Dihydrobenzofuran and inden analogs as cardiac sarcomere inhibitors

Abstract

To provide methods for treating diseases.SOLUTION: Provided are compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein A, Z, B, R1, R2, R3, G1, G2 and G3 are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in methods for the treatment of heart diseases through cardiac sarcomere inhibition.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 619,643, filed on January 19, 2018, entitled "CARDIAC SARCOMERE INHIBITORS" and U.S. Provisional Patent Application No. 62 / 745,724, filed on October 15, 2018, entitled "CARDIAC SARCOMERE INHIBITORS", the entire contents of which are hereby incorporated by reference for all purposes.

[0002] Heterocyclic compounds, pharmaceutical compositions containing such compounds, and methods of treating various heart diseases and conditions with such compounds are provided herein.

Background Art

[0003] This disclosure relates to certain chemical entities that selectively modulate the sarcomere, specifically, certain chemical entities, pharmaceutical compositions, and methods for treating various heart diseases and conditions.

[0004] The sarcomere is composed of a network of contractile and structural proteins that regulate myocardial function. The components of the sarcomere are targeted for the treatment of various heart diseases and conditions, for example, by increasing contractility or promoting complete relaxation to modulate contractile and diastolic functions respectively. The force and velocity of myocardial contraction are major determinants of organ function and are modulated by the periodic interaction of actin and myosin. The regulation of actin - myosin binding is determined by the network of thin - filament regulatory proteins and the intracellular Ca 2+ level. Troponin complex and tropomyosin are thin - filament proteins that govern the availability of the actin - binding site, and essential and regulatory light chains, as well as myosin - binding protein C, modulate the position and mechanical properties of myosin.

[0005] Abnormalities in the sarcomere have been identified as a cause driving various heart diseases and conditions such as hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF). Mutations in sarcomeric proteins cause disease by bringing about either "high" or "low" contractility in the myocardium. By using sarcomere modulators, contractility can be rebalanced, and the disease process can be halted or reversed. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0006] Current agents targeting the sarcomere, such as inotropes (drugs that increase the contractile ability of the heart), lack selectivity for heart tissue, thereby resulting in recognized adverse effects that limit the use of inotropes. These adverse effects include cell damage caused by increased energy consumption rate, aversion to relaxation abnormalities, and potential arrhythmogenic side effects that may result from increased cytosolic Ca++ and cyclic AMP concentrations in the myocardium stimulated by the inotropic action. Considering the limitations of current agents, new approaches are needed to improve cardiac function in HCM and HFpEF.

[0007] There remains a strong need for agents that explore new mechanisms of action and can have better outcomes with respect to symptom relief, safety, and patient mortality both in the short - term and long - term. New agents with an improved therapeutic index compared to current agents will provide a means to achieve these clinical outcomes. The selectivity of agents targeting the sarcomere (e.g., by targeting cardiac myosin) has been identified as an important means to achieve this improved therapeutic index. The present disclosure provides such agents (particularly sarcomere inhibitors), and methods of using them. These agents are selective allosteric inhibitors of cardiac myosin that have little or no effect on smooth muscle myosin. The benefits of these compounds include a broader therapeutic index, less impact on heart relaxation, better pharmacokinetics, and better safety. ​

[0008] The present disclosure provides chemical entities, pharmaceutical compositions and methods for the treatment of heart failure, including HCM and HFpEF. The compositions are inhibitors of the myocardial segment, for example, inhibitors of myocardial myosin.

[0009] In one aspect, Formula (I):

Chemical formula

[0010] In some embodiments of formula (I) or any variant thereof, such as formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik) or a pharmaceutically acceptable salt thereof, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each H.

[0011] In some embodiments of formula (I) or any variant thereof, G1 is -CR 4 R 5 -. In some embodiments, G1 is -CH2-. In other embodiments, G1 is -O-. In some embodiments, G2 is a bond. In some embodiments, G2 is -CR 6 R 7 -. In other embodiments, G2 is -CH2-. In some embodiments, G3 is -CR 8 -. In certain embodiments, G3 is -CH-. In some embodiments, G3 is -N-.

[0012] In some embodiments of formula (I) or any variant thereof, R 1 , R 2 and R 3are each H. In some embodiments, Z is a bond. In some embodiments, Z is -O-. In other embodiments, Z is -N(R 9 ).

[0013] In some embodiments of formula (I) or any variant thereof, A is selected from the group consisting of substituted C2 alkynyl, unsubstituted C2 alkynyl, substituted phenyl, unsubstituted phenyl, and 5- or 6-membered heteroaryl containing at least one ring N atom, the 5- or 6-membered heteroaryl being unsubstituted or substituted with one or more R 10 substituents, each R 10 being independently selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, 3- to 12-membered substituted or unsubstituted heterocycloalkyl and -C(O)OR a . In some embodiments, each R 10 is independently selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, 5- to 6-membered substituted or unsubstituted heterocycloalkyl and -C(O)OR a .

[0014] In some embodiments of formula (I) or any variant thereof, A is selected from the group consisting of substituted phenyl, unsubstituted phenyl, and 5- or 6-membered heteroaryl containing at least one ring N atom, the 5- or 6-membered heteroaryl being unsubstituted or substituted with one or more R 10 substituents. In some embodiments, A is selected from the group consisting of phenyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, tetrazolyl , triazolyl, thiazolyl, pyrimidinyl, pyridinyl, pyrazinyl and pyridazinyl, each of which is unsubstituted or substituted with one or more R 10 substituents.

[0015] In some embodiments of formula (I) or any variant thereof, A is:

Chemical formula

[0016] In some embodiments of formula (I) or any variant thereof, A is oxadiazolyl, which is unsubstituted or substituted with methyl; methyl substituted with -OCH3, -OH or -OC(O)CH3; ethyl; ethyl substituted with -OCH3, -OH or -OC(O)CH3; isopropyl; isopropyl substituted with -OCH3, -OH or -OC(O)CH3; difluoromethyl; cyclopropyl; cyclobutyl; oxetanyl; and one substituent selected from the group consisting of -C(O)OCH3. In some embodiments, A is oxadiazolyl, which is unsubstituted or substituted with one substituent selected from the group consisting of methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl and cyclobutyl.

[0017] In some embodiments of formula (I) or any variant thereof, A is isoxazolyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of methyl, ethyl and difluoromethyl. In some embodiments, A is isoxazolyl, which is unsubstituted or substituted with one substituent selected from the group consisting of methyl, ethyl and difluoromethyl.

[0018] In some embodiments of formula (I) or any variant thereof, A is

Chemical formula

[0019] In some embodiments of formula (I) or any variant thereof, B is selected from the group consisting of H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl of B is unsubstituted or substituted by one or more R 11 substituents, and each R 11 is independently selected from the group consisting of heterocycloalkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, halo, fluoroalkyl, -OR b , -C(O)R c , -C(O)OR d , oxo, and -NR e R f , and each heterocycloalkyl and heteroaryl of R 11 is unsubstituted or substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, -C(O)R n , -C(O)OR p , and -C(O)NR q R r , and each R b , R c , R d , R e , R f , R n , R p , R q and R r is independently H or C1-C6 alkyl. In some embodiments of formula (I) or any variant thereof, B is selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 12 aryl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, and the C1-C6 alkyl, C3-C8 cycloalkyl, C6-C12 Aryl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are each unsubstituted or substituted by one or more R 11 substituents. In some embodiments, B is unsubstituted or substituted by one or more R 11 substituents, and each R 11 is independently selected from the group consisting of 3- to 12-membered substituted or unsubstituted heterocycloalkyl, 5- to 10-membered substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 12 aryl, unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted by one or more R 12 substituents, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halo, -OR b , -C(O)R c , -C(O)OR d , oxo, and -NR e R f selected independently from the group consisting of. In some embodiments, B is unsubstituted or substituted by one or more R 11 substituents, and each R 11 is independently selected from the group consisting of 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl, C6-C 12 aryl, C1-C6 alkyl, halo, fluoroalkyl, -OR b , -C(O)R c , -C(O)OR d , oxo, and -NR e R f selected independently from the group consisting of, and each heterocycloalkyl and heteroaryl of R 11 is unsubstituted or substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, -C(O)R n , -C(O)OR p and -C(O)NR q R r selected from the group consisting of, and each R b , R c , R d , Re , R f , R n , R p , R q and R r are, independently, H or C1-C6 alkyl. In some embodiments, each heterocycloalkyl or heteroaryl of R 11 contains 1, 2, 3, 4 or 5 heteroatoms selected from the group consisting of N, O and S. In some embodiments of formula (I) or any variant thereof, B is phenyl which is unsubstituted or substituted by one or more R 11 substituents. In some embodiments, B is a 5- to 6-membered heterocycloalkyl which is unsubstituted or substituted by one or more R 11 substituents. In other embodiments, B is a 5- to 6-membered heteroaryl which is unsubstituted or substituted by one or more R 11 substituents.

[0020] In some embodiments of formula (I) or any variant thereof, B is selected from the group consisting of C1-C4 alkyl, C3-C5 cycloalkyl, 6- to 10-membered aryl (e.g., 6- to 9-membered aryl), 4- to 6-membered heterocycloalkyl containing at least one ring N or O atom, 5- or 6-membered monocyclic heteroaryl containing at least one ring N atom, and 8- or 9-membered bicyclic heteroaryl containing at least one ring N atom, each of which is substituted or unsubstituted. In some embodiments, B is selected from the group consisting of C1-C4 alkyl, C3-C5 cycloalkyl, 6- to 10-membered aryl, 4- to 6-membered heterocycloalkyl containing at least one ring N or O atom, 5- or 6-membered monocyclic heteroaryl containing at least one ring N atom, or 8- or 9-membered bicyclic heteroaryl containing at least one ring N atom, each of which is unsubstituted or substituted by one or more R 11 substituents, and each R 11 is heterocycloalkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, halo, fluoroalkyl, -ORb 、 -C(O)R c 、 -C(O)OR d 、 oxo and -NR e R f independently selected from the group consisting of, R 11 each heterocycloalkyl and heteroaryl of is unsubstituted or C1-C6 alkyl, -C(O)R n 、 -C(O)OR p and -C(O)NR q R r selected from the group consisting of one or more substituents, R 11 each C1-C6 alkyl of is unsubstituted or -OR b substituted by, each R b 、 R c 、 R d 、 R e 、 R f 、 R n 、 R p 、 R q and R r is independently H or C1-C6 alkyl.

[0021] In some embodiments of formula (I) or any variant thereof, B is methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, indanyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, indanyl, pyrrolopyrazolyl and benzimidazolyl selected from the group consisting of, each of which is unsubstituted or one or more R 11 substituted by substituents, each R 11 is heterocycloalkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, halo, fluoroalkyl, -OR b 、 -C(O)R c 、 -C(O)ORd 、 oxo and -NR e R f independently selected from the group consisting of, and each heterocycloalkyl and heteroaryl of R 11 is unsubstituted or is substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, -C(O)R n 、 -C(O)OR p and -C(O)NR q R r wherein each C1-C6 alkyl of R 11 is unsubstituted or is substituted by -OR b and each R b 、 R c 、 R d 、 R e 、 R f 、 R n 、 R p 、 R q and R r is independently H or C1-C6 alkyl. In some embodiments, each R 11 is independently selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, oxo, -C(O)CH3, -C(O)OtBu, -OCH3, -OH, -NH2, -Cl, oxetanyl, oxadiazolyl and azetidinyl, and each oxadiazolyl and azetidinyl of R 11 is unsubstituted or is substituted with one or more substituents selected from the group consisting of ethyl, -C(O)CH3, -C(O)OtBu, -C(O)OCH3, -C(O)NHCH3, -C(O)NH2 and -OCH3, and each methyl, ethyl and isopropyl of R 11 is unsubstituted or is substituted by -OH.

[0022] In some embodiments of formula (I) or any variant thereof, B is methyl, pyrazolyl, oxazolyl, tetrazolyl, isoxazolyl, thiazolyl, imidazolyl or pyridinyl, each of which is unsubstituted or is substituted with one or more R 11 substituents, and each R11 is selected independently from the group consisting of heterocycloalkyl, heteroaryl, halo, C1-C6 alkyl, C1-C6 alkyl substituted with one or two R 12 substituents, cycloalkyl, cycloalkyl substituted with one or two R 12 substituents, fluoroalkyl, -OR b , -C(O)R c , -C(O)OR d , oxo and -NR e R f and is selected independently from the group consisting of each R 12 is halo, -OR b , -C(O)R g , -C(O)OR h and -C(O)NR i R j and is selected independently from the group consisting of each R b , R c , R d , R e , and R f , R g , R h , R i , and R j is independently H or C1-C6 alkyl. In some embodiments, B is pyrazolyl, oxazolyl, tetrazolyl, isoxazolyl, thiazolyl, imidazolyl or pyridinyl, each of which is unsubstituted or substituted with one or more R 11 substituents, and each R 11 is selected independently from the group consisting of heterocycloalkyl, heteroaryl, halo, C1-C6 alkyl, C1-C6 alkyl substituted with one or two R 12 substituents, cycloalkyl, cycloalkyl substituted with one or two R 12 substituents, fluoroalkyl, -OR b , oxo and -NR e R f and is selected independently from the group consisting of each R 12 is halo, -OR b and -C(O)NR i R j and is selected independently from the group consisting of Rb , R e , R f , R i and R j are, independently, H or C1-C6 alkyl. In some embodiments, R b is H.

[0023] In some embodiments of formula (I) or any variant thereof, B is

Chemical formula

[0024] In some embodiments of formula (I) or any variant thereof, B is

Chemical formula

Chem.

[0025] In some embodiments, compounds selected from the group consisting of the compounds of Table 1, or pharmaceutically acceptable salts thereof, are provided.

[0026] In one aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0027] In one aspect, there is provided a method of treating a heart disease in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or any variant thereof. In some embodiments, the heart disease is hypertrophic cardiomyopathy (HCM). In some embodiments, the HCM is obstructive or non-obstructive, or is caused by sarcomeric and / or non-sarcomeric mutations. In some embodiments, the heart disease is heart failure with preserved ejection fraction (HFpEF). In some embodiments, the heart disease is selected from the group consisting of diastolic dysfunction, primary or secondary restrictive cardiomyopathy, myocardial infarction and angina, and left ventricular outflow tract obstruction. In some embodiments, the heart disease is hypertensive heart disease, congenital heart disease, myocardial ischemia, coronary artery disease, diabetic heart disease, congestive heart failure, right heart failure, cardiorenal syndrome or infiltrative cardiomyopathy. In some embodiments, the heart disease is or is associated with cardiac senescence and / or diastolic dysfunction due to aging. In some embodiments, the heart disease is or is associated with left ventricular hypertrophy and / or concentric left ventricular remodeling.

[0028] In another aspect, there is provided a method of treating a disease or condition associated with HCM in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or any variant thereof. In some embodiments, the disease or condition is selected from the group consisting of Fabry disease, Danon disease, mitochondrial cardiomyopathy, and Noonan syndrome.

[0029] In some aspects, there is provided a method of treating a disease or condition associated with secondary left ventricular wall thickening in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or any variant thereof. In some embodiments, the disease or condition is selected from the group consisting of hypertension, valvular heart disease (aortic stenosis, mitral regurgitation), metabolic syndrome (diabetes, obesity), end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich's ataxia, Danon disease, Noonan syndrome, and Pompe disease.

[0030] In other aspects, there are provided methods of treating diseases or conditions associated with small left ventricular cavity and lumen obstruction, hyperdynamic left ventricular contraction, myocardial ischemia, or myocardial fibrosis. Also provided are methods of treating muscular dystrophy (e.g., Duchenne muscular dystrophy) or glycogenosis.

[0031] There is also provided a method of inhibiting a cardiomyocyte, the method comprising contacting the cardiomyocyte with a compound of formula (I) or any variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or any variant thereof. DETAILED DESCRIPTION OF THE INVENTION

[0032] Definition As used herein, the following words and phrases generally are intended to have the meanings as set forth below, unless the context in which they are used indicates otherwise.

[0033] Throughout this application, unless the context specifically indicates otherwise, references to compounds of formula (I) include all substructures, subgenera, priorities, embodiments, examples, and specific compounds as defined and / or described herein, including all subgroups of formula (I) as defined herein, such as formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik). References to compounds of formula (I) and their subgroups, such as formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik), include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes, and / or their protected forms. In some embodiments, references to compounds of formula (I) and their subgroups, such as formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik), include their polymorphs, solvates, co-crystals, isomers, tautomers, and / or oxides. In some embodiments, references to compounds of formula (I) and their subgroups, such as formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik), include their polymorphs, solvates, and / or co-crystals. In some embodiments, references to compounds of formula (I) and their subgroups, such as formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik), include their isomers, tautomers, and / or oxides. In some embodiments, references to compounds of formula (I) and their subgroups, such as formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik), include their solvates. Similarly, the term "salt" includes solvates of the salts of the compounds.

[0034] "Alkyl" includes straight-chain and branched carbon chains having the indicated number of carbon atoms, for example, from 1 to 20 carbon atoms, or from 1 to 8 carbon atoms, or from 1 to 6 carbon atoms. For example, C 1~6 Alkyl includes both straight-chain and branched-chain alkyls of 1 to 6 carbon atoms. When naming an alkyl residue having a specific number of carbons, all branched and straight-chain versions having that number of carbons are intended to be included. Thus, for example, "propyl" includes n-propyl and isopropyl, and "butyl" includes n-butyl, sec-butyl, isobutyl, and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0035] When a range of values is given (e.g., C 1~6 alkyl), each value within the range, and all intervening ranges, are included. For example, "C 1~6 alkyl" includes C1, C2, C3, C4, C5, C6, C 1~6 , C 2~6 , C 3~6 , C 4~6 , C 5~6 , C 1~5 , C 2~5 , C 3~5 , C 4~5 , C 1~4 , C 2~4 , C 3~4 , C 1~3 , C 2~3 and C 1~2 alkyl.

[0036] "Alkenyl" refers to a branched or straight-chain unsaturated alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group can be in either the cis or trans configuration (Z or E configuration) with respect to the double bond. Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl) and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl -prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl).

[0037] "Alkynyl" refers to a branched or straight-chain unsaturated alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl) and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl).

[0038] "Cycloalkyl" refers to a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10 or 3 to 8 or 3 to 6 ring carbon atoms. The cycloalkyl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, as well as bridged and cage-type ring groups (e.g., norbornane, bicyclo[2.2.2]octane). Further, one ring of a polycyclic cycloalkyl group may be aromatic, provided that the polycyclic cycloalkyl group is attached to the parent structure via a non-aromatic carbon. For example, the 1,2,3,4-tetrahydronaphthalen-1-yl group (the moiety is attached to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (the moiety is attached to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of cycloalkyl groups fused to an aromatic ring are described below.

[0039] "Cycloalkenyl" refers to a non-aromatic carbocyclic ring containing the indicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond. The cycloalkenyl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl, as well as bridged and basket-type ring groups (e.g., bicyclo[2.2.2]octene). Further, one ring of a polycyclic cycloalkenyl group may be aromatic, provided that the polycyclic cycloalkenyl group is attached to the parent structure through a non-aromatic carbon atom. For example, inden-1-yl (the moiety is attached to the parent structure through a non-aromatic carbon atom) is considered a cycloalkenyl group, while inden-4-yl (the moiety is attached to the parent structure through an aromatic carbon atom) is not considered a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups consisting of cycloalkenyl groups fused to an aromatic ring are described below.

[0040] "Aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon atoms, e.g., 6 to 12 or 6 to 10 carbon atoms. The aryl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some examples, both rings of the polycyclic aryl group are aromatic (e.g., naphthyl). In other examples, the polycyclic aryl group may include a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is attached to the parent structure through an atom in the aromatic ring. Thus, the 1,2,3,4-tetrahydronaphthalen-5-yl group (the moiety is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydronaphthalen-1-yl (the moiety is attached to the parent structure through a non-aromatic carbon atom) ) is not considered an aryl group. However, the term "aryl" does not include, and is not overlapping with, "heteroaryl" as defined herein regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some examples, aryl is phenyl or naphthyl. In certain cases, aryl is phenyl. Additional examples of aryl groups containing an aromatic carbocyclic ring fused to a non-aromatic ring are described below.

[0041] "Heteroaryl" refers to an aromatic ring (e.g., 5- to 12-membered or 5- to 10-membered heteroaryl) containing a display number of atoms composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon. The heteroaryl group does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the heteroaryl group is 1 or less. Unless otherwise indicated, the heteroaryl group may be attached to the parent structure by a carbon or nitrogen atom as permitted by valence. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl groups, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl groups.

[0042] In some examples, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine), and tetrazine.

[0043] In some examples, both rings of the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pi Lysine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole are included.

[0044] In other examples, the polycyclic heteroaryl group may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the heteroaryl ring, provided that the polycyclic heteroaryl group is attached to the parent structure through an atom in the aromatic ring. For example, the 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (the moiety is attached to the parent structure through an aromatic carbon atom) is regarded as a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (the moiety is attached to the parent structure through a non-aromatic carbon atom) is not regarded as a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non-aromatic ring are described below.

[0045] "Heterocycloalkyl" refers to a non-aromatic, fully saturated ring (e.g., 3- to 10-membered or 3- to 7-membered heterocycloalkyl) having a indicated number of atoms composed of one or more heteroatoms selected from N, O, and S (e.g., one, two, three, or four heteroatoms), with the remaining ring atoms being carbon. The heterocycloalkyl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Further, one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkyl group is attached to the parent structure via a non-aromatic carbon or nitrogen atom. For example, the 1,2,3,4-tetrahydroquinolin-1-yl group (the moiety is attached to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while the 1,2,3,4-tetrahydroquinolin-8-yl group (the moiety is attached to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of heterocycloalkyl groups fused to an aromatic ring are described below.

[0046] "Heterocycloalkenyl" has a number of atoms composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon, and at least one double bond being derived from the removal of one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl, and represents a non-aromatic ring (e.g., 3- to 10-membered or 3- to 7-membered heterocycloalkyl). The heterocycloalkenyl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro- 1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). Further, one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkenyl group is attached to the parent structure via a non-aromatic carbon or nitrogen atom. For example, the 1,2-dihydroquinolin-1-yl group (the moiety is attached to the parent structure via a non-aromatic nitrogen atom) is regarded as a heterocycloalkenyl group, while the 1,2-dihydroquinolin-8-yl group (the moiety is attached to the parent structure via an aromatic carbon atom) is not regarded as a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups composed of heterocycloalkenyl groups fused to an aromatic ring are described below.

[0047] Examples of polycyclic rings composed of aromatic rings (e.g., aryl or heteroaryl) fused to non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one, 1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran-3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)-one, benzo[d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one, benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazolin-2,4(1H,3H)-dione, quinoxalin-2(1H)-one, quinoxalin-2,3(1H,4H)-dione, cinnolin-4(3H)-one, pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one and 4,5-dihydropyrrolo[3,4-d]thiazol-6-one are included. As discussed herein, whether each ring is considered to be an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group depends on the atom to which the moiety is attached to the parent structure, which is determined.

[0048] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0049] Unless otherwise indicated, the compounds disclosed and / or described herein include all possible enantiomers, diastereomers, meso isomers and other stereoisomeric forms, including racemic mixtures, optically pure forms and intermediate mixtures thereof. Enantiomers, diastereomers, meso isomers and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. Unless otherwise specified, when a compound disclosed and / or described herein contains an olefinic double bond or other center of geometric asymmetry, this compound is intended to include both E and Z isomers. When a compound described herein contains a moiety capable of tautomerization and unless otherwise specified, the compound is intended to include all possible tautomers.

[0050] "Protecting group" has, in organic synthesis, the meaning customarily associated with "protecting group", i.e., a group that has the ability to selectively block one or more reactive sites in a polyfunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can be readily removed after completion of the selective reaction. A variety of protecting groups are disclosed, for example, in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a "hydroxy-protected form" contains at least one hydroxy group protected by a hydroxy protecting group. Similarly, amines and other reactive groups may be protected as well.

[0051] The term "pharmaceutically acceptable salt" refers to any salt of a compound herein that is known to be non-toxic and is commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salts of the compounds retain the biological effectiveness of the compounds described herein and are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from the salts of ammonium, potassium, sodium, calcium, and magnesium.

[0052] When the compounds described herein are obtained as acid addition salts, the free base is It can be obtained by making the solution of the acid salt basic. Conversely, when the compound is a free base, addition salts, particularly pharmaceutically acceptable addition salts, can be formed by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art are aware of the various synthetic methodologies that can be used to prepare pharmaceutically acceptable addition salts.

[0053] A "solvate" is formed by the interaction of a solvent with a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates having any ratio of the compound to water, such as monohydrates, dihydrates, and hemihydrates.

[0054] The term "substituted" means that the specified group or moiety has one or more substituents including, but not limited to, substituents such as alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyl-oxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azide, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocyclyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy. The term "unsubstituted" means that the specified group has no substituents. When the term "substituted" is used to describe a structural system, substitution means that substitution occurs at any position allowed by the valency of the atoms in the system. It is understood that when a group or moiety has more than one substituent, the substituents may be the same or different from each other. In some embodiments, the substituted group or moiety has 1 to 5 substituents. In some embodiments, the substituted group or moiety has 1 substituent. In some embodiments, the substituted group or moiety has 2 substituents. In some embodiments, the substituted group or moiety has 3 substituents. In some embodiments, the substituted group or moiety has 4 substituents. In some embodiments, the substituted group or moiety has 5 substituents.

[0055] "Optional" or "optionally" means that the event or situation described thereafter may or may not occur, and that the description includes both the case where the event or situation occurs and the case where it does not occur. For example, "optionally substituted alkyl" includes both "alkyl" and "substituted alkyl" as defined herein. With respect to any group containing one or more substituents, it will be understood by those skilled in the art that such groups are not intended to introduce any substitutions or substitution patterns that are sterically impracticable, synthetically infeasible, and / or inherently unstable. It will also be understood that when a group or moiety is optionally substituted, the present disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0056] The compounds disclosed and / or described herein can be in enriched isotopic forms, such as 2 H, 3 H, 11 C, 13 C and / or 14 C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be prepared, for example, by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds may improve the effectiveness of the compounds disclosed and / or described herein and increase their duration of action. Deuterium-substituted compounds can be synthesized using a variety of methods, such as those described in Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0057] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. The use of any conventional media or agent is contemplated in the pharmaceutical composition, except where any such media or agent would be incompatible with the active ingredient. Optionally active ingredients can also be incorporated into the pharmaceutical composition.

[0058] The terms "patient", "individual" and "subject" refer to an animal such as a mammal, bird or fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans. In some embodiments, the patient or subject is a human, e.g., a human who is the target of treatment, observation or experiment, or who will be the target of these. The compounds, compositions and methods described herein can be useful for both human therapy and veterinary applications.

[0059] As used herein, the term "therapeutic" refers to the ability to modulate a myocardial segment. As used herein, "modulation" refers to a change in activity as a direct or indirect response to the presence of a chemical entity described herein, compared to the activity in the absence of the chemical entity. The change can be an increase or a decrease in activity and can be due to a direct interaction of the chemical entity with its target or due to an interaction of the chemical entity with one or more other factors that later affect the activity of the target. For example, the presence of a chemical entity can increase or decrease target activity (directly or indirectly) by, for example, directly binding to the target, increasing or decreasing target activity (directly or indirectly) of another factor, or increasing or decreasing (directly or indirectly) the amount of target present in a cell or organism.

[0060] The term "therapeutically effective amount" or "effective amount" refers to the amount of a compound disclosed and / or described herein that is sufficient to affect a treatment as defined herein when administered to a patient in need of such treatment. The therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation of a myocardial segment. The therapeutically effective amount will vary depending, for example, on the subject being treated and the disease state, the body weight and age of the subject, the severity of the disease state, the particular compound, the dosing regimen followed, the timing of administration, the mode of administration, all of which can be readily determined by one of ordinary skill in the art. The therapeutically effective amount may be determined experimentally, for example, by assaying the blood concentration of the chemical entity or theoretically by calculating the bioavailability.

[0061] "Treatment" (and related terms such as "treat", "treated", "treating") means preventing a disease or disorder (i.e., not causing the clinical symptoms of the disease or disorder) including one or more of inhibiting a disease or disorder, slowing or arresting the onset of clinical symptoms of a disease or disorder, and / or alleviating a disease or disorder (i.e., causing alleviation or regression from clinical symptoms). The terms encompass situations where the disease or disorder has already been experienced by the patient and situations where the disease or disorder has not currently been experienced but is expected to occur. The terms encompass both complete or partial reduction or prevention of a condition or disorder and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, the compounds described and / or disclosed herein can prevent an existing disease or disorder from worsening, assist in the management of a disease or disorder, or reduce or eliminate a disease or disorder. When used prophylactically, the compounds disclosed and / or described herein can prevent a disease or disorder from occurring or reduce the extent of a disease or disorder that is at risk of occurring.

[0062] "ATPase" refers to an enzyme that hydrolyzes ATP. ATPases include proteins that include molecular motors such as myosin.

[0063] As used herein, "selectively bind" or "binds selectively" refers to preferentially binding to a target protein in one type of muscle or muscle fiber as contrasted with other types. For example, if a compound preferentially binds to troponin C in the troponin complex of fast skeletal muscle fibers or sarcomeres as compared to troponin C in the troponin complex of slow muscle fibers or sarcomeres, or in the troponin complex of cardiac sarcomeres, the compound selectively binds to fast skeletal troponin C.

[0064] Compound Compounds and their salts (such as pharmaceutically acceptable salts) are detailed herein, including in the brief summary and the appended claims. Also provided are the uses of all compounds described herein, including racemic mixtures, salts, and solvates of the compounds described, and all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and mixtures thereof in any ratio, as well as methods for making such compounds. Any compound described herein may also be referred to as a drug.

[0065] In one aspect, formula (I):

Chemical formula

[0066] In some embodiments of formula (I), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently H. In some embodiments of formula (I), at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is not H.

[0067] In some variant forms of formula (I) described herein, G1 is -CR 4 R 5 -. In some embodiments, one of R 4 and R 5 is H, C1-C6 alkyl, halo or hydroxyl, and the other is C1-C6 alkyl, halo or hydroxyl. In some embodiments, one of R 4 and R 5 is H and the other is C1-C6 alkyl, halo or hydroxyl. In some embodiments, R4 and R 5 Both are H, and thus, G1 becomes -CH2-. In some embodiments of formula (I) described herein, G1 is -O-.

[0068] In some embodiments of formula (I), G2 is a bond. In some embodiments, G2 is -CR 6 R 7 -. In some embodiments, R 6 and R 7 One of them is H, C1-C6 alkyl, halo or hydroxyl, and the other is C1-C6 alkyl, halo or hydroxyl. In some embodiments, R 6 and R 7 One of them is H, and the other is C1-C6 alkyl, halo or hydroxyl. In some embodiments, R 6 and R 7 Both are H, and thus, G2 becomes -CH2-.

