Effective and selective inhibitors of her2

Abstract

Compounds that are effective and selective inhibitors of HER2, as well as their pharmaceutically acceptable salts and stereoisomers, are disclosed. Pharmaceutical compositions containing said compounds are also disclosed, along with methods for preparing said compounds and using said compounds to treat HER2-related diseases and conditions.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 087,517, filed October 5, 2020, and U.S. Provisional Application No. 63 / 232,450, filed August 12, 2021, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Mutations in human epidermal growth factor receptor 2 (HER2, ERBB2) have been identified as oncogenic drivers. They occur in 2%–3% of non-small cell lung cancer (NSCLC) (Shigema et al., Cancer Res., 65(5):1642–1646 (2005); Buttitta et al., Int. J. Cancer, 119(11):2586–2591 (2006); Tomizawa et al., Lung Cancer, 74(1):139–144 (2011); Mazieres et al., J. Clin. Oncol., 31(16):1997–2003 (2013)), and occur in up to 6.7% of EGFR / ALK / ROS1 triple-negative NSCLC (Li et al., BMC Cancer, 16(1):828 (2016)). In addition, approximately 15%–25% of breast cancers exhibit HER2 gene amplification, HER2 protein overexpression, or both, and these breast cancers are classified as HER2 positive (Slamon et al., Science, 235(4785):177–182(1987); Slamon et al., Science, 244(4905):707–712(1989)). The most common HER2 mutation is the exon 20 insertion mutant (Shigemat et al., Cancer Res., 65(5):1642–1646(2005)). The most common HER2 exon 20 insertion mutant consists of a 12-base-pair in-frame insertion YVMA (p.A775_G776insYVMA), which causes downstream activation of the PI3'K-AKT and RAS-MAPK pathways (Tomizawa et al., Lung Cancer, 74(1):139-144(2011)). Historically, the median overall survival (OS) of HER2-mutant NSCLC patients from stage IV diagnosis is 1.6–1.9 years (Kris et al., Jama-J.Am.Med.Assoc., 311(19):1998–2006(2014)).Several patient reports and series of reports on HER2-targeted drugs (including afatinib, dacomitinib, neratinib, and trastuzumab) in patients with HER2-mutant NSCLC have shown limited clinical activity (De Greve et al., Lung Cancer, 76(1):123-127 (2012); Kris et al., Ann. Oncol., 26(7):1421-1427 (2015); Gandhi et al., J. Clin. Onol., 32(2):68-75 (2014); Mazieres et al., Ann. Oncol., 27(2):281-286 (2016)). Therefore, chemotherapy remains the primary strategy for this patient population (Eng et al., Lung Cancer, 99:53-56 (2016)).

[0004] There is a demand for compounds with activity against HER2 mutations because they could have expanded applications in treating tumors with such mutations. Summary of the Invention

[0005] The first aspect of this disclosure relates to a compound represented by the structure of formula (I):

[0006]

[0007] R1, R2, R3, X, m, n, and A are as defined herein, or pharmaceutically acceptable salts or stereoisomers thereof.

[0008] Another aspect of this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0009] Another aspect of this disclosure relates to methods for treating diseases or conditions characterized by or mediated by abnormal human epidermal growth factor receptor 2 (HER2) activity.

[0010] In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, gastrointestinal cancer, lung cancer, colon cancer, endometrial cancer, or thyroid cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC) or EGFR / ALK / ROS1 triple-negative NSCLC.

[0011] As shown in the working examples, the compounds disclosed herein are effective and selective inhibitors of HER2. Detailed Implementation

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter pertains. As used in the specification and appended claims, unless otherwise indicated, the following terms have the meanings specified for the purpose of understanding this disclosure.

[0013] As used in the specification and appended claims, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural references. Thus, for example, reference to “a composition” includes a mixture of two or more such compositions, reference to “an inhibitor” includes a mixture of two or more such inhibitors, and so on.

[0014] Unless otherwise stated, the term “about” means within 10% of the specific value modified by the term “about” (e.g., within 5%, 2%, or 1%).

[0015] The transitional term "comprising," synonymous with "including," "containing," or "characterized in," is inclusive or open-ended and does not exclude additional, unlisted elements or method steps. When used in the context of the number of heteroatoms in a heterocyclic structure, it means that the heterocyclic group has a minimum number of heteroatoms. In contrast, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting substantially of" limits the scope of the claim to specific materials or steps "and those materials or steps that do not substantially affect the essential and novel features of the claimed compound."

[0016] With respect to the compounds disclosed herein, and to the extent that they are further described herein using the following terms, the following definitions apply.

[0017] As used herein, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. In one embodiment, the alkyl group is C1-C2. 18 Alkyl groups. In other embodiments, the alkyl groups are C0-C6, C0-C5, C0-C3, C1-C6, C0-C5, C0 ... 12C1-C8, C1-C6, C1-C5, C1-C4 or C1-C3 groups (where C0 alkyl refers to a bond). Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, isopropyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. In some embodiments, the alkyl group is a C1-C3 alkyl group. In some embodiments, the alkyl group is a C1-C2 alkyl group or a methyl group.

[0018] As used herein, the term "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain that links the remainder of a molecule to a group, consisting only of carbon and hydrogen, containing no unsaturation, and having one to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain can be attached to the remainder of the molecule and to the group via single bonds. In some embodiments, the alkylene group contains one to eight carbon atoms (C1-C8 alkylene). In other embodiments, the alkylene group contains one to five carbon atoms (C1-C5 alkylene). In other embodiments, the alkylene group contains one to four carbon atoms (C1-C4 alkylene). In other embodiments, the alkylene group contains one to three carbon atoms (C1-C3 alkylene). In other embodiments, the alkylene group contains one to two carbon atoms (C1-C2 alkylene). In other embodiments, the alkylene group contains one carbon atom (C1 alkylene).

[0019] As used herein, the term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having at least one carbon-carbon double bond. Alkenyl groups include groups having "cis" and "trans" orientations, or "E" and "Z" orientations. In one example, the alkenyl group is C2-C. 18 Alkenyl groups. In other embodiments, the alkenyl group is C2-C. 12 C2-C 10 C2-C8, C2-C6, or C2-C3 groups. Examples include ethenyl (or vinyl), propenyl, propenyl, 2-methylpropenyl, butenyl, butenyl, butenyl, 3-butenyl, butenyl, 2-methylbutenyl, hexenyl, hexenyl, 3-butenyl, hexenyl, and 1,3-dienyl.

[0020] As used herein, the term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond. In one example, the alkynyl group is C2-C. 18 Group. In other examples, the alkynyl group is C2-C. 12 C2-C 10 C2-C8, C2-C6, or C2-C3. Examples include ethynylprop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, and but-3-ynyl.

[0021] As used herein, the term "alkoxy" or "alkyloxy" refers to an alkyl group with an attached oxygen group as defined above, and that alkyl group is the attachment point. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc. An "ether" is two hydrocarbon groups covalently linked by oxygen. Therefore, the substituent of the alkyl group that makes an alkyl group an ether is an alkoxy or similar alkoxy group, such as that which can be represented by one of -O-alkyl, -O-alkenyl, and -O-ynyl.

[0022] As used in this article, the term "halogen" (or "halogenated group" or "halogenated compound") refers to fluorine, chlorine, bromine or iodine.

[0023] As used herein, the term "cyclic group" broadly refers to any group used alone or as part of a larger part that contains a saturated, partially saturated, or aromatic ring system, such as a carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocyclic alkyl, heterocyclic alkenyl), aryl, and heteroaryl group. A cyclic group may have one or more (e.g., fused) ring systems. Thus, for example, a cyclic group may contain one or more carbocyclic, heterocyclic, aryl, or heteroaryl groups.

[0024] As used herein, the term "carbocyclic" (also referred to as "carbocyclic group") refers to a group used alone or as part of a larger part of a saturated, partially unsaturated, or aromatic ring system having 3 to 20 carbon atoms, the ring system being used alone or as part of a larger part (e.g., an alkyl carbocyclic group). The term carbocyclic group includes monocyclic, bicyclic, tricyclic, fused, bridged, and spirocyclic systems, as well as combinations thereof. In one embodiment, the carbocyclic group comprises 3 to 15 carbon atoms (C3-C4). 15 In one embodiment, the carbocyclic group comprises 3 to 12 carbon atoms (C3-C4). 12 In another embodiment, the carbocyclic group includes C3-C8, C3-C... 10 Or C5-C 10 In another embodiment, the monocyclic carbocyclic group comprises C3-C8, C3-C6, or C5-C6. In some embodiments, the bicyclic carbocyclic group comprises C7-C8.12 In another embodiment, the helical form of the carbocyclic group includes C5-C 12 Representative examples of monocyclic carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, fully deuterated cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicyclic carbocyclic groups having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, such as bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, naphthalene, and bicyclic [3.2.2]nonane. Representative examples of spirocyclocyclic groups include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane. The term carbocyclic includes aromatic rings as defined herein. The term carbocyclic also includes cycloalkyl rings (e.g., saturated or partially unsaturated monocyclic, bicyclic, or spirocyclic rings). The term carbocyclic group also includes a carbocyclic ring fused with one or more (e.g., 1, 2, or 3) distinct cyclic groups (e.g., aryl or heterocyclic groups), wherein the attachment group or dot is located on the carbocyclic ring.

