Indazole compounds

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 356,585, filed June 29, 2022, and U.S. Provisional Application No. 63 / 476,051, filed December 19, 2022, the entireties of each of which are incorporated herein by reference.

[0002] The present disclosure relates to indazole compounds useful in the treatment of cancer, pharmaceutical compositions comprising one or more such indazole compounds, and methods of using such indazole compounds in the treatment of cancer. [Background technology]

[0003] Kinase inhibitors are used to block the activity of kinases, thereby treating cancer (e.g., by inhibiting the mitotic process). These kinase inhibitors are often small molecules that target kinases to prevent the development, growth, or spread of cancer.

[0004] However, although various inhibitors of kinases are known, there remains a need for selective inhibitors that can be used to treat diseases, such as hyperproliferative diseases, and that offer one or more advantages over current compounds. These advantages include improved activity and / or efficacy, a beneficial kinase selectivity profile tailored to the respective therapeutic need, an improved side effect profile, such as fewer unwanted side effects, less intense side effects, 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, e.g., allowing for reduced dosages or simpler dosing regimens, and easier drug substance manufacture, e.g., by shortening the synthetic route or simplifying purification. Summary of the Invention [Problem to be solved by the invention]

[0005] The compounds disclosed herein provide potent and selective small molecule kinase inhibitors. [Means for solving the problem]

[0006] In some embodiments, the present disclosure is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0007] [ka]

[0008] During the ceremony, 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 and 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- to 6-membered heterocycloalkyl, C(O)(CH2)2-3 OH or C(O)(CH2) 0-3 NR 4d R 4e and Or R 3 and R 4 together with the N atom to which they are both attached form a 3- to 6-membered heterocycloalkyl optionally substituted with one or more substituents, each of which is C1-C6 alkyl, C1-C6 alkoxyl, F, or OH; Or R 3 and R 4 together with the N atom to which they are both attached 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 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 atom to which they are both attached 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 form a 3- to 5-membered cycloalkyl ring; Q 1 , Q 2 , Q 3 , Q 4 one or two of which are N, and the rest are each independently CR 5a and 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 are each independently N or CR 5 Among them, Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One or two of these are N and the rest are CR 5 and R 5 is H, halogen, C1-C3 alkyl, C1-C3 alkoxyl or cycloalkyl; R 6 is C1-C6 alkyl, R 7 is H, halogen, -C1-C6 alkyl, -C1-C6 alkoxyl or -cycloalkyl; R 8 is H, halogen, -C1-C6 alkyl, -C1-C6 alkoxyl or -cycloalkyl.

[0009] In another embodiment, the compound of formula (I) is: X=O, S or NR; R is H or C1-C3 alkyl; n=1 or 2, m=1 or 2, R 1 is H or optionally substituted C1-C6 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 and R 9 is H, 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- to 6-membered heterocycloalkyl, or C(O)(CH2) 0-3 NR 4d R 4e and Or R 3 and R 4 together with the N atom to which they are both attached form a 3- to 6-membered heterocycloalkyl optionally substituted with one or more substituents, each of which is C1-C6 alkyl, C1-C6 alkoxyl, F, or OH; 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 R 4b and R 4c together with the phosphorus atom to which they are both attached 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 atom to which they are both attached 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 form a 3- to 5-membered cycloalkyl ring; Q 1 , Q 2 , Q 3 , Q 4 one or two of which are N, and the rest are each independently CR 5a and R 5a is H, halogen, —CN, —S(O)2C1-C3 alkyl, OCF3, OC1-C3 alkyl or C1-C3 alkyl; Q 5 , Q6 , Q 7 , Q 8 and Q 9 are each independently N or CR 5 Among them, Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One or two of these are N and the rest are CR 5 and R 5 is H, halogen, C1-C3 alkyl, C1-C3 alkoxyl or cycloalkyl; R 6 is C1-C6 alkyl, R 7 is H, halogen, -C1-C6 alkyl, -C1-C6 alkoxyl or -cycloalkyl; R 8 is H, halogen, -C1-C6 alkyl, -C1-C6 alkoxyl or -cycloalkyl.

[0010] Stereoisomers of the compounds of formula (I), as well as pharmaceutical salts and solvates thereof, are also described. Methods of using the compounds of formula (I), and pharmaceutical compositions containing the compounds of formula (I) are also described. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present disclosure may be more fully understood by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods that are described herein in the context of separate embodiments may also be provided in combination in a single embodiment. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment may also be provided separately or in any subcombination.

[0012] The terms "optionally substituted" or "substituted" as used herein to describe substituents defined herein include those substituents that are halo (i.e., -F, -Cl, -Br, -I), cyano, -OH, -C1-C6 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, -C3-C6 spirocycloalkyl, 3-7 membered spiroheterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1- C6 haloalkyl (e.g., -CF3, -CHF2, -CH2CF3, etc.), -C1-C6 alkoxy, -C1-C6 haloalkoxy (e.g., -OCF3, -OCHF2, -OCH2CF3, etc.), C1-C6 alkylthio (e.g., -SCH3, -SCH2CH3, etc.), C1-C6 alkylamino (e.g., -CH2NH2, -CH2CH2NH2, etc.), -NH2, -NH(C1-C6 alkyl), -N(C1-C -6 alkyl), -NH(C1-C6 alkoxy), -C(O)NHC1-C6 alkyl, -C(O)N(C1-C6 alkyl), -COOH, -C 1- C6 alkyl COOH 、- C 3- C6 cycloalkylCOOH, -C(O)NH2, -C 1- C6 alkyl CONH 2、 -C3-C6 cycloalkylCONH2, -C1-C6 alkylCONHC1-C6 alkyl 、 -C1-C6 alkylCON(C 1- C6 alkyl) 2、 -C(O)C 1-In other embodiments, "optionally substituted" or "substituted" means that the substituent may, but need not, be substituted with one or more of: -C alkyl, -C(O)OC-C alkyl, -NHCO(C-C alkyl), -N(C-C alkyl)C(O)(C-C alkyl), -S(O)C-C alkyl, -S(O)C-C alkyl, oxo (i.e., =O), 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-C haloalkyl), -NHSO(C-C alkyl), -N(C-C alkyl)SO(C-C alkyl), or -P(O)(C-C alkyl) (e.g., -P(O)(CH)). In other embodiments, "optionally substituted" or "substituted" means that a substituent may, but need not, be substituted with one or more -P(O)(OCi_6 alkyl) groups. In other embodiments, "optionally substituted" or "substituted" means that a substituent may, but need not, be substituted with one or more -C(O)NR'R" where R' and R" taken 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 a substituent may, but need not be substituted with one or more -P(O)R'R" where R' and R" taken 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 with one or two of these groups.

[0013] When a range of carbon atoms is used herein, such as C1-C6, all ranges and individual numbers of carbon atoms are included. For example, "C1-C3" means C 1- C3, C 1- C2, C 2-This includes C3, C1, C2, and C3. Thus, for example, a "C1-C4 alkyl" group refers to any alkyl group having 1 to 4 carbons (e.g., 1, 2, 3, or 4), i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. A "C1-C6 alkyl" group refers to any alkyl group having 1 to 6 carbons (e.g., 1, 2, 3, 4, 5, or 6). "C0" means that there are no carbon atoms present. Thus, for example, a "C0-C3 alkyl" group means that the alkyl group is absent or present and has 1, 2, or 3 carbon atoms.

[0014] 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-chain alkyl groups include, but are not limited to, isopropyl, sec-butyl, t-butyl, and the like. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. An alkyl group may have 1 to 30 carbon atoms (wherever it appears herein, numerical ranges such as "1 to 30" refer to each integer within the specified 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 this definition also includes appearances of the term "alkyl" where no numerical range is specified). An "alkyl" group may also be a medium-sized alkyl having 1 to 12 carbon atoms. An "alkyl" group may also be a lower alkyl having 1 to 6 carbon atoms. An alkyl group may be substituted or unsubstituted, i.e., optionally substituted. By way of example only, "C1-C5 alkyl" indicates that the alkyl chain has 1 to 5 carbon atoms, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight chain), etc. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. In some embodiments, "Me" is methyl (e.g., CH3).

[0015] 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 can be unsubstituted or substituted, i.e., optionally substituted.

[0016] 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, i.e., optionally substituted.

[0017] 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, the rings may be linked together in a fused fashion. A cycloalkyl group may contain 3 to 12 carbon atoms. For example, a C3-C6 cycloalkyl group indicates that there are 3 to 6 carbon atoms in the ring, i.e., the ring is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. A cycloalkyl group may be unsubstituted or substituted, i.e., optionally substituted.

[0018] 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, which shares a single carbon atom with another cyclic ring. By way of illustration, an exemplary 3- to 7-membered spirocycloalkyl group attached to a piperidine ring is shown below: [ka]

[0019] 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 completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6-C6 14 Aryl groups, C6-C 10 The aryl group may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0020] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully 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(s) of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s), or 5 to 6 atoms in the ring(s). Furthermore, the term "heteroaryl" includes fused ring systems in which two rings share at least one chemical bond, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings. 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. The heteroaryl ring may also contain a bridgehead nitrogen atom. Examples, without limitation, are pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, and pyrazolo[1,5-a]pyrimidine. Heteroaryl groups can be substituted or unsubstituted.

[0021] As used herein, "heterocycloalkyl" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and up to 18-membered monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms, together with 1 to 5 heteroatoms, comprise the ring system. However, heterocycloalkyls may optionally contain one or more unsaturated bonds positioned in such a way that a completely delocalized π-electron system does not occur throughout the entire ring. Heteroatom(s) are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycloalkyls may further contain one or more carbonyl or thiocarbonyl functional groups, and the definition is intended to include oxo and thio systems such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be linked together in a fused manner. Additionally, any nitrogen in a heterocycloalkyl may be quaternized. Heterocycloalkyl groups may be unsubstituted or substituted. Examples of such "heterocycloalkyl" groups are 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isopropyl alcohol, methyl alcohol, methyl methyl alcohol, methyl ethyl ... Examples of suitable benzo- or benzophenone derivatives include, but are not limited to, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and benzo-fused analogs thereof (e.g., benzimidazolidinone, tetrahydroquinoline, 3,4-methylenedioxyphenyl).

[0022] 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. By way of illustration, an exemplary 3- to 7-membered spiroheterocycloalkyl group attached to a piperidine ring is shown below: [ka]

[0023] As used herein, the term "bridged bicyclic ring" refers to a ring system comprising two linked cycloalkyl or heterocycloalkyl rings that share at least three atoms. For example, a 6-9 membered bridged bicyclic ring indicates that there are 6, 7, 8, or 9 atoms in the bridged bicyclic ring. By way of example, exemplary 6-9 membered bridged bicyclic rings are shown below: [ka]

[0024] As used herein, the term "amino" refers to the group --NH.sub.2.

[0025] As used herein, the term "hydroxy" refers to an --OH group.

[0026] As used herein, the term "halogen atom" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0027] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not eliminate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a 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 a compound with an organic acid such as an aliphatic or aromatic carboxylic or sulfonic acid, for example, 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 a compound with a base to form ammonium salts, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), salts of organic bases (e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine), and salts with amino acids (e.g., arginine and lysine).

[0028] In any compound described herein having one or more chiral centers, unless the absolute configuration is explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. Additionally, in any compound described herein having one or more double bonds that produce geometric isomers that may be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof. It is understood that in any compound described herein having one or more chiral centers, all possible diastereomers are also contemplated. It is understood that in any compound described herein, all tautomers are also contemplated. It is also understood that in any compound described herein, all isotopes of the atoms involved are contemplated. 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; and any example of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

[0029] As used herein, the term "kinase inhibitor" refers to 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., by competing with the phosphorylating entity adenosine triphosphate (ATP)), by binding to a site outside the active site and affecting its activity through a conformational change, or by denying the kinase access to molecular chaperone systems on which it depends for cellular stability, leading to ubiquitination and degradation.

[0030] As used herein, "subject," "host," "patient," and "individual" are used interchangeably and shall be given their ordinary meanings and shall refer to an organism that possesses an FGFR protein. This includes mammals, such as humans, non-human primates, ungulates, canines, felines, equines, mice, rats, etc. The term "mammal" includes both human and non-human mammals.

[0031] The terms "sample" or "biological sample" shall be given their ordinary meaning and encompass various types of samples obtained from an organism and can be used in imaging, diagnostic, prognostic, or monitoring assays. The term encompasses blood and other liquid samples of biological origin, solid tissue samples such as biopsy specimens or tissue cultures or cells derived therefrom and their progeny. The term includes samples that have been manipulated in any way after procurement, such as by treatment with reagents, solubilization, or enrichment for particular components. The term encompasses clinical samples, and also includes cells in cell culture, cell supernatants, cell lysates, serum, plasma, body fluid, and tissue samples.

[0032] The terms "treatment," "treating," "treat," and the like shall be given their ordinary meaning and shall, as used herein, encompass a general reference to obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic, in that a disease or its symptoms are completely or partially prevented, and / or therapeutic, in that a disease and / or side effects resulting from the disease are partially or completely stabilized or cured. As used herein, "treatment" shall be given its ordinary meaning and shall include any treatment of disease in a mammal, particularly a human, including (a) preventing a disease or condition from occurring in a subject who may be susceptible to, but has not yet been diagnosed with, the disease or condition; (b) inhibiting a symptom of the disease, e.g., preventing its onset; and / or (c) alleviating a symptom of the disease, e.g., causing regression of the disease or condition.

[0033] The terms "cancer," "neoplasm," and "tumor" are used interchangeably herein and are given their ordinary meaning to refer to an abnormal growth phenotype characterized by relatively autonomous growth and a significant loss of control of cell proliferation. Generally, cells of interest for detection or treatment in this application include precursor, pre-cancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells. As used herein, "FGFR-associated cancer" refers to those cancers associated with increased activity in mutant FGFR kinases, e.g., continuous activation of FGFR.

[0034] The term "control" shall be given its ordinary meaning and shall also include a sample or standard used for comparison with a sample being tested, processed, characterized, analyzed, etc. In some embodiments, a control is a sample obtained from a healthy patient or a non-tumor tissue sample obtained from a patient diagnosed with a tumor. In some embodiments, a control is a historical control or standard reference value or range of values. In some embodiments, a control is a comparison with a wild-type FGFR configuration or scenario.

[0035] With respect to the use of virtually any plural and / or singular term herein, those skilled in the art can convert from the plural to the singular and / or from the singular to the plural as appropriate to the context and / or application. Various singular / plural permutations may be expressly indicated herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere 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.

[0036] In some embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka]

[0037] In some embodiments, R in the compound of formula (I) 9 is H.

[0038] In another embodiment, R in the compound of formula (I) 9 is C1-C3 alkyl, for example C3 alkyl, C2 alkyl, C1 alkyl, methyl, ethyl, propyl, etc.

[0039] In some embodiments, R in the compound of formula (I) 9 is methyl.

[0040] In some embodiments, X in the compound of formula (I) is O, S, or NR, wherein R is H or C1-C3 alkyl.

[0041] In some embodiments, X is O.

[0042] In some embodiments, X is S.

[0043] In some embodiments, X is NR.

[0044] In some embodiments, R is H.

[0045] In other embodiments, R is C1-C3 alkyl, for example, C3 alkyl, C2 alkyl, C1 alkyl, methyl, ethyl, propyl, etc.

[0046] In some embodiments, n in the compound of formula (I) is 1 or 2.

[0047] In some embodiments, n is 1.

[0048] In some embodiments, n is 2.

[0049] In some embodiments, m in the compound of formula (I) is 1 or 2.

[0050] In some embodiments, m is 1.

[0051] In some embodiments, m is 2.

[0052] In some embodiments, n is 1 and m is 1.

[0053] In some embodiments, n is 1 and m is 2.

[0054] In some embodiments, n is 2 and m is 1.

[0055] In some embodiments, n is 2 and m is 2.

[0056] In some embodiments, R in the compound of formula (I) 1 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, C3-C5 cycloalkyl, -C(O)NR 3 R 4 , -C(O)OR 3 , optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

[0057] In some embodiments, R in the compound of formula (I) 1 is H or optionally substituted C1-C6 alkyl.

[0058] In some embodiments, R in the compound of formula (I) 1 is H or C1-C6 alkyl.

[0059] In some embodiments, R in the compound of formula (I) 1 is H.

[0060] In some embodiments, R 1 is, for example, optionally substituted C1-C6 alkyl, optionally substituted C1-C5 alkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C3 alkyl, optionally substituted C1-C2 alkyl, optionally substituted C1 alkyl, optionally substituted C2 alkyl, optionally substituted C3 alkyl, optionally substituted C4 alkyl, optionally substituted C5 alkyl, optionally substituted C6 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 pentanyl, optionally substituted hexanyl, and other optionally substituted C1-C6 alkyl.

[0061] R in the compound of formula (I) 1 In some embodiments, where R is an optionally substituted C1-C6 alkyl, the optionally substituted C1-C6 alkyl is selected from the group consisting of -CH2CH2OH, -CH2CH2OCH3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CN, -CH2CH2CH2OH, -CH2OCH3, -CH2OCH(CH3)2, -CH2OCH2CH3, [ka] is.

[0062] R in the compound of formula (I) 1 In some embodiments where is optionally substituted C1-C6 alkyl, the optionally substituted C1-C6 alkyl is [ka] is.

[0063] R in the compound of formula (I) 1 In some embodiments where is optionally substituted C1-C6 alkyl, the optionally substituted C1-C6 alkyl is [ka] is.

[0064] In some embodiments, R 1 is C1-C6 alkyl, for example C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1-C6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0065] In some embodiments, R in the compound of formula (I) 1 is methyl.

[0066] In another embodiment, R in the compound of formula (I) 1 is isopropyl.

[0067] In another embodiment, R in the compound of formula (I) 1 is isobutyl.

[0068] In another embodiment, R in the compound of formula (I) 1 is sec-butyl.

[0069] In another embodiment, R in the compound of formula (I) 1 is n-propyl.

[0070] In some embodiments, R in the compound of formula (I) 1 is a methyl substituted with cyano, i.e., —CH 2 CN.

[0071] In some embodiments, R in the compound of formula (I) 1 is a methyl substituted with a hydroxyl, i.e., —CHOH.

[0072] In another embodiment, R in the compound of formula (I) 1 is ethyl.

[0073] In some embodiments, R in the compound of formula (I) 1 is, for example, an optionally substituted C2-C6 alkenyl such as optionally substituted C2-C6 alkenyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C3 alkenyl, optionally substituted C2 alkenyl, optionally substituted C3 alkenyl, optionally substituted C4 alkenyl, optionally substituted C5 alkenyl, optionally substituted C6 alkenyl, optionally substituted ethenyl, optionally substituted n-propenyl, optionally substituted isopropenyl, optionally substituted n-butenyl, optionally substituted isobutenyl, optionally substituted sec-butenyl, optionally substituted pentenyl, or optionally substituted hexenyl.

[0074] In some embodiments, R 1 is unsubstituted C2-C6 alkenyl.

[0075] In some embodiments, R 1 is a substituted C2-C6 alkenyl.

[0076] In some embodiments, R 1 teeth [ka] is.

[0077] In some embodiments, R in the compound of formula (I) 1 is, for example, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C3-C5 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, etc.

[0078] In some embodiments, R in the compound of formula (I) 1 is cyclobutyl.

[0079] In some embodiments, R in the compound of formula (I) 1 is an optionally substituted heterocycloalkyl.

[0080] In some embodiments, R in the compound of formula (I) 1 is a substituted heterocycloalkyl.

[0081] In another embodiment, R in the compound of formula (I) 1 is an unsubstituted heterocycloalkyl.

[0082] In some embodiments, R in the compound of formula (I) 1 teeth [ka] is.

[0083] In some embodiments, R in the compound of formula (I) 1 is an optionally substituted heteroaryl.

[0084] In some embodiments, R in the compound of formula (I) 1 is a substituted heteroaryl.

[0085] In some embodiments, R in the compound of formula (I) 1 teeth [ka] is.

[0086] In some embodiments, R in the compound of formula (I) 1 is an unsubstituted heteroaryl.

[0087] In some embodiments, R in the compound of formula (I) 1 teeth [ka] is.

[0088] In some embodiments, R in the compound of formula (I) 1 -C(O)OR 3 is.

[0089] In some embodiments, R in the compound of formula (I) 1 teeth [ka] is.

[0090] In some embodiments, R in the compound of formula (I) 1 is -C(O)NR 3 R 4 is.

[0091] In some embodiments, R in the compound of formula (I) 1 teeth [ka] is.

[0092] In some embodiments, R in the compound of formula (I) 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)NR3 R 4 is.

[0093] In some embodiments, R in the compound of formula (I) 2 is H, optionally substituted C1-C6 alkyl, -NR 3 R 4 -OR 4a is.

[0094] In some embodiments, R 2 is H.

[0095] In some embodiments, R 2 is, for example, optionally substituted C1-C6 alkyl including optionally substituted C1-C5 alkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C3 alkyl, optionally substituted C1-C2 alkyl, optionally substituted C1 alkyl, optionally substituted C2 alkyl, optionally substituted C3 alkyl, optionally substituted C4 alkyl, optionally substituted C5 alkyl, optionally substituted C6 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 hexanyl, and the like.

[0096] In some embodiments, R 2 is unsubstituted C1-C6 alkyl.

[0097] In some embodiments, R 2 is CH3.

[0098] In some embodiments, R 2is a substituted C1-C6 alkyl.

[0099] In some embodiments, R 2 is —NHSO2(C1-C6 alkyl), —N(C1-C6 alkyl)SO2(C1-C6 alkyl), C1-C6 alkyl substituted with 5- to 6-membered heterocycloalkyl, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or —P(O)(C1-C6 alkyl)2.

[0100] In some embodiments, R 2 is a C1-C6 alkyl substituted with -SO2(C1-C6 alkyl).

[0101] In some embodiments, R 2 teeth, [ka] is.

[0102] In some embodiments, R 2 is C1-C6 alkyl substituted with -NH2, for example -CH2NH2.

[0103] In some embodiments, R 2 is C1-C6 alkyl substituted with NHSO2(C1-C6 alkyl), for example NHSO2(CH3), NHSO2(CH2CH3), NHSO2(CH2CH2CH3), NHSO2(CH2CH2CH2CH3), NHSO2(CH2CH2CH2CH3).

[0104] In some embodiments, R 2 is -CH2-NHSO2(CH3).

[0105] In some embodiments, R 2is C-C alkyl substituted with —N(C-C alkyl)SO(C-C alkyl), such as, for example, —N(CH)SO(CH), —N(CH)SO(CHCH), —N(CH)SO(CHCHCH), —N(CHCH)SO(CH), —N(CHCH)SO(CHCH).

[0106] In some embodiments, R 2 is -CH2-N(CH3)SO2(CH3).

[0107] In some embodiments, R 2 is C1-C6 alkyl substituted with a 5-6 membered heterocycloalkyl, such as, for example, pyrrolyl, furanyl, piperidinyl, piperazinyl, morpholinyl, and the like.

[0108] In some embodiments, R 2 teeth, [ka] is.

[0109] In some embodiments, R 2 is C1-C6 alkyl substituted with -NH(C1-C6 alkyl), for example, -NH(C6 alkyl), -NH(C5 alkyl), -NH(C4 alkyl), -NH(C3 alkyl), -NH(C2 alkyl), -NH(C1 alkyl), NH(CH3), NH(CH2CH3), etc.

[0110] In some embodiments, R 2 is —CH2—NH(CH3) or —CH2—NH(CH(CH3)2).

[0111] In some embodiments, R 2 is -CH2-NH(CH2CH2OH).

[0112] In some embodiments, R 2is C1-C6 substituted with —N(C1-C6 alkyl)2, for example, —N(C6 alkyl)2, —N(C5 alkyl)2, —N(C4 alkyl)2, —N(C3 alkyl)2, —N(C2 alkyl)2, —N(C1 alkyl)2, —N(CH3)2, —N(CH2CH3)2, —N(CH3)(CH2CH3).

[0113] In some embodiments, R 2 is -CH2-N(CH3)2.

[0114] In some embodiments, R 2 is -P(O)R 4b R 4c C1-C6 alkyl substituted with, wherein R 4b and R 4c are independently C1-C6 alkyl or -OC1-C6 alkyl, or R 4b and R 4c taken together with the phosphorus atom to which they are both attached, form a 4- to 6-membered heterocycloalkyl ring.

[0115] In some embodiments, R 4b is, for example, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1-C6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, etc.

[0116] In some embodiments, R 4b is CH3.

[0117] In some embodiments, R 4bis, for example, -OC1-C6 alkyl, -OC1-C5 alkyl, -OC1-C4 alkyl, -OC1-C3 alkyl, -OC1-C2 alkyl, -OC1 alkyl, -OC2 alkyl, -OC3 alkyl, -OC4 alkyl, -OC5 alkyl, -OC6 alkyl, methoxyl, ethoxyl, n-propoxyl, isopropoxyl, n-butoxyl, isobutoxyl, sec-butoxyl, and the like.

[0118] In some embodiments, R 4b is -OCH3.

[0119] In some embodiments, R 4c is C1-C6 alkyl, for example C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1-C6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0120] In some embodiments, R 4c is CH3.

[0121] In some embodiments, R 4c is, for example, -OC1-C6 alkyl, -OC1-C5 alkyl, -OC1-C4 alkyl, -OC1-C3 alkyl, -OC1-C2 alkyl, -OC1 alkyl, -OC2 alkyl, -OC3 alkyl, -OC4 alkyl, -OC5 alkyl, -OC6 alkyl, methoxyl, ethoxyl, n-propoxyl, isopropoxyl, n-butoxyl, isobutoxyl, sec-butoxyl, and the like.

[0122] In some embodiments, R 4c is -OCH3.

[0123] In some embodiments, R 2is a C1-C6 alkyl substituted with -P(O)(C6 alkyl)2, -P(O)(C5 alkyl)2, -P(O)(C4 alkyl)2, -P(O)(C3 alkyl)2, -P(O)(C2 alkyl)2, -P(O)(C1 alkyl)2, -P(O)(CH3)2, -P(O)(CH2CH3)2, -P(O)(CH3)(CH2CH3), etc.

[0124] In some embodiments, R 2 is -CH2-P(O)(CH3)2.

[0125] In some embodiments, R 2 is a C1-C6 alkyl substituted with -P(O)(OC6 alkyl)2, -P(O)(OC5 alkyl)2, -P(O)(OC4 alkyl)2, -P(O)(OC3 alkyl)2, -P(O)(OC2 alkyl)2, -P(O)(OC1 alkyl)2, -P(O)(OCH3)2, -P(O)(OCH2CH3)2, -P(O)(OCH3)(OCH2CH3), etc.

[0126] In some embodiments, R 2 is -CH2-P(O)(OCH3)2.

[0127] In some embodiments, R 4b and R 4c taken together with the phosphorus atom to which they are both attached form a 4- to 6-membered heterocycloalkyl ring, e.g., a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl.

[0128] In some embodiments, R 2 teeth, [ka] is C1-C6 alkyl substituted with

[0129] In some embodiments, R 2 Ha-NR 3 R 4where R 3 is H or C1-C6 alkyl, and R 4 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, C3-C5 cycloalkyl, 3- 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 taken together with the N atom to which they are both attached form a 3-6 membered heterocycloalkyl optionally substituted with one or more substituents, each of which is C1-C6 alkyl, C1-C6 alkoxyl, F, or OH.

[0130] In other embodiments, R 2 Ha-NR 3 R 4 where R 3 is H or C1-C6 alkyl, and R 4 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, C3-C5 cycloalkyl, 3- to 6-membered heterocycloalkyl, or C(O)CH2NR 4d R 4e or R 3 and R 4 taken together with the N atom to which they are both attached form a 3-6 membered heterocycloalkyl optionally substituted with one or more substituents, each of which is C1-C6 alkyl, C1-C6 alkoxyl, F, or OH.

[0131] In some embodiments, R 2 Ha-NR 3 R 4 where R 3 is H or C1-C6 alkyl, and R 4 is H, optionally substituted C1-C6 alkyl, C3-C5 cycloalkyl, 3- to 6-membered heterocycloalkyl, or C(O)CH2NR 4d R 4eor R 3 and R 4 taken together with the N atom to which they are both attached form a 3-6 membered heterocycloalkyl optionally substituted with one or more substituents, each of which is C1-C6 alkyl, C1-C6 alkoxyl, F, or OH.

[0132] In some embodiments, R 3 is H.

[0133] In some embodiments, R 3 is, for example, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1-C6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0134] In some embodiments, R 3 is CH3.

[0135] In some embodiments, R 4 is H.