[0069] In some embodiments of formula (I), G3 is -CR 8 -, and R 8 is C1-C6 alkyl, halo or hydroxyl. In some embodiments, R 8 is H, and thus, G3 becomes -CH-. In some embodiments, G3 is -N-.

[0070] In some embodiments of formula (I), G1 is -CR 4 R 5 -, and G2 is a bond. In certain embodiments, G1 is -CH2-, and G2 is a bond. In some embodiments, G1 is -CR 4 R 5 -, and G2 is -CR 6 R 7 -. In certain embodiments, G1 and G2 are each -CH2-. In some embodiments, G1 is -O-, and G2 is a bond. In some embodiments, G1 is -O-, and G2 is -CR 6 R 7- is. In certain embodiments, G1 is -O-, and G2 is -CH2-. In some embodiments, G1 is -CR 4 R 5 -, G2 is a bond, and G3 is -CR 8 -. In certain embodiments, G1 is -CH2-, G2 is a bond, and G3 is -CH-. In some embodiments, G1 is -CR 4 R 5 -, G2 is -CR 6 R 7 -, and G3 is -CR 8 -. In certain embodiments, G1 and G2 are each -CH2-, and G3 is -CH-. In some embodiments, G1 is -O-, G2 is a bond, and G3 is -CR 8 -. In certain embodiments, G1 is -O-, G2 is a bond, and G3 is -CH-. In some embodiments, G1 is -O-, G2 is -CR 6 R 7 -, and G3 is -CR 8 -. In certain embodiments, G1 is -O-, G2 is -CH2-, and G3 is -CH-. In some embodiments, G1 is -CR 4 R 5 -, G2 is a bond, and G3 is -N-. In certain embodiments, G1 is -CH2-, G2 is a bond, and G3 is -N-. In some embodiments, G1 is -CR 4 R 5 -, G2 is -CR 6 R 7 -, and G3 is -N-. In certain embodiments, G1 and G2 are each -CH2-, and G3 is -N-. In some embodiments, G1 is -O-, G2 is a bond, and G3 is -N-. In some embodiments, G1 is -O-, G2 is -CR 6 R 7 -, and G3 is -N-. In certain embodiments, G1 is -O-, G2 is -CH2-, and G3 is -N.

[0071] In some embodiments of formula (I), R 1 and R 3 are each independently H, C1-C6 alkyl, halo or hydroxyl, and R 2 is H. In some embodiments, one of R 1 and R 3 is H and the other is C1-C6 alkyl, halo or hydroxyl, and R 2 is H, C2-C6 alkyl, halo or hydroxyl. In some embodiments, R 1 and R 3 are each H, and R 2 is C2-C6 alkyl, halo or hydroxyl. In some embodiments, at least one of R 1 , R 2 and R 3 is H. In some embodiments, at least one of R 1 , R 2 and R 3 is not H. In some embodiments, R 1 , R 2 and R 3 are each H.

[0072] In some embodiments, when any particular group is substituted, the groups shown are oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -CN, -OR A1 , -SR A1 , -NR A2 R A3 , -NO2, -C=NH(OR A1 ), -C(O)R A1 , -OC(O)R A1 , -C(O)OR A1 , -C(O)NR A2 R A3 , -OC(O)NR A2 R A3 , -NR A1 C(O)R A2 , -NR A1 C(O)OR A2 , -NR A1C(O)NR A2 R A3 、 -S(O)R A1 、 -S(O)2R A1 、 -NR A1 S(O)R A2 、 -C(O)NR A1 S(O)R A2 、 -NR A1 S(O)2R A2 、 -C(O)NR A1 S(O)2R A2 、 -S(O)NR A2 R A3 、 -S(O)2NR A2 R A3 、 -P(O)(OR A2 )(OR A3 )、 C3 - C6 cycloalkyl, 3 - 12 - membered heterocyclyl, 5 - 10 - membered heteroaryl, C6 - C 14 aryl, -(C1 - C3 alkylene)CN, -(C1 - C3 alkylene)OR A1 、 -(C1 - C3 alkylene)SR A1 、 -(C1 - C3 alkylene)NR A2 R A3 、 -(C1 - C3 alkylene)CF3, -(C1 - C3 alkylene)NO2, -C = NH(OR A1 )、 -(C1 - C3 alkylene)C(O)R A1 、 -(C1 - C3 alkylene)OC(O)R A1 、 -(C1 - C3 alkylene)C(O)OR A1 、 -(C1 - C3 alkylene)C(O)NR A2 R A3 、 -(C1 - C3 alkylene)OC(O)NR A2 R A3 、 -(C1 - C3 alkylene)NR A1 C(O)R A2 、 -(C1 - C3 alkylene)NR A1 C(O)OR A2 、 -(C1 - C3 alkylene)NR A1 C(O)NR A2 R A3 、 -(C1 - C3 alkylene)S(O)R A1 、 -(C1 - C3 alkylene)S(O)2R A1, -(C1-C3 alkylene)NR A1 S(O)R A2 , -C(O)(C1-C3 alkylene)NR A1 S(O)R A2 , -(C1-C3 alkylene)NR A1 S(O)2R A2 , -(C1-C3 alkylene)C(O)NR A1 S(O)2R A2 , -(C1-C3 alkylene)S(O)NR A2 R A3 , -(C1-C3 alkylene)S(O)2NR A2 R A3 , -(C1-C3 alkylene)P(O)(OR A2 )(OR A3 ), -(C1-C3 alkylene)(C3-C6 cycloalkyl), -(C1-C3 alkylene)(3-12 membered heterocyclyl), -(C1-C3 alkylene)(5-10 membered heteroaryl) and -(C1-C3 alkylene)(C6-C 14 aryl) and is substituted with one or more substituents selected from the group consisting of, one or more substituents are each independently unsubstituted or halogen, oxo, -OR A4 , -NR A4 R A5 , -C(O)R A4 , -CN, -S(O)R A4 , -S(O)2R A4 , -P(O)(OR A4 )(OR A5 ), -(C1-C3 alkylene)OR A4 , -(C1-C3 alkylene)NR A4 R A5 , -(C1-C3 alkylene)C(O)R A4 , -(C1-C3 alkylene)S(O)R A4 , -(C1-C3 alkylene)S(O)2R A4 , -(C1-C3 alkylene)P(O)(OR A4 )(OR A5) one or more additional substituents selected from the group consisting of C3-C8 cycloalkyl, C1-C6 alkyl, and C1-C6 alkyl substituted with oxo, -OH or halogen, and each R A1 is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are, independently, unsubstituted or substituted with halogen, oxo, -CN, -OR A6 , -NR A6 R A7 , -P(O)(OR A6 )(OR A6 ), phenyl, phenyl substituted with halogen, C1-C6 alkyl, or C1-C6 alkyl substituted with halogen, -OH or oxo, and R A2 and R A3 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are each independently unsubstituted or substituted with halogen, oxo, -CN, -OR A6 , -NR A6 R A7 , C1-C6 alkyl, or C1-C6 alkyl substituted with halogen, -OH or oxo, and R A4 , R A5 , R A6 and R A7is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl substituted with one or more halogens, C2-C6 alkenyl substituted with one or more halogens, or C2-C6 alkynyl substituted with one or more halogens.

[0073] In another aspect, the compound of formula (I) is a compound of formula (Ia):

Chemical formula

[0074] or a salt thereof, wherein A, B, G1, G3 and Z are as defined for formula (I) or any variant or embodiment thereof.

[0075] In some embodiments of formula (Ia), R 1 , R 2 , R 3 , R 4 , R 5 and R 8 are each independently H. In some embodiments of formula (Ia), at least one of R 1 , R 2 , R 3 , R 4 , R 5 and R 8 is not H.

[0076] In some variants of formula (Ia) described herein, G1 is -CR 4 R 5 -. In some embodiments, one of R 4 and R 5 is H, C1-C6 alkyl, halo or hydroxyl, and the other is C1-C6 alkyl, halo or hydroxyl. In some embodiments, one of R 4 and R 5 is H, and the other is C1-C6 alkyl, halo or hydroxyl. In some embodiments, one of R 4 and R5 Both are H, and thus, G1 becomes -CH2-. In some embodiments of formula (Ia) described herein, G1 is -O-.

[0077] In some embodiments of formula (Ia), G3 is -CR 8 -, and R 8 is C1-C6 alkyl, halo or hydroxyl. In some embodiments, R 8 is H, and thus, G3 becomes -CH-. In some embodiments, G3 is -N-.

[0078] In some embodiments of formula (I) or (Ia), G1 is -CR 4 R 5 -, and G3 is -CR 8 -. In certain embodiments, G1 is -CH2- and G3 is -CH-. In some embodiments, G1 is -CR 4 R 5 -, and G3 is -N-. In some embodiments, G1 is -O- and G3 is -CR 8 -. In certain embodiments, G1 is -O- and G3 is -CH-. In some embodiments, G1 is -O- and G3 is -N-.

[0079] In some embodiments of formula (Ia), R 1 and R 3 are each independently H, C1-C6 alkyl, halo or hydroxyl, and R 2 is H. In some embodiments, one of R 1 and R 3 is H and the other is C1-C6 alkyl, halo or hydroxyl, and R 2 is H, C2-C6 alkyl, halo or hydroxyl. In some embodiments, one of R 1 and R 3 is H and the other is C1-C6 alkyl, halo or hydroxyl, and R 2is H, C2-C6 alkyl, halo or hydroxyl. In some embodiments, R 1 , R 2 and R 3 are such that at least one of them is H. In some embodiments, R 1 , R 2 and R 3 are such that at least one of them is not H. In some embodiments, R 1 , R 2 and R 3 are each H.

[0080] In another aspect, a compound of formula (I) is a compound of formula (Ib):

Chemical formula

[0081] In some embodiments of formula (Ib), R 1 , R 2 , R 3 , R 4 , R 5 and R 8 are each independently H. In some embodiments of formula (Ib), at least one of R 1 , R 2 , R 3 , R 4 , R 5 and R 8 8 is not H. In some embodiments, one of R 4 and R 5 is H, C1-C6 alkyl, halo or hydroxyl and the other is C1-C6 alkyl, halo or hydroxyl. In some embodiments, R 4 and R 5One of them is H, and the other is C1-C6 alkyl, halo or hydroxyl. In some embodiments, R 4 and R 5 are both H, and thus G1 is -CH2-. In some embodiments, R 8 is C1-C6 alkyl, halo or hydroxyl. In some embodiments, R 8 is H.

[0082] In some embodiments of formula (Ib), R 1 and R 3 are each independently H, C1-C6 alkyl, halo or hydroxyl, and R 2 is H. In some embodiments, one of R 1 and R 3 is H and the other is C1-C6 alkyl, halo or hydroxyl, and R 2 is H, C2-C6 alkyl, halo or hydroxyl. In some embodiments, one of R 1 and R 3 is H and the other is C1-C6 alkyl, halo or hydroxyl, and R 2 is H, C2-C6 alkyl, halo or hydroxyl. In some embodiments, at least one of R 1 , R 2 and R 3 is H. In some embodiments, at least one of R 1 , R 2 and R 3 is not H. In some embodiments, R 1 , R 2 and R 3 are each H.

[0083] In another aspect, the compound of formula (I) is a compound of formula (Ic):

Chemical formula

[0084] In some embodiments of formula (Ic), R 1 , R 2 , R 3 and R 8 are each independently H. In some embodiments of formula (Ic), at least one of R 1 , R 2 , R 3 and R 8 is not H. In some embodiments of formula (Ic), R 1 and R 3 are each independently H, C1-C6 alkyl, halo or hydroxyl, and R 2 is H. In some embodiments, one of R 1 and R 3 is H and the other is C1-C6 alkyl, halo or hydroxyl, and R 2 is H, C2-C6 alkyl, halo or hydroxyl. In some embodiments, one of R 1 and R 3 is H and the other is C1-C6 alkyl, halo or hydroxyl, and R 2 is H, C2-C6 alkyl, halo or hydroxyl. In some embodiments, at least one of R 1 , R 2 and R 3 is H. In some embodiments, at least one of R 1 , R 2 and R 3 is not H. In some embodiments, R 1 , R 2 and R 3 are each H. In some embodiments, R 8 is C1-C6 alkyl, halo or hydroxyl. In some embodiments, R 8 is H.

[0085] In another aspect, the compound of formula (I) is a compound of formula (Id): [Chemical formula] or a salt thereof, wherein A, Z, B, R 1 , R 2 , R 3 , R 4 and R 5 are as defined with respect to formula (I) or any variant or embodiment thereof.

[0086] In some embodiments of formula (Id), R 1 , R 2 , R 3 , R 4 and R 5 are each independently H. In some embodiments of formula (Id), at least one of R 1 , R 2 , R 3 , R 4 and R 5 is not H.

[0087] In some embodiments of formula (Id), one of R 4 and R 5 is H, C1-C6 alkyl, halo or hydroxyl, and the other is C1-C6 alkyl, halo or hydroxyl. In some embodiments, one of R 4 and R 5 is H and the other is C1-C6 alkyl, halo or hydroxyl. In some embodiments, both R 4 and R 5 are H.

[0088] In some embodiments of formula (Id), R 1 and R 3 are each independently H, C1-C6 alkyl, halo or hydroxyl, and R 2 is H. In some embodiments, one of R 1 and R 3 is H and the other is C1-C6 alkyl, halo or hydroxyl, and R 2is H, C2-C6 alkyl, halo or hydroxyl. In some embodiments, R 1 and R 3 one of which is H and the other is C1-C6 alkyl, halo or hydroxyl, and R 2 is H, C2-C6 alkyl, halo or hydroxyl. In some embodiments, at least one of R 1 , R 2 and R 3 is H. In some embodiments, at least one of R 1 , R 2 and R 3 is not H. In some embodiments, R 1 , R 2 and R 3 are each H.

[0089] In another aspect, the compound of formula (I) is a compound of formula (Ie):

Chemical formula

[0090] In some embodiments of formula (Ie), R 1 , R 2 and R 3 are each H. In some embodiments, R 1 and R 3 are each independently H, C1-C6 alkyl, halo or hydroxyl, and R 2 is H. In some embodiments, one of R 1 and R 3 is H and the other is C1-C6 alkyl, halo or hydroxyl, and R 2 is H, C2-C6 alkyl, halo or hydroxyl. In some embodiments, R 1 and R 3One of them is H, and the other is C1-C6 alkyl, halo or hydroxyl, and R 2 is H, C2-C6 alkyl, halo or hydroxyl. In some embodiments, R 1 , R 2 and R 3 at least one of is H. In some embodiments, R 1 , R 2 and R 3 at least one of is not H.

[0091] In another aspect, the compound of formula (I) is a compound of formula (If) or (Ig):

Chemical formula

[0092] In another aspect, the compound of formula (I) is a compound of formula (Ih), (Ii), (Ij) or (Ik):

Chemical formula

[0093] or a salt thereof, wherein A, Z, B, R 1 , R 2 , R 3 , G1, G2 and G3 are as defined for formula (I) or any variant or embodiment thereof.

[0094] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), Z is a bond. In some embodiments, Z is C1-C6 alkyl. In some embodiments, Z is methylene. In some embodiments, Z is ethylene or propylene. In some embodiments, Z is -O-. In some of these embodiments, Z is -N(R 9 ), where R 9 is H, C1-C6 alkyl or cycloalkyl. In some of these embodiments, Z is -N(R 9 ), where R 9 is H, C1-C6 alkyl or is C3-C8 cycloalkyl. In some embodiments, Z is -NH-. In some embodiments, Z is -N(CH3)-. In some embodiments, Z is -R x O-, -OR y - or -R z S-, where R x , R y and R z are each C1-C6 alkyl. In some embodiments, Z is -CH2O-. In some embodiments, Z is -OCH2-. In some embodiments, Z is -CH2CH2O-, -CH2CH2CH2O-, -OCH2CH2- or -OCH2CH2CH2-. In some embodiments, Z is -CH2S-, -CH2CH2S-, -CH2CH2CH2S-, -SCH2-, -SCH2CH2- or SCH2CH2CH2-.

[0095] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is selected from the group consisting of substituted C2 alkynyl, unsubstituted C2 alkynyl, substituted phenyl, unsubstituted phenyl, and 5- or 6-membered heteroaryl containing at least 1 ring N atom, and the 5- or 6-membered heteroaryl is unsubstituted or substituted with one or more R 10 substituents, and each R 10is independently selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, 3- to 12-membered substituted or unsubstituted heterocycloalkyl, and -C(O)OR a wherein in some embodiments, each R 10 is independently selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, 5- to 6-membered substituted or unsubstituted heterocycloalkyl, and -C(O)OR a wherein in some embodiments, each R 10 is unsubstituted C1-C6 alkyl; C1-C6 alkyl substituted by one or more groups selected from D, halo, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl, and C3-C8 cycloalkyl; unsubstituted C2-C6 alkenyl; C2-C6 alkenyl substituted by one or more groups selected from D, halo, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl, and C3-C8 cycloalkyl; unsubstituted C2-C6 alkynyl; C2-C6 alkynyl substituted by one or more groups selected from D, halo, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl, and C3-C8 cycloalkyl; unsubstituted C3-C8 cycloalkyl; C3-C8 cycloalkyl substituted by one or more C1-C6 alkyl groups; 5- to 6-membered unsubstituted heterocycloalkyl; 5- to 6-membered heterocycloalkyl substituted by one or more C1-C6 alkyl groups; and -C(O)OR a is independently selected from the group consisting of, and R a is H or C1-C6 alkyl.

[0096] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is unsubstituted C2 alkynyl or substituted C2 alkynyl. In some embodiments, A is unsubstituted C2 alkynyl, and thus A is acetylene. In other embodiments, A is C2 alkynyl substituted by C1-C6 alkyl or C3-C8 cycloalkyl.

[0097] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is selected from the group consisting of substituted phenyl, unsubstituted phenyl, and 5- or 6-membered heteroaryl containing at least one ring N atom, and the 5- or 6-membered heteroaryl is unsubstituted or substituted by one or more R 10 substituents.

[0098] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) , (Ih), (Ii), (Ij) or (Ik), A is unsubstituted or substituted by one or more substituents selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl and -C(O)OR a and is phenyl, and R a is H or C1-C6 alkyl. In some embodiments, A is unsubstituted phenyl. In some embodiments, A is unsubstituted phenyl, and Z is a bond, C1-C6 alkyl, -N(R 9 ), -R x O-, -OR y - and -R z S-, and R x , R y and R zis each independently C1-C6 alkyl. In some embodiments, A is phenyl, and the phenyl is unsubstituted C1-C6 alkyl; C1-C6 alkyl substituted by one or more groups selected from D, halo, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl; unsubstituted C2-C6 alkenyl; C2-C6 alkenyl substituted by one or more groups selected from D, halo, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl; unsubstituted C2-C6 alkynyl; C2-C6 alkynyl substituted by one or more groups selected from D, halo, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl; unsubstituted C3-C8 cycloalkyl; C3-C8 cycloalkyl substituted by one or more C1-C6 alkyl groups; 5- to 6-membered unsubstituted heterocycloalkyl; 5- to 6-membered heterocycloalkyl substituted by one or more C1-C6 alkyl groups; and -C(O)OR a and is substituted by one or more substituents selected from the group consisting of, R a is H or C1-C6 alkyl. In some embodiments, A is phenyl substituted by one or more substituted or unsubstituted C1-C6 alkyl. In some embodiments, A is phenyl substituted by C1-C6 alkyl, and the C1-C6 alkyl is further unsubstituted. In some embodiments, A is phenyl substituted by C1-C6 alkyl, and the C1-C6 alkyl is further substituted. In some embodiments, A is phenyl substituted by C1-C6 alkyl, and the C1-C6 alkyl is not further substituted by halo. In some embodiments, A is phenyl substituted by methyl.

[0099] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is a 5- or 6-membered heteroaryl containing at least one ring N atom. In some embodiments, the 5- or 6-membered heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl and -C(O)OR a is phenyl substituted with one or more substituents selected from the group consisting of R a is H or C1-C6 alkyl. In some embodiments, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl is substituted with one or more groups selected from halo, -OR a , -OC(O)R a , cycloalkyl, heterocycloalkyl, where R a is H or C1-C6 alkyl. In some embodiments, A is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is unsubstituted C1-C6 alkyl; C1-C6 alkyl substituted with one or more groups selected from D, halo, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl; unsubstituted C2-C6 alkenyl; C2-C6 alkenyl substituted with one or more groups selected from D, halo, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl; unsubstituted C2-C6 alkynyl; D, halo, -C(O)OH, -C C2-C6 alkynyl substituted by one or more groups selected from (O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl; unsubstituted C3-C8 cycloalkyl; C3-C8 cycloalkyl substituted by one or more C1-C6 alkyl groups; 5-6 membered unsubstituted heterocycloalkyl; 5-6 membered heterocycloalkyl substituted by one or more C1-C6 alkyl groups; and -C(O)OR a substituted by one or more substituents selected from the group consisting of a R is H or C1-C6 alkyl.

[0100] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is selected from the group consisting of phenyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, tetrazolyl, triazolyl, thiazolyl, pyrimidinyl, pyridinyl, pyrazinyl and pyridazinyl, each of which is unsubstituted or substituted by one or more R 10 substituents, and each R 10 is independently selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl and -C(O)OR a wherein R a is H or C1-C6 alkyl. In some embodiments, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl is substituted by one or more groups selected from halo, -OR a , -OC(O)R a , cycloalkyl, heterocycloalkyl, and R ais H or C1-C6 alkyl. In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is oxadiazolyl or isoxazolyl, each of which is unsubstituted or substituted with one or more R 10 substituents. In some embodiments, A is phenyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, tetrazolyl, triazolyl, thiazolyl, pyrimidinyl, pyridinyl, pyrazinyl and pyridazinyl, each of which is unsubstituted C1-C6 alkyl; C1-C6 alkyl substituted with one or more groups selected from D, halo, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl; unsubstituted C2-C6 alkenyl; C2-C6 alkenyl substituted with one or more groups selected from D, halo, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl; unsubstituted C2-C6 alkynyl; C2-C6 alkynyl substituted with one or more groups selected from D, halo, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl; unsubstituted C3-C8 cycloalkyl; C3-C8 cycloalkyl substituted with one or more C1-C6 alkyl groups; 5-6 membered unsubstituted heterocycloalkyl; 5-6 membered heterocycloalkyl substituted with one or more C1-C6 alkyl groups; and -C(O)OR a substituted with one or more substituents selected from the group consisting of, R a is H or C1-C6 alkyl.

[0101] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is: [Chemical formula] Selected from the group consisting of, each of which is unsubstituted or substituted with one or more R 10 substituents. In some embodiments, each C1-C6 alkyl of R 10 is independently unsubstituted or further substituted with one additional substituent independently selected from the group consisting of -OR k and -OC(O)R m where R k and R m are each independently H or C1-C6 alkyl. In some embodiments, each R 10 is independently selected from the group consisting of -C(O)OCH3, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, cyclobutyl and oxetanyl, and each methyl, ethyl and isopropyl of R 10 is independently unsubstituted or further substituted with one additional substituent independently selected from the group consisting of -OCH3, -OH and -OC(O)CH3. In some embodiments, R 10 is methyl or -CD3.

[0102] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is oxadiazolyl, which is unsubstituted or methyl substituted by -OCH3, -OH or -OC(O)CH3; ethyl; ethyl substituted by -OCH3, -OH, -C(O)OCH3 or -OC(O)CH3; ethenyl; isopropyl; isopropyl substituted by -OCH3, -OH or -OC(O)CH3; difluoromethyl; cyclopropyl; cyclobutyl; oxetanyl; acetyl; and substituted by one substituent selected from the group consisting of -C(O)OCH3. In some embodiments, A is isoxazolyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of methyl, ethyl and difluoromethyl. In some embodiments, A is isoxazolyl, which is unsubstituted or substituted by one substituent selected from the group consisting of methyl, ethyl and difluoromethyl.

[0103] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is:

Chemical formula

[0104] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is phenyl which is unsubstituted or substituted by methyl. In some embodiments, A is pyridine which is unsubstituted or substituted by one or two methyls. In some embodiments, A is pyrazine which is unsubstituted or substituted by methyl. In some embodiments, A is pyrimidine which is unsubstituted or substituted by methyl. In some embodiments, A is pyridazine which is unsubstituted or substituted by methyl. In some embodiments, A is pyrazole which is unsubstituted or substituted by methyl. In some embodiments, A is thiazole which is unsubstituted or substituted by methyl. In some embodiments, A is oxazole which is unsubstituted or substituted by methyl. In some embodiments, A is tetrazole which is unsubstituted or substituted by methyl. In some embodiments, A is triazole which is unsubstituted or substituted by methyl. In some embodiments, A is isoxazole substituted by methyl, ethyl, or CF2. In some embodiments, A is methyl, ethyl An oxadiazole substituted by CF2, CD3, cyclopropyl, isopropyl, cyclobutyl, oxetane or C(O)OCH3, each of which may be further substituted as necessary. In some embodiments, A is an oxadiazole substituted by methyl, and the methyl may be further substituted by methoxy, OH or -OC(O)CH3 as necessary. In some embodiments, A is an oxadiazole substituted by ethyl, and the ethyl may be further substituted by methoxy, OH or -OC(O)CH3 as necessary. In some embodiments, A is an oxadiazole substituted by isopropyl, and the isopropyl may be further substituted by OH or -OC(O)CH3 as necessary. In some embodiments, A is an oxadiazole substituted by methyl, ethyl, CD3, CF2 or cyclopropyl. In some embodiments, A is an oxadiazole substituted by ethyl or CF2.

[0105] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), B is selected from the group consisting of H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or is substituted by one or more R 11 substituents, and each R 11 is independently selected from the group consisting of heterocycloalkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, C1-C6 alkyl-OH, halo, fluoroalkyl, -OR b , -C(O)R c , -C(O)OR d , oxo and -NR e R f and each heterocycloalkyl and heteroaryl of R 11 is unsubstituted or is C1-C6 alkyl, C1-C6 alkyl-OH, -C(O)R n、 -C(O)OR p and -C(O)NR q R r is substituted with one or more substituents selected from the group consisting of, each R b 、R c 、R d 、R e 、R f 、R n 、R p 、R q and R r is, independently, H or C1 - C6 alkyl.

[0106] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), B is selected from the group consisting of H, C1 - C6 alkyl, C3 - C8 cycloalkyl, C6 - C 12 aryl, 3 - 12 - membered heterocycloalkyl and 5 - 10 - membered heteroaryl, and the C1 - C6 alkyl, C3 - C8 cycloalkyl, C6 - C 12 aryl, 3 - 12 - membered heterocycloalkyl and 5 - 10 - membered heteroaryl of B are each unsubstituted or substituted with one or more R 11 substituents. In some embodiments, B is unsubstituted or substituted with one or more R 11 substituents, and each R 11 is 3 - 12 - membered substituted or unsubstituted heterocycloalkyl, 5 - 10 - membered substituted or unsubstituted heteroaryl, substituted or unsubstituted C3 - C8 cycloalkyl, substituted or unsubstituted C6 - C 12 aryl, unsubstituted C1 - C6 alkyl, C1 - C6 alkyl substituted with one or more R 12 substituents, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 - C6 alkynyl, halo, -OR b 、 -C(O)R c 、 -C(O)OR d 、 oxo and -NR e R fis independently selected from the group consisting of. In some embodiments, B is unsubstituted or one or more R 11 substituents, each R 11 is a 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl, C6-C 12 aryl, C1-C6 alkyl, halo, fluoroalkyl, -OR b , -C(O)R c , -C(O)OR d , oxo and -NR e R f is independently selected from the group consisting of, and each heterocycloalkyl and heteroaryl of R 11 is unsubstituted or is substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, -C(O)R n , -C(O)OR p and -C(O)NR q R r , and each R b , R c , R d , R e , R f , R n , R p , R q and R r is independently H or C1-C6 alkyl. In some embodiments, each heterocyclo 11 alkyl or heteroaryl of R contains 1, 2, 3, 4 or 5 heteroatoms selected from the group consisting of N, O and S. In some embodiments of formula (I) or any variant thereof, B is unsubstituted or phenyl substituted by one or more R 11 substituents. In some embodiments, B is unsubstituted or a 5- to 6-membered heterocycloalkyl substituted by one or more R 11 substituents. In other embodiments, B is unsubstituted or a 5- to 6-membered heteroaryl substituted by one or more R 11 substituents.

[0107] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), B is selected from the group consisting of cycloalkyl, aryl, heterocycloalkyl and heteroaryl, each of which is optionally substituted or unsubstituted. In some embodiments, the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is unsubstituted or has one or more R 11 substituents, and each R 11 is independently selected from the group consisting of heterocycloalkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, C1-C6 alkyl-OH, halo, fluoroalkyl, -OR b , -C(O)R c , -C(O)OR d , oxo and -NR e R f , and each heterocycloalkyl and heteroaryl of R 11 is unsubstituted or is substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, -C(O)R n , -C(O)OR p and -C(O)NR q R r , and each R b , R c , R d , R e , R f , R n , R p , R q and R r is independently H or C1-C6 alkyl.

[0108] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), B is selected from the group consisting of C1-C4 alkyl, C3-C5 cycloalkyl, 6-10 membered aryl (e.g., 6-9 membered aryl), 4-6 membered heterocycloalkyl containing at least 1 ring N or O atom, 5- or 6-membered monocyclic heteroaryl containing at least 1 ring N atom, and 8- or 9-membered bicyclic heteroaryl containing at least 1 ring N atom, each of which is optionally substituted or unsubstituted. In some embodiments, C1-C4 alkyl, C3-C5 cycloalkyl, 6-10 membered aryl (e.g., 6-9 membered aryl), 4-6 membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl, or 8- or 9-membered bicyclic heteroaryl is unsubstituted or is substituted with one or more R 11 substituents, each R 11 is independently selected from the group consisting of heterocycloalkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, C1-C6 alkyl-OH, halo, fluoroalkyl, -OR b , -C(O)R c , -C(O)OR d , oxo and -NR e R f , and each heterocycloalkyl and heteroaryl of R 11 is unsubstituted or is substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, -C(O)R n , -C(O)OR p and -C(O)NR q R r , and each R b , R c , R d , R e , R f , R n , R p , R q and R r is independently H or C1-C6 alkyl.

