Synthesis of compounds that promote hair growth

Abstract

The present disclosure relates to methods of synthesizing compounds of formula I. The present disclosure further relates to compounds of formula I (A, B, or C) that can inhibit the mitochondrial pyruvate carrier and promote hair growth.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 951,667, filed December 20, 2019, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Hair follicle stem cells (HFSCs) undergo successive rounds of resting phase (telogen) punctuated by a short period of proliferation that correlates with the initiation of the hair cycle (telogen-anagen transition). It is well known that proliferation or activation of HFSCs is a prerequisite for progression of the hair cycle. Recent advances in treatment options have led to the identification of many small molecule MPC inhibitors that can regulate the hair cycle. However, new methods for synthesizing these compounds are needed. Summary of the Invention

[0003] In certain aspects, the present disclosure provides a compound of formula (I) [ka] (In the formula, Each A is independently CH, CR 4 , or N, Y is a carboxyl, ester, amide, or [ka] and R 2 is CN or carboxyl, R 3 is H, aryl, aralkyl, or aralkylacyl, and one or more R 5 is optionally replaced by R 4 each instance of is independently alkyl, carboxyl, halo, hydroxy, ester, or CN; R 5 each instance of is independently selected from alkyl, alkoxy, or halo; R 7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; R 10 is hydrogen or alkyl) or a pharmaceutically acceptable salt thereof and providing a method for preparing The method comprises: Reacting a compound of formula (Ic) with an acylating (e.g., formylating) reagent to produce a compound of formula (Id): [ka] reacting a compound of formula (Id) with a condensing agent of formula (Ie) to form a compound of formula (I): [ka] Includes: DETAILED DESCRIPTION OF THE INVENTION

[0004] Hair follicle stem cells (HFSCs) are dormant, long-lived cells that are involved in maintaining cellular homeostasis in the hair follicle. Although normally dormant, HFSCs are readily activated to divide during a new hair cycle. HFSC dormancy is known to be regulated by many intrinsic and extrinsic mechanisms.

[0005] Compounds have been developed that can modulate these mechanisms, for example, by inhibiting MPC, thereby promoting hair growth. Such compounds and related disclosures can be found, for example, in PCT Publication No. WO2018039612, PCT Publication No. WO2019006359, and U.S. Provisional Application No. 62 / 787609, now International Application PCT / US019 / 068905, published as WO2020 / 142413, each of which is incorporated by reference herein as if fully set forth herein, particularly with respect to the MPC inhibitory compounds disclosed therein.

[0006] Thus, in certain aspects, the present disclosure provides methods for synthesizing compounds as further described herein. In one aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, Each A is independently CH, CR 4 , or N, Y is a carboxyl, ester, amide, or [ka] and R 2 is CN or carboxyl, R 3 is H, aryl, aralkyl, or aralkylacyl, and one or more R 5 is optionally replaced by R 4 each instance of is independently alkyl, carboxyl, halo, hydroxy, ester, or CN; R 5 each instance of is independently selected from alkyl, alkoxy, or halo; R 7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; R 10 is hydrogen or alkyl) or a pharmaceutically acceptable salt thereof and providing a method for preparing The method comprises: Reacting a compound of formula (Ic) with an acylating (e.g., formylating) reagent to produce a compound of formula (Id): [ka] reacting a compound of formula (Id) with a condensing agent of formula (Ie) to form a compound of formula (I): [ka] Includes:

[0007] In certain embodiments, the methods described herein further comprise hydrolyzing the compound of formula (I) to produce a compound of formula (If): [ka]

[0008] In certain embodiments, the methods described herein further comprise reacting the compound of formula (Ia) with an alkylating reagent of formula (Ib) to produce a compound of formula (Ic): [ka] where W is a leaving group (e.g., halo).

[0009] In certain embodiments, at least one A is N. In certain preferred embodiments, exactly one A is N.

[0010] In certain preferred embodiments, the compound of formula (Ia) is [ka] and the compounds of formulae (Ic), (Id), (I), and (If) contain the corresponding heterocycles.

[0011] In certain embodiments, the compound of formula (Ia) is [ka] and the compounds of formulae (Ic), (Id), (I), and (If) contain the corresponding heterocycles.

[0012] In certain embodiments, R 2 But it is CN.

[0013] In certain embodiments, R 3 is benzyl. In certain embodiments, R3 is benzyl and one or more R 5 In certain preferred embodiments, R 3 But one or two R 5 and each R 5 is independently selected from fluoroalkyl or fluoro. In certain further preferred embodiments, R 3 But two R 5 and each R 5 is trifluoromethyl.

[0014] In certain embodiments, R 7 is hydrogen, hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetoxy). In certain preferred embodiments, R 7 is hydrogen.

[0015] In certain embodiments, the leaving group W of the alkylating reagent is halo. In certain preferred embodiments, the leaving group W of the alkylating reagent is bromide.