[0025] Therefore, the term carbocyclic also includes carbocyclic alkyl groups, as used herein, which refer to the formula --R c - A carbocyclic group, wherein R c It is an alkylene chain. The term carbocyclic also includes carbocyclic alkoxy groups, as used herein, which refer to the --O--R group bonded by an oxygen atom. c - A carbocyclic group, wherein R c It is an alkylene chain.

[0026] As used herein, the term "aryl" alone or as part of a larger subset (e.g., "aralkyl," where the terminal carbon atom on the alkyl group is the attachment point, e.g., a benzyl group; "aralkyloxy," where an oxygen atom is the attachment point; or "aryloxyalkyl," where the attachment point is on the aryl group) refers to a group comprising a monocyclic, bicyclic, or tricyclic carbocyclic system (including fused rings), wherein at least one ring in the system is aromatic. In some embodiments, the aralkyloxy group is a benzoyloxy group. The term "aryl" may be used interchangeably with the term "aryl ring." In one embodiment, an aryl group comprises a group having 6-18 carbon atoms. In another embodiment, an aryl group comprises a group having 6-10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracene, biphenyl, phenanthrene, fused tetraphenyl, 1,2,3,4-tetrahydronaphthyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, naphthidyl, etc., which can be substituted by one or more substituents described herein or substituted independently. A specific aryl group is phenyl. In some embodiments, the aryl group comprises an aryl ring fused with one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic), wherein the attachment group or dot is located on the aryl ring.

[0027] Therefore, the term aryl includes aralkyl groups (e.g., benzyl), as disclosed above, which refers to the formula --R c -aryl groups, where R c It is an alkylene chain, such as methylene or ethylene. In some embodiments, the aryl group is optionally substituted with a benzyl group. The term aryl also includes an arylalkoxy group, as used herein, which refers to a group of formula -OR bonded by an oxygen atom. c --A group of aryl groups, where R c It is an alkylene chain, such as methylene or ethylene.

[0028] As used herein, the term "heterocyclic group" refers to a "carbocyclic group" used alone or as part of a larger part, which contains a saturated, partially unsaturated, or aromatic ring system in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., O, N, N(O), S, S(O), or S(O)₂). The term heterocyclic group includes monocyclic, bicyclic, tricyclic, fused ring, bridged ring, and spirocyclic systems, as well as combinations thereof. In some embodiments, a heterocyclic group refers to a 3- to 15-membered heterocyclic ring system. In some embodiments, a heterocyclic group refers to a 3- to 12-membered heterocyclic ring system. In some embodiments, a heterocyclic group refers to a saturated ring system, such as a 3- to 12-membered saturated heterocyclic ring system. In some embodiments, a heterocyclic group refers to a heteroaryl ring system, such as a 5- to 14-membered heteroaryl ring system. The term heterocyclic also includes C3-C8 heterocyclic alkyl, which is a saturated or partially unsaturated monocyclic, bicyclic or spirocyclic system containing 3-8 carbon atoms and one or more (1, 2, 3 or 4) heteroatoms.

[0029] In some embodiments, the heterocyclic group comprises 3-12 ring atoms and includes monocyclic, bicyclic, tricyclic, and spirocyclic systems, wherein the ring atoms are carbon, and one to five ring atoms are heteroatoms, such as nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclic group comprises a 3- to 7-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclic group comprises a 4- to 6-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclic group comprises a 3-membered monocyclic ring. In some embodiments, the heterocyclic group comprises a 4-membered monocyclic ring. In some embodiments, the heterocyclic group comprises a 5- to 6-membered monocyclic ring. In some embodiments, the heterocyclic group comprises 0 to 3 double bonds. In any of the foregoing embodiments, the heterocyclic group comprises 1, 2, 3, or 4 heteroatoms. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR4]). + Cl - [NR4] + OH - Representative examples of heterocyclic groups include ethylene oxide, aziridinyl, cyclothioethane, aziridine, oxetane, thiohepane, 1,2-dithiohepane, 1,3-dithiohepane, pyrrolyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothiophenyl, tetrahydrothiophenyl, imidazoalkyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiaranyl, hexahydropyrimidinyl, oxazinyl, thiazinyl, thiaoxazinyl, homopiperazinyl, homopiperidinyl, aziridine, oxetane, thiohepane, and oxazinyl. alkyl, oxazheptanyl, diazaheptanyl, 1,4-diazaheptanyl, diazaheptanyl Basic, sulfur-nitrogen alkyl, thiazolyl, heptyl, tetrahydrothiaranyl, oxazolyl, thiazolyl, isothiazolyl, 1,1-dioxoisothiazolinone, oxazolidinone, imidazolinone, 4,5,6,7-tetrahydro[2H]indazole, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzi[d]imidazolyl, 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridyl, thiazinyl, thiophenyl, oxazinyl, thiadiazinyl, oxazinyl Diazinyl, dithiazinyl, dioxazinyl, oxahiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiaranyl, 2H-pyranyl, 4H-pyranyl, dioxalyl, 1,3-dioxolaneyl, pyrazolinyl, pyrazolylalkyl, dithiocyclohexyl, dithiopentanyl, pyrimidinoneyl, pyrimidinedionyl, pyrimidin-2,4- Diketyl, piperazinone, piperazin diketyl, pyrazolinyl imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl 2-azabicyclo[2.2.2]octyl, 8-azabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonyl, azaspiro[2.5]octyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]dec-2-one, azaspiro[5.5]undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazoleyl, 1,1-dioxohexahydrothiaranyl. Examples of five-membered heterocyclic groups containing sulfur or oxygen atoms and one to three nitrogen atoms are thiazolyl, including thiazolyl-2-yl and thiazolyl-2-yl N-oxide; thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl; oxazolyl, such as oxazol-2-yl; and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Examples of five-membered heterocyclic groups containing two to four nitrogen atoms include imidazolel, such as imidazole-2-yl; triazolyl, such as 1,3,4-triazol-5-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl; and tetrazolyl, such as 1H-tetrazole-5-yl. Representative examples of benzofused 5-membered heterocyclic groups are benzoxazol-2-yl, benzothiazol-2-yl, and benzimidazol-2-yl.Examples of 6-membered heterocyclic groups contain one to three nitrogen atoms and optionally sulfur or oxygen atoms, such as pyridyl groups, such as pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; pyrimidinyl groups, such as pyrimidin-2-yl and pyrimidin-4-yl; triazine groups, such as 1,3,4-triazine-2-yl and 1,3,5-triazine-4-yl; pyridazine groups, especially pyridazine-3-yl; and pyrazine groups. Pyridine N-oxides and pyridazine N-oxides, as well as pyridyl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazine, and 1,3,4-triazine-2-yl groups, are other examples of heterocyclic groups. In some embodiments, the heterocyclic group comprises a heterocycle fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., a carbocyclic or heterocyclic ring), wherein the attachment group or point is on the heterocycle, and in some embodiments, the attachment point is a heteroatom contained in the heterocycle.

[0030] Therefore, the term heterocyclic includes N-heterocyclic groups, as used herein, which refer to heterocyclic groups containing at least one nitrogen atom, and wherein the attachment point of the heterocyclic group to the remainder of the molecule is through the nitrogen atom in the heterocyclic group. Representative examples of N-heterocyclic groups include 1-morpholino, 1-piperidino, 1-piperazino, 1-pyrrolidinyl, pyrazolyl, imidazolino, and imidazoalkyl. The term heterocyclic also includes C-heterocyclic groups, as used herein, which refer to heterocyclic groups containing at least one heteroatom, and wherein the attachment point of the heterocyclic group to the remainder of the molecule is through the carbon atom in the heterocyclic group. Representative examples of C-heterocyclic groups include 2-morpholino, 2-piperidino, or 3-piperidino, or 4-piperidino, 2-piperazino, and 2-pyrrolidinyl or 3-pyrrolidinyl. The term heterocyclic also includes heterocyclic alkyl groups, as disclosed above, which refer to formula --R c - A heterocyclic group, wherein R c It is an alkylene chain. The term heterocyclic also includes heterocyclic alkoxy groups, as used herein, which refer to the --O--R group bonded by an oxygen atom. c - A heterocyclic group, wherein R c It is an alkylene chain.

[0031] As used herein, the term "heteroaryl" alone or as part of a larger group (e.g., "heteroarylalkyl" (also known as "heteroarylalkyl"), or "heteroarylalkoxy" (also known as "heteroarylalkoxy")) refers to a monocyclic, bicyclic, or tricyclic cyclic system having 5 to 14 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, a heteroaryl comprises a 5-6 membered monocyclic aromatic group, wherein one or more ring atoms are nitrogen, sulfur, or oxygen. Representative examples of heteroaryl groups include thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxtriazolyl, pyridyl, pyrimidinyl, imidazopyridyl, pyrazinyl, pyridazinyl, triazinyl, tetraazinyl, tetrazo[1,5-b]pyridazinyl, purinyl, denitropurinyl, benzoxazolyl, and benzofuranyl. Benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazole-5-yl, 1,2,3-triazol-5-yl, and pyridin-2-yl N-oxide. The term "heteroaryl" also includes groups in which the heteroaryl group is fused to one or more cyclic (e.g., carbocyclic or heterocyclic) rings, wherein the attachment group or dot is on the heteroaryl ring. Non-limiting examples include indolyl, indolazinyl, isoindolyl, benzothienyl / benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzodioxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazoleyl, acridineyl, phenazinyl, phenthiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group can be monocyclic, bicyclic, or tricyclic. In some embodiments, the heteroaryl group comprises a heteroaryl ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic), wherein the attachment group or point is on the heteroaryl ring, and in some embodiments, the attachment point is a heteroatom contained in the heterocyclic ring.

