Potent and selective inhibitors of HER2

Abstract

Disclosed are compounds and pharmaceutically acceptable salts and stereoisomers thereof that are potent and selective inhibitors of HER2. Also disclosed are pharmaceutical compositions containing them and methods of making and using the compounds for treating HER2-associated diseases and disorders.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Application No. 63 / 087,517, filed on 5 October 2020, and U.S. Provisional Application No. 63 / 232,450, filed on 12 August 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Mutations in the human epidermal growth factor receptor 2 (HER2, ERBB2) have been identified as oncogenic factors. They occur in 2% to 3% of non-small cell lung cancer (NSCLC) cases (Shigematsu 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 are as high as 6.7% in EGFR / ALK / ROS1 triple-negative NSCLC (Li et al., BMC Cancer, 16(1):828 (2016)). In addition, amplification of the HER2 gene, overexpression of the HER2 protein, or both occur in approximately 15-25% of breast cancers classified as HER2-positive (Slamon et al., Science, 235(4785):177-182(1987); Slamon et al., Science, 244(4905):707-712(1989)). HER2 mutations most commonly consist of exon 20 insertion mutations (Shigematsu et al., Cancer Res., 65(5):1642-1646(2005)). The most frequent HER2 exon 20 insertion mutation is a 12-base pair in-frame insertion YVMA (p.A775_G776insYVMA), which leads to 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) for HER2-mutated NSCLC patients has been 1.6–1.9 years from stage IV diagnosis (Kris et al., Jama-J.Am.Med.Assoc., 311(19):1998–2006 (2014)).Several patient reports and series reports on HER2-targeted drugs in HER2-mutated NSCLC patients, including afatinib, dacomitinib, neratinib, and trastuzumab, 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. Oncol., 32(2):68-75(2014)); Mazieres et al., Ann. Oncol., 27(2):281-286(2016)). Therefore, chemotherapy remains the main strategy for this patient population (Eng et al., Lung Cancer, 99:53-56(2016)).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] Compounds that are active against HER2 mutations are needed because they may have extended utility in treating tumors containing such mutations. [Means for solving the problem]

[0006] A first aspect of this disclosure is a compound represented by the structure of formula (I): [ka] (In the formula, R1, R2, R3, X, m, n, and A are 、 This relates to a substance as defined herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0007] 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.

[0008] Further aspects of this disclosure relate to methods for treating diseases or disorders characterized by or mediated by abnormal human epidermal growth factor receptor 2 (HER2) activity.

[0009] In some embodiments, the disease or disorder 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.

[0010] As demonstrated in the examples, the compounds of this disclosure are potent and selective inhibitors of HER2. [Modes for carrying out the invention]

[0011] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the subject matter of this specification pertains. Where used herein and in the appended claims, unless otherwise specified, the following terms have the meanings provided for the convenience of understanding this disclosure.

[0012] As used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple subjects unless the context clearly indicates otherwise. For example, a reference to "a composition" includes mixtures of two or more such compositions, and a reference to "an inhibitor" includes mixtures of two or more such inhibitors, and so on.

[0013] Unless otherwise stated, the term “approximately” means within 10% (e.g., within 5%, 2%, or 1%) of the specific value modified by the term “approximately.”

[0014] The transitional term "comprising," which is synonymous with "including," "containing," or "characterized by," is comprehensive 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 is the minimum number of heteroatoms. In contrast, the transitional phrase "consisting of" excludes any elements, steps, or components not specified in the claims. The transitional phrase "essentially consisting of" limits the claims to the specified materials or steps of the claimed compound "and not substantially affect the basic and novel features(s)."

[0015] With respect to the compounds disclosed herein, and to the extent that the following terms are used herein to further illustrate them, the following definitions apply:

[0016] As used herein, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon radical. In one embodiment, the alkyl radical is C1-C 18 It is a group. In other embodiments, alkyl radicals are C0-C6, C0-C5, C0-C3, C1-C 12 These are C1-C8, C1-C6, C1-C5, C1-C4, or C1-C3 groups (C0 alkyl refers to a bond). Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, i-propyl, 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.

[0017] As used herein, the term "alkylene" refers to a linear or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, unsaturated, and having 1 to 12 carbon atoms, which links the rest of the molecule to a radical group, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain can be bonded to the rest of the molecule via single bonds and to the radical group via single bonds. In some embodiments, the alkylene group contains 1 to 8 carbon atoms (C1-C8 alkylene). In other embodiments, the alkylene group contains 1 to 5 carbon atoms (C1-C5 alkylene). In other embodiments, the alkylene group contains 1 to 4 carbon atoms (C1-C4 alkylene). In other embodiments, the alkylene group contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, the alkylene group contains 1 to 2 carbon atoms (C1-C2 alkylene). In other embodiments, the alkylene group contains one carbon atom (C1 alkylene).

[0018] As used herein, the term “alkenyl” refers to a monovalent hydrocarbon radical, either linear or branched, having at least one carbon-carbon double bond. Alkenyls include radicals having “cis” and “trans” directions, or alternatively, “E” and “Z” directions. For example, an alkenyl radical is C2-C 18 It is a group. In other embodiments, the alkenyl radical is C2-C 12 , C2-C 10 These are C2-C8, C2-C6, or C2-C3 groups. Examples include ethenyl or vinyl, propa-1-enyl, propa-2-enyl, 2-methylpropa-1-enyl, buta-1-enyl, buta-2-enyl, buta-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl.

[0019] As used herein, the term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. In one example, an alkynyl radical is a C2-C 18 group. In other examples, an alkynyl radical is C2-C 12 , C2-C 10 , C2-C8, C2-C6 or C2-C3. Examples include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, and but-3-ynyl.

[0020] As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group as defined above to which an oxygen radical is attached and which is the point of attachment. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, etc. "Ether" is two hydrocarbyl groups covalently bonded by oxygen. Thus, the substituents of the alkyl that make it an ether can be alkoxyl, such as those that can be represented by one of -O-alkyl, -O-alkenyl, and O-alkynyl, or are similar to alkoxyl.

[0021] As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine, or iodine.

[0022] As used herein, the term "cyclic group" broadly refers to any group used alone or as part of a larger moiety, including saturated, partially saturated, or aromatic ring systems, such as carbocyclic groups (cycloalkyl, cycloalkenyl), heterocyclic groups (heterocycloalkyl, heterocycloalkenyl), aryl and heteroaryl groups. The cyclic group can have one or more (e.g., fused) ring systems. Thus, for example, the cyclic group can include one or more carbocyclic groups, heterocyclic groups, aryl groups or heteroaryl groups.

[0023] As used herein, the term “carbocyclic” (or “carbocyclyl”) refers to a group used alone or as part of a larger part, and includes saturated, partially unsaturated, or aromatic ring systems having 3 to 20 carbon atoms, either alone or as part of a larger part (e.g., alkyl carbocyclic groups). The term “carbocyclyl” includes monocyclic, dicyclic, tricyclic, fused, bridging, and spirocyclic systems, as well as combinations thereof. In one embodiment, a carbocyclyl has 3 to 15 carbon atoms (C3-C3-C3). 15 ) contains. In one embodiment, carbocyclyl has 3 to 12 carbon atoms (C3-C 12 ) contains. In another embodiment, carbocyclyl is C3-C8, C3-C 10 Or C5-C 10 In another embodiment, the carbocyclyl comprises a monocyclic ring of C3-C8, C3-C6, or C5-C6. In some embodiments, the carbocyclyl comprises a bicyclic ring of C7-C 12 It includes. In another embodiment, carbocyclyl is C5-C as a spirosystem. 12Includes. Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, perduteriocyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl. Bicyclic carbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spirocarbocyclyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane. The term “carbocyclyl” includes aryl ring systems as defined herein. The term carbocycline also includes cycloalkyl rings (e.g., saturated or partially unsaturated monocyclic, dicyclic, or spirocarbocyclines). The term “carbocyclic group” also includes carbocyclic groups fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., aryl or heterocyclic) whose radicals or bonds are located on the carbocyclic ring.

[0024] Therefore, the term "carbocyclic formula" also means, when used herein, formula --R c -Carbocyclyl (in the formula, R c The term carbocyclic formula also includes carbocyclylalkyl groups, which refer to the group of an alkylene chain. The term carbocyclic formula also refers to the formula --O--R as used herein. c -Carbocyclyl (in the formula, R c This also includes carbocyclylalkyl groups, which refer to groups bonded via the oxygen atom of an alkylene chain.