[0109] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), B is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, indanyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, indanyl, pyrrolopyrazolyl and benzimidazolyl, each of which is unsubstituted or substituted by one or more R 11 substituents , each R 11 is independently selected from the group consisting of heterocycloalkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, C1-C6 alkyl-OH, halo, fluoroalkyl, -OR b , -C(O)R c , -C(O)OR d , oxo and -NR e R f , and each heterocycloalkyl and heteroaryl of R 11 is unsubstituted or substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, -C(O)R n , -C(O)OR p and -C(O)NR q R r , and each R b , R c , R d , R e , R f , R n , R p , R q and R r is independently H or C1-C6 alkyl. In some embodiments, each R 11is independently selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, oxo, -C(O)CH3, -C(O)OtBu, -OCH3, -OH, -NH2, -Cl, oxetanyl, oxadiazolyl and azetidinyl, R 11 each oxadiazolyl and azetidinyl of which is unsubstituted or substituted by one or more substituents selected from the group consisting of ethyl, -C(O)CH3, -C(O)OtBu, -C(O)OCH3, -C(O)NHCH3, -C(O)NH2 and -OCH3.

[0110] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), B is C1-C6 alkyl substituted by -OR b wherein R b is H or C1-C6 alkyl. In some embodiments, B is C1-C6 alkyl optionally substituted by -OR b wherein Z is -O- or -N(R 9 ). In some embodiments, B is C1-C6 alkyl substituted by -OH. In some embodiments, B is C1-C6 alkyl substituted by -OH and Z is -O-. In some embodiments, B is C1-C6 alkyl substituted by -OH and Z is -N(R 9 ). In some embodiments, B is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, each of which is optionally substituted by -OH.

[0111] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), B is methyl, pyrazolyl, oxazolyl, tetrazolyl, isoxazolyl, thiazolyl, imidazolyl or pyridinyl, each of which is unsubstituted or one or more R 11is substituted by a substituent, each R 11 is independently selected from the group consisting of heterocycloalkyl, heteroaryl, halo, alkyl, alkyl-OH, cycloalkyl, fluoroalkyl, -OR b , -C(O)R c , -C(O)OR d , oxo and -NR e R f is independently selected from the group consisting of H or C1-C6 alkyl. Each R b , R c , R d , R e and R f is independently H or C1-C6 alkyl.

[0112] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), B is pyrazolyl, oxazolyl, tetrazolyl, isoxazolyl or pyridinyl, each of which is unsubstituted or substituted by one or more C1-C6 alkyl substituents.

[0113] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), B is:

Chemical formula

[0114] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), B is:

Chemical formula

[0115] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), B is H. In some embodiments, B is methyl. In some embodiments, B is CD3. In some embodiments, B is CF2. In some embodiments, B is phenyl. In some embodiments, B is unsubstituted or is azetidine optionally substituted with methyl, -C(O)CH3, -C(O)OCH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3 or oxo. In some embodiments, B is benzimidazole substituted with oxo. In some embodiments, B is cyclobutyl. In some embodiments, B is cyclopentyl. In some embodiments, B is cyclopropyl. In some embodiments, B is unsubstituted or is ethyl optionally substituted with methoxy. In some embodiments, B is imidazole substituted with two methyls. In some embodiments, B is indane substituted with oxadiazole further substituted with ethyl. In some embodiments, B is unsubstituted or is isobutyl optionally substituted with methoxy. In some embodiments, B is unsubstituted or is isopropyl optionally substituted with OH. In some embodiments, B is isoxazole substituted with one or two methyls or isopropyl. In some embodiments, B is isoxazole substituted with methyl. In some embodiments, B is unsubstituted or is methyl optionally substituted with CF2, cyclopropyl, methoxy, oxetane or azetidine, and the azetidine is further substituted with -C(O)CH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3 or -C(O)OCH3. In some embodiments, B is methyl substituted with cyclopropyl or cyclopropyl substituted with methyl.In some embodiments, B is morpholine that is unsubstituted or optionally substituted with -C(O)CH3 or -C(O)OC(CH3)3. In some embodiments, B is oxadiazole substituted with methyl. In some embodiments, B is oxazole substituted with one or two methyl or cyclopropyl groups. In some embodiments, B is oxetane. In some embodiments, B is piperazine substituted with methyl. In some embodiments, B is piperidine that is unsubstituted or optionally substituted with one or more groups selected from methyl, oxo, -C(O)CH3, and -C(O)OC(CH3)3. In some embodiments, B is pyrazine that is unsubstituted or optionally substituted with one or two methyl groups. In some embodiments, B is pyrazole that is unsubstituted or optionally substituted with one or more groups selected from methyl, ethyl, and CF3. In some embodiments, B is pyrazole substituted with one or two methyl groups. In some embodiments, B is pyridazine that is unsubstituted or optionally substituted with methyl. In some embodiments, B is pyridine that is unsubstituted or optionally substituted with amino, hydroxyl, -NH2, -OH, or one or more methyl groups. In some embodiments, B is pyridine substituted with methyl. In some embodiments, B is pyrimidine that is unsubstituted or optionally substituted with methyl. In some embodiments, B is pyrrolidine that is unsubstituted or optionally substituted with methyl, oxo, -C(O)CH3, or -C(O)OC(CH3)3. In some embodiments, B is pyrrolopyrazole. In some embodiments, B is tert-butyl. In some embodiments, B is tetrahydrofuran. In some embodiments, B is tetrazole substituted with methyl. In some embodiments, B is thiazole that is unsubstituted or optionally substituted with chloro or methyl.In some embodiments, B is a triazole substituted with one or more groups selected from methyl and ethyl.

[0116] In some embodiments of any of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is a 5-membered heteroaryl containing at least 1 ring N atom, and the 5-membered heteroaryl is unsubstituted or one or more R 10 substituents as defined herein, B is selected from the group consisting of H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or one or more R 11 substituents as defined herein. In some embodiments, A is unsubstituted or substituted pyrazole, thiazole, oxazole, tetrazole, triazole, isoxazole or oxadiazole, and Z is a bond, -NR 9 -, -O-, -R x O- or -OR y -, and R 9 is H, C1-C6 alkyl or cycloalkyl, and R x and R y are each independently C1-C6 alkyl, and B is C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or one or more R 11 substituents as defined herein. In some embodiments, A is unsubstituted or substituted pyrazole, thiazole, oxazole, tetrazole, triazole, isoxazole or oxadiazole, and Z is a bond, -NR 9 - or -O-, -R x O- or -OR y -, and R9 is H, C1-C6 alkyl or cycloalkyl, R x and R y are each independently C1-C6 alkyl, and B is unsubstituted or substituted methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, indanyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, indanyl, pyrrolopyrazolyl and benzimidazolyl.

[0117] In some embodiments of any of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is selected from pyrazole, thiazole, oxazole, tetrazole, triazole, isoxazole and oxadiazole, each being unsubstituted or substituted with one or more substituents selected from the group consisting of unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl and -C(O)OR a and is substituted by one or more substituents selected from the group consisting of R ais H or C1-C6 alkyl, Z is a bond, -NH-, -NCH3-, or -O-, -CH3O-, or -OCH3-, B is selected from methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, indanyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, indanyl, pyrrolopyrazolyl, and benzimidazolyl, each being unsubstituted or substituted by one or more groups selected from heterocycloalkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, halo, fluoroalkyl, -OR b , -C(O)R c , -C(O)OR d , oxo, and -NR e R f and is substituted by one or more groups selected therefrom, each R b , R c , R d , R e and R f is independently H or C1-C6 alkyl. In some of these embodiments, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl of A is , halo, -OR a , -OC(O)R a , cycloalkyl, heterocycloalkyl, and is substituted by one or more groups selected therefrom, and R a is H or C1-C6 alkyl.

[0118] In some embodiments of any one of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl or -C(O)OR a is an oxadiazole optionally substituted by a , R a is H or C1-C6 alkyl, Z is a bond, -NR 9 -, -O-, -R x O- or -OR y -, R 9 is H, C1-C6 alkyl or cycloalkyl, R x and R y are each independently C1-C6 alkyl, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or substituted by one or more R 11 substituents as defined herein. In some embodiments of any one of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is an oxadiazole substituted by C1-C6 alkyl, and the C1-C6 alkyl is further optionally substituted by halo, -OR a or -C(O)OR a and R a is H or C1-C6 alkyl, Z is a bond, -NR 9 - or -O-, R 9is H, C1-C6 alkyl or cycloalkyl, B is cyclopropyl, cyclobutyl, cyclopentyl, phenyl, indanyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, indanyl, pyrrolopyrazolyl or benzimidazolyl, each of which is unsubstituted or substituted with one or more Rs defined herein 11 is substituted with a substituent. In some embodiments, A is an oxadiazole substituted with C1-C6 alkyl, and the C1-C6 alkyl is further optionally substituted with halo, -OR a or -C(O)OR a and R a is H or C1-C6 alkyl, Z is a bond, -NH-, -O-, -OCH2- or -CH2O-, R 9 is H, C1-C6 alkyl or cycloalkyl, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or substituted with one or more Rs defined herein 11 is substituted with a substituent. In some embodiments, A is an oxadiazole substituted with methyl, -CD3, -CF2, ethyl, isopropyl, cyclopropyl or cyclobutyl, Z is a bond, -NR 9 -, -O-, -OCH2- or -CH2O-, R 9 is H, C1-C6 alkyl or cycloalkyl, B is aryl or heteroaryl optionally substituted with one or more groups selected from C1-C6 alkyl, cycloalkyl, OR b and -NR e R f and R b 、R e and Rf is, independently of each other, H or C1-C6 alkyl. In some embodiments, A is an oxadiazole substituted by methyl, -CD3, -CF2, ethyl, isopropyl, cyclopropyl or cyclobutyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, and B is C1-C6 alkyl or cycloalkyl, each being unsubstituted or substituted by halo. In some embodiments, A is an oxadiazole substituted by methyl, -CD3, -CF2, ethyl, -CH2OCH3, isopropyl, cyclopropyl or cyclobutyl, Z is -O-, -OCH2- or -CH2O-, and B is C 1-C6 alkyl, cycloalkyl or heterocycloalkyl, and C1-C6 alkyl is unsubstituted or substituted by halo. In some embodiments, A is an oxadiazole substituted by methyl, -CD3, -CF2, ethyl, isopropyl, cyclopropyl or cyclobutyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, and B is C1-C6 alkyl, cycloalkyl, OR b and -NR e R f is aryl or heteroaryl optionally substituted by one or more groups selected from R b R e and R fis, independently of each other, H or C1-C6 alkyl. In some embodiments, A is an oxadiazole substituted by methyl, -CD3, -CF2, ethyl, isopropyl, cyclopropyl or cyclobutyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, and B is aryl or heteroaryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 cycloalkyl, OH and -NH2. In some embodiments, A is an oxadiazole substituted by methyl, -CD3, -CF2, ethyl, isopropyl, cyclopropyl or cyclobutyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, and B is aryl or heteroaryl optionally substituted by one or more groups selected from C1-C6 alkyl, cycloalkyl, OR b and -NR e R f and is optionally substituted by one or more groups selected from b R e and R fEach is independently H or C1-C6 alkyl. In some embodiments, A is an oxadiazole substituted with methyl, -CD3, -CF2, ethyl, isopropyl, cyclopropyl or cyclobutyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, and B is methyl; CD3; CF2; phenyl; azetidine which is unsubstituted or optionally substituted with methyl, -C(O)CH3, -C(O)OCH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3 or oxo; benzimidazole substituted with oxo; cyclobutyl; cyclopentyl; cyclopropyl; ethyl which is unsubstituted or optionally substituted with methoxy; imidazole substituted with two methyls; indane substituted with an oxadiazole further substituted with ethyl; isobutyl which is unsubstituted or optionally substituted with methoxy; isopropyl which is unsubstituted or optionally substituted with OH; isoxazole substituted with one or two methyls or isopropyl; isoxazole substituted with methyl; methyl which is unsubstituted or optionally substituted with CF2, cyclopropyl, methoxy, oxetane or azetidine (the azetidine is further substituted with -C(O)CH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3 or -C(O)OCH3); methyl substituted with cyclopropyl or methyl substituted with cyclopropyl substituted with methyl; morpholine which is unsubstituted or optionally substituted with -C(O)CH3 or -C(O)OC(CH3)3; oxadiazole substituted with methyl; oxazole substituted with one or two methyls or cyclopropyl; oxetane; piperazine substituted with methyl; piperidine which is unsubstituted or optionally substituted with one or more groups selected from methyl, oxo, -C(O)CH3 and -C(O)OC(CH3)3; pyrazine which is unsubstituted or optionally substituted with one or two methyls;A pyrazole which is unsubstituted or optionally substituted by one or more groups selected from methyl, ethyl and CF3; a pyrazole substituted by one or two methyls; a pyridazine which is unsubstituted or optionally substituted by methyl; a pyridine which is unsubstituted or optionally substituted by amino, hydroxyl, -NH2, -OH or one or more methyls; a pyridine substituted by methyl; a pyrimidine which is unsubstituted or optionally substituted by methyl; a pyrimidine which is unsubstituted or optionally substituted by methyl, oxo, -C(O)CH3 or -C(O; )OC(CH3)3; a pyrrolidine optionally substituted by methyl, oxo, -C(O)CH3 or -C(O)OC(CH3)3; a pyrrolopyrazole; tert-butyl; tetrahydrofuran; a tetrazole substituted by methyl; a thiazole which is unsubstituted or optionally substituted by chloro or methyl; or a triazole substituted by one or more groups selected from methyl and ethyl.

[0119] In some embodiments, A is an oxadiazole substituted by methyl, and the methyl is further optionally substituted by methoxy, OH or -OC(O)CH3, Z is a bond, -NR 9 - or -O-, R 9 is H, C1-C6 alkyl or cycloalkyl, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or one or more R defined herein 11It is substituted by a substituent. In some embodiments, A is an oxadiazole substituted by methyl, Z is a bond, -NH- or -O-, B is C1-C6 alkyl, cycloalkyl, aryl and heteroaryl, and C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl are each unsubstituted or substituted by one or more groups selected from those defined herein. In some embodiments, A is an oxadiazole substituted by ethyl, and ethyl is further optionally substituted by methoxy, OH or -OC(O)CH3, Z is a bond, -NH- or -O-, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or one or more Rs defined herein 11 It is substituted by a substituent. In some embodiments, A is an oxadiazole substituted by ethyl, Z is a bond, and B is a 5- to 6-membered unsubstituted heteroaryl or one or more Rs defined herein 11 It is a 5- to 6-membered heteroaryl substituted by a substituent. In some embodiments, A is an oxadiazole substituted by -CF2, Z is a bond, -NH- or -O-, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or one or more Rs defined herein 11 It is substituted by a substituent. In some embodiments, A is an oxadiazole substituted by -CF2, Z is a bond, and B is a 5- to 6-membered unsubstituted heteroaryl or one or more Rs defined herein 11It is a 5- to 6-membered heteroaryl substituted by a substituent. In some embodiments, A is an oxadiazole substituted by isopropyl, Z is a bond, -NH-, or -O-, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl of B is unsubstituted or one or more Rs defined herein 11 substituted by a substituent. In some embodiments, A is an oxadiazole substituted by isopropyl, Z is a bond, and B is a 5- to 6-membered unsubstituted heteroaryl or one or more Rs defined herein 11 It is a 5- to 6-membered heteroaryl substituted by a substituent. In some embodiments, A is an oxadiazole substituted by cyclopropyl, Z is a bond, -NH-, or -O-, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl of B is unsubstituted or one or more Rs defined herein 11 substituted by a substituent. In some embodiments, A is an oxadiazole substituted by -C(O)OR a wherein R a is H or C1-C6 alkyl, Z is a bond, -NH-, or -O-, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl of B is unsubstituted or one or more Rs defined herein 11It is substituted by a substituent. In some embodiments, A is an oxadiazole substituted by oxetanyl, Z is a bond, -NH- or -O-, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or one or more Rs defined herein 11 It is substituted by a substituent. In some embodiments, A is an oxadiazole substituted by cyclobutyl, Z is a bond, -NH- or -O-, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or one or more Rs defined herein 11 It is substituted by a substituent. In some embodiments, A is 5-ethyl-1,2,4-oxadiazol-3-yl, 5-(difluoromethyl)-1,2,4-oxadiazol-3-yl or 5-isopropyl-1,2,4-oxadiazol-3-yl, Z is a bond, and B is a 5- to 6-membered heteroaryl substituted by one or more C1-C6 alkyls.

[0120] In some embodiments of any of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl or -C(O)OR a is an oxazole optionally substituted by a R is H or C1-C6 alkyl, Z is a bond, -NR 9 -, -O-, -R x O- or -OR y -, and R 9is H, C1-C6 alkyl or cycloalkyl, R x and R y are each independently C1-C6 alkyl, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or one or more R 11 substituents as defined herein. In some embodiments of any of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl or -C(O)OR a is oxazole optionally substituted by, R a is H or C1-C6 alkyl, Z is a bond, -O- or -NH-, B is cyclopropyl, cyclobutyl, cyclopentyl, phenyl, indanyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, indanyl, pyrrolopyrazolyl or benzimidazolyl, each unsubstituted or substituted by one or more R 11 substituents as defined herein. In some embodiments, A is oxazole substituted by methyl, ethyl, CF2 or isopropyl, Z is a bond, -NH- or -O-, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsub is substituted or is one or more Rs as defined herein 11 by a substituent. In some embodiments of any of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl or -C(O)OR a is an isoxazole optionally substituted by; R a is H or C1-C6 alkyl, Z is a bond, -NR 9 -, or -O-, and R 9 is H, C1-C6 alkyl or cycloalkyl, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or is substituted by one or more Rs as defined herein 11 by a substituent. In some embodiments of any of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl or -C(O)OR a is an isoxazole optionally substituted by; R ais H or C1-C6 alkyl, Z is a bond, -O-, or -NH-, B is cyclopropyl, cyclobutyl, cyclopentyl, phenyl, indanyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, indanyl, pyrrolopyrazolyl or benzimidazolyl, each of which is unsubstituted or substituted by one or more C1-C6 alkyls. In some embodiments, A is isoxazole substituted by methyl, ethyl, CF2 or isopropyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or substituted by one or more R 11 substituents as defined herein. In some embodiments, A is tetrazole substituted by methyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or substituted by one or more R 11It is substituted by a substituent. In some embodiments of any one of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is a tetrazole substituted by methyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, and B is cyclopropyl, cyclobutyl, cyclopentyl, phenyl, indanyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, indanyl, pyrrolopyrazolyl or benzimidazolyl, each of which is unsubstituted or substituted by one or more C1-C6 alkyls.

[0121] In some embodiments of any one of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is a 6-membered heteroaryl containing at least one ring N atom, and the 6-membered heteroaryl is unsubstituted or substituted by one or more R 10 substituents as defined herein, and B is selected from the group consisting of H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or substituted by one or more R 11 substituents as defined herein. In some embodiments, A is unsubstituted or substituted pyridine, pyrazine, pyrimidine or pyridazine, Z is a bond, -NR 9 -, -O-, -R x O- or -OR y -, and R 9 is H, C1-C6 alkyl or cycloalkyl, and R x and R yEach is independently C1-C6 alkyl, B is C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or one or more Rs as defined herein 11It is substituted by a substituent. In some embodiments, A is unsubstituted or substituted pyridine, pyrazine, pyrimidine or pyridazine, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, B is C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or substituted methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, indanyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, indanyl, pyrrolopyrazolyl and benzimidazolyl. In some embodiments, A is unsubstituted or substituted pyridine, pyrazine, pyrimidine or pyridazine, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, B is methyl; CD3; CF2; phenyl; azetidine which is unsubstituted or optionally substituted by methyl, -C(O)CH3, -C(O)OCH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3 or oxo; benzimidazole substituted by oxo; cyclobutyl; cyclopentyl; cyclopropyl; ethyl which is unsubstituted or optionally substituted by methoxy; imidazole substituted by two methyls; indane substituted by oxadiazole further substituted by ethyl; isobutyl which is unsubstituted or optionally substituted by methoxy; isopropyl which is unsubstituted or optionally substituted by OH; isoxazole substituted by one or two methyls or isopropyl; isoxazole substituted by methyl;Methyl which is unsubstituted or optionally substituted by CF2, cyclopropyl, methoxy, oxetane or azetidine (azetidine is further substituted by -C(O)CH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3 or -C(O)OCH3); methyl substituted by cyclopropyl or methyl substituted by cyclopropyl substituted by methyl; morpholine which is unsubstituted or optionally substituted by -C(O)CH3 or -C(O)OC(CH3)3; oxadiazole substituted by methyl; oxazole substituted by one or two methyls or cyclopropyls; oxetane; piperazine substituted by methyl; piperidine which is unsubstituted or optionally substituted by one or more groups selected from methyl, oxo, -C(O)CH3 and -C(O)OC(CH3)3; pyrazine which is unsubstituted or optionally substituted by one or two methyls; pyrazole which is unsubstituted or optionally substituted by one or more groups selected from methyl, ethyl and CF3; pyrazole substituted by one or two methyls; unsubstituted or... Or pyridazine optionally substituted by methyl; pyridine which is unsubstituted or optionally substituted by amino, hydroxyl, -NH2, -OH or one or more methyls; pyridine substituted by methyl; pyrimidine which is unsubstituted or optionally substituted by methyl; pyrrolidine which is unsubstituted or optionally substituted by methyl, oxo, -C(O)CH3 or -C(O)OC(CH3)3; pyrrolopyrazole; tert-butyl; tetrahydrofuran; tetrazole substituted by methyl; thiazole which is unsubstituted or optionally substituted by chloro or methyl; or triazole substituted by one or more groups selected from methyl and ethyl.

[0122] In some embodiments, A is phenyl optionally substituted by methyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, B is C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or one or more R 11 substituted by substituents. In some embodiments, A is pyridinyl optionally substituted by one or two methyls, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, B is C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or one or more R 11 substituted by substituents. In some embodiments, A is pyrimidinyl optionally substituted by methyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, B is C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or one or more R 11 substituted by substituents. In some embodiments, A is pyrimidinyl optionally substituted by methyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, B is one or more R 11 aryl or heteroaryl optionally substituted by substituents as defined herein. In some embodiments, A is pyrimidinyl optionally substituted by methyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O, B is C1-C6 alkyl, halo, -ORb 、 -C(O)R c 、 -C(O)OR d 、 oxo and -NR e R f An aryl or heteroaryl optionally substituted by one or more substituents selected from the group consisting of, R b 、 R c 、 R d 、 R e and R f are, independently, H or C1-C6 alkyl. In some embodiments, A is pyrimidinyl which is unsubstituted or substituted by methyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O, and B is pyrazolyl substituted by methyl. In some embodiments, A is pyrazinyl optionally substituted by methyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O, and B is C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or substituted by one or more R 11 substituents defined herein. In some embodiments, A is pyridazinyl optionally substituted by methyl, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O, and B is C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or substituted by one or more R 11 substituents defined herein.

[0123] In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), A is phenyl which is unsubstituted or substituted by methyl; pyridine which is unsubstituted or substituted by one or two methyls; pyrazine which is unsubstituted or substituted by methyl; pyrimidine which is unsubstituted or substituted by methyl; pyridazine which is unsubstituted or substituted by methyl; pyrazole which is unsubstituted or substituted by methyl; thiazole which is unsubstituted or substituted by methyl; oxazole which is unsubstituted or substituted by methyl; tetrazole which is unsubstituted or substituted by methyl; triazole which is unsubstituted or substituted by methyl; isoxazole substituted by methyl, ethyl or CF2; oxadiazole substituted by methyl, ethyl, CF2, CD3, cyclopropyl, isopropyl, cyclobutyl, oxetane or C(O)OCH3 (each of which may be further substituted as necessary); oxadiazole substituted by methyl which is further substituted as necessary by methoxy, OH or -OC(O)CH3; oxadiazole substituted by ethyl which is further substituted as necessary by methoxy, OH or -OC(O)CH3; oxadiazole substituted by isopropyl which is further substituted as necessary by OH or -OC(O)CH3; oxadiazole substituted by methyl, ethyl, CD3, CF2 or cyclopropyl; or oxadiazole substituted by ethyl or CF2, Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2- or -CH2O-, and B is H; methyl; CD3; CF2; phenyl; azetidine which is unsubstituted or substituted as necessary by methyl, -C(O)CH3, -C(O)OCH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3 or oxo; benzimidazole substituted by oxo; cyclobutyl; cyclopentyl; cyclopropyl;Ethyl which is unsubstituted or substituted by methoxy as needed; imidazole substituted by two methyls; indane substituted by oxadiazole which is further substituted by ethyl; isobutyl which is unsubstituted or substituted by methoxy as needed; isopropyl which is unsubstituted or substituted by OH as needed; isoxazole substituted by one or two methyls or isopropyl; isoxazole substituted by methyl; methyl which is unsubstituted or substituted by CF2, cyclopropyl, methoxy, oxetane or azetidine (azetidine is further substituted by -C(O)CH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3 or -C(O)OCH3) as needed; methyl substituted by cyclopropyl or methyl substituted by cyclopropyl; morpholine which is unsubstituted or substituted by -C(O)CH3 or -C(O)OC(CH3)3 as needed; oxadiazole substituted by methyl; oxazole substituted by one or two methyls or cyclopropyl; oxetane; piperazine substituted by methyl; piperidine which is unsubstituted or substituted by one or more groups selected from methyl, oxo, -C(O)CH3 and -C(O)OC(CH3)3 as needed; pyrazine which is unsubstituted or substituted by one or two methyls as needed; pyrazole which is unsubstituted or substituted by one or more groups selected from methyl, ethyl and CF3 as needed; pyrazole substituted by one or two methyls; pyridazine which is unsubstituted or substituted by methyl as needed; pyridine which is unsubstituted or substituted by amino, hydroxyl, -NH2, -OH or one or more methyls as needed; pyridine substituted by methyl; unsubstituted; a pyrimidine which is unsubstituted or substituted with methyl as required; a pyrrolidine which is unsubstituted or substituted with methyl, oxo, -C(O)CH3 or -C(O)OC(CH3)3 as required; a pyrrolopyrazole; tert-butyl; tetrahydrofuran; a tetrazole substituted with methyl; a thiazole which is unsubstituted or substituted with chloro or methyl as required; or a triazole substituted with one or more groups selected from methyl and ethyl.

[0124] In some embodiments, compounds described in Table 1 and their salts are provided herein.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-78

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

Table 1-102

Table 1-103

Table 1-104

Table 1-105

Table 1-106

Table 1-107

Table 1-108

[0125] In some alternative forms, a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or any variant thereof, or a compound described herein such as those in Table 1 Any of the compounds may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom). In some of these variants, the compound is deuterated at a single site. In other variants, the compound is deuterated at multiple sites. The deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compounds. The hydrogen atoms may be replaced by deuterium atoms using other methods known in the art.

[0126] Any formula shown herein, such as formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), is intended to represent a structural formula and a compound having a structure represented by a particular variant form or form. In particular, compounds of any formula shown herein may have asymmetric centers and thus exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, as well as mixtures thereof in any ratio, are considered to be within the scope of the formula. Thus, any formula shown herein is intended to represent racemates, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and compounds thereof in any ratio. When the compounds in Table 1 are shown in a particular stereochemical configuration, alternative stereochemical configurations of the compounds, as well as mixtures of any ratio of the stereoisomers of the compounds, are also provided herein. For example, if the compound in Table 1 has a stereocenter in the "S" stereochemical configuration, the enantiomer of the compound in which the stereocenter is in the "R" stereochemical configuration is also provided herein. Similarly, if the compound in Table 1 has a stereocenter in the "R" configuration, the enantiomer of the compound in the "S" stereochemical configuration is also provided herein. Mixtures of compounds having both the "S" and "R" stereochemical configurations are also provided. Further, if the compounds in Table 1 have two or more stereocenters, any enantiomer or diastereomer of the compound is also provided. For example, if the compound in Table 1 contains a first stereocenter and a second stereocenter having "R" and "R" stereochemical configurations, respectively, stereoisomers of the compound having "S" and "S" stereochemical configurations, "S" and "R" stereochemical configurations, and "R" and "S" stereochemical configurations, respectively, for the first and second stereocenters are also provided.When the compounds of Table 1 each contain a first stereocenter and a second stereocenter having “S” and “S” stereochemical configurations, respectively, stereoisomers of the compounds having first and second stereocenters having “R” and “R” stereochemical configurations, “S” and “R” stereochemical configurations, respectively, and “R” and “S” stereochemical configurations, respectively, are also provided. When the compounds of Table 1 each contain a first stereocenter and a second stereocenter having “S” and “R” stereochemical configurations, respectively, stereoisomers of the compounds having first and second stereocenters having “R” and “S” stereochemical configurations, “R” and “R” stereochemical configurations, respectively, and “S” and “S” stereochemical configurations, respectively, are also provided. Similarly, when the compounds of Table 1 each contain a first stereocenter and a second stereocenter having “R” and “S” stereochemical configurations, respectively, stereoisomers of the compounds having first and second stereocenters having “S” and “R” stereochemical configurations, “R” and “R” stereochemical configurations, respectively, and “S” and “S” stereochemical configurations, respectively, are also provided. Further, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Further, any formula shown herein is also intended to refer to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not explicitly listed. In some embodiments, the solvent is water and the solvate is a hydrate.

[0127] Representative examples of the compounds detailed herein, including intermediates and final compounds, are shown in the tables and elsewhere in this specification. In one aspect, any of these compounds is also understood to be optionally used in the methods detailed herein, including intermediate compounds that can be isolated and administered to an individual or subject as appropriate.

[0128] The compounds shown in this specification may exist as salts even when no salts are shown, and the compositions and methods provided herein are understood to include all salts and solvates of the compounds shown herein, as well as the non-salt and non-solvate forms of the compounds, as is well understood by those skilled in the art. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0129] In one variant, the compounds herein are synthetic compounds prepared for administration to an individual or subject. In another variant, a composition containing the compound in substantially pure form is provided. In another embodiment, a pharmaceutical composition is provided that includes the compounds detailed herein and a pharmaceutically acceptable carrier. In another variant, a method of administering the compound is provided. The purified form of the compound, the pharmaceutical composition, and the method of administering the same are suitable for any of the compounds or forms thereof detailed herein.

[0130] The G1, G2, G3, Z, A, B, R provided herein 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R x 、R y 、R z 、R a 、R b 、R c 、R d 、R e 、R f 、R g 、R h 、R i 、R j 、R n 、R p 、Rq and R r Any variant or embodiment of, each combination being as if it were individually and specifically recited, G1, G2, G3, Z, A, B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R x , R y , R z , R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R n , R p , R q and R r can be combined with any other variant or embodiment of.

[0131] Other embodiments will be apparent to those skilled in the art from the following detailed description.

[0132] As used herein, when any variable appears more than once in a chemical formula, its definition is independent of its definition at all other occurrences.

[0133] Formula (I) includes all of its sub-formulas. For example, formula (I) includes compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) and (Ik).