[0032] Therefore, the term heteroaryl includes an N-heteroaryl group, as used herein, which refers to a heteroaryl group containing at least one nitrogen atom as defined above, and wherein the attachment point of the heteroaryl group to the remainder of the molecule is through a nitrogen atom in the heteroaryl group. The term heteroaryl also includes a C-heteroaryl group, as used herein, which refers to a heteroaryl group as defined above, and wherein the attachment point of the heteroaryl group to the remainder of the molecule is through a carbon atom in the heteroaryl group. The term heteroaryl also includes a heteroarylalkyl group, as disclosed above, which refers to a group of formula --R c - A heteroaryl group, wherein R c It is an alkylene chain as defined above. The term heteroaryl also includes heteroarylalkoxy (or heteroarylalkoxy) groups, as used herein, which refer to the --O--R group bonded by an oxygen atom. c - A heteroaryl group, wherein R c It is an alkylene group as defined above.

[0033] Unless otherwise stated, and to the extent that no particular group is further defined, any of the groups described herein may be substituted or unsubstituted. As used herein, the term “substituted” broadly refers to all permissible substituents, implicitly provided that such substitution is consistent with the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, i.e., a compound that does not spontaneously transform, such as through rearrangement, cyclization, elimination, etc. Representative substituents include halogens, hydroxyl groups, and any other organic group containing any number of carbon atoms (e.g., 1-14 carbon atoms), and said organic group may contain one or more (e.g., 1, 2, 3, or 4) heteroatoms, such as oxygen, sulfur, and nitrogen, said atoms in a straight-chain, branched, or cyclic structure.

[0034] Unless otherwise disclosed, representative examples of substituents may include alkyl groups, substituted alkyl groups (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), alkoxy groups (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), substituted alkoxy groups (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), and haloalkane groups. Alkenyl (e.g., CF3), alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), cycloyl (e.g., C3-C...). 12C5-C6), substituted cyclic groups (e.g., C3-C6), and substituted cyclic groups (e.g., C3-C6). 12 C5-C6), carbocyclic groups (e.g., C3-C6), and carbonyl groups (e.g., C5-C6). 12 (C5-C6), substituted carbocyclic groups (e.g., C3-C6), and substituted carbocyclic groups (e.g., C3-C6). 12 (C5-C6), heterocyclic groups (e.g., C3-C6), heterocyclic groups (e.g., C3-C6). 12 C5-C6), substituted heterocyclic groups (e.g., C3-C6), and substituted heterocyclic groups. 12 (C5-C6), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or phenyl), heteroaryl (e.g., pyridyl or pyrimidinyl), substituted heteroaryl (e.g., substituted pyridyl or pyrimidinyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halogroup, hydroxyl group, aryloxy group (e.g., C6-C6), aryl group (C5 ... 12 C6), substituted aryl groups (e.g., C6-C4), and substituted aryl groups. 12 C6), alkylthio (e.g., C1-C6), substituted alkylthio (e.g., C1-C6), arylthio (e.g., C6-C6), alkylthio (e.g., C6-C6), alkylthio (e.g., C1-C6), arylthio (e.g., C6-C6), alkylthio (e.g., C1 ...6-C6), alkylthio (e.g., C1-C6), alkylthio (e.g 12 C6), substituted aryl thiols (e.g., C6-C4), and substituted aryl thiols (e.g., C6-C4). 12 (C6), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amide, substituted amide, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinamide, substituted sulfinamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acid and peptide groups.

[0035] In one respect, this paper provides compounds represented by formula (I):

[0036]

[0037] Or its pharmaceutically acceptable salts or stereoisomers.

[0038] in:

[0039] X does not exist; it is -CH2-, -O-, or C(O).

[0040] A is absent, and is a naphthyl group, a 5-membered heterocyclic group containing 1-3 heteroatoms selected from N, O, and S, or a fused heterobicyclic group having a 5- or 6-membered ring and containing 1-4 heteroatoms selected from N, O, and S, wherein A is optionally surrounded by one or more R groups. A replace;

[0041] Each R AIt is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogroup, hydroxyl, cyano, nitro, amino, C1-C6 alkylamino or di-C1-C6 alkylamino.

[0042] Each R1 is independently a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamido, halogroup, hydroxyl, cyano, nitro, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C6 carbocyclic, or a 5- or 6-membered heterocyclic group, wherein R1 is optionally surrounded by one or more R A replace,

[0043] Alternatively, the two R1 groups together with the atoms to which they are attached can form a 5- or 6-membered carbon cyclic group or a heterocyclic group;

[0044]

[0045] R3 is hydrogen, fluorine, or methyl;

[0046] m is 1 or 2; and

[0047] n is 0, 1, or 2.

[0048] In some implementations, X does not exist.

[0049] In some implementations, X is -CH2-.

[0050] In some implementations, X is -O-.

[0051] In some implementations, X is C(O).

[0052] In some implementations, A is optionally represented by one or more R A Substituted naphthyl group.

[0053] In some embodiments, A is a fused heterobicyclic group having 5- and 6-membered rings and containing 1-4 heteroatoms selected from N, O, and S, wherein A is optionally surrounded by one or more R atoms. A replace.

[0054] In some embodiments, A is a fused heterobicyclic group comprising two 6-membered rings and containing 1-4 heteroatoms selected from N, O, and S, wherein A is optionally surrounded by one or more R atoms. A replace.

[0055] In some embodiments, A is a 5-membered heterocyclic group containing 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group is optionally surrounded by one or more R atoms. A replace.

[0056] In some implementation schemes, A is And optionally by one or more R A replace.

[0057] In some implementation schemes, A is

[0058] And optionally by one or more R A replace.

[0059] In some implementation schemes, A is Optionally by one or more R A replace.

[0060] In some implementation schemes, A is

[0061] In some implementation schemes, A is And optionally by one or more R A replace.

[0062] In some implementation schemes, A is Optionally by one or more R A replace.

[0063] In some implementation schemes, A is

[0064] In some implementation schemes, A is And optionally by one or more R A replace.

[0065] In some implementation schemes, A is And optionally by one or more R A replace.

[0066] In some implementation schemes, A is And optionally by one or more R A replace.

[0067] In some implementation schemes, A is And optionally by one or more R A replace.

[0068] In some implementation schemes, A is And optionally by one or more R A replace.

[0069] In some implementation schemes, A is Optionally by one or more R A replace.

[0070] In some implementation schemes, A is Optionally by one or more R A replace.

[0071] In some implementation schemes, A is

[0072] In some implementation schemes, A is

[0073] In some implementation schemes, A is Optionally by one or more R A replace.

[0074] In some implementation schemes, A is

[0075] In some implementation schemes, A is And optionally by one or more R A replace.

[0076] In some implementation schemes, A is

[0077] In some implementation schemes, A is And optionally by one or more R A replace.

[0078] In some embodiments, R1 is independently a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamide, halogroup, cyano, di-C1-C6 alkylamino, C3-C6 carbocyclic, or a 5- or 6-membered heterocyclic group.

[0079] In some embodiments, R1 is independently methyl, ethyl, fluorine, chlorine, bromine, methoxy, cyano, -OCHF2, -OCH2F, -NMe2,

[0080] In some implementations, R1 is methyl.

[0081] In some implementations, R1 is chlorine.

[0082] In some implementations, R1 is

[0083] In some embodiments, the two R1 groups together with the atoms to which they are attached form a 5- to 6-membered carbocyclic or heterocyclic group.

[0084] In some embodiments, the two R1 groups together with the atoms to which they are attached form a phenyl, pyridyl, or dioxolane ring.

[0085] In some implementations, R2 is

[0086] In some implementations, R3 is hydrogen.

[0087] In some implementations, m is 2.

[0088] In some implementations, n is 1.

[0089] In some implementations, n is 2.

[0090] In some embodiments, the compounds of formula I are compounds of formulas Ia-Ih:

[0091]

[0092] Or their pharmaceutically acceptable salts or stereoisomers. In some embodiments of formulas Ia-Ih, R1 is methyl. In some embodiments of formulas Ia-Ih, R1 is chlorine.

[0093] In some implementations of formulas Ia-Ih, n is 1.

[0094] In some implementations of formulas Ia-Ih, n is 2.

[0095] The compound of the representative formula (I) has the following structure:

[0096]

[0097]

[0098] Or their pharmaceutically acceptable salts or stereoisomers.

[0099] The compounds disclosed herein may be in the form of free acids or free bases or pharmaceutically acceptable salts. As used herein, in the context of salts, the term "pharmaceutically acceptable" means a salt of a compound that does not eliminate the biological activity or properties of the compound and is relatively non-toxic, i.e., the salt form of the compound can be administered to a subject without causing undesirable biological effects (such as dizziness or stomach upset) or interacting harmfully with any other component of the composition comprising it. The term "pharmaceutically acceptable salt" refers to a product obtained by reacting a compound of the disclosed invention with a suitable acid or base. Examples of pharmaceutically acceptable salts of the compounds of the disclosed invention include those derived from suitable inorganic bases, such as Li salts, Na salts, K salts, Ca salts, Mg salts, Fe salts, Cu salts, Al salts, Zn salts, and Mn salts. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by an amino group and an inorganic acid, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentianate, fumarate, gluconate, glucuronide, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate, or p-toluenesulfonate, etc. Some of the compounds described herein can form pharmaceutically acceptable salts with various organic bases (such as lysine, arginine, guanidine, diethanolamine, or metformin). Suitable base salts include aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc salts.

