Dihydrobenzofuran and indene analogs as inhibitors of the cardiac muscle band

Abstract

The present invention relates to dihydrobenzofuran and indene analogs as inhibitors of the cardiac muscle node. In particular, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein A, Z, B, R 1 , R 2 , R 3 , G1, G2, and G3 are as defined herein. Also provided are pharmaceutically acceptable compositions 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 the treatment of heart disease by inhibition of the cardiac muscle node.

Description

[0001] This application is a divisional application of Chinese invention patent application (application date: January 18, 2019; application number: 201980009128.5 (international application number: PCT / US2019 / 014344); invention title: dihydrobenzofuran and indene analogues as myocardial ganglion inhibitors).

[0002] Cross-reference of related applications

[0003] This application requests the U.S. Provisional Application No. 62 / 2018 entitled "CARDIAC SARCOMERE INHIBITBITORS" filed on January 19, 2018.

[0004] Priority to U.S. Provisional Application 62 / 745,724 entitled “CARDIAC SARCOMERE INHIBITBITORS”, filed October 15, 2018, is incorporated herein by reference in its entirety for all purposes. Technical Field

[0005] This article provides heterocyclic compounds, pharmaceutical compositions comprising said compounds, and methods of using said compounds to treat various heart diseases and conditions. Background Technology

[0006] This disclosure relates to certain chemical entities that selectively regulate myocardial ganglia, and more particularly to certain chemical entities, pharmaceutical compositions, and methods for treating various heart diseases and conditions.

[0007] Cardiac ganglia are composed of a network of contractile and structural proteins that regulate myocardial function. Components of the cardiac ganglia present targets for the treatment of various cardiac diseases and conditions; these targets regulate systolic and diastolic function, respectively, by increasing contractility or promoting complete relaxation. The strength and velocity of myocardial contraction are major determinants of organ function and are regulated by the periodic interaction between actin and myosin. The regulation of actin and myosin binding is controlled by a network of myofilament regulatory proteins and intracellular calcium... 2+ The level determines this. Troponin complex and tropomyosin are filament proteins that control the availability of actin binding sites, and essential and regulatory light chains and myosin-binding protein C regulate the position and mechanical properties of myosin.

[0008] Abnormalities in sarcomeres have been identified as a driving force behind a variety of heart diseases and conditions, such as hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF). Mutations in sarcomere proteins cause disease by causing the myocardium to contract 'excessively' or 'under-'excessively'. Sarcomere modulators can be used to rebalance contractility and to stop or reverse the disease process.

[0009] Current drugs targeting myocardial ganglia (such as inotropic drugs, which increase the heart's contractility) have poor selectivity for cardiac tissue, leading to recognized adverse effects that limit their use. These adverse effects include cellular damage due to increased energy expenditure rates, worsening of relaxation abnormalities, and potential arrhythmogenic side effects due to increased cytoplasmic Ca++ and cyclic AMP concentrations in the myocardium caused by inotropic stimulation. Given the limitations of current drugs, new approaches are needed to improve cardiac function in HCM and HFpEF.

[0010] There remains a strong need for drugs with novel mechanisms of action and superior short- and long-term outcomes in symptom relief, safety, and patient mortality. New drugs with improved therapeutic indices compared to current agents will provide a means to achieve these clinical outcomes. Selectivity of drugs targeting myocardial ganglia (e.g., by targeting myosin) has been identified as an important means to achieve this improved therapeutic index. This disclosure provides said drugs (specifically, myocardial ganglion inhibitors) and methods of administration thereof. These agents are selective site inhibitors of myosin, with minimal to no effect on smooth muscle myosin. The benefits of these compounds include a wider therapeutic index, less impact on cardiac relaxation, better pharmacokinetics, and improved safety.

[0011] This disclosure provides chemical entities, pharmaceutical compositions, and methods for treating heart failure (including HCM and HFpEF). These compositions are inhibitors of myocardial ganglia, such as inhibitors of myocardial glycoproteins. Summary of the Invention

[0012] In one respect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided:

[0013]

[0014] in:

[0015] G1 is -CR 4 R 5 -or -O-;

[0016] G2 is a key or -CR 6 R 7 -;

[0017] G3 is -CR 8 -or -N-;

[0018] R 1 R 3 R 4 R 5 R 6 R 7 and R 8Each is independently H, C1-C6 alkyl, halogen, or hydroxyl;

[0019] R 2 It is H, C2-C6 alkyl, halogen or hydroxyl;

[0020] Z is selected from the following groups: bond, C1-C6 alkyl, -O-, -N(R) 9 )-、-R x O-、-OR y -and-R z S-;

[0021] R 9 It is H, C1-C6 alkyl or cycloalkyl;

[0022] A is selected from the group consisting of: substituted C2-alkynyl, unsubstituted C2-alkynyl, substituted phenyl, unsubstituted phenyl, and a 5- or 6-membered heteroaryl containing at least one ring N atom, wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted with one or more R atoms. 10 Substituent substitution;

[0023] Each R 10 Independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and -C(O)OR a ;

[0024] B is selected from the group consisting of: H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or has one or more R groups. 11 Substituent substitution;

[0025] Each R 11 Independently selected from the group consisting of: substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, unsubstituted C1-C6 alkyl, and alkyl with one or more R... 12 Substituents: C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C2-C6 alkynyl groups, halogens, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f ;

[0026] Each R 12Independently select from the following groups: halogen, -OR b -C(O)R g -C(O)OR h and -C(O)NR i R j ;

[0027] Each R a R b R c R d R e R f R g R h R i and R j It is independently H or C1-C6 alkyl; and

[0028] R x R y and R z Each is a C1-C6 alkyl group.

[0029] Where A is an unsubstituted phenyl or 5-trifluoromethyl-1,2,4-oxadiazolyl, the -ZB moiety is not -OC(CH3)3 or 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrole-2-one.

[0030] In some embodiments, the compound of formula (I) is the compound of formula (If):

[0031]

[0032] In some embodiments of formula (I) or any variation 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 Each is H.

[0033] In some embodiments of equation (I) or any variation thereof, G1 is -CR 4 R 5 In some implementations, G1 is -CH2-. In other implementations, G1 is -O-. In some implementations, G2 is a bond. In some implementations, G2 is -CR. 6 R 7In other implementations, G2 is -CH2-. In some implementations, G3 is -CR 8 In some implementations, G3 is -CH-. In some implementations, G3 is -N-.

[0034] In some implementations of formula (I) or any variation thereof, R 1 R 2 and R 3 Each is H. In some implementations, Z is the key. In some implementations, Z is -O-. In other implementations, Z is -N(R) 9 )-.

[0035] In some embodiments of formula (I) or any variation thereof, A is selected from the group consisting of: substituted C2-alkynyl, unsubstituted C2-alkynyl, substituted phenyl, unsubstituted phenyl, and a 5- or 6-membered heteroaryl containing at least one ring N atom, wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted with one or more R atoms. 10 Substituent substitution; wherein each R 10 Independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclic alkyl and -C(O)OR a In some implementations, each R 10 Independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5- to 6-membered heterocyclic alkyl and -C(O)OR a .

[0036] In some embodiments of formula (I) or any variation thereof, A is selected from the group consisting of: substituted phenyl, unsubstituted phenyl, and 5- or 6-membered heteroaryl containing at least one cyclic N atom, wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted with one or more R atoms. 10 Substituent substitution. 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 has been substituted by one or more R groups. 10 Substituent substitution. In some embodiments of formula (I) or any variation thereof or a pharmaceutically acceptable salt thereof, A is an oxadiazolyl or isoxazolyl group, each unsubstituted or substituted with one or more R groups. 10 Substituent substitution.

[0037] In some implementations of equation (I) or any variation thereof, A is selected from the group consisting of:

[0038]

[0039] and Each of them has not been replaced or has been replaced by one or more R 10 Substituent substitution. In some implementations, R 10 Each C1-C6 alkyl, cycloalkyl, or heterocycloalkyl group is independently unsubstituted or independently selected from -OR k and -OC(O)R m The group consists of substituents, where R is substituted. k and R m Each is independently an H or C1-C6 alkyl group. In some embodiments, each R 10 Independently selected from the group consisting of: -C(O)OCH3, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, cyclobutyl, and oxecyclobutyl, wherein R 10 Each methyl, ethyl, and isopropyl group is independently unsubstituted or substituted by one or more substituents independently selected from the group consisting of -OCH3, -OH, and -OC(O)CH3.

[0040] In some embodiments of formula (I) or any variation thereof, A is an oxadiazolyl group, which is unsubstituted or substituted with a substituent selected from the group consisting of: 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, oxacyclobutyl, and -C(O)OCH3. In some embodiments, A is an oxadiazolyl group, which is unsubstituted or substituted with a substituent selected from the group consisting of: methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, and cyclobutyl.

[0041] In some embodiments of formula (I) or any variation thereof, A is an isoxazolyl group, 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 an isoxazolyl group, which is unsubstituted or substituted with one substituent selected from the group consisting of methyl, ethyl, and difluoromethyl.

[0042] In some implementations of equation (I) or any variation thereof, A is selected from the group consisting of:

[0043]

[0044] and Each R 13 Independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, and -C(O)OR. a And R a It is an H or C1-C6 alkyl group. In some embodiments, each R 13 Independently selected from the group consisting of: H, -C(O)OCH3, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, cyclobutyl, and oxecyclobutyl, wherein R 13 Each methyl, ethyl, and isopropyl group is independently unsubstituted or substituted by one or more substituents independently selected from the group consisting of -OCH3, -OH, and -OC(O)CH.

[0045] In some embodiments of formula (I) or any variation thereof, B is selected from the group consisting of: H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl of B is unsubstituted or has one or more R groups. 11 Substituent substitution; each R 11 Independently selected from the group consisting of: heterocyclic alkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, halogen, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f , where R 11 Each heterocyclic alkyl and heteroaryl group 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 Independently, it is H or C1-C6 alkyl. In some embodiments of formula (I) or any variation thereof, B is selected from the group consisting of: H, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 12aryl, 3- to 12-membered heterocyclic alkyl and 5- to 10-membered heteroaryl, wherein B is a C1-C6 alkyl, a C3-C8 cycloalkyl, or a C6-C 12 The aryl group, the 3- to 12-membered heterocyclic alkyl group, and the 5- to 10-membered heteroaryl group are each unsubstituted or have one or more R groups. 11 Substituent substitution. In some embodiments, B is unsubstituted or substituted with one or more R groups. 11 Substituent substitution; wherein each R 11 Independently selected from the group consisting of: substituted or unsubstituted 3- to 12-membered heterocyclic alkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C6-C8 cycloalkyl groups. 12 aryl, unsubstituted C1-C6 alkyl, via one or more R 12 Substituents: C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C2-C6 alkynyl groups, halogens, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f In some implementations, B is not replaced or is processed by one or more R... 11 Substituent substitution; wherein each R 11 Independently selected from the group consisting of: 3- to 12-membered heterocyclic alkyl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl, C6-C 12 Aryl, C1-C6 alkyl, halogen, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f , where R 11 Each heterocyclic alkyl and heteroaryl group 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 It is independently H or C1-C6 alkyl. In some embodiments, R 11Each heterocyclic alkyl or heteroaryl group comprises one, two, three, four, or five heteroatoms selected from the group consisting of N, O, and S. In some embodiments of formula (I) or any variation thereof, B is unsubstituted or derived from one or more R groups. 11 A phenyl group substituted with a substituent. In some embodiments, B is unsubstituted or substituted with one or more R groups. 11 A 5- to 6-membered heterocyclic alkyl group substituted with a substituent. In other embodiments, B is unsubstituted or substituted with one or more R groups. 11 Substituent-substituted 5- to 6-membered heteroaryl groups.

[0046] In some embodiments of formula (I) or any variation 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 heterocyclic alkyl containing at least one cyclic N or O atom, 5- or 6-membered monocyclic heteroaryl containing at least one cyclic N atom, and 8- or 9-membered bicyclic heteroaryl containing at least one cyclic N atom, each 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 (e.g., 6- to 9-membered aryl), 4- to 6-membered heterocyclic alkyl containing at least one cyclic N or O atom, 5- or 6-membered monocyclic heteroaryl containing at least one cyclic N atom, or 8- or 9-membered bicyclic heteroaryl containing at least one cyclic N atom, each unsubstituted or substituted with one or more R atoms. 11 Substituent substitution; each R 11 Independently selected from the group consisting of: heterocyclic alkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, halogen, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f , where R 11 Each heterocyclic alkyl and heteroaryl group 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 R 11 Each C1-C6 alkyl group is unsubstituted or -OR b Replace; and each R b R c R d R e R f R n R p R q and Rr It is independently H or C1-C6 alkyl.

[0047] In some embodiments of formula (I) or any variation thereof, B is selected from the group consisting of: methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, dihydroindenyl, aziridine, oxaziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazine, pyrimidinyl, pyridinyl, dihydroindenyl, pyrrolopyrazolyl, and benzimidazolyl, each of which is unsubstituted or has been modified by one or more R... 11 Substituent substitution; each R 11 Independently selected from the group consisting of: heterocyclic alkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, halogen, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f , where R 11 Each heterocyclic alkyl and heteroaryl group 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 R 11 Each C1-C6 alkyl group is unsubstituted or -OR b Replace; and each R b R c R d R e R f R n R p R q and R r Independently, it is an H or C1-C6 alkyl group. In some embodiments, each R 11 Independently selected from the group consisting of: methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, oxo, -C(O)CH3, -C(O)OtBu, -OCH3, -OH, -NH2, -Cl, oxadiazolyl, oxadiazolyl, and aziridine, wherein R 11 Each of the oxadiazolyl and aziridine groups 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, and wherein R 11Each methyl, ethyl, and isopropyl group is unsubstituted or substituted with -OH.

[0048] In some embodiments of formula (I) or any variation thereof, B is methyl, pyrazolyl, oxazolyl, tetrazolyl, isoxazolyl, thiazolyl, imidazoleyl, or pyridinyl, each unsubstituted or derived from one or more R groups. 11 Substituent substitution; each R 11 Independently selected from the group consisting of: heterocyclic alkyl, heteroaryl, halogen, C1-C6 alkyl, via one or two R 12 Substituents: C1-C6 alkyl, cycloalkyl, or alkyl groups with one or two R groups 12 Substituents: cycloalkyl, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f ; Each R 12 Independently select from the following groups: halogen, -OR b -C(O)R g -C(O)OR h and -C(O)NR i R j And each R b R c R d R e and R f R g R h R i and R j Independently, it is H or a C1-C6 alkyl group. In some embodiments, B is pyrazolyl, oxazolyl, tetrazolyl, isoxazolyl, thiazolyl, imidazole, or pyridinyl, each unsubstituted or derived from one or more R groups. 11 Substituent substitution; each R 11 Independently selected from the group consisting of: heterocyclic alkyl, heteroaryl, halogen, C1-C6 alkyl, via one or two R 12 Substituents: C1-C6 alkyl, cycloalkyl, or alkyl groups with one or two R groups 12 Substituents: cycloalkyl, fluoroalkyl, -OR b Oxygenation and -NR e R f ; Each R 12 Independently select from the following groups: halogen, -OR b and -C(O)NR i R j And each R b R e R fR i and R j It is independently H or C1-C6 alkyl. In some embodiments, R b It's H.

[0049] In some implementations of equation (I) or any variation thereof, B is selected from the group consisting of:

[0050]

[0051] and Each of them has not been replaced or has been replaced by one or more R 11 Substituent substitution; each R 11 Independently selected from the group consisting of: heterocyclic alkyl, heteroaryl, halogen, C1-C6 alkyl, via one or two R 12 Substituents: C1-C6 alkyl, cycloalkyl, or alkyl groups with one or two R groups 12 Substituents: cycloalkyl, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f ; Each R 12 Independently select from the following groups: halogen, -OR b -C(O)R g -C(O)OR h and -C(O)NR i R j And each R b R c R d R e and R f R g R h R i and R j It is independently H or C1-C6 alkyl.

[0052] In some implementations of equation (I) or any variation thereof, B is selected from the group consisting of:

[0053]

[0054] and Each R 14 Independently selected from the group consisting of: heterocyclic alkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, via one or more R 12 Substituents: C1-C6 alkyl, halogen, fluoroalkyl, -OR b-C(O)R c -C(O)OR d Oxygenation and -NR e R f , where R 14 Each heterocyclic alkyl and heteroaryl group 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 ; Each R 12 Choose independently from the following groups: halogens, -OH, -C(O)R g -C(O)OR h and -C(O)NR i R j And each R b R c R d R e R f R g R h R i and R j R n R p R q and R r It is independently H or C1-C6 alkyl.

[0055] Some implementations provide compounds selected from the group consisting of compounds in Table 1, or pharmaceutically acceptable salts thereof.

[0056] Some aspects provide pharmaceutical compositions comprising a compound of formula (I) or any variation thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0057] Some aspects provide methods for treating heart disease in a subject in need, the method comprising administering to the subject a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula (I) or any variation thereof. In some embodiments, the heart disease is hypertrophic cardiomyopathy (HCM). In some embodiments, HCM is obstructive or non-obstructive or caused by sarcomere and / or non-sarcomere 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, ischemic heart disease, coronary heart disease, diabetic heart disease, congestive heart failure, right heart failure, cardiorenal syndrome, or infiltrative cardiomyopathy. In some embodiments, the heart disease is a condition of aging-related cardiac aging and / or diastolic dysfunction, or a condition related thereto. In some implementations, heart disease is a symptom or a symptom associated with left ventricular hypertrophy and / or left ventricular concentric remodeling.

[0058] Other aspects provide methods for treating a subject with a disease or symptom related to HCM, wherein the method involves administering to the subject a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula (I) or any variation thereof. In some embodiments, the disease or symptom is selected from the group consisting of Fabry's disease, Danon disease, mitochondrial cardiomyopathy, and Noonan syndrome.

[0059] Some aspects provide methods for treating a disease or symptom associated with secondary left ventricular wall thickening in a subject of need, wherein the method involves administering to the subject a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula (I) or any variation thereof. In some embodiments, the disease or symptom is selected from the group consisting of:

[0060] Hypertension, valvular heart disease (aortic stenosis, mitral regurgitation), metabolic syndrome (diabetes, obesity), end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich ataxia, Danon disease, Noonan syndrome, and Pompe disease.

[0061] Other aspects provide methods for treating diseases or symptoms associated with small left ventricular chambers and chamber occlusion, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis. Methods for treating muscular dystrophy (e.g., Duchenne muscular dystrophy) or glycogen storage disease are also provided.

[0062] Methods for inhibiting myocardial ganglia are also provided, wherein the method involves contacting the myocardial ganglia with a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula (I) or any variation thereof. Detailed Implementation

[0063] definition

[0064] As used in this specification, unless otherwise indicated in the context of their use, the following words and phrases are generally intended to have the meanings described below.

[0065] Throughout this application, unless the context otherwise indicates, references to compounds of formula (I) include all subgroups of formula (I) as defined herein (such as formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik)), including all substructures, subclasses, preferences, embodiments, examples, and specific compounds as defined and / or described herein. References to compounds of formula (I) and their subgroups (such as formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik)) include their ionic form, polymorph, pseudopolymorph, amorphous form, solvate, eutectic, chelate, isomer, tautomer, oxide (e.g., N-oxide, S-oxide), ester, prodrug, isotope, and / or protected form. In some embodiments, references to compounds of formula (I) and their subgroups (such as (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik)) include their polymorphs, solvates, eutectics, isomers, tautomers, and / or oxides. In some embodiments, references to compounds of formula (I) and their subgroups (such as (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik)) include their polymorphs, solvates, and / or eutectics. In some embodiments, references to compounds of formula (I) and their subgroups (such as (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 (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik)) include their solvates. Similarly, the term "salt" includes solvates of salts of compounds.

[0066] "alkyl" encompasses straight-chain and branched carbon chains having an indicated number of carbon atoms (e.g., 1 to 20 carbon atoms, 1 to 8 carbon atoms, or 1 to 6 carbon atoms). For example, C 1-6Alkyl groups encompass both straight-chain and branched alkyl groups with 1 to 6 carbon atoms. When naming alkyl residues with a specific number of carbon atoms, all geometrically branched and straight-chain forms with that number of carbon atoms are intended to be included; thus, for example, "propyl" includes n-propyl and isopropyl; and "butyl" includes n-butyl, sec-butyl, isobutyl, and tert-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.

[0067] When a range of values ​​is given (e.g., C), 1-6 When alkyl), every value in that range, as well as all intermediate values, are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 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.

[0068] "Alkenyl" refers to an unsaturated branched or straight-chain alkyl group having an 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 may be in a cis or trans configuration (Z or E configuration) with respect to the one or more double bonds. Alkenyl groups include (but are not limited to) vinyl, propenyl (e.g., propen-1-en-1-yl, propen-2-yl, propen-2-en-1-yl (allyl), propen-2-en-2-yl), and butenyl (e.g., buten-1-en-1-yl, buten-2-yl, 2-methyl-propen-1-en-1-yl, buten-2-en-1-yl, buten-2-en-2-yl, buten-1,3-dien-1-yl, buten-1,3-dien-2-yl).

[0069] "Alynyl" refers to an unsaturated branched or straight-chain alkyl group having an indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alynyl 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).

[0070] “Cycloalkyl” indicates a non-aromatic, fully saturated carbocyclic ring having an indicated number of carbon atoms (e.g., 3 to 10, 3 to 8, or 3 to 6 ring carbon atoms). Cycloalkyl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridging and cage-like cyclic groups (e.g., norcamphene, bicyclo[2.2.2]octane). Additionally, one ring of a polycyclic cycloalkyl group may be aromatic, provided that the polycyclic cycloalkyl group is bonded to the parent structure via a non-aromatic carbon atom. For example, 1,2,3,4-tetrahydronaphth-1-yl (wherein this moiety is bonded to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphth-5-yl (wherein this moiety is bonded to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups composed of cycloalkyl groups fused to an aromatic ring are described below.

[0071] “Cycloalkenyl” indicates a non-aromatic carbon ring containing an indicated number of carbon atoms (e.g., 3 to 10, 3 to 8, or 3 to 6 cyclic carbon atoms) and at least one carbon-carbon double bond. Cycloalkenyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as well as bridging and cage-like cyclic groups (e.g., bicyclic [2.2.2]octene). Additionally, one ring of a polycyclic cycloalkenyl group can be aromatic, provided that the polycyclic cycloalkenyl group is bonded to the parent structure via a non-aromatic carbon atom. For example, indene-1-yl (where this portion is bonded to the parent structure via a non-aromatic carbon atom) is considered a cycloalkenyl group, while indene-4-yl (where this portion is bonded to the parent structure via an aromatic carbon atom) is not considered a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups composed of cycloalkenyl groups fused to an aromatic ring are described below.

[0072] "Aryl" indicates an aromatic carbon ring having an indicated number of carbon atoms (6 to 12 or 6 to 10 carbon atoms). Aryl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other cases, a polycyclic aryl group may include a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is bonded to the parent structure via atoms in the aromatic ring. Therefore, 1,2,3,4-tetrahydronaphth-5-yl (where this portion is bonded to the parent structure via aromatic carbon atoms) is considered an aryl group, while 1,2,3,4-tetrahydronaphth-1-yl (where this portion is bonded to the parent structure via non-aromatic carbon atoms) is not considered an aryl group. Similarly, 1,2,3,4-tetrahydroquinoline-8-yl (where the moiety is bonded to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydroquinoline-1-yl (where the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is not. However, the term "aryl" does not encompass or overlap with "heteroaryl" as defined herein, regardless of the bonding point (e.g., both quinoline-5-yl and quinoline-2-yl are heteroaryl groups). In some cases, the aryl group is phenyl or naphthyl. In some cases, the aryl group is phenyl. Other examples of aryl groups comprising aromatic carbon rings fused to a non-aromatic ring are described below.

[0073] "Heteroaryl" refers to an aromatic ring containing an indicated number of atoms (e.g., 5- to 12-membered or 5- to 10-membered heteroaryls) consisting of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms) and the remaining ring atoms being carbon. The heteroaryl does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl does not exceed 2. In some embodiments, the total number of S and O atoms in the heteroaryl does not exceed 1. Unless otherwise indicated, the heteroaryl may be bonded to the parent structure by a carbon or nitrogen atom, provided the valence allows. For example, "pyridinyl" includes 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl, and "pyrroleyl" includes 1-pyrroleyl, 2-pyrroleyl, and 3-pyrroleyl.

[0074] In some cases, the heteroaryl group is a monocyclic ring. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazolium, 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.

[0075] In some cases, both rings of a polycyclic heteroaryl group are aromatic.Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benziisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benziisothiazole, 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- Imidazolo[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, furano[2,3-b]pyridine, oxazolo [5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furano[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furano[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furano[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, thiazo[ [5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazo[5 [4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazo[4,5-c]pyridine, quinoline, isoquinoline, cinnaline, quinazoline, quinoxaline, phthalazine, diazanathine (e.g., 1,8-diazanathine, 1,7-diazanathine, 1,6-diazanathine, 1,5-diazanathine, 2,7-diazanathine, 2,6-diazanathine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole.

[0076] In other cases, polycyclic heteroaryl groups may include non-aromatic rings fused to a heteroaryl ring (e.g., cycloalkyl, cycloalkenyl, heterocyclic alkyl, heterocyclic alkenyl), provided that the polycyclic heteroaryl group is bonded to the parent structure via atoms in the aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (wherein this moiety is bonded to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein this moiety is bonded to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of heteroaryl rings fused to a non-aromatic ring are illustrated below.

[0077] "Heterocyclic alkyl" refers to a non-aromatic, fully saturated ring consisting of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms) and the remaining ring atoms being carbon atoms, having an indicated number of atoms (e.g., 3- to 10- or 3- to 7-membered heterocyclic alkyl). Heterocyclic alkyl can be monocyclic or polycyclic (e.g., bicyclic or tricyclic). Examples of heterocyclic alkyl include epoxyethyl, aziridinyl, aziridine, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Additionally, one ring of a polycyclic heterocyclic alkyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocyclic alkyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom. For example, 1,2,3,4-tetrahydroquinoline-1-yl (wherein the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocyclic alkyl group, while 1,2,3,4-tetrahydroquinoline-8-yl (wherein the moiety is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocyclic alkyl group. Examples of polycyclic heterocyclic alkyl groups composed of heterocyclic alkyl groups fused to an aromatic ring are illustrated below.

[0078] "Heterocyclic alkenyl" indicates a non-aromatic ring consisting of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms) and the remaining ring atoms being carbon atoms (e.g., 3- to 10- or 3- to 7-membered heterocyclic alkyl groups) and at least one double bond derived from the removal of a hydrogen atom from the adjacent carbon atom, adjacent nitrogen atom, or adjacent carbon and nitrogen atom of the respective heterocyclic alkyl group. Heterocyclic alkenyl groups can be monocyclic or polycyclic (e.g., bicyclic or tricyclic). Examples of heterocyclic alkenyl 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), dihydroimidazoyl (e.g., 2,3-dihydro-1H-imidazoyl, 4,5-dihydro-1H-imidazoyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridyl (e.g., 1,2,3,4-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). Furthermore, one ring of a polycyclic heterocyclic alkenyl group can be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocyclic alkenyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom. For example, 1,2-dihydroquinoline-1-yl (where this portion is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocyclic alkenyl group, while 1,2-dihydroquinoline-8-yl (where this portion is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocyclic alkenyl group. Examples of polycyclic heterocyclic alkenyl groups composed of heterocyclic alkenyl groups fused to an aromatic ring are illustrated below.

[0079] Examples of polycyclic compounds 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-

[0080] 1H-Indene, 1,2,3,4-Tetrahydronaphthyl, Benzo[1,3]dioxacyclopentenyl, Tetrahydroquinolinyl, 2,3-Dihydrobenzo[1,4]dioxacyclohexenyl, Dihydroindolyl, Isodihydroindolyl, 2,3-Dihydro-1H-indazolyl, 2,3-Dihydro-1H-benzo[d]imidazolyl, 2,3-Dihydrobenzofuranyl, 1,3-Dihydroisobenzofuranyl, 1,3-Dihydrobenzo[c]isooxazolyl, 2,3-Dihydrobenzo[d]isooxazolyl, 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-cyclopentadien[d]thiazolyl, 4,5,6,7-Tetrahydrobenzo[d]thiazolyl, 5,6-Dihydro-4H-pyrrolo[3,4-d]thiazolyl, 4,5,6,7-Tetrahydrothiazo[5,4-c]pyridyl, dihydroindole-2-one, dihydroindole-3-one, isodihydroindole-1-one, 1,2-dihydroindole-3-one, 1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran-3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazole -3(1H)-one, benzo[d]isoxazol-3(2H)-one, benzo[d]oxazol-2(3H)-one, benzo[b]thiophene-2(3H)-one, benzo[b]thiophene-3(2H)-one, benzo[c]thiophene-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, quinoline-4(3H)-one, quinazoline-4(3H)-one, quinazoline-2,4(1H,3H)-dione, Quinoxalo-2(1H)-one, quinoxalo-2,3(1H,4H)-dione, cyclophosphine-4(3H)-one, pyridin-2(1H)-one, pyrimidine-2(1H)-one, pyrimidine-4(3H)-one, pyridazine-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]thiazolyl-3-one and 4,5-dihydropyrrolo[3,4-d]thiazolyl-6-one. As discussed in this paper, whether each ring is considered aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is determined by the atoms of that moiety that are bonded to the parent structure.

