supercritical fluid chromatography. The pure stereochemical isomeric forms can also be derived from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, when a particular stereoisomer is desired, the compounds will be synthesized by stereospecific methods of preparation. Such methods advantageously use enantiomerically pure starting materials.

[0172] In the preparation of the compounds of the present invention, it may be necessary to protect remote functional groups of the intermediates (e.g., primary or secondary amines). The need for such protection will vary depending on the nature of the remote functional group and the conditions of the preparation method. Suitable amino protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection can be readily determined by one skilled in the art. For an overview of protecting groups and their use, see T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007.

[0173] In all of these preparations, the reaction product can be isolated from the reaction medium and, if necessary, further purified by methods generally known in the art, such as extraction, crystallization, trituration, and chromatography. The purity of the reaction product can be determined according to methodologies generally known in the art, such as LC-MS, TLC, HPLC, etc.

[0174] A further aspect of the present invention is a method for preparing a compound of formula (I) as defined herein, comprising: (i) in the presence of a suitable base (e.g., N,N-diisopropylethylamine, potassium bicarbonate, or sodium bicarbonate), a suitable phase transfer catalyst (e.g., tetrabutylammonium iodide or 18-crown-6), and a suitable solvent (e.g., dichloromethane, chloroform, N,N-dimethylacetamide, or an alcohol such as ethanol), an intermediate of formula (XI)

Chemical formula

Chemical formula

Chemical formula

[0175] its pharmaceutically acceptable salt, solvate, or derivative In this section, as in all other sections of this application, unless the context otherwise indicates, references to formula (I) include references to all other sub-groups, alternatives, embodiments, and examples defined herein.

[0176] Unless otherwise indicated, reference to a particular compound includes its ionic forms, salts, solvates, isomers, tautomers, and isotopes, e.g., preferably its salts or isomers or solvates. Compounds of formula (I) may exist in the form of salts, e.g., acid addition salts or, in certain cases, salts with organic and inorganic bases such as carboxylates, sulfonates, and phosphates. All such salts are within the scope of the present invention, and reference to a compound of formula (I) includes the salt forms of this compound.

[0177] The salt forms of the compounds of the present invention are typically pharmaceutically acceptable salts, examples of which are discussed in Berge et al. (1977) “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, pharmaceutically unacceptable salts can also be prepared as intermediate forms and then converted to pharmaceutically acceptable salts. Such pharmaceutically unacceptable salt forms may be useful, for example, in the purification or isolation of the compounds of the present invention and also form part of the present invention.

[0178] The salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods such as those described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or free base form of the compound in water or an organic solvent or a mixture of the two (generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used) with an appropriate base or acid. The compounds of the present invention can exist as mono- or di-salts depending on the pKa of the acid by which the salt is formed.

[0179] The acid addition salts can be formed with a variety of both inorganic and organic acids. Examples of acid addition salts include the following: acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+)-camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalenesulfonic acid (e.g., naphthalene-2-sulfonic acid), naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, pyruvic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, toluenesulfonic acid (e.g., p-toluenesulfonic acid), undecylenic acid, and valeric acid, and salts formed with acylated amino acids and cation exchange resins.

[0180] A specific group of salts consists of salts formed from acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid (mesylate), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propanoic acid, butanoic acid, malonic acid, glucuronic acid, and lactobionic acid. Another group of acid addition salts includes salts formed from acetic acid, adipic acid, ascorbic acid, aspartic acid, citric acid, DL-lactic acid, fumaric acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloric acid, glutamic acid, DL-malic acid, methanesulfonic acid, sebacic acid, stearic acid, succinic acid, and tartaric acid.

[0181] If the compound is anionic or has a functional group that can be anionic (e.g., -COOH can be -COO - ), the salt can be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to: Na + and K + and other alkali metal ions such as Ca 2+ and Mg 2+ and other alkaline earth metal cations, and other cations such as Al 3+ . Examples of suitable organic cations include, but are not limited to: ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).

[0182] Examples of some suitable replacement ammonium ions are derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, and amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH 3 ) 4 + is.

[0183] When the compound of formula (I) contains an amine functional group, this can form a quaternary ammonium salt by methods well known to those skilled in the art, for example, by reaction with an alkylating agent. Such quaternary ammonium compounds are within the scope of formula (I).

[0184] The compounds of the present invention can form solvates with, for example, water (i.e., hydrates) or common organic solvents. As used herein, the term "solvate" means that the compound of the present invention is physically associated with one or more solvent molecules, as well as their pharmaceutically acceptable addition salts. This physical association includes various degrees of ionic and covalent bonds, including hydrogen bonds. In certain cases, the solvate may be isolable, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The term "solvate" is intended to encompass both the solution phase and isolable solvates. Non-limiting examples of suitable solvates include the compounds of the present invention combined with water (hydrates), isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine, and the like. The compounds of the present invention can exert their biological action in solution.

[0185] Solvates can be important for the process of substance preparation (e.g., the process related to the purification of this substance), the storage of the substance (e.g., the stability of this substance), and the ease of handling of the substance, and are often formed as part of the isolation or purification stage of chemical synthesis. A person skilled in the art can determine whether a hydrate or other solvate was formed by the isolation or purification conditions used to prepare a given compound by standard and long-used techniques. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single-crystal X-ray crystallography or X-ray powder diffraction), and solid-state NMR (SS-NMR, also known as magic angle spinning NMR or MAS-NMR). Such techniques are part of the standard set of analytical tools for skilled chemists, along with NMR, IR, HPLC, and MS. Alternatively, a person skilled in the art can intentionally form a solvate using crystallization conditions that include the amount of solvent required for a particular solvate. Thereafter, the standard methods described above can be used to confirm whether a solvate was formed.

[0186] Furthermore, the compounds of the present invention may have one or more polymorphic (crystalline) or amorphous forms, and these forms are intended to be included within the scope of the present invention in themselves.

[0187] The compounds of formula (I) may exist in several different geometric isomeric forms and tautomeric forms, and the reference to the compounds of formula (I) includes all such forms. For the sake of avoiding misunderstanding, it should be noted that a compound may exist as one of several geometric isomeric forms or tautomeric forms, and even if only one is specifically described or shown, all others are included by formula (I). Examples of tautomeric forms include, for example, keto forms, enol forms, and enolate forms such as the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / enediamine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.

Chemical Formula

[0188] Such forms are intended to be included within the scope of the present invention to the extent possible. Thus, it follows that a compound may exist in both stereoisomeric and tautomeric forms.

[0189] When the compounds of formula (I) contain one or more chiral centers and can exist in the form of two or more optical isomers, reference to a compound of formula (I) includes, unless the context requires a contrary meaning, all of its optical isomeric forms (e.g., enantiomers, epimers, and diastereoisomers), either as individual optical isomers or as a mixture of two or more optical isomers (e.g., a racemic mixture). When the compounds of formula (I) have a plurality of chiral centers and one chiral center is shown as having an absolute configuration in a compound of formula (I-a), (I-A-a), (I-B-a), (I-C-a), or (I-D-a), etc., the other chiral centers include, unless the context requires a contrary meaning, all optical isomers, either as individual optical isomers or as a mixture of two or more of its optical isomers (such as a racemic mixture). Optical isomers can be characterized and identified by their optical activity (i.e., as + and - isomers or d and l isomers depending on the direction in which they rotate plane-polarized light), or they can be characterized in terms of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold, and Prelog. See Advanced Organic Chemistry, 4th th Edition, John Wiley & Sons, New York, 1992, pages 109 - 114, and also see Cahn, Ingold & Prelog (1966) Angew. Chem. Int. Ed. Engl., 5, 385 - 415. For example, a resolved enantiomer of unknown absolute configuration can be designated as (+) or (-) depending on the direction in which it rotates plane-polarized light.

[0190] Optical isomers can be separated by several techniques including chiral chromatography (chromatography on a chiral support), such techniques being well known to those skilled in the art. As an alternative to chiral chromatography, chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid can be used to form diastereoisomeric salts, and the diastereoisomers can be separated by preferential crystallization and then the salts dissociated to give the individual enantiomers of the free base, thereby separating the optical isomers.

[0191] When the compound of formula (I) exists in two or more isomeric forms, one isomeric form, for example one enantiomer of a pair of enantiomers, may have advantages over other isomeric forms, for example in terms of biological activity, over other enantiomers. Therefore, in certain circumstances, it may be desirable to use only one of a pair of enantiomers, or only one of a plurality of diastereoisomers, as a therapeutic agent. The following structure

Chemical formula

[0192] As used herein, any chemical formula in which the bond is shown only as a solid line, rather than as a solid wedge bond or a dashed wedge bond, or any chemical formula that is not shown as having a specific configuration (e.g., R, S) around one or more atoms, contemplates each possible stereoisomer, or a mixture of two or more stereoisomers.

[0193] The terms "stereoisomer", "stereoisomeric form", or "stereochemical isomeric form" are used interchangeably above and below.

[0194] Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

[0195] Atropisomers (or atropoisomers) are stereoisomers having a specific spatial arrangement that results from restricted rotation around a single bond due to large steric hindrance. All atropisomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.

[0196] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not in a mirror image relationship. When a compound contains a double bond, the substituents can be in the E configuration or the Z configuration. Substituents on a divalent cyclic (partially) saturated group can have a cis configuration or a trans configuration. For example, when a compound contains a disubstituted cycloalkyl group, the substituents can be in the cis configuration or the trans configuration. Accordingly, the present invention always includes, where chemically possible, enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof.

[0197] The meaning of all these terms, i.e., enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, is known to those skilled in the art.

[0198] The compounds of the present invention include compounds having one or more isotope substitutions, and references to a particular element include all isotopes of that element, whether naturally occurring or synthetically produced, whether naturally abundant or in isotopically enriched form, within the scope of this compound. For example, reference to hydrogen includes within its scope 1 H, 2 H(D), and 3 H(T). Similarly, references to carbon and oxygen include within their scope, respectively 12 C, 13 C, and 14 C, as well as 16 O and 18 O. Isotopes may be radioactive or non-radioactive. In one embodiment of the present invention, the compound does not contain radioactive isotopes. Such compounds are preferred for therapeutic use. However, in another embodiment, the compound may contain one or more radioactive isotopes. Compounds containing such radioactive isotopes may be useful from a diagnostic perspective. A radiolabeled compound of formula (I) is 2 H, 3 H, 11 C, 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 Br may contain a radioactive isotope selected from the group. Preferably, the radioactive isotope is 2 H, 3 H, 11 C, and 18 F selected from the group. More preferably, the radioactive isotope is 2 H.

[0199] In particular, deuterated compounds are intended to be included within the scope of the present invention.

[0200] Pharmacodynamics Protein tyrosine kinase (PTK) The compounds of the invention described herein inhibit or modulate the activity of certain tyrosine kinases and are therefore useful for the treatment or prevention, particularly treatment, of conditions or disorders mediated by these tyrosine kinases, particularly FGFR.

[0201] FGFR The fibroblast growth factor (FGF) family of protein tyrosine kinase (PTK) receptors controls a diverse array of physiological functions including mitogenesis, wound healing, cell differentiation and angiogenesis, and development. Both normal and malignant cell growth and proliferation are affected by changes in the local concentration of FGF, an extracellular signaling molecule that acts as an autocrine and paracrine factor. Autocrine FGF signaling can be particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state. FGF and its receptors are expressed at increased levels in several tissues and cell lines, and overexpression is thought to contribute to the malignant phenotype. Furthermore, some oncogenes are homologs of genes encoding growth factor receptors and there is a potential for abnormal activation of FGF-dependent signaling in human pancreatic cancer (Knights et al., Pharmacology and Therapeutics 2010 125:1(105 - 117); Korc M. et al Current Cancer Drug Targets 2009 9:5(639 - 651)).

[0202] Two prototype members are acidic fibroblast growth factor (aFGF or FGF1) and basic fibroblast growth factor (bFGF or FGF2), and at least 20 different FGF family members have been identified to date. Cellular responses to FGF are mediated by four high-affinity transmembrane protein tyrosine kinase fibroblast growth factor receptors (FGFRs) numbered 1 - 4 (FGFR1 - FGFR4).

[0203] In addition to promoting the proliferation of endothelial cells, this kinase is activated in many tumor types, so disruption of the FGFR1 pathway should affect tumor cell proliferation. Overexpression and activation of FGFR1 in tumor-associated vasculature suggest the role of this molecule in tumor angiogenesis.

[0204] Recent studies have shown an association between FGFR1 expression and carcinogenicity in Classic Lobular Carcinomas (CLCs). CLCs account for 10 - 15% of all breast cancers and generally lack p53 and Her2 expression while maintaining estrogen receptor expression. Gene amplification at 8p12 - p11.2 has been shown in approximately 50% of CLC cases, which has been shown to be associated with increased FGFR1 expression. Preliminary tests with siRNA directed against FGFR1 or small molecule inhibitors of the receptor have shown that cell lines with this amplification are particularly sensitive to inhibition of this signaling pathway. Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, probably arising from abnormal proliferation and differentiation during skeletal myogenesis. FGFR1 is overexpressed in primary rhabdomyosarcoma tumors and is associated with hypomethylation of the 5’ CpG island and abnormal expression of the AKT1, NOG, and BMP4 genes.

