Indazole compounds

Abstract

Disclosed herein are compounds and methods for treating diseases and / or conditions associated with FGFR inhibition.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 356,585, filed on June 29, 2022, and U.S. Provisional Application No. 63 / 476,051, filed on December 19, 2022. The entire contents of each of these applications are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to indazole compounds useful for treating cancer, pharmaceutical compositions comprising one or more such indazole compounds, and methods of using such indazole compounds to treat cancer. Background Art

[0004] Kinase inhibitors have been used to block the activity of kinases and thereby treat cancer (e.g., by inhibiting the mitotic process). These kinase inhibitors are generally small molecules that target kinases to block the development, growth, or spread of cancer.

[0005] However, although various kinase inhibitors are known, there is still a need for selective inhibitors for the treatment of diseases such as hyperproliferative diseases, which offer one or more advantages over current compounds. These advantages include: improved activity and / or efficacy; a beneficial kinase selectivity profile, depending on the respective therapeutic need; an improved side effect profile, such as fewer undesirable side effects, lower side effect intensity or reduced (cyto)toxicity; improved targeting of mutant receptors in diseased cells; improved physicochemical properties, such as solubility / stability in water, body fluids and / or pharmaceutical formulations; improved pharmacokinetic properties, for example for reduced dosage or simpler dosing regimens; easier drug substance manufacturing, for example by shorter synthetic routes or easier purification. Summary of the invention

[0006] The compounds disclosed herein provide potent and selective small molecule kinase inhibitors.

[0007] In some aspects, the present disclosure relates to compounds of formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein:

[0010] X = O, S or NR;

[0011] R is H or C 1 -C 3 alkyl;

[0012] n = 1 or 2;

[0013] m = 1 or 2;

[0014] R 1 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, C 3 -C 6 Cycloalkyl, -C(O)NR 3 R 4 、-C(O)OR 3 , optionally substituted heterocycloalkyl or optionally substituted heteroaryl;

[0015] R 9 Is H or C 1 -C 3 alkyl;

[0016] R 2 is H, optionally substituted C 1 -C 6 Alkyl, -NR 3 R 4 、-OR 4a 、-P(O)R 4b R 4c 、-SO 2 R 3 or -C(O)NR 3 R 4 ;

[0017] R 3 Is H or C 1 -C 6 alkyl;

[0018] R 4 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, C 3 -C 5 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C(O)(CH 2 ) 2-3 OH or C(O)(CH 2 ) 0-3 NR 4d R 4e ;

[0019] or R 3 and R 4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C6 The substituent of alkoxy, F or OH is optionally substituted 3- to 6-membered heterocycloalkyl;

[0020] or R 3 and R 4 Together with the N atoms to which they are both attached, they form a 6- to 8-membered bridged heterocycloalkyl ring system;

[0021] R 4a is H, optionally substituted C 1 -C 6 Alkyl or C 3 -C 5 Cycloalkyl;

[0022] R 4b and R 4c Each is independently C 1 -C 6 Alkyl or -OC 1 -C 6 Alkyl; or R 4b and R 4c Together with the phosphorus atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring;

[0023] R 4d and R 4e Each independently is H or C 1 -C 6 Alkyl, or R 4d and R 4e Together with the nitrogen atoms to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring;

[0024] or R 1 and R 2 Together with the carbon atoms to which they are both attached, they form a 3- to 5-membered cycloalkyl ring;

[0025] Q 1 , Q 2 , Q 3 , Q 4 One or both of them are N, and the others are each independently CR 5a ;

[0026] R 5a H, halogen, -CN, -S(O) 2 C 1 -C 6 Alkyl, OCF 3 , OC 1 -C 3 Alkyl or C 1 -C 3 alkyl;

[0027] Q 5, Q 6 , Q 7 , Q 8 and Q 9 Each independently is N or CR 5 , where Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One of

[0028] One or both are N, and the rest are CR 5 ;

[0029] R 5 H, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or cycloalkyl;

[0030] R 6 It is C 1 -C 6 alkyl;

[0031] R 7 H, halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkoxy or -cycloalkyl; and

[0032] R 8 H, halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkoxy or -cycloalkyl.

[0033] In other aspects, compounds of formula (I) are those wherein:

[0034] X = O, S or NR;

[0035] R is H or C 1 -C 3 alkyl;

[0036] n = 1 or 2;

[0037] m = 1 or 2;

[0038] R 1 is H or optionally substituted C 1 -C 6 alkyl;

[0039] R 2 is H, optionally substituted C 1 -C6 Alkyl, -NR 3 R 4 、-OR 4a 、-P(O)R 4b R 4c 、-SO 2 R 3 or -C(O)NR 3 R 4 ;

[0040] R 9 It's H.

[0041] R 3 Is H or C 1 -C 6 alkyl;

[0042] R 4 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, C 3 -C 5 Cycloalkyl, 3- to 6-membered heterocycloalkyl or C(O)(CH 2 ) 0-3 NR 4d R 4e ;

[0043] or R 3 and R 4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C 6 The substituent of alkoxy, F or OH is optionally substituted 3- to 6-membered heterocycloalkyl;

[0044] R 4a is H, optionally substituted C 1 -C 6 Alkyl or C 3 -C 5 Cycloalkyl;

[0045] R 4b and R 4c Each is independently C 1 -C 6 Alkyl; or R 4b and R 4c Together with the phosphorus atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring;

[0046] R 4d and R 4eEach independently is H or C 1 -C 6 Alkyl, or R 4d and R 4e Together with the nitrogen atoms to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring;

[0047] or R 1 and R 2 Together with the carbon atoms to which they are both attached, they form a 3- to 5-membered cycloalkyl ring;

[0048] Q 1 , Q 2 , Q 3 , Q 4 One or both of them are N, and the others are each independently CR 5a ;

[0049] R 5a H, halogen, -CN, -S(O) 2 C 1 -C 3 Alkyl, OCF 3 , OC 1 -C 3 Alkyl or C 1 -C 3 alkyl;

[0050] Q 5 , Q 6 , Q 7 , Q 8 and Q 9 Each independently is N or CR 5 , where Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One or two of them are N, and the rest are CR 5 ;

[0051] R 5 H, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or cycloalkyl;

[0052] R 6 It is C 1 -C 6 alkyl;

[0053] R 7 H, halogen, -C 1 -C 6 Alkyl, -C 1 -C6 Alkoxy or -cycloalkyl; and

[0054] R 8 H, halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkoxy or -cycloalkyl.

[0055] Also described are stereoisomers of compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof.Methods of using compounds of formula (I) and pharmaceutical compositions comprising compounds of formula (I) are described. DETAILED DESCRIPTION

[0056] By reference to the following description, including the following definitions and examples, the present disclosure can be more fully understood. Certain features of the disclosed compositions and methods described herein in the context of separate aspects may also be provided in combination in a single aspect. Alternatively, for the sake of brevity, the various features of the disclosed compositions and methods described in the context of a single aspect may also be provided individually or in the form of any sub-combination.

[0057] The term "optionally substituted" or "substituted" as used herein to describe a substituent as defined herein means that the substituent may, but need not, be substituted with one or more of: halo (i.e., -F, -Cl, -Br, -I), cyano, -OH, -C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 3- to 7-membered heterocycloalkyl, -C 3 -C 6 Spirocycloalkyl, 3-membered to 7-membered spiroheterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1- C 6 Haloalkyl (e.g., -CF 3 ; -CHF 2 、-CH 2 CF 3 etc.), -C 1 -C 6 Alkoxy, -C 1 -C 6 Haloalkoxy (e.g., -OCF 3 ;-OCHF 2 、-OCH 2 CF 3 etc.), C 1 -C 6Alkylthio (e.g., -SCH 3 ;-SCH 2 CH 3 etc.), C 1 -C 6 Alkylamino (e.g., -CH 2 NH 2 ; -CH 2 CH 2 NH 2 etc.), -NH 2 、-NH(C 1 -C 6 Alkyl), -N(C 1 -C -6 alkyl) 2 、-NH(C 1 -C 6 Alkoxy), -C(O)NHC 1 -C 6 Alkyl, -C(O)N(C 1 -C 6 alkyl) 2 , -COOH, -C 1- C 6 AlkylCOOH, -C 3- C 6 CycloalkylCOOH, -C(O)NH 2 , -C 1- C 6 AlkylCONH 2 , -C 3 -C 6 CycloalkylCONH 2 , -C 1 -C 6 Alkyl CONHC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl CON(C 1- C 6 alkyl) 2 、-C(O)C 1- C 6 Alkyl, -C(O)OC 1 -C 6 Alkyl, -NHCO(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl)C(O)(C 1 -C 6 Alkyl), -S(O)C 1 -C 6 Alkyl, -S(O) 2C 1 -C 6 alkyl, oxo (i.e., =0), 6- to 12-membered aryl, or 5- to 12-membered heteroaryl groups. In other embodiments, "optionally substituted" or "substituted" means that the substituent may, but need not, be substituted with one or more of: -C(O)(C 1 -C 6 Haloalkyl), -NHSO 2 (C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl)SO 2 (C 1 -C 6 alkyl) or -P(O)(C 1 -C 6 alkyl) 2 (e.g., -P(O)(CH 3 ) 2 In other embodiments, "optionally substituted" or "substituted" means that the substituents may, but need not, be replaced by one or more -P(O)(OC 1-6 alkyl) 2 In other embodiments, "optionally substituted" or "substituted" means that the substituent may, but need not, be substituted by one or more of -C(O)NR'R", wherein R' and R" together with the N atom to which they are both attached form a 3- to 6-membered heterocycloalkyl ring. In other embodiments, "optionally substituted" or "substituted" means that the substituent may, but need not, be substituted by one or more of -P(O)R'R", wherein R' and R" together with the P atom to which they are both attached form a 3- to 6-membered heterocycloalkyl ring. In some embodiments, each of the above optional substituents is itself optionally substituted by one or both of these groups.

[0058] When a range of carbon atoms (e.g., C 1 -C 6 ), all ranges as well as individual carbon atom numbers are included. For example, “C 1 -C 3 "Including C 1- C 3 , C 1- C 2 , C 2- C 3 , C 1 , C 2 and C 3 . So, for example, "C 1 To C 4 An "alkyl" group refers to all alkyl groups having 1 to 4 carbon atoms (e.g., 1, 2, 3, or 4), i.e., CH3 -、CH 3 CH 2 -、CH 3 CH 2 CH 2 -、(CH 3 ) 2 CH-、CH 3 CH 2 CH 2 CH 2 -、CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-. "C 1 To C 6 "Alkyl" groups refer to all alkyl groups having 1 to 6 carbons (e.g., 1, 2, 3, 4, 5, or 6). "C 0 ” means that there are no carbon atoms. Thus, for example, “C 0 -C 3 An "alkyl" group means that the alkyl group is not present, or it is present and has 1, 2 or 3 carbon atoms.

[0059] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight-chain. Examples of branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, tert-butyl, etc. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, etc. The alkyl group may have 1 to 30 carbon atoms (whenever it occurs in this article, a numerical range such as "1 to 30" refers to each integer in a given range; for example, "1 to 30 carbon atoms" means that the alkyl group may be composed of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 carbon atoms, although the present definition also encompasses the appearance of the term "alkyl" (wherein no numerical range is specified)). An "alkyl" group may also be a medium-sized alkyl group having 1 to 12 carbon atoms. An "alkyl" group may also be a low-sized alkyl group having 1 to 6 carbon atoms. An alkyl group may be substituted or unsubstituted, i.e., optionally substituted. By way of example only, an "alkyl" group may be a low-sized alkyl group having 1 to 6 carbon atoms. 1 -C 5 "Alkyl" indicates that there are one to five carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight chain). Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl. In several embodiments, "Me" is methyl (e.g., CH3 ).

[0060] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. An alkenyl group may be unsubstituted or substituted, ie, optionally substituted.

[0061] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in the straight or branched hydrocarbon chain. Alkynyl groups can be unsubstituted or substituted, ie, optionally substituted.

[0062] As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, these rings may be joined together in a fused manner. A cycloalkyl group may contain 3 to 12 carbon atoms. For example, C 3 -C 6 A cycloalkyl group indicates that there are three to six carbon atoms in the ring, ie the ring is a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. A cycloalkyl group may be unsubstituted or substituted, ie optionally substituted.

[0063] As used herein, the term "spirocycloalkyl ring" refers to a cycloalkyl ring that shares one carbon atom with another cyclic ring. For example, a 3- to 7-membered spirocycloalkyl ring indicates that there are 3, 4, 5, 6, or 7 carbon atoms in the cycloalkyl ring that shares one carbon atom with another cyclic ring. For example, shown below are exemplary 3- to 7-membered spirocycloalkyl groups attached to a piperidine ring:

[0064]

[0065] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a fully delocalized π electron system in all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C 6 -C 14 Aryl group, C 6 -C 10 Aryl group or C 6 Aryl groups. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups may be substituted or unsubstituted.

[0066] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system with a completely delocalized π electron system) containing one or more heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen and sulfur. The number of atoms in the ring of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. In addition, the term "heteroaryl" includes fused ring systems in which two rings (such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings) share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl rings may also include bridgehead nitrogen atoms. For example, but not limited to, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, and pyrazolo[1,5-a]pyrimidine. Heteroaryl groups can be substituted or unsubstituted.

[0067] As used herein, "heterocycloalkyl" refers to a three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system, wherein carbon atoms together with 1 to 5 heteroatoms constitute the ring system. However, heterocycloalkyl may optionally contain one or more unsaturated bonds, which are positioned in such a way that a completely delocalized π electron system does not appear in all rings. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur and nitrogen. Heterocycloalkyl may further contain one or more carbonyl or thiocarbonyl functional groups, so that the definition includes oxo-systems and thio-systems, such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, these rings can be joined together in a fused manner. In addition, any nitrogen in heterocycloalkyl can be quaternized. The heterocycloalkyl group can be unsubstituted or substituted. Examples of such "heterocycloalkyl" groups include, but are not limited to, 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiinane, 1,4-oxathiinene, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiinane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid,

[00136] The invention further comprises the following: acid), thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, ethylene oxide, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, and benzo-fused analogs thereof (e.g., benzimidazolone, tetrahydroquinoline, 3,4-methylenedioxyphenyl).

[0068] As used herein, the term "spiroheterocycloalkyl ring" refers to a heterocycloalkyl ring that shares one carbon atom with another cyclic ring. For example, a 3- to 7-membered spiroheterocycloalkyl ring indicates that there are 3, 4, 5, 6, or 7 atoms in the heterocycloalkyl ring, and only one of the carbon atoms in the heterocycloalkyl ring is also a member of another cyclic ring. For example, shown below are exemplary 3- to 7-membered spiroheterocycloalkyl groups attached to a piperidine ring:

[0069]

[0070] As used herein, the term "bridged bicyclic ring" refers to a ring system comprising two joined cycloalkyl or heterocycloalkyl rings that share at least three atoms. For example, a 6- to 9-membered bridged bicyclic ring indicates that there are 6, 7, 8, or 9 atoms in the bridged bicyclic ring. For example, shown below are exemplary 6- to 9-membered bridged bicyclic rings:

[0071]

[0072] As used herein, the term "amino" refers to -NH 2 Group.

[0073] As used herein, the term "hydroxy" refers to an -OH group.

[0074] As used herein, the term "halogen atom" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0075] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is applied and does not eliminate the biological activity and properties of the compound. In several embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting the compound with an inorganic acid such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting the compound with an organic acid such as an aliphatic or aromatic carboxylic acid or sulfonic acid, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, trifluoroacetic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting the compound with a base to form a salt such as an ammonium salt, an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 -C 7 The amines are obtained from salts of amines (eg, alkylamines, cyclohexylamine, triethanolamine, ethylenediamine) and salts with amino acids such as arginine and lysine.

[0076] It should be understood that in any compound with one or more chiral centers described herein, if absolute stereochemistry is not clearly indicated, each center can independently have R configuration or S configuration or a mixture thereof. Therefore, the compounds provided herein can be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure, diastereomerically enriched or stereoisomeric mixtures. In addition, it should be understood that in any compound with one or more double bonds that produce geometric isomers that can be defined as E or Z described herein, each double bond can independently be E or Z, a mixture thereof. It should be understood that in any compound with one or more chiral centers described herein, all possible diastereomers are also envisioned. It should be understood that in any compound described herein, all tautomers are envisioned. It should also be understood that in any compound described herein, all isotopes of the atoms included are envisioned. For example, any example of hydrogen may include hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium), or other isotopes; any example of carbon may include carbon-12, carbon-13, carbon-14, or other isotopes; any example of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes; any example of fluorine may include one or more of fluorine-18, fluorine-19, or other isotopes; any example of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

[0077] As used herein, the term "kinase inhibitor" means any compound, molecule or composition that inhibits or reduces the activity of a kinase. Inhibition can be achieved, for example, by blocking phosphorylation of the kinase (e.g., competing with the phosphorylating entity adenosine triphosphate (ATP)), by binding to sites outside the active site, by affecting its activity through conformational changes, or by depriving the kinase of access to molecular chaperone systems on which their cellular stability depends, leading to their ubiquitination and degradation.

[0078] As used herein, "subject", "host", "patient" and "individual" are used interchangeably and should be given their ordinary meanings, and should also refer to organisms with FGFR proteins. This includes mammals, such as humans, non-human primates, ungulates, canines, felines, equines, mice, rats, etc. The term "mammal" includes both humans and non-human mammals.

[0079] The term "sample" or "biological sample" should be given its ordinary meaning, and also covers a variety of sample types obtained from an organism, and can be used for imaging, diagnosis, prognosis or monitoring determination. The term covers blood and other liquid samples of biological origin, solid tissue samples, such as biopsy specimens or tissue cultures, or cells and their descendants derived therefrom. The term covers samples that are manipulated in any way after their procurement, such as by treating with reagents, dissolving or enriching certain components. The term covers clinical samples, and also includes cells in cell culture, cell supernatants, cell lysates, serum, plasma, biological fluids and tissue samples.

[0080] The terms "treatment / treating / treat" and the like shall be given their ordinary meanings and shall also include herein generally referring to obtaining a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms and / or therapeutic in terms of partially or completely stabilizing or curing a disease and / or side effects caused by the disease. As used herein, "treatment" shall be given its ordinary meaning and shall also cover any treatment of a disease in a mammal, particularly a human, and shall include: (a) preventing the occurrence of a disease or symptom in a subject who may be susceptible to the disease or symptom but has not yet been diagnosed with the disease or symptom; (b) inhibiting disease symptoms, such as curbing their development; and / or (c) alleviating disease symptoms, such as causing regression of the disease or symptom.

[0081] The terms "cancer", "neoplasm" and "tumor" are used interchangeably herein, should be given their ordinary meaning, and should also refer to cells that exhibit relatively autonomous growth, so that they exhibit an abnormal growth phenotype characterized by a significant loss of control over cell proliferation. In general, the cells of interest for detection or treatment in the present application include precursor cells, precancerous cells (e.g., benign cells), malignant cells, pre-metastatic cells, metastatic cells, and non-metastatic cells. As used herein, "FGFR-related cancers" refer to those cancers involving increased mutant FGFR kinase activity (e.g., sustained activation of FGFR).

[0082] The term "control" should be given its ordinary meaning and should also include samples or standards for comparison with samples being examined, processed, characterized, analyzed, etc. In several embodiments, the control is a sample obtained from a healthy patient or a non-tumor tissue sample obtained from a patient diagnosed with a tumor. In several embodiments, the control is a historical control or a standard reference value or range of values. In several embodiments, the control is a comparison with a wild-type FGFR arrangement or regimen.

[0083] With respect to the use of substantially any plural and / or singular terms herein, those skilled in the art may convert from the plural to the singular and / or from the singular to the plural where appropriate to the context and / or application. For the sake of clarity, various singular / plural arrangements may be expressly set forth herein. The indefinite article "a / an" does not exclude a plurality. The fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0084] In some aspects, the present disclosure relates to compounds of formula (I):

[0085]

[0086] or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, R in the compound of formula (I) 9 It's H.

[0088] In other embodiments, R in the compound of formula (I) 9 It is C 1 -C 3 Alkyl groups, such as, for example, C 3 Alkyl, C 2 Alkyl, C 1 Alkyl, methyl, ethyl, propyl, etc.

[0089] In some embodiments, R in the compound of formula (I) 9 It's methyl.

[0090] In some aspects, X in the compound of formula (I) is O, S or NR, wherein R is H or C 1 -C 3 alkyl.

[0091] In some embodiments, X is O.

[0092] In other embodiments, X is S.

[0093] In some embodiments, X is NR.

[0094] In some embodiments, R is H.

[0095] In other embodiments, R is C 1 -C 3 Alkyl groups, such as, for example, C 3 Alkyl, C 2 Alkyl, C 1 Alkyl, methyl, ethyl, propyl, etc.

[0096] In some aspects, n in the compound of formula (I) is 1 or 2.

[0097] In some embodiments, n is 1.

[0098] In some embodiments, n is 2.

[0099] In some aspects, m in the compound of formula (I) is 1 or 2.

[0100] In some embodiments, m is 1.

[0101] In some embodiments, m is 2.

[0102] In some embodiments, n is 1 and m is 1.

[0103] In some embodiments, n is 1 and m is 2.

[0104] In some embodiments, n is 2 and m is 1.

[0105] In some embodiments, n is 2 and m is 2.

[0106] In some aspects, R in the compound of formula (I) 1 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, C 3 -C 5 Cycloalkyl, -C(O)NR 3 R 4 、-C(O)OR 3 , optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

[0107] In some aspects, R in the compound of formula (I) 1 is H or optionally substituted C 1 -C 6 alkyl.

[0108] In some aspects, R in the compound of formula (I) 1 Is H or C 1 -C 6 alkyl.

[0109] In some aspects, R in the compound of formula (I) 1 It's H.

[0110] In some embodiments, R 1 is an optionally substituted C 1 -C 6 Alkyl, such as, for example, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C5 Alkyl, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 3 Alkyl, optionally substituted C 1 -C 2 Alkyl, optionally substituted C 1 Alkyl, optionally substituted C 2 Alkyl, optionally substituted C 3 Alkyl, optionally substituted C 4 Alkyl, optionally substituted C 5 Alkyl, optionally substituted C 6 Alkyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted isobutyl, optionally substituted sec-butyl, optionally substituted pentyl, optionally substituted hexyl and the like.

[0111] In some embodiments, R 1 is an optionally substituted C 1 -C 6 Alkyl, the optionally substituted C 1 -C 6 Alkyl is -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 CH 2 CN、-CH 2 CH 2 CH 2 OH, -CH 2 OCH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 OCH 2 CH 3 ,

[0112]

[0113] In some embodiments, R 1 is an optionally substituted C 1 -C 6Alkyl, the optionally substituted C 1 -C 6 Alkyl is

[0114]

[0115] In some embodiments, R 1 is an optionally substituted C 1 -C 6 Alkyl, the optionally substituted C 1 -C 6 Alkyl is

[0116] In some embodiments, R 1 It is C 1 -C 6 Alkyl groups, such as, for example, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, etc.

[0117] In some embodiments, R in the compound of formula (I) 1 It's methyl.

[0118] In other embodiments, R in the compound of formula (I) 1 It is isopropyl.

[0119] In other embodiments, R in the compound of formula (I) 1 It is isobutyl.

[0120] In other embodiments, R in the compound of formula (I) 1 It is sec-butyl.

[0121] In other embodiments, R in the compound of formula (I) 1 It's n-propyl.

[0122] In some embodiments, R in the compound of formula (I) 1 is a methyl group substituted with a cyano group, i.e., -CH 2CN.

[0123] In some embodiments, R in the compound of formula (I) 1 is a methyl group substituted by a hydroxyl group, i.e., -CH 2 OH.

[0124] In other embodiments, R in the compound of formula (I) 1 It is ethyl.

[0125] In some aspects, R in the compound of formula (I) 1 is an optionally substituted C 2 -C 6 Alkenyl, such as, for example, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 5 Alkenyl, optionally substituted C 2 -C 4 Alkenyl, optionally substituted C 2 -C 3 Alkenyl, optionally substituted C 2 Alkenyl, optionally substituted C 3 Alkenyl, optionally substituted C 4 Alkenyl, optionally substituted C 5 Alkenyl, optionally substituted C 6 Optionally substituted alkenyl, optionally substituted vinyl, optionally substituted n-propenyl, optionally substituted isopropenyl, optionally substituted n-butenyl, optionally substituted isobutenyl, optionally substituted sec-butenyl, optionally substituted pentenyl, optionally substituted hexenyl and the like.

[0126] In some embodiments, R 1 is unsubstituted C 2 -C 6 Alkenyl.

[0127] In some embodiments, R 1 is replaced by C 2 -C 6 Alkenyl.

[0128] In some embodiments, R 1 yes

[0129] In some aspects, R in the compound of formula (I) 1 It is C 3 -C 5 Cycloalkyl, such as, for example, C 3 Cycloalkyl, C 4 Cycloalkyl, C 5 Cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, etc.

[0130] In some aspects, R in the compound of formula (I) 1 It is cyclobutyl.

[0131] In some aspects, R in the compound of formula (I) 1 is optionally substituted heterocycloalkyl.

[0132] In some embodiments, R in the compound of formula (I) 1 is a substituted heterocycloalkyl.

[0133] In other embodiments, R in the compound of formula (I) 1 is an unsubstituted heterocycloalkyl group.

[0134] In some embodiments, R in the compound of formula (I) 1 yes

[0135] In some aspects, R in the compound of formula (I) 1 is an optionally substituted heteroaryl.

[0136] In some embodiments, R in the compound of formula (I) 1 is a substituted heteroaryl.

[0137] In some embodiments, R in the compound of formula (I) 1 yes

[0138]

[0139] In some aspects, R in the compound of formula (I) 1 is an unsubstituted heteroaryl.

[0140] In some embodiments, R in the compound of formula (I) 1 yes

[0141] In some aspects, R in the compound of formula (I) 1 Yes -C(O)OR 3 .

[0142] In some embodiments, R in the compound of formula (I) 1 yes

[0143] In some aspects, R in the compound of formula (I) 1 Yes-C(O)NR 3 R 4 .

[0144] In some embodiments, R in the compound of formula (I) 1 yes

[0145]

[0146] In some aspects, R in the compound of formula (I) 2 is H, optionally substituted C 1 -C 6 Alkyl, -NR 3 R 4 、-OR 4a 、-P(O)R 4b R 4c 、-SO 2 R 3 or -C(O)NR 3 R 4 .

[0147] In some aspects, R in the compound of formula (I) 2 is H, optionally substituted C 1 -C 6 Alkyl, -NR 3 R 4 OR 4a .

[0148] In some embodiments, R 2 It's H.

[0149] In some embodiments, R 2 is an optionally substituted C 1 -C 6 Alkyl, such as, for example, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 5 Alkyl, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 3 Alkyl, optionally substituted C 1 -C 2 Alkyl, optionally substituted C 1 Alkyl, optionally substituted C 2 Alkyl, optionally substituted C 3 Alkyl, optionally substituted C 4 Alkyl, optionally substituted C 5 Alkyl, optionally substituted C 6 Alkyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted isobutyl, optionally substituted sec-butyl, optionally substituted pentyl, optionally substituted hexyl and the like.

[0150] In some embodiments, R 2 is unsubstituted C 1-C 6 alkyl.

[0151] In some embodiments, R 2 Yes CH 3 .

[0152] In some embodiments, R 2 is replaced by C 1 -C 6 alkyl.

[0153] In some embodiments, R 2 It is NHSO 2 (C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl)SO 2 (C 1 -C 6 alkyl), 5- to 6-membered heterocycloalkyl, -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl) 2 or -P(O)(C 1 -C 6 alkyl) 2 Substituted C 1 -C 6 alkyl.

[0154] In some embodiments, R 2 is SO 2 (C 1 -C 6 Alkyl) substituted C 1 -C 6 alkyl.

[0155] In some embodiments, R 2 yes

[0156] In some embodiments, R 2 Is -NH 2 Substituted C 1 -C 6 Alkyl groups, such as, for example, -CH 2 NH 2 .

[0157] In some embodiments, R 2 It is NHSO 2 (C 1 -C 6 Alkyl) substituted C 1 -C 6Alkyl groups, such as, for example, NHSO 2 (CH 3 ), NHSO 2 (CH 2 CH 3 ), NHSO 2 (CH 2 CH 2 CH 3 ), NHSO 2 (CH 2 CH 2 CH 2 CH 3 )wait.

[0158] In some embodiments, R 2 Yes-CH 2 -NHSO 2 (CH 3 ).

[0159] In some embodiments, R 2 Is -N(C 1 -C 6 alkyl)SO 2 (C 1 -C 6 Alkyl) substituted C 1 -C 6 Alkyl groups, such as, for example, -N(CH 3 )SO 2 (CH 3 )、-N(CH 3 )SO 2 (CH 2 CH 3 )、-N(CH 3 )SO 2 (CH 2 CH 2 CH 3 )、-N(CH 2 CH 3 )SO 2 (CH 3 )、-N(CH 2 CH 3 )SO 2 (CH 2 CH 3 )wait.

[0160] In some embodiments, R 2 Yes-CH 2 -N(CH 3 )SO 2 (CH 3 ).

[0161] In some embodiments, R 2 is a C substituted by a 5- to 6-membered heterocycloalkyl 1 -C 6 Alkyl such as, for example, pyrrolyl, furanyl, piperidinyl, piperazinyl, morpholinyl, and the like.

[0162] In some embodiments, R 2 yes

[0163] In some embodiments, R 2 is -NH(C 1 -C 6 Alkyl) substituted C 1 -C 6 Alkyl groups, such as, for example, -NH(C 6 Alkyl), -NH(C 5 Alkyl), -NH(C 4 Alkyl), -NH(C 3 Alkyl), -NH(C 2 Alkyl), -NH(C 1 alkyl), NH(CH 3 ), NH(CH 2 CH 3 )wait.

[0164] In some embodiments, R 2 Yes-CH 2 -NH(CH 3 ) or -CH 2 -NH(CH(CH 3 ) 2 ).

[0165] In some embodiments, R 2 Yes-CH 2 -NH(CH 2 CH 2 OH).

[0166] In some embodiments, R 2 Is -N(C 1 -C 6 alkyl) 2 Substituted C 1 -C 6 Alkyl groups, such as, for example, -N(C 6 alkyl) 2 、-N(C 5 alkyl) 2 、-N(C 4 alkyl) 2 、-N(C 3 alkyl) 2、-N(C 2 alkyl) 2 、-N(C 1 alkyl) 2 、-N(CH 3 ) 2 、-N(CH 2 CH 3 ) 2 、-N(CH 3 )(CH 2 CH 3 )wait.

[0167] In some embodiments, R 2 Yes-CH 2 -N(CH 3 ) 2 .

[0168] In some embodiments, R 2 Is -P(O)R 4b R 4c Substituted C 1 -C 6 Alkyl, where R 4b and R 4c Independently C 1 -C 6 Alkyl or -OC 1 -C 6 Alkyl; or R 4b and R 4c Together with the phosphorus atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring.

[0169] In some embodiments, R 4b It is C 1 -C 6 Alkyl groups, such as, for example, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, etc.

[0170] In some embodiments, R4b Yes CH 3 .

[0171] In some embodiments, R 4b Yes-OC 1 -C 6 Alkyl, such as, for example, -OC 1 -C 6 Alkyl, -OC 1 -C 5 Alkyl, -OC 1 -C 4 Alkyl, -OC 1 -C 3 Alkyl, -OC 1 -C 2 Alkyl, -OC 1 Alkyl, -OC 2 Alkyl, -OC 3 Alkyl, -OC 4 Alkyl, -OC 5 Alkyl, -OC 6 Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and the like.

[0172] In some embodiments, R 4b Yes-OCH 3 .

[0173] In some embodiments, R 4c It is C 1 -C 6 Alkyl groups, such as, for example, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, etc.

[0174] In some embodiments, R 4c Yes CH 3 .

[0175] In some embodiments, R 4c Yes-OC1 -C 6 Alkyl, such as, for example, -OC 1 -C 6 Alkyl, -OC 1 -C 5 Alkyl, -OC 1 -C 4 Alkyl, -OC 1 -C 3 Alkyl, -OC 1 -C 2 Alkyl, -OC 1 Alkyl, -OC 2 Alkyl, -OC 3 Alkyl, -OC 4 Alkyl, -OC 5 Alkyl, -OC 6 Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and the like.

[0176] In some embodiments, R 4c Yes-OCH 3 .

[0177] In some embodiments, R 2 is -P(O)(C 6 alkyl) 2 、-P(O)(C 5 alkyl) 2 、-P(O)(C 4 alkyl) 2 、-P(O)(C 3 alkyl) 2 、-P(O)(C 2 alkyl) 2 、-P(O)(C 1 alkyl) 2 、-P(O)(CH 3 ) 2 、-P(O)(CH 2 CH 3 ) 2 、-P(O)(CH 3 )(CH 2 CH 3 ) etc. substituted C 1 -C 6 alkyl.

[0178] In some embodiments, R 2 Yes-CH 2 -P(O)(CH 3 ) 2 .

[0179] In some embodiments, R 2 Is -P(O)(OC 6 alkyl) 2 、-P(O)(OC 5 alkyl) 2 、-P(O)(OC 4 alkyl) 2 、-P(O)(OC 3 alkyl) 2 、-P(O)(OC 2 alkyl) 2 、-P(O)(OC 1 alkyl) 2 、-P(O)(OCH 3 ) 2 、-P(O)(OCH 2 CH 3 ) 2 、-P(O)(OCH 3 )(OCH 2 CH 3 ) etc. substituted C 1 -C 6 alkyl.

[0180] In some embodiments, R 2 Yes-CH 2 -P(O)(OCH 3 ) 2 .

[0181] In some embodiments, R 4b and R 4c Together with the phosphorus atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring, such as, for example, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl or a 6-membered heterocycloalkyl.

[0182] In some embodiments, R 2 is C replaced by 1 -C 6 alkyl:

[0183]

[0184] In some embodiments, R 2 Yes - NR 3 R 4 , where R 3 Is H or C 1 -C 6 alkyl; and R 4 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6Alkenyl, C 3 -C 5 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C(O)(CH 2 ) 2-3 OH or C(O)(CH 2 ) 0-3 NR 4d R 4e ; or R 3 and R 4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C 6 The substituent of alkoxy, F or OH is optionally substituted 3- to 6-membered heterocycloalkyl.