[0081] "Halogen" or "halogenated" refers to fluorine, chlorine, bromine, or iodine.

[0082] Unless otherwise specified, the compounds disclosed and / or described herein include all possible enantiomers, diastereomers, meso isomers, and other stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures thereof. Enantiomers, diastereomers, meso isomers, and other stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using common techniques. Unless otherwise specified, when the compounds disclosed and / or described herein contain an olefinic double bond or other geometrically asymmetric center, these compounds are intended to include both E and Z isomers. When the compounds described herein contain a tautomerizable moiety, these compounds are intended to include all possible tautomers unless otherwise specified.

[0083] The term "protecting group" has its common meaning in organic synthesis, referring to a group that selectively blocks one or more reactive sites in a polyfunctional compound, thereby allowing a chemical reaction to occur selectively at another unprotected reactive site and enabling the group to be easily removed after the selective reaction is complete. Various protecting groups are disclosed, for example, in TH Greene and PGMUTS, *Protective Groups in Organic Synthesis*, 3rd edition, John Wiley & Sons, New York (1999). For instance, a "hydroxyl-protected form" contains at least one hydroxyl group protected by a hydroxyl protecting group. Similarly, amines and other reactive groups can be similarly protected.

[0084] The term "pharmaceutically acceptable salt" refers to a salt of any of the compounds described herein that is known to be nontoxic and commonly used in the medical literature. In some embodiments, a pharmaceutically acceptable salt of a compound retains the biological efficacy of the compound described herein and is biologically or otherwise desirable. 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 using 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 using 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 implementations, the pharmaceutically acceptable base addition salt is selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0085] If the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the compound is a free base, the addition salt, specifically a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to a common procedure for preparing acid addition salts from base compounds (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize the various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0086] A solvate is formed by the interaction of a solvent and a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates having a ratio of any compound to water, such as monohydrates, dihydrates, and hemihydrates.

[0087] The term "substituted" means that the specified group or portion has one or more substituents, including (but not limited to) substituents such as: alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azide, halogen, hydroxyl, nitro, carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocyclic, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy, etc. The term "unsubstituted" means that the specified group does not have substituents. When the term "substituted" is used to describe a structural system, substitution is intended to occur at any position permissible by the valence of the compound in that system. When a group or portion has more than one substituent, it should be understood that these substituents may be the same as or different from each other. In some embodiments, the substituted group or portion has 1 to 5 substituents. In some embodiments, the substituted group or portion has one substituent. In some embodiments, the substituted group or portion has two substituents. In some embodiments, the substituted group or portion has three substituents. In some embodiments, the substituted group or portion has four substituents. In some embodiments, the substituted group or portion has five substituents.

[0088] The terms "optional" or "optional" mean that the event or condition described below may or may not occur, and the description includes both scenarios in which the event or condition occurs and scenarios in which the event or condition does not occur. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. With respect to any group containing one or more substituents, those skilled in the art will understand that the group is not intended to introduce any substitution or substitution pattern that is stereologically impractical, synthetically infeasible, and / or inherently unstable. It should also be understood that if a group or portion is optionally substituted, this disclosure includes both embodiments in which the group or portion is substituted and embodiments in which the group or portion is unsubstituted.

[0089] The compounds disclosed and / or described herein may be in enriched isotopic forms, such as those rich in... 2 H, 3 H, 11 C 13 C and / or 14The content of C. In one embodiment, the compound contains at least one deuterium atom. The deuterated form can be prepared by, for example, the procedures set forth in U.S. Patent Nos. 5,846,514 and 6,334,997. The deuterated compound can improve the efficacy of the compounds disclosed and / or described herein and prolong their duration of action. Deuterated compounds can be synthesized using various methods, such as those described in the following literature: 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.

[0090] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents, etc. The use of such media and reagents for pharmaceutically active substances is well known in the art. This invention covers the use of any commonly used media or agents in pharmaceutical compositions, except where they are incompatible with the active ingredient. Complementary active ingredients may also be incorporated into pharmaceutical compositions.

[0091] The terms "patient," "individual," and "subject" refer to animals, such as mammals, birds, or fish. In some embodiments, the patient or individual is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cattle, and humans. In some embodiments, the patient or subject is a human, such as a human who has been or will be a subject of treatment, observation, or experimentation. The compounds, compositions, and methods described herein are for both human therapeutic and veterinary applications.

[0092] As used herein, the term "therapeutic" refers to the ability to modulate myocardial ganglia. As used herein, "modulation" refers to a change in activity as a direct or indirect response to the presence of a chemical entity, relative to its activity in the absence of the chemical entity. This change can be an increase or decrease in activity and can be due to a direct interaction between the chemical entity and the target or due to the interaction between the chemical entity and one or more other factors that affect the activity of the target. For example, the presence of a chemical entity can, for instance, increase or decrease target activity by directly binding to the target, by increasing or decreasing the activity of the target by another factor, or by increasing or decreasing the amount of the target present in a cell or organism.

[0093] The term "therapeutic effective amount" or "effective amount" means, as defined herein, an amount of a compound disclosed and / or described herein that is sufficient to affect treatment when administered to a patient requiring this treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease that responds to regulation of the myocardial ganglion. The therapeutically effective amount will vary depending on, for example, the subject being treated and their disease condition, the subject's weight and age, the severity of the disease condition, the specific compound, the intended dosing regimen, the time of administration, and the manner of administration, all of which can be readily determined by those skilled in the art. The therapeutically effective amount may be determined experimentally (e.g., by analyzing the blood concentration of the chemical entity) or theoretically (e.g., by calculating bioavailability).

[0094] "Treatment" (and related terms such as "treat," "treated," "treating") includes one or more of the following: prevention of a disease or condition (i.e., preventing the development of clinical symptoms of a disease or condition); suppression of a disease or condition; slowing or stopping the development of clinical symptoms of a disease or condition; and / or alleviating a disease or condition (i.e., relieving or eliminating clinical symptoms). This term covers situations where a patient has already experienced the disease or condition, and situations where the patient is not currently experiencing the disease or condition but is expected to experience it. This term covers both complete and partial reduction or prevention of symptoms or conditions and complete or partial reduction of clinical symptoms of a disease or condition. Therefore, the compounds described and / or disclosed herein may prevent the worsening of an existing disease or condition, help manage the disease or condition, or reduce or eliminate the disease or condition. When used in a preventative manner, the compounds disclosed and / or described herein may prevent the development of a disease or condition or reduce the extent of a potentially developing disease or condition.

[0095] "ATPase" refers to an enzyme that hydrolyzes ATP. ATPases include proteins that contain molecular motors (such as myosin).

[0096] As used herein, "selective binding" or "selectively binding" means that a compound preferentially binds to a target protein in one type of muscle or muscle fiber relative to other types. For example, if a compound preferentially binds to troponin C in the troponin complex of a fast skeletal muscle fiber or sarcomere compared to troponin C in the troponin complex of a slow muscle fiber or sarcomere, or to troponin C in the troponin complex of a cardiac ganglion, then the compound selectively binds to fast skeletal troponin C.

[0097] compound

[0098] The compounds and their salts (such as pharmaceutically acceptable salts) are described in detail herein, including in the summary and claims. Uses of all compounds described herein (including any and all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers) and mixtures thereof in any ratios (including racemic mixtures), uses of the salts and solvates of the compounds described herein, and methods for preparing the compounds are also provided. Any compound described herein may also be called a drug.

[0099] In one respect, compounds of formula (I) are provided:

[0100]

[0101] or its salt, wherein

[0102] G1 is -CR 4 R 5 -or -O-;

[0103] G2 is a key or -CR 6 R 7 -;

[0104] G3 is -CR 8 -or -N-;

[0105] R 1 R 3 R 4 R 5 R 6 R 7 and R 8 Each is independently H, C1-C6 alkyl, halogen, or hydroxyl;

[0106] R 2 It is H, C2-C6 alkyl, halogen or hydroxyl;

[0107] Z is selected from the following groups: bond, C1-C6 alkyl, -O-, -N(R)9 )-、-R x O-、-OR y -and-R z S-;

[0108] R 9 It is H, C1-C6 alkyl or cycloalkyl;

[0109] A is selected from the group consisting of: substituted C2-alkynyl, unsubstituted C2-alkynyl, substituted phenyl, unsubstituted phenyl, and a 5- or 6-membered heteroaryl containing at least one ring N atom, wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted with one or more R atoms. 10 Substituent substitution;

[0110] Each R 10 Independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and -C(O)OR a ;

[0111] B is selected from the group consisting of: H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or has one or more R groups. 11 Substituent substitution;

[0112] Each R 11 Independently selected from the group consisting of: substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, unsubstituted C1-C6 alkyl, and alkyl with one or more R... 12 Substituents: C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C2-C6 alkynyl groups, halogens, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f ;

[0113] Each R 12 Independently select from the following groups: halogen, -OR b -C(O)R g -C(O)OR h and -C(O)NR i R j ;

[0114] Each Ra R b R c R d R e R f R g R h R i and R j It is independently H or C1-C6 alkyl; and

[0115] R x R y and R z Each is a C1-C6 alkyl group.

[0116] Where A is an unsubstituted phenyl or 5-trifluoromethyl-1,2,4-oxadiazolyl, the -ZB moiety is not -OC(CH3)3 or 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrole-2-one.

[0117] In some implementations of formula (I), R 1 R 2 R 3 R 4 R 5 R 6 R 7 and R 8 Each is H independently. In some implementations of equation (I), R 1 R 2 R 3 R 4 R 5 R 6 R 7 and R 8 At least one of them is not H.

[0118] In some variations of equation (I) described in this paper, G1 is -CR 4 R 5 - In some implementations, R 4 and R 5 One of them is H, C1-C6 alkyl, halogen, or hydroxyl, and the other is C1-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 4 and R 5 One of them is H, and the other is a C1-C6 alkyl, halogen, or hydroxyl group. In some embodiments, R 4 and R 5 Both are H, making G1 -CH2-. In some embodiments of formula (I) described herein, G1 is -O-.

[0119] In some embodiments of equation (I), G2 is a bond. In some embodiments, G2 is -CR 6 R 7 - In some implementations, R 6 and R 7 One of them is H, C1-C6 alkyl, halogen, or hydroxyl, and the other is C1-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 6 and R 7 One of them is H, and the other is a C1-C6 alkyl, halogen, or hydroxyl group. In some embodiments, R 6 and R 7 Both are H, making G2 -CH2-.

[0120] In some implementations of formula (I), G3 is -CR 8 -, where R 8 It is a C1-C6 alkyl, halogen, or hydroxyl group. In some embodiments, R 8 H makes G3 -CH-. In some implementations, G3 is -N-.

[0121] In some implementations of formula (I), G1 is -CR 4 R 5 -And G2 is a key. In some implementations, G1 is -CH2- and G2 is a key. In some implementations, G1 is -CR 4 R 5 -and G2 is -CR 6 R 7 In some 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 In some implementations, G1 is -O- and G2 is -CH2-. In some implementations, G1 is -CR. 4 R 5 -, G2 is a key, and G3 is -CR 8 In some implementations, G1 is -CH2-, G2 is a bond, and G3 is -CH-. In some implementations, G1 is -CR. 4 R 5 -, G2 is -CR 6 R 7 - and G3 is -CR 8 In some implementations, G1 and G2 are each -CH2-, and G3 is -CH-. In some implementations, G1 is -O-, G2 is a bond, and G3 is -CR. 8In some implementations, G1 is -O-, G2 is a bond, and G3 is -CH-. In some implementations, G1 is -O-, and G2 is -CR. 6 R 7 - and G3 is -CR 8 In some implementations, G1 is -O-, G2 is -CH2-, and G3 is -CH-. In some implementations, G1 is -CR. 4 R 5 -G1 is -CH2-, G2 is a bond, and G3 is -N-. In some embodiments, G1 is -CR2-, G2 is a bond, and G3 is -N-. In some embodiments, G1 is -CR2-. 4 R 5 -, G2 is -CR 6 R 7 - and G3 is -N-. In some 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 some implementations, G1 is -O-, G2 is -CH2-, and G3 is -N-.

[0122] In some implementations of formula (I), R 1 and R 3 Each is independently H, C1-C6 alkyl, halogen, or hydroxyl, and R 2 It is H. In some implementations, R 1 and R 3 One of them is H and the other is a C1-C6 alkyl, halogen, or hydroxyl group, and R 2 It is H, C2-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 1 and R 3 Each is H, and R 2 It is a C2-C6 alkyl, halogen, or hydroxyl group. In some embodiments, R 1 R 2 and R 3 At least one of them is H. In some implementations, R 1 R 2 and R 3 At least one of them is not H. In some implementations, R 1 R 2 and R 3 Each is H.

[0123] In some embodiments, when any specific group is substituted, the indicated group is substituted with one or more substituents selected from the group consisting of: 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 A1 C(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- to 12-membered heterocyclic, 5- to 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- to 12-membered heterocyclic), -(C1-C3 alkylene)(5- to 10-membered heteroaryl), and -(C1-C3 alkylene)(C6-C 14 aryl), wherein the one or more substituents are each independently unsubstituted or substituted by one or more other substituents selected from the group consisting of: 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 ), C3-C8 cycloalkyl, C1-C6 alkyl and C1-C6 alkyl substituted with oxo, -OH or halogen; wherein each R A1 Independently, it is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclic, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C6 cycloalkyl, or the C6-C 14 The aryl group, the 5- to 6-membered heteroaryl group, and the 3- to 6-membered heterocyclic group are independently unsubstituted or substituted by the following: halogen, oxo, -CN, -OR. A6 -NR A6 R A7 -P(O)(OR) A6 (OR) A6 ), phenyl, halogen-substituted phenyl, C1-C6 alkyl, or C1-C6 alkyl substituted with halogen, -OH, or oxo; R A2 and R A3 Each of these can be independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclic, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C6 cycloalkyl, or the C6-C 14 The aryl group, the 5- to 6-membered heteroaryl group, and the 3- to 6-membered heterocyclic group are each independently unsubstituted or substituted by the following: 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 A7 Each is 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.

[0124] In another respect, the compound of formula (I) is the same as the compound of formula (Ia):

[0125]

[0126] or its salts, wherein A, B, G1, G3 and Z are as defined for formula (I) or any variation or implementation thereof.

[0127] In some implementations of formula (Ia), R 1 R 2 R 3 R 4 R 5 and R 8 Each is H independently. In some implementations of formula (Ia), R 1 R 2 R 3 R 4 R 5 and R 8 At least one of them is not H.

[0128] In some variations of equation (Ia) described in this paper, G1 is -CR 4 R 5 - In some implementations, R 4 and R 5 One of them is H, C1-C6 alkyl, halogen, or hydroxyl, and the other is C1-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 4 and R 5 One of them is H, and the other is a C1-C6 alkyl, halogen, or hydroxyl group. In some embodiments, R 4 and R 5 Both are H, making G1 -CH2-. In some embodiments of formula (Ia) described herein, G1 is -O-.

[0129] In some implementations of formula (Ia), G3 is -CR 8 -, where R 8 It is a C1-C6 alkyl, halogen, or hydroxyl group. In some embodiments, R 8 H makes G3 -CH-. In some implementations, G3 is -N-.

[0130] In some embodiments of formula (I) or (Ia), G1 is -CR 4 R 5 -and G3 is -CR 8 In some implementations, G1 is -CH2- and G3 is -CH-. In some implementations, G1 is -CR. 4 R5 -And G3 is -N-. In some implementations, G1 is -O- and G3 is -CR. 8 In some implementations, G1 is -O- and G3 is -CH-. In some implementations, G1 is -O- and G3 is -N-.

[0131] In some implementations of formula (Ia), R 1 and R 3 Each is independently H, C1-C6 alkyl, halogen, or hydroxyl, and R 2 It is H. In some implementations, R 1 and R 3 One of them is H and the other is a C1-C6 alkyl, halogen, or hydroxyl group, and R 2 It is H, C2-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 1 and R 3 One of them is H and the other is a C1-C6 alkyl, halogen, or hydroxyl group, and R 2 It is H, C2-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 1 R 2 and R 3 At least one of them is H. In some implementations, R 1 R 2 and R 3 At least one of them is not H. In some implementations, R 1 R 2 and R 3 Each is H.

[0132] In another respect, the compound of formula (I) is the same as the compound of formula (Ib):

[0133]

[0134] Or its salts, wherein A, Z, B, R 1 R 2 R 3 R 4 R 5 and R 8 It is as defined for formula (I) or any variation or implementation thereof.

[0135] In some implementations of formula (Ib), R 1 R 2 R 3 R 4 R 5 and R 8 Each is H independently. In some implementations of formula (Ib), R 1 R2 R 3 R 4 R 5 and R 8 At least one of them is not H. In some implementations, R 4 and R 5 One of them is H, C1-C6 alkyl, halogen, or hydroxyl, and the other is C1-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 4 and R 5 One of them is H, and the other is a C1-C6 alkyl, halogen, or hydroxyl group. In some embodiments, R 4 and R 5 Both are H, making G1 -CH2-. In some implementations, R 8 It is a C1-C6 alkyl, halogen, or hydroxyl group. In some embodiments, R 8 It's H.

[0136] In some implementations of formula (Ib), R 1 and R 3 Each is independently H, C1-C6 alkyl, halogen, or hydroxyl, and R 2 It is H. In some implementations, R 1 and R 3 One of them is H and the other is a C1-C6 alkyl, halogen, or hydroxyl group, and R 2 It is H, C2-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 1 and R 3 One of them is H and the other is a C1-C6 alkyl, halogen, or hydroxyl group, and R 2 It is H, C2-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 1 R 2 and R 3 At least one of them is H. In some implementations, R 1 R 2 and R 3 At least one of them is not H. In some implementations, R 1 R 2 and R 3 Each is H.

[0137] In the other case, the compound of formula (I) is the compound of formula (Ic):

[0138]

[0139] Or its salts, wherein A, Z, B, R 1 R 2 R 3 and R8 It is as defined for formula (I) or any variation or implementation thereof.

[0140] In some implementations of formula (Ic), R 1 R 2 R 3 and R 8 Each is H independently. In some implementations of formula (Ic), R 1 R 2 R 3 and R 8 At least one of them is not H. In some implementations of formula (Ic), R 1 and R 3 Each is independently H, C1-C6 alkyl, halogen, or hydroxyl, and R 2 It is H. In some implementations, R 1 and R 3 One of them is H and the other is a C1-C6 alkyl, halogen, or hydroxyl group, and R 2 It is H, C2-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 1 and R 3 One of them is H and the other is a C1-C6 alkyl, halogen, or hydroxyl group, and R 2 It is H, C2-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 1 R 2 and R 3 At least one of them is H. In some implementations, R 1 R 2 and R 3 At least one of them is not H. In some implementations, R 1 R 2 and R 3 Each is H. In some implementations, R 8 It is a C1-C6 alkyl, halogen, or hydroxyl group. In some embodiments, R 8 It's H.

[0141] In the other case, the compound of formula (I) is the compound of formula (Id):

[0142]

[0143] Or its salts, wherein A, Z, B, R 1 R 2 R 3 R 4 and R 5 It is as defined for formula (I) or any variation or implementation thereof.

[0144] In some implementations of formula (Id), R 1 R 2 R 3 R 4 and R 5 Each is H independently.

[0145] In some implementations of formula (Id), R 1 R 2 R 3 R 4 and R 5 At least one of them is not H.

[0146] In some implementations of formula (Id), R 4 and R 5 One of them is H, C1-C6 alkyl, halogen, or hydroxyl, and the other is C1-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 4 and R 5 One of them is H, and the other is a C1-C6 alkyl, halogen, or hydroxyl group. In some embodiments, R 4 and R 5 Both are H.

[0147] In some implementations of formula (Id), R 1 and R 3 Each is independently H, C1-C6 alkyl, halogen, or hydroxyl, and R 2 It is H. In some implementations, R 1 and R 3 One of them is H and the other is a C1-C6 alkyl, halogen, or hydroxyl group, and R 2 It is H, C2-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 1 and R 3 One of them is H and the other is a C1-C6 alkyl, halogen, or hydroxyl group, and R 2 It is H, C2-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 1 R 2 and R 3 At least one of them is H. In some implementations, R 1 R 2 and R 3 At least one of them is not H. In some implementations, R 1 R 2 and R 3 Each is H.

[0148] In the other case, the compound of formula (I) is the compound of formula (Ie):

[0149]

[0150] Or its salts, wherein A, Z, B, R 1 R 2 and R 3 It is as defined for formula (I) or any variation or implementation thereof.

[0151] In some implementations of formula (Ie), R 1 R 2 and R 3 Each is H. In some implementations, R 1 and R 3 Each is independently H, C1-C6 alkyl, halogen, or hydroxyl, and R 2 It is H. In some implementations, R 1 and R 3 One of them is H and the other is a C1-C6 alkyl, halogen, or hydroxyl group, and R 2 It is H, C2-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 1 and R 3 One of them is H and the other is a C1-C6 alkyl, halogen, or hydroxyl group, and R 2 It is H, C2-C6 alkyl, halogen, or hydroxyl. In some embodiments, R 1 R 2 and R 3 At least one of them is H. In some implementations, R 1 R 2 and R 3 At least one of them is not H.

[0152] In the other case, the compound of formula (I) is a compound of formula (If) or (Ig):

[0153]

[0154] Or its salts, wherein A, Z, B, R 1 R 2 R 3 G1, G2 and G3 are as defined for formula (I) or any variation or implementation thereof.

[0155] In the other case, the compound of formula (I) is a compound of formula (Ih), (Ii), (Ij), or (Ik):

[0156]

[0157]

[0158] Or its salts, wherein A, Z, B, R1 R 2 R 3 G1, G2 and G3 are as defined for formula (I) or any variation or implementation thereof.

[0159] In some embodiments of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), Z is a bond. In some embodiments, Z is a C1-C6 alkyl group. 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 It is H, C1-C6 alkyl, or cycloalkyl. In some of these embodiments, Z is -N(R) 9 )-, where R 9 It is H, a C1-C6 alkyl, or a 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 Each is a C1-C6 alkyl group. 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-.

[0160] In some embodiments of formulas (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 a 5- or 6-membered heteroaryl containing at least one cyclic N atom, wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted with one or more R atoms. 10 Substituent substitution; wherein each R 10Independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclic alkyl and -C(O)OR a In some implementations, each R 10 Independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5- to 6-membered heterocyclic alkyl and -C(O)OR a In some implementations, each R 10 Independently selected from the group consisting of: unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted with one or more groups selected from D, halogen, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl, unsubstituted C2-C6 alkenyl, and C2-C6 alkenyl substituted with one or more groups selected from D, halogen, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl. -C6 alkenyl, unsubstituted C2-C6 ynyl, C2-C6 ynyl substituted with one or more groups selected from D, halogen, -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, unsubstituted 5- to 6-membered heterocyclic alkyl, 5- to 6-membered heterocyclic alkyl substituted with one or more C1-C6 alkyl and -C(O)OR a , where R a It is H or C1-C6 alkyl.

[0161] In some embodiments of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is an unsubstituted C2 ynyl group or a substituted C2 ynyl group. In some embodiments, A is an unsubstituted C2 ynyl group, such that A is acetylene. In other embodiments, A is a C2 ynyl group substituted with a C1-C6 alkyl or a C3-C8 cycloalkyl group.

[0162] In some embodiments of formulas (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 a 5- or 6-membered heteroaryl containing at least one cyclic N atom, wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted with one or more R atoms. 10 Substituent substitution.

[0163] In some embodiments of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is a phenyl group that 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 ynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and -C(O)OR a , where R a It is H or a C1-C6 alkyl group. In some embodiments, A is an unsubstituted phenyl group. In some embodiments, A is an unsubstituted phenyl group and Z is a bond, C1-C6 alkyl group, -N(R) 9 )-、-R x O-、-OR y -and-R z S-, where R x R y and R z Each is a C1-C6 alkyl group. In some embodiments, A is a phenyl group, wherein the phenyl group is substituted with one or more substituents selected from the group consisting of: unsubstituted C1-C6 alkyl groups, C1-C6 alkyl groups substituted with one or more groups selected from D, halogens, -C(O)OH, -C(O)OC1-C6 alkyl groups, -OH, -OC1-C6 alkyl groups and C3-C8 cycloalkyl groups, unsubstituted C2-C6 alkenyl groups, and C1-C6 alkyl groups substituted with one or more groups selected from D, halogens, -C(O)OH, -C(O)OC1-C6 alkyl groups, -OH, -OC1-C6 alkyl groups and C3-C8 cycloalkyl groups. C2-C6 alkenyl groups substituted with C8 cycloalkyl groups, unsubstituted C2-C6 alkynyl groups, C2-C6 alkynyl groups substituted with one or more groups selected from D, halogens, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl groups, unsubstituted C3-C8 cycloalkyl groups, C3-C8 cycloalkyl groups substituted with one or more C1-C6 alkyl groups, unsubstituted 5- to 6-membered heterocyclic alkyl groups, 5- to 6-membered heterocyclic alkyl groups substituted with one or more C1-C6 alkyl groups and -C(O)OR a , where R aIt is H or a C1-C6 alkyl group. In some embodiments, A is a phenyl group substituted with one or more substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, A is a phenyl group substituted with a C1-C6 alkyl group, wherein the C1-C6 alkyl group is not further substituted. In some embodiments, A is a phenyl group substituted with a C1-C6 alkyl group, wherein the C1-C6 alkyl group is not further substituted with a halogen. In some embodiments, A is a phenyl group substituted with a methyl group.

[0164] In some embodiments of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is a 5- or 6-membered heteroaryl group containing at least one cyclic N atom. In some embodiments, the 5- or 6-membered heteroaryl group 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 ynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and -C(O)OR. a , where R a It is an H or C1-C6 alkyl group. In some embodiments, the C1-C6 alkyl group, the C2-C6 alkenyl group, the C2-C6 ynyl group, the cycloalkyl group, or the heterocycloalkyl group is substituted with one or more groups selected from: halogen, -OR a -OC(O)R a , cycloalkyl, heterocycloalkyl, wherein R aIt is H or a C1-C6 alkyl group. In some embodiments, A is a 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered heteroaryl group is substituted with one or more substituents selected from the group consisting of: unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted with one or more groups selected from D, halogens, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl, unsubstituted C2-C6 alkenyl, and C1-C6 alkyl substituted with one or more groups selected from D, halogens, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 C2-C6 alkenyl groups substituted with alkyl and C3-C8 cycloalkyl groups, unsubstituted C2-C6 ynyl groups, C2-C6 ynyl groups substituted with one or more groups selected from D, halogens, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl and C3-C8 cycloalkyl groups, unsubstituted C3-C8 cycloalkyl groups, C3-C8 cycloalkyl groups substituted with one or more C1-C6 alkyl groups, unsubstituted 5- to 6-membered heterocyclic alkyl groups, 5- to 6-membered heterocyclic alkyl groups substituted with one or more C1-C6 alkyl groups and -C(O)OR a , where R a It is H or C1-C6 alkyl.

[0165] In some embodiments of formulas (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 has been modified by one or more R... 10 Substituent substitution, wherein each R 10 Independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and -C(O)OR a , where R a It is an H or C1-C6 alkyl group. In some embodiments, the C1-C6 alkyl group, the C2-C6 alkenyl group, the C2-C6 ynyl group, the cycloalkyl group, or the heterocycloalkyl group is substituted with one or more groups selected from: halogen, -OR a -OC(O)R a , cycloalkyl, heterocycloalkyl, wherein R aIt is an H or C1-C6 alkyl group. In some embodiments of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is an oxadiazolyl or isoxazolyl group, each of which is unsubstituted or derived from one or more R groups. 10 Substituent substitution. In some embodiments, A is phenyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, tetrazolyl, triazolyl, thiazolyl, pyrimidinyl, pyridinyl, pyrazinyl, and pyridazinyl, each substituted with one or more substituents selected from the group consisting of: unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted with one or more groups selected from D, halogen, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl, and C3-C8 cycloalkyl, unsubstituted C2-C6 alkenyl, and C2-C6 alkenyl substituted with one or more groups selected from D, halogen, -C(O)OH, -C(O)OC1- C2-C6 alkenyl groups substituted with C6 alkyl, -OH, -OC1-C6 alkyl, and C3-C8 cycloalkyl groups; unsubstituted C2-C6 alkynyl groups; C2-C6 alkynyl groups substituted with one or more groups selected from D, halogens, -C(O)OH, -C(O)OC1-C6 alkyl, -OH, -OC1-C6 alkyl, and C3-C8 cycloalkyl groups; unsubstituted C3-C8 cycloalkyl groups; C3-C8 cycloalkyl groups substituted with one or more C1-C6 alkyl groups; unsubstituted 5- to 6-membered heterocyclic alkyl groups; 5- to 6-membered heterocyclic alkyl groups substituted with one or more C1-C6 alkyl groups; and -C(O)OR a , where R a It is H or C1-C6 alkyl.