[0205] Fibroblast growth factor receptor 2 has a high affinity for acidic and / or basic fibroblast growth factors, as well as keratinocyte growth factor ligands. Fibroblast growth factor receptor 2 also transmits the potent osteogenic effect of FGF during the growth and differentiation of osteoblasts. Mutations in fibroblast growth factor receptor 2 lead to complex functional alterations, but have been shown to induce abnormal ossification of cranial sutures (craniosynostosis), meaning a major role of FGFR signaling in intramembranous ossification. For example, in Apert (AP) syndrome, which is characterized by early cranial suture ossification, most cases are associated with point mutations that cause a gain of function in fibroblast growth factor receptor 2. In addition, mutation screening in patients with symptomatic craniosynostosis has shown that several FGFR2 recurrent mutations are the cause of severe forms of Pfeiffer syndrome. Specific mutations of FGFR2 include W290C, D321A, Y340C, C342R, C342S, C342W, N549H, K641R in FGFR2.

[0206] Some severe abnormalities in human skeletal development, including Apert, Crouzon, Jackson-Weiss, Beare-Stevenson cutis gyrata syndrome, and Pfeiffer syndrome, are associated with the occurrence of mutations in fibroblast growth factor receptor 2. Most, if not all, cases of Pfeiffer syndrome (PS) are caused by novel mutations in the fibroblast growth factor receptor 2 gene, and it has recently been shown that mutations in fibroblast growth factor receptor 2 break one of the basic rules governing ligand specificity. That is, the two mutant splice forms of fibroblast growth factor receptor, FGFR2c and FGFR2b, have acquired the ability to bind to and thereby be activated by atypical FGF ligands. This loss of ligand specificity leads to abnormal signaling, suggesting that the severe phenotypes of these disease syndromes result from ectopic ligand-dependent activation of fibroblast growth factor receptor 2.

[0207] Genetic abnormalities of the FGFR3 receptor tyrosine kinase, such as chromosomal translocations or point mutations, result in ectopically expressed or deregulated constitutively active FGFR3 receptors. Such abnormalities have been associated with a subset of multiple myeloma and also in bladder cancer, hepatocellular carcinoma, oral squamous cell carcinoma, and cervical cancer. Thus, an FGFR3 inhibitor would be useful for the treatment of multiple myeloma, bladder cancer, and cervical cancer. FGFR3 is also overexpressed in bladder cancer, particularly invasive bladder cancer. FGFR3 is frequently activated by mutation in urothelial carcinoma (UC). Increased expression was associated with mutation (85% of mutant tumors showed high-level expression), but 42% of tumors without detectable mutations, including many muscle-invasive tumors, also showed overexpression.

[0208] Overexpression of FGFR4 has been associated with poor prognosis in both prostate cancer and thyroid cancer. In addition, a germline polymorphism (Gly388Arg) has been associated with increased incidence of lung cancer, breast cancer, colon cancer, liver cancer (HCC), and prostate cancer. In addition, a deletion type of FGFR4 (including the kinase domain) has been found to be present in 40% of pituitary tumors but not in normal tissues. FGFR4 overexpression has been observed in liver tumors, colon tumors, and lung tumors. FGFR4 has been causally linked to colorectal cancer and liver cancer in which the expression of its ligand FGF19 is frequently increased.

[0209] The pathological condition of fibrosis is a major medical problem resulting from abnormal or excessive deposition of fibrous tissue. This occurs in many diseases including cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, as well as in the natural process of wound healing. The mechanisms of pathological fibrosis are not fully understood but are thought to result from the action of various cytokines (tumor necrosis factor (TNF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and transforming growth factor beta (TGFβ)) involved in fibroblast proliferation and deposition of extracellular matrix proteins (including collagen and fibronectin). This causes changes in tissue structure and function and subsequent pathological conditions.

[0210] Several preclinical studies have demonstrated upregulation of fibroblast growth factor in preclinical models of pulmonary fibrosis. TGFβ1 and PDGF have been reported to be involved in the fibrogenic process, and published studies further suggest that the elevation of FGF and the resulting increase in fibroblast proliferation may be a response to elevated TGFβ1. The potential therapeutic effect of targeting the fibrogenic mechanism in conditions such as idiopathic pulmonary fibrosis (IPF) is suggested by the reported clinical effect of the antifibrotic agent pirfenidone. Idiopathic pulmonary fibrosis, also known as cryptogenic fibrosing alveolitis, is a progressive condition associated with scarring of the lungs. The alveoli of the lungs are gradually replaced by fibrous tissue, which thickens and causes an irreversible loss of the ability of the tissue to carry oxygen to the bloodstream. Symptoms of this condition include shortness of breath, chronic dry cough, fatigue, chest pain, and loss of appetite resulting in rapid weight loss. The condition is very severe, and the mortality rate after 5 years is approximately 50%.

[0211] Therefore, compounds that inhibit FGFR would be useful in providing a means to prevent tumor growth or induce apoptosis of tumors, particularly by inhibiting angiogenesis. Accordingly, it is expected that compounds will be found to be useful in the treatment or prevention of proliferative diseases such as cancer. In particular, tumors having activating mutants of receptor tyrosine kinases or upregulation of receptor tyrosine kinases may be particularly sensitive to inhibitors. Patients having activating mutants of any of the specific RTK isoforms discussed herein will also notice that treatment with RTK inhibitors may be particularly beneficial.

[0212] As indicated above in this specification, various FGFR inhibitors are in clinical trials and have shown clinical responses in patients with FGFR abnormalities. However, mutations that affect the amino acids of FGFR, such as FGFR1, 2, or 3, have been reported to cause resistance to FGFR inhibitors or reduce sensitivity to FGFR inhibitors. The occurrence of secondary FGFR kinase domain mutations during treatment with FGFR inhibitors is an important mechanism of acquired resistance to FGFR inhibition. Equivalent FGFR point mutations also newly exist in cancers. Gatekeeper mutations have been reported as one of the major mechanisms leading to resistance to tyrosine kinase inhibitors. Examples of gatekeeper mutations include FGFR3 V555L / V555M, FGFR1 V561M, FGFR2 V564F / V564I / V564M, and FGFR4 V550L. FGFR resistance mutations have been reported in clinical trials and in vitro cell lines. Therefore, new (second-generation) FGFR inhibitors are needed to overcome clinically acquired resistance to first-generation FGFR inhibitor therapies and at the same time maintain FGFR inhibitory activity against primary activating FGFR mutations.

[0213] The compounds of the present invention are active against wild-type FGFR, particularly FGFR1, 2, 3, or 4, more specifically FGFR3, but also against mutant FGFR, particularly FGFR having gatekeeper mutations, or against mutant FGFR1 or mutant FGFR2 or mutant FGFR3, particularly against FGFR3 V555L, FGFR3 V555M, FGFR1 V561M, and FGFR2 V564I, and especially against FGFR3 V555L and FGFR3 V555M.

[0214] Biological Activity and Therapeutic Use The compounds of the present invention and subgroups thereof have fibroblast growth factor receptor (FGFR) inhibitory or regulatory activity and would be useful for the prevention or treatment, particularly treatment, of the medical conditions or disorders described herein. In addition, the compounds of the present invention and subgroups thereof would be useful for the prevention or treatment, particularly treatment, of diseases or disorders mediated by kinases. References to the prevention (preventing) or prophylaxis or treatment of a medical condition or disorder such as cancer include, within its scope, moderating or reducing the incidence of cancer.

[0215] In one embodiment, the compound of formula (I) is an ATP-competitive inhibitor of FGFR kinase.

[0216] As used herein, the term "regulate" when applied to the activity of a kinase is intended to define a change in the level of the biological activity of a protein kinase. Thus, regulation encompasses physiological changes that result in an increase or decrease in the associated protein kinase activity. In the latter case, regulation may be described as "inhibition". Regulation may occur directly or indirectly and by any mechanism, for example, at any physiological level including the level of gene expression (including, for example, transcription, translation, and / or post-translational modification), the level of expression of genes encoding regulatory elements that act directly or indirectly on the level of kinase activity. Thus, regulation may mean increased / suppressed expression or over- or under-expression of a kinase, including gene amplification (i.e., multiple gene copies) and / or increased or decreased expression by transcriptional effects, as well as over- (or under-) activity and (de)activation (including (de)activation) of a protein kinase by mutation. The terms "regulated", "regulating", and "regulate" shall be construed accordingly.

[0217] As used herein, for example, the term "mediated" when used with a kinase as described herein (and, for example, applied to various physiological processes, diseases, conditions, pathologies, therapies, treatments, or interventions) is intended to be limited to act such that the various processes, diseases, conditions, pathologies, treatments, and interventions to which the term applies are those in which the kinase plays a biological role. When the term is applied to a medical condition or pathology, the biological role played by the kinase may be direct or indirect and may be necessary and / or sufficient for the manifestation of the symptoms (or the cause or progression thereof) of the medical condition or pathology. Thus, kinase activity (in particular, abnormal levels of kinase activity, such as kinase overexpression) is not necessarily the proximate cause of this medical condition or pathology; rather, diseases, conditions, or pathologies mediated by a kinase are expected to include those having a multifactorial etiology and a complex progression in which the kinase in question is only partially involved. When the term is applied to a treatment, prevention, or intervention, the role played by the kinase may be direct or indirect and may be necessary and / or sufficient for the result of the treatment, prevention maneuver, or intervention. Thus, diseases or conditions mediated by a kinase include the development of resistance to any particular cancer drug or treatment.

[0218] Thus, for example, the compounds of the present invention may be useful for alleviating or reducing the incidence of cancer.

[0219] More specifically, the compounds of formula (I) and their subgroups are inhibitors of FGFR. For example, the compounds of the present invention are active against FGFR1, FGFR2, FGFR3, and / or FGFR4, particularly against FGFR1, 2, and 3. More specifically, the compounds of the present invention are active against wild-type FGFR and / or mutant FGFR, particularly FGFR having point mutations, and more specifically against gatekeeper mutations. Examples of gatekeeper mutations include FGFR3 V555L / V555M, FGFR1 V561M, FGFR2 V564F / V564I / V564M, and FGFR4 V550L. In particular, the compounds of the present invention are active against gatekeeper mutant FGFR1, FGFR2, and FGFR3, more specifically against FGFR3 V555L, FGFR3 V555M, FGFR1 V561M, and FGFR2 V564I, and particularly against FGFR3 V555L and FGFR3 V555M.

[0220] The diagnosis of tumors having mutations can be carried out using techniques known to those skilled in the art and described herein, such as RT-PCR and FISH.

[0221] Examples of cancers that can be treated (or inhibited) include, but are not limited to: cancer, such as bladder cancer, breast cancer, colon cancer (e.g., colorectal cancer such as colon adenocarcinoma and colon adenoma), kidney cancer, urothelial cancer, uterine cancer, epidermal cancer, liver cancer, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer (e.g., adenocarcinoma and squamous cell carcinoma)), esophageal cancer, head and neck cancer, gallbladder cancer, ovarian cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), gastric cancer, gastrointestinal (also known as GI) cancer (e.g., gastrointestinal stromal tumor), cervical cancer, endometrial cancer, thyroid cancer, prostate cancer, or skin cancer (e.g., squamous cell carcinoma or dermatofibrosarcoma protuberans); pituitary cancer, lymphoid hematopoietic tumors, such as leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, or Burkitt lymphoma; myeloid hematopoietic tumors, such as leukemia, acute and chronic myeloid leukemia, chronic myelomonocytic leukemia (CMML), myeloproliferative disorders, myeloproliferative syndromes, myelodysplastic syndromes, or promyelocytic leukemia; multiple myeloma; follicular thyroid cancer; hepatocellular carcinoma, tumors derived from mesenchyme (e.g., Ewing sarcoma), such as fibrosarcoma or rhabdomyosarcoma; central or peripheral nervous system tumors, such as astrocytoma, neuroblastoma, glioma (such as glioblastoma multiforme), or schwannoma; melanoma; seminoma; teratoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; follicular thyroid cancer; or Kaposi sarcoma. In particular, squamous cell lung cancer, breast cancer, colorectal cancer, glioblastoma, astrocytoma, prostate cancer, small cell lung cancer, melanoma, head and neck cancer, thyroid cancer, uterine cancer, gastric cancer, hepatocellular carcinoma, cervical cancer, multiple myeloma, bladder cancer, endometrial cancer, urothelial carcinoma, colon cancer, rhabdomyosarcoma, pituitary cancer, cholangiocarcinoma.

[0222] Examples of cancers that can be treated (or inhibited) include, but are not limited to: bladder cancer, urothelial cancer, metastatic urothelial cancer, inoperable urothelial cancer, breast cancer, glioblastoma, lung cancer, non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma of the lung, pulmonary adenocarcinoma, small cell lung cancer, ovarian cancer, endometrial cancer, cervical cancer, soft tissue sarcoma, head and neck squamous cell carcinoma, gastric cancer, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, cholangiocarcinoma, hepatocellular carcinoma.