[0185] In other embodiments, R 2 Yes - NR 3 R 4 , where R 3 Is H or C 1 -C 6 alkyl; and R 4 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, C 3 -C 5 Cycloalkyl, 3- to 6-membered heterocycloalkyl or C(O)CH 2 NR 4d R 4e ; or R 3 and R 4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C 6 The substituent of alkoxy, F or OH is optionally substituted 3- to 6-membered heterocycloalkyl.

[0186] In some embodiments, R 2 Yes - NR 3 R 4 , where R 3 Is H or C 1 -C 6 alkyl; and R 4 is H, optionally substituted C 1 -C 6 Alkyl, C 3 -C 5 Cycloalkyl, 3- to 6-membered heterocycloalkyl or C(O)CH 2NR 4d R 4e ; or R 3 and R 4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C 6 The substituent of alkoxy, F or OH is optionally substituted 3- to 6-membered heterocycloalkyl.

[0187] In some embodiments, R 3 It's H.

[0188] In some embodiments, R 3 It is C 1 -C 6 Alkyl groups, such as, for example, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, etc.

[0189] In some embodiments, R 3 Yes CH 3 .

[0190] In some embodiments, R 4 It's H.

[0191] In some embodiments, R 4 is an optionally substituted C 1 -C 6 Alkyl, such as, for example, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 5 Alkyl, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 3 Alkyl, optionally substituted C 1 -C 2Alkyl, optionally substituted C 1 Alkyl, optionally substituted C 2 Alkyl, optionally substituted C 3 Alkyl, optionally substituted C 4 Alkyl, optionally substituted C 5 Alkyl, optionally substituted C 6 Alkyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted isobutyl, optionally substituted sec-butyl, optionally substituted pentyl, optionally substituted hexyl and the like.

[0192] In some embodiments, R 4 is unsubstituted C 1 -C 6 alkyl.

[0193] In some embodiments, R 4 Yes CH 3 、-CH 2 CH 3 or -CH(CH 3 ) 2 .

[0194] In other embodiments, R 4 Yes-CH 2 CH(CH 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3 ,

[0195] In some embodiments, R 4 is replaced by C 1 -C 6 alkyl.

[0196] In some embodiments, R 4 Yes-CH 2 -cyclopropyl, -CH 2 CH 2 SO 2 CH 3 、-CH 2 CH 2 CHF 2 、-CH 2 CHF 2 、-CH 2 CH 2 OH, -CH 2 CH2 OCH 3 、-CH 2 CH 2 O-iso-Pr, -CH 2 C(CH 3 ) 2 OH, -CH 2 CHCH 3 OH, -CH 2 CHOCH 3 ,

[0197] In some embodiments, R 4 Yes-CH 2 CH 2 CN,

[0198] In some embodiments, R 4 Yes-(CH 2 ) 1-3 P(O)(C 1 -C 6 alkyl) 2 , such as, for example -CH 2 P(O)(CH 3 ) 2 、-CH 2 CH 2 P(O)(CH 2 CH 3 ) 2 、-CH 2 CH 2 P(O)(CH 2 CH 2 CH 3 ) 2 、-CH 2 CH 2 P(O)(CH 3 )(CH 2 CH 3 )wait.

[0199] In some embodiments, R 4 Yes-(CH 2 ) 1-3 P(O), such as, for example, -CH 2 P(O), -CH 2 CH 2 P(O), -CH 2 CH 2 P(O), -CH 2 CH 2 P(O), etc.

[0200] In some embodiments, R4 yes

[0201] In some embodiments, R 4 is an optionally substituted C 2 -C 6 Alkenyl, such as, for example, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 5 Alkenyl, optionally substituted C 2 -C 4 Alkenyl, optionally substituted C 2 -C 3 Alkenyl, optionally substituted C 2 Alkenyl, optionally substituted C 3 Alkenyl, optionally substituted C 4 Alkenyl, optionally substituted C 5 Alkenyl, optionally substituted C 6 Optionally substituted alkenyl, optionally substituted vinyl, optionally substituted n-propenyl, optionally substituted isopropenyl, optionally substituted n-butenyl, optionally substituted isobutenyl, optionally substituted sec-butenyl, optionally substituted pentenyl, optionally substituted hexenyl and the like.

[0202] In some embodiments, R 4 is unsubstituted C 2 -C 6 Alkenyl.

[0203] In some embodiments, R 4 Yes-CH 2 CH=CH 2 .

[0204] In some embodiments, R 4 It is C 3 -C 5 Cycloalkyl, such as, for example, cyclopropyl, cyclobutyl or cyclopentyl.

[0205] In some embodiments, R 4 It is cyclobutyl.

[0206] In some embodiments, R 4 is a 3- to 6-membered heterocycloalkyl group, such as, for example, a 3-membered heterocycloalkyl group, a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group, a 6-membered heterocycloalkyl group, an aziridinyl group, an oxiranyl group, an azetidinyl group, an oxetanyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, and the like.

[0207] In some embodiments, R 4It is oxetane-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl,

[0208] In some embodiments, R 4 is C(O)(CH 2 ) 0-3 NR 4d R 4e , such as, for example, C(O)NR 4d R 4e 、C(O)(CH 2 )NR 4d R 4e 、C(O)(CH 2 ) 2 NR 4d R 4e or C(O)(CH 2 ) 3 NR 4d R 4e .

[0209] In some embodiments, R 4 is C(O)(CH 2 ) 0-3 NR 4d R 4e , where R 4d and R 4e Each independently is H or C 1 -C 6 Alkyl, or R 4d and R 4e Together with the nitrogen atoms to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring.

[0210] In some embodiments, R 4 is C(O)(CH 2 ) 0-3 NR 4d R 4e , where R 4d and R 4e Each independently is H or C 1 -C 6 alkyl.

[0211] In some embodiments, R 4 is C(O)CH 2 N(C 1 -C 6 alkyl) 2 , such as, for example, C(O)CH 2 N(C 6 alkyl) 2 、C(O)CH 2N(C 5 alkyl) 2 、C(O)CH 2 N(C 4 alkyl) 2 、C(O)CH 2 N(C 3 alkyl) 2 、C(O)CH 2 N(C 2 alkyl) 2 、C(O)CH 2 N(C 1 alkyl) 2 、C(O)CH 2 N(CH 3 ) 2 、C(O)CH 2 N(CH 2 CH 3 ) 2 、C(O)CH 2 N(CH 3 )(CH 2 CH 3 )wait.

[0212] In some embodiments, R 4 is C(O)CH 2 N(CH 3 ) 2 .

[0213] In other embodiments, R 4 is C(O)(CH 2 ) 0-3 NR 4d R 4e , where R 4d and R 4e Together with the nitrogen atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring, such as, for example, pyrrolidinyl, piperidinyl, morpholinyl, and the like.

[0214] In some embodiments, R 3 and R 4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C 6 The substituent of alkoxy, F or OH is optionally substituted 3- to 6-membered heterocycloalkyl.

[0215] In some embodiments, R 4 is C(O)(CH 2 ) 2-3 OH, such as, for example, C(O)CH2 CH 2 OH or C(O)CH 2 CH 2 CH 2 OH. In some embodiments, R 4 is C(O)CH 2 CH 2 OH.

[0216] In some embodiments, R 3 and R 4 Together with the N atom to which they are both attached, they form an unsubstituted 3- to 6-membered heterocycloalkyl group, such as, for example, a 3-membered heterocycloalkyl group, a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group, a 6-membered heterocycloalkyl group, an aziridinyl group, an oxirane group, an azetidinyl group, an oxetanyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, and the like.

[0217] In some embodiments, R 3 and R 4 Together with the N atom to which they are both attached they form an unsubstituted pyrrolidin-1-yl, azetidin-1-yl or morpholin-4-yl.

[0218] In some embodiments, R 3 and R 4 Together with the N atom to which both of them are attached, they form a substituted 3- to 6-membered heterocycloalkyl, such as, for example, a substituted 3-membered heterocycloalkyl, a substituted 4-membered heterocycloalkyl, a substituted 5-membered heterocycloalkyl, a substituted 6-membered heterocycloalkyl, a substituted aziridinyl, a substituted oxirane, a substituted azetidinyl, a substituted oxetanyl, a substituted pyrrolidinyl, a substituted tetrahydrofuranyl, a substituted tetrahydropyranyl, a substituted piperidinyl, a substituted piperazinyl, a substituted morpholinyl, and the like.

[0219] In some embodiments, R 3 and R 4 Together with the N atom to which they are both attached, they form 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphorinane-4-yl 1-oxide, 1-methyl-4-azaphosphorinane-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphorinane-4-yl 1-oxide or

[0220] In some embodiments, R 3 and R 4 Together with the N atoms to which they are connected, they form

[0221] In some embodiments, R3 and R 4 Together with the N atoms to which they are connected, they form

[0222] In some embodiments, R 3 and R 4 Together with the N atom to which they are both attached, they form a 6- to 8-membered bridged heterocycloalkyl ring system such as, for example

[0223] In some embodiments, R 2 Yes-OR 4a , where R 4a is H, optionally substituted C 1 -C 6 Alkyl or C 3 -C 5 Cycloalkyl.

[0224] In some embodiments, R 2 It is -OH.

[0225] In some embodiments, R 4a It's H.

[0226] In some embodiments, R 4a is an optionally substituted C 1 -C 6 Alkyl, such as, for example, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 5 Alkyl, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 3 Alkyl, optionally substituted C 1 -C 2 Alkyl, optionally substituted C 1 Alkyl, optionally substituted C 2 Alkyl, optionally substituted C 3 Alkyl, optionally substituted C 4 Alkyl, optionally substituted C 5 Alkyl, optionally substituted C 6 Alkyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted isobutyl, optionally substituted sec-butyl, optionally substituted pentyl, optionally substituted hexyl and the like.

[0227] In some embodiments, R 4a is unsubstituted C 1 -C 6 alkyl.

[0228] In some embodiments, R 4a It is -CH(CH 3 ).

[0229] In some embodiments, R 4a is replaced by C 1 -C 6 alkyl.

[0230] In some embodiments, R 4a Yes-CH 2 CH 2 OH or -CH 2 C(CH 3 ) 2 OH.

[0231] In some embodiments, R 4a It is C 3 -C 5 Cycloalkyl, such as, for example, cyclopropyl, cyclobutyl or cyclopentyl.

[0232] In some embodiments, R 4a It is cyclopropyl.

[0233] In some embodiments, R 4a It is cyclobutyl.

[0234] In some embodiments, R 4a It is cyclopentyl.

[0235] In some embodiments, R 2 yes

[0236] In some embodiments, R 2 Yes-P(O)R 4b R 4c , where R 4b and R 4c Independently C 1 -C 6 Alkyl; or R 4b and R 4c Together with the phosphorus atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring.

[0237] In some embodiments, R 4b It is C 1 -C 6 Alkyl groups, such as, for example, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, etc.

[0238] In some embodiments, R 4b Yes CH 3 .

[0239] In some embodiments, R 4c It is C 1 -C 6 Alkyl groups, such as, for example, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, etc.

[0240] In some embodiments, R 4c Yes CH 3 .

[0241] In some embodiments, R 2 Yes -P(O)(CH 3 ) 2 .

[0242] In some embodiments, R 4b and R 4c Together with the phosphorus atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring, such as, for example, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl or a 6-membered heterocycloalkyl.

[0243] In some embodiments, R 2 yes:

[0244]

[0245] In some embodiments, R 2 Yes-SO 2 R 3 , such as, for example -SO 2 H or -SO 2 C 1 -C 6 Alkyl groups, such as, for example, -SO 2 C 6 Alkyl, -SO 2 C 5 Alkyl, -SO 2 C 4 Alkyl, -SO 2 C 3 Alkyl, -SO 2 C 2 Alkyl, -SO 2 C 1 Alkyl or -SO 2 CH 3 .

[0246] In some embodiments, R 2 Yes-C(O)NR 3 R 4 , such as, for example -C(O)NH 2 、-C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 Alkyl)(C 1 -C 6 alkyl), -C(O)NHCH 3 、-C(O)N(CH 3 ) 2 、-C(O)NHCH 2 CH 3 、-C(O)N(CH 2 CH 3 ) 2 、-C(O)NHCH 2 CH 2 OH, etc.

[0247] In some aspects, R in the compound of formula (I) 1 and R 2 Together with the carbon atoms to which they are both attached they form a 3- to 5-membered cycloalkyl ring such as, for example, cyclopropyl, cyclobutyl or cyclopentyl.

[0248] In some embodiments, R in the compound of formula (I) 1 and R 2Together with the carbon atoms to which they are both attached they form a cyclopropyl ring.

[0249] In some embodiments, R in the compound of formula (I) 1 and R 2 Together with the carbon atoms to which they are both attached they form a cyclobutyl ring.

[0250] In some embodiments, R in the compound of formula (I) 1 and R 2 Together with the carbon atoms to which they are both attached they form a cyclopentyl ring.

[0251] In some aspects, Q in the compound of formula (I) 1 , Q 2 , Q 3 , Q 4 One or both of them are N, and the others are each independently CR 5a .

[0252] In some embodiments, Q 1 is N, and Q 2 , Q 3 and Q 4 Each is independently CR 5a .

[0253] In some embodiments, Q 2 is N, and Q 1 , Q 3 and Q 4 Each is independently CR 5a .

[0254] In some embodiments, Q 3 is N, and Q 1 , Q 2 and Q 4 Each is independently CR 5a .

[0255] In some embodiments, Q 4 is N, and Q 1 , Q 2 and Q 3 Each is independently CR 5a .

[0256] In other embodiments, Q 1 , Q 2 , Q 3 , Q 4 Two of them are N, and the others are each independently CR 5a .

[0257] In some embodiments, Q 1 and Q2 Each is N, and Q 3 and Q 4 Each is independently CR 5a .

[0258] In some embodiments, Q 1 and Q 3 Each is N, and Q 2 and Q 4 Each is independently CR 5a .

[0259] In some embodiments, Q 1 and Q 4 Each is N, and Q 2 and Q 3 Each is independently CR 5a .

[0260] In some embodiments, Q 2 and Q 3 Each is N, and Q 1 and Q 4 Each is independently CR 5a .

[0261] In some embodiments, Q 2 and Q 4 Each is N, and Q 1 and Q 3 Each is independently CR 5a .

[0262] In some embodiments, Q 3 and Q 4 Each is N, and Q 1 and Q 2 Each is independently CR 5a .

[0263] In some aspects of the compounds of formula (I), each R 5a H, halogen, -CN, -S(O) 2 C 1 -C 3 Alkyl, OCF 3 , OC 1 -C 3 Alkyl or C 1 -C 3 alkyl.

[0264] In some embodiments, at least one R 5a It's H.

[0265] In some embodiments, at least one R 5a is a halogen, i.e., -F, -Cl, -Br or -I.

[0266] In some embodiments, at least one R 5a It's F.

[0267] In some embodiments, at least one R 5a Yes-CN.

[0268] In some embodiments, at least one R 5a Yes-SO 2 C 1 -C 3 Alkyl groups, such as, for example, -SO 2 C 1 Alkyl, -SO 2 C 2 Alkyl, -SO 2 C 3 Alkyl, -SO 2 CH 2 CH 3 、-SO 2 CH 3 In some embodiments, at least one R 5a Yes-SO 2 CH 3 .

[0269] In some embodiments, R 5a OCF 3 .

[0270] In some embodiments, at least one R 5a It's OC 1 -C 3 Alkyl groups, such as, for example, OC 1 -C 3 Alkyl, OC 1 -C 2 Alkyl, OC 1 Alkyl, OC 2 Alkyl, OC 3 Alkyl, -OCH 3 、-OCH 2 CH 3 , -O propyl, etc. In some embodiments, at least one R 5a Yes-OCH 3 .

[0271] In some embodiments, at least one R 5a It is C 1 -C 3 Alkyl groups, such as, for example, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1Alkyl, C 2 Alkyl, C 3 Alkyl, -CH 3 、-CH 2 CH 3 , -propyl, etc. In some embodiments, at least one R 5a Yes-CH 3 .

[0272] In some aspects, Q in the compound of formula (I) 5 , Q 6 , Q 7 , Q 8 and Q 9 Each independently is N or CR 5 , where Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One or both of them are N, and the others are each independently CR 5 .

[0273] In some embodiments, Q 5 , Q 6 , Q 7 , Q 8 or Q 9 One of them is N, and the others are each independently CR 5 .

[0274] In some embodiments, Q 5 is N, and Q 6 , Q 7 , Q 8 and Q 9 Each is independently CR 5 .

[0275] In some embodiments, Q 6 is N, and Q 5 , Q 7 , Q 8 and Q 9 Each is independently CR 5 .

[0276] In some embodiments, Q 7 is N, and Q 5 , Q 6 , Q 8 and Q 9 Each is independently CR 5 .

[0277] In some embodiments, Q 8 is N, and Q 5 , Q6 , Q 7 and Q 9 Each is independently CR 5 .

[0278] In some embodiments, Q 9 is N, and Q 5 , Q 6 , Q 7 and Q 8 Each is independently CR 5 .

[0279] In other embodiments, Q 5 , Q 6 , Q 7 , Q 8 or Q 9 Two of them are each N, and the others are each independently CR 5 .

[0280] In some embodiments, Q 5 and Q 6 Each is N, and Q 7 , Q 8 and Q 9 Each is independently CR 5 .

[0281] In some embodiments, Q 5 and Q 7 Each is N, and Q 6 , Q 8 and Q 9 Each is independently CR 5 .

[0282] In some embodiments, Q 5 and Q 8 Each is N, and Q 6 , Q 7 and Q 9 Each is independently CR 5 .

[0283] In some embodiments, Q 5 and Q 9 Each is N, and Q 6 , Q 7 and Q 8 Each is independently CR 5 .

[0284] In some embodiments, Q 6 and Q 7 Each is N, and Q 5 , Q 8 and Q 9Each is independently CR 5 .

[0285] In some embodiments, Q 6 and Q 8 Each is N, and Q 5 , Q 7 and Q 9 Each is independently CR 5 .

[0286] In some embodiments, Q 6 and Q 9 Each is N, and Q 5 , Q 7 and Q 8 Each is independently CR 5 .

[0287] In some embodiments, Q 7 and Q 8 Each is N, and Q 5 , Q 6 and Q 9 Each is independently CR 5 .

[0288] In some embodiments, Q 7 and Q 9 Each is N, and Q 5 , Q 6 and Q 8 Each is independently CR 5 .

[0289] In some embodiments, Q 8 and Q 9 Each is N, and Q 5 , Q 6 and Q 7 Each is independently CR 5 .

[0290] In some aspects of the present disclosure, each R in the compound of formula (I) 5 are independently H, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or cycloalkyl.

[0291] In some embodiments of compounds of Formula (I), at least one R 5 It's H.

[0292] In some embodiments of compounds of Formula (I), at least one R 5 is a halogen such as -F, -Cl, -Br or -I.

[0293] In some embodiments, at least one R 5 It is -Cl.

[0294] In some embodiments of compounds of Formula (I), at least one R 5 It is C 1 -C 3 Alkyl groups, such as, for example, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, -CH 3 、-CH 2 CH 3 , -propyl, etc.

[0295] In some embodiments, at least one R 5 Yes-CH 3 .

[0296] In some embodiments of compounds of Formula (I), at least one R 5 It is C 1 -C 3 Alkoxy, such as, for example, C 1 -C 3 Alkoxy, C 1 -C 2 Alkoxy, C 1 Alkoxy, C 2 Alkoxy, C 3 Alkoxy, -OCH 3 、-OCH 2 CH 3 , -propoxy, etc.

[0297] In some embodiments, at least one R 5 Yes-OCH 3 .

[0298] In some embodiments of compounds of Formula (I), at least one R 5 is cycloalkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl and the like.

[0299] In some embodiments of compounds of Formula (I), two R 5 is a halogen, and the remaining R 5 It's H.

[0300] In other embodiments of the compounds of formula (I), both R 5 is -Cl, and the remaining R 5 It's H.

[0301] In some embodiments of compounds of Formula (I), Q 5 and Q 9 Each is independently CR 5 , where each R 5 are independently halogen; Q 6 and Q 8 Each is independently CR 5 , where each R 5 is H; and Q 7 It is N.

[0302] In some embodiments of compounds of Formula (I), Q 5 , Q 8 and Q 9 Each is independently CR 5 , where each R 5 are independently halogen; Q 6 Yes CR 5 , where R 5 is H; and Q 7 It is N.

[0303] In some embodiments of compounds of Formula (I), Q 5 and Q 9 Each is independently CR 5 , where each R 5 is -Cl; Q 6 and Q 8 Each is independently CR 5 , where R 5 is H; and Q 7 It is N.

[0304] In some embodiments of compounds of Formula (I), Q 5 and Q 9 Each is independently CR 5 , where each R 5 is -Cl; Q 6 Yes CR 5 , where R 5 Yes H; Q 8 Yes CR 5 , where R 5 is -F; and Q 7 It is N.

[0305] In some embodiments of compounds of Formula (I), Q 5 and Q 9 Each is independently CR 5 , where each R 5 are independently halogen; Q 6 Yes CR 5 , where R 5It is H and Q 8 Yes CR 5 , where R 5 It is C 1 -C 3 Alkyl; and Q 7 It is N.

[0306] In some embodiments of compounds of Formula (I), Q 5 and Q 9 Each is independently CR 5 , where each R 5 is -Cl; Q 6 Yes CR 5 , where R 5 It is H and Q 8 Yes CR 5 , where R 5 Yes-CH 3 ; and Q 7 It is N.

[0307] In some embodiments of compounds of Formula (I), Q 5 and Q 9 Each is independently CR 5 , where each R 5 It is a halogen; Q 6 Yes CR 5 , where R 5 It is H and Q 8 is N; and Q 7 Yes CR 5 , where R 5 It's H.

[0308] In some embodiments of compounds of Formula (I), Q 5 and Q 9 Each is independently CR 5 , where each R 5 is -Cl; Q 6 Yes CR 5 , where R 5 It is H and Q 8 is N; and Q 7 Yes CR 5 , where R 5 It's H.

[0309] In some embodiments of compounds of Formula (I), Q 5 and Q 9 Each is independently CR 5 , where each R 5 are independently halogen; Q 6 Yes CR 5 , where R 5 It is H and Q8 is N; and Q 7 It is N.

[0310] In some embodiments of compounds of Formula (I), Q 5 and Q 9 Each is independently CR 5 , where each R 5 is -Cl; Q 6 Yes CR 5 , where R 5 It is H and Q 8 is N; and Q 7 It is N.

[0311] In some embodiments of compounds of Formula (I), Q 5 and Q 9 Each is independently CR 5 , where each R 5 Independently C 1 -C 3 Alkyl; Q 6 Yes CR 5 , where R 5 It is H and Q 8 is N; and Q 7 It is N.

[0312] In some embodiments of compounds of Formula (I), Q 5 and Q 9 Each is independently CR 5 , where each R 5 Yes-CH 3 ;Q 6 Yes CR 5 , where R 5 It is H and Q 8 is N; and Q 7 It is N.

[0313] In some aspects of the present disclosure, R 6 It is C 1 -C 6 Alkyl groups, such as, for example, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, etc.

[0314] In some embodiments of the disclosed compounds, R 6 Yes-CH 3 .

[0315] In some aspects, R in the compound of formula (I) 7 H, halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkoxy or -cycloalkyl.

[0316] In some embodiments, R in the compound of formula (I) 7 It's H.

[0317] In some embodiments, R in the compound of formula (I) 7 is a halogen, such as, for example, -F, -Cl, -Br or -I.

[0318] In some embodiments, R in the compound of formula (I) 7 Yes -F.

[0319] In other embodiments, R in the compound of formula (I) 7 It is -Cl.

[0320] In some embodiments, R in the compound of formula (I) 7 Yes-C 1 -C 6 Alkyl, such as, for example, substituted or unsubstituted C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, etc.

[0321] In some embodiments, R 7 Yes-CH3 .

[0322] In some embodiments, R in the compound of formula (I) 7 Yes-C 1 -C 6 Alkoxy groups, such as, for example, -C 1 -C 6 Alkoxy, -C 1 -C 5 Alkoxy, -C 1 -C 4 Alkoxy, -C 1 -C 3 Alkoxy, -C 1 -C 2 Alkoxy, -C 1 Alkoxy, -C 2 Alkoxy, -C 3 Alkoxy, -C 4 Alkoxy, -C 5 Alkoxy, -C 6 Alkoxy, -OCH 3 、-OCH 2 CH 3 , -propoxy, etc.

[0323] In some embodiments, R 7 Yes-OCH 3 .

[0324] In some embodiments, R in the compound of formula (I) 7 is -cycloalkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl and the like.

[0325] In some respects, R 8 H, halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkoxy or -cycloalkyl.

[0326] In some embodiments, R in the compound of formula (I) 8 It's H.

[0327] In some embodiments, R in the compound of formula (I) 8 is a halogen, such as, for example, -F, -Cl, -Br or -I.

[0328] In some embodiments, R in the compound of formula (I) 8 Yes -F.

[0329] In some embodiments, R in the compound of formula (I) 8 Yes-C1 -C 6 Alkyl, such as, for example, substituted or unsubstituted C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, etc.

[0330] In some embodiments, R 8 Yes-CH 3 .

[0331] In some embodiments, R in the compound of formula (I) 8 Yes-C 1 -C 6 Alkoxy groups, such as, for example, -C 1 -C 6 Alkoxy, -C 1 -C 5 Alkoxy, -C 1 -C 4 Alkoxy, -C 1 -C 3 Alkoxy, -C 1 -C 2 Alkoxy, -C 1 Alkoxy, -C 2 Alkoxy, -C 3 Alkoxy, -C 4 Alkoxy, -C 5 Alkoxy, -C 6 Alkoxy, -OCH 3 、-OCH 2 CH 3 , -propoxy, etc.

[0332] In some embodiments, R 8 Yes-OCH 3 .

[0333] In some embodiments, R in the compound of formula (I) 8 is -cycloalkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl and the like.

[0334] In some embodiments of compounds of Formula (I), R 7 Yes -F and R 8 It's H.

[0335] In some embodiments of compounds of Formula (I), R 7 is -Cl and R 8 It's H.

[0336] In some embodiments of compounds of Formula (I), R 7 Yes-CH 3 And R 8 It's H.

[0337] In some embodiments of compounds of Formula (I), R 7 Yes-OCH 3 And R 8 It's H.

[0338] In some embodiments of compounds of Formula (I), R 7 Yes -H and R 8 Yes -F.

[0339] In some embodiments of compounds of Formula (I), R 7 Yes -H and R 8 It is -Cl.

[0340] In some embodiments of compounds of Formula (I), R 7 Yes -H and R 8 Yes-CH 3 .

[0341] In some embodiments of compounds of Formula (I), R 7 Yes -H and R 8 OCH 3 .

[0342] In some aspects, the present disclosure relates to compounds of formula (I), which are compounds of formula (IA):

[0343]

[0344] or a pharmaceutically acceptable salt thereof, wherein

[0345] Q 2 and Q 4 Each is N or Q 2 or Q 4 One of them is N, and the other is CR 5a ;

[0346] R 5a It is H, F, -SO 2CH 3 or -CN;

[0347] R 5 is H or CH 3 ;as well as

[0348] R 7 is H, F or OCH 3 , and R 1 and R 2 As described above for formula (I).

[0349] In some embodiments of compounds of Formula (IA), R 5 It's H.

[0350] In some embodiments of compounds of Formula (IA), R 5 Yes CH 3 .

[0351] In some embodiments of compounds of Formula (IA), R 7 It's H.

[0352] In some embodiments of compounds of Formula (IA), R 7 It's F.

[0353] In some embodiments of compounds of Formula (IA), R 7 OCH 3 .

[0354] In some embodiments of compounds of Formula (IA), Q 2 and Q 4 Each is N.

[0355] In some embodiments of compounds of Formula (IA), Q 2 or Q 4 One of them is N, and the other is CR 5a .

[0356] In some embodiments of compounds of Formula (IA), wherein Q 2 or Q 4 One of them is N, and the other is CR 5a , R 5a It is H or F.

[0357] In some embodiments of compounds of Formula (IA), Q 2 or Q 4 One of them is N, and the other is CR 5a , R 5a It's H.

[0358] In some embodiments of compounds of Formula (IA), Q 2 or Q4 One of them is N, and the other is CR 5a , R 5a It's F.

[0359] In some embodiments of compounds of Formula (IA), Q 2 or Q 4 One of them is N, and the other is CR 5a , R 5a Is CN or SO 2 CH 3 .

[0360] In some embodiments of compounds of Formula (IA), Q 2 or Q 4 One of them is N, and the other is CR 5a , R 5a It is CN.

[0361] In some embodiments of compounds of Formula (IA), Q 2 or Q 4 One of them is N, and the other is CR 5a , R 5a Yes SO 2 CH 3 .

[0362] In some embodiments, the compound of formula (IA) is a compound of formula (IA-1-1):

[0363]

[0364] or a pharmaceutically acceptable salt thereof, wherein

[0365] R 5 is H or CH 3 ;as well as

[0366] R 7 is H, F or OCH 3 ;as well as

[0367] R 1 and R 2 As described above for formula (I).

[0368] In some embodiments of compounds of formula (IA-1-1), R 5 It's H.

[0369] In some embodiments of compounds of formula (IA-1-1), R 5 Yes CH 3 .

[0370] In some embodiments of compounds of formula (IA-1-1), R7 It's H.

[0371] In some embodiments of compounds of formula (IA-1-1), R 7 It's F.

[0372] In some embodiments of compounds of formula (IA-1-1), R 7 OCH 3 .

[0373] In some embodiments of compounds of formula (IA-1-1), R 1 is an optionally substituted C 1 -C 6 Alkyl, such as, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CH 2 CN、-CH 2 CH 2 CH 2 OH, -CH 2 OCH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 OCH 2 CH 3 ,

[0374]

[0375] In some embodiments of compounds of formula (IA-1-1), R 1 is an optionally substituted C 2 -C 6 Alkenyl, such as, for example

[0376] In some embodiments of compounds of formula (IA-1-1), R 1 It is C 3 -C 6 Cycloalkyl, such as, for example, cyclobutyl.

[0377] In some embodiments of compounds of formula (IA-1-1), R 1 It's H.

[0378] In some embodiments of compounds of formula (IA-1-1), R 2 is an optionally substituted C 1 -C 6 Alkyl, -NR 3 R 4 OR 4a .

[0379] In some embodiments, the compound of formula (IA) is a compound of formula (IA-1):

[0380]

[0381] or a pharmaceutically acceptable salt thereof, wherein

[0382] R 5 is H or CH 3 ;as well as

[0383] R 7 is H, F or OCH 3 ;as well as

[0384] R 2 As described above for formula (I).

[0385] In some embodiments of compounds of Formula (IA-1), R 5 It's H.

[0386] In some embodiments of compounds of Formula (IA-1), R 5 Yes CH 3 .

[0387] In some embodiments of compounds of Formula (IA-1), R 7 It's H.

[0388] In some embodiments of compounds of Formula (IA-1), R 7 It's F.

[0389] In some embodiments of compounds of Formula (IA-1), R 7 OCH 3 .

[0390] In some embodiments of compounds of Formula (IA-1), R 2 is an optionally substituted C 1 -C 6 alkyl.

[0391] In some embodiments of compounds of Formula (IA-1), R 2 Yes CH 3 、-CH 2 -NHSO 2 (CH 3 ),-CH2 -N(CH 3 )SO 2 (CH 3 ), -CH 2 -NH(CH 3 ),-CH 2 -NH(-CH(CH 3 ) 2 ),-CH 2 -N(CH 3 ) 2 or -CH 2 -P(O)(CH 3 ) 2 .

[0392] In some embodiments of compounds of Formula (IA-1), R 2 Yes - NR 3 R 4 , where R 3 and R 4 As described above for formula (I).

[0393] In some embodiments of compounds of Formula (IA-1), R 3 It's H.

[0394] In some embodiments of compounds of Formula (IA-1), R 3 Yes CH 3 .

[0395] In some embodiments of compounds of Formula (IA-1), R 4 It's H.

[0396] In some embodiments of compounds of Formula (IA-1), R 4 Yes CH 3 、-CH 2 CH 3 、-CH(CH 3 ),-CH 2 -cyclopropyl, -CH 2 CH 2 CHF 2 、-CH 2 CHF 2 、-CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 CHOCH 3 、-C(O)CH 2 N(CH 3 )2 ,

[0397] In other embodiments of the compound of formula (IA-1), R 4 Yes-CH 2 CH(CH 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3 ,

[0398] In some embodiments, R 4 Yes-CH 2 CH=CH 2 .

[0399] In some embodiments of compounds of Formula (IA-1), R 4 is cyclopropyl, cyclobutyl or cyclopentyl.

[0400] In some embodiments of compounds of Formula (IA-1), R 4 It is oxetane-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl,

[0401] In some embodiments of compounds of Formula (IA-1), R 4 is C(O)CH 2 N(CH 3 ) 2 .

[0402] In some embodiments of compounds of Formula (IA-1), R 3 and R 4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C 6 The substituent of the alkoxy group or OH is optionally substituted 3- to 6-membered heterocycloalkyl.

[0403] In some embodiments, R 3 and R 4 Together with the N atom to which they are both attached, they form 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphorinane-4-yl 1-oxide, 1-methyl-4-azaphosphorinane-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0404] In some embodiments of compounds of Formula (IA-1), R 2 Yes-P(O)R 4b R 4c , where R 4b and R 4c As described above for formula (I).

[0405] In some embodiments of compounds of Formula (IA-1), R 2 Yes-OR 4a , where R 4a As described above for formula (I).

[0406] In some embodiments of compounds of Formula (IA-1), R 4a It is -CH(CH 3 ),-CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, cyclopropyl, cyclobutyl or cyclopentyl.

[0407] In some embodiments, the compound of formula (IA) is a compound of formula (IA-2):

[0408]

[0409] or a pharmaceutically acceptable salt thereof, wherein

[0410] R 5 is H or CH 3 ;as well as

[0411] R 7 is H, F or OCH 3 ;as well as

[0412] R 2 As described above for formula (I).

[0413] In some embodiments of compounds of Formula (IA-2), R 5 It's H.

[0414] In some embodiments of compounds of Formula (IA-2), R 5 Yes CH 3 .

[0415] In some embodiments of compounds of Formula (IA-2), R 7 It's H.

[0416] In some embodiments of compounds of Formula (IA-2), R 7 It's F.

[0417] In some embodiments of compounds of Formula (IA-2), R 7 OCH 3 .