[0166] In some implementations of equations (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is selected from the group consisting of:

[0167] and Each of them has not been replaced or has been replaced by one or more R 10 Substituent substitution. In some implementations, R 10 Each C1-C6 alkyl group is independently unsubstituted or independently selected from -OR k and -OC(O)R m The group consists of substituents, where R is substituted. k and R m Each is independently an H or C1-C6 alkyl group. In some embodiments, each R 10Independently selected from the group consisting of: -C(O)OCH3, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, cyclobutyl, and oxecyclobutyl, wherein R 10 Each methyl, ethyl, and isopropyl group is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OCH3, -OH, and -OC(O)CH3. In some embodiments, R 10 It is either methyl or -CD3.

[0168] In some embodiments of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is an oxadiazolyl group, which is unsubstituted or substituted with a substituent selected from the group consisting of: methyl, methyl substituted with -OCH3, -OH, or -OC(O)CH3, ethyl, ethyl substituted with -OCH3, -OH, -C(O)OCH3, or -OC(O)CH3, vinyl, isopropyl, isopropyl substituted with -OCH3, -OH, or -OC(O)CH3, difluoromethyl, cyclopropyl, cyclobutyl, oxadiazolyl, acetyl, and -C(O)OCH3. In some embodiments, A is an isoxadiazolyl group, 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 an isoxazolyl group, which is either unsubstituted or substituted with a substituent selected from the group consisting of methyl, ethyl, and difluoromethyl.

[0169] In some implementations of equations (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is selected from the group consisting of:

[0170] and Each R 13 Independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, and -C(O)OR. a And R a It is an H or C1-C6 alkyl group. In some embodiments, the C1-C6 alkyl group, the C2-C6 alkenyl group, the C2-C6 ynyl group, the cycloalkyl group, or the heterocycloalkyl group is substituted with one or more groups selected from: halogen, -OR a -OC(O)R a -C(O)OR a -C(O)R a , cycloalkyl, heterocycloalkyl, wherein R aIt is an H or C1-C6 alkyl group. In some embodiments, each R 13 Independently selected from the group consisting of: H, -C(O)OCH3, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, cyclobutyl, and oxecyclobutyl, wherein R 13 Each methyl, ethyl, and isopropyl group is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OCH3, -OH, and -OC(O)CH3. In some embodiments, R 13 It is either methyl or -CD3.

[0171] In some embodiments of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is an unsubstituted or methyl-substituted phenyl. In some embodiments, A is an unsubstituted or methyl-substituted pyridine. In some embodiments, A is an unsubstituted or methyl-substituted pyrazine. In some embodiments, A is an unsubstituted or methyl-substituted pyrimidine. In some embodiments, A is an unsubstituted or methyl-substituted pyridazine. In some embodiments, A is an unsubstituted or methyl-substituted pyrazole. In some embodiments, A is an unsubstituted or methyl-substituted thiazole. In some embodiments, A is an unsubstituted or methyl-substituted oxazole. In some embodiments, A is an unsubstituted or methyl-substituted tetrazolium. In some embodiments, A is an unsubstituted or methyl-substituted triazole. In some embodiments, A is an isoxazole substituted with methyl, ethyl, or CF2. In some embodiments, A is an oxadiazole substituted with methyl, ethyl, CF2, CD3, cyclopropyl, isopropyl, cyclobutyl, oxadiane, or C(O)OCH3, each optionally further substituted. In some embodiments, A is a methyl-substituted oxadiazole, wherein the methyl group is optionally further substituted with methoxy, OH, or -OC(O)CH3. In some embodiments, A is an ethyl-substituted oxadiazole, wherein the ethyl group is optionally further substituted with methoxy, OH, or -OC(O)CH3. In some embodiments, A is an isopropyl-substituted oxadiazole, wherein the isopropyl group is optionally further substituted with OH or -OC(O)CH3. In some embodiments, A is an oxadiazole substituted with methyl, ethyl, CD3, CF2, or cyclopropyl. In some embodiments, A is an ethyl or CF2-substituted oxadiazole.

[0172] In some embodiments of formulas (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, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl of B is unsubstituted or has one or more R... 11 Substituent substitution; each R 11 Independently selected from the group consisting of: heterocyclic alkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, C1-C6 alkyl-OH, halogen, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f , where R 11 Each heterocyclic alkyl and heteroaryl group is unsubstituted or substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 alkyl-OH, -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 It is independently H or C1-C6 alkyl.

[0173] In some embodiments of formulas (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- to 12-membered heterocyclic alkyl and 5- to 10-membered heteroaryl, wherein B is a C1-C6 alkyl, a C3-C8 cycloalkyl, or a C6-C 12 The aryl group, the 3- to 12-membered heterocyclic alkyl group, and the 5- to 10-membered heteroaryl group are each unsubstituted or have one or more R groups. 11 Substituent substitution. In some embodiments, B is unsubstituted or substituted with one or more R groups. 11 Substituent substitution; wherein each R 11Independently selected from the group consisting of: substituted or unsubstituted 3- to 12-membered heterocyclic alkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C6-C8 cycloalkyl groups. 12 aryl, unsubstituted C1-C6 alkyl, via one or more R 12 Substituents: C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C2-C6 alkynyl groups, halogens, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f In some implementations, B is not replaced or is processed by one or more R... 11 Substituent substitution; wherein each R 11 Independently selected from the group consisting of: 3- to 12-membered heterocyclic alkyl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl, C6-C 12 Aryl, C1-C6 alkyl, halogen, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f , where R 11 Each heterocyclic alkyl and heteroaryl group 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 It is independently H or C1-C6 alkyl. In some embodiments, R 11 Each heterocyclic alkyl or heteroaryl group comprises one, two, three, four, or five heteroatoms selected from the group consisting of N, O, and S. In some embodiments of formula (I) or any variation thereof, B is unsubstituted or derived from one or more R groups. 11 A phenyl group substituted with a substituent. In some embodiments, B is unsubstituted or substituted with one or more R groups. 11 A 5- to 6-membered heterocyclic alkyl group substituted with a substituent. In other embodiments, B is unsubstituted or substituted with one or more R groups. 11Substituent-substituted 5- to 6-membered heteroaryl groups.

[0174] In some embodiments of formulas (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 substituted or unsubstituted. In some embodiments, the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted with one or more R groups. 11 Substituent substitution; each R 11 Independently selected from the group consisting of: heterocyclic alkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, C1-C6 alkyl-OH, halogen, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f , where R 11 Each heterocyclic alkyl and heteroaryl group 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 It is independently H or C1-C6 alkyl.

[0175] In some embodiments of formulas (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- to 10-membered aryl (e.g., 6- to 9-membered aryl), 4- to 6-membered heterocyclic alkyl containing at least one cyclic N or O atom, 5- or 6-membered monocyclic heteroaryl containing at least one cyclic N atom, and 8- or 9-membered bicyclic heteroaryl containing at least one cyclic N atom, each substituted or unsubstituted. In some embodiments, the C1-C4 alkyl, the C3-C5 cycloalkyl, the 6- to 10-membered aryl (e.g., 6- to 9-membered aryl), the 4- to 6-membered heterocyclic alkyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- or 9-membered bicyclic heteroaryl is unsubstituted or substituted with one or more R... 11 Substituent substitution; each R11 Independently selected from the group consisting of: heterocyclic alkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, C1-C6 alkyl-OH, halogen, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f , where R 11 Each heterocyclic alkyl and heteroaryl group 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 It is independently H or C1-C6 alkyl.

[0176] In some embodiments of formulas (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, dihydroindenyl, azacyclobutyl, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyrimidinyl, pyridinyl, dihydroindenyl, pyrrolopyrazolyl, and benzimidazolyl, each of which is unsubstituted or has been modified by one or more R... 11 Substituent substitution; each R 11 Independently selected from the group consisting of: heterocyclic alkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, C1-C6 alkyl-OH, halogen, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f , where R 11 Each heterocyclic alkyl and heteroaryl group 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)NRq R r And each R b R c R d R e R f R n R p R q and R r Independently, it is an H or C1-C6 alkyl group. In some embodiments, each R 11 Independently selected from the group consisting of: methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, oxo, -C(O)CH3, -C(O)OtBu, -OCH3, -OH, -NH2, -Cl, oxadiazolyl, oxadiazolyl, and aziridine, wherein R 11 Each of the oxadiazolyl and azacyclobutyl groups is either unsubstituted or substituted by one or more substituents selected from the group consisting of:

[0177] Ethyl, -C(O)CH3, -C(O)OtBu, -C(O)OCH3, -C(O)NHCH3, -C(O)NH2 and -OCH3.

[0178] In some implementations of equations (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), B is via -OR b Substituted C1-C6 alkyl groups, wherein R b It is an H or C1-C6 alkyl group. In some embodiments, B is optionally -OR b Substituted C1-C6 alkyl groups, where Z is -O- or -N(R) 9 In some embodiments, B is a C1-C6 alkyl group substituted with -OH. In some embodiments, B is a C1-C6 alkyl group substituted with -OH, and Z is -O-. In some embodiments, B is a C1-C6 alkyl group substituted with -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 optionally substituted with -OH.

[0179] In some embodiments of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), B is methyl, pyrazolyl, oxazolyl, tetrazolyl, isoxazolyl, thiazolyl, imidazole, or pyridinyl, each of which is unsubstituted or has been modified by one or more R groups. 11 Substituent substitution; each R 11Independently selected from the group consisting of: heterocyclic alkyl, heteroaryl, halogen, alkyl, alkyl-OH, cycloalkyl, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f And each R b R c R d R e and R f It is independently H or C1-C6 alkyl.

[0180] In some embodiments of formulas (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 with one or more C1-C6 alkyl substituents.

[0181] In some implementations of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), B is selected from the group consisting of:

[0182]

[0183] and Each of them has not been replaced or has been replaced by one or more R 11 Substituent substitution; each R 11 Independently selected from the group consisting of: heterocyclic alkyl, heteroaryl, halogen, alkyl, -OH substituted alkyl, cycloalkyl, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f And each R b R c R d R e and R f It is independently H or C1-C6 alkyl. In some embodiments, B is via one or more R... 11 Substituent substitution, wherein each R 11Independently selected from the group consisting of: heterocyclic alkyl; heteroaryl; halogen; unsubstituted C1-C6 alkyl; unsubstituted C2-C6 alkenyl; C1-C6 alkyl substituted with halogen, -OH, -OC1-C6 alkyl, -C(O)OH or -C(O)OC1-C6 alkyl; C3-C8 cycloalkyl; -OR b ;-C(O)R c ;-C(O)OR d ; Oxygenation; and -NR e R f , where each R b R c R d R e and R f It is independently H or C1-C6 alkyl.

[0184] In some implementations of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), B is selected from the group consisting of:

[0185]

[0186] and Each R 14 Independently selected from the group consisting of: hydrogen, heterocyclic alkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, C1-C6 alkyl substituted with -OH, halogen, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f Each heterocyclic alkyl and heteroaryl group 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 It is independently H or C1-C6 alkyl.

[0187] In some embodiments of formulas (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 an unsubstituted or optionally substituted methyl, -C(O)CH3, -C(O)OCH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3, or oxosubstituted azacyclobutane. In some embodiments, B is an oxosubstituted benzimidazole. In some embodiments, B is cyclobutyl. In some embodiments, B is cyclopentyl. In some embodiments, B is cyclopropyl. In some embodiments, B is an unsubstituted or optionally methoxysubstituted ethyl. In some embodiments, B is an imidazole substituted with two methyl groups. In some embodiments, B is a dihydroindene substituted with an oxadiazole, which is further substituted with an ethyl group. In some embodiments, B is an unsubstituted or optionally methoxy-substituted isobutyl group. In some embodiments, B is an unsubstituted or optionally OH-substituted isopropyl group. In some embodiments, B is an isoxazole substituted with one or two methyl or isopropyl groups. In some embodiments, B is a methyl-substituted isoxazole group. In some embodiments, B is an unsubstituted or optionally substituted methyl group with CF2, cyclopropyl, methoxy, oxetane, or azirbutane, wherein the azirbutane 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 a cyclopropyl-substituted methyl group or a methyl-substituted cyclopropyl group. In some embodiments, B is an unsubstituted or optionally substituted morpholine with -C(O)CH3 or -C(O)OC(CH3)3. In some embodiments, B is a methyl-substituted oxadiazole. In some embodiments, B is an oxazole substituted with one or two methyl or cyclopropyl groups. In some embodiments, B is an oxacyclobutane. In some embodiments, B is a methyl-substituted piperazine. In some embodiments, B is an unsubstituted or optionally substituted piperidine with one or more groups selected from methyl, oxo, -C(O)CH3, and -C(O)OC(CH3)3. In some embodiments, B is an unsubstituted or optionally substituted pyrazine with one or two methyl groups. In some embodiments, B is an unsubstituted or optionally substituted pyrazole with one or more groups selected from methyl, ethyl, and CF3 groups. In some embodiments, B is a pyrazole substituted with one or two methyl groups. In some embodiments, B is an unsubstituted or optionally methyl-substituted pyridazine. In some embodiments, B is an unsubstituted or optionally substituted pyridine with an amino, hydroxyl, -NH2, -OH or one or more methyl groups.In some embodiments, B is a methyl-substituted pyridine. In some embodiments, B is an unsubstituted or optionally methyl-substituted pyrimidine. In some embodiments, B is an unsubstituted or optionally methyl, oxo, -C(O)CH3, or -C(O)OC(CH3)3-substituted pyrrolidine. In some embodiments, B is a pyrrolopyrazole. In some embodiments, B is tert-butyl. In some embodiments, B is tetrahydrofuran. In some embodiments, B is a methyl-substituted tetraazole. In some embodiments, B is an unsubstituted or optionally chloro- or methyl-substituted thiazole. In some embodiments, B is a triazole substituted with one or more groups selected from methyl and ethyl groups.

[0188] In some embodiments of any of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is a 5-membered heteroaryl group comprising at least one cyclic N atom, wherein the 5-membered heteroaryl group is unsubstituted or via one or more R atoms as defined herein. 10 The substituent is substituted, and B is selected from the group consisting of: H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is an unsubstituted or substituted pyrazole, thiazole, oxazole, tetraazole, triazole, isoxazole, or oxadiazole; Z is a bond, -NR 9 -、-O-、-R x O- or -OR y -, where R 9 It is H, C1-C6 alkyl or cycloalkyl, and R x and R y Each is independently a C1-C6 alkyl group; and B is a C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or has one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is an unsubstituted or substituted pyrazole, thiazole, oxazole, tetraazole, triazole, isoxazole, or oxadiazole, and Z is a bond, -NR 9 -、or -O-、-R x O- or -OR y -, where R 9 It is H, C1-C6 alkyl or cycloalkyl, and R x and R yEach of them is independently a C1-C6 alkyl group; and B is an unsubstituted or substituted methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, dihydroindyl, aziridine, oxaziridine, pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyrimidinyl, pyridinyl, dihydroindyl, pyrrolopyrazolyl, and benzimidazolyl.

[0189] In some embodiments of any of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is selected from pyrazole, thiazole, oxazole, tetrazolium, triazole, isoxazole, and oxadiazole, each of which 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 , where R a H is an H or C1-C6 alkyl group; Z is a bond, -NH-, -NCH3-, or -O-, -CH3O-, or -OCH3-; and B is selected from methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, dihydroindyl, aziridine, oxaziridine, pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazine, pyrimidinyl, pyridinyl, dihydroindyl, pyrrolopyrazolyl, and benzimidazolyl, each of which is unsubstituted or substituted by one or more groups selected from the following: heterocyclic alkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, halogen, fluoroalkyl, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f , where each R b R c R d R e and R f Independently, it is an H or C1-C6 alkyl group. In some of these embodiments, the C1-C6 alkyl group, the C2-C6 alkenyl group, the C2-C6 ynyl group, the cycloalkyl group, or the heterocycloalkyl group of A is substituted with one or more groups selected from: halogen, -OR a -OC(O)R a , cycloalkyl, heterocycloalkyl, wherein R aIt is H or C1-C6 alkyl.

[0190] In some embodiments of any of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is an oxadiazole, optionally composed of a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or -C(O)OR a Replace, where R a It is H or C1-C6 alkyl; Z is a bond, -NR 9 -、-O-、-R x O- or -OR y -, where R 9 It is H, C1-C6 alkyl or cycloalkyl, and R x and R y Each is independently a C1-C6 alkyl group; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or has one or more R groups as defined herein. 11 Substituent substitution. In some embodiments of any of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is a C1-C6 alkyl-substituted oxadiazole, optionally further substituted with a halogen, -OR a or -C(O)OR a Replace, where R a It is H or C1-C6 alkyl; Z is a bond, -NR 9 - or -O-, where R 9 H is a C1-C6 alkyl or cycloalkyl group; and B is cyclopropyl, cyclobutyl, cyclopentyl, phenyl, dihydroindenyl, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyrimidinyl, pyridinyl, dihydroindenyl, pyrrolopyrazolyl, or benzimidazolyl, each of which is unsubstituted or has been modified by one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is a C1-C6 alkyl-substituted oxadiazole, optionally further substituted with halogen, -OR a or -C(O)OR a Replace, where R aIt is H or C1-C6 alkyl; Z is a bond, -NH-, -O-, -OCH2- or -CH2O-, where R 9 H is a C1-C6 alkyl or cycloalkyl; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl of B is unsubstituted or has one or more Rs as defined herein. 11 Substituent substitution. In some embodiments, A is an oxadiazole substituted with methyl, -CD3, -CF2, ethyl, isopropyl, cyclopropyl, or cyclobutyl groups; Z is a bond, -NR 9 -, -O-, -OCH2- or -CH2O-, where R 9 H is a C1-C6 alkyl or cycloalkyl; and B is optionally derived from one or more C1-C6 alkyl, cycloalkyl, OR b and -NR e R f The aryl or heteroaryl group substituted with the group, wherein R b R e and R f Each is independently H or a C1-C6 alkyl group. 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 a C1-C6 alkyl or cycloalkyl group, each of which is unsubstituted or halogenated. In some embodiments, A is an oxadiazole substituted with methyl, -CD3, -CF2, ethyl, -CH2OCH3, isopropyl, cyclopropyl, or cyclobutyl; Z is -O-, -OCH2-, or -CH2O-; and B is a C1-C6 alkyl, cycloalkyl, or heterocycloalkyl group, wherein the C1-C6 alkyl group is unsubstituted or halogenated. 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 optionally substituted with one or more alkyl, cycloalkyl, or OR groups selected from C1-C6 alkyl groups. b and -NR e R f The aryl or heteroaryl group substituted with the group, wherein R 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 an aryl or heteroaryl group optionally substituted with one or more groups selected from C1-C6 alkyl, C1-C6 cycloalkyl, OH, and -NH2. 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 optionally substituted with one or more groups selected from C1-C6 alkyl, cycloalkyl, OR b and -NR e R f The aryl or heteroaryl group substituted with the group, wherein R b R e and R f Each is independently an H or C1-C6 alkyl group. 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;

[0191] CD3; CF2; phenyl; 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-substituted azacyclobutane; oxo-substituted benzimidazole; cyclobutyl; cyclopentyl; cyclopropyl; unsubstituted or optionally methoxy-substituted ethyl; imidazole substituted with two methyl groups; dihydroindene substituted with oxadiazole, wherein the oxadiazole is further substituted with ethyl; unsubstituted or optionally methoxy-substituted isobutyl; Isopropyl groups substituted or optionally OH-substituted; isoxazoles substituted with one or two methyl groups or isopropyl groups; methyl-substituted isoxazoles; unsubstituted or optionally substituted methyl groups with CF2, cyclopropyl, methoxy, oxetane, or azirbutane, wherein the azirbutane is further substituted with -C(O)CH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3, or -C(O)OCH3; cyclopropyl-substituted methyl groups or methyl-substituted cyclopropyl groups; unsubstituted or optionally substituted methyl groups with -C(O)C Morpholine substituted with H3 or -C(O)OC(CH3)3; methyl-substituted oxadiazole; oxazole substituted with one or two methyl or cyclopropyl groups; oxacyclobutane; methyl-substituted piperazine; unsubstituted piperidine or optionally substituted with one or more groups selected from methyl, oxo, -C(O)CH3 and -C(O)OC(CH3)3; unsubstituted pyrazine or optionally substituted with one or two methyl groups; unsubstituted pyrazole or optionally substituted with one or more groups selected from methyl, ethyl and CF3 groups; pyrazole substituted with one or two methyl groups; Pyridazines that are substituted or optionally substituted with methyl; pyridines that are unsubstituted or optionally substituted with amino, hydroxyl, -NH2, -OH or one or more methyl groups; pyridines that are substituted with methyl; pyrimidines that are unsubstituted or optionally substituted with methyl; pyrrolidines that are unsubstituted or optionally substituted with methyl, oxo, -C(O)CH3 or -C(O)OC(CH3)3; pyrrolopyrazoles; tert-butyl; tetrahydrofurans; tetrazoliums that are substituted with methyl; thiazoles that are unsubstituted or optionally substituted with chloro or methyl groups; or triazoles substituted with one or more groups selected from methyl and ethyl groups.

[0192] In some embodiments, A is a methyl-substituted oxadiazole, wherein the methyl group may optionally be further substituted with a methoxy group, OH, or -OC(O)CH3; Z is a bond, -NR 9 - or -O-, where R 9 H is a C1-C6 alkyl or cycloalkyl; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl of B is unsubstituted or has one or more Rs as defined herein. 11Substituent substitution. In some embodiments, A is a methyl-substituted oxadiazole; Z is a bond, -NH- or -O-; and B is a C1-C6 alkyl, cycloalkyl, aryl, or heteroaryl group, wherein the C1-C6 alkyl, cycloalkyl, aryl, or heterocycloalkyl group is unsubstituted or substituted with one or more groups selected as defined herein. In some embodiments, A is an ethyl-substituted oxadiazole, wherein the ethyl group is optionally further substituted with a methoxy, OH, or -OC(O)CH3 group; Z is a bond, -NH- or -O-; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is an ethyl-substituted oxadiazole; Z is a bond, and B is an unsubstituted 5- to 6-membered heteroaryl group or a group substituted with one or more R groups as defined herein. 11 The substituent is a 5- to 6-membered heteroaryl group. In some embodiments, A is an oxadiazole substituted with -CF2, Z is a bond, -NH- or -O-, and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is an oxadiazole substituted with -CF2, Z is a bond, and B is an unsubstituted 5- to 6-membered heteroaryl group or substituted with one or more R groups as defined herein. 11 The substituent is a 5- to 6-membered heteroaryl group. In some embodiments, A is an isopropyl-substituted oxadiazole, Z is a bond, -NH- or -O-; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is an isopropyl-substituted oxadiazole, Z is a bond, and B is an unsubstituted 5- to 6-membered heteroaryl group or a group substituted with one or more R groups as defined herein. 11 The substituent is a 5- to 6-membered heteroaryl group. In some embodiments, A is a cyclopropyl-substituted oxadiazole, Z is a bond, -NH- or -O-; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is substituted with -C(O)OR a Substituted oxadiazole, in which R aIt is H or C1-C6 alkyl; Z is a bond, -NH- or -O-; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl of B is unsubstituted or has one or more Rs as defined herein. 11 Substituent substitution. In some embodiments, A is an oxadiazole substituted with an oxadiazole; Z is a bond, -NH- or -O-; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is a cyclobutyl-substituted oxadiazole; Z is a bond, -NH- or -O-; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution. 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 group substituted with one or more C1-C6 alkyl groups.

[0193] In some embodiments of any of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is optionally composed of a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or -C(O)OR. a Substituted oxazoles, in which R a It is H or C1-C6 alkyl; Z is a bond, -NR 9 -、-O-、-R x O- or -OR y -, where R 9 It is H, C1-C6 alkyl or cycloalkyl, and R x and R y Each is independently a C1-C6 alkyl group; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or has one or more R groups as defined herein. 11Substituent substitution. In some embodiments of any of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is optionally composed of a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or -C(O)OR. a Substituted oxazoles, in which R a H is an H or C1-C6 alkyl group; Z is a bond, -O- or -NH-; and B is cyclopropyl, cyclobutyl, cyclopentyl, phenyl, dihydroindenyl, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyrimidinyl, pyridinyl, dihydroindenyl, pyrrolopyrazolyl, or benzimidazolyl, each of which is unsubstituted or has been modified by one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is an oxazole substituted with methyl, ethyl, CF2, or isopropyl; Z is a bond, -NH-, or -O-; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution. In some embodiments of any of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is optionally composed of a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or -C(O)OR. a Substituted isoxazoles, in which R a It is H or C1-C6 alkyl; Z is a bond, -NR 9 - or -O-, where R 9 H is a C1-C6 alkyl or cycloalkyl; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl of B is unsubstituted or has one or more Rs as defined herein. 11Substituent substitution. In some embodiments of any of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is optionally composed of a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or -C(O)OR. a Substituted isoxazoles, in which R a H is an H or C1-C6 alkyl group; Z is a bond, -O- or -NH-; and B is cyclopropyl, cyclobutyl, cyclopentyl, phenyl, dihydroindyl, aziridine, oxaziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridinyl, pyrimidinyl, pyridinyl, dihydroindyl, pyrrolopyrazolyl or benzimidazolyl, each of which is unsubstituted or substituted with one or more C1-C6 alkyl groups. In some embodiments, A is an isoxazole substituted with methyl, ethyl, CF2, or isopropyl; Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O-; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is a methyl-substituted tetrazolium; Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O-; and B is H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution. In some embodiments of any of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is a methyl-substituted tetrazolium; Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O-; and B is cyclopropyl, cyclobutyl, cyclopentyl, phenyl, dihydroindole, aziridine, oxaziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridinyl, pyrimidinyl, dihydroindole, pyrrolopyrazolyl, or benzimidazolyl, each of which is unsubstituted or substituted with one or more C1-C6 alkyl groups.

[0194] In some embodiments of any of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is a 6-membered heteroaryl group comprising at least one cyclic N atom, wherein the 6-membered heteroaryl group is unsubstituted or via one or more R atoms as defined herein. 10 The substituent is substituted, and B is selected from the group consisting of: H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is an unsubstituted or substituted pyridine, pyrazine, pyrimidine, or pyridazine; Z is a bond, -NR 9 -、-O-、-R x O- or -OR y -, where R 9 It is H, C1-C6 alkyl or cycloalkyl, and R x and R y Each is independently a C1-C6 alkyl group; and B is a C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or has one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is an unsubstituted or substituted pyridine, pyrazine, pyrimidine, or pyridazine; Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O-; and B is a C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with the following: A The compounds include methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, dihydroindyl, azacyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyrimidinyl, pyridinyl, dihydroindyl, pyrrolopyrazolyl, and benzimidazolyl. In some embodiments, A is an unsubstituted or substituted pyridine, pyrazine, pyrimidinyl, or pyrazine; Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O-; and B is methyl.