[0025] As used herein, the terms “aryl” (e.g., “aralkyl” where the terminal carbon atom on an alkyl group is the bond site, e.g., a benzyl group), “aralkoxy” where the oxygen atom is the bond site, or “aloxyalkyl” where the bond site is on an aryl group), used alone or as part of a larger part, refer to a group comprising a monocyclic, bicyclic, or tricyclic carbocyclic system including a fused ring, wherein at least one ring in the system is aromatic. In some embodiments, the aralkoxy group is a benzoxy group. The term “aryl” may be used interchangeably with the term “aryl ring.” In one embodiment, aryl comprises a group having 6 to 18 carbon atoms. In another embodiment, aryl comprises a group having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthrasyl, biphenyl, phenantrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, naphthilidinyl, etc., which may be substituted or independently substituted by one or more substituents as described herein. A particular aryl is phenyl. In some embodiments, the aryl group includes an aryl ring fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., carbocyclic or heterocyclic) whose radical or bond site is located on the aryl ring.

[0026] Therefore, the term aryl is defined as in the formula --R, as disclosed above. c -aryl(in the formula, R) c The term aryl also includes aralkyl groups (e.g., benzyl) that refer to groups of alkylene chains such as methylene or ethylene. In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl also refers to the formula --O--R as used herein. c --aryl (in the formula, R c This includes aralkoxy groups, which refer to groups bonded via an oxygen atom of an alkylene chain (such as methylene or ethylene).

[0027] As used herein, the term “heterocyclyl” refers to a “carbocyclyl,” used alone or as part of a larger part, and includes saturated, partially unsaturated, or aromatic ring systems in which one or more (e.g., one, two, three, or four) carbon atoms are replaced by heteroatoms (e.g., O, N, N(O), S, S(O), or S(O)2). The term “heterocyclyl” includes monocyclic, dicyclic, tricyclic, fused, bridging, and spirocyclic systems, as well as combinations thereof. In some embodiments, heterocyclyl refers to a 3- to 15-membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a 3- to 12-membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a saturated ring system, such as a 3- to 12-membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a heteroaryl ring system, such as a 5- to 14-membered heteroaryl ring system. The term "heterocyclyl" also includes C3-C8 heterocycloalkyls, which are saturated or partially unsaturated monocyclic, dicyclic, or spirocyclic systems containing 3 to 8 carbon atoms and one or more (1, 2, 3, or 4) heteroatoms.

[0028] In some embodiments, the heterocyclyl group comprises 3 to 12 ring atoms and includes monocyclic, dicyclic, tricyclic, and spirocyclic systems, where the ring atoms are carbon and 1 to 5 ring atoms are heteroatoms such as nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl comprises a 3 to 7-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl comprises a 4 to 6-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl comprises a 3-membered monocyclic ring. In some embodiments, the heterocyclyl comprises a 4-membered monocyclic ring. In some embodiments, the heterocyclyl comprises a 5 to 6-membered monocyclic ring. In some embodiments, the heterocyclyl group comprises 0 to 3 double bonds. In any of the embodiments described above, the heterocyclyl comprises 1, 2, 3, or 4 heteroatoms. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may be optionally quaternized (e.g., [NR4]). + Cl - [NR4] + OH -Typical examples of heterocyclyls include oxyranil, azilidinil, thiranil, azetidinil, oxetanil, thietanil, 1,2-dithietanil, 1,3-dithietanil, pyrrolidinil, dihydro-1H-pyrrolyl, dihydrofuranil, tetrahydropyranil, dihydrothienyl, tetrahydrothienyl, imidazolidinil, piperidinil, piperazinil, morpholinil, thiomorpholinil, 1,1-dioxo-thiomorpholinil, dihydropyranil, tetrahydropyranil, hexahydrothiopyranil, hexahydropyrimidinil, oxadi Nanyl, thiadinyl, thioxanil, homopiperazinil, homopiperidinil, azepanil, oxepanil, thiepanil, oxazepinyl, oxazepanil, diazepanil, 1,4-diazepanil, diazepinyl, thiazepinyl, thiazepanil, tetrahydrothiopyranil, oxazolidinil, thiazolidinil, isothiazolidinil, 1,1-dioxoisothiazolidinol, oxazolidinol, imidazolidinol, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo [d]Imidazolyl, 1,6-dihydroimidazole [4,5-d]pyrrolo [2,3-b]pyridinyl, thiadinyl, thiophenyl, oxazinyl, thiadiadinyl, oxadiadinyl, dithiadinyl, dioxazinyl, oxathiadinyl, thiatriazinyl, oxatriazinyl, dithiadiadinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinil, 2-pyrrolinil, 3-pyrrolinil, indolinyl, thiapyranil, 2H-pyranil, 4H-pyranil, dioxanil, 1,3-dioxolanil, pyrazolinil, py Lazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperadinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1] Octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azabicyclo[4.5]decane-2-onyl, azaspiro[5.5] Examples include undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranyl. Examples of five-membered heterocyclyls containing a sulfur or oxygen atom and 1 to 3 nitrogen atoms include thiazolyls containing thiazole-2-yl and thiazole-2-yl N-oxide, thiadiazolyls containing 1,3,4-thiadiazole-5-yl and 1,2,4-thiadiazole-5-yl, oxazoles such as oxazole-2-yl, and oxadiazoles such as 1,3,4-oxadiazole-5-yl and 1,2,4-oxadiazole-5-yl. Examples of five-membered heterocyclyl rings containing 2 to 4 nitrogen atoms include imidazolyls such as imidazole-2-yl; triazolyls such as 1,3,4-triazole-5-yl; and tetrazolyls such as 1,2,3-triazole-5-yl, 1,2,4-triazole-5-yl, and 1H-tetrazole-5-yl. Representative examples of benzo-condensed five-membered heterocyclyls are benzoxazole-2-yl, benzthiazole-2-yl, and benzimidazole-2-yl. Exemplary six-membered heterocyclyls include one to three nitrogen atoms and optionally sulfur or oxygen atoms, e.g., pyridyls such as pyrido-2-yl, pyrido-3-yl, and pyrido-4-yl; pyrimidyls such as pyrimido-2-yl and pyrimido-4-yl; triazinyls such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyls, especially pyridazin-3-yl, and pyrazinyl. Pyridine N-oxide and pyridazine N-oxide, as well as pyridyl, pyrimido-2-yl, pyrimido-4-yl, pyridazinyl, and 1,3,4-triazin-2-yl groups, are yet another example of heterocyclyl groups. In some embodiments, the heterocyclic group comprises a heterocycle fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., a carbocyclic or heterocyclic ring), where the radical or bond site is located on the heterocycle, and in some embodiments, the bond site is a heteroatom contained within the heterocycle.

[0029] Therefore, as used herein, the term "heterocyclic" refers to a heterocyclyl group that contains at least one nitrogen atom and whose bonding site to the rest of the molecule of the heterocyclyl group is via the nitrogen atom in the heterocyclyl group, and includes N-heterocyclyl groups. Representative examples of N-heterocyclyl groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. The term "heterocyclic" also, as used herein, refers to a heterocyclyl group that contains at least one heteroatom and includes C-heterocyclyl groups where the bonding site to the rest of the molecule of the heterocyclyl group is via the carbon atom in the heterocyclyl group. Representative examples of C-heterocyclyl radicals include 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl. The term "heterocyclic algebra" is also used, as disclosed above, in the formula --R c -heterocycline (wherein R is R in the formula) c The term heterocyclic formula also refers to the group of an alkylene chain, encompassing heterocyclylalkyl groups. c -heterocycline (wherein R is R in the formula) c This includes heterocyclylalkoxy groups, which refer to radicals bonded via the oxygen atom of an alkylene chain.

[0030] As used herein, the terms “heteroaryl” (e.g., “heteroarylalkyl” (including “heteroarylalkyl”)) or “heteroarylalkoxy” (including “heteroarylcoxy”), used alone or as part of a larger part, refer to a monocyclic, bicyclic, or tricyclic ring system having 5 to 14 ring atoms, with at least one ring being aromatic and containing at least one heteroatom. In one embodiment, a heteroaryl comprises a 5- to 6-membered monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. Typical examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, imidazopyridyl, pyrazinyl, pyridadinyl, triazinyl, tetradinyl, tetrazolo[1,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, and benzoxazolyl. Examples include furyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazole-2-yl, 1,3,4-triazole-5-yl, 1,3-oxazole-2-yl, 1,3,4-oxadiazole-5-yl, 1,2,4-oxadiazole-5-yl, 1,3,4-thiadiazole-5-yl, 1H-tetrazole-5-yl, 1,2,3-triazole-5-yl, and pyrido-2-yl N-oxide. The term "heteroaryl" also includes groups in which a heteroaryl is condensed on one or more cyclic (e.g., carbocyclyl or heterocyclyl) rings, and whose radical or bond site is located on the heteroaryl ring.Non-limiting examples include indolyl, indolidinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. Heteroaryl groups can be monocyclic, bicyclic, or tricyclic. In some embodiments, the heteroaryl group comprises a heteroaryl ring fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., a carbocyclic or heterocyclic ring) where the radical or bond site is located on the heteroaryl ring, and in some embodiments, the bond site is a heteroatom contained in a heterocyclic ring.