[0136] In some embodiments, R 4is, for example, optionally substituted C1-C6 alkyl, optionally substituted C1-C5 alkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C3 alkyl, optionally substituted C1-C2 alkyl, optionally substituted C1 alkyl, optionally substituted C2 alkyl, optionally substituted C3 alkyl, optionally substituted C4 alkyl, optionally substituted C5 alkyl, optionally substituted C6 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 pentanyl, optionally substituted hexanyl, and other optionally substituted C1-C6 alkyl.

[0137] In some embodiments, R 4 is unsubstituted C1-C6 alkyl.

[0138] In some embodiments, R 4 is -CH3, -CH2CH3 or -CH(CH3)2.

[0139] In other embodiments, R 4 -CH2CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, [ka] is.

[0140] In some embodiments, R 4 is a substituted C1-C6 alkyl.

[0141] In some embodiments, R 4are -CH2-cyclopropyl, -CH2CH2SO2CH3, -CH2CH2CHF2, -CH2CHF2, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2O-iso-Pr, -CH2C(CH3)2OH, -CH2CHCH3OH, -CH2CHOCH3, [ka] is.

[0142] In some embodiments, R 4 is -CH2CH2CN, [ka] is.

[0143] In some embodiments, R 4 is, for example, -(CH2) such as -CH2P(O)(CH3)2, -CH2CH2P(O)(CH2CH3)2, -CH2CH2P(O)(CH2CH2CH3)2, -CH2CH2P(O)(CH3)(CH2CH3). 1-3 P(O)(C1-C6 alkyl)2.

[0144] In some embodiments, R 4 is -(CH2) such as -CH2P(O), -CH2CH2P(O), -CH2CH2P(O), -CH2CH2P(O), etc. 1-3 P(O).

[0145] In some embodiments, R 4 teeth [ka] is.

[0146] In some embodiments, R 4is, for example, an optionally substituted C2-C6 alkenyl such as optionally substituted C2-C5 alkenyl, optionally substituted C2-C4 alkenyl, optionally substituted alkenyl, optionally substituted C2 alkenyl, optionally substituted C3 alkenyl, optionally substituted C4 alkenyl, optionally substituted C5 alkenyl, optionally substituted C6 alkenyl, optionally substituted ethenyl, optionally substituted n-propenyl, optionally substituted isopropenyl, optionally substituted n-butenyl, optionally substituted isosubtenyl, optionally substituted sec-butynyl, optionally substituted pentenyl, or optionally substituted hexenyl.

[0147] In some embodiments, R 4 is unsubstituted C2-C6 alkenyl.

[0148] In some embodiments, R 4 is -CH2CH=CH2.

[0149] In some embodiments, R 4 is C3-C5 cycloalkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl.

[0150] In some embodiments, R 4 is cyclobutyl.

[0151] In some embodiments, R 4 is, for example, a 3- to 6-membered heterocycloalkyl such as a 3-membered heterocycloalkyl, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, a 6-membered heterocycloalkyl, aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl.

[0152] In some embodiments, R 4 oxetan-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl, [ka] is.

[0153] In some embodiments, R 4 is, for example, C(O)NR 4d R 4e , C(O)(CH2)NR 4d R 4e , C(O)(CH2)2NR 4d R 4e , or C(O)(CH2)3NR 4d R 4e such as C(O)(CH2) 0-3 NR 4d R 4e is.

[0154] In some embodiments, R 4 is C(O)(CH2) 0-3 NR 4d R 4e where R 4d and R 4e are each independently H or C1-C6 alkyl, or R 4d and R 4e taken together with the nitrogen atom to which they are both attached form a 4- to 6-membered heterocycloalkyl ring.

[0155] In some embodiments, R 4 is C(O)(CH2) 0-3 NR 4d R 4e where R 4d and R 4e are each independently H or C1-C6 alkyl.

[0156] In some embodiments, R 4is C(O)CHN(C1-C6 alkyl) such as C(O)CHN(C6 alkyl), C(O)CHN(C5 alkyl), C(O)CHN(C4 alkyl), C(O)CHN(C3 alkyl), C(O)CHN(C2 alkyl), C(O)CHN(C1 alkyl), C(O)CHN(CH3), C(O)CH2N(CH2CH3), C(O)CH2N(CH3)(CH2CH3).

[0157] In some embodiments, R 4 is C(O)CH2N(CH3)2.

[0158] In other embodiments, R 4 is C(O)(CH2) 0-3 NR 4d R 4e where R 4d and R 4e taken together with the nitrogen atom to which they are both attached form a 4-6 membered heterocycloalkyl ring, for example, pyrrolidinyl, piperidinyl, morpholinyl, etc.

[0159] In some embodiments, R 3 and R 4 taken together with the N atom to which they are both attached form a 3-6 membered heterocycloalkyl optionally substituted with one or more substituents, each of which is C1-C6 alkyl, C1-C6 alkoxyl, F, or OH.

[0160] In some embodiments, R 4 is C(O)(CH), such as C(O)CHCHOH or C(O)CHCHCHOH. 2-3 In some embodiments, R 4 is C(O)CH2CH2OH.

[0161] In some embodiments, R 3 and R 4taken together with the N atom to which they are both attached form an unsubstituted 3- to 6-membered heterocycloalkyl, such as a 3-membered heterocycloalkyl, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, a 6-membered heterocycloalkyl, aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, etc.

[0162] In some embodiments, R 3 and R 4 taken together with the N atom to which they are both attached form unsubstituted pyrrolidin-1-yl, azetidin-1-yl or morpholin-4-yl.

[0163] In some embodiments, R 3 and R 4 taken together with the N atom to which they are both attached 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 oxiranyl, a substituted azetidinyl, a substituted oxetanyl, a substituted pyrrolidinyl, a substituted tetrahydrofuranyl, a substituted tetrahydropyranyl, a substituted piperidinyl, a substituted piperazinyl, a substituted morpholinyl, or the like.

[0164] In some embodiments, R 3 and R 4 together with the N atom to which they are both attached, represent 3,3-dimethylazetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphinan-4-yl 1-oxide, 1-methyl-4-azaphosphinan-4-yl 1-oxide, or 3-methoxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphinan-4-yl 1-oxide, or [ka] Form.

[0165] In some embodiments, R 3 and R 4 together with the N atom to which they are both attached, [ka] Form.

[0166] In some embodiments, R 3 and R 4 together with the N atom to which they are both attached, [ka] Form.

[0167] In some embodiments, R 3 and R 4 together with the N atom to which they are both attached form a 6-8 membered bridged heterocycloalkyl ring system, e.g. [ka] etc. are formed.

[0168] In some embodiments, R 2 HA-OR 4a where R 4a is H, optionally substituted C1-C6 alkyl or C3-C5 cycloalkyl.

[0169] In some embodiments, R 2 is -OH.

[0170] In some embodiments, R 4a is H.

[0171] In some embodiments, R 4ais, for example, optionally substituted C1-C6 alkyl, optionally substituted C1-C5 alkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C3 alkyl, optionally substituted C1-C2 alkyl, optionally substituted C1 alkyl, optionally substituted C2 alkyl, optionally substituted C3 alkyl, optionally substituted C4 alkyl, optionally substituted C5 alkyl, optionally substituted C6 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 pentanyl, optionally substituted hexanyl, and other optionally substituted C1-C6 alkyl.

[0172] In some embodiments, R 4a is unsubstituted C1-C6 alkyl.

[0173] In some embodiments, R 4a is -CH(CH3).

[0174] In some embodiments, R 4a is a substituted C1-C6 alkyl.

[0175] In some embodiments, R 4a is —CH2CH2OH or —CH2C(CH3)2OH.

[0176] In some embodiments, R 4a is C3-C5 cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl.

[0177] In some embodiments, R 4a is cyclopropyl.

[0178] In some embodiments, R 4a is cyclobutyl.

[0179] In some embodiments, R 4a is cyclopentyl.

[0180] In some embodiments, R 2 teeth, [ka] is.

[0181] In some embodiments, R 2 HA-P(O)R 4b R 4c where R 4b and R 4c are independently C1-C6 alkyl, or R 4b and R 4c taken together with the phosphorus atom to which they are both attached, form a 4- to 6-membered heterocycloalkyl ring.

[0182] In some embodiments, R 4b is C1-C6 alkyl, for example C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1-C6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0183] In some embodiments, R 4b is CH3.

[0184] In some embodiments, R 4cis C1-C6 alkyl, for example C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1-C6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0185] In some embodiments, R 4c is CH3.

[0186] In some embodiments, R 2 is -P(O)(CH3)2.

[0187] In some embodiments, R 4b and R 4c taken together with the phosphorus atom to which they are both attached form a 4- to 6-membered heterocycloalkyl ring, e.g., a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl.

[0188] In some embodiments, R 2 is as follows: [ka]

[0189] In some embodiments, R 2 is -SO2R 3 , such as -SO2H or -SO2C1-C6 alkyl, such as -SO2C6 alkyl, -SO2C5 alkyl, -SO2C4 alkyl, -SO2C3 alkyl, -SO2C2 alkyl, -SO2C1 alkyl or -SO2CH3.

[0190] In some embodiments, R 2is, for example, -C(O)NR such as -C(O)NH, -C(O)NH(C-C alkyl), -C(O)N(C-C alkyl)(C-C alkyl), -C(O)NHCH, -C(O)N(CH), -C(O)NHCHCH, -C(O)N(CHCH), and -C(O)NHCHCHOH. 3 R 4 is.

[0191] In some embodiments, R in the compound of formula (I) 1 and R 2 taken together with the carbon atom to which they are both attached form a 3- to 5-membered cycloalkyl ring, for example cyclopropyl, cyclobutyl, or cyclopentyl.

[0192] In some embodiments, R in the compound of formula (I) 1 and R 2 taken together with the carbon atoms to which they are both attached form a cyclopropyl ring.

[0193] In some embodiments, R in the compound of formula (I) 1 and R 2 taken together with the carbon atoms to which they are both attached form a cyclobutyl ring.

[0194] In some embodiments, R in the compound of formula (I) 1 and R 2 taken together with the carbon atoms to which they are both attached form a cyclopentyl ring.

[0195] In some embodiments, Q in the compound of formula (I) 1 , Q 2 , Q 3 , Q 4 one or two of which are N, and the rest are each independently CR 5a is.

[0196] In some embodiments, Q 1 is N and Q2 , Q 3 and Q 4 are each independently CR 5a is.

[0197] In some embodiments, Q 2 is N and Q 1 , Q 3 and Q 4 are each independently CR 5a is.

[0198] In some embodiments, Q 3 is N and Q 1 , Q 2 and Q 4 are each independently CR 5a is.

[0199] In some embodiments, Q 4 is N and Q 1 , Q 2 and Q 3 are each independently CR 5a is.

[0200] In other embodiments, Q 1 , Q 2 , Q 3 , Q 4 Two of them are N, and the rest are independently CR 5a is.

[0201] In some embodiments, Q 1 and Q 2 are N and Q 3 and Q 4 are each independently CR 5a is.

[0202] In some embodiments, Q 1 and Q 3 are N and Q 2 and Q 4 are each independently CR 5a is.

[0203] In some embodiments, Q 1 and Q 4 are N and Q 2 and Q 3 are each independently CR 5a is.

[0204] In some embodiments, Q 2 and Q 3 are N and Q 1 and Q 4 are each independently CR 5a is.

[0205] In some embodiments, Q 2 and Q 4 are N and Q 1 and Q 3 are each independently CR 5a is.

[0206] In some embodiments, Q 3 and Q 4 are N and Q 1 and Q 2 are each independently CR 5a is.

[0207] In some embodiments of the compound of Formula (I), each R 5a are independently H, halogen, —CN, —S(O)2C1-C3 alkyl, OCF3, OC1-C3 alkyl, or C1-C3 alkyl.

[0208] In some embodiments, at least one R 5a is H.

[0209] In some embodiments, at least one R 5a is a halogen, i.e., —F, —Cl, —Br, or —I.

[0210] In some embodiments, at least one R 5a is -F.

[0211] In some embodiments, at least one R 5a is -CN.

[0212] In some embodiments, at least one R 5a is -SO2C1-C3 alkyl, for example, -SO2C1 alkyl, -SO2C2 alkyl, -SO2C3 alkyl, -SO2CH2CH3, -SO2CH3, etc. In some embodiments, at least one R 5a is -SO2CH3.

[0213] In some embodiments, R 5a is OCF3.

[0214] In some embodiments, at least one R 5a is OC1-C3 alkyl, for example, OC1-C3 alkyl, OC1-C2 alkyl, OC1 alkyl, OC2 alkyl, OC3 alkyl, -OCH3, -OCH2CH3, -propyl, etc. In some embodiments, at least one R 5a is -OCH3.

[0215] In some embodiments, at least one R 5a is C1-C3 alkyl, for example, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3, -propyl, etc. In some embodiments, at least one R 5a is -CH3.

[0216] In some embodiments, Q in the compound of formula (I) 5 , Q 6 , Q 7 , Q 8 and Q 9 are each independently N or CR 5 where Q 5 , Q 6 , Q 7 , Q 8 and Q 9one or two of which are N, and the rest are each independently CR 5 is.

[0217] In some embodiments, Q 5 , Q 6 , Q 7 , Q 8 or Q 9 One of them is N, and the rest are each independently CR 5 is.

[0218] In some embodiments, Q 5 is N and Q 6 , Q 7 , Q 8 and Q 9 are each independently CR 5 is.

[0219] In some embodiments, Q 6 is N and Q 5 , Q 7 , Q 8 and Q 9 are each independently CR 5 is.

[0220] In some embodiments, Q 7 is N and Q 5 , Q 6 , Q 8 and Q 9 are each independently CR 5 is.

[0221] In some embodiments, Q 8 is N and Q 5 , Q 6 , Q 7 and Q 9 are each independently CR 5 is.

[0222] In some embodiments, Q 9 is N and Q 5 , Q 6 , Q 7 and Q 8are each independently CR 5 is.

[0223] In other embodiments, Q 5 , Q 6 , Q 7 , Q 8 or Q 9 Two of them are N, and the rest are CR 5 is.

[0224] In some embodiments, Q 5 and Q 6 are N and Q 7 , Q 8 and Q 9 are each independently CR 5 is.

[0225] In some embodiments, Q 5 and Q 7 are N and Q 6 , Q 8 and Q 9 are each independently CR 5 is.

[0226] In some embodiments, Q 5 and Q 8 are N and Q 6 , Q 7 and Q 9 are each independently CR 5 is.

[0227] In some embodiments, Q 5 and Q 9 are N and Q 6 , Q 7 and Q 8 are each independently CR 5 is.

[0228] In some embodiments, Q 6 and Q 7 are N and Q 5 , Q 8 and Q 9are each independently CR 5 is.

[0229] In some embodiments, Q 6 and Q 8 are N and Q 5 , Q 7 and Q 9 are each independently CR 5 is.

[0230] In some embodiments, Q 6 and Q 9 are N and Q 5 , Q 7 and Q 8 are each independently CR 5 is.

[0231] In some embodiments, Q 7 and Q 8 are N and Q 5 , Q 6 and Q 9 are each independently CR 5 is.

[0232] In some embodiments, Q 7 and Q 9 are N and Q 5 , Q 6 and Q 8 are each independently CR 5 is.

[0233] In some embodiments, Q 8 and Q 9 are N and Q 5 , Q 6 and Q 7 are each independently CR 5 is.

[0234] In some embodiments of the present disclosure, each R in the compound of formula (I) 5 are independently H, halogen, C1-C3 alkyl, C1-C3 alkoxyl, or cycloalkyl.

[0235] In some embodiments of the compounds of Formula (I), at least one R 5 is H.

[0236] In some embodiments of the compounds of Formula (I), at least one R 5 is a halogen such as -F, -Cl, -Br or -I.

[0237] In some embodiments, at least one R 5 is -Cl.

[0238] In some embodiments of the compounds of Formula (I), at least one R 5 is C1-C3 alkyl, for example C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3, -propyl, etc.

[0239] In some embodiments, at least one R 5 is -CH3.

[0240] In some embodiments of the compounds of Formula (I), at least one R 5 is C1-C3 alkoxyl, for example C1-C3 alkoxyl, C1-C2 alkoxyl, C1 alkoxyl, C2 alkoxyl, C3 alkoxyl, -OCH3, -OCH2CH3, -propoxyl, etc.

[0241] In some embodiments, at least one R 5 is -OCH3.

[0242] In some embodiments of the compounds of Formula (I), at least one R 5 is cycloalkyl, such as for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0243] In some embodiments of the compounds of Formula (I), two R 5are halogens, and the remaining R 5 is H.

[0244] In other embodiments of the compounds of Formula (I), two R 5 is -Cl, and the remaining R 5 is H.

[0245] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 where each R 5 are independently halogens, and Q 6 and Q 8 are each independently CR 5 and each R 5 is H and Q 7 is N.

[0246] In some embodiments of the compounds of Formula (I), Q 5 , Q 8 and Q 9 are each independently CR 5 where each R 5 are independently halogens, and Q 6 is CR 5 where R 5 is H and Q 7 is N.

[0247] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 where each R 5 is -Cl, and Q 6 and Q 8 are each independently CR 5 where R 5 is H and Q 7 is N.

[0248] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5where each R 5 is -Cl, and Q 6 is CR 5 where R 5 is H and Q 8 is CR 5 and R 5 is -F and Q 7 is N.

[0249] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 where each R 5 are independently halogens, and Q 6 is CR 5 where R 5 is H and Q 8 is CR 5 where R 5 is C1-C3 alkyl, and Q 7 is N.

[0250] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 where each R 5 is -Cl, and Q 6 is CR 5 where R 5 is H and Q 8 is CR 5 where R 5 is -CH3 and Q 7 is N.

[0251] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 where each R 5 is a halogen. 6 is CR 5 where R 5 is H and Q 8 is N and Q 7 is CR 5 where R5 is H.

[0252] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 where each R 5 is -Cl, and Q 6 is CR 5 where R 5 is H and Q 8 is N and Q 7 is CR 5 where R 5 is H.

[0253] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 where each R 5 are independently halogens, and Q 6 is CR 5 where R 5 is H and Q 8 is N and Q 7 is N.

[0254] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 where each R 5 is -Cl, and Q 6 is CR 5 where R 5 is H and Q 8 is N and Q 7 is N.

[0255] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 where each R 5 are independently C1-C3 alkyl, and Q 6 is CR 5 where R 5is H and Q 8 is N and Q 7 is N.

[0256] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 where each R 5 is -CH3 and Q 6 is CR 5 where R 5 is H and Q 8 is N and Q 7 is N.

[0257] In some embodiments of the present disclosure, R in compounds of formula (I) 6 is C1-C6 alkyl, for example C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1-C6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0258] In some embodiments of the compounds of the present disclosure, R 6 is -CH3.

[0259] In some embodiments, R in the compound of formula (I) 7 is H, halogen, -C1-C6 alkyl, -C1-C6 alkoxyl or -cycloalkyl.

[0260] In some embodiments, R in the compound of formula (I) 7 is H.

[0261] In some embodiments, R in the compound of formula (I) 7 is a halogen such as, for example, —F, —Cl, —Br, or —I.

[0262] In some embodiments, R in the compound of formula (I) 7 is -F.

[0263] In some embodiments, R in the compound of formula (I) 7 is -Cl.

[0264] In some embodiments, R in the compound of formula (I) 7 is, for example, substituted or unsubstituted -C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, and the like.

[0265] In some embodiments, R 7 is -CH3.

[0266] In some embodiments, R in the compound of formula (I) 7 is, for example, -C1-C6 alkoxyl, -C1-C5 alkoxyl, -C1-C4 alkoxyl, -C1-C3 alkoxyl, -C1-C2 alkoxyl, -C1 alkoxyl, -C2 alkoxyl, -C3 alkoxyl, -C4 alkoxyl, -C5 alkoxyl, -C6 alkoxyl, -OCH3, -OCH2CH3, -propyloxy and the like.

[0267] In some embodiments, R 7 is -OCH3.

[0268] In some embodiments, R in the compound of formula (I) 7 is for example -cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0269] In some embodiments, R 8is H, halogen, -C1-C6 alkyl, -C1-C6 alkoxyl or -cycloalkyl.

[0270] In some embodiments, R in the compound of formula (I) 8 is H.

[0271] In some embodiments, R in the compound of formula (I) 8 is a halogen such as, for example, —F, —Cl, —Br, or —I.

[0272] In some embodiments, R in the compound of formula (I) 8 is -F.

[0273] In some embodiments, R in the compound of formula (I) 8 is, for example, substituted or unsubstituted -C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, and the like.

[0274] In some embodiments, R 8 is -CH3.

[0275] In some embodiments, R in the compound of formula (I) 8 is, for example, -C1-C6 alkoxyl, -C1-C5 alkoxyl, -C1-C4 alkoxyl, -C1-C3 alkoxyl, -C1-C2 alkoxyl, -C1 alkoxyl, -C2 alkoxyl, -C3 alkoxyl, -C4 alkoxyl, -C5 alkoxyl, -C6 alkoxyl, -OCH3, -OCH2CH3, -propoxyl, and the like.

[0276] In some embodiments, R 8 is -OCH3.

[0277] In some embodiments, R in the compound of formula (I) 8 is for example -cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0278] In some embodiments of the compounds of Formula (I), R 7 is -F and R 8 is H.

[0279] In some embodiments of the compounds of Formula (I), R 7 is -Cl, and R 8 is H.

[0280] In some embodiments of the compounds of Formula (I), R 7 is -CH3 and R 8 is H.

[0281] In some embodiments of the compounds of Formula (I), R 7 is -OCH3 and R 8 is H.

[0282] In some embodiments of the compounds of Formula (I), R 7 is -H and R 8 is -F.

[0283] In some embodiments of the compounds of Formula (I), R 7 is -H and R 8 is -Cl.

[0284] In some embodiments of the compounds of Formula (I), R 7 is -H and R 8 is -CH3.

[0285] In some embodiments of the compounds of Formula (I), R 7 is -H and R 8 is OCH3.

[0286] In some embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, of formula (IA): [ka]

[0287] During the ceremony, Q 2 and Q 4 are N or Q 2 or Q 4 One of them is N and the other is CR 5a and R 5a is H, F, -SO2CH3 or -CN, R 5 is H or CH3, R 7 is H, F or OCH3, R 1 and R 2 is as described above for formula (I).

[0288] In some embodiments of the compound of Formula (IA), R 5 is H.

[0289] In some embodiments of the compound of Formula (IA), R 5 is CH3.

[0290] In some embodiments of the compound of Formula (IA), R 7 is H.

[0291] In some embodiments of the compound of Formula (IA), R 7 is F.

[0292] In some embodiments of the compound of Formula (IA), R 7 is OCH3.

[0293] In some embodiments of the compound of Formula (IA), Q 2 and Q 4are N respectively.

[0294] In some embodiments of the compound of Formula (IA), Q 2 or Q 4 One of them is N and the other is CR 5a is.

[0295] In some embodiments of the compound of Formula (IA), wherein Q 2 or Q 4 One of them is N and the other is CR 5a and R 5a is H or F.

[0296] In some embodiments of the compound of Formula (IA), Q 2 or Q 4 One of them is N and the other is CR 5a and R 5a is H.

[0297] In some embodiments of the compound of Formula (IA), Q 2 or Q 4 One of them is N and the other is CR 5a and R 5a is F.

[0298] In some embodiments of the compound of Formula (IA), Q 2 or Q 4 One of them is N and the other is CR 5a and R 5a is CN or SO2CH3.

[0299] In some embodiments of the compound of Formula (IA), Q 2 or Q 4 One of them is N and the other is CR 5a and R 5a is CN.

[0300] In some embodiments of the compound of Formula (IA), Q 2 or Q 4 One of them is N and the other is CR5a and R 5a is SO2CH3.

[0301] In some embodiments, the compound of formula (IA) is a compound of formula (IA-1-1), or a pharmaceutically acceptable salt thereof: [ka]

[0302] During the ceremony R 5 is H or CH3, R 7 is H, F or OCH3, R 1 and R 2 is as described above for formula (I).

[0303] In some embodiments of the compound of Formula (IA-1-1), R 5 is H.

[0304] In some embodiments of the compound of Formula (IA-1-1), R 5 is CH3.

[0305] In some embodiments of the compound of Formula (IA-1-1), R 7 is H.

[0306] In some embodiments of the compound of Formula (IA-1-1), R 7 is F.

[0307] In some embodiments of the compound of Formula (IA-1-1), R 7 is OCH3.

[0308] In some embodiments of the compound of Formula (IA-1-1), R 1is optionally substituted C1-C6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2F, -CH2CHF2, -CH2CH2CN, -CH2CH2CH2OH, -CH2OCH3, -CH2OCH(CH3)2, -CH2OCH2CH3, [ka] is.

[0309] In some embodiments of the compound of Formula (IA-1-1), R 1 is optionally substituted C2-C6 alkenyl, for example, [ka] And so on.

[0310] In some embodiments of the compound of Formula (IA-1-1), R 1 is, for example, C3-C6 cycloalkyl, such as cyclobutyl.

[0311] In some embodiments of the compound of Formula (IA-1-1), R 1 is H.

[0312] In some embodiments of the compound of Formula (IA-1-1), R 2 is optionally substituted C1-C6 alkyl, -NR 3 R 4 -OR 4a is.

[0313] In some embodiments, the compound of formula (IA) is a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof: [ka]

[0314] During the ceremony, R5 is H or CH3, R 7 is H, F or OCH3, R 2 is as described above for formula (I).

[0315] In some embodiments of the compound of formula (IA-1), R 5 is H.

[0316] In some embodiments of the compound of formula (IA-1), R 5 is CH3.

[0317] In some embodiments of the compound of formula (IA-1), R 7 is H.

[0318] In some embodiments of the compound of formula (IA-1), R 7 is F.

[0319] In some embodiments of the compound of formula (IA-1), R 7 is OCH3.

[0320] In some embodiments of the compound of formula (IA-1), R 2 is optionally substituted C1-C6 alkyl.

[0321] In some embodiments of the compound of formula (IA-1), R 2 is CH3, -CH2-NHSO2(CH3), -CH2-N(CH3)SO2(CH3), [ka] -CH2-NH(CH3), -CH2-NH(-CH(CH3)2), -CH2-N(CH3)2 or -CH2-P(O)(CH3)2.

[0322] In some embodiments of the compound of formula (IA-1), R 2 Ha-NR 3 R4 where R 3 and R 4 is as defined above for formula (I).

[0323] In some embodiments of the compound of formula (IA-1), R 3 is H.

[0324] In some embodiments of the compound of formula (IA-1), R 3 is CH3.

[0325] In some embodiments of the compound of formula (IA-1), R 4 is H.

[0326] In some embodiments of the compound of formula (IA-1), R 4 are CH3, -CH2CH3, -CH(CH3), -CH2-cyclopropyl, -CH2CH2CHF2, -CH2CHF2, -CH2CH2OH, -CH2C(CH3)2OH, -CH2CHOCH3, -C(O)CH2N(CH3)2, [ka] is.

[0327] In other embodiments of the compounds of formula (IA-1), R 4 -CH2CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, [ka] is.

[0328] In some embodiments, R 4 is -CH2CH=CH2.

[0329] In some embodiments of the compound of formula (IA-1), R 4 is cyclopropyl, cyclobutyl or cyclopentyl.

[0330] In some embodiments of the compound of formula (IA-1), R 4 oxetan-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl, [ka] is.

[0331] In some embodiments of the compound of formula (IA-1), R 4 is C(O)CH2N(CH3)2.

[0332] In some embodiments of the compound of formula (IA-1), R 3 and R 4 taken together with the N atom to which they are both attached form a 3-6 membered heterocycloalkyl optionally substituted with one or more substituents, each of which is C1-C6 alkyl, C1-C6 alkoxyl, or OH.

[0333] In some embodiments, R 3 and R 4 together with the N atom to which they are both attached to form 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphinan-4-yl 1-oxide, 1-methyl-4-azaphosphinan-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0334] In some embodiments of the compound of formula (IA-1), R 2 HA-P(O)R 4b R 4c where R 4b and R 4c is as defined above for formula (I).

[0335] In some embodiments of the compound of formula (IA-1), R 2 HA-OR 4a where R 4ais as defined above for formula (I).

[0336] In some embodiments of the compound of formula (IA-1), R 4a is —CH(CH3), —CH2CH2OH, —CH2C(CH3)2OH, cyclopropyl, cyclobutyl or cyclopentyl.

[0337] In some embodiments, the compound of formula (IA) is a compound of formula (IA-2), or a pharmaceutically acceptable salt thereof: [ka]

[0338] During the ceremony, R 5 is H or CH3, R 7 is H, F or OCH3, R 2 is as described above for formula (I).