[0223] Examples of cancers that can be treated (or inhibited) include, but are not limited to: progressive or refractory NSCLC (non-small cell lung cancer), breast cancer, glioblastoma multiforme, urothelial cancer, locally advanced or metastatic urothelial cancer, ovarian cancer, head and neck cancer, esophageal cancer, gastric cancer, and cholangiocarcinoma, particularly progressive or refractory NSCLC, breast cancer, glioblastoma multiforme, urothelial cancer, locally advanced or metastatic urothelial cancer, ovarian cancer, head and neck cancer, esophageal cancer, gastric cancer, and cholangiocarcinoma having FGFR genomic alterations (translocations, fusions, and / or mutations).

[0224] Examples of cancers that can be treated (or inhibited) include, but are not limited to: metastatic, locally advanced, or surgically unresectable urothelial cancer, particularly metastatic, locally advanced, or surgically unresectable urothelial cancer having FGFR genomic alterations (translocations, fusions, and / or mutations).

[0225] Examples of cancers that can be treated (or inhibited) include, but are not limited to: urothelial cancer, locally advanced or metastatic urothelial cancer, particularly urothelial cancer, locally advanced or metastatic urothelial cancer having FGFR genomic alterations (translocations, fusions, and / or mutations).

[0226] Examples of cancers that can be treated (or inhibited) include, but are not limited to: muscle-invasive bladder cancer, particularly muscle-invasive bladder cancer having FGFR genomic alterations (translocations, fusions, and / or mutations).

[0227] Examples of cancers that can be treated (or inhibited) include, but are not limited to: non-small cell lung cancer (NSCLC), squamous cell lung cancer, and non-squamous cell lung cancer, particularly non-small cell lung cancer (NSCLC), squamous cell lung cancer, and non-squamous cell lung cancer having FGFR genomic alterations (translocations, fusions, and / or mutations).

[0228] Certain cancers are resistant to treatment with specific drugs. This can be due to the type of tumor or can occur as a result of treatment with a compound. In this regard, reference to multiple myeloma includes bortezomib-sensitive multiple myeloma or refractory multiple myeloma. Similarly, reference to chronic myelogenous leukemia includes imitanib-sensitive chronic myelogenous leukemia and refractory chronic myelogenous leukemia. Chronic myelogenous leukemia is also known as chronic myeloid leukemia, chronic granulocytic leukemia, or CML. Similarly, acute myelogenous leukemia is also referred to as acute myeloblastic leukemia, acute granulocytic leukemia, acute non-lymphocytic leukemia, or AML.

[0229] The compounds of the present invention can also be used in the treatment of hematopoietic diseases of abnormal cell proliferation, such as myeloproliferative diseases, regardless of whether they are in a precancerous or stable state. Myeloproliferative diseases ("MPD") are a group of diseases of the bone marrow in which an excessive amount of cells are produced. This is related to myelodysplastic syndromes and can evolve into myelodysplastic syndromes. Myeloproliferative diseases include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. A further hematological disorder is hypereosinophilic syndrome. T cell lymphoproliferative diseases include those derived from natural killer cells.

[0230] In addition, the compounds of the present invention can be used to treat gastrointestinal (alias, stomach) cancers, such as gastrointestinal stromal tumors. Gastrointestinal cancers refer to pathological conditions of the digestive tract including the esophagus, stomach, liver, biliary tract, pancreas, intestine, and anus.

[0231] Therefore, in the pharmaceutical composition, use, or method of the present invention for treating a disease or condition including abnormal cell proliferation, the disease or condition including abnormal cell proliferation in one embodiment is cancer.

[0232] Specific subsets of cancer include multiple myeloma, bladder cancer, cervical cancer, prostate cancer, thyroid cancer, lung cancer, breast cancer, and colon cancer.

[0233] Additional subsets of cancer include multiple myeloma, bladder cancer, hepatocellular carcinoma, oral squamous cell carcinoma, and cervical cancer.

[0234] The compounds of the present invention having FGFR inhibitory activity such as FGFR1 may be particularly useful for the treatment or prevention of breast cancer, particularly classical lobular carcinoma (CLC), and lung cancer having FGFR1 amplification or FGFR1 mutation.

[0235] Since the compounds of the present invention have FGFR4 activity, this compound may also be useful for the treatment of prostate cancer or pituitary cancer, or this compound may be useful for the treatment of breast cancer, lung cancer, prostate cancer, liver cancer (e.g., HCC (hepatocellular carcinoma)), or lung cancer.

[0236] In particular, the compounds of the present invention as FGFR inhibitors are useful for the treatment of multiple myeloma, myeloproliferative disorders, endometrial cancer, prostate cancer, bladder cancer, lung cancer, ovarian cancer, breast cancer, gastric cancer, colorectal cancer, and oral squamous cell carcinoma.

[0237] Additional subsets of cancer are multiple myeloma, endometrial cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer, colorectal cancer, and thyroid cancer.

[0238] In particular, the compounds of the present invention are useful for the treatment of multiple myeloma (particularly multiple myeloma having t(4;14) translocation or overexpressed FGFR3), prostate cancer (hormone-refractory prostrate carcinoma), endometrial cancer (particularly endometrial tumors having activating mutations in FGFR2), and breast cancer (particularly lobular carcinoma).

[0239] In particular, the compounds of the present invention are useful for the treatment of cholangiocarcinoma, particularly cholangiocarcinoma having FGFR translocation and mutation, or FGF19 amplification.

[0240] In particular, this compound is useful for the treatment of lobular cancer such as CLC (classical lobular carcinoma).

[0241] Since this compound has activity against FGFR3, this compound may be useful for the treatment of multiple myeloma and bladder cancer.

[0242] In particular, the present compound is active against tumors having an FGFR3-TACC3 translocation, particularly bladder or brain tumors having an FGFR3-TACC3 translocation.

[0243] In particular, the present compound is useful for the treatment of t(4;14) translocation-positive multiple myeloma.

[0244] In one embodiment, the present compound may be useful for the treatment of sarcoma. In one embodiment, the present compound may be useful for the treatment of lung cancer, such as squamous cell carcinoma.

[0245] Since the present compound has activity against FGFR2, this compound would be useful for the treatment of endometrial cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, uterine cancer, cervical cancer, and colorectal cancer. Since FGFR2 is also overexpressed in epithelial ovarian cancer, the compounds of the present invention may be particularly useful for the treatment of ovarian cancers such as epithelial ovarian cancer.

[0246] In one embodiment, the present compound may be useful for the treatment of lung cancer, particularly NSCLC (non-small cell lung cancer), squamous cell carcinoma, liver cancer, kidney cancer, breast cancer, colon cancer, colorectal cancer, and prostate cancer.

[0247] The cancer can be a cancer that is sensitive to the inhibition of any one or more FGFRs selected from FGFR1, FGFR2, FGFR3, FGFR4, for example, one or more FGFRs selected from FGFR1, FGFR2, or FGFR3.

[0248] Whether a particular cancer is sensitive to the inhibition of FGFR signaling can be determined by the cell growth assays described below or by the methods described in the section entitled "Methods of Diagnosis".

[0249] The compounds of the present invention may be useful for the treatment or prevention of cancers of the type associated with or characterized by the presence of high levels of FGFR, in particular.

[0250] The compounds of the present invention may be useful for the treatment of type 2 diabetes, i.e., non-insulin-dependent diabetes, autoimmune diseases, head trauma, stroke, epilepsy, neurodegenerative diseases such as Alzheimer's disease, motor neuron diseases, progressive supranuclear palsy, corticobasal degeneration, and Pick's disease, and other pathological conditions caused by abnormal proliferation, such as autoimmune diseases and neurodegenerative diseases.

[0251] The subgroup of conditions and pathologies for which the compounds of the present invention may be useful consists of inflammatory diseases, cardiovascular diseases, and wound healing.

[0252] FGFR is also known to play roles in apoptosis, angiogenesis, proliferation, differentiation, and transcription. Therefore, the compounds of the present invention may also be useful for the treatment of the following diseases other than cancer: chronic inflammatory diseases such as systemic lupus erythematosus, autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes, eczematous allergic reactions, asthma, COPD (chronic obstructive pulmonary disease), rhinitis, and upper airway diseases; cardiovascular diseases such as cardiac hypertrophy, restenosis, and atherosclerosis; neurodegenerative diseases such as Alzheimer's disease, AIDS (acquired immunodeficiency syndrome)-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and cerebellar degeneration; glomerulonephritis; myelodysplastic syndrome, myocardial infarction, stroke, and reperfusion injury associated with ischemic injury, arrhythmia, atherosclerosis, liver diseases caused by toxins or related to alcohol, blood diseases such as chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system such as osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases, and cancer pain.

[0253] In addition, mutations in FGFR2 are associated with several severe abnormalities in human skeletal development. Therefore, the compounds of the present invention may be useful for the treatment of abnormalities in human skeletal development, including abnormal ossification of cranial sutures (craniosynostosis), Apert (AP) syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Baehr-Stevenson cutis gyrate syndrome, and Pfeiffer syndrome.

[0254] The compounds of the present invention having FGFR inhibitory activity such as FGFR2 or FGFR3 may be particularly useful for the treatment or prevention of skeletal diseases. Specific skeletal diseases are achondroplasia or lethal dwarfism (also known as lethal osteodysplasia).

[0255] The compounds of the present invention having FGFR inhibitory activity such as FGFR1, FGFR2, or FGFR3 may be particularly useful for the treatment or prevention of lesions with progressive fibrosis as a symptom. Fibrotic conditions in which the compounds of the present invention may be useful in treatment include diseases showing abnormal or excessive deposition of fibrous tissue, such as cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and the natural process of wound healing. In particular, the compounds of the present invention may also be useful for the treatment of pulmonary fibrosis, particularly idiopathic pulmonary fibrosis.

[0256] The overexpression and activation of FGFR and VEGFR in tumor-related vasculature also suggest the role of the compounds of the present invention in preventing tumor angiogenesis and interrupting its initiation. In particular, the compounds of the present invention may be useful for the treatment of cancer, metastasis, leukemia such as CLL, age-related macular degeneration, particularly exudative age-related macular degeneration, ischemic proliferative retinopathies such as retinopathy of prematurity (ROP), and eye diseases such as diabetic retinopathy, rheumatoid arthritis, and hemangioma.

[0257] The activity of the compounds of the present invention as inhibitors of FGFR1-4, particularly point mutant FGFR3 such as FGFR3 V555L and FGFR3 V555M, for example, can be measured using the assays described in the following examples, and the level of activity exhibited by a given compound can be defined in terms of the IC 50 value. Preferred compounds of the present invention are compounds having an IC 50 value of less than 1 μM, more preferably less than 0.1 μM, less than 0.01 μM, or less than 0.001 μM.

[0258] The present invention provides compounds having FGFR inhibitory or regulatory activity that may be useful for the prevention or treatment, particularly treatment, of conditions or states mediated by FGFR kinase.

[0259] In one embodiment, there is provided a compound as defined herein for use in therapy, for use as a medicament. In a further embodiment, there is provided a compound as defined herein for the prevention or treatment of a FGFR kinase-mediated condition or disorder, particularly for use in treatment.

[0260] Thus, for example, the compounds of the invention may be useful for alleviating or reducing the incidence of cancer. Accordingly, in a further embodiment, there is provided a compound as defined herein for the prevention or treatment of cancer, particularly for use in treatment. In one embodiment, the compound as defined herein is for the prevention or treatment of FGFR-dependent cancer, particularly for use in treatment. In one embodiment, the compound as defined herein is for the prevention or treatment of cancer mediated by FGFR kinase, particularly for use in treatment.

[0261] Accordingly, the present invention particularly provides: - A method for the prevention or treatment of a FGFR kinase-mediated condition or disorder, particularly a method of treatment, comprising administering to a subject in need thereof a compound of formula (I) as defined herein.

[0262] - A method for the prevention or treatment of a condition or disorder as described herein, particularly a method of treatment, comprising administering to a subject in need thereof a compound of formula (I) as defined herein.

[0263] - A method for the prevention or treatment, particularly treatment, of cancer (especially cancer having a gatekeeper mutation in FGFR1, FGFR2, or FGFR3, more particularly cancer having FGFR3 V555L, FGFR3 V555M, FGFR1 V561M, or FGFR2 V564I, especially cancer having FGFR3 V555L or FGFR3 V555M), which comprises administering to a subject in need thereof a compound of formula (I) as defined herein. In one embodiment, this cancer has, in addition to the gatekeeper mutation in FGFR1, FGFR2, or FGFR3, one or more other FGFR abnormalities, such as one or more FGFR mutations, or one or more FGFR translocations, such as those defined herein.

[0264] - A method for alleviating or reducing the incidence of a condition or disorder mediated by FGFR kinase, which comprises administering to a subject in need thereof a compound of formula (I) as defined herein.

[0265] - A method for inhibiting FGFR kinase, which comprises contacting the kinase with a compound that inhibits the kinase of formula (I) as defined herein.

[0266] - A method for regulating a cellular process (e.g., cell division) by inhibiting the activity of FGFR kinase using a compound of formula (I) as defined herein.

[0267] - A compound of formula (I) as defined herein for use as a modulator of a cellular process (e.g., cell division) by inhibiting the activity of FGFR kinase.