[0031] Therefore, as used herein, the term heteroaryl encompasses N-heteroaryl groups, which refer to the heteroaryl group defined above, having at least one nitrogen atom and whose bonding site to the rest of the molecule is via a nitrogen atom in the heteroaryl group. The term "heteroaryl" also encompasses C-heteroaryl groups, which refer to the heteroaryl group defined above and whose bonding site to the rest of the molecule is via a carbon atom in the heteroaryl group. The term heteroaryl also encompasses formula --R c -heteroaryl(wherein R) c The term "heteroaryl" also includes heteroarylalkyl groups, where is an alkylene chain as defined above. c -heteroaryl(wherein R) c This includes heteroaralkoxy (or heteroarylalkoxy) groups, which refer to groups bonded via the oxygen atom of an alkylene chain (as defined above).

[0032] Unless otherwise stated, and to the extent not further defined for any particular group(s), any group described herein may be substituted or unsubstituted. As used herein, the term “substituted” refers to all permissible substituents, with the implicit conditions that such substitution conforms to the permissible valencies of the substituted atom and substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation by recombination, cyclization, removal, etc. Typical substituents include halogens, hydroxyl groups, and any other organic groups containing any number of carbon atoms, e.g., 1 to 14 carbon atoms, which may include one or more (e.g., 1, 2, 3, or 4) heteroatoms such as oxygen, sulfur, and nitrogen grouped in linear, branched, or cyclic structural forms.

[0033] Unless otherwise disclosed for any specific group(s), typical examples of substituents include alkyl, substituted alkyl (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), alkoxy (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), substituted alkoxy (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), Haloalkyl (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), cyclic (e.g., C3-C 12 , C5-C6), substitution rings (e.g., C3-C 12 , C5-C6), carbon ring (e.g., C3-C 12 , C5-C6), substituted carbon rings (e.g., C3-C 12 , C5-C6), complex algebras (e.g., C3-C 12 , C5-C6), substitution complex algebras (e.g., C3-C 12C5-C6), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or phenyl), heteroaryl (e.g., pyridyl or pyrimidyl), substituted heteroaryl (e.g., substituted pyridyl or pyrimidyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxyl, aryloxy (e.g., C6-C6) 12 , C6), substituted aryloxy (e.g., C6-C 12 , C6), alkylthio (e.g., C1-C6), substituted alkylthio (e.g., C1-C6), arylthio (e.g., C6-C) 12 , C6), substitution arylthio (e.g., C6-C 12 Examples include 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 acids, and peptide groups.

[0034] In one embodiment, the compound represented by formula (I) is used herein. [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, During the ceremony, X either does not exist, or is -CH2-, -O-, or C(O). A is either absent, a naphthyl, a five-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, or a condensed heterobicyclyl having a five- or six-membered ring and containing 1 to 4 heteroatoms selected from N, O, and S, and A optionally contains one or more R A Replaced by, Each R AThese are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, hydroxyl, cyano, nitro, amino, C1-C6 alkylamino, or di-C1-C6 alkylamino. Each R1 is independently a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamide, halo, hydroxyl, cyano, nitro, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C6 carbocyclyl, or a 5-membered or 6-membered heterocyclyl, and R1 is optionally composed of one or more R A It is replaced by, Alternatively, two R1 groups, together with the atom to which they are bonded, form a 5-6 membered carbocyclyl or heterocyclyl. R2 is [ka] And, R3 is hydrogen, fluoro, or methyl. m is either 1 or 2. A compound is provided in which n is 0, 1, or 2.

[0035] In some embodiments, X does not exist.

[0036] In some embodiments, X is -CH2-.

[0037] In some embodiments, X is -O-.

[0038] In some embodiments, X is C(O).

[0039] In some embodiments, A optionally includes one or more R A It is naphthyl substituted with [another compound].

[0040] In some embodiments, A is a condensed heterobisicryl having 5-membered and 6-membered rings and containing 1 to 4 heteroatoms selected from N, O, and S, and A optionally contains 1 or more R A It has been replaced with.

[0041] In some embodiments, A is a condensed heterobisicryl comprising two 6-membered rings and containing 1 to 4 heteroatoms selected from N, O, and S, and A optionally contains 1 or more R A It has been replaced with.

[0042] In some embodiments, A is a 5-membered heterocycline containing 1 to 3 heteroatoms selected from N, O, and S, and optionally 1 or more R A It has been replaced with.

[0043] In some embodiments, A is [ka] Therefore, one or more R can be selected at will. A It has been replaced with.

[0044] In some embodiments, A is [ka] Therefore, one or more R can be selected at will. A It has been replaced with.

[0045] In some embodiments, A optionally includes one or more R A Replaced with [ka] That is the case.

[0046] In some embodiments, A is [ka] That is the case.

[0047] In some embodiments, A is [ka] Therefore, one or more R can be selected at will. A It has been replaced with.

[0048] In some embodiments, A optionally includes one or more R A Replaced with [ka] That is the case.

[0049] In some embodiments, A is [ka] That is the case.

[0050] In some embodiments, A is [ka] Therefore, one or more R can be selected at will. A It has been replaced with.

[0051] In some embodiments, A is [ka] Therefore, one or more R can be selected at will. A It has been replaced with.

[0052] In some embodiments, A is [ka] Therefore, one or more R can be selected at will. A It is replaced by

[0053] In some embodiments, A is [ka] Therefore, one or more R can be selected at will. A It is replaced by

[0054] In some embodiments, A is [ka] Therefore, one or more R can be selected at will. A It has been replaced with.

[0055] In some embodiments, A optionally includes one or more R A Replaced with [ka] That is the case.

[0056] In some embodiments, A optionally includes one or more R A Replaced with [ka] That is the case.

[0057] In some embodiments, A is [ka] That is the case.

[0058] In some embodiments, A is [ka] That is the case.

[0059] In some embodiments, A optionally includes one or more R A Replaced with [ka] That is the case.

[0060] In some embodiments, A is [ka] That is the case.

[0061] In some embodiments, A is [ka] Therefore, one or more R can be selected at will. A It has been replaced with.

[0062] In some embodiments, A is [ka] That is the case.

[0063] In some embodiments, A is [ka] Therefore, one or more R can be selected at will. A It has been replaced with.

[0064] In some embodiments, R1 is independently a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamide, halo, cyano, di-C1-C6 alkylamino, C3-C6 carbocykyl, or a 5-membered or 6-membered heterocyclyl.

[0065] In some embodiments, R1 is independently methyl, ethyl, fluoro, chloro, bromo, methoxy, cyano, -OCHF2, -OCH2F, -NMe2, [ka] That is the case.

[0066] In some embodiments, R1 is methyl.

[0067] In some embodiments, R1 is chloroform.

[0068] In some embodiments, R1 is [ka] That is the case.

[0069] In some embodiments, the two R1 groups, together with the atom to which they are bonded, form a 5-6 membered carbocyclyl or heterocyclyl.

[0070] In some embodiments, the two R1 groups, together with the atom to which they are bonded, form a phenyl, pyridinyl, or dioxolane.

[0071] In some embodiments, R2 is [ka] That is the case.

[0072] In some embodiments, R3 is hydrogen.

[0073] In some embodiments, m is 2.

[0074] In some embodiments, n is 1.

[0075] In some embodiments, n is 2.

[0076] In some embodiments, compounds of formula I are: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0077] In some embodiments of formulas Ia to Ih, R1 is methyl.

[0078] In some embodiments of formulas Ia to Ih, R1 is chloro.

[0079] In some embodiments of formulas Ia to Ih, n is 1.

[0080] In some embodiments of formulas Ia to Ih, n is 2.

[0081] A typical compound of formula (I) has the following structure: [ka] [ka] Do you have, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0082] The compounds of this disclosure may be in the form of free acids or free bases, or pharmaceutically acceptable salts. As used herein, the term “pharmaceutically acceptable” in the context of salts means a salt of a compound that does not neutralize the biological activity or properties of the compound and is relatively non-toxic; that is, a salt of a compound can be administered to a subject without causing undesirable biological effects (such as dizziness or stomach upset) or interacting in an adverse manner with any other component of the composition containing it. The term “pharmaceutically acceptable salt” means a product obtained by reacting the compounds of this disclosure with a suitable acid or base. Examples of pharmaceutically acceptable salts of the compounds of this disclosure include salts derived from suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn, and Mn salts. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids, such as hydrochlorides, hydrobroms, hydroiodides, nitrates, sulfates, bisulfates, phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, pantothenates, vitalates, ascorbicates, succinates, maleates, gentisinates, fumarates, glucons, glucarons, sugarates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, 4-methylbenzenesulfons, or p-toluenesulfons. Certain compounds provided herein can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine, or metformin. Suitable basic salts include aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, or zinc salts.