[0418] In some embodiments of compounds of Formula (IA-2), R 2 is an optionally substituted C 1 -C 6 alkyl.

[0419] In some embodiments of compounds of Formula (IA-2), R 2 Yes CH 3 、-CH 2 -NHSO 2 (CH 3 ),-CH 2 -N(CH 3 )SO 2 (CH 3 ), -CH 2 -NH(CH 3 ),-CH 2 -NH(-CH(CH 3 ) 2 ),-CH 2 -N(CH 3 ) 2 or -CH 2 -P(O)(CH 3 ) 2 .

[0420] In some embodiments of compounds of Formula (IA-2), R 2 Yes - NR 3 R 4 , where R 3 and R 4 As described above for formula (I).

[0421] In some embodiments of compounds of Formula (IA-2), R 3 It's H.

[0422] In some embodiments of compounds of Formula (IA-2), R 3 Yes CH 3 .

[0423] In some embodiments of compounds of Formula (IA-2), R 4 It's H.

[0424] In some embodiments of compounds of Formula (IA-2), R 4 Yes CH 3 、-CH 2CH 3 、-CH(CH 3 ),-CH 2 -cyclopropyl, -CH 2 CH 2 CHF 2 、-CH 2 CHF 2 、-CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 CHOCH 3 、-C(O)CH 2 N(CH 3 ) 2 ,

[0425] In other embodiments of the compound of formula (IA-2), R 4 Yes-CH 2 CH(CH 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3 ,

[0426] In some embodiments of compounds of Formula (IA-2), R 4 Yes-CH 2 CH=CH 2 .

[0427] In some embodiments of compounds of Formula (IA-2), R 4 is cyclopropyl, cyclobutyl or cyclopentyl.

[0428] In some embodiments of compounds of Formula (IA-2), R 4 It is oxetane-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl,

[0429] In some embodiments of compounds of Formula (IA-2), R 4 is C(O)CH 2 N(CH 3 ) 2 .

[0430] In some embodiments of compounds of Formula (IA-2), R 3 and R4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C 6 The substituent of the alkoxy group or OH is optionally substituted 3- to 6-membered heterocycloalkyl.

[0431] In some embodiments, R 3 and R 4 Together with the N atom to which they are both attached, they form 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphorinane-4-yl 1-oxide, 1-methyl-4-azaphosphorinane-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0432] In some embodiments of compounds of Formula (IA-2), R 2 Yes-P(O)R 4b R 4c , where R 4b and R 4c As described above for formula (I).

[0433] In some embodiments of compounds of Formula (IA-2), R 2 Yes-OR 4a , where R 4a As described above for formula (I).

[0434] In some embodiments of compounds of Formula (IA-2), R 4a It is -CH(CH 3 ),-CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, cyclopropyl, cyclobutyl or cyclopentyl.

[0435] In some embodiments, the compound of formula (IA) is a compound of formula (IA-3-1):

[0436]

[0437] or a pharmaceutically acceptable salt thereof, wherein

[0438] R 5 is H or CH 3 ;as well as

[0439] R 7 is H, F or OCH 3 ;as well as

[0440] R 1 and R 2 As described above for formula (I).

[0441] In some embodiments of compounds of Formula (IA-3-1), R 5 It's H.

[0442] In some embodiments of compounds of Formula (IA-3-1), R 5 Yes CH 3 .

[0443] In some embodiments of compounds of Formula (IA-3-1), R 7 It's H.

[0444] In some embodiments of compounds of Formula (IA-3-1), R 7 It's F.

[0445] In some embodiments of compounds of Formula (IA-3-1), R 7 OCH 3 .

[0446] In some embodiments of compounds of Formula (IA-3-1), R 1 It's H.

[0447] In some embodiments of compounds of Formula (IA-3-1), R 1 is an optionally substituted C 1 -C 6 Alkyl, such as, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CH 2 CN、-CH 2 CH 2 CH 2 OH, -CH 2 OCH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 OCH 2 CH 3 ,

[0448]

[0449] In some embodiments of compounds of Formula (IA-3-1), R 1 is an optionally substituted C 2 -C 6 Alkenyl, such as, for example

[0450] In some embodiments of compounds of Formula (IA-3-1), R 1 It is C 3 -C 6 Cycloalkyl, such as, for example, cyclobutyl.

[0451] In some embodiments of compounds of Formula (IA-3-1), R 1 is an optionally substituted heterocycloalkyl group, such as, for example

[0452] In some embodiments of compounds of Formula (IA-3-1), R 1 is an optionally substituted heteroaryl group, such as, for example

[0453] In some embodiments of compounds of Formula (IA-3-1), R 1 Yes -C(O)OR 3 , such as, for example

[0454] In some embodiments of compounds of Formula (IA-3-1), R 1 Yes-C(O)NR 3 R 4 , such as, for example

[0455] In some embodiments of compounds of Formula (IA-3-1), R 2 is an optionally substituted C 1 -C 6 Alkyl, -NR 3 R 4 、-OR 4a or -C(O)NR 3 R 4 .

[0456] In some embodiments of compounds of Formula (IA-3-1), R 2 Yes - NR 3 R 4 .

[0457] In some embodiments, the compound of formula (IA) is a compound of formula (IA-3):

[0458]

[0459] or a pharmaceutically acceptable salt thereof, wherein

[0460] R 5 is H or CH 3 ;as well as

[0461] R 7 is H, F or OCH 3 ;as well as

[0462] R 2 As described above for formula (I).

[0463] In some embodiments of compounds of Formula (IA-3), R 5 It's H.

[0464] In some embodiments of compounds of Formula (IA-3), R 5 Yes CH 3 .

[0465] In some embodiments of compounds of Formula (IA-3), R 7 It's H.

[0466] In some embodiments of compounds of Formula (IA-3), R 7 It's F.

[0467] In some embodiments of compounds of Formula (IA-3), R 7 OCH 3 .

[0468] In some embodiments of compounds of Formula (IA-3), R 2 is an optionally substituted C 1 -C 6 alkyl.

[0469] In some embodiments of compounds of Formula (IA-3), R 2 Yes CH 3 、-CH 2 -NHSO 2 (CH 3 ),-CH 2 -N(CH 3 )SO 2 (CH 3 ), -CH 2 -NH(CH 3 ),-CH 2 -NH(-CH(CH 3 ) 2 ),-CH 2 -N(CH 3 ) 2 or -CH2 -P(O)(CH 3 ) 2 .

[0470] In some embodiments of compounds of Formula (IA-3), R 2 Yes - NR 3 R 4 , where R 3 and R 4 As described above for formula (I).

[0471] In some embodiments of compounds of Formula (IA-3), R 3 It's H.

[0472] In some embodiments of compounds of Formula (IA-3), R 3 Yes CH 3 .

[0473] In some embodiments of compounds of Formula (IA-3), R 4 It's H.

[0474] In some embodiments of compounds of Formula (IA-3), R 4 Yes CH 3 、-CH 2 CH 3 、-CH(CH 3 ),-CH 2 -cyclopropyl, -CH 2 CH 2 CHF 2 、-CH 2 CHF 2 、-CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 CHOCH 3 、-C(O)CH 2 N(CH 3 ) 2 ,

[0475] In other embodiments of the compound of formula (IA-3), R 4 Yes-CH 2 CH(CH 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3,

[0476] In some embodiments of compounds of Formula (IA-3), R 4 Yes-CH 2 CH=CH 2 .

[0477] In some embodiments of compounds of Formula (IA-3), R 4 is cyclopropyl, cyclobutyl or cyclopentyl.

[0478] In some embodiments of compounds of Formula (IA-3), R 4 It is oxetane-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl,

[0479] In some embodiments of compounds of Formula (IA-3), R 4 is C(O)CH 2 N(CH 3 ) 2 .

[0480] In some embodiments of compounds of Formula (IA-3), R 3 and R 4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C 6 The substituent of the alkoxy group or OH is optionally substituted 3- to 6-membered heterocycloalkyl.

[0481] In some embodiments, R 3 and R 4 Together with the N atom to which they are both attached, they form 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphorinane-4-yl 1-oxide, 1-methyl-4-azaphosphorinane-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0482] In some embodiments of compounds of Formula (IA-3), R 2 Yes-P(O)R 4b R 4c , where R 4b and R 4c As described above for formula (I).

[0483] In some embodiments of compounds of Formula (IA-3), R 2 Yes-OR 4a , where R 4aAs described above for formula (I).

[0484] In some embodiments of compounds of Formula (IA-3), R 4a It is -CH(CH 3 ),-CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, cyclopropyl, cyclobutyl or cyclopentyl.

[0485] In some embodiments, the compound of formula (IA) is a compound of formula (IA-4-1):

[0486]

[0487] or a pharmaceutically acceptable salt thereof, wherein

[0488] R 5 is H or CH 3 ;as well as

[0489] R 7 is H, F or OCH 3 ;as well as

[0490] R 1 and R 2 As described above for formula (I).

[0491] In some embodiments of compounds of Formula (IA-4-1), R 5 It's H.

[0492] In some embodiments of compounds of Formula (IA-4-1), R 5 Yes CH 3 .

[0493] In some embodiments of compounds of Formula (IA-4-1), R 7 It's H.

[0494] In some embodiments of compounds of Formula (IA-4-1), R 7 It's F.

[0495] In some embodiments of compounds of Formula (IA-4-1), R 7 OCH 3 .

[0496] In some embodiments of compounds of Formula (IA-4-1), R 1 It's H.

[0497] In some embodiments of compounds of Formula (IA-4-1), R 1 is an optionally substituted C1 -C 6 Alkyl, such as, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CH 2 CN、-CH 2 CH 2 CH 2 OH, -CH 2 OCH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 OCH 2 CH 3 ,

[0498]

[0499] In some embodiments of compounds of Formula (IA-4-1), R 1 is an optionally substituted C 2 -C 6 Alkenyl, such as, for example

[0500] In some embodiments of compounds of Formula (IA-4-1), R 1 is an optionally substituted heteroaryl group, such as, for example

[0501] In some embodiments of compounds of Formula (IA-4-1), R 1 Yes -C(O)OR 3 , such as, for example

[0502] In some embodiments of compounds of Formula (IA-4-1), R 1 Yes-C(O)NR 3 R 4 , such as, for example

[0503] In some embodiments of compounds of Formula (IA-4-1), R 2 is an optionally substituted C 1 -C 6 Alkyl, -NR 3 R4 OR 4a .

[0504] In some embodiments of compounds of Formula (IA-4-1), R 2 Yes - NR 3 R 4 .

[0505] In some embodiments of compounds of Formula (IA-4-1), R 2 is an optionally substituted C 1 -C 6 alkyl.

[0506] In some embodiments, the compound of formula (IA) is a compound of formula (IA-4):

[0507]

[0508] or a pharmaceutically acceptable salt thereof, wherein

[0509] R 5 is H or CH 3 ;as well as

[0510] R 7 is H, F or OCH 3 ;as well as

[0511] R 2 As described above for formula (I).

[0512] In some embodiments of compounds of Formula (IA-4), R 5 It's H.

[0513] In some embodiments of compounds of Formula (IA-4), R 5 Yes CH 3 .

[0514] In some embodiments of compounds of Formula (IA-4), R 7 It's H.

[0515] In some embodiments of compounds of Formula (IA-4), R 7 It's F.

[0516] In some embodiments of compounds of Formula (IA-4), R 7 OCH 3 .

[0517] In some embodiments of compounds of Formula (IA-4), R 2 is an optionally substituted C 1 -C 6 alkyl.

[0518] In some embodiments of compounds of Formula (IA-4), R 2 Yes CH 3 、-CH 2 -NHSO 2 (CH 3 ),-CH 2 -N(CH 3 )SO 2 (CH 3 ), -CH 2 -NH(CH 3 ),-CH 2 -NH(-CH(CH 3 ) 2 ),-CH 2 -N(CH 3 ) 2 or -CH 2 -P(O)(CH 3 ) 2 .

[0519] In some embodiments of compounds of Formula (IA-4), R 2 Yes - NR 3 R 4 , where R 3 and R 4 As described above for formula (I).

[0520] In some embodiments of compounds of Formula (IA-4), R 3 It's H.

[0521] In some embodiments of compounds of Formula (IA-4), R 3 Yes CH 3 .

[0522] In some embodiments of compounds of Formula (IA-4), R 4 It's H.

[0523] In some embodiments of compounds of Formula (IA-4), R 4 Yes CH 3 、-CH 2 CH 3 、-CH(CH 3 ),-CH 2 -cyclopropyl, -CH 2 CH 2 CHF 2 、-CH 2 CHF 2 、-CH 2 CH 2 OH, -CH 2 C(CH3 ) 2 OH, -CH 2 CHOCH 3 、-C(O)CH 2 N(CH 3 ) 2 ,

[0524] In other embodiments of the compound of formula (IA-4), R 4 Yes-CH 2 CH(CH 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3 ,

[0525] In some embodiments of compounds of Formula (IA-4), R 4 Yes-CH 2 CH=CH 2 .

[0526] In some embodiments of compounds of Formula (IA-4), R 4 is cyclopropyl, cyclobutyl or cyclopentyl.

[0527] In some embodiments of compounds of Formula (IA-4), R 4 It is oxetane-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl,

[0528] In some embodiments of compounds of Formula (IA-4), R 4 is C(O)CH 2 N(CH 3 ) 2 .

[0529] In some embodiments of compounds of Formula (IA-4), R 3 and R 4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C 6 The substituent of the alkoxy group or OH is optionally substituted 3- to 6-membered heterocycloalkyl.

[0530] In some embodiments, R 3 and R 4Together with the N atom to which they are both attached, they form 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphorinane-4-yl 1-oxide, 1-methyl-4-azaphosphorinane-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0531] In some embodiments of compounds of Formula (IA-4), R 2 Yes-P(O)R 4b R 4c , where R 4b and R 4c As described above for formula (I).

[0532] In some embodiments of compounds of Formula (IA-4), R 2 Yes-OR 4a , where R 4a As described above for formula (I).

[0533] In some embodiments of compounds of Formula (IA-4), R 4a It is -CH(CH 3 ),-CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, cyclopropyl, cyclobutyl or cyclopentyl.

[0534] In some embodiments, the compound of formula (IA) is a compound of formula (IA-5):

[0535]

[0536] or a pharmaceutically acceptable salt thereof, wherein

[0537] R 5 is H or CH 3 ;as well as

[0538] R 7 is H, F or OCH 3 ;as well as

[0539] R 2 As described above for formula (I).

[0540] In some embodiments of compounds of Formula (IA-5), R 5 It's H.

[0541] In some embodiments of compounds of Formula (IA-5), R 5 Yes CH 3 .

[0542] In some embodiments of compounds of Formula (IA-5), R 7 It's H.

[0543] In some embodiments of compounds of Formula (IA-5), R 7 It's F.

[0544] In some embodiments of compounds of Formula (IA-5), R 7 OCH 3 .

[0545] In some embodiments of compounds of Formula (IA-5), R 2 is an optionally substituted C 1 -C 6 alkyl.

[0546] In some embodiments of compounds of Formula (IA-5), R 2 Yes CH 3 、-CH 2 -NHSO 2 (CH 3 ),-CH 2 -N(CH 3 )SO 2 (CH 3 ), -CH 2 -NH(CH 3 ),-CH 2 -NH(-CH(CH 3 ) 2 ),-CH 2 -N(CH 3 ) 2 or -CH 2 -P(O)(CH 3 ) 2 .

[0547] In some embodiments of compounds of Formula (IA-5), R 2 Yes - NR 3 R 4 , where R 3 and R 4 As described above for formula (I).

[0548] In some embodiments of compounds of Formula (IA-5), R 3 It's H.

[0549] In some embodiments of compounds of Formula (IA-5), R 3 Yes CH 3 .

[0550] In some embodiments of compounds of Formula (IA-5), R 4 It's H.

[0551] In some embodiments of compounds of Formula (IA-5), R 4 Yes CH 3 、-CH 2 CH 3 、-CH(CH 3 ),-CH 2 -cyclopropyl, -CH 2 CH 2 CHF 2 、-CH 2 CHF 2 、-CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 CHOCH 3 、-C(O)CH 2 N(CH 3 ) 2 ,

[0552] In other embodiments of the compound of formula (IA-5), R 4 Yes-CH 2 CH(CH 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3 ,

[0553] In some embodiments of compounds of Formula (IA-5), R 4 Yes-CH 2 CH=CH 2 .

[0554] In some embodiments of compounds of Formula (IA-5), R 4 is cyclopropyl, cyclobutyl or cyclopentyl.

[0555] In some embodiments of compounds of Formula (IA-5), R 4 It is oxetane-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl,

[0556] In some embodiments of compounds of Formula (IA-5), R4 is C(O)CH 2 N(CH 3 ) 2 .

[0557] In some embodiments of compounds of Formula (IA-5), R 3 and R 4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C 6 The substituent of the alkoxy group or OH is optionally substituted 3- to 6-membered heterocycloalkyl.

[0558] In some embodiments, R 3 and R 4 Together with the N atom to which they are both attached, they form 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphorinane-4-yl 1-oxide, 1-methyl-4-azaphosphorinane-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0559] In some embodiments of compounds of Formula (IA-5), R 2 Yes-P(O)R 4b R 4c , where R 4b and R 4c As described above for formula (I).

[0560] In some embodiments of compounds of Formula (IA-5), R 2 Yes-OR 4a , where R 4a As described above for formula (I).

[0561] In some embodiments of compounds of Formula (IA-5), R 4a It is -CH(CH 3 ),-CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, cyclopropyl, cyclobutyl or cyclopentyl.

[0562] In some embodiments, the compound of formula (IA) is a compound of formula (IA-6):

[0563]

[0564] or a pharmaceutically acceptable salt thereof.

[0565] In some aspects, the present disclosure relates to compounds of formula (I), which are compounds of formula (IB):

[0566]

[0567] or a pharmaceutically acceptable salt thereof, wherein

[0568] R 5a is H, F or -CN;

[0569] R 5 is H or CH 3 ;as well as

[0570] R 7 is H, F or OCH 3 ,

[0571] And R 1 and R 2 As described above for formula (I).

[0572] In some embodiments of compounds of Formula (IB), R 5 It's H.

[0573] In some embodiments of compounds of Formula (IB), R 5 Yes CH 3 .

[0574] In some embodiments of compounds of Formula (IB), R 7 It's H.

[0575] In some embodiments of compounds of Formula (IB), R 7 It's F.

[0576] In some embodiments of compounds of Formula (IB), R 7 OCH 3 .

[0577] In some embodiments of compounds of Formula (IB), R 5a It is H or F.

[0578] In some embodiments of compounds of Formula (IB), R 5a It's H.

[0579] In some embodiments of compounds of Formula (IB), R 5a It's F.

[0580] In some embodiments of compounds of Formula (IB), R 1 It's H.

[0581] In some embodiments of compounds of Formula (IB), R 1 is an optionally substituted C1 -C 6 Alkyl, such as, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CH 2 CN、-CH 2 CH 2 CH 2 OH, -CH 2 OCH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 OCH 2 CH 3 ,

[0582]

[0583] In some embodiments of compounds of Formula (IB), R 1 is an optionally substituted C 2 -C 6 Alkenyl, such as, for example

[0584] In some embodiments of compounds of Formula (IB), R 1 is an optionally substituted heteroaryl group, such as, for example

[0585] In some embodiments of compounds of Formula (IB), R 1 Yes -C(O)OR 3 , such as, for example

[0586] In some embodiments of compounds of Formula (IB), R 1 Yes-C(O)NR 3 R 4 , such as, for example

[0587] In some embodiments of compounds of Formula (IB), R 2 is an optionally substituted C 1 -C 6 Alkyl, -NR 3 R 4 OR4a .

[0588] In some embodiments of compounds of Formula (IB), R 2 Yes - NR 3 R 4 .

[0589] In some embodiments of compounds of Formula (IB), R 2 Yes-OR 4a .

[0590] In some embodiments, the compound of the present disclosure is a compound of Examples 1-153 described herein, or a pharmaceutically acceptable salt thereof.

[0591] In other embodiments, the compound of the present disclosure is a compound of Examples 154-449 described herein, or a pharmaceutically acceptable salt thereof.

[0592] In other embodiments, the compound of the present disclosure is a compound shown in the following table or a pharmaceutically acceptable salt thereof:

[0593]

[0594]

[0595]

[0596]

[0597]

[0598] In other embodiments, the compound of the present disclosure is a compound shown in the following table or a pharmaceutically acceptable salt thereof:

[0599]

[0600]

[0601]

[0602]

[0603]

[0604] In some embodiments, Formula (I) and any subgenus thereof disclosed herein conditionally exclude any compound disclosed in International Patent Application No. PCT / US2021 / 065679 filed on December 30, 2021.

[0605] In some embodiments, Formula (I) and any subgenus thereof disclosed herein proviso excludes any of the compounds shown in the following table:

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615] In some aspects, the present disclosure relates to the compounds shown in the following examples, or pharmaceutically acceptable salts thereof.

[0616] References herein to formula (I) or its subgenus are intended to encompass the identified formula as well as any subgenus of those disclosed herein. For example, reference to formula (I) also encompasses subgenus formula IA, IA-1-1, IA-1, IA-2, IA-3-1, IA-3, IA-4-1, IA-4, IA-5, IA-6, IB.

[0617] The present disclosure also contemplates stereoisomers of compounds of formula (I). Accordingly, the present disclosure encompasses all stereoisomers and structural isomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers, or mixtures thereof.

[0618] Pharmaceutically acceptable salts and solvates of the compounds of formula (I) are also within the scope of the present disclosure.

[0619] It should be understood that, for the sake of clarity, certain features of the invention described herein in the case of separate embodiments may also be provided in a single embodiment in combination. That is, unless clearly incompatible or explicitly excluded, each separate embodiment is considered to be combinable with any other embodiment, and such combination is considered to be another embodiment. On the contrary, for the sake of brevity, the various features of the invention described in the context of a single embodiment may also be provided separately or in any sub-combination. Although an embodiment may be described as part of a series of steps or part of a more general structure, each of the steps may also be considered to be an independent embodiment in itself, which may be combined with other embodiments.

[0620] Pharmaceutical compositions and methods of administration

[0621] The subject pharmaceutical compositions are generally formulated to provide a therapeutically effective amount of a compound of the present disclosure as an active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In some embodiments, the pharmaceutical composition contains a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), permeation enhancers, solubilizers and adjuvants.

[0622] The subject pharmaceutical composition can be used alone or in combination with one or more other medicaments, and other medicaments are also usually used in the form of pharmaceutical composition. When necessary, one or more compounds of the present invention and other medicaments can be mixed into preparations, or two components can be formulated into separate preparations to use them individually or in combination simultaneously.

[0623] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06% , 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number within a range bounded by and including any two of the above numbers) w / w, w / v or v / v.

[0624] In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14. 50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.2 5%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number within a range bounded by and including any two of the above numbers) w / w, w / v or v / v.

[0625] In some embodiments, the concentration of one or more compounds of the invention is between about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 26%. about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v or v / v range.

[0626] In some embodiments, the concentration of one or more compounds of the invention is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v, or v / v.

[0627] In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g 0.0007g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g or 0.0001g (or a number within the range limited by and including any two of the above numbers).

[0628] In some embodiments, the amount of one or more compounds of the invention is greater than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0. 045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g ,0.1g,,0.15g,0.2g,,0.25g,0.3g,,0.35g,0.4g,,0.45g,0.5g,0.55g,0.6g,,0.65 g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or 10g (or numbers within the range limited by and including any two of the above numbers).

[0629] In some embodiments, the amount of one or more compounds of the invention ranges from 0.0001 g-10 g, 0.0005 g-9 g, 0.001 g-8 g, 0.005 g-7 g, 0.01 g-6 g, 0.05 g-5 g, 0.1 g-4 g, 0.5 g-4 g, or 1 g-3 g.

[0630] In certain embodiments, the compound according to the present invention is effective in a wide dosage range. For example, in the treatment of adults, 0.01mg to 1000mg, 0.5mg to 100mg, 1mg to 50mg, and 5mg to 40mg dosages per day are examples of usable dosages. An exemplary dosage is 10mg to 30mg per day. Exact dosage will depend on route of administration, the administration form of the compound, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0631] Unless otherwise indicated, the amounts of the compounds described herein are given on a free base basis. That is, the amount indicates the amount of compound administered, excluding, for example, solvent (such as in a solvate) or counter ion (such as in a pharmaceutically acceptable salt).

[0632] Non-limiting exemplary pharmaceutical compositions and methods for preparing the same are described below.

[0633] A pharmaceutical composition for oral administration.

[0634] In some embodiments, the present invention provides a pharmaceutical composition for oral administration, which contains a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0635] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration, which contains: (i) an effective amount of a compound of the present invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent.

[0636] In some embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral consumption. The pharmaceutical composition of the present invention suitable for oral administration can exist in discrete dosage forms, such as capsules, cachets or tablets, or liquid or aerosol sprays, each containing a predetermined amount of active ingredients, as a powder or granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or an oil-in-water liquid emulsion. Such dosage forms can be prepared by any pharmaceutical method, but all methods include the step of associating the active ingredient with a carrier constituting one or more essential ingredients. In general, the composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely dispersed solid carrier or both, and then, if necessary, molding the product into a desired appearance. For example, tablets can be prepared by optionally compressing or molding with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient (such as a powder or granules) in a free-flowing form in a suitable machine, optionally mixed with an excipient, such as but not limited to an adhesive, a lubricant, an inert diluent and / or a surfactant or a dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0637] The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, because water can promote the degradation of some compounds. For example, water (e.g., 5%) can be added in the pharmaceutical field as a means of simulating long-term storage, so as to determine characteristics such as the shelf life of the formulation or stability over time. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. If it is expected that there will be a large amount of contact with moisture and / or moisture during manufacture, packaging and / or storage, the pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous. Anhydrous pharmaceutical compositions can be prepared and stored so as to maintain their anhydrous properties. Therefore, anhydrous compositions can be packaged using known materials that prevent exposure to water so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, etc., unit dose containers, blister packs, and strip packs.

[0638] Active ingredients can be combined into a close mixture with a pharmaceutical carrier according to conventional pharmaceutical mixing techniques. Depending on the form of the preparation desired for administration, the carrier can take a variety of forms. When preparing a composition for oral dosage forms, any one of the common pharmaceutical media can be used as a carrier, such as, for example, in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols, water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, etc. can be used; or in the case of oral solid preparations, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders and disintegrants can be used, and lactose is not used in some embodiments. For example, suitable carriers include powders, capsules and tablets and solid oral preparations. If necessary, tablets can be coated by standard aqueous or non-aqueous techniques.

[0639] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as gum arabic, sodium alginate, alginic acid, other alginates, powdered gum tragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0640] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0641] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant may produce tablets that disintegrate in the bottle. Too little may not be enough to disintegrate, and thus may change the rate and extent of release of the active ingredient from the dosage form. Therefore, a sufficient amount of disintegrant can be used to form a dosage form of the compound disclosed herein, and the amount of the disintegrant is neither too little nor too little, and will not adversely change the release of the active ingredient. The amount of disintegrant used can vary according to the type of formulation and the mode of administration, and can be easily distinguished by a person of ordinary skill in the art. About 0.5% to about 15% by weight of disintegrant, or about 1% to about 5% by weight of disintegrant can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0642] Lubricants that can be used to form pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower seed oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or a mixture thereof. Additional lubricants include, for example, syloid silica gel, a condensed aerosol of synthetic silicon dioxide, or a mixture thereof. Lubricants may optionally be added in an amount less than about 1% by weight of the pharmaceutical composition.

[0643] When aqueous suspensions and / or elixirs are required for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring agents or dyes and, if desired, emulsifying and / or suspending agents and diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[0644] Tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, and thereby provide a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use can also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules, in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0645] Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0646] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophile-lipophile balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions.

[0647] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide that is generally used in the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0648] The hydrophilic surfactant may be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysolecithin and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; monoacetylated tartaric acid esters and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0649] In the above group, ionic surfactants include, for example: lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; monoacetylated tartaric acid esters and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0650] The ionic surfactant may be an ionized form of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearoyl-2-lactate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linolenate, stearate, dodecyl sulfate, tetradecyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0651] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glycosides; alkyl maltosides; alkyl thioglucosides; lauryl polyethylene glycol glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters, such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of polyols with at least one member of the group consisting of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a sugar.

[0652] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate. 0 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric / Caprylic Glycerides, PEG-8 Capric / Caprylic Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Plant Sterols, P EG-30 soybean sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopherol PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series and poloxamer.

[0653] By way of example only, suitable lipophilic surfactants include: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and diglycerides; hydrophobic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters and mixtures thereof, or hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils and triglycerides.

[0654] In one embodiment, the composition may include a solubilizing agent to ensure good solubilization and / or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This is particularly important for compositions for non-oral use, such as compositions for injection. A solubilizing agent may also be added to increase the solubility of hydrophilic drugs and / or other components such as surfactants, or to keep the composition as a stable or uniform solution or dispersion.

[0655] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols such as ethanol, isopropanol, butyl alcohol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether and water.

[0656] Mixtures of solubilizing agents may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methyl pyrrolidone, N-hydroxyethyl pyrrolidone, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, carbitol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizing agents include sorbitol, glycerol, triacetin, ethanol, PEG-400, glycofurol, and propylene glycol.

[0657] The amount of the solubilizing agent that can be included is not particularly limited.The amount of a given solubilizing agent can be limited to the biologically acceptable amount that those skilled in the art can easily determine.In some cases, the amount of the solubilizing agent that far exceeds the biologically acceptable amount can be advantageously included, for example, to maximize drug concentration, before providing the pharmaceutical composition to the subject, conventional techniques are used, such as distillation or evaporation to remove excessive solubilizing agent.Therefore, if there is a solubilizing agent, it can be 10%, 25%, 50%, 100% or a weight ratio of about 200% by weight based on the combined weight of medicine and other excipients.If desired, a very small amount of solubilizing agent can also be used, such as being greater than 5%, greater than 2%, 1% or even less.Usually, the solubilizing agent can be greater than 1% to about 100% by weight, more generally greater than about 5% to greater than about 25% amount exists.

[0658] The composition may further comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-adherents, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers (viscomodulators), tension modifiers, spices, colorants, odorants, opacifiers, suspending agents, adhesives, fillers, plasticizers, lubricants and mixtures thereof.

[0659] In addition, acid or base can be incorporated into the composition to facilitate processing, enhance stability or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris (hydroxymethyl) -aminomethane (TRIS) and the like. Pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc., are also suitable. Salts of polyacids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, may also be used. When the base is a salt, the cation may be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, etc. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0660] Suitable acid is a pharmaceutically acceptable organic or inorganic acid. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0661] Pharmaceutical composition for injection.

[0662] In some embodiments, the present invention provides a pharmaceutical composition for injection, which contains a compound of the present invention and a pharmaceutical excipient suitable for injection. The components and amounts of the pharmaceutical agents in the composition are as described herein.

[0663] The novel compositions of the present invention may be incorporated into forms for administration by injection including aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, glucose or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0664] Aqueous solutions in saline are also routinely used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. Can be used, for example, by using a coating (such as lecithin), in the case of a dispersion to maintain the desired particle size and by using a surfactant to maintain appropriate fluidity. Prevention of the effects of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0665] Sterile injectable solutions are prepared by mixing the desired amount of the compound of the invention in a suitable solvent as needed with the various other ingredients listed above, followed by filtration sterilization. Typically, dispersions are prepared by incorporating various sterile active ingredients into sterile vehicles containing the basic dispersion medium and other required ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, some ideal preparation methods are vacuum drying and freeze-drying techniques, which produce a powder of the active ingredient plus any additional desired ingredients from its previously sterile filtered solution.

[0666] Pharmaceutical compositions for topical (eg, transdermal) delivery.

[0667] In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery, which contains a compound of the present invention and a pharmaceutically acceptable excipient suitable for transdermal delivery.

[0668] The composition of the present invention can be formulated into a solid, semisolid or liquid preparation suitable for topical or external use, such as a gel, a water-soluble colloid, a cream, a lotion, a suspension, a foam, a powder, a slurry, an ointment, a solution, an oil, a paste, a suppository, a spray, an emulsion, a saline solution, a solution based on dimethyl sulfoxide (DMSO). In general, a carrier with a higher density enables an area to be exposed to the active ingredient for a longer period of time. In contrast, a solution formulation can provide a more immediate exposure of the active ingredient to the selected area.

[0669] The pharmaceutical composition may also include suitable solid or gel phase carriers or excipients which are compounds capable of increasing the penetration of therapeutic molecules across the stratum corneum permeability barrier of the skin or aiding in the delivery of therapeutic molecules across the stratum corneum permeability barrier of the skin. Many of these penetration enhancing molecules are known to those skilled in the art of topical formulations.

[0670] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glyceryl monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0671] Another exemplary formulation for use in the methods of the present invention employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts, with or without another agent.

[0672] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on-demand delivery of an agent.

[0673] Pharmaceutical compositions for inhalation.

[0674] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered by the respiratory route of the mouth or nose for local or systemic effect. Compositions preferably in pharmaceutically acceptable solvents may be atomized by the use of an inert gas. Atomized solutions may be inhaled directly from an atomizing device, or the atomizing device may be attached to a mask tampons or intermittent positive pressure breathing machine. Solutions, suspensions or powder compositions may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0675] Other pharmaceutical compositions.

[0676] Pharmaceutical compositions can also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural or intraspinal administration. The formulation of such pharmaceutical compositions is well known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, 10th ed., McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, 3rd ed., Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th ed., McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, 32nd ed. (The Pharmaceutical Press, London, 1999); all of which are incorporated herein by reference in their entirety.

[0677] The administration of the compounds or pharmaceutical compositions of the present invention may be effected by any method capable of delivering the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, local delivery by catheter or stent, or by inhalation. The compounds may also be administered intrafatally or intrathecally.

[0678] The amount of compound administered will depend on the subject being treated, the severity of the illness or condition, the rate of administration, the disposal of the compound, and the judgment of the prescribing physician. However, the effective dose is in the range of about 0.001 to about 100 mg / kg body weight / day, preferably about 1 to about 35 mg / kg / day, in a single dose or divided dose. For a 70 kg person, this will be equivalent to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases, larger doses may be used without causing any harmful side effects, for example, by dividing such larger doses into several small doses for administration throughout the day.

[0679] In some embodiments, the compounds of the invention are administered in a single dose.