[0195] CD3; CF2; phenyl; 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-substituted azacyclobutane; oxo-substituted benzimidazole; cyclobutyl; cyclopentyl; cyclopropyl; unsubstituted or optionally methoxy-substituted ethyl; imidazole substituted with two methyl groups; dihydroindene substituted with oxadiazole, wherein the oxadiazole is further substituted with ethyl; unsubstituted or optionally methoxy-substituted isobutyl; Isopropyl groups substituted or optionally OH-substituted; isoxazoles substituted with one or two methyl groups or isopropyl groups; methyl-substituted isoxazoles; unsubstituted or optionally substituted methyl groups with CF2, cyclopropyl, methoxy, oxetane, or azirbutane, wherein the azirbutane is further substituted with -C(O)CH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3, or -C(O)OCH3; cyclopropyl-substituted methyl groups or methyl-substituted cyclopropyl groups; unsubstituted or optionally substituted methyl groups with -C(O)C Morpholine substituted with H3 or -C(O)OC(CH3)3; methyl-substituted oxadiazole; oxazole substituted with one or two methyl or cyclopropyl groups; oxacyclobutane; methyl-substituted piperazine; unsubstituted piperidine or optionally substituted with one or more groups selected from methyl, oxo, -C(O)CH3 and -C(O)OC(CH3)3; unsubstituted pyrazine or optionally substituted with one or two methyl groups; unsubstituted pyrazole or optionally substituted with one or more groups selected from methyl, ethyl and CF3 groups; pyrazole substituted with one or two methyl groups; Pyridazines that are substituted or optionally substituted with methyl; pyridines that are unsubstituted or optionally substituted with amino, hydroxyl, -NH2, -OH or one or more methyl groups; pyridines that are substituted with methyl; pyrimidines that are unsubstituted or optionally substituted with methyl; pyrrolidines that are unsubstituted or optionally substituted with methyl, oxo, -C(O)CH3 or -C(O)OC(CH3)3; pyrrolopyrazoles; tert-butyl; tetrahydrofurans; tetrazoliums that are substituted with methyl; thiazoles that are unsubstituted or optionally substituted with chloro or methyl groups; or triazoles substituted with one or more groups selected from methyl and ethyl groups.

[0196] In some embodiments, A is an optionally methyl-substituted phenyl group; Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O-; and B is a C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or has one or more R groups as defined herein. 11Substituent substitution. In some embodiments, A is a pyridyl group optionally substituted with one or two methyl groups; Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O-; and B is a C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is a pyrimidinyl group optionally substituted with a methyl group; Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O-; and B is a C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution. In some embodiments, A is a pyrimidinyl group optionally substituted with a methyl group; Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O-; and B is optionally substituted with one or more R groups as defined herein. 11 Substituent-substituted aryl or heteroaryl groups. In some embodiments, A is a pyrimidinyl group optionally substituted with a methyl group; Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O; and B is an aryl or heteroaryl group optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl, halogen, -OR b -C(O)R c -C(O)OR d Oxygenation and -NR e R f , where R b R c R d R e and R f Independently, it is an H or C1-C6 alkyl group. In some embodiments, A is an unsubstituted or methyl-substituted pyrimidinyl group; Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O; and B is a methyl-substituted pyrazolyl group. In some embodiments, A is optionally methyl-substituted pyrazinyl group; Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O; and B is a C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11Substituent substitution. In some embodiments, A is optionally methyl-substituted pyridazinyl; Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O; and B is a C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group of B is unsubstituted or substituted with one or more R groups as defined herein. 11 Substituent substitution.

[0197] In some embodiments of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), A is an unsubstituted or methyl-substituted phenyl; an unsubstituted or methyl-substituted pyridine; an unsubstituted or methyl-substituted pyrazine; an unsubstituted or methyl-substituted pyrimidine; an unsubstituted or methyl-substituted pyridazine; an unsubstituted or methyl-substituted pyrazole; an unsubstituted or methyl-substituted thiazole; an unsubstituted or methyl-substituted oxazole; an unsubstituted or methyl-substituted tetrazolium; an unsubstituted or methyl-substituted triazole; an isoxazole substituted with methyl, ethyl, or CF2; or an isoxazole substituted with methyl, ethyl, CF2, CD3, or cyclic phenyl groups. Oxadiazoles substituted with propyl, isopropyl, cyclobutyl, oxadiane, or C(O)OCH3, each optionally further substituted; methyl-substituted oxadiazoles, wherein the methyl group is optionally further substituted with methoxy, OH, or -OC(O)CH3; ethyl-substituted oxadiazoles, wherein the ethyl group is optionally further substituted with methoxy, OH, or -OC(O)CH3; isopropyl-substituted oxadiazoles, wherein the isopropyl group is optionally further substituted with OH or -OC(O)CH3; methyl, ethyl, CD3, CF2, or cyclopropyl-substituted oxadiazoles; or ethyl or CF2-substituted oxadiazoles, where Z is a bond, -NH-, -N(CH3)-, -O-, -OCH2-, or -CH2O-, and B is H; methyl; CD 3; CF2; phenyl; 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-substituted azacyclobutane; oxo-substituted benzimidazole; cyclobutyl; cyclopentyl; cyclopropyl; unsubstituted or optionally methoxy-substituted ethyl; imidazole substituted with two methyl groups; dihydroindene substituted with oxadiazole, said oxadiazole further substituted with ethyl; unsubstituted or optionally methoxy-substituted isobutyl; unsubstituted or optionally OH-substituted isopropyl; isoxazole substituted with one or two methyl groups or isopropyl groups; isoxazole substituted with methyl groups; unsubstituted or optionally substituted with CF2, cyclopropyl, methoxy, or oxadiazole Methyl group substituted with aziridine, wherein the aziridine is further substituted with -C(O)CH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3 or -C(O)OCH3; methyl group substituted with cyclopropyl or cyclopropyl group substituted with methyl; morpholine unsubstituted or optionally substituted with -C(O)CH3 or -C(O)OC(CH3)3; oxadiazole substituted with methyl; oxazole substituted with one or two methyl or cyclopropyl groups; oxadiazole; piperazine substituted with methyl; piperidine unsubstituted or optionally substituted with one or more groups selected from methyl, oxo, -C(O)CH3 and -C(O)OC(CH3)3; pyrazine unsubstituted or optionally substituted with one or two methyl groups;Pyrazoles that are unsubstituted or optionally substituted with one or more groups selected from methyl, ethyl, and CF3; pyrazoles substituted with one or two methyl groups; pyridazines that are unsubstituted or optionally substituted with methyl groups; pyridines that are unsubstituted or optionally substituted with amino, hydroxyl, -NH2, -OH, or one or more methyl groups; pyridines substituted with methyl groups; pyrimidines that are unsubstituted or optionally substituted with methyl groups; pyrrolidines that are unsubstituted or optionally substituted with methyl, oxo, -C(O)CH3, or -C(O)OC(CH3)3 groups; pyrrolopyrazoles; tert-butyl; tetrahydrofurans; tetraazoles substituted with methyl groups; thiazoles that are unsubstituted or optionally substituted with chloro or methyl groups; or triazoles substituted with one or more groups selected from methyl and ethyl groups.

[0198] In some embodiments, the compounds and their salts described in Table 1 are provided herein.

[0199] Table 1.

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293] In some variations, any compound described herein (such as compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or any variation thereof) or any of the compounds in Table 1 may be deuterated (e.g., hydrogen atoms are replaced by deuterium atoms). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding undeuterated compounds. Other methods known in the art can also be used to replace hydrogen atoms with deuterium atoms.

[0294] Any formula given herein (such as formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik)) is intended to represent compounds having the structure shown by the structural formula, as well as certain variations or forms. Specifically, compounds of any formula given herein may have an asymmetric center and therefore exist in different enantiomeric or diastereomeric forms. All optical and stereoisomers of the general formula, and mixtures thereof in any ratio, are considered to be within the scope of that formula. Therefore, any formula given herein is intended to represent racemic compounds, one or more enantiomers, one or more diastereomeric forms, one or more transisomers, and mixtures thereof in any ratio. When the compounds in Table 1 are shown with specific stereochemical configurations, this document also provides any alternative stereochemical configurations of the compound, and mixtures of any ratios of the stereoisomers of the compound. For example, when a compound in Table 1 has a stereocenter with an "S" stereochemical configuration, this document also provides enantiomers of the compound in which the stereocenter has an "R" stereochemical configuration. Similarly, when a compound in Table 1 has a stereocenter with an "R" configuration, this document also provides enantiomers of the compound in which the stereocenter has an "S" stereochemical configuration. Mixtures of compounds having both "S" and "R" stereochemical configurations are also provided. Furthermore, if a compound in Table 1 has two or more stereocenters, any enantiomer or diastereomer of the compound is also provided. For example, if a compound in Table 1 contains a first stereocenter and a second stereocenter having "R" and "R" stereochemical configurations respectively, stereoisomers of compounds having "S" and "S" stereochemical configurations respectively, and stereoisomers having "S" and "R" stereochemical configurations respectively are also provided. If the compounds in Table 1 contain a first stereocenter and a second stereocenter having stereochemical configurations of “S” and “S” respectively, then stereoisomers of compounds having stereochemical configurations of “R” and “R” respectively, having stereochemical configurations of “S” and “R” respectively, and having stereochemical configurations of “R” and “S” respectively are also provided. Similarly, if the compounds in Table 1 contain a first stereocenter and a second stereocenter having stereochemical configurations of “R” and “S” respectively, then stereoisomers of compounds having stereochemical configurations of “S” and “R” respectively, having stereochemical configurations of “R” and “R” respectively, and having stereochemical configurations of “S” and “S” respectively are also provided.Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or inhibited trans isomers. Additionally, any formula given herein is intended to refer to any of the hydrates, solvates, and amorphous and polymorphic forms of the compound, and mixtures thereof, even if the forms are not explicitly listed. In some embodiments, the solvent is water and the solvate is a hydrate.

[0295] Representative examples of the compounds (including intermediates and final compounds) detailed herein are shown in the tables and elsewhere herein. It should be understood that, in one respect, any of these compounds may be used in the methods detailed herein, including separable intermediate compounds that are administered to an individual or subject (if applicable).

[0296] As will be fully understood by those skilled in the art, the compounds shown herein may exist as salts even if no salt is shown, and it should be understood that the compositions and methods provided herein encompass all salts and solvates of the compounds shown herein, as well as non-salt and non-solvent forms of the compounds. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0297] In one variation, the compounds described herein are synthetic compounds prepared for administration to an individual or subject. In another variation, a composition comprising the compound in its substantially pure form is provided. In yet another variation, a pharmaceutical composition comprising the compounds detailed herein and a pharmaceutically acceptable carrier is provided. In yet another variation, a method of administering the compound is provided. The purified form, pharmaceutical composition, and method of administering the compound are applicable to any of the compounds or forms thereof detailed herein.

[0298] The G1, G2, G3, Z, A, B, and R values ​​provided in this article 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 fR g R h R i R j R n R p R q and R r Any variation or implementation scheme may be related to 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 Each other variation or combination of implementation schemes is described as if each combination were presented individually and explicitly.

[0299] Other implementation schemes will become clear to those skilled in the art from the following detailed description.

[0300] As used in this article, when any variable appears more than once in a chemical formula, its definition for each occurrence is independent of its definition for each of the other occurrences.

[0301] Formula (I) includes all its sub-formulas. For example, formula (I) includes compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik).

[0302] The compound names provided herein (including Table 1) are provided by ChemBioDraw Professional 15.0.0.106. Those skilled in the art will understand that various recognized nomenclature systems and symbols can be used to name or identify compounds. For example, common names, systematic or non-systematic names can be used to name or identify compounds. Recognized nomenclature systems and symbols in the field of chemistry include, for example, the Chemical Abstracts Service (CAS), ChemBioDraw Ultra, and the International Union of Pure and Applied Chemistry (IUPAC).

[0303] Composition

[0304] Compositions (such as pharmaceutical compositions) are also provided, comprising compounds disclosed and / or described herein and one or more other medical agents, pharmaceuticals, excipients, carriers, excipients, etc. Suitable medical agents and pharmaceuticals include those drugs described herein. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient or excipient and at least one chemical entity as 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) are provided containing one or more compounds described herein or pharmaceutically acceptable salts thereof.

[0305] In some embodiments, a pharmaceutically acceptable composition is provided 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 a synthetic intermediate that can be used to prepare the compounds described herein. The compositions described herein may contain any other suitable active or inactive agent.

[0306] Any composition described herein may be sterile or contain sterile components. Sterilization may be achieved by methods known in the art. Any composition described herein may contain one or more substantially pure compounds or conjugates.

[0307] Packaged pharmaceutical compositions are also provided, which contain the pharmaceutical composition as described herein and instructions for use in treating patients with the diseases or conditions described herein.

[0308] How to use

[0309] The compounds and pharmaceutical compositions described herein may be used to treat or prevent diseases or conditions in individuals or subjects.

[0310] Not limited to theory, the compounds and pharmaceutical compositions disclosed herein are believed to act by inhibiting myosin. This inhibition potentially reduces the number of independent myosin heads interacting with actin filaments, thereby reducing contractile volume. Reducing myocardial contractility is important for treating heart disease in which excessive contraction is a problem. In some embodiments, a method of treating or preventing heart disease in an individual or subject is provided, comprising administering to the individual or subject in need 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, a method of treating or preventing heart disease in a subject in need is provided, comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein. In some embodiments, a method of treating heart disease in a subject in need is provided, comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein. In some embodiments, a method of treating established or diagnosed heart disease in a subject in need is provided, comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein. In some implementations, a method for preventing heart disease in a subject in need is provided, which includes administering to the subject a therapeutically effective amount of at least one chemical entity as described herein.

[0311] This document also provides the use of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for treating a subject with heart disease. In some aspects, compounds or compositions as described herein are provided for use in a method of therapeutically treating a human or animal body. In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, are provided herein for use in a method of therapeutically treating a human or animal body. In some embodiments, this document provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, for the treatment or prevention of heart disease. In some embodiments, this document provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, for the treatment of heart disease. In some embodiments, this document provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, for the treatment of established or diagnosed heart disease. In other embodiments, this document provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, for the prevention of heart disease. In some embodiments, this document provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, for the treatment of diseases or conditions associated with HCM. In some embodiments, this document provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, for the treatment of diseases or conditions associated with secondary left ventricular wall thickening.In some embodiments, this document provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, for the purpose of improving symptoms associated with heart disease. In other embodiments, this document provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, for the purpose of reducing the risk of symptoms associated with heart disease. In other embodiments, this document provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, for the treatment of diseases or conditions associated with: small left ventricular cavity, cavity occlusion, hyperdynamic left ventricular contraction, obstruction of blood outflow from the left ventricle, cardiac hypertrophy, low stroke volume, impaired left ventricular relaxation, high left ventricular filling pressure, myocardial ischemia, or cardiac fibrosis. In some embodiments, this document provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, for the treatment of diseases or conditions associated with small left ventricular cavity and cavity occlusion, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis. In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, are provided herein for the treatment of muscular dystrophy. In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, are provided herein for the treatment of glycogen storage disease. In other embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or compounds in Table 1, or pharmaceutically acceptable salts thereof, are provided herein for the regulation of myocardial ganglia, such as inhibition of myocardial ganglia. In other embodiments, this document provides 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 enhancing myocardial coagulation proteins.

[0312] 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 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 one of the following: myosin heavy chain β (MHC-β), cardiac troponin T (cTnT), tropomyosin α-1 chain (TPM1), cardiac myosin-binding protein C (MYBPC3), cardiac troponin I (cTnI), essential light chain of myosin (ELC), titin (TTN), myosin regulatory light chain 2 ventricular / myocardial isoform (MLC-2), cardiac α-actin, muscle LIM protein (MLP), or the non-catalytic subunit γ2 activated by protein kinase AMP (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 no confirmed genetic cause.

[0313] In some implementations, the subject is at high risk of progressive symptoms. In some implementations, the subject is at high risk of atrial fibrillation, ventricular tachyarrhythmias, stroke, and / or sudden death. In some implementations, the subject has reduced exercise capacity. In some implementations, reduced exercise capacity is compared to an age-matched control group. In some implementations, the subject is eligible for surgical intervention or percutaneous ablation to treat heart disease.

[0314] 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 sarcomere mutations. In some embodiments, HCM is associated with non-sarcomere mutations. In some embodiments, the heart disease is obstructive or non-obstructive HCM caused by sarcomere and / or non-sarcomere mutations. In some embodiments, the sarcomere mutation is a mutation in one of the following: myosin heavy chain β (MHC-β), cardiac troponin T (cTnT), tropomyosin α-1 chain (TPM1), cardiac type myosin-binding protein C (MYBPC3), cardiac troponin I (cTnI), essential light chain of myosin (ELC), titin (TTN), myosin regulatory light chain 2 ventricular / myocardial isoform (MLC-2), cardiac α-actin, or muscle LIM protein (MLP). In some embodiments, the sarcomere mutation is a mutation in MHC-β. In some implementations, the non-sarcomere mutation is a mutation in the non-catalytic subunit γ2 (PRKAG2) of protein kinase AMP activation.

[0315] In some embodiments, this document provides methods for treating diseases or symptoms associated with HCM, comprising administering to an individual or subject in need a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or a compound listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or symptom is Fabry disease, Danon disease, mitochondrial cardiomyopathy, or Noonan syndrome.

[0316] This document also provides the use of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik) or the compounds in Table 1 or their pharmaceutically acceptable salts, for the manufacture of medicaments for the treatment of diseases or symptoms associated with HCM.

[0317] 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 symptom or condition caused by coronary artery disease. In some embodiments, the heart disease is myocardial infarction or angina. 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 ischemic heart disease and / or coronary artery 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 a symptom or related to diastolic dysfunction due to or associated with cardiac aging or degeneration. In some implementations, heart disease is a symptom or a symptom associated with left ventricular hypertrophy and / or left ventricular concentric remodeling.

[0318] In some embodiments, a method of treating an individual or subject for a disease or symptom associated with secondary left ventricular wall thickening is provided, comprising administering to the individual or subject in need a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or a compound from 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 ataxia, Danon disease, Noonan syndrome, or Pompe disease.

[0319] This document also provides the use of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik) or the compounds in Table 1 or their pharmaceutically acceptable salts, for the manufacture of medicaments for the treatment of diseases or conditions associated with secondary left ventricular wall thickening.

[0320] In some implementations, a method is provided to improve heart disease-related symptoms in a subject, comprising administering to an individual or subject in need 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 symptom is selected from one or more of the following: poor or reduced cardiac elasticity, poor or reduced diastolic left ventricular relaxation, abnormal left atrial pressure (e.g., abnormally high left atrial pressure), paroxysmal or permanent atrial fibrillation, increased left atrial and pulmonary capillary wedge pressure, increased left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular mass, increased left ventricular wall thickness, left ventricular mid-cavity obstruction, increased mitral valve systolic forward motion, left ventricular outflow tract obstruction, chest pain, exercise-induced dyspnea, presyncope, abnormal exercise capacity, and fatigue.

[0321] In some implementations, methods are provided to reduce the risk of heart disease-related symptoms in subjects, including administering to an individual or subject in need 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 symptom is selected from one or more of the following: sudden cardiac death, poor or reduced cardiac elasticity, poor or reduced diastolic left ventricular relaxation, abnormal left atrial pressure (e.g., abnormally high left atrial pressure), paroxysmal or permanent atrial fibrillation, increased left atrial and pulmonary capillary wedge pressure, increased left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular mass, increased left ventricular wall thickness, left ventricular mid-cavity obstruction, increased mitral valve systolic forward motion, left ventricular outflow tract obstruction, chest pain, exercise-induced dyspnea, presyncope, abnormal exercise capacity, and fatigue.

[0322] In some implementations, a method of treating an individual or subject for a disease or condition associated with small left ventricular cavity, cavity occlusion, hyperdynamic left ventricular contraction, obstruction of blood outflow from the left ventricle, cardiac hypertrophy, low stroke volume, impaired left ventricular relaxation, high left ventricular filling pressure, myocardial ischemia, or cardiac fibrosis is provided, comprising administering to the individual or subject in need 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.

[0323] In some implementations, a method of treating an individual or subject for a disease or symptom associated with small left ventricular cavity and cavity occlusion, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis is provided, comprising administering to the individual or subject in need 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.

[0324] This document also provides the use of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik) or the compounds in Table 1 or their pharmaceutically acceptable salts, for the manufacture of medicaments for the treatment of diseases or conditions associated with small left ventricular cavity and cavity occlusion, hyperdynamic left ventricular contraction, myocardial ischemia or cardiac fibrosis.

[0325] In some embodiments, a method of treating an individual or subject with muscular dystrophy (e.g., Duchenne muscular dystrophy) is provided, comprising administering to the individual or subject in need 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. This document also provides 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, for the manufacture of a medicament for the treatment of muscular dystrophy (e.g., Duchenne muscular dystrophy).

[0326] In some embodiments, a method of treating glycogen storage disease in an individual or subject is provided, comprising administering to the individual or subject in need 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. This document also provides 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, for the manufacture of a medicament for the treatment of glycogen storage disease.

[0327] Methods for modulating myocardial ganglia in individuals or subjects are also provided, the method comprising administering to the individual or subject in need a therapeutically effective amount of at least one chemical entity as described herein. In some embodiments, a method for inhibiting myocardial ganglia is provided, comprising contacting the myocardial ganglia with at least one chemical entity as 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). Additionally, the use of at least one chemical entity as 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) for the manufacture of a medicament for inhibiting myocardial ganglia in individuals or subjects is provided herein.

[0328] Methods for enhancing myocardial coagulation in individuals or subjects are also provided, comprising administering to an individual or subject a therapeutically effective amount of at least one chemical entity as 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). Additionally, the use of at least one chemical entity as 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) for the manufacture of a medicament for enhancing myocardial coagulation in individuals or subjects is provided herein.

[0329] In some implementations, the methods provided herein further include monitoring the effectiveness of treatment. Examples of indicators include (but are not limited to) improvements in one or more of the following: New York Heart Association (NYHA) functional classification, exercise capacity, cardiac elasticity, diastolic left ventricular relaxation, left atrial pressure, paroxysmal or permanent atrial fibrillation, left atrial and pulmonary capillary wedge pressure, left ventricular diastolic pressure, syncope, diastolic ventricular relaxation, ventricular fibrosis, left ventricular hypertrophy, left ventricular mass, left ventricular wall thickness, left ventricular mid-cavity obstruction, mitral valve systolic forward motion, left ventricular outflow tract obstruction, chest pain, exercise-induced dyspnea, presyncope, exercise-induced abnormalities, and fatigue. These indicators can be monitored using techniques known in the art, including self-reporting; ECG, including mobile ECG; echocardiography; cardiac MRI; CT; biopsy; cardiopulmonary exercise testing (CPET); and activity recording examination.

[0330] In some embodiments, the compound reduces the contractile rate of cardiomyocytes. In some embodiments, the compound reduces the contractile rate of cardiomyocytes by more than 40%, such as more than 45%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the compound reduces the contractile rate 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 calcium transients in cardiomyocytes. In some embodiments, the compound reduces ATPase activity in cardiomyocytes. Methods for measuring contractile rate, ATPase activity, and calcium transients are known in the art, such as by calcium labeling, electrophysiological recording, and microscopic imaging. In some embodiments, the compound does not significantly inhibit or induce cytochrome P450 (CYP) proteins.

[0331] In some implementations, the subject's left ventricular wall is thicker than normal prior to treatment. In some implementations, the subject's left ventricular wall thickness is greater than 15 mm prior to treatment, such as greater than 18 mm, 20 mm, 22 mm, 25 mm, or 30 mm. In some implementations, the left ventricular wall thickness decreases by more than 5% after treatment, such as greater than 8%, 10%, 12%, 15%, 20%, or 30%. Left ventricular wall thickness can be measured by methods known in the art, such as by echocardiography, CT scan, or cardiac MRI.

[0332] In some embodiments, the subject has abnormal cardiac fibrosis prior to treatment. In some embodiments, after treatment, the abnormal cardiac fibrosis decreases by more than 5%, such as more than 8%, 10%, 12%, 15%, 20%, or 30%. Cardiac fibrosis can be measured by methods known in the art, such as by biopsy or cardiac MRI.

[0333] In some implementations, the subject had reduced exercise capacity prior to treatment. In some implementations, the subject's exercise capacity increased by more than 5% after treatment, such as more than 8%, 10%, 12%, 15%, 20%, or 30%. In some implementations, exercise capacity was measured by cardiopulmonary exercise testing (CPET). CPET measures changes in oxygen consumption (maximum VO2). Methods for measuring CPET and maximum VO2 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 implementations, maximum VO2 improved by more than 1 mL / kg / m² after treatment. 2 Such as exceeding 1.2 mL / kg / m 2 1.4 mL / kg / m 2 1.5 mL / kg / m 2 1.7 mL / kg / m 2 2mL / kg / m 2 2.2 mL / kg / m 2 2.5 mL / kg / m 2 3mL / kg / m 2 3.2 mL / kg / m 2 Or 3.5 mL / kg / m 2 .

[0334] In some implementations, prior to treatment, the subject's New York Heart Association (NYHA) functional classification was II, III, or IV. In some implementations, prior to treatment, the subject's New York Heart Association (NYHA) functional classification was III or IV. In some implementations, prior to treatment, the subject's New York Heart Association (NYHA) functional classification was IV. In some implementations, after treatment, the subject maintained the same NYHA functional category or had a reduced NYHA functional category.

[0335] In some implementations, the maximum VO2 improvement after treatment exceeds 1 mL / kg / m 2 Such as exceeding 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 2mL / kg / m 2Furthermore, the subjects had a reduced NYHA functional class. In some implementations, maximum VO2 improvement exceeding 2.5 mL / kg / m² was observed after treatment. 2 3mL / kg / m 2 3.2 mL / kg / m 2 Or 3.5 mL / kg / m 2 Furthermore, the subjects maintained the same NYHA functional category or had a reduced NYHA functional category.

[0336] In some implementations, subject daily functioning and / or activity levels improve after treatment. This improvement can be measured, for example, through logs or activity tracking checks (such as FitBit or FitBit-like monitors).

[0337] In some implementation schemes, subjects experience one or more of the following after treatment: reduced shortness of breath, reduced chest pain, reduced psychological burden (such as atrial fibrillation and ventricular psychological disorders), reduced incidence of heart failure, and reduced ventricular outflow obstruction.

[0338] dose

[0339] The compounds and compositions disclosed and / or described herein are administered at therapeutically effective doses, such as doses sufficient to provide treatment for a disease state. While human dose levels of the chemical entities described herein have not been optimized, the typical daily dose is in the range of about 0.01 mg / kg body weight to 100 mg / kg body weight; in some embodiments, it is in the range of about 0.05 mg / kg body weight to 10.0 mg / kg body weight; and in some embodiments, it is in the range of about 0.10 mg / kg body weight to 1.4 mg / kg body weight. Therefore, for administration to a 70 kg person, in some embodiments, the dose range would be about 0.7 mg / day to 7000 mg / day; in some embodiments, it would be about 3.5 mg / day to 700.0 mg / day; and in some embodiments, it would be about 7 mg / day to 100.0 mg / day. The amount of chemical entity administered will depend on, for example, the subject being treated and the disease state, the severity of the ailment, the method and schedule of administration, and the prescribing physician's judgment. For example, depending on the pharmacokinetics of the compound, the exemplary dose range for oral administration is about 5 mg / day to about 500 mg / day, and the exemplary dose for intravenous administration is about 5 mg / day to about 500 mg / day.

[0340] A daily dose is the total amount administered throughout the day. Daily doses can be administered (but are not limited to) daily, every other day, weekly, every two weeks, monthly, or at various intervals. In some implementations, the daily dose is administered over a period of one day to the subject's lifetime. In some implementations, the daily dose is administered once daily. In some implementations, the daily dose is administered in multiple separate doses, such as two, three, or four separate doses. In some implementations, the daily dose is administered in two separate doses.

[0341] The compounds and compositions disclosed and / or described herein may be administered via any acceptable mode of therapeutic administration, including (but not limited to) oral, sublingual, subcutaneous, non-enteral, intravenous, intranasal, topical, percutaneous, 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.

[0342] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms, such as tablets, capsules, powders, liquids, suspensions, suppositories, and aerosols. The compounds disclosed and / or described herein may also be administered in sustained-release or controlled-release dosage forms (e.g., controlled / sustained-release pills, reservoir-type injections, osmotic pumps, or transdermal (including electrotransport) patches) for prolonged, timed, and / or pulsed administration at a predetermined rate. In some embodiments, the composition is provided in a unit dosage form suitable for a single, precise dose.

[0343] The compounds disclosed and / or described herein may be administered alone or in combination with one or more commonly used 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 may also contain small amounts of non-toxic excipients, such as wetting agents, emulsifiers, solubilizers, pH buffers, etc. (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, desorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Typically, depending on the intended administration regimen, the pharmaceutical composition will contain from about 0.005% by weight to 95% by weight or from about 0.5% by weight to 50% by weight of the compounds disclosed and / or described herein. Practical methods for preparing the dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0344] In some embodiments, the composition will be in the form of pills or tablets, and therefore the composition may contain compounds disclosed and / or described herein, as well as one or more of the following: diluents (e.g., lactose, sucrose, dicalcium phosphate), lubricants (e.g., magnesium stearate), and / or binders (e.g., starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include powders, granules, solutions, or suspensions (e.g., in propylene carbonate, vegetable oil, or triglycerides) encapsulated in gelatin capsules.