[0100] The compounds of this disclosure may have at least one chiral center and are therefore in stereoisomer form, as used herein, where stereoisomers include all isomers of a single compound that differ only in the spatial orientation of their atoms. The term stereoisomer includes mirror-image isomers of a compound (enantiomers, which include (R-) or (S-) configurations of the compound), mixtures of mirror-image isomers (physical mixtures of enantiomers, and racemic mixtures or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of a compound, and isomers of a compound having more than one chiral center and not being mirror images of each other (diastereomers). The chiral center of a compound may undergo bulk epimerization; therefore, for these compounds, administration of the compound in (R-) form is considered equivalent to administration of the compound in (S-) form. Thus, the compounds of this disclosure can be prepared and used as individual isomers and substantially free of other isomers, or as mixtures of various isomers (e.g., racemic mixtures of stereoisomers).

[0101] In some embodiments, the compound is an isotopic derivative because it has at least one isotopic substitution of a desired atom, with the substitution amount exceeding the natural abundance of the isotope, i.e., enrichment. In one embodiment, the compound contains deuterium or multiple deuterium atoms. Heavier isotopes (such as deuterium, i.e., 2 Substitutions performed by H) may offer certain therapeutic advantages due to higher metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may therefore be advantageous in some cases.

[0102] The compounds disclosed herein can be prepared by crystallization under different conditions and can exist as one or a combination of polymorphs of the compounds. For example, different polymorphs can be identified and / or prepared by crystallization at different temperatures or by using various cooling modes (from very fast to very slow cooling during crystallization). Polymorphs can also be obtained by heating or melting the compound and then cooling it gradually or rapidly. The presence of polymorphs can be determined by solid-state probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction, and / or other known techniques.

[0103] In some embodiments, the pharmaceutical composition comprises a cocrystal of the compounds of the present invention. As used herein, the term "cocrystal" refers to a stoichiometric multicomponent system comprising the compounds provided herein and a cocrystal forming agent, wherein the compounds provided herein and the cocrystal forming agent are linked by non-covalent interactions. As used herein, the term "cocrystal forming agent" refers to a compound that can form intermolecular interactions with and cocrystallize with the compounds provided herein. Representative examples of eutectic forming agents include benzoic acid, succinic acid, fumaric acid, glutaric acid, trans-cinnamic acid, 2,5-dihydroxybenzoic acid, glycolic acid, trans-2-hexanoic acid, 2-hydroxyhexanoic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, succinic acid, pyridinecarboxylic acid, salicylic acid, maleic acid, saccharin, 4,4'-bipyridine-p-aminosalicylic acid, nicotinamide, urea, isonicotinamide, methyl 4-hydroxybenzoate, adipic acid, terephthalic acid, resorcinol, pyrogallol, phlorogallol, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone, etofylline, and phenobarbital.

[0104] Synthesis method

[0105] In another aspect, this disclosure relates to a method for preparing the compounds of the present invention or pharmaceutically acceptable salts or stereoisomers thereof. In a broader sense, the compounds of the present invention or pharmaceutically acceptable salts or stereoisomers thereof can be prepared by any method known to be suitable for preparing chemically related compounds. A better understanding of the compounds of this disclosure will be achieved by considering the synthetic schemes described in the various working examples, which demonstrate non-limiting methods that can be used to prepare the compounds of this disclosure.

[0106] Pharmaceutical Composition

[0107] Another aspect of this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. As is known in the art, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or medium suitable for administering the compound of the present disclosure to a mammal. Suitable carriers may include, for example, liquids (aqueous and non-aqueous, and combinations thereof), solids, encapsulating materials, gases and combinations thereof (e.g., semi-solids), and gases, which function to carry or transport the compound from one organ or part of the body to another organ or part of the body. The carrier is "acceptable" in the sense of being physiologically inert and compatible with other components of the formulation and harmless to the subject or patient. Depending on the type of formulation, the composition may also contain one or more pharmaceutically acceptable excipients.

[0108] In a broad sense, the compounds disclosed herein, as well as their pharmaceutically acceptable salts or stereoisomers, can be formulated into compositions of a specified type according to conventional pharmaceutical practices such as conventional mixing, dissolving, granulation, tablet preparation, grinding, emulsification, encapsulation, embedding, and compression processes (see, for example, Remington: The Science and Practice of Pharmacy (20th edition), ed. ARGennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York). The type of formulation depends on the route of administration, which may include enteral administration (e.g., oral, sublingual, sublingual, and rectal), parenteral administration (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im), and intrasternal injection or infusion techniques, intraocular, intra-arterial, intramedullary, intrathecal, intracardiac, transdermal, intradermal, intravaginal, intraperitoneal, mucosal, nasal, tracheal, bronchial, and inhalation), and topical administration (e.g., transdermal). Generally, the most suitable route of administration will depend on a number of factors, including, for example, the nature of the drug (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). For example, parenteral (e.g., intravenous) administration may also be advantageous because, for example, in cases of single-dose treatment and / or acute illness, the compound can be administered relatively rapidly.

[0109] In some embodiments, the compound is formulated for oral or intravenous administration (e.g., systemic intravenous injection).

[0110] Therefore, the compounds provided herein can be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, pouches, and suppositories), liquid compositions (e.g., solutions containing the compound, suspensions containing solid particles of the compound, emulsions, and solutions, syrups, and elixirs containing liposomes, micelles, or nanoparticles); semi-solid compositions (e.g., gels, suspensions, and creams); and gases (e.g., propellants for aerosol compositions). The compounds can also be formulated for rapid, immediate, or prolonged release.

[0111] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with a carrier and additional carriers or excipients, such as sodium citrate or calcium hydrogen phosphate, and the excipients include a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; and d) disintegrants, such as crosslinked polymers (e.g., crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose). Sodium, sodium glycolate starch, agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate, e) solution blocking agents, such as paraffin, f) absorption enhancers, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glyceryl monostearate, h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffers. Similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycol. Solid dosage forms of tablets, lozenges, capsules, pills and granules can be prepared by coating and shell (such as enteric coating and other coatings). They may also contain light-blocking agents.

[0112] In some embodiments, the compounds provided herein can be formulated in hard or soft gelatin capsules. Representative excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearoyl fumarate, anhydrous lactose, microcrystalline cellulose, and croscarmellose sodium. The gelatin shell may contain gelatin, titanium dioxide, iron oxide, and colorants.

[0113] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, microemulsions, syrups, and elixirs. In addition to the compound, liquid dosage forms may also contain aqueous or non-aqueous carriers commonly used in the art (depending on the solubility of the compound), such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol, as well as mixtures thereof. Oral compositions may also contain any excipients, such as wetting agents, suspending agents, coloring agents, sweeteners, flavoring agents, and aromatizers.

[0114] Injectable formulations for parenteral administration may include sterile aqueous solutions or oily suspensions. They can be formulated using suitable dispersants or wetting agents and suspending agents according to standard techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions contained in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable media and solvents that can be used are water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid are used in the preparation of injectable formulations. Injectable formulations may be sterilized, for example, by filtration through a bacterial trap or by incorporating a sterilizing agent in the form of a sterile solid composition, which may be dissolved or dispersed in sterile water or other sterile injectable media before use. The effects of a compound can be prolonged by slowing down its absorption, which can be achieved by using a liquid suspension with poor water solubility or by using crystalline or amorphous materials. Prolonged absorption of parenteral formulations can also be achieved by suspending the compound in an oily medium.

[0115] In some embodiments, the compounds provided herein can be administered locally rather than systemically, for example, by injecting the conjugate directly into an organ, typically in the form of a reservoir formulation or a sustained-release formulation. In specific embodiments, long-acting formulations are administered via implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Injectable reservoir forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer, such as polylactide-polyglycolic acid, poly(orthoester), and poly(anhydride). The release rate of the compound can be controlled by varying the ratio of the compound to the polymer and the properties of the specific polymer used. Reservoir-type injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, such as in liposomes coated with organ-specific antibodies. In these embodiments, the liposomes target the organ and are selectively absorbed by the organ.

[0116] The composition can be formulated for sublingual or oral administration, examples of which include tablets, lozenges, and gels.

[0117] The compounds described herein can be formulated for inhalation administration. Various forms suitable for inhalation administration include aerosols, inhalers, or powders. Pharmaceutical compositions can be delivered as aerosol sprays via pressurized packaging or nebulizers using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases). In some embodiments, the dosage unit of the pressurized aerosol can be determined by providing a valve to deliver a measured amount. In some embodiments, gelatin-containing capsules and cartridges, for example for use in inhalers or blowpipes, can be formulated as a powder mixture containing the compound with a suitable powder matrix (such as lactose or starch).

[0118] The compounds described herein can be formulated for topical application, as used herein, where topical application refers to intradermal application by formulation onto the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions, and sprays.

[0119] Representative examples of carriers that can be used to formulate topical compounds include solvents (e.g., alcohols, polyols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffer solutions (e.g., hypotonic or buffered saline). For example, creams can be formulated using saturated or unsaturated fatty acids (such as stearic acid, palmitic acid, oleic acid, palmitoleic acid), cetyl alcohol, or oleyl alcohol. Creams may also contain nonionic surfactants, such as polyoxy-40-stearate.