[0680] Typically, such administration will be by injection, such as intravenous injection, in order to quickly introduce the agent. However, other routes may be used depending on the circumstances. A single dose of a compound of the invention may also be used to treat acute conditions.

[0681] In some embodiments, the compounds of the present invention are administered in multiple doses. Administration may be about once, twice, three times, four times, five times, six times or more than six times a day. Administration may be about once a month, once every two weeks, once a week or once every other day. In another embodiment, the compounds of the present invention and another medicament are administered together about once a day to about 6 times a day. In another embodiment, the administration of the compounds of the present invention and the medicament continues for less than about 7 days. In yet another embodiment, administration continues for more than about 6 days, 10 days, 14 days, 28 days, two months, six months or one year. In some cases, continuous administration is achieved and continuous administration continues for the required duration.

[0682] As long as necessary, the administration of the compounds of the present invention can be continued. In some embodiments, the compounds of the present invention are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the present invention are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the present invention are administered for a long time on a continuous basis, for example, for the treatment of chronic effects.

[0683] An effective amount of the compounds of the present invention may be administered in single or multiple doses by any of the accepted modes of administration for agents with similar utilities, including rectal, buccal, intranasal and transdermal routes, by intraarterial injection, intravenous injection, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topically or as an inhalant.

[0684] The compositions of the present invention can also be delivered via an impregnated or coated device such as a stent or a cylindrical polymer inserted into an artery. Such methods of administration can, for example, help prevent or improve restenosis after surgery (such as balloon angioplasty). Without being bound by theory, the compounds of the present invention can slow down or inhibit the migration and proliferation of smooth muscle cells that cause restenosis in the arterial wall. The compounds of the present invention can be administered, for example, by local delivery from the struts of the stent, from the stent graft, from the graft, or from the covering or sheath of the stent. In certain embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix can be a polymer matrix and can be used to bind the compound to the stent. Polymer matrices suitable for such uses include, for example, lactone-based polyesters or copolyesters, such as polylactide, polycaprolactone glycolide, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polymethyl methacrylate hydroxyethyl ester, polyvinyl pyrrolidone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be non-degradable or degradable over time, releasing one or more compounds. The compounds of the present invention may be applied to the surface of the stent by various methods, such as dip / spin coating, spray coating, dip coating and / or brush coating. The compound may be applied in a solvent and the solvent may be evaporated, thereby forming a compound layer on the stent. Alternatively, the compound may be located in the body of the stent or graft, such as in a microchannel or micropore. After implantation, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents can be prepared by immersing a stent made to contain such micropores or microchannels in a solution of the compound of the present invention in a suitable solvent, followed by evaporation of the solvent. Excess drugs on the stent surface can be removed by additional brief solvent washings. In yet other embodiments, the compounds of the present invention can be covalently linked to a stent or graft. Covalent linkers can be used, which degrade in vivo, resulting in the release of the compounds of the present invention. Any biologically unstable linkage can be used for such purposes, such as ester, amide or anhydride linkages. The compounds of the present invention can also be administered intravascularly from the balloon used during angioplasty. Extravascular administration of the compound can also be performed by applying the formulation of the present invention through the pericardium or through the adventitia to reduce restenosis.

[0685] For example, various stent devices that may be used as described are disclosed in the following references, all of which are incorporated herein by reference: U.S. Patent No. 5,451,233; U.S. Patent No. 5,040,548; U.S. Patent No. 5,061,273; U.S. Patent No. 5,496,346; U.S. Patent No. 5,292,331; U.S. Patent No. 5,674,278; U.S. Patent No. 3,657,744; U.S. Patent No. 4,739,762; U.S. Patent No. 5,195,984; U.S. Patent No. 5,292,331; U.S. Patent No. 5,674,278; U.S. Patent No. 5,879,382; U.S. Patent No. 6,344,053.

[0686] The compounds of the present invention can be administered in doses. It is known in the art that due to the variability of compound pharmacokinetics between subjects, individualization of dosing regimens is necessary for optimal therapy. The dosage of the compounds of the present invention can be found by routine experimentation according to the present disclosure.

[0687] When the compound of the invention is administered as a composition comprising one or more agents and such agents have a shorter half-life than the compound of the invention, the unit dosage forms of such agents and the compound of the invention may be adjusted accordingly.

[0688] For example, the subject pharmaceutical composition can be in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions, suitable for parenteral injection, as sterile solutions, suspensions or emulsions, suitable for topical administration, as ointments or creams or suitable for rectal administration, as suppositories. The pharmaceutical composition can be in a unit dosage form suitable for single administration of an exact dose. The pharmaceutical composition will comprise conventional pharmaceutical carriers or excipients and a compound according to the present invention as an active ingredient. In addition, other drugs or medicaments, carriers, adjuvants, etc. may also be included.

[0689] Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions (e.g., aqueous propylene glycol or aqueous dextrose). Such dosage forms can be suitably buffered, if necessary.

[0690] How to use

[0691] FGFR receptors (FGFR1, FGFR2, FGFR3 and FGFR4) share several common structural features, including three extracellular immunoglobulin-like (Ig) domains, a hydrophobic transmembrane domain and an intracellular tyrosine kinase domain separated by a kinase insert domain, followed by a cytoplasmic c-terminal tail (Johnson et al., Adv. Cancer Res. 60: 1-40, 1993; and Wilkie et al., Curr. Biol. 5: 500-507, 1995). In FGFR1, the kinase insert domain spans positions 582 to 595 of the αA1 isoform of FGFR1. In FGFR2, the kinase insert domain spans positions 585 to 598 of the FGFR2 Ille isoform. In FGFR3, the kinase insert domain spans positions 576 to 589 of the FGFR3 Ille isoform. In FGFR4, the kinase insert domain spans positions 571 to 584 of the FGFR4 isoform 1. The c-terminal tail of FGFR begins at the end of the tyrosine kinase domain and extends to the c-terminal of the protein. Several isoforms of each FGFR have been identified, and these isoforms are the result of their mRNA alternative splicing (Johnson et al., Mol. Cell. Biol. 11: 4627-4634, 1995; and Chellaiah et al., J. Biol. Chem. 269: 11620-11627, 1994).

[0692] Several receptor variants produced by this alternative splicing have different ligand binding specificity and affinity (Zimmer et al., J.Biol.Chem.268:7899-7903,1993; Cheon et al., Proc.Natl.Acad.Sci.USA91:989-993,1994; and Miki et al., Proc.Natl.Acad.Sci.USA89:246-250,1992). The protein sequence of FGFR protein and the nucleic acid encoding FGFR protein are known in the art. The signal transduction of FGFR regulates key biological processes, including cell proliferation, survival, migration and differentiation. The disorder of FGFR gene, FGFR protein or its expression or activity or level is associated with many types of cancer. For example, the disorder of FGFR can occur by a variety of mechanisms, such as FGFR gene overexpression, FGFR gene amplification, activating mutation (e.g., point mutation or truncation) and the chromosome rearrangement that produces FGFR fusion protein. Dysregulation of FGFR genes, FGFR proteins, or their expression or activity or levels may lead to (or be partially responsible for) the development of a variety of different FGFR-related cancers.

[0693] FGFR fusion proteins are known in the art. See, e.g., Baroy et al., PloS One; 11(9):e0163859. doi: 10.1371 / journal.pone.0163859, 2016; Ren et al., Int. J. Cancer, 139(4):836-40, 2016; Marchwicka et al., Cell Biosci., 6:7. doi: 10.1186 / s13578-016-0075-9, 2016; PCT Patent Application Publication No. WO 2014 / 071419A2; U.S. Patent Application Publication No. 2015 / 0366866A1; PCT Patent Application Publication No. WO 2016 / 084883A1; PCT Patent Application Publication No. WO 2016 / 030509A1; PCT Patent Application Publication No. WO 2015 / 150900A2; PCT Patent Application Publication No. WO 2015 / 120094A2; Kasaian et al., BMC Cancer., 15:984, 2015; Vakil et al., Neuro-Oncology, 18:Supp. 3, p.iii93. Abstract number: LG-64, 17th edition International Symposium on Pediatric Neuro-Oncology, Liverpool, United Kingdom, 2016; Astsaturov et al., Journal of Clinical Oncology, 34:Supp. 15, Abstract number: 11504, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Heinrich et al., Journal of Clinical Oncology, 34:Supp.Suppl. 15, Abstract No. 11012, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Hall et al., Molecular Cancer Therapeutics, Vol. 14, No. 12, Suppl. 2, Abstract No. B151, AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, 2015; Reuther et al., Journal of Molecular Diagnostics, Vol. 17, No. 6, p. 813, Abstract No. ST02, 2015 Annual Meeting of the Association for Molecular Pathology, Austin, TX; Moeini et al., Clin. Cancer. Res., 22(2):291-300, 2016; Schrock et al., J Thorac. Oneal. pii S1556-0864(18)30674-9,2018.doi:10.1016 / j.jtho.2018.05.027; Pekmezci et al., Acta Nurotapho / .Commun.6(1):47.doi:10.1186 / s40478-018-0551-z; Lowery et al. Clin Cancer Res.pii:clincanres.0078.2018.doi:10.1158 / 1078-0432.CCR-18-0078; Ryland et al. J Clin Patho / pii:jclinpath-2018-205195,2018.doi:10.1136 / jclinpath-2018-205195; Ferguson et al. J Neuropatho / ExpNeural 77(6):437-442, 2018. doi:10.1093 / jnen / nly022; Wu et al., BMC Cancer 18(1):343, 2018. doi:10.1186 / s12885-018-4236-6; Shibata et al., Cancer Sci 109(5):1282-1291, 2018. doi:10.1111 / cas.13582; Papdopoulos et al., Br J Cancer, 1117(11):1592-1599, 2017.doi:10.1038 / bjc.2017.330; Hall et al., PLoS One, 11(9):e1062594, 2016. doi:10.1371 / journal.pone.0162594; Johnson et al., Oncologist, 22(12):1478-1490, 2017. doi:10.1634 / theoncologist.2017-0242; Yang et al., Am J Hum Genet, 98(5):843-856, 2016. doi:10.1016 / j.ajhg.2016.03.017; U.S. Patent Application Publication No. 2013 / 009621; Babina and Turner, Nat Rev Cancer 17(5):318-332,2017.doi:10.1038 / nrc.2017.8;Ryland et al.,J Clin Patho / .,2018May 14.pii:jclinpath-2018-205195.doi:10.1136 / jclinpath-2018-205195;Kumar et al.,Am J Clin Patho / .143(5):738-748,2015.doi:10.1309 / AJCPUD6W1JLQQMNA;Grand et al.,Genes Chromosomes Cancer40(1):78-83,2004.doi:10.1002 / gcc.20023;Reeser et al.,J Mo / Diagn,19(5):682-696,2017.doi:10.1016 / j.jmoldx.2017.05.006; Basturk et al., Mod Patho / ,30(12):1760-1772,2017.doi:10.1038 / modpathol.2017.60; Wang et al., Cancer123(20):3916-3924,2017.doi:10.1002 / cncr.30837; Kim et al., Oncotarget,8(9):15014-15022,2017.doi:10.18632 / oncotarget.14788; Busse et al., Genes Chromosomes Cancer, 56(10):730-749, 2017. doi:10.1002 / gcc.22477; Shi et al., J Transl Med., 14(1):339, 2016. doi:10.1186 / s12967-016-1075-6, each of which is incorporated herein by reference.

[0694] FGFR point mutations are known in the art. See, e.g., UniParc entry UPI00000534B8; UniParc entry UPI0000001COF; UniParc entry UPI000002A99A; UniParc entry UPI000012A72A; UniParc entry UPI000059D1C2; UniParc entry UPI000002A9AC; Uniparc entry UPI000012A72C; Uniparc entry UPI000012A72D; Uniparc entry UPI000013EOB8; Uniparc entry UPI0001CE06A3; Gen bank entry BAD92868.1; Ang et al., Diagn. Mo / .Patho / . Feb. 24, 2014; U.S. Patent Application Publication No. 2011 / 0008347; Gallo et al., Cytokine Growth Factor Rev. 26: 425-449, 2015; Davies et al., J. Cancer Res. 65: 7591, 2005; Kelleher et al., Carcinogenesis 34: 2198, 2013; Cazier et al., Nat. Commun. 5: 3756, 2014; Liu et al., Genet. Mo / . Res. 13: 1109, 2014; Trudel et al., Blood 107: 4039, 2006; Gallo et al., Cytokine Growth Factor Rev. 26: 425, 2015; Liao et al., Cancer Res. 73: 5195-5205, 2013; Martincorena et al., Science 348:880 (2015); U.S. Patent Application Publication No. US2016 / 0235744A1; U.S. Patent No. 9254288B2; U.S. Patent No. 9267176B2; U.S. Patent Application Publication No. S2016 / 0215350A1; European Patent Application Publication No. EP3023101A1; PCT Patent Application Publication No. WO2016105503A1; Rivera et al., Acta. Neuropatho / ., 131(6):847-63, 2016; Lo Iacono et al., Oncotarget., 7(12):14394-404, 2016; Deeken et al., Journal of Clinical Oncology, 34:Supp. 15, p. iii93.Abstract number: el 7520, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Sullivan et al., Journal of Clinical Oncology, 34: Supp. 15, p. iii93. Abstract number: 11596, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Nguyen et al., Molecular Cancer Therapeutics, Vol. 14, No. 12, Supp. 2, Abstract number: C199, AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, 2015; Li et al., Hum. Patho / ., 55: 143-50, 2016; European Patent No. EP2203449B1; Yoza et al., Genes Cells.,(10):1049-1058,2016; U.S. Patent No. 9,254,288B2; European Patent Application Publication No. 3023101A1; PCT Application Publication No. WO 2015 / 099127A1; European Patent No. EP2203449B1; Yoza et al., Genes Cells.,(10):1049-1058,2016; Bunney et al., EbioMedicine,2(3):194-204,2015; Byron et al., Neop / asia,15(8):975-88,2013; European Patent Application Publication No. EP3023101A1; PCT Application Publication No. WO 2015 / 099127Al; Thussbas et al., J. Clin. Oneal., 24(23):3747-55, 2006; Chell et al., Oncogene, 32(25):3059-70, 2013; Tanizaki et al., Cancer Res. 75(15):3149-3146doi:10.1158 / 0008-5472.CAN-14-3771; Yang et al., EBioMedicine pii S2352-3964(18)30218-4.doi:10.1016 / j.ebiom.2018.06.011; Jakobsen et al. Oncotarget 9(40):26195-26208, 2018.doi:10.18632 / oncotarget.25490; Stone et al. Acta Neuropatho / 135(1):115-129, 2017. doi:10.1007 / s00401-017-1773-z; Pekmezci et al. Acta Nurotaphol. Commun.6(1):47. doi:10.1186 / s40478-018-0551-z; De Mattos-Arruda et al. Oncotarget 9(29):20617-20630, 2018. doi:10.18632 / oncotarget.25041; Oliveira et al. J Exp Clin Cancer Res 37(1):84, 2018. doi:10.1186 / s13046-018-0746-y; Cha et al., Mo / Oneal 12(7):993-1003, 2018. doi:10.1002 / 1878-0261.12194; Ikeda et al., Oncologist, 23(5):586-593, 2018. doi:10.1634 / theoncologist.2017-0479; Pelaez-Garda et al., PLoS One, 8(5):e63695, 2013. doi:10.1371 / journal.pone.0063695; Shimada et al., Oncotarget, 8(55):93567-93579, 2017. doi:10.18632 / oncotarget.20510; Welander et al., World J Surg, 42(2):482-489, 2018. doi:10.1007 / s00268-01 7-4320-0; Chandrani et al., Ann Oneal, 28(3):597-603, 2017. doi:10.1093 / annonc / mdw636; Dalin et al., Nat Surg. Commun, 8(1):1197, 2017. doi:10.1038 / s41467-017-01178-z; Taurin et al., Intl Gyneco / Cancer, 28(1):152-160, 2018. doi:10.1097 / IGC.0000000000001129; Haugh et al., J Invest Dermatol 138(2):384-393, 2018. doi:10.1016 / j.jid.2017.08.022; Babina and Turner, Nat Rev Cancer 17(5):318-332, 2017. doi:10.1038 / nrc.2017.8; Greenman et al., Nature 446(7132):153-158, 2007. doi:10.1038 / nature05610; Helsten et al., Clin Cancer Res, 22(1):259-267, 2016. doi:10.1158 / 1078-0432.CCR-14-3212; Kim et al., BMC Urol, 18:68, 2018. doi:10.1186 / s12894-018-0380-1; Goyal et al., Cancer Discov, 7(3):252-263, 2017. doi:10.1158 / 2159-8290.CD-16-1000; Premov et al., Oncogene, 36(22):3168-3177, 2017. doi:10.1038 / onc.2016.464; Geelvink et al., Int J Mo / Sci. 19(9):pii:E2548, 2018. doi:10.3390 / ijms19092548; Lee et al., Exp Ther Med. 16(2):1343-1349, 2018. doi:10.3892 / etm.2018.6323; Kas et al., Cancer Res, 78(19):5668-5679, 2018. doi:10.1158 / 0008-5472.CAN-18-0757; Chesi et al., Blood, 97(3):729-736, 2001. PMID:11157491. Note that deletion of FGFR3 isoform IIle residues 795-808 also deletes the stop codon, extending the protein by 99 amino acids (ATGPQQCEGSLAAHPAAGAQPLPGMRLSADGETATQSFGLCVCVCVCVCVCTSACACVRA HLASRCRGTLGVPAA VQRSPDWCCSTEGPLFWGDPVQNVSGPTRWDPVGQGAGPDMARPLPLHHGTSQGALGPS HTQS); Ge et al., Am J Cancer Res. 7(7):1540-1553, 2017. PMID:28744403; Jiao et al., Nat Genet, 45(12):1470-1473, 2013. doi:10.1038 / ng.2813; Jusakul et al., Cancer Discov.7(10):1116-1135,2017.doi:10.1158 / 2159-8290.CD-17-0368;Guyard et al., Respir Res.,18(1):120,2018.doi:10.1186 / s12931-017-0605-y;Paik et al., Clin Cancer Res.,23(18):5366-5373,2017.doi:10.1158 / 1078-0432.CCR-17-0645;Roy et al., Mod Patho / .,30(8):1133-1143,2017.doi:10.1038 / modpathol.2017.33;Chakrabarty et al., Br J Cancer, 117(1):136-143, 2017.doi:10.1038 / bjc.2017.148; Hoang et al., Sci Transl Med., 5(197):197ra102.doi:10.1126 / scitranslmed.3006200; Kim et al., Ann Oneal., 28(6):1250-1259.doi:10.1093 / annonc / mdx098, each of which is incorporated herein by reference.

[0695] It has been found that the compounds of the present disclosure inhibit FGFR1, FGFR2, FGFR3 and / or FGFR4, and are therefore considered to be useful for treating diseases and disorders that can be treated with inhibitors of FGFR1, FGFR2, FGFR3 and / or FGFR4. For example, the compounds of the present disclosure can be used to treat FGFR-related diseases and disorders, such as proliferative diseases such as cancer, including blood cancers and solid tumors, and angiogenesis-related disorders. The compounds of the present disclosure can also be used to treat disorders caused by autosomal dominant mutations of FGFR such as FGFR3, including, for example, developmental disorders. Developmental disorders treated with the compounds of the present disclosure include achondroplasia (Ach) and related chondroplasia syndromes, including chondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and lethal dysplasia (TD).

[0696] Non-limiting examples of FGFR-related diseases and disorders include acanthosis nigricans, achondroplasia, Apert syndrome, Beare-Stevenson syndrome (BSS), congenital flexor digitorum-tall stature-hearing loss (CATSHL) syndrome, cleft lip and palate, congenital heart disease (e.g., associated with ambiguous genitalia), craniosynostosis, Crouzon syndrome, ectrodactyly, encephalocraniocutaneous lipomatosis, Hartsfield syndrome, and ectrodactyly. syndrome), chondrodysplasia, hypogonadotropic hypogonadism (e.g., hypogonadotropic hypogonadism 2 with or without anosmia, Kallman syndrome), ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, lethal alveolar dysplasia, microphthalmia, Muenke coronal craniosynostosis, osteoarthrosis, Pfeiffer syndrome, seborrheic keratosis, syndactyly, lethal craniosynostosis dysplasia (e.g., type I or type II), trigonocephaly 1 (also known as ectopic craniosynostosis), and tumor-induced osteomalacia.

[0697] Non-limiting examples of FGFR1-associated diseases and disorders include congenital heart disease (e.g., associated with ambiguous genital sex), craniosynostosis, lipomatosis, Hartsfield syndrome, hypogonadotropic hypogonadism (e.g., hypogonadotropic hypogonadism 2 with or without anosmia, Kallmann syndrome), ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, osteoarticular dysplasia, Pfeffer syndrome, trigonocephaly 1 (also known as ectopic craniosynostosis), and tumor-induced osteomalacia.

[0698] Non-limiting examples of FGFR2-related diseases and disorders include Apat syndrome, Bill-Stevenson syndrome (BSS), Crouzon syndrome, ectrodactyly, Jackson-Weiss syndrome, lethal pulmonary alveolar dysplasia, Pfeffer syndrome and syndactyly. Non-limiting examples of FGFR3-related diseases and disorders include acanthosis nigricans, achondroplasia, congenital flexor syndactyly-tall stature-hearing loss syndrome (CATSHL) syndrome, cleft lip and palate, craniosynostosis, chondrodysplasia, microphthalmia, Muenke coronal craniosynostosis, seborrheic keratosis and lethal craniosynostosis dysplasia (e.g., type I or type II). See also, see UniParc entry UPI00000534B8; UniParc entry UPI0000001COF; Uni Pare entry UPI000002A99A; UniParc entry UPI000012A72A; Yong-Xing et al., Hum. Mol. Genet. 9(13):2001-2008, 2000; Eeva-Maria Laitinen et al., PLoS One 7(6):e39450, 2012; Hart et al., Oncogene 19(29):3309-3320, 2000; Shiang et al., Cell 76:335-342, 1994; Rosseau et al., Nature 371:252-254, 1994; Tavormina et al., Nature Genet.9:321-328,1995; Bellus et al., Nature Genet.10:357-359,1995; Muenke et al., Nature Genet.8:269-274,1994; Rutland et al., Nature Genet.9:173-176,1995; Reardon et al., Nature Genet.8:98-103,1994; Wilkie et al., Nature Genet.9:165-172,1995; Jabs et al., Nature Genet.8:275-279,1994; Japanese Patent No. JP05868992B2; Ye et al., Plast.Reconstr.Surg.,137(3):952-61,2016; U.S. Patent No. 9447098B2; Bellus et al., Am.J.Med.Genet.85(1):53-65,1999; PCT Patent Application Publication No. WO2016139227A1; Australian Patent Application Publication No. AU2014362227A1; Chinese Patent No. CN102741256B; Ohishi et al., Am.J.Med.Genet.A.,doi:10.1002 / ajmg.a.37992, 2016; Nagahara et al., Clin. Pediatr. Endocrinol., 25(3):103-106, 2016; Hibberd et al., Am. J. Med. Genet. A., doi:10.1002 / ajmg.a.37862, 2016; Dias et al., Exp. Mol. Pathol., 101(1):116-23, 2016; Lin et al., Mol .Med.Rep.,14(3):1941-6,2016;Barnett et al.,Hum.Mutat.,37(9):955-63,2016;Krstevska-Konstantinova et al.,Med.Arch.,70(2):148-50,2016;Kuentz et al.,Br.J.Dermatol.,doi:10.1111 / bjd.14681,2016;Ron et al.,Am.J.Case Rep., 15; 17: 254-8, 2016; Fernandes et al., Am. J. Med. Genet. A., 170(6): 1532-7, 2016; Lindy et al., Am. J. Med. Genet. A., 170(6): 1573-9, 2016; Bennett et al., Am. J. Hum. Genet., 98(3): 579-87, 2016; Ichiyama et al., J. Eur. Acad. Dermatol. Venereal., 30(3): 442-5, 2016; Zhao et al., Int. J. Clin. Exp. Med., 8(10): 19241-9, 2015; Hasegawa et al., Am. J. Med. Genet. A., 170A(5): 1370-2, 2016; Legeai-Mallet, Endocr. Dev., 30: 98-105, 2016; Takagi, Am. J. Med. Genet. A., 167A(ll): 2851-4, 2015; Goncalves, Fertil. Steril., 104(5): 1261-7. el, 2015; Miller et al., Journal of Clinical Oncology, 34: Supp. 15, iii93. Abstract number: e22500, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Sarabipour et al., J. Mol. Biol.,428(20):3903-3910,2016;Escobar et al.,Am.J.Med.Genet.A.,170(7):1908-11,2016;Mazen et al.,Sex Dev.,10(1):16-22,2016;Taylan et al.,J Allergy Clin lmmunol,136(2):507-9,2015.doi:10.1016 / j.jaci.2015.02.010;Kant et al.,EuroJourn Endocrinol,172(6):763-770,2015.doi:10.1530 / EJE-14-0945;Gonzalez-Del Angel et al.,Am J med Genet A, 176(1):161-166, 2018. doi:10.1002 / ajmg.a.38526; Lei and Deng, Int J Biol Sci 13(9):1163:1171, 2017. doi:10.7150 / ijbs.20792; Lajeunie et al., Eur J Hum Genet, 14(3):289-298, 2006. doi:10.1038 / sj.ejhg.5201558; Karadimas et al., Prenat Diagn, 26(3):258-261, 2006. doi:10.1002 / pd.1392; Ibrahimi et al., Hum Mo / Genet 13(19):2313-2324, 2004. doi:10.1093 / hmg / ddh235; Trarbach et al., J Clin Endocrinol Metab., 91(10):4006-4012, 2006. doi:10.1210 / jc.2005-2793; Dode et al., Nat Genet, 33(4):463-465, 2003. doi:10.1038 / ng1122, each of which is incorporated herein by reference.

[0699] The term "angiogenesis-related disorder" means a disease characterized in part by an increase in the number or size of blood vessels in a tissue of a subject or patient compared to a similar tissue of a subject not suffering from the disease. Non-limiting examples of angiogenesis-related disorders include: cancer (e.g., any of the exemplary cancers described herein, such as prostate cancer, lung cancer, breast cancer, bladder cancer, kidney cancer, colon cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, hepatoma, sarcoma, and lymphoma), exudative macular degeneration, proliferative diabetic retinopathy, ischemic retinopathy, retinopathy of prematurity, neovascular glaucoma, iris rubeosis, corneal neovascularization, cyclitis, sickle cell retinopathy, and pterygium.

[0700] The compounds of the present disclosure inhibit wild-type FGFR1, FGFR2, FGFR3 and / or FGFR4. In other aspects, the compounds of the present disclosure inhibit mutant FGFR1, FGFR2, FGFR3 and / or FGFR4. In other aspects, the compounds of the present disclosure inhibit FGFR1, FGFR2, FGFR3 and / or FGFR4 including FGFR kinase inhibitor resistance mutations.

[0701] In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-related cancer) is a blood cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-related cancer) is a solid tumor.

[0702] In some embodiments of any of the methods or uses described herein, the cancer (e.g., a FGFR-related cancer) is lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, lung adenocarcinoma, large cell carcinoma, mesothelioma, lung neuroendocrine cancer, smoking-related lung cancer), prostate cancer, colorectal cancer (e.g., rectal adenocarcinoma), endometrial cancer (e.g., endometrioid endometrial cancer, endometrial adenocarcinoma), breast cancer (e.g., hormone receptor-positive breast cancer, triple-negative breast cancer, breast neuroendocrine cancer), skin cancer (e.g., melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma, large squamous cell carcinoma), gallbladder cancer, liposarcoma (e.g., dedifferentiated liposarcoma, myxoid liposarcoma) , pheochromocytoma, myoepithelioma, urothelial carcinoma, seminoma, gastric cancer, head and neck cancer (e.g., head and neck (squamous) carcinoma, head and neck adenoid cystic carcinoma), brain cancer (e.g., glioma, neuroblastoma, glioblastoma, pilocytic astrocytoma, rosette-forming glioma, dysembryoplastic neuroepithelioma, anaplastic astrocytoma, medulloblastoma, ganglioglioma, oligodendroglioma), malignant peripheral nerve sheath tumor, sarcoma (e.g., soft tissue sarcoma (e.g., leiomyosarcoma), osteosarcoma), esophageal cancer (e.g., esophageal adenocarcinoma), lymphoma, bladder cancer (e.g., bladder urothelial (transitional cell) carcinoma), cervical cancer (e.g., cervical squamous cell carcinoma), ovarian cancer (e.g., ovarian serous carcinoma, ovarian mucinous carcinoma), bile duct cancer, adenoid cystic carcinoma, pancreatic cancer (e.g., exocrine pancreatic cancer, pancreatic ductal adenocarcinoma, pancreatic intraepithelial neoplasia), salivary gland cancer (e.g., pleomorphic salivary gland carcinoma, salivary gland adenoid cystic carcinoma), oral cancer (e.g., oral squamous cell carcinoma), uterine cancer, gastric (gastric / stomach) cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor, myeloma (e.g., multiple myeloma), lymphoepithelioma, anal cancer (e.g., anal squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), renal cell carcinoma, thymic carcinoma, gastroesophageal junction adenocarcinoma, testicular cancer carcinoma, rhabdomyosarcoma (e.g., alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma), renal papillary carcinoma, liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma), carcinoid, myeloproliferative disorders (also known as myeloproliferative neoplasms (MPNs); for example, 8pll myeloproliferative syndrome (EMS, also known as stem cell leukemia / lymphoma), acute myeloid leukemia (AML), chronic myeloid leukemia (CML)), lymphoma (e.g., T-cell lymphoma, T-lymphoblastic lymphoma, acute lymphoblastic leukemia (ALL), B-cell lymphoma), myeloid and lymphoid neoplasms, chronic neutrophilic leukemia, phosphaturic mesenchymal tumors, thyroid cancer (e.g., anaplastic thyroid cancer), or bile duct cancer.

[0703] In some embodiments of any of the methods or uses described herein, the cancer (e.g., a FGFR-related cancer) is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), juvenile cancer, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid, cancer of unknown primary, heart tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, Neoplasms by Location, Neoplasms, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-cell Lymphoma, Cutaneous Angiosarcoma, Cholangiocarcinoma, Ductal Carcinoma in Situ, Embryonal Tumors, Endometrial Cancer, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Biliary Cancer, Eye Cancer, Fallopian Tube Cancer, Fibrous Histiocytoma of Bone, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor (GIST), Germ Cell Tumor, Gestational Trophoblastic Disease, Glioma, Hairy Cell Tumor, Hairy Cell Leukemia, Head and Neck Cancer, Chest Tumors, Head and Neck Tumors, CNS Tumors, Primary CNS Tumors, Heart Cancer, Hepatocellular Carcinoma, Histiocytic Hyperplasia, Hodgkin lymphoma, Hypopharyngeal cancer, Intraocular melanoma, Islet cell tumor, Pancreatic neuroendocrine tumor, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, Laryngeal cancer, Leukemia, Lip and oral cancer, Liver cancer, Lung cancer, Lymphoma, Macroglobulinemia, Malignant fibrous histiocytoma of bone, Bone cancer, Melanoma, Merkel cell carcinoma, Mesothelioma, Metastatic squamous neck cancer, Midline tract cancer, Oral cancer, Multiple endocrine neoplasms syndrome, Multiple myeloma, Mycosis fungoides, Myelodysplastic syndrome, Myelodysplastic / myeloproliferative neoplasms, Neoplasms by site, Neoplasms, Myeloid leukemia, Myeloid leukemia, Multiple myeloma, Myeloproliferative neoplasms, Nose Cancer of the sinuses and nasal cavity, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, lung neoplasms, lung cancer, lung neoplasms, respiratory tract tumors, bronchial cancer, bronchial neoplasms, oral cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasma cell tumor, pleuropulmonary blastoma, pregnancy-related breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colon tumors, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, Spitz tumortumor), small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, cancer of unknown primary, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer and Wilms' tumor.

[0704] In some embodiments, the blood cancer (e.g., a blood cancer that is a FGFR-related cancer) is selected from the group consisting of: leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also known as Hodgkin's lymphoma), and myeloma, for example, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD) and multiple myeloma (MM).

[0705] Other examples of hematological cancers include myelodysplasia (MPD), such as polycythemia vera (PV), essential thrombocytopenia (ET) and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, hematological cancer (e.g., hematological cancer as FGFR-related cancer) is AML or CMML. In some embodiments, cancer (e.g., FGFR-related cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors of FGFR-related cancers) include, for example, lung cancer (e.g., lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer), bladder cancer, colorectal cancer, brain cancer, testicular cancer, bile duct cancer, cervical cancer, prostate cancer and seminoma. See, for example, Turner and Grose, Nat. Rev. Cancer, 10 (2): 116-129, 2010.

[0706] In some embodiments, the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, bile duct cancer, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, and uterine cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer.

[0707] In some embodiments, the cancer is hepatocellular carcinoma.

[0708] In some embodiments, the FGFR1 -related cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer.

[0709] In some embodiments, the cancer is selected from the group consisting of breast cancer, uterine cancer, bile duct cancer, and lung cancer.

[0710] In some embodiments, the FGFR2-related cancer is selected from the group consisting of breast cancer, uterine cancer, bile duct cancer and lung cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma and head and neck cancer.

[0711] In some embodiments, the FGFR3 -related cancer is selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer.

[0712] In some embodiments, the cancer is selected from lung cancer, rhabdomyosarcoma, and breast cancer.

[0713] In some embodiments, the FGFR4-related cancer is selected from hepatocellular carcinoma, lung cancer, rhabdomyosarcoma, and breast cancer.

[0714] In some aspects, the compounds of the present disclosure can be used to treat cancers associated with amplification or overexpression of FGFR1, for example, breast cancer (cancer / carcinoma) (e.g., hormone receptor-positive breast cancer, ductal carcinoma in situ (breast)), pancreatic ductal carcinoma adenocarcinoma, pancreatic exocrine carcinoma, smoking-related lung cancer, small cell lung cancer, lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer, prostate cancer, ovarian cancer, fallopian tube cancer, bladder cancer, rhabdomyosarcoma, head and neck cancer (e.g., head and neck squamous cell carcinoma) , esophageal cancer (e.g., esophageal squamous cell carcinoma), sarcoma (e.g., osteosarcoma), hepatocellular carcinoma, renal cell carcinoma, colorectal cancer (e.g., colorectal adenocarcinoma), prostate cancer, salivary gland tumors, glioblastoma multiforme, urinary bladder cancer, urothelial carcinoma, cancer of unknown primary, squamous non-lung tumors, gastric cancer, gastroesophageal junction cancer, adenoid cystic carcinoma, anal squamous cell carcinoma, oral squamous cell carcinoma, bile duct cancer, hemangioendothelioma, leiomyosarcoma, melanoma, neuroendocrine cancer, squamous cell carcinoma, uterine carcinosarcoma.