[0268] - Compounds of formula (I) as defined herein for the prevention or treatment of cancer, particularly for use in treatment, especially cancer having a gatekeeper mutation in FGFR1, FGFR2, or FGFR3, more particularly cancer having FGFR3 V555L, FGFR3 V555M, FGFR1 V561M, or FGFR2 V564I, especially cancer having FGFR3 V555L or FGFR3 V555M. In one embodiment, this cancer has, in addition to the gatekeeper mutation in FGFR1, FGFR2, or FGFR3, one or more other FGFR abnormalities, such as one or more FGFR mutations, or one or more FGFR translocations, such as those defined herein.

[0269] - Compounds of formula (I) as defined herein for use as a modulator (e.g., inhibitor) of FGFR.

[0270] - Use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prevention or treatment, particularly treatment, of a condition or disorder mediated by FGFR kinase, wherein the compound has the formula (I) as defined herein.

[0271] - Use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prevention or treatment, particularly treatment, of the conditions or disorders described herein.

[0272] - Use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prevention or treatment, particularly treatment, of cancer (especially cancer having a gatekeeper mutation in FGFR1, FGFR2, or FGFR3, more particularly cancer having FGFR3 V555L, FGFR3 V555M, FGFR1 V561M, or FGFR2 V564I, especially cancer having FGFR3 V555L or FGFR3 V555M). In one embodiment, this cancer has, in addition to the gatekeeper mutation in FGFR1, FGFR2, or FGFR3, one or more other FGFR abnormalities, such as one or more FGFR mutations, or one or more FGFR translocations, such as those defined herein.

[0273] - Use of a compound of formula (I) as defined herein for the manufacture of a medicament for modulating (e.g., inhibiting) the activity of FGFR.

[0274] - Use of a compound of formula (I) as defined herein in the manufacture of a medicament for modulating a cellular process (e.g., cell division) by inhibiting the activity of an FGFR kinase.

[0275] - Use of a compound of formula (I) as defined herein for the prevention or treatment, particularly treatment, of a disease or condition characterized by upregulation of an FGFR kinase (e.g., FGFR1, or FGFR2, or FGFR3, or FGFR4), for the manufacture of a medicament therefor.

[0276] - Use of a compound of formula (I) as defined herein for the prevention or treatment, particularly treatment, of cancer characterized by upregulation of an FGFR kinase (e.g., FGFR1, or FGFR2, or FGFR3, or FGFR4), for the manufacture of a medicament for treating cancer.

[0277] - Use of a compound of formula (I) as defined herein for the prevention or treatment, particularly treatment, of cancer in a patient selected from a subpopulation having a genetic abnormality of an FGFR kinase, particularly an FGFR3 kinase, for the manufacture of a medicament therefor.

[0278] - Use of a compound of formula (I) as defined herein for the prevention or treatment of cancer, particularly for the manufacture of a medicament for treatment, in a patient diagnosed as forming part of a subpopulation having a genetic abnormality of FGFR kinase, particularly FGFR3 kinase.

[0279] - A method for the prevention or treatment of a disease or disorder characterized by upregulation of FGFR kinase (such as FGFR1, or FGFR2, or FGFR3, or FGFR4), particularly a method of treatment, comprising administering a compound of formula (I) as defined herein.

[0280] - A method for alleviating or reducing the incidence of a disease or disorder characterized by upregulation of FGFR kinase (such as FGFR1, or FGFR2, or FGFR3, or FGFR4), comprising administering a compound of formula (I) as defined herein.

[0281] - A method for the prevention or treatment of cancer, particularly a method of treatment (or of alleviating or reducing the incidence of cancer), in a patient having or suspected of having cancer, comprising: (i) subjecting the patient to a diagnostic test to determine whether the patient has a genetic abnormality of the FGFR3 gene; and (ii) if the patient has said variant, subsequently administering to the patient a compound of formula (I) as defined herein having FGFR3 kinase inhibitory activity.

[0282] - A method for preventing or treating a condition or disorder characterized by upregulation of an FGFR kinase (e.g., FGFR1, or FGFR2, or FGFR3, or FGFR4), particularly a method of treatment (or alleviating or reducing the incidence of the condition or disorder), comprising: (i) subjecting a patient to a diagnostic test to detect a marker characteristic of upregulation of an FGFR kinase (e.g., FGFR1, or FGFR2, or FGFR3, or FGFR4), and (ii) if the diagnostic test indicates upregulation of the FGFR kinase, subsequently administering to the patient a compound of formula (I) as defined herein having FGFR kinase inhibitory activity.

[0283] In one embodiment, the disease mediated by an FGFR kinase is an oncology-related disease (e.g., cancer). In one embodiment, the disease mediated by an FGFR kinase is a non-oncology-related disease (e.g., any disease disclosed herein other than cancer). In one embodiment, the disease mediated by an FGFR kinase is the condition described herein. In one embodiment, the disease mediated by an FGFR kinase is the skeletal condition described herein. Specific abnormalities in human skeletal development include abnormal ossification of cranial sutures (craniosynostosis), Apert (AP) syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Pfeiffer syndrome, achondroplasia, and lethal micromelia (also known as lethal osteogenesis imperfecta).

[0284] mutated kinase As indicated above herein, drug-resistant kinase mutations can occur in patient populations treated with kinase inhibitors. This occurs, in part, in regions of proteins that bind to or interact with the specific inhibitors used in the therapy. Such mutations decrease or increase the ability of the inhibitor to bind to and inhibit the kinase in question. This can occur in any of the amino acid residues that are important for interacting with the inhibitor or for supporting binding of the inhibitor to its target. Inhibitors that bind to the target kinase without the need to interact with the mutated amino acid residue will likely remain effective inhibitors of the enzyme, unaffected by the mutation.

[0285] Studies of gastric cancer patient samples showed the presence of two mutations in FGFR2, namely Ser167Pro in exon IIIa and the splice site mutation 940-2A-G in exon IIIc. These mutations are identical to germline activating mutations that cause craniosynostosis syndrome and were observed in 13% of the primary gastric cancer tissues tested. In addition, activating mutations in FGFR3 were observed in 5% of the patient samples tested, and overexpression of FGFR was correlated with poor prognosis in this patient group.

[0286] In addition, there are chromosomal translocations or point mutations observed in FGFR that result in gain-of-function, overexpression, or constitutively active biological states.

[0287] Thus, the compounds of the present invention will find particular uses in relation to cancers that express mutated molecular targets such as FGFR. Diagnosis of tumors having such mutations can be carried out using techniques known to those of skill in the art and described herein, such as RT-PCR and FISH.

[0288] It has been suggested that mutations of conserved threonine residues at the ATP-binding site of FGFR may cause inhibitor resistance. Amino acid valine 561 mutated to methionine in FGFR1, which corresponds to the already reported mutations found in Abl (T315) and EGFR (T766) that confer resistance to selective inhibitors. Assay data of FGFR1 V561M showed that this mutation confers resistance to tyrosine kinase inhibitors compared to the wild-type. Other mutations identified are the gatekeeper mutations FGFR3 V555L / V555M, FGFR1 V561M, FGFR2 V564F / V564I / V564M, and FGFR4 V550L. The compounds of the present invention are active, inter alia, against gatekeeper mutations, particularly against FGFR3 V555L, FGFR3 V555M, FGFR1 V561M, and FGFR2 V564I, and particularly against FGFR3 V555L and FGFR3 V555M.

[0289] The compounds of the present invention may be useful for the treatment of the adult population. The compounds of the present invention may be useful for the treatment of the pediatric population.

[0290] Diagnostic method Prior to administration of a compound of formula (I), a patient is screened to determine whether a disease or condition that the patient has or may have is susceptible to treatment with a compound having activity against FGFR, particularly FGFR having point mutations, particularly, for example, FGFR3 V555L, FGFR3 V555M, FGFR1 V561M, and FGFR2 V564I, particularly FGFR gatekeeper mutations such as FGFR3 V555L and FGFR3 V555M. In one embodiment, the cancer has, in addition to an FGFR gatekeeper mutation, particularly a gatekeeper mutation of FGFR1, FGFR2, or FGFR3, such as FGFR3 V555L, FGFR3 V555M, FGFR1 V561M, and FGFR2 V564I, particularly FGFR3 V555L and FGFR3 V555M, one or more other FGFR abnormalities, such as one or more FGFR mutations, or one or more FGFR translocations, such as those defined herein.

[0291] For example, a biological sample taken from the patient is analyzed to determine whether a condition or disease such as cancer that the patient has or may have is characterized by genetic abnormalities or abnormal protein expression that result in upregulation of the level or activity of FGFR, or sensitization of the pathway to normal FGFR activity, or upregulation of these growth factor signaling pathways such as growth factor ligand level or growth factor ligand activity, or upregulation of the biochemical pathway downstream of FGFR activation.

[0292] Examples of such abnormalities that result in activation or sensitization of FGFR signaling include loss or inhibition of the apoptotic pathway, upregulation of the receptor or ligand, or the presence of mutant variants of the receptor or ligand, such as PTK variants. Tumors having variants of FGFR1, FGFR2, or FGFR3, or FGFR4, or upregulation of FGFR1, particularly overexpression, or gain-of-function mutants of FGFR2 or FGFR3 may be particularly sensitive to FGFR inhibitors.

[0293] For example, point mutations that cause gain-of-function in FGFR2 have been identified in a number of pathologies. In particular, activating mutations in FGFR2 have been identified in 10% of endometrial tumors.

[0294] In addition, genetic abnormalities of FGFR3 receptor tyrosine kinases, such as chromosomal translocations or point mutations that result in ectopically expressed or deregulated constitutively active FGFR3 receptors, have been identified and are associated with subsets of multiple myeloma, bladder cancer, and cervical cancer. A specific mutation, T674I, of the PDGF receptor has been identified in patients treated with imatinib. In addition, gene amplification of 8p12-p11.2 has been shown in approximately 50% of lobular breast cancer (CLC) cases, which has been shown to be associated with increased expression of FGFR1. Preliminary tests with siRNA against FGFR1 or small molecule inhibitors of the receptor have shown that cell lines with this amplification are particularly sensitive to inhibition of this signaling pathway.

[0295] Alternatively, a biological sample taken from a patient can be analyzed for loss of negative regulators or suppressors of FGFR. In this context, the term "loss" includes deletion of a gene encoding a regulator or suppressor, shortening of the gene (e.g., due to a mutation), shortening of the gene transcript, or inactivation of the transcript (e.g., due to a point mutation), or sequestration by another gene product.

[0296] The term upregulation includes increased expression or overexpression, including gene amplification (i.e., multiple gene copies) and increased expression due to transcriptional effects, as well as overactivity and activation, including activation by mutation. Therefore, a patient can be subjected to a diagnostic test to detect markers characteristic of FGFR upregulation. The term diagnosis includes screening. Markers include, for example, genetic markers that include measurement of a DNA composition that identifies a mutation in FGFR. The term marker also includes markers characteristic of FGFR upregulation, including the enzymatic activity, enzyme level, enzyme state (e.g., whether phosphorylated or not), and mRNA level of the aforementioned proteins.

[0297] Diagnostic tests and screenings are typically performed on biological samples selected from tumor biopsy material samples, blood samples (isolation and enrichment of shed tumor cells), fecal biopsies, sputum, chromosome analysis, pleural fluid, ascites, buccal spear, biopsy material, or urine.

[0298] Methods for the identification and analysis of protein mutations and upregulation are known to those skilled in the art. Screening methods include, but are not limited to, the following: standard methods such as in-situ hybridization such as reverse transcription polymerase chain reaction (RT-PCR) or fluorescence in-situ hybridization (FISH).

[0299] Identification of individuals having mutations in FGFR may mean that the patient would be particularly suitable for treatment with an FGFR inhibitor. Tumors may preferentially be screened for the presence of FGFR variants prior to treatment. The screening process will typically include direct sequencing, oligonucleotide microarray analysis, or mutant-specific antibodies. In addition, diagnosis of tumors having such mutations can be performed using techniques known to those skilled in the art and described herein such as RT-PCR and FISH.

[0300] In addition, for example, mutant forms of FGFR can be identified by direct sequencing of tumor biopsies using methods such as PCR and direct sequencing of the PCR products described earlier herein. Those skilled in the art will recognize that all such well-known techniques for the detection of protein overexpression, activation, or mutation described above are applicable to the present case.

[0301] In screening by RT-PCR, the level of mRNA in a tumor is evaluated by creating cDNA copies of the mRNA followed by amplification of the cDNA by PCR. Methods of PCR amplification, selection of primers, and conditions of amplification are known to those skilled in the art. Nucleic acid manipulation and PCR are performed by standard methods described, for example, in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc. or Innis, M.A. et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Similarly, reactions and manipulations involving nucleic acid techniques are described in Sambrook et al., (2001), 3 rd Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, commercially available kits for RT-PCR (e.g., Roche Molecular Biochemicals), or the methodologies described in U.S. Patent Nos. 4,666,828; 4,683,202; 4,801,531; 5,192,659, 5,272,057, 5,882,864, and 6,218,529 (incorporated herein by reference) may be used. An example of an in-situ hybridization technique for evaluating mRNA expression would be fluorescence in-situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152:649).