[0120] In some embodiments, the topical formulation may also contain excipients, examples of which are penetration enhancers. These agents are capable of transporting pharmacologically active compounds across the stratum corneum and preferably into the epidermis or dermis with little or no systemic absorption. Various compounds have been evaluated for their effectiveness in increasing the rate of drug penetration across the skin. See, for example, Percutaneous Penetration Enhancers, Maibach HI and Smith H.E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which investigated the use and testing of various skin penetration enhancers, and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh T.K., Pfister WR, Yum SI (eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997). Representative examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe vera compositions (e.g., aloe vera gel), ethanol, isopropanol, octylphenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decyl methyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glyceryl monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

[0121] Representative examples of other excipients that can be included in topical formulations and other types of formulations (to the extent compatible with them) include preservatives, antioxidants, humectants, emollients, buffers, solubilizers, skin protectants, and surfactants. Suitable preservatives include alcohols, quaternary ammonium compounds, organic acids, parabens, and phenols. Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents such as EDTA and citric acid. Suitable humectants include glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Suitable buffers include citric acid, hydrochloric acid, and lactic acid buffers. Suitable solubilizers include quaternary ammonium chlorides, cyclodextrins, methyl benzoate, lecithin, and polysorbate esters. Suitable skin protectants include vitamin E oil, allantoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0122] Transdermal formulations typically employ transdermal delivery devices and transdermal patches, in which compounds are formulated as lipophilic emulsions or buffered aqueous solutions, dissolved and / or dispersed in polymers or adhesives. Patches can be constructed for continuous, pulsed, or on-demand delivery of pharmaceutical agents. Transdermal delivery of compounds can be achieved using iontophoresis patches. Transdermal patches can provide controlled delivery of compounds, where the absorption rate is slowed by using rate-controlled membranes or by trapping the compound in a polymer matrix or gel. Absorption enhancers can be used to increase absorption; examples of absorption enhancers include pharmaceutically acceptable solvents that facilitate absorption through the skin.

[0123] Ophthalmic preparations include eye drops.

[0124] Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retention enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides and synthetic polymers (such as polyvinylpyrrolidone, PEG, etc.). Compositions for rectal or vaginal administration can also be formulated as suppositories, which can be prepared by mixing the compound with a suitable non-irritating carrier and excipients such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository waxes, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature, thus melting and releasing the compound in the rectal or vaginal cavity.

[0125] dose

[0126] As used herein, the term "therapeuticly effective amount" refers to an amount of such a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof, which is effective in producing a desired therapeutic response in a patient suffering from a disease or condition characterized by or mediated by abnormal human epidermal growth factor receptor 2 (Her2) activity. Therefore, the term "therapeuticly effective amount" includes an amount of such a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof, which, upon administration, induces a positive change in the disease or condition to be treated, or is sufficient to prevent the development or progression of the disease or condition, or alleviates to some extent one or more of the symptoms of the disease or condition being treated in the subject, or inhibits the growth of diseased cells, or reduces the amount of HER2 in diseased cells.

[0127] The total daily dose of compounds and their administration can be determined according to standard medical practice, such as by the attending physician using reasonable medical judgment. The specific therapeutically effective dose for any particular subject will depend on a number of factors, including: the disease or condition being treated and its severity (e.g., its current state); the activity of the compound used; the specific composition used; the subject's age, weight, general health condition, sex, and diet; the time of administration, route of administration, and excretion rate of the compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field (see, for example, Hardman et al., eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill Press, pp. 155-173, 2001).

[0128] The compounds provided herein are effective over a wide dosage range. In some embodiments, the total daily dose (e.g., for adults) can range from about 0.001 to about 1600 mg, 0.01 to about 1000 mg, 0.01 to about 500 mg, about 0.01 to about 100 mg, about 0.5 to about 100 mg, 1 to about 100 to 400 mg / day, about 1 to about 50 mg / day, about 5 to about 40 mg / day, and in other embodiments about 10 to about 30 mg / day. Depending on the frequency of daily administration of the compound, individual doses containing the desired dosage can be formulated. For example, capsules can be formulated with about 1 to about 200 mg of the compound (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg). In some embodiments, the compound can be administered at a dose ranging from about 0.01 mg to about 200 mg / kg body weight per day. In some implementations, a dose of 0.1 to 100 mg / kg per day, for example, 1 to 30 mg / kg, may be effective in one or more dosages. For example, a dose suitable for oral administration may be in the range of 1-30 mg / kg body weight per day, and a dose suitable for intravenous administration may be in the range of 1-10 mg / kg body weight per day.

[0129] How to use

[0130] In some respects, this disclosure relates to methods for treating diseases or conditions involving HER2, said methods necessarily involving administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof to a subject in need.

[0131] In a broad sense, diseases or conditions suitable for treatment with the compounds of this disclosure involve abnormal HER2 activity or other functional abnormalities relative to a non-pathological state. A “disease” is generally considered a health state of a subject in which the subject is unable to maintain homeostasis, and in which the subject’s health continues to deteriorate if the disease does not improve. In contrast, a “condition” of a subject is a health state in which the subject is able to maintain homeostasis, but in which the subject’s health is not as good as it would be without the condition. A condition does not necessarily lead to a further decline in the subject’s health without treatment. In some embodiments, the compounds of formula (I) can be used to treat proliferative disorders and conditions (e.g., cancer or benign growths). As used herein, the term “proliferative disorder or condition” refers to a condition characterized by disordered or abnormal cell growth or both, including non-cancerous conditions such as growths, precancerous conditions, benign tumors, and cancer.

[0132] In some implementations, the disease or condition is characterized by or mediated by the activity of the HER2 mutant.

[0133] In some implementations, the HER2 mutant is an exon 20 insertion mutant.

[0134] As used herein, the term "subject" (or "patient") includes all members of the animal kingdom who are susceptible to or suffer from the specified disease or condition. In some embodiments, the subject is a mammal, such as a human or a non-human mammal. The methods are also applicable to companion animals, such as dogs and cats, and livestock, such as cows, horses, sheep, goats, pigs, and other domesticated and wild animals. Subjects who "need" treatment according to this disclosure may "have or be suspected of having" the specific disease or condition, and may have been diagnosed or present with a sufficient number of risk factors or a sufficient number of signs or symptoms, or combinations of signs or symptoms, to enable a medical professional to diagnose or suspect that the subject has the disease or condition. Therefore, subjects who have and are suspected of having the specific disease or condition are not necessarily two distinct groups.

[0135] Exemplary types of non-cancerous (e.g., proliferative) diseases or conditions that may be suitable for treatment with the compounds disclosed herein include inflammatory diseases and disorders, autoimmune diseases, neurodegenerative diseases, heart diseases, viral diseases, chronic and acute kidney diseases or injuries, metabolic diseases, and allergies and genetic diseases.

[0136] Representative examples of specific non-cancerous diseases and conditions include rheumatoid arthritis, alopecia areata, lymphoproliferative disorders, autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, anhidrotic ectodermal dysplasia, pure red cell anemia, and idiopathic thrombocytopenic purpura), cholecystitis, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, scleroderma, sepsis, septic shock, dacryoadenitis, cryptothermal protein-related periodic syndrome (CAPS), endotoxic shock, endometritis, Gram-negative sepsis, keratoconjunctivitis sicca, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic lung inflammation, chronic transplant rejection, hidradenitis suppurativa, inflammatory bowel disease, Crohn's disease, and Behcet's syndrome. Systemic lupus erythematosus, glomerulonephritis, multiple sclerosis, juvenile diabetes mellitus, autoimmune uveitis, autoimmune vasculitis, thyroiditis, Addison's disease, lichen planus, appendicitis, bullous pemphigus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, myasthenia gravis, immunoglobulin nephropathy, Hashimoto's disease, Sjogren's syndrome, vitiligo, Wegener's granulomatosis, granulomatous orchitis, autoimmune oophoritis, sarcoidosis, rheumatic carditis, ankylosing spondylitis, Graves' disease. Diseases, autoimmune thrombocytopenic purpura, psoriasis, psoriatic arthritis, eczema, herpetic dermatitis, ulcerative colitis, pancreatic fibrosis, hepatitis, liver fibrosis, CD14-mediated sepsis, non-CD14-mediated sepsis, acute and chronic kidney disease, irritable bowel syndrome, fever, restenosis, cervicitis, stroke and ischemic injury, nerve trauma, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, congestive heart failure, acute coronary syndrome, cachexia, malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome Syndrome), acute synovitis, muscle degeneration, bursitis, tendinitis, tenosynovitis, hernia, ruptured or prolapsed disc syndrome, osteoporosis, sinusitis, thrombosis, silicosis, pulmonary sarcoma, bone resorption diseases (such as osteoporosis), fibromyalgia, AIDS and other viral diseases (such as herpes zoster, herpes simplex type I or II, influenza virus disease and cytomegalovirus disease), type I and type II diabetes, obesity, insulin resistance and diabetic retinopathy, 22q11.2. Deficiency syndromes, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, color blindness, cat-like crying, Down syndrome, cystic fibrosis, Duchenne muscular dystrophy, hemophilia, Klinefleter's syndrome, neurofibromatosis, phenylketonuria, Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome Syndrome, urea cycle disorder, thalassemia, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, uveitis, polymyositis, proctitis, interstitial pulmonary fibrosis, dermatomyositis, atherosclerosis, arteriosclerosis, amyotrophic lateral sclerosis, asocial disorder, varicose veins, vaginitis, depression, and sudden infant death syndrome.