[0134] The names of the compounds provided herein, including those in Table 1, are brought about by ChemBioDraw Professional 15.0.0.106. Those skilled in the art would likely understand that compounds can be named or identified using various generally recognized naming systems and symbols. By way of example, compounds can be named or identified by common names, systematic or non-systematic names. Naming systems and symbols generally recognized in the chemical arts include, for example, Chemical Abstract Service (CAS), ChemBioDraw Ultra, and the International Union of Pure and Applied Chemistry (IUPAC).

[0135] Composition Compositions such as pharmaceutical compositions are also provided that include the compounds disclosed and / or described herein, as well as one or more additional therapeutic agents, pharmaceutical agents, adjuvants, carriers, excipients, etc. Suitable therapeutic and pharmaceutical agents include those described herein. In some embodiments, the pharmaceutical composition includes a pharmaceutically acceptable excipient or adjuvant, and includes at least one chemical entity described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, compositions such as pharmaceutical compositions containing one or more of the compounds described herein or pharmaceutically acceptable salts thereof are provided.

[0136] In some embodiments, there is provided a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some aspects, the composition may contain synthetic intermediates that can be used in the preparation of the compounds described herein. The compositions described herein may contain any other suitable active or inactive agent.

[0137] Any of the compositions described herein may be sterilized or may contain sterilized components. Sterilization can be achieved by methods known in the art. Any of the compositions described herein may contain one or more compounds or conjugates that are substantially pure.

[0138] There is also provided a packaged pharmaceutical composition comprising the pharmaceutical compositions described herein and instructions for use of the compositions for treating a patient afflicted with a disease or condition described herein.

[0139] Method of Use The compounds and pharmaceutical compositions herein can be used to treat or prevent a disease or condition in an individual or subject.

[0140] While not bound by theory, the compounds and pharmaceutical compositions disclosed herein are thought to act by inhibiting myosin. This inhibition potentially reduces the number of independent myosin heads that interact with actin filaments to decrease the amount of contraction. A decrease in myocardial contraction can be important in the treatment of heart diseases where overcontraction is a problem. In some embodiments, a method of treating or preventing a heart disease in an individual or subject, comprising administering to the individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, is provided. In some embodiments, a method of treating or preventing a heart disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one chemical entity described herein, is provided. In some embodiments, a method of treating a heart disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one chemical entity described herein, is provided. In some embodiments, a method of treating an established or diagnosed heart disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one chemical entity described herein, is provided. In some embodiments, a method of preventing a heart disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one chemical entity described herein, is provided.

[0141] In a subject, in the manufacture of a medicament for the treatment of a heart disease, a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof The use of these salts is also provided herein. In some embodiments, compounds or compositions described herein are provided for use in a method of treating the human or animal body by therapy. In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or compounds of Table 1, or pharmaceutically acceptable salts thereof, are provided for use in a method of treating the human or animal body by therapy. In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or compounds of Table 1, or pharmaceutically acceptable salts thereof, are provided for use in treating or preventing heart disease. In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or compounds of Table 1, or pharmaceutically acceptable salts thereof, are provided for use in treating heart disease. In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or compounds of Table 1, or pharmaceutically acceptable salts thereof, are provided for use in treating established or diagnosed heart disease. In other embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or compounds of Table 1, or pharmaceutically acceptable salts thereof, are provided for use in preventing heart disease. In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or compounds of Table 1, or pharmaceutically acceptable salts thereof, are provided for use in treating diseases or conditions associated with HCM.In some embodiments, provided herein are compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or compounds of Table 1, or pharmaceutically acceptable salts thereof, for use in treating a disease or condition associated with secondary left ventricular wall hypertrophy. In some embodiments, provided herein are compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or compounds of Table 1, or pharmaceutically acceptable salts thereof, for use in ameliorating symptoms associated with a heart disease. In other embodiments, provided herein are compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or compounds of Table 1, or pharmaceutically acceptable salts thereof, for use in reducing the risk of symptoms associated with a heart disease. In other embodiments, provided herein are compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or compounds of Table 1, or pharmaceutically acceptable salts thereof, for use in treating a disease or condition associated with a small left ventricular cavity, lumen occlusion, hyperdynamic left ventricular contraction, occlusion of blood flow from the left ventricle, cardiac hypertrophy, low cardiac output, left ventricular relaxation disorder, high left ventricular filling pressure, myocardial ischemia or myocardial fibrosis. In certain embodiments, provided herein are compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or compounds of Table 1, or pharmaceutically acceptable salts thereof, for use in treating a disease or condition associated with a small left ventricular cavity and lumen occlusion, hyperdynamic left ventricular contraction, myocardial ischemia or myocardial fibrosis.In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or the compounds of Table 1, or pharmaceutically acceptable salts thereof, are provided herein for use in treating muscular dystrophy. In some embodiments, for use in treating glycogenosis. Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or the compounds of Table 1, or pharmaceutically acceptable salts thereof, are provided herein for use in modulating cardiac myocytes, such as inhibiting cardiac myocytes. In other embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or the compounds of Table 1, or pharmaceutically acceptable salts thereof, are provided herein for use in activating cardiac myosin.

[0142] In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse, rat, dog, cat, pig, sheep, horse, cow, or human. In some embodiments, the subject is a human. In some embodiments, the subject has an established or diagnosed heart disease. In some embodiments, the subject has an established or diagnosed hypertrophic cardiomyopathy (HCM). In some embodiments, the subject is at risk of developing a heart disease. In some embodiments, the subject has a mutation that increases the risk of heart disease. In some embodiments, the subject has a mutation that increases the risk of hypertrophic cardiomyopathy (HCM). In some embodiments, the mutation is a sarcomere mutation. In some embodiments, the mutation is a mutation in myosin heavy chain β (MHC-β), cardiac troponin T (cTnT), tropomyosin alpha-1 chain (TPM1), myosin-binding protein C cardiac type (MYBPC3), cardiac troponin I (cTnI), myosin essential light chain (ELC), titin (TTN), myosin regulatory light chain 2 ventricular / myocardial isoform (MLC-2), cardiac alpha-actin, muscle LIM protein (MLP), or protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2). In some embodiments, the mutation is a mutation in MHC-β. In some embodiments, the subject has an established or diagnosed hypertrophic cardiomyopathy with an unconfirmed genetic etiology.

[0143] In some embodiments, the subject has a high risk of progressive symptoms. In some embodiments, the subject has a high risk of atrial fibrillation, ventricular tachyarrhythmia, stroke, and / or sudden death. In some embodiments, the subject has a reduced exercise capacity. In some embodiments, the reduced exercise capacity is compared to an age-matched control population. In some embodiments, the subject is eligible for surgical intervention or percutaneous ablation to treat the heart disease.

[0144] In some embodiments, the heart disease is hypertrophic cardiomyopathy (HCM). In some embodiments, the heart disease is obstructive HCM. In some embodiments, the heart disease is non-obstructive HCM. In some embodiments, HCM is associated with sarcomeric mutations. In some embodiments, HCM is associated with non-sarcomeric mutations. In some embodiments, the heart disease is obstructive or non-obstructive HCM caused by sarcomeric and / or non-sarcomeric mutations. In some embodiments, the sarcomeric mutations are mutations in myosin heavy chain β (MHC-β), cardiac troponin T (cTnT), tropomyosin alpha-1 chain (TPM1), myosin-binding protein C cardiac type (MYBPC3), cardiac troponin I (cTnI), myosin essential light chain (ELC), titin (TTN), myosin regulatory light chain 2 ventricular / myocardial isoform (MLC-2), cardiac alpha-actin or muscle LIM protein (MLP). In some embodiments, the sarcomeric mutation is a mutation in MHC-β. In some embodiments, the non-sarcomeric mutation is a mutation in protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2).

[0145] In some embodiments, a method of treating a disease or condition associated with HCM, the method comprising administering to an individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, is provided herein. In some embodiments, the disease or condition is Fabry disease, Danon disease, mitochondrial cardiomyopathy or Noonan syndrome.

[0146] The use of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with HCM is also provided herein.

[0147] ​In some embodiments, the heart disease is heart failure with preserved ejection fraction (HFpEF). In some embodiments, the heart disease is diastolic dysfunction. In some embodiments, the heart disease is cardiomyopathy. In some embodiments, the heart disease is primary or secondary restrictive cardiomyopathy. In some embodiments, the heart disease is a condition or symptom caused by coronary artery disease. In some embodiments, the heart disease is myocardial infarction or angina pectoris. In some embodiments, the heart disease is left ventricular outflow tract obstruction. In some embodiments, the heart disease is hypertensive heart disease. In some embodiments, the heart disease is congenital heart disease. In some embodiments, the heart disease is myocardial ischemia and / or coronary artery heart disease. In some embodiments, the heart disease is diabetic heart disease. In other embodiments, the heart disease is congestive heart failure. In some embodiments, the heart disease is right heart failure. In other embodiments, the heart disease is cardiorenal syndrome. In some embodiments, the heart disease is infiltrative cardiomyopathy. In some embodiments, the heart disease is heart aging or diastolic dysfunction due to aging, or a condition related thereto. In some embodiments, the heart disease is left ventricular hypertrophy and / or concentric left ventricular remodeling, or a condition related thereto.

[0148] In some embodiments, there is provided a method of treating a disease or condition associated with secondary left ventricular wall hypertrophy in an individual or subject, the method comprising administering to an individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is hypertension, valvular heart disease (aortic stenosis, mitral regurgitation), metabolic syndrome (diabetes, obesity), end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich's ataxia, Danon disease, Noonan syndrome or Pompe disease.

[0149] The use of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with secondary left ventricular wall hypertrophy is also provided herein.

[0150] In some embodiments, a method of ameliorating symptoms associated with a heart disease in a subject, the method comprising administering to an individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, wherein the symptoms are one or more selected from poor or reduced myocardial elasticity, poor or reduced diastolic left ventricular relaxation, abnormal left atrial pressure (e.g., abnormally high left atrial pressure), paroxysmal or persistent atrial fibrillation, elevated left atrial pressure and pulmonary capillary wedge pressure, elevated left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, increased left ventricular mass, increased left ventricular wall thickness, left ventricular mid-cavity obstruction ), increased systolic anterior motion of the mitral valve, left ventricular outflow tract obstruction, chest pain, exertional dyspnea, pre-syncope, abnormal exercise capacity and fatigue.

[0151] In some embodiments, a method for reducing the risk of symptoms associated with heart disease in a subject, the method comprising administering to an individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, wherein the symptoms are selected from one or more of sudden cardiac death, poor or reduced myocardial elasticity, poor or reduced diastolic left ventricular relaxation, abnormal left atrial pressure (e.g., abnormally high left atrial pressure), paroxysmal or persistent atrial fibrillation, elevated left atrial pressure and pulmonary capillary wedge pressure, elevated left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular mass, increased left ventricular wall thickness, left ventricular central cavity obstruction, increased systolic anterior motion of the mitral valve, left ventricular outflow tract obstruction, chest pain, exertional dyspnea, pre-syncope, abnormal exercise capacity, and fatigue.

[0152] In some embodiments, a method for treating a disease or condition associated with a small left ventricular cavity, cavity obstruction, hyperdynamic left ventricular contraction, obstruction of blood flow from the left ventricle, cardiac hypertrophy, low cardiac output, left ventricular relaxation disorder, high filling pressure of the left ventricle, myocardial ischemia or myocardial fibrosis in an individual or subject, the method comprising administering to an individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, a method for treating a disease or condition associated with a small left ventricular cavity and cavity obstruction, hyperdynamic left ventricular contraction, myocardial ischemia or myocardial fibrosis in an individual or subject, the method comprising administering to an individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0154] Use of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with a small left ventricular cavity and lumen obstruction, hyperdynamic left ventricular contraction, myocardial ischemia or myocardial fibrosis is also provided herein.

[0155] In some embodiments, a method of treating muscular dystrophy (e.g., Duchenne muscular dystrophy) in an individual or subject, the method comprising administering to an individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Use of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of muscular dystrophy (e.g., Duchenne muscular dystrophy) is also provided herein.

[0156] In some embodiments, a method of treating glycogenosis in an individual or subject, the method comprising administering to an individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Use of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of glycogenosis is also provided herein.

[0157] A method of modulating cardiomyocytes in an individual or subject, the method comprising administering to the individual or subject in need thereof a therapeutically effective amount of at least one chemical entity described herein is also provided. In some embodiments, a method of inhibiting cardiomyocytes, the method comprising contacting the cardiomyocytes with at least one chemical entity described herein, such as a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, is provided. Further provided herein is the use of at least one chemical entity described herein, such as a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting cardiomyocytes in an individual or subject.

[0158] A method for activating cardiac myosin in an individual or subject, the method comprising administering to the individual or subject in need thereof a therapeutically effective amount of at least one chemical entity described herein, such as a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, is also provided. Further provided herein is the use of at least one chemical entity described herein, such as a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for activating cardiac myosin in an individual or subject.

[0159] In some embodiments, the methods provided herein further include the step of monitoring the effectiveness of treatment. Examples of metrics include, but are not limited to, the following: functional classification by the New York Heart Association (NYHA), exercise capacity, myocardial elasticity, diastolic left ventricular relaxation, left atrial pressure, paroxysmal or persistent atrial fibrillation, left atrial pressure and pulmonary capillary wedge pressure, left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular mass, left ventricular wall thickness, left ventricular central chamber occlusion, systolic anterior motion of the mitral valve, left ventricular outflow tract obstruction, chest pain, exertional dyspnea, pre-syncope, abnormal exercise capacity, and one or more improvements in fatigue. These metrics can be monitored by techniques known in the art, including self-reporting; electrocardiogram (ECG), including ambulatory ECG; echocardiogram; cardiac magnetic resonance imaging (MRI); computed tomography (CT); biopsy; cardiopulmonary exercise testing (CPET); and actigraphy.

[0160] In some embodiments, the compound decreases the contractility of cardiomyocytes. In some embodiments, the compound decreases the contractility of cardiomyocytes by more than 40%, such as by more than 45%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the compound decreases the contractility of cardiomyocytes by 40% - 90%, such as 40% - 80%, 40 - 70%, 50% - 90%, 50% - 80%, or 50% - 70%. In some embodiments, the compound does not significantly alter the calcium transient in cardiomyocytes. In some embodiments, the compound decreases the ATPase activity in cardiomyocytes. Methods for measuring contractility, ATPase activity, and calcium transient, such as by calcium labeling, electrophysiological recording, and microscopic imaging, are known in the art. In some embodiments, the compound does not significantly inhibit or induce cytochrome P450 (CYP) proteins.

[0161] In some embodiments, the subject has a left ventricular wall that is thicker than normal prior to treatment. In some embodiments, the subject has a left ventricular wall thickness greater than 15 mm prior to treatment, such as greater than 18 mm, 20 mm, 22 mm, 25 mm, or 30 mm. In some embodiments, the left ventricular wall thickness decreases by more than 5% after treatment, such as more than 8%, 10%, 12%, 15%, 20%, or 30%. The left ventricular wall thickness can be measured by methods known in the art, such as by echocardiogram, CT scan, or cardiac MRI.

[0162] In some embodiments, the subject has abnormal myocardial fibrosis prior to treatment. In some embodiments, the abnormal myocardial fibrosis is reduced by more than 5% after treatment, such as more than 8%, 10%, 12%, 15%, 20%, or 30%. Myocardial fibrosis can be measured by methods known in the art, such as by biopsy or cardiac MRI.

[0163] In some embodiments, the subject has reduced exercise capacity prior to treatment. In some embodiments, the subject's exercise capacity is improved by more than 5% after treatment, such as more than 8%, 10%, 12%, 15%, 20%, or 30%. In some embodiments, exercise capacity is measured by a cardiopulmonary exercise test (CPET). CPET measures the change in oxygen consumption (VO2max). Methods for measuring CPET and VO2max are well known in the art (Malhotra et al., JACC: Heart Failure, 2016, 4(8): 607-616; Guazzi et al., J Amer College Cardiol, 2017, 70 (13): 1618-1636; Rowin et al., JACC: Cariovasc Imaging, 2017, 10(11):1374-1386). In some embodiments, VO2max is more than 1 mL / kg / m 2 after treatment, such as 1.2 mL / kg / m 2 、1.4 mL / kg / m 2 、1.5 mL / kg / m 2 、1.7 mL / kg / m 2 、2 mL / kg / m2 , 2.2 mL / kg / m 2 , 2.5 mL / kg / m 2 , 3 mL / kg / m 2 , 3.2 mL / kg / m 2 or 3.5 mL / kg / m 2 is more improved.

[0164] In some embodiments, the subject has a pre-treatment functional classification by the New York Heart Association (NYHA) of II, III, or IV. In some embodiments, the subject has a pre-treatment functional classification by the New York Heart Association (NYHA) of III or IV. In some embodiments, the subject has a pre-treatment functional classification by the New York Heart Association (NYHA) of IV. In some embodiments, the subject remains in the same NYHA functional class or has a decreased NYHA functional class after treatment.

[0165] In some embodiments, VO2max is more than 1 mL / kg / m 2 , for example, 1.2 mL / kg / m 2 , 1.4 mL / kg / m 2 , 1.5 mL / kg / m 2 , 1.7 mL / kg / m 2 or 2 mL / kg / m 2 is more improved, and the subject has a decreased NYHA functional class after treatment. In some embodiments, VO2max is 2.5 mL / kg / m 2 , 3 mL / kg / m 2 , 3.2 mL / kg / m 2 or 3.5 mL / kg / m 2 is more improved, and the subject remains in the same NYHA functional class or has a decreased NYHA functional class.

[0166] In some embodiments, the subject's daily function and / or activity level is improved after treatment. The improvement in daily function and / or activity level can be measured, for example, by journaling or actigraphy using a FitBit or FitBit-like monitor.

[0167] In some embodiments, after treatment, the subject has a reduction in shortness of breath, a reduction in chest pain, a reduction in arrhythmia burden such as atrial fibrillation and ventricular arrhythmia, a reduction in the incidence of heart failure, and / or a reduction in ventricular outflow tract obstruction, one or more of which.

[0168] Dosage The compounds and compositions disclosed and / or described herein are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment of a disease state. Human dosage levels have not yet been optimized for the chemical entities described herein, but generally the daily dosage is about 0.01-100 mg per kg of body weight, in some embodiments about 0.05-10.0 mg per kg of body weight, and in some embodiments about 0.10-1.4 mg per kg of body weight. Thus, in some embodiments, for administration to a 70 kg person, the dosage range would be about 0.7-7000 mg per day, in some embodiments about 3.5-700.0 mg per day, and in some embodiments about 7-100.0 mg per day. The amount of chemical entity administered depends, for example, on the subject being treated and the disease state, the severity of the affliction, the mode and schedule of administration, and the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is about 5 mg to about 500 mg per day, and an exemplary dosage for intravenous administration is about 5 mg to about 500 mg per day, each depending on the pharmacokinetics of the compound.

[0169] The daily dosage is the total amount administered in a day. The daily dosage is not limited to the following, but may be administered daily, every other day, weekly, every two weeks, monthly or at various intervals. In some embodiments, the daily dosage is administered for a period ranging from a single day to the entire life of the subject. In some embodiments, the daily dosage is administered once a day. In some embodiments, the daily dosage is administered in multiple divided doses, such as 2, 3 or 4 divided doses. In some embodiments, the daily dosage is administered in 2 divided doses.

[0170] Administration of the compounds and compositions disclosed and / or described herein can be by any acceptable mode of administration of a therapeutic agent, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compounds or compositions disclosed and / or described herein are administered orally.

[0171] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms such as tablets, capsules, powders, liquids, suspensions, suppositories, and aerosol forms. The compounds disclosed and / or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled / sustained release pills, depot injections, osmotic pumps, or transdermal (including electrotransport) patches) over a long period of time and / or at a predetermined rate of pulsed administration. In some embodiments, the composition is provided in unit dosage form suitable for single administration of an exact dosage.

[0172] The compounds disclosed and / or described herein can be administered either alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition can also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, etc. (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, the pharmaceutical composition contains from about 0.005 wt% to 95 wt% or from about 0.5 wt% to 50 wt% of the compounds disclosed and / or described herein, depending on the intended mode of administration. The actual method of preparing such dosage forms is known or will be apparent to those skilled in the art. See, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0173] In some embodiments, the composition is in the form of a pill or tablet, and thus the composition may contain, together with the compounds disclosed and / or described herein, a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate) and / or a binder (e.g., starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives), one or more of them. Other solid dosage forms include powders, marume, solutions or suspensions (e.g., in propylene carbonate, vegetable oil or triglycerides) encapsulated in gelatin capsules.

[0174] For example, a liquid pharmaceutically administrable composition can be prepared by forming a solution or suspension, for example, by dissolving, dispersing or suspending the compounds disclosed and / or described herein and, if necessary, pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc.). Injectables can be prepared in conventional forms, either as a liquid solution or suspension, as an emulsion, or in a solid form suitable for dissolving or suspending in a liquid prior to injection. The percentage of the compound contained in such parenteral compositions depends, for example, on the physical properties of the compound, the activity of the compound and the needs of the subject. However, percentages of active ingredient from 0.01 to 10% can be used in solution, and may be higher in the case of solids which are later diluted to another concentration. In some embodiments, the composition contains from about 0.2 to 2% of the compounds disclosed and / or described herein in solution.

[0175] The pharmaceutical compositions of the compounds disclosed and / or described herein may also be administered to the airway, alone or in combination with an inert carrier such as lactose, as an aerosol or solution for a nebulizer, or as an ultrafine powder for insufflation. In such cases, the particles of the pharmaceutical composition can have a diameter of less than 50 microns, or in some embodiments, less than 10 microns.

[0176] Furthermore, the pharmaceutical composition can contain the compounds disclosed and / or described herein, as well as one or more additional therapeutic agents, pharmaceutical agents, adjuvants, etc. Suitable therapeutic and pharmaceutical agents include those described herein.

[0177] Kit Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The article of manufacture may include a container having a label. Suitable containers include, for example, bottles, vials, and test tubes. The container can be formed from a variety of materials such as glass or plastic. The container can hold the pharmaceutical composition provided herein. The label on the container can indicate that the pharmaceutical composition is used for preventing, treating, or suppressing the conditions described herein, and can also indicate instructions regarding any use in vivo or in vitro. In one aspect, provided herein is a kit containing the compounds or compositions described herein and instructions for use. The kit may contain instructions for use in the treatment of heart disease in an individual or subject in need thereof. The kit may further contain any material, or an instrument that can be used for administering the compound or composition, such as a vial, syringe, or IV bag. The kit may also contain a sterile packaging -aging.

[0178] Combination The compounds and compositions described and / or disclosed herein may be administered alone or in combination with other therapies and / or therapeutic agents useful for the treatment of the above disorders, diseases or conditions.

[0179] The compounds and compositions described and / or disclosed herein may be combined with one or more other therapies for treating heart diseases such as HCM or HFpEF. In some embodiments, the one or more therapies include treatments that delay the progression of heart failure by downregulating the stimulation of cardiac neurohormones, and attempts to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists or neprilysin inhibitors). In some embodiments, the one or more therapies include treatments that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone). In other embodiments, the one or more therapies include treatments that reduce cardiac preload (e.g., diuretics such as furosemide) or cardiac afterload (any class of vasodilators including, but not limited to, calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin modulators).

[0180] The compounds and compositions described and / or disclosed herein may be combined with one or more other therapies for treating HCM or HFpEF. In some embodiments, the compounds and / or compositions may be combined with verapamil and / or disopyramide, which are β-blockers.

[0181] General synthetic method The compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) and (Ik) are described herein by reference to exemplary synthetic schemes for their general preparation and subsequent specific examples thereof. One of ordinary skill in the art will recognize that, in order to obtain the various compounds herein, the starting materials can be suitably selected such that the ultimately desired substituents are carried through the reaction scheme, optionally with protection or without protection, as appropriate, to obtain the desired product. Alternatively, it may be necessary or desirable to use suitable groups that are carried through the reaction scheme and optionally replaced by the ultimately desired substituents. Further, one of ordinary skill in the art will recognize that protecting groups can be used to protect certain functional groups (amino, carboxy or side chain groups) from the reaction conditions and that such groups are removed under standard conditions when appropriate. Unless otherwise specified, for formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) and (Ik), the variables are as defined above.

[0182] If it is desired to obtain a particular enantiomer of a compound, this can be accomplished from the corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives can be produced by reaction of a mixture of enantiomers (e.g., a racemate and a suitable chiral compound). The diastereomers can then be separated by any convenient means, e.g., by crystallization, and the desired enantiomer recovered. In another resolution process, a racemate can be separated using chiral high performance liquid chromatography. Alternatively, if desired, a particular enantiomer can be obtained by using a suitable chiral intermediate in one of the described processes.

[0183] If it is desired to obtain a specific isomer of the compound or otherwise purify the reaction product, chromatography, recrystallization and other conventional separation procedures may also be used with the intermediate or the final product.

[0184] The general methods for preparing the compounds described herein are shown in the methods exemplified below. The variable groups in the schemes provided herein are defined with respect to formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) and (Ik) or any variant thereof. Other compounds described herein can be prepared by similar methods.

[0185] In some embodiments, the compounds provided herein can be synthesized according to Scheme A.

Chemical formula

[0186] In some embodiments, the compounds provided herein can be synthesized according to Scheme B.

Chemical formula

[0187] In some embodiments, the compounds provided herein can be synthesized according to Scheme C.

Chemical formula

[0188] In some embodiments, the compounds provided herein can be synthesized according to Scheme D. synthesized.

Chemical formula

[0189] In some embodiments, the compounds provided herein can be synthesized according to any one of Schemes E1, E2, E3, and E4.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0190] In some embodiments, the compounds provided herein can be synthesized according to any one of Schemes F1, F2, and F3.

Chemical formula

Chemical formula

Chemical formula

[0191] In some embodiments, the compounds provided herein can be synthesized according to Scheme G.

Chemical formula

[0192] In some embodiments, the compounds provided herein can be synthesized according to Scheme H.

Chemical formula

[0193] In some embodiments, the compounds provided herein can be synthesized according to Scheme I.

Chemical Structure

[0194] In some embodiments, the compounds provided herein can be synthesized according to Scheme J.

Chemical Structure

[0195] In some embodiments, the compounds provided herein can be synthesized according to Scheme K.

Chemical Structure

[0196] In some embodiments, the compounds provided herein can be synthesized according to Schemes L1 and L2.

Chemical Structure

Chem.

[0197] In some embodiments, the compounds provided herein can be synthesized according to Scheme M.

Chem.

[0198] In some embodiments, the compounds provided herein can be synthesized according to Schemes N1 and N2.

Chem.

Chem.

[0199] In some embodiments, the compounds provided herein can be synthesized according to Scheme O.

Chem.

[0200] Specific non-limiting examples are provided in the Examples section below.

Examples

[0201] The following examples are provided to illustrate the compositions, uses, and methods provided herein, but are not limited to the following. Compounds are prepared using the general methods described above.