[0016] In certain embodiments, the alkylating reagent is [ka] is.

[0017] In certain embodiments, the acylating reagent is phosphorus oxychloride.

[0018] In certain such embodiments, the condensing agent is ethyl 2-cyanoacetate or tert-butyl 2-cyanoacetate. [ka] is.

[0019] In certain embodiments, the compound of formula (If) is [ka] is.

[0020] The methods described above may be utilized by one of ordinary skill in the art to arrive at the compounds described below (e.g., compounds of Formulas A, B, and C) using starting materials and techniques available to one of ordinary skill in the art.

[0021] In certain embodiments, the present disclosure further provides a compound according to formula (A), as described herein: [ka] or a pharmaceutically acceptable salt thereof A method for preparing

[0022] Further embodiments of Formula A are provided in PCT Publication No. WO2018 / 039612.

[0023] In certain embodiments, the present disclosure further provides a compound according to formula (B), as described herein. [ka] (In the formula, Each A is independently CH, CR B4 , or N, Y is a carboxyl, ester, amide, or [ka] and Z is CH, CR B4 , or N, R B2 is CN or carboxyl, R B3 is H, aryl, aralkyl, or aralkylacyl, and one or more R B5 and each R B5 is independently selected from alkyl, alkoxy, or halo; R B4each instance of is independently alkyl, carboxyl, halo, hydroxy, ester, or CN; R B6 is derived from H, alkyl, or cycloalkyl, R B7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; R B10 is hydrogen or alkyl, n is 0 to 4) or a pharmaceutically acceptable salt thereof A method for preparing

[0024] In certain embodiments, the present disclosure provides a compound according to formula BI [ka] (In the formula, Y is a carboxyl, ester, amide, or [ka] and R B2 is CN or carboxyl, R B3 is H, aryl, aralkyl, or aralkylacyl, and one or more R B5 and each R B5 is independently selected from alkyl, alkoxy, or halo; R B4 each instance of is independently alkyl, carboxyl, halo, hydroxy, ester, or CN; R B6 is derived from H, alkyl, or cycloalkyl, R B7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; R B10 is hydrogen or alkyl, R B11 is hydrogen or alkyl, n is 0 to 4) or a pharmaceutically acceptable salt thereof A method for preparing

[0025] In certain embodiments of formula B or BI, Y is [ka] In certain embodiments, R B10 is H. In certain embodiments, R B10 is alkyl (e.g., ethyl). In certain embodiments, Y is an ester or amide.

[0026] In certain embodiments of Formula B or BI, R B11 is alkyl (e.g., methyl).

[0027] In certain embodiments, the present disclosure provides a compound of formula BII [ka] (In the formula, Each A is independently CH, CR B4 , or N, X is NR B6 or O, R B1 is H or lower alkyl, or R B1 and R B6 Or R B1 and R B2 complete a heterocyclic ring together with the atoms separating them, R B2 is CN or carboxyl, R B3 is H, aryl, aralkyl, or aralkylacyl, and one or more R B5 and each R B5 is independently selected from alkyl, alkoxy, and halo; R B4 each instance of is independently alkyl, carboxyl, halo, hydroxy, or CN; R B6 is derived from H, alkyl, or cycloalkyl, R B7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy or a pharmaceutically acceptable salt thereof to provide.

[0028] In certain embodiments of formula B, BI, or BII, at least one A is N, and preferably no more than two occurrences of A are N. In certain preferred embodiments, exactly one A is N, and preferably NR B3 A is bonded to the same carbon as

[0029] In certain embodiments, the present disclosure provides a compound of formula BIII [ka] (In the formula, X is NR B6 or O, R B1 is H or lower alkyl; R B2 is CN or carboxyl, or R B1 and R B2 together with the atoms separating them complete a heterocycle, R B3 is H, phenyl, or benzyl, and one or more R B5 and each R B5 is independently selected from alkyl, alkoxy, or halo; R B4 each instance of is independently selected from alkyl, carboxyl, halo, hydroxy, or CN; R B6 is selected from H, alkyl, or cycloalkyl and pharmaceutically acceptable salts thereof. to provide.

[0030] In certain embodiments of formula B, BI, BII, or BIII, X is NH. In certain embodiments, X is O.

[0031] In certain embodiments of Formula B, BI, BII, or BIII, R B1 is H. In certain embodiments, R B1 is lower alkyl. In certain embodiments, R B1 and R B6 together with the atoms separating them complete a heterocyclic ring (eg, morpholinyl).

[0032] In certain embodiments of Formula B, BI, BII, or BIII, R B6 is hydrogen.

[0033] In certain embodiments of formula VB, BI, BII, or BIII, R B2 is CN. In certain embodiments, R B2 is carboxyl. In certain embodiments, R B1 and R B2 together with the atoms separating them complete a heterocyclyl selected from thiazolidine-2,4-dione-5-ylidene or 2-iminothiazolidin-4-one-5-ylidene.