[0137] In other embodiments, the method involves treating a subject with cancer. Generally, the compounds disclosed herein are effective in treating cancers (solid tumors, including both primary and metastatic tumors), sarcomas, melanomas, and blood cancers (cancers affecting the blood (including lymphocytes, bone marrow, and / or lymph nodes)) such as leukemia, lymphoma, and multiple myeloma. Both adult and pediatric tumors / cancers are included. Cancers can be vascularized, not substantially vascularized, or non-vascularized.

[0138] Representative examples of cancers include adrenocortical carcinoma, AIDS-related cancers (e.g., Kaposi's sarcoma and AIDS-related lymphoma), appendix cancer, childhood cancers (e.g., pediatric cerebellar astrocytoma, pediatric cerebral astrocytoma), basal cell carcinoma, skin cancer (non-melanoma), bile duct cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urobladder cancer, and brain cancers (e.g., gliomas and glioblastomas, such as brainstem glioma, gestational trophoblastic glioma, cerebellar astrocytoma). Spectrum astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, optic pathway and hypothalamic glioma, breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, nervous system cancers (e.g., central nervous system cancers, central nervous system lymphoma), cervical cancer, chronic myeloproliferative disorders, colorectal cancers (e.g., colon cancer, rectal cancer), polycythemia vera, lymphoid vegetations, mycosis fungoides, Sezary syndrome. Syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, gonadal germ cell tumors, extrahepatic bile duct cancer, ocular cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal cancer (e.g., gastric cancer, small bowel cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST)), germ cell tumors, ovarian germ cell tumors, head and neck cancer, Hodgkin's lymphoma, leukemia, lymphoma, multiple myeloma, hepatocellular carcinoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet cell tumors (endocrine pancreas), renal cancer (e.g., Wilms' tumor, clear cell renal cancer), liver cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), Waldenstrom's macroglobulinema, melanoma, intraocular (ocular) melanoma, Merkel cell carcinoma. Carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary origin, multiple endocrine tumors (MEN), myelodysplastic syndrome, idiopathic thrombocythemia, myelodysplastic / myeloproliferative disorders, nasopharyngeal carcinoma, neuroblastoma, oral cancer (e.g., oral cancer, lip cancer, oral cavity cancer, tongue cancer, oropharyngeal cancer, pharyngeal cancer, laryngeal cancer), ovarian cancer (e.g., ovarian epithelial cancer, ovarian germ cell tumors, low-grade malignant potential ovarian tumors), pancreatic cancer, islet cell pancreatic cancer. Cancers of the sinuses and nasal cavity, parathyroid carcinoma, penile cancer, pharyngeal cancer, pheochromocytoma, pineal blastoma, pituitary adenoma, plasma cell vegetations, pleural pulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, uterine cancer (e.g., endometrial uterine cancer, uterine sarcoma, endometrial cancer), squamous cell carcinoma, testicular cancer, thymoma, thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other urinary organs, urethral cancer, gestational trophoblastoma, vaginal cancer, and vulvar cancer.

[0139] Sarcomas that can be treated with the compounds disclosed herein include similar soft tissue and bone cancers, representative examples of which include osteosarcoma or osteoblastoma (bone) (e.g., Ewing's sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesothelial sarcoma or mesothelioma (membranous lining of body cavities), fibrosarcoma (fibrous tissue), angiosarcoma or angioendothelioma (vascular), liposarcoma (adipose tissue), glioma or astrocytoma (neurogenic connective tissue present in the brain), myxosarcoma (primordial embryonic connective tissue), and mesenchymal or mixed mesodermal tumors (mixed connective tissue types).

[0140] In some implementations, the methods disclosed herein necessarily involve treating subjects with proliferative diseases or conditions of the blood system, liver, brain, lungs, colon, pancreas, prostate, ovaries, breasts, skin, and endometrium.

[0141] As used herein, “hematologic proliferative disorders or conditions” include lymphoma, leukemia, myeloid vegetations, mast cell vegetations, myelodysplastic syndromes, benign monoclonal gammopathy, polycythemia vera, chronic myeloid leukemia, myeloid metaplasia of unknown cause, and idiopathic thrombocythemia. Therefore, representative examples of hematologic malignancies may include multiple myeloma, lymphomas (including T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma (diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and ALK+ anaplastic large cell lymphoma)) (e.g., B-cell non-Hodgkin lymphoma selected from diffuse large B-cell lymphoma) (e.g., germinal center B-cell-like diffuse large B-cell lymphoma or activated B-cell-like diffuse large B-cell lymphoma), Burkitt's lymphoma. Leukemia (including childhood leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, metastatic pancreatic adenocarcinoma, refractory B-cell non-Hodgkin lymphoma, and relapsed B-cell non-Hodgkin lymphoma, childhood lymphoma and lymphoma of lymphocytic and cutaneous origin (e.g., small lymphocytic lymphoma)), leukemia (including childhood leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, small lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia and mast cell leukemia), myeloid vegetations and mast cell vegetations.

[0142] As used herein, “hepatic proliferative disorders or conditions” encompasses all forms of proliferative disorders affecting the liver. Hepatic proliferative disorders can include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and hepatoblastoma), early or precancerous lesions of the liver, benign growths or lesions of the liver, malignant growths or lesions of the liver, and metastatic lesions of other tissues and organs in the body. Hepatic proliferative disorders can include liver hyperplasia, metaplasia, and developmental abnormalities.

[0143] As used herein, “cytoproliferative disorders or conditions of the brain” includes all forms of cytoproliferative disorders affecting the brain. Cytoproliferative disorders of the brain can include brain cancers (e.g., gliomas, glioblastomas, meningiomas, pituitary adenomas, vestibular schwannomas, and primitive neuroectodermal tumors (medulloblastomas)), early or precancerous conditions of the brain, benign growths or lesions of the brain, malignant growths or lesions of the brain, and metastatic lesions of other tissues and organs in the body. Cytoproliferative disorders of the brain can include hyperplasia, metaplasia, and developmental abnormalities of the brain.

[0144] As used herein, “cytoproliferative disorders or conditions of the lung” includes all forms of cytoproliferative disorders affecting lung cells. Cytoproliferative disorders of the lung include lung cancer, early and precancerous lesions of the lung, benign growths or lesions of the lung, lung hyperplasia, metaplasia, and developmental abnormalities, and metastatic lesions in other tissues and organs of the body besides the lung. Lung cancer includes all forms of lung cancer, such as malignant lung vegetations, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Lung cancer includes small cell lung cancer (“SLCL”), non-small cell lung cancer (“NSCLC”), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, squamous cell carcinoma, and mesothelioma. Lung cancer can include “scar carcinoma”, bronchoalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer also includes lung vegetations with histological and ultrastructural heterogeneity (e.g., mixed cell types). In some embodiments, the compounds disclosed herein can be used to treat non-metastatic or metastatic lung cancer (e.g., NSCLC, ALK-positive NSCLC, NSCLC with ROS1 rearrangement, lung adenocarcinoma, and squamous cell lung cancer).

[0145] As used herein, “cell proliferative disorders or conditions of the colon” ​​includes all forms of cell proliferative disorders affecting colonic cells, including colon cancer, early or precancerous lesions of the colon, adenomatous polyps of the colon, and metachronic lesions of the colon. Colon cancer includes sporadic and hereditary colon cancer, malignant colonic vegetations, carcinoma in situ, typical carcinoid tumors, atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma, and squamous cell carcinoma. Colon cancer can be associated with hereditary syndromes such as hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, MYH-associated polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome, and juvenile polyposis. Cell proliferative disorders of the colon can also be characterized by hyperplasia, metaplasia, or developmental abnormalities of the colon.

[0146] As used herein, “cell proliferative disorders or lesions of the pancreas” includes all forms of cell proliferative disorders affecting pancreatic cells. Cell proliferative disorders of the pancreas can include pancreatic cancer, early or precancerous lesions of the pancreas, pancreatic hyperplasia, pancreatic developmental abnormalities, benign growths or lesions of the pancreas, malignant growths or lesions of the pancreas, and metastatic lesions of other tissues and organs of the body besides the pancreas. Pancreatic cancer includes all forms of cancer of the pancreas, including ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary growths, mucinous cystadenoma, papillary cystic growths, and serous cystadenoma, as well as pancreatic growths with histological and ultrastructural heterogeneity (e.g., mixed cell types).

[0147] As used herein, "proliferative disorders or conditions of the prostate" includes all forms of proliferative disorders affecting the prostate. Proliferative disorders of the prostate can include prostate cancer, early or precancerous lesions of the prostate, benign growths or lesions of the prostate, malignant growths or lesions of the prostate, and metastatic lesions of other tissues and organs in the body besides the prostate. Proliferative disorders of the prostate can include hyperplasia, metaplasia, and developmental abnormalities of the prostate.

[0148] As used in this article, "cellular proliferative disorders or conditions of the ovary" includes all forms of cellular proliferative disorders affecting ovarian cells. Ovarian cellular proliferative disorders can include early or precancerous lesions of the ovary, benign growths or abnormalities of the ovary, ovarian cancer, and metastatic lesions in other tissues and organs of the body besides the ovary. Ovarian cellular proliferative disorders can include ovarian hyperplasia, metaplasia, and developmental abnormalities.

