Myocardial sarcomere inhibitor

Abstract

To provide cardiac sarcomere inhibitors.SOLUTION: Provided are compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1, R2A, R2B, R3, R4, and R5 are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 726,162, filed August 31, 2018, entitled "CARDIAC SARCOMERE INHIBITORS," the contents of which are incorporated herein by reference in their entirety for all purposes. (Technical field) Provided herein are heterocyclic compounds, pharmaceutical compositions containing such compounds, and methods for treating various cardiac diseases and conditions with such compounds. [Background technology]

[0002] The present disclosure relates to certain chemical entities that selectively modulate cardiac sarcomeres and are specific for certain chemical entities, pharmaceutical compositions and methods for treating various cardiac diseases and conditions.

[0003] The cardiac sarcomere consists of a network of contractile and structural proteins that regulate myocardial function. Components of the cardiac sarcomere present targets for the treatment of various cardiac diseases and conditions, for example, by increasing contractility or promoting complete relaxation, thereby modulating systolic and diastolic function, respectively. The force and velocity of myocardial contraction are major determinants of organ function and are regulated by the cyclic interaction of actin and myosin. Regulation of actin-myosin binding is mediated by myofilament regulatory proteins and intracellular Ca. 2+ The troponin complex and tropomyosin are thin filament proteins that govern the availability of actin-binding sites, while essential and regulatory light chains and myosin-binding protein C regulate myosin positioning and mechanical properties.

[0004] Abnormalities in cardiac sarcomeres have been identified as a driving factor in various cardiac diseases and conditions, such as hypertrophic cardiomyopathy (HCM) and heart failure with preserved left ventricular ejection fraction (HFpEF). Mutations in sarcomere proteins cause disease by rendering the myocardium either "hyper" or "hypo" contractile. Modulators of cardiac sarcomeres can be used to restore balance in contractility and halt or reverse the course of the disease.

[0005] Current drugs that target the myocardial sarcomere, such as inotropes (drugs that increase the heart's ability to contract), are poorly selective for cardiac tissue, which limits their use due to the well-documented side effects. These side effects include increased energy expenditure, worsening of relaxation abnormalities, and increased cytosolic Ca in isotropically stimulated myocardium. 2+ These include cellular damage caused by increased cyclic AMP levels and potential arrhythmogenic side effects that may result from increased cyclic AMP levels. Given the limitations of current medications, novel approaches are needed to improve cardiac function in HCM and HFpEF.

[0006] There remains a great need for drugs that utilize novel mechanisms of action and can produce better outcomes in terms of symptom relief, safety, and patient mortality in both the short and long term. Novel drugs with improved therapeutic indices compared to currently available drugs may provide a means to achieve these clinical outcomes. The selectivity of drugs that target cardiac sarcomeres (e.g., by targeting cardiac myosin) has been identified as an important means to achieve this improved therapeutic index. The present invention provides such drugs, particularly cardiac sarcomere inhibitors, and methods of use thereof. These drugs are allosteric inhibitors of cardiac myosin. Advantages of these compounds include a wide therapeutic index, minimal effect on cardiac relaxation, favorable pharmacokinetics, and favorable safety.

[0007] The present disclosure provides chemical entities, pharmaceutical compositions, and methods for the treatment of heart failure, including HCM and HFpEF. The compositions are inhibitors of cardiac sarcomeres, such as inhibitors of cardiac myosin. Summary of the Invention

[0008] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] (I) During the ceremony: R 1 is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted pyridyl; R 2A , R 2B , and R 3 is defined by one of (i) to (iii): (i) R 2A is H or substituted or unsubstituted alkyl; R 2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and R 3 is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; or (ii)R 2A is H or substituted or unsubstituted alkyl; R 2B is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; and R 3 is substituted or unsubstituted alkyl; or (iii)R 2A and R 2Btogether with the carbon atoms to which they are attached, form G 1 wherein G 1 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl ring, each of which is optionally fused to a phenyl ring; and R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 4 is H or substituted or unsubstituted alkyl; and R 5 is H or substituted or unsubstituted alkyl; where, when one or more of provisions (a) to (c) apply, R 1 is a substituted or unsubstituted pyridyl or a phenyl substituted with at least one substituent other than methyl or methoxy; (a)R 2A and R 2B is defined by (i) and R 3 is a substituted or unsubstituted phenyl; (b)R 2A and R 3 is defined by (ii) and R 2B is 4-methoxyphenyl and; (c)R 2A , and R 2B is defined by (iii) and R 3 provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0009] In another embodiment, a compound of formula (Ia) or a pharmaceutically acceptable salt thereof: [ka] (Ia) During the ceremony: R 1 is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted pyridyl; R 2A is H or substituted or unsubstituted alkyl; R 2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 3 is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; R 4 is H or substituted or unsubstituted alkyl; and R 5 is H or substituted or unsubstituted alkyl; In the formula, R 3 is substituted or unsubstituted phenyl, R 1 is a substituted or unsubstituted pyridyl, or a phenyl substituted with at least one substituent other than methyl or methoxy, or a pharmaceutically acceptable salt thereof.