[0034] In certain embodiments of Formula B, BI, BII, or BIII, R B3 is H. In certain embodiments, R B3 is phenyl. In certain embodiments, R B3 is phenyl and one or more R B5 In certain embodiments, R B3 But one R B5 is substituted with R B5 is alkoxy. In certain embodiments, R B3 is aralkyl (e.g., benzyl or phenethyl). In certain embodiments, R B3 is aralkyl acyl (e.g., phenylacetyl). In certain embodiments, R B3is benzyl. In certain embodiments, R B3 is benzyl and one or more R B5 In certain embodiments, R B3 is aralkyl (e.g., benzyl or phenethyl) and (preferably on the phenyl ring) one or more R B5 In certain embodiments, R B3 is aralkyl acyl (e.g., phenylacetyl) and (preferably on the phenyl ring) one or more R B5 In certain embodiments, R B3 But one or two R B5 and each R 5 is independently selected from fluoroalkyl or fluoro. In certain embodiments, R B3 But two R B5 and each R B5 is trifluoromethyl.

[0035] In certain embodiments of formula B, BI, BII, or BIII, n is 0.

[0036] In certain preferred embodiments, the present disclosure provides compounds of formula BIV: [ka]

[0037] In certain embodiments, the present disclosure provides a compound of formula BV: [ka]

[0038] In certain embodiments of formula B, BI, BII, BIII, BIV, or BV, n is 1.

[0039] In certain preferred embodiments, the present disclosure provides compounds of formula BVI: [ka]

[0040] In certain embodiments, the present disclosure provides a compound of formula BVII: [ka]

[0041] In certain embodiments of Formula B, BI, BII, BIII, BIV, BV, BVI, or BVII, R B4 is selected from halo or haloalkyl. In certain preferred embodiments, R B4 is halo (e.g., chloro or bromo). In other preferred embodiments, R B4 is a carboxyl or an ester.

[0042] In certain embodiments of Formula B, BI, BII, BIII, BIV, BV, BVI, or BVII, n is 0. In certain embodiments, n is 2 and R B4 is selected from halo or haloalkyl.

[0043] In certain embodiments of Formula B, BI, BII, BIII, BIV, BV, BVI, or BVII, R B7 is hydrogen, hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy). B7 is hydroxyl, halo (eg, chloro), or acyloxy (eg, acetyloxy).

[0044] In certain embodiments of Formula B, BI, BII, BIII, BIV, BV, BVI, or BVII, the compound is not JXL001.

[0045] Further embodiments of Formula B are provided in PCT Publication No. WO2019 / 006359.

[0046] In certain embodiments, the present disclosure provides methods of preparing compounds according to formula (C), as further described herein: [ka] (In the formula, Y is a carboxyl, ester, amide, or [ka] and R C1 is H, aryl, aralkyl, or aralkylacyl, and one or more R C5 is optionally replaced by R C2 is CN or carboxyl, R C4 is independently alkyl, alkenyl, alkynyl, carboxyl, azido, halo, hydroxy, ester, or CN; R C5 is independently selected from alkyl, alkoxy, or halo; n is 0 to 4).

[0047] In certain embodiments of Formula C, Y is: [ka] In certain such embodiments, R C10 is H. In other such embodiments, R C10 is alkyl (e.g., methyl, ethyl, propyl).

[0048] In other preferred embodiments of Formula I, Y is an ester or a carboxyl.

[0049] In certain preferred embodiments of Formula I, R C2 is CN. In other embodiments, R C2 is carboxyl.

[0050] In certain embodiments of Formula I, RC1 But it's H.

[0051] In another preferred embodiment of Formula I, R C1 is aralkyl (e.g., benzyl or phenethyl). In certain such embodiments, the aralkyl (e.g., benzyl or phenethyl) is a phenyl ring having one or more R C5 In yet another embodiment, R C1 is aralkyl acyl (e.g., phenylacetyl) and (preferably on the phenyl ring) one or more R C5 is replaced by .

[0052] In certain embodiments of Formula I, R 1 But one or two R C5 and each R C5 is independently selected from fluoroalkyl or fluoro. In certain preferred embodiments, R C1 But two R C5 and each R C5 is trifluoromethyl.

[0053] In certain embodiments of Formula I, R C4 is an electron withdrawing group. In certain embodiments, R C4 is selected from iodo, fluoro, alkenyl (e.g., vinyl), CN, azido, alkynyl (e.g., acetylenyl), fluoroalkyl (e.g., trifluoromethyl), carboxyl, and ester (e.g., methyl ester or ethyl ester). In certain preferred embodiments, R C4 is fluoro. In another preferred embodiment, R C4 is an ester (e.g., a methyl ester or an ethyl ester).