[0339] In some embodiments of the compound of formula (IA-2), R 5 is H.

[0340] In some embodiments of the compound of formula (IA-2), R 5 is CH3.

[0341] In some embodiments of the compound of formula (IA-2), R 7 is H.

[0342] In some embodiments of the compound of formula (IA-2), R 7 is F.

[0343] In some embodiments of the compound of formula (IA-2), R 7 is OCH3.

[0344] In some embodiments of the compound of formula (IA-2), R2 is optionally substituted C1-C6 alkyl.

[0345] In some embodiments of the compound of formula (IA-2), R 2 is CH3, -CH2-NHSO2(CH3), -CH2-N(CH3)SO2(CH3), [ka] -CH2-NH(CH3), -CH2-NH(-CH(CH3)2), -CH2-N(CH3)2 or -CH2-P(O)(CH3)2.

[0346] In some embodiments of the compound of formula (IA-2), R 2 Ha-NR 3 R 4 where R 3 and R 4 is as defined above for formula (I).

[0347] In some embodiments of the compound of formula (IA-2), R 3 is H.

[0348] In some embodiments of the compound of formula (IA-2), R 3 is CH3.

[0349] In some embodiments of the compound of formula (IA-2), R 4 is H.

[0350] In some embodiments of the compound of formula (IA-2), R 4 are CH3, -CH2CH3, -CH(CH3), -CH2-cyclopropyl, -CH2CH2CHF2, -CH2CHF2, -CH2CH2OH, -CH2C(CH3)2OH, -CH2CHOCH3, -C(O)CH2N(CH3)2, [ka] is.

[0351] In other embodiments of the compound of formula (IA-2), R 4 -CH2CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, [ka] is.

[0352] In some embodiments of the compound of formula (IA-2), R 4 is -CH2CH=CH2.

[0353] In some embodiments of the compound of formula (IA-2), R 4 is cyclopropyl, cyclobutyl or cyclopentyl.

[0354] In some embodiments of the compound of formula (IA-2), R 4 oxetan-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl, [ka] is.

[0355] In some embodiments of the compound of formula (IA-2), R 4 is C(O)CH2N(CH3)2.

[0356] In some embodiments of the compound of formula (IA-2), R 3 and R 4 taken together with the N atom to which they are both attached form a 3-6 membered heterocycloalkyl optionally substituted with one or more substituents, each of which is C1-C6 alkyl, C1-C6 alkoxyl, or OH.

[0357] In some embodiments, R 3 and R 4together with the N atom to which they are both attached to form 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphinan-4-yl 1-oxide, 1-methyl-4-azaphosphinan-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0358] In some embodiments of the compound of formula (IA-2), R 2 HA-P(O)R 4b R 4c where R 4b and R 4c is as defined above for formula (I).

[0359] In some embodiments of the compound of formula (IA-2), R 2 HA-OR 4a where R 4a is as defined above for formula (I).

[0360] In some embodiments of the compound of formula (IA-2), R 4a is —CH(CH3), —CH2CH2OH, —CH2C(CH3)2OH, cyclopropyl, cyclobutyl or cyclopentyl.

[0361] In some embodiments, the compound of formula (IA) is a compound of formula (IA-3-1), or a pharmaceutically acceptable salt thereof: [ka]

[0362] During the ceremony, R 5 is H or CH3, R 7 is H, F or OCH3, R 1 and R 2 is as described above for formula (I).

[0363] In some embodiments of the compound of formula (IA-3-1), R 5 is H.

[0364] In some embodiments of the compound of formula (IA-3-1), R 5 is CH3.

[0365] In some embodiments of the compound of formula (IA-3-1), R 7 is H.

[0366] In some embodiments of the compound of formula (IA-3-1), R 7 is F.

[0367] In some embodiments of the compound of formula (IA-3-1), R 7 is OCH3.

[0368] In some embodiments of the compound of formula (IA-3-1), R 1 is H.

[0369] In some embodiments of the compound of formula (IA-3-1), R 1 is optionally substituted C1-C6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2F, -CH2CHF2, -CH2CH2CN, -CH2CH2CH2OH, -CH2OCH3, -CH2OCH(CH3)2, -CH2OCH2CH3, [ka] is.

[0370] In some embodiments of the compound of formula (IA-3-1), R 1 is optionally substituted C2-C6 alkenyl, for example, [ka] And so on.

[0371] In some embodiments of the compound of formula (IA-3-1), R 1 is, for example, C3-C6 cycloalkyl, such as cyclobutyl.

[0372] In some embodiments of the compound of formula (IA-3-1), R 1 is an optionally substituted heterocycloalkyl, such as [ka] And so on.

[0373] In some embodiments of the compound of formula (IA-3-1), R 1 is an optionally substituted heteroaryl, such as [ka] And so on.

[0374] In some embodiments of the compound of formula (IA-3-1), R 1 is -C(O)OR 3 ,for example, [ka] And so on.

[0375] In some embodiments of the compound of formula (IA-3-1), R 1 is -C(O)NR 3 R 4 ,for example, [ka] And so on.

[0376] In some embodiments of the compound of formula (IA-3-1), R 2 is optionally substituted C1-C6 alkyl, -NR 3 R 4 , -OR 4aor -C(O)NR 3 R 4 is.

[0377] In some embodiments of the compound of formula (IA-3-1), R 2 Ha-NR 3 R 4 is.

[0378] In some embodiments, the compound of formula (IA) is a compound of formula (IA-3), or a pharmaceutically acceptable salt thereof: [ka]

[0379] During the ceremony, R 5 is H or CH3, R 7 is H, F or OCH3, R 2 is as described above for formula (I).

[0380] In some embodiments of the compound of formula (IA-3), R 5 is H.

[0381] In some embodiments of the compound of formula (IA-3), R 5 is CH3.

[0382] In some embodiments of the compound of formula (IA-3), R 7 is H.

[0383] In some embodiments of the compound of formula (IA-3), R 7 is F.

[0384] In some embodiments of the compound of formula (IA-3), R 7 is OCH3.

[0385] In some embodiments of the compound of formula (IA-3), R 2is optionally substituted C1-C6 alkyl.

[0386] In some embodiments of the compound of formula (IA-3), R 2 is CH3, -CH2-NHSO2(CH3), -CH2-N(CH3)SO2(CH3), [ka] -CH2-NH(CH3), -CH2-NH(-CH(CH3)2), -CH2-N(CH3)2 or -CH2-P(O)(CH3)2.

[0387] In some embodiments of the compound of formula (IA-3), R 2 Ha-NR 3 R 4 where R 3 and R 4 is as defined above for formula (I).

[0388] In some embodiments of the compound of formula (IA-3), R 3 is H.

[0389] In some embodiments of the compound of formula (IA-3), R 3 is CH3.

[0390] In some embodiments of the compound of formula (IA-3), R 4 is H.

[0391] In some embodiments of the compound of formula (IA-3), R 4 are CH3, -CH2CH3, -CH(CH3), -CH2-cyclopropyl, -CH2CH2CHF2, -CH2CHF2, -CH2CH2OH, -CH2C(CH3)2OH, -CH2CHOCH3, -C(O)CH2N(CH3)2, [ka] is.

[0392] In other embodiments of compounds of formula (IA-3), R 4 -CH2CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, [ka] is.

[0393] In some embodiments of the compound of formula (IA-3), R 4 is -CH2CH=CH2.

[0394] In some embodiments of the compound of formula (IA-3), R 4 is cyclopropyl, cyclobutyl or cyclopentyl.

[0395] In some embodiments of the compound of formula (IA-3), R 4 oxetan-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl, [ka] is.

[0396] In some embodiments of the compound of formula (IA-3), R 4 is C(O)CH2N(CH3)2.

[0397] In some embodiments of the compound of formula (IA-3), R 3 and R 4 taken together with the N atom to which they are both attached form a 3-6 membered heterocycloalkyl optionally substituted with one or more substituents, each of which is C1-C6 alkyl, C1-C6 alkoxyl, or OH.

[0398] In some embodiments, R 3 and R 4together with the N atom to which they are both attached to form 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphinan-4-yl 1-oxide, 1-methyl-4-azaphosphinan-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0399] In some embodiments of the compound of formula (IA-3), R 2 HA-P(O)R 4b R 4c where R 4b and R 4c is as defined above for formula (I).

[0400] In some embodiments of the compound of formula (IA-3), R 2 HA-OR 4a where R 4a is as defined above for formula (I).

[0401] In some embodiments of the compound of formula (IA-3), R 4a is —CH(CH3), —CH2CH2OH, —CH2C(CH3)2OH, cyclopropyl, cyclobutyl or cyclopentyl.

[0402] In some embodiments, the compound of formula (IA) is a compound of formula (IA-4-1), or a pharmaceutically acceptable salt thereof: [ka]

[0403] During the ceremony, R 5 is H or CH3, R 7 is H, F or OCH3, R 1 and R 2 is as described above for formula (I).

[0404] In some embodiments of the compound of formula (IA-4-1), R 5 is H.

[0405] In some embodiments of the compound of formula (IA-4-1), R 5 is CH3.

[0406] In some embodiments of the compound of formula (IA-4-1), R 7 is H.

[0407] In some embodiments of the compound of formula (IA-4-1), R 7 is F.

[0408] In some embodiments of the compound of formula (IA-4-1), R 7 is OCH3.

[0409] In some embodiments of the compound of formula (IA-4-1), R 1 is H.

[0410] In some embodiments of the compound of formula (IA-4-1), R 1 is optionally substituted C1-C6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2F, -CH2CHF2, -CH2CH2CN, -CH2CH2CH2OH, -CH2OCH3, -CH2OCH(CH3)2, -CH2OCH2CH3, [ka] is.

[0411] In some embodiments of the compound of formula (IA-4-1), R 1 is optionally substituted C2-C6 alkenyl, for example, [ka] And so on.

[0412] In some embodiments of the compound of formula (IA-4-1), R 1 , optionally substituted heteroaryl, such as [ka] And so on.

[0413] In some embodiments of the compound of formula (IA-4-1), R 1 is -C(O)OR 3 ,for example, [ka] And so on.

[0414] In some embodiments of the compound of formula (IA-4-1), R 1 is -C(O)NR 3 R 4 ,for example, [ka] And so on.

[0415] In some embodiments of the compound of formula (IA-4-1), R 2 is optionally substituted C1-C6 alkyl, -NR 3 R 4 -OR 4a is.

[0416] In some embodiments of the compound of formula (IA-4-1), R 2 Ha-NR 3 R 4 is.

[0417] In some embodiments of the compound of formula (IA-4-1), R 2 is optionally substituted C1-C6 alkyl.

[0418] In some embodiments, the compound of formula (IA) is a compound of formula (IA-4), or a pharmaceutically acceptable salt thereof: [ka]

[0419] During the ceremony, R 5 is H or CH3, R 7 is H, F or OCH3, R 2 is as described above for formula (I).

[0420] In some embodiments of the compound of formula (IA-4), R 5 is H.

[0421] In some embodiments of the compound of formula (IA-4), R 5 is CH3.

[0422] In some embodiments of the compound of formula (IA-4), R 7 is H.

[0423] In some embodiments of the compound of formula (IA-4), R 7 is F.

[0424] In some embodiments of the compound of formula (IA-4), R 7 is OCH3.

[0425] In some embodiments of the compound of formula (IA-4), R 2 is optionally substituted C1-C6 alkyl.

[0426] In some embodiments of the compound of formula (IA-4), R 2 is CH3, -CH2-NHSO2(CH3), -CH2-N(CH3)SO2(CH3), [ka] -CH2-NH(CH3), -CH2-NH(-CH(CH3)2), -CH2-N(CH3)2 or -CH2-P(O)(CH3)2.

[0427] In some embodiments of the compound of formula (IA-4), R 2 Ha-NR 3 R 4 where R 3 and R 4 is as defined above for formula (I).

[0428] In some embodiments of the compound of formula (IA-4), R 3 is H.

[0429] In some embodiments of the compound of formula (IA-4), R 3 is CH3.

[0430] In some embodiments of the compound of formula (IA-4), R 4 is H.

[0431] In some embodiments of the compound of formula (IA-4), R 4 are CH3, -CH2CH3, -CH(CH3), -CH2-cyclopropyl, -CH2CH2CHF2, -CH2CHF2, -CH2CH2OH, -CH2C(CH3)2OH, -CH2CHOCH3, -C(O)CH2N(CH3)2, [ka] is.

[0432] In other embodiments of compounds of formula (IA-4), R 4 -CH2CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, [ka] is.

[0433] In some embodiments of the compound of formula (IA-4), R 4 is -CH2CH=CH2.

[0434] In some embodiments of the compound of formula (IA-4), R 4 is cyclopropyl, cyclobutyl or cyclopentyl.

[0435] In some embodiments of the compound of formula (IA-4), R 4 oxetan-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl, [ka] is.

[0436] In some embodiments of the compound of formula (IA-4), R 4 is C(O)CH2N(CH3)2.

[0437] In some embodiments of the compound of formula (IA-4), R 3 and R 4 taken together with the N atom to which they are both attached form a 3-6 membered heterocycloalkyl optionally substituted with one or more substituents, each of which is C1-C6 alkyl, C1-C6 alkoxyl, or OH.

[0438] In some embodiments, R 3 and R 4 together with the N atom to which they are both attached to form 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphinan-4-yl 1-oxide, 1-methyl-4-azaphosphinan-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0439] In some embodiments of the compound of formula (IA-4), R 2 HA-P(O)R 4b R4c where R 4b and R 4c is as defined above for formula (I).

[0440] In some embodiments of the compound of formula (IA-4), R 2 HA-OR 4a where R 4a is as defined above for formula (I).

[0441] In some embodiments of the compound of formula (IA-4), R 4a is —CH(CH3), —CH2CH2OH, —CH2C(CH3)2OH, cyclopropyl, cyclobutyl or cyclopentyl.

[0442] In some embodiments, the compound of formula (IA) is a compound of formula (IA-5), or a pharmaceutically acceptable salt thereof: [ka]

[0443] During the ceremony, R 5 is H or CH3, R 7 is H, F or OCH3, R 2 is as described above for formula (I).

[0444] In some embodiments of the compound of formula (IA-5), R 5 is H.

[0445] In some embodiments of the compound of formula (IA-5), R 5 is CH3.

[0446] In some embodiments of the compound of formula (IA-5), R 7 is H.

[0447] In some embodiments of the compound of formula (IA-5), R 7 is F.

[0448] In some embodiments of the compound of formula (IA-5), R 7 is OCH3.

[0449] In some embodiments of the compound of formula (IA-5), R 2 is optionally substituted C1-C6 alkyl.

[0450] In some embodiments of the compound of formula (IA-5), R 2 is CH3, -CH2-NHSO2(CH3), -CH2-N(CH3)SO2(CH3), [ka] -CH2-NH(CH3), -CH2-NH(-CH(CH3)2), -CH2-N(CH3)2 or -CH2-P(O)(CH3)2.

[0451] In some embodiments of the compound of formula (IA-5), R 2 Ha-NR 3 R 4 where R 3 and R 4 is as defined above for formula (I).

[0452] In some embodiments of the compound of formula (IA-5), R 3 is H.

[0453] In some embodiments of the compound of formula (IA-5), R 3 is CH3.

[0454] In some embodiments of the compound of formula (IA-5), R 4 is H.

[0455] In some embodiments of the compound of formula (IA-5), R 4are CH3, -CH2CH3, -CH(CH3), -CH2-cyclopropyl, -CH2CH2CHF2, -CH2CHF2, -CH2CH2OH, -CH2C(CH3)2OH, -CH2CHOCH3, -C(O)CH2N(CH3)2, [ka] is.

[0456] In other embodiments of compounds of formula (IA-5), R 4 -CH2CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, [ka] is.

[0457] In some embodiments of the compound of formula (IA-5), R 4 is -CH2CH=CH2.

[0458] In some embodiments of the compound of formula (IA-5), R 4 is cyclopropyl, cyclobutyl or cyclopentyl.

[0459] In some embodiments of the compound of formula (IA-5), R 4 oxetan-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl, [ka] is.

[0460] In some embodiments of the compound of formula (IA-5), R 4 is C(O)CH2N(CH3)2.

[0461] In some embodiments of the compound of formula (IA-5), R 3 and R 4taken together with the N atom to which they are both attached form a 3-6 membered heterocycloalkyl optionally substituted with one or more substituents, each of which is C1-C6 alkyl, C1-C6 alkoxyl, or OH.

[0462] In some embodiments, R 3 and R 4 together with the N atom to which they are both attached to form 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphinan-4-yl 1-oxide, 1-methyl-4-azaphosphinan-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0463] In some embodiments of the compound of formula (IA-5), R 2 HA-P(O)R 4b R 4c where R 4b and R 4c is as defined above for formula (I).

[0464] In some embodiments of the compound of formula (IA-5), R 2 HA-OR 4a where R 4a is as defined above for formula (I).

[0465] In some embodiments of the compound of formula (IA-5), R 4a is —CH(CH3), —CH2CH2OH, —CH2C(CH3)2OH, cyclopropyl, cyclobutyl or cyclopentyl.

[0466] In some embodiments, the compound of formula (IA) is a compound of formula (IA-6), or a pharmaceutically acceptable salt thereof: [ka]

[0467] In some embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, of formula (IB): [ka]

[0468] During the ceremony, R 5a is H, F or —CN. R 5 is H or CH3, R 7 is H, F or OCH3, R 1 and R 2 is as described above for formula (I).

[0469] In some embodiments of the compound of Formula (IB), R 5 is H.

[0470] In some embodiments of the compound of Formula (IB), R 5 is CH3.

[0471] In some embodiments of the compound of Formula (IB), R 7 is H.

[0472] In some embodiments of the compound of Formula (IB), R 7 is F.

[0473] In some embodiments of the compound of Formula (IB), R 7 is OCH3.

[0474] In some embodiments of the compound of Formula (IB), R 5a is H or F.

[0475] In some embodiments of the compound of Formula (IB), R 5a is H.

[0476] In some embodiments of the compound of Formula (IB), R 5a is F.

[0477] In some embodiments of the compound of Formula (IB), R 1 is H.

[0478] In some embodiments of the compound of Formula (IB), R 1 is optionally substituted C1-C6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2F, -CH2CHF2, -CH2CH2CN, -CH2CH2CH2OH, -CH2OCH3, -CH2OCH(CH3)2, -CH2OCH2CH3, [ka] is.

[0479] In some embodiments of the compound of Formula (IB), R 1 is optionally substituted C2-C6 alkenyl, for example, [ka] And so on.

[0480] In some embodiments of the compound of Formula (IB), R 1 is an optionally substituted heteroaryl, such as [ka] And so on.

[0481] In some embodiments of the compound of Formula (IB), R 1 is -C(O)OR 3 ,for example, [ka] And so on.

[0482] In some embodiments of the compound of Formula (IB), R 1 is -C(O)NR 3 R 4 ,for example, [ka] And so on.

[0483] In some embodiments of the compound of Formula (IB), R 2 is optionally substituted C1-C6 alkyl, -NR 3 R 4 -OR 4a is.

[0484] In some embodiments of the compound of Formula (IB), R 2 Ha-NR 3 R 4 is.

[0485] In some embodiments of the compound of Formula (IB), R 2 HA-OR 4a is.

[0486] In some embodiments, the compounds of the present disclosure are compounds of Examples 1-153 described herein, or pharmaceutically acceptable salts thereof.

[0487] In other embodiments, the compounds of the present disclosure are compounds of Examples 154-449 described herein, or pharmaceutically acceptable salts thereof.

[0488] In other embodiments, the compound of the present disclosure is a compound shown in the table below, or a pharmaceutically acceptable salt thereof:

[0489] [Table 1-1]

[0490] [Table 1-2]

[0491] [Table 1-3]

[0492] [Table 1-4]

[0493] In other embodiments, the compound of the present disclosure is a compound shown in the table below, or a pharmaceutically acceptable salt thereof.

[0494] [Table 2-1]

[0495] [Table 2-2]

[0496] [Table 2-3]

[0497] [Table 2-4]

[0498] [Table 2-5]

[0499] [Table 2-6]

[0500] [Table 2-7]

[0501] In some embodiments, Formula (I) and any subgenus thereof disclosed herein excludes, by proviso, any compound disclosed in International Patent Application No. PCT / US2021 / 065679, filed December 30, 2021.

[0502] In some embodiments, Formula (I) and any subgenus thereof disclosed herein excludes, by way of provisos, any one of the compounds set forth in the following table:

[0503] [Table 3-1]

[0504] [Table 3-2]

[0505] [Table 3-3]

[0506] [Table 3-4]

[0507] [Table 3-5]

[0508] [Table 3-6]

[0509] [Table 3-7]

[0510] [Table 3-8]

[0511] [Table 3-9]

[0512] [Table 3-10]

[0513] [Table 3-11]

[0514] [Table 3-12]

[0515] [Table 3-13]

[0516] In some aspects, the present disclosure is directed to the compounds set forth in the Examples below, or pharmaceutically acceptable salts thereof.

[0517] Reference herein to formula (I) or any subgenus thereof is meant to encompass the identified formula disclosed herein and all subgenuses of those formulas, for example, reference to formula (I) also encompasses the subgenus formulas IA, IA-1-1, IA-1, IA-2, IA-3-1, IA-3, IA-4-1, IA-4, IA-5, IA-6, IB.

[0518] Stereoisomers of the compounds of formula (I) are also contemplated by the present disclosure. 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.

[0519] Pharmaceutically acceptable salts and solvates of the compounds of formula (I) are also within the scope of this disclosure.

[0520] For clarity, it is understood that certain features of the invention that are described herein in the context of separate embodiments may also be provided in combination in a single embodiment. That is, unless clearly incompatible or specifically excluded, individual embodiments are considered combinable with other embodiment(s), and such combinations are considered separate embodiments. Conversely, various features of the invention that are described for brevity in the context of a single embodiment may also be provided separately or in any subcombination. While an embodiment may be described as part of a series of steps or as part of a more general structure, each step may also be considered an independent embodiment in itself and combinable with other embodiments.

[0521] Pharmaceutical Compositions and Administration Methods The pharmaceutical compositions of the present invention are typically 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 compositions comprise 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, penetration enhancers, solubilizers, and adjuvants.

[0522] The pharmaceutical composition of the present invention can be administered alone or in combination with one or more other drugs, which are typically administered in the form of a pharmaceutical composition. If desired, one or more compounds of the present invention and the other drug(s) can be mixed in a formulation, or both components can be formulated in separate formulations and used separately or in combination at the same time.

[0523] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is 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%, 0.10%, 0.12%, 0.14%, 0.16%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65 %, 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 range defined by any two of the foregoing values inclusive) w / w, w / v or v / v.

[0524] In some embodiments, the concentration of one or more compounds of the present invention is 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%, 6.25%, 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%,0.03%,0.02%,0 Greater than 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 range defined by and inclusive of any two of the foregoing values) w / w, w / v or v / v.

[0525] In some embodiments, the concentration of one or more compounds of the present invention is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.0 The range is 8% to 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%, or about 1% to about 10% w / w, w / v, or v / v.

[0526] In some embodiments, the concentration of one or more compounds of the present invention ranges from 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%, or about 0.1% to about 0.9% w / w, w / v, or v / v.

[0527] In some embodiments, the amount of one or more compounds of the present invention is 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, 0.09 g , 0.08g, 0.07g, 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 range defined by and including any two of the foregoing values).

[0528] In some embodiments, the amount of one or more compounds of the present invention is 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.004g, 0.004g, 0.005g, 0.006g, 0.007g, 0.008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.004g, 0.005g, 035g, 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, 0.0 45g, 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, 0.65g, 0.7g, 0.7 greater than 5g, 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 a range defined by and including any two of the above numbers).

[0529] In some embodiments, the amount of one or more compounds of the present invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0530] In some embodiments, the compounds according to the present invention are effective over a wide dosage range. For example, in the treatment of an adult, dosages of 0.01 to 1000 mg per day, 0.5 to 100 mg per day, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the subject's weight, and the preference and experience of the attending physician.

[0531] Unless otherwise specified, amounts of compounds described herein are provided on a free base basis, i.e., amounts indicate the amount of compound administered excluding, for example, solvent (such as a solvate) or counterion (such as a pharmaceutically acceptable salt).

[0532] The following describes non-limiting exemplary pharmaceutical compositions and methods for their preparation.

[0533] <Pharmaceutical composition for oral administration> In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0534] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising: (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 comprises (iv) an effective amount of a third agent.

[0535] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral ingestion. Pharmaceutical compositions of the present invention suitable for oral administration can be provided in discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays containing a predetermined amount of the active ingredient as a powder or granules, solution, or suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, respectively. Such dosage forms can be prepared by any method of pharmacy, but all methods include the step of bringing the active ingredient into association with a carrier, which constitutes one or more necessary ingredients. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with a liquid carrier or finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired form. For example, tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with excipients such as binders, lubricants, inert diluents, and / or surfactants or dispersants. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0536] Because water can accelerate the degradation of some compounds, the present invention further encompasses anhydrous pharmaceutical compositions and dosage forms containing active ingredients. For example, in the pharmaceutical field, water (e.g., 5%) may be added as a means of simulating long-term storage to determine properties such as the shelf life or stability over time of a formulation. Anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture-containing ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water, allowing them to be included in suitable compounding kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit-dose containers, blister packs, and strip packs.

[0537] The active ingredient can be intimately mixed and combined with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a variety of forms, depending on the form of preparation desired for administration. When preparing compositions for oral dosage forms, any of the usual pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used as a carrier for oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or, in some embodiments, for oral solid preparations, lactose can be omitted, and carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used. For example, suitable carriers include powders, capsules, and tablets, as well as solid oral preparations. If necessary, tablets can be coated by standard aqueous or non-aqueous techniques.

[0538] 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 acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0539] Examples of fillers suitable 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.

[0540] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Using too much disintegrant can result in tablets that disintegrate in the bottle. Using too little can result in insufficient disintegration, which can alter the rate and extent of release of the active ingredient(s) from the dosage form. Therefore, a sufficient amount of disintegrant, but not too little or too much to adversely affect the release of the active ingredient(s), can be used to form a dosage form of the compounds disclosed herein. The amount of disintegrant used can vary based on the type of formulation and method of administration and is readily discernible to those skilled in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent 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.

[0541] 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, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. Lubricants can optionally be added in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0542] When aqueous suspensions and / or elixirs for oral administration are desired, the active ingredient therein can be combined with various sweetening or flavoring agents, coloring agents or pigments, as well as emulsifying and / or suspending agents, if necessary, and diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0543] Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0544] 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, i.e., 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.

[0545] 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. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with low HLB values are more lipophilic or hydrophobic and more soluble in oil, while surfactants with high HLB values are more hydrophilic and more soluble in aqueous solutions.

[0546] Hydrophilic surfactants are generally considered to be compounds having an HLB value greater than about 10, as well as anionic, cationic, or amphoteric ionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value of about 10 or less. However, the HLB value of a surfactant is only an approximate guide generally used to enable the formulation of emulsions for industrial, pharmaceutical, and cosmetic applications.

[0547] The hydrophilic surfactant may be either ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fusidate 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 derivatives thereof, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, alkyl sulfate salts, fatty acid salts, sodium docusate, acyl lactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0548] Within the aforementioned group, ionic surfactants include, by way of example only, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives, carnitine fatty acid ester salts, alkyl sulfates, fatty acid salts, docusate sodium, acyl lactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0549] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactate esters of fatty acids, stearoyl-2-lactate, stearoyl lactylate ... Acids, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholyl sarcosine, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, oleic acid, ricinoleic acid, linoleic acid, linolenic acid, stearic acid, lauryl sulfate, teraceyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0550] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl macrogol 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, polyethylene glycol fatty acid diesters, polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol glycerin fatty acid esters, polyglycerin fatty acid esters, polyethylene glycol sorbitan fatty acid esters, hydrophilic transesterification products of polyols and 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 and any one 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.

[0551] 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-1 stearate, 00, PEG-20 Dilaurate, PEG-25 Glyceryl Trioleate, PEG-32 Dioleate, PEG-20 Glyceryl Laurate, Glyceryl PEG-30 Laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil Canola 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 Phytosterols, PEG-30 Soy Sterols, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Acetone PEG-10 oleyl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl 10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol series, PEG15-100 octylphenol series, and poloxamer.

[0552] Suitable lipophilic surfactants include, but are not limited to, fatty alcohols, glycerin fatty acid esters, acetylated glycerin 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 esters, mono- and diglyceride lactic acid derivatives, the hydrophobic transesterification product of polyols and 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.In this group, preferred lipophilic surfactants include glycerin fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or the hydrophobic transesterification product of polyols and at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils and triglycerides.