[0149] As used herein, "proliferative disorders or conditions of the breast" includes all forms of proliferative disorders affecting breast cells. Proliferative disorders of the breast can include breast cancer, early or precancerous lesions of the breast, benign growths or lesions of the breast, and metastatic lesions in other tissues and organs of the body besides the breast. Proliferative disorders of the breast can include hyperplasia, metaplasia, and developmental abnormalities of the breast.

[0150] As used herein, "cell proliferation disorders or conditions of the skin" includes all forms of cell proliferation disorders affecting skin cells. Cell proliferation disorders of the skin can include early or precancerous lesions of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma of the skin or other malignant growths or lesions, and metastatic lesions of body tissues and organs other than the skin. Cell proliferation disorders of the skin can include hyperplasia, metaplasia, and developmental abnormalities of the skin.

[0151] As used herein, "endometrial proliferative disorders or conditions" encompasses all forms of proliferative disorders affecting endometrial cells. Endometrial proliferative disorders can include early or precancerous lesions of the endometrium, benign growths or abnormalities of the endometrium, endometrial cancer, and metastatic lesions in other tissues and organs of the body besides the endometrium. Endometrial proliferative disorders can include endometrial hyperplasia, metaplasia, and developmental abnormalities.

[0152] In some embodiments, the compounds disclosed herein can be used to treat breast cancer, ovarian cancer, gastrointestinal cancer, lung cancer, colon cancer, endometrial cancer, or thyroid cancer.

[0153] In some embodiments, the compounds disclosed herein can be used to treat non-small cell lung cancer (NSCLC) or EGFR / ALK / ROS1 triple-negative NSCLC.

[0154] The compounds disclosed herein, along with their pharmaceutically acceptable salts and stereoisomers, can be administered to patients, for example, cancer patients, as monotherapy or in combination therapy. The therapy can be “first-line” treatment, i.e., alone or in combination with other treatments, as initial treatment for patients who have not received prior anticancer therapy; or “second-line” treatment, alone or in combination with other treatments, as treatment for patients who have received prior anticancer therapy; or alone or in combination with other treatments, as “third-line,” “fourth-line,” etc., treatments. The therapy can also be given to patients who have previously received unsuccessful or partially successful treatments but are unresponsive or intolerant to a particular treatment. The therapy can also be given as adjuvant therapy, i.e., to prevent cancer recurrence in patients with currently undetectable disease or after surgical removal of a tumor. Therefore, in some embodiments, the compounds can be administered to patients who have already received prior therapy (such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiotherapy, targeted therapy, or any combination thereof).

[0155] The methods disclosed herein may necessarily involve administering the compounds of the invention or pharmaceutical compositions thereof to a patient in a single dose or in multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20 or more doses). For example, the frequency of administration may range from once daily to once every eight weeks. In some embodiments, the frequency of administration ranges from about once daily for 1, 2, 3, 4, 5 or 6 weeks, and in other embodiments necessarily involves at least one 28-day cycle comprising daily administration for 3 weeks (21 days) followed by a 7-day rest period. In other embodiments, the compound may be administered twice daily (BID) over a two-and-a-half-day period (QD) (total of 5 doses) or once daily (QD) over a two-day period (QD) (total of 2 doses). In other embodiments, the compound may be administered once daily (QD) over a five-day period.

[0156] Combination therapy

[0157] The compounds disclosed herein, as well as their pharmaceutically acceptable salts or stereoisomers, can be used in combination with or simultaneously with at least one other active agent (e.g., an anticancer agent or regimen) to treat diseases and conditions. In this context, the terms "combination" and "simultaneously" mean that the agents are co-administered, including substantially simultaneously, by the same or separate dosage forms, and by the same or different methods of administration, or sequentially, for example, as part of the same treatment regimen or by a series of treatment regimens. Thus, if administered sequentially, the first of the two agents may still be detectable at the treatment site in some cases when the second agent is administered. The order and time intervals can be determined so that they can act together (e.g., synergistically to provide more beneficial effects than if they were otherwise administered). For example, the agents can be administered simultaneously or sequentially at different time points in any order; however, if they are not administered simultaneously, they can be administered at sufficiently close times to provide the desired therapeutic effect, which may be synergistic. Therefore, the terminology is not limited to exactly simultaneous administration of the active agents.

[0158] In some embodiments, the treatment regimen may include administration of a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof in combination with one or more other therapeutic agents known for treating diseases or conditions (e.g., cancer). The dose of the additional anticancer therapeutic agent may be the same as or even lower than the known or recommended dose. See Hardman et al., eds., Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics, 10th edition, McGraw-Hill, New York, 2001; Physician's Desk Reference, 60th edition, 2006. For example, anticancer agents that can be used in combination with the compounds of the present invention are known in the art. See, for example, U.S. Patent 9,101,622 (of which section 5.2) and U.S. Patent 9,345,705B2 (of which columns 12-18). Other representative examples of anticancer agents and treatment regimens include radiotherapy, chemotherapy (e.g., mitosis inhibitors, angiogenesis inhibitors, anti-hormones, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, anti-androgens, signal transduction pathway inhibitors, anti-microtubule agents, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulators, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapy.

[0159] In some embodiments, the compounds provided herein and other anticancer therapeutic agents may be administered at intervals of less than 5 minutes, less than 30 minutes, less than 1 hour, about 1 hour, about 1 to about 2 hours, about 2 to about 3 hours, about 3 to about 4 hours, about 4 to about 5 hours, about 5 to about 6 hours, about 6 to about 7 hours, about 7 to about 8 hours, about 8 to about 9 hours, about 9 to about 10 hours, about 10 to about 11 hours, about 11 to about 12 hours, about 12 to 18 hours, 18 to 24 hours, 24 to 36 hours, 36 to 48 hours, 48 ​​to 52 hours, 52 to 60 hours, 60 to 72 hours, 72 to 84 hours, 84 to 96 hours, or 96 to 120 hours. Two or more anticancer therapies may be administered during the same patient visit.

[0160] In some embodiments, the compounds of this disclosure and other therapeutic agents (e.g., anticancer therapeutic agents) are administered periodically. For example, in the context of cancer treatment, periodic therapy involves administering one anticancer therapeutic agent for a period of time, then administering a second anticancer therapeutic agent for a period of time, and repeating this sequential administration, i.e., a cycle, to reduce the development of tolerance to one or both of the anticancer therapeutic agents, to avoid or reduce the side effects of one or both of the anticancer therapeutic agents, and / or to improve the efficacy of the therapy. In one example, periodic therapy involves administering a first anticancer therapeutic agent for a period of time, then administering a second anticancer therapeutic agent for a period of time, optionally then administering a third anticancer therapeutic agent for a period of time, and so on, and repeating this sequential administration, i.e., a cycle, to reduce the development of tolerance to one of the anticancer therapeutic agents, to avoid or reduce the side effects of one of the anticancer therapeutic agents, and / or to improve the efficacy of the anticancer therapeutic agent.

[0161] In some embodiments, and depending on the specific cancer being treated, the compounds of this disclosure may be used in combination with at least one other anticancer agent, such as paclitaxel (e.g., ovarian cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer), topotecan (e.g., ovarian cancer and lung cancer), irinotecan (e.g., colon cancer and small cell lung cancer), etoposide (e.g., testicular cancer, lung cancer, lymphoma, and non-lymphocytic leukemia), vincristine (e.g., leukemia), leucovorin (e.g., colon cancer), artretamine (e.g., ovarian cancer), and daunorubicin (e.g., acute...). For various cancers including myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and Kaposi's sarcoma; trastuzumab (e.g., breast cancer, gastric cancer, and esophageal cancer); rituximab (e.g., non-Hodgkin's lymphoma); cetuximab (e.g., colorectal cancer, metastatic non-small cell lung cancer, and head and neck cancer); pertuzumab (e.g., metastatic HER2-positive breast cancer); and alemtuzumab (e.g., chronic lymphocytic leukemia (CLL), cutaneous T-cell leukemia). The following are listed as treatments for various cancers: CTCL and T-cell lymphoma, panitumumab (e.g., colon and rectal cancer), tamoxifen (e.g., breast cancer), fulvestrant (e.g., breast cancer), letrazole (e.g., breast cancer), exemestane (e.g., breast cancer), azacytidine (e.g., myelodysplastic syndromes), mitomycin C (e.g., gastrointestinal cancer, anal cancer, and breast cancer), and actinomycin D (e.g., Wilms' tumor, rhabdomyosarcoma). Tumors, Ewing's sarcoma, trophoblastic cell growths, testicular cancer and ovarian cancer), erlotinib (e.g., non-small cell lung cancer and pancreatic cancer), sorafenib (e.g., kidney cancer and liver cancer), temsirolimus (e.g., kidney cancer), bortezomib (e.g., multiple myeloma and mantle cell lymphoma), pegaspargase (e.g., acute lymphoblastic leukemia), cabometyx (e.g., hepatocellular carcinoma, medullary thyroid carcinoma and renal cell carcinoma), Keytruda (e.g.,Cervical cancer, gastric cancer, hepatocellular carcinoma, Hodgkin's lymphoma, melanoma, Merkel cell carcinoma, non-small cell lung cancer, urothelial carcinoma, and head and neck squamous cell carcinoma; nivolumab (e.g., colorectal cancer, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, small cell lung cancer, and urothelial carcinoma); and regorafenib (e.g., colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma).