[0345] Pharmaceutically administerable liquid compositions may be prepared, for example, by dissolving, dispersing, or suspending the compounds disclosed and / or described herein, along with optional pharmaceutical additives, in a carrier (e.g., water, saline, aqueous dextran, glycerol, glycol, ethanol, or the like) to form a solution or suspension. Injectables may be prepared as liquid solutions or suspensions, as emulsions in their usual form, or in a solid form suitable for dissolution or suspension in a liquid prior to injection. The percentage of compounds contained in the non-enterogonal composition depends, for example, the physical properties of the compounds, the activity of the compounds, and the needs of the subject. However, a percentage of the active ingredient in solution of 0.01% to 10% may be used, and may be higher if the composition is a solid, which will subsequently be diluted to another concentration. In some embodiments, the composition will contain about 0.2% to 2% of the compounds disclosed and / or described herein in solution.

[0346] Pharmaceutical compositions of the compounds disclosed and / or described herein, alone or in combination with an inert carrier (such as lactose), may also be administered to the respiratory tract as an aerosol or solution for use in a nebulizer, or as a fine powder for inhalation. In this case, the particle diameter of the pharmaceutical composition may be less than 50 micrometers, or in some embodiments, less than 10 micrometers.

[0347] In addition, pharmaceutical compositions may include the compounds disclosed and / or described herein, and one or more other medical agents, pharmaceutical preparations, excipients, etc. Suitable medical agents and pharmaceutical preparations include those described herein.

[0348] Reagent test kit

[0349] Products containing any of the compounds or pharmaceutical compositions provided herein are also provided, as well as kits. The products may include labeled containers. Suitable containers include, for example, bottles, vials, and test tubes. Containers may be formed from a variety of materials, such as glass or plastic. Containers may contain the pharmaceutical compositions provided herein. Labels on the containers may indicate that the pharmaceutical composition is intended for the prevention, treatment, or suppression of the conditions described herein, and may also indicate instructions for use in vivo or in vitro.

[0350] In one aspect, this document provides kits containing the compounds or compositions described herein, along with instructions for use. These kits may contain instructions for use in treating heart disease in an individual or subject of need. The kits may additionally contain any materials or devices that can be used to administer the compounds or compositions, such as vials, syringes, or IV bags. The kits may also contain sterile packaging.

[0351] combination

[0352] The compounds and compositions described and / or disclosed herein may be administered alone or in combination with other therapies and / or treatments that may be used to treat the conditions, diseases or symptoms mentioned above.

[0353] The compounds and compositions described and / or disclosed herein may be combined with one or more other therapies to treat heart disease (such as HCM or HFpEF). In some embodiments, the one or more therapies include those that block the progression of heart failure and attempt to prevent cardiac remodeling by downregulating neurohormonal stimulation of the heart (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors). In some embodiments, the one or more therapies include those that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropic agents, such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone). In other embodiments, the one or more therapies include those that reduce cardiac preload (e.g., diuretics such as furosemide) or 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).

[0354] The compounds and compositions described and / or disclosed herein may be combined with one or more other therapies to treat HCM or HFpEF. In some embodiments, the compounds and compositions may be combined with a beta-blocker, verapamil, and / or disopyramide.

[0355] General synthesis methods

[0356] The compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik) will now be described with reference to the illustrative synthetic schemes for their general preparation described below and the specific examples that follow. Those skilled in the art will recognize that, to obtain the various compounds described herein, the starting materials may be suitably selected such that the ultimately desired substituent, if appropriate, will be carried throughout the reaction scheme, with or without protection, to produce the desired product. Alternatively, it may be necessary or desirable to employ a suitable group at the position of the ultimately desired substituent, which can be carried throughout the reaction scheme and, if appropriate, substituted by the desired substituent. Furthermore, those skilled in the art will recognize that protecting groups can be used to protect certain functional groups (amino, carboxyl, or side-chain groups) from the reaction conditions, and that said groups are removed under standard conditions, if appropriate. Unless otherwise specified, the variables are as defined above with respect to equations (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) and (Ik).

[0357] If it is desired to obtain a specific enantiomer of a compound, this can be accomplished from the corresponding enantiomer mixture using any suitable and commonly used procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives can be generated by reacting a mixture of enantiomers (e.g., a racemic mixture) with a suitable chiral compound. The diastereomeric derivatives can then be separated by any convenient means (e.g., by crystallization), and the desired enantiomer can be recovered. In another resolution method, the racemic mixture can be separated using chiral high-performance liquid chromatography. Alternatively, if desired, the specific enantiomer can be obtained in one of these methods by using a suitable chiral intermediate.

[0358] If it is desired to obtain a specific isomer of the compound or to purify the reaction product in other ways, chromatography, recrystallization and other common separation procedures can also be used for intermediates or end products.

[0359] The general method for preparing the compounds described herein is illustrated in the illustrative methods below. The variable groups in the schemes provided herein are as defined with respect to formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik), or any variation thereof. Other compounds described herein can be prepared by similar methods.

[0360] In some embodiments, the compounds provided herein can be synthesized according to scheme A.

[0361] Option A

[0362]

[0363] Among them, G1, G2, G3, R 1 R 2 R 3 R 11 Z and B are defined as with respect to formula (I) or any of its variations as detailed herein, LG is a leaving group and PG is a protecting group.

[0364] In some embodiments, the compounds provided herein can be synthesized according to scheme B.

[0365] Option B

[0366]

[0367] Among them, G1, G2, G3, R 1 R 2 R 3 R 11 Z and B are defined as for equation (I) or any of its variations as detailed herein, and LG is a leaving basis.

[0368] In some embodiments, the compounds provided herein can be synthesized according to scheme C.

[0369] Option C

[0370]

[0371] Among them, G1, G2, G3, R 1 R 2 R 3 R 11 Z and B are defined as for equation (I) or any of its variations as detailed herein, and LG is a leaving basis.

[0372] In some embodiments, the compounds provided herein can be synthesized according to scheme D.

[0373] Option D

[0374]

[0375] Among them, G1, G2, G3, R 1 R 2 R 3 R 11 Z and B are defined as for equation (I) or any of its variations as detailed herein, and LG is a leaving basis.

[0376] In some embodiments, the compounds provided herein can be synthesized according to any of schemes E1, E2, E3 and E4.

[0377] Option E1

[0378]

[0379] Option E2

[0380]

[0381] Solution E3

[0382]

[0383] Solution E4

[0384]

[0385] Among them, G1, G2, G3, R 1 R 2 R 3 R 11 Z and B are defined as with respect to formula (I) or any of its variations as detailed herein, LG is a leaving group and PG is a protecting group.

[0386] In some embodiments, the compounds provided herein can be synthesized according to any of schemes F1, F2 and F3.

[0387] Option F1

[0388]

[0389] Option F2

[0390]

[0391] Solution F3

[0392]

[0393] Among them, G1, G2, G3, R 1 R 2 R 3 R 11 Z and B are as defined with respect to formula (I) or any of its variations as detailed herein, and PG is a protecting group.

[0394] In some embodiments, the compounds provided herein can be synthesized according to scheme G.

[0395] Option G

[0396]

[0397] Among them, G1, G2, G3, R 1 R 2 R 3R 11 Z and B are defined as for equation (I) or any of its variations as detailed herein, and LG is a leaving basis.

[0398] In some embodiments, the compounds provided herein can be synthesized according to scheme H.

[0399] Option H

[0400]

[0401] Among them, G1, G2, G3, R 1 R 2 R 3 Z, A, and B are defined as with respect to equation (I) or any of its variations as detailed herein, and LG is a leaving basis.

[0402] In some embodiments, the compounds provided herein can be synthesized according to Scheme I.

[0403] Option I

[0404]

[0405] Among them, G1, G2, G3, R 1 R 2 R 3 Z, A, and B are defined as with respect to equation (I) or any of its variations as detailed herein, and LG is a leaving basis.

[0406] In some embodiments, the compounds provided herein can be synthesized according to scheme J.

[0407] Scheme J

[0408]

[0409] Among them, G1, G2, G3, R 1 R 2 R 3 Z, B and R 11 It is defined as for equation (I) or any of its variations as detailed herein.

[0410] In some implementations, the compounds provided herein can be synthesized according to scheme K.

[0411] Option K

[0412]

[0413] Among them, Z, B and R 11 It is defined as for equation (I) or any of its variations as detailed herein.

[0414] In some embodiments, the compounds provided herein can be synthesized according to schemes L1 and L2.

[0415] Solution L1

[0416]

[0417] Solution L2

[0418]

[0419] Among them, G1, G2, G3, R 1 R 2 R 3 Z, B and R 11 It is defined as for equation (I) or any of its variations as detailed herein.

[0420] In some embodiments, the compounds provided herein can be synthesized according to scheme M.

[0421] Option M

[0422]

[0423] Among them, G1, G3, R 1 R 2 R 3 Z, B and R 11 It is defined as for equation (I) or any of its variations as detailed herein.

[0424] In some embodiments, the compounds provided herein can be synthesized according to schemes N1 and N2.

[0425] Option N1

[0426]

[0427] Option N2

[0428]

[0429] Among them G3, R 2 R 3 Z and B are defined as with respect to formula (I) or any variation thereof as detailed herein, X is a halogen, and PG is a protecting group.

[0430] In some embodiments, the compounds provided herein can be synthesized according to scheme O.

[0431] Option O

[0432]

[0433] Among them, G1, G2, G3, R 1 R 2 R 3 A and B are as defined with respect to formula (I) or any of its variations as detailed herein, PG is a protecting group, and y is HO-, HN(R) 9 )- or HOR y - and Y is -O-, -N(R) 9 - or - OR y -

[0434] Specific, non-limiting embodiments are provided in the Examples section below.

[0435] Example

[0436] The following examples are provided to illustrate (but not limit) the compositions, uses, and methods provided herein. The compounds are prepared using the general methods described above.

[0437] 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-isopropylpropyl-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 (propanol), ACN (acetonitrile), TFA (trifluoroacetic acid), DPPA (diphenyl azidophosphate), DBU (1,8-diazabicyclo(5.4.0)undecyl-7-ene), THF (tetrahydrofuran), PPh3 (triphenylphosphine), SM (starting material), Hex (hexane), NCS (N-chlorosuccinimide), rt (room temperature), DCE (dichloroethane), FA (formic acid), CHCl3 (chloroform), BnBr (benzyl bromide), HCl (hydrochloric acid), equiv (equivalent) and DSC (bis(2,5-dioxopyrrolidone-1-yl) carbonate).

[0438] Example 1

[0439] Synthesis of Compound 17

[0440] 1. Synthesis of intermediates 1-2:

[0441]

[0442] (Aminooxy)sulfonic acid (116 g, 1.0 mol, 3.0 equivalent) was added to a solution of 50 g, 340 mmol, 1.0 equivalent of 4-bromo-1H-pyrazole in sodium hydroxide (3.7 N, 555 mL). The mixture was stirred for 30 min 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). NaIO4 (147 g, 685 mmol, 2.0 equivalent) was added to the resulting solution 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 a brown oily 5-bromo-1,2,3-triazine.

[0443] 2. Synthesis of intermediates 1-3:

[0444]

[0445] 1-(cyclopent-1-en-1-yl)pyrrolidine (25.8 g, 188 mmol, 1.1 equivalent) was added to a solution of 5-bromo-1,2,3-triazine (25 g, 156 mmol, 1.0 equivalent) in CHCl3 (500 mL). The mixture was stirred at 45 °C for 1 h, 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 obtain 11 g (36%) of 3-bromo-5H,6H,7H-cyclopentadien[b]pyridine as a brown solid.

[0446] 3. Synthesis of intermediates 1-4:

[0447]

[0448] m-CPBA (20.7 g, 120 mmol, 2.0 equivalent) was added to a solution of 3-bromo-5H,6H,7H-cyclopentadieno[b]pyridine (11.9 g, 60.0 mmol, 1.0 equivalent) in DCE (120 mL). The mixture was stirred overnight at 70 °C, 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-cyclopentadieno[b]pyridine-1-onthium-1-olate as a grayish-white solid.

[0449] 4. Synthesis of intermediates 1-5:

[0450]

[0451] A solution of 12.2 g (57.0 mmol, 1.0 equivalent) of 3-bromo-5H,6H,7H-cyclopentadieno[b]pyridine-1-onthium-1-ol 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 (1 N, 30 mL) and MeOH (30 mL). The mixture was stirred overnight at room temperature, 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-cyclopentadieno[b]pyridine-7-ol as a brown solid.

[0452] 5. Synthesis of intermediates 1-6:

[0453]

[0454] Under nitrogen atmosphere, 2,3-dihydro-1H-isoindole-1,3-dione (4.4 g, 29.9 mmol, 1.1 equivalent), PPh3 (8.9 g, 34.0 mmol, 1.25 equivalent) and DBAD (7.52 g, 32.7 mmol, 1.21 equivalent) were added to a solution of 3-bromo-5H,6H,7H-cyclopentadien[b]pyridin-7-ol (5.8 g, 27.1 mmol, 1.0 equivalent) in THF (100 mL). The mixture was stirred for 3 hours, 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-cyclopentadien[b]pyridin-7-yl]-2,3-dihydro-1H-isoindole-1,3-dione as a brown solid.

[0455] 6. Synthesis of intermediates 1-7:

[0456]

[0457] Hydrazine hydrate (4.4 g, 88.7 mmol, 4.0 equivalents) was added to a solution of 2-[3-bromo-5H,6H,7H-cyclopentadieno[b]pyridin-7-yl]-2,3-dihydro-1H-isoindol-1,3-dione (7.6 g, 22.2 mmol, 1.0 equivalent) in ethanol (80 mL). 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-cyclopentadieno[b]pyridin-7-amine as a brown solid.

[0458] 7. Synthesis of intermediates 1-8:

[0459]

[0460] Benzoyl chloride (317 mg, 2.3 mmol, 1.0 equivalent) and TEA (114 mg, 1.1 mmol, 0.05 equivalent) were added to a solution of 3-bromo-5H,6H,7H-cyclopentadieno[b]pyridin-7-yl]benzamide cooled to 0 °C in DCM (10 mL). The mixture was stirred for 30 min, 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-cyclopentadieno[b]pyridin-7-yl]benzamide as a white solid.

[0461] 8. Synthesis of intermediates 1-9:

[0462]

[0463] FeK4(CN)6·3H2O (376 mg, 1.2 equivalents), second-generation Xphos (112 mg, 0.2 equivalents), X-phos (72 mg, 0.2 equivalents), and KOAc (214 mg, 2.2 mmol, 3.0 equivalents) were added to a solution of N-[3-bromo-5H,6H,7H-cyclopentadien[b]pyridin-7-yl]benzamide (230 mg, 0.7 mmol, 1.0 equivalents) in a mixture of dioxane (6 mL) and water (6 mL) under nitrogen atmosphere. The mixture was stirred overnight at 90°C, 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 obtain 100 mg (52%) of N-[3-cyano-5H,6H,7H-cyclopentadien[b]pyridin-7-yl]benzamide as a grayish-white solid.

[0464] 9. Synthesis of intermediates 1-10:

[0465]

[0466] Hydroxylamine hydrochloride (79 mg, 1.15 mmol, 3.0 equivalent) and sodium bicarbonate (128 mg, 1.5 mmol, 4.0 equivalent) were added to a solution of N-[3-cyano-5H,6H,7H-cyclopentadieno[b]pyridin-7-yl]benzamide (100 mg, 0.38 mmol, 1.00 equivalent) in MeOH (8 mL). The mixture was stirred at 80 °C for 2 h and concentrated under reduced pressure to give 110 mg of N-[3-(N-hydroxymethylammonium)-5H,6H,7H-cyclopentadieno[b]pyridin-7-yl]benzamide as a grayish-white solid.

[0467] 10. Synthesis of Compound 17:

[0468]

[0469] Propionyl propionate (0.8 mL) was added to a solution of N-[3-(N-hydroxymethylammonium)-5H,6H,7H-cyclopentadieno[b]pyridin-7-yl]benzamide (100 mg, 0.34 mmol, 1.0 equivalent) in dioxane (8 mL). The mixture was stirred at 90 °C for 2 h and concentrated under reduced pressure. The mixture was then redissolved in toluene (3 mL) and heated at 150 °C for 2 h. The mixture was then cooled to room temperature, concentrated under reduced pressure, and purified by preparative HPLC under the following conditions: (2-Analytical HPLC-SHIMADZU (HPLC-10)): Column, XBridge Shield RP18 OBD column, 5 μm, 19*150 mm; Mobile phase, water (0.05% NH3H2O) and ACN (24.0% within 8 min).

[0470] ACN up to 54.0% ACN); detector, UV 220nm. This produces 5.9 mg (5%) of N-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-7-yl)benzamide (compound 17) as a white solid. LRMS(ES) m / z 335 (M+H). 1 H-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).

[0471] The following compounds were prepared by a method similar to that used for compound 17:

[0472]

[0473]

[0474] Example 2

[0475] Synthesis of Compound 42

[0476]

[0477] Add (1,1-dimethoxyethyl)dimethylamine (144 mg, 1.08 mmol, 4.0 equivalent) to a solution of N-[3-(N-hydroxymethamidinyl)-5H,6H,7H-cyclopentadienyl[b]pyridin-7-yl]benzamide (80 mg, 0.27 mmol, 1.0 equivalent) in dioxane (6 mL). The mixture was stirred at 90 °C for 2 h, concentrated under reduced pressure, and purified by preparative HPLC under the following conditions: (column, X-Bridge, C18, Shield RP, 19*150 mm 5 μm; mobile phase, water with 0.05% NH3H2O ​​and ACN (20.0% ACN up to 48.0% ACN over 8 min); detector, UV 210 / 254 nm). This purification yielded 7.6 mg (9%) of N-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-6,7-dihydro-5H-cyclopentadien[b]pyridin-7-yl)benzamide (compound 42) as a white solid. LRMS(ES) m / z 321 (M+H). 1 H-NMR: (300MHz, methanol-d4, ppm) δ9.02-8.95(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, 6.5Hz, 2H), 5.62 (t, J = 8.5Hz, 1H), 3.22-2.93 (m, 2H), 2.82-2.64 (m, 1H), 2.65 (s, 3H), 2.11 (dq, J = 12.8, 9.0Hz, 1H).

[0478] Example 3

[0479] Synthesis of Compound 94

[0480]

[0481] Add 2,2-difluoroacetic acid 2,2-difluoroacetate (53 mg, 0.3 mmol, 1.5 equivalent) to a solution of N-[3-(N-hydroxymethylammonium)-5H,6H,7H-cyclopentadieno[b]pyridin-7-yl]benzamide (60 mg, 0.2 mmol, 1.0 equivalent) in dioxane (5 mL). The mixture was stirred at 60 °C for 2 h, concentrated under reduced pressure, and purified by preparative HPLC under the following conditions: (column, X-Bridge, C18, Shield RP, 19*150 mm 5 μm; mobile phase, water with 0.05% NH3H2O ​​and ACN (27.0% ACN up to 57.0% ACN in 8 min); detector, UV 210 / 254 nm). This purification yielded 7.5 mg (10%) of N-(3-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-6,7-dihydro-5H-cyclopentadien[b]pyridin-7-yl)benzamide (compound 94) as a white solid. LRMS(ES) mz / 357; 1 H-NMR: (300MHz, methanol-d4, ppm) δ9.09-9.01(m,1H),8.37(dt,J=2.0,1.0Hz,1H),7.93-7.82(m,2H),7.58-7.35(m, 3H), 5.63 (t, J = 8.5Hz, 1H), 3.25-2.95 (m, 3H), 2.74 (dtd, J = 12.9, 8.1, 2.9Hz, 1H), 2.13 (dq, J = 12.8, 9.1Hz, 1H).

[0482] Example 4

[0483] Synthesis of Compound 62

[0484] 1. Synthesis of intermediate 4-2:

[0485]

[0486] DSC (432 mg, 1.69 mmol, 1.82 equivalents) was added to a solution of 5-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-amine (200 mg, 0.93 mmol, 1.00 equivalent) in DMF (10 mL). The solution was stirred at room temperature for 2 h and then at 60 °C for 4 h. The resulting solution was diluted with EA (60 mL). The mixture was washed twice with water (30 mL) and then with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 260 mg of N-[5-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate 2,5-dioxopyrrolidine-1-yl ester as a yellow solid. This yellow solid was used in the next step without further purification. LRMS(ES)m / z 357(M+H).

[0487] 2. Synthesis of compound 62:

[0488]

[0489] Add pyridine-3-amine (40 mg, 0.43 mmol, 2.52 equivalents) and TEA (100 mg, 0.99 mmol, 5.87 equivalents) to a solution of N-[5-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate 2,5-dioxopyrrolidine-1-yl ester (60 mg, 0.17 mmol, 1.00 equivalents) in ACN (5 mL). The mixture was stirred at 80°C for 4 h, concentrated under vacuum, and purified by preparative HPLC under the following conditions: (2-Analytical HPLC-SHIMADZU (HPLC-10)): Column, XBridge Shield RP18 OBD column, 5 μm, 19*150 mm; Mobile phase, water (0.05% NH3·H2O) and ACN (20.0% ACN up to 50.0% ACN over 8 min); Detector, UV 254 nm. This produced 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). 1H-NMR: (400MHz, DMSO-d6, ppm) δ8.64(s,1H),8.56(s,1H),8.13(d,J=4.6Hz,1H), 7.93(ddd,J=8.4,2.7,1.5Hz,1H),7.89-7.81(m,2H),7.44(d,J=7.8Hz,1H),7.27( dd,J=8.4,4.6Hz,1H),6.78(d,J=8.1Hz,1H),5.24(q,J=8.0Hz,1H),2.99(dd,J=8. 1,5.1Hz,1H),2.88(q,J=8.0Hz,1H),2.64(s,3H),2.49(m,1H),1.92-1.77(m,1H).

[0490] The following compounds were prepared by a method similar to that used for compound 62:

[0491] Compound numbering LRMS(ES)m / z Compound numbering LRMS(ES)m / z 31 M+H=335.1 86 M+H=335 33 M+H=336 87 M+H=326 34 M+H=325 88 M+H=325 43 M+H=337 89 M+H=325 44 M+H=325 96 M+H=337 45 M+H=338 97 M+H=337 46 M+H=325 98 M+H=337 47 M+H=338 105 M+H=325 48 M+H=325 106 M+H=338 63 M+H=341 107 M+H=324 64 M+H=326 109 M+H=336 65 M+H=324 110 M+H=337 66 M+H=324.1 111 M+H=338 85 M+H=336 112 M+H=339

[0492] Example 5

[0493] Synthesis of Compound 100

[0494] 1. Synthesis of intermediate 5-2:

[0495]

[0496] TEA (39.8 g, 393.3 mmol, 2.2 equivalents) and a solution of (Boc)₂O (42.9 g, 196.3 mmol, 1.1 equivalents) in DCM (330 mL) were added dropwise over a 1-hour period at 0 °C. 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 NH4Cl aqueous solution (500 mL) and twice with brine (500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 57.4 g (92%) of N-[(1R)-5-bromo-2,3-dihydro-1H-indene-1-yl] tert-butyl carbamate as a white solid.

[0497] 2. Synthesis of intermediate 5-3:

[0498]

[0499] Potassium acetate (36.0 g, 367 mmol, 2.0 equivalent), K₄Fe(CN)₆·3H₂O (31.1 g, 73.5 mmol, 0.4 equivalent), XPhos (1.3 g, 2.8 mmol, 0.015 equivalent), and a second-generation XPhos pre-catalyst (2.2 g, 2.8 mmol, 0.015 equivalent) were added to a solution of N-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate tert-butyl ester (57.4 g, 184 mmol, 1.0 equivalent) in a mixture of dioxane (285 mL) and water (285 mL) under nitrogen atmosphere. The mixture was stirred at 100 °C for 2 h, cooled to room temperature, and filtered to remove solids. The aqueous layer was extracted twice with EA (500 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and ground together with a mixture of ethyl acetate and hexane (300 mL, 1 / 10) to obtain 42 g (88%) of N-[(1R)-5-cyano-2,3-dihydro-1H-inden-1-yl]carbamate tert-butyl ester as a pale yellow solid. LRMS(ES) m / z 203 (M+H-56).

[0500] 3. Synthesis of intermediate 5-4:

[0501]

[0502] Hydroxylamine hydrochloride (22.7 g, 326.7 mmol, 2.0 equivalents) and TEA (33.1 g, 326.7 mmol, 2.0 equivalents) were added to a solution of N-[(1R)-5-cyano-2,3-dihydro-1H-indene-1-yl]carbamate (42.2 g, 163.4 mmol, 1 equivalent) in ethanol (420 mL). 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 obtain 54.6 g (98%) of N-[(1R)-5-(N-hydroxymethylammonium)-2,3-dihydro-1H-indene-1-yl]carbamate (tert-butyl) as a grayish-white solid. LRMS(ES) m / z 292 (M+H).

[0503] 4. Synthesis of intermediate 5-5:

[0504]

[0505] Add 2,2-difluoroacetic acid tert-butyl ester (34.2 g, 196.8 mmol, 1.05 equivalent) to a solution of N-[(1R)-5-(N-hydroxymethylammonium)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (54.6 g, 187.4 mmol, 1 equivalent) in dioxane (500 mL). Stir the mixture at 50 °C for 1 h and then at 100 °C for 2 h. Cool the solution to room temperature and pour it into water (500 mL). Extract the aqueous layer twice with EA (500 mL). The combined organic layers were washed with brine (1 L), dried over Na2SO4, and concentrated under reduced pressure to obtain 53.2 g (73%) of N-[(1R)-5-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester as a white solid. LRMS(ES) m / z 295 (M+H-56).

[0506] 5. Synthesis of intermediates 5-6:

[0507]

[0508] HCl (4 M in dioxane, 125 mL, 4.1 mol, 27.2 equivalents) was added to a solution of N-[(1R)-5-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (53.2 g, 151.4 mmol, 1 equivalent) in DCM (375 mL). 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-indene-1-amine hydrochloride as a grayish-white solid. LRMS(ES) m / z 235 (M+H-17).

[0509] 6. Synthesis of Compound 100:

[0510]

[0511] Add HOAt (16.0 g, 117.4 mmol, 1.5 equivalents), EDCI (22.5 g, 117.4 mmol, 1.5 equivalents), and DIEA (40.5 g, 313.1 mmol, 4.0 equivalents) to a solution of 2-methyl-1,3-oxazol-5-carboxylic acid (10.0 g, 78.3 mmol, 1.0 equivalents) in DMF (220 mL). Stir the mixture for 15 min and add (1R)-5-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-indene-1-amine hydrochloride (22.6 g, 78.3 mmol, 1.05 equivalents). Continue stirring overnight. Add ice water (700 mL) and stir the mixture for another 1 h. The precipitate was collected, dissolved in EA (500 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was ground together with a mixture of EA and PE (700 mL, 1 / 20) to obtain 26 g of a light brown solid. This batch was combined with another batch (7.5 g from 24.33 mmol amine) prepared using the same procedure. The combined product was dissolved in a mixture of DCM and MeOH (500 mL, 10 / 1), concentrated to approximately 100 mL, and diluted with hexane (1 L). The precipitate was collected and dried to obtain 32.8 g of (R)-N-(5-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-methyloxazol-5-carboxamide (compound 100) as a grayish-white solid. LRMS(ES) m / z 361 (M+H). 1 H-NMR: (400MHz, chloroform-d, ppm) δ8.03(s,1H),8.02-7.97(m,1H),7.66(s,1H),7.4 9(d,J=7.9Hz,1H),6.88(t,J=52.2Hz,1H),6.42(d,J=8.7Hz,1H),5.74(q,J=8 .0Hz,1H),3.14(ddd,J=16.2,8.9,3.6Hz,1H),3.02(dt,J=16.4,8.3Hz,1H),2 .76(dtd,J=13.0,7.9,3.6Hz,1H),2.53(s,3H),2.01(dq,J=13.0,8.5Hz,1H).

[0512] The following compounds were prepared by a method similar to that used for compound 100:

[0513]

[0514]

[0515] Example 6

[0516] Synthesis of Compound 107

[0517] 1. Synthesis of intermediate 6-2:

[0518]

[0519] DIEA (630 mg, 3.00 equivalent) and HATU (928 mg, 2.44 mmol, 1.50 equivalent) were added to a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (205 mg, 1.6 mmol, 1.0 equivalent) in DMF (6 mL). The mixture was stirred for 15 min and 5-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-

[0520] 1H-Indene-1-amine (350 mg, 1.63 mmol, 1.00 equivalent). 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-indene-1-yl]-1H-pyrazole-5-carboxamide as a white solid. LRMS(ES) m / z 324 (M+H).