[0054] In certain embodiments, the present disclosure provides a compound of formula CIa or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R 6 is H, alkyl, aryl, or aralkyl).

[0055] In certain preferred embodiments of formula Ia, R C6 is H or alkyl (e.g., methyl or ethyl).

[0056] Further embodiments of Formula B are provided in PCT Publication No. WO2020 / 142413.

[0057] In certain embodiments, the present disclosure provides methods for preparing the compounds of Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0058] Pharmaceutical Composition The present disclosure includes the preparation and use of pharmaceutically acceptable salts of compounds prepared by the methods of the present invention. In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.In certain embodiments, contemplated salts of the present invention include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptano ... Acid salts of acetic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0059] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as, for example, with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, may be inherent in the solvent of preparation or crystallization, or may be adventitious to such solvent.

[0060] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature and techniques used in connection with chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are well known and commonly used in the art.

[0061] Unless otherwise indicated, the methods and techniques of the present disclosure are generally performed according to conventional methods known in the art and as described in various general and more specific references cited and discussed throughout this specification. See, e.g., "Principles of Neural Science," McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics," Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.", W.H. Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", W.H. Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

[0062] Unless otherwise defined herein, chemical terms used herein are used in accordance with conventional usage in the art, as exemplified by "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0063] All of the above, and any other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including specific definitions, will control.

[0064] The term "agent" is used herein to refer to a compound (e.g., an organic or inorganic compound, a mixture of compounds), a biopolymer (e.g., a nucleic acid, an antibody, including portions thereof, and humanized, chimeric, and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, lipid, carbohydrate), or an extract made from biological material, e.g., a bacterial, plant, fungal, or animal (particularly mammalian) cell or tissue. Agents include, for example, agents with known structures and agents with unknown structures. The ability of an agent to inhibit AR or promote AR degradation may make it suitable as a "therapeutic agent" for the methods and compositions of the present disclosure.

[0065] "Patient," "subject," or "individual" are used interchangeably and refer to either a human or non-human animal. These terms include mammals such as humans, primates, livestock animals (including cows, pigs, etc.), pets (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

[0066] "Treating" a condition or patient refers to taking measures to obtain beneficial or desired results, including clinical results. As used herein and as well understood in the art, "treatment" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, reduction in the extent of disease, stabilization of disease condition (i.e., not worsening), prevention of disease spread, delay or slowing of disease progression, improvement or palliation of disease condition, and remission (whether partial or total). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0067] The term "preventing," when used in reference to a condition, e.g., local recurrence (e.g., pain), a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition, is well understood in the art and includes administration of a composition that reduces the frequency of or delays the onset of symptoms of the condition in a subject compared to subjects who do not receive the composition. Thus, preventing cancer includes, for example, reducing the number of detectable cancer growths in a population of patients receiving prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancer growths in a treated population versus an untreated control population, for example, by a statistically and / or clinically significant amount.

[0068] "Administering" or "administration" of a substance, compound, or agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, the compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, intraocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through the skin tract). The compound or agent can also be suitably delivered via rechargeable or biodegradable polymeric or other devices, e.g., patches and pumps, or formulations that provide sustained, sustained, or controlled release of the compound or agent. Administration can also be carried out, for example, once, multiple times, and / or over one or more extended periods.

[0069] The appropriate method of administering a substance, compound, or agent to a subject will depend, for example, on the age and / or physical condition of the subject, as well as the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or agent is administered to the subject orally, e.g., by ingestion. In some embodiments, the orally administered compound or agent is in a sustained- or time-release formulation or is administered using such a sustained- or time-release device.

[0070] As used herein, the term "co-administration" refers to any form of administration of two or more different therapeutic agents such that the previously administered therapeutic agent remains effective in the body while the second agent is administered (e.g., the two agents are effective in the patient at the same time, which may include a synergistic effect of the two agents). For example, the various therapeutic compounds can be administered simultaneously or sequentially in the same formulation or in separate formulations. Thus, an individual receiving such treatment can benefit from the combined effects of the various therapeutic agents.

[0071] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is an amount of the drug or agent that has the intended therapeutic effect when administered to a subject. The full therapeutic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount required for a subject will depend, for example, on the subject's size, health, and age, as well as the nature and extent of the condition, such as cancer or MDS, being treated. One of ordinary skill in the art can readily determine the effective amount for a given situation by routine experimentation.

[0072] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0073] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0074] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0075] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

[0076] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0077] The term "alkyl" refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, straight-chain or branched-chain alkyl groups have 30 or fewer carbon atoms in their main chain (e.g., C for straight chain). 1-30 , for branched chains, C 3-30 ), more preferably having 20 or fewer carbon atoms.

[0078] Furthermore, the term "alkyl," as used throughout the specification, examples, and claims, is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including, for example, haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0079] "C x-y " or "C x -C y The term " when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. CO alkyl indicates a hydrogen in the group's terminal position, and if internal, indicates a bond. For example, C 1-6 Alkyl groups contain 1 to 6 carbon atoms in the chain.