[0302] Generally, in situ hybridization involves the following main steps: (1) fixation of the tissue to be analyzed; (2) prehybridization treatment of the sample to increase the accessibility of the target nucleic acid and reduce nonspecific binding; (3) hybridization of a mixture of nucleic acids to the nucleic acids in the biological structure or tissue; (4) post-hybridization washing to remove nucleic acid fragments that did not bind during hybridization; and (5) detection of the hybridized nucleic acid fragments. Probes used for such applications are typically labeled, for example, with a radioisotope or a fluorescent reporter. Preferred probes are long enough to allow specific hybridization to the target nucleic acid under stringent conditions, for example, from about 50, 100, or 200 nucleotides to about 1000 nucleotides or more. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M.S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.

[0303] A method of gene expression profiling is described by (DePrimo et al. (2003), BMC Cancer, 3:3). Briefly, this protocol is as follows: Double-stranded cDNA is synthesized from total RNA using (dT)24 oligomers to prime first-strand cDNA synthesis, followed by second-strand cDNA synthesis using random hexamer primers. The double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. The cRNA is chemically fragmented according to the protocol described by Affymetrix (Santa Clara, CA, USA) and then hybridized overnight on a Human Genome Array.

[0304] Alternatively, the protein products expressed from the mRNA can be assayed by immunohistochemistry of tumor samples, solid-phase immunoassays by microtiter plates, Western blotting, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods for detecting specific proteins known in the art. The detection methods will include the use of site-specific antibodies. One of ordinary skill in the art will recognize that such well-known techniques in their entirety for the detection of upregulation of FGFR or for the detection of FGFR variants or mutants are applicable to the present case.

[0305] Abnormal levels of proteins such as FGFR can be measured using standard enzyme assays, such as the assays described herein. Activation or overexpression can also be detected in tissue samples, such as tumor tissue. By measuring tyrosine kinase activity by an assay such as that obtained from Chemicon International. The tyrosine kinase of interest will be immunoprecipitated from the sample lysate and its activity measured.

[0306] Alternative methods for measuring the overexpression or activation of FGFR, including isoforms, include measuring microvessel density. This can be measured, for example, using the method described by Orre and Rogers (Int J Cancer (1999), 84(2) 101-8).

[0307] Thus, using all of these techniques, tumors particularly suitable for treatment with the compounds of the invention can also be identified.

[0308] The compounds of the invention are particularly useful for the treatment of patients having a mutated FGFR. The G697C mutation in FGFR3 is observed in 62% of oral squamous cell carcinomas and causes constitutive activation of kinase activity. Activating mutations of FGFR3 have also been identified in cases of bladder cancer. These mutations were the following six with various prevalences: R248C, S249C, G372C, S373C, Y375C, K652Q. In addition, the Gly388Arg polymorphism in FGFR4 has been found to be associated with an increased incidence and aggressiveness of prostate cancer, colon cancer, lung cancer, hepatocellular carcinoma (HCC), and breast cancer. The compounds of the invention are particularly useful for the treatment of patients having an FGFR3-TACC3 translocation.

[0309] Accordingly, in a further aspect, the invention includes the use of a compound according to the invention for the manufacture of a medicament for the treatment or prevention of a medical condition or disorder in a patient who has been screened and determined to be suffering from or at risk of suffering from a disease or disorder that would be sensitive to treatment with a compound having activity against FGFR.

[0310] Particular mutations for which a patient may be screened include the G697C, R248C, S249C, G372C, S373C, Y373C, K652Q mutations in FGFR3, and the Gly388Arg polymorphism in FGFR4, particularly FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, or FGFR3 Y373C.

[0311] Particular mutations for which patients are screened include, in particular, FGFR gatekeeper mutations. Gatekeeper mutations include FGFR3 V555L / V555M, FGFR1 V561M, FGFR2 V564F / V564I / V564M, and FGFR4 V550L. Particular mutations for which patients are screened include FGFR3 V555L, FGFR3 V555M, FGFR1 V561M, and FGFR2 V564I, in particular FGFR3 V555L and FGFR3 V555M.

[0312] In another aspect, the invention includes a compound of the invention for use in the prevention or treatment of cancer in a patient selected from a subpopulation having a variant of the FGFR gene (e.g., the G697C mutation in FGFR3 and the Gly388Arg polymorphism in FGFR4).

[0313] The compounds of the present invention are particularly useful in the treatment of patients having FGFR fusions or translocations, particularly FGFR3:TACC3 v1; FGFR3:TACC3 v3; FGFR3:TACC3 Intron; FGFR3:BAIAP2L1; FGFR2:AFF3; FGFR2:BICC1; FGFR2:CASP7; FGFR2:CCDC6; and FGFR2:OFD1. The following abbreviations are used: FGFR (fibroblast growth factor receptor); FGFR3:TACC3 (fusion of the gene encoding FGFR3 and the gene encoding transforming acidic coiled-coil containing protein 3); FGFR3:BAIAP2L1 (fusion of the gene encoding FGFR3 and the gene encoding brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1); FGFR2:AFF3 (fusion of the gene encoding FGFR2 and the gene encoding AF4 / FMR2 family, member 3); FGFR2:BICC1 (fusion of the gene encoding FGFR2 and the gene encoding bicoid C homolog 1); FGFR2:CASP7 (fusion of the gene encoding FGFR2 and the gene encoding caspase 7); FGFR2:CCDC6 (fusion of the gene encoding FGFR2 and the gene encoding coiled-coil domain containing 6); FGFR2:OFD1 (fusion of the gene encoding FGFR2 and the gene encoding oral-facial-digital syndrome 1).

[0314] Pharmaceutical Compositions and Combinations Considering the useful pharmacological properties, the compounds of the present subject matter can be formulated into various pharmaceutical forms for the purpose of administration.

[0315] In one embodiment, the pharmaceutical composition (e.g., formulation) comprises at least one active compound of the present invention together with a pharmaceutically acceptable carrier which may include adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, or other substances well known to those skilled in the art, and optionally other therapeutic or prophylactic agents.

[0316] To prepare the pharmaceutical composition of the present invention, an effective amount of the compound of the present invention as an active ingredient is thoroughly mixed and incorporated with a pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the dosage form desired for administration. This pharmaceutical composition can be in any form suitable for oral, parenteral, topical, intranasal, ocular, otic, rectal, intravaginal, or transdermal administration. This pharmaceutical composition is preferably in a unit dosage form suitable for oral administration, rectal administration, transdermal administration, or administration by parenteral injection. For example, when preparing this composition in an oral dosage form, in the case of oral liquid preparations such as suspensions, syrups, elixirs, and solutions, for example, water, glycols, oils, alcohols, and the like; or, in the case of powders, pills, capsules, and tablets, any of the usual pharmaceutical media such as solid carriers, for example, starch, sugars, kaolin, lubricants, binders, disintegrants, and the like can be used.

[0317] Tablets and capsules are the most advantageous oral unit dosage forms because their administration is easy, and in that case, a solid pharmaceutical carrier is of course used. In the case of parenteral compositions, the carrier usually consists at least largely of sterile water, but other components such as, for example, those that assist solubility may also be included. For example, an injectable solution can be prepared in which the carrier contains physiological saline, a glucose solution, or a mixture of physiological saline and a glucose solution. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents, and the like can be used. In a composition suitable for transdermal administration, the carrier optionally contains a penetration enhancer and / or a suitable wetting agent, optionally in combination with suitable additives having any nature in a low ratio, provided that these additives do not cause any significant harmful effects on the skin. The said additives can facilitate administration to the skin and / or can be useful for the preparation of the desired composition.

[0318] This composition can be administered in various ways, for example, as a transdermal patch, as a spot-on preparation, or as an ointment. For ease of administration and uniform dosage, it is particularly advantageous to formulate the above-described pharmaceutical composition into a unit dosage form. As used herein, the unit dosage form refers to physically discrete units suitable as a unit dose, each unit containing a defined amount of the active ingredient calculated to produce the desired therapeutic effect in association with the necessary pharmaceutical carrier. Examples of such unit dosage forms include tablets (including scored or coated tablets), capsules, pills, subpackaged powders, cachets, injection solutions or suspensions, teaspoonfuls, tablespoonfuls, and the like, as well as those divided and combined thereof.

[0319] The compounds of the present invention are administered in an amount sufficient to exhibit their anti-tumor activity or their FGFR inhibitory effect.

[0320] In one embodiment, the compound of the present invention or the pharmaceutical composition of the present invention is for oral administration.

[0321] One skilled in the art will be able to determine the effective amount from the test results presented below. Generally, it is contemplated that the therapeutically effective amount will be from 0.005 mg / kg to 100 mg / kg body weight, particularly from 0.005 mg / kg to 10 mg / kg body weight. It may be appropriate to administer the required dosage as 1, 2, 3, 4, or more sub-dosages at appropriate intervals over a day. Said sub-dosages can be formulated into unit dosage forms, for example, unit dosage forms containing from 0.5 to 500 mg, particularly from 1 mg to 500 mg, more specifically from 10 mg to 500 mg of the active ingredient per unit dosage form.

[0322] Depending on the mode of administration, the pharmaceutical composition preferably contains from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of the compound of the present invention, and from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, with all percentages based on the total weight of this composition.

[0323] It has been discovered that some FGFR inhibitors can be used in combination with other anti-cancer drugs. For example, it may be beneficial to combine an inhibitor that induces apoptosis with another agent that acts through a different mechanism to control cell growth to treat two of the unique features of cancer development. Examples of such combinations are described below.

[0324] As another aspect of the present invention, a combination of a compound of the present invention and another anti-cancer agent is envisioned, particularly for use as a pharmaceutical, more specifically for use in the treatment of cancer or related diseases, particularly conditions or diseases mediated by FGFR kinase.

[0325] For the treatment of the above conditions, the compounds of the present invention may advantageously be used in combination with one or more other agents, more specifically other anti-cancer agents or adjuvants in cancer treatment. Examples of anti-cancer agents or adjuvants (auxiliary agents in treatment) include, but are not limited to: - Platinum coordination compounds, such as cisplatin, optionally in combination with amifostine, carboplatin, or oxaliplatin; - Taxane compounds, such as paclitaxel, paclitaxel protein-bound particles (Abraxane (trademark)), or docetaxel; - Topoisomerase I inhibitors, such as camptothecin compounds, e.g., irinotecan, SN-38, topotecan, topotecan hcl; - Topoisomerase II inhibitors, such as antitumor epipodophyllotoxins or podophyllotoxin derivatives, e.g., etoposide, etoposide phosphate, or teniposide; - Antitumor vinca alkaloids, such as vinblastine, vincristine, or vinorelbine; - Antitumor nucleoside derivatives, such as 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hcl, capecitabine, cladribine, fludarabine, nelarabine; - Alkylating agents such as nitrogen mustard or nitrosourea, for example, mesna, pipobroman, procarbazine, streptozocin, telozolomide, cyclophosphamide optionally combined with uracil, chlorambucil, carmustine, thiotepa, melphalan (merphalan), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide; - Antitumor anthracycline derivatives, for example, daunorubicin, doxorubicin optionally combined with dexrazoxane, doxyl, idarubicin, mitoxantrone, epirubicin, epirubicin hcl, valrubicin; - Molecules targeting the IGF-1 receptor, for example picropodophyllin; - Tetracarcin derivatives, for example tetracarcin A; - Glucocorticoids, for example prednisone; - Antibodies, for example, trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab tiuxetan, ofatumumab, panitumumab, tositumomab, CNTO328; - Estrogen receptor antagonists, or selective estrogen receptor modulators, or inhibitors of estrogen synthesis, for example, tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene, or letrozole; - Aromatase inhibitors such as exemestane, anastrozole, letrozole, testolactone, and vorozole; - Differentiating agents such as retinoids, vitamin D, or retinoic acid, and retinoic acid metabolism blockers (RAMBA), for example acutane; - DNA methyltransferase inhibitors, for example, azacitidine or decitabine; - Antifolate agents, for example pemetrexed disodium; - Antibiotics, such as actinomycin D, bleomycin, mitomycin C, dactinomycin, calminomycin, daunomycin, levamisole, plicamycin, mitramycin; - Antimetabolites, such as clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine; - Apoptosis inducers and anti-angiogenic agents such as Bcl-2 inhibitors, e.g., YC137, BH312, ABT737, gossypol, HA14-1, TW37, or decanoic acid; - Tubulin binders, such as combretastatin, colchicine, or nocodazole; - Kinase inhibitors (e.g., EGFR (epidermal growth factor receptor) inhibitors, MTKI (multi-target kinase inhibitors), mTOR inhibitors, cmet inhibitors), e.g., flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib tosylate, sorafenib, sunitinib, sunitinib maleate, temsirolimus, 6-{difluoro[6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl}quinoline or a pharmaceutically acceptable salt thereof, 6-[difluoro(6-pyridin-4-yl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl]quinoline or a pharmaceutically acceptable salt thereof; - Farnesyl transferase inhibitors, such as tipifarnib; - Histone deacetylase (HDAC) inhibitors, such as sodium butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465, JNJ26481585, trichostatin A, vorinostat; - Inhibitors of the ubiquitin-proteasome pathway, such as PS-341, MLN.41, or bortezomib; - Yondelis; - Telomerase inhibitors, such as telomestatin; - Matrix metalloproteinase inhibitors, for example, batimastat, marimastat, prinomastat, or metastat. - Recombinant interleukins, for example, aldesleukin, denileukin diftitox, interferon alpha 2a, interferon alpha 2b, pegylated interferon alpha 2b - MAPK inhibitors - Retinoids, for example, alitretinoin, bexarotene, tretinoin; - Arsenic trioxide - Asparaginase - Steroids, for example, drostanolone propionate, megestrol acetate, nandrolone (decanoate, fenpropionate), dexamethasone - Gonadotropin-releasing hormone agonists or antagonists, for example, abarelix, goserelin acetate, histrelin acetate, leuprolide acetate - Thalidomide, lenalidomide - Mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase, rasburicase - BH3 mimetics, for example ABT-737 - MEK inhibitors, for example, PD98059, AZD6244, CI-1040 - Colony-stimulating factor analogs, for example, filgrastim, pegfilgrastim, sargramostim; erythropoietin or its analogs (for example darbepoetin alpha); interleukin 11; oprelvekin; zoledronic acid; fentanyl; bisphosphonates; palifermin. - Steroid cytochrome P450 17 alpha-hydroxylase-17,20-lyase inhibitors (CYP17), for example, abiraterone, abiraterone acetate - Antibodies that block the interaction between PD-1 and PD-L1.