[0715] In some aspects, the compounds of the present disclosure can be used to treat cancers associated with amplification of FGFR2, e.g., gastric cancer, gastroesophageal junction adenocarcinoma, breast cancer (e.g., triple-negative breast cancer), colon cancer, colorectal cancer (e.g., colorectal adenocarcinoma), urothelial carcinoma, bladder adenocarcinoma, cancer of unknown primary, bile duct carcinoma, endometrial adenocarcinoma, esophageal adenocarcinoma, gallbladder cancer, ovarian cancer, fallopian tube cancer, exocrine pancreatic cancer, sarcoma, squamous cell carcinoma.

[0716] In some aspects, the compounds of the present disclosure can be used to treat cancers associated with overexpression of FGFR2, for example, myxoid lipoma, colorectal cancer, renal cell carcinoma, breast cancer.

[0717] In some aspects, the compounds of the present disclosure can be used to treat cancers related to the upregulation of the activity of FGFR3, for example, colorectal cancer, hepatocellular carcinoma, pancreatic exocrine cancer. In some aspects, the compounds of the present disclosure can be used to treat cancers related to the overexpression of the activity of FGFR3, for example, multiple myeloma, thyroid cancer. In some aspects, the compounds of the present disclosure can be used to treat cancers related to the amplification of the activity of FGFR3, for example, bladder cancer and salivary gland adenoid cystic carcinoma, urothelial carcinoma, breast cancer, carcinoid, unidentified primary cancer, colorectal cancer (for example, colorectal adenocarcinoma), gallbladder cancer, gastric cancer, gastroesophageal junction adenocarcinoma, glioma, mesothelioma, non-small cell lung cancer, small cell lung cancer, ovarian cancer, fallopian tube cancer, pancreatic exocrine cancer.

[0718] In some aspects, the compounds of the present disclosure can be used to treat cancers associated with amplification of FGFR4, e.g., rhabdomyosarcoma, prostate cancer or tumors, breast cancer, urothelial carcinoma, carcinoid, carcinoma of unknown primary, esophageal adenocarcinoma, head and neck cancer, hepatocellular carcinoma, non-small cell lung cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, renal cell carcinoma.

[0719] In some aspects, the compounds of the present disclosure can be used to treat cancers associated with up-regulation of the activity of FGFR4, for example, colorectal cancer, hepatocellular carcinoma, adrenal cancer, breast cancer.

[0720] In some aspects, the compounds of the present disclosure can be used to treat cancers associated with overexpression of FGFR4 activity, for example, pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma.

[0721] In some aspects, the selectivity of compounds of the present disclosure to a kind of FGFR is higher than the selectivity to another kind.As used herein, the "selectivity" of a compound to a first target is higher than a second target, which means that the compound has a stronger activity to the first target than to the second target.Multiple selectivity can be calculated by any method known in the art.For example, multiple selectivity can be calculated by dividing the IC50 value (or Kd value) of the compound to the second target (for example, FGFR1) by the IC50 value of the same compound to the first target (for example, FGFR2 or FGFR3).IC50 value (or Kd value) can be determined by any method known in the art.In certain embodiments, it is first determined that the compound has an activity less than 500nM to the first target.In certain embodiments, it is first determined that the compound has an activity less than 500nM to the second target.

[0722] For example, in some aspects, the selectivity of the compounds of the present disclosure to FGFR3 is higher than the selectivity to FGFR1. In some aspects, the selectivity of the compounds to FGFR3 is at least 3 times higher than the selectivity to FGFR1. In some aspects, the selectivity of the compounds to FGFR3 is 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500 or 1000 times higher than the selectivity to FGFR1.

[0723] For example, in some aspects, the selectivity of compounds of the present disclosure to FGFR4 is higher than the selectivity to FGFR1. In some aspects, the selectivity of compounds to FGFR4 is at least 3 times higher than the selectivity to FGFR1. In some aspects, the selectivity of compounds to FGFR4 is 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500 or 1000 times higher than the selectivity to FGFR1.

[0724] In some aspects, the selectivity of compounds of the present disclosure to FGFR2 is higher than the selectivity to FGFR1. In some aspects, the selectivity of compounds to FGFR2 is at least 3 times higher than the selectivity to FGFR1. In some aspects, the selectivity of compounds to FGFR2 is 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500 or 1000 times higher than the selectivity to FGFR1.

[0725] In some aspects, the selectivity of compounds of the present disclosure to the first FGFR family member (for example, FGFR2 or FGFR3) is higher than the selectivity to the second FGFR family member (for example, FGFR1 or FGFR4). In some aspects, the selectivity of compounds of the present disclosure to the first FGFR family member is at least 3 times higher than the selectivity of the second FGFR family member. In some aspects, the selectivity of compounds to the first FGFR family member is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900 or at least 1000 times higher than the selectivity of the second FGFR family member.

[0726] In some aspects, the selectivity of compounds of the present disclosure to the first FGFR family member (for example, FGFR4 or FGFR3) is higher than the selectivity to the second FGFR family member (for example, FGFR1 or FGFR2). In some aspects, the selectivity of compounds of the present disclosure to the first FGFR family member is at least 3 times higher than the selectivity of the second FGFR family member. In some aspects, the selectivity of compounds to the first FGFR family member is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900 or at least 1000 times higher than the selectivity of the second FGFR family member.

[0727] In some aspects, the selectivity of compounds of the present disclosure to FGFR kinases is higher than the selectivity to another kinase of non-FGFR kinases. For example, the selectivity of compounds of the present disclosure to FGFR kinases is at least 3 times higher than the selectivity of another kinase of non-FGFR kinases. In some aspects, the selectivity of compounds of the present disclosure to FGFR kinases is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900 or at least 1000 times higher than the selectivity of the kinases of non-FGFR kinases. The kinases of non-FGFR kinases include, for example, KDR kinases and Aurora B kinases.

[0728] In some embodiments, the compounds of the present disclosure exhibit brain and / or central nervous system (CNS) permeability. Such compounds can pass through the blood-brain barrier and inhibit FGFR kinases in the brain and / or other CNS structures. In some embodiments, the compounds provided herein can pass through the blood-brain barrier in a therapeutically effective amount. For example, treatment of a subject suffering from cancer (e.g., FGFR-related cancers, such as FGFR-related brain cancer or CNS cancer) can include administering (e.g., orally administering) the compound to the subject. In some such embodiments, the compounds provided herein can be used to treat primary brain tumors or metastatic brain tumors. For example, primary brain tumors or metastatic brain tumors associated with FGFR.

[0729] In some embodiments, compounds of the present disclosure exhibit one or more of high GI absorption, low clearance, and low drug-drug interaction potential.

[0730] In some aspects, the compounds of the present disclosure can be used to treat subjects diagnosed with (or identified as having) FGFR related diseases or illnesses (e.g., FGFR related cancers), including administering a therapeutically effective amount of the compounds of the present disclosure to the subject. Also provided herein is a method for treating a subject identified or diagnosed as having FGFR related diseases or illnesses (e.g., FGFR related cancers), including administering a therapeutically effective amount of the compounds of the present disclosure to the subject. In some embodiments, approved by the use of regulatory agencies, for example, FDA approved tests or assays for identifying FGFR genes, FGFR kinases, or any expression or activity or level disorders in a subject or from a biopsy sample of a subject, or by performing any one of the non-limiting assay examples described herein, identifying or diagnosing a subject with FGFR related diseases or illnesses (e.g., FGFR related cancers). In some embodiments, testing or assays are provided as a kit. In some embodiments, FGFR related diseases or illnesses are FGFR related cancers. For example, FGFR related cancers can be cancers including one or more FGFR inhibitor resistance mutations.

[0731] Also provided is a method for treating a disease or illness of a subject in need thereof, including: (a) detecting a subject's FGFR-related disease or illness; (b) administering a therapeutically effective amount of a compound of the present disclosure to a subject. Some embodiments of these methods further include administering another therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or immunotherapy) to a subject. In some embodiments, the subject was previously treated with a first FGFR inhibitor or was previously treated with another treatment. In some embodiments, by using a regulatory agency approved, for example, FDA approved test or assay for identifying a FGFR gene, FGFR kinase, or any expression or activity or level disorder in a subject or from a subject's biopsy sample, or by performing any of the non-limiting assay examples described herein, it is determined that the subject suffers from a FGFR-related disease or illness. In some embodiments, the test or assay is provided as a kit.

[0732] Also provided are methods for treating cancer in a subject in need thereof, including: (a) detecting the FGFR-related cancer of the subject; (b) administering a therapeutically effective amount of a compound of the present disclosure to the subject. Some embodiments of these methods further include administering another therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or immunotherapy) to the subject. In some embodiments, the subject was previously treated with a first FGFR inhibitor or previously treated with another anticancer treatment such as at least partial tumor resection or radiotherapy. In some embodiments, by using a regulatory agency approved, for example, FDA approved test or assay for identifying FGFR genes, FGFR kinases, or any expression or activity or level disorder in a subject or a biopsy sample from a subject, or by performing any of the non-limiting assay examples described herein, it is determined that the subject suffers from FGFR-related cancer. In some embodiments, the test or assay is provided as a kit. In some embodiments, cancer is FGFR-related cancer. For example, FGFR-related cancer can be a cancer including one or more FGFR inhibitor resistance mutations. In some embodiments, cancer is FGFR-related cancer. For example, FGFR-related cancer can be a cancer including one or more FGFR activating mutations.

[0733] Also provided are methods for treating a subject, including assaying a sample obtained from a subject to determine whether the subject has a FGFR gene, a FGFR kinase, or any expression or activity or level disorder thereof, and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof to a subject determined to have a FGFR gene, a FGFR kinase, or any expression or activity or level disorder thereof. Some embodiments of these methods further include administering another therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or immunotherapy) to the subject. In some embodiments of these methods, the subject was previously treated with a first FGFR inhibitor or was previously treated with another anticancer treatment such as at least partial tumor resection or radiotherapy. In some embodiments, the subject is a subject suspected of having a FGFR-related disease or illness (e.g., FGFR-related cancer), a subject presenting one or more symptoms of a FGFR-related disease or illness (e.g., FGFR-related cancer), or a subject with an increased risk of developing a FGFR-related disease or illness (e.g., FGFR-related cancer). In certain embodiments, the assay utilizes next generation sequencing, pyrophosphate sequencing, immunohistochemistry or decomposition FISH analysis. In certain embodiments, the assay is an assay approved by a regulatory agency, for example, a kit approved by the FDA. In certain embodiments, the assay is a liquid biopsy. Other non-limiting assays that can be used for these methods are described herein. Other assays are also known in the art. In certain embodiments, FGFR genes, FGFR kinases, or any expression or activity or level thereof are dysregulated, including one or more FGFR inhibitor resistance mutations.

[0734] Also provided herein is a method for selecting treatment for a subject, wherein these methods include the following steps: assaying a sample obtained from a subject to determine whether the subject has a FGFR gene, a FGFR kinase, or any expression or activity or level disorder thereof (e.g., one or more FGFR inhibitor resistance mutations), and identifying or diagnosing that the subject has a FGFR gene, a FGFR kinase, or any expression or activity or level disorder thereof, such as suffering from FGFR-related cancer. Some embodiments further include administering the selected treatment to a subject identified or diagnosed as suffering from FGFR-related cancer. For example, in some embodiments, the selected treatment may include administering a therapeutically effective amount of a compound of the present disclosure to a subject identified or diagnosed as suffering from FGFR-related cancer. In some embodiments, the assay is an in vitro assay. For example, the assay utilizes next generation sequencing, immunohistochemistry, or decomposition FISH analysis. In some embodiments, the assay is approved by a regulatory agency, for example, a kit approved by the FDA. In some embodiments, the assay is a liquid biopsy.

[0735] Also provided herein are methods for treating FGFR-related cancers in subjects, comprising (a) administering one or more (e.g., two or more, three or more, four or more, five or more, or ten or more) of a first FGFR kinase inhibitor to a subject identified or diagnosed with FGFR-related cancer (e.g., any type of FGFR-related cancer described herein) (e.g., identified or diagnosed as having FGFR-related cancer using any of the exemplary methods described herein or known in the art); (b) after step (a), determining the level of circulating tumor DNA in a biological sample obtained from the subject (e.g., a biological sample comprising blood, serum, or plasma); (c) administering a therapeutically effective amount of a second FGFR inhibitor or a compound of the present disclosure as a monotherapy or in combination with another therapy or therapeutic agent to a subject identified as having the same or elevated level of circulating tumor DNA compared to a reference level of circulating tumor DNA (e.g., any reference level of circulating tumor DNA described herein). In some examples of these methods, the reference level of circulating tumor DNA is the level of circulating tumor DNA in a biological sample obtained from the subject prior to step (a). Some embodiments of these methods further include determining the level of circulating tumor DNA in a biological sample obtained from a subject prior to step (a). In some examples of these methods, the reference level of circulating tumor DNA is a threshold level of circulating tumor DNA (e.g., the average level of circulating tumor DNA in a population of subjects with similar FGFR-related cancers and with similar staged FGFR-related cancers, but receiving ineffective treatment or placebo, or not yet receiving treatment, or circulating tumor DNA levels in a population of subjects with similar FGFR-related cancers and with similar staged FGFR-related cancers but receiving ineffective treatment or placebo, or not yet receiving treatment).In some examples of these methods, the first FGFR inhibitor is: ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, roblitinib, ICP-105, BIO-1262, futibatinib, fisogatinib, LOXO-435, or RLY-4008.

[0736] The compounds of the present disclosure may also be administered with additional therapies or therapeutic agents. In some aspects, additional therapies or therapeutic agents include one or more of the following: radiotherapy, chemotherapeutic agents (e.g., any of the exemplary chemotherapeutic agents described herein or known in the art), check point inhibitors (e.g., any of the exemplary check point inhibitors described herein or known in the art), surgery (e.g., at least partial resection of a tumor), and one or more other kinase inhibitors (e.g., any of the kinase inhibitors described herein or known in the art).

[0737] The compounds of the present disclosure may also be used as adjuvants for cancer treatment, that is, they may be used in combination with one or more additional therapies or therapeutic agents, such as chemotherapeutics that work by the same or by different mechanisms of action. In some embodiments, the compounds of the present disclosure may be used before the administration of additional therapeutic agents or additional therapies. For example, a subject in need may be administered one or more doses of the compounds of the present disclosure for a period of time, and then at least a partial resection of the tumor is performed. In some embodiments, before at least a partial resection of the tumor, the treatment performed with one or more doses of the compounds of the present disclosure reduces the size of the tumor (e.g., tumor burden). In some embodiments, the subject suffers from cancer (e.g., locally advanced or metastatic tumors), which is refractory or intolerant to standard therapy (e.g., administration of chemotherapeutics, such as the first FGFR inhibitor or multikinase inhibitor, immunotherapy, radiation or platinum-based agents (e.g., cisplatin)). In some embodiments, the subject suffers from cancer (e.g., locally advanced or metastatic tumors), which is refractory or intolerant to previous therapy (e.g., administration of chemotherapeutics, such as the first FGFR inhibitor or multikinase inhibitor, immunotherapy, radiation or platinum-based agents (e.g., cisplatin)).

[0738] In some embodiments of any method described herein, the compounds of the present disclosure are administered in combination with at least one additional therapeutic agent selected from one or more additional therapies or treatments (e.g., chemotherapy) agents of a therapeutically effective amount. Non-limiting examples of additional therapeutic agents include: other FGFR targeted therapeutic agents (i.e., first or second FGFR kinase inhibitors), other kinase inhibitors (e.g., therapeutic agents targeted by receptor tyrosine kinases (e.g., Trk inhibitors or EGFR inhibitors)), signal transduction pathway inhibitors, checkpoint inhibitors, regulators of apoptosis pathways (e.g., obataclax); cytotoxic chemotherapeutics, angiogenesis targeted therapies, immune targeting agents, including immunotherapy and radiotherapy.

[0739] Also provided herein are methods for treating a disease or illness, which methods include administering to a subject in need thereof a drug combination for treating a disease or illness, the drug combination comprising (a) a compound of the present disclosure, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate, or sequential use in treating a disease or illness, wherein the amount of the compound of the present disclosure and the additional therapeutic agent together effectively treat the disease or illness. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered simultaneously with a separate dose. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered sequentially with a separate dose in any order with a combined therapeutic effective amount, such as daily or intermittent doses. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered simultaneously with a combined dose. In some embodiments, the disease or illness is a FGFR-related disease or illness. In some embodiments, before administering the pharmaceutical composition, the subject has been administered one or more doses of the compound of the present disclosure.

[0740] In some embodiments, the treatment cycle is at least 7 days (e.g., at least or about 8 days, at least or about 9 days, at least or about 10 days, at least or about 11 days, at least or about 12 days, at least or about 13 days, at least or about 14 days, at least or about 15 days, at least or about 16 days, at least or about 17 days, at least or about 18 days, at least or about 19 days, at least or about 20 days, at least or about 21 days, at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, or at least or about 30 days).

[0741] In some embodiments, the treatment cycle is at least 21 days (e.g., at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, at least or about 30 days, at least or about 31 days, at least or about 32 days, at least or about 33 days, at least or about 34 days, at least or about 35 days, at least or about 36 days, at least or about 37 days, at least or about 38 days, at least or about 39 days, or at least or about 40 days).

[0742] Also provided herein are pharmaceutical compositions containing compounds of the present disclosure as active ingredients in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the compositions are suitable for oral administration. When preparing the compositions provided herein, the active ingredients are usually mixed with excipients, diluted with excipients or encapsulated in such carriers, which are in the form of, for example, capsules, sachets, paper or other containers. When the excipient is used as a diluent, it can be a solid, semi-solid or liquid material, which can act as a medium, carrier or medium for the active ingredient. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of active compounds, soft gelatin capsules and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is formulated into tablets or capsules.

[0743] Compositions containing compounds of the present disclosure can be formulated in unit dosage form, each dose containing from about 5 mg to about 1,000 mg (1 g), more usually from about 100 mg to about 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units for human subjects and other subjects, each unit containing a predetermined amount of active material (i.e., a compound of the present disclosure) to produce the desired therapeutic effect, and with a suitable pharmaceutical excipient.

[0744] In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of active ingredient, i.e., compounds of the present disclosure. It will be understood by those of ordinary skill in the art that this embodies a compound or composition containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of active ingredient. In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of active ingredient. It will be understood by those of ordinary skill in the art that this embodies a compound or composition containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of active ingredient. In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of active ingredient. One of ordinary skill in the art will appreciate that this embodies a compound or composition containing from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1,000 mg of active ingredient.

[0745] The active compound can be effective in a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it should be understood that the amount of the compound actually administered is generally determined by a physician based on relevant circumstances, including the condition to be treated, the selected route of administration, the compound actually administered, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0746] In some embodiments, the compounds provided herein can be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein can be administered in an amount ranging from about 1 mg / kg to about 20 mg / kg, from about 5 mg / kg to about 50 mg / kg, from about 10 mg / kg to about 40 mg / kg, from about 15 mg / kg to about 45 mg / kg, from about 20 mg / kg to about 60 mg / kg, or from about 40 mg / kg to about 70 mg / kg. For example, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg or about 100 mg / kg. In some embodiments, this administration can be once a day or twice a day (BID) administration.

[0747] The present disclosure also relates to the following aspects:

[0748] Aspect 1. A compound of formula (I):

[0749]

[0750] or a pharmaceutically acceptable salt thereof, wherein

[0751] X = O, S or NR;

[0752] R is H or C 1 -C 3 alkyl;

[0753] n = 1 or 2;

[0754] m = 1 or 2;

[0755] R 1 is H or optionally substituted C 1 -C 6 alkyl;

[0756] R 2 is H, optionally substituted C 1 -C 6 Alkyl, -NR 3 R 4 、-OR 4a 、-P(O)R 4b R 4c 、-SO 2 R 3 or -C(O)NR 3 R4 ;

[0757] R 3 Is H or C 1 -C 6 alkyl;

[0758] R 4 is H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, C 3 -C 5 Cycloalkyl, 3- to 6-membered heterocycloalkyl or C(O)(CH 2 ) 0-3 NR 4d R 4e ;

[0759] or R 3 and R 4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C 6 The substituent of alkoxy, F or OH is optionally substituted 3- to 6-membered heterocycloalkyl;

[0760] R 4a is H, optionally substituted C 1 -C 6 Alkyl or C 3 -C 5 Cycloalkyl;

[0761] R 4b and R 4c Each is independently C 1 -C 6 Alkyl; or R 4b and R 4c Together with the phosphorus atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring;

[0762] R 4d and R 4e Each independently is H or C 1 -C 6 Alkyl, or R 4d and R 4e Together with the nitrogen atoms to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring;

[0763] or R 1 and R 2 Together with the carbon atoms to which they are both attached, they form a 3- to 5-membered cycloalkyl ring;

[0764] Q 1 , Q 2 , Q 3 , Q 4 One or both of them are N, and the others are each independently CR 5a ;

[0765] R 5a H, halogen, -CN, -S(O) 2 C 1 -C 6 Alkyl, OCF 3 , OC 1 -C 3 Alkyl or C 1 -C 3 alkyl;

[0766] Q 5 , Q 6 , Q 7 , Q 8 and Q 9 Each independently is N or CR 5 , where Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One or two of them are N, and the rest are CR 5 ;

[0767] R 5 H, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or cycloalkyl;

[0768] R 6 It is C 1 -C 6 alkyl;

[0769] R 7 H, halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkoxy or -cycloalkyl; and

[0770] R 8 H, halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkoxy or -cycloalkyl.

[0771] Aspect 2. The compound according to aspect 1, wherein R 1Is H or C 1 -C 6 alkyl; and R 4 is H, optionally substituted C 1 -C 6 Alkyl, C 3 -C 5 Cycloalkyl, 3- to 6-membered heterocycloalkyl or C(O)(CH 2 ) 0-3 NR 4d R 4e .

[0772] Aspect 3. The compound according to aspect 1 or aspect 2, wherein X is O.

[0773] Aspect 4. A compound according to any one of aspects 1 to 3, wherein R 6 Yes CH 3 .

[0774] Aspect 5. A compound according to any one of the preceding aspects, wherein R 8 It's H.

[0775] Aspect 6. A compound according to any one of the preceding aspects, wherein R 7 is H, F or OCH 3 .

[0776] Aspect 7. A compound according to any one of the preceding aspects, wherein Q 1 and Q 3 Each is CR 5a , where R 5a It's H.

[0777] Aspect 8. A compound according to any one of the preceding aspects, wherein Q 2 and Q 4 Each is N.

[0778] Aspect 9. A compound according to any one of aspects 1 to 7, wherein Q 2 is N and Q 4 Yes CR 5a , where R 5a It is H or F.

[0779] Aspect 10. A compound according to any one of aspects 1 to 7, wherein Q 2 is N and Q 4 Yes CR 5a , where R 5a is CN, S(O) 2 C 1 -C 6 Alkyl, OC 1 -C 3Alkyl or C 1 -C 3 alkyl.

[0780] Aspect 11. A compound according to any one of the preceding aspects, wherein Q 5 and Q 9 Each is CR 5 , where each R 5 It is Cl; Q 7 Yes N; Q 6 Yes CR 5 , where R 5 is H; and Q 8 Yes CR 5 , where R 5 is H or CH 3 .

[0781] Aspect 12. The compound according to any one of the preceding aspects, wherein n is 1 and m is 1.

[0782] Aspect 13. A compound according to any one of the preceding aspects, wherein the compound of formula (I) is a compound of formula (IA):

[0783]

[0784] or a pharmaceutically acceptable salt thereof, wherein

[0785] Q 2 and Q 4 Each is N or Q 2 or Q 4 One of them is N, and the other is CR 5a ;

[0786] R 5a It is H, F, -SO 2 CH 3 or -CN;

[0787] R 5 is H or CH 3 ;as well as

[0788] R 7 is H, F or OCH 3 .

[0789] Aspect 14. The compound according to aspect 13, wherein R 5 It's H.

[0790] Aspect 15. The compound according to aspect 13, wherein R 5 Yes CH 3 .

[0791] Aspect 16. A compound according to any one of aspects 13 to 15, wherein R 7 It's H.

[0792] Aspect 17. A compound according to any one of aspects 13 to 15, wherein R 7 It's F.

[0793] Aspect 18. A compound according to any one of aspects 13 to 15, wherein R 7 OCH 3 .

[0794] Aspect 19. A compound according to any one of aspects 13 to 18, wherein Q 2 and Q 4 Each is N.

[0795] Aspect 20. A compound according to any one of aspects 13 to 18, wherein Q 2 or Q 4 is N, and the other is CR 5a .

[0796] Aspect 21. The compound according to aspect 20, wherein R 5a It is H or F.

[0797] Aspect 22. The compound according to aspect 21, wherein R 5a It's H.

[0798] Aspect 23. The compound according to aspect 21, wherein R 5a It's F.

[0799] Aspect 24. The compound according to aspect 20, wherein R 5a Is CN or SO 2 CH 3 .

[0800] Aspect 25. The compound according to aspect 24, wherein R 5a It is CN.

[0801] Aspect 26. The compound according to aspect 24, wherein R 5a Yes SO 2 CH 3 .

[0802] Aspect 27. The compound according to aspect 1 or aspect 2, wherein R 5a OCF 3 .

[0803] Aspect 28. A compound according to any one of aspects 1 to 27, wherein R 1 It's H.

[0804] Aspect 29. A compound according to any one of aspects 1 to 27, wherein R 1 is an optionally substituted C 1 -C 6 alkyl.

[0805] Aspect 30. The compound according to aspect 29, wherein R 1 Yes-CH 2 CN.

[0806] Aspect 31. The compound according to aspect 29, wherein R 1 Yes CH 3 .

[0807] Aspect 32. A compound according to any one of aspects 1 to 31, wherein R 2 It's H.

[0808] Aspect 33. A compound according to any one of aspects 1 to 31, wherein R 2 is an optionally substituted C 1 -C 6 alkyl.

[0809] Aspect 34. The compound according to aspect 33, wherein R 2 is unsubstituted C 1 -C 6 Alkyl groups, such as CH 3 .

[0810] Aspect 35. The compound according to aspect 33, wherein R 2 is replaced by C 1 -C 6 alkyl.

[0811] Aspect 36. The compound according to aspect 35, wherein the C 1 -C 6 Alkyl is -NHSO 2 (C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl)SO 2 (C 1 -C 6 alkyl), 5- to 6-membered heterocycloalkyl, -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl) 2 or -P(O)R 4b R 4c Substitution, where R 4b and R4c Independently C 1 -C 6 Alkyl; or R 4b and R 4c Together with the phosphorus atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring.

[0812] Aspect 37. The compound according to aspect 36, wherein R 2 Yes-CH 2 -NHSO 2 (CH 3 ),-CH 2 -N(CH 3 )SO 2 (CH 3 ), -CH 2 -NH(CH 3 ),-CH 2 -NH(-CH(CH 3 ) 2 ),-CH 2 -N(CH 3 ) 2 or -CH 2 P(O)(CH 3 ) 2 .

[0813] Aspect 38. A compound according to any one of aspects 1 to 31, wherein R 2 Yes - NR 3 R 4 .

[0814] Aspect 39. The compound according to aspect 38, wherein R 3 It's H.

[0815] Aspect 40. The compound according to aspect 38, wherein R 3 It is C 1 -C 6 Alkyl groups, such as CH 3 .

[0816] Aspect 41. A compound according to any one of aspects 38 to 40, wherein R 4 It's H.

[0817] Aspect 42. A compound according to any one of aspects 38 to 40, wherein R 4 is an optionally substituted C 1 -C 6 alkyl.

[0818] Aspect 43. The compound according to aspect 42, wherein R 4is unsubstituted C 1 -C 6 Alkyl groups, such as CH 3 or -CH 2 CH 3 、-CH(CH 3 ) 2 .

[0819] Aspect 44. The compound according to aspect 42, wherein R 4 Yes-CH 2 CH(CH 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3 ,

[0820] Aspect 45. The compound according to aspect 42, wherein R 4 is replaced by C 1 -C 6 alkyl.

[0821] Aspect 46. The compound according to aspect 45, wherein R 4 Yes-CH 2 -cyclopropyl, -CH 2 CH 2 CHF 2 、-CH 2 CHF 2 、-CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 、-CH 2 CH 2 O-iso-Pr, -CH 2 C(CH 3 ) 2 OH, -CH 2 CHCH 3 OH, -CH 2 CHOCH 3 、-C(O)CH 2 N(C 1 -C 6 alkyl) 2 ,

[0822] Aspect 47. A compound according to any one of aspects 38 to 40, wherein R 4 is an optionally substituted C2 -C 6 Alkenyl, such as -CH 2 CH=CH 2 .

[0823] Aspect 48. A compound according to any one of aspects 38 to 40, wherein R 4 It is C 3 -C 5 Cycloalkyl, such as cyclobutyl.

[0824] Aspect 49. A compound according to any one of aspects 38 to 40, wherein R 4 It is a 3- to 6-membered heterocycloalkyl group.

[0825] Aspect 50. The compound according to aspect 49, wherein the 3- to 6-membered heterocycloalkyl group is oxetan-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl,

[0826] Aspect 51. A compound according to any one of aspects 38 to 40, wherein R 4 is C(O)CH 2 NR 4d R 4e , such as C(O)CH 2 N(C 1 -C 6 alkyl) 2 or C(O)CH 2 N(CH 3 ) 2 .

[0827] Aspect 52. The compound according to aspect 38, wherein R 3 and R 4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C 6 The substituent of alkoxy, F or OH is optionally substituted 3- to 6-membered heterocycloalkyl.

[0828] Aspect 53. The compound according to aspect 38, wherein R 3 and R 4 Together with the N atom to which they are both attached they form an unsubstituted 3- to 6-membered heterocycloalkyl group such as pyrrolidin-1-yl, azetidin-1-yl or morpholin-4-yl.

[0829] Aspect 54. The compound according to aspect 38, wherein R 3 and R 4Together with the N atom to which they are both attached, they form a substituted 3- to 6-membered heterocycloalkyl group such as 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphorinan-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0830] Aspect 55. A compound according to any one of aspects 1 to 31, wherein R 2 Yes-OR 4a .

[0831] Aspect 56. The compound according to aspect 55, wherein R 4a It's H.

[0832] Aspect 57. The compound according to aspect 55, wherein R 4a is an optionally substituted C 1 -C 6 alkyl.

[0833] Aspect 58. The compound according to aspect 57, wherein R 4a is unsubstituted C 1 -C 6 Alkyl groups, such as -CH(CH 3 ).

[0834] Aspect 59. The compound according to aspect 57, wherein R 4a is replaced by C 1 -C 6 alkyl.

[0835] Aspect 60. The compound according to aspect 59, wherein R 4a Yes-CH 2 CH 2 OH or -CH 2 C(CH 3 ) 2 OH.

[0836] Aspect 61. A compound according to any one of aspects 1 to 31, wherein R 2 Yes-P(O)R 4b R 4c .

[0837] Aspect 62. A compound according to any one of aspects 1 to 31, wherein R 2 Yes-SO 2 R 3 .

[0838] Aspect 63. A compound according to any one of aspects 1 to 27, wherein R 1 and R 2Together with the carbon atoms to which they are both attached, they form a 3- to 5-membered cycloalkyl ring, such as a cyclopropyl ring.

[0839] Aspect 64. The compound according to aspect 13, wherein the compound of formula (IA) is a compound of formula (IA-1):

[0840] or a pharmaceutically acceptable salt thereof.

[0841] Aspect 65. The compound according to aspect 13, wherein the compound of formula (IA) is a compound of formula (IA-2):

[0842]

[0843] or a pharmaceutically acceptable salt thereof.

[0844] Aspect 66. The compound according to Aspect 13, wherein the compound of formula (IA) is a compound of formula (IA-3):

[0845]

[0846] or a pharmaceutically acceptable salt thereof.

[0847] Aspect 67. The compound according to Aspect 13, wherein the compound of formula (IA) is a compound of formula (IA-4):

[0848]

[0849] or a pharmaceutically acceptable salt thereof.

[0850] Aspect 68. The compound according to Aspect 13, wherein the compound of formula (IA) is a compound of formula (IA-5):

[0851]

[0852] or a pharmaceutically acceptable salt thereof.

[0853] Aspect 69. A compound according to any one of aspects 64 to 68, wherein R 5 It's H.

[0854] Aspect 70. A compound according to any one of aspects 64 to 68, wherein R 5 Yes CH 3 .

[0855] Aspect 71. A compound according to any one of aspects 64 to 70, wherein R 7 It's H.

[0856] Aspect 72. A compound according to any one of aspects 64 to 70, wherein R 7 It's F.

[0857] Aspect 73. A compound according to any one of aspects 64 to 70, wherein R 7 OCH 3 .

[0858] Aspect 74. A compound according to any one of aspects 64 to 73, wherein R 2 is an optionally substituted C 1 -C 6 alkyl.

[0859] Aspect 75. The compound according to aspect 74, wherein R 2 Yes CH 3 、-CH 2 -NHSO 2 (CH 3 ),-CH 2 -N(CH 3 )SO 2 (CH 3 ), -CH 2 -NH(CH 3 ),-CH 2 -NH(-CH(CH 3 ) 2 ),-CH 2 -N(CH 3 ) 2 or -CH 2 -P(O)(CH 3 ) 2 .

[0860] Aspect 76. A compound according to any one of aspects 64 to 73, wherein R 2 Yes - NR 3 R 4 .

[0861] Aspect 77. The compound according to aspect 76, wherein R 3 It's H.

[0862] Aspect 78. The compound according to aspect 76, wherein R 3 Yes CH 3 .

[0863] Aspect 79. A compound according to any one of aspects 76 to 78, wherein R 4 It's H.

[0864] Aspect 80. A compound according to any one of aspects 76 to 78, wherein R4 Yes CH 3 、-CH 2 CH 3 、-CH(CH 3 ),-CH 2 -cyclopropyl, -CH 2 CH 2 CHF 2 、-CH 2 CHF 2 、-CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 CHOCH 3 、-C(O)CH 2 N(CH 3 ) 2 ,

[0865] Aspect 81. A compound according to any one of aspects 76 to 78, wherein R 4 Yes-CH 2 CH(CH 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3 ,

[0866] Aspect 82. A compound according to any one of aspects 76 to 78, wherein R 4 Yes-CH 2 CH=CH 2 .