[0080] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0081] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0082] As used herein, the term "amide" refers to the following group: [ka] (In the formula, R 9 and R 10 each independently represents hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which it is attached, complete a heterocycle with 4 to 8 atoms in the ring structure.

[0083] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, for example, moieties that can be represented as: [ka] (In the formula, R 9 , R 10 , and R 10 ' each independently represent a hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle with 4 to 8 atoms in the ring structure).

[0084] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0085] The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group.

[0086] As used herein, the term "aryl" includes substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which at least one of the rings is aromatic and two or more carbons are common to two adjacent rings; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0087] The term "carbamate" is art-recognized and refers to the following group: [ka] (In the formula, R 9 and R 10 independently represent hydrogen or a hydrocarbyl group).

[0088] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0089] As used herein, the terms "carbocycle," "carbocyclyl," and "carbocyclic" refer to a non-aromatic saturated or unsaturated ring in which each atom of the ring is carbon. Preferably, the carbocycle contains 3 to 10 atoms, more preferably 5 to 7 atoms.

[0090] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0091] The term "carbonate" is art-recognized and refers to an --OCO.sub.2-- group.

[0092] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0093] As used herein, the term "ester" refers to an ester of -C(O)OR 9 R refers to the group 9 represents a hydrocarbyl group.

[0094] The term "ether," as used herein, refers to a hydrocarbyl group that is bonded to another hydrocarbyl group through an oxygen. Thus, an ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be either symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula: alkyl-O-alkyl.

[0095] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo, and iodo.

[0096] The terms "hetaralkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0097] The terms "heteroaryl" and "hetaryl" refer to a substituted or unsubstituted aromatic monocyclic ring structure, preferably a 5- to 7-membered ring, more preferably a 5- or 6-membered ring, in which the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, in which at least one of the rings is heteroaromatic, and the other cyclic rings, for example, can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0098] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0099] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocycle group.

[0100] The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to a substituted or unsubstituted non-aromatic ring structure, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring, which ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings and at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0101] The term "hydrocarbyl," as used herein, refers to a group bonded through a carbon atom that does not have an =O or =S substituent, typically having at least one carbon-hydrogen bond and a primarily carbon backbone, but which may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl for purposes of this application, but without substituents such as acetyl (which has an =O substituent on the bonded carbon) and ethoxy (which is bonded through an oxygen rather than a carbon). Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0102] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0103] The term "lower" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups in which there are 10 or fewer, preferably 6 or fewer atoms in the substituent. For example, "lower alkyl" refers to an alkyl group containing 10 or fewer, preferably 6 or fewer, carbon atoms. In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituent as defined herein, whether appearing alone or in combination with other substituents such as, specifically, hydroxyalkyl and aralkyl, is a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively (in which case, for example, when counting the carbon atoms in an alkyl substituent, the atoms in an aryl group are not counted).

[0104] The terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each of the rings of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10 atoms, preferably 5 to 7 atoms, in the ring.

[0105] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0106] The term "sulfonamide" is art-recognized and refers to a group that may be represented by the general formula: [ka] (In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl).

[0107] The term "sulfoxide" is art-recognized and refers to the group --S(O)--.

[0108] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0109] The term "sulfone" is art-recognized and refers to a -S(O)2- group.

[0110] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more backbone carbons. "Substituted" or "substituted with" will be understood to include the implicit proviso that such substitution results in a stable compound (e.g., one that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, etc.), subject to the permissible valences of the replacing atom and substituent. As used herein, the term "substituted" is considered to include all permissible substituents of organic compounds. In one broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. Substituents can include any of the substituents described herein, such as halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0111] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0112] As used herein, the term "thioester" refers to a thioester of -C(O)SR 9 group or -SC(O)R 9 R refers to the group 9 represents a hydrocarbyl.

[0113] The term "thioether" as used herein is equivalent to an ether where the oxygen has been replaced with a sulfur.

[0114] The term "urea" is art-recognized and may be represented by the general formula: [ka] (In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl).

[0115] As used herein, the term "modulate" includes inhibiting or suppressing a function or activity (eg, cell proliferation), as well as enhancing a function or activity.

[0116] The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers, and other materials, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0117] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to an acid addition salt or a base addition salt that is suitable or compatible for treatment in patients.

[0118] As used herein, the term "pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic salt of any basic compound represented by Formula I. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromide, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include monocarboxylic, dicarboxylic, and tricarboxylic acids, such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, and sulfonic acids, such as p-toluenesulfonic acid and methanesulfonic acid. Either mono- or di-acid salts can be formed, and such salts can exist in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points than their free base forms. The selection of an appropriate salt will be known to one skilled in the art. Other pharmaceutically unacceptable salts, such as oxalate, may be used, for example, in the isolation of compounds of formula I for laboratory use or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0119] As used herein, the term "pharmaceutically acceptable base addition salt" refers to any non-toxic organic or inorganic base addition salt of any acidic compound represented by Formula I or any of its intermediates. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and picoline or ammonia. The selection of an appropriate salt will be known to those skilled in the art.