[0326] In one embodiment, the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, or any subgroup and example thereof, in combination with 6-{difluoro[6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl}quinoline or a pharmaceutically acceptable salt thereof.

[0327] In one embodiment, the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, or any subgroup and example thereof, in combination with 6-[difluoro(6-pyridin-4-yl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl]quinoline or a pharmaceutically acceptable salt thereof.

[0328] In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, or any subgroup and example thereof, and 6-{difluoro[6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl}quinoline or a pharmaceutically acceptable salt thereof.

[0329] In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, or any subgroup and example thereof, and 6-[difluoro(6-pyridin-4-yl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl]quinoline or a pharmaceutically acceptable salt thereof.

[0330] The compounds of the present invention also have therapeutic use in the sensitization of tumor cells to radiotherapy and chemotherapy.

[0331] Accordingly, the compounds of the present invention can be used as "radiosensitizers" and / or "chemotherapy sensitizers", or administered in combination with another "radiosensitizer" and / or "chemotherapy sensitizer".

[0332] As used herein, the term "radiosensitizer" is defined as a molecule, preferably a low molecular weight molecule, that is administered to an animal in a therapeutically effective amount to enhance the sensitivity of cells to ionizing radiation and / or to facilitate the treatment of diseases treatable by ionizing radiation.

[0333] As used herein, the term "chemosensitizer" is defined as a molecule, preferably a low molecular weight molecule, that is administered to an animal in a therapeutically effective amount to enhance the sensitivity of cells to chemotherapy and / or to facilitate the treatment of diseases treatable by chemotherapy.

[0334] For example, hypoxia cell radiosensitizers that mimic oxygen or act like in vivo reducing agents under hypoxia (e.g., 2-nitroimidazole compounds and benzotriazine dioxide compounds); non-hypoxia cell radiosensitizers (e.g., halogenated pyrimidines), which can be analogs of DNA bases and can be preferentially incorporated into the DNA of cancer cells, thereby promoting the cleavage of DNA molecules induced by radiation and / or blocking normal DNA repair mechanisms, among other mechanisms of action of radiosensitizers, have been suggested in the literature, and various other hypotheses of potential mechanisms of action for radiosensitizers in the treatment of diseases have been proposed.

[0335] Many cancer treatment protocols currently use radiosensitizers in combination with X-ray irradiation. Examples of X-ray-activated radiosensitizers include, but are not limited to: metronidazole, misonidazole, demethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives thereof.

[0336] Photodynamic therapy (PDT) of cancer utilizes visible light as a radiation activator of a photosensitizer. Examples of photosensitizing radiation agents include, but are not limited to: hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tin etioporphyrin, pheophorbide-a, bacteriochlorophyll-a, naphthalocyanine, phthalocyanine, zinc phthalocyanine, and therapeutically effective analogs and derivatives thereof.

[0337] The radiosensitizer may be administered in combination with one or more other compounds in a therapeutically effective amount, including, but not limited to: compounds that enhance the uptake of the radiosensitizer into target cells; compounds that control the flow of therapeutic agents, nutrients, and / or oxygen into target cells; chemotherapeutic agents that act on tumors either by further radiation or otherwise; or other therapeutically effective compounds for treating cancer or other diseases.

[0338] The chemosensitizer may be administered in combination with one or more other compounds in a therapeutically effective amount, including, but not limited to: compounds that enhance the uptake of the chemosensitizer into target cells; compounds that control the flow of therapeutic agents, nutrients, and / or oxygen into target cells; chemotherapeutic agents that act on tumors; or other therapeutically effective compounds for treating cancer or other diseases. Calcium antagonists, such as verapamil, have been found to be useful in combination with antineoplastic agents to establish chemosensitivity in tumor cells that are resistant to commonly recognized chemotherapeutic agents and to enhance the efficacy of such compounds in drug-sensitive malignancies.

[0339] In view of their useful pharmacological properties, the components of the combination according to the present invention, namely one or more other medicinal agents and the compound according to the present invention, can be formulated into various pharmaceutical forms for administration purposes. These components may be formulated separately into individual pharmaceutical compositions or into a unit pharmaceutical composition containing all the components.

[0340] Accordingly, the present invention also relates to a pharmaceutical composition comprising one or more other pharmaceutical agents and a compound according to the present invention, together with a pharmaceutically acceptable carrier.

[0341] The present invention further relates to the use of the combination according to the present invention in the manufacture of a pharmaceutical composition for inhibiting the growth of tumor cells.

[0342] The present invention further relates to a product comprising a compound according to the present invention as a first active ingredient and one or more anti-cancer agents as further active ingredients, as a combined preparation for use simultaneously, separately, or sequentially in the treatment of a patient suffering from cancer.

[0343] One or more other pharmaceutical agents and the compound according to the present invention may be administered simultaneously (e.g., in separate compositions or unit compositions) or sequentially in any order. In the latter case, two or more compounds are administered in amounts and by a method within a period sufficient to ensure an advantageous or synergistic effect. It will be understood that the preferred method and order of administration, as well as the respective dosages and dosing schedules of the combined components, will vary depending on the particular other pharmaceutical agent and the compound of the present invention being administered, their route of administration, the particular tumor being treated, and the particular host being treated. A person skilled in the art can readily determine the optimal method and order of administration, as well as the dosage and dosing schedule, using conventional methods and taking into account the information described herein.

[0344] When administered in combination, one of ordinary skill in the art can determine the weight ratio of the compound according to the present invention to one or more other anti-cancer agents. As is well known to those of ordinary skill in the art, the said ratio, as well as the exact dosage and dosing frequency, depend on the specific compound according to the present invention used, and other anti-cancer agents, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, diet, dosing time, and general health of the specific patient, the mode of administration, and other pharmaceutical agents that the individual may be taking. Further, it is clear that the effective daily dose can be decreased or increased according to the response of the subject being treated and / or according to the evaluation of the physician prescribing the compound of the present invention. The specific weight ratio of the present compound of formula (I) to another anti-cancer agent can range from 1 / 10 to 10 / 1, more specifically from 1 / 5 to 5 / 1, and even more specifically from 1 / 3 to 3 / 1.

[0345] Platinum coordination compounds are administered at a dosage of 1 to 500 mg (mg / m 2 ) per square meter of body surface area for each series of treatments, for example 50 to 400 mg / m 2 , and in particular cisplatin at a dosage of about 75 mg / m 2 , and carboplatin at a dosage of about 300 mg / m 2 per square meter of body surface area for each series of treatments, which is advantageous.

[0346] Taxane compounds are administered at a dosage of 50 to 400 mg (mg / m 2 ) per square meter of body surface area for each series of treatments, for example 75 to 250 mg / m 2 , and in particular paclitaxel at a dosage of about 175 to 250 mg / m 2 , and docetaxel at a dosage of about 75 to 150 mg / m 2 per square meter of body surface area for each series of treatments, which is advantageous.

[0347] Camptothecin compounds are administered at a dosage of 0.1 to 400 mg (mg / m 2 ) per square meter of body surface area for each series of treatments, for example 1 to 300 g / m 2 , and in particular irinotecan at a dosage of about 100 to 350 mg / m 2 , and topotecan at a dosage of about 1 to 2 mg / m 2It is advantageous to administer at the dosage.

[0348] For each series of treatments, the anti-tumor podophyllotoxin derivative is administered at a dosage of 30 to 300 mg (mg / m 2 ) per square meter of body surface area, for example, 50 to 250 mg / m 2 , and in particular for etoposide at a dosage of about 35 to 100 mg / m 2 , and for teniposide at a dosage of about 50 to 250 mg / m 2 It is advantageous to administer at the dosage.

[0349] For each series of treatments, the anti-tumor vinca alkaloid is administered at a dosage of 2 to 30 mg (mg / m 2 ) per square meter of body surface area, and in particular for vinblastine at a dosage of about 3 to 12 mg / m 2 , for vincristine at a dosage of about 1 to 2 mg / m 2 , and for vinorelbine at a dosage of about 10 to 30 mg / m 2 It is advantageous to administer at the dosage.

[0350] For each series of treatments, the anti-tumor nucleoside derivative is administered at a dosage of 200 to 2500 mg (mg / m 2 ) per square meter of body surface area, for example, 700 to 1500 mg / m 2 , and in particular for 5-FU at a dosage of 200 to 500 mg / m 2 , for gemcitabine at a dosage of about 800 to 1200 mg / m 2 , and for capecitabine at a dosage of about 1000 to 2500 mg / m 2 It is advantageous to administer at the dosage.

[0351] Alkylating agents such as nitrogen mustard or nitrosourea are administered at a dosage of 100 to 500 mg (mg / m 2 ) per square meter of body surface area for each series of treatments, for example, 120 to 200 mg / m 2 , and in particular for cyclophosphamide at a dosage of about 100 to 500 mg / m 2 , for chlorambucil at a dosage of about 0.1 to 0.2 mg / kg, and for carmustine at a dosage of about 150 to 200 mg / m2 At a dosage of, in the case of romustatin, about 100 to 150 mg / m 2 It is advantageous to administer at this dosage.

[0352] Antitumor anthracycline derivatives, for each series of treatments, are at a dosage of 10 to 75 mg per square meter of body surface area (mg / m 2 ), for example 15 to 60 mg / m 2 At a dosage of, in the case of doxorubicin, about 40 to 75 mg / m 2 At a dosage of, in the case of daunorubicin, about 25 to 45 mg / m 2 At a dosage of, and in the case of idarubicin, about 10 to 15 mg / m 2 It is advantageous to administer at this dosage.

[0353] Antiestrogens are advantageously administered at a dosage of about 1 to 100 mg per day, depending on the specific drug and the condition being treated. Tamoxifen is orally administered at a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day, and it is advantageous to continue the treatment for a period sufficient to achieve and maintain the therapeutic effect. Toremifene is orally administered at a dosage of about 60 mg once a day, and it is advantageous to continue the treatment for a period sufficient to achieve and maintain the therapeutic effect. Anastrozole is advantageously orally administered at a dosage of about 1 mg once a day. Droloxifene is advantageously orally administered at a dosage of about 20 to 100 mg once a day. Raloxifene is advantageously orally administered at a dosage of about 60 mg once a day. Exemestane is advantageously orally administered at a dosage of about 25 mg once a day.

[0354] Antibodies are administered at a dosage of about 1 to 5 mg per square meter of body surface area (mg / m 2 ), or, if different, are administered as known in the art. Trastuzumab, for each series of treatments, is at a dosage of 1 to 5 mg per square meter of body surface area (mg / m 2 ), in particular, 2 to 4 mg / m 2It is advantageous to administer at these dosages. These dosages may be administered, for example, one or more times per series of treatments, and it may be repeated, for example, every 7 days, every 14 days, every 21 days, or every 28 days.

[0355] The compounds of formula (I), their pharmaceutically acceptable addition salts, especially pharmaceutically acceptable acid addition salts, and stereoisomeric forms may have diagnostic properties useful in that they can be used for the detection or identification of the formation of complexes between the labeled compounds and other molecules, peptides, proteins, enzymes, or receptors.

[0356] For the detection or identification method, compounds labeled with labeling agents such as radioisotopes, enzymes, fluorescent substances, luminescent substances, etc. may be used. Examples of radioisotopes include 125 I, 131 I, 3 H, and 14 C. Enzymes usually become detectable by conjugation with a suitable substrate that catalyzes a detectable reaction. Examples thereof include, for example, beta-galactosidase, beta-glucosidase, alkaline phosphatase, peroxidase, and malate dehydrogenase, preferably horseradish peroxidase. Examples of luminescent substances include, for example, luminol, luminol derivatives, luciferin, aequorin, and luciferase.

[0357] Biological samples can be defined as body tissues or body fluids. Examples of body fluids are cerebrospinal fluid, blood, plasma, serum, urine, sputum, saliva, and the like.