[0202] The following abbreviations are used throughout the examples: TEA (trimethylamine), DCM (dichloromethane), (Boc)2O (di-tert-butyl dicarbonate), EA (ethyl acetate), PE (petroleum ether), DMF (N,N-dimethylformamide), DIEA (N-ethyl-N-isopropylpropan-2-amine), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HOAt (1-hydroxy-7-azabenzotriazole), HOBt (hydroxybenzotriazole), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), MeOH (methanol), EtOH (ethanol), iPrOH (propan-2-ol), ACN (acetonitrile), TFA (trifluoroacetic acid), DPPA (diphenylphosphoryl azide), DBU (1,8-diazabicyclo(5.4.0)undec-7-ene), THF (tetrahydrofuran), PPh3 (triphenylphosphane), SM (starting material), Hex (hexane), NCS (N-chlorosuccinimide), r.t. (room temperature), DCE (dichloroethane), FA (formic acid), CHCl3 (chloroform), BnBr (benzyl bromide), HCl (hydrogen chloride), equiv (equivalent) and DSC (bis(2,5-dioxopyrrolidin-1-yl) carbonate). (Example 1) Synthesis of Compound 17 1. Synthesis of Intermediate 1-2:

Chemical Structure

[0203] To a solution of 4-bromo-1H-pyrazole (50 g, 340 mmol, 1.0 eq) in sodium hydroxide (3.7 N, 555 mL) was added (aminooxy)sulfonic acid (116 g, 1.0 mol, 3.0 eq). The mixture was stirred for 30 minutes and extracted with DCM (500 mL). The organic layer was washed twice with brine (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and poured into DCM (400 mL) and water (200 mL). To the resulting solution was added NaIO4 (147 g, 685 mmol, 2.0 eq) at 0 °C. The mixture was stirred overnight, diluted with DCM (500 mL), washed twice with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 25 g of 5-bromo-1,2,3-triazine as a brown oil. 2. Synthesis of Intermediate 1-3:

Chemical formula

[0204] To a solution of 5-bromo-1,2,3-triazine (25 g, 156 mmol, 1.0 eq) in CHCl3 (500 mL) was added 1-(cyclopenta-1-en-1-yl)pyrrolidine (25.8 g, 188 mmol, 1.1 eq). The mixture was stirred at 45 °C for 1 hour, diluted with DCM (500 mL), washed twice with brine (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 10 / 90) to give 11 g (36%) of 3-bromo-5H,6H,7H-cyclopenta[b]pyridine as a brown solid. 3. Synthesis of Intermediate 1-4:

Chemical formula

[0205] To a solution of 3-bromo-5H,6H,7H-cyclopenta[b]pyridine (11.9 g, 60.0 mmol, 1.0 equiv) in DCE (120 mL) was added m-CPBA (20.7 g, 120 mmol, 2.0 equiv). The mixture was stirred at 70 °C overnight, cooled to room temperature, diluted with DCM (200 mL), washed twice with saturated sodium bicarbonate solution (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (MeOH / DCM, 10 / 90) to give 12 g (93%) of 3-bromo-5H,6H,7H-cyclopenta[b]pyridin-1-ium-1-olate as an off-white solid. 4. Synthesis of Intermediate 1-5: [Chemical formula]

[0206] A solution of 3-bromo-5H,6H,7H-cyclopenta[b]pyridin-1-ium-1-olate (12.2 g, 57.0 mmol, 1.0 equiv) in acetic anhydride (30 mL) was stirred at 110 °C for 3 h, cooled to room temperature, concentrated under reduced pressure, and poured into NaOH solution (1N, 30 mL) and MeOH (30 mL). The mixture was stirred at room temperature overnight, diluted with EA (300 mL), washed twice with brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 50 / 50) to give 5.7 g (47%) of 3-bromo-5H,6H,7H-cyclopenta[b]pyridin-7-ol as a brown solid. 5. Synthesis of Intermediate 1-6: [Chemical formula]

[0207] To a solution of 3-bromo-5H,6H,7H-cyclopenta[b]pyridin-7-ol (5.8 g, 27.1 mmol, 1.0 eq) in THF (100 mL) was added 2,3-dihydro-1H-isoindole-1,3-dione (4.4 g, 29.9 mmol, 1.1 eq), PPh3 (8.9 g, 34.0 mmol, 1.25 eq) and DBAD (7.52 g, 32.7 mmol, 1.21 eq) under nitrogen. The mixture was stirred for 3 h, diluted with EA (300 mL), washed twice with brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography (EA / PE, 10 / 90) to give 7.3 g (79%) of 2-[3-bromo-5H,6H,7H-cyclopenta[b]pyridin-7-yl]-2,3-dihydro-1H-isoindole-1,3-dione as a brown solid. 6. Synthesis of Intermediate 1-7:

Chemical Structure

[0208] 2-[3-bromo-5H,6H,7H-cyclopenta[b]pyridin-7-yl]-2 ,3-dihydro-1H-isoindole-1,3-dione (7.6 g, 22.2 mmol, 1.0 eq) in ethanol (80 mL) was added hydrazine hydrate (4.4 g, 88.7 mmol, 4.0 eq). The mixture was stirred at 80 °C for 2 h, cooled to room temperature, concentrated under reduced pressure and purified by silica gel chromatography (MeOH / DCM, 15 / 85) to give 1.5 g (32%) of 3-bromo-5H,6H,7H-cyclopenta[b]pyridin-7-amine as a brown solid. 7. Synthesis of Intermediate 1-8:

Chemical Structure

[0209] To a solution of 3-bromo-5H,6H,7H-cyclopenta[b]pyridin-7-amine (480 mg, 2.3 mmol, 1.0 eq) cooled to 0 °C in DCM (10 mL) was added benzoyl chloride (317 mg, 2.3 mmol, 1.0 eq) and TEA (114 mg, 1.1 mmol, 0.05 eq). The mixture was stirred for 30 minutes, diluted with EA (100 mL), washed twice with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 30 / 70) to give 240 mg (34%) of N-[3-bromo-5H,6H,7H-cyclopenta[b]pyridin-7-yl]benzamide as a white solid. 8. Synthesis of Intermediate 1-9: [Chemical formula]

[0210] To a solution of N-[3-bromo-5H,6H,7H-cyclopenta[b]pyridin-7-yl]benzamide (230 mg, 0.7 mmol, 1.0 eq) in a mixture of dioxane (6 mL) and water (6 mL) was added FeK4(CN)6.3H2O (376 mg, 1.2 eq), second-generation Xphos (112 mg, 0.2 eq), X-phos (72 mg, 0.2 eq), and KOAc (214 mg, 2.2 mmol, 3.0 eq) under nitrogen. The mixture was stirred at 90 °C overnight, cooled to room temperature, diluted with EA (50 mL), washed twice with brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 30 / 70) to give 100 mg (52%) of N-[3-cyano-5H,6H,7H-cyclopenta[b]pyridin-7-yl]benzamide as an off-white solid. 9. Synthesis of Intermediate 1-10: [Chemical formula]

[0211] To a solution of N-[3-cyano-5H,6H,7H-cyclopenta[b]pyridin-7-yl]benzamide (100 mg, 0.38 mmol, 1.00 equiv) in MeOH (8 mL) were added hydroxylamine hydrochloride (79 mg, 1.15 mmol, 3.0 equiv) and sodium hydrogen carbonate (128 mg, 1.5 mmol, 4.0 equiv). The mixture was stirred at 80 °C for 2 h and concentrated under reduced pressure to give 110 mg of N-[3-(N-hydroxycarbamimidoyl)-5H,6H,7H-cyclopenta[b]pyridin-7-yl]benzamide as an off-white solid. 10. Synthesis of Compound 17:

Chemical Structure

[0212] To a solution of N-[3-(N-hydroxycarbamimidoyl)-5H,6H,7H-cyclopenta[b]pyridin-7-yl]benzamide (100 mg, 0.34 mmol, 1.0 equiv) in dioxane (8 mL) was added propanoyl propanoate (0.8 mL). The mixture was stirred at 90 °C for 2 h and concentrated under reduced pressure. The mixture was redissolved in toluene (3 mL) and heated at 150 °C for 2 h. Then, the mixture was cooled to room temperature and concentrated under reduced pressure, and purified by preparative HPLC under the following conditions: (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): column, XBridge Shield RP18 OBD column, 5 um, 19*150 mm; mobile phase, water (0.05% NH3H2O) and ACN (ACN from 24.0% to 54.0% in 8 min); detector, UV220 nm. Thereby, 5.9 mg (5%) of N-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)benzamide (Compound 17) was obtained as a white solid. LRMS (ES) m / z 335 (M+H). 1 1H-NMR: (CDCl3, ppm): 8.93 (m, 1H), 8.85 (m, 1H), 8.19 (m, 1H), 7.86 (m, 2H), 7.46 (m, 3H), 5.55 (m, 1H), 3.01 (m, 4H), 2.53 (m, 1H), 2.02 (m, 1H), 1.31 (m, 3H).

[0213] The following compounds were prepared by a method similar to the method described for Compound 17.

Chemical formula

Chemical formula

[0214] To a solution of N-[3-(N-hydroxycarbamimidoyl)-5H,6H,7H-cyclopenta[b]pyridin-7-yl]benzamide (80 mg, 0.27 mmol, 1.0 equiv) in dioxane (6 mL) was added (1,1-dimethoxyethyl)dimethylamine (144 mg, 1.08 mmol, 4.0 equiv). The mixture was stirred at 90 °C for 2 h and concentrated under reduced pressure, and purified by preparative HPLC under the following conditions: (column, X-Bridge, C18, Shield RP, 19*150 mm 5 um; mobile phase, water containing 0.05% NH3H2O and ACN (from 20.0% to 48.0% of ACN in 8 min); detector, UV210 / 254 nm). This purification gave 7.6 mg (9%) of N-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)benzamide (Compound 42) as a white solid. LRMS (ES) m / z 321 (M+H). 1 H-NMR: (300 MHz, methanol-d 4,ppm) δ 9.02 - 8.95 (m, 1H), 8.33 - 8.26 (m, 1H), 7.92 - 7.82 (m, 2H), 7.57 - 7.45 (m, 1H), 7.44 (dd, J = 8.3, 6.5 Hz, 2H), 5.62 (t, J = 8.5 Hz, 1H), 3.22 - 2.93 (m, 2H), 2.82 - 2.64 (m, 1H), 2.65 (s, 3H), 2.11 (dq, J = 12.8, 9.0 Hz, 1H). (Example 3) Synthesis of Compound 94 [Chemical Structure]

[0215] To a solution of N-[3-(N-hydroxycarbamimidoyl)-5H,6H,7H-cyclopenta[b]pyridin-7-yl]benzamide (60 mg, 0.2 mmol, 1.0 eq) in dioxane (5 mL) was added 2,2-difluoroacetyl 2,2-difluoroacetate (53 mg, 0.3 mmol, 1.5 eq). The mixture was stirred at 60 °C for 2 h and concentrated under reduced pressure, and purified by preparative HPLC under the following conditions: (column, X-Bridge, C18, Shield RP, 19*150 mm 5um; mobile phase, water containing 0.05% NH3H2O and ACN (from 27.0% to 57.0% ACN in 8 min); detector, UV210 / 254 nm). This purification gave 7.5 mg (10%) of N- (3-(5-(Difluoromethyl)-1,2,4-oxadiazol-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)benzamide (Compound 94) as a white solid. LRMS (ES) mz / 357; 1 1H-NMR: (300 MHz, methanol-d 4, ppm) δ 9.09 - 9.01 (m, 1H), 8.37 (dt, J = 2.0, 1.0 Hz, 1H), 7.93 - 7.82 (m, 2H), 7.58 - 7.35 (m, 3H), 5.63 (t, J = 8.5 Hz, 1H), 3.25 - 2.95 (m, 3H), 2.74 (dtd, J = 12.9, 8.1, 2.9 Hz, 1H), 2.13 (dq, J = 12.8, 9.1 Hz, 1H). (Example 4) Synthesis of Compound 62 1. Synthesis of Intermediate 4-2: [Chemical formula]

[0216] To a solution of 5-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine (200 mg, 0.93 mmol, 1.00 eq) in DMF (10 mL) was added DSC (432 mg, 1.69 mmol, 1.82 eq). After stirring at room temperature for 2 hours and at 60 °C for 4 hours, the resulting solution was diluted with EA (60 mL). The mixture was washed twice with water (30 mL) and with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 260 mg of 2,5-dioxopyrrolidin-1-yl N-[5-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate as a yellow solid. This yellow solid was used in the next step without further purification. LRMS (ES) m / z 357 (M+H). 2. Synthesis of Compound 62: [Chemical formula]

[0217] To a solution of 2,5-dioxopyrrolidin-1-yl N-[5-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate (60 mg, 0.17 mmol, 1.00 equiv) in ACN (5 mL) were added pyridin-3-amine (40 mg, 0.43 mmol, 2.52 equiv) and TEA (100 mg, 0.99 mmol, 5.87 equiv). The mixture was stirred at 80 °C for 4 h and concentrated under vacuum, and purified by preparative HPLC under the following conditions: (2#-AnalyseHPLC-SHIMADZU(HPLC -10)): Column, XBridge Shield RP18 OBD column, 5um, 19*150mm; Mobile phase, water (0.05% NH3.H2O) and ACN (from 20.0% to 50.0% of ACN in 8 min); Detector, UV254nm. This gave 10 mg (18%) of 1-(5-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-3-(pyridin-3-yl)urea (Compound 62) as a white solid. LRMS (ES) m / z 336 (M+H). 1 H-NMR: (400 MHz, DMSO-d6, ppm) δ 8.64 (s, 1H), 8.56 (s, 1H), 8.13 (d, J = 4.6 Hz, 1H), 7.93 (ddd, J = 8.4, 2.7, 1.5 Hz, 1H), 7.89 - 7.81 (m, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.27 (dd, J = 8.4, 4.6 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 5.24 (q, J = 8.0 Hz, 1H), 2.99 (dd, J = 8.1, 5.1 Hz, 1H), 2.88 (q, J = 8.0 Hz, 1H), 2.64 (s, 3H), 2.49 (m, 1H), 1.92 - 1.77 (m, 1H).

[0218] The following compounds were prepared by a method similar to the method described for Compound 62. [Chemical formula] (Example 5) Synthesis of Compound 100 1. Synthesis of Intermediate 5-2: [Chemical formula]

[0219] To a solution of (1R)-5-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride (44.4 g, 178.8 mmol, 1 equiv) in DCM (330 mL) at 0 °C was added dropwise a solution of TEA (39.8 g, 393.3 mmol, 2.2 equiv) and (Boc)2O (42.9 g, 196.3 mmol, 1.1 equiv) in DCM (120 mL) over a period of 1 hour. The mixture was stirred at room temperature for 3 hours. Water (500 mL) was added and the mixture was extracted twice with DCM (500 mL). The combined organic layers were washed twice with an aqueous NH4Cl solution (500 mL) and twice with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 57.4 g (92%) of tert-butyl N-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate as a white solid. 2. Synthesis of Intermediate 5-3: [Chemical formula]

[0220] A solution of tert-butyl N-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate (57.4 g, 184 mmol, 1.0 equiv) in a mixture of dioxane (285 mL) and water (285 mL) was added with potassium acetate (36.0 g, 367 mmol, 2.0 equiv), K4Fe(CN)6·3H2O (31.1 g, 73.5 mmol, 0.4 equiv), XPhos (1.3 g, 2.8 mmol, 0.015 equiv) and second-generation XPhos catalyst precursor (2.2 g, 2.8 mmol, 0.015 equiv) under nitrogen. The mixture was stirred at 100 °C for 2 h, cooled to room temperature, filtered to remove the solid. The aqueous layer was extracted twice with EA (500 ml). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, triturated with a mixture of ethyl acetate and hexane (300 mL, 1 / 10) to give 42 g (88%) of tert-butyl N-[(1R)-5-cyano-2,3-dihydro-1H-inden-1-yl]carbamate as a pale yellow solid. LRMS(ES) m / z 203 (M+H-56). 3. Synthesis of Intermediate 5-4: [Chemical formula]

[0221] To a solution of tert-butyl N-[(1R)-5-cyano-2,3-dihydro-1H-inden-1-yl]carbamate (42.2 g, 163.4 mmol, 1 equiv) in ethanol (420 mL) was added hydroxylamine hydrochloride (22.7 g, 326.7 mmol, 2.0 equiv) and TEA (33.1 g, 326.7 mmol, 2.0 equiv). The mixture was stirred at 50 °C for 4 h, concentrated under reduced pressure, dissolved in EA (1 L), washed with water, dried over Na2SO4 and concentrated under reduced pressure to give 54.6 g (98%) of tert-butyl N-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl]carbamate as an off-white solid. LRMS(ES) m / z 292 (M+H). 4. Synthesis of Intermediate 5-5: [Chemical formula]

[0222] To a solution of tert-butyl N-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl]carbamate (54.6 g, 187.4 mmol, 1 equiv) in dioxane (500 mL) was added 2,2-difluoroacetyl 2,2-difluoroacetate (34.2 g, 196.8 mmol, 1.05 equiv). The mixture was stirred at 50 °C for 1 h and at 100 °C for 2 h. The solution was then cooled to room temperature and poured into water (500 mL). The aqueous layer was extracted twice with EA (500 mL). The combined organic layers were washed with brine (1 L), dried over Na2SO4, and concentrated under reduced pressure to give 53.2 g (73%) of tert-butyl N-[(1R)-5-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate as a white solid. LRMS (ES) m / z 295 (M+H-56). 5. Synthesis of Intermediate 5-6:

Chemical Structure

[0223] To a solution of tert-butyl N-[(1R)-5-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (53.2 g, 151.4 mmol, 1 equiv) in DCM (375 mL) was added HCl (4 M in dioxane, 125 mL, 4.1 mol, 27.2 equiv). The mixture was stirred at room temperature for 3 h and diluted with ethyl acetate (300 mL). The precipitate was collected and dried under high vacuum to give 44 g (94%) of (1R)-5-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-amine hydrochloride as an off-white solid. LRMS (ES) m / z 235 (M+H-17). 6. Synthesis of Compound 100:

Chemical Structure

[0224] To a solution of 2-methyl-1,3-oxazole-5-carboxylic acid (10.0 g, 78.3 mmol, 1.0 eq) in DMF (220 mL) were added HOAt (16.0 g, 117.4 mmol, 1.5 eq), EDCI (22.5 g, 117.4 mmol, 1.5 eq) and DIEA (40.5 g, 313.1 mmol, 4.0 eq). The mixture was stirred for 15 minutes, and (1R)-5-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-amine hydrochloride (22.6 g, 78.3 mmol, 1.05 eq) was added. Stirring of the mixture was continued overnight. Ice water (700 mL) was added and the mixture was stirred for an additional 1 hour. The precipitate was collected, dissolved in EA (500 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with a mixture of EA and PE (700 mL, 1 / 20) to give 26 g of a light brown solid. This batch was combined with another batch prepared using the same procedure (7.5 g was obtained from 24.33 mmol of the amine). The combined product was dissolved in a mixture of DCM and MeOH (500 mL, 10 / 1), concentrated to a volume of about 100 mL and diluted with hexane (1 L). The precipitate was collected and dried to give 32.8 g of (R)-N-(5-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-methyloxazole-5-carboxamide (Compound 100) as an off-white solid. LRMS (ES) m / z 361 (M+H). 1 H-NMR: (400 MHz, chloroform-d, ppm) δ 8.03 (s, 1H), 8.02 - 7.97 (m, 1H), 7.66 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 6.88 (t, J = 52.2 Hz, 1H), 6.42 (d, J = 8.7 Hz, 1H), 5.74 (q, J = 8.0 Hz, 1H), 3.14 (ddd, J = 16.2, 8.9, 3.6 Hz, 1H), 3.02 (dt, J = 16.4, 8.3 Hz, 1H), 2.76 (dtd, J = 13.0, 7.9, 3.6 Hz, 1H), 2.53 (s, 3H), 2.01 (dq, J = 13.0, 8.5 Hz, 1H).

[0225] The following compounds were prepared by a method similar to the method described for Compound 100.

Chemical Structure

Chemical Structure

[0226] To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (205 mg, 1.6 mmol, 1.0 equiv) in DMF (6 mL) were added DIEA (630 mg, 3.00 equiv) and HA TU (928 mg, 2.44 mmol, 1.50 equiv). The mixture was stirred for 15 minutes, and 5-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine (350 mg, 1.63 mmol, 1.00 equiv) was added. The mixture was then stirred overnight, diluted with EA (100 mL), washed three times with brine (100 mL), concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 3) to give 390 mg (74%) of 1-methyl-N-[5-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]-1H-pyrazole-5-carboxamide as a white solid. LRMS (ES) m / z 324 (M+H). 2. Synthesis of Compound 107: [Chemical formula]

[0227] The racemic mixture (390 mg) was purified by chiral preparative HPLC under the following conditions (Preparative HPLC - 009): column, Chiralpak ID - 2, 2 * 25 cm, 5 μm; mobile phase, hexane and ethanol (holding 25.0% ethanol for 20 minutes); detector, UV220 / 254 nm. This separation yielded 114.5 mg (29%) of (R)-1 - methyl - N-(5-(5 - methyl - 1,2,4 - oxadiazol - 3 - yl)-2,3 - dihydro - 1H - inden - 1 - yl)-1H - pyrazole - 5 - carboxamide (Compound 107) as a white solid. LRMS (ES) m / z 324 (M + H). 1 1H - NMR: (DMSO, 400 MHz, ppm): δ 8.84 - 8.82 (1H, d, J = 8.0), 7.89 - 7.86 (2H, m), 7.45 - 7.38 (2H, m), 6.92 (1H, s), 5.60 - 5.53 (1H, dd, J = 8.4, 16.8), 4.11 (3H, s), 3.10 - 3.04 (1H, m), 2.97 - 2.89 (1H, m), 2.65 (3H, s), 2.50 (1H, m), 2.07 - 1.97 (1H, m) (Example 7) Synthesis of Compound 108 1. Synthesis of Intermediate 7 - 2: [Chemical formula]

[0228] To a solution of 3-bromo-5H,6H,7H-cyclopenta[b]pyridin-7-amine (480 mg, 2.25 mmol, 1.0 eq) in DMF (10 mL) were added 2-methylpyridine-4-carboxylic acid (620 mg, 4.5 mmol, 2.0 eq), HATU (1.3 g, 3.4 mmol, 1.5 eq) and DIEA (876 mg, 6.8 mmol, 3.0 eq). The mixture was stirred for 2 h, diluted with EA (100 mL), washed twice with brine ( 30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography (EA / PE, 70 / 30) to afford 460 mg (61%) of N-[3-bromo-5H,6H,7H-cyclopenta[b]pyridin-7-yl]-2-methylpyridine-4-carboxamide as a brown solid. 2. Synthesis of Intermediate 7-3:

Chemical Structure

[0229] To a solution of N-[3-bromo-5H,6H,7H-cyclopenta[b]pyridin-7-yl]-2-methylpyridine-4-carboxamide (450 mg, 1.4 mmol, 1.0 eq) in dioxane (5 mL) were added K4Fe(CN)6·3H2O (586 mg, 1.4 mmol, 1.0 eq), X-phos (67 mg, 0.14 mmol, 0.1 eq), second-generation Xphos (105 mg, 0.14 mmol, 0.1 eq), KOAc (266 mg, 2.7 mmol, 2.0 eq) and water (5 mL) under nitrogen. The mixture was stirred at 80 °C for 6 h, cooled to room temperature, diluted with EA (100 mL), washed twice with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography (EA / PE, 99 / 1) to afford 40 mg (11%) of N-[3-cyano-5H,6H,7H-cyclopenta[b]pyridin-7-yl]-2-methylpyridine-4-carboxamide as a brown solid. 3. Synthesis of Intermediate 7-4:

Chemical Structure

[0230] To a solution of N-[3-cyano-5H,6H,7H-cyclopenta[b]pyridin-7-yl]-2-methylpyridine-4-carboxamide (40 mg, 0.14 mmol, 1.0 eq) in MeOH (6 mL) were added hydroxylamine hydrochloride (20 mg, 0.3 mmol, 2.0 eq) and sodium bicarbonate (36 mg, 0.4 mmol, 3.0 eq). The mixture was stirred at 80 °C for 5 h, cooled to room temperature, and concentrated under reduced pressure to give 50 mg of N-[3-(N-hydroxycarbamimidoyl)-5H,6H,7H-cyclopenta[b]pyridin-7-yl]-2-methylpyridine-4-carboxamide as a white solid. 4. Synthesis of Compound 108:

Chemical Structure

[0231] To a solution of N-[3-(N-hydroxycarbamimidoyl)-5H,6H,7H-cyclopenta[b]pyridin-7-yl]-2-methylpyridine-4-carboxamide (45 mg, 0.14 mmol, 1.0 eq) in dioxane (5 mL) was added propanoyl propanoate (56 mg, 0.4 mmol, 3.0 eq). The mixture was stirred at 90 °C for 2 h, cooled to room temperature, and concentrated under reduced pressure. Then xylene (5 mL) was added, and the mixture was heated at 150 °C for 2 h, cooled to room temperature, and concentrated under reduced pressure. Purification was carried out by preparative HPLC under the following conditions: (column, X-Bridge, C18, Shield RP, 19*150 mm 5um; mobile phase, water containing 0.05% NH3H2O and ACN (ACN decreased from 20.0% to 40.0% in 8 min, to 100.0% in 5 min, and to 0% in 1 min); detector, UV210 / 254 nm). This purification gave 12.3 mg (24%) of N-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-2-methylisonicotinamide (Compound 108) as a white solid. LRMS (ES) m / z 350 (M+H). 11H-NMR: (300 MHz, DMSO-d6, ppm): δ 9.09 (d, J = 8.4 Hz, 1H), 8.94 (d, J = 1.9 Hz, 1H), 8.55 (dd, J = 5.2, 0.8 Hz, 1H), 8.21 (d, J = 1.9 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.56 (dd, J = 5.1, 1.6 Hz, 1H), 5.54 (q, J = 8.5 Hz, 1H), 3.14 - 2.98 (m, 2H), 3.02 - 2.84 (m, 2H), 2.62 - 2.48 (m, 1H), 2.49 (s, 3H), 2.01 (dq, J = 12.6, 9.0 Hz, 1H), 1.31 (t, J = 7.6 Hz, 3H). (Example 8) Synthesis of Compound 122 1. Synthesis of Intermediate 8-2: [Chemical formula]

[0232] To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (592 mg, 4.79 mmol, 1.0 equiv) in DMF (10 mL) were added DIEA (1.8 g, 13.9 mmol, 3.0 equiv) and HATU (2.7 g, 7.1 mmol, 1.5 equiv). The mixture was stirred for 15 min, and 6-bromo-2,3-dihydro-1-benzofuran-3-amine (1 g, 4.7 mmol, 1.0 equiv) was added. The mixture was then stirred overnight, diluted with EA (200 mL), washed three times with brine (200 mL), concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 1) to afford 1.3 g (86%) of N-(6-bromo-2,3-dihydro-1-benzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide as an off-white solid. 2. Synthesis of Intermediate 8-3: [Chemical formula] ​

[0233] To a solution of N-(6-bromo-2,3-dihydro-1-benzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide (1.4 g, 4.4 mmol, 1.0 eq) in DMF (10 mL) was added CuCN (587 mg, 6.6 mmol, 1.5 eq). The mixture was stirred at 160 °C for 2 days, diluted with EA (200 mL), washed three times with brine (200 mL), concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 2) to give 530 mg (45%) of N-(6-cyano-2,3-dihydro-1-benzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide as an off-white solid. 3. Synthesis of Intermediate 8-4:

Chemical formula

[0234] To a solution of N-(6-cyano-2,3-dihydro-1-benzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide (530 mg, 2.0 mmol, 1.0 eq) in MeOH (8 mL) were added sodium hydrogen carbonate (250 mg, 1.5 eq) and hydroxylamine hydrochloride (164 mg, 2.4 mmol, 1.2 eq). The mixture was heated at 60 °C for 2 hours and concentrated under reduced pressure to give 580 mg of N-[6-(N-hydroxycarbamimidoyl)-2,3-dihydro-1-benzofuran-3-yl]-1-methyl-1H-pyrazole-5-carboxamide as a pale yellow solid. This pale yellow solid was used in the next step without further purification. 4. Synthesis of Intermediate 8-5:

Chemical formula

[0235] To a solution of N-[6-(N-hydroxycarbamimidoyl)-2,3-dihydro-1-benzofuran-3-yl]-1-methyl-1H-pyrazole-5-carboxamide (190 mg, 0.6 mmol, 1.0 eq) in dioxane (5 mL) was added (1,1-dimethoxyethyl)dimethylamine (168 mg, 1.3 mmol, 2.0 eq). The mixture was stirred at 80 °C for 2 h, concentrated under reduced pressure, and purified by preparative HPLC under the following conditions: (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): column, XBridge Shield RP18 OBD column, 5 μm, 19*150 mm; mobile phase, water (0.05% NH3.H2O) and ACN (from 25.0% to 45.0% of ACN in 8 min); detector, UV220 nm. This purification gave 133 mg of 1-methyl-N-[6-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]-1H-pyrazole-5-carboxamide as a white solid. LRMS (ES) m / z 326 (M+H). 1 1H-NMR: (CD3OD, 400 MHz, ppm): δ 7.67 - 7.65 (1H, d, J = 8.0), 7.54 - 7.45 (3H, m), 6.82 (1H, m), 5.89 - 5.85 (1H, m), 4.86 - 4.84 (1H, m), 4.51 - 4.48 (1H, dd, J = 5.2, 9.6), 4.17 (3H, s), 2.66 (3H, s) 5. Synthesis of Compound 122:

Chemical Structure

[0236] This racemic mixture (95 mg) was purified by chiral preparative HPLC under the following conditions: (Preparative HPLC - 004): column, CHIRAL ART Cellulose - SB, 2 * 25 cm, 5 μm; mobile phase, hexane and ethanol (holding 50.0% ethanol at 9 min); detector, UV254 / 220 nm. This purification yielded 28.3 mg (30%) of (S) - 1 - methyl - N - (6 - (5 - methyl - 1,2,4 - oxadiazol - 3 - yl) - 2,3 - dihydrobenzofuran - 3 - yl) - 1H - pyrazole - 5 - carboxamide (Compound 122) as a white solid. LRMS (ES) m / z 326 (M + H). 1 1H - NMR: (CD3OD, 300 MHz, ppm): δ7.62 - 7.59 (1H, dd, J = 1.2, 7.8), 7.49 - 7.40 (3H, m), 6.77 - 6.76 (1H, d, J = 2.1), 5.84 - 5.79 (1H, dd, J = 4.8, 8.7), 4.80 - 4.77 (1H, m), 4.47 - 4.42 (1H, dd, J = 4.8, 9.9), 4.11 (3H, s), 2.61 (3H, s)

[0237] The following compounds were prepared by a method similar to the method described for Compound 122. [Chemical formula] (Example 9) Synthesis of Compound 124 1. Synthesis of Intermediate 9 - 2: [Chemical formula]

[0238] To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (592 mg, 4.7 mmol, 1.0 equiv) in DMF (10 mL) were added DIEA (1.8 g, 13.9 mmol, 3.0 equiv) and HATU (2.7 g, 7.1 mmol, 1.5 equiv). The mixture was stirred for 15 minutes, then 6-bromo-2,3-dihydro-1-benzofuran-3-amine (1 g, 4.7 mmol, 1.0 equiv) was added. The mixture was then stirred overnight, diluted with ethyl acetate (200 mL), washed three times with brine (200 mL), concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 1) to give 1.3 g (86%) of N-(6-bromo-2,3-dihydro-1-benzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide as an off-white solid. 2. Synthesis of Intermediate 9-3:

Chemical formula

[0239] To a solution of N-(6-bromo-2,3-dihydro-1-benzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide (1.4 g, 4.4 mmol, 1.0 equiv) in DMF (10 mL) was added CuCN (587 mg, 6.6 mmol, 1.5 equiv). The mixture was stirred at 160 °C for 2 days, diluted with EA (200 mL), washed three times with brine (200 mL), concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 2) to give 530 mg (45%) of N-(6-cyano-2,3-dihydro-1-benzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide as an off-white solid. 3. Synthesis of Intermediate 9-4:

Chemical formula

[0240] A solution of N-(6-cyano-2,3-dihydro-1-benzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide (530 mg, 2.0 mmol, 1.0 eq) in MeOH (8 mL) was added with sodium hydrogen carbonate (250 mg, 1.5 eq) and hydroxylamine hydrochloride (164 mg, 2.4 mmol, 1.2 eq). The mixture was heated at 60 °C for 2 h and concentrated under reduced pressure to give 580 mg of N-[6-(N-hydroxy carbamimidoyl)-2,3-dihydro-1-benzofuran-3-yl]-1-methyl-1H-pyrazole-5-carboxamide as a pale yellow solid. This pale yellow solid was used in the next step without further purification. 4. Synthesis of Intermediate 9-5:

Chemical Structure

[0241] To a solution of N-[6-(N-hydroxycarbamimidoyl)-2,3-dihydro-1-benzofuran-3-yl]-1-methyl-1H-pyrazole-5-carboxamide (190 mg, 0.6 mmol, 1.0 eq) in dioxane (5 mL) was added dropwise 2,2-difluoroacetyl 2,2-difluoroacetate (220 mg, 1.3 mmol, 2.0 eq). After stirring at 80 °C for 2 h, the resulting mixture was concentrated under reduced pressure and purified by preparative HPLC under the following conditions: (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): column, XBridge Shield RP18 OBD column, 5 um, 19*150 mm; mobile phase, water (0.05% NH3H2O) and ACN (from 33.0% to 55.0% ACN in 8 min); detector, UV220 nm. This purification gave 130 mg of N-[6-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1-benzofuran-3-yl]-1-methyl-1H-pyrazole-5-carboxamide as a white solid. LRMS (ES) m / z 362 (M+H). 5. Synthesis of Compound 124:

Chemical Structure

[0242] This racemic mixture (85 mg) was purified by chiral preparative HPLC under the following conditions: (Preparative HPLC - 004): column, CHIRAL ART Cellulose - SB, 2 * 25 cm, 5 μm; mobile phase, hexane and ethanol (holding 35.0% ethanol after 8 minutes); detector, UV254 / 220 nm. This purification gave 26.8 mg (32%) of (S)-N-(6-(5-(difluoromethyl)-1,2,4 - oxadiazol - 3 - yl)-2,3 - dihydrobenzofuran - 3 - yl)-1 - methyl - 1H - pyrazole - 5 - carboxamide (Compound 124) as a white solid. LRMS (ES) m / z 362 (M + H). 1 H - NMR: (CD3OD, 300 MHz, ppm): δ 7.70 - 7.67 (1H, dd, J = 1.5, 7.8), 7.54 - 7.50 (2H, m), 7.41 - 7.40 (1H, m), 7.34 - 7.00 (1H, t, J = 51.9), 6.77 - 6.76 (1H, d, J = 2.1), 5.86 - 5.81 (1H, dd, J = 5.1, 9), 4.86 - 4.79 (1H, m), 4.49 - 4.44 (1H, dd, J = 5.1, 9.9), 4.11 (3H, s). (Example 10) Synthesis of Compound 139 1. Synthesis of Intermediate 10 - 2: [Chemical Structure Diagram]