[0083] The compounds of this disclosure may have at least one chiral center and, as used herein, may be in the form of stereoisomers encompassing all isomers of the individual compounds, differing only in the orientation of their atoms in space. The term “stereoisomer” includes enantiomeric isomers (enantiomers containing the (R-) or (S-) configuration of a compound), mixtures of enantiomeric isomers of a compound (physical mixtures of enantiomers, and racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of a compound, and isomers of a compound having two or more chiral centers that are not mirror images of each other (diastereoisomers). The chiral centers of a compound can undergo epimerization in vivo, and therefore, for these compounds, administration in the (R-) form is considered equivalent to administration in the (S-) form of the compound. Accordingly, the compounds of this disclosure may be prepared and used in the form of individual isomers and substantially free of other isomers, or in the form of mixtures of various isomers, e.g., racemic mixtures of stereoisomers.

[0084] In some embodiments, the compound is an isotopic derivative in that it has at least one desired isotopic substitution of an atom in an amount exceeding the natural abundance of the isotope, i.e., a concentrated amount. In one embodiment, the compound contains deuterium or multiple deuterium atoms. Deuterium, i.e. 2 Substitution with heavier isotopes such as 1H can offer certain therapeutic benefits derived from higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be advantageous in some situations.

[0085] The compounds of this disclosure can be prepared by crystallization under different conditions and may exist as one compound or a combination of polymorphs. For example, different polymorphs can be identified and / or prepared using different solvents or different mixtures of solvents for recrystallization by crystallizing at different temperatures or by using various cooling modes ranging from very rapid to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting the compound and subsequently cooling it gradually or rapidly. The presence of polymorphs may be determined by solid-state probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction and / or other known techniques.

[0086] In some embodiments, the pharmaceutical composition comprises a cocrystal of the compound of the present invention. The term "cocrystal," as used herein, refers to a stoichiometric multicomponent system comprising the compound and cocrystal form provided herein, wherein the compound and cocrystal form are linked by non-covalent interactions. The term "cocrystal form," as used herein, refers to a compound that can form intermolecular interactions with the compound provided herein and cocrystallize with it. Typical examples of cocrystal-forming compounds include benzoic acid, succinic acid, fumaric acid, glutaric acid, trans cinnamic acid, 2,5-dihydroxybenzoic acid, glycolic acid, trans-2-hexanoic acid, 2-hydroxycaproic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, suberic acid, picolinic acid, salicylic acid, maleic acid, saccharin, 4,4'-bipyridine p-aminosalitic acid, nicotinamide, urea, isonicotinamide, methyl-4-hydroxyphenic acid, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, hydroxyquinol, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone, etophylline, and phenobarbital.

[0087] Synthesis method In another aspect, the present disclosure relates to methods for preparing the compounds of the present invention, or pharmaceutically acceptable salts or stereoisomers thereof. Broadly speaking, the compounds of the present invention, or pharmaceutically acceptable salts or stereoisomers thereof, can be prepared by any method known to be applicable to the preparation of chemically related compounds. The compounds of the present disclosure will be better understood in relation to synthetic schemes illustrating non-limiting methods by which the compounds of the present disclosure can be prepared, as illustrated in various examples.

[0088] Pharmaceutical composition 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. The term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or vehicle suitable for administering the compound of the present disclosure to a mammal, as is known in the art. Suitable carriers may include, for example, liquids (both 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 that it is physiologically inert and compatible with the other components of the formulation and is not harmful to the subject or patient. Depending on the type of formulation, the composition may also include one or more pharmaceutically acceptable excipients.

[0089] In a broad sense, the compounds of this disclosure and their pharmaceutically acceptable salts or stereoisomers can be formulated into compositions of a given type according to conventional pharmaceutical practices such as mixing, dissolution, granulation, sugar-coated tablet manufacturing, polishing, emulsification, encapsulation, encapsulation, and compression processes (see, for example, Remington: The Science and Practice of Pharmacy (20th ed.), ed. ARGennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988-1999, Marcel Dekker, New York). The type of formulation depends on the mode of administration, which may include enteral (e.g., oral, buccal, sublingual, and rectal), parenteral (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im), and intrasternal injection or infusion techniques, intraocular, intra-arterial, intramedullary, intrathecal, intraventricular, percutaneous, intradermal, vaginal, intraperitoneal, mucosal, nasal, tracheal, bronchial, and inhalation) and topical (e.g., percutaneous). Generally, the most appropriate route of administration depends on various factors, including, for example, the properties 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 in that the compound can be administered relatively quickly, such as in single-dose treatments and / or in cases of acute conditions.

[0090] In some embodiments, the compound is formulated for oral or intravenous administration (e.g., systemic intravenous injection).

[0091] Accordingly, the compounds provided herein can be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, cachets, and suppositories), liquid compositions (e.g., solutions in which the compound is dissolved, suspensions in which solid particles of the compound are dispersed, 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 release, intermediate release, or sustained release.

[0092] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is a carrier such as sodium citrate or dicalcium phosphate, and a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, and d) crosslinked polymers (e.g., crosslinked polyvinylpyrrolidone (crospovidone), crosslinked carboxymethylcellulose). The solid is mixed with carriers such as sodium cellulose (croscarmellose sodium) starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption enhancers such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, 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 include a buffer. Similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings. They may also contain opacifying agents.

[0093] In some embodiments, the compounds provided herein can be formulated into hard or soft gelatin capsules. Typical excipients that may be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, anhydrous lactose, microcrystalline cellulose, and sodium croscarmellose. The gelatin shell may contain gelatin, titanium dioxide, iron oxide, and colorants.

[0094] Liquid dosage forms for oral administration include liquids, suspensions, emulsions, microemulsions, syrups, and elixirs. In addition to compounds, liquid dosage forms may 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 ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof. Oral compositions may also contain optional excipients such as wetting agents, suspending agents, colorants, sweeteners, flavoring agents, and fragrances.

[0095] Injectable preparations for parenteral administration may include sterile aqueous solutions or oily suspensions. They may be formulated according to standard techniques using suitable dispersants or wetting and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, USP, and isotonic sodium chloride solutions. Furthermore, sterile fixative oils are conventionally used as solvents or suspension media. For this purpose, any brand of fixative oil, including synthetic mono- or diglycerides, may be used. In addition, fatty acids such as oleic acid may be used in the preparation of injectable preparations. Injectable preparations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection medium before use. The effects of a compound can be prolonged by slowing its absorption, which can be achieved by using a liquid suspension or a crystalline or amorphous material with low water solubility. Longer absorption of a compound from a parenterally administered formulation can also be achieved by suspending the compound in an oily vehicle.

[0096] In certain embodiments, the compounds provided herein may be administered topically rather than systemically, for example, often in depot preparations or sustained-release formulations, by direct injection of the conjugate into an organ. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Injectable depot formulations are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer, such as polylactide-polyglycolide, poly(orthoester), and poly(anhydride). The release rate of the compound can be controlled by changing the ratio of the compound to the polymer and the properties of the particular polymer used. Depot injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with biological tissues. Furthermore, in other embodiments, the compound is delivered by a targeted drug delivery system, such as liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target an organ and are selectively taken up by the organ.

[0097] The composition may be formulated for buccal or sublingual administration, such as tablets, lozenges, and gels.

[0098] The compounds provided herein may be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosols, mists, or powders. The pharmaceutical compositions may be delivered in the form of aerosol spray presentation from a pressurized pack or nebulizer, 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 may be determined by providing a valve for delivering a measured amount. In some embodiments, capsules and cartridges containing gelatin for use in inhalers or injectors may be formulated, for example, containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0099] The compounds provided herein may be formulated for topical administration, which, when used herein, refers to intradermal administration by formulations applied to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions, and sprays.

[0100] Typical examples of carriers useful for formulating compounds for topical application include solvents (e.g., alcohols, polyalcohols, water), creams, lotions, ointments, oils, gypsum, liposomes, powders, emulsions, microemulsions, and buffer solutions (e.g., hypotonic or buffered saline). Creams can be formulated using saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmitoleic acid, cetyl, or oleyl alcohol. Creams may also contain nonionic surfactants such as polyoxy-40-stearate.