Examples

[0358] Some methods for preparing the compounds of the present invention are described in the following examples. Unless otherwise specified, all starting materials were obtained from commercial vendors and used without further purification.

[0359] When the stereocenter is designated as "RS", unless otherwise indicated, this means that a mixture of stereoisomers was obtained at this indicated center. The stereochemical configuration for the stereocenters in some compounds is known to be indicated by "R" or "S", and / or by a solid wedge or dashed wedge bond indicating the absolute stereoconfiguration. For some compounds, the stereochemical configuration at the indicated stereocenter is shown as "R * " or "S * ", or the solid wedge or dashed wedge bond indicating the absolute stereochemistry at the stereocenter is absolute but undetermined. Thus, a stereocenter designated as S * means an absolute stereocenter, but whether it is S or R is not discriminated.

[0360] When used hereinafter, the terms: "RT" or "rt" mean room temperature; "TFA" means trifluoroacetic acid, "FA" means formic acid, "TfOH" means trifluoromethanesulfonic acid, "DIPEA" or "DIEA" means ethyldiisopropylamine, or N-ethyl-N-isopropylpropan-2-amine, or N,N-diisopropylethylamine, "R T " or "R t " mean retention time, "SFC" means supercritical fluid chromatography, "ACN" means acetonitrile, "DEA" means diethylamine, "IPA" means isopropyl alcohol, "DMF" means N,N-dimethylformamide, "DCM" means dichloromethane, "TBAI" means tetrabutylammonium iodide, "M.P." or "m.p." means melting point, "HPLC" means high performance liquid chromatography, "TLC" means thin layer chromatography, "LC-MS" means liquid chromatography - mass spectrometry, and "ee" means enantiomeric excess.

[0361] Example 1

Chem.

Chemical formula

[0362] b) Preparation of Intermediate 2 6-((Phenylamino)methylene)thieno[3,2-b]pyridine-5,7(4H,6H)-dione

Chemical formula

[0363] c) Preparation of Intermediate 3 7 - Chloro - 5 - oxo - 4,5 - dihydrothieno[3,2 - b]pyridine - 6 - carbaldehyde

Chemical Structure

[0364] d) Preparation of Intermediate 4 6 - Morpholinopyridine - 3,4 - diamine

Chemical Structure

[0365] e) Preparation of Intermediate 5 7-Chloro-6-(6-morpholino-1H-imidazo[4,5-c]pyridin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

Chemical Structure

[0366] f) Preparation of Compounds 1, 2, and 3 6-(6-Morpholino-1H-imidazo[4,5-c]pyridin-2-yl)-7-((1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one; (S)-6-(6-Morpholino-1H-imidazo[4,5-c]pyridin-2-yl)-7-((1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one; and (R)-6-(6-Morpholino-1H-imidazo[4,5-c]pyridin-2-yl)-7-((1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one

Chem.

[0367] Compound 2 (S)-6-(6-Morpholino-1H-imidazo[4,5-c]pyridin-2-yl)-7-((1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one

Chemical Structure

[0368] Compound 3 (R)-6-(6-Morpholino-1H-imidazo[4,5-c]pyridin-2-yl)-7-((1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one

Chemical Structure

[0369] Example 2

Chemical formula

Chemical formula

[0370] b) Preparation of Intermediate 10 6-(cis-2,6-Dimethylmorpholino)pyridine-3,4-diamine

Chemical formula

[0371] c) Preparation of intermediate 12 7-chloro-6-(6-cis-2,6-dimethylmorpholino)-1H-imidazo[4,5-c]pyridin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

Chemical Structure

[0372] d) Preparation of Compound 6, Compound 7, and Compound 8 (rac)-6-(6-(cis-2,6-Dimethylmorpholino)-1H-imidazo[4,5-c]pyridin-2-yl)-7-((2-methoxy-1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one; (S*)-6-(6-(cis-2,6-Dimethylmorpholino)-1H-imidazo[4,5-c]pyridin-2-yl)-7-((2-methoxy-1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one; and (R*)-6-(6-(cis-2,6-Dimethylmorpholino)-1H-imidazo[4,5-c]pyridin-2-yl)-7-((2-methoxy-1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one

Chemical Structure

[0373] Compounds 7 and 8 were separated by SFC of Compound 6 (separation conditions: OJ (250 mm×30 mm, 10um); mobile phase: A: supercritical CO 2 、B: 0.1% NH 3 H 2Obtained by [MeOH:A:B = 55:45 (80 mL / min); column temperature: 38 °C; nozzle pressure: 100 Bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; trimmer temperature: 25 °C; wavelength: 220 nm]. The pure fractions were collected and the volatile substances were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). This solution was lyophilized to give Compound 7 (11.6 mg, purity 99.0%, yield 23.0%) as a yellow powder, and Compound 8 (16.6 mg, purity 100%, yield 33.2%) as a yellow powder.

[0374] Compound 7 (S*)-6-(6-(cis-2,6-Dimethylmorpholino)-1H-imidazo[4,5-c]pyridin-2-yl)-7-((2-methoxy-1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one

Chemical Structure

[0375] Compound 8 (R*)-6-(6-(cis-2,6-dimethylmorpholino)-1H-imidazo[4,5-c]pyridin-2-yl)-7-((2-methoxy-1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one

Chemical Structure

[0376] The following compound was prepared according to the reaction protocol of one of the above examples using alternative starting materials as necessary. (In Table 1, Ex.X indicates that the preparation of this compound is described in Example X or prepared according to Example X).

[0377] As will be appreciated by those skilled in the art, compounds synthesized using the indicated protocols may exist as solvates, such as hydrates, and / or may contain residual solvents or minor impurities. Compounds isolated in salt form may be in stoichiometric integers, i.e., mono - or di - salts, or may have intermediate stoichiometry.

[0378]

Table 1

[0379]

Table 2

[0380] The purification methods, LCMS, SFC, and NMR for the compounds were prepared according to the procedures shown in Table 1.

[0381] Compound 4 6-(6-(4-Methylpiperazin-1-yl)-1H-imidazo[4,5-c]pyridin-2-yl)-7-((1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one

Chem.

Chem.

[0382] Compound 9, Compound 10, and Compound 11 6-(5-(cis-2,6-Dimethylmorpholino)-3H-imidazo[4,5-b]pyridin-2-yl)-7-(((S*)-2-methoxy-1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one; (S*)-6-(5-(cis-2,6-dimethylmorpholino)-3H-imidazo[4,5-b]pyridin-2-yl)-7-(((S*)-2-methoxy-1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one; and (R*)-6-(5-(cis-2,6-dimethylmorpholino)-3H-imidazo[4,5-b]pyridin-2-yl)-7-(((S*)-2-methoxy-1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one

Chem.

[0383] Compound 10 (S*)-6-(5-(cis-2,6-dimethylmorpholino)-3H-imidazo[4,5-b]pyridin-2-yl)-7-(((S*)-2-methoxy-1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one

Chemical Structure

[0384] Compound 11 (R*)-6-(5-(cis-2,6-dimethylmorpholino)-3H-imidazo[4,5-b]pyridin-2-yl)-7-(((R*)-2-methoxy-1-(pyrimidin-2-yl)ethyl)amino)thieno[3,2-b]pyridin-5(4H)-one

Chem.

[0385] Compound 12 (S*)-7-((2-Methyl-1-(pyrimidin-2-yl)propyl)amino)-6-(6-(4-methylpiperazin-1-yl)-1H-imidazo[4,5-c]pyridin-2-yl)thieno[3,2-b]pyridin-5(4H)-one 0.6 formate

Chem.

[0386] Analysis part LCMS HPLC Basic procedure A LCMS measurements were performed using a Shimadzu LCMS-2010 EV series system including a quaternary pump equipped with a degassing device, an autosampler, a column oven (set at 50 °C unless otherwise indicated), a diode array detector (DAD), and a column specified in each of the following methods. The flow from the column was split and sent to the MS spectrometer. The MS detector was equipped with an electrospray ion source. Mass spectra were acquired by scanning from 100 to 1000 using a cycle time of 0.25 seconds. The detector voltage was 1.6 kV, and the ion source temperature was maintained at 250 °C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with the LCMS solution data system.

[0387] Method 1 In addition to the basic procedure A: Reverse-phase HPLC was performed using an Xtimate C18 column (2.1 * 30 mm, 3 μm) at a flow rate of 0.8 mL / min. Two mobile phases (mobile phase A: water (4 L) + TFA (1.5 mL); mobile phase B: acetonitrile (4 L) + TFA (0.75 mL)) were used to perform gradient conditions (from 90% A, 10% B to 20% A, 80% B in 6 minutes, then holding this condition for 0.5 minutes, going to 90% A and 10% B in 0.01 minutes, and then re-equilibrating with 90% A, 10% B for 0.49 minutes). An injection volume of 0.1 - 20 μL was used. The cone voltage was 70 V in the positive ionization mode.

[0388] Basic procedure B LC measurements were performed using an Agilent 1200 HPLC system including a degassing device, a binary pump, an autosampler, a column heater, a diode array detector (DAD), and a column specified in each of the following methods. The flow from the DAD was split and sent to an MS spectrometer (Agilent 6110 or 6140) and an ELSD. The MS detector was equipped with an electrospray ionization source. Nitrogen was used as the nebulizer gas. The drying gas temperature was maintained at 350 °C. The capillary voltage was 2.5 V in the positive ionization mode and 3.0 V in the negative ionization mode. Mass spectra were acquired by scanning from 100 to 1000 with a step size of 0.1. The cycle time was 0.89 seconds / cycle. Data acquisition was performed with Chemstation B.04.03.

[0389] Method 1 In addition to Basic Procedure B: Reversed-phase HPLC was run at a flow rate of 0.8 ml / min on an Agilent TC-C18 column (5 μm, 2.1 × 50 mm). Two mobile phases (Mobile Phase A: water + 0.1% TFA; Mobile Phase B: acetonitrile + 0.05% TFA) were used. 100% A was held for 1 minute, a gradient from 100% A to 40% A was applied for 4 minutes, and decreased from 40% A to 15% A in 2.5 minutes. Then, it was returned to 100% A in 2 minutes and held for 0.5 minute. The post time was 0.5 minute. The oven temperature was 50 °C. The injection volume was 2 μL. (MS polarity: positive)

[0390] Basic Procedure C HPLC measurements were carried out using an Agilent 1200 series system including a quaternary pump equipped with a degassing device, an autosampler, a column oven (set at 50 °C unless otherwise indicated), a diode array detector (DAD), and a column specified in each of the following methods. The flow from the column was split and sent to an MS spectrometer. The MS detector was equipped with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 using a cycle time of 0.52 seconds. The capillary needle voltage was 2.5 kV and the ion source temperature was maintained at 350 °C. Nitrogen was used as the nebulizer gas. Data acquisition was carried out with an LC / MSD ChemStation data system.

[0391] Method 1 In addition to basic procedure C: Reverse-phase HPLC was performed at a flow rate of 0.8 mL / min on an Xbridge Shield RP-18 column (5 µm, 2.1 * 50 mm). Two mobile phases (mobile phase A: water (1 L) + NH 3 H 2 O (0.5 mL); mobile phase B: acetonitrile) were used with gradient conditions (from 90% A, 10% B to 20% A, 80% B in 6 minutes, then holding this condition for 0.5 minutes, to 90% A and 10% B in 0.01 minutes, then re-equilibrating with 90% A, 10% B for 0.49 minutes). An injection volume of 0.1 - 20 µL was used. The cone voltage was 70 V in the positive ionization mode.

[0392] NMR Basic procedure A for NMR NMR experiments were carried out at ambient temperature using an internal deuterium lock and equipped with a BBO 400 MHz probe head in the case of a Bruker Avance III 400, and a Varian 400 ASW PFG 4nuc ( 1 H, 13 C, 19 F, 31P) Performed using Bruker Avance III 400 and Varian 400 spectrometers equipped with a probe head. Chemical shifts (δ) are reported in parts per million (ppm).

[0393] Pharmacology part Biological assay FGFR3 wild-type mobility shift assay (enzymatic assay) In a final reaction volume of 25 μL, 0.04 ng / μL of human FGFR3 wild-type enzyme (cytoplasmic domain from Carna Biosciences) was incubated with 75 μM ATP, 1 μM FL-peptide 30 substrate, and 250 nL of test compound (1% DMSO final) in assay buffer (100 mM HEPES pH 7.4, 10 mM MgCl 2 , 0.003% Brij35, 1 mM DTT). After incubation at 30 °C for 50 minutes, the reaction was stopped with 10 μL of 0.5 M EDTA pH 8.0, and then 25 μL of the reaction mixture was transferred to a reading plate and measured with a Caliper EZ Reader II. The substrate-product conversion rate was used as raw data for normalization, and a concentration-response curve (10 dose points at 4-fold serial dilutions starting from 10 μM) was plotted using Prism, and IC 50 (M), pIC 50 (-logIC 50 ) and Hill Slope values were calculated.