[0867] Aspect 83. A compound according to any one of aspects 76 to 78, wherein R 4 is cyclopropyl, cyclobutyl or cyclopentyl.

[0868] Aspect 84. A compound according to any one of aspects 76 to 78, wherein R 4 It is oxetane-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl,

[0869] Aspect 85. A compound according to any one of aspects 76 to 78, wherein R 4 is C(O)CH 2 N(CH 3) 2 .

[0870] Aspect 86. The compound according to aspect 76, wherein R 3 and R 4 Together with the nitrogen atoms to which they are connected, they form a 1 -C 6 Alkyl, C 1 -C 6 The substituent of the alkoxy group or OH is optionally substituted 3- to 6-membered heterocycloalkyl.

[0871] Aspect 87. The compound according to aspect 86, wherein R 3 and R 4 Together with the N atom to which they are both attached, they form 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphorinane-4-yl 1-oxide, 1-methyl-4-azaphosphorinane-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0872] Aspect 88. A compound according to any one of aspects 64 to 73, R 2 Yes-P(O)R 4b R 4c

[0873] Aspect 89. The compound according to any one of aspects 64 to 73, R 2 Yes-OR 4a .

[0874] Aspect 90. The compound according to aspect 89, wherein R 4a It is -CH(CH 3 ),-CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, cyclopropyl, cyclobutyl or cyclopentyl.

[0875] Aspect 91. The compound according to Aspect 13, wherein the compound of formula (IA) is a compound of formula (IA-6):

[0876]

[0877] or a pharmaceutically acceptable salt thereof.

[0878] Aspect 92. A pharmaceutical composition comprising a compound according to any one of Aspects 1 to 91 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0879] Aspect 93. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound according to any one of Aspects 1 to 91, or a pharmaceutically acceptable salt thereof.

[0880] Aspect 94. The method according to Aspect 93, wherein the disease or condition is cancer.

[0881] Aspect 95. The method according to Aspect 94, wherein the cancer is urothelial carcinoma, hepatocellular carcinoma, breast cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, bile duct carcinoma, gastric adenocarcinoma, non-small cell lung cancer, exocrine pancreatic cancer, oral cancer, prostate cancer, bladder cancer, colorectal cancer, renal cell carcinoma, neuroendocrine cancer, myeloproliferative neoplasms, head and neck (squamous), melanoma, leiomyosarcoma and / or sarcoma.

[0882] Aspect 96. The method according to Aspect 95, wherein the cancer is bladder cancer.

[0883] Aspect 97. The method according to Aspect 95, wherein the cancer is urothelial carcinoma.

[0884] Aspect 98. The method according to Aspect 95, wherein the cancer is hepatocellular carcinoma.

[0885] Aspect 99. The method according to any one of Aspects 94 to 98, wherein the cancer is a FGFR mutant cancer.

[0886] Aspect 100. The method according to aspect 93, wherein the disease or disorder is a developmental disorder.

[0887] Aspect 101. The method according to aspect 100, wherein the developmental disorder is achondroplasia.

[0888] Aspect 102. A method of inhibiting FGFR in a cell, the method comprising contacting the cell with a compound according to any one of aspects 1 to 91.

[0889] Examples

[0890] The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of making such compounds. It should be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations.

[0891] In several embodiments providing single enantiomers, the enantiomers can be separated by conventional means (chiral chromatography, preparation of diastereomeric salts, chiral derivatization, crystallization, enzymatic reactions, etc.) In several embodiments, chiral intermediate compounds are purified to prepare enantiomerically pure (or substantially enantiomerically pure, enantiomerically enriched, etc.) intermediates.

[0892] Scheme for 6-methoxyindazole Example 3

[0893]

[0894] Example 3. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(5-azaspiro[2.3]hexan-5-yl)nicotinonitrile

[0895]

[0896] Step 1. (E)-N'-(2-bromo-5-hydroxy-4-methoxybenzylidene)-4-methylbenzenesulfonylhydrazide. p-Toluenesulfonylhydrazide (0.56 g, 3.0 mmol, 1.0 equiv) was added to a solution of 2-bromo-5-hydroxy-4-methoxy-benzaldehyde (0.7 g, 3.0 mmol, 1.0 equiv) in methanol (7.0 mL) at room temperature. The resulting mixture was heated at 60 °C for 2 h. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and heptane (80 mL) was added to give a light yellow solid (1.21 g, 100%). LCMS m / z=399.0 (M+H).

[0897] Step 2.6-methoxy-1-tosyl-1H-indazole-5-ol. Copper (I) oxide (0.22 g, 1.5 mmol, 0.5 eq) was added to a solution of (E)-N'-(2-bromo-5-hydroxy-4-methoxybenzylidene)-4-methylbenzenesulfonyl hydrazide (1.2 g, 3.0 mmol, 1.0 eq) in isoamyl alcohol (30 mL) at room temperature. After heating at 132 °C for 2 hours, the mixture was cooled to room temperature and diluted with water (80 mL). The mixture was extracted with ethyl acetate (4x50 mL). The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated onto silica gel (8.0 g) and purified on a Biotage automated purification system (Biotage Silica, 50 g; 0% to 100% ethyl acetate in heptane) to give a light yellow solid (0.66 g, 70% yield). LCMS m / z = 319.1 (M+H).

[0898] Step 3. (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1-tosyl-1H-indazole. (1S)-1-(3,5-dichloro-4-pyridinyl)ethyl]methanesulfonate (0.57 g, 2.1 mmol, 1.0 equiv) and cesium carbonate (1.03 g, 3.2 mmol, 1.5 equiv) were added to a solution of 6-methoxy-1-tosyl-1H-indazol-5-ol (0.67 g, 2.1 mmol, 1.0 equiv) in acetonitrile (21 mL) at room temperature. After heating at 90 °C overnight, the mixture was cooled to room temperature and concentrated under reduced pressure onto silica gel (6.0 g). The product was purified on a Biotage automated purification system (Sorbtech silica, 40 g) using a gradient elution of 0% to 60% ethyl acetate in heptane to give a white solid (0.71 g, 70% yield). LCMS m / z = 492.1 (M+H).

[0899] Step 4. (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazole. 1 M tetrabutylammonium fluoride in THF (7.2 mL, 7.2 mmol, 18.0 equiv) was added to a solution of (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1-tosyl-1H-indazole (0.20 g, 0.4 mmol, 1.0 equiv) in tetrahydrofuran (4 mL) at room temperature. After heating at 50 °C for 4 days, the solvent was removed under reduced pressure. The residue was concentrated onto silica gel (2.0 g) and purified on a Biotage automated purification system (Sorbtech silica, 12 g) with a gradient elution of 0% to 100% ethyl acetate in heptane to give a white solid (74.7 mg, 54%). LCMS m / z = 338.0 (M+H).

[0900] Step 5. (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methoxy-1H-indazole. Potassium hydroxide (27.9 mg, 0.50 mmol, 2.25 equiv) and iodine (84.1 mg, 0.33 mmol, 1.5 equiv) were added to a solution of (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazole (74.7 mg, 0.22 mmol, 1.0 equiv) in N,N-dimethylformamide (2.2 mL) at 0°C. The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was diluted with ethyl acetate (10 mL) and washed with water (4x5 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure onto silica gel (1.5 g). The product was purified on a Biotage automated purification system (Sorbtech silica, 12 g) eluting with a gradient of 0% to 100% ethyl acetate in heptane to give an off-white solid (80 mg, 77%). LCMS m / z = 463.9 (M+H).

[0901] Step 6. 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. 5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-3-iodo-6-methoxy-1H-indazole (0.5 g, 1.1 mmol, 1 eq) was treated with 3,4-dihydro-2H-pyran (0.2 mL, 2.2 mmol, 2 eq) and p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol, 0.05 eq) in anhydrous dichloromethane (6 mL) at room temperature overnight. The mixture was diluted with dichloromethane (8 mL) and washed with water (8 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure onto silica gel (6 g). The residue was purified on a Biotage automated chromatography system (Sorbtech, 12 g silica column) eluting with a gradient of 0% to 20% ethyl acetate in heptane to give a white solid (510 mg, 86% yield). m / z = 548 (M+H).

[0902] Step 7. 5-Bromo-2-(5-azaspiro[2.3]hexane-5-yl)nicotinonitrile. 5-Bromo-2-chloropyridine-3-carbonitrile (0.50 g, 2.3 mmol, 1 eq.) in acetonitrile (13 mL) was treated with N,N-diisopropylethylamine (1.2 mL, 6.4 mmol, 3 eq.) and 5-azaspiro[2.3]hexane hydrochloride (0.30 g, 2.5 mmol, 1.1 eq.) at 60°C overnight. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure, then azeotroped with heptane (20 mL) and dried at 40°C under vacuum for 2 hours to give a yellow solid (0.57 g, 94%). LCMS m / z=264 (M+H).

[0903] Step 8A. 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-(5-azaspiro[2.3]hexan-5-yl)nicotinonitrile. 5-Bromo-2-(5-azaspiro[2.3]-hexan-5-yl)nicotinonitrile (264 mg, 1.0 mmol, 1 eq) in 1,4-dioxane (3.0 mL) was treated with [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (51 mg, 70.0 μmol, 0.07 eq), potassium acetate (0.29 g, 3.0 mmol, 3 eq) and bis(pinacol)diboron (508 mg, 2.0 mmol, 2 eq) at 100° C. for 3 h to give 2-(5-azaspiro[2.3]hexan-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile as confirmed by LCMS analysis (mz=312 (M+H)). Step 8B. Additional [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (51 mg, 70.0 μmol, 0.07 equiv), potassium carbonate (0.28 g, 2.0 mmol, 2.0 equiv), 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.41 g, 0.75 mmol, 0.75 equiv) and water (0.3 mL) were added and the mixture was heated at 100 °C overnight. After cooling to room temperature, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (4 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (Sorbtech 25 g silica column) eluting with a gradient of 0% to 100% ethyl acetate in heptane to give a yellow oil (305 mg, 66%). LCMS m / z = 605.2 (M+H).

[0904] Step 9. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(5-azaspiro[2.3]hexan-5-yl)nicotinonitrile trifluoroacetate. Trifluoroacetic acid (3.2 mL) was added to a solution of the product of step 8 (320 mg) in dichloromethane (3.2 mL) at room temperature. After stirring at room temperature for 4 hours, the volatiles were removed under reduced pressure and the residue was purified on an Interchim automated chromatography system (RediSep Rf GOLD 15g HP C18 column) eluting with a gradient of 0% to 100% acetonitrile in water to give the product (110 mg, trifluoroacetate, 34%) as a pale yellow solid with TFA. LCMS m / z=521.1 (free base) (M+H); 1H NMR (400 MHz, DMSO-d6) δ=12.96 (s, 1H), 8.73 (d, J=2.3 Hz, 1H), 8.59 (s, 2H), 8.09 (d, J=2.3 Hz, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 6.03-5.96 (m, 1H), 5.75 (s, 1H), 4.38 (s, 4H), 3.86 (s, 3H), 1.76 (d, J=6.6 Hz, 3H), 0.73 (s, 4H).

[0905]

[0906] Example 5.

[0907] Step 1. 5-((tert-butyldimethylsilyl)oxy)-6-fluoro-1H-indazole. Imidazole (10 g, 148 mmol) and tert-butyldimethylsilyl chloride (10.7 g, 71 mmol, 1.2 eq) were added sequentially to a solution of 6-fluoro-1H-indazole-5-ol (9 g, 59 mmol, 1.0 eq) in N,N-dimethylformamide (59 mL) at 0 °C. After stirring at room temperature for 3 hours. The mixture was diluted with ethyl acetate (120 mL), washed with water (4x60 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil (15.1 g, 99%). LCMS (ESI) m / z=267.1 (M+H). The material was used directly in the next step.

[0908]

[0136] Step 2. 5-((tert-Butyldimethylsilyl)oxy)-6-fluoro-3-iodo-1H-indazole. 5-((tert-Butyldimethylsilyl)oxy)-6-fluoro-1H-indazole (15.1 g, 57 mmol, 1.0 equiv) in dichloromethane (590 mL) was treated with potassium hydroxide (7.5 g, 128 mmol, 2.25 equiv) and iodine (22.6 g, 85 mmol, 1.5 equiv) at room temperature. After stirring overnight, the reaction was diluted with dichloromethane (1 L) and washed with water (1 L). The organic layer was separated, filtered through a pad of silica gel (20 g), which was washed with a 1:1 mixture of ethyl acetate in heptane (1 L). The filtrate was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil (16.5 g, 71% crude yield for 2 steps). LCMS m / z=393.0 (M+H). The material was used directly in the next step.

[0909] Step 3. 5-((tert-butyldimethylsilyl)oxy)-6-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. 5-((tert-butyldimethylsilyl)oxy)-6-fluoro-3-iodo-1H-indazole (16.5 g, 42 mmol, 1.0 equiv) in dichloromethane (420 mL) was treated with 3,4-dihydro-2H-pyran (7.7 mL, 84 mmol, 2.0 equiv) and p-toluenesulfonic acid (0.4 g, 2 mmol, 0.05 equiv) at room temperature. After stirring overnight, the reaction was diluted with dichloromethane (400 mL) and washed with saturated sodium bicarbonate (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure onto silica gel (60 g). The residue was purified by chromatography on a Biotage automated chromatography system (Biotage HC, 200 g, silica gel) using a gradient elution of 0% to 20% ethyl acetate in heptane to give a yellow oil (11.2 g, 56% yield over 3 steps). LCMS m / z = 477.1 (M+H).

[0910] Step 4. 6-Fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol. 5-((tert-butyldimethylsilyl)oxy)-6-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (11.2 g, 23.5 mmol, 1.0 equiv) in tetrahydrofuran (235 mL) was treated with 1 M tetrabutylammonium fluoride in THF (47 mL, 47 mmol, 2.0 equiv) at 0°C. After stirring at 0°C for 4 hours, the reaction was diluted with dichloromethane (800 mL) and washed with saturated sodium bicarbonate (300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure onto silica gel (30 g). The residue was purified by chromatography on a Biotage automated chromatography system (Biotage HC, 200 g, silica gel) using a gradient elution of 0% to 10% methanol in dichloromethane to give a white solid (8.07 g, 95%). LCMS m / z = 363.0 (M+H).

[0911] Step 5. 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A mixture of 6-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol (3.0 g, 8.3 mmol, 1.0 equiv), (1S)-1-(3,5-dichloro-4-pyridinyl)ethyl]methanesulfonate (2.3 g, 8.3 mmol, 1.0 equiv) and cesium carbonate (4.1 g, 12.4 mmol, 1.5 equiv) in acetonitrile (82 mL) was heated at 90° C. overnight. After cooling to room temperature, the reaction was diluted with ethyl acetate (200 mL) and washed with water (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure onto silica gel (30 g). The residue was purified by a Biotage automated chromatography system (Biotage HC, 200 g, silica gel) using a gradient elution of 0% to 100% ethyl acetate in heptane to give a white solid (3.0 g, 68%). LCMS m / z = M+H.

[0912] Step 6. 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-(5-azaspiro[2.3]hexan-5-yl)nicotinonitrile. A mixture of 5-bromo-2-(5-azaspiro[2.3]hexan-5-yl)nicotinonitrile (0.12 g, 0.45 mmol, 1.2 equiv), bis(pinacol)diboron (0.14 g, 0.54 mmol, 1.5 equiv), potassium acetate (66 mg, 0.67 mmol, 1.8 equiv) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (32 mg, 0.04 mmol, 0.1 equiv) in 1,4-dioxane (10 mL) was sparged with nitrogen for 10 min and then heated at 90 °C for 3 h to give 2-(5-azaspiro[2.3]hexan-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile. The mixture was cooled to room temperature, and potassium carbonate (0.16 g, 1.1 mmol, 3 eq.), water (1 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (32 mg, 0.04 mmol, 0.1 eq.) and 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-3-iodo-1-tetrahydropyran-2-ylindazole (0.20 g, 1 eq.) were added. The mixture was sparged with nitrogen for 10 minutes and then heated at 90 °C overnight. The mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were concentrated onto silica gel (6 g) under reduced pressure. The residue was purified on a Biotage automated chromatography system (Sorbtech, 25 g silica column) eluting with a gradient of 0% to 50% ethyl acetate in heptane to give a tan solid (173 mg, 78%) after drying overnight at 40°C under vacuum. LCMS m / z=593 (M+H).

[0913] Step 7. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-fluoro-1H-indazol-3-yl)-2-(5-azaspiro[2.3]hexan-5-yl)nicotinonitrile. 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-(5-azaspiro[2.3]hexan-5-yl)nicotinonitrile (171 mg, 0.28 mmol) was treated with a 1:1 mixture of dichloromethane and trifluoroacetic acid (4 mL) overnight. The mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and saturated sodium bicarbonate (20 mL). The layers were separated and the organic layer was concentrated onto silica gel (4 g). The residue was purified on a Biotage automated chromatography system (Sorbtech, 12 g silica gel column) with a gradient elution of 0% to 5% methanol in dichloromethane to give a tan solid. The product was further purified by preparative HPLC on a Gilson automated chromatography system (Waters Atlantis T3 Prep OBD column, 5 μm, 19x250 mm) with a gradient elution of 10% to 100% acetonitrile in water with 0.1% trifluoroacetic acid to give an off-white solid (25 mg, 14%) as a TFA salt after lyophilization. LCMS m / z=509(M+H); (free base); 1H NMR (400MHz, DMSO-d6) δ = 13.23 (s, 1H), 8.75 (d, J = 2.3Hz, 1H), 8.60 (s, 2H), 8.15 (d, J = 2.3Hz, 1H), 7.47 (d, J =10.9Hz, 1H), 7.26 (d, J = 7.8Hz, 1H), 6.18 (q, J = 6.6Hz, 1H), 4.40 (s, 4H), 1.80 (d, J = 6.7Hz, 3H), 0.74 (s, 4H).

[0914]

[0915] Example 6. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(3-((dimethylphosphoryl)methyl)-3-methylazetidin-1-yl)nicotinonitrile

[0916] Step 1. 3-(Bromomethyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester. To 3-(hydroxymethyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (500 mg, 2.50 mmol, 1.0 equiv) and PPh 3 To a solution of (1.3 g, 4.97 mmol, 2.0 equiv) in DCM (10.0 mL) was added CBr in portions4 (1.6 g, 4.97 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 5 h. After the reaction was complete, the mixture was concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (petroleum ether / EtOAc=5 / 1) to give a brown solid (620 mg, 94% yield). LCMS m / z=264.3 (M+H).

[0917] Step 2. 3-(Dimethylphosphorylmethyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester. 2 To a solution of methylphosphonomethane (507 mg, 6.50 mmol, 3.0 equiv) in THF (2 mL) was added NaHMDS (3.25 mL, 6.50 mmol, 2 M in THF, 3.0 equiv) dropwise at -70°C. The reaction mixture was stirred at room temperature for 1 h. 2 The mixture was protected and a solution of tert-butyl 3-(bromomethyl)-3-methyl-azetidine-1-carboxylate (570 mg, 2.17 mmol, 1.0 equiv) in THF (3 mL) was added dropwise at 0°C and stirred for 4 h. After the reaction was completed, the reaction was heated with saturated NH 4 The mixture was quenched with aqueous Cl (20 mL) at 0 °C and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2) and purified by Na 2 SO 4 Drying and concentration gave an off-white semi-solid (500 mg, 89% yield). LCMS m / z = 262.3 (M+H).

[0918] Step 3. 3-(Dimethylphosphorylmethyl)-3-methyl-azetidine. To a solution of tert-butyl 3-(dimethylphosphorylmethyl)-3-methyl-azetidine-1-carboxylate (450 mg, 1.73 mmol, 1.0 equiv) in DCM (10.0 mL) was added TFA (2.0 mL) and stirred at room temperature for 3 h. The mixture was concentrated to give a yellow oil as a TFA salt. LCMS m / z=162.3 (M+H).

[0919] Step 4. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-[3-(dimethylphosphorylmethyl)-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile. To a solution of 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-fluoro-pyridine-3-carbonitrile (190 mg, 0.37 mmol, 1.0 equiv) and 3-(dimethylphosphorylmethyl)-3-methyl-azetidine TFA salt (150 mg) in DMSO (5 mL) was added DIEA (240 mg, 1.86 mmol, 5.0 equiv). The reaction mixture was stirred at 90° C. for 16 h. After completion of the reaction, the reaction was diluted with EtOAc (20 mL), washed with brine (20 mL x 3) and concentrated. The crude product was purified by preparative TLC (DCM / MeOH=15 / 1) to give a yellow solid (120 mg, yield 50%). LCMS m / z=653.2 (M+H).

[0920] Step 5. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(3-((dimethylphosphoryl)methyl)-3-methylazetidin-1-yl)nicotinonitrile. To a solution of the product of step 4 (110 mg, 0.17 mmol, 1.0 equiv) in DCM (2 mL) was added TFA (0.4 mL) and stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was washed with saturated NaHCO 3 The solution was adjusted to pH 7-8 and extracted with DCM (10 mL x3). The combined organic layers were concentrated in vacuo. The crude product was purified by preparative HPLC (preparative C18, 5 μM Triart columns, 20 × 150 mm, YMC-Actus; from 15% MeCN in aqueous solution to 30% MeCN / with 0.05% NH 3 .H 20 water gradient elution) to give a white solid (58 mg, 61% yield). LCMS m / z=569.4 (M+H); 1H NMR (400MHz, DMSO-d6) δ13.17(brs,1H),8.76(d,J=2.4Hz,1H),8.57(s,2H),8.13( d,J=2.4Hz,1H),7.48(d,J=8.8Hz,1H),7.15(d,J=2.0Hz,1H),7.10(dd,J=8.8Hz,2 .4Hz,1H),6.13(q,J=6.8Hz,1H),4.27(d,J=8.4Hz,2H),4.03(d,J=8.8Hz,2H),2.2 3(d,J=10.8Hz,2H),1.75(d,J=6.8Hz,3H),1.56(s,3H),1.46(s,3H),1.43(s,3H).

[0921]

[0922] Example 8.

[0923] Step 1. 1-Benzhydryl-3-methylazetidine-3-yl methanesulfonate. Methanesulfonyl chloride (6.2 mL, 80 mmol, 2 eq) was added dropwise to a solution of 1-benzhydryl-3-methyl-azetidine-3-ol (10.13 g, 40 mmol, 1 eq) and triethylamine (14.0 mL, 100 mmol, 2.5 eq) in anhydrous dichloromethane (150 mL) at 0 °C. After stirring at 0 to 5 °C for 6 hours, water (50 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (3x50 mL). The combined organic layers were washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (220 g Sorbtech silica column) eluting with a gradient of 0% to 40% ethyl acetate in heptane to give a white solid (4.63 g, 35% yield). LCMS m / z=332 (M+H).

[0924] Step 2.1-benzhydryl-N-isopropyl-3-methylazetidine-3-amine dihydrochloride. A mixture of 1-benzhydryl-3-methylazetidine-3-yl methanesulfonate (4.14 g, 12.491 mmol, 1 equivalent) and isopropylamine (6.44 mL, 75 mmol, 6 equivalents) in 2-MeTHF (60 mL) was heated at 80 ° C for 24 hours in a sealed pressure bottle. LCMS analysis indicated that the reaction was complete. The mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (100 mL). The solid was filtered out and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether (100 mL) and a solution of 2M HCL in diethyl ether (40 mL, 80 mmol) was added. After stirring at room temperature for 30 minutes, the obtained solid was filtered and dried overnight under vacuum at 40 ° C to obtain a white solid (4.36 g, 95% yield) as a diHCl salt. LCMS m / z = 295 (free base) (M+H).

[0925] Step 3.N-isopropyl-3-methylazetidine-3-amine dihydrochloride. A mixture of 1-dibenzyl-N-isopropyl-3-methylazetidine-3-amine dihydrochloride (4.36g, 11.863mmol, 1 equivalent) and 20% palladium hydroxide (0.87g, 50% wet) in methanol (440mL) was hydrogenated at room temperature and 50psi for 16 hours. The mixture was filtered through diatomaceous earth and washed with methanol (3x40mL). The filtrate was concentrated under reduced pressure and the residue was wet-milled with heptane (5x20mL) to remove the by-product diphenylmethane. The residue was dried at 40°C and vacuum to obtain a yellow solid (2.58g,>100% yield) containing a small amount of diphenylmethane by-product. LCMS m / z=129 (free base) (M+H).

[0926] Step 4.5-bromo-2-(3-(isopropylamino)-3-methylazetidine-1-yl)nicotinonitrile. N,N-diisopropylethylamine (1.74 mL, 10 mmol, 5 eq) was added to a mixture of N-isopropyl-3-methylazetidine-3-amine dihydrochloride (0.402 g, 2 mmol, 1 eq) in acetonitrile (10 mL). After stirring at room temperature for 10 minutes, 5-bromo-2-chloro-3-cyano-pyridine (0.435 g, 2 mmol, 1 eq) was added and the mixture was stirred at room temperature over the weekend. The mixture was pre-adsorbed onto diatomaceous earth (10 g) under reduced pressure and purified on an Interchim automated chromatography system (RediSep Rf GOLD 100 g HP C18 column) with a gradient elution of 0% to 100% acetonitrile in water to give a yellow solid (0.36 g, 58% yield). LCMS m / z=310 (M+H).

[0927] Step 5. 2-(3-(isopropylamino)-3-methylazetidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile. A mixture of 5-bromo-2-(3-(isopropylamino)-3-methylazetidin-1-yl)nicotinonitrile (0.36 g, 1.164 mmol, 1 eq), bis(pinacol)diboron (0.443 g, 1.746 mmol, 1.5 eq), potassium acetate (0.228 g, 2.328 mmol, 2 eq) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (85 mg, 0.116 mmol, 0.1 eq) in 1,4-dioxane (15 mL) was sparged with nitrogen for 15 min and then heated at 90° C. for 16 h. LCMS analysis indicated that the reaction of the mixture of borane and boronic acid was complete. The reaction mixture was cooled to room temperature and then used in the next step. LCMS m / z=275 (boronic acid) and 357 (M+H).

[0928] Step 6. 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-(3-(isopropylamino)-3-methylazetidin-1-yl)nicotinonitrile. The reaction mixture from the previous step (0.588 mmol, 1.5 eq) in 1,4-dioxane was treated with 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.215 g, 0.392 mmol, 1 eq), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.05 mmol, 0.1 eq) and potassium carbonate (0.108 g, 0.784 mmol, 2 eq) and water (1.0 mL). After sparging with nitrogen for 10 minutes, the reaction was heated at 90° C. for 20 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on an Interchim automated chromatography system (Sorbtech 40 g silica gel column) using a gradient elution of 0% to 10% methanol in dichloromethane to give a brown solid (0.250 g, 85% purity, 98% yield over 2 steps). LCMS m / z=650 (M+H).

[0929] Step 7. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(3-(isopropylamino)-3-methylazetidin-1-yl)nicotinonitrile. Trifluoroacetic acid (2.5 mL) was added to a solution of 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-(3-(isopropylamino)-3-methylazetidin-1-yl)nicotinonitrile (0.250 g, 0.384 mmol, 1.0 equiv) in dichloromethane (2.5 mL) at room temperature. After stirring at room temperature for 20 h, the volatiles were removed under reduced pressure. The residue was dry loaded onto celite (8 g) and purified on an InterChim automated chromatography system (RediSep Rf GOLD 50 g HP C18 column) eluting with a gradient of 0% to 100% acetonitrile in water to give a white solid as a TFA salt (96 mg, 44% yield). LCMS m / z=566 (free base) (M+H); 1H NMR (400 MHz, DMSO-d6) δ=9.20 (br s, 2H), 8.79 (d, J=2.2 Hz, 1H), 8.58 (s, 2H), 8.19 (d, J=2.3 Hz, 1H), 7.06 (s, 1H), 7.02 (s, 1H), 6.03-5.97 (m, 1H), 4.49 (d, J=9.7 Hz, 2H), 4.34 (d, J=9.4 Hz, 2H), 3.86 (s, 3H), 3.55 (br s, 1H), 3.33 (br s, 3H), 1.79-1.75 (m, 3H), 1.26 (d, J=6.4 Hz, 6H).

[0930]

[0931] Example 9. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[3-methyl-3-(methylamino)azetidin-1-yl]pyridine-3-carbonitrile

[0932] Step 1. (1-(5-bromo-3-cyanopyridin-2-yl)-3-methylazetidine-3-yl)(methyl)carbamic acid tert-butyl ester. A mixture of 5-bromo-2-chloro-pyridine-3-carbonitrile (326 mg, 1.5 mmol, 1.0 equiv), N-methyl-N-(3-methylazetidine-3-yl)carbamic acid tert-butyl ester HCl (355 mg, 1.5 mmol, 1.0 equiv) and N,N-diisopropylethylamine (1.4 mL, 8.1 mmol, 5.3 equiv) in acetonitrile (10 mL) was heated at 70 ° C. After 24 hours, the reaction was cooled to room temperature and diluted with water (70 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with saturated brine (30 mL), dried over magnesium sulfate, filtered and concentrated to give a yellow oil (460 mg, 80% yield) after drying at 50° C. under vacuum for 16 h. LCMS m / z=381 (M+H).

[0933] Step 2. Tert-butyl (1-(3-cyano-5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)-3-methylazetidin-3-yl)(methyl)carbamate. Tert-butyl (1-(5-bromo-3-cyanopyridin-2-yl)-3-methylazetidin-3-yl)(methyl)carbamate (150 mg, 0.39 mmol, 1.0 equiv) in 1,4-dioxane (5 mL) was treated with [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (20 mg, 0.03 mmol, 0.07 equiv), bis(pinacol)diboron (109 mg, 0.43 mmol, 1.1 equiv) and potassium acetate (46 mg, 0.47 mmol, 1.2 equiv). The mixture was sparged with argon for 5 minutes and then heated at 90°C. After 15 hours, the reaction mixture was cooled to room temperature. 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-6-methoxy-1-tetrahydropyran-2-yl-indazole (215 mg, 0.39 mmol, 1.00 equiv), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (28 mg, 0.04 mmol, 0.1 equiv), potassium carbonate (162 mg, 1.17 mmol, 3.0 equiv) and water (1.5 mL) were added and the mixture was sparged with argon for 5 minutes. After heating at 90 ° C for 16 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL) and saturated aqueous sodium carbonate solution (35 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x20 mL). The combined organic layer was washed with saturated brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (50 g Biotage, 20 μm silica column) using a gradient elution of 0% to 60% ethyl acetate in heptane to give a light yellow oil (110 mg, 38% yield). LCMS m / z=722 (M+H).

[0934] Step 3. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-methyl-3-(methylamino)azetidine-1-yl)nicotinonitrile. A solution of the product of step 2 (110 mg, 0.15 mmol, 1.0 equiv) in dichloromethane (5 mL) was treated with trifluoroacetic acid (3 mL) at room temperature. After 16 hours, the reaction mixture was cooled to 0 ° C and quenched with saturated sodium bicarbonate (50 mL). The mixture was extracted with dichloromethane (2x15 mL). The combined organic layers were washed with saturated brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100g HP C18 column) with a gradient elution of 0% to 100% acetonitrile in water. The pure fractions were lyophilized to give a white solid (25 mg, 31% yield). LCMS m / z=538.1 (M+H); 1H NMR (400 MHz, DMSO-d6) δ=12.96 (s, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.59 (s, 2H), 8.07 (d, J=2.4 Hz, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 6.00 (q, J=6.6 Hz, 1H), 4.18-4.08 (m, 2H), 4.08-3.98 (m, 2H), 3.86 (s, 3H), 2.28 (s, 3H), 1.76 (d, J=6.8 Hz, 3H), 1.51-1.38 (m, 3H).

[0935]

[0936] Example 10. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[3-(dimethylamino)-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile

[0937] Step 1.5-Bromo-2-(3-(dimethylamino)-3-methylazetidin-1-yl)nicotinonitrile. 5-Bromo-2-chloro-pyridine-3-carbonitrile (0.53 g, 2.43 mmol, 1 eq.) in acetonitrile (15 mL) was treated with N,N-3-trimethylazetidin-3-amine HCl (0.5 g, 2.67 mmol, 1.1 eq.) and N,N-diisopropylethylamine (0.94 g, 7.28 mmol, 3 eq.) at 60 °C. After 13 hours, the reaction mixture was cooled to room temperature and diluted with water (70 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with saturated brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid (0.65 g, 91% yield). LCMS m / z = 295.0 (M+H).

[0938] Step 2. 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-(3-(dimethylamino)-3-methylazetidin-1-yl)nicotinonitrile. 5-Bromo-2-(3-(dimethylamino)-3-methylazetidin-1-yl)nicotinonitrile (295 mg, 1.0 mmol, 1 eq) in 1,4-dioxane (3.0 mL) was treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (51 mg, 70.0 μmol, 0.07 eq), potassium acetate (0.29 g, 3.0 mmol, 3 eq), bis(pinacol)diboron (508 mg, 2.0 mmol, 2 eq) at 100° C. for 3 hours. LCMS analysis confirmed the product. Additional 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (51 mg, 70.0 μmol, 0.07 equiv), potassium carbonate (0.28 g, 2.0 mmol, 2.0 equiv), 5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-3-iodo-6-methoxy-1-tetrahydropyran-2-yl-indazole (0.41 g, 0.75 mmol, 0.75 equiv) and water (0.3 mL) were then added. After heating at 100 °C overnight, the reaction was cooled to room temperature and diluted with water (20 mL). The mixture was extracted with ethyl acetate (4 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (Sorbtech 25 g silica column) eluting with a gradient of 0% to 100% ethyl acetate in heptane to give a dark red oil (340 mg, 57% yield). LCMS m / z = 636.3 (M+H).