[0120] Many of the compounds useful in the methods and compositions of the present disclosure have at least one stereocenter in their structure. This stereocenter may exist in the R or S configuration, and the R and S notations are used according to the rules set forth below: Pure Appl. Chem. (1976), 45, 11-30. The present disclosure contemplates all stereoisomeric forms, including enantiomeric and diastereomeric forms of compounds, salts, prodrugs, or mixtures thereof, including all possible mixtures of stereoisomers. See, for example, WO01 / 062726.

[0121] Furthermore, certain compounds containing alkenyl groups may exist as Z (Z-isomers) or E (E-isomers). In each case, the present disclosure includes both mixtures and separate individual isomers.

[0122] Some of the compounds may also exist in tautomeric forms, and such forms, although not explicitly represented in the formulae given herein, are intended to be included within the scope of the present disclosure.

[0123] A "prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized in a host after administration, e.g., hydrolyzed or oxidized, to form a compound of the present disclosure (e.g., a compound of Formula I). ​​Representative examples of prodrugs include compounds that have a biologically labile or cleavable (protecting) group on the functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to yield the active compound. Examples of prodrugs that use esters or phosphoramidates as the biologically labile or cleavable (protecting) group are disclosed in U.S. Pat. Nos. 6,875,751, 7,585,851, and 7,964,580 (the disclosures of which are incorporated herein by reference). The prodrugs of the present disclosure are metabolized to produce a compound of Formula I. The present disclosure includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs," Ed. H. Bundgaard, Elsevier, 1985.

[0124] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, useful in formulating a medicinal or therapeutic drug.

[0125] As used herein, the terms "Log of Solubility," "LogS," or "logS" are used in the art to quantify the water solubility of a compound. The water solubility of a compound significantly affects its absorption and distribution properties. Low solubility often results in poor absorption. The LogS value is the unit stripped logarithm (base 10) of solubility measured in mol / liter. [Example]

[0126] Having now generally described the invention, it will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0127] Example 1: Synthesis of JXL082 [ka] 1-(3,5-bis(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridine(2) To a solution of 7-azaindole 1 (5 mmol, 590 mg) in dry dimethylformamide (DMF, 10 mL) was added 3,5-bis(trifluoromethyl)benzyl bromide (1.2 equiv., 6 mmol, 1.32 mL) and KOH (1.2 equiv., 6 mmol, 402 mg) at 0 °C. The reaction mixture was stirred at 21 °C for 2 h. After completion of the reaction as indicated by TLC, water (30 mL) was added to the reaction vial. The reaction mixture was extracted with dichloromethane (30 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate = 12:1) to give the desired product 2 in 90% yield.

[0128] 1 H NMR (300 MHz, CDCl3) δ 8.40 (d, J = 4.7 Hz, 1H), 8.00 (dd, 1H, J = 7.8, 1.3 Hz, 1H), 7.84 (s, 1H), 7.72 (s, 2H), 7.24 (d, J = 3.5 Hz, 1H), 7.16 (dd, J = 7.8, 4.7 Hz, 1H), 6.60 (d, J = 3.5 Hz, 1H), 5.65 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 147.6, 143.5, 140.5, 132.1 (q, Jc-f = 33.6 Hz), 129.3, 127.5, 127.4, 123.1 (q, Jc-f = 273.3 Hz), 121.7, 120.5, 116.4, 101.3, 47.1.

[0129] 1-(3,5-bis(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (3) Phosphorus oxychloride (POCl3, 2 mmol, 180 μL) was added dropwise to DMF (4 mL) at 0 °C under argon. The reaction was stirred for 10 min, and then a solution of compound 2 (2 mmol, 668 mg) in DMF (4 mL) was added slowly with stirring. The mixture was kept at 21 °C overnight. The reaction was quenched by adding water (10 mL) at 0 °C and then extracted with dichloromethane (10 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate = 4:1) to give the desired aldehyde 3 in 85% yield.

[0130] 1 H NMR (500 MHz, CDCl3) δ 10.00 (s, 1H), 8.59 (d, J = 7.7 Hz, 1H), 8.46 (d, J = 4.6 Hz, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.77 (s, 2H), 7.32 (dd, J = 7.6, 4.8 Hz, 1H), 5.66 (s, 2H). 13 C NMR (126 MHz, CDCl3) δ 184.6, 148.3, 145.7, 138.7, 136.9, 132.5 (q, Jc-f = 33.6 Hz), 131.0, 128.0, 123.0 (q, Jc-f = 272.8 Hz), 122.4, 119.5, 117.6, 47.9.