[0101] In some embodiments, topical formulations may also contain excipients, examples of which are penetration enhancers. These agents can preferably deliver pharmacologically active compounds through the stratum corneum to the epidermis or dermis with little or no systemic absorption. A wide variety of compounds have been evaluated for their effectiveness in enhancing the penetration rate of drugs through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which investigates 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 TK, Pfister WR, Yum SI (eds.), Interpharm Press Inc., Buffalo Grove, Ill (1997). Typical examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe vera gel), ethyl alcohol, isopropyl alcohol, octriphenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decyl methyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

[0102] Typical examples of other excipients that may be included in topical and other types of formulations (to the extent that they are compatible) include preservatives, antioxidants, humectants, emollients, buffers, solubilizers, skin protectants, and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens, and phenols. Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, 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 chloride, cyclodextrin, benzyl benzoate, lecithin, and polysorbate. Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0103] Transdermal formulations typically utilize transdermal delivery devices and transdermal delivery patches, where compounds are formulated in lipophilic emulsions or buffered aqueous solutions and dissolved and / or dispersed in polymers or adhesives. Patches can be constructed for continuous, pulsed, or on-demand delivery of pharmaceuticals. Transdermal delivery of compounds can be achieved by iontophoresis patches. Transdermal patches can provide controlled delivery of compounds by using a rate-controlling membrane or by delaying the absorption rate by trapping the compound within a polymer matrix or gel. Absorption can be increased using absorption enhancers, examples of which include absorbable, pharmaceutically acceptable solvents that help the compound pass through the skin.

[0104] Examples of ophthalmic preparations include eye drops.

[0105] Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retained enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone and PEG. Compositions for rectal or vaginal administration may also be formulated as suppositories, which can be prepared by mixing the compound with suitable non-irritating carriers and excipients such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository wax, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature, and therefore melt in the rectum or vaginal cavity to release the compound.

[0106] Dosage As used herein, the term “therapeutic dose” means the amount of the compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof that is effective in producing a desired therapeutic response in a patient suffering from a disease or disorder characterized by or mediated by abnormal human epidermal growth factor receptor 2 (Her2) activity. Accordingly, the term “therapeutic dose” includes the amount of the compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof that, when administered, induces a positive change in the disease or disorder being treated, or is sufficient to prevent the onset or progression of the disease or disorder, or to some extent alleviates one or more symptoms of the disease or disorder being treated in a subject, or inhibits the proliferation of diseased cells, or reduces the amount of HER2 in diseased cells.

[0107] The total daily dose of a compound and its method of use may be determined by the attending physician, for example, using sound medical judgment, in accordance with standard medical practice. The specific therapeutically effective dose for any particular subject depends on a variety of factors, including: the disease or disorder being treated and its severity (e.g., current condition); the activity of the compound used; the specific composition used; the subject's age, weight, general health, sex, and diet; the timing 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 Edition, McGraw-Hill Press, 155-173, 2001).

[0108] The compounds provided herein may be effective over a wide range of dosages. In some embodiments, the total daily dose (e.g., for human adults) may 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 yet other embodiments, about 10 to about 30 mg / day. Individual doses may be formulated to contain the desired dose depending on the number of times the compound is administered per day. For example, capsules may 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 may be administered in doses ranging from about 0.01 mg to about 200 mg / kg body weight / day. In some embodiments, doses of 0.1 to 100 mg, for example, 1 to 30 mg / kg body weight / day, may be effective with one or more doses per day. For example, suitable doses for oral administration may range from 1 to 30 mg / kg body weight / day, and suitable doses for intravenous administration may range from 1 to 10 mg / kg body weight / day.

[0109] How to use In some embodiments, the present disclosure relates to a method for treating a disease or disorder involving HER2, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need.

[0110] In a broad sense, diseases or disorders that may be suitable for treatment with the compounds of this disclosure involve HER2 activity or functionally abnormal HER2 activity compared to otherwise non-pathological conditions. A “disease” is generally considered a health condition of a subject in which the subject is unable to maintain homeostasis and, if the disease does not improve, the subject’s health continues to deteriorate. In contrast, a “disorder” in a subject is a health condition in which the subject is able to maintain homeostasis, but the subject’s health condition is less desirable than if the disorder were absent. Leaving a disorder untreated does not necessarily lead to a further deterioration of the subject’s health condition. In some embodiments, compounds of formula (I) may be useful in treating cell proliferation disorders and disorders (e.g., cancer or benign neoplasms). As used herein, the term “cell proliferation disorder or disorder” refers to a condition characterized by uncontrolled or abnormal cell proliferation, or both, including neoplasms, precancerous conditions, benign tumors, and noncancerous conditions such as cancer.

[0111] In some embodiments, the disease or disorder is characterized by or mediated by the activity of a HER2 mutation.

[0112] In some embodiments, the HER2 mutation is an exon 20 insertion mutation.

[0113] As used herein, the term “subject” (or “patient”) includes all members of the animal kingdom who are susceptible to or suffering from the disease or disorder described herein. In some embodiments, the subject is a mammal, e.g., human or non-human mammal. The method is also applicable to companion animals such as dogs and cats, as well as livestock such as cattle, horses, sheep, goats, and pigs, as well as other domesticated and wild animals. A subject who “needs” treatment according to this disclosure may “suffer from or be suspected of suffering from” a particular disease or disorder, and has been reliably diagnosed with, or otherwise may exhibit, a sufficient number of risk factors or a sufficient number or combination of signs or symptoms, to allow a medical professional to diagnose or suspect that the subject has the disease or disorder. Thus, subjects who have and are suspected of having a particular disease or disorder are not necessarily two different groups.

[0114] Examples of non-cancerous (e.g., proliferative) diseases or disorders that may be suitable for treatment with the compounds of this disclosure include inflammatory diseases and conditions, autoimmune diseases, neurodegenerative diseases, cardiac diseases, viral diseases, chronic and acute kidney diseases or injuries, metabolic diseases, and allergic and genetic disorders.

[0115] Representative examples of specific non-cancerous diseases and disorders include rheumatoid arthritis, alopecia areata, lymphoproliferative disorders, autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, anhidrotic ectodermal dysplasia, pure erythrocytic anemia, and idiopathic thrombocytopenia), cholecystitis, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, scleroderma, sepsis, septic shock, dacryoadenitis, cryopyrin-associated periodic syndromes (CAPS), endotoxic shock, endometritis, gram-negative sepsis, keratoconjunctivitis sicca, toxic shock syndrome, asthma, and adult conditions. Respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pneumonia, chronic graft rejection, hidradenitis suppurativa, inflammatory bowel disease, Crohn's disease, Behçet's syndrome, systemic lupus erythematosus, glomerulonephritis, multiple sclerosis, juvenile-onset diabetes mellitus, autoimmune uveoretinitis, autoimmune vasculitis, thyroiditis, Addison's disease, lichen planus, appendicitis, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, myasthenia gravis, immunoglobulin A nephropathy, Hashimoto's disease, Sjögren's syndrome, vitiligo, Wegener's granulomatosis, testicular sarcoma, autoimmune Ovarian oophoritis, sarcoidosis, rheumatic carditis, ankylosing spondylitis, Graves' disease, autoimmune thrombocytopenic purpura, psoriasis, psoriatic arthritis, eczema, herpetiform dermatitis, ulcerative colitis, pancreatic fibrosis, hepatitis, hepatic fibrosis, CD14-mediated sepsis, non-CD14-mediated sepsis, acute and chronic kidney disease, irritable bowel syndrome, fever, restenosis, cervicitis, stroke and ischemic injury, neurological trauma, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, congestive heart failure, acute coronary syndrome, cachexia, malaria, leprosy Diseases, leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendinitis, tenosynovitis, herniated disc syndrome, ruptured or prolapsed disc syndrome, osteopetrosis, sinusitis, thrombosis, pulmonary sarcosis, osteoporosis and other bone resorption diseases, fibromyalgia, AIDS, and other viral diseases, such as herpes zoster, herpes simplex virus type 1 or 2, influenza virus and cytomegalovirus, type 1 and type 2 diabetes, obesity, insulin resistance, diabetic retinopathy, 22q11.2-deletion syndrome, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, color blindness, cat-meow syndrome, Down syndrome, cystic fibrosis, Duchenne muscular dystrophy, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, Prader-Willi syndrome, Down syndrome, cystic fibrosis, Duchenne muscular dystrophy, hemophilia, Klinefelter syndrome These include neurofibromatosis, phenylketonuria, Prader-Willi syndrome, Turner syndrome, urea cycle disorders, thalassemia, otitis media, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, interstitial pneumonia, uveitis, polymyositis, proctitis, interstitial pulmonary fibrosis, dermatomyositis, arteriosclerosis, atherosclerosis, amyotrophic lateral sclerosis, antisocial disorder, varicose veins, vaginitis, depression, and sudden infant death syndrome.