[0243] To a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (100 g, 474 mmol, 1.00 equiv) in methanol (1.5 L) was added ammonium formate (300 g, 4.76 mol, 10.0 equiv). After stirring for 1 h, NaBH3CN (90 g, 1.43 mol, 3.02 equiv) was added. The mixture was heated at 60 °C for 2 h, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 10) to afford 64 g (64%) of 5-bromo-2,3-dihydro-1H-inden-1-amine as a brown solid. 2. Synthesis of Intermediate 10-3: [Chemical Formula]

[0244] To a solution of 2-methylpyridine-4-carboxylic acid (1.95 g, 14.2 mmol, 1.00 equiv) in DMF (20 mL) were added DIEA (5.5 g, 42.6 mmol, 3.00 equiv) and HATU (8.1 g, 21.3 mmol, 1.50 equiv). After stirring at room temperature for 15 min, 5-bromo-2,3-dihydro-1H-inden-1-amine (3.0 g, 14.2 mmol, 1.00 equiv) was added and the solution was stirred for 3 h. The resulting solution was diluted with aqueous NH4Cl solution and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column (EA / PE = 2 / 1) to afford 4 g (85%) of N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpyridine-4-carboxamide as a yellow solid. 3. Synthesis of Intermediate 10-4: [Chemical Formula]

[0245] N-(5-Bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpyridine-4-carboxa in a mixture of ethanol (120 mL) and DMSO (12 mL) To a solution of Mido (4.28 g, 13.0 mmol, 1.00 equiv), TEA (3.9 g, 38.6 mmol, 3.00 equiv) and Pd(dppf)Cl2·CH2Cl2 (1.06 g, 1.3 mmol, 0.1 equiv) were added. Then, the mixture was charged with CO (20 atm). The mixture was stirred at 120 °C for 2 days under CO, purged with CO and released, poured into water, and extracted 3 times with EA. The combined organic layers were concentrated under reduced pressure and purified by silica gel chromatography (EA / PE, 3 / 2) to obtain 3.5 g (83%) of ethyl 1-(2-methylpyridin-4-amide)-2,3-dihydro-1H-indene-5-carboxylate as a yellow solid. 4. Synthesis of Intermediate 10-5:

Chemical Structure

[0246] To a solution of ethyl 1-(2-methylpyridin-4-amide)-2,3-dihydro-1H-indene-5-carboxylate (1.2 g, 3.70 mmol, 1.00 equiv) in ethanol (10 mL) was added sodium hydroxide (300 mg, 7.50 mmol, 2.03 equiv) in water (2 mL). After stirring at room temperature for 12 h, the pH of the solution was adjusted to 4 - 5 with HCl (1 N). The solid was collected by filtration and dried in an oven to obtain 0.9 g (82%) of 1-(2-methylpyridin-4-amide)-2,3-dihydro-1H-indene-5-carboxylic acid as a white solid. 5. Synthesis of Intermediate 10-6:

Chemical Structure

[0247] To a solution of 1-(2-methylpyridin-4-carboxamido)-2,3-dihydro-1H-indene-5-carboxylic acid (300 mg, 1.01 mmol, 1.00 equiv) in DMF (5 mL) were added DIEA (523 mg, 4.05 equiv) and HATU (578 mg, 1.52 mmol, 1.50 equiv). After stirring at room temperature for 15 minutes, propargyl-1-amine (167 mg, 3.03 mmol, 3.00 equiv) was added. Stirring of the mixture was continued for 2 hours and purified by Combi-Flash equipped with a C18 column: mobile phase, mobile phase A: water (in H2O, 0.05% NH4HCO3), mobile phase B: ACN; flow rate: 50 mL / min; gradient: from 5% B to 70% B in 26 minutes; detector, UV254 nm. Thereby, 160 mg (47%) of 2-methyl-N-[5-[(prop-2-yn-1-yl)carbamoyl]-2,3-dihydro-1H-inden-1-yl]pyridine-4-carboxamide was obtained as a white solid. 6. Synthesis of Intermediate 10-7: [Chemical formula]

[0248] To a solution of 2-methyl-N-[5-[(prop-2-yn-1-yl)carbamoyl]-2,3-dihydro-1H-inden-1-yl]pyridine-4-carboxamide (150 mg, 0.45 mmol, 1.00 equiv) in DCE (5 mL) was added FeCl3 (37 mg, 0.23 mmol, 0.50 equiv). The mixture was stirred at 80 °C for 2 days, concentrated under reduced pressure, and purified by Combi-Flash equipped with a C18 column: mobile phase, mobile phase A: water (in H2O, 0.05% NH4HCO3), mobile phase B: ACN; flow rate: 50 mL / min; gradient: from 5% B to 70% B in 36 minutes; detector, UV254 nm. Thereby, 91.7 mg (61%) of 2-methyl-N-[5-(5-methyl-1,3-oxazol-2-yl)-2,3-dihydro-1H-inden-1-yl]pyridine-4-carboxamide was obtained as a white solid. 7. Synthesis of Compound 139: [Chemical formula]

[0249] The racemic mixture (80 mg) was purified by chiral preparative HPLC. Column: Chiralpak IB, 2 * 25 cm, 5 μm; mobile phase A: hexane-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: from 30% B to 30% B in 8 minutes; 220 / 254 nm; RT1: 5.20; RT2: 6.55. Thereby, 32.4 mg (41%) of (R)-2-methyl-N-(5-(5-methyloxazol-2-yl)-2,3-dihydro-1H-inden-1-yl)isonicotinamide (Compound 139) was obtained as a white solid. LRMS (ES) m / z 334 (M+H). 1 1H-NMR: (CD3OD, 300 MHz, ppm): δ 8.55-8.53 (1H, d, J = 5.4), 7.88-7.83 (2H, m), 7.70 (1H, s), 7.63-7.61 (1H, d, J = 5.1), 7.43-7.41 (1H, d, J = 7.8), 6.90 (1H, s), 5.71-5.65 (1H, t, J = 7.8), 3.20-3.10 (1H, m), 3.08-2.94 (1H, m), 2.70-2.60 (4H, m), 2.41 (3H, s), 2.15-2.05 (1H, m).

[0250] The following compounds were prepared by a method similar to the method described for Compound 139.

Chemical formula

Chemical formula

[0251] To a solution of tert-butyl N-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl]carbamate (22 g, 75.5 mmol, 1.0 equiv) in pyridine (350 mL) was added cyclopropanecarbonyl chloride (8.7 g, 82.8 mmol, 1.1 equiv). The mixture was heated at 60 °C for 2 h and then at 100 °C overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure and purified by silica gel chromatography (EA / PE, 15 / 85) to give 15 g (58%) of tert-butyl N-[(1R)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate as a white solid. LRMS (ES) m / z 286 (M+H-56). 2. Synthesis of Intermediate 11-3: [Chemical formula]

[0252] To a solution of tert-butyl N-[(1R)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate (2.9 g, 8.4 mmol, 1.0 equiv) in DCM (42 mL) was added HCl (4 M in dioxane, 21 mL, 10.0 equiv). The mixture was stirred overnight, and the precipitate was collected and dried to give 2.9 g of (1R)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine dihydrochloride as a white solid. LRMS (ES) m / z 225 (M+H-17). 3. Synthesis of Compound 141: [Chemical formula]

[0253] To a solution of 2-methyl-2H-1,2,3,4-tetrazole-5-carboxylic acid (5 g, 39.1 mmol, 2.3 equiv) in DMF (150 mL) were added HOAt (6 g, 44.1 mmol, 2.5 equiv), EDCI (8 g, 41.7 mmol, 2.5 equiv), DIEA (11.3 g, 87.4 mmol, 5.0 equiv) and (1R)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride (4.8 g, 17.3 mmol, 1.0 equiv). The mixture was stirred at room temperature for 1 h, heated to 60 °C for 4 h, cooled to room temperature, diluted with EA (300 mL), washed twice with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography (DCM / MeOH, 95 / 5) to give the intermediate product. The intermediate product was then triturated with a mixture of hexane and EA (15 / 1) to give 4.75 g (88%) of the product as a grey solid. This batch was combined with the previous batch (6.5 g obtained from 11.6 g of amine). The mixture was dissolved in DCM (120 mL) and added dropwise to n-hexane (1.5 L) with stirring. The precipitate was collected and dried to give 10.8 g of (R)-N-(5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-methyl-2H-tetrazole-5-carboxamide (Compound 141) as an off-white solid. LRMS (ES) m / z 352 (M+H). 11H-NMR: (400 MHz, chloroform-d, ppm) δ 7.95 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H), 5.78 (q, J = 7.9 Hz, 1H), 4.44 (s, 3H), 3.11 (ddd, J = 16.2, 8.8, 3.8 Hz, 1H), 2.98 (dt, J = 16.2, 8.1 Hz, 1H), 2.75 (dtd, J = 12.0, 7.8, 3.9 Hz, 1H), 2.25 (ddd, J = 9.6, 7.4, 4.1 Hz, 1H), 2.03 (dq, J = 12.9, 8.2 Hz, 1H), 1.45 - 1.19 (m, 4H).

[0254] The following compounds were prepared by a method similar to the method described for Compound 141.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0255] To a solution of tert-butyl N-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl]carbamate (50.0 g, 172 mmol, 1.00 equiv) in dioxane (500 mL) was added 2-methylpropanoyl 2-methylpropanoate (28.5 g, 180 mmol, 1.1 equiv). The mixture was stirred at 60 °C for 1 h, then at 100 °C for 6 h, cooled to room temperature, diluted with EA (500 mL), washed with water (300 mL) and brine (500 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography (EA / PE, 1 / 9) to afford 47 g (79%) of tert-butyl N-[(1R)-5-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate as a white solid. 2. Synthesis of Intermediate 12-3:

Chemical Structure

[0256] To a solution of tert-butyl N-[(1R)-5-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (21.2 g, 61.7 mmol, 1.0 equiv) in DCM (400 mL) was added hydrogen chloride (4 M in dioxane, 155 mL, 10.0 equiv). The mixture was stirred at room temperature overnight, the solid was collected and dried to afford 16.3 g (83%) of (1R)-5-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-amine hydrochloride as a white solid. 3. Synthesis of Compound 142:

Chemical Structure

[0257] To a solution of 2-methyl-2H-1,2,3,4-tetrazole-5-carboxylic acid (37.8 g, 295 mmol, 1.5 equiv) in DMF (500 mL) were added HOAt (40.1 g, 295 mmol, 1.5 equiv), EDCI (56.7 g, 296 mmol, 1.50 equiv), DIEA (102 g, 785 mmol, 4.0 equiv) and (1R)-5-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-amine hydrochloride (55.0 g, 197 mmol, 1.0 equiv). The mixture was stirred at 40 °C for 2 h and combined with four other batches prepared using the same procedure (scales of 3.6, 35.7, 197 and 197 mmol of the amine of the SM) for further workup. Water was added to the combined solution. The precipitate was collected by filtration, washed with further water and redissolved in DCM. The DCM solution was washed with water and saturated NH4Cl solution and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 210 g of (R)-N-(5-(5-isopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-methyl-2H-tetrazole-5-carboxamide (Compound 142) as an off-white solid. LRMS (ES) m / z 354 (M+H). 1 1H-NMR: (300 MHz, chloroform-d, ppm) δ 7.97 (d, J = 1.4 Hz, 1H), 7.93 (dd, J = 7.9, 1.1 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 5.77 (q, J = 7.9 Hz, 1H), 4.42 (s, 3H), 3.26 (hept, J = 7.0 Hz, 1H), 3.10 (ddd, J = 16.2, 8.7, 3.9 Hz, 1H), 2.97 (dt, J = 16.1, 8.0 Hz, 1H), 2.83 - 2.65 (m, 1H), 2.02 (dt, J = 13.0, 8.1 Hz, 1H), 1.44 (d, J = 7.0 Hz, 6H). (Example 13) Synthesis of Compound 143 1. Synthesis of Intermediate 13-2:

Chem.

[0258] To a solution of tert-butyl N-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl]carbamate (4 g, 13.7 mmol, 1.0 equiv) in pyridine (80 mL) was added cyclobutanecarbonyl chloride (2 g, 16.9 mmol, 1.2 equiv). The mixture was heated at 60 °C for 3 h and then at 100 °C overnight. The reaction was then cooled to room temperature and concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 5 / 95) to give 3.3 g (68%) of tert-butyl N-[(1R)-5-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate as an off-white solid. 2. Synthesis of Intermediate 13-3:

Chem.

[0259] To a solution of tert-butyl N-[(1R)-5-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate (3 g, 8.4 mmol, 1.0 equiv) in dichloromethane (60 mL) was added hydrogen chloride (4 M in dioxane, 21 mL, 10.0 equiv). The mixture was stirred at room temperature overnight, and the precipitate was collected and dried to give 2 g (81%) of (1R)-5-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride as a white solid. 3. Synthesis of Compound 143:

Chem.

[0260] To a solution of 2-methyl-2H-1,2,3,4-tetrazole-5-carboxylic acid (1.0 g, 7.8 mmol, 1.3 equiv) in DMF (100 mL) were added (1R)-5-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride (1.8 g, 6.2 mmol, 1.0 equiv), HOAt (1.5 g, 11.0 mmol, 1.8 equiv), EDCI (2.1 g, 11.0 mmol, 1.8 equiv) and DIEA (4.0 g, 31.0 mmol, 5.0 equiv). The mixture was stirred for 30 minutes, and EA (100 mL) and water (100 mL) were added. The aqueous layer was extracted three times with EA (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and purified by a C18 column using ACN:H2O (35:65) as the eluent to obtain 946 mg (42%) of (R)-N-(5-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-methyl-2H-tetrazole-5-carboxamide (Compound 143) as a white solid. LRMS (ES) m / z 366.0 (M+H). 1 H-NMR: (300 MHz, methanol-d4, ppm): δ 8.01 - 7.88 (m, 2H), 7.44 (d, J = 7.9 Hz, 1H), 5.74 (t, J = 8.0 Hz, 1H), 4.45 (s, 3H), 3.97 - 3.79 (m, 1H), 3.26 - 3.09 (m, 1H), 3.00 (dd, J = 16.1, 8.4 Hz, 1H), 2.75 - 2.45 (m, 5H), 2.32 - 2.05 (m, 3H). (Example 14) Synthesis of Compound 183: [Chemical formula]

[0261] To a solution of 2-methyl-2H-1,2,3,4-tetrazole-5-carboxylic acid (5 g, 39.0 mmol, 1.00 equiv) in DMF (150 mL) were added HOAt (9.6 g, 70.5 mmol, 1.8 equiv), EDCI (13.5 g, 70.4 mmol, 1.0 equiv), a solution of (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine (9.0 g, 39.0 mmol, 1.0 equiv) in DIEA (19.2 g, 148.2 mmol, 3.80 equiv) and DMF (50 mL). The mixture was stirred at 60 °C for 3 h, cooled to room temperature, and poured into DCM (1 L) and water (1 L). The aqueous layer was extracted 5 times with DCM (500 mL). The combined organic layers were washed 5 times with saturated NH4Cl solution (500 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 2 / 3) to give 8.7 g (66%) of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-methyl-2H-tetrazole-5-carboxamide (Compound 183) as a white solid. LRMS (ES) m / z 340 (M+H). 1 H-NMR: 1H NMR (300 MHz, DMSO-d6) δ 9.42 (d, J = 8.4 Hz, 1H), 7.89 - 7.76 (m, 2H), 7.34 (d, J = 7.9 Hz, 1H), 5.58 (q, J = 8.2 Hz, 1H), 4.41 (s, 3H), 3.14 - 2.80 (m, 4H), 2.47 - 2.38 (m, 1H), 2.13 (dq, J = 12.5, 8.7 Hz, 1H), 1.31 (t, J = 7.5 Hz, 3H). (Example 15) Synthesis of Compound 184 1. Synthesis of Intermediate 15-2:

Chemical Structure

[0262] To a solution of tert-butyl N-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl]carbamate (16 g, 54.9 mmol, 1.0 equiv) in dioxane (300 mL) was added propanoyl propanoate (8.4 g, 64.5 mmol, 1.2 equiv). The mixture was stirred at 105 °C for 8 h, cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 9) to afford 17.5 g (97%) of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate as a white solid. 2. Synthesis of Intermediate 15-3:

Chemical formula

[0263] To a solution of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate (17.6 g, 53.4 mmol, 1.0 equiv) in DCM (120 mL) was added TFA (24 mL). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The mixture was then poured into ethanol (50 mL) and water (5 mL), and the pH was adjusted to 12 with sodium hydroxide solution (2N). The mixture was then extracted three times with dichloromethane (200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 11.2 g of (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine as a brown oil. 3. Synthesis of Compound 184:

Chemical formula

[0264] To a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (6.1 g, 48.4 mmol, 1.0 eq) in DMF (300 mL) were added DIEA (12.6 g, 97.5 mmol, 2.0 eq), HOAt (19.8 g, 145.8 mmol, 3.0 eq) and EDCI (28 g, 146.1 mmol, 3.0 eq). The mixture was stirred for 15 minutes and then (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine (11.2 g, 48.9 mmol, 1.0 eq) was added. The mixture was then stirred for 3 hours, diluted with DCM, washed three times with NH4Cl solution, dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography (EA / PE, 74 / 26) to obtain the intermediate product. The intermediate product was triturated with a mixture of EA and PE (1 / 10) to give 14.5 g (88%) of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 184) as a white solid. LRMS (ES) m / z 338 (M+H). 1 H-NMR: (DMSO, 300 MHz, ppm): δ 8.41 (1H, d, J = 8.4 Hz), 8.16 (1H, s), 7.91 - 7.79 (3H, m), 7.34 (1H, d, J = 7.9 Hz), 5.53 (1H, q, J = 8.3 Hz), 3.84 (3H, s), 3.13 - 2.81 (4H, m), 2.44 (1H, dd, J = 7.9, 4.7 Hz), 1.95 (1H, m), 1.33 (3H, t, J = 7.5 Hz). (Example 16) Synthesis of Compound 196 1. Synthesis of Intermediate 16 - 2: [Chemical formula]

[0265] To a solution of 5-bromopyridin-3-ol (25 g, 144 mmol, 1.0 eq) in water (500 mL) was added sodium carbonate (45.9 g, 434 mmol, 3.0 eq) and I2 (36.6 g, 144 mmol, 1.00 eq) portionwise over a period of 3 hours. The mixture was stirred for 1 hour and adjusted to pH 7 with hydrogen chloride (2N). The resulting precipitate was collected and dried to afford 39 g (91%) of 5-bromo-2-iodopyridin-3-ol as a white solid. 2. Synthesis of Intermediate 16-3: [Chemical formula]

[0266] To a solution of 5-bromo-2-iodopyridin-3-ol (39.5 g, 132 mmol, 1.1 eq) in ACN (600 mL) was added potassium carbonate (54.5 g, 396 mmol, 3.0 eq) and BnBr (23.6 g, 138 mmol, 1.05 eq) dropwise with stirring at 0 °C. The mixture was stirred at room temperature for 5.5 hours, cooled to 0 °C, and quenched by dropwise addition of water at 0 °C. The solid was collected by filtration and triturated with 5% EA in PE (100 mL) to afford 44.4 g (86%) of 3-(benzyloxy)-5-bromo-2-iodopyridine as a white solid. 3. Synthesis of Intermediate 16-4: [Chemical formula]

[0267] A solution of 3-(benzyloxy)-5-bromo-2-iodopyridine (40 g, 103 mmol, 1.0 eq) cooled to -20 °C in THF (1 L) was added dropwise with i-PrMgCl·LiCl (1.3 M in THF, 87 mL, 103 mmol, 1.1 eq). The mixture was stirred at -20 °C for 2 h, then DMF (11.2 g, 154 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 2 h, cooled back to -20 °C, and quenched with aqueous NH4Cl solution. The resulting solution was extracted twice with EA (500 mL). The combined organic layers were washed twice with brine (500 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 10) to obtain 28 g (93%) of 3-(benzyloxy)-5-bromopyridine-2-carbaldehyde as an off-white solid. 4. Synthesis of Intermediate 16-5:

Chemical formula

[0268] To a solution of 3-(benzyloxy)-5-bromopyridine-2-carbaldehyde ( 27 g, 92.4 mmol, 1.0 eq) cooled to 0 °C in DCM (600 mL) was added FeCl3 (30 g, 185 mmol, 2.00 eq). The mixture was stirred at room temperature for 2 h, poured into water (1 L), and extracted three times with DCM (500 mL). The combined organic layers were washed three times with brine (500 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 10) to obtain 11 g (59%) of 5-bromo-3-hydroxypyridine-2-carbaldehyde as a pale yellow solid. 5. Synthesis of Intermediate 16-6:

Chemical formula

[0269] To a solution of 5-bromo-3-hydroxypyridine-2-carbaldehyde (11 g, 54.5 mmol, 1.0 eq) in DMSO (200 mL) was added trimethyl(oxo)-6-sulfanylium iodide (30 g, 136 mmol, 2.5 eq) and t-BuOK (15.3 g, 136 mmol, 2.5 eq) portionwise over a period of 20 minutes. The mixture was stirred at room temperature for 1 hour, cooled to 0 °C, and quenched with saturated NH4Cl solution (300 mL) at 0 °C. The resulting solution was extracted 4 times with EA (100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 3) to afford 7.6 g (65%) of 6-bromo-2H,3H-furo[3,2-b]pyridin-3-ol as a yellow solid. 6. Synthesis of Intermediate 16-7:

Chemical formula

[0270] To a solution of 6-bromo-2H,3H-furo[3,2-b]pyridin-3-ol (4.1 g, 18.8 mmol, 1.0 eq) in toluene (85 mL) cooled to 0 °C was added DPPA (5.7 g, 20.6 mmol, 1.1 eq) and DBU (3.1 g, 20.6 mmol, 1.1 eq) dropwise over 20 minutes. After stirring at room temperature for 1 hour, the resulting solution was diluted with EA (150 mL), washed twice with water (100 mL) and once with brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 9) to afford 1.6 g (35%) of 3-azido-6-bromo-2H,3H-furo[3,2-b]pyridine as a colorless oil. 7. Synthesis of Intermediate 16-8:

Chemical formula

[0271] To a solution of 3-azido-6-bromo-2H,3H-furo[3,2-b]pyridine (1.0 g, 4.2 mmol, 1.0 equiv) in THF (22 mL) was added a solution of PPh3 (1.3 g, 5.0 mmol, 1.2 equiv) and potassium hydroxide (583 mg, 10.4 mmol, 2.5 equiv) in water (5.5 mL). The mixture was stirred at room temperature for 1 h, then at 55 °C for 4 h, cooled to room temperature, and diluted with sodium hydroxide (2N, 20 mL). The resulting solution was extracted three times with EA (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA) to give 1.0 g of 6-bromo-2H,3H-furo[3,2-b]pyridin-3-amine as a yellow oil. 8. Synthesis of Intermediate 16-9:

Chemical Structure

[0272] To a solution of 2-methylpyridine-4-carboxylic acid (306 mg, 2.3 mmol, 1.3 equiv) in DMF (5 mL) were added HATU (981 mg, 2.6 mmol, 1.5 equiv) and DIEA (666 mg, 5.2 mmol, 3.0 equiv). The mixture was stirred for 5 min, then 6-bromo-2H,3H-furo[3,2-b]pyridin-3-amine (370 mg, 1.7 mmol, 1.0 equiv) was added. The mixture was then stirred for 2 h and poured into EA and water. The aqueous layer was extracted twice with EA (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative TLC (MeOH / DCM, 1 / 10) to give 440 mg (77%) of N-[6-bromo-2H,3H-furo[3,2-b]pyridin-3-yl]-2-methylpyridine-4-carboxamide as a yellow solid. 9. Synthesis of Intermediate 16-10:

Chemical Structure

[0273] To a solution of N-[6-bromo-2H,3H-furo[3,2-b]pyridin-3-yl]-2-methylpyridine-4-carboxamide (700 mg, 2.1 mmol, 1.0 equiv) in DMF (20 mL) were added Zn(CN)2 (243 mg, 2.1 mmol, 1.0 equiv) and Pd(PPh3)4 (242 mg, 0.2 mmol, 0.1 equiv). The mixture was stirred at 110 °C overnight, cooled to room temperature, diluted with EA (80 mL), washed twice with water (40 mL) and then with brine (40 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (MeOH / DCM, 1 / 15) to afford 400 mg (68%) of N-[6-cyano-2H,3H-furo[3,2-b]pyridin-3-yl]-2-methylpyridine-4-carboxamide as a pale yellow solid. 10. Synthesis of Intermediate 16-11:

Chemical Structure

[0274] To a solution of N-[6-cyano-2H,3H-furo[3,2-b]pyridin-3-yl]-2-methylpyridine-4-carboxamide (50 mg, 0.18 mmol, 1.00 equiv) in ethanol (5 mL) were added NH2OH·HCl (25 mg, 0.36 mmol, 2.3 equiv) and TEA (55 mg, 0.54 mmol, 3.05 equiv). The mixture was stirred at 75 °C for 2 h and concentrated under reduced pressure to afford 50 mg of N-[6-(N-hydroxycarbamimidoyl)-2H,3H-furo[3,2-b]pyridin-3-yl]-2-methylpyridine-4-carboxamide as a yellow solid. 11. Synthesis of Intermediate 16-12:

Chemical Structure

[0275] To a solution of N-[6-(N-hydroxycarbamimidoyl)-2H,3H-furo[3,2-b]pyridin-3-yl]-2-methylpyridine-4-carboxamide (300 mg, 0.96 mmol, 1.0 equiv) in dioxane (10 mL) was added 2,2-difluoroacetyl 2,2-difluoroacetate (416 mg, 2.39 mmol, 2.5 equiv). The mixture was stirred at 60 °C for 1.5 h and concentrated under reduced pressure, and purified by flash preparative HPLC under the following conditions: (CombiFlash®-1): column, C18 silica gel; mobile phase, water (0.5% NH4HCO3) / ACN = 95 / 5 increasing to water (0.5% NH4HCO3) / ACN = 75 / 25 within 10 min; detector, UV254 nm. This purification gave 120 mg (30%) of N-[6-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-2H,3H-furo[3,2-b]pyridin-3-yl]-2-methylpyridine-4-carboxamide as a white solid. LRMS (ES) m / z 374 (M+H). 1 1H-NMR: (400 MHz, methanol-d4, ppm): δ 8.82 (d, J = 1.7 Hz, 1H), 8.54 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.69 (s, 1H), 7.64 - 7.57 (m, 1H), 7.24 (t, J = 51.8 Hz, 1H), 5.86 (dd, J = 9.2, 5.7 Hz, 1H), 5.05 (t, J = 9.6 Hz, 1H), 4.60 (dd, J = 10.1, 5.7 Hz, 1H), 2.59 (s, 3H). Synthesis of Compound 196:

Chemical Structure

[0276] N-[6-[5-(Difluoromethyl)-1,2,4-oxadiazol-3-yl]-2H,3H-furo[3,2-b]pyridin-3-yl]-2-methylpyridine-4-carboxamide (90 mg, 0.24 mmol, 1.00 eq) was purified by chiral preparative HPLC under the following conditions: (Preparative HPLC - 009): column, CHIRALPAK IA, 2.12 * 15 cm, 5 μm; mobile phase, hexane and ethanol (holding 50.0% ethanol at 13 min); detector, UV220 / 254 nm. This purification gave 37.4 mg (42%) of (S)-N-(6-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydrofuro[3,2-b]pyridin-3-yl)-2-methylisonicotinamide (Compound 196) as a white solid. LRMS (ES) m / z 374 (M + H). 1 1H-NMR: (400 MHz, methanol-d4, ppm): δ 8.82 (d, J = 1.7 Hz, 1H), 8.54 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.69 (s, 1H), 7.64 - 7.57 (m, 1H), 7.24 (t, J = 51.8 Hz, 1H), 5.86 (dd, J = 9.2, 5.7 Hz, 1H), 5.05 (t, J = 9.6 Hz, 1H), 4.60 (dd, J = 10.1, 5.7 Hz, 1H), 2.59 (s, 3H).

[0277] The following compounds were prepared by a method similar to the method described for Compound 196.