[0521] 2. Synthesis of compound 107:

[0522]

[0523] 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 (hold for 25.0% ethanol for 20 min); detector, UV 220 / 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). 1H-NMR: (DMSO, 400MHz, ppm): δ8.84-8.82(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)

[0524] Example 7

[0525] Synthesis of Compound 108

[0526] 1. Synthesis of intermediate 7-2:

[0527]

[0528] To a solution of 3-bromo-5H,6H,7H-cyclopentadieno[b]pyridin-7-amine (480 mg, 2.25 mmol, 1.0 equivalent) in DMF (10 mL), 2-methylpyridin-4-carboxylic acid (620 mg, 4.5 mmol, 2.0 equivalent), HATU (1.3 g, 3.4 mmol, 1.5 equivalent), and DIEA (876 mg, 6.8 mmol, 3.0 equivalent) were added. 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 obtain 460 mg (61%) of N-[3-bromo-5H,6H,7H-cyclopentadieno[b]pyridin-7-yl]-2-methylpyridin-4-carboxamide as a brown solid.

[0529] 2. Synthesis of intermediate 7-3:

[0530]

[0531] Under nitrogen atmosphere, a solution of N-[3-bromo-5H,6H,7H-cyclopentadieno[b]pyridin-7-yl]-2-methylpyridin-4-carboxamide (450 mg, 1.4 mmol, 1.0 equivalent) in dioxane (5 mL) was added with K4Fe(CN)6·3H2O (586 mg, 1.4 mmol, 1.0 equivalent), X-phos (67 mg, 0.14 mmol, 0.1 equivalent), second-generation Xphos (105 mg, 0.14 mmol, 0.1 equivalent), KOAc (266 mg, 2.7 mmol, 2.0 equivalent), and water (5 mL). 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 obtain 40 mg (11%) of N-[3-cyano-5H,6H,7H-cyclopentadien[b]pyridin-7-yl]-2-methylpyridin-4-carboxamide as a brown solid.

[0532] 3. Synthesis of intermediate 7-4:

[0533]

[0534] Hydroxylamine hydrochloride (20 mg, 0.3 mmol, 2.0 equivalent) and sodium bicarbonate (36 mg, 0.4 mmol, 3.0 equivalent) were added to a solution of N-[3-cyano-5H,6H,7H-cyclopentadieno[b]pyridin-7-yl]-2-methylpyridin-4-carboxamide (40 mg, 0.14 mmol, 1.0 equivalent) in MeOH (6 mL). 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-hydroxymethylamidine)-5H,6H,7H-cyclopentadieno[b]pyridin-7-yl]-2-methylpyridin-4-carboxamide as a white solid.

[0535] 4. Synthesis of compound 108:

[0536]

[0537] Propionyl propionate (56 mg, 0.4 mmol, 3.0 equivalent) was added to a solution of N-[3-(N-hydroxymethylammonium)-5H,6H,7H-cyclopentadieno[b]pyridin-7-yl]-2-methylpyridin-4-carboxamide (45 mg, 0.14 mmol, 1.0 equivalent) in dioxane (5 mL). The mixture was stirred at 90 °C for 2 h, cooled to room temperature, and concentrated under reduced pressure. Next, xylene (5 mL) was added, and the mixture was heated to 150 °C for 2 h, cooled to room temperature, concentrated under reduced pressure, and purified by preparative HPLC under the following conditions: (column, X-Bridge, C18, Shield RP, 19*150 mm 5 μm; mobile phase, water with 0.05% NH3H2O ​​and ACN (20.0% ACN to 40.0% ACN in 8 min, to 100.0% ACN in 5 min, decreasing to 0% ACN in 1 min); detector, UV 210 / 254 nm. This purification yielded 12.3 mg (24%) of N-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)-6,7-dihydro-5H-cyclopentadien[b]pyridin-7-yl)-2-methylisonicotinamide (compound 108) as a white solid. LRMS(ES) m / z 350 (M+H). 1 H-NMR: (300MHz, DMSO-d6, ppm): δ9.09(d,J=8.4Hz,1H),8.94(d,J=1.9Hz,1H),8 .55(dd,J=5.2,0.8Hz,1H),8.21(d,J=1.9Hz,1H),7.68-7.60(m,1H),7.56(dd,J= 5.1,1.6Hz,1H),5.54(q,J=8.5Hz,1H),3.14-2.98(m,2H),3.02-2.84(m,2H),2.6 2-2.48(m,1H),2.49(s,3H),2.01(dq,J=12.6,9.0Hz,1H),1.31(t,J=7.6Hz,3H).

[0538] Example 8

[0539] Synthesis of Compound 122

[0540] 1. Synthesis of intermediate 8-2:

[0541]

[0542] DIEA (1.8 g, 13.9 mmol, 3.0 equivalent) and HATU (2.7 g, 7.1 mmol, 1.5 equivalent) were added to a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (592 mg, 479 mmol, 1.0 equivalent) in DMF (10 mL). The mixture was stirred for 15 min and 6-bromo-2,3-dihydro-1-benzofuran-3-amine (1 g, 4.7 mmol, 1.0 equivalent) 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 obtain 1.3 g (86%) of N-(6-bromo-2,3-dihydro-1-benzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide as a grayish-white solid.

[0543] 2. Synthesis of intermediate 8-3:

[0544]

[0545] CuCN (587 mg, 6.6 mmol, 1.5 equivalent) was added 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 equivalent) in DMF (10 mL). 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 obtain 530 mg (45%) of N-(6-cyano-2,3-dihydro-1-benzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide as a grayish-white solid.

[0546] 3. Synthesis of intermediate 8-4:

[0547]

[0548] Sodium bicarbonate (250 mg, 1.5 equivalents) and hydroxylamine hydrochloride (164 mg, 2.4 mmol, 1.2 equivalents) were added 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 equivalents) in MeOH (8 mL). The mixture was heated at 60 °C for 2 h and concentrated under reduced pressure to obtain 580 mg of N-[6-(N-hydroxymethylamidine)-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.

[0549] 4. Synthesis of intermediate 8-5:

[0550]

[0551] Add (1,1-dimethoxyethyl)dimethylamine (168 mg, 1.3 mmol, 2.0 equivalent) to a solution of N-[6-(N-hydroxymethylammonium)-2,3-dihydro-1-benzofuran-3-yl]-1-methyl-1H-pyrazole-5-carboxamide (190 mg, 0.6 mmol, 1.0 equivalent) in dioxane (5 mL). Stir the mixture at 80 °C for 2 h, concentrate under reduced pressure, and purify by preparative HPLC under the following conditions: (2-Analytical HPLC-SHIMADZU (HPLC-10)): Column, XBridge Shield RP18 OBD column, 5 μm, 19*150 mm; Mobile phase, water (0.05% NH3·H2O) and ACN (25.0% ACN up to 45.0% ACN over 8 min); Detector, UV 220 nm. This purification yields 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 H-NMR: (CD3OD, 400MHz, ppm): δ7.67-7.65(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)

[0552] 5. Synthesis of compound 122:

[0553]

[0554] The 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 (50.0% ethanol maintained for 9 min); Detector, UV 254 / 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). 1H-NMR: (CD3OD, 300MHz, 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)

[0555] The following compounds were prepared by a method similar to that used for compound 122:

[0556] Compound numbering LRMS(ES)m / z 15 M+H=322 18 M+H=337 121 M+H=326 123 M+H=362

[0557] Example 9

[0558] Synthesis of Compound 124

[0559] 1. Synthesis of intermediate 9-2:

[0560]

[0561] DIEA (1.8 g, 13.9 mmol, 3.0 equivalent) and HATU (2.7 g, 7.1 mmol, 1.5 equivalent) were added to a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (592 mg, 4.7 mmol, 1.0 equivalent) in DMF (10 mL). The mixture was stirred for 15 min, and then 6-bromo-2,3-dihydro-1-benzofuran-3-amine (1 g, 4.7 mmol, 1.0 equivalent) 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 a grayish-white solid.

[0562] 2. Synthesis of intermediate 9-3:

[0563]

[0564] CuCN (587 mg, 6.6 mmol, 1.5 equivalent) was added 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 equivalent) in DMF (10 mL). 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 obtain 530 mg (45%) of N-(6-cyano-2,3-dihydro-1-benzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide as a grayish-white solid.

[0565] 3. Synthesis of intermediate 9-4:

[0566]

[0567] Sodium bicarbonate (250 mg, 1.5 equivalents) and hydroxylamine hydrochloride (164 mg, 2.4 mmol, 1.2 equivalents) were added 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 equivalents) in MeOH (8 mL). The mixture was heated at 60 °C for 2 h and concentrated under reduced pressure to obtain 580 mg of N-[6-(N-hydroxymethylamidine)-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.

[0568] 4. Synthesis of intermediate 9-5:

[0569]

[0570] A solution of N-[6-(N-hydroxymethylammonium)-2,3-dihydro-1-benzofuran-3-yl]-1-methyl-1H-pyrazole-5-carboxamide (190 mg, 0.6 mmol, 1.0 equivalent) in dioxane (5 mL) was added dropwise to 2,2-difluoroacetic acid 2,2-difluoroacetyl ester (220 mg, 1.3 mmol, 2.0 equivalent). 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-Analytical HPLC-SHIMADZU (HPLC-10)): Column, XBridgeShield RP18 OBD column, 5 μm, 19*150 mm; Mobile phase, water (0.05% NH3H2O) and ACN (33.0% ACN up to 55.0% ACN over 8 min); Detector, UV 220 nm. This purification yields 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).

[0571] 5. Synthesis of compound 124:

[0572]

[0573] Purification of a racemic mixture (85 mg) 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 (35.0% ethanol for 8 min); Detector, UV 254 / 220 nm. This purification yielded 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, 300MHz, ppm): δ7.70-7.67(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).

[0574] Example 10

[0575] Synthesis of Compound 139

[0576] 1. Synthesis of intermediate 10⁻²:

[0577]

[0578] Ammonium formate (300 g, 4.76 mol, 10.0 equivalent) was added to a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (100 g, 474 mmol, 1.00 equivalent) in methanol (1.5 L). After stirring for 1 h, NaBH3CN (90 g, 1.43 mol, 3.02 equivalent) 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 give 64 g (64%) of 5-bromo-2,3-dihydro-1H-inden-1-amine as a brown solid.

[0579] 2. Synthesis of intermediate 10⁻³:

[0580]

[0581] DIEA (5.5 g, 42.6 mmol, 3.00 equivalent) and HATU (8.1 g, 21.3 mmol, 1.50 equivalent) were added to a solution of 2-methylpyridin-4-carboxylic acid (1.95 g, 14.2 mmol, 1.00 equivalent) in DMF (20 mL). After stirring at room temperature for 15 min, 5-bromo-2,3-dihydro-1H-indene-1-amine (3.0 g, 14.2 mmol, 1.00 equivalent) 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 chromatography (EA / PE = 2 / 1) to give 4 g (85%) of N-(5-bromo-2,3-dihydro-1H-indene-1-yl)-2-methylpyridin-4-carboxamide as a yellow solid.

[0582] 3. Synthesis of intermediate 10⁻⁴:

[0583]

[0584] TEA (3.9 g, 38.6 mmol, 3.00 equivalent) and Pd(dppf)Cl2.CH2Cl2 (1.06 g, 1.3 mmol, 0.1 equivalent) were added to a solution of N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpyridin-4-carboxamide (4.28 g, 13.0 mmol, 1.00 equivalent) in a mixture of ethanol (120 mL) and DMSO (12 mL). The mixture was then charged with CO (20 atm). The mixture was stirred at 120 °C under CO for 2 days, purged to release CO, decanted into water, and extracted three times with EA. The combined organic layers were concentrated under reduced pressure and purified by silica gel chromatography (EA / PE, 3 / 2) to give 3.5 g (83%) of ethyl 1-(2-methylpyridin-4-acylamino)-2,3-dihydro-1H-indene-5-carboxylate as a yellow solid.

[0585] 4. Synthesis of intermediate 10⁻⁵:

[0586]

[0587] A solution of ethyl 1-(2-methylpyridin-4-acylamino)-2,3-dihydro-1H-indene-5-carboxylic acid (1.2 g, 3.70 mmol, 1.00 equivalent) in ethanol (10 mL) was added to sodium hydroxide (300 mg, 7.50 mmol, 2.03 equivalent) in water (2 mL). After stirring at room temperature for 12 h, the pH of the solution was adjusted to 4 to 5 using HCl (1N). The solid was collected by filtration and dried in an oven to give 0.9 g (82%) of 1-(2-methylpyridin-4-acylamino)-2,3-dihydro-1H-indene-5-carboxylic acid as a white solid.

[0588] 5. Synthesis of intermediate 10⁻⁶:

[0589]

[0590] DIEA (523 mg, 4.05 equivalents) and HATU (578 mg, 1.52 mmol, 1.50 equivalents) were added to a solution of 1-(2-methylpyridin-4-acylamino)-2,3-dihydro-1H-indene-5-carboxylic acid (300 mg, 1.01 mmol, 1.00 equivalents) in DMF (5 mL). After stirring for 15 min at room temperature, propyne-1-amine (167 mg, 3.03 mmol, 3.00 equivalents) was added. The mixture was stirred for another 2 h and purified by Combi-Flash using a C18 column: mobile phase A: water (0.05% in H2O).

[0591] NH4HCO3), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 5% B to 70% B over 26 min; detector, UV 254 nm. This produces 160 mg (47%) of 2-methyl-N-[5-[(prop-2-yn-1-yl)carbamoyl]-2,3-dihydro-1H-inden-1-yl]pyridine-4-carboxamide as a white solid.

[0592] 6. Synthesis of intermediate 10⁻⁷:

[0593]

[0594] FeCl3 (37 mg, 0.23 mmol, 0.50 equivalent) was added to a solution of 2-methyl-N-[5-[(prop-2-yn-1-yl)carbamoyl]-2,3-dihydro-1H-indene-1-yl]pyridine-4-carboxamide (150 mg, 0.45 mmol, 1.00 equivalent) in DCE (5 mL). The mixture was stirred at 80 °C for 2 days, concentrated under reduced pressure, and purified by Combi-Flash using a C18 column: mobile phase A: water (0.05% NH4HCO3 in H2O), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 5% B to 70% B over 36 min; detector: UV 254 nm. This produces 91.7 mg (61%) of 2-methyl-N-[5-(5-methyl-1,3-oxazol-2-yl)-2,3-dihydro-1H-indene-1-yl]pyridine-4-carboxamide as a white solid.

[0595] 7. Synthesis of compound 139:

[0596]

[0597] Purification of a racemic mixture (80 mg) 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: 30B to 30B over 8 min; 220 / 254 nm; RT1:

[0598] 5.20; RT2: 6.55. This yielded 32.4 mg (41%) of (R)-2-methyl-N-(5-(5-methyloxazol-2-yl)-2,3-dihydro-1H-inden-1-yl)isonicotinamide (compound 139) as a white solid. LRMS(ES) m / z 334 (M+H). 1H-NMR: (CD3OD, 300MHz, ppm): δ8.55-8.53(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).

[0599] The following compounds were prepared by a method similar to that used for compound 139:

[0600] Compound numbering LRMS(ES)m / z 140 M+H=334

[0601] Example 11

[0602] Synthesis of Compound 141

[0603] 1. Synthesis of intermediate 11-2:

[0604]

[0605] Cyclopropaneformyl chloride (8.7 g, 82.8 mmol, 1.1 equivalent) was added to a solution of N-[(1R)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (22 g, 75.5 mmol, 1.0 equivalent) in pyridine (350 mL). The mixture was heated to 60 °C for 2 h, then to 100 °C overnight. The mixture was then cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 15 / 85) to give 15 g (58%) of N-[(1R)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester as a white solid. LRMS(ES) m / z 286 (M+H-56).

[0606] 2. Synthesis of intermediate 11-3:

[0607]

[0608] HCl (4 M in dioxane, 21 mL, 10.0 equivalent) was added to a solution of N-[(1R)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (2.9 g, 8.4 mmol, 1.0 equivalent) in DCM (42 mL). 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-indene-1-amine dihydrochloride as a white solid. LRMS(ES) m / z 225 (M+H-17).

[0609] 3. Synthesis of compound 141:

[0610]

[0611] Add HOAt (6 g, 44.1 mmol, 2.5 equivalents), EDCI (8 g, 41.7 mmol, 2.5 equivalents), DIEA (11.3 g, 87.4 mmol, 5.0 equivalents) and (1R)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-amine hydrochloride (4.8 g, 17.3 mmol, 1.0 equivalents) to a solution of 2-methyl-2H-1,2,3,4-tetrazol-5-carboxylic acid (5 g, 39.1 mmol, 2.3 equivalents) in DMF (150 mL). 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 obtain an intermediate product. This intermediate product was then ground with a mixture of hexane and EA (15 / 1) to obtain 4.75 g (88%) of product as a gray solid. This batch was combined with a 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 a grayish-white solid. LRMS(ES) m / z 352 (M+H). 1¹H-NMR: (400MHz, chloroform-d, ppm) δ 7.95 (s, 1H), 7.91 (d, J = 7.9Hz, 1H), 7.43 (d, J = 7.9Hz, 1H), 7.33 (d, J = 8.7Hz, 1H), 5.78 (q, J = 7.9Hz, 1H), 4.44 (s, 3H), 3.11 (ddd, J = 16.2, 8.8,3.8Hz,1H),2.98(dt,J=16.2,8.1Hz,1H),2.75(dtd,J=12.0,7.8,3.9Hz,1H), 2.25(ddd,J=9.6,7.4,4.1Hz,1H), 2.03(dq,J=12.9,8.2Hz,1H), 1.45-1.19(m,4H).

[0612] The following compounds were prepared by a method similar to that used for compound 141:

[0613]

[0614]

[0615]

[0616]

[0617]

[0618] Example 12

[0619] Synthesis of Compound 142

[0620] 1. Synthesis of intermediate 12-2:

[0621]

[0622] Add 2-methylpropionyl ester of 2-methylpropionate (28.5 g, 180 mmol, 1.1 equivalent) to a solution of N-[(1R)-5-(N-hydroxymethylammonium)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (50.0 g, 172 mmol, 1.00 equivalent) in dioxane (500 mL). 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 obtain 47 g (79%) of N-[(1R)-5-[5-(propyl-2-yl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-indene-1-yl] tert-butyl carbamate as a white solid.

[0623] 2. Synthesis of intermediate 12-3:

[0624]

[0625] Hydrochloric acid (4 M in dioxane, 155 mL, 10.0 equivalent) was added to a solution of N-[(1R)-5-[5-(propyl-2-yl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (21.2 g, 61.7 mmol, 1.0 equivalent) in DCM (400 mL). The mixture was stirred overnight at room temperature and the solid was collected and dried to give 16.3 g (83%) of (1R)-5-[5-(propyl-2-yl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-indene-1-amine hydrochloride as a white solid.

[0626] 3. Synthesis of compound 142:

[0627]

[0628] To a solution of 2-methyl-2H-1,2,3,4-tetrazol-5-carboxylic acid (37.8 g, 295 mmol, 1.5 equivalents) in DMF (500 mL), HOAt (40.1 g, 295 mmol, 1.5 equivalents), EDCI (56.7 g, 296 mmol, 1.50 equivalents), DIEA (102 g, 785 mmol, 4.0 equivalents), and (1R)-5-[5-(propyl-2-yl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-indene-1-amine hydrochloride (55.0 g, 197 mmol, 1.0 equivalents) were added. The mixture was stirred at 40 °C for 2 h and combined with four other batches prepared using the same procedure (3.6 mmol, 35.7 mmol, 197 mmol, and 197 mmol scales of starting material amines) for further processing. Water was added to the combined solutions. The precipitate was collected by filtration, washed with more water, and redissolved in DCM. The DCM solution was washed with water and saturated NH4Cl solution, 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 a grayish-white solid. LRMS(ES) m / z 354 (M+H). 1 H-NMR: (300MHz, chloroform-d, ppm)δ

[0629] 7.97(d,J=1.4Hz,1H),7.93(dd,J=7.9,1.1Hz,1H),7.42(d,J=7.9Hz,1H), 7.30(d,J=8.8Hz,1H),5.77(q,J=7.9Hz,1H),4.42(s,3H),3.26(hept,J=7 .0Hz,1H),3.10(ddd,J=16.2,8.7,3.9Hz,1H),2.97(dt,J=16.1,8.0Hz,1H ), 2.83-2.65 (m, 1H), 2.02 (dt, J = 13.0, 8.1Hz, 1H), 1.44 (d, J = 7.0Hz, 6H).

[0630] Example 13

[0631] Synthesis of Compound 143

[0632] 1. Synthesis of intermediate 13-2:

[0633]

[0634] Cyclobutane formyl chloride (2 g, 16.9 mmol, 1.2 equivalents) was added to a solution of N-[(1R)-5-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate (4 g, 13.7 mmol, 1.0 equivalent) in pyridine (80 mL). The mixture was heated to 60 °C for 3 h, followed by heating to 100 °C overnight. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 5 / 95) to give 3.3 g (68%) of N-[(1R)-5-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate as a grayish-white solid.

[0635] 2. Synthesis of intermediate 13-3:

[0636]

[0637] Hydrochloric acid (4M in dioxane, 21 mL, 10.0 equivalent) was added to a solution of N-[(1R)-5-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (3 g, 8.4 mmol, 1.0 equivalent) in dichloromethane (60 mL). The mixture was stirred overnight at room temperature, 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-indene-1-amine hydrochloride as a white solid.

[0638] 3. Synthesis of compound 143:

[0639]

[0640] Add (1R)-5-(5-cyclobutyl-1,2,3,4-tetrazol-5-carboxylic acid (1.0 g, 7.8 mmol, 1.3 equivalents) to a solution of 2-methyl-2H-1,2,3,4-tetrazol-5-carboxylic acid (1.0 g, 7.8 mmol, 1.3 equivalents) in DMF (100 mL) to (1.0 g, 6.2 mmol, 1.0 equivalents), HOAt (1.5 g, 11.0 mmol, 1.8 equivalents), EDCI (2.1 g, 11.0 mmol, 1.8 equivalents), and DIEA (4.0 g, 31.0 mmol, 5.0 equivalents). Stir the mixture for 30 min and add EA (100 mL) and water (100 mL). Extract the aqueous layer three times with EA (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by passing through a C18 column with 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: (300MHz, methanol-d4, ppm): δ8.01-7.88(m,2H),7.44(d,J=7.9Hz,1H),5.74(t,J=8.0Hz,1H),4.45(s,3H) ,3.97-3.79(m,1H),3.26-3.09(m,1H),3.00(dd,J=16.1,8.4Hz,1H),2.75-2.45(m,5H),2.32-2.05(m,3H).

[0641] Example 14

[0642] Synthesis of Compound 183

[0643]

[0644] A solution of HOAt (9.6 g, 70.5 mmol, 1.8 equivalent), EDCI (13.5 g, 70.4 mmol, 1.0 equivalent), DIEA (19.2 g, 148.2 mmol, 3.80 equivalent) in DMF (150 mL) was added to a solution of 2-methyl-2H-1,2,3,4-tetrazol-5-carboxylic acid (5 g, 39.0 mmol, 1.0 equivalent) and (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-amine (9.0 g, 39.0 mmol, 1.0 equivalent) in 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 five times with DCM (500 mL). The combined organic layers were washed five 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 obtain 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(300MHz,DMSO-d6)δ9.42(d,J=8.4Hz,1H),7.89-7.76(m,2H),7.34(d,J=7.9Hz,1H),5.58(q,J=8.2Hz,1 H), 4.41 (s, 3H), 3.14-2.80 (m, 4H), 2.47-2.38 (m, 1H), 2.13 (dq, J = 12.5, 8.7Hz, 1H), 1.31 (t, J = 7.5Hz, 3H).

[0645] Example 15

[0646] Synthesis of Compound 184

[0647] 1. Synthesis of intermediate 15-2:

[0648]

[0649] A solution of N-[(1R)-5-(N-hydroxymethylammonium)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (16 g, 54.9 mmol, 1.0 equivalent) in dioxane (300 mL) was added with propionyl propionate (8.4 g, 64.5 mmol, 1.2 equivalent). 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 obtain 17.5 g (97%) of N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester as a white solid.

[0650] 2. Synthesis of intermediate 15-3:

[0651]

[0652] TFA (24 mL) was added to a solution of N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (17.6 g, 53.4 mmol, 1.0 equivalent) in DCM (120 mL). The mixture was stirred overnight at room temperature 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 using 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 give 11.2 g of (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-amine as a brown oil.

[0653] 3. Synthesis of compound 184:

[0654]

[0655] DIEA (12.6 g, 97.5 mmol, 2.0 equivalent), HOAt (19.8 g, 145.8 mmol, 3.0 equivalent), and EDCI (28 g, 146.1 mmol, 3.0 equivalent) were added to a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (6.1 g, 48.4 mmol, 1.0 equivalent) in DMF (300 mL). The mixture was stirred for 15 min, and then (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-amine (11.2 g, 48.9 mmol, 1.0 equivalent) was added. The mixture was then stirred for 3 h, 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 ground together 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, 300MHz, ppm): δ8.41 (1H, d, J = 8.4Hz), 8.16 (1H, s), 7.91-7.79 (3H, m), 7.34 (1H, d, J = 7.9Hz), 5.53 ( 1H,q,J=8.3Hz),3.84(3H,s),3.13-2.81(4H,m),2.44(1H,dd,J=7.9,4.7Hz),1.95(1H,m),1.33(3H,t,J=7.5Hz).

[0656] Example 16

[0657] Synthesis of Compound 196

[0658] 1. Synthesis of intermediate 16-2:

[0659]

[0660] Sodium carbonate (45.9 g, 434 mmol, 3.0 equivalent) and I₂ (36.6 g, 144 mmol, 1.0 equivalent) were added in multiple portions over a 3-hour period to a solution of 5-bromopyridin-3-ol (25 g, 144 mmol, 1.0 equivalent) in water (500 mL). The mixture was stirred for 1 hour and the pH was adjusted to 7 using hydrochloric acid (2N). The resulting precipitate was collected and dried to give 39 g (91%) of 5-bromo-2-iodopyridin-3-ol as a white solid.

[0661] 2. Synthesis of intermediate 16-3:

[0662]

[0663] Potassium carbonate (54.5 g, 396 mmol, 3.0 equivalent) and BnBr (23.6 g, 138 mmol, 1.05 equivalent) were added dropwise to a solution of 5-bromo-2-iodopyridin-3-ol (39.5 g, 132 mmol, 1.1 equivalent) in ACN (600 mL) under stirring at 0 °C. The mixture was stirred at room temperature for 5.5 h, cooled to 0 °C, and quenched dropwise with water at 0 °C. The solid was collected by filtration and ground together with 5% EA in PE (100 mL) to give 44.4 g (86%) of 3-(benzyloxy)-5-bromo-2-iodopyridin as a white solid.

[0664] 3. Synthesis of intermediate 16-4:

[0665]

[0666] To a solution of 40 g (103 mmol, 1.0 equivalent) of 3-(benzyloxy)-5-bromo-2-iodopyridine in 1 L THF cooled to -20 °C, i-PrMgCl·LiCl (1.3 M in THF, 87 mL, 103 mmol, 1.1 equivalent) was added dropwise. The mixture was stirred at -20 °C for 2 h and DMF (11.2 g, 154 mmol, 1.5 equivalent) 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-carboxaldehyde as a grayish-white solid.

[0667] 4. Synthesis of intermediate 16-5:

[0668]

[0669] FeCl3 (30 g, 185 mmol, 2.00 equivalent) was added to a solution of 27 g (92.4 mmol, 1.0 equivalent) of 3-(benzyloxy)-5-bromopyridine-2-carboxaldehyde (cooled to 0 °C) in DCM (600 mL). 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-carboxaldehyde as a pale yellow solid.

[0670] 5. Synthesis of intermediate 16-6:

[0671]

[0672] Trimethyl(oxo)-6-sulfanylium iodide (30 g, 136 mmol, 2.5 equivalent) and t-BuOK (15.3 g, 136 mmol, 2.5 equivalent) were added in multiple portions over a 20-minute period to a solution of 5-bromo-3-hydroxypyridine-2-carboxaldehyde (11 g, 54.5 mmol, 1.0 equivalent) in DMSO (200 mL). The mixture was stirred at room temperature for 1 h, cooled to 0 °C, and quenched at 0 °C with saturated NH4Cl solution (300 mL). The resulting solution was extracted four 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 obtain 7.6 g (65%) of 6-bromo-2H,3H-furano[3,2-b]pyridine-3-ol as a yellow solid.

[0673] 6. Synthesis of intermediate 16-7:

[0674]

[0675] Over a 20-minute period, DPPA (5.7 g, 20.6 mmol, 1.1 equivalent) and DBU (3.1 g, 20.6 mmol, 1.1 equivalent) were added dropwise to a solution of 6-bromo-2H,3H-furano[3,2-b]pyridine-3-ol (4.1 g, 18.8 mmol, 1.0 equivalent) cooled to 0 °C in toluene (85 mL). After stirring at room temperature for 1 h, the resulting solution was diluted with EA (150 mL), washed twice with water (100 mL) and then with brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 9) to obtain 1.6 g (35%) of 3-azido-6-bromo-2H,3H-furano[3,2-b]pyridine as a colorless oil.