[0116] In other embodiments, the method is intended for treating subjects having cancer. Generally, the compounds of the disclosure may be effective in treating cancer (solid tumors, including both primary and metastatic tumors), sarcomas, melanomas, and hematological malignancies such as leukemia, lymphoma, and multiple myeloma (cancers affecting the blood, including lymphocytes, bone marrow, and / or lymph nodes). This includes adult tumors / cancers and pediatric tumors / cancers. Cancers may be angiogenic tumors, tumors that are not yet substantially angiogenic, or non-angiogenic tumors.

[0117] Typical examples of cancer include adrenocortical carcinoma, AIDS-related cancers (e.g., Kaposi's disease and AIDS-related lymphoma), appendiceal cancer, childhood cancers (e.g., childhood cerebellar astrocytoma), basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, and urinary bladder cancer. Cancer), brain cancer (e.g., glioma and glioblastoma, e.g., brainstem glioma, pregnancy trophoblast tumor, glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, optic tract and hypothalamic glioma), breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, nervous system cancer (e.g., central nervous system cancer, central nervous system lymphoma), cervical cancer, chronic myeloproliferative disorders, colorectal cancer (e.g., colon cancer, rectal cancer), polycythemia vera, phosphorus Pa-type neoplasms, mycosis fungoides, Sézary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic cholangiocarcinoma, ocular cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal cancers (e.g., gastric cancer, small intestine cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST)), germ cell tumors, ovarian germ cell tumors, head and neck cancers, Hodgkin lymphoma, leukemia, lymphoma, multiple myeloma, hepatocellular carcinoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, pancreatic islet cell tumors (endocrine pancreas), renal cancer (e.g., Wilms' tumor) (e.g., clear cell renal cell carcinoma), liver cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), Waldenström hypergammaglobulinemia, melanoma, intraocular melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of unknown primary origin for the neck, multiple endocrine neoplasia (MEN), myelodysplastic syndrome, essential thrombocythemia, myelodysplastic-myeloproliferative syndrome, nasopharyngeal cancer, neuroblastoma, oral cancer (e.g., mouth cancer, lip cancer, oral cancer, tongue cancer, oropharyngeal cancer, pharyngeal cancer, laryngeal cancer), ovarian cancer (e.g., ovarian epithelium) Examples include cancer (ovarian germ cell tumors, low-grade ovarian tumors), pancreatic cancer, islet cell pancreatic cancer, paranasal sinus cancer and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal blastoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary 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 carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other parts of the urinary tract, urethral cancer, gestational trophoblastic tumor, vaginal cancer and vulvar cancer.

[0118] Sarcomas that may be treatable with the compounds of this disclosure include both soft tissue cancers and bone cancers, representative examples of which include osteosarcoma or osteogenic sarcoma (bone) (e.g., Ewing's sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesosarcoma or mesothelioma (under the membrane of the body cavity), fibrosarcoma (fibrous tissue), angiosarcoma or hemangioendothelioma (blood vessels), liposarcoma (adipose tissue), astrocytoma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primitive embryonic connective tissue), and mesenchymal or mixed mesodermal tumors (mixed connective tissue type).

[0119] In some embodiments, the methods of the present disclosure involve the treatment of subjects having proliferative disorders or impairments of the blood system, liver, brain, lungs, colon, pancreas, prostate, ovaries, breasts, skin, and endometrium.

[0120] As used herein, “cytoproliferative disorders or disorders of the hematological system” includes lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, spinal dysplasia, benign monoclonal gamma globulin disorders, polycythemia vera, chronic myeloid leukemia, primary myelofibrosis, and essential thrombocythemia. Therefore, typical examples of hematological cancers include multiple myeloma, lymphoma (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., diffuse large B-cell lymphoma (e.g., B-cell non-Hodgkin lymphoma selected from germinal center B-cell-like diffuse large B-cell lymphoma or activated B-cell-like diffuse large B-cell lymphoma)), Burkitt lymphoma / leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma Examples of lymphomas include lymphoma, lymphoplasmacytic lymphoma / Waldenstrem hypergammaglobulinemia, metastatic pancreatic adenocarcinoma, B-cell non-Hodgkin lymphoma selected from refractory B-cell non-Hodgkin lymphoma and relapsed B-cell non-Hodgkin lymphoma, pediatric lymphomas, and lymphocytic and cutaneous lymphomas, such as small lymphocytic lymphoma, pediatric 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, as well as leukemias, myeloid neoplasms and mast cell neoplasms.

[0121] As used herein, “proliferative disorders or disorders of the liver” include all forms of proliferative disorders affecting the liver. Proliferative disorders of the liver may include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and hepatoblastoma), precancerous or precancerous conditions of the liver, benign proliferation or lesions of the liver, and malignant proliferation or lesions of the liver, as well as metastatic lesions in other tissues and organs of the body. Proliferative disorders of the liver may include hepatic hyperplasia, metaplasia, and dysplasia.

[0122] As used herein, “cytoproliferative disorders or disorders of the brain” includes all forms of cytoproliferative disorders affecting the brain. Cytoproliferative disorders of the brain may include brain cancers (e.g., gliomas, glioblastomas, meningiomas, pituitary adenomas, vestibular schwannomas, and primitive neuroectodermal tumors (medulloblastomas)), precancerous or precancerous conditions of the brain, benign proliferations or lesions of the brain, as well as malignant proliferations or lesions of the brain, and metastatic lesions in tissues and organs of the body other than the brain. Cytoproliferative disorders of the brain may include brain hyperplasia, metaplasia, and dysplasia.

[0123] As used herein, “cellular proliferative disorders or disorders of the lung” include all forms of cellular proliferative disorders affecting lung cells. Cellular proliferative disorders of the lung include lung cancer, precancerous and precancerous conditions of the lung, benign proliferation or lesions of the lung, lung hyperplasia, metaplasia, and dysplasia, as well as metastatic lesions in tissues and organs of the body other than the lungs. Lung cancer includes all forms of lung cancer, e.g., malignant lung neoplasms, 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 may also include “scar carcinoma,” bronchoalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer also includes lung neoplasms that have histological and ultrastructural heterogeneity (e.g., mixed cell type). In some embodiments, the compounds of the present disclosure may be used to treat non-metastatic or metastatic lung cancer (e.g., NSCLC, ALK-positive NSCLC, NSCLC with ROS1 rearrangement, lung adenocarcinoma, and lung squamous cell carcinoma).

[0124] As used herein, “cytoproliferative disorders or disorders of the colon” ​​include all forms of cytoproliferative disorders affecting colonic cells, including colon cancer, precancerous or precancerous conditions of the colon, adenomatous polyps of the colon, and metachronous lesions of the colon. Colon cancer includes sporadic and hereditary colon cancer, malignant colonic neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma, and squamous cell carcinoma. Colon cancer may be associated with hereditary syndromes such as hereditary nonpolyposis colorectal cancer, adenomatous polyposis of the colon, MYH-associated polyposis, Gardner syndrome, Peutz-Jegers syndrome, Turcott syndrome, and juvenile polyposis. Cytoproliferative disorders of the colon may also be characterized by colonic hyperplasia, metaplasia, or dysplasia.

[0125] As used herein, “cytoproliferative disorders or disorders of the pancreas” includes all forms of cytoproliferative disorders affecting pancreatic cells. Pancreatic cytoproliferative disorders may include pancreatic cancer, precancerous or precancerous conditions of the pancreas, pancreatic hyperplasia, pancreatic dysplasia, benign proliferation or lesions of the pancreas, as well as malignant proliferation or lesions of the pancreas, and metastatic lesions in other tissues and organs of the body. Pancreatic cancer includes all forms of pancreatic cancer, including ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclastoid giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreaticblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma, as well as pancreatic neoplasms having histological and ultrastructural heterogeneity (e.g., mixed cell type).

[0126] As used herein, “proliferative disorders or conditions of the prostate” include all forms of proliferative disorders affecting the prostate. Proliferative disorders of the prostate may include prostate cancer, precancerous or precancerous conditions of the prostate, benign proliferative disorders or lesions of the prostate, as well as malignant proliferative disorders or lesions of the prostate, and metastatic lesions in other tissues and organs of the body. Proliferative disorders of the prostate may include prostatic hyperplasia, metaplasia, and dysplasia.