[0131] Ethyl (E)-3-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyanoacrylate (JXL082) To a solution of aldehyde 3 (1 mmol, 372 mg) in ethanol (2 mL) was added ethyl 2-cyanoacetate (1.3 equiv., 1.3 mmol, 140 μL) and L-proline (40 mol%, 0.4 mmol, 58 mg). The reaction was stirred at 21 °C for 12 h, and a yellow solid gradually precipitated. After the reaction was complete, ice-cold water (2 mL) was added to the reaction vial. The solid was isolated by Buchner funnel filtration, washed with water (2 mL × 3), and dried to give the desired product JXL082 in 93% yield.

[0132] 1 H NMR (500 MHz, CDCl3) δ 8.64 (s, 1H), 8.51 (s, 1H), 8.48 (dd, J = 4.6, 1.2 Hz, 1H), 8.21 (dd, J = 7.9, 1.2 Hz, 1H), 7.83 (s, 1H), 7.77 (s, 2H), 7.34 (dd, J = 7.9, 4.6 Hz, 1H), 5.69 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 163.3, 147.6, 145.7, 145.0, 138.5, 132.7, 132.3 (q, Jc-f = 33.6 Hz), 127.9, 127.7, 123.1 (q, Jc-f = 273.3 Hz), 122.5, 120.3, 119.0, 117.6, 109.4, 97.0, 62.3, 48.3, 14.3.

[0133] Example 2: Synthesis of JXL069 Method 1: [ka] (E)-3-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyanoacrylic acid (JXL069) To a solution of JXL082 (0.21 mmol, 100 mg) in THF (2 mL) was added 0.5 N LiOH solution (3 equiv., 0.4 mmol, 0.8 mL). The reaction mixture was stirred at 21 °C for 1 h. After completion of the reaction as indicated by TLC, the THF was evaporated. Concentrated HCl was added dropwise to acidify the reaction mixture until the pH was below 1, during which a yellow solid precipitated. Ice-cold water (5 mL) was added to the reaction mixture, and the solid was filtered using a PYREX™ Hirsch funnel equipped with a fritted disk and washed with water (5 mL x 3). After drying in vacuo, the solid was washed 5–10 times with 2 mL of a 5:1 hexane:ethyl acetate solvent mixture and monitored by TLC until the disappearance of the nonpolar impurity (the nonpolar compound was the retroaldol condensation product 3, which could be recovered from the filtrate). Finally, the purity of the product JXL069 was checked by NMR. The product (50.7 mg) was isolated in 55% yield. See below for NMR data.

[0134] Method 2: (E)-3-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyanoacrylic acid (JXL069) [ka] tert-Butyl (E)-3-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyanoacrylate (4) To a solution of aldehyde 3 (1 mmol, 372 mg) in ethanol (2 mL) was added tert-butyl 2-cyanoacetate (1.3 equiv., 1.3 mmol, 183 μL) and L-proline (40 mol%, 0.4 mmol, 58 mg). The reaction was stirred at 21 °C for 12 h, and a yellow solid gradually precipitated. After completion of the reaction, ice-cold water (2 mL) was added to the reaction vial. The solid was isolated by Buchner funnel filtration, washed with water (2 mL × 3), and dried to give the desired product 4 in 90% yield.

[0135] 1 H NMR (500 MHz, CDCl3) δ 8.61 (s, 1H), 8.46 (d, J = 4.6 Hz, 1H), 8.42 (s, 1H), 8.17 (d, J = 7.9 Hz, 1H), 7.81 (s, 1H), 7.75 (s, 2H), 7.32 (dd, J = 7.9, 4.6 Hz, 1H), 5.69 (s, 2H), 1.58 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ 162.1, 147.5, 145.6, 144.0, 138.6, 132.4 (q, Jc-f = 32.8 Hz), 132.36, 127.8, 127.6, 123.6 (q, Jc-f = 274.0 Hz), 122.4, 120.3, 118.8, 117.7, 109.3, 98.5, 83.2, 48.2, 28.1.

[0136] (E)-3-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyanoacrylic acid (JXL069) To a solution of 4 (0.5 mmol, 247.5 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (5 equiv., 2.5 mmol, 191 μL). The reaction mixture was stirred at 21 °C for 30 min, and a yellow solid precipitated. After the reaction was complete as indicated by TLC, the reaction solvent was evaporated by ventilating the open flask. The solid was washed 5–10 times with 2 mL of a 5:1 hexane / EtOAc solvent mixture and monitored by TLC until all nonpolar impurities had disappeared. Finally, the purity of the product was checked by NMR. The product (208.5 mg) was isolated in 95% yield.