[0553] In one embodiment, the composition may contain a solubilizing agent to ensure good solubilization and / or dissolution of the compound of the present invention and minimize precipitation of the compound of the present invention. This may be particularly important for compositions for parenteral use, such as injectable compositions. A solubilizing agent may also be added to increase the solubility of other components, such as hydrophilic drugs and / or surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0554] Examples of suitable solubilizers are alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerin, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin 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, 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxybenzoates, ... These include, but are not limited to, alkylpyrrolidones, N-alkylpiperidones, N-alkylcaprolactams, amides and other nitrogen-containing compounds such as dimethylacetamide and polyvinylpyrrolidone, esters such as ethyl propionate, tributyl citrate, acetyltriethyl citrate, acetyltributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, 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, dimethylisosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0555] Mixtures of solubilizers can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0556] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited by its biotolerance, which can be easily determined by one of ordinary skill in the art. In some situations, it may be advantageous to remove excess solubilizer using conventional techniques such as distillation or evaporation before providing the composition to a subject, for example, to maximize drug concentration, and to include an amount of solubilizer that far exceeds its biotolerance. Thus, when present, the solubilizer may be present in an amount of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the total weight of the drug and other excipients. If necessary, very small amounts of solubilizer, such as 5%, 2%, 1%, or less, can also be used. Typically, the solubilizer may be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0557] The composition may further comprise one or more pharmaceutically acceptable additives and excipients, including, but not limited to, anti-adherents, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavors, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0558] Additionally, acids or bases can be incorporated into the composition for ease of processing, increased stability, or 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 hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like. Also suitable are bases that are salts of pharmaceutically acceptable acids such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, and the like. Also suitable are bases that are salts of pharmaceutically acceptable acids, such as fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. Salts of polybasic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, can also be used. When the base is a salt, the cation can be any convenient pharmaceutically acceptable cation, such as ammonium, an alkali metal, or an alkaline earth metal. Examples include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0559] Suitable acids are pharmaceutically acceptable organic or inorganic acids. 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 acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0560] <Injectable pharmaceutical composition> In some embodiments, the present invention provides an injectable pharmaceutical composition comprising a compound of the present invention and a pharmaceutical excipient suitable for injection, wherein the amounts of ingredients and agents in the composition are as described herein.

[0561] Forms into which the novel compositions of the present invention can be incorporated for administration by injection include aqueous or oily suspensions or emulsions, including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0562] Aqueous solutions of physiological saline have also been conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin to maintain the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0563] Sterile injectable solution is prepared by incorporating the compound of the present invention in the required amount in a suitable solvent with various other ingredients as listed above, as needed, followed by filtration sterilization.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and other necessary ingredients listed above.For the preparation of sterile powder for preparing sterile injectable solution, a particular preferred method is vacuum drying and freeze-drying technology, which obtains a powder of active ingredient and any additional desired ingredients from its previously sterile-filtered solution.

[0564] Pharmaceutical Compositions for Topical (e.g., Transdermal) Delivery

[0565] In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery comprising a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0566] The composition of the present invention can be formulated into a solid, semi-solid or liquid form suitable for topical or local administration, such as gel, water-soluble jelly, cream, lotion, suspension, foam, powder, slurry, ointment, solution, oil, paste, suppository, spray, emulsion, saline, dimethyl sulfoxide (DMSO)-based solution, etc. Generally, a carrier with high density can provide a specific area with prolonged exposure to the active ingredient. In contrast, a solution formulation can provide a selected area with a more rapid exposure of the active ingredient.

[0567] The pharmaceutical composition may also include suitable solid or gel phase carriers or excipients, which are compounds that increase penetration or aid in the delivery of therapeutic molecules through the stratum corneum permeability barrier of the skin. Many of these penetration-enhancing molecules are known to those trained in the art of topical formulations.

[0568] 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), pyrrolidone, glycerol 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 glycol.

[0569] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts, with or without other agents.

[0570] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., 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 pharmaceutical agents.

[0571] <Pharmaceutical composition for inhalation> Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0572] <Other pharmaceutical compositions> 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 preparation of such pharmaceutical compositions is well known in the art. For example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all of which are incorporated herein by reference in their entireties.

[0573] The compounds or pharmaceutical compositions of the present invention can be administered by any method that allows delivery of the compound to the site of action. These methods include oral, intraduodenal, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), topical (e.g., transdermal application), rectal administration, local delivery via catheter or stent, or administration by inhalation. The compounds can also be administered intraadiposely or intrathecally.

[0574] The amount of compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the discretion of the prescribing physician. However, effective doses range from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would be 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 end of the above range may be more than sufficient, while in other cases, even larger doses may be used without causing adverse side effects, for example, by dividing such larger doses into several smaller doses to be administered throughout the day.

[0575] In some embodiments, the compounds of the invention are administered in a single dose.

[0576] Typically, such administration is by injection, e.g., intravenous injection, to rapidly introduce the drug, although other routes can be used if necessary. A single dose of the compounds of the present disclosure can also be used to treat acute conditions.

[0577] In some embodiments, the compound of the present invention is administered in multiple doses. In some embodiments, administration may be about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, administration may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compound of the present invention and another agent are administered together about once a day to about six times a day. In another embodiment, administration of the compound of the present invention and another agent continues for less than about seven days. In yet another embodiment, administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous dosing is implemented and maintained as long as necessary.

[0578] Administration of the compounds of the invention may continue for as long as necessary. In some embodiments, the compounds of the invention are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the invention are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the invention are administered continuously, chronically, for example, to treat chronic effects.

[0579] An effective amount of a compound of this invention can be administered in single or multiple doses by any of the accepted modes of administration for drugs having similar uses, including rectal, buccal, intranasal and transdermal routes, intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or by inhalant administration.

[0580] The compositions of the present invention can also be delivered via impregnated or coated devices, such as stents or cylindrical polymers inserted into an artery. Such administration methods can be useful for preventing or ameliorating restenosis after procedures such as balloon angioplasty. Without being bound by theory, the compounds of the present invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall, which contribute to restenosis. The compounds of the present invention can be administered by local delivery, for example, from stent struts, stent grafts, grafts, or stent covers or sheaths. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix may be a polymer matrix and may serve to bind the compound to the stent. Suitable polymer matrices for such applications include, for example, polylactic acid, polycaprolactone glycolide, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, lactone-based polyesters or copolyesters such as poly(ether-ester) copolymers (e.g., PEO-PLLA), polydimethylsiloxane, poly(ethylene vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethylmethylmethacrylate, polyvinylpyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be non-degradable or may degrade over time to release the compound. 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 evaporate to form a layer of the compound on the stent. Alternatively, the compound may be disposed within the body of the stent or graft, for example, within microchannels or micropores. Upon implantation, the compound diffuses from the body of the stent to contact the arterial wall. Such stents can be prepared by immersing a stent fabricated to contain such micropores or microchannels in a solution of a compound of the invention dissolved in a suitable solvent, followed by evaporation of the solvent.Excess drug on the stent surface can be removed by additional simple solvent washing. In yet another embodiment, the compounds of the present invention may be covalently attached to a stent or graft. A covalent linker may be used that decomposes in vivo, resulting in the release of the compounds of the present invention. For such purposes, biodegradable bonds, such as ester bonds, amide bonds, anhydride bonds, etc., may be used. The compounds of the present invention may also be administered intravascularly from a balloon used during angioplasty. To reduce restenosis, the compounds may also be administered extravascularly via the pericardium or extramembrane application of the formulations of the present invention.

[0581] Various stent devices that can be used as described are disclosed, for example, in the following references, all of which are incorporated herein by reference: US Pat. No. 5,451,233; US Pat. No. 5,040,548; US Pat. No. 5,061,273; US Pat. No. 5,496,346; US Pat. No. 5,292,331; US Pat. No. 5,674,278; US Pat. No. 3,657,744; US Pat. No. 4,739,762; US Pat. No. 5,195,984; US Pat. No. 5,292,331; US Pat. No. 5,674,278; US Pat. No. 5,879,382; US Pat. No. 6,344,053.

[0582] The compound of the present invention can be administered in a certain dosage.It is known in the art that due to the intrasubject variation of the pharmacokinetics of compound, optimal treatment requires individualized dosing regimen.The dosage of the compound of the present invention can be found by routine experimentation in light of the present disclosure.

[0583] When a compound of the invention is administered in a composition containing one or more drugs, and the drugs have a shorter half-life than the compound of the invention, the unit dosage forms of the drugs and the compound of the invention may be adjusted accordingly.

[0584] The pharmaceutical compositions of the present invention may be in a form suitable for oral administration, for example, as tablets, capsules, pills, powders, sustained-release formulations, solutions, or 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 compositions may also be in unit dosage form suitable for single administration of a precise dosage. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound of the present invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0585] Exemplary parenteral dosage forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.

[0586] <How to use> 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 582-595 of the alpha A1 isoform of FGFR1. In FGFR2, the kinase insert domain spans positions 585-598 of the FGFR2 Ile isoform. In FGFR3, the kinase insert domain spans positions 576-589 of the FGFR3 Ile isoform. In FGFR4, the kinase insert domain spans positions 571 to 584 in FGFR4 isoform 1. The C-terminal tail of the FGFR begins following the end of the tyrosine kinase domain and extends to the C-terminus of the protein. Several isoforms of each FGFR have been identified and are the result of alternative splicing of their mRNAs (Johnson et al., Mol. Cell. Biol. 11:4627-4634, 1995; and Chellaiah et al., J. Biol. Chem. 269:11620-11627, 1994).

[0587] Some of the receptor variants resulting from this alternative splicing have different ligand-binding specificities and affinities (Zimmer et al., J. Biol. Chem. 268:7899-7903, 1993; Cheon et al., Proc. Natl. Acad. Sci. USA 91:989-993, 1994; and Miki et al., Proc. Natl. Acad. Sci. USA 89:246-250, 1992). Protein sequences of FGFR proteins and nucleic acids encoding FGFR proteins are known in the art. Signal transduction by FGFRs controls important biological processes such as cell proliferation, survival, migration, and differentiation. Dysregulation of FGFR genes, FGFR proteins, or their expression, activity, or levels has been associated with many types of cancer. For example, dysregulation of FGFRs can occur through multiple mechanisms, including overexpression of FGFR genes, amplification of FGFR genes, activating mutations (e.g., point mutations or truncations), and chromosomal rearrangements resulting in FGFR fusion proteins. Dysregulation of FGFR genes, FGFR proteins, or their expression or activity or levels can cause (or partially cause) the development of a variety of different FGFR-associated cancers.

[0588] 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 / 0366866Al; PCT Patent Application Publication No. WO2016 / 084883Al; PCT Patent Application Publication No. WO2016 / 030509Al; PCT Patent Application Publication No. WO2015 / 150900A2; PCT Patent Application Publication No. WO2015 / 120094A2; Kasaian et al., BMC Cancer., 15:984, 2015; Vakil et al., Neuro-Oncology, 18:Supp. Supplement 3, pp. iii93. Abstract Number: LG-64, 17 thInternational Symposium on Pediatric Neuro-Oncology,Liverpool,United Kingdom,2016;Astsaturov et al.,Journal of Clinical Oncology,34:Supp.Supplement 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.Supplement 15,Abstract Number:11012,2016 Annual Meeting of the American Society of Clinical Oncology,Chicago,IL;Hall et al.,Molecular Cancer Therapeutics,Vol.14,No.12,Supp.2,Abstract Number:B151,AACR-NCI-EORTC International Conference:Molecular Targets and Cancer Therapeutics,2015;Reuther et al.,Journal of Molecular Diagnostics,Vol.17,No.6,pp.813,Abstract Number: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.more:clincanres.0078.2018.doi:10.1158 / 1078-0432.CCR-18-0078;Ryland et al.J Clin Patho / more:clincanres.0078.2018.doi:10.1136 / jclinpath-2018-205195;Ferguson et al.J Neuropatho / Exp Neural 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;Doi:10.1016 / j.ajhg.2016.03.017; 17(5):318-332,2017.doi:10.1038 / nrc.2017.8;Ryland et al,J Clin Patho / ,2018 May 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,Cancer 123(20):3916-3924,2017.doi:10.1002 / cncr.30837;Kim,et al. 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.

[0589] FGFR point mutations are known in the art. For example, UniParc entry UPI00000534B8;UniParc entry UPI000000lCOF;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.l;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. 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 / 0235744Al; U.S. Patent Application Publication No. 9254288B2; U.S. Patent Application Publication No. 9267176B2; U.S. Patent Application Publication No. S2016 / 0215350Al; European Patent Application Publication No. EP3023101Al; PCT Patent Application Publication No. WO2016105503Al; 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.Supplement 15,pp.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.Supplement 15,pp.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. 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. 3023101Al; PCT Application Publication No. WO2015 / 099127Al; European Patent No. EP2203449Bl; 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. EP3023101Al; PCT Application Publication No. WO2015 / 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):3149-3146 doi: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,Stone et al; 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-De Mattos-Arruda et al. 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 / s13046-2018-Cha et al. 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.2077-Garda; 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.World et al.,2015; Surg,42(2):482-489,2018.doi:10.1007 / s00268-0l 7-4320-0; Chandrani et al, Ann Oncol, 28(3):597-603, 2017. doi:10.1093 / annonc / mdw636; Dalin et al, Nat 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 residues 795-808 of the FGFR3 isoform also removes the stop codon, lengthening the protein by 99 amino acids (ATGPQQCEGSLAAHPAAGAQPLPGMRLSADGETATQSFGLCVCVCVCVCVCTSACACVRAHLASRCRGTLGVPAA VQRSPDWCCSTEGPLFWGDPVQNVSGPTRWDPVGQGAGPDMARPLPLHHGTSQGALGPSHTQS); 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.

[0590] The compounds of the present disclosure have been found to inhibit FGFR1, FGFR2, FGFR3, and / or FGFR4 and are therefore believed to be useful in treating diseases and disorders treatable with inhibitors of FGFR1, FGFR2, FGFR3, and / or FGFR4. For example, the compounds of the present disclosure may be useful in treating FGFR-related diseases and disorders, e.g., proliferative disorders such as cancer, including hematological cancers and solid tumors, and angiogenesis-related disorders. The compounds of the present disclosure may also be useful in treating disorders resulting from autosomal dominant mutations in FGFRs, e.g., FGFR3, including developmental disorders. Developmental disorders treatable with the compounds of the present disclosure include achondroplasia (Ach) and related chondrodysplastic syndromes, including hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and lethal skeletal dysplasia (TD).

[0591] Non-limiting examples of FGFR-related diseases and disorders include acanthosis nigricans, achondroplasia, Apert syndrome, Beare-Stevenson syndrome (BSS), camptodactyly, tall stature, and deafness syndrome (CATSHL), cleft lip and palate, congenital heart disease (e.g., associated with ambiguous genitalia), craniosynostosis, Crouzon syndrome, ectrodactyly, cerebrocranial dermatolipomatosis, Hartsfield syndrome, hypochondroplasia, hypogonadotropic hypogonadism (e.g., anosmia), and These conditions include hypogonadotropic hypogonadism with or without eczema, Kallmann syndrome, ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, lethal pulmonary acinar dysplasia, microphthalmia, Muenke coronal craniosynostosis, cavitary dysplasia, Pfeiffer syndrome, seborrheic keratosis, syndactyly, lethal skeletal dysplasia (e.g., type I or type II), trigonocephaly (also called heterotopic craniosynostosis), and tumor-induced osteomalacia.

[0592] Non-limiting examples of FGFR1-related diseases and disorders include congenital heart disease (e.g., associated with ambiguous genitalia), craniosynostosis, cerebrocranial lipomatosis, Hartsfield's syndrome, hypogonadotropic hypogonadism (e.g., hypogonadotropic hypogonadism 2 with or without olfactory dysfunction, Kallmann syndrome), ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, cavitary dysplasia, Pfeiffer syndrome, trigonocephaly 1 (also known as heterotopic craniosynostosis), and tumor-induced osteomalacia.

[0593] Non-limiting examples of FGFR2-associated diseases and disorders include Apert syndrome, Beare-Stevenson syndrome (BSS), Crouzon syndrome, ectrodactyly, Jackson-Weiss syndrome, lethal pulmonary acinar dysplasia, Pfeiffer syndrome, and syndactyly. Non-limiting examples of FGFR3-associated diseases and disorders include acanthosis nigricans, achondroplasia, camptodactyly, tall stature, and deafness syndrome (CATSHL), cleft lip and palate, craniosynostosis, hypochondroplasia, microphthalmia, Muenke coronal craniosynostosis, seborrheic keratosis, and lethal skeletal dysplasia (e.g., Type I or Type II). Also, UniParc entry UPI00000534B8;UniParc entry UPI000000lCOF;Uni Parc 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. 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. al.,Plast.Reconstr.Surg.,137(3):952-61,2016;US 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(11):2851 - 4, 2015; Goncalves, Fertil. Steril., 104(5):1261 - 7.e1, 2015; Miller et al., Journal of Clinical Oncology, 34: Supp. Supplement 15, pp. iii93. AbstractNumber: 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 Immunol, 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 Mol 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.

[0594] The term "angiogenesis-associated disorder" refers to a disease characterized by an increase in the number or size of blood vessels in the tissue of a subject or patient, compared to the similar tissue of a subject without the disease. Non-limiting examples of angiogenesis-associated 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, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, hepatocellular carcinoma, sarcoma, and lymphoma), exudative macular degeneration, proliferative diabetic retinopathy, ischemic retinopathy, retinopathy of prematurity, neovascular glaucoma, rubeosis iridis, corneal neovascularization, cyclitis, sickle cell retinopathy, and pterygium.

[0595] The compounds of the present disclosure inhibit wild-type FGFR1, FGFR2, FGFR3, and / or FGFR4. In other embodiments, the compounds of the present disclosure inhibit mutated FGFR1, FGFR2, FGFR3, and / or FGFR4. In other embodiments, the compounds of the present disclosure inhibit FGFR1, FGFR2, FGFR3, and / or FGFR4 containing FGFR kinase inhibitor-resistant mutations.

[0596] In some embodiments of any of the methods or uses described herein, the cancer (e.g., an FGFR-associated cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., an FGFR-associated cancer) is a solid tumor.

[0597] In some embodiments of any of the methods or uses described herein, the cancer (e.g., an FGFR-associated cancer) is selected from the group consisting of lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, lung adenocarcinoma, large cell carcinoma, mesothelioma, lung neuroendocrine carcinoma, smoking-related lung cancer), prostate cancer, colorectal cancer (e.g., rectal adenocarcinoma), endometrial cancer (e.g., endometrioid endometrial carcinoma, endometrial adenocarcinoma), breast cancer (e.g., hormone receptor-positive breast cancer, triple-negative breast cancer, breast neuroendocrine carcinoma), skin cancer (e.g., malignant melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma, large squamous cell carcinoma), gallbladder cancer, liposarcoma (e.g., dedifferentiated liposarcoma, liposarcoma, myxoid liposarcoma), pheochromocytoma, myoepithelial carcinoma, urothelial carcinoma, spermatocytic seminoma, gastric cancer, head and neck cancer (e.g., head and neck (squamous cell) carcinoma, head and neck adenoid cystadenocarcinoma), brain tumors (e.g., glioneuronal tumor, glioma, neuroblastoma, glioblastoma, pilocytic astrocytoma, rosette-forming glioma, dysplastic neuroepithelial tumor, 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 ( For example, cervical squamous cell carcinoma, cervical adenocarcinoma), fallopian tube cancer (e.g., fallopian tube carcinoma), ovarian cancer (e.g., ovarian serous carcinoma, ovarian mucinous carcinoma), bile duct cancer, adenoid cystic carcinoma, pancreatic cancer (e.g., pancreatic exocrine carcinoma, pancreatic ductal adenocarcinoma, pancreatic intraepithelial neoplasia), salivary gland cancer (e.g., pleomorphic salivary gland adenocarcinoma, salivary gland adenoid cystic carcinoma), oral cancer (e.g., oral squamous cell carcinoma), uterine cancer, gastric 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, rhabdomyosarcoma (e.g., alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma), papillary renal carcinoma, liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma), carcinoid, myeloproliferative disorders (also called myeloproliferative neoplasms (MPN)), e.g., 8pll myeloproliferative syndrome (EMS, also called 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 tumors, chronic neutrophilic leukemia, phosphaturic mesenchymal tumor, thyroid cancer (e.g.,anaplastic thyroid carcinoma) or bile duct carcinoma.

[0598] In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-associated cancer) is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), cancer in adolescents, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoma / rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinomatous tumor, carcinoma of unknown primary, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasm, site-specific neoplasm, or leukemia. Biology, Neoplasms, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma, Cutaneous Angiosarcoma, Cholangiocarcinoma, Ductal Carcinoma in Situ, Embryonal Tumors, Endometrial Cancer, Ependymoma, Esophageal Cancer, Nasal Neuroblastoma, Ewing's Sarcoma, Extracranial Germ Cell Tumors, Extragonadal Germ Cell Tumors, Extrahepatic Bile Duct Carcinoma, Eye Cancer, Fallopian Tube Cancer, Fibrous Histiocytoma of Bone, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumors, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumors, Gestational Trophoblastic Disease, Glioma, Hairy Cell Tumors, Hairy Cell Leukemia, Head and Neck Cancer, Breast Neoplasms, Head and Neck Neoplasms, CNS Tumors, Primary CNS Tumors, Cardiac Cancer, Hepatocellular Carcinoma, Histiocytosis, Hodgkin's Disease melanoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell neck cancer, midline duct carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, neoplasm by site, neoplasm, myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma , neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, lung neoplasms, lung cancer, lung neoplasms, respiratory tract neoplasms, bronchogenic carcinoma, bronchial neoplasms, mouth cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasma cell neoplasms, pleuropulmonary blastoma, pregnancy-associated breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colon neoplasms, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, Spitz tumor, small cell lung cancer, small intestine cancer,Selected from the group consisting of soft tissue sarcoma, squamous cell carcinoma, squamous cell cervical carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, carcinoma of unknown primary, uterine cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0599] In some embodiments, the hematological cancer (e.g., a hematological cancer that is an FGFR-associated cancer) is a leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), and chronic myelomonocytic leukemia (CMML). ), chronic neutrophilic leukemia (CNL), acute anaplastic 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 disorder (MPD), and multiple myeloma (MM).

[0600] Additional examples of hematological cancers include myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the hematological cancer (e.g., a hematological cancer that is an FGFR-associated cancer) is AML or CMML. In some embodiments, the cancer (e.g., an FGFR-associated cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are FGFR-associated cancers) include, for example, lung cancer (e.g., lung adenocarcinoma, non-small cell lung cancer, squamous cell carcinoma), bladder cancer, colorectal cancer, brain tumor, testicular cancer, cholangiocarcinoma, cervical cancer, prostate cancer, and spermatocytic seminoma. See, e.g., Turner and Grose, Nat. Rev. Cancer, 10(2):116-129, 2010.

[0601] 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.

[0602] In some embodiments, the cancer is hepatocellular carcinoma.

[0603] In some embodiments, the FGFR1-associated cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer.

[0604] In some embodiments, the cancer is selected from the group consisting of breast cancer, uterine cancer, bile duct cancer, and lung cancer.

[0605] In some embodiments, the FGFR2-associated 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.

[0606] In some embodiments, the FGFR3-associated cancer is selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer.

[0607] In some embodiments, the cancer is selected from lung cancer, rhabdomyosarcoma, and breast cancer.

[0608] In some embodiments, the FGFR4-associated cancer is selected from hepatocellular carcinoma, lung cancer, rhabdomyosarcoma, and breast cancer.

[0609] In some embodiments, the compounds of the present disclosure are useful in treating cancers associated with amplification or overexpression of FGFR1, such as breast cancer or carcinoma (e.g., hormone receptor positive breast cancer, ductal carcinoma in situ (breast)), pancreatic ductal adenocarcinoma, pancreatic exocrine cancer, smoking-related lung cancer, small cell lung cancer, lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer or carcinoma, prostate cancer or carcinoma, ovarian cancer, fallopian tube cancer, bladder cancer, rhabdomyosarcoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), esophageal cancer, The compositions are useful in treating cancers including esophageal squamous cell carcinoma (e.g., esophageal squamous cell carcinoma), sarcoma (e.g., osteosarcoma), hepatocellular carcinoma, renal cell carcinoma, colon cancer (e.g., colorectal adenocarcinoma), prostate cancer, salivary gland tumors, glioblastoma multiforme, bladder cancer, urothelial carcinoma, carcinoma of unknown primary origin, non-pulmonary squamous cell tumor, gastric cancer, esophagogastric junction cancer, adenoid cystic carcinoma, anal squamous cell carcinoma, oral squamous cell carcinoma, cholangiocarcinoma, hemangioendothelioma, leiomyosarcoma, melanoma, neuroendocrine carcinoma, squamous cell carcinoma, and uterine carcinosarcoma.

[0610] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with FGFR2 amplification, such as 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, carcinoma of unknown primary site, bile duct carcinoma, endometrial adenocarcinoma, esophageal adenocarcinoma, gallbladder cancer, ovarian cancer, fallopian tube cancer, exocrine pancreatic carcinoma, sarcoma, and squamous cell carcinoma.

[0611] In some embodiments, the compounds of the present disclosure are useful in treating cancers associated with overexpression of FGFR2, such as mucinous lipoma, rectal cancer, renal cell carcinoma, and breast cancer.

[0612] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with upregulated FGFR3 activity, such as colon cancer, hepatocellular carcinoma, and exocrine pancreatic cancer. In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with overexpression of FGFR3 activity, such as multiple myeloma and thyroid cancer. In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with amplification of FGFR3 activity, such as bladder cancer and salivary gland adenoid cystic carcinoma, urothelial carcinoma, breast cancer, carcinoid tumor, carcinoma of unknown primary site, colon cancer (e.g., colon adenocarcinoma), gallbladder cancer, gastric cancer, gastroesophageal junction adenocarcinoma, glioma, mesothelioma, non-small cell lung cancer, small cell lung cancer, ovarian cancer, fallopian tube cancer, and exocrine pancreatic cancer.

[0613] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with FGFR4 amplification, such as rhabdomyosarcoma, prostate cancer or carcinoma, breast cancer, urothelial carcinoma, carcinoid, carcinoma of unknown primary origin, esophageal adenocarcinoma, head and neck cancer, hepatocellular carcinoma, non-small cell lung cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, and renal cell carcinoma.

[0614] In some embodiments, compounds of the present disclosure are useful for treating cancers associated with upregulated activity of FGFR4, such as colon cancer, hepatocellular carcinoma, adrenal cancer, and breast cancer.

[0615] In some embodiments, compounds of the present disclosure are useful in treating cancers associated with overexpression of FGFR4 activity, such as pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma.

[0616] In some embodiments, the compounds of the present disclosure are selective for one FGFR over another. As used herein, the "selectivity" of a compound for a first target over a second target means that the compound has more potent activity on the first target than on the second target. The selectivity factor can be determined by any method known in the art. For example, the selectivity factor can be calculated by dividing the IC50 value (or Kd value) of a compound for a second target (e.g., FGFR1) by the IC50 value (or Kd value) of the same compound for a first target (e.g., FGFR2 or FGFR3). The IC50 value (or Kd value) can be determined by any method known in the art. In some embodiments, the compound is initially determined to have an activity of less than 500 nM against the first target. In some embodiments, the compound is initially determined to have an activity of less than 500 nM against the second target.

[0617] For example, in some embodiments, the compounds of the present disclosure are more selective for FGFR3 over FGFR1. In some embodiments, the compounds are at least 3-fold selective for FGFR3 over FGFR1. In some embodiments, the compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000-fold selective for FGFR3 over FGFR1.

[0618] For example, in some embodiments, the compounds of the present disclosure are more selective for FGFR4 over FGFR1. In some embodiments, the compounds are at least 3-fold selective for FGFR4 over FGFR1. In some embodiments, the compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000-fold selective for FGFR4 over FGFR1.

[0619] In some embodiments, the compounds of the present disclosure are more selective for FGFR2 over FGFR1. In some embodiments, the compounds are at least 3-fold selective for FGFR2 over FGFR1. In some embodiments, the compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000-fold selective for FGFR2 over FGFR1.

[0620] In some embodiments, the compounds of the disclosure are more selective for a first FGFR family member (e.g., FGFR2 or FGFR3) over a second FGFR family member (e.g., FGFR1 or FGFR4). In some embodiments, the compounds of the disclosure are at least 3-fold selective for a first FGFR family member over a second FGFR family member. In some embodiments, the compounds are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000-fold selective for a first FGFR family member over a second FGFR family member.