[0127] As used herein, “ovarian proliferative disorders or disorders” include all forms of cytoproliferative disorders affecting ovarian cells. Ovarian proliferative disorders may include ovarian precancerous or precancerous conditions, benign ovarian proliferation or lesions, ovarian cancer, and metastatic lesions in other tissues and organs of the body. Ovarian proliferative disorders may include ovarian hyperplasia, metaplasia, and dysplasia.

[0128] As used herein, “cytoproliferative disorders or disorders of the breast” include all forms of cytoproliferative disorders affecting breast cells. Cytoproliferative disorders of the breast may include breast cancer, precancerous or precancerous conditions of the breast, benign proliferations or lesions of the breast, and metastatic lesions of other tissues and organs of the body. Cytoproliferative disorders of the breast may include breast hyperplasia, metaplasia, and dysplasia.

[0129] As used herein, “Cellular proliferative disorders or disorders of the skin” includes all forms of cell proliferative disorders affecting skin cells. Cellular proliferative disorders may include precancerous or precancerous conditions of the skin, benign proliferations or lesions of the skin, melanoma, malignant melanoma or other malignant proliferations or lesions of the skin, and metastatic lesions in tissues and organs of the body other than the skin. Cellular proliferative disorders may include hyperplasia, metaplasia, and dysplasia of the skin.

[0130] As used herein, “endometrial proliferative disorders or disorders” include all forms of cytoproliferative disorders affecting endometrial cells. Endometrial proliferative disorders may include endometrial precancerous or precancerous conditions, benign endometrial proliferation or lesions, endometrial cancer, and metastatic lesions in other tissues and organs of the body. Endometrial proliferative disorders may include endometrial hyperplasia, metaplasia, and dysplasia.

[0131] In some embodiments, the compounds of the present disclosure may be used to treat breast cancer, ovarian cancer, gastrointestinal cancer, lung cancer, colon cancer, endometrial cancer, or thyroid cancer.

[0132] In some embodiments, the compounds of the present disclosure may be used to treat non-small cell lung cancer (NSCLC) or EGFR / ALK / ROS1 triple-negative NSCLC.

[0133] The compounds of this disclosure, as well as their pharmaceutically acceptable salts and stereoisomers, may be administered to patients, for example, cancer patients, as monotherapy or in combination therapy. The treatment may be “first-line / first-line,” i.e., as initial treatment for patients who have not previously received an anti-cancer treatment regimen, either alone or in combination with other treatments, or as “second-line,” as treatment for patients who have previously received an anti-cancer treatment regimen, or as “third-line,” “fourth-line,” etc., treatment, either alone or in combination with other treatments. The treatment may also be given to patients who have previously received treatment but have been unsuccessful or partially successful, but have become unresponsive or intolerant to a particular treatment. The treatment may also be given as adjuvant therapy, i.e., to prevent cancer recurrence in patients who currently do not have detectable disease, or after surgical removal of a tumor. Accordingly, in some embodiments, the compounds may be administered to patients who have previously received treatment such as chemotherapy, radioimmunotherapy, surgery, immunotherapy, radiotherapy, targeted therapy, or any combination thereof.

[0134] The methods of the present disclosure may involve administering the compound or pharmaceutical composition of the present invention to a patient in single doses or 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 about once every 8 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, involves at least one 28-day cycle including a 7-day off period following 3 weeks (21 days) of daily administration. In other embodiments, the compound may be administered twice daily (BID) over 2.5 days (total of 5 doses) or once daily (QD) over 2 days (total of 2 doses). In other embodiments, the compound may be administered once daily (QD) over 5 days.

[0135] Combination therapy The compounds of this disclosure and their pharmaceutically acceptable salts or stereoisomers may be used in combination with or concurrently with at least one other active agent, e.g., an anticancer agent or regimen, in the treatment of diseases and disorders. In this context, the terms “combined” and “concurrently” mean that the agents are administered simultaneously, including substantially simultaneous administration by the same or distinct dosage forms and by the same or different modes of administration, or sequential administration, e.g., as part of the same treatment regimen or in a sequential treatment regimen. Therefore, when administered sequentially, at the commencement of administration of the second agent, the first of the two agents may still be detectable at an effective concentration at the treatment site. The order and time intervals may be determined so that they can act together (e.g., synergistically to provide increased benefits than if they were administered separately). For example, the agents may be administered simultaneously or sequentially in any order at different times, but if not simultaneously, they may be administered at sufficiently close intervals to provide the desired therapeutic effect, which may be in a synergistic manner. Therefore, this term is not limited to administering the active agents exactly simultaneously.

[0136] In some embodiments, a treatment regimen may include administration of the compounds of the present disclosure or pharmaceutically acceptable salts or stereoisomers thereof in combination with one or more additional therapeutic agents known to be used to treat a disease or disorder (e.g., cancer). The dose of the additional anticancer agents may be the same as or less than known or recommended doses. See Hardman et al., eds., Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill, New York, 2001; Physician's Desk Reference, 60th ed., 2006. For example, anticancer agents that may be used in combination with the compounds of the present invention are known in the art. See, for example, U.S. Patent No. 9,101,622 (Section 5.2) and U.S. Patent No. 9,345,705 B2 (Columns 12-18). Typical examples of additional anticancer drugs and treatment regimens include radiotherapy, chemotherapeutic agents (e.g., mitotic inhibitors, angiogenesis inhibitors, antihormones, autophagy inhibitors, alkylating agents, insertive antibiotics, growth factor inhibitors, antiandrogens, signaling pathway inhibitors, microtubule inhibitors, platinum-coordinated complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulators, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapy.

[0137] In some embodiments, the compounds and additional anticancer agents provided in the present invention may be administered at intervals of less than 5 minutes, less than 30 minutes, less than 1 hour, about 1 hour, about 1 hour to about 2 hours, about 2 hours to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 5 hours, about 5 hours to about 6 hours, about 6 hours to about 7 hours, about 7 hours to about 8 hours, about 8 hours to about 9 hours, about 9 hours to about 10 hours, about 10 hours to about 11 hours, about 11 hours to about 12 hours, about 12 hours to 18 hours, 18 hours to 24 hours, 24 hours to 36 hours, 36 hours to 48 hours, 48 ​​hours to 52 hours, 52 hours to 60 hours, 60 hours to 72 hours, 72 hours to 84 hours, 84 hours to 96 hours, or 96 hours to 120 hours. Two or more anticancer drugs may be administered to the same patient during a single visit.

[0138] In some embodiments, the compounds and additional therapeutic agents (e.g., anticancer agents) of the present disclosure are administered cyclically. As an example in the context of cancer treatment, cycling therapy involves administering one anticancer agent over a period of time, followed by a second anticancer agent over a period of time, and repeating this sequence of administrations, i.e., cycle, in order to reduce the development of resistance to one or both anticancer agents, to avoid or reduce the side effects of one or both anticancer agents, and / or to improve the effectiveness of the therapy. In one example, cycling therapy involves administering a first anticancer agent over a period of time, followed by a second anticancer agent over a period of time, and then optionally a third anticancer agent over a period of time, and repeating this sequence of administrations, i.e., cycle, in order to reduce the development of resistance to one or both anticancer agents, to avoid or reduce the side effects of one or both anticancer agents, and / or to improve the effectiveness of the anticancer agent.

[0139] In some embodiments, depending on the specific cancer being treated, the compounds of the Disclosure include 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), altoretamine (e.g., ovarian cancer), and daunorubicin (e.g., acute myeloid leukemia (AML), acute lymphoblastic leukemia). Hematological cancers (ALL), chronic myeloid leukemia (CML), and Kaposi's sarcoma), trastuzumab (e.g., breast cancer, gastric cancer, and esophageal cancer), rituximab (e.g., non-Hodgkin lymphoma), cetuximab (e.g., colorectal cancer, metastatic non-small cell lung cancer, and trophoblastic cell carcinoma), pertuzumab (e.g., metastatic HER2-positive breast cancer), alemtuzumab (e.g., chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL), and T-cell lymphoma), panitumab (e.g., colorectal cancer), tamoxifen (e.g., breast cancer), fulvestrant (e.g., breast cancer) Letrozole (e.g., breast cancer), exemestane (e.g., breast cancer), azacitidine (e.g., myelodysplastic syndromes), mitomycin C (e.g., gastrointestinal cancer, anal cancer, and breast cancer), tagchinomycin (e.g., Wilms' tumor, rhabdomyosarcoma, Ewing's sarcoma, chorionic neoplasm, 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., It may be used in combination with at least one other anticancer agent such as 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 lymphoma, melanoma, Merkel cell carcinoma, non-small cell lung cancer, urothelial carcinoma, and squamous cell carcinoma of the head and neck), 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).