[0162] medicine box

[0163] The compositions of the present invention can be assembled into a pillbox or pharmaceutical system. A pillbox or pharmaceutical system according to this aspect of the present disclosure includes a carrier or packaging (such as a box, carton, tube, etc.) having one or more containers, such as vials, tubes, ampoules, or bottles, sealed within the packaging, the containers containing a compound of the present disclosure or a pharmaceutical composition containing said compound and a pharmaceutically acceptable carrier, wherein the compound and the carrier may be placed in the same or separate containers. The pillbox or pharmaceutical system of the present disclosure may also include printed instructions for using the compound and composition.

[0164] These and other aspects of this disclosure will be further understood as one considers the following embodiments, which are intended to illustrate certain particular implementations but are not intended to limit the scope of this disclosure as defined in the claims.

[0165] Example

[0166] Example 1: (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2,3-dimethylphenyl)- Synthesis of 1-(1-Acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (1)

[0167]

[0168] (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2,3-dimethylphenyl)-4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide hydrochloride (3). A solution of acid 1 (150 mg, 0.414 mmol) (PBLJ7889, from Pharmaclock) in DMF (4 mL) was supplemented with azirmona-benzotriazole tetramethylureonium hexafluorophosphate (HATU, 189 mg, 0.497 mmol) and N,N-diisopropylethylamine (DIPEA, 144 μL, 0.828 mmol). Aniline 2 (116 mg, 0.455 mmol) was then added and stirred at room temperature for 3 hours. The reaction mixture was extracted with EtOAc, washed with H2O 3x and brine, dried over Na2SO3, filtered, and concentrated by rotary evaporation. The crude residue was dissolved in 4M HCl (3 mL) in dioxane and stirred for 1 hour. The reaction mixture was concentrated to provide crude intermediate amine 3 as a light orange solid.

[0169] (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2,3-dimethylphenyl)-1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (1). Triethylamine (Et3N, 160 μL, 1.12 mmol) and acryloyl chloride (45 μL, 0.561 mmol) were added to a solution of intermediate amine 3 (200 mg, 0.374 mmol) in CH2Cl2 (3 mL, 0.12 M) at 0 °C. After stirring at 0 °C for 15 min, the reaction mixture was heated to room temperature, concentrated by rotary evaporation, and purified by preparative HPLC to give compound (1) as a white solid (61 mg, yield of 14% from the three steps starting from 1).

[0170] 1H NMR(500MHz,DMSO-d6)δ10.38-10.09(m,1H),8.95(d,J=7.5Hz,1H),8.56(s,1H),8.38(s,1H),8.28(s,1H),8.10 (s,1H),7.39(d,J=8.4Hz,1H),7.10(d,J=8.6Hz,1H),7.03(dd,J=7.5,2.7Hz,1H),6.92-6.66(m,2H),6.16-6.06 (m,1H),5.74-5.59(m,1H),4.85-4.68(m,1H),4.62-4.24(m,1H),4.23-4.01(m,1H),3.88-3.36(m,1H),3.27-3. 01(m,1H),2.42-2.27(m,1H),2.23(s,3H),2.23-2.17(m,1H),2.15(s,3H),2.03-1.96(m,1H),1.69-1.54(m,1H). LC-MS m / z:(pos)553.55([M+H] + ).

[0171] Example 2: (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-1- Synthesis of (1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (2)

[0172]

[0173] (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide hydrochloride (5). HATU (151 mg, 0.397 mmol) and DIPEA (115 μL, 0.662 mmol) were added to a solution of acid 1 (120 mg, 0.331 mmol) in DMF (3 mL). Then aniline 4 (88 mg, 0.364 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with EtOAc, washed with H2O 3x and brine, dried on Na2SO3, filtered, and concentrated by rotary evaporation. The crude residue was dissolved in 4 M HCl (3 mL) in dioxane and stirred for 1 hour. The reaction mixture was concentrated to provide crude intermediate amine 5 as a light orange solid.

[0174] (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (2). Triethylamine (Et3N, 140 μL, 0.99 mmol) and acryloyl chloride (40 μL, 0.497 mmol) were added to a solution of intermediate amine 5 (160 mg, 0.331 mmol) in CH2Cl2 (3 mL, 0.11 M) at 0 °C. After stirring at 0 °C for 15 min, the reaction mixture was heated to room temperature, concentrated by rotary evaporation, and purified by preparative HPLC to give (2) as a white solid (59 mg, yield of 33% from the three steps starting from 1).

[0175] 1 H NMR(500MHz,DMSO-d6)δ10.49-10.25(m,1H),8.94(d,J=7.5Hz,1H),8.49(s,1H),8.38(s,1H),8.29(s,1H), 8.17(s,1H),7.91(s,1H),7.80(d,J=8.5Hz,1H),7.22(d,J=8.5Hz,1H),7.02(dd,J=7.5,2.6Hz,1H),6.93-6 .73(m,2H),6.19-6.05(m,1H),5.75-5.60(m,1H),4.90-4.49(m,2H),4.33-4.13(m,1H),4.11-3.80(m,1H), 3.51-3.33(m,1H),3.30-3.07(m,1H),2.46-2.26(m,1H),2.20(s,3H),2.02-1.85(m,1H),1.71-1.52(m,1H). LC-MS m / z:(pos)539.57([M+H] + ).

[0176] Example 3: (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-1-(1- Synthesis of Acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

[0177]

[0178] (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide hydrochloride (7). HATU (189 mg, 0.497 mmol) and DIPEA (144 μL, 0.828 mmol) were added to a solution of acid 1 (150 mg, 0.414 mmol) in DMF (4 mL). Then aniline 6 (119 mg, 0.455 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with EtOAc, washed with H2O3x and brine, dried on Na2SO3, filtered, and concentrated by rotary evaporation. The crude residue was dissolved in 4 M HCl (3 mL) in dioxane and stirred for 1 hour. The reaction mixture was concentrated to provide crude intermediate amine 7 as a light orange solid.

[0179] (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (3). Triethylamine (Et3N, 173 μL, 1.24 mmol) and acryloyl chloride (50 μL, 0.62 mmol) were added to a solution of intermediate amine 7 (200 mg, 0.396 mmol) in CH2Cl2 (3 mL, 0.13 M) at 0 °C. After stirring at 0 °C for 15 min, the reaction mixture was heated to room temperature, concentrated by rotary evaporation, and purified by preparative HPLC to give (3) as a white solid (39 mg, yield of 17% from the three steps starting from 1).

[0180] 1H NMR (500MHz, DMSO-d6) δ10.76-10.47(m,1H),8.97(d,J=7.5Hz,1H),8.50-8.34(m,2H),8.30(s,1H),8.25(s,1H) ),8.20(s,1H),7.96(dd,J=8.9,2.3Hz,1H),7.48(d,J=8.7Hz,1H),7.07(dd,J=7.5,2.6Hz,1H),6.96(d,J=2.4Hz ,1H),6.93-6.70(m,1H),6.13(t,1H),5.68(dd,1H),4.86-4.71(m,1H),4.62-4.25(m,1H),4.25-4.03(m,1H),3. 91-3.39(m,1H),3.27-3.01(m,1H),2.46-2.27(m,1H),2.26-2.12(m,2H),2.01-1.85(m,1H),1.74-1.53(m,1H). LC-MS m / z:(pos)559.51([M+H] + ).

[0181] Example 4: HER2 inhibitory activity

[0182] The IC50 of the compounds provided in this article 50 The values ​​were measured against kinases in Ba / F3 cells.

[0183] Tables 1 and 2 summarize the compounds disclosed in this paper and TAS0728, namely...

[0184]

[0185] Data compared to (commercially available HER2 inhibitors).

[0186] The activity of the representative compounds in this application in inhibiting EGFR and HER2 was demonstrated by MTS assay in Ba / F3 cells. Testing was conducted. For assays using Ba / F3 cells, 3000 cells were seeded in each well of a 96-well plate and exposed to the designated compound at concentrations from 3.3 to 10 μM for 72 hours. Data in Tables 1 and 2 show that the compounds of the present invention, particularly compounds 1-3, are highly effective and selective inhibitors of Her2 and Her2 20 insertion mutants compared to EGFR wild-type and EGFR mutants.

[0187] Table 1. IC50 of compounds 1-3 50 (μM)Ba / F3 data

[0188]

[0189]

[0190] Table 2. IC50 of compound 4-11 50 (μM)Ba / F3 data

[0191]

[0192] All patent and non-patent publications represent the technical skill of a person skilled in the art to which this disclosure pertains. All such publications are incorporated herein by reference to the extent that each individual publication is specifically and individually designated as incorporated by reference.

[0193] While this disclosure has been described herein with reference to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of this disclosure. Therefore, it should be understood that various modifications can be made to the illustrative embodiments, and other arrangements can be designed without departing from the spirit and scope of this disclosure as defined by the appended claims.

Claims

1. A compound having a structure represented by the formula Ia, Ib, Ic, Id, Ie, If, Ig, or Ih: (It)、 (Ib)、 (Ic)、 (Id)、 (Ie)、 (If)、 (Ig), or (Ih), Or their pharmaceutically acceptable salts or stereoisomers. Each R1 is independently either methyl or chlorine; and n is 1 or 2.

2. The compound of claim 1, wherein R1 is a methyl group.

3. The compound of claim 1, wherein R1 is chlorine.

4. The compound of claim 1, wherein n is 1.

5. The compound of claim 1, wherein n is 2.

6. The compound of claim 1, wherein: 、 、 、 、 、 、 、 、 or , Or their pharmaceutically acceptable salts or stereoisomers.

7. A pharmaceutical composition comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer as described in any one of claims 1 to 6, and a pharmaceutically acceptable carrier.

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