[0621] In some embodiments, the compounds of the disclosure are more selective for a first FGFR family member (e.g., FGFR4 or FGFR3) over a second FGFR family member (e.g., FGFR1 or FGFR2). In some embodiments, the compounds of the disclosure are at least 3-fold selective for a first FGFR family member over a second FGFR family member. In some embodiments, the compounds are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000-fold selective for a first FGFR family member over a second FGFR family member.

[0622] In some embodiments, the compounds of the present disclosure are more selective for FGFR kinase than other kinases that are not FGFR kinases. For example, the compounds of the present disclosure are at least 3 times more selective for FGFR kinase than other kinases that are not FGFR kinases. In some embodiments, the compounds of the present disclosure are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000 times more selective for FGFR kinase than other kinases that are not FGFR kinases. Kinases that are not FGFR kinases include, for example, KDR kinase and Aurora B kinase.

[0623] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) penetrance. Such compounds are capable of crossing the blood-brain barrier and inhibiting FGFR kinases in the brain and / or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood-brain barrier in therapeutically effective amounts. For example, treating a subject with cancer (e.g., an FGFR-associated cancer, such as an FGFR-associated brain or CNS cancer) can include administering (e.g., orally administering) a compound to the subject. In some such embodiments, the compounds provided herein are useful for treating primary or metastatic brain tumors, such as FGFR-associated primary or metastatic brain tumors.

[0624] In some embodiments, compounds of the present disclosure exhibit one or more of high GI absorption, low clearance, and low potential for drug-drug interactions.

[0625] In some embodiments, the compounds of the present disclosure can be used to treat a subject diagnosed with (or identified as having) an FGFR-related disease or disorder (e.g., an FGFR-related cancer), comprising administering a therapeutically effective amount of a compound of the present disclosure to the subject. Also provided herein are methods of treating a subject identified or diagnosed with an FGFR-related disease or disorder (e.g., an FGFR-related cancer), comprising administering a therapeutically effective amount of a compound of the present disclosure to the subject. In some embodiments, the subject has been identified or diagnosed with an FGFR-related disease or disorder (e.g., an FGFR-related cancer) through the use of a regulatory-approved, e.g., FDA-approved, test or assay to identify dysregulation of an FGFR gene, an FGFR kinase, or expression or activity or levels thereof in the subject or in a biopsy sample from the subject, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the FGFR-related disease or disorder is an FGFR-related cancer. For example, the FGFR-related cancer can be a cancer containing one or more FGFR inhibitor-resistant mutations.

[0626] Also provided are methods for treating a disease or disorder in a subject in need thereof, the methods comprising: (a) detecting an FGFR-related disease or disorder in the subject; and (b) administering a therapeutically effective amount of a compound of the present disclosure to the subject. Some embodiments of these methods further comprise administering an additional therapy or therapeutic agent to the subject (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or an immunotherapy). In some embodiments, the subject has been previously treated with a first FGFR inhibitor or has been previously treated with another treatment. In some embodiments, the subject is determined to have an FGFR-related disease or disorder through the use of a regulatory-approved, e.g., FDA-approved, test or assay to identify dysregulation of an FGFR gene, an FGFR kinase, or expression or activity or levels thereof in the subject or in a biopsy sample from the subject, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit.

[0627] Also provided are methods for treating cancer in a subject in need thereof, comprising: (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure. Some embodiments of these methods further comprise administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or immunotherapy). In some embodiments, the subject has been previously treated with a first FGFR inhibitor or has been previously treated with another anti-cancer treatment, e.g., at least partial tumor resection or radiation therapy. In some embodiments, the subject is determined to have an FGFR-associated cancer through the use of a regulatory-approved, e.g., FDA-approved, test or assay to identify an FGFR gene, an FGFR kinase, or dysregulation of expression, activity, or levels thereof in the subject or a biopsy sample from the subject, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an FGFR-associated cancer. For example, the FGFR-associated cancer can be a cancer containing one or more FGFR inhibitor-resistant mutations. In some embodiments, the cancer is an FGFR-associated cancer. For example, an FGFR-associated cancer can be a cancer that contains one or more FGFR activating mutations.

[0628] Also provided are methods of treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of an FGFR gene, an FGFR kinase, or any of them; 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 the subject determined to have dysregulated expression, activity, or level of an FGFR gene, an FGFR kinase, or any of them. Some embodiments of these methods further comprise administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or an immunotherapy). In some embodiments of these methods, the subject has been previously treated with a first FGFR inhibitor or has been previously treated with another anti-cancer treatment, e.g., at least partial tumor resection or radiation therapy. In some embodiments, the subject is suspected of having an FGFR-related disease or disorder (e.g., an FGFR-related cancer), exhibits one or more symptoms of an FGFR-related disease or disorder (e.g., an FGFR-related cancer), or is at high risk for developing an FGFR-related disease or disorder (e.g., an FGFR-related cancer). In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory-approved assay, e.g., an FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art. In some embodiments, the dysregulation of the expression or activity or level of the FGFR gene, FGFR kinase, or any of them comprises one or more FGFR inhibitor-resistant mutations.

[0629] Also provided herein are methods of selecting a treatment for a subject, the methods comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of an FGFR gene, an FGFR kinase, or any of them (e.g., one or more FGFR inhibitor-resistant mutations); and identifying or diagnosing the subject determined to have dysregulated expression, activity, or level of an FGFR gene, an FGFR kinase, or any of them as having an FGFR-associated cancer. Some embodiments further comprise administering the selected treatment to the subject identified or diagnosed with an FGFR-associated cancer. For example, in some embodiments, the selected treatment may comprise administering a therapeutically effective amount of a compound of the present disclosure to the subject identified or diagnosed with an FGFR-associated cancer. In some embodiments, the assay is an in vitro assay, such as an assay utilizing next-generation sequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e.g., FDA-approved, kit. In some embodiments, the assay is a liquid biopsy.

[0630] Also provided herein are methods of treating an FGFR-associated cancer in a subject, the methods comprising: (a) administering one or more (e.g., two or more, three or more, four or more, five or more, or ten or more) doses of a first FGFR kinase inhibitor to a subject (e.g., identified or diagnosed as having an FGFR-associated cancer using any of the exemplary methods described herein or known in the art) identified as having an FGFR-associated cancer (e.g., any of the types of FGFR-associated cancer described herein); (b) determining the level of circulating tumor DNA in a biological sample (e.g., a biological sample comprising blood, serum, or plasma) obtained from the subject after step (a); and (c) administering a therapeutically effective amount of a second FGFR inhibitor or a compound of the present disclosure, as monotherapy or in combination with an additional therapy or therapeutic agent, to a subject identified as having approximately the same or elevated levels of circulating tumor DNA compared to a baseline level of circulating tumor DNA (e.g., any of the baseline levels 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 before step (a). Some embodiments of these methods further include measuring the level of circulating tumor DNA in a biological sample obtained from the subject before 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 a similar FGFR-associated cancer and a similar stage of the FGFR-associated cancer but who are receiving ineffective treatment or placebo or have not yet received therapeutic treatment, or the level of circulating tumor DNA in subjects with a similar FGFR-associated cancer and a similar stage of the FGFR-associated cancer but who are receiving ineffective treatment or placebo or have not yet received therapeutic treatment).In some examples of these methods, the first FGFR inhibitor is selected from the group consisting of ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Devio1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB0548 28, lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, surufatinib, robritinib, ICP-105, BIO-1262, futibatinib, fisogatinib, LOXO-435, or RLY-4008.

[0631] The compounds of the present disclosure can also be administered with additional therapies or therapeutic agents. In some embodiments, the additional therapies or therapeutic agents include one or more of radiation therapy, a chemotherapeutic agent (e.g., any of the exemplary chemotherapeutic agents described herein or known in the art), a checkpoint inhibitor (e.g., any of the exemplary checkpoint inhibitors described herein or known in the art), surgery (e.g., at least partial resection of the tumor), and one or more other kinase inhibitors (e.g., any of the kinase inhibitors described herein or known in the art).

[0632] The compounds of the present disclosure may also be useful as adjuvants for cancer treatment, i.e., they may be used in combination with one or more additional therapies or therapeutic agents, e.g., chemotherapeutic agents that function by the same or different mechanisms of action. In some embodiments, the compounds of the present disclosure may be used prior to the administration of the additional therapeutic agent or therapy. For example, a subject in need thereof may be administered one or more doses of a compound of the present disclosure for a period of time, followed by at least partial resection of the tumor. In some embodiments, treatment with one or more doses of a compound of the present disclosure reduces tumor size (e.g., tumor burden) prior to at least partial resection of the tumor. In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumors) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent such as a first FGFR inhibitor or multikinase inhibitor, immunotherapy, radiation, or a platinum-based agent (e.g., cisplatin)). In some embodiments, the subject has cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to previous therapy (e.g., administration of a chemotherapeutic agent such as a first FGFR inhibitor or multikinase inhibitor, immunotherapy, radiation, or a platinum-based agent (e.g., cisplatin)).

[0633] In some embodiments of any of the methods described herein, a compound of the present disclosure is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic agents (e.g., chemotherapeutic agents). 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., receptor tyrosine kinase-targeted therapeutic agents (e.g., Trk inhibitors or EGFR inhibitors)), signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptosis pathways (e.g., obataclax), cytotoxic chemotherapy, angiogenesis-targeted therapy, immune-targeted agents including immunotherapy, and radiation therapy.

[0634] Also provided herein are methods for treating a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical combination for treating the disease or disorder, the pharmaceutical 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 for treating the disease or disorder, wherein the amounts of the compound of the present disclosure and the additional therapeutic agent together are effective to treat the disease or disorder. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered together as separate dosages, sequentially in any order, in therapeutically effective amounts, e.g., daily or intermittently. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered simultaneously as a combined dosage. In some embodiments, the disease or disorder is an FGFR disease or disorder. In some embodiments, the subject has been administered one or more doses of a compound of the present disclosure prior to administration of the pharmaceutical composition.

[0635] In some embodiments, the treatment period 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).

[0636] In some embodiments, the treatment period 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).

[0637] Also provided herein are pharmaceutical compositions comprising, as an active ingredient, a compound of the present disclosure in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the compositions are suitable for topical administration. In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid vehicles), ointments, for example, containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders. In some embodiments, the compositions are formulated for oral administration. In some embodiments, the composition is formulated as a tablet or capsule.

[0638] Compositions containing compounds of the present disclosure can be formulated in unit dosage form, each dosage containing from about 5 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 and other subjects, each unit containing a predetermined amount of the active agent (i.e., a compound of the present disclosure) to produce the desired therapeutic effect, together with suitable pharmaceutical excipients.

[0639] In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of active ingredient, i.e., a compound of the present disclosure. One of skill in the art will appreciate 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 the active ingredient. In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of the active ingredient. One of ordinary skill in the art will appreciate that this embodies compounds or compositions 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 the active ingredient. In some embodiments, the compositions provided herein contain about 500 mg to about 1,000 mg of the active ingredient. One of ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.

[0640] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by a physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual subject, the severity of the subject's symptoms, etc.

[0641] In some embodiments, the compounds provided herein may be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein may be administered in an amount ranging from about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or 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, such administration can be once daily or twice daily (BID).

[0642] The present disclosure is also directed to the following aspects: Aspect 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X=O, S or NR; R is H or C1-C3 alkyl; n=1 or 2, m=1 or 2, R 1 is H or optionally substituted C1-C6 alkyl, R 2is 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 and 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- to 6-membered heterocycloalkyl, or C(O)(CH2) 0-3 NR 4d R 4e and Or R 3 and R 4 together with the N atom to which they are both attached form a 3- to 6-membered heterocycloalkyl optionally substituted with one or more substituents, each of which is C1-C6 alkyl, C1-C6 alkoxyl, F, or OH; 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 R 4b and R 4c together with the phosphorus atom to which they are both attached 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 atom to which they are both attached 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 form a 3- to 5-membered cycloalkyl ring; Q1 , Q 2 , Q 3 , Q 4 one or two of which are N, and the rest are each independently CR 5a and 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 are each independently N or CR 5 Among them, Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One or two of these are N and the rest are CR 5 and R 5 is H, halogen, C1-C3 alkyl, C1-C3 alkoxyl or cycloalkyl; R 6 is C1-C6 alkyl, R 7 is H, halogen, -C1-C6 alkyl, -C1-C6 alkoxyl or -cycloalkyl; R 8 is H, halogen, -C1-C6 alkyl, -C1-C6 alkoxyl or -cycloalkyl.

[0643] Embodiment 2. The compound of embodiment 1, wherein R 1 is H or C1-C6 alkyl, and R 4 is H, optionally substituted C1-C6 alkyl, C3-C5 cycloalkyl, 3- to 6-membered heterocycloalkyl, or C(O)(CH2) 0-3 NR 4d R 4e is.

[0644] Embodiment 3. The compound of embodiment 1 or embodiment 2, wherein X is O.

[0645] Aspect 4. The compound of any one of Aspects 1-3, wherein R 6 is -CH3.

[0646] Aspect 5. The compound of any one of the preceding aspects, wherein R 8 is H.

[0647] Aspect 6. The compound of any one of the preceding aspects, wherein R 7 is H, F or OCH3.

[0648] Embodiment 7. The compound of any one of the preceding embodiments, wherein Q 1 and Q 3 are CR 5a where R 5a is H.

[0649] Embodiment 8. The compound of any one of the preceding embodiments, wherein Q 2 and Q 4 are N respectively.

[0650] Aspect 9. The compound of any one of aspects 1-7, wherein Q 2 is N and Q 4 is CR 5a where R 5a is H or F.

[0651] Aspect 10. The compound of any one of Aspects 1-7, wherein Q 2 is N and Q 4 is CR 5a where R 5a is CN, S(O)2C1-C6 alkyl, OC1-C3 alkyl, or C1-C3 alkyl.

[0652] Embodiment 11. The compound of any one of the preceding embodiments, wherein Q 5 and Q 9 are CR 5 where each R 5 is Cl and G 7 is N and Q 6is CR 5 where R 5 is H and Q 8 is CR 5 where R 5 is H or CH3.

[0653] Embodiment 12. The compound of any one of the preceding embodiments, wherein n is 1 and m is 1.

[0654] Aspect 13. The compound of any one of the preceding aspects, wherein the compound of formula (I) is a compound of formula (IA): [ka] During the ceremony, Q 2 and Q 4 are N or Q 2 or Q 4 One of them is N and the other is CR 5a and R 5a is H, F, -SO2CH3 or -CN, R 5 is H or CH3, R 7 is H, F or OCH3.

[0655] Aspect 14. The compound of aspect 13, wherein R 5 is H.

[0656] Aspect 15. The compound of aspect 13, wherein R 5 is CH3.

[0657] Aspect 16. The compound of any one of Aspects 13-15, wherein R 7 is H.

[0658] Aspect 17. The compound of any one of Aspects 13-15, wherein R 7 is F.

[0659] Aspect 18. The compound of any one of Aspects 13-15, wherein R 7 is OCH3.

[0660] Aspect 19. The compound of any one of Aspects 13-18, wherein Q 2 and Q 4 are N respectively.

[0661] Aspect 20. The compound of any one of Aspects 13-18, wherein Q 2 or Q 4 One of them is N and the other is CR 5a is.

[0662] Aspect 21. The compound of aspect 20, wherein R 5a is H or F.

[0663] Aspect 22. The compound of aspect 21, wherein R 5a is H.

[0664] Aspect 23. The compound of aspect 21, wherein R 5a is F.

[0665] Aspect 24. The compound of aspect 20, wherein R 5a is CN or SO2CH3.

[0666] Aspect 25. The compound of aspect 24, wherein R 5a is CN.

[0667] Aspect 26. The compound of aspect 24, wherein R 5a is SO2CH3.

[0668] Aspect 27. The compound of Aspect 1 or Aspect 2, wherein R 5a is OCF3.

[0669] Aspect 28. The compound of any one of Aspects 1 to 27, wherein R 1 is H.

[0670] Aspect 29. The compound of any one of Aspects 1 to 27, wherein R 1 is optionally substituted C1-C6 alkyl.

[0671] Aspect 30. The compound of aspect 29, wherein R 1 is -CH2CN.

[0672] Aspect 31. The compound of aspect 29, wherein R 1 is CH3.

[0673] Aspect 32. The compound of any one of Aspects 1 to 31, wherein R 2 is H.

[0674] Aspect 33. The compound of any one of Aspects 1-31, wherein R 2 is optionally substituted C1-C6 alkyl.

[0675] Aspect 34. The compound of aspect 33, wherein R 2 is an unsubstituted C1-C6 alkyl such as CH3.

[0676] Aspect 35. The compound of aspect 33, wherein R 2 is a substituted C1-C6 alkyl.

[0677] Aspect 36. The compound according to aspect 35, wherein C1-C6 alkyl is —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)R 4b R 4c are substituted with, among which R 4b and R 4c are independently C1-C6 alkyl, or R 4b and R 4c taken together with the phosphorus atom to which they are both attached, form a 4- to 6-membered heterocycloalkyl ring.

[0678] Aspect 37. The compound of aspect 36, wherein R 2 is -CH2-NHSO2(CH3), -CH2-N(CH3)SO2(CH3), [ka] -CH2-NH(CH3), -CH2-NH(-CH(CH3)2), -CH2-N(CH3)2 or -CH2P(O)(CH3)2.

[0679] Aspect 38. The compound of any one of Aspects 1-31, wherein R 2 Ha-NR 3 R 4 is.

[0680] Aspect 39. The compound of aspect 38, wherein R 3 is H.

[0681] Embodiment 40. The compound of embodiment 38, wherein R 3 is a C1-C6 alkyl such as CH3.

[0682] Aspect 41. The compound of any one of Aspects 38-40, wherein R 4 is H.

[0683] Aspect 42. The compound of any one of Aspects 38-40, wherein R 1 is optionally substituted C1-C6 alkyl.

[0684] Aspect 43. The compound of aspect 42, wherein R 4 is CH3 or unsubstituted C1-C6 alkyl such as -CH2CH3, -CH(CH3)2.

[0685] Embodiment 44. The compound of embodiment 42, wherein R 4 -CH2CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, [ka] is.

[0686] Embodiment 45. The compound of embodiment 42, wherein R 4 is a substituted C1-C6 alkyl.

[0687] Embodiment 46. The compound of embodiment 45, wherein R 4 -CH2-cyclopropyl, -CH2CH2CHF2, -CH2CHF2, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2O-iso-Pr, -CH2C(CH3)2OH, -CH2CHCH3OH, -CH2CHOCH3, -C(O)CH2N(C1-C6 alkyl)2, [ka] is.

[0688] Aspect 47. The compound of any one of aspects 38-40, wherein R 4 is an optionally substituted C2-C6 alkenyl such as -CH2CH=CH2.

[0689] Aspect 48. The compound of any one of aspects 38-40, wherein R 4 is a C3-C5 cycloalkyl such as cyclobutyl.

[0690] Aspect 49. The compound of any one of aspects 38-40, wherein R 4 is a 3- to 6-membered heterocycloalkyl.

[0691] Embodiment 50. The compound according to embodiment 49, wherein the 3- to 6-membered heterocycloalkyl is oxetan-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl, [ka] is.

[0692] Aspect 51. The compound of any one of Aspects 38-40, wherein R 4 is C(O)CHNR such as C(O)CHN(C-C alkyl) or C(O)CHN(CH) 4d R 4e is.

[0693] Embodiment 52. The compound of embodiment 38, wherein R 3 and R 4 taken together with the N atom to which they are both attached, is a 3-6 membered heterocycloalkyl optionally substituted with one or more substituents which are C1-C6 alkyl, C1-C6 alkoxyl, F, or OH.

[0694] Embodiment 53. The compound of embodiment 38, wherein R 3 and R 4 taken together with the N atom to which they are both attached form an unsubstituted 3- to 6-membered heterocycloalkyl such as pyrrolidin-1-yl, azetidin-1-yl or morpholin-4-yl.

[0695] Embodiment 54. The compound of embodiment 38, wherein R 3 and R 4 taken together with the N atom to which they are both attached form a substituted 3- to 6-membered heterocycloalkyl such as 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphinan-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0696] Aspect 55. The compound of any one of Aspects 1-31, wherein R 2 HA-OR 4a is.

[0697] Embodiment 56. The compound of embodiment 55, wherein R 4a is H.

[0698] Embodiment 57. The compound of embodiment 55, wherein R 4ais optionally substituted C1-C6 alkyl.

[0699] Embodiment 58. The compound of embodiment 57, wherein R 4a is an unsubstituted C1-C6 alkyl such as -CH(CH3).

[0700] Embodiment 59. The compound of embodiment 57, wherein R 4a is a substituted C1-C6 alkyl.

[0701] Aspect 60. The compound of aspect 59, wherein R 4a is —CH2CH2OH or —CH2C(CH3)2OH.

[0702] Aspect 61. The compound of any one of Aspects 1-31, wherein R 2 HA-P(O)R 4b R 4c is.

[0703] Aspect 62. The compound of any one of Aspects 1-31, wherein R 2 Ha-SO2R 3 is.

[0704] Aspect 63. The compound of any one of aspects 1-27, wherein R 1 and R 2 taken together with the carbon atom to which they are both attached form a 3- to 5-membered cycloalkyl ring, such as a cyclopropyl ring.

[0705] Embodiment 64. The compound according to embodiment 13, wherein the compound of formula (IA) is a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof: [ka]

[0706] Embodiment 65. The compound according to embodiment 13, wherein the compound of formula (IA) is a compound of formula (IA-2), or a pharmaceutically acceptable salt thereof: [ka]

[0707] Embodiment 66. The compound according to embodiment 13, wherein the compound of formula (IA) is a compound of formula (IA-3), or a pharmaceutically acceptable salt thereof: [ka]

[0708] Embodiment 67. The compound according to embodiment 13, wherein the compound of formula (IA) is a compound of formula (IA-4), or a pharmaceutically acceptable salt thereof: [ka]

[0709] Embodiment 68. The compound according to embodiment 13, wherein the compound of formula (IA) is a compound of formula (IA-5), or a pharmaceutically acceptable salt thereof: [ka]

[0710] Embodiment 69. The compound of any one of embodiments 64-68, wherein R 5 is H.

[0711] Embodiment 70. The compound of any one of embodiments 64-68, wherein R 5 is CH3.

[0712] Embodiment 71. The compound of any one of embodiments 64-70, wherein R 7 is H.

[0713] Embodiment 72. The compound of any one of embodiments 64-70, wherein R 7 is F.

[0714] Embodiment 73. The compound of any one of embodiments 64-70, wherein R 7 is OCH3.

[0715] Embodiment 74. The compound of any one of embodiments 64-73, wherein R 2 is optionally substituted C1-C6 alkyl.

[0716] Embodiment 75. The compound of embodiment 74, wherein R 2 is CH3, -CH2-NHSO2(CH3), -CH2-N(CH3)SO2(CH3), [ka] -CH2-NH(CH3), -CH2-NH(-CH(CH3)2), -CH2-N(CH3)2 or -CH2-P(O)(CH3)2.

[0717] Embodiment 76. The compound of any one of embodiments 64-73, wherein R 2 Ha-NR 3 R 4 is.

[0718] Embodiment 77. The compound of embodiment 76, wherein R 3 is H.

[0719] Embodiment 78. The compound of embodiment 76, wherein R 3 is CH3.

[0720] Embodiment 79. The compound of any one of embodiments 76-78, wherein R 4 is H.

[0721] Embodiment 80. The compound of any one of embodiments 76-78, wherein R 4 are CH3, -CH2CH3, -CH(CH3), -CH2-cyclopropyl, -CH2CH2CHF2, -CH2CHF2, -CH2CH2OH, -CH2C(CH3)2OH, -CH2CHOCH3, -C(O)CH2N(CH3)2, [ka] is.

[0722] Embodiment 81. The compound of any one of embodiments 76-78, wherein R 4 -CH2CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, [ka] is.

[0723] Embodiment 82. The compound of any one of embodiments 76-78, wherein R 4 is -CH2CH=CH2.

[0724] Embodiment 83. The compound of any one of embodiments 76-78, wherein R 4 is cyclopropyl, cyclobutyl or cyclopentyl.

[0725] Embodiment 84. The compound of any one of embodiments 76-78, wherein R 4 oxetan-3-yl, thietan-3-yl-1,1-dioxide, tetrahydrofuran-3-yl, [ka] is.

[0726] Embodiment 85. The compound of any one of embodiments 76-78, wherein R 4 is C(O)CH2N(CH3)2.

[0727] Embodiment 86. The compound of embodiment 76, wherein R 3 and R 4 taken together with the N atom to which they are both attached form a 3-6 membered heterocycloalkyl optionally substituted with one or more substituents, each of which is C1-C6 alkyl, C1-C6 alkoxyl, or OH.

[0728] Embodiment 87. The compound of embodiment 86, wherein R 3 and R 4together with the N atom to which they are both attached are 3,3-dimethyl-azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 1-methyl-4-azaphosphinan-4-yl 1-oxide, 1-methyl-4-azaphosphinan-4-yl 1-oxide or 3-methoxy-3-methylazetidin-1-yl.

[0729] Embodiment 88. The compound of any one of embodiments 64-73, wherein R 2 HA-P(O)R 4b R 4c is.

[0730] Embodiment 89. The compound of any one of embodiments 64-73, wherein R 2 HA-OR 4a is.

[0731] Embodiment 90. The compound according to embodiment 89, wherein R 4a is —CH(CH3), —CH2CH2OH, —CH2C(CH3)2OH, cyclopropyl, cyclobutyl or cyclopentyl.

[0732] Embodiment 91. The compound according to embodiment 13, wherein the compound of formula (IA) is a compound of formula (IA-6), or a pharmaceutically acceptable salt thereof: [ka]

[0733] 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.

[0734] Aspect 93. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound according to any one of aspects 1 to 91, or a pharmaceutically acceptable salt thereof.

[0735] Embodiment 94. The method according to embodiment 93, wherein the disease or disorder is cancer.

[0736] Aspect 95. The method of aspect 94, wherein the cancer is urothelial carcinoma, hepatocellular carcinoma, breast cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung cancer, exocrine pancreatic carcinoma, oral cancer, prostate cancer, bladder cancer, colorectal cancer, renal cell carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous), melanoma, leiomyosarcoma, and / or sarcoma.

[0737] Embodiment 96 The method according to embodiment 95, wherein the cancer is bladder cancer.

[0738] Embodiment 97. The method according to embodiment 95, wherein the cancer is urothelial carcinoma.

[0739] Embodiment 98. The method according to embodiment 95, wherein the cancer is hepatocellular carcinoma.

[0740] Embodiment 99. The method according to any one of embodiments 94 to 98, wherein the cancer is an FGFR-mutated cancer.

[0741] Embodiment 100. The method according to embodiment 93, wherein the disease or disorder is a developmental disorder.

[0742] Embodiment 101. The method according to embodiment 100, wherein the developmental disorder is achondroplasia.

[0743] Embodiment 102. A method of inhibiting an FGFR in a cell, comprising contacting the cell with a compound of any one of embodiments 1 to 91. [Example]

[0744] The examples and preparations provided below further describe and illustrate the compounds of the present invention and methods for making such compounds. It is understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations.

[0745] In some embodiments, when single enantiomers are provided, the enantiomers may be separated by conventional means (chiral chromatography, diastereomeric salt preparation, chiral derivatization, crystallization, enzymatic reaction, etc.). In some embodiments, chiral intermediate compounds are purified to prepare enantiomerically pure (or substantially enantiomerically pure, enantiomerically enriched, etc.) intermediates.

[0746] Scheme of 6-Methoxyindazole Example 3 [ka]

[0747] 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 [ka]

[0748] Step 1. (E)-N'-(2-Bromo-5-hydroxy-4-methoxybenzylidene)-4-methylbenzenesulfonohydrazide. p-Toluenesulfonylhydrazide (0.56 g, 3.0 mmol, 1.0 equiv) was added to a solution of 2-bromo-5-hydroxy-4-methoxybenzaldehyde (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), followed by the addition of heptane (80 mL) to give a pale yellow solid (1.21 g, 100%). LCMS m / z = 399.0 (M+H).