[0137] 1 H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.47 (m, 2H), 8.43 (m, 1H), 8.09 (s, 2H), 8.04 (s, 1H), 7.35 (dd, J = 7.1, 4.6 Hz, 1H), 5.84 (s, 2H). 13 C NMR (126 MHz, DMSO-d6) δ 164.6, 147.8, 146.1, 145.5, 140.6, 135.2, 131.0 (q, Jc-f = 32.8 Hz), 129.4, 129.2, 123.6 (q, Jc-f = 274.0 Hz), 122.3, 120.1, 119.1, 118.2, 108.7, 97.1, 47.8.

[0138] Incorporation by Reference All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0139] equivalent While specific embodiments of the invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of the specification and the following claims. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. The following are examples of embodiments of the present invention. [Embodiment 1] Compounds of formula (I) [ka] (In the formula, Each A is independently CH, CR 4 , or N, Y is a carboxyl, ester, amide, or [ka] and R 2 is CN or carboxyl, R 3 is H, aryl, aralkyl, or aralkylacyl, and one or more R 5 is optionally replaced by R 4 each instance of is independently alkyl, carboxyl, halo, hydroxy, ester, or CN; R 5 each instance of is independently selected from alkyl, alkoxy, or halo; R 7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; R 10 is hydrogen or alkyl) Alternatively, a process for preparing a pharmaceutically acceptable salt thereof, comprising the steps of: The method comprises: Reacting a compound of formula (Ic) with an acylating (e.g., formylating) reagent to produce a compound of formula (Id): [ka] reacting said compound of formula (Id) with a condensing agent of formula (Ie) to produce said compound of formula (I):

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Claims

1. A process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising: 【Chemical 1】 (In the formula, Each A is independently CH, CR ４ or N, with the proviso that at least one A is N; Y is a carboxyl, ester, amide, or 【Chemistry 2】 and R ２ is CN or carboxyl, R ３ is H, aryl, aralkyl, or aralkylacyl, and the aryl, aralkyl, or aralkylacyl is selected from one or more R ５ is optionally replaced by Each R ４ is independently unsubstituted or substituted alkyl, carboxyl, halo, hydroxy, ester, or CN; Each R ５ is independently selected from unsubstituted or substituted alkyl, alkoxy, or halo; R ７ is hydrogen, unsubstituted or substituted alkyl, halo, hydroxyl, alkoxy, or acyloxy; R １０ is hydrogen or unsubstituted or substituted alkyl The method comprises: reacting a compound of formula (Ic) with an acylating (e.g., formylating) reagent to produce a compound of formula (Id); and 【Chemistry 3】 reacting said compound of formula (Id) with a condensing agent of formula (Ie) to produce said compound of formula (I): 【Chemistry 4】 The method comprising:

2. 10. The method of claim 1, further comprising hydrolyzing the compound of formula (I) to produce a compound of formula (If): 【Chemistry 5】

3. further comprising reacting the compound of formula (Ia) with an alkylating reagent of formula (Ib) to produce a compound of formula (Ic): 【Chemistry 6】 wherein W is a leaving group (e.g., halo).

3. The method of claim 1 or 2, wherein R3 is aryl, aralkyl, or aralkylacyl, and R3 is optionally substituted with one or more R5.

4. A method according to any one of claims 1 to 3, wherein one A is N.

5. The method of claim 3, wherein compound (Ia) is: 【Chemistry 7】

6. R ２ The method according to any one of claims 1 to 5, wherein is CN.

7. R ３ The method according to any one of claims 1 to 6, wherein is benzyl.

8. R ３ is benzyl, and one or more R ５ The method of any one of claims 1 to 6, wherein the substituted

9. R ３ is aryl, aralkyl, or aralkylacyl, and one or two R ５ and each R ５ The method of any one of claims 1 to 8, wherein is independently selected from fluoroalkyl or fluoro.

10. R ３ is aryl, aralkyl, or aralkylacyl, and two R ５ and each R ５ The method of any one of claims 1 to 8, wherein is trifluoromethyl.

11. R ７ The method of any one of claims 1 to 10, wherein is hydrogen, hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy).

12. R ７ The method of any one of claims 1 to 11, wherein is hydrogen.

13. The method of any one of claims 3 to 12, wherein the leaving group W of the alkylating reagent is halo.

14. 14. The method of any one of claims 3 to 13, wherein the leaving group W of the alkylating reagent is bromide.

15. The method of any one of claims 3 to 14, wherein the alkylating reagent is: 【Chemistry 8】

16. The method of any one of claims 1 to 15, wherein the acylating reagent is phosphorus oxychloride.

17. The method of any one of claims 1 to 16, wherein the condensing agent is ethyl 2-cyanoacetate or tert-butyl 2-cyanoacetate.

18. The method of any one of claims 1 to 17, wherein the compound of formula (I) is: 【Chemistry 9】

19. The method of any one of claims 2 to 18, wherein the compound of formula (If) is: 【Chemistry 10】

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