[0676] 7. Synthesis of intermediate 16-8:

[0677]

[0678] A solution of 1.0 g, 4.2 mmol, 1.0 equivalent of 3-azido-6-bromo-2H,3H-furano[3,2-b]pyridine in THF (22 mL) was added to a solution of PPh3 (1.3 g, 5.0 mmol, 1.2 equivalent) and potassium hydroxide (583 mg, 10.4 mmol, 2.5 equivalent) in water (5.5 mL). The mixture was stirred at room temperature for 1 h, then stirred 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-furano[3,2-b]pyridine-3-amine as a yellow oil.

[0679] 8. Synthesis of intermediate 16-9:

[0680]

[0681] HATU (981 mg, 2.6 mmol, 1.5 equivalents) and DIEA (666 mg, 5.2 mmol, 3.0 equivalents) were added to a solution of 2-methylpyridin-4-carboxylic acid (306 mg, 2.3 mmol, 1.3 equivalents) in DMF (5 mL). The mixture was stirred for 5 min, and then 6-bromo-2H,3H-furano[3,2-b]pyridin-3-amine (370 mg, 1.7 mmol, 1.0 equivalents) was added. The mixture was then stirred for 2 h and decanted 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 obtain 440 mg (77%) of N-[6-bromo-2H,3H-furano[3,2-b]pyridin-3-yl]-2-methylpyridin-4-carboxamide as a yellow solid.

[0682] 9. Synthesis of intermediate 16-10:

[0683]

[0684] Zn(CN)2 (243 mg, 2.1 mmol, 1.0 equivalent) and Pd(PPh3)4 (242 mg, 0.2 mmol, 0.1 equivalent) were added to a solution of N-[6-bromo-2H,3H-furano[3,2-b]pyridin-3-yl]-2-methylpyridin-4-carboxamide (700 mg, 2.1 mmol, 1.0 equivalent) in DMF (20 mL). The mixture was stirred overnight at 110°C, 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 obtain 400 mg (68%) of N-[6-cyano-2H,3H-furano[3,2-b]pyridin-3-yl]-2-methylpyridin-4-carboxamide as a pale yellow solid.

[0685] 10. Synthesis of intermediates 16-11:

[0686]

[0687] A solution of N-[6-cyano-2H,3H-furano[3,2-b]pyridin-3-yl]-2-methylpyridin-4-carboxamide (50 mg, 0.18 mmol, 1.00 equivalent) in ethanol (5 mL) was supplemented with NH₂OH·HCl (25 mg, 0.36 mmol, 2.3 equivalent) and TEA (55 mg, 0.54 mmol, 3.05 equivalent). The mixture was stirred at 75 °C for 2 h and concentrated under reduced pressure to give 50 mg of N-[6-(N-hydroxymethylammonium)-2H,3H-furano[3,2-b]pyridin-3-yl]-2-methylpyridin-4-carboxamide as a yellow solid.

[0688] 11. Synthesis of intermediates 16-12:

[0689]

[0690] A solution of N-[6-(N-hydroxymethylammonium)-2H,3H-furano[3,2-b]pyridin-3-yl]-2-methylpyridin-4-carboxamide (300 mg, 0.96 mmol, 1.0 equivalent) in dioxane (10 mL) was supplemented with 2,2-difluoroacetic acid 2,2-difluoroacetyl ester (416 mg, 2.39 mmol, 2.5 equivalent). The mixture was stirred at 60 °C for 1.5 h, concentrated under reduced pressure, and purified by preparative HPLC under the following conditions: (CombiFlash-1): column, C18 silica gel; mobile phase, water (0.5% NH4HCO3) / ACN = 95 / 5 increased to water (0.5% NH4HCO3) / ACN = 75 / 25 over 10 min; detector, UV 254 nm. This purification yielded 120 mg (30%) of N-[6-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-2H,3H-furano[3,2-b]pyridin-3-yl]-2-methylpyridin-4-carboxamide as a white solid. LRMS(ES) m / z 374 (M+H). 1 ¹H-NMR: (400MHz, methanol-d⁴, ppm): δ 8.82 (d, J = 1.7Hz, 1H), 8.54 (d, J = 5.3Hz, 1H), 7.87 (d, J = 1.7Hz, 1H), 7.69 (s, 1H), 7.64-

[0691] 7.57 (m, 1H), 7.24 (t, J = 51.8Hz, 1H), 5.86 (dd, J = 9.2, 5.7Hz, 1H), 5.05 (t, J = 9.6Hz, 1H), 4.60 (dd, J = 10.1, 5.7Hz, 1H), 2.59 (s, 3H).

[0692] 12. Synthesis of compound 196:

[0693]

[0694] N-[6-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-2H,3H-furano[3,2-b]pyridin-3-yl]-2-methylpyridin-4-carboxamide (90 mg, 0.24 mmol, 1.00 equivalent) 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 (maintained at 50.0% ethanol for 13 min); Detector, UV 220 / 254 nm. This purification yielded 37.4 mg (42%) of (S)-N-(6-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydrofurano[3,2-b]pyridin-3-yl)-2-methylisonicotinamide (compound 196) as a white solid. LRMS(ES) m / z 374 (M+H). 1 H-NMR: (400MHz, methanol-d4, ppm): δ8.82(d,J=1.7Hz,1H),8.54(d,J=5.3Hz,1H),7.87(d,J=1.7Hz,1H),7.69(s,1H),7.64-7.57( m, 1H), 7.24 (t, J = 51.8Hz, 1H), 5.86 (dd, J = 9.2, 5.7Hz, 1H), 5.05 (t, J = 9.6Hz, 1H), 4.60 (dd, J = 10.1, 5.7Hz, 1H), 2.59 (s, 3H).

[0695] The following compounds were prepared by a method similar to that used for compound 196:

[0696] Compound numbering LRMS(ES)m / z 187 M+H=338 188 M+H=338 196 M+H=374

[0697] Example 17

[0698] Synthesis of Compound 217

[0699] 1. Synthesis of intermediate 17-2:

[0700]

[0701] NH₂OH (23 g, 349 mmol, 1.1 equivalent, 50 wt% in water) was added to a solution of 2,2-difluoroacetonitrile (25 g, 325 mmol, 1.00 equivalent) in ethanol (100 mL) cooled to -10 °C. The mixture was stirred overnight at room temperature, concentrated under reduced pressure, and azeotropically reacted twice with THF to give 37 g of (Z)-2,2-difluoro-N'-hydroxyacetamidine as a green liquid.

[0702] 2. Synthesis of intermediate 17-3:

[0703]

[0704] Add DIEA (2.8 g, 21.7 mmol, 3.0 equivalent), HATU (4.11 g, 10.8 mmol, 1.50 equivalent), and (Z)-2,2-difluoro-N'-hydroxyacetamidine (2.38 g, 21.6 mmol, 3.0 equivalent) 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 equivalent) in DMF (20 mL). Stir the mixture for 2 h and pour it into a saturated NH4Cl solution (200 mL). Extract the resulting solution 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 obtain 2.52 g (95%) of N-[(1R)-5-[[(1Z)-2,2-difluoro-1-(hydroxyimino)ethyl]carbamoyl]-2,3-dihydro-1H-indene-1-yl]tert-butyl carbamate as a brown solid.

[0705] 3. Synthesis of intermediate 17-4:

[0706]

[0707] TBAF (1M in THF, 8.3 mL, 2.0 equivalent) was added to a solution of N-[(1R)-5-[[(1Z)-2,2-difluoro-1-(hydroxyimino)ethyl]carbamoyl]-2,3-dihydro-1H-indene-1-yl]tert-butyl carbamate (1.53 g, 4.1 mmol, 1.0 equivalent) in 70 mL of THF. The mixture was stirred overnight at 60 °C, cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 3) to give 490 mg (33%) of N-[(1R)-5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-2,3-dihydro-1H-indene-1-yl]tert-butyl carbamate as a light orange solid.

[0708] 4. Synthesis of intermediate 17-5:

[0709]

[0710] TFA (1 mL) was added to a solution of N-[(1R)-5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (490 mg, 1.4 mmol, 1.0 equivalent) in DCM (5 mL). The mixture was stirred for 1 h, concentrated under reduced pressure, and redissolved in THF and water. The pH of the solution was adjusted to 12 using NaOH (2N), and the solution was extracted four times with EA. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum to give 500 mg of (1R)-5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-2,3-dihydro-1H-indene-1-amine as a green oil.

[0711] 5. Synthesis of Compound 217

[0712]

[0713] Add DIEA (62 mg, 0.48 mmol, 2.00 equivalence), EDCI (138 mg, 0.72 mmol, 3.00 equivalence), and HOAt (98 mg, 0.72 mmol, 3.00 equivalence) to a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (30 mg, 0.24 mmol, 1.0 equivalence) in DMF (4 mL). Stir the mixture for 5 min and add (1R)-5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-2,3-dihydro-1H-indene-1-amine (60 mg, 0.24 mmol, 1.0 equivalence). The mixture was stirred for 1 h, filtered to remove solid precipitate, and purified by preparative HPLC under the following conditions: (2-Analytical HPLC-SHIMADZU (HPLC-10)): Column, XBridge Shield RP18 OBD column, 5 μm, 19*150 mm; Mobile phase, water (0.05% NH3H2O) and ACN (35.0% ACN up to 55.0% ACN over 8 min); Detector, UV 220 nm. This purification yielded 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). 1H-NMR: (CD3OD, 300MHz, δppm): δ8.10-8.07(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).

[0714] The following compounds were prepared by a method similar to that used for compound 217:

[0715] Compound numbering LRMS(ES)m / z 213 M+H=374 215 M+H=361 216 M+H=362

[0716] Example 18

[0717] Synthesis of Compound 222

[0718] 1. Synthesis of intermediate 18-2:

[0719]

[0720] Pyridine (158 g, 2.0 mol, 3.0 equivalent) was added to a solution of 100 g (666.7 mmol, 1.0 equivalent) in DCM (2.5 L). The mixture was cooled to -10 °C, and a solution of trifluoromethanesulfonate (300 g, 1.1 mol, 1.6 equivalent) in DCM (0.5 L) was added dropwise over a period of 2 h. The mixture was then stirred at 0 °C to 4 °C for 3 h, quenched with water (1 L), and extracted three times with dichloromethane (300 mL). The combined organic layers were washed twice with citric acid (1N, 500mL), then with saturated sodium bicarbonate (500mL) and brine (500mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 194.5g of a black solid, 3-oxo-2,3-dihydro-1-benzofuran-6-yl trifluoromethanesulfonic acid. This black solid was used in the next step without further purification. LRMS(ES) m / z 285 (M+H).

[0721] 2. Synthesis of intermediate 18-3:

[0722]

[0723] TEA (76 g, 751.1 mmol, 2.3 equivalence) was added dropwise to formic acid (107.3 g, 2.3 mmol, 3.5 equivalence) cooled to 0 °C in an RB flask and stirred for 30 min. A solution of 3-oxo-2,3-dihydro-1-benzofuran-6-yl trifluoromethanesulfonic acid (194.5 g, 666.7 mmol, 1.0 equivalence) in DCM (4 L) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (chloro)(p-propyltoluene)ruthenium(II) (6.45 g, 10.1 mmol, 0.015 equivalence) were added to this mixture. The mixture was stirred overnight and an additional amount of (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine(chloro)(p-propyltoluene)ruthenium(II) (2 g, 3.2 mmol, 0.05 equivalents) was added. The mixture was stirred for another day, poured into water, stirred for 30 min, and filtered to remove solid byproducts. 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)-trifluoromethanesulfonic acid 3-hydroxy-2,3-dihydro-1-benzofuran-6-yl ester as a dark brown oil. This dark brown oil was used in the next step without further purification. LRMS(ES) m / z 267 (M+H).

[0724] 3. Synthesis of intermediate 18-4:

[0725]

[0726] Over a 50-minute period, DPPA (228.8 g, 831.9 mmol, 1.25 equivalents) and DBU (151.7 g, 998.249 mmol, 1.50 equivalents) were added dropwise to a solution of (3R)-trifluoromethanesulfonic acid 3-hydroxy-2,3-dihydro-1-benzofuran-6-yl ester (208 g, 665.5 mmol, 1.0 equivalents) cooled to 0 °C in toluene (2.5 L). The mixture was stirred overnight, poured into EA (2 L) and water (1 L), stirred for 30 min, 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 obtain 162 g of (3S)-trifluoromethanesulfonic acid 3-azido-2,3-dihydro-1-benzofuran-6-yl ester, which was a yellow oil.

[0727] 4. Synthesis of intermediate 18-5:

[0728]

[0729] PPh3 (165.2 g, 629.9 mmol, 1.2 equivalents) was slowly added to a solution of (3S)-trifluoromethanesulfonic acid 3-azoyl-2,3-dihydro-1-benzofuran-6-yl ester (162.4 g, 525.2 mmol, 1.0 equivalent) in THF (1.5 L). The mixture was stirred for 30 min, poured into water (300 mL), heated to 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 obtain 338.5 g of (3S)-trifluoromethanesulfonic acid 3-amino-2,3-dihydro-1-benzofuran-6-yl ester as a dark red oil, which was used in the next step without further purification. LRMS(ES) m / z 267 (M+H-17).

[0730] 5. Synthesis of intermediate 18-6:

[0731]

[0732] A solution of TEA (158 g, 1.6 mol, 3.0 equivalent) and a solution of Boc₂O (228 g, 1.0 mol, 2.0 equivalent) in DCM (500 mL) was added dropwise to a solution of (3S)-trifluoromethanesulfonic acid 3-amino-2,3-dihydro-1-benzofuran-6-yl ester (338 g, from the dark red oil from the previous step, 0.52 mol, 1.0 equivalent) in DCM (3 L). 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 N-[(3S)-6-[(trifluoromethane)sulfonyloxy]-2,3-dihydro-1-benzofuran-3-yl] tert-butyl carbamate as a white solid. LRMS(ES)m / z328(M+H-56).

[0733] 6. Synthesis of intermediate 18-7:

[0734]

[0735] Under nitrogen atmosphere, a solution of N-[(3S)-6-[(trifluoromethane)sulfonyloxy]-2,3-dihydro-1-benzofuran-3-yl]tert-butyl carbamate (62.3 g, 162.5 mmol, 1.0 equivalent) in dioxane (620 mL) was added with K4Fe(CN)6·3H2O (34.3 g, 81.3 mmol, 0.5 equivalent), second-generation XPhos pre-catalyst (1.9 g, 2.4 mmol, 0.015 equivalent), X-Phos (1.2 g, 2.4 mmol, 0.015 equivalent), KOAc (31.9 g, 325.0 mmol, 2.0 equivalent), and water (620 mL). The mixture was stirred at 100 °C for 4 h, cooled to room temperature, and combined with other batches (total 100 g of trifluoromethanesulfonate starting material). 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, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 15 / 85) to obtain the intermediate. The intermediate was purified using a mixture of EtOH and water (3 / 2), and after filtration and drying, 45 g (23% after 6 steps) of N-[(3S)-6-cyano-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester was obtained as a white solid. LRMS(ES) m / z 261 (M+H). Chirality_SFC: 98.6% ee., CHIRALPAK AD-H (4.6*100 mm, 5 μm).

[0736] 7. Synthesis of intermediate 18-8:

[0737]

[0738] Hydroxylamine hydrochloride (5.8 g, 84.0 mmol, 2.0 equivalence) and TEA (10.7 g, 105.7 mmol, 2.5 equivalence) were added to a solution of N-[(3S)-6-cyano-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (11 g, 42.3 mmol, 1.0 equivalence) in ethanol (240 mL). The mixture was stirred at 55 °C for 4 h, cooled to room temperature, combined with a previous batch (300 mg, 1.2 mmol nitrile starting material), and concentrated under reduced pressure. The mixture was dissolved in EA (500 mL), washed twice with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 12.8 g of N-[(3S)-6-(N-hydroxymethylammonium)-2,3-dihydro-1-benzofuran-3-yl] tert-butyl carbamate as a white solid. This white solid product was used directly in the next step without further purification. LRMS(ES) m / z 294 (M+H).

[0739] 8. Synthesis of intermediate 18-9:

[0740]

[0741] Cyclopropaneformyl chloride (6.3 g, 59.8 mmol, 1.1 equivalent) was added to a solution of N-[(3S)-6-(N-hydroxymethylammonium)-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (16 g, 54.6 mmol, 1.0 equivalent) in pyridine (200 mL). 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 a saturated NH4Cl solution (500 mL). The aqueous layer was extracted four times with EA (500 mL), and the combined organic layer was washed four times with NH4Cl solution (500 mL). After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure and purified by silica gel chromatography (EA / PE, 1 / 3) to obtain 17 g (91%) of N-[(3S)-6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl] tert-butyl carbamate as a pale yellow solid. LRMS(ES) m / z 288 (M+H-56).

[0742] 9. Synthesis of intermediate 18-10:

[0743]

[0744] Hydrochloric acid (4 M in dioxane, 125 mL, 10.0 equivalent) was added to a solution of N-[(3S)-6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (17 g, 49.5 mmol, 1.0 equivalent) in DCM (500 mL). The mixture was stirred overnight at room temperature 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).

[0745] 10. Synthesis of compound 222:

[0746]

[0747] Add (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 equivalent), HOAt (10.9 g, 79.9 mmol, 1.6 equivalent), EDCI (15.4 g, 80.1 mmol, 1.6 equivalent), and DIEA (32.3 g, 249.5 mmol, 5.0 equivalent) to a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (8.2 g, 64.9 mmol, 1.3 equivalent) in DMF (200 mL). Stir the mixture overnight at room temperature and pour it into DCM (200 mL) and water (200 mL). Extract the aqueous layer five times with DCM (200 mL). The combined organic layers were washed six times with saturated NH4Cl solution (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and ground together with ACN to obtain 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) as a white solid. LRMS(ES) m / z 352 (M+H). 1H-NMR: (300MHz, DMSO-d6, ppm) δ9.12 (d, J=7.6Hz, 1H), 7.56 (dd, J=7.8, 1.4Hz, 1H), 7.51(d,J=7.8Hz,1H),7.46(d,J=2.1Hz,1H),7.38(d,J=1.3Hz,1H),6.92(d,J=2.1H z,1H),5.82(td,J=8.3,5.1Hz,1H),4.85(t,J=9.4Hz,1H),4.46(dd,J=9.7,5.2Hz,1 H), 4.10 (s, 3H), 2.41 (tt, J = 8.2, 4.8Hz, 1H), 1.35-1.25 (m, 2H), 1.25-1.15 (m, 2H).

[0748] The following compounds were prepared by a method similar to that used for compound 222:

[0749]

[0750]

[0751]

[0752] Example 19

[0753] Synthesis of Compound 228

[0754] 1. Synthesis of intermediate 19-2:

[0755]

[0756] To a solution of N-[6-(N-hydroxymethylammonium)-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (3 g, 10.2 mmol, 1.0 equivalent) in dioxane (30 mL), propionyl propionate (2.7 g, 20.5 mmol, 2.0 equivalent) was added. 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, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 3) to give 1.9 g (56%) of N-[6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester as a grayish-white solid.

[0757] 2. Synthesis of intermediate 19-3:

[0758]

[0759] TFA (5 mL) was added to a solution of N-[6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (1.9 g, 5.7 mmol, 1.0 equivalent) in DCM (30 mL). The mixture was stirred for 1 h, concentrated under reduced pressure, and dissolved in water (100 mL). The pH of the mixture was then adjusted to 7 using a 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 give 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.

[0760] 3. Synthesis of intermediate 19-4:

[0761]

[0762] Add 1-methyl-1H-pyrazole-5-carboxylic acid (54.5 mg, 0.4 mmol, 1.0 equivalent), HOAt (176.6 mg, 1.0 mmol, 3.0 equivalent), EDCI (249 mg, 1.3 mmol, 3.0 equivalent) and DIEA (112 mg, 0.9 mmol, 2.0 equivalent) 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 equivalent) in DMF (10 mL). The mixture was stirred for 2 h and then directly purified by preparative HPLC under the following conditions: (HPLC-2 - Analytical HPLC - SHIMADZU (HPLC-10)): Column, XBridge Shield RP18 OBD column, 5 μm, 19*150 mm; Mobile phase, water (0.05% NH3H2O) and ACN (30.0% ACN up to 50.0% ACN over 8 min); Detector, UV 220 nm. This purification yielded 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.

[0763] 4. Synthesis of compound 228:

[0764]

[0765] 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 equivalent) was purified by chiral preparative HPLC under the following conditions: (Preparative HPLC-009): Column, CHIRAL ART Cellulose-SB, 250*20 mm ID; Mobile phase, hexane and ethanol (50.0% ethanol for 9 min); Detector, UV 254 / 220 nm. This purification yielded 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: (300MHz, DMSO-d6, ppm): δ9.09(d,J=7.7Hz,1H),7.56(dd,J=7.7,1.4Hz,1H),7.48(d,J=7.8Hz,1H),7.39(dd,J=13.0,1.7Hz,2H),6.87(d,J=2 .1Hz,1H),5.78(td,J=8.2,5.2Hz,1H),4.80(t,J=9.3Hz,1H),4.41(dd,J= 9.8, 5.3Hz, 1H), 4.05 (s, 3H), 2.97 (q, J = 7.6Hz, 2H), 1.30 (t, J = 7.6Hz, 3H).

[0766] Example 20

[0767] Synthesis of Compound 236

[0768] 1. Synthesis of intermediate 20-2:

[0769]

[0770] Cyclopropaneformyl chloride (1.3 g, 12.4 mmol, 1.2 equivalent) was added to a solution of N-[6-(N-hydroxymethylammonium)-2,3-dihydro-1-benzofuran-3-yl]carbamate (3 g, 10.2 mmol, 1.0 equivalent) in pyridine (50 mL) under nitrogen atmosphere. 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 give 1.47 g (42%) of N-[6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate as a white solid.

[0771] 2. Synthesis of intermediate 20-3:

[0772]

[0773] TFA (5 mL) was added to a solution of N-[6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (1.47 g, 4.3 mmol, 1.0 equivalent) in DCM (25 mL). The mixture was stirred at room temperature for 2 h and then cooled to 0 °C. The pH of the mixture was then adjusted to 9 using saturated NaHCO3 solution and extracted five times with ethyl acetate (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1 g of 6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine as a grayish-white solid. This grayish-white solid was used directly in the next step without further purification.

[0774] 3. Synthesis of intermediate 20-4:

[0775]

[0776] Add HOAt (101 mg, 0.7 mmol, 1.2 equivalent), EDCI (142 mg, 0.7 mmol, 1.2 equivalent), DIEA (160 mg, 1.2 mmol, 2.0 equivalent) and 6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine (150 mg, 0.6 mmol, 1.0 equivalent) to a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (78 mg, 0.6 mmol, 1.0 equivalent) in DMF (4 mL). The mixture was stirred overnight at room temperature and purified by rapid 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 over 15 min; detector, UV 254 nm. This purification yielded 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). 1H-NMR: (400MHz, methanol-d4, ppm): δ8.06 (s, 1H), 7.90 (d, J = 0.9 Hz, 1H), 7.60 (dd, J = 7. 8,1.4Hz,1H),7.48(d,J=7.8Hz,1H),7.43(d,J=1.4Hz,1H),5.83(dd,J=8.6,4.7H z,1H),4.82(dd,J=9.9,8.6Hz,1H),4.44(dd,J=9.9,4.8Hz,1H),3.90(s,3H),2.3 2(tt,J=8.2,5.0Hz,1H), 1.29(dt,J=7.7,2.6Hz,2H), 1.25(dt,J=5.1,3.0Hz,2H).

[0777] 4. Synthesis of compound 236:

[0778]

[0779] 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 equivalent) 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 (maintained at 50.0% ethanol for 15 min); Detector, UV 220 / 254 nm, R t = 1.569 min. This produces 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: (400MHz, methanol-d4, ppm): δ8.06 (s, 1H), 7.90 (d, J = 0.9 Hz, 1H), 7.60 (dd, J = 7. 8,1.4Hz,1H),7.48(d,J=7.8Hz,1H),7.43(d,J=1.4Hz,1H),5.83(dd,J=8.6,4.7H z,1H),4.82(dd,J=9.9,8.6Hz,1H),4.44(dd,J=9.9,4.8Hz,1H),3.90(s,3H),2.3 2(tt,J=8.2,5.0Hz,1H), 1.29(dt,J=7.7,2.6Hz,2H), 1.25(dt,J=5.1,3.0Hz,2H).

[0780] Example 21

[0781] Synthesis of Compound 238

[0782] 1. Synthesis of intermediate 21-2:

[0783]

[0784] A solution of N-[(3S)-6-(N-hydroxymethylammonium)-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (24.7 g, 84.2 mmol, 1.0 equivalent) in dioxane (700 mL) was added to propionyl propionate (16.4 g, 126.0 mmol, 1.5 equivalent). 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 obtain 18.4 g (66%) of N-[(3S)-6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester as a white powder.

[0785] 2. Synthesis of intermediate 21-3:

[0786]

[0787] Hydrochloric acid (4M in dioxane, 122 mL) was added to a solution of N-[(3S)-6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (16.3 g, 49.2 mmol, 1.0 equivalent) in DCM (350 mL). The mixture was stirred overnight at room temperature and diluted with PE (100 mL). The solid was collected and dried to give 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.

[0788] 3. Synthesis of compound 238:

[0789]

[0790] To a solution of (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 equivalent) in DMF (200 mL), HOAt (5.5 g, 40.4 mmol, 1.2 equivalent), DIEA (13.0 g, 100.6 mmol, 3.0 equivalent), EDCI (7.7 g, 40.2 mmol, 1.2 equivalent), and 1-methyl-1H-pyrazole-4-carboxylic acid (4.4 g, 34.9 mmol, 1.04 equivalent) were added. 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 a previous batch (2.4 g of amine starting material) and purified using 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 H-NMR: (400MHz, DMSO-d6, ppm): δ8.71(d,J=7.6Hz,1H),8.16(s,1H),7.86(s,1H),7.57(dd,J=7.7,1.4Hz,1H),7.47(d,J=7.7Hz,1H),7.38(d,J=1. 4Hz,1H),5.76(td,J=8.3,5.3Hz,1H),4.80(t,J=9.3Hz,1H),4.39(dd,J=9 .7,5.2Hz,1H),3.82(s,3H),2.99(q,J=7.5Hz,2H),1.32(t,J=7.6Hz,3H).

[0791] Example 22

[0792] Synthesis of Compound 253

[0793] 1. Synthesis of intermediate 22-2:

[0794]

[0795] MeLi (4.8 mL, 1.6 M) was added dropwise to a solution of N-[(1R)-5-bromo-2,3-dihydro-1H-indene-1-yl]carbamate (2 g, 6.4 mmol, 1.0 equivalent) cooled to -78 °C in 30 mL of THF under argon atmosphere. The mixture was stirred at -78 °C for 15 min and n-BuLi (5.2 mL, 2.5 M) was added dropwise. The mixture was then stirred at -78 °C for 1 h and DMF (1.43 g, 19.2 mmol, 3.0 equivalent) was added dropwise. The solution was stirred at -78 °C for 1 h, quenched with saturated NH4Cl solution (5 mL), and concentrated under vacuum. The residue was purified by silica gel chromatography (EA / PE, 1 / 10) to obtain 1.5 g (90%) of N-[(1R)-5-formyl-2,3-dihydro-1H-indene-1-yl] tert-butyl carbamate as a yellow solid.

[0796] 2. Synthesis of intermediate 22-3:

[0797]

[0798] A solution of N-[(1R)-5-formyl-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (1.6 g, 6.1 mmol, 1.0 equivalent) in a mixture of ethanol and pyridine (21 mL, 2 / 1) was added with NH₂OH·HCl (509 mg, 1.2 equivalent). The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give 1.7 g of N-[(1R)-5-[(1E)-(hydroxyimino)methyl]-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester as a white solid.

[0799] 3. Synthesis of intermediate 22-4:

[0800]

[0801] NCS (977 mg, 7.3 mmol, 1.2 equivalents) was added to a solution of N-[(1R)-5-[(1E)-(hydroxyimino)methyl]-2,3-dihydro-1H-indene-1-yl]tert-butyl carbamate (1.7 g, 6.1 mmol, 1.0 equivalent) in DMF (15 mL). 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 obtain 1.8 g (95%) of N-[(1R)-5-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1H-indene-1-yl]tert-butyl carbamate as a brown oil.