[0749] Step 2. 6-Methoxy-1-tosyl-1H-indazol-5-ol. Copper(I) oxide (0.22 g, 1.5 mmol, 0.5 equiv.) was added to a solution of (E)-N'-(2-bromo-5-hydroxy-4-methoxybenzylidene)-4-methylbenzenesulfonohydrazide (1.2 g, 3.0 mmol, 1.0 equiv.) in isoamyl alcohol (30 mL) at room temperature. After heating at 132 °C for 2 h, the mixture was cooled to room temperature and diluted with water (80 mL). The mixture was extracted with ethyl acetate (4 × 50 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 Sfaer silica, 50 g, 0% to 100% ethyl acetate in heptane) to give a pale yellow solid (0.66 g, 70% yield). LCMS m / z=319.1 (M+H).

[0750] Step 3. (R)-5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-6-methoxy-1-tosyl-1H-indazole. (1S)-1-(3,5-Dichloro-4-pyridyl)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) eluting with a gradient 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).

[0751] 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) eluting with a gradient of 0% to 100% ethyl acetate in heptane to give a white solid (74.7 mg, 54%). LCMS m / z=338.0 (M+H).

[0752] 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 (4 × 5 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).

[0753] 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-pyridyl)ethoxy]-3-iodo-6-methoxy-1H-indazole (0.5 g, 1.1 mmol, 1 equiv.) was treated with 3,4-dihydro-2H-pyran (0.2 mL, 2.2 mmol, 2 equiv.) and p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol, 0.05 equiv.) 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 gel 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).

[0754] Step 7. 5-Bromo-2-(5-azaspiro[2.3]hexan-5-yl)nicotinonitrile. 5-Bromo-2-chloropyridine-3-carbonitrile (0.50 g, 2.3 mmol, 1 equiv.) in acetonitrile (13 mL) was treated with N,N-diisopropylethylamine (1.2 mL, 6.4 mmol, 3 equiv.) and 5-azaspiro[2.3]hexane hydrochloride (0.30 g, 2.5 mmol, 1.1 equiv.) at 60 °C overnight. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was then azeotroped with heptane (20 mL) and dried under vacuum at 40 °C for 2 h to give a yellow solid (0.57 g, 94%). LCMS m / z = 264 (M+H).

[0755] 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 equiv.) in 1,4-dioxane (3.0 mL) was heated at 100 °C with [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (51 mg, 70.0 μmol, 0.07 equiv.), potassium acetate (0.29 g, 3.0 mmol), and 1 equiv. of 1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II). ol, 3 equiv) and bis(pinacolato)diboron (508 mg, 2.0 mmol, 2 equiv) 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]palladium(II) dichloride (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 × 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 gel column) eluting with a gradient of 0-100% ethyl acetate in heptane to give a yellow oil (305 mg, 66%). LCMS m / z=605.2 (M+H).

[0756] 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 salt. Trifluoroacetic acid (3.2 mL) was added to a solution of the product from Step 8 (320 mg) in dichloromethane (3.2 mL) at room temperature. After stirring for 4 h at room temperature, the volatiles were removed under reduced pressure, and the residue was purified on an Interchim automated chromatography system (RediSep Rf GOLD, 15 g HP C18 column) eluting with a gradient of 0% to 100% acetonitrile in water to afford the product (110 mg, trifluoroacetate salt, 34%) as a pale yellow solid. 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).

[0757] [ka]

[0758] Example 5. 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 equiv.) were added sequentially to a solution of 6-fluoro-1H-indazol-5-ol (9 g, 59 mmol, 1.0 equiv.) in N,N-dimethylformamide (59 mL) at 0 °C. After stirring at room temperature for 3 h, the mixture was diluted with ethyl acetate (120 mL) and washed with water (4 × 60 mL). 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). This material was used directly in the next step.

[0759] 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), and 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 over two steps). LCMS m / z=393.0 (M+H). This material was used directly in the next step.

[0760] 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 on a Biotage automated chromatography system (Biotage Sfaer HC, 200 g, silica gel) eluting with a gradient of 0-20% ethyl acetate in heptane to give a yellow oil (11.2 g, 56% yield over three steps). LCMS m / z = 477.1 (M+H).

[0761] 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 h, 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 on a Biotage automated chromatography system (Biotage Sfaer HC, 200 g, silica gel) eluting with a gradient of 0-10% methanol in dichloromethane to give a white solid (8.07 g, 95%). LCMS m / z=363.0 (M+H).

[0762] 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-pyridyl)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 on a Biotage automated chromatography system (Biotage Sfaer HC, 200 g, silica gel) eluting with a gradient of 0 to 100% ethyl acetate in heptane to give a white solid (3.0 g, 68%). LCMS m / z = M+H.

[0763] 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(pinacolato)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 minutes and then heated at 90 °C for 3 hours 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. After the mixture was cooled to room temperature, potassium carbonate (0.16 g, 1.1 mmol, 3 equiv.), water (1 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (32 mg, 0.04 mmol, 0.1 equiv.), and 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-3-iodo-1-tetrahydropyran-2-yl-indazole (0.20 g, 1 equiv.) 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 (3 × 20 mL). The combined organic layers were concentrated under reduced pressure onto silica gel (6 g). The residue was purified on a Biotage automated chromatography system (Sorbtech, 25 g silica gel column) eluting with a gradient of 0-50% ethyl acetate in heptane to give a tan solid (173 mg, 78%) after drying under vacuum at 40 °C overnight. LCMS m / z = 593 (M+H).

[0764] 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) eluting with a gradient of 0–5% 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, 19 × 250 mm) eluting with a gradient of 10–100% acetonitrile in water containing 0.1% trifluoroacetic acid to give an off-white solid (25 mg, 14%) that was the TFA salt after lyophilization. LCMS m / z=509(M+H);(free base);1H NMR(400 MHz,DMSO-d6)δ=13.23(s,1H),8.75(d,J=2.3 Hz,1H),8.60(s,2H),8.15(d,J=2.3 Hz,1H),7.47(d,J=10.9 Hz,1H),7.26(d,J=7.8 Hz,1H),6.18(q,J=6.6 Hz,1H),4.40(s,4H),1.80(d,J=6.7 Hz,3H),0.74(s,4H).

[0765] [ka]

[0766] 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 Step 1. tert-Butyl 3-(bromomethyl)-3-methyl-azetidine-1-carboxylate. To a solution of tert-butyl 3-(hydroxymethyl)-3-methyl-azetidine-1-carboxylate (500 mg, 2.50 mmol, 1.0 equiv.) and PPh3 (1.3 g, 4.97 mmol, 2.0 equiv.) in DCM (10.0 mL) was added CBr4 (1.6 g, 4.97 mmol, 2.0 equiv.) portionwise at 0 °C. 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 silica gel flash column chromatography (petroleum ether / EtOAc = 5 / 1) to give a brown solid (620 mg, 94% yield). LCMS m / z = 264.3 (M+H).

[0767] Step 2. tert-Butyl 3-(dimethylphosphorylmethyl)-3-methyl-azetidine-1-carboxylate. To a solution of methylphosphonoylmethane (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 under N2 protection. The reaction mixture was stirred at room temperature for 1 h. 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 under N2 protection and stirred for 4 h. After completion of the reaction, the reaction was quenched with saturated aqueous NH4Cl (20 mL) at 0 °C and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, and concentrated to give an off-white semi-solid (500 mg, 89% yield). LCMS m / z = 262.3 (M+H).

[0768] 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 hours. The mixture was concentrated to give a yellow oil, the TFA salt. LCMS m / z = 162.3 (M+H).

[0769] Step 4. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-[3-(dimethylphosphorylmethyl)-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)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) were added with DIEA (240 mg, 1.86 mmol, 5.0 equiv.). The reaction mixture was stirred at 90 °C for 16 h. After the reaction was completed, the reaction mixture 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, 50% yield). LCMS m / z = 653.2 (M+H).

[0770] 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 the reaction was complete, the reaction mixture was concentrated in vacuo. The pH of the residue was adjusted to 7-8 with saturated NaHCO3 solution and extracted with DCM (10 mL × 3). The combined organic layers were concentrated in vacuo. The crude product was purified by preparative HPLC (preparative C18, 5 μM Triart column, 20 × 150 mm, YMC-Actus, gradient elution from 15% MeCN in water with 0.05% NH3.HO to 30% MeCN in water over 11 min to give a white solid (58 mg, 61% yield). LCMS m / z = 569.4 (M + H); 1H NMR (400 MHz, DMSO-d6) δ 13.17 (brs, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.57 (s, 2H), 8.13 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.10 (dd, J = 8.8 Hz, 2H). Hz,1H),6.13(q,J=6.8 Hz,1H),4.27(d,J=8.4 Hz,2H),4.03(d,J=8.8 Hz,2H),2.23(d,J=10.8 Hz,2H),1.75(d,J=6.8 Hz,3H),1.56(s,3H),1.46(s,3H),1.43(s,3H).

[0771] [ka]

[0772] Example 8 Step 1. 1-Benzhydryl-3-methylazetidin-3-yl methanesulfonate. Methanesulfonyl chloride (6.2 mL, 80 mmol, 2 equiv.) was added dropwise to a solution of 1-benzhydryl-3-methyl-azetidin-3-ol (10.13 g, 40 mmol, 1 equiv.) and triethylamine (14.0 mL, 100 mmol, 2.5 equiv.) in anhydrous dichloromethane (150 mL) at 0 °C. After stirring at 0-5 °C for 6 h, water (50 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 50 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 gel column) eluting with a gradient of 0-40% ethyl acetate in heptane to give a white solid (4.63 g, 35% yield). LCMS m / z=332 (M+H).

[0773] Step 2. 1-Benzhydryl-N-isopropyl-3-methylazetidin-3-amine dihydrochloride. A mixture of 1-benzhydryl-3-methylazetidin-3-yl methanesulfonate (4.14 g, 12.491 mmol, 1 equiv.) and isopropylamine (6.44 mL, 75 mmol, 6 equiv.) in 2-MeTHF (60 mL) was heated at 80 °C for 24 h in a sealed pressure bottle. LCMS analysis indicated 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, and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether (100 mL), and 2 M HCl in diethyl ether (40 mL, 80 mmol) was added. After stirring at room temperature for 30 min, the resulting solid was filtered and dried under vacuum at 40 °C overnight to give the diHCl salt (4.36 g, 95% yield) as a white solid. LCMS m / z=295 (free base) (M+H).

[0774] Step 3. N-Isopropyl-3-methylazetidin-3-amine dihydrochloride. A mixture of 1-benzhydryl-N-isopropyl-3-methylazetidin-3-amine dihydrochloride (4.36 g, 11.863 mmol, 1 equiv.) and 20% palladium hydroxide (0.87 g, 50% wet) in methanol (440 mL) was hydrogenated at 50 psi and room temperature for 16 hours. The mixture was filtered through Celite and washed with methanol (3 × 40 mL). The filtrate was concentrated under reduced pressure, and the residue was triturated with heptane (5 × 20 mL) to remove the by-product diphenylmethane. The residue was dried under vacuum at 40 °C to give a yellow solid containing a small amount of diphenylmethane by-product (2.58 g, >100% yield). LCMS m / z = 129 (free base) (M+H).

[0775] Step 4. 5-Bromo-2-(3-(isopropylamino)-3-methylazetidin-1-yl)nicotinonitrile. N,N-Diisopropylethylamine (1.74 mL, 10 mmol, 5 equiv.) was added to a mixture of N-isopropyl-3-methylazetidin-3-amine dihydrochloride (0.402 g, 2 mmol, 1 equiv.) in acetonitrile (10 mL). After stirring at room temperature for 10 min, 5-bromo-2-chloro-3-cyano-pyridine (0.435 g, 2 mmol, 1 equiv.) was added, and the mixture was stirred at room temperature over the weekend. The mixture was pre-absorbed onto Celite (10 g) under reduced pressure and purified on an Interchim automated chromatography system (RediSep Rf GOLD, 100 g HP C18 column) eluting with a gradient of 0–100% acetonitrile in water to give a yellow solid (0.36 g, 58% yield). LCMS m / z=310 (M+H).

[0776] 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 equiv.), bis(pinacolato)diboron (0.443 g, 1.746 mmol, 1.5 equiv.), potassium acetate (0.228 g, 2.328 mmol, 2 equiv.), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (85 mg, 0.116 mmol, 0.1 equiv.) in 1,4-dioxane (15 mL) was sparged with nitrogen for 15 minutes and then heated at 90 °C for 16 hours. LCMS analysis indicated the reaction was complete with a mixture of borane and boronic acid. 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).

[0777] 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 equiv.) 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 equiv.), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.05 mmol, 0.1 equiv.), potassium carbonate (0.108 g, 0.784 mmol, 2 equiv.), 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 x 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) eluting with a gradient of 0 to 10% methanol in dichloromethane to give a brown solid (0.250 g, 85% purity, 98% yield over two steps). LCMS m / z = 650 (M+H).

[0778] 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 dissolved in 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 0–100% acetonitrile in water to give a white solid as the 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).

[0779] [ka]

[0780] Example 9. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[3-methyl-3-(methylamino)azetidin-1-yl]pyridine-3-carbonitrile Step 1. tert-Butyl (1-(5-bromo-3-cyanopyridin-2-yl)-3-methylazetidin-3-yl)(methyl)carbamate. A mixture of 5-bromo-2-chloro-pyridine-3-carbonitrile (326 mg, 1.5 mmol, 1.0 equiv), tert-butyl N-methyl-N-(3-methylazetidin-3-yl)carbamate 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 h, 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 (2 × 50 mL). The combined organic layers were washed with saturated brine (30 mL), dried over magnesium sulfate, filtered, concentrated, and dried under vacuum at 50° C. for 16 hours to give a yellow oil (460 mg, 80% yield). LCMS m / z=381 (M+H).

[0781] 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(pinacolato)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 to 90 °C. After 15 h, 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 (35 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 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 (50 g Biotage, 20 μm silica gel column) eluting with a gradient of 0 to 60% ethyl acetate in heptane to give a pale yellow oil (110 mg, 38% yield). LCMS m / z=722 (M+H).

[0782] Step 3. (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(3-methyl-3-(methylamino)azetidin-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 h, the reaction mixture was cooled to 0 °C and quenched with saturated sodium bicarbonate (50 mL). The mixture was extracted with dichloromethane (2 × 15 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, 100 g HP C18 column) eluting with a gradient of 0–100% 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).

[0783] [ka]

[0784] Example 10. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[3-(dimethylamino)-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile 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 equiv.) in acetonitrile (15 mL) was treated with N,N-3-trimethylazetidin-3-amine HCl (0.5 g, 2.67 mmol, 1.1 equiv.) and N,N-diisopropylethylamine (0.94 g, 7.28 mmol, 3 equiv.) at 60 °C. After 13 h, 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 (2 × 50 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).

[0785] 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 equiv.) in 1,4-dioxane (3.0 mL) was treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (51 mg, 70.0 μmol, 0.07 equiv.), potassium acetate (0.29 g, 3.0 mmol, 3 equiv.), and bis(pinacolato)diboron (508 mg, 2.0 mmol, 2 equiv.) at 100 °C for 3 h. LCMS analytically acceptable product. Subsequently, additional 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (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-pyridyl)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 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 × 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 gel 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).

[0786] 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 salt. Trifluoroacetic acid (3.0 mL) was added to a solution of the product from Step 2 (300 mg) in dichloromethane (3.0 mL) at room temperature. After stirring for 3 h at room temperature, the volatiles were removed under reduced pressure. The residue was purified on an Interchim automated chromatography system (RediSep Rf GOLD, 15 g HP C18 column) eluting with a gradient of 0 to 100% acetonitrile in water to give a pale yellow solid (95 mg, trifluoroacetate salt, 33% yield). LCMS m / z=552.1(M+H);1H NMR(400 MHz,DMSO-d6)δ=13.04(br s,1H),10.63(br s,1H),8.78(d,J=2.2 Hz,1H),8.59(s,2H),8.20(d,J=2.3 Hz,1H),7.06(s,1H),7.03(s,1H),6.03-5.97(m,1H),4.51(br d,J=10.1 Hz,2H),4.26(d,J=10.0 Hz,2H),3.87(s,3H),2.80(br s,6H),1.77(d,J=6.6 Hz,3H),1.68(s,3H).

[0787] [ka]

[0788] Example 14. 2-[3-(Cyclopropylmethylamino)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]pyridine-3-carbonitrile Step 1. To a solution of [1-[3-cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridyl]-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 hours. After the reaction was complete, EtOAc (20 mL) was added to the mixture, and the organic layer was washed with brine (20 mL x 2), dried over Na SO , and concentrated 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).

[0789] Step 2. 2-[3-(Cyclopropylmethylamino)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]pyridine-3-carbonitrile. To a solution of the product from Step 1 (190 mg, 0.29 mmol, 1.0 equiv) 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 solid NaHCO3 was added to the solution and stirred for 20 min. 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, both solvents containing 0.05% NH3·H2O) to give a white solid (54 mg, 32% yield). LCMS m / z=578.30(M+H);1H NMR(400 MHz,DMSO-d6)δ 12.96(brs,1H),8.71(d,J=2.0 Hz,1H),8.59(s,2H),8.06(d,J=2 Hz,1H),7.03(s,1H),7.00(s,1H),6.00(q,J=6.4 Hz,1H),4.14(d,J=8.4 Hz,2H),4.02(d,J=8.4 Hz,2H),3.86(s,3H),2.42(d,J=6.4 Hz,2H),1.76(d,J=6.4 Hz,3H),1.43(s,3H),0.93-0.82(m,1H),0.44-0.38(m,2H),0.17-0.14(m,2H).

[0790] Example 15. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-(3-methyl-3-pyrrolidin-1-yl-azetidin-1-yl)pyridine-3-carbonitrile [ka]

[0791] To a solution of [1-[3-cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridyl]-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 the reaction was complete, the mixture was diluted with EtOAc (100 mL) and washed with brine (20 mL × 5). The organic layer was dried over Na SO and concentrated. The crude product was purified by preparative TLC (DCM / MeOH=20 / 1) to give a yellow solid (120 mg, 42% yield). LCMS m / z=662.1 (M+H).

[0792] Step 2. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)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 from Step 1 (120 mg, 0.18 mmol, 1.0 equiv) in DCM (4 mL) was added TFA (2 mL). The solution was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated in vacuo. The crude product was basified with saturated NaHCO3 solution and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC (preparative C18, 5 μM Triart column, 20 × 150 mm, YMC-Actus, gradient elution of 40% to 50% MeCN in water (containing 0.05% NH₃·H₂O) over 15 min to give a pale yellow solid (55 mg, 53% yield). LCMS m / z = 578.3 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ 12.97 (brs, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.59 (s, 2H), 8.07 (d, J = 2.4 Hz, 1H), 7.04 (s, 1H), 7.00 (s, 1H), 6.00 (q, J = 6.4 Hz,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=6.4 Hz,3H),1.74-1.68(m,4H),1.45(s,3H).

[0793] [ka]

[0794] 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 Step 1. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)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-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridyl]-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 × 2) and brine (50 mL × 2), dried over Na SO , 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).

[0795] 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 in vacuo. The crude product was treated with DCM / MeOH (V:V=5:1, 20 mL), solid NaHCO was added, and stirred for 30 min. 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 60% MeCN in water with 0.05% NH3.HO over 10 min to give a yellow solid (47 mg, 34% yield). LCMS m / z = 548.2 (M + H); 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.57 (s, 2H), 8.14 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.11 (dd, J = 8.8 Hz, 2H). Hz,1H),6.14(q,J=6.4 Hz,1H),4.30(d,J=8.8 Hz,2H),3.99(d,J=8.8 Hz,2H),2.69-2.59(m,4H),1.79-1.70(m,7H),1.45(s,3H).

[0796] [ka]

[0797] Example 27. 2-[3-(cyclopropylmethylamino)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyridine-3-carbonitrile 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-pyridyl)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 (3 × 50 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 gel 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).

[0798] Step 2. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)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 KCO (2.66 g, 19.30 mmol, 1.0 equiv.) and Pd(dppf)Cl (705 mg, 0.965 mmol, 0.1 equiv.) at 25° C. The resulting mixture was stirred at 90° C. under N for 2 h. After cooling to room temperature, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. 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).

[0799] Step 3. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)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-pyridyl)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 hours, cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. 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).

[0800] Step 4. [1-[3-Cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridyl]-3-methyl-azetidin-3-yl]methanesulfonate. To a solution of the product from Step 3 (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 h 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).

[0801] Step 5. 2-[3-(Cyclopropylmethylamino)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)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 stirred at 90 °C for 12 h under N2. After cooling to room temperature, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. 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).

[0802] Step 6. 2-[3-(Cyclopropylmethylamino)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)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) at room temperature and stirred for 3 h. Upon completion, the reaction was concentrated in vacuo. The crude product was treated with DCM / MeOH (5:1, 10 mL), and solid NaHCO was added to the solution and stirred for 20 min. The solid was filtered, and the filtrate was concentrated. 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(400 MHz,DMSO-d6)δ 13.17(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=6.8 Hz,1H),4.14(d,J=8.8 Hz,2H),4.03(d,J=8.4 Hz,2H),2.41(d,J=7.2 Hz,2H),1.76(d,J=6.4 Hz,3H),1.42(s,3H),0.90-0.83(m,1H),0.44-0.38(m,2H),0.17-0.13(m,2H).

[0803] [ka]

[0804] Example 34. Step 1. 4-(1-Benzhydryl-3-methyl-azetidin-3-yl)morpholine. To a solution of (1-benzhydryl-3-methyl-azetidin-3-yl)methanesulfonic acid (880 mg, 2.65 mmol, 1.0 equiv.) and morpholine (692 mg, 7.95 mmol, 3.0 equiv.) in MeCN (10 mL) was added CsCO (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 × 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).

[0805] 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, charged with hydrogen three times, and stirred under a H2 balloon 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 product). This material was used directly in the next step. LCMS m / z = 157.3 (M+H).

[0806] Step 3. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-(3-methyl-3-morpholino-azetidin-1-yl)pyridine-3-carbonitrile. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)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).

[0807] Step 4. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-(3-methyl-3-morpholino-azetidin-1-yl)pyridine-3-carbonitrile. To a solution of the product from Step 3 (290 mg, 0.45 mmol, 1.0 equiv.) in DCM (5 mL) was added TFA (1 mL) and stirred at 25 °C for 3 h. After the reaction was complete, the reaction mixture was concentrated in vacuo. The pH of the crude product was adjusted to 7-8 by adding saturated NaHCO3 solution and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated. The crude product was purified by preparative HPLC (preparative C18, 5 μM Triart column, 20 × 150 mm, YMC-Actus, gradient elution from 35% MeCN in water with 0.05% NH3.H2O to 60% MeCN in water over 11 min) to give a white solid (151 mg, 60% yield). LCMS m / z=564.3(M+H);1H NMR(400 MHz,DMSO-d6)δ 13.18(s,1H),8.76(d,J=2.4 Hz,1H),8.57(s,2H),8.15(d,J=1.6 Hz,1H),7.49(d,J=8.8 Hz,1H),7.15(s,1H),7.10(dd,J=9.2 Hz,2.0 Hz,1H),6.14(q,J=6.4 Hz,1H),4.12(d,J=8.8 Hz,2H),3.98(d,J=8.4 Hz,2H),3.67-3.57(m,4H),2.47-2.40(m,4H),1.76(d,J=6.4 Hz,3H),1.35(s,3H).

[0808] [ka]

[0809] Example 37. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[3-(2-methoxyethylamino)-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile 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-methylazetidin-1-yl)pyridine-3-carbonitrile (1.724 g, 6.43 mmol, 1 equiv.), bis(pinacolato)diboron (2.45 g, 9.645 mmol, 1.5 equiv.), potassium acetate (1.26 g, 12.86 mmol, 2 equiv.), and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.47 mg, 0.643 mmol, 0.1 equiv.) in 1,4-dioxane (10 mL) was sparged with nitrogen for 15 min and then heated at 90 °C for 17 h. LCMS analysis showed the reaction was complete and was then used in the next step: LCMS m / z=234 (boronic acid) and 316 (M+H).

[0810] 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. A mixture of the reactant from Step 1 (6.43 mmol, 1.5 equiv.) in 1,4-dioxane was treated with 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-6-methoxy-1-tetrahydropyran-2-yl-indazole (2.35 g, 4.287 mmol, 1 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (314 mg, 0.429 mmol, 0.1 equiv.), potassium carbonate (1.18 g, 8.573 mmol, 2 equiv.), 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 (3 × 30 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) eluting with a gradient of 0 to 100% ethyl acetate in heptane to give a brown solid (1.77 g, 68% yield over two steps). LCMS m / z = 610 (M+H).

[0811] 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 equiv) was added to a suspension of the product of Step 2 (1.77 g, 2.904 mmol, 1 equiv) 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 equiv) was added, and the mixture was stirred at room temperature for 2.5 hours. LCMS analysis indicated the reaction was complete. Water (50 mL) was added, and the layers were separated. The aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified on an Interchim automated chromatography system (Sorbtech, 120 g silica gel column) eluting with a gradient of 0 to 100% ethyl acetate in heptane to give a white foam (1.40 g, 70% yield). LCMS m / z = 687 (M+H).

[0812] 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 equiv), 2-methoxyethan-1-amine (163 mg, 2.2 mmol, 5 equiv), and sodium tert-butoxide (125 mg, 1.53 mmol, 3 equiv) in acetonitrile (5 mL) was heated at 60 °C for 16 h. After cooling to room temperature, the mixture was diluted with water (1 mL) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL) and washed with saturated sodium carbonate (10 mL). LCMS m / z=666.3 (M+H).

[0813] 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 bicarbonate (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) eluting with a gradient of 0 to 100% acetonitrile in water. After lyophilization, the product was obtained as an off-white solid (56 mg, 42% yield). LCMS m / z=582.2(M+H);1H NMR(400 MHz,DMSO-d6)δ=12.96(br s,1H),8.71(d,J=2.3 Hz,1H),8.59(s,2H),8.05(d,J=2.3 Hz,1H),7.04(s,1H),7.01(s,1H),5.99(q,J=6.7 Hz,1H),4.11(d,J=8.8 Hz,2H),4.03(d,J=8.7 Hz,2H),3.86(s,3H),3.44-3.34(m,2H),3.28-3.25(m,3H),2.70(q,J=6.1 Hz,2H),2.48-2.27(m,1H),1.76(d,J=6.6 Hz,3H),1.45-1.36(m,3H).

[0814] [ka]

[0815] 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 Step 1. 3-(2-Chloropyrimidin-5-yl)-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazole. To a solution of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (4.0 g, 7.72 mmol, 1.0 equiv.) in dioxane (100 mL) and HO (10 mL) was 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.), KCO (3.2 g, 23.16 mmol, 3.0 equiv.), and Pd(dppf)Cl (565 mg, 0.772 mmol, 0.1 equiv.) at 25 °C. The resulting mixture was stirred at 90 °C under N for 3 h. After cooling to room temperature, the mixture was concentrated in vacuo. 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).

[0816] Step 2. 1-[5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]pyrimidin-2-yl]-3-methyl-azetidin-3-ol. To a solution of the product from Step 1 (3.2 g, 6.34 mmol, 1.0 equiv.) in DMSO (30 mL) was added 3-methylazetidin-3-ol (940 mg, 7.61 mmol, 1.2 equiv.) and DIEA (2.45 g, 19.02 mmol, 3.0 equiv.), and the mixture was stirred at 100 °C under N for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (200 mL) and washed with water (100 mL × 2). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a yellow oil (2.7 g). This material was used directly in the next step: LCMS m / z=555.3 (M+H).

[0817] Step 3. [1-[5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]pyrimidin-2-yl]-3-methyl-azetidin-3-yl]methanesulfonate. To a solution of the product of Step 2 (2.7 g, crude) 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. Upon completion, the reaction was concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum ether / EtOAc = 3 / 1) to give a yellow solid (2.5 g, 63% yield for two steps). LCMS m / z = 633.2 (M+H).

[0818] Step 4. 4-[1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]pyrimidin-2-yl]-3-methyl-azetidin-3-yl]morpholine

[0819] To a solution of the product of Step 3 (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 in vacuo. 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).

[0820] 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 NaHCO3 was added to the solution until pH 8 and stirred for 20 min. The solid was filtered 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 35% MeCN in water with 0.05% NH3.HO to 65% MeCN in water over 10 min to give a white solid (36 mg, 28% yield). LCMS m / z = 540.3 (M + H); 1H NMR (400 MHz, DMSO-d6) δ 13.13 (brs, 1H), 8.78 (s, 2H), 8.57 (s, 2H), 7.47 (d, J = 9.2 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.10 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.15 (q, J = 6.4 Hz, 1H), 3.94 (d, J = 8.4 Hz, 1H). Hz,2H),3.76(d,J=8.4 Hz,2H),3.61(t,J=4.0 Hz,4H),2.44(t,J=4.0 Hz,4H),1.75(d,J=6.4 Hz,3H),1.32(s,3H).