[0140] Pharmaceutical kit The composition can be assembled into a kit or pharmaceutical system. A kit or pharmaceutical system according to this aspect of the disclosure includes a carrier or package such as a box, carton, or tube, which tightly houses one or more containers such as vials, tubes, ampoules, or bottles, which contain the compound of the disclosure, or a pharmaceutical composition containing the compound and a pharmaceutically acceptable carrier, and the compound and carrier may be placed in the same or separate containers. The kit or pharmaceutical system of the disclosure may also include printed instructions for using the compound and composition.

[0141] These and other embodiments of the present disclosure will be further understood by considering the following embodiments, which are intended to illustrate certain embodiments but are not intended to limit the scope defined by the claims. [Examples]

[0142] Example 1: Synthesis of (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-2,3-dimethylphenyl)-1-(1-acryloylpiperidine-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (1) [ka] (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-2,3-dimethylphenyl)-4-amino-1-(piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide hydrochloride (3). To a solution of acid 1 (150 mg, 0.414 mmol) (PBLJ7889 from Pharmablock) in DMF (4 mL), azabenzotriazole tetramethyluronium hexafluorophosphate (HATU, 189 mg, 0.497 mmol) and N,N-diisopropylethylamine (DIPEA, 144 μL, 0.828 mmol) were added. Then, aniline 2 (116 mg, 0.455 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with dimethylammonium phosphate, washed with H2O 3x and brine, dried over Na2SO3, filtered, and concentrated by rotary evaporation. The crude residue was dissolved in 4M HCl in 3 mL of dioxane and stirred for 1 hour. The reaction mixture was concentrated to obtain crude intermediate amine 3 as a pale orange solid.

[0143] (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-2,3-dimethylphenyl)-1-(1-acryloylpiperidine-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (1). To a solution of intermediate amine 3 (200 mg, 0.374 mmol) in CH2Cl2 (3 mL, 0.12 M) at 0°C, triethylamine (Et3N, 160 μL, 1.12 mmol) and acryloyl chloride (45 μL, 0.561 mmol) were added. After stirring at 0°C for 15 minutes, the reaction mixture was heated to room temperature, concentrated by rotary evaporation, and purified by preparative HPLC to obtain compound (1) as a white solid (61 mg, 14%) over steps 1 to 3.

[0144] 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] + )

[0145] Example 2: Synthesis of (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-1-(1-acryloylpiperidine-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (2) [ka] (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-4-amino-1-(piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide hydrochloride (5). To a solution of acid 1 (120 mg, 0.331 mmol) in DMF (3 mL), HATU (151 mg, 0.397 mmol) and DIPEA (115 μL, 0.662 mmol) were added. 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 ELISA, washed with H2O 3x and brine, dried over Na2SO3, filtered, and concentrated by rotary evaporation. The crude residue was dissolved in 4 M HCl in dioxane (3 mL) and stirred for 1 hour. The reaction mixture was concentrated to obtain crude intermediate amine 5 as a pale orange solid.

[0146] (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-1-(1-acryloylpiperidine-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (2). To a solution of intermediate amine 5 (160 mg, 0.331 mmol) in CH2Cl2 (3 mL, 0.11 M) at 0°C, triethylamine (Et3N, 140 μL, 0.99 mmol) and acryloyl chloride (40 μL, 0.497 mmol) were added. After stirring at 0°C for 15 minutes, the reaction mixture was heated to room temperature, concentrated by rotary evaporation, and purified by preparative HPLC to obtain (2) as a white solid (59 mg, 33%) over three steps from 1).

[0147] 1H NMR(500MHz,DMSO-d6)δ 10.49-10.25(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),6.1 9-6.05(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] + )

[0148] Example 3: Synthesis of (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-chlorophenyl)-1-(1-acryloylpiperidine-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide [ka] (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-chlorophenyl)-4-amino-1-(piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide hydrochloride (7). To a solution of acid 1 (150 mg, 0.414 mmol) in DMF (4 mL), HATU (189 mg, 0.497 mmol) and DIPEA (144 μL, 0.828 mmol) were added. 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 ELISA, washed with H2O 3x and brine, dried over Na2SO3, filtered, and concentrated by rotary evaporation. The crude residue was dissolved in 4 M HCl in dioxane (3 mL) and stirred for 1 hour. The reaction mixture was concentrated to obtain crude intermediate amine 7 as a pale orange solid.

[0149] (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-chlorophenyl)-1-(1-acryloylpiperidine-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (3). To a solution of intermediate amine 7 (200 mg, 0.396 mmol) in CH2Cl2 (3 mL, 0.13 M) at 0°C, triethylamine (Et3N, 173 μL, 1.24 mmol) and acryloyl chloride (50 μL, 0.62 mmol) were added. After stirring at 0°C for 15 minutes, the reaction mixture was heated to room temperature, concentrated by rotary evaporation, and purified by preparative HPLC to obtain (3) as a white solid (39 mg, 17%) over steps 1 to 3.

[0150] 1 H NMR(500MHz,DMSO-d6)δ 10.76-10.47(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),6.93-6.7 0(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] + )

[0151] Example 4: HER2 inhibitory activity IC of the compounds provided herein 50The values ​​were measured against kinases in Ba / F3 cells. Tables 1 and 2 summarize the data for the compounds disclosed herein compared to the commercially available HER2 inhibitor TAS0728. [ka]

[0152] The activity of representative compounds of this application in inhibiting EGFR and HER2 was tested by the MTS assay (abcam®) of Ba / F3 cells. In the Ba / F3 cell assay, 3000 cells per well were seeded in a 96-well plate and exposed to the specified compounds at concentrations of 3.3–10 μM for 72 hours. The data in Tables 1 and 2 demonstrate that the compounds of the present invention, particularly compounds 1–3, are highly potent and selective inhibitors of Her2 and Her2 exon 20 insertion mutations rather than EGFR wt and EGFR mutations. [Table 1] [Table 2]

[0153] All patent and non-patent publications represent the level of skill of those skilled in the art to which this disclosure belongs. All such publications are incorporated herein by reference as if each individual publication were specifically and individually indicated as being incorporated by reference.

[0154] While the disclosures herein have been described with reference to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and uses of the disclosure. Therefore, it should be understood that numerous modifications to the exemplary embodiments and other configurations may be devised without departing from the spirit and scope of the disclosure as defined by the appended claims.

Claims

1. A compound having the structure represented by formula I, 【Chemistry 1】 or a pharmaceutically acceptable salt or stereoisomer thereof, During the ceremony, X does not exist, or -CH ２ -, -O-, or -C(O)-, A is a condensed heterocyclyl having a five-membered or six-membered ring containing no heteroatoms, or one to four heteroatoms selected from N, O, and S, or a five-membered heterocyclyl containing one to three heteroatoms selected from N, O, and S. Each R Ａ Independently, C １ -C ６ It is alkyl, Each R １ is independently C １ -C ６ alkyl, halo, or optionally C Ａ substituted with one or more Rs １ -C ６ alkylamide, n is 0, 1, or 2, wherein the compound or a pharmaceutically acceptable salt or stereoisomer thereof.

2. X does not exist, or -CH ２ - The compound according to claim 1.

3. The compound according to claim 1, wherein X is -O- or -C(O)-.

4. The compound according to claim 1, wherein A is a five-membered heterocycline comprising one to three heteroatoms selected from N, O, and S.

5. The compound according to claim 4, wherein A is a five-membered heterocycline containing 1 to 3 N atoms.

6. A, 【Chemistry 2】 A compound according to claim 5, selected from the above.

7. The compound according to claim 1, wherein A is a condensed heterobisicryl having a five-membered or six-membered ring containing one to four heteroatoms selected from N, O, and S.

8. A, 【Transformation 3】 A compound according to claim 7, selected from the above.

9. R １ However, independently, C １ -C ６ The compound according to claim 1, wherein it is alkyl or halo.

10. The compound according to claim 9, wherein n is 1 or 2. 【Request Item 11】 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 The compound according to claim 1, which is either or a pharmaceutically acceptable salt or stereoisomer thereof.

12. A pharmaceutical composition comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer described in any one of claims 1 to 11, and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 12 for use in a method of treating cancer characterized by or mediated by abnormal human epidermal growth factor receptor 2 (HER2) activity.

14. The pharmaceutical composition according to claim 13, wherein the cancer is breast cancer, ovarian cancer, gastrointestinal cancer, lung cancer, colon cancer, endometrial cancer, or thyroid cancer.

15. The pharmaceutical composition according to claim 13, wherein the cancer is non-small cell lung cancer (NSCLC).

Images