Chemical Structure

Chemical Structure

[0278] To a solution of 2,2-difluoroacetonitrile (25 g, 325 mmol, 1.00 eq) cooled to -10 °C in ethanol (100 mL) was added NH₂OH (23 g, 349 mmol, 1.1 eq, 50 wt% in water). The mixture was stirred at room temperature overnight, concentrated under reduced pressure, and azeotroped twice with THF to afford 37 g of (Z)-2,2-difluoro-N'-hydroxyacetimidamide as a green liquid. 2. Synthesis of Intermediate 17-3:

Chemical formula

[0279] To a solution of (1R)-1-[[(tert-butoxy)carbonyl]amino]-2,3-dihydro-1H-indene-5-carboxylic acid (2.0 g, 7.2 mmol, 1.0 eq) in DMF (20 mL) were added DIEA (2.8 g, 21.7 mmol, 3.0 eq), HATU (4.11 g, 10.8 mmol, 1.50 eq), and (Z)-2,2-difluoro-N'-hydroxyacetimidamide (2.38 g, 21.6 mmol, 3.0 eq). The mixture was stirred for 2 h and poured into saturated NH₄Cl solution (200 mL). The resulting solution was extracted twice with DCM (200 mL). The combined organic layers were concentrated under reduced pressure and purified by silica gel chromatography (EA / PE, 3 / 2) to afford 2.52 g (95%) of tert-butyl N-[(1R)-5-[[(1Z)-2,2-difluoro-1-(hydroxyimino)ethyl]carbamoyl]-2,3-dihydro-1H-indene-1-yl]carbamate as a brown solid. 3. Synthesis of Intermediate 17-4:

Chemical formula

[0280] To a solution of tert-butyl N-[(1R)-5-[[(1Z)-2,2-difluoro-1-(hydroxyimino)ethyl]carbamoyl]-2,3-dihydro-1H-inden-1-yl]carbamate (1.53 g, 4.1 mmol, 1.0 eq) in THF (70 mL) was added TBAF (1 M in THF, 8.3 mL, 2.0 eq). The mixture was stirred at 60 °C overnight, cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 3) to afford 490 mg (33%) of tert-butyl N-[(1R)-5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-2,3-dihydro-1H-inden-1-yl]carbamate as a pale orange solid. 4. Synthesis of Intermediate 17-5:

Chemical Structure

[0281] To a solution of tert-butyl N-[(1R)-5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (490 mg, 1.4 mmol, 1.0 eq) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred for 1 h, concentrated under reduced pressure, redissolved in THF and water. The pH of the solution was adjusted to 12 with NaOH (2 N), and the solution was extracted 4 times with EA. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum to afford 500 mg of (1R)-5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-2,3-dihydro-1H-inden-1-amine as a green oil. 5. Synthesis of Compound 217

Chemical Structure

[0282] To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (30 mg, 0.24 mmol, 1.0 equiv) in DMF (4 mL) were added DIEA (62 mg, 0.48 mmol, 2.00 equiv), EDCI (138 mg, 0.72 mmol, 3.00 equiv) and HOAt (98 mg, 0.72 mmol, 3.00 equiv). The mixture was stirred for 5 minutes and (1R)-5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-2,3-dihydro-1H-inden-1-amine (60 mg, 0.24 mmol, 1.0 equiv) was added. The mixture was stirred for 1 hour, filtered to remove the solid precipitate, and purified by preparative HPLC under the following conditions: (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): column, XBridge Shield RP18 OBD column, 5 μm, 19*150 mm; mobile phase, water (0.05% NH3H2O) and ACN (from 35.0% to 55.0% ACN in 8 minutes); detector, UV220 nm. This purification gave 31.4 mg (37%) of (R)-N-(5-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-5-carboxamide (Compound 217) as a white solid. LRMS (ES) m / z 360 (M+H). 1 1H-NMR: (CD3OD, 300 MHz, δ ppm): δ 8.10 - 8.07 (2H, m), 7.56 - 7.48 (2H, m), 7.25 - 6.90 (1H, t, J = 52.2), 6.84 (1H, s), 5.72 - 5.67 (1H, t, J = 8.1), 4.19 (3H, s), 3.25 - 3. 10 (1H, m), 3.07 - 2.99 (1H, m), 2.75 - 2.59 (1H, m), 2.21 - 2.02 (1H, m).

[0283] The following compounds were prepared by a method similar to the method described for Compound 217.

Chemical Structure

[0284] To a solution of 6-hydroxy-2,3-dihydro-1-benzofuran-3-one (100 g, 666.7 mmol, 1.0 equiv) in DCM (2.5 L) was added pyridine (158 g, 2.0 mol, 3.0 equiv). The mixture was cooled to -10 °C, and a solution of (trifluoromethane)sulfonyl trifluoromethanesulfonate (300 g, 1.1 mol, 1.6 equiv) in DCM (0.5 L) was added dropwise over a period of 2 hours. The mixture was then stirred at 0 - 4 °C for 3 hours, quenched with water (1 L), and extracted three times with dichloromethane (300 mL). The combined organic layers were washed twice with citric acid (1 N, 500 mL), saturated sodium bicarbonate (500 mL), and brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 194.5 g of 3-oxo-2,3-dihydro-1-benzofuran-6-yl trifluoromethanesulfonate as a black solid. The black solid was used in the next step without further purification. LRMS (ES) m / z 285 (M+H). 2. Synthesis of Intermediate 18-3: [Chemical formula]

[0285] To formic acid (107.3 g, 2.3 mol, 3.5 equiv) in an RB flask cooled to 0 °C was added dropwise TEA (76 g, 751.1 mmol, 2.3 equiv) with stirring over a period of 30 minutes. To this mixture was added a solution of 3-oxo-2,3-dihydro-1-benzofuran-6-yl trifluoromethanesulfonate (194.5 g, 666.7 mmol, 1.0 equiv) in DCM (4 L), and (S,S)-N-(p-toluenesulfonyl)-1-2 -Diphenylethylenediamine(chloro)(p-cymene)ruthenium(II) (6.45 g, 10.1 mmol, 0.015 eq) was added. The mixture was stirred overnight, and an additional amount of (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine(chloro)(p-cymene)ruthenium(II) (2 g, 3.2 mmol, 0.05 eq) was added. The mixture was stirred for an additional day, poured into water, stirred for 30 minutes, and filtered to remove solid by-products. The aqueous layer was extracted twice with DCM (1 L). The combined organic layers were washed with brine (1 L), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 208 g of (3R)-3-hydroxy-2,3-dihydro-1-benzofuran-6-yl trifluoromethanesulfonate as a dark brown oil. The dark brown oil was used in the next step without further purification. LRMS (ES) m / z 267 (M+H). 3. Synthesis of Intermediate 18-4:

Chemical formula

[0286] To a solution of (3R)-3-hydroxy-2,3-dihydro-1-benzofuran-6-yl trifluoromethanesulfonate (208 g, 665.5 mmol, 1.0 eq) in toluene (2.5 L) cooled to 0 °C, DPPA (228.8 g, 831.9 mmol, 1.25 eq) and DBU (151.7 g, 998.249 mmol, 1.50 eq) were added dropwise over a period of 50 minutes. The mixture was stirred overnight, poured into EA (2 L) and water (1 L), stirred for 30 minutes, and extracted three times with EA (500 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 5 / 95) to give 162 g of (3S)-3-azido-2,3-dihydro-1-benzofuran-6-yl trifluoromethanesulfonate as a yellow oil. 4. Synthesis of Intermediate 18-5:

Chemical formula

[0287] (3S)-3-Azido-2,3-dihydro-1-benzofuran-6-yl trifluoromethanesulfonate (162.4 g, 525.2 mmol, 1.0 equiv) in THF (1.5 L) was slowly added to PPh3 (165.2 g, 629.9 mmol, 1.2 equiv). The mixture was stirred for 30 min, poured into water (300 mL), heated at 50 °C for 4 h, diluted with EA (800 mL), washed three times with water (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 338.5 g of (3S)-3-amino-2,3-dihydro-1-benzofuran-6-yl trifluoromethanesulfonate as a dark red oil, which was used in the next step without further purification. LRMS (ES) m / z 267 (M+H−17). 5. Synthesis of Intermediate 18-6:

Chemical formula

[0288] To a solution of (3S)-3-amino-2,3-dihydro-1-benzofuran-6-yl trifluoromethanesulfonate (338 g, dark red oil from the previous step, 0.52 mol, 1.0 equiv) in DCM (3 L) cooled to 0 °C was added dropwise TEA (158 g, 1.6 mol, 3.0 equiv) and a solution of Boc2O (228 g, 1.0 mol, 2.0 equiv) in DCM (500 mL). The mixture was stirred overnight at room temperature, washed twice with water (2 L), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (DCM / PE, 4 / 6) to give 101.2 g of tert-butyl N-[(3S)-6-[(trifluoromethane)sulfonyloxy]-2,3-dihydro-1-benzofuran-3-yl]carbamate as a white solid. LRMS (ES) m / z 328 (M+H−56). 6. Synthesis of Intermediate 18-7:

Chemical formula

[0289] To a solution of tert-butyl N-[(3S)-6-[(trifluoromethane)sulfonyloxy]-2,3-dihydro-1-benzofuran-3-yl]carbamate (62.3 g, 162.5 mmol, 1.0 equiv) in dioxane (620 mL) under nitrogen were added K4Fe(CN)6·3H2O (34.3 g, 81.3 mmol, 0.5 equiv), second-generation XPhos catalyst precursor (1.9 g, 2.4 mmol, 0.015 equiv), X-Phos (1.2 g, 2.4 mmol, 0.015 equiv), KOAc (31.9 g, 325.0 mmol, 2.0 equiv) and water (620 mL). The mixture was stirred at 100 °C for 4 h, cooled to room temperature and combined with other batches (total triflate of SM 100 g). The resulting solution was poured into EA (1 L) and brine (500 mL), and the solid was removed by filtration. The aqueous layer was extracted three times with ethyl acetate (600 mL). The combined organic layers were washed with brine (600 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 15 / 85) to give the intermediate product. The intermediate product was purified by a mixture of EtOH and water (3 / 2), and after filtration and drying, 45 g (23% over 6 steps in total) of tert-butyl N-[(3S)-6-cyano-2,3-dihydro-1-benzofuran-3-yl]carbamate was obtained as a white solid. LRMS (ES) m / z 261 (M+H). Chiral_SFC: 98.6% ee., CHIRALPAK AD-H (4.6*100 mm, 5um) 7. Synthesis of Intermediate 18-8:

Chemical formula

[0290] To a solution of tert-butyl N-[(3S)-6-cyano-2,3-dihydro-1-benzofuran-3-yl]carbamate (11 g, 42.3 mmol, 1.0 equiv) in ethanol (240 mL) was added hydroxylamine hydrochloride (5.8 g, 84.0 mmol, 2.0 equiv) and TEA (10.7 g, 105.7 mmol, 2.5 equiv). The mixture was stirred at 55 °C for 4 h, cooled to room temperature, combined with the previous batch (300 mg, 1.2 mmol of the SM nitrile), and concentrated under reduced pressure. The mixture was dissolved in EA (500 mL), washed twice with water (200 mL) and then with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 12.8 g of tert-butyl N-[(3S)-6-(N-hydroxycarbamimidoyl)-2,3-dihydro-1-benzofuran-3-yl]carbamate as a white solid. The white solid product was used directly in the next step without further purification. LRMS (ES) m / z 294 (M+H). 8. Synthesis of Intermediate 18-9: [Chemical formula]

[0291] To a solution of tert-butyl N-[(3S)-6-(N-hydroxycarbamimidoyl)-2,3-dihydro-1-benzofuran-3-yl]carbamate (16 g, 54.6 mmol, 1.0 equiv) in pyridine (200 mL) was added cyclopropanecarbonyl chloride (6.3 g, 59.8 mmol, 1.1 equiv). The mixture was stirred at 100 °C for 2 h, cooled to room temperature, concentrated under reduced pressure, dissolved in EA (500 mL), and poured into saturated NH4Cl solution (500 mL). The aqueous layer was extracted 4 times with EA (500 mL), the combined organic layers were washed 4 times with NH4Cl solution (500 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 3) to give 17 g (91%) of tert-butyl N-[(3S)-6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate as a pale yellow solid. LRMS(ES) m / z 288 (M+H-56). 9. Synthesis of Intermediate 18-10:

Chemical Structure

[0292] To a solution of tert-butyl N-[(3S)-6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate (17 g, 49.5 mmol, 1.0 equiv) in DCM (500 mL) was added hydrogen chloride (4 M in dioxane, 125 mL, 10.0 equiv). The mixture was stirred at room temperature overnight and diluted with a mixture of EA and PE (1.1 L, 1 / 10). The solid was collected and dried to give 13.5 g (97%) of (3S)-6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine hydrochloride as a white solid. LRMS(ES) m / z 227 (M+H-17). 10. Synthesis of Compound 222:

Chemical Structure

[0293] To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (8.2 g, 64.9 mmol, 1.3 equiv) in DMF (200 mL) were added (3S)-6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine hydrochloride (14 g, 50.1 mmol, 1.0 equiv), HOAt (10.9 g, 79.9 mmol, 1.6 equiv), EDCI (15.4 g, 80.1 mmol, 1.6 equiv) and DIEA (32.3 g, 249.5 mmol, 5.0 equiv). The mixture was stirred at room temperature overnight and poured into DCM (200 mL) and water (200 mL). The aqueous layer was extracted 5 times with DCM (200 mL). The combined organic layers were washed 6 times with saturated NH4Cl solution (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, triturated with ACN, and 12.2 g (69%) of (S)-N-(6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydrobenzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide (Compound 222) was obtained as a white solid. LRMS (ES) m / z 352 (M+H). 1 H-NMR: (300 MHz, DMSO-d6, ppm) δ 9.12 (d, J = 7.6 Hz, 1H), 7.56 (dd, J = 7.8, 1.4 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 1.3 Hz, 1H), 6.92 (d, J = 2.1 Hz, 1H), 5.82 (td, J = 8.3, 5.1 Hz, 1H), 4.85 (t, J = 9.4 Hz, 1H), 4.46 (dd, J = 9.7, 5.2 Hz, 1H), 4.10 (s, 3H), 2.41 (tt, J = 8.2, 4.8 Hz, 1H), 1.35 - 1.25 (m, 2H), 1.25 - 1.15 (m, 2H).

[0294] The following compounds were prepared by a method similar to the method described for Compound 222.

Chem.

Chem.

Chem.

[0295] To a solution of tert-butyl N-[6-(N-hydroxycarbamimidoyl)-2,3-dihydro-1-benzofuran-3-yl]carbamate (3 g, 10.2 mmol, 1.0 equiv) in dioxane (30 mL) was added propanoyl propanoate (2.7 g, 20.5 mmol, 2.0 equiv). The mixture was stirred at 80 °C for 7 h, cooled to room temperature, and poured into EA (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 3) to give 1.9 g (56%) of tert-butyl N-[6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate as an off-white solid. 2. Synthesis of Intermediate 19-3:

Chem.

[0296] To a solution of tert-butyl N-[6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate (1.9 g, 5.7 mmol, 1.0 equiv) in DCM (30 mL) was added TFA (5 mL). The mixture was stirred for 1 h, concentrated under reduced pressure, and dissolved in water (100 mL). Then, the pH of the mixture was adjusted to 7 with saturated sodium bicarbonate solution and extracted twice with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1.3 g (98%) of 6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine as a brown oil. 3. Synthesis of Intermediate 19-4:

Chemical formula

[0297] To a solution of 6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine (100 mg, 0.4 mmol, 1.0 equiv) in DMF (10 mL) were added 1-methyl-1H-pyrazole-5-carboxylic acid (54.5 mg, 0.4 mmol, 1.0 equiv), HOAt (176.6 mg, 1.0 mmol, 3.0 equiv), EDCI (249 mg, 1.3 mmol, 3.0 equiv) and DIEA (112 mg, 0.9 mmol, 2.0 equiv). The mixture was stirred for 2 h and directly purified by preparative HPLC under the following conditions: (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): column, XBridge Shield RP18 OBD column, 5um, 19*150mm; mobile phase, water (0.05% NH3H2O) and ACN (from 30.0% to 50.0% ACN in 8 min); detector, UV220nm. This purification afforded 90 mg (61%) of N-[6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]-1-methyl-1H-pyrazole-5-carboxamide as a white solid. 4. Synthesis of Compound 228: [Chemical]

[0298] N-[6-(5-Ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]-1-methyl-1H-pyrazole-5-carboxamide (80 mg, 0.2 mmol, 1.0 eq) was purified by chiral preparative HPLC under the following conditions: (Preparative HPLC-009): column, CHIRAL ART Cellulose-SB, 250 * 20 mm I.D.; mobile phase, hexane and ethanol (holding 50.0% ethanol at 9 min); detector, UV254 / 220 nm. This purification gave 32.7 mg (41%) of (S)-N-(6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydrobenzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide (Compound 228) as a white solid. LRMS (ES) m / z 340 (M+H). 1 H-NMR: (300 MHz, DMSO-d6, ppm): δ 9.09 (d, J = 7.7 Hz, 1H), 7.56 (dd, J = 7.7, 1.4 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.39 (dd, J = 13.0, 1.7 Hz, 2H), 6.87 (d, J = 2.1 Hz, 1H), 5.78 (td, J = 8.2, 5.2 Hz, 1H), 4.80 (t, J = 9.3 Hz, 1H), 4.41 (dd, J = 9.8, 5.3 Hz, 1H), 4.05 (s, 3H), 2.97 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H). (Example 20) Synthesis of Compound 236 1. Synthesis of Intermediate 20-2: [Chemical]

[0299] To a solution of tert-butyl N-[6-(N-hydroxycarbamimidoyl)-2,3-dihydro-1-benzofuran-3-yl]carbamate (3 g, 10.2 mmol, 1.0 equiv) in pyridine (50 mL) was added cyclopropanecarbonyl chloride (1.3 g, 12.4 mmol, 1.2 equiv) under nitrogen. The mixture was stirred at 100 °C for 6 h, cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 9) to afford 1.47 g (42%) of tert-butyl N-[6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate as a white solid. 2. Synthesis of Intermediate 20-3: [Chemical formula]

[0300] To a solution of tert-butyl N-[6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate (1.47 g, 4.3 mmol, 1.0 equiv) in DCM (25 mL) was added TFA (5 mL). The mixture was stirred at room temperature for 2 h and then cooled to 0 °C. Then, the pH of the mixture was adjusted to 9 with saturated NaHCO3 solution and extracted 5 times with ethyl acetate (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1 g of 6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine as an off-white solid. The off-white solid was used directly in the next step without further purification. 3. Synthesis of Intermediate 20-4: [Chemical formula]

[0301] To a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (78 mg, 0.6 mmol, 1.0 equiv) in DMF (4 mL) were added HOAt (101 mg, 0.7 mmol, 1.2 equiv), EDCI (142 mg, 0.7 mmol, 1.2 equiv), DIEA (160 mg, 1.2 mmol, 2.0 equiv) and 6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine (150 mg, 0.6 mmol, 1.0 equiv). The mixture was stirred at room temperature overnight and purified by flash preparative HPLC under the following conditions: (CombiFlash®-1): column, C18 silica gel; mobile phase, H2O (0.5% NH4HCO3) / ACN = 90 / 10 increased to H2O (0.5% NH4HCO3) / ACN = 70 / 30 within 15 min; detector, UV254 nm. This purification gave 120 mg of N-[6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]-1-methyl-1H-pyrazole-4-carboxamide as a white solid. LRMS (ES) m / z 352 (M+H). 1 H-NMR: (400 MHz, methanol-d4, ppm): δ 8.06 (s, 1H), 7.90 (d, J = 0.9 Hz, 1H), 7.60 (dd, J = 7.8, 1.4 Hz, 1H ), 7.48 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 1.4 Hz, 1H), 5.83 (dd, J = 8.6, 4.7 Hz, 1H), 4.82 (dd, J = 9.9, 8.6 Hz, 1H), 4.44 (dd, J = 9.9, 4.8 Hz, 1H), 3.90 (s, 3H), 2.32 (tt, J = 8.2, 5.0 Hz, 1H), 1.29 (dt, J = 7.7, 2.6 Hz, 2H), 1.25 (dt, J = 5.1, 3.0 Hz, 2H). Synthesis of Compound 236:

Chemical Structure

[0302] N-[6-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]-1-methyl-1H-pyrazole-4-carboxamide (90 mg, 0.3 mmol, 1.0 equiv) was purified by chiral preparative HPLC under the following conditions: (Preparative HPLC - 009): column, Chiralpak IA, 2 * 25 cm, 5 μm; mobile phase, hexane and ethanol (holding 50.0% ethanol in 15 minutes); detector, UV220 / 254 nm, R t = 1.569 minutes. This gave 37.8 mg (42%) of (S)-N-(6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydrobenzofuran-3-yl)-1-methyl -1H-pyrazole-4-carboxamide (Compound 236) as a white solid. LRMS (ES) m / z 352 (M + H). 1 H-NMR: (400 MHz, methanol-d4, ppm): δ 8.06 (s, 1H), 7.90 (d, J = 0.9 Hz, 1H), 7.60 (dd, J = 7.8, 1.4 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 1.4 Hz, 1H), 5.83 (dd, J = 8.6, 4.7 Hz, 1H), 4.82 (dd, J = 9.9, 8.6 Hz, 1H), 4.44 (dd, J = 9.9, 4.8 Hz, 1H), 3.90 (s, 3H), 2.32 (tt, J = 8.2, 5.0 Hz, 1H), 1.29 (dt, J = 7.7, 2.6 Hz, 2H), 1.25 (dt, J = 5.1, 3.0 Hz, 2H). (Example 21) Synthesis of Compound 238 1. Synthesis of Intermediate 21 - 2:

Chemical Structure

[0303] To a solution of tert-butyl N-[(3S)-6-(N-hydroxycarbamimidoyl)-2,3-dihydro-1-benzofuran-3-yl]carbamate (24.7 g, 84.2 mmol, 1.0 equiv) in dioxane (700 mL) was added propanoyl propanoate (16.4 g, 126.0 mmol, 1.5 equiv). The mixture was stirred at 60 °C for 2 h, diluted with EA (500 mL), washed with water (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 7 / 93) to afford 18.4 g (66%) of tert-butyl N-[(3S)-6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate as a white powder. 2. Synthesis of Intermediate 21-3:

Chemical Structure

[0304] To a solution of tert-butyl N-[(3S)-6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate (16.3 g, 49.2 mmol, 1.0 equiv) in DCM (350 mL) was added hydrogen chloride (4 M in dioxane, 122 mL). The mixture was stirred at room temperature overnight and diluted with PE (100 mL). The solid was collected and dried to afford 13.0 g of (3S)-6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine hydrochloride as an off-white solid. 3. Synthesis of Compound 238:

Chemical Structure

[0305] (3S)-6-(5-Ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine hydrochloride (9.0 g, 33.6 mmol, 1.0 equiv) in DMF (200 mL) was added to HOAt (5.5 g, 40.4 mmol, 1.2 equiv), DIEA (13.0 g, 100.6 mmol, 3.0 equiv), EDCI (7.7 g, 40.2 mmol, 1.2 equiv) and 1-methyl-1H-pyrazole-4-carboxylic acid (4.4 g, 34.9 mmol, 1.04 equiv). The mixture was stirred overnight at room temperature, diluted with EA (300 mL), washed three times with water (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product from the above procedure was combined with the previous batch (2.4 g of the amine of the SM) and purified by DCM / PE. After filtration and drying, 12.0 g of (S)-N-(6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydrobenzofuran-3-yl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 238) was obtained as a white solid. LRMS (ES) m / z 340 (M+H). 1 1H-NMR: (400 MHz, DMSO-d6, ppm): δ 8.71 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.86 (s, 1H), 7.57 (dd, J = 7.7, 1.4 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 1.4 Hz, 1H), 5.76 (td, J = 8.3, 5.3 Hz, 1H), 4.80 (t, J = 9.3 Hz, 1H), 4.39 (dd, J = 9.7, 5.2 Hz, 1H), 3.82 (s, 3H), 2.99 (q, J = 7.5 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H). (Example 22) Synthesis of Compound 253 1. Synthesis of Intermediate 22-2:

Chemical Structure

[0306] To a solution of tert-butyl N-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate (2 g, 6.4 mmol, 1.0 equiv) in THF (30 mL) cooled to -78 °C, MeLi (4.8 mL, 1.6 M) was added dropwise under argon at -78 °C. The mixture was stirred at -78 °C for 15 minutes, and then n-BuLi (5.2 mL, 2.5 M) was added dropwise. Subsequently, the mixture was stirred at -78 °C for 1 hour, and DMF (1.43 g, 19.2 mmol, 3.0 equiv) was added dropwise. The solution was stirred at -78 °C for 1 hour, quenched with saturated NH4Cl solution (5 mL), and concentrated under vacuum. The residue was purified by silica gel column chromatography (EA / PE, 1 / 10) to obtain 1.5 g (90%) of tert-butyl N-[(1R)-5-formyl-2,3-dihydro-1H-inden-1-yl]carbamate as a yellow solid. 2. Synthesis of Intermediate 22-3:

Chemical Structure

[0307] To a solution of tert-butyl N-[(1R)-5-formyl-2,3-dihydro-1H-inden-1-yl]carbamate (1.6 g, 6.1 mmol, 1.0 equiv) in a mixture of ethanol and pyridine (21 mL, 2 / 1), NH2OH·HCl (509 mg, 1.2 equiv) was added. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain 1.7 g of tert-butyl N-[(1R)-5-[(1E)-(hydroxyimino)methyl]-2,3-dihydro-1H-inden-1-yl]carbamate as a white solid. 3. Synthesis of Intermediate 22-4:

Chemical Structure

[0308] ​To a solution of tert-butyl N-[(1R)-5-[(1E)-(hydroxyimino)methyl]-2,3-dihydro-1H-inden-1-yl]carbamate (1.7 g, 6.1 mmol, 1.0 equiv) in DMF (15 mL) was added NCS (977 mg, 7.3 mmol, 1.2 equiv). The mixture was stirred overnight at room temperature, diluted with EA (50 mL), washed twice with saturated NH4Cl solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give 1.8 g (95%) of tert-butyl N-[(1R)-5-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1H-inden-1-yl]carbamate as a brown oil. 4. Synthesis of Intermediate 22-5:

Chemical Structure

[0309] To a solution of 2-bromobut-1-ene (2 g, 14.8 mmol, 1.0 equiv) in THF (30 mL) were added tert-butyl N-[(1R)-5-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1H-inden-1-yl]carbamate (955 mg, 3.1 mmol, 1.1 equiv) and TEA (1.3 g, 12.9 mmol, 2. 1 equiv). The mixture was stirred at room temperature for 1 hour, heated to 60 °C for 5 hours, cooled to room temperature, diluted with EA (200 mL), washed twice with saturated NH4Cl solution (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 10) to give 1.1 g (23%) of tert-butyl N-[(1R)-5-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate as a yellow solid. 5. Synthesis of Intermediate 22-6:

Chemical Structure

[0310] To a solution of tert-butyl N-[(1R)-5-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate (1.08 g, 3.3 mmol, 1.0 eq) in DCM (15 ml) was added hydrochloric acid (4 M in dioxane, 15 mL, 18.2 eq). The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to afford 870 mg of (1R)-5-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride as an off-white solid. Synthesis of Compound 253: [Chemical formula]

[0311] To a solution of (1R)-5-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride (625 mg, 2.4 mmol, 1.0 eq) in DMF (20 mL) were added 2-methyl-2H-1,2,3,4-tetrazole-5-carboxylic acid (606 mg, 4.7 mmol, 2.0 eq), EDCI (909 mg, 4.7 mmol, 2.0 eq), HOAt (643 mg, 4.7 mmol, 2.0 eq) and DIEA (1.53 g, 11.9 mmol, 5.0 eq). The mixture was stirred at room temperature for 2 h, heated to 60 °C for 2 h, cooled to room temperature and poured into EA (100 mL) and water (100 mL). The aqueous layer was extracted twice with ethyl acetate (100 mL). The combined organic layers were washed twice with saturated NH4Cl solution (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was carried out under the following conditions: (IntelFlash-1): column, C18 silica gel; mobile phase, ACN / H2O = 1:3 increased to ACN / H2O = 1:2 within 10 min; detector, flash preparative HPLC at UV254 nm. This purification afforded 758 mg (82%) of (R)-N-(5-(5-ethylisoxazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-methyl-2H-tetrazole-5-carboxamide (Compound 253) as an off-white solid. LRMS (ES) m / z 338 (M+H). 11H-NMR: (300 MHz, DMSO-d6, ppm) δ 9.38 (d, J = 8.4 Hz, 1H), 7.74 - 7.59 (m, 2H), 7.29 (d, J = 7.9 Hz, 1H), 6.79 - 6.71 (m, 1H), 5.56 (q, J = 8.1 Hz, 1H), 4.41 (s, 3H), 3.04 (ddd, J = 16.0, 8.9, 3.3 Hz, 1H), 2.96 - 2.69 (m, 3H), 2.41 (td, J = 8.1, 3.6 Hz, 1H), 2.21 - 2.01 (m, 1H), 1.23 (t, J = 7.6 Hz, 3H).

[0312] The following compound was prepared by a method similar to the method described for compound 253. [Chemical formula] (Example 23) Synthesis of compound 414: [Chemical formula]

[0313] To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (166 mg, 1.3 mmol, 1.7 equiv) in DMF (4 mL) were added DIEA (566 mg, 4.4 mmol, 5.8 equiv), EDCI (337 mg, 1.7 mmol, 2.3 equiv) and HOAt (238 mg, 1.8 mmol, 2.3 equiv). The mixture was stirred at room temperature for 5 min, and (1R)-5-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride (200 mg, 0.8 mmol, 1.00 equiv) was added. The mixture was then stirred at room temperature for 2 h and filtered to remove solids. The filtrate was purified by preparative HPLC under the following conditions: (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): column, XBridge Shield RP18 OBD column, 5um, 19*150mm; mobile phase, water (10MMOL / L NH4HCO3) and ACN (from 38.0% to 52.0% in 8 min); detector, UV254nm. This purification gave 111.4 mg (38%) of (R)-N-(5-(5-ethylisoxazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-5-carboxamide (Compound 414) as a white solid. LRMS (ES) m / z 337 (M+H). 1 H-NMR: (300MHz, CD3OD, ppm): δ 7.76-7.63 (m, 2H), 7.49-7.34 (m, 2H), 6.81 (d, J=2.1 Hz, 1H), 6.57 (d, J=1.0 Hz, 1H), 5.64 (t, J=8.0 Hz, 1H), 4.17 (d, J=1.1 Hz, 3H), 3.13 (m, 1H), 2.98 (m, 1H) , 2.91-2.77 (m, 2H), 2.71-2.54 (m, 1H), 2.06 (m, 1H), 1.35 (t, J=7.6 Hz, 3H).