[0394] FGFR3 V555M mobility shift assay (enzymatic assay) In a final reaction volume of 25 μL, 0.04 ng / μL of human FGFR3 V555M enzyme (cytoplasmic domain carrying the V555M mutation from Carna Biosciences) was incubated with 30 μM ATP, 1 μM FL-peptide 30 substrate, and 250 nL of test compound (1% DMSO final) in assay buffer (100 mM HEPES pH 7.4, 10 mM MgCl 2were incubated in (0.003% Brij35, 1 mM DTT). After incubation at 30 °C for 45 minutes, the reaction was stopped with 10 μL of 0.5 M EDTA pH 8.0, and then 25 μL of the reaction mixture was transferred to a reading plate and measured with a Caliper EZ Reader II. The substrate-product conversion rate was used as the raw data for normalization, and a concentration-response curve (10 dose points at 4-fold serial dilutions starting from 10 μM) was plotted using Prism, and IC 50 (M), pIC 50 (-logIC 50 ) and Hill Slope values were calculated.

[0395] FGFR3 V555L Mobility Shift Assay (Enzyme Assay) In a final reaction volume of 25 μL, 0.04 ng / μL of human FGFR3 V555L enzyme (cytoplasmic domain carrying the V555L mutation from Carna Biosciences) was incubated with 40 μM ATP, 1 μM FL-peptide 30 substrate, and 250 nL of test compound (1% DMSO final) in assay buffer (100 mM HEPES pH 7.4, 10 mM MgCl 2 , 0.003% Brij35, 1 mM DTT). After incubation at 30 °C for 50 minutes, the reaction was stopped with 10 μL of 0.5 M EDTA pH 8.0, and then 25 μL of the reaction mixture was transferred to a reading plate and measured with a Caliper EZ Reader II. The substrate-product conversion rate was used as the raw data for normalization, and a concentration-response curve (10 dose points at 4-fold serial dilutions starting from 10 μM) was plotted using Prism, and IC 50 (M), pIC 50 (-logIC 50 ) and Hill Slope values were calculated.

[0396] NIH / 3T3 FGFR3 WT-TACC3 Cell Proliferation Assay On the first day, 90 μL of cell suspension (NIH / 3T3 cells overexpressing FGFR3 WT-TACC3 fusion protein) (a total of 30,000 cells per well in growth medium (DMEM containing 1% Glutamax, 10% FBS, and 1% Pen / Strep)) was seeded into a 96-well plate and then incubated overnight at 37 °C and 5% CO 2 2. On the second day, 10 μL of growth medium containing a 10-fold stock solution of the test compound was added to the cell culture (9 dose points at 4-fold serial dilutions starting from 10 μM, 0.1% DMSO final). After incubation at 37 °C and 5% CO 2 for 72 hours, on the fifth day, 50 μL of CellTiter Glo (CTG) reagent was added to the 96-well plate containing the cells. After incubating this plate at room temperature for 10 minutes, the relative light units (RLU) were measured using a microplate reader with a luminescence detection module. The RLU values were normalized to the percentage of viability, and the concentration-response curve was plotted using Prism, and the IC 50 (M), pIC 50 (-logIC 50 ) and Hill Slope values were calculated.

[0397] NIH / 3T3 FGFR3 V555M-TACC3 Cell Proliferation Assay On the first day, 90 μL of cell suspension (NIH / 3T3 cells overexpressing FGFR3 V555M-TACC3 fusion protein) (a total of 30,000 cells per well in growth medium (DMEM containing 1% Glutamax, 10% FBS, and 1% Pen / Strep)) was seeded into a 96-well plate and then incubated overnight at 37 °C and 5% CO 2 2. On the second day, 10 μL of growth medium containing a 10-fold stock solution of the test compound was added to the cell culture (9 dose points at 4-fold serial dilutions starting from 10 μM, 0.1% DMSO final). After incubation at 37 °C and 5% CO 2After 72 hours of incubation at [condition], on the 5th day, 50 μL of CellTiter Glo (CTG) reagent was added into the 96-well plate containing the cells. After incubating this plate at room temperature for 10 minutes, the relative light units (RLU) were measured using a microplate reader with a luminescence detection module. The RLU values were normalized to the percentage of survival, and the concentration-response curve was plotted using Prism, and the IC 50 (M), pIC 50 (-logIC 50 ) and HillSlope values were calculated.

[0398] NIH / 3T3 Mock Cell Proliferation Assay On the 1st day, 90 μL of cell suspension (NIH / 3T3 cells transfected with the same control vector as the above two proliferation assays) (a total of 30,000 cells per well in growth medium (DMEM containing 1% Glutamax, 10% FBS, and 1% Pen / Strep)) was seeded into a 96-well plate and then incubated overnight at 37 °C and 5% CO 2 . On the 2nd day, 10 μL of growth medium containing a 10-fold stock solution of the test compound was added into the cell culture (9 dose points in a 3-fold serial dilution starting from 30 μM, 0.3% DMSO final). After incubating at 37 °C and 5% CO 2 for 72 hours, on the 5th day, 50 μL of CellTiter Glo (CTG) reagent was added into the 96-well plate containing the cells. After incubating the plate at room temperature for 10 minutes, the relative light units (RLU) were measured using a microplate reader with a luminescence detection module. The RLU values were normalized to the percentage of survival, and the concentration-response curve was plotted using Prism, and the IC 50 (M), pIC 50 (-logIC 50 ) and HillSlope values were calculated. This assay functions as a counterassay for the NIH / 3T3 FGFR WT / V555M-TACC3 cell proliferation assay and shows the general toxicity of the test compound caused by off-target effects.

[0399] NIH / 3T3 FGFR3 WT-TACC3 cell phospho-ERK assay (PD assay in vitro) 50 μL of cell suspension (NIH / 3T3 cells overexpressing the FGFR3 WT-TACC3 fusion protein) (a total of 10,000 cells per well in growth medium (DMEM containing 1% Glutamax, 10% FBS, and 1% Pen / Strep)) was seeded into a 384-well plate. At 37 °C and 5% CO 2 After overnight incubation, 5.5 μL of growth medium containing 10-fold the test compound was added into the cell culture (10 dose points at 4-fold serial dilutions starting from 10 μM, 0.1% DMSO final). At 37 °C and 5% CO 2 After incubation for 1 hour, the medium was exhausted, and the AlphaLISA SureFire Ultra p-ERK1 / 2 (Thr202 / Tyr204) assay kit (from PerkinElmer) was applied for phospho-ERK level detection according to the kit instructions. RFU (relative fluorescence units) was measured with an EnVision microplate reader (ex. 680 nm, em. 615 nm), and the concentration-response curve was plotted using Prism, and IC 50 (M), pIC 50 (-logIC 50 ) and HillSlope values were calculated.

[0400] NIH / 3T3 FGFR3 V555M-TACC3 cell phospho-ERK assay (PD assay in vitro) 50 μL of cell suspension (NIH / 3T3 cells overexpressing the FGFR3 V555M-TACC3 fusion protein) (a total of 10,000 cells per well in growth medium (DMEM containing 1% Glutamax, 10% FBS, and 1% Pen / Strep)) was seeded into a 384-well plate. At 37 °C and 5% CO 2 After overnight incubation, 5.5 μL of growth medium containing 10-fold the test compound was added into the cell culture (10 dose points at 4-fold serial dilutions starting from 10 μM, 0.1% DMSO final). At 37 °C and 5% CO2 After incubation for 1 hour at [condition not provided], the medium was exhausted, and the AlphaLISA SureFire Ultra p-ERK1 / 2 (Thr202 / Tyr204) assay kit (from PerkinElmer) was applied for phospho-ERK level detection according to the kit instructions. RFU (Relative Fluorescence Unit) was measured with an EnVision microplate reader (ex. 680 nm, em. 615 nm), and the concentration-response curve was plotted using Prism, and IC 50 (M), pIC 50 (-logIC 50 ) and the Hill Slope value were calculated.

[0401]

Table 3

Chemical Structure

Chem.

[10] C 1 and C 2 ​ 1~4 ​

[11] C 1 ​ 2 The compound according to any one of [1] to [8], which is hydrogen.

[12] Each R b The compound according to any one of [1] to

[11] , which is hydrogen.

[13] D is optionally substituted with one or two R c substituents, and each R c is independently oxo; C 1~6 alkyl, such as methyl; halo, such as fluoro; C 1~6 alkoxy, such as methoxy; and halo C 1~6 alkyl, such as trifluoromethyl or trifluoroethyl, the compound according to any one of [1] to

[12] .

[14] Each R c is C 1~6 alkyl, such as methyl, the compound according to

[13] .

[15] The compound according to any one of [1] to

[14] , wherein D is unsubstituted.

[16] B is a 5- or 6-membered heterocyclyl containing at least one heteroatom selected from N, O, or S, and the heterocyclyl is optionally substituted with 1 to 5 R substituents, the compound according to any one of [1] to

[15] .

[17] The compound according to

[16] , wherein B is an aromatic heterocyclyl.

[18] A 1 And A 3 represents CH, and A 2 represents N, or A 3 represents N, and A 1 and A 2 represent CH; C1 is hydrogen or C 1~4 alkyl, particularly hydrogen or methyl; C2 is hydrogen, or C 1~4 alkyl, or C 1~4 alkoxy, particularly hydrogen, methyl, or methoxy; Y is a direct bond; Each R b is hydrogen; D is a 6-membered monocyclic saturated heterocyclyl containing at least one heteroatom selected from N or O, and the heterocyclyl is optionally substituted with one or two R c substituents; particularly D is piperazinyl or morpholinyl, and the ring system is optionally substituted with one or two R csubstituents; particularly D is optionally substituted piperazinyl or optionally substituted morpholinyl, and the ring system is optionally substituted with one or two R c substituents, such as one or two C 1~4 alkyl, such as one or two methyl; B is a 6-membered aromatic monocyclic heterocyclyl containing one or two N heteroatoms; particularly B is unsubstituted pyrimidinyl. The compound according to [1] or [2].

[19] The compound is

Chem.

[20] A pharmaceutical composition comprising the compound according to any one of [1] to

[19] and a pharmaceutically acceptable carrier.

[21] A compound according to any one of [1] to

[19] for use in therapy.

[22] A compound according to any one of [1] to

[19] for use in the prevention or treatment of a condition or disorder mediated by FGFR kinase.

[23] A compound according to any one of [1] to

[19] for use in the prevention or treatment of cancer.

[24] A compound for use according to

[23] for use in the treatment of cancer.

[25] The compound for use according to

[24] , wherein the cancer has FGFR3 V555M.

[26] Use of a compound according to any one of [1] to

[19] for the manufacture of a medicament for the prevention or treatment of a condition or disorder mediated by FGFR kinase.

[27] Use of a compound according to any one of [1] to

[19] for the manufacture of a medicament for the prevention or treatment of cancer.

[28] Use of a compound according to

[27] for the treatment of cancer.

[29] The use of the compound according to

[28] , wherein the cancer has FGFR3 V555M.

[30] A method for the prevention or treatment of a condition or disorder mediated by FGFR kinase, the method comprising administering to a subject in need thereof a compound according to any one of [1] to

[19] .

Claims

1. Formula (I): 【Chemical 1】 wherein A ２ represents N, and A １ and A ３ each represent CH, or A ３ represents N, and A １ and A ２ each represent CH; C1 is hydrogen or C １～４ alkyl; C2 is hydrogen, C １～４ alkyl, or C １～４ alkoxy; Y is a direct bond; Each R ｂ is, independently, hydrogen; D is a 6-membered monocyclic saturated heterocyclyl containing at least 1 heteroatom selected from N or O, and said heterocyclyl is optionally substituted with 1 to 2 R ｃ substituents; Each R ｃ is independently C １～６ alkyl; B is a 6-membered aromatic monocyclic heterocyclyl containing one or two N heteroatoms]] a compound of, its tautomer, its stereochemical isomer, its pharmaceutically acceptable salt or its solvate.

2. The compound has the following formula (I-a) 【Chemical Formula 2】 The compound, tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate according to Claim 1.

3. D is piperazin-1-yl, and the piperazin-1-yl is optionally substituted with 1 to 2 R ｃ substituents, a compound, tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate according to claim 1 or 2.

4. D is morpholin-1-yl, and the morpholin-1-yl is optionally substituted with 1 to 2 R ｃ The compound, tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate according to claim 1 or 2, which is substituted with substituents.

5. A ２ represents N, and A １ and A ３ each represent CH, a compound, tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 4.

6. A ３ represents N, and A １ and A ２ each represent CH, a compound, tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 4.

7. C １ is hydrogen, and C ２ is C １～４ is alkoxy, the compound, tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 6.

8. C １ and C ２ is C １～４ alkyl, a compound, tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 6.

9. C １ and C ２ is hydrogen, the compound, tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 6.

10. D is unsubstituted. The compound, tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 9.

11. D is piperazinyl or morpholinyl, and the piperazinyl or morpholinyl is optionally substituted with one or two R ｃ substituents, and B is unsubstituted pyrimidinyl, a compound, tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 10.

12. The compound is 【Chemical Formula 3】 selected from. The compound, tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate according to Claim 1.

13. A pharmaceutical composition comprising the compound, tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 12 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to Claim 13 for use in the treatment of cancer, wherein the cancer is a cancer having FGFR3 V555M.

15. Use of the compound, tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 12 for the manufacture of a medicament for the treatment of cancer, wherein the cancer is a cancer having FGFR3 V555M.

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