[0821] [ka]

[0822] (R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol and (S)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol 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 portionwise, and the mixture was stirred at -70 °C for 1 h. The reaction was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate (200 mL x 3), dried over NaSO, and concentrated. The residue was purified on a silica gel column (PE / EA = 30 / 1) to give a yellow liquid (33 g, 77%). LCMS m / z = 227 (M+H).

[0823] Step 2. 1-(3,5-Dichloro-2-methyl-4-pyridyl)ethanol. A mixture of the product from Step 1 (33 g, 0.147 mmol), methylboronic acid (26.3 g, 0.429 mmol), K2CO3 (40 g, 0.290 mmol), and Pd(PPh3)2Cl2 (3 g) in dioxane (300 mL) was stirred at 110 °C overnight. The resulting mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product, which was further purified by silica gel column chromatography to give a yellow liquid (15 g, 50%). LCMS m / z = 206.1 (M+H). The products were separated by preparative HPLC (Chiralpak ID 5 × 25 cm, hexane / ethanol (80 / 20), 60 mL / min, 38 °C) to give (S)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol (5 g) and (R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol (5 g) as yellow liquids. Peak 15.5 min. (S)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol. LCMS m / z = 206.1 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 5.57 (m, 1H), 2.93 (b, 1H), 2.64 (s, 3H), 1.65 (d, 3H). Peak 26.9 min; (R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol. LCMS m / z = 206.1 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 5.57 (m, 1H), 2.93 (b, 1H), 2.64 (s, 3H), 1.65 (d, 3H).

[0824] [ka]

[0825] Example 46. Step 1. 1-Benzhydryl-3-cyclobutoxy-3-methylazetidine. In a sealed tube, a solution of 1-benzhydryl-3-methylazetidin-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).

[0826] 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 4 M HCl in 1,4-dioxane (3.9 mL, 15.63 mmol, 4.0 equiv) at room temperature for 16 h. 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).

[0827] 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 50 psi and room temperature 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).

[0828] Step 4. 5-Bromo-2-(3-cyclobutoxy-3-methylazetidin-1-yl)nicotinonitrile. A solution of 5-bromo-2-chloro-3-cyanopyridine (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 h. 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) eluting with a gradient of 0 to 50% ethyl acetate in heptane. Product-containing fractions were pooled together and concentrated to dryness under reduced pressure, and the residue was dried under vacuum at 50 °C for 16 h to give a light brown oil (344 mg, 36% yield). LCMS m / z = 322.2 (M+H).

[0829] Step 5. (S)-1-(3,5-Dichloro-2-methylpyridin-4-yl)ethyl methanesulfonate. Methanesulfonyl chloride (1.35 mL, 17.5 mmol, 1.2 equiv.) was added to a solution of compound (S)-263-1 (3 g, 14.6 mmol, 1 equiv.) and triethylamine (4 mL, 29.1 mmol, 2 equiv.) in anhydrous dichloromethane (30 mL) at -10 °C. After 2 h, 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 (3 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude yellow oil was adsorbed onto Celite (20 g) and purified on an Interchim automated chromatography system (Sorbtech, 100 g silica gel column) eluting with a gradient of 0-100% methyl tert-butyl ether and heptane to give the compound as a white solid (4.04 g, 96%): LCMS m / z = 284.1 (M+H).

[0830] 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 the compound 3-iodo-1-tetrahydropyran-2-yl-indazol-5-ol (5.38 g, 15.6 mmol, 1.1 equiv.), (S)-1-(3,5-dichloro-2-methylpyridin-4-yl)ethyl methanesulfonate (4.04 g, 14.2 mmol, 1 equiv.), and cesium carbonate (9.27 g, 28.5 mmol, 2 equiv.) 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 (3 x 30 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) eluting with a gradient of 0 to 100% ethyl acetate in heptane to give a white solid (6.5 g, 86%). LCMS m / z = 532.1 (M+H).

[0831] 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(pinacolato)diboron (400 mg, 1.6 mmol, 1.5 equiv), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (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 showed 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]palladium(II) dichloride (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) eluting with a gradient of 0-20% ethyl acetate in heptane. Product-containing fractions were pooled together and concentrated to dryness under reduced pressure. The resulting residue was dried under vacuum at 50 °C for 16 h to give compound 585-3 (149 mg, 25% yield) as a light brown solid. LCMS m / z = 650.1 (M+H).

[0832] 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 h. The volatiles were removed under reduced pressure. The residue was diluted with dichloromethane (5 mL) and 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 Celite (10 g). This material was purified on a Büchi automated chromatography system (RediSep C18, 100 g column) eluting with a gradient of 0 to 80% acetonitrile in water. Fractions containing the product were pooled together and 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);1H NMR(400 MHz,DMSO-d6)δ=13.18(s,1H),8.70(d,J=2.2 Hz,1H),8.41(s,1H),8.16(d,J=2.2 Hz,1H),7.49(d,J=8.9 Hz,1H),7.11(dd,J=2.3,9.0 Hz,1H),7.07(s,1H),6.10(q,J=6.7 Hz,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=6.7 Hz,3H),1.61(q,J=10.0 Hz,1H),1.50(s,3H),1.49-1.39(m,1H).

[0833] [ka]

[0834] Example 47. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[3-(2-hydroxyethylamino)-3-methyl-azetidin-1-yl]pyridine-3-carbonitrile Step 1. (1-Benzhydryl-3-methyl-azetidin-3-yl) methanesulfonate. To a solution of 1-benzhydryl-3-methyl-azetidin-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.), followed by the dropwise addition of MsCl (3.2 g, 27.6 mmol, 1.4 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the mixture was diluted with DCM (50 mL) and washed with brine (30 mL × 3). The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 3 / 1) to give a white solid (3.5 g, 54% yield). LCMS m / z = 332.3 (M+H).

[0835] Step 2. 2-[(1-benzhydryl-3-methyl-azetidin-3-yl)amino]ethanol. To a solution of (1-benzhydryl-3-methyl-azetidin-3-yl)methanesulfonate (1.5 g, 4.5 mmol, 1.0 equiv.) in CH3CN (15 mL) was added 2-aminoethanol (1.4 g, 22.6 mmol, 5.0 equiv.) and Cs2CO3 (4.5 g, 13.6 mmol, 3.0 equiv.) at room temperature. 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% yield). LCMS m / e = 297.3 (M+H).

[0836] Step 3. 2-[(3-Methylazetidin-3-yl)amino]ethanol. 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) portionwise under N. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred at room temperature under a H balloon for 16 h. The solid was filtered off, and the filtrate was concentrated to give a colorless oil. LCMS m / e=131.3 (M+H).

[0837] 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 equiv.) and bis(pinacolato)diboron (25.3 g, 99.5 mmol, 2.0 equiv.) in dioxane (200 mL) was added KOAc (20.6 g, 149.3 mmol, 3.0 equiv.) and Pd(dppf)Cl (2.0 g, 20 wt%). The reaction mixture was stirred at 90 °C under N protection for 5 h. 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)δ 8.68(d,J=1.6 Hz,1H),8.63(dd,J=9.2 Hz,1.6 Hz,1H),1.32(s,12H).

[0838] Step 5. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-fluoro-pyridine-3-carbonitrile. To a solution of 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-pyridyl)ethoxy]-3-iodo-6-methoxy-1-tetrahydropyran-2-yl-indazole (1.0 g, 1.8 mmol, 1.0 equiv.) in dioxane (20 mL) and HO (2 mL) was added KCO (745 mg, 5.4 mmol, 3.0 equiv.) and Pd(dppf)Cl (100 mg, 10 wt%) at room temperature. The mixture was stirred at 90 °C for 2 h under N 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).

[0839] Step 6. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)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 from Step 4 (150 mg, 0.28 mmol, 1.0 equiv.) and 2-[(3-methylazetidin-3-yl)amino]ethanol (54 mg, 0.41 mmol, 1.5 equiv.) in DMSO (2 mL) was added DIEA (178 mg, 1.38 mmol, 5.0 equiv.). The reaction mixture was stirred at 90 °C for 16 h. After the reaction was complete, the mixture was diluted with EtOAc (30 mL) and washed with brine (20 mL × 3). The organic layer was dried over Na SO 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).

[0840] Step 7. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)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 from Step 5 (110 mg, 0.17 mmol, 1.0 equiv) in DCM (6 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 5 hours and concentrated in vacuo. The crude product was treated with DCM / MeOH (15 mL, V:V = 5 / 1), then NaHCO3 (excess) was added to the solution. After stirring at room temperature for 20 minutes, 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(400 MHz,DMSO-d6)δ12.98(s,1H),8.73(d,J=2.0 Hz,1H),8.59(s,2H),8.09(d,J=2.0 Hz,1H),7.03(s,1H),7.01(s,1H),6.00(q,J=6.4 Hz,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=6.8 Hz,3H),1.49(s,3H).

[0841] [ka]

[0842] 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 Step 1. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)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-pyridyl)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 hours. After the reaction was complete, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with brine, dried over Na SO , 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).

[0843] Step 2. 2-[3-(Aminomethyl)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]pyridine-3-carbonitrile. To a solution of 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)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).

[0844] Step 3. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)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 from Step 2 (200 mg, 0.37 mmol, 1.0 equiv.) and HCl (221 mg, 1.85 mmol, 5.0 equiv., 37% aqueous solution) in DCE (4 mL) was added NaBHCN (93 mg, 1.50 mmol, 4.0 equiv.) and AcOH (2.4 mg, 0.04 mmol, 0.1 equiv.). The reaction mixture was stirred at room temperature for 3 h, poured into saturated aqueous NaHCO (10 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a yellow solid (130 mg). LCMS m / z=596.1 (M+H).

[0845] 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 A solution of the product of Step 3 (100 mg, 0.17 mmol, 1.0 equiv) in NH3 / MeOH (3 mL) was stirred at room temperature for 4 h. After the reaction was complete, the reaction mixture was poured into water (10 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. 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, gradient elution from 50% MeCN in water with 0.05% NH₃·H₂O to 80% MeCN in water over 10 min to give a white solid (19 mg, 33% yield). LCMS m / z = 566.3 (M + H); 1H NMR (400 MHz, DMSO-d₆) δ 12.97 (s, 1H), 8.71 (d, J = 2.8 Hz, 1H), 8.59 (s, 2H), 8.06 (d, J = 2.4 Hz, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 6.00 (q, J = 6.8 Hz,1H),4.07(d,J=8.4 Hz,2H),3.98(d,J=8.8 Hz,2H),3.86(s,3H),3.28-3.32(m,2H),2.18(s,6H),1.76(d,J=6.8 Hz,3H),1.38(s,3H).

[0846] [ka]

[0847] 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 To a solution of 2-[3-(aminomethyl)-3-methyl-azetidin-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)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) (318 mg, 1.50 mmol, 4.0 equiv.) and AcOH (2.4 mg, 0.04 mmol, 0.1 equiv.). The reaction mixture was stirred at room temperature for 2 hours, poured into saturated aqueous NaHCO (10 mL), and extracted with DCM (20 mL × 3). The combined organic layer was washed with brine, dried over NaSO, 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(400 MHz,DMSO- d6)δ 12.99(s,1H),8.71(d,J=2.4 Hz,1H),8.59(s,2H),8.06(d,J=2.4 Hz,1H),7.03(s,1H)7.01(s,1H),6.01(q,J=7.2 Hz,1H),4.17(d,J=8.4 Hz,2H),3.92(d,J=8.0 Hz,2H),3.86(s,3H),3.21-3.32(2H),2.93-2.80(m,1H),1.76(d,J=6.8 Hz,3H),1.35(s,3H),1.10(s,6H).

[0848] [ka]

[0849] Example 52. 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 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 solution of [1-[3-cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl-2-pyridyl]-3-methyl-azetidin-3-yl]methanesulfonate (290 mg, 0.44 mmol, 1.0 equiv.), 2-[tert-butyl(dimethyl)silyl]oxyethanamine (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 h, 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 (2 × 10 mL). The combined organic layers were 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 gel column, 60 μM) eluting with a gradient of 0 to 80% ethyl acetate in hexanes to give a pale yellow solid (100 mg, 30% yield). LCMS m / z = 736 (M+H).

[0850] 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 from 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 h, 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 (15 mL). The mixture was extracted with dichloromethane (2 × 15 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 0–100% acetonitrile in water to give an off-white solid (36 mg, 49% yield) after lyophilization. LCMS m / z=538.1(M+H);1H NMR(400 MHz,CDCl3)δ=13.17(br s,1H),8.76(d,J=2.3 Hz,1H),8.58(s,2H),8.13(d,J=2.3 Hz,1H),7.49(d,J=9.0 Hz,1H),7.16(d,J=2.2 Hz,1H),7.10(dd,J=2.3,9.0 Hz,1H),6.14(q,J=6.7 Hz,1H),4.53(br s,1H),4.15-4.11(m,2H),4.07-4.04(m,2H),3.47(br t,J=5.6 Hz,2H),2.62(br d,J=5.1 Hz,2H),2.34-2.29(m,1H),1.76(d,J=6.7 Hz,3H),1.43(s,3H).

[0851] [ka]

[0852] 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 Step 1. tert-Butyl 3-(bromomethyl)-3-methyl-azetidine-1-carboxylate. To a solution of tert-butyl 3-(hydroxymethyl)-3-methyl-azetidine-1-carboxylate (200 mg, 1.0 mmol, 1.0 equiv) and PPh3 (521 mg, 1.99 mmol, 2.0 equiv) in DCM (5.0 mL) was added CBr4 (653 mg, 1.99 mmol, 2.0 equiv) portionwise at 0 °C. 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 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).

[0853] Step 2. tert-Butyl 3-(dimethylphosphorylmethyl)-3-methyl-azetidine-1-carboxylate. To a solution of methylphosphonoylmethane (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 under N2 protection. The reaction mixture was stirred at room temperature for 1 h. 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 under N2 protection and stirred for 4 h. After completion of the reaction, the reaction was quenched with saturated aqueous NH4Cl (10 mL) at 0 °C and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4 and concentrated to give an off-white oil (150 mg, 93% yield). LCMS m / z = 262.3 (M+H).

[0854] 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 hours. The mixture was concentrated to give a yellow oil, the TFA salt. LCMS m / z = 162.3 (M+H).

[0855] Step 4. 5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)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-pyridyl)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 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc (20 mL), washed with brine (20 mL×3), and concentrated. The crude product was purified by preparative TLC (DCM / MeOH=15 / 1) to give a yellow solid (105 mg, 56% yield). LCMS m / z=683.2 (M+H).

[0856] 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 the reaction was complete, the reaction mixture was concentrated in vacuo. The pH of the residue was adjusted to 7-8 with saturated NaHCO3 solution and extracted with DCM (10 mL × 3). The combined organic layers were concentrated in vacuo. The crude product was purified by preparative HPLC (preparative C18, 5 μM Triart column, 20 × 150 mm, YMC-Actus, gradient elution from 15% MeCN in water with 0.05% NH3.HO to 30% MeCN in water over 11 min to give a white solid (49 mg, 58% yield). LCMS m / z = 599.3 (M + H); 1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.59 (s, 2H), 8.06 (d, J = 2.4 Hz, 1H), 7.03 (s, 1H), 7.00 (s, 1H), 5.99 (q, J = 6.8 Hz, 1H), 4.27 (d, J = 8.4 Hz,2H),4.03(d,J=8.8 Hz,2H),3.85(s,3H),2.23(d,J=11.2 Hz,2H),1.76(d,J=6.8 Hz,3H),1.56(s,3H),1.46(s,3H),1.43(s,3H).

[0857] [ka]

[0858] 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 Step 1. 5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-3-(5,6-difluoro-3-pyridyl)-1-tetrahydropyran-2-yl-indazole. To a solution of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)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 KCO (3.60 g, 26.05 mmol, 3.0 equiv.) and Pd(dppf)Cl (708 mg, 0.87 mmol, 0.1 equiv.). The reaction mixture was stirred at 90 °C for 3 hours under N 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).

[0859] Step 2. 1-[5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-3-fluoro-2-pyridyl]-3-methyl-azetidin-3-ol. To a solution of the product from Step 1 (2.0 g, 3.96 mmol, 1.0 equiv) and 3-methylazetidin-3-ol (587 mg, 4.75 mol, 1.2 equiv) in DMSO (20 mL) was added DIEA (2.56 g, 19.79 mmol, 5.0 equiv). 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 mL × 3). The organic layer was dried over Na SO and concentrated. The crude product was purified by silica gel column (DCM / MeOH=40 / 1) to give a white solid (1.5 g, 66% yield). LCMS m / z=572.1 (M+H).

[0860] Step 3. [1-[5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-3-fluoro-2-pyridyl]-3-methyl-azetidin-3-yl]methanesulfonate. To a solution of the product from Step 2 (1.5 g, 2.61 mmol, 1.0 equiv.) and TEA (793 mg, 7.83 mmol, 3.0 equiv.) in DCM (20 mL) was added MsCl (449 mg, 3.92 mmol, 1.5 equiv.) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel column (DCM / MeOH=40 / 1) to give a white solid (1.4 g, 82% yield). LCMS m / z=650.2 (M+H).

[0861] Step 4. 4-[1-[5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-3-fluoro-2-pyridyl]-3-methyl-azetidin-3-yl]morpholine. To a solution of the product from Step 3 (200 mg, 0.31 mmol, 1.0 equiv.) and morpholine (2.70 g, 3.07 mmol, 10.0 equiv.) in MeCN (5 mL) was added t-BuONa (148 mg, 1.54 mmol, 5.0 equiv.) and DMAP (75 mg, 0.62 mmol, 2.0 equiv.). The reaction mixture was stirred at 80 °C for 16 h. The reaction was cooled to room temperature, diluted with EtOAc (50 mL), and washed with water (50 mL × 3). The organic layer was dried over Na SO and concentrated in vacuo. The crude product was purified by preparative TLC (DCM / MeOH=30 / 1) to give a yellow solid (70 mg, 36% yield). LCMS m / z=641.2 (M+H).

[0862] Step 5. 4-[1-[5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]-3-methyl-azetidin-3-yl]morpholine. To a solution of the product from Step 4 (70 mg, 0.11 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the solution was concentrated. The crude product was treated with aqueous NaHCO3 to adjust the pH to 7-8 and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by preparative HPLC (preparative C18, 5 μM Triart column, 20 × 150 mm, YMC-Actus, gradient elution from 40% MeCN in water with 0.05% NH3.HO to 50% MeCN in water over 6 min to give a white solid (20 mg, 34% yield). LCMS m / z = 557.3 (M + H); 1H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.57 (s, 2H), 8.36 (s, 1H), 7.71 (dd, J = 13.2 Hz, 1.2 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 1.6 Hz, 1H), 7.10 (dd, J = 8.8 Hz, 2.0 Hz,1H),6.14(q,J=6.4 Hz,1H),3.98(d,J=7.6 Hz,2H),3.81(dd,J=8.0 Hz,1.6 Hz,2H),3.61-3.59(m,4H),2.43-2.41(m,4H),1.76(d,J=6.8 Hz,3H),1.35(s,3H).

[0863] [ka]

[0864] Example 81 (R)-1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-3-fluoropyridin-2-yl)-N,N,3-trimethylazetidin-3-amine Step 1. 1-[5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-3-fluoro-2-pyridyl]-N,N,3-trimethyl-azetidin-3-amine. To a solution of [1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-3-fluoro-2-pyridyl]-3-methyl-azetidin-3-yl]methanesulfonate (300 mg, 0.46 mmol, 1.0 equiv.) and dimethylamine hydrochloride (752 mg, 9.22 mmol, 20.0 equiv.) in MeCN (5 mL) was added t-BuONa (1.11 g, 11.53 mmol, 25.0 equiv.). The reaction mixture was stirred at 80 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with EtOAc (30 mL), and washed with water (30 mL × 3). The organic layer was dried over Na SO and concentrated. The crude product was purified by preparative TLC (DCM / MeOH=30 / 1) to give a yellow solid (80 mg, 29% yield). LCMS m / z=599.3 (M+H).

[0865] Step 2. (R)-1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-3-fluoropyridin-2-yl)-N,N,3-trimethylazetidin-3-amine. To a solution of the product of Step 1 (80 mg, 0.11 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for ...

Claims

1. Compounds of formula (I), or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula, X = O, S, or NR, R is H or C １ -C ３ It is alkyl, n = 1 or 2, m = 1 or 2, 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, and R ９ is H or C １ -C ３ It is alkyl, R ２ H, and C may be substituted as desired. 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 And, R ３ is H or C １ -C ６ It is alkyl, R ４ H, and C may be substituted as desired. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenil, C ３ -C ５ Cycloalkyl, 3-6 member heterocycloalkyl, C(O)(CH ２ ) ２－３ OH or C(O)(CH ２ ) ０－３ NR ４ｄ R ４ｅ And, Or, R ３ and R ４ They both combine with the N atom to which they are bonded, and each is C １ -C ６ Alkyl, C １ -C ６ A 3- to 6-membered heterocycloalkyl group is formed, which may be optionally substituted with one or more substituents that are alkoxyl, F, or OH. Or, R ３ and R ４ These, together with the N atom to which they are both bonded, form a 6-8 membered bridging heterocycloalkyl ring system. R ４ａ H, and C may be substituted as desired. １ -C ６ Alkyl or C ３ -C ５ It is a cycloalkyl, R ４ｂ and R ４ｃ Each of them 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 bonded, they form a 4-6 membered heterocycloalkyl ring. R ４ｄ and R ４ｅ These are H or C, respectively, independently. １ -C ６ Alkyl or R ４ｄ and R ４ｅ These, together with the nitrogen atom to which they are both bonded, form a 4-6 membered heterocycloalkyl ring. Or, R １ and R ２ These, together with the carbon atoms to which they are bonded, form a 3- to 5-membered cycloalkyl ring. Q １ Q ２ Q ３ Q ４ One or two of them are N, and the rest are each independently CR ５ａ And, 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 It is alkyl, Q ５ 、Q ６ 、Q ７ 、Q ８ and Q ９ are each independently N or CR ５ wherein, Q ５ 、Q ６ 、Q ７ 、Q ８ and Q ９ one or two of which are N and the remainder are CR ５ wherein R ５ H, halogen, C １ -C ３ Alkyl, C １ -C ３ It is an alkoxyl or cycloalkyl, R ６ C １ -C ６ It is alkyl, R ７ H, halogen, -C １ -C ６ Alkyl, -C １ -C ６ It is an alkoxyl or cycloalkyl, R ８ H, halogen, -C １ -C ６ Alkyl, -C １ -C ６ (It is alkoxyl or cycloalkyl).

2. The compound of formula (I) is the compound of formula (IA), or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 (In the formula, Q ２ and Q ４ Each of these is either N or Q. ２ Or Q ４ One of them is N, and the other is CR ５ａ And, R ５ａ H, F, -SO ２ CH ３ or -CN, R ５ is H or CH ３ And, R ７ is H, F, or OCH ３ (is) The compound according to claim 1.

3. The compound of formula (IA) is the compound of formula (IA-1-1) below, or a pharmaceutically acceptable salt thereof, according to claim 2: 【Transformation 3】

4. The compound according to claim 2, wherein the compound of formula (IA) is the compound of formula (IA-2) below, or a pharmaceutically acceptable salt thereof: 【Chemistry 4】

5. The compound of formula (IA) is the compound of formula (IA-3-1) below, or a pharmaceutically acceptable salt thereof, according to claim 2: 【Transformation 5】

6. The compound of formula (IA) is the compound of formula (IA-4-1) below, or a pharmaceutically acceptable salt thereof, according to claim 2: 【Transformation 6】

7. The compound of formula (IA) is the compound of formula (IA-5) below, or a pharmaceutically acceptable salt thereof, according to claim 2: 【Transformation 7】

8. The compound of formula (IA) is the compound of formula (IA-6) below, or a pharmaceutically acceptable salt thereof, according to claim 2: 【Transformation 8】

9. The compound of formula (I) is the compound of formula (IB) below, or a pharmaceutically acceptable salt thereof: 【Chemistry 9】 (In the formula, R ５ａ (This is H, F, or -CN) The compound according to claim 1.