[0939] Step 3. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(3-(dimethylamino)-3-methylazetidin-1-yl)nicotinonitrile trifluoroacetate. Trifluoroacetic acid (3.0 mL) was added to a solution of the product of step 2 (300 mg) in dichloromethane (3.0 mL) at room temperature. After stirring for 3 hours at room temperature, the volatiles were removed under reduced pressure. The residue was purified on an Interchim automated chromatography system (RediSep Rf GOLD 15g HP C18 column) with a gradient elution of 0% to 100% acetonitrile in water to give a light yellow solid (95 mg, trifluoroacetate, 33% yield). LCMS m / z=552.1(M+H); 1H NMR(400MHz, DMSO-d6)δ=13.04(br s,1H),10.63(br s,1H),8.78(d,J=2.2Hz,1H),8.59(s,2H),8.20(d,J=2.3Hz,1H),7.06(s,1H),7.03(s,1H),6.03-5.97(m,1H),4.51(br d,J=10.1Hz,2H),4.26(d,J=10.0Hz,2H),3.87(s,3H),2.80(br s,6H),1.77(d,J=6.6Hz,3H),1.68(s,3H).

[0940]

[0941] Example 14. 2-[3-(Cyclopropylmethylamino)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1H-indazol-3-yl]pyridine-3-carbonitrile

[0942] Step 1. To a solution of [1-[3-cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridinyl]-3-methyl-azetidin-3-yl]methanesulfonate (300 mg, 0.43 mmol, 1.0 equiv) and cyclopropylmethylamine (310 mg, 4.36 mmol, 10.0 equiv) in ACN (10 mL) was added t-BuONa (126 mg, 1.31 mmol, 3.0 equiv). The reaction mixture was stirred at 90 °C for 2 h. After completion of the reaction, EtOAc (20 mL) was added to the mixture, the organic layer was washed with brine (20 mL x 2), and Na 2 SO 4Dry and concentrate in vacuo. The crude product was purified by preparative TLC (DCM / MeOH=20 / 1) to give a yellow oil (190 mg, 66% yield). LCMS m / z=662.3 (M+H).

[0943] Step 2. 2-[3-(Cyclopropylmethylamino)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1H-indazol-3-yl]pyridine-3-carbonitrile To a solution of the product of step 1 (190 mg, 0.29 mmol, 1.0 eq.) in DCM (5 mL) was added TFA (1 mL) and stirred at room temperature for 16 h. Upon completion, the reaction mixture was concentrated in vacuo. The crude product was treated with DCM / MeOH (5:1, 10 mL) and NaHCO 3 The solid was added to the solution and stirred for 20 minutes. The solid was filtered off and the filtrate was concentrated. The residue was purified by preparative HPLC (preparative C18, 5 μM Triart column, 20×150 mm, YMC-Actus; gradient elution from 40% MeCN in water to 65% MeCN in water over 8 min, with both solvents containing 0.05% NH 3 ·H 2 O) to give a white solid (54 mg, 32% yield). LCMS m / z=578.30 (M+H); 1H NMR(400MHz,DMSO-d6)δ12.96(brs,1H),8.71(d,J=2.0Hz,1H),8.59(s,2H),8.0 6(d,J=2Hz,1H),7.03(s,1H),7.00(s,1H),6.00(q,J=6.4Hz,1H),4.14(d,J=8.4 Hz, 2H), 4.02 (d, J = 8.4Hz, 2H), 3.86 (s, 3H), 2.42 (d, J = 6.4Hz, 2H), 1.76 (d, J = 6. 4Hz,3H),1.43(s,3H),0.93-0.82(m,1H),0.44-0.38(m,2H),0.17-0.14(m,2H).

[0944] Example 15. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-(3-methyl-3-pyrrolidin-1-yl-azetidin-1-yl)pyridine-3-carbonitrile

[0945]

[0946] To a solution of [1-[3-cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridinyl]-3-methyl-azetidin-3-yl] methanesulfonate (300 mg, 0.44 mmol, 1.0 equiv), DMAP (107 mg, 0.87 mmol, 2.0 equiv) and pyrrolidine (621 mg, 8.76 mmol, 20.0 equiv) in ACN (6 mL) was added t-BuONa (214 mg, 2.18 mmol, 5.0 equiv). The reaction mixture was stirred at 80 ° C for 6 h. After completion of the reaction, the mixture was diluted with EtOAc (100 mL) and washed with brine (20 mLx5). The organic layer was purified by Na 2 SO 4 Dried and concentrated. The crude product was purified by preparative TLC (DCM / MeOH=20 / 1) to give a yellow solid (120 mg, yield 42%). LCMS m / z=662.1 (M+H).

[0947] Step 2. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-(3-methyl-3-pyrrolidin-1-yl-azetidin-1-yl)pyridine-3-carbonitrile. To a solution of the product of step 1 (120 mg, 0.18 mmol, 1.0 eq.) in DCM (4 mL) was added TFA (2 mL). The solution was stirred at room temperature for 3 h. After completion of the reaction, the mixture was concentrated in vacuo. The crude product was washed with saturated NaHCO 3 The solution was basified and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2) and purified by Na 2 SO 4 The residue was purified by preparative HPLC (preparative C18, 5 μM Triart column, 20×150 mm, YMC-Actus; gradient elution from 40% to 50% MeCN in water (containing 0.05% NH 3 ·H 2(O)) to give a light yellow solid (55 mg, 53% yield). LCMS m / z=578.3(M+1); 1H NMR (400MHz, DMSO-d6) δ12.97(brs,1H),8.71(d,J=2.0Hz,1H),8.59(s,2H),8.07(d,J=2.4Hz,1H),7.04(s,1H),7.00(s,1H),6.00(q,J= 6.4Hz,1H),4.31-4.29(m,2H),4.00-3.98(m,2H),3.86(s,3H),2.66-2.58(m,4H),1.76(d,J=6.4Hz,3H),1.74-1.68(m,4H),1.45(s,3H).

[0948]

[0949] Example 17. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(3-methyl-3-(pyrrolidin-1-yl)azetidin-1-yl)nicotinonitrile

[0950] Step 1. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-(3-methyl-3-pyrrolidin-1-yl-azetidin-1-yl)pyridine-3-carbonitrile. To a solution of [1-[3-cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridinyl]-3-methyl-azetidin-3-yl] methanesulfonate (250 mg, 0.38 mmol, 1.0 equiv) and pyrrolidine (540 mg, 7.60 mmol, 20.0 equiv) in ACN (250 mL) was added t-BuONa (182 mg, 1.90 mmol, 5.0 equiv) at 25 °C. The reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the mixture was concentrated and the residue was diluted with DCM (100 mL). The organic layer was washed with water (50 mL x 2) and brine (50 mL x 2) and purified by Na 2 SO 4 Dried and concentrated. The crude product was purified by silica gel column (DCM / MeOH=15 / 1) to give a yellow solid (160 mg, 66% yield). LCMS m / z=642.3 (M+H).

[0951] Step 2. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(3-methyl-3-(pyrrolidin-1-yl)azetidin-1-yl)nicotinonitrile. To a solution of the product of step 1 (160 mg, 0.25 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 4 h. Upon completion, the solution was concentrated under vacuum. The crude product was treated with DCM / MeOH (V:V=5:1, 20 mL), and NaHCO was added. 3 The solid was stirred for 30 minutes. The solid was filtered off and the filtrate was concentrated. The residue was purified by preparative HPLC (preparative C18, 5 μM Triart column, 20×150 mm, YMC-Actus; 40% MeCN in water to 60% MeCN containing 0.05% NH 3 .H 2 O in water (gradient elution) to give a yellow solid (47 mg, 34% yield). LCMS m / z=548.2(M+H); 1H NMR (400MHz, DMSO-d6) δ13.17(s,1H),8.76(d,J=2.4Hz,1H),8.57(s,2H),8.14(d,J=2.4Hz,1H),7.48(d,J=9.2Hz,1H),7.16(d,J=2.0Hz,1H),7.1 1(dd,J=8.8Hz,2.0Hz,1H),6.14(q,J=6.4Hz,1H),4.30(d,J=8.8Hz,2H), 3.99(d,J=8.8Hz,2H),2.69-2.59(m,4H),1.79-1.70(m,7H),1.45(s,3H).

[0952]

[0953] Example 27. 2-[3-(Cyclopropylmethylamino)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1H-indazol-3-yl]pyridine-3-carbonitrile

[0954] Step 1. 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A mixture of 3-iodo-1-tetrahydropyran-2-yl-indazol-5-ol (1.0 g, 2.90 mmol, 1.0 equiv), [(1S)-1-(3,5-dichloro-4-pyridinyl)ethyl]methanesulfonate (780 mg, 2.90 mmol, 1.0 equiv) and cesium carbonate (1.41 g, 14.45 mmol, 1.5 equiv) in N,N-dimethylformamide (20 mL) was heated at 130 °C for 16 h. The volatiles were removed under reduced pressure and the residue was suspended in saturated ammonium chloride (50 mL). The solution was extracted with ethyl acetate (3x50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on a Büchi automated chromatography system (Sorbtech 40 g silica column) eluting with a gradient of 0% to 30% ethyl acetate in heptane to give a white solid (1.01 g, 88% yield). LCMS m / z = 517.2 (M+H).

[0955] Step 2. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-fluoro-pyridine-3-carbonitrile. To a solution of 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (5.0 g, 9.65 mmol, 1.0 equiv) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (3.11 g, 12.54 mmol, 1.3 equiv) in dioxane (100 mL) and water (10 mL) was added K 2 CO 3 (2.66 g, 19.30 mmol, 1.0 equiv) and Pd(dppf)Cl 2 (705 mg, 0.965 mmol, 0.1 eq.). 2 and stirred at 90 °C for 2 h. After cooling to room temperature, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (100 mL) and purified by anhydrous Na2SO 4 Dry, filter and concentrate. The crude product was purified by silica gel chromatography (petroleum ether / EtOAc=3 / 1) to give a white solid (4.8 g, 97% yield). LCMS m / z=512.2 (M+H).

[0956] Step 3. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-(3-hydroxy-3-methyl-azetidin-1-yl)pyridine-3-carbonitrile. To a solution of 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-fluoro-pyridine-3-carbonitrile (3.2 g, 6.25 mmol, 1.0 equiv) and 3-methylazetidin-3-ol (1.54 g, 12.49 mmol, 2.0 equiv) in DMSO (10 mL) was added DIEA (2.42 g, 18.74 mmol, 3.0 equiv) at 25 °C. The resulting solution was stirred at 90 °C for 3 h, cooled to room temperature, quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (30 mL) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate. The crude product was purified by silica gel chromatography (petroleum ether / EtOAc=2 / 1) to give a white solid (3.1 g, 86% yield). LCMS m / z=579.3 (M+H).

[0957] Step 4. [1-[3-cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridinyl]-3-methyl-azetidin-3-yl] methanesulfonate. To a solution of the step 3 product (3.1 g, 5.35 mmol, 1.0 equiv) in DCM (50 mL) was added TEA (1.08 g, 10.7 mmol, 2.0 equiv). Methanesulfonyl chloride (738 mg, 6.42 mmol, 1.2 equiv) was added dropwise at 0°C. The resulting solution was stirred at room temperature for 2 hours and concentrated. The crude product was purified by silica gel chromatography (petroleum ether / EtOAc=3 / 1) to give a white solid (3.3 g, 94% yield). LCMS m / z=657.2 (M+1).

[0958] Step 5. 2-[3-(Cyclopropylmethylamino)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]pyridine-3-carbonitrile. To a solution of the product of step 4 (250 mg, 0.381 mmol, 1.0 equiv) and cyclopropylmethylamine (271 mg, 3.81 mmol, 10.0 equiv) in ACN (5 mL) was added t-BuONa (183 mg, 1.91 mmol, 5.0 equiv) at 25°C. The resulting mixture was heated under N 2and stirred at 90°C for 12 h. After cooling to room temperature, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were purified by anhydrous Na 2 SO 4 Dry, filter and concentrate. The crude product was purified by silica gel chromatography (petroleum ether / EtOAc=1 / 1) to give a yellow solid (180 mg, 73% yield). LCMS m / z=632.3 (M+H).

[0959] Step 6. 2-[3-(Cyclopropylmethylamino)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1H-indazol-3-yl]pyridine-3-carbonitrile. To a solution of the product of step 5 (180 mg, 0.285 mmol) in DCM (1 mL) was added TFA (0.5 mL) and stirred for 3 h at room temperature. After completion, the reaction was concentrated in vacuo. The crude product was treated with DCM / MeOH (5:1, 10 mL) and solid NaHCO 3 Add to the solution and stir for 20 minutes. Filter out the solid and concentrate the filtrate. The residue was purified by preparative TLC (petroleum ether / EtOAc=1 / 1) to give a yellow solid (54 mg, 35% yield). LCMS m / z=548.3 (M+H); 1H NMR (400MHz, DMSO-d6) δ13.17 (s, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.57 (s, 2H), 8.12 (d, J=2.4 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.11 (dd, J=8.8 Hz, 2.0 Hz, 1H), 6.14 (q,J=6.8Hz,1H),4.14(d,J=8.8Hz,2H),4.03(d,J=8.4Hz,2H),2.41(d,J=7.2Hz,2H),1.7 6(d,J=6.4Hz,3H),1.42(s,3H),0.90-0.83(m,1H),0.44-0.38(m,2H),0.17-0.13(m,2H).

[0960]

[0961] Example 34.

[0962] Step 1. 4-(1-Benzhydryl-3-methyl-azetidin-3-yl)morpholine. To a solution of (1-benzhydryl-3-methyl-azetidin-3-yl)methanesulfonate (880 mg, 2.65 mmol, 1.0 eq.) and morpholine (692 mg, 7.95 mmol, 3.0 eq.) in MeCN (10 mL) was added Cs 2 CO 3 (2.58 g, 7.95 mmol, 3.0 equiv.). The reaction mixture was stirred at 80 °C for 16 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), washed with brine (20 mL x 2) and concentrated. The crude product was purified by silica gel flash column chromatography (petroleum ether / EtOAc=2 / 1) to give a yellow solid (680 mg, 79% yield). LCMS m / z=323.3 (M+H).

[0963] Step 2. 4-(3-methylazetidin-3-yl)morpholine. To a solution of 4-(1-benzhydryl-3-methyl-azetidin-3-yl)morpholine (580 mg, 1.80 mmol, 1.0 equiv) in MeOH (20 mL) was added Pd / C (580 mg, 1.0% wt). The suspension was degassed under vacuum and charged with hydrogen three times and heated in H 2 Balloon and stirred at room temperature for 16 h. After the reaction was complete, the solid was filtered off and the filtrate was concentrated to give a yellow oil (600 mg, crude material). The material was used directly in the next step. LCMS m / z=157.3 (M+H).

[0964] Step 3. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-(3-methyl-3-morpholino-azetidin-1-yl)pyridine-3-carbonitrile. To a solution of 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-fluoro-pyridine-3-carbonitrile (400 mg, 0.78 mmol, 1.0 equiv) and 4-(3-methylazetidin-3-yl)morpholine (300 mg, crude) in DMSO (5.0 mL) was added DIEA (805 mg, 6.24 mmol, 8.0 equiv). The reaction mixture was stirred at 80° C. for 2 h. After the reaction was completed, the mixture was diluted with EtOAc (40 mL), washed with brine (30 mL x 2) and concentrated. The crude product was purified by silica gel flash column chromatography (DCM / MeOH=20 / 1) to give a yellow solid (320 mg, 63% yield). LCMS m / z=648.3 (M+H).

[0965] Step 4. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1H-indazol-3-yl]-2-(3-methyl-3-morpholino-azetidin-1-yl)pyridine-3-carbonitrile. To a solution of the product of step 3 (290 mg, 0.45 mmol, 1.0 eq.) in DCM (5 mL) was added TFA (1 mL) and stirred at 25 °C for 3 h. After completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was purified by addition of saturated NaHCO 3 The pH of the crude product was adjusted to 7-8 and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 The crude product was purified by preparative HPLC (preparative C18, 5 μM Triart column, 20×150 mm, YMC-Actus; from 35% MeCN in water to 60% MeCN with 0.05% NH 3 .H 2 O in water (gradient elution) to give a white solid (151 mg, 60% yield). LCMS m / z=564.3 (M+H); 1H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 8.76 (d, J = 2.4Hz, 1H), 8.57 (s, 2H), 8. 15(d,J=1.6Hz,1H),7.49(d,J=8.8Hz,1H),7.15(s,1H),7.10(dd,J=9.2Hz,2 .0Hz,1H),6.14(q,J=6.4Hz,1H),4.12(d,J=8.8Hz,2H),3.98(d,J=8.4Hz,2H ),3.67-3.57(m,4H),2.47-2.40(m,4H),1.76(d,J=6.4Hz,3H),1.35(s,3H).

[0966]

[0967] Example 37. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[3-(2-methoxyethylamino)-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile

[0968] Step 1. 2-(3-Hydroxy-3-methylazetidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile. A mixture of 5-bromo-2-(3-hydroxy-3-methyl-azetidin-1-yl)pyridine-3-carbonitrile (1.724 g, 6.43 mmol, 1 eq.), bis(pinacol)diboron (2.45 g, 9.645 mmol, 1.5 eq.), potassium acetate (1.26 g, 12.86 mmol, 2 eq.) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.47 mg, 0.643 mmol, 0.1 eq.) in 1,4-dioxane (10 mL) was sparged with nitrogen for 15 min and then heated at 90° C. for 17 h. LCMS analysis indicated the reaction was complete and was subsequently used in the next step. LCMS m / z = 234 (boronic acid) and 316 (M+H).

[0969] Step 2. 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-(3-hydroxy-3-methylazetidin-1-yl)nicotinonitrile. The mixture of reaction step 1 in 1,4-dioxane (6.43 mmol, 1.5 eq) was treated with 5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-3-iodo-6-methoxy-1-tetrahydropyran-2-yl-indazole (2.35 g, 4.287 mmol, 1 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (314 mg, 0.429 mmol, 0.1 eq) and potassium carbonate (1.18 g, 8.573 mmol, 2 eq) and water (7.0 mL). After sparging with nitrogen for 10 minutes, the reaction was heated at 90 °C for 20 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and water (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on an Interchim automated chromatography system (Sorbtech 120 g silica gel column) using a gradient elution of 0% to 100% ethyl acetate in heptane to give a brown solid (1.77 g, 68% yield over 2 steps). LCMS m / z=610 (M+H).

[0970] Step 3. 1-(3-cyano-5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)-3-methylazetidin-3-yl methanesulfonate. N,N-diisopropylethylamine (1.52 mL, 8.712 mmol, 23 eq) was added to a suspension of the product of step 2 (1.77 g, 2.904 mmol, 1 eq) in anhydrous dichloromethane (120 mL) at room temperature. After stirring at room temperature for 30 minutes, methanesulfonic anhydride (1.01 g, 5.808 mmol, 2 eq) was added and the mixture was stirred at room temperature for 2.5 hours. LCMS analysis indicated that the reaction was complete. Water (50 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (3x50mL). The combined organic layers were washed with saturated brine (50mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified on an Interchim automated chromatography system (Sorbtech 120g silica gel column) using a gradient elution of 0% to 100% ethyl acetate in heptane to give a white foam (1.40g, 70% yield). LCMS m / z=687 (M+H).

[0971] Step 4. 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-(3-((2-methoxyethyl)amino)-3-methylazetidin-1-yl)nicotinonitrile. A mixture of the product of step 3 (299 mg, 0.44 mmol, 1.0 eq), 2-methoxyethane-1-amine (163 mg, 2.2 mmol, 5 eq) and sodium tert-butoxide (125 mg, 1.53 mmol, 3 eq) in acetonitrile (5 mL) was heated at 60 °C for 16 hours. After cooling to room temperature, the mixture was diluted with water (1 mL) and concentrated under reduced pressure. The residue was redissolved in dimethyl sulfoxide (10 mL) and purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column) eluting with a gradient of 0% to 100% acetonitrile in water to give an off-white solid (155 mg, 53% yield). LCMS m / z=666.3 (M+H).

[0972] Step 5. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(3-((2-methoxyethyl)amino)-3-methylazetidin-1-yl)nicotinonitrile. 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-(3-((2-methoxyethyl)amino)-3-methylazetidin-1-yl)nicotinonitrile (155 mg, 0.23 mmol, 1.0 equiv) was treated with a 1:1 mixture of TFA in dichloromethane (4 mL) at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL) and washed with saturated sodium carbonate (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was redissolved in dimethyl sulfoxide (10 mL) and purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column) using a gradient elution of 0% to 100% acetonitrile in water to give an off-white solid (56 mg, 42% yield) after lyophilization of the product. LCMS m / z=582.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ=12.96 (br s,1H),8.71(d,J=2.3Hz,1H),8.59(s,2H),8.05(d,J=2.3Hz,1H),7.04(s ,1H),7.01(s,1H),5.99(q,J=6.7Hz,1H),4.11(d,J=8.8Hz,2H),4.03(d,J =8.7Hz,2H),3.86(s,3H),3.44-3.34(m,2H),3.28-3.25(m,3H),2.70(q,J =6.1Hz,2H),2.48-2.27(m,1H),1.76(d,J=6.6Hz,3H),1.45-1.36(m,3H).

[0973]

[0974] Example 43. (R)-4-(1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyrimidin-2-yl)-3-methylazetidin-3-yl)morpholine

[0975] Step 1. 3-(2-Chloropyrimidin-5-yl)-5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazole. 5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (4.0 g, 7.72 mmol, 1.0 equiv) was dissolved in dioxane (100 mL) and H2O at 25 °C. 2 To the solution in 2% CO (10 mL) were added 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (3.71 g, 15.44 mmol, 2.0 equiv), K 2 CO 3 (3.2 g, 23.16 mmol, 3.0 equiv) and Pd(dppf)Cl 2 (565 mg, 0.772 mmol, 0.1 eq.). 2 and stirred at 90°C for 3 h. After cooling to room temperature, the mixture was concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / EtOAc=2 / 1) to give a yellow solid (3.5 g, 90% yield). LCMS m / z=504.2 (M+H).

[0976] Step 2. 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]pyrimidin-2-yl]-3-methyl-azetidin-3-ol. To a solution of the product of step 1 (3.2 g, 6.34 mmol, 1.0 eq.) in DMSO (30 mL) were added 3-methylazetidin-3-ol (940 mg, 7.61 mmol, 1.2 eq.) and DIEA (2.45 g, 19.02 mmol, 3.0 eq.) and the mixture was stirred at N 2 and stirred at 100°C for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (200 mL) and washed with water (100 mL x 2). The organic layer was purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a light yellow oil (2.7 g). The material was used directly in the next step. LCMS m / z = 555.3 (M+H).

[0977] Step 3. [1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]pyrimidin-2-yl]-3-methyl-azetidin-3-yl]methanesulfonate. To a solution of the step 2 product (2.7 g, crude material) in DCM (100 mL) was added TEA (984 mg, 9.72 mmol, 2.0 equiv) and MsCl (7.29 mmol, 832 mg, 1.5 equiv) at 0°C. The resulting mixture was stirred at room temperature for 2 h. After completion, the reaction was concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / EtOAc=3 / 1) to give a yellow solid (2.5 g, two-step yield 63%). LCMS m / z=633.2 (M+H).

[0978] Step 4. 4-[1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]pyrimidin-2-yl]-3-methyl-azetidin-3-yl]morpholine

[0979] To a solution of step 3 product (200 mg, 0.316 mol, 1.0 equiv) in ACN (2 mL) was added morpholine (138 mg, 1.58 mmol, 5.0 equiv) and t-BuONa (177 mg, 1.58 mmol, 5.0 equiv). The mixture was stirred at 90 ° C for 12 h. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / EtOAc=1 / 1) to give a yellow solid (150 mg, 76% yield). LCMS m / z=624.3 (M+H).

[0980] Step 5. (R)-4-(1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyrimidin-2-yl)-3-methylazetidin-3-yl)morpholine. To a solution of the product of step 4 (150 mg, 0.24 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1.5 mL) and the mixture was stirred at room temperature for 3 h. Upon completion, the reaction mixture was concentrated in vacuo. The crude product was treated with DCM / MeOH (V:V=5:1, 10 mL) and solid NaHCO 3 Add to the solution to pH 8 and stir for 20 minutes. Filter out the solid and concentrate the filtrate. The residue was purified by preparative HPLC (preparative C18, 5 μM Triart column, 20×150 mm, YMC-Actus; 35% MeCN in water to 65% MeCN containing 0.05% NH 3 .H 2The product was purified by HPLC-MS / MS (5% by weight elution with a gradient of 0 in water) to give a white solid (36 mg, 28% yield). LCMS m / z=540.3(M+H); 1H NMR (400MHz, DMSO-d6) δ13.13(brs,1H),8.78(s,2H),8.57(s,2H),7.47(d,J=9.2Hz,1H),7.23(d,J=2.0Hz,1H),7.10(dd,J=8.8Hz,2.4Hz,1H),6. 15(q,J=6.4Hz,1H),3.94(d,J=8.4Hz,2H),3.76(d,J=8.4Hz,2H),3.61(t ,J=4.0Hz,4H),2.44(t,J=4.0Hz,4H),1.75(d,J=6.4Hz,3H),1.32(s,3H).

[0981]

[0982] (R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol and (S)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol

[0983] Step 1. (Trichloro-4-pyridyl)ethanol. A 500 mL three-necked round-bottom flask was charged with 2,3,5-trichloropyridine-4-carbaldehyde (40 g, 0.19 mol) and THF (200 mL). MeMgBr (70 mL, 0.21 mol) was added in batches and the mixture was stirred at -70 °C for 1 h. The reaction was quenched with aqueous ammonium chloride, extracted with ethyl acetate (200 mL x 3), and washed with Na 2 SO 4 Dried and concentrated. The residue was purified by silica gel column (PE / EA=30 / 1) to give (33 g) yellow liquid (33 g, 77%). LCMS m / z=227 (M+H).

[0984] Step 2. 1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol. The product of step 1 (33 g, 0.147 mmol), methylboronic acid (26.3 g, 0.429 mmol), K 2 CO 3 (40 g, 0.290 mmol) and Pd(PPh 3 ) 2 Cl 2A mixture of (3g) in dioxane (300mL) was stirred at 110°C overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give a crude product, which was further purified by silica gel column chromatography to give a yellow liquid (15g, 50%). LCMS m / z=206.1 (M+H). The product was separated by preparative HPLC (Chiralpak ID 5x25cm, hexane / ethanol (80 / 20), 60mL / min.38°C) to give (S)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol (5g) and (R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol (5g) as yellow liquids. Peak 1 5.5min; (S)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol. LCMS m / z=206.1 (M+H). 1H NMR (400MHz, CDCl3) δ8.36 (s, 1H), 5.57 (m, 1H), 2.93 (b, 1H), 2.64 (s, 3H), 1.65 (d, 3H). Peak 2 6.9min; (R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol. LCMS m / z=206.1 (M+H). 1HNMR (400MHz, CDCl3) δ8.36 (s, 1H), 5.57 (m, 1H), 2.93 (b, 1H), 2.64 (s, 3H), 1.65 (d, 3H).

[0985]

[0986] Example 46.

[0987] Step 1.1-Benzhydryl-3-cyclobutoxy-3-methylazetidine. In a sealed tube, a solution of 1-benzhydryl-3-methylazetidine-3-yl methanesulfonate (3.0 g, 9.06 mmol, 1.0 equiv) in 1,4-dioxane (20 mL) was treated with cyclobutanol (1.3 g, 18.12 mmol, 2.0 equiv) and N,N-diisopropylethylamine (4.7 mL, 27.18 mmol, 3.0 equiv) at 100 ° C. After stirring for 4 days, the solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL) and washed with water (20 mL). The organic layer was concentrated under reduced pressure to give a light brown oil (500 mg, 18%). LCMS m / z=307.2(M+H).

[0988] Step 2. 1-Benzhydryl-3-cyclobutoxy-3-methylazetidine hydrochloride. A solution of 1-benzhydryl-3-cyclobutoxy-3-methylazetidine (1.2 g, 3.9 mmol, 1.0 equiv) in 1,4-dioxane (10 mL) was treated with 4M HCl in 1,4-dioxane (3.9 mL, 15.63 mmol, 4.0 equiv) at room temperature for 16 hours. The mixture was concentrated under reduced pressure to give a light brown oil (505 mg, 37% yield). LCMS m / z=307.2 (free base, M+H).

[0989] Step 3.3-cyclobutoxy-3-methylazetidine hydrochloride. A mixture of 1-benzhydryl-3-cyclobutoxy-3-methylazetidine hydrochloride (1.19 g, 3.46 mmol, 1.0 equiv) and 20% palladium hydroxide on carbon (0.24 g, 50% wet) in methanol (100 mL) was hydrogenated at room temperature and 50 psi for 16 hours. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give a dark brown oil (1.0 g, 62% yield). LCMS m / z=141.2 (free base, M+H).

[0990] Step 4.5-bromo-2-(3-cyclobutoxy-3-methylazetidine-1-yl)nicotinonitrile. A solution of 5-bromo-2-chloro-3-cyano-pyridine (633 mg, 2.98 mmol, 1.0 equiv) in acetonitrile (10 mL) was treated with 3-cyclobutoxy-3-methylazetidine hydrochloride (626 mg, 3.58 mmol, 1.2 equiv) and N,N-diisopropylethylamine (1.1 mL, 5.96 mmol, 2.0 equiv) at 60 ° C for 16 hours. The crude mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The residue was suspended in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate (20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified on a Büchi automated chromatography system (Sorbtech 40 g column) with a gradient elution of 0% to 50% ethyl acetate in heptane. Fractions containing product were combined, concentrated to dryness under reduced pressure, and the residue was dried under vacuum at 50°C for 16 hours to give a light brown oil (344 mg, 36% yield). LCMS m / z = 322.2 (M+H).

[0991] Step 5. (S)-1-(3,5-dichloro-2-methylpyridin-4-yl)ethyl methanesulfonate. Methanesulfonyl chloride (1.35 mL, 17.5 mmol, 1.2 eq) was added to a solution of compound (S)-263-1 (3 g, 14.6 mmol, 1 eq) and triethylamine (4 mL, 29.1 mmol, 2 eq) in anhydrous dichloromethane (30 mL) at -10 °C. After two hours, the reaction was warmed to room temperature and diluted with deionized water (30 mL, 0 °C). The layers were separated and the aqueous layer was extracted with dichloromethane (3x15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude yellow oil was absorbed onto celite (20 g) and purified on an Interchim automated chromatography system (Sorbtech, 100 g silica column) eluting with a gradient of 0% to 100% methyl tert-butyl ether and heptane to afford the compound as a white solid (4.04 g, 96%). LCMS m / z=284.1 (M+H).

[0992] Step 6.5-((R)-1-(3,5-dichloro-2-methylpyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A mixture of compound 3-iodo-1-tetrahydropyran-2-yl-indazole-5-ol (5.38 g, 15.6 mmol, 1.1 eq), (S)-1-(3,5-dichloro-2-methylpyridin-4-yl)ethyl methanesulfonate (4.04 g, 14.2 mmol, 1 eq) and cesium carbonate (9.27 g, 28.5 mmol, 2 eq) in acetonitrile (80 mL) was heated at 80 °C overnight. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL) and saturated brine solution (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3x30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was adsorbed onto celite (30 g) and purified on an Interchim automated chromatography system (Sorbtech, 80 g silica gel column) using a gradient elution of 0% to 100% ethyl acetate in heptane to give a white solid (6.5 g, 86%). LCMS m / z=532.1 (M+H).

[0993] Step 7. 2-(3-Cyclobutoxy-3-methylazetidin-1-yl)-5-(5-((R)-1-(3,5-dichloro-2-methyl-pyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)nicotinonitrile. A mixture of 5-bromo-2-(3-cyclobutoxy-3-methylazetidin-1-yl)nicotinonitrile (344 mg, 1.06 mmol, 1.0 equiv), bis(pinacol)diboron (400 mg, 1.6 mmol, 1.5 equiv), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (77 mg, 0.11 mmol, 0.1 equiv) and potassium acetate (207 mg, 2.12 mmol, 2.0 equiv) in 1,4-dioxane (20 mL) was sparged with nitrogen for 10 minutes and then heated at 90° C. for 32 hours. LC / MS analysis indicated complete conversion. The crude reaction mixture was cooled to room temperature and treated with 5-((R)-1-(3,5-dichloro-2-methylpyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (473 mg, 0.89 mmol, 1.0 equiv), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (65 mg, 0.09 mmol, 0.1 equiv), potassium carbonate (245 mg, 1.78 mmol, 2.0 equiv) and water (1.0 mL). The crude mixture was sparged with nitrogen for 10 minutes and then heated at 100 °C for 16 hours. The crude mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated to dryness under reduced pressure. The residue was diluted with ethyl acetate (30 mL) and washed with water (20 mL). The organic layer was concentrated under reduced pressure. The residue was purified on a Büchi automated chromatography system (Sorbtech 80 g column) using a gradient elution of 0% to 20% ethyl acetate in heptane. The fractions containing the product were combined, concentrated to dryness under reduced pressure, and the resulting residue was dried under vacuum at 50 ° C for 16 hours to give compound 585-3 (149 mg, 25% yield) as a light brown solid. LCMS m / z=650.1 (M+H).

[0994] Step 8. (R)-2-(3-Cyclobutoxy-3-methylazetidin-1-yl)-5-(5-(1-(3,5-dichloro-2-methyl-pyridin-4-yl)ethoxy)-1H-indazol-3-yl)nicotinonitrile. 2-(3-Cyclobutoxy-3-methylazetidin-1-yl)-5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)nicotinonitrile (147 mg, 0.22 mmol, 1.0 equiv) was treated with a 1:1 mixture of dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL, 19.6 mmol, 89.1 equiv) at room temperature for 6 hours. The volatiles were removed under reduced pressure. The residue was diluted with dichloromethane (5 mL), then treated with water (2 mL) and sodium bicarbonate (500 mg). The layers were separated and the organic layer was concentrated under reduced pressure onto diatomaceous earth (10 g). The material was purified on a Büchi automated chromatography system (RediSep C18 100 g column) with a gradient elution of 0% to 80% acetonitrile in water. The fractions containing the product were combined, concentrated under reduced pressure, and the resulting residue was dried under vacuum at 50 ° C for 16 hours to give an off-white solid (35 mg, 27% yield) LCMS m / z=563.2(M+H); 1HNMR(400MHz, DMSO-d6)δ=13.18(s,1H),8.70(d,J=2.2Hz,1H),8.41(s ,1H),8.16(d,J=2.2Hz,1H),7.49(d,J=8.9Hz,1H),7.11(dd,J=2.3,9.0Hz,1H),7.07(s,1H ),6.10(q,J=6.7Hz,1H),4.20-3.98(m,5H),2.58-2.53(m,3H),2.26-2.10(m,2H),2.02-1 .84(m,2H),1.75(d,J=6.7Hz,3H),1.61(q,J=10.0Hz,1H),1.50(s,3H),1.49-1.39(m,1H).