[0802] 4. Synthesis of intermediate 22-5:

[0803]

[0804] Add N-[(1R)-5-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1H-indene-1-yl] tert-butyl carbamate (955 mg, 3.1 mmol, 1.1 equivalent) and TEA (1.3 g, 12.9 mmol, 2.1 equivalent) to a solution of 2-bromobut-1-ene (2 g, 14.8 mmol, 1.0 equivalent) in THF (30 mL). The mixture was stirred at room temperature for 1 h, heated to 60 °C for 5 h, 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 obtain 1.1 g (23%) of N-[(1R)-5-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1H-indene-1-yl] tert-butyl carbamate as a yellow solid.

[0805] 5. Synthesis of intermediate 22-6:

[0806]

[0807] Hydrochloric acid (4 M in dioxane, 15 mL, 18.2 equivalents) was added to a solution of N-[(1R)-5-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (1.08 g, 3.3 mmol, 1.0 equivalent) in DCM (15 mL). The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give 870 mg of (1R)-5-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1H-indene-1-amine hydrochloride as a grayish-white solid.

[0808] 6. Synthesis of compound 253:

[0809]

[0810] Add 2-methyl-2H-1,2,3,4-tetrazol-5-carboxylic acid (606 mg, 4.7 mmol, 2.0 equivalent), EDCI (909 mg, 4.7 mmol, 2.0 equivalent), HOAt (643 mg, 4.7 mmol, 2.0 equivalent), and DIEA (1.53 g, 11.9 mmol, 5.0 equivalent) to a solution of (1R)-5-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1H-indene-1-amine hydrochloride (625 mg, 2.4 mmol, 1.0 equivalent) in DMF (20 mL), EDCI (909 mg, 4.7 mmol, 2.0 equivalent), HOAt (643 mg, 4.7 mmol, 2.0 equivalent), and DIEA (1.53 g, 11.9 mmol, 5.0 equivalent). Stir the mixture at room temperature for 2 h, heat to 60 °C for 2 h, cool to room temperature, and pour into EA (100 mL) and water (100 mL). Extract the aqueous layer twice with ethyl acetate (100 mL). The combined organic layers were washed twice with saturated NH4Cl solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by rapid preparative HPLC under the following conditions: (IntelFlash-1): column, C18 silica gel; mobile phase, ACN / H2O = 1:3 increased to ACN / H2O = 1:2 over 10 min; detector, UV 254 nm. This purification yielded 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 a grayish-white solid. LRMS(ES) m / z 338 (M+H). 1 H-NMR: (300MHz, DMSO-d6, ppm) δ9.38(d,J=8.4Hz,1H),7.74-7.59(m,2H),7.29(d,J=7.9Hz,1H),6.79-6.71(m,1H),5.56(q,J=8.1Hz,1H), 4.41(s,3H),3.04(ddd,J=16.0,8.9,3.3Hz,1H),2.96-2.69(m,3H),2.41(td,J=8.1,3.6Hz,1H),2.21-2.01(m,1H),1.23(t,J=7.6Hz,3H).

[0811] The following compounds were prepared by a method similar to that used for compound 253:

[0812]

[0813] Example 23

[0814] Synthesis of Compound 414

[0815]

[0816] DIEA (566 mg, 4.4 mmol, 5.8 equivalents), EDCI (337 mg, 1.7 mmol, 2.3 equivalents), and HOAt (238 mg, 1.8 mmol, 2.3 equivalents) were added to a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (166 mg, 1.3 mmol, 1.7 equivalents) in DMF (4 mL). The mixture was stirred at room temperature for 5 min, and (1R)-5-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1H-indene-1-amine hydrochloride (200 mg, 0.8 mmol, 1.00 equivalents) 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-Analytical HPLC-SHIMADZU (HPLC-10)): Column, XBridge Shield RP18 OBD column, 5 μm, 19*150 mm; Mobile phase, water (10 mmol / L NH4HCO3) and ACN (38.0% ACN to 52.0% ACN over 8 min); Detector, UV 254 nm. This purification yielded 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): δ7.76-7.63(m,2H),7.49-7.34(m,2H),6.81(d,J=2.1Hz,1H),6.57(d,J=1.0Hz,1H),5.64(t,J=8.0H z,1H),4.17(d,J=1.1Hz,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=7.6Hz,3H).

[0817] The following compounds were prepared by a method similar to that used for compound 414:

[0818] Compound numbering LRMS(ES)m / z Compound numbering LRMS(ES)m / z 137 M+H=334 415 M+H=338 138 M+H=334 416 M+H=324 252 M+H=335 417 M+H=338 253 M+H=339 418 M+H=324 413 M+H=337 432 M+H=323

[0819] Example 24

[0820] Synthesis of Compound 261

[0821] 1. Synthesis of intermediate 23-2:

[0822]

[0823] MeLi (30.1 mL, 1.6 M, 1.5 equivalence) was added dropwise to a solution of N-[(1R)-5-bromo-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (10 g, 32.2 mmol, 1.0 equivalence) cooled to -78 °C in 300 mL of THF. The mixture was stirred at -78 °C for 10 min, and n-BuLi (25.7 mL, 2.5 M, 2.0 equivalence) was added dropwise at -78 °C. The mixture was stirred at -78 °C for another 1 h and dry ice (30 g) was added. The mixture was then stirred at -78 °C for 30 min 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 ground together with a mixture of EA, PE and diethyl ether (1 / 20 / 10) to obtain 6.2 g (70%) of (1R)-1-[[(tert-butoxy)carbonyl]amino]-2,3-dihydro-1H-indene-5-carboxylic acid as a white solid.

[0824] 2. Synthesis of intermediate 23-3:

[0825]

[0826] Add DIEA (2.1 g, 16.3 mmol, 3.0 equivalent) and HATU (3.1 g, 8.2 mmol, 1.5 equivalent) to a solution of (1R)-1-[[(tert-butoxy)carbonyl]amino]-2,3-dihydro-1H-indene-5-carboxylic acid (1.5 g, 5.4 mmol, 1.0 equivalent) in DMF (20 mL). Stir the mixture for 5 min and add (Z)-N-hydroxycyclopropyl-1-formamidinium (542 mg, 5.4 mmol, 1.0 equivalent). The mixture was then stirred for 2 hours, 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 obtain 800 mg (41%) of N-[(1R)-5-[[(1Z)-cyclopropyl(hydroxyimino)methyl]carbamoyl]-2,3-dihydro-1H-indene-1-yl]tert-butyl carbamate as a grayish-white solid.

[0827] 3. Synthesis of intermediate 23-4:

[0828]

[0829] A solution of N-[(1R)-5-[[(1Z)-cyclopropyl(hydroxyimino)methyl]carbamoyl]-2,3-dihydro-1H-indene-1-yl]tert-butyl carbamate (680 mg, 1.9 mmol, 1.0 equivalent) in toluene (10 mL) was heated to 100 °C overnight, cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 9) to obtain 540 mg (84%) of N-[(1R)-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-dihydro-1H-indene-1-yl]tert-butyl carbamate as a pale yellow solid.

[0830] 4. Synthesis of intermediate 23-5:

[0831]

[0832] Hydrochloric acid (4M in dioxane, 10 mL) was added to a solution of N-[(1R)-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (490 mg, 1.4 mmol, 1.0 equivalent) in DCM (5 mL). The mixture was stirred overnight and concentrated to give 660 mg of (1R)-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-dihydro-1H-indene-1-amine hydrochloride as a pale yellow solid.

[0833] 5. Synthesis of compound 261:

[0834]

[0835] DIEA (80 mg, 0.62 mmol, 3.50 equivalence), HOAt (60 mg, 0.4 mmol, 2.3 equivalence), and EDCI (84 mg, 0.4 mmol, 2.3 equivalence) were added to a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (26 mg, 0.2 mmol, 1.2 equivalence) in DMF (4 mL). The mixture was stirred for 5 min and (1R)-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-dihydro-1H-indene-1-amine hydrochloride (50 mg, 0.2 mmol, 1.0 equivalence) was added. The mixture was then stirred for 2 h and purified by preparative HPLC under the following conditions: (CombiFlash-1): column, C18 silica gel; mobile phase, ACN / H2O (0.05% NH4HCO3); detector, UV 254 nm. This purification yielded 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). 1 H-NMR: (CD3OD, 300MHz, ppm): δ7.99-7.88(2H,m),7.49-7.39(2H,m),6.79(1H,d,J=2.2Hz), 5.63(1H,t,J=8.1Hz),4.14(3H,s),3.20-2.88(2H,m),2.61(1H,m),2.08(2H,m),1.07(4H,m)

[0836] The following compounds were prepared by a method similar to that used for compound 261:

[0837]

[0838]

[0839] Example 25

[0840] Synthesis of Compound 372

[0841] 1. Synthesis of intermediate 24-2:

[0842]

[0843] Add 1-methyl-1H-pyrazole-5-carboxylic acid (1.65 g, 13.1 mmol, 1.08 equivalent), HOAt (2.5 g, 18.37 mmol, 1.52 equivalent), EDCI (3.5 g, 18.3 mmol, 1.51 equivalent) and DIEA (6.3 g, 48.8 mmol, 4.04 equivalent) to a solution of (1R)-5-bromo-2,3-dihydro-1H-indene-1-amine hydrochloride (3.0 g, 12.1 mmol, 1.00 equivalent) in DMF (60 mL). 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 obtain a solid. This solid was ground together 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 a grayish-white solid. LRMS (ES) m / z 320 (M+H). LC-MS: (ES, m / z): [M+H] + 320 322

[0844] 2. Synthesis of compound 372:

[0845]

[0846] 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 equivalent) in dioxane (5 mL) was supplemented with phenylboronic acid (57 mg, 0.47 mmol, 1.50 equivalent), Pd(dppf)Cl2CH2Cl2 (26 mg, 0.03 mmol, 0.10 equivalent), Cs2CO3 (204 mg, 0.63 mmol, 2.00 equivalent), 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 rapid preparative HPLC under the following conditions: (CombiFlash-1): column, C18 silica gel; mobile phase, water (0.5% NH4HCO3) / ACN = 95 / 5 increased to water (0.5% NH4HCO3) / ACN = 90 / 10 over 10 min; detector, UV 254 nm. This yielded 46.7 mg (47%) of (R)-1-methyl-N-(5-phenyl-2,3-dihydro-1H-inden-1-yl)-1H-pyrazole-5-carboxamide (compound 372) as a white solid. LRMS(ES) m / z 318 (M+H).

[0847] 1 H-NMR: (400MHz, DMSO-d6, ppm): δ8.76 (d, J=8.4Hz, 1H), 7.65-7.57 (m, 2H), 7 .53(d,J=1.6Hz,1H),7.50-7.39(m,4H),7.38-7.26(m,2H),6.91(d,J=2.1Hz, 1H),5.54(q,J=8.1Hz,1H),4.10(s,3H),3.04(ddd,J=15.9,8.9,3.2Hz,1H), 2.90(dt,J=16.1,8.4Hz,1H),2.48-2.43(m,1H),1.99(dq,J=12.5,8.7Hz,1H)

[0848] The following compounds were prepared by a method similar to that used for compound 372:

[0849]

[0850] Example 26

[0851] Synthesis of Compound 378

[0852]

[0853] Pd(dppf)Cl2.CH2Cl2 (44 mg, 0.05 mmol, 0.20 equivalent), K3PO4 (116 mg, 0.55 mmol, 2.00 equivalent), and 2-bromo-4-methylpyrimidine (94 mg, 0.54 mmol, 2.00 equivalent) were added to a solution of 1-methyl-N-[(1R)-5-(tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3-dihydro-1H-indene-1-yl]-1H-pyrazole-5-carboxamide (100 mg, 0.27 mmol, 1.00 equivalent) in DMF (4 mL) under nitrogen atmosphere. 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. Further purification was performed by preparative HPLC under the following conditions: (2-Analytical HPLC-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 (31.0% ACN up to 44.0% ACN over 8 min); Detector, UV 220 nm. This produces 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) as a white solid. LRMS(ES) m / z 334 (M+H). 1 H-NMR: (300MHz, methanol-d4, ppm): δ8.65(d,J=5.1Hz,3H),8.28(s,4H),7.50-7.38(m,4H),7 .23(s,1H),6.83(d,J=2.1Hz,2H),5.66(s,1H),4.18(s,7H),2.59(s,7H),0.20(s,1H).

[0854] The following compounds were prepared by a method similar to that used for compound 378:

[0855]

[0856] Example 27

[0857] Synthesis of Compound 383

[0858] 1. Synthesis of intermediate 26-2:

[0859]

[0860] Under stirring, pyridine (1.1 g, 13.9 mmol, 3.06 equivalents) and a solution of trifluoromethanesulfonate (2.0 g, 7.09 mmol, 1.56 equivalents) in DCM (10 mL) cooled to -15 °C were added dropwise to a solution of 5-methylpyridin-3-ol (500 mg, 4.54 mmol, 1.00 equivalents) cooled to -15 °C in DCM (5 mL). The mixture was stirred under nitrogen at -15 °C to 0 °C for 2 h, and then 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-methylpyridazine-3-yl trifluoromethanesulfonic acid as a colorless oil.

[0861] 2. Synthesis of compound 383:

[0862]

[0863] A solution of 1-methyl-N-[(1R)-5-(tetramethyl-1,3,2-dioxaborphane-2-yl)-2,3-dihydro-1H-inden-1-yl]-1H-pyrazole-5-carboxamide (100 mg, 0.27 mmol, 1.00 equivalent) in toluene (9 mL) was added to a solution of 5-methylpyridazin-3-yl trifluoromethanesulfonate (80 mg, 0.33 mmol, 1.21 equivalent), ethanol (3 mL), Pd(PPh3)4 (47 mg, 0.04 mmol, 0.15 equivalent), and sodium carbonate (318 mg, 3.00 mmol, 11.0 equivalent) in water (1.5 mL). After stirring at 80 °C for 3 h, the resulting solution was diluted with 30 mL of EA. 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) followed by preparative HPLC under the following conditions: (2-Analytical HPLC-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 (25.0% ACN up to 38.0% ACN over 8 min); Detector, UV 220 nm. This yielded 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: (300MHz, methanol-d⁴, ppm) δ 9.01 (d, J = 1.9Hz, 1H), 8.04–7.99 (m, 1H), 7.99–7.95 (m, 1H), 7.91 (d, J = 7.8Hz, 1H), 7.51–7.42 (m, 2H), 6.83 (d, J = 2.1Hz, 1H), 5.68 (t, J = 7 .8Hz,1H),4.18(s,3H),3.18(ddd,J=15.9,9.1,3.5Hz,1H),3.01(dd,J=16.0,8.3Hz ,1H),2.65(dtd,J=12.6,7.9,3.5Hz,1H),2.48(s,3H),2.09(dq,J=12.8,8.6Hz,1H).

[0864] The following compounds were prepared by a method similar to that used for compound 383:

[0865] Compound numbering LRMS(ES)m / z 382 M+H=334

[0866] Example 28

[0867] Synthesis of Compound 423

[0868] 1. Synthesis of intermediate 28-2:

[0869]

[0870] MeLi (5.07 mL, 1.50 equivalents) was added to a solution of N-[(3S)-6-bromo-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (1.7 g, 5.4 mmol, 1.0 equivalent) in THF (20 mL) cooled to -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 10 min and n-BuLi (2.5 M, 4.32 mL, 2.0 equivalents) was added. The mixture was then stirred at -78 °C for 30 min and DMF (1.19 g, 16.3 mmol, 3.0 equivalents) was added. The mixture was then stirred at -78 °C for another 1 h 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, and ground together with n-hexane (30 mL) to obtain 1.32 g (93%) of N-[(3S)-6-formyl-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester as a pale yellow solid.

[0871] 2. Synthesis of intermediate 28-3:

[0872]

[0873] Hydroxylamine hydrochloride (1.83 g, 26.3 mmol, 1.2 equivalents) was added to a solution of N-[(3S)-6-formyl-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (5.8 g, 22.0 mmol, 1.0 equivalents) in a mixture of ethanol (100 mL) and pyridine (50 mL). The mixture was stirred for 3 h, concentrated under reduced pressure, and decanted 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 N-[(3S)-6-[(1E)-(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester as a white solid.

[0874] 3. Synthesis of intermediate 28-4:

[0875]

[0876] Pyridine (1.36 g, 17.1 mmol, 0.98 equivalents) and NCS (5.17 mg, 38.7 mmol, 1.8 equivalents) were added to a solution of N-[(3S)-6-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (6.0 g, 21.5 mmol, 1.0 equivalents) in THF (120 mL). 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 N-[(3S)-6-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester as a white solid.

[0877] 4. Synthesis of intermediate 28-5:

[0878]

[0879] TEA (4.3 g, 42.9 mmol, 5.0 equivalent) and 2-bromobut-1-ene (1.74 g, 12.9 mmol, 1.5 equivalent) were added to a solution of N-[(3S)-6-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (3.6 g, 11.6 mmol, 1.0 equivalent) in THF (80 mL). The resulting solution was stirred at room temperature for 2 h, heated at 60 °C for 2 h, poured into water, and extracted twice with EA. The combined organic layers were washed with NH4Cl aqueous 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 N-[(3S)-6-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl] tert-butyl carbamate as a white solid.

[0880] 5. Synthesis of intermediate 28-6:

[0881]

[0882] Hydrochloric acid (4M in dioxane, 3.2 mL, 10.0 equivalent) was added to a solution of N-[(3S)-6-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (420 mg, 1.3 mmol, 1.0 equivalent) in DCM (20 mL). The resulting solution was stirred overnight at room temperature. 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.

[0883] 6. Synthesis of compound 423:

[0884]

[0885] Add 1-methyl-1H-pyrazole-4-carboxylic acid (37 mg, 0.29 mmol, 1.2 equivalence), EDCI (56 mg, 0.29 mmol, 1.2 equivalence), HOAt (40 mg, 0.29 mmol, 1.20 equivalence), and DIEA (94 mg, 0.73 mmol, 3.0 equivalence) to a solution of (3S)-6-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine hydrochloride (65 mg, 0.24 mmol, 1.0 equivalence) in DMF (2 mL). Stir the mixture overnight at room temperature and combine it with previous batches (0.21 mmol and 1.16 mmol of amine starting material). Decant the resulting solution into water (10 mL) and extract 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: (400MHz, DMSO-d6, ppm): δ8.68(d,J=7.5Hz,1H),8.18(s,1H),7.88(d,J=0.8Hz,1H),7.43(d,J=1.6Hz,2H),7.33(d,J=1.2Hz,1H),6.82(t,J=0. 9Hz,1H),5.81-5.70(m,1H),4.80(dd,J=9.7,8.8Hz,1H),4.38(dd,J=9.7,5 .0Hz, 1H), 3.85 (s, 3H), 2.81 (qd, J=7.6, 0.9Hz, 2H), 1.28 (t, J=7.6Hz, 3H).

[0886] The following compounds were prepared by a method similar to that used for compound 423:

[0887]

[0888] Example 29

[0889] Synthesis of Compound 431

[0890]

[0891] Add HOAt (105 mg, 0.8 mmol, 2.0 equivalent), EDCI (148 mg, 0.8 mmol, 2.0 equivalent), DIEA (249 mg, 1.9 mmol, 5.0 equivalent) and (R)-5-(5-ethylisoxazol-3-yl)-2,3-dihydro-1H-indene-1-amine hydrochloride (102.5 mg, 0.4 mmol, 1.00 equivalent) to a solution of 5-methyl-1H-pyrazole-4-carboxylic acid (73 mg, 0.58 mmol, 1.50 equivalent) in DMF (2 mL) to a solution of 5-methyl-1H-pyrazole-4-carboxylic acid (73 mg, 0.58 mmol, 1.50 equivalent) in DMF (2 mL). The mixture was stirred overnight at room temperature and purified by preparative HPLC under the following conditions: (2-Analytical HPLC-SHIMADZU (HPLC-10): Column, X-Bridge Shield RP18 OBD column, 5 μm, 19*150 mm; Mobile phase, water (10 mmol / L NH4HCO3) and ACN (30.0% ACN up to 45.0% ACN over 8 min; Detector, UV 254 nm). This purification yielded 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 H-NMR: (400MHz, methanol-d4)δ7.96(s,1H),7.74(s,1H),7.71-7.65(m,1H),7.40( d,J=7.9Hz,1H),6.58(t,J=0.9Hz,1H),5.65(t,J=8.0Hz,1H),3.19-3.07(m, 1H),3.05-2.93(m,1H),2.86(qd,J=7.4,0.9Hz,2H),2.64(ddd,J=12.7,7.9, 3.2Hz, 1H), 2.56 (s, 3H), 2.05 (dq, J = 12.8, 8.7Hz, 1H), 1.37 (t, J = 7.6Hz, 3H).

[0892] Example 30

[0893] Synthesis of Compound 433

[0894] 1. Synthesis of intermediate 30-2:

[0895]

[0896] DIBAL-H (43.9 mL, 2.20 equivalents) was added dropwise to a solution of N-[(3S)-6-cyano-2,3-dihydro-1-benzofuran-3-yl]carbamate (6.4 g, 24.6 mmol, 1.0 equivalent) cooled to 0 °C in toluene (100 mL) under nitrogen atmosphere. The mixture was stirred at 0 °C for 2 h, quenched with ice water (10 mL) and NaOH solution (10% 10 mL), and filtered to remove solids. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5.8 g of 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.

[0897] 2. Synthesis of intermediate 30-3:

[0898]

[0899] Hydroxylamine hydrochloride (1.83 g, 26.3 mmol, 1.2 equivalents) was added to a solution of N-[(3S)-6-formyl-2,3-dihydro-1-benzofuran-3-yl]carbamate (5.8 g, 22.0 mmol, 1.0 equivalent) in a mixture of ethanol and Py (100 mL / 50 mL). The mixture was stirred at room temperature for 3 h, concentrated under vacuum to approximately 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 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.

[0900] 3. Synthesis of intermediate 30-4:

[0901]

[0902] Pyridine (1.4 g, 17.1 mmol, 0.8 equivalence) and NCS (5.2 g, 38.7 mmol, 1.80 equivalence) were added to a solution of N-[(3S)-6-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (6.0 g, 21.5 mmol, 1.0 equivalence) in THF (10 mL). The mixture was stirred overnight at room temperature and concentrated to dryness to give 9.1 g of N-[(3S)-6-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester as a white solid, which was used in the next step without further purification.

[0903] 4. Synthesis of intermediate 30-5:

[0904]

[0905] TEA (4.3 g, 42.9 mmol, 5.0 equivalent) and 2-bromobut-1-ene (1.7 g, 12.9 mmol, 1.5 equivalent) were added to a solution of N-[(3S)-6-[(1Z)-chloro(hydroxyimino)methyl]-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (3.6 g, 11.6 mmol, 1.0 equivalent) in THF (80 mL). 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, concentrated under reduced pressure, and purified by passing through a C18 column using H2O:ACN (50:50) as the eluent to obtain 424 mg (11%) of N-[(3S)-6-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl] tert-butyl carbamate as a white solid.

[0906] 5. Synthesis of intermediate 30-6:

[0907]

[0908] Hydrochloric acid (4M in dioxane, 3.2 mL, 10.0 equivalent) was added to a solution of N-[(3S)-6-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-yl]carbamate tert-butyl ester (420 mg, 1.8 mmol, 1.0 equivalent) in DCM (20 mL). The mixture was stirred overnight at room temperature and the solid was collected by filtration to give 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.

[0909] 6. Synthesis of compound 433:

[0910]

[0911] Add 5-methyl-1H-pyrazole-4-carboxylic acid (40 mg, 0.3 mmol, 1.2 equivalent), EDCI (60 mg, 0.3 mmol, 1.2 equivalent), HOAt (43 mg, 0.3 mmol, 1.2 equivalent), and DIEA (101 mg, 3.00 equivalent) to a solution of (3S)-6-(5-ethyl-1,2-oxazol-3-yl)-2,3-dihydro-1-benzofuran-3-amine hydrochloride (70 mg, 0.3 mmol, 1.2 equivalent) in DMF (2 mL). Stir the mixture overnight, dilute with water (20 mL), and extract three times with EA (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC under the following conditions: (HPLC-2 - Analytical HPLC - SHIMADZU (HPLC-10)): Column, XBridge Prep C18 OBD column, 5 μm, 19*150 mm; Mobile phase, water (10 mmol / L NH4HCO3) and ACN (29.0% ACN up to 43.0% ACN over 8 min); Detector, UV 254 nm. This purification yielded 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). 1H-NMR: (400MHz, DMSO-d6, ppm): δ12.87(s,1H),8.52(d,J=7.5Hz,1H),7.92(s,1H),7.48-7.38(m,2H),7.32(s,1H),6.82(d,J=1.0Hz,1H),5 .77(d,J=8.1Hz,1H),4.81(t,J=9.2Hz,1H),4.37(dd,J=9.6,5.4Hz,1H),2.86-2.75(m,2H),2.46(s,2H),2.38(s,1H),1.28(t,J=7.6Hz,3H).

[0912] Example 31

[0913] Synthesis of Compound 474

[0914] 1. Synthesis of intermediate 31-2:

[0915]

[0916] HCl (4 M in dioxane, 174.8 mL, 698.3 mmol, 10 equivalents) was added to a solution of N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (23 g, 70 mmol, 1 equivalent) in DCM at room temperature. The mixture was stirred overnight at room temperature 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-indene-1-amine hydrochloride (16 g, 86%) as a white solid.

[0917] 2. Synthesis of intermediate 31-3:

[0918]

[0919] At room temperature, HOAt (11.5 g, 84.5 mmol, 1.5 equivalence), DIEA (29.2 g, 225.9 mmol, 4.0 equivalence), and EDCI (16.2 g, 84.5 mmol, 1.5 equivalence) were added in portions to a solution of (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-amine hydrochloride (15 g, 56.5 mmol, 1.0 equivalence) and 1H-pyrazole-4-carboxylic acid (6.4 g, 57.1 mmol, 1.0 equivalence) in DMF (300 mL). After stirring overnight at room temperature, water (450 mL) was slowly added with stirring at 0 °C. The precipitated solid was collected by filtration, washed twice with water (150 mL), and dried under vacuum to obtain (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl)-1H-pyrazole-4-carboxamide (14 g, 76.7%), which was a grayish-white solid.

[0920] 3. Synthesis of compound 474:

[0921]

[0922] 2-Bromoethanol (5.2 g, 41.3 mmol, 1.2 equivalent) was added dropwise 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 equivalent) and Cs₂CO₃ (22.8 g, 70.1 mmol, 2.0 equivalent) in DMF (200 mL) 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 / EA10 / 90) to give a product as a grayish-white solid (8.3 g, 92% purity). This grayish-white solid was combined with a previous batch (compound 474, 1.8 g, 92% purity) and purified by reverse-phase chromatography to give a product as a white solid (8.1 g, 98% purity, 92.4% ee). This product was then stirred in a mixture of THF / EA (1 / 2) and filtered to give a white solid (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). LRMS(ES)m / z 368(M+H). LC-MS: (ES, m / z): [M+H]+ 368. 1 H-NMR: (400MHz, DMSO...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in: G1 is -CR 4 R 5 ; G2 is a key; G3 is -CR 8 ; R 1 R 3 R 4 R 5 and R 8 Each is H; R 2 It is H; Z is a key; A is an oxadiazolyl group, which is substituted by a substituent selected from the group consisting of: methyl, ethyl, and isopropyl; and Option B is selected from the following groups: pyrazolyl, oxazolyl, tetrazolyl, isoxazolyl, thiazolyl, and imidazoleyl, each of which is substituted with one or two methyl substituents.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is the compound of formula (If):

3. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein A is an oxadiazolyl group substituted with an ethyl group.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is: Where R 13 It is an ethyl group.

5. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein B is a pyrazolyl group substituted with a methyl group.

6. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein B is It is substituted with one methyl group.

7. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein B is Where R 14 It is a methyl group.

8. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

9. Use of a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 8 in the preparation of a medicament for treating heart disease in a subject in need.

10. The use as claimed in claim 9, wherein the heart disease is hypertrophic cardiomyopathy (HCM).

11. The use as claimed in claim 10, wherein the HCM is obstructive or non-obstructive or associated with sarcomere and / or non-sarcomere mutations.

12. The use as claimed in claim 9, wherein the heart disease is heart failure with preserved ejection fraction (HFpEF).

13. Use of a compound of any one of claims 1 to 7 or a pharmaceutical composition of claim 8 in the preparation of a medicament for inhibiting myocardial ganglia.

14. Use of a compound of any one of claims 1 to 7 or a pharmaceutical composition of claim 8 in the preparation of a medicament for treating obstructive hypertrophic cardiomyopathy (HCM) in subjects of need.

15. Use of a compound of any one of claims 1 to 7 or a pharmaceutical composition of claim 8 in the preparation of a medicament for treating non-obstructive hypertrophic cardiomyopathy (HCM) in subjects of need.

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