10. (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-3-(methylsulfonyl)pyridine-2-yl)-N,N,3-trimethylazetidine-3-amine; (R)-2-(3-(cyclobutylamino)-3-methylazetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(5-azaspiro[2.3]hexane-5-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-methyl-3-(oxetane-3-ylamino)azetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)-2-(5-azaspiro[2.3]hexane-5-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-((dimethylphosphoryl)methyl)-3-methylazetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-((1,1-dioxidethiethane-3-yl)amino)-3-methylazetidine-1-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]-2-[3-(isopropylamino)-3-methylazetidine-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]-2-[3-methyl-3-(methylamino)azetidine-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]-2-[3-(dimethylamino)-3-methylazetidine-1-yl]pyridine-3-carbonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)-2-(3-((dimethylphosphoryl)methyl)-3-methylazetidine-1-yl)nicotinonitrile; (R)-2-(3-(cyclobutylamino)-3-methylazetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-(3-isopropoxy-3-methylazetidine-1-yl)pyridine-3-carbonitrile; (R)-2-(3-((cyclopropylmethyl)amino)-3-methylazetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-methyl-3-(pyrrolidine-1-yl)azetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-methyl-3-morpholinoazetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-methyl-3-(pyrrolidine-1-yl)azetidine-1-yl)nicotinonitrile; (R)-N-((1-(3-cyano-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)methyl)methanesulfonamide; 2-[3-(cyclobutylamino)-3-methylazetidine-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]pyridine-3-carbonitrile; 5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-methyl-3-(((S)-tetrahydrofuran-3-yl)amino)azetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-((3,3-difluoropropyl)amino)-3-methylazetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-((2,2-difluoroethyl)amino)-3-methylazetidine-1-yl)nicotinonitrile; (R)-N-((1-(3-cyano-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)methyl)-N-methylmethanesulfonamide; 5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-methyl-3-(((S)-tetrahydrofuran-3-yl)amino)azetidine-1-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-methyl-3-(((R)-tetrahydrofuran-3-yl)amino)azetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3'-methyl-[1,3'-biazethidine]-1'-yl)nicotinonitrile; (R)-2-(3-((cyclopropylmethyl)amino)-3-methylazetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3'-methyl-[1,3'-biazethidine]-1'-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-(dimethylamino)-3-methylazetidine-1-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-[3-methyl-3-(oxetane-3-ylamino)azetidine-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-[3-(diethylamino)-3-methylazetidine-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-[3-methyl-3-(methylamino)azetidine-1-yl]pyridine-3-carbonitrile; 5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-methyl-3-(((R)-tetrahydrofuran-3-yl)amino)azetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-methyl-3-morpholinoazetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-(ethylamino)-3-methylazetidine-1-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-[3-(diethylamino)-3-methylazetidine-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]-2-[3-(2-methoxyethylamino)-3-methylazetidine-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-(3-methyl-3-morpholino-azetidine-1-yl)pyridine-3-carbonitride; 2-(3-amino-3-methylazetidine-1-yl)-5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-[3-(ethylamino)-3-methylazetidine-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]-2-[3-(3,3-difluoropropylamino)-3-methylazetidine-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]-2-[3-(2,2-difluoroethylamino)-3-methylazetidine-1-yl]pyridine-3-carbonitrile; (R)-4-(1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyrimidine-2-yl)-3-methylazetidine-3-yl)morpholine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyrimidine-2-yl)-N,N,3-trimethylazetidine-3-amine; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-[3-(dimethylamino)-3-methylazetidine-1-yl]pyridine-3-carbonitrile; 2-[3-(cyclobutoxy)-3-methylazetidine-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]-2-[3-(2-hydroxyethylamino)-3-methylazetidine-1-yl]pyridine-3-carbonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-(isopropylamino)-3-methylazetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-((dimethylamino)methyl)-3-methylazetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-((isopropylamino)methyl)-3-methylazetidine-1-yl)nicotinonitrile; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyrimidine-2-yl)-N,N,3-trimethylazetidine-3-amine; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-[3-(2-hydroxyethylamino)-3-methylazetidine-1-yl]pyridine-3-carbonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-((dimethylphosphoryl)methyl)-3-methylazetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-((2-hydroxy-2-methylpropyl)amino)-3-methylazetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-((2-hydroxy-2-methylpropyl)amino)-3-methylazetidine-1-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-(((R)-2-hydroxypropyl)amino)-3-methylazetidine-1-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-(((S)-2-hydroxypropyl)amino)-3-methylazetidine-1-yl)nicotinonitrile; 3-[6-(azetidine-1-yl)-5-fluoro-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-methoxy-1H-indazole; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-1H-indazole-3-yl]-2-pyridyl]-N,3-dimethylazetidine-3-amine; 3-[2-(5-azaspiro[2,3]hexane-5-yl)pyrimidine-5-yl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-(3,3-dimethylazetidine-1-yl)pyrimidine-5-yl]-6-methoxy-1H-indazole; 3-[2-(5-azaspiro[2,3]hexane-5-yl)pyrimidine-5-yl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole; (R)-N-cyclobutyl-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methyl-N-(oxetan-3-yl)azetidine-3-amine; 2-(5-azaspiro[2,3]hexane-5-yl)-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]pyridine-3-carbonitrile; 1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyridine-2-yl)-3-methyl-N-((S)-tetrahydrofuran-3-yl)azetidine-3-amine; (R)-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)methyl)dimethylphosphine oxide; N-cyclobutyl-1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-1H-indazole-3-yl]-2-pyridyl]-3-methylazetidine-3-amine; (R)-N-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)methyl)methanesulfonamide; 1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-3-methyl-N-(oxetan-3-yl)azetidine-3-amine; N-cyclobutyl-1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-3-methylazetidine-3-amine; 1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-N,N-diethyl-3-methylazetidine-3-amine; 1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyridine-2-yl)-3-methyl-N-((R)-tetrahydrofuran-3-yl)azetidine-3-amine; (R)-N-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)methyl)-N-methylmethanesulfonamide; 3-[6-[3-(cyclobutoxy)-3-methylazetidine-1-yl]-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole; 1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-N,3-dimethylazetidine-3-amine; 4-[1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-3-methylazetidine-3-yl]morpholine; 1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-N,N,3-trimethylazetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyrimidine-2-yl)-N-(2-methoxyethyl)-N,3-dimethylazetidine-3-amine; (R)-4-(1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)morpholine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-N,N,3-trimethylazetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyrimidine-2-yl)-N-isopropyl-3-methylazetidine-3-amine; (R)-2-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)amino)ethane-1-ol; (R)-N-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyrimidine-2-yl)-3-methylazetidine-3-yl)methyl)propan-2-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-N-(2-methoxyethyl)-N,3-dimethylazetidine-3-amine; (R)-2-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyrimidine-2-yl)-3-methylazetidine-3-yl)amino)ethane-1-ol; (R)-N-(1-(3-cyano-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)-2-(dimethylamino)acetamide; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-((2-methoxyethyl)amino)-3-methylazetidine-1-yl)nicotinonitrile; (R)-2-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)amino)ethane-1-ol; (S)-1-((1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)amino)propan-2-ol; (R)-1-((1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)amino)propan-2-ol; (R)-2-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)oxy)ethane-1-ol; (R)-1-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)oxy)-2-methylpropan-2-ol; 4-[1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-3-methylazetidine-3-yl]morpholine; (R)-N-(1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)-2-(dimethylamino)acetamide; (R)-1'-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3,3'-dimethyl-[1,3'-biazethidine]-3-ol; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(5-fluoro-6-(3-methoxy-3,3'-dimethyl-[1,3'-biazethidine]-1'-yl)pyridine-3-yl)-1H-indazole; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-((2-isopropoxyethyl)amino)-3-methylazetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-hydroxy-3,3'-dimethyl-[1,3'-biazethidine]-1'-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-hydroxy-3,3'-dimethyl-[1,3'-biazethidine]-1'-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-methoxy-3,3'-dimethyl-[1,3'-biazethidine]-1'-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-methoxy-3,3'-dimethyl-[1,3'-biazethidine]-1'-yl)nicotinonitrile; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(5-fluoro-6-(3'-methyl-[1,3'-biazethidine]-1'-yl)pyridine-3-yl)-1H-indazole; (R)-1-((1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)propan-2-ol; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)nicotinonitrile; (R)-N-(cyclopropylmethyl)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-amine; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(5-fluoro-6-(3-methyl-3-(pyrrolidine-1-yl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; (R)-N-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)methyl)propan-2-amine; (R)-4-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)methyl)morpholine; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(5-fluoro-6-(3-methyl-3-(pyrrolidine-1-ylmethyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(5-fluoro-6-(3,3,3'-trimethyl-[1,3'-biazethidine]-1'-yl)pyridine-3-yl)-1H-indazole; (S)-1-((1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)propan-2-ol; (R)-1-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)-2-methylpropane-2-ol; (R)-2-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)ethane-1-ol; (R)-1-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)amino)-2-methylpropane-2-ol; 3-[6-[3-(azetidine-1-yl)-3-methylazetidine-1-yl]-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-N-isopropyl-3-methylazetidine-3-amine; (R)-1-(((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)methyl)cyclopropane-1-ol; (R)-1-(((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)methyl)cyclopropane-1-ol; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-(((1-hydroxycyclopropyl)methyl)amino)-3-methylazetidine-1-yl)nicotinonitrile; (R)-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)methyl)dimethylphosphine oxide; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-methyl-3-(morpholinomethyl)azetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-methyl-3-(pyrrolidine-1-ylmethyl)azetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)-2-(3-methyl-3-morpholinoazetidine-1-yl)nicotinonitrile; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-N-(2,2-difluoroethyl)-3-methylazetidine-3-amine; (R)-N-(cyclopropylmethyl)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-N-isopropyl-3-methylazetidine-3-amine; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-3-(5-fluoro-6-(3-methyl-3-(pyrrolidine-1-yl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)-2-(3-((2-hydroxyethyl)amino)-3-methylazetidine-1-yl)nicotinonitrile; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-N,N,3-trimethylazetidine-3-amine; N-(cyclopropylmethyl)-1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-methylazetidine-3-amine; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-[3-[(isopropylamino)methyl]-3-methylazetidine-1-yl]pyridine-3-carbonitrile; (R)-2-(3-((cyclopropylmethyl)amino)-3-methylazetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)-2-(3-methyl-3-(pyrrolidine-1-yl)azetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)-2-(3'-methyl-[1,3'-biazethidine]-1'-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)-2-(3-methyl-3-(morpholinomethyl)azetidine-1-yl)nicotinonitrile; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-methylazetidine-3-ol; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-N-(2,2-difluoroethyl)-3-methylazetidine-3-amine; N-(1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)-2-(dimethylamino)-acetamide; 1-[1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-3-methylazetidine-3-yl]-3-methylazetidine-3-ol; 4-[1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-methylazetidine-3-yl]morpholine; 1-[[1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-methyl-azetidine-3-yl]amino]-2-methyl-propan-2-ol; (S)-1-((1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)propan-2-ol; (R)-1-((1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)propan-2-ol; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-N-(2-hydroxyethyl)-3-methylazetidine-3-carboxamide; 3-[6-[3-(azetidine-1-yl)-3-methylazetidine-1-yl]-5-fluoro-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-1H-indazole; (R)-2-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)ethane-1-ol; 2-[[1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-methyl-azetidine-3-yl]aminoethanol; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-methyl-N-(2-methylsulfonylethyl)azetidine-3-amine; 4-[1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-methylazetidine-3-yl]-1,4-thiadinane 1,1-dioxide; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-3-(5-fluoro-6-(3-methyl-3-(pyrrolidine-1-yl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; (R)-1-((1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)propan-2-ol; (R)-1-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)-2-methylpropane-2-ol; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-N,3-dimethylazetidine-3-amine; (R)-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)methyl)dimethylphosphine oxide; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)pyridine-2-yl)-N-isopropyl-3-methylazetidine-3-amine; (R)-N-(cyclopropylmethyl)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-amine; (R)-2-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)ethane-1-ol; (S)-1-((1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)propan-2-ol; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-3-(6-(3-methyl-3-(pyrrolidine-1-yl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; (R)-2-(((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)methyl)amino)ethanol; (R)-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)methyl)dimethylphosphine oxide; (R)-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)methyl)dimethylphosphine oxide; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(6-(3-methyl-3-((methylsulfonyl)-methyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-N-(dimethylphosphorylmethyl)-3-methylazetidine-3-amine; (R)-4-(1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)morpholine; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-3-(5-fluoro-6-(3'-methyl-[1,3'-biazethidine]-1'-yl)pyridine-3-yl)-1H-indazole; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-3-(5-fluoro-6-(3-methyl-3-(pyrrolidine-1-ylmethyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; (R)-4-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)methyl)morpholine; (R)-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)methyl)dimethylphosphine oxide; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-3-(6-(3-methyl-3-(pyrroridine-1-ylmethyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; (R)-N-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)methyl)propan-2-amine; (R)-N-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)methyl)propan-2-amine; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-3-(6-(3-methyl-3-(pyrrolidine-1-ylmethyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; (R)-2-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)amino)ethanol; (R)-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)methyl)dimethylphosphine oxide; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(5-fluoro-6-(3-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)pyridine-3-yl)-6-methoxy-1H-indazole; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(2-(3-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)pyrimidine-5-yl)-1H-indazole; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-3-(5-fluoro-6-(3-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-N,3-dimethylazetidine-3-amine; (R)-1-(1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)-4-methyl-1,4-azaphosfinan 4-oxide; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(5-fluoro-6-(3-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; (S)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(5-fluoro-6-(3-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; 1-[5-[5-[(1S)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-N,N,3-trimethylazetidine-3-amine; 5-((S)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(5-fluoro-6-((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(6-((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(6-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; 1-[5-[5-[(1S)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-N,3-dimethylazetidine-3-amine; 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(5-fluoro-6-((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(5-fluoro-6-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; 5-((S)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(5-fluoro-6-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)pyridine-3-yl)-1H-indazole; N-(cyclopropylmethyl)-1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-methylazetidine-3-amine; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[5-fluoro-6-[3-methyl-3-(methylsulfonylmethyl)azetidine-1-yl]-3-pyridyl]-1H-indazole; (R)-4-(1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)-2-methylmorpholine; (S)-4-(1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)-2-methylmorpholine; (R)-4-(1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)-2-methylmorpholine; (R)-dimethyl((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)methyl)phosphonate; (R)-dimethyl((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)methyl)phosphonate; (S)-4-(1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)-2-methylmorpholine; 3-(1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)-6-oxa-3-azabicyclo[3.1.1]heptane; (1S,4S)-5-(1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; (R)-N-(cyclopropylmethyl)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-amine; 1-[4-[1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-methylazetidine-3-yl]piperazine-1-yl]ethenone; 1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-N-isopropyl-3-methylazetidine-3-amine; 3-(1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)-6-oxa-3-azabicyclo[3.1.1]heptane; (1R,4R)-5-(1-(5-(5-(((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-N-isobutyl-3-methylazetidine-3-amine; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-3-methyl-N-[(1R)-1-methylpropyl]azetidine-3-amine; (R)-1-(1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)-4-methyl-1,4-azaphosfinan 4-oxide; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-3-methyl-N-propyl-azetidine-3-amine; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-3-methyl-N-[(1S)-1-methylpropyl]azetidine-3-amine; (1S,4S)-5-(1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-N-(dimethylphosphorylmethyl)-3-methylazetidine-3-amine; (1R,4R)-5-(1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; (R)-N-allyl-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-N,3-dimethylazetidine-3-amine; (R)-N-allyl-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyrimidine-2-yl)-3-methylazetidine-3-amine; (R)-N-(cyclopropylmethyl)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyrimidine-2-yl)-3-methylazetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyrimidine-2-yl)-N-isopropyl-3-methylazetidine-3-amine; (R)-N-(cyclopropylmethyl)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-6-fluoropyridine-2-yl)-3-methylazetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyrimidine-2-yl)-N-ethyl-3-methylazetidine-3-amine; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-N-ethyl-3-methylazetidine-3-amine; (R)-N-allyl-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-6-fluoropyridine-2-yl)-3-methylazetidine-3-amine; (R)-2-(3-amino-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)azetidine-3-yl)acetonitrile; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-N-isobutyl-3-methylazetidine-3-amine; (R)-N-(cyclopropylmethyl)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-4-fluoropyridine-2-yl)-3-methylazetidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-N-isopropyl-3-methylazetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-N-isobutyl-N,3-dimethylazetidine-3-amine; (R)-N-(cyclopropylmethyl)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-N,3-dimethylazetidine-3-amine; N-(cyclopropylmethyl)-1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-ethyl-azetidine-3-amine; 2-[3-(allylamino)-1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]azetidine-3-yl]acetonitrile; (R)-N-(cyclopropylmethyl)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-methylazetidine-3-amine; 2-[3-(cyclopropylmethylamino)-1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]azetidine-3-yl]acetonitrile; (R)-2-(1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(pyrrolidine-1-yl)azetidine-3-yl)acetonitrile; (R)-2-(1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(dimethylamino)azetidine-3-yl)acetonitrile; (R)-2-(1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(isobutylamino)azetidine-3-yl)acetonitrile dihydrochloride; (R)-2-(1-(5-(5-(1-(3,5-dichloro-2-methylpyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(isobutylamino)azetidine-3-yl)acetonitrile; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-isopropylazetidine-3-amine; (R)-3-cyclobutyl-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)azetidine-3-amine; (R)-2-(1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(isopropyl(methyl)amino)azetidine-3-yl)acetonitrile; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-isobutylazetidine-3-amine; (R)-2-(3-amino-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)azetidine-3-yl)ethanol; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-ethyl-azetidine-3-amine; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(5-fluoro-6-(3-methyl-3-(2-(pyrrolidine-1-yl)ethoxy)azetidine-1-yl)pyridine-3-yl)-1H-indazole; (R)-3-(cyclopropylmethyl)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(tetrahydro-2H-pyran-4-yl)azetidine-3-amine; (R)-3-allyl-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-propylazetidine-3-amine; (R)-1-(3-amino-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)azetidine-3-yl)-2-methylpropan-2-ol; (R)-2-(3-amino-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)azetidine-3-yl)ethanol; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methyl-N-(2-(pyrrolidine-1-yl)ethyl)azetidine-3-amine; (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(6-(3-methyl-3-(2-(pyrrolidine-1-yl)ethoxy)azetidine-1-yl)pyridazin-3-yl)-1H-indazole; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(2-(methylsulfonyl)ethyl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(3-methylbuto-2-en-1-yl)azetidine-3-amine; (R)-3-(cyclopropylmethyl)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(2-methoxyethyl)azetidine-3-amine; (R)-3-allyl-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)azetidine-3-amine; (R)-1-(3-amino-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)azetidine-3-yl)-2-methylpropan-2-ol; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(1-methyl-1H-pyrazole-4-yl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(1-methyl-1H-pyrazole-4-yl)azetidine-3-amine; (R)-1-(3-amino-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)azetidine-3-yl)-2-methylpropan-2-ol; (R)-2-(3-amino-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)azetidine-3-yl)ethanol; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-sec-butylazetidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-((1-methyl-1H-pyrazole-5-yl)methyl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-((1-methyl-1H-pyrazole-3-yl)methyl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-((1-methyl-1H-pyrazole-5-yl)methyl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(2-fluoroethyl)azetidine-3-amine; (R)-3-(3-amino-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)azetidine-3-yl)propanenitrile; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-methylazetidine-3-amine; (R)-Isopropyl 3-amino-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)azetidine-3-carboxylate; 1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-((tetrahydrofuran-2-yl)methyl)azetidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-((1-methyl-1H-pyrazole-4-yl)methyl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-((1-methyl-1H-pyrazole-4-yl)methyl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3-((1-methyl-1H-pyrazole-3-yl)methyl)azetidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(2-fluoroethyl)azetidine-3-amine; (R)-3-amino-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-N,N-dimethylazetidine-3-carboxamide; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(2-(methylsulfonyl)ethyl)azetidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-propylazetidine-3-amine; (R)-3-amino-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-N-methylazetidine-3-carboxamide; R)-N-(1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-methylazetidine-3-yl)-2-(dimethylamino)acetamide; (R)-3-(3-amino-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)azetidine-3-yl)propanenitrile; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-ethylazetidine-3-amine; (R)-3-amino-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)-N-methylazetidine-3-carboxamide; (R)-3-amino-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)-N,N-dimethylazetidine-3-carboxamide; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyrimidine-2-yl)-3-methylazetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-N-(2-fluoroethyl)-3-methylazetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-amine; 1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-((tetrahydrofuran-2-yl)methyl)azetidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-((1-methyl-1H-pyrazole-3-yl)methyl)azetidine-3-amine; (R)-3-(3-amino-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)azetidine-3-yl)propan-1-ol; (R)-Isopropyl 3-amino-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)azetidine-3-carboxylate; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-N-(2-fluoroethyl)-3-methylazetidine-3-amine; (R)-3-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)propanenitrile; (R)-2-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)-N,N-dimethylacetamide; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-N-(2,2-difluoroethyl)-3-methylazetidine-3-amine; (R)-3-((1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)-3-methylazetidine-3-yl)amino)propanenitrile; (R)-2-((1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-methylazetidine-3-yl)amino)-N,N-dimethylacetamide; (R)-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylpyrrolidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(ethoxymethyl)azetidine-3-amine; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-fluoro-1H-indazole-3-yl)-2-(3-methyl-3-(pyrrolidine-1-ylmethyl)azetidine-1-yl)nicotinonitrile; (R)-2-(3-((cyclopropylmethyl)amino)-3-methylazetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-2-(3-(isopropylamino)-3-methylazetidine-1-yl)nicotinonitrile; (R)-1-(3-cyano-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-N-(2-hydroxyethyl)-3-methylazetidine-3-carboxamide; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-(1,1-dioxidethiomorpholino)-3-methylazetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-2-(3-methyl-3-(pyrrolidine-1-yl)azetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-2-(3-((dimethylphosphoryl)methyl)-3-methylazetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-2-(3-((2-hydroxyethyl)amino)-3-methylazetidine-1-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-[3-methyl-3-(2-methylsulfonylethylamino)azetidine-1-yl]pyridine-3-carbonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-2-(3-((isopropylamino)methyl)-3-methylazetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-4-fluoro-1H-indazole-3-yl)-2-(3-methyl-3-morpholinoazetidine-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-2-(3-methyl-3-(4-methyl-4-oxide-1,4-azaphosfinan-1-yl)azetidine-1-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]-2-[3-(dimethylphosphorylmethylamino)-3-methylazetidine-1-yl]pyridine-3-carbonitrile; (S)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-(isopropylamino)-3-methylazetidine-1-yl)nicotinonitrile; (S)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-((2-hydroxy-2-methylpropyl)amino)-3-methylazetidine-1-yl)nicotinonitrile; (S)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)nicotinonitrile; (S)-2-(3-((cyclopropylmethyl)amino)-3-methylazetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-(1,1-dioxidethiomorpholino)-3-methylazetidine-1-yl)nicotinonitrile; 5-(5-((S)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)nicotinonitrile; - (3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-methylazetidine-1-yl)-5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 2-(3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-3-methylazetidine-1-yl)-5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 2-(3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-methylazetidine-1-yl)-5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-N-(cyclopropylmethyl)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyrimidine-2-yl)-3-methylazetidine-3-amine; (R)-N-(1-(3-cyano-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-yl)-2-(dimethylamino)-acetamide; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-(ethylamino)-3-methylazetidine-1-yl)nicotinonitrile hydrochloride; (R)-6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-3-(3-(isobutylamino)-3-methylazetidine-1-yl)pyridazine-4-carbonitriel; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-(isobutyl(methyl)amino)-3-methylazetidine-1-yl)nicotinonitrile; (R)-2-(3-((cyclopropylmethyl)(methyl)amino)-3-methylazetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 2-[3-amino-3-(cyanomethyl)azetidine-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]pyridine-3-carbonitrile; (R)-2-(3-(cyanomethyl)-3-((cyclopropylmethyl)-amino)azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-3-(3-((cyclopropylmethyl)amino)-3-methylazetidine-1-yl)-6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyridazine-4-carbonitriel; 2-[3-(cyclopropylmethylamino)-3-ethyl-azetidine-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]pyridine-3-carbonitrile hydrochloride; (R)-6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-3-(3-(dimethylamino)-3-methylazetidine-1-yl)pyridazine-4-carbonitrile; (R)-2-(3-(cyanomethyl)-3-((cyclopropylmethyl)amino)azetidine-1-yl)-5-(5-(1-(3,5-dichloro-2-methylpyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-2-(3-ethyl-3-(methylamino)azetidine-1-yl)nicotinonitrile dihydrochloride; (R)-2-(3-(cyanomethyl)-3-(dimethylamino)-azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(3-amino-3-isopropylazetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(3-(cyanomethyl)-3-(pyrrolidine-1-yl)azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]-2-[3-(isobutylamino)-3-methylazetidine-1-yl]pyridine-3-carbonitrile; (R)-2-(3-amino-3-cyclobutylazetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(3-amino-3-isobutylazetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(3-(cyanomethyl)-3-(isopropyl(methyl)amino)azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(3-amino-3-(cyclopropylmethyl)azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(3-amino-3-propylazetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(3-amino-3-(2-hydroxy-2-methylpropyl)azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(3-allyl-3-aminoazetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(3-amino-3-(3-methylbuto-2-en-1-yl)azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(3-amino-3-(2-(methylsulfonyl)ethyl)azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 2-(3-amino-3-ethyl-azetidine-1-yl)-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]pyridine-3-carbonitrile; (R)-2-(3-amino-3-((1-methyl-1H-pyrazole-3-yl)methyl)azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 2-((S)-3-amino-3-methylpyrrolidine-1-yl)-5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(4-amino-4-methylpiperidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 2-((R)-3-amino-3-methylpyrrolidine-1-yl)-5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]-2-(3-hydroxy-3-methylazetidine-1-yl)pyridine-3-carbonitrile; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-(methoxymethyl)azetidine-3-amine; (R)-3-(3-amino-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)azetidine-3-yl)propan-1-ol; (S)-1-(3-amino-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)azetidine-3-yl)propan-2-ol; (R)-1-(3-amino-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)azetidine-3-yl)propan-2-ol; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-4-((methylsulfonyl)methyl)piperidine-4-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(methoxymethyl)azetidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(isopropoxymethyl)azetidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(3-methylbuto-2-en-1-yl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyridine-2-yl)-3-methylazetidine-3-amine; (R)-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyridine-2-yl)-3-methylpyrrolidine-3-amine; (S)-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyridine-2-yl)-3-methylpyrrolidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyridine-2-yl)-4-methylpiperidine-4-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-4-methylpiperidine-4-amine; (S)-1-(3-amino-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)azetidine-3-yl)propan-2-ol; (R)-1-(3-amino-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)azetidine-3-yl)propan-2-ol; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-4-((methylsulfonyl)methyl)piperidine-4-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-((methylsulfonyl)methyl)azetidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(1-methyl-1H-pyrazole-3-yl)azetidine-3-amine; (S)-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylpyrrolidine-3-amine; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-(ethoxymethyl)azetidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(1-methyl-1H-pyrazole-5-yl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(1-methyl-1H-pyrazole-5-yl)azetidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)pyridazin-3-yl)-3-methylazetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(2,2-difluoroethyl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-4-(2-(methylsulfonyl)ethyl)piperidine-4-amine; (S)-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylpyrrolidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(2,2-difluoroethyl)azetidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-4-(2-(methylsulfonyl)ethyl)piperidine-4-amine; (R)-2-((1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylazetidine-3-yl)amino)-N-methylacetamide; (R)-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylpyrrolidine-3-amine-fluoropyridine-2-yl)-4-methylpiperidine-4-amine; (R)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-ethylpyrrolidine-3-amine; (S)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-ethylpyrrolidine-3-amine; (R)-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(1-methyl-1H-pyrazole-5-yl)pyrrolidine-3-amine; (S)-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(1-methyl-1H-pyrazole-5-yl)pyrrolidine-3-amine; (R)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-methylpyrrolidine-3-amine; (S)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-methylpyrrolidine-3-amine; (R)-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-methylpyrrolidine-3-amine; 2-((R)-3-((cyclopropylmethyl)-amino)-3-methylpyrrolidine-1-yl)-5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 2-((S)-3-((cyclopropylmethyl)-amino)-3-methylpyrrolidine-1-yl)-5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(4-((cyclopropylmethyl)amino)-4-methylpiperidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-(methylsulfonylmethyl)azetidine-3-amine; (R)-2-((1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)-3-methylazetidine-3-yl)amino)-N-methylacetamide; (R)-3-(cyclopropylmethyl)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)pyrrolidine-3-amine; (S)-3-(cyclopropylmethyl)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)pyrrolidine-3-amine; (R)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(1-methyl-1H-pyrazole-5-yl)pyrrolidine-3-amine; (S)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(1-methyl-1H-pyrazole-5-yl)pyrrolidine-3-amine; (R)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(1-methyl-1H-pyrazole-3-yl)pyrrolidine-3-amine; (S)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(1-methyl-1H-pyrazole-3-yl)pyrrolidine-3-amine; (S)-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-((1-methyl-1H-pyrazole-5-yl)methyl)pyrrolidine-3-amine; (R)-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-((1-methyl-1H-pyrazole-5-yl)methyl)pyrrolidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-4-ethylpiperidine-4-amine; (R)-2-(3-amino-3-((1-methyl-1H-pyrazole-5-yl)methyl)azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (S)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-((1-methyl-1H-pyrazole-5-yl)methyl)pyrrolidine-3-amine; (R)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-((1-methyl-1H-pyrazole-5-yl)methyl)pyrrolidine-3-amine; (S)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-((1-methyl-1H-pyrazole-3-yl)methyl)pyrrolidine-3-amine; (R)-1-(6-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-((1-methyl-1H-pyrazole-3-yl)methyl)pyrrolidine-3-amine; (S)-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-((1-methyl-1H-pyrazole-3-yl)methyl)pyrrolidine-3-amine; (R)-1-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-((1-methyl-1H-pyrazole-3-yl)methyl)pyrrolidine-3-amine; (R)-2-(3-amino-3-(pyridine-2-ylmethyl)azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(3-amino-3-(pyrimidine-2-ylmethyl)azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(3-amino-3-(pyrimidine-2-yl)azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 2-((R)-3-amino-3-(1-methyl-1H-pyrazole-3-yl)pyrrolidine-1-yl)-5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 2-((S)-3-amino-3-(1-methyl-1H-pyrazole-3-yl)pyrrolidine-1-yl)-5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-2-(3-amino-3-(1-methyl-1H-pyrazole-3-yl)azetidine-1-yl)-5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 2-[3-amino-3-(methoxymethyl)azetidine-1-yl]-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazole-3-yl]pyridine-3-carbonitrile; 2-((R)-3-amino-3-(1-methyl-1H-pyrazole-5-yl)pyrrolidine-1-yl)-5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; 2-((S)-3-amino-3-(1-methyl-1H-pyrazole-5-yl)pyrrolidine-1-yl)-5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methoxy-1H-indazole-3-yl)nicotinonitrile; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-((1-methyl-1H-imidazole-2-yl)methyl)azetidine-3-amine; (R)-2-(3-amino-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)azetidine-3-yl)-1-(pyrrolidine-1-yl)ethenone; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-3-(isopropoxymethyl)azetidine-3-amine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-((1-methyl-1H-imidazole-5-yl)methyl)azetidine-3-amine; (R)-2-(3-amino-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)azetidine-3-yl)-N-methylacetamide; (R)-2-(3-amino-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)azetidine-3-yl)-N-methylacetamide; (R)-(3-(cyclopropylmethyl)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)azetidine-3-yl)methanamine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-((4-methyl-4H-1,2,4-triazole-3-yl)methyl)azetidine-3-amine; (R)-1-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)-3-(pyrimidine-2-ylmethyl)azetidine-3-amine; (R)-(1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazin-3-yl)-3-(2-(methylsulfonyl)ethyl)azetidine-3-yl)methanamine; (R)-1-(6-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridazine-3-yl)-3-(pyrimidine-2-yl)azetidine-3-amine; or The compound according to claim 1, which is a pharmaceutically acceptable salt thereof.

11. The compound is 【Chemistry 10】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for treating a disease or disorder in a subject requiring treatment of the disease or disorder, comprising administering the compound to the subject.

14. The use according to claim 13, wherein the disease or disorder is cancer, and the cancer is urothelial carcinoma, hepatocellular carcinoma, breast cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung cancer, pancreatic exocrine carcinoma, oral cancer, prostate cancer, bladder cancer, colorectal cancer, renal cell carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous epithelial), melanoma, leiomyosarcoma, and / or sarcoma.

15. The use according to claim 13, wherein the disease or disorder is a developmental disorder, and the developmental disorder is an associated chondrodysplastic syndrome, including achondroplasia (Ach), hypochondrodysplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and fatal dysplasia (TD).

16. Use of a compound according to any one of claims 1 to 11 in the manufacture of a pharmaceutical product for inhibiting FGFR in cells, the use comprising contacting the cells with the compound.

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