[0314] The following compounds were prepared by a method similar to the method described for Compound 414. [Chemical formula] (Example 24) Synthesis of Compound 261 1. Synthesis of Intermediate 23-2: [Chemical formula]

[0315] To a solution of tert-butyl N-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate (10 g, 32.2 mmol, 1.0 eq) in THF (300 mL) cooled to -78 °C was added dropwise MeLi (30.1 mL, 1.6 M, 1.5 eq). The mixture was stirred at -78 °C for 10 minutes, and n-BuLi (25.7 mL, 2.5 M, 2.0 eq) was added dropwise at -78 °C. The mixture was stirred at -78 °C for an additional 1 hour, and dry ice (30 g) was added. Then, the mixture was stirred at -78 °C for 30 minutes and quenched by slowly adding saturated NH4Cl solution (30 mL) at -78 °C. The resulting solution was warmed to room temperature and extracted twice with EA (400 mL). The combined organic layers were concentrated under reduced pressure and triturated with a mixture of EA, PE, and ethyl ether (1 / 20 / 10) to obtain 6.2 g (70%) of (1R)-1-[[(tert-butoxy)carbonyl]amino]-2,3-dihydro-1H-inden-5-carboxylic acid as a white solid. 2. Synthesis of Intermediate 23-3: [Chemical formula]

[0316] (1R)-1-[[(tert-butoxy)carbonyl]amino]-2,3-dihydro-1H-inden-5-carboxylic acid (1.5 g, 5.4 mmol, 1.0 eq) in DMF (20 mL) was added DIEA (2.1 g, 16.3 mmol, 3.0 eq) and HATU (3.1 g, 8.2 mmol, 1.5 eq). The mixture was stirred for 5 minutes, and (Z)-N-hydroxycyclopropane-1-carboxylic acid Cyanoimidamide (542 mg, 5.4 mmol, 1.0 equiv) was added. The mixture was then stirred for 2 h, diluted with DCM (200 mL), washed three times with saturated NH4Cl solution (200 mL), concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 14 / 86) to give 800 mg (41%) of tert-butyl-N-[(1R)-5-[[(1Z)-cyclopropyl(hydroxyimino)methyl]carbamoyl]-2,3-dihydro-1H-inden-1-yl]carbamate as an off-white solid. 3. Synthesis of Intermediate 23-4:

Chemical formula

[0317] A solution of tert-butyl N-[(1R)-5-[[(1Z)-cyclopropyl(hydroxyimino)methyl]carbamoyl]-2,3-dihydro-1H-inden-1-yl]carbamate (680 mg, 1.9 mmol, 1.0 equiv) in toluene (10 mL) was heated at 100 °C overnight, cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 9) to give 540 mg (84%) of tert-butyl N-[(1R)-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-dihydro-1H-inden-1-yl]carbamate as a pale yellow solid. 4. Synthesis of Intermediate 23-5:

Chemical formula

[0318] To a solution of tert-butyl N-[(1R)-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-dihydro-1H-inden-1-yl]carbamate (490 mg, 1.4 mmol, 1.0 eq) in DCM (5 mL) was added hydrogen chloride (4 M in dioxane, 10 mL). The mixture was stirred overnight and concentrated to afford 660 mg of (1R)-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride as a pale yellow solid. Synthesis of Compound 261:

Chemical Structure

[0319] To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (26 mg, 0.2 mmol, 1.2 eq) in DMF (4 mL) were added DIEA (80 mg, 0.62 mmol, 3.50 eq), HOAt (60 mg, 0.4 mmol, 2.3 eq) and EDCI (84 mg, 0.4 mmol, 2.3 eq). The mixture was stirred for 5 minutes and (1R)-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride (50 mg, 0.2 mmol, 1.0 eq) was added. The mixture was then stirred for 2 hours and purified by flash preparative HPLC under the following conditions: (CombiFlash®-1): column, C18 silica gel; mobile phase, ACN / H2O (0.05% NH4HCO3); detector, UV254 nm. This purification afforded 20.8 mg (33%) of (R)-N-(5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-5-carboxamide (Compound 261) as a white solid. LRMS (ES) m / z 350 (M+H). 1H-NMR: (CD3OD, 300 MHz, ppm): δ 7.99 - 7.88 (2H, m), 7.49 - 7.39 (2H, m), 6.79 (1H, d, J = 2.2 Hz), 5.63 (1H, t, J = 8.1 Hz), 4.14 (3H, s), 3.20 - 2.88 (2H, m), 2.61 (1H, m), 2.08 (2H, m), 1.07 (4H, m)

[0320] The following compounds were prepared by a method similar to the method described for Compound 261.

Chemical Structure

Chemical Structure

[0321] (1R)-5-Bromo-2,3-dihydro-1H-inden-1-amine hydrochloride (3.0 g, 12.1 mmol, 1.00 equivalent) in DMF (60 mL) was added 1-methyl-1H-pyrazole-5-carboxylic acid (1.65 g, 13.1 mmol, 1.08 equivalents), HOAt (2.5 g, 18.37 mmol, 1.52 equivalents), EDCI (3.5 g, 18.3 mmol, 1.51 equivalents) and DIEA (6.3 g, 48.8 mmol, 4.04 equivalents). The mixture was stirred overnight at room temperature, diluted with EA (200 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated under vacuum and purified by silica gel chromatography (EA / PE, 19 / 81) to give a solid, which was triturated with PE to give 2.67 g (69%) of N-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-1-methyl-1H-pyrazole-5-carboxamide as an off-white solid. LRMS (ES) m / z 320 (M+H). LC-MS: (ES, m / z): [M+H]+ 320 322 Synthesis of Compound 372:

Chemical formula

[0322] To a solution of N-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-1-methyl-1H-pyrazole-5-carboxamide (100 mg, 0.31 mmol, 1.00 equiv) in dioxane (5 mL) were added phenylboronic acid (57 mg, 0.47 mmol, 1.50 equiv), Pd(dppf)Cl2CH2Cl2 (26 mg, 0.03 mmol, 0.10 equiv), Cs2CO3 (204 mg, 0.63 mmol, 2.00 equiv) and water (0.5 mL). After stirring at 80 °C for 3 h, the resulting solution was diluted with EA (20 mL) and filtered to remove solids. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by preparative TLC (PE / EA, 1 / 1). This product (67 mg) was further purified by flash preparative HPLC under the following conditions: (CombiFlash®-1): column, C18 silica gel; mobile phase, water (0.5% NH4HCO3) / ACN = 95 / 5 increasing to water (0.5% NH4HCO3) / ACN = 90 / 10 within 10 min; detector, UV 254 nm. Thereby, 46.7 mg (47%) of (R)-1-methyl-N-(5-phenyl-2,3-dihydro-1H-inden-1-yl)-1H-pyrazole-5-carboxamide (Compound 372) was obtained as a white solid. LRMS (ES) m / z 318 (M+H). 1 1H-NMR: (400 MHz, DMSO-d6, ppm): δ 8.76 (d, J = 8.4 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.53 (d, J = 1.6 Hz, 1H), 7.50 - 7.39 (m, 4H), 7.38 - 7.26 (m, 2H), 6.91 (d, J = 2.1 Hz, 1H), 5.54 (q, J = 8.1 Hz, 1H), 4.10 (s, 3H), 3.04 (ddd, J = 15.9, 8.9, 3.2 Hz, 1H), 2.90 (dt, J = 16.1, 8.4 Hz, 1H), 2.48 - 2.43 (m, 1H), 1.99 (dq, J = 12.5, 8.7 Hz, 1H)

[0323] The following compound was prepared by a method similar to the method described for Compound 372.

Chemical Structure

Chemical Structure

[0324] A solution of 1-methyl-N-[(1R)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl]-1H-pyrazole-5-carboxamide (100 mg, 0.27 mmol, 1.00 eq) in DMF (4 mL) was added with Pd(dppf)Cl2·CH2Cl2 (44 mg, 0.05 mmol, 0.20 eq), K3PO4 (116 mg, 0.55 mmol, 2.00 eq) and 2-bromo-4-methylpyrimidine (94 mg, 0.54 mmol, 2.00 eq) under nitrogen. The mixture was stirred at 80 °C for 2 h, cooled to room temperature, diluted with EA (10 mL), washed with water (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography (EA / PE, 1 / 1) to obtain the product, which was further purified by preparative HPLC under the following conditions: (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): column, XBridge Shield RP18 OBD column, 5 μm, 19*150 mm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O) and ACN (from 31.0% to 44.0% of ACN in 8 min); detector, UV220 nm. Thereby, 17.6 mg (19%) of (R)-1-methyl-N-(5-(4-methylpyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazole-5-carboxamide (Compound 378) was obtained as a white solid. LRMS (ES) m / z 334 (M+H). 1 1H-NMR: (300 MHz, methanol-d4, ppm): δ 8.65 (d, J = 5.1 Hz, 3H), 8.28 (s, 4H), 7.50 - 7.38 (m, 4H), 7.23 (s, 1H), 6.83 (d, J = 2.1 Hz, 2H), 5.66 (s, 1H), 4.18 (s, 7H), 2.59 (s, 7H), 0.20 (s, 1H).

[0325] The following compounds were prepared by a method similar to the method described for Compound 378. [Chemistry] (Example 27) Synthesis of Compound 383 1. Synthesis of Intermediate 26-2: [Chemistry]

[0326] To a solution of 5-methylpyridazin-3-ol (500 mg, 4.54 mmol, 1.00 equiv) in DCM (10 mL) cooled to -15 °C, a solution of pyridine (1.1 g, 13.9 mmol, 3.06 equiv) and (trifluoromethane)sulfonyl trifluoromethanesulfonate (2.0 g, 7.09 mmol, 1.56 equiv) in DCM (5 mL) was added dropwise with stirring at -15 °C. After stirring at -15 to 0 °C for 2 h under nitrogen, the reaction was quenched with water (20 mL). The resulting solution was separated and the aqueous layer was extracted twice with DCM (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 16 / 84) to give 400 mg (36%) of 5-methylpyridazin-3-yl trifluoromethanesulfonate as a colorless oil. 2. Synthesis of Compound 383: [Chemistry]

[0327] To a solution of 1-methyl-N-[(1R)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl]-1H-pyrazole-5-carboxamide (100 mg, 0.27 mmol, 1.00 equiv) in toluene (9 mL) was added a solution of 5-methylpyridazin-3-yl trifluoromethanesulfonate (80 mg, 0.33 mmol, 1.21 equiv), ethanol (3 mL), Pd(PPh3)4 (47 mg, 0.04 mmol, 0.15 equiv) and sodium carbonate (318 mg, 3.00 mmol, 11.0 equiv) in water (1.5 mL). After stirring at 80 °C for 3 h, the resulting solution was diluted with EA (30 mL). The mixture was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified by preparative TLC (EA), then under the following conditions: (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): column, XBridge Shield RP18 OBD column, 5um, 19*150mm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (from 25.0% ACN to 3 8.0% in 8 min); detector, preparative HPLC with UV220 nm. This gave 7.9 mg (9%) of (R)-1-methyl-N-(5-(5-methylpyridazin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazole-5-carboxamide (Compound 383) as a white solid. LRMS (ES) m / z 334 (M+H). 1 1H-NMR: (300 MHz, methanol-d 4, ppm) δ 9.01 (d, J = 1.9 Hz, 1H), 8.04 - 7.99 (m, 1H), 7.99 - 7.95 (m, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.51 - 7.42 (m, 2H), 6.83 (d, J = 2.1 Hz, 1H), 5.68 (t, J = 7.8 Hz, 1H), 4.18 (s, 3H), 3.18 (ddd, J = 15.9, 9.1, 3.5 Hz, 1H), 3.01 (dd, J = 16.0, 8.3 Hz, 1H), 2.65 (dtd, J = 12.6, 7.9, 3.5 Hz, 1H), 2.48 (s, 3H), 2.09 (dq, J = 12.8, 8.6 Hz, 1H).

[0328] The following compounds were prepared by a method similar to the method described for Compound 383.

Chemical formula

Chemical formula

[0329] To a solution of tert-butyl N-[(3S)-6-bromo-2,3-dihydro-1-benzofuran-3-yl]carbamate (1.7 g, 5.4 mmol, 1.0 equiv) in THF (20 mL) cooled to -78 °C was added MeLi (5.07 mL, 1.50 equiv) under nitrogen. The mixture was stirred at -78 °C for 10 minutes and n-BuLi (2.5 M, 4.32 mL, 2.0 equiv) was added. The mixture was then stirred at -78 °C for 30 minutes and DMF (1.19 g, 16.3 mmol, 3.0 equiv) was added. The mixture was then stirred at -78 °C for an additional 1 hour and quenched with saturated NH4Cl solution. The resulting solution was extracted three times with EA (300 mL). The combined organic layers were washed with saturated NH4Cl solution (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, triturated with n-hexane (30 ml), and 1.32 g (93%) of tert-butyl N-[(3S)-6-formyl-2,3-dihydro-1-benzofuran-3-yl]carbamate was obtained as a pale yellow solid. 2. Synthesis of Intermediate 28-3:

Chemical formula

[0330] To a solution of tert-butyl N-[(3S)-6-formyl-2,3-dihydro-1-benzofuran-3-yl]carbamate (5.8 g, 22.0 mmol, 1.0 equiv) in a mixture of ethanol (100 mL) and pyridine (50 mL) was added hydroxylamine hydrochloride (1.83 g, 26.3 mmol, 1.2 equiv). The mixture was stirred for 3 h, concentrated under reduced pressure, and poured into water. The aqueous solution was extracted twice with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 6.0 g of tert-butyl N-[(3S)-6-[(1E)-(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate as a white solid. 3. Synthesis of Intermediate 28-4:

Chemical formula

[0331] To a solution of tert-butyl N-[(3S)-6-[(1E)-(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate (6.0 g, 21.5 mmol, 1.0 equiv) in THF (120 mL) were added pyridine (1.36 g, 17.1 mmol, 0.98 equiv) and NCS (5.17 mg, 38.7 mmol, 1.8 equiv). The resulting solution was stirred overnight, diluted with EA, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 9.1 g of tert-butyl N-[(3S)-6-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate as a white solid. 4. Synthesis of Intermediate 28-5:

Chemical formula

[0332] To a solution of tert-butyl N-[(3S)-6-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate (3.6 g, 11.6 mmol, 1.0 equiv) in THF (80 mL) were added TEA (4.3 g, 42.9 mmol, 5.0 equiv) and 2-bromobut-1-ene (1.74 g, 12.9 mmol, 1.5 equiv). The resulting solution was stirred at room temperature for 2 h and heated at 60 °C for 2 h and poured into water and extracted twice with EA. The combined organic layers were washed with an aqueous NH4Cl solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 9) to give 424 mg (11%) of tert-butyl N-[(3S)-6-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate as a white solid. 5. Synthesis of Intermediate 28-6:

Chemical formula

[0333] To a solution of tert-butyl N-[(3S)-6-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate (420 mg, 1.3 mmol, 1.0 equiv) in DCM (20 mL) was added hydrogen chloride (4 M in dioxane, 3.2 mL, 10.0 equiv). The resulting solution was stirred at room temperature overnight. The solid was collected by filtration to give 275 mg (81%) of (3S)-6-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine hydrochloride as a pale yellow solid. 6. Synthesis of Compound 423:

Chemical formula

[0334] (3S)-6-(5-Ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine hydrochloride (65 mg, 0.24 mmol, 1.0 equiv) in DMF (2 mL) was added 1-methyl-1H-pyrazole-4-carboxylic acid (37 mg, 0.29 mmol, 1.2 equiv), EDCI (56 mg, 0.29 mmol, 1.2 equiv), HOAt (40 mg, 0.29 mmol, 1.20 equiv) and DIEA (94 mg, 0.73 mmol, 3.0 equiv). The mixture was stirred overnight at room temperature and combined with the previous batch (amines of 0.21 and 1.16 mmol of SM). The resulting solution was poured into water (10 mL) and extracted three times with EA (10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by C-18 column chromatography (H2O / ACN = 45 / 55) to give 111 mg of (S)-N-(6-(5-ethylisoxazol-3-yl)-2,3-dihydrobenzofuran-3-yl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 423) as a white solid. LRMS (ES) m / z 339 (M+H). 1 H-NMR: (400 MHz, DMSO-d6, ppm): δ 8.68 (d, J = 7.5 Hz, 1H), 8.18 (s, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.43 (d, J = 1.6 Hz, 2H), 7.33 (d, J = 1.2 Hz, 1H), 6.82 (t, J = 0.9 Hz, 1H), 5.81 - 5.70 (m, 1H), 4.80 (dd, J = 9.7, 8.8 Hz, 1H), 4.38 (dd, J = 9.7, 5.0 Hz, 1H), 3.85 (s, 3H), 2.81 (qd, J = 7.6, 0.9 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H).

[0335] The following compounds were prepared by a method similar to the method described for Compound 423.

Chemical Structure

[0336] To a solution of 5-methyl-1H-pyrazole-4-carboxylic acid (73 mg, 0.58 mmol, 1.50 equiv) in DMF (2 mL) were added HOAt (105 mg, 0.8 mmol, 2.0 equiv), EDCI (148 mg, 0.8 mmol, 2.00 equiv), DIEA (249 mg, 1.9 mmol, 5.0 equiv) and (R)-5-(5-ethylisoxazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride (102.5 mg, 0.4 mmol, 1.00 equiv). The mixture was stirred at room temperature overnight and purified by preparative HPLC under the following conditions: (2#-AnalyseHPLC-SHIMADZU (HPLC-10): column, X-Bridge Shield RP18 OBD column, 5um, 19*150mm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (from 30.0% to 45.0% of ACN in 8 minutes); detector, UV254 nm). This purification gave 28.5 mg (22%) of (R)-N-(5-(5-ethylisoxazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-5-methyl-1H-pyrazole-4-carboxamide (Compound 431) as a white solid. LRMS (ES) m / z 337 (M+H). 1 1H-NMR: (400 MHz, methanol-d4) δ 7.96 (s, 1H), 7.74 (s, 1H), 7.71 - 7.65 (m, 1H), 7.40 (d, J = 7.9 Hz, 1H), 6.58 (t, J = 0.9 Hz, 1H), 5.65 (t, J = 8.0 Hz, 1H), 3.19 - 3.07 (m, 1H), 3.05 - 2.93(m, 1H), 2.86 (qd, J = 7.4, 0.9 Hz, 2H), 2.64 (ddd, J = 12.7, 7.9, 3.2 Hz, 1H), 2.56 (s, 3H), 2.05 (dq, J = 12.8, 8.7 Hz, 1H), 1.37 (t, J = 7.6 Hz, 3H). (Example 30) Synthesis of Compound 433 1. Synthesis of Intermediate 30-2: [Chemical formula]

[0337] To a solution of tert-butyl N-[(3S)-6-cyano-2,3-dihydro-1-benzofuran-3-yl]carbamate (6.4 g, 24.6 mmol, 1.0 equivalent) in toluene (100 mL) cooled to 0 °C, DIBAL-H (43.9 mL, 2.20 equivalents) was added dropwise under nitrogen. The mixture was stirred at 0 °C for 2 hours, quenched with ice water (10 mL) and NaOH solution (10%, 10 mL), and filtered to remove the solid. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5.8 g of tert-butyl N-[(3S)-6-formyl-2,3-dihydro-1-benzofuran-3-yl]carbamate as a pale yellow solid, which was used in the next step without further purification. 2. Synthesis of Intermediate 30-3: [Chemical formula]

[0338] A solution of tert-butyl N-[(3S)-6-formyl-2,3-dihydro-1-benzofuran-3-yl]carbamate (5.8 g, 22.0 mmol, 1.0 eq) in a mixture of ethanol and pyridine (100 / 50 mL) was added to hydroxylamine hydrochloride (1.83 g, 26.3 mmol, 1.2 eq). The mixture was stirred at room temperature for 3 h, concentrated under vacuum to a volume of about 20 mL, and poured into EA (40 mL) and water (40 mL). The aqueous layer was extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with brine (100 mL) and concentrated under vacuum to give 6.0 g of tert-butyl N-[(3S)-6-[(1E)-(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate as a white solid, which was used in the next step without further purification. 3. Synthesis of Intermediate 30-4:

Chemical formula

[0339] To a solution of tert-butyl N-[(3S)-6-[(1E)-(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate (6.0 g, 21.5 mmol, 1.0 eq) in THF (10 mL) were added pyridine (1.4 g, 17.1 mmol, 0.8 eq) and NCS (5.2 g, 38.7 mmol, 1.80 eq). The mixture was stirred at room temperature overnight and concentrated to dryness to give 9.1 g of tert-butyl N-[(3S)-6-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate as a white solid, which was used in the next step without further purification. 4. Synthesis of Intermediate 30-5:

Chemical formula

[0340] ​To a solution of tert-butyl N-[(3S)-6-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate (3.6 g, 11.6 mmol, 1.0 equiv) in THF (80 mL) were added TEA (4.3 g, 42.9 mmol, 5.0 equiv) and 2-bromobut-1-ene (1.7 g, 12.9 mmol, 1.5 equiv). The mixture was stirred at room temperature for 2 h, heated to 60 °C for 2 h, and poured into EA (100 mL) and water (100 mL). The aqueous layer was extracted three times with ethyl acetate (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and purified by a C18 column using H2O:ACN (50:50) as the eluent to obtain 424 mg (11%) of tert-butyl N-[(3S)-6-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate as a white solid. 5. Synthesis of Intermediate 30-6:

Chemical formula

[0341] To a solution of tert-butyl N-[(3S)-6-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate (420 mg, 1.8 mmol, 1.0 equiv) in DCM (20 mL) was added hydrogen chloride (4 M in dioxane, 3.2 mL, 10.0 equiv). The mixture was stirred at room temperature overnight, and the solid was collected by filtration to obtain 275 mg of (3S)-6-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine hydrochloride as a pale yellow solid, which was used in the next step without further purification. 6. Synthesis of Compound 433:

Chemical formula

[0342] (3S)-6-(5-Ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine hydrochloride (70 mg, 0.3 mmol, 1.0 eq) in DMF (2 mL) was added to 5-methyl-1H-pyrazole-4-carboxylic acid (40 mg, 0.3 mmol, 1.2 eq), EDCI (60 mg, 0.3 mmol, 1.2 eq), HOAt (43 mg, 0.3 mmol, 1.2 eq) and DIEA (101 mg, 3.00 eq). The mixture was stirred overnight, diluted with water (20 mL), and extracted three times with EA (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and purified by preparative HPLC under the following conditions: (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): column, XBridge preparative C18 OBD column, 5um, 19*150mm; mobile phase, water (10MMOL / L NH4HCO3) and ACN (ACN from 29.0% to 43.0% in 8 minutes); detector, UV254nm. This purification gave 60.3 mg (68%) of (S)-N-(6-(5-ethylisoxazol-3-yl)-2,3-dihydrobenzofuran-3-yl)-5-methyl-1H-pyrazole-4-carboxamide (Compound 433) as a white solid. LRMS (ES) m / z 339 (M+H). 1 H-NMR: (400 MHz, DMSO-d6, ppm): δ 12.87 (s, 1H), 8.52 (d, J = 7.5 Hz, 1H), 7.92 (s, 1H), 7.48 - 7.38 (m, 2H), 7.32 (s, 1H), 6.82 (d, J = 1.0 Hz, 1H), 5.77 (d, J = 8.1 Hz, 1H), 4.81 (t, J = 9.2 Hz, 1H), 4.37 (dd, J = 9.6, 5.4 Hz, 1H), 2.86 - 2.75 (m, 2H), 2.46 (s, 2H), 2.38 (s, 1H), 1.28 (t, J = 7.6 Hz, 3H). (Example 31) Synthesis of Compound 474 1. Synthesis of Intermediate 31-2: [Chem.]

[0343] To a solution of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate (23 g, 70 mmol, 1 equiv) in DCM, HCl (4 M in dioxane, 174.8 mL, 698.3 mmol, 10 equiv) was added at room temperature. The mixture was stirred at room temperature overnight and diluted with EA (500 mL). The precipitated solid was collected by filtration, washed twice with PE (200 mL), and dried under high vacuum to give (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride (16 g, 86%) as a white solid. (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride (15 g, 56.5 mmol, 1.0 equiv) and 1H-pyrazole-4-carboxylic acid (6.4 g, 57.1 mmol, 1.0 equiv) in DMF (300 mL) solution, at room temperature, HOAt (11.5 g, 84.5 mmol, 1.5 equiv), DIEA (29.2 g, 225.9 mmol, 4.0 equiv), and EDCI (16.2 g, 84.5 mmol, 1.5 equiv) were added portionwise. After stirring at room temperature overnight, water (450 mL) was slowly added while stirring at 0 °C. The precipitated solid was collected by filtration, washed twice with water (150 mL), and dried under vacuum to give (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazole-4-carboxamide (14 g, 76.7%) as an off-white solid. 2. Synthesis of Intermediate 31-3: [Chem.]

[0344] (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride (15 g, 56.5 mmol, 1.0 equiv) and 1H-pyrazole-4-carboxylic acid (6.4 g, 57.1 mmol, 1.0 equiv) in DMF (300 mL) solution, at room temperature, HOAt (11.5 g, 84.5 mmol, 1.5 equiv), DIEA (29.2 g, 225.9 mmol, 4.0 equiv), and EDCI (16.2 g, 84.5 mmol, 1.5 equiv) were added portionwise. After stirring at room temperature overnight, water (450 mL) was slowly added while stirring at 0 °C. The precipitated solid was collected by filtration, washed twice with water (150 mL), and dried under vacuum to give (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazole-4-carboxamide (14 g, 76.7%) as an off-white solid. 3. Synthesis of Compound 474: [Chem.]

[0345] To a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazole-4-carboxamide (11.2 g, 34.67 mmol, 1 equiv) and Cs2CO3 (22.8 g, 70.1 mmol, 2.0 equiv) in DMF (200 mL), 2-bromoethan-1-ol (5.2 g, 41.3 mmol, 1.2 equiv) was added dropwise at room temperature under a nitrogen atmosphere. After stirring at 100 °C for 1.5 h under a nitrogen atmosphere, the resulting mixture was filtered, diluted with water (1 L), and extracted three times with EA (600 mL). The combined organic layers were washed with brine (600 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA 10 / 90) to obtain the product (8.3 g, 92% purity) as an off-white solid. The off-white solid was combined with the previous batch (Compound 474, 1.8 g, 92% purity) and purified by reverse phase to obtain the product (8.1 g, 98% purity, 92.4% ee) as a white solid. Then, this was stirred in a mixture of THF / EA (1 / 2), filtered to obtain (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide (Compound 474) (5.36 g, 99.6% ee) as a white solid. LRMS (ES) m / z 368 (M+H). LC-MS: (ES, m / z): [M+H] + 368 . 1 H-NMR: (400 MHz, DMSO-d6 , ppm) δ 8.46 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.90 (s, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 5.56 (q, J = 8.3 Hz, 1H), 4.94 (t, J = 5.3 Hz, 1H), 4.15 (t, J = 5.4 Hz, 2H), 3.73 (q, J = 5.4 Hz, 2H), 3.03 (m, 3H), 2.92 (dt, J = 16.4, 8.5 Hz, 1H), 2.57 - 2.34 (m, 1H), 1.99 (dt, J = 12.5, 8.9 Hz, 1H), 1.35 (t, J = 7.6 Hz, 3H).

[0346] The following compound was prepared by a method similar to the method described for Compound 474. [Chemical formula] Alternative synthesis of Compound 474 1. Synthesis of Intermediate 31-2a: [Chemical formula]

[0347] To a solution of ethyl 2-formyl-3-oxopropanoate (25.3 g, 144.1 mmol, 1.09 equiv) in EtOH (100 mL) was added 2-hydrazinylethane-1-ol (96% pure, 12.4 g, 156 mmol, 1.00 equiv) in EtOH (50.0 mL) at 0 °C. The mixture was stirred at room temperature overnight, LiOH (7.5 g, 312.5 mmol) was added, and the mixture was heated to reflux overnight, cooled to room temperature, and MTBE (400 mL) was added. The solid was collected and dried. The solid was then transferred to a 500 mL RB in an ice bath. HCl (6 N) was added to the mixture until the mixture reached pH 1, stirring was continued at 0 °C for 30 minutes, and then the mixture was filtered. The solid was collected and dried to give 1-(2-hydroxyethyl)-1H-pyrazole-4-carboxylic acid (18.8 g, 120.4 mmol, 77.1%) as a pale yellow solid. LRMS (ES) m / z 157.1 (M+H). 1 H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.18 (d, J = 0.7 Hz, 1H), 7.79 (d, J = 0.7 Hz, 1H), 4.92 (t, J = 5.3 Hz, 1H), 4.17 (t, J = 5.5 Hz, 2H), 3.77 - 3.70 (m, 2H). Synthesis of Compound 474:

Chemical Structure

[0348] 1-(2-Hydroxyethyl)-1H-pyrazole-4-carboxylic acid (15.0 g, 96.1 mmol, 1.05 eq), (R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride (24.3 g, 91.5 mmol, 1.0 eq), HOBt (0.62 g, 4.6 mmol, 9.05 mmol), and N-methylmorpholine (32.4 g, 320.2 mmol, 3.5 eq) in EtOH (200 mL) were added with EDCI (19.3 g, 100.6 mmol, 1.10 eq) at room temperature. Subsequently, the mixture was heated to 45 °C overnight, water (700 mL) was added, and the mixture was stirred for 1 hour while cooling, and then filtered. The solid was washed with additional water (200 mL) and dried to obtain (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide (Compound 474) (32.9 g, 89.5 mmol) as an off-white solid. LRMS (ES) m / z 368.2 (M+H). 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 0.7 Hz, 1H), 7.94 - 7.88 (m, 2H), 7.85 (dd, J = 7.8, 1.5 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 5.56 (q, J = 8.3 Hz, 1H), 4.94 (t, J = 5.3 Hz, 1H), 4.15 (t, J = 5.4 Hz, 2H), 3.72 (q, J = 5.4 Hz, 2H), 3.11 - 2.86 (m, 4H), 2.43-2.51 (m, 1H), 1.98 (dq, J = 12.5, 9.0 Hz, 1H), 1.35 (t, J = 7.6 Hz, 3H).

[0349] The following compounds were prepared by a method similar to the method described for the alternative synthesis of Compound 474.

Chemical Structure

Chemical Structure

[0350] To a solution of 4-(3-phenylpropyl)pyridine-N-oxide (230 mg, 0.02 equiv) in DCM (20 mL) cooled to 0 °C, under nitrogen, R,R-Jacobsen catalyst (200 mg, 0.07 equiv) and sodium hypochlorite (8% - 10% aqueous solution, 21.9 g, 1.7 equiv) were added dropwise. The mixture was stirred at 0 °C for 15 minutes, and a solution of 6-bromo-1H-indene (3.0 g, 15.4 mmol, 1.00 equiv) in DCM (20 mL) was then added dropwise at 0 °C, followed by sodium hypochlorite (8% - 10% aqueous solution, 21.9 g, 1.7 equiv). The mixture was then stirred at 0 °C for 1 hour and at room temperature for 2.5 hours, poured into water (100 mL) and DCM (50 mL), and filtered to remove solids. The aqueous layer was extracted twice with DCM (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 3) to obtain 700 mg (22%) of a mixture of (1aS,6bR)-4-bromo-1aH,2H,6bH-indenol[1,2-b]oxirene and (1aR,6aS)-4-bromo-1a,6a-dihydro-6H-indenol[1,2-b]oxirene. 2. Synthesis of Intermediate 32-3:

Chemical Structure

[0351] To a solution of (1aR,6aS)-4-bromo-1a,6a-dihydro-6H-inden[1,2-b]oxirene (700 mg, 3.32 mmol, 1.0 eq) in THF (7 mL) was added ammonium hydroxide (25% - 28%, 7 mL). The mixture was stirred at 80 °C overnight and concentrated under reduced pressure to give 760 mg of (1S,2S)-1-amino-5-bromo-2,3-dihydro-1H-inden-2-ol as a brown solid. 3. Synthesis of Intermediate 32-4:

Chemical formula

[0352] To a solution of (1S,2S)-1-amino-5-bromo-2,3-dihydro-1H-inden-2-ol (760 mg, 3.3 mmol, 1.0 eq) in THF (6 mL) was added dropwise a solution of sodium hydrogen carbonate (844 mg, 10.0 mmol, 3.0 eq) and (Boc)2O (876 mg, 4.01 mmol, 1.2 eq) in THF (4 mL). The mixtu...

Claims

【Claim 1】 Heart disease.

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