[0995]

[0996] Example 47. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[3-(2-hydroxyethylamino)-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile

[0997] Step 1. (1-benzhydryl-3-methyl-azetidine-3-yl) methanesulfonate. To a solution of 1-benzhydryl-3-methyl-azetidine-3-ol (5.0 g, 19.7 mmol, 1.0 equiv) in DCM (50 mL) was added TEA (6.0 g, 59.2 mmol, 3.0 equiv), and then MsCl (3.2 g, 27.6 mmol, 1.4 equiv) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was diluted with DCM (50 mL) and washed with brine (30 mL x 3). The organic layer was purified by Na 2 SO 4 Dried and concentrated. The crude product was purified by flash column chromatography on silica gel (petroleum ether / EtOAc=3 / 1) to give a white solid (3.5 g, 54% yield). LCMS m / z=332.3 (M+H).

[0998] Step 2. 2-[(1-Benzhydryl-3-methyl-azetidin-3-yl)amino]ethanol. To (1-Benzhydryl-3-methyl-azetidin-3-yl) methanesulfonate (1.5 g, 4.5 mmol, 1.0 equiv) was added to CH 3 To a solution in CN (15 mL) were added 2-aminoethanol (1.4 g, 22.6 mmol, 5.0 equiv) and Cs 2 CO 3 (4.5 g, 13.6 mmol, 3.0 equiv.). The reaction mixture was stirred at 80°C for 16 h. After the reaction was complete, the solid was filtered off, the filtrate was concentrated, and the crude product was purified by silica gel flash column chromatography (DCM / MeOH=20 / 1) to give a white solid (1.1 g, 82%). LCMS m / e=297.3 (M+H).

[0999] Step 3. 2-[(3-methylazetidin-3-yl)amino]ethanol. 2 To a solution of 2-[(1-benzhydryl-3-methyl-azetidin-3-yl)amino]ethanol (1.0 g, 3.4 mmol, 1.0 equiv) in MeOH (10 mL) was added Pd / C (1.23 g, 10% wt) in portions. The suspension was degassed under vacuum and charged with hydrogen three times. The mixture was stirred under H 2 Stir under balloon at room temperature for 16 h. Filter off the solid and concentrate the filtrate to give a colorless oil. LCMS m / e=131.3 (M+H).

[1000] Step 4. 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile. To a solution of 5-bromo-2-fluoro-pyridine-3-carbonitrile (10 g, 49.8 mmol, 1.0 eq.) and bis(pinacolato)diboron (25.3 g, 99.5 mmol, 2.0 eq.) in dioxane (200 mL) were added KOAc (20.6 g, 149.3 mmol, 3.0 eq.) and Pd(dppf)Cl 2 (2.0 g, 20 wt%). The reaction mixture was stirred at N 2 The mixture was stirred at 90 °C for 5 h under protection. After the reaction was complete, the solid was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column (petroleum ether / EtOAc=10 / 1) to give a white solid (12 g, 59% yield). LCMS m / z=249.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ8.68 (d, J=1.6 Hz, 1H), 8.63 (dd, J=9.2 Hz, 1.6 Hz, 1H), 1.32 (s, 12H).

[1001] Step 5. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-fluoro-pyridine-3-carbonitrile. 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (1.0 g, 4.0 mmol, 2.2 equiv) and 5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-3-iodo-6-methoxy-1-tetrahydropyran-2-yl-indazole (1.0 g, 1.8 mmol, 1.0 equiv) were added to dioxane (20 mL) and H2O at room temperature. 2 O (2 mL) was added to the solution 2 CO3 (745 mg, 5.4 mmol, 3.0 equiv) and Pd(dppf)Cl 2 (100 mg, 10% wt). The mixture was stirred at N 2 The mixture was stirred at 90°C for 2 h under protection. After the reaction was complete, the solid was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column (petroleum ether / EtOAc=1 / 1) to give an off-white solid (900 mg, 91% yield). LCMS m / z=542.2 (M+H).

[1002] Step 6.5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-[3-(2-hydroxyethylamino)-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile. To a solution of the product of step 4 (150 mg, 0.28 mmol, 1.0 eq) and 2-[(3-methylazetidin-3-yl)amino]ethanol (54 mg, 0.41 mmol, 1.5 eq) in DMSO (2 mL) was added DIEA (178 mg, 1.38 mmol, 5.0 eq). The reaction mixture was stirred at 90 ° C for 16 h. After completion of the reaction, the mixture was diluted with EtOAc (30 mL) and washed with brine (20 mLx3). The organic layer was purified by Na 2 SO 4 Dried and concentrated. The crude product was purified by preparative TLC (DCM / MeOH=12 / 1) to give a white solid (120 mg, 67% yield). LCMS m / z=652.3 (M+H).

[1003] Step 7. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[3-(2-hydroxyethylamino)-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile. To a solution of the product of step 5 (110 mg, 0.17 mmol, 1.0 eq.) in DCM (6 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 5 h and concentrated in vacuo. The crude product was treated with DCM / MeOH (15 mL, V:V=5 / 1) and then NaHCO 3 (excess) was added to the solution and stirred at room temperature for 20 minutes, and then DCM (20 mL) was added. The solid was filtered off and the filtrate was concentrated. The residue was purified by preparative TLC (DCM / MeOH=7 / 1) to give a white solid (54 mg, 57% yield). LCMS m / z=568.3(M+H); 1H NMR (400MHz, DMSO-d6) δ12.98(s,1H),8.73(d,J=2.0Hz,1H),8.59(s,2H),8.09(d,J=2.0Hz,1H),7.03(s,1H),7.01(s,1H),6.00(q,J=6.4Hz,1H) ,4.85-4.68(m,1H),4.23-4.20(m,2H),4.11-4.09(m,2H),3.86(s,3H),3 .57-3.49(m,2H),2.80-2.70(m,2H),1.76(d,J=6.8Hz,3H),1.49(s,3H).

[1004]

[1005] Example 49. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(3-((dimethylamino)methyl)-3-methylazetidin-1-yl)nicotinonitrile

[1006] Step 1. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-[3-methyl-3-(methylaminomethyl)azetidin-1-yl]pyridine-3-carbonitrile. To a solution of 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-fluoro-pyridine-3-carbonitrile (600 mg, 1.11 mmol, 1.0 equiv) and tert-butyl N-[(3-methylazetidin-3-yl)methyl]carbamate HCl (525 mg, 2.22 mmol, 2.0 equiv) in DMSO (15 mL) was added DIEA (2.2 g, 16.7 mmol, 15.0 equiv) at room temperature. The mixture was stirred at 60 ° C for 3 h. After completion of the reaction, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mLx3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dried and concentrated. The crude product was purified by silica gel chromatography eluting with DCM / MeOH (20 / 1) to give a white solid (500 mg, 63% yield). LCMS m / z=722.4 (M+H).

[1007] Step 2. 2-[3-(Aminomethyl)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1H-indazol-3-yl]pyridine-3-carbonitrile. To a solution of 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-[3-methyl-3-(methylaminomethyl)azetidin-1-yl]pyridine-3-carbonitrile (460 mg, 0.64 mmol, 1.0 equiv) in DCM (4 mL) was added TFA (2 mL) at 0°C. The solution was stirred at room temperature for 4 h and concentrated in vacuo to give a yellow solid (550 mg). LCMS m / z=538.2 (M+H).

[1008] Step 3. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-(hydroxymethyl)-6-methoxy-indazol-3-yl]-2-[3-[(dimethylamino)methyl]-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile. To a solution of the product of step 2 (200 mg, 0.37 mmol, 1.0 equiv) and HCHO (221 mg, 1.85 mmol, 5.0 equiv, 37% aqueous solution) in DCE (4 mL) was added NaBH 3 CN (93 mg, 1.50 mmol, 4.0 eq.) and AcOH (2.4 mg, 0.04 mmol, 0.1 eq.). The reaction mixture was stirred at room temperature for 3 h and poured into saturated NaHCO 3 The solution was added to an aqueous solution (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine and washed with Na 2 SO 4 Dry and concentrate to give a yellow solid (130 mg). LCMS m / z = 596.1 (M+H).

[1009] Step 4. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(3-((dimethylamino)methyl)-3-methylazetidin-1-yl)nicotinonitrile The product of step 3 (100 mg, 0.17 mmol, 1.0 equiv) was dissolved in NH 3 / MeOH (3mL) was stirred at room temperature for 4h. After the reaction was completed, the reaction mixture was poured into water (10mL) and extracted with DCM (20mLx3). The combined organic layer was washed with brine and purified by Na 2 SO 4 The crude product was first purified by preparative TLC (DCM / MeOH=12 / 1) and then by preparative HPLC (preparative C18, 5 μM Triart column, 20×150 mm, YMC-Actus; 50% MeCN in water to 80% MeCN containing 0.05% NH 3 .H 2O in water (gradient elution) to give a white solid (19 mg, 33% yield). LCMSm / z=566.3(M+H); 1H NMR (400MHz, DMSO-d6) δ12.97(s,1H),8.71(d,J=2.8Hz,1H),8.59(s,2H),8.06(d,J=2.4Hz,1H),7.04(s,1H),7.01(s,1H),6.00(q,J=6. 8Hz,1H),4.07(d,J=8.4Hz,2H),3.98(d,J=8.8Hz,2H),3.86(s,3H),3.28-3.32(m,2H),2.18(s,6H),1.76(d,J=6.8Hz,3H),1.38(s,3H).

[1010]

[1011] Example 50. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(3-((isopropylamino)methyl)-3-methylazetidin-1-yl)nicotinonitrile

[1012] To a solution of 2-[3-(aminomethyl)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1H-indazol-3-yl]pyridine-3-carbonitrile (200 mg, 0.37 mmol, 1.0 equiv) and acetone (108 mg, 1.85 mmol, 5.0 equiv) in DCE (4 mL) was added NaBH(AcO) 3 (318 mg, 1.50 mmol, 4.0 eq) and AcOH (2.4 mg, 0.04 mmol, 0.1 eq). The reaction mixture was stirred at room temperature for 2 h and poured into saturated NaHCO 3 The mixture was added into aqueous solution (10 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4Dried and concentrated.The product was purified by preparative TLC (DCM / MeOH=12 / 1) to give an off-white solid (48 mg, 22% yield). LCMS m / z=580.3(M+H); 1H NMR (400MHz, DMSO-d6) δ12.99(s,1H),8.71(d,J=2.4Hz,1H),8.59(s,2H),8.06(d,J=2.4Hz,1H),7.03(s,1H)7.01(s,1H),6.01(q,J=7.2Hz,1H) ,4.17(d,J=8.4Hz,2H),3.92(d,J=8.0Hz,2H),3.86(s,3H),3.21-3.32( 2H), 2.93-2.80 (m, 1H), 1.76 (d, J = 6.8Hz, 3H), 1.35 (s, 3H), 1.10 (s, 6H).

[1013]

[1014] Example 52. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1H-indazol-3-yl]-2-[3-(2-hydroxyethylamino)-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile

[1015] Step 1. 2-(3-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-3-methylazetidin-1-yl)-5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)nicotinonitrile. A mixture of [1-[3-cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridinyl]-3-methyl-azetidin-3-yl] methanesulfonate (290 mg, 0.44 mmol, 1.0 equiv), 2-[tert-butyl(dimethyl)silyl]oxyethylamine (386 mg, 2.2 mmol, 5 equiv) and sodium tert-butoxide (127 mg, 1.32 mmol, 3 equiv) in acetonitrile (5 mL) was heated at 60 ° C. After 18 hours, the mixture was cooled to room temperature and diluted with water (25 mL) and ethyl acetate (15 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2x10 mL). The combined organic layer was washed with saturated brine (25 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage 25 g silica column, 60 μM) using a gradient elution of 0% to 80% ethyl acetate in hexanes to give a light yellow solid (100 mg, 30% yield). LCMS m / z=736 (M+H).

[1016] Step 2.5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-[3-(2-hydroxyethylamino)-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile. A solution of the product of step 1 (100 mg, 0.14 mmol, 1.0 equiv.) in dichloromethane (5 mL) was treated with trifluoroacetic acid (4 mL) at room temperature. After 16 hours, the reaction mixture was concentrated under reduced pressure. The residue was treated with a mixture of saturated sodium carbonate (20 mL) and 20% aqueous sodium hydroxide solution (15 mL). The mixture was extracted with dichloromethane (2x15 mL). The combined organic layers were washed with saturated brine (20 mL), dried over magnesium sulfate, filtered and concentrated. The residue was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column) eluting with a gradient of 0% to 100% acetonitrile in water to afford an off-white solid (36 mg, 49% yield) after lyophilization. LCMS m / z=538.1(M+H); 1H NMR(400MHz, CDCl3)δ=13.17(br s,1H),8.76(d,J=2.3Hz,1H),8.58(s,2H),8.13(d,J=2.3Hz,1H),7.49(d,J=9.0Hz,1 H),7.16(d,J=2.2Hz,1H),7.10(dd,J=2.3,9.0Hz,1H),6.14(q,J=6.7Hz,1H),4.53(br s,1H),4.15-4.11(m,2H),4.07-4.04(m,2H),3.47(br t,J=5.6Hz,2H),2.62(br d,J=5.1Hz,2H),2.34-2.29(m,1H),1.76(d,J=6.7Hz,3H),1.43(s,3H).

[1017]

[1018] Example 53. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(3-((dimethylphosphoryl)methyl)-3-methylazetidin-1-yl)nicotinonitrile

[1019] Step 1. 3-(Bromomethyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester. To 3-(hydroxymethyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (200 mg, 1.0 mmol, 1.0 equiv) and PPh 3To a solution of (521 mg, 1.99 mmol, 2.0 equiv) in DCM (5.0 mL) was added CBr in portions 4 (653 mg, 1.99 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 5 h. After the reaction was completed, the mixture was concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (petroleum ether / EtOAc=5 / 1) to give a brown solid (182 mg, 69% yield). LCMS m / z=264.3 (M+H).

[1020] Step 2. 3-(Dimethylphosphorylmethyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester. 2 To a solution of methylphosphonomethane (144 mg, 1.84 mmol, 3.0 equiv) in THF (2 mL) was added NaHMDS (0.92 mL, 1.84 mmol, 2 M in THF, 3.0 equiv) dropwise at -70°C. The reaction mixture was stirred at room temperature for 1 h. 2 The mixture was protected and a solution of tert-butyl 3-(bromomethyl)-3-methyl-azetidine-1-carboxylate (162 mg, 0.62 mmol, 1.0 equiv) in THF (2 mL) was added dropwise at 0°C and stirred for 4 h. After the reaction was completed, the reaction was heated with saturated NH 4 The mixture was quenched with aqueous Cl (10 mL) at 0 °C and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2) and purified by Na 2 SO 4 Drying and concentration gave an off-white oil (150 mg, 93% yield). LCMS m / z = 262.3 (M+H).

[1021] Step 3. 3-(Dimethylphosphorylmethyl)-3-methyl-azetidine. To a solution of tert-butyl 3-(dimethylphosphorylmethyl)-3-methyl-azetidine-1-carboxylate (150 mg, 0.57 mmol, 1.0 equiv) in DCM (5.0 mL) was added TFA (1.0 mL) and stirred at room temperature for 3 h. The mixture was concentrated to give a yellow oil as a TFA salt. LCMS m / z=162.3 (M+H).

[1022] Step 4. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-[3-(dimethylphosphorylmethyl)-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile. To a solution of 5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-fluoro-pyridine-3-carbonitrile (150 mg, 0.28 mmol, 1.0 equiv) and 3-(dimethylphosphorylmethyl)-3-methyl-azetidine TFA salt (190 mg, crude) in DMSO (5 mL) was added DIEA (179 mg, 1.39 mmol, 5.0 equiv). The reaction mixture was stirred at 90 ° C for 16 h. After the reaction was completed, the reaction was diluted with EtOAc (20 mL), washed with brine (20 mL x 3) and concentrated. The crude product was purified by preparative TLC (DCM / MeOH = 15 / 1) to give a yellow solid (105 mg, yield 56%). LCMS m / z = 683.2 (M + H).

[1023] Step 5. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(3-((dimethylphosphoryl)methyl)-3-methylazetidin-1-yl)nicotinonitrile. To a solution of the product of step 4 (95 mg, 0.14 mmol, 1.0 equiv) in DCM (2 mL) was added TFA (0.4 mL) and stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was washed with saturated NaHCO 3 The solution was adjusted to pH 7-8 and extracted with DCM (10 mL x3). The combined organic layers were concentrated in vacuo. The crude product was purified by preparative HPLC (preparative C18, 5 μM Triart columns, 20 × 150 mm, YMC-Actus; from 15% MeCN in aqueous solution to 30% MeCN / with 0.05% NH 3 .H 2The product was purified by HPLC-MS / MS (50% yield). LCMS m / z=599.3(M+H); 1H NMR (400MHz, DMSO-d6) δ12.96(s,1H),8.71(d,J=2.4Hz,1H),8.59(s,2H),8.06(d,J=2.4Hz,1H),7.03(s,1H),7.00(s,1H),5.99(q,J=6.8Hz,1H) ,4.27(d,J=8.4Hz,2H),4.03(d,J=8.8Hz,2H),3.85(s,3H),2.23(d,J=11 .2Hz,2H),1.76(d,J=6.8Hz,3H),1.56(s,3H),1.46(s,3H),1.43(s,3H).

[1024]

[1025] Example 80. (R)-4-(1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-3-fluoropyridin-2-yl)-3-methylazetidin-3-yl)morpholine

[1026] Step 1. 5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-3-(5,6-difluoro-3-pyridinyl)-1-tetrahydropyran-2-yl-indazole. To a solution of 5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (4.50 g, 8.68 mmol, 1.0 equiv) and 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.14 g, 13.03 mmol, 1.5 equiv) in dioxane (50 mL) and water (5 mL) was added K 2 CO 3 (3.60 g, 26.05 mmol, 3.0 equiv) and Pd(dppf)Cl 2 (708 mg, 0.87 mmol, 0.1 eq.). The reaction mixture was stirred at N 2 The mixture was stirred at 90°C for 3 h under protection. After the reaction was complete, the solid was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column (petroleum ether / EtOAc=10 / 1) to give a white solid (2.3 g, 52% yield). LCMS m / z=505.2 (M+H).

[1027] Step 2.1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-3-fluoro-2-pyridinyl]-3-methyl-azetidine-3-ol. To a solution of step 1 product (2.0 g, 3.96 mmol, 1.0 eq) and 3-methylazetidine-3-ol (587 mg, 4.75 mol, 1.2 eq) in DMSO (20 mL) was added DIEA (2.56 g, 19.79 mmol, 5.0 eq). The reaction mixture was stirred at 100 °C for 4 h. The reaction was cooled to room temperature, diluted with EtOAc (30 mL) and washed with brine (30 mLx3). The organic layer was purified by Na 2...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein X = O, S or NR; R is H or C1-C3 alkyl; n = 1 or 2; m = 1 or 2; R 1 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, C3-C6 cycloalkyl, -C(O)NR 3 R 4 、-C(O)OR 3 , optionally substituted heterocycloalkyl or optionally substituted heteroaryl; R 9 is H or C1-C3 alkyl; R 2 is H, optionally substituted C1-C6 alkyl, -NR 3 R 4 、-OR 4a 、-P(O)R 4b R 4c 、-SO2R 3 or -C(O)NR 3 R 4 ; R 3 is H or C1-C6 alkyl; R 4 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, C3-C5 cycloalkyl, 3-membered to 6-membered heterocycloalkyl, C(O)(CH2) 2-3 OH or C(O)(CH2) 0-3 NR 4d R 4e ; or R 3 and R 4 Together with the N atom to which they are both attached, they form a 3- to 6-membered heterocycloalkyl group optionally substituted by one or more substituents each of which is C1-C6 alkyl, C1-C6 alkoxy, F or OH; or R 3 and R 4 Together with the N atoms to which they are both attached, they form a 6- to 8-membered bridged heterocycloalkyl ring system; R 4a is H, optionally substituted C1-C6 alkyl or C3-C5 cycloalkyl; R 4b and R 4c are each independently C1-C6 alkyl or -OC1-C6 alkyl; or R 4b and R 4c Together with the phosphorus atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring; R 4d and R 4e are each independently H or C1-C6 alkyl, or R 4d and R 4e Together with the nitrogen atoms to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring; or R 1 and R 2 Together with the carbon atoms to which they are both attached, they form a 3- to 5-membered cycloalkyl ring; Q 1 , Q 2 , Q 3 , Q 4 One or both of them are N, and the others are each independently CR 5a ; R 5a is H, halogen, -CN, -S(O)2C1-C6 alkyl, OCF3, OC1-C3 alkyl or C1-C3 alkyl; Q 5 , Q 6 , Q 7 , Q 8 and Q 9 Each independently is N or CR 5 , where Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One or two of them are N, and the rest are CR 5 ; R 5 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy or cycloalkyl; R 6 is a C1-C6 alkyl group; R 7 is H, halogen, -C1-C6 alkyl, -C1-C6 alkoxy or -cycloalkyl; and R 8 It is H, halogen, -C1-C6 alkyl, -C1-C6 alkoxy or -cycloalkyl.

2. The compound according to claim 1, wherein X is O.

3. A compound according to any one of claims 1 to 2, wherein R 6 It is CH3.

4. A compound according to any one of the preceding claims, wherein R 8 It is H or F.

5. A compound according to any one of the preceding claims, wherein the compound of formula (I) is a compound of formula (IA): or a pharmaceutically acceptable salt thereof, wherein Q 2 and Q 4 Each is N or Q 2 or Q 4 One of them is N, and the other is CR 5a ; R 5a is H, F, -SO2CH3 or -CN; R 5 is H or CH3; and R 7 It is H, F or OCH3.

6. The compound according to claim 5, wherein the compound of formula (IA) is a compound of formula (IA-1-1): or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 5, wherein the compound of formula (IA) is a compound of formula (IA-2): or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 5, wherein the compound of formula (IA) is a compound of formula (IA-3-1): or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 5, wherein the compound of formula (IA) is a compound of formula (IA-4-1): or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 5, wherein the compound of formula (IA) is a compound of formula (IA-5): or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 5, wherein the compound of formula (IA) is a compound of formula (IA-6): or a pharmaceutically acceptable salt thereof.

12. A compound according to any one of claims 1 to 4, wherein the compound of formula (I) is a compound of formula (IB): or a pharmaceutically acceptable salt thereof, wherein R 5a It is H, F or -CN.

13. A compound according to any one of claims 5 to 12, wherein R 5 It's H.

14. A compound according to any one of claims 5 to 10 or 12, wherein R 5 It is CH3.

15. A compound according to any one of the preceding claims, wherein R 7 It's H.

16. A compound according to any one of claims 1 to 14, wherein R 7 It's F.

17. A compound according to any one of claims 1 to 14, wherein R 7 It is OCH3.

18. A compound according to any one of claims 1 to 11 or 13 to 17, wherein Q 1 and Q 3 Each is CR 5a , where R 5a It's H.

19. A compound according to any one of claims 1 to 5, 10 to 11 or 13 to 18, wherein Q 2 and Q 4 Each is N.

20. A compound according to any one of claims 1 to 4 or 12 to 17, wherein Q 3 and Q 4 Each is N.

21. A compound according to any one of claims 1 to 9 or 11 to 18, wherein Q 2 is N and Q 4 Yes CR 5a , where R 5a It is H or F.

22. The compound according to claim 21, wherein R 5a It's H.

23. The compound according to claim 21, wherein R 5a It's F.

24. A compound according to any one of claims 1 to 9 or 11 to 18, wherein Q 2 is N and Q 4 Yes CR 5a , where R 5a It is CN, S(O)2C1-C6 alkyl, OC1-C3 alkyl or C1-C3 alkyl.

25. The compound according to claim 24, wherein R 5a It is CN or SO2CH3.

26. The compound according to claim 24, wherein R 5a It is CN.

27. The compound according to claim 24, wherein R 5a It is SO2CH3.

28. The compound according to claim 1, wherein Q 4 Yes CR 5a , where R 5a It's OCF3.

29. A compound according to any one of the preceding claims, wherein Q 5 and Q 9 Each is CR 5 , where each R 5 It is Cl; Q 7 Yes N; Q 6 Yes CR 5 , where R 5 is H; and Q 8 Yes CR 5 , where R 5 It is H or CH3.

30. The compound according to claim 29, Q 8 Yes CR 5 , where R 5 It's H.

31. The compound according to any one of the preceding claims, wherein n is 1 and m is 1.

32. A compound according to any one of claims 1 to 30, wherein n is 2 and m is 1.

33. A compound according to any one of claims 1 to 30, wherein n is 2 and m is 2.

34. A compound according to any one of claims 1 to 6, 8, 9 or 12 to 33, wherein R 1 It's H.

35. A compound according to any one of claims 1 to 6, 8, 9 or 12 to 33, wherein R 1 is an optionally substituted C1-C6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -CH2CH2OH, -CH2OH, -CH2CH2OCH3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CN, -CH2CH2CN, -CH2CH2CH2OH, -CH2OCH3, -CH2OCH(CH3)2, -CH2OCH2CH3, 36. A compound according to any one of claims 1 to 6, 8, 9 or 12 to 33, wherein R 1 is an optionally substituted C2-C6 alkenyl group, such as 37. A compound according to any one of claims 1 to 6, 8, 9 or 12 to 33, wherein R 1 is a C3-C6 cycloalkyl group, such as cyclobutyl.

38. A compound according to any one of claims 1 to 6, 8, 9 or 12 to 33, wherein R 1 is an optionally substituted heterocycloalkyl group such as 39. A compound according to any one of claims 1 to 6, 8, 9 or 12 to 33, wherein R 1 is an optionally substituted heteroaryl group such as 40. A compound according to any one of claims 1 to 6, 8, 9 or 12 to 33, wherein R 1 Yes-C(O)OR 3 , such as 41. A compound according to any one of claims 1 to 6, 8, 9 or 12 to 33, wherein R 1 yes -C(O)NR 3 R 4 , such as 42. A compound according to any one of claims 1 to 10 or 12 to 41, wherein R 2 It's H.

43. A compound according to any one of claims 1 to 10 or 12 to 41, wherein R 2 is an optionally substituted C1-C6 alkyl group, such as: -NHSO2(C1-C6 alkyl), -N(C1-C6 alkyl)SO2(C1-C6 alkyl), 5- to 6-membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or -P(O)(C1-C6 alkyl)2 substituted C1-C6 alkyl; C1-C6 alkyl substituted by -SO2(C1-C6 alkyl); C1-C6 alkyl substituted with -NHSO2(C1-C6 alkyl), NHSO2(CH3), NHSO2(CH2CH3), NHSO2(CH2CH2CH3) or NHSO2(CH2CH2CH2CH3); -N(C1-C6 alkyl)SO2(C1-C6 alkyl), -N(CH3)SO2(CH3), -N(CH3)SO2(CH2CH3), -C1-C6 alkyl substituted with -N(CH3)SO2(CH2 CH2CH3), -N(CH2CH3)SO2(CH3) or -N(CH2CH3)SO2(CH2CH3); C1-C6 alkyl substituted by 5- to 6-membered heterocycloalkyl, pyrrolyl, furyl, piperidinyl, piperazinyl or morpholinyl; C1-C6 alkyl substituted by -NH(C1-C6 alkyl), NH(CH3) or NH(CH2CH3); C1-C6 alkyl substituted by N(C1-C6 alkyl)2, -N(CH3)2, -N(CH2CH3)2 or -N(CH3)(CH2CH3); C1-C6 alkyl substituted by NH2, -CH2NH2; P(O)R 4b R 4c Substituted C1-C6 alkyl, wherein R 4b and R 4c are independently C1-C6 alkyl or -OC1-C6 alkyl; or R 4b and R 4c Together with the phosphorus atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring; C1-C6 alkyl substituted by -P(O)(CH3)2, -P(O)(CH2CH3)2, -P(O)(CH3)(CH2CH3); C1-C6 alkyl substituted by P(O)(OCH3)2, -P(O)(OCH2CH3)2, -P(O)(OCH3)(OCH2CH3); or quilt Substituted C1-C6 alkyl.

44. The compound according to claim 43, wherein R 2 It is CH3; -CH2-NHSO2(CH3); <h2 style=";text-align:left;direction:ltr">-CH2-N(CH3)SO2(CH3);<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> -CH2-NH(CH3); -CH2-NH(CH(CH3)2); -CH2-NH(CH2CH2OH); -CH2-N(CH3)2; -CH2-P(O)(CH3)2; or -CH2-P(O)(OCH3)2.

45. A compound according to any one of claims 1 to 10 or 12 to 41, wherein R 2 Yes-OR 4a , where R 4a is H, optionally substituted C1-C6 alkyl or C3-C5 cycloalkyl.

46. ​​The compound according to claim 45, wherein R 4a It's H.

47. The compound according to claim 45, wherein R 4a is optionally substituted C1-C6 alkyl, -CH(CH3), -CH2CH2OH or -CH2C(CH3)2OH.

48. The compound according to claim 45, wherein R 4a It is C3-C5 cycloalkyl, cyclopropyl, cyclobutyl or cyclopentyl.

49. The compound according to claim 45, wherein R 2 is -OH or 50. A compound according to any one of claims 1 to 10 or 12 to 41, wherein R 2 Yes-P(O)R 4b R 4c , where R 4b and R 4c are independently C1-C6 alkyl; or R 4b and R 4c Together with the phosphorus atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring.

51. The compound according to claim 50, wherein R 4b It is C1-C6 alkyl or CH3.

52. The compound according to claim 50, wherein R 4c It is C1-C6 alkyl or CH3.

53. The compound according to claim 50, wherein R 2 It is -P(O)(CH3)2.

54. The compound according to claim 50, wherein R 4b and R 4c Together with the phosphorus atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring, a 4-membered heterocycloalkyl ring, a 5-membered heterocycloalkyl ring or a 6-membered heterocycloalkyl ring.

55. The compound according to claim 50, wherein R 2 Yes: -P(O)(CH3)2, 56. A compound according to any one of claims 1 to 10 or 12 to 41, wherein R 2 Yes - NR 3 R 4 .

57. A compound according to any one of claims 1 to 10 or 12 to 41, wherein R 2 Yes-SO2R 3 Or -SO2CH3.

58. A compound according to any one of claims 1 to 10 or 12 to 41, wherein R 2 Yes-C(O)NR 3 R 4 , -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)NHCH2CH3, -C(O)N(CH2CH3)2 or -C(O)NHCH2CH2OH.

59. according to the compound described in any one of claims 56 to 58, wherein R 3 It's H.

60. A compound according to any one of claims 56 to 58, wherein R 3 It is C1-C6 alkyl or CH3.

61. according to the compound described in any one of claims 56 to 60, wherein R 4 It's H.

62. A compound according to any one of claims 56 to 60, wherein R 4 is an optionally substituted C1-C6 alkyl, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, -CH2-cyclopropyl, -CH2CH2SO2CH3, -CH2CH2CHF2, -CH2CHF2, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2O-iso-Pr, -CH2C(CH3)2OH, -CH2CHCH3OH, -CH2CHOCH3, -CH2CH2CN, or 63. A compound according to any one of claims 56 to 60, wherein R 4 It is an optionally substituted C2-C6 alkenyl group or -CH2CH=CH2.

64. according to the compound described in any one of claims 56 to 60, wherein R 4 It is C3-C5 cycloalkyl or cyclobutyl.

65. according to the compound described in any one of claims 56 to 60, wherein R 4 is a 3- to 6-membered heterocycloalkyl, oxetane-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl, 66. A compound according to any one of claims 56 to 60, wherein R 4 is C(O)(CH2) 0-3 NR 4d R 4e , where R 4d and R 4e Each independently is H or C1-C6 alkyl, such as C(O)CH2N(CH3)2, or R 4d and R 4e Together with the nitrogen atom to which they are both attached, they form a 4- to 6-membered heterocycloalkyl ring, pyrrolidinyl, piperidinyl or morpholinyl.

67. A compound according to any one of claims 56 to 60, wherein R 4 is C(O)(CH2) 2-3 OH or C(O)CH2CH2OH.

68. according to the compound described in any one of claim 56 or 58, wherein R 3 and R 4 Together with the N atom to which they are both attached, they form an unsubstituted 3- to 6-membered heterocycloalkyl, pyrrolidin-1-yl, azetidin-1-yl or morpholin-4-yl.

69. according to the compound described in any one of claim 56 or 58, wherein R 3 and R 4 Together with the N atom to which they are both attached, they form a substituted 3- to 6-membered heterocycloalkyl, 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphorinane-4-yl 1-oxide, 3-methoxy-3-methylazetidin-1-yl, 70. A compound according to any one of claims 56 or 58, wherein R 3 and R 4 Together with the N atoms to which they are both attached, they form a 6- to 8-membered bridged heterocycloalkyl ring system, 71. according to any one of claims 1 to 6, 8, 9 or 11 to 33, wherein R 1 and R 2 Together with the carbon atoms to which they are both attached, they form a 3- to 5-membered cycloalkyl ring or a cyclopropyl ring.

72. A pharmaceutical composition comprising a compound according to any one of claims 1 to 71 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

73. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound according to any one of claims 1 to 71, or a pharmaceutically acceptable salt thereof.

74. The method of claim 73, wherein the disease or condition is cancer.

75. The method of claim 74, wherein the cancer is urothelial carcinoma, hepatocellular carcinoma, breast cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, bile duct carcinoma, gastric adenocarcinoma, non-small cell lung cancer, exocrine pancreatic cancer, oral cancer, prostate cancer, bladder cancer, colorectal cancer, renal cell carcinoma, neuroendocrine cancer, myeloproliferative neoplasms, head and neck (squamous), melanoma, leiomyosarcoma and / or sarcoma.

76. The method of claim 75, wherein the cancer is bladder cancer.

77. The method of claim 75, wherein the cancer is urothelial carcinoma.

78. The method of claim 75, wherein the cancer is hepatocellular carcinoma.

79. The method of any one of claims 74 to 78, wherein the cancer is a FGFR mutant cancer.

80. The method of claim 73, wherein the disease or disorder is a developmental disorder.

81. The method of claim 80, wherein the developmental disorder is achondroplasia (Ach) and related hypochondroplasia syndromes, including hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD).

82. A method of inhibiting FGFR in a cell, the method comprising contacting the cell with a compound according to any one of claims 1 to 71.

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