[0010] In another embodiment, a compound of formula (Ib) or a pharmaceutically acceptable salt thereof: [ka] (Ib) During the ceremony: R 1 is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted pyridyl; R 2Ais H or substituted or unsubstituted alkyl; R 2B is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; R 3 is substituted or unsubstituted alkyl; R 4 is H or substituted or unsubstituted alkyl; and R 5 is H or substituted or unsubstituted alkyl; In the formula, R 2B is 4-methoxyphenyl, R 1 is substituted or unsubstituted pyridyl, or phenyl substituted with at least one substituent other than methyl or methoxy, or a pharmaceutically acceptable salt thereof.

[0011] In another embodiment, a compound of formula (Ic) or a pharmaceutically acceptable salt thereof: [ka] (I C) During the ceremony: R 1 is selected from the group consisting of substituted or unsubstituted pyridyl, and substituted or unsubstituted pyridyl; R 2A and R 2B together with the carbon atoms to which they are attached, form G 1 wherein G 1 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl ring, each of which is optionally fused to a phenyl ring; R 3is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 4 is H or substituted or unsubstituted alkyl; and R 5 is H or substituted or unsubstituted alkyl; In the formula, R 3 is 4-methoxyphenylmethyl, R 1 is a substituted or unsubstituted pyridyl, or a phenyl substituted with at least one substituent other than methyl or methoxy, or a pharmaceutically acceptable salt thereof.

[0012] In another embodiment, a compound of formula (Id) or a pharmaceutically acceptable salt thereof: [ka] (Id) During the ceremony: R 2A is H or substituted or unsubstituted alkyl; R 2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; n is 0, 1, or 2; R 3a is selected from the group consisting of halo and cyano; and R 4 is H, or a pharmaceutically acceptable salt thereof.

[0013] In another embodiment, a compound of formula (Ie) or a pharmaceutically acceptable salt thereof: [ka] (Ie) During the ceremony: R 1 is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted pyridyl; R 2A is H or substituted or unsubstituted alkyl; R 2B is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; and R 4 is H; In the formula, R 2B is 4-methoxyphenyl, R 1 is substituted or unsubstituted pyridyl, or phenyl substituted with at least one substituent other than methyl or methoxy, or a pharmaceutically acceptable salt thereof.

[0014] In another embodiment, a compound of formula (If) or a pharmaceutically acceptable salt thereof: [ka] (If) During the ceremony: G 1 is selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, and substituted or unsubstituted heterocyclyl rings, each of which is optionally fused to a phenyl ring; R 1a is selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl; R 2ais selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl; n is 0, 1, 2, or 3; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl; and R 4 is H; In the formula, R 3 is 4-methoxyphenylmethyl, R 1a provides a compound of formula (If) or a pharmaceutically acceptable salt thereof, wherein: is not methyl or methoxy.

[0015] In another embodiment, a compound of formula (Ig) or a pharmaceutically acceptable salt thereof: [ka] (Ig) During the ceremony: R 1a is selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl; R 2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl; n is 0, 1, 2, or 3; R 3a is selected from the group consisting of halo and cyano; and R 4is H, or a pharmaceutically acceptable salt thereof.

[0016] In another embodiment, a compound of formula (Ih) or a pharmaceutically acceptable salt thereof: [ka] (Ih) During the ceremony: R 1a is selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl; R 2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl; and R 4 is H; In the formula, R 3 is 4-methoxyphenylmethyl, R 1a provides a compound of formula (Ih) or a pharmaceutically acceptable salt thereof, wherein: is not methyl or methoxy.

[0017] In another embodiment, a compound of formula (Ii) or a pharmaceutically acceptable salt thereof: [ka] (II)

[0018] During the ceremony: R 1ais selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl; R 2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl; R 4 is H; R 5 is H or substituted or unsubstituted alkyl; and X is -CH2- or -C(O)-; In the formula, R 3 is 4-methoxyphenylmethyl, R 1a provides a compound of formula (Ii) or a pharmaceutically acceptable salt thereof, wherein: is not methyl or methoxy.

[0019] In another embodiment, a compound of formula (Ij) or a pharmaceutically acceptable salt thereof: [ka] (Ij) During the ceremony: R 1 is a substituted or unsubstituted phenyl; Each R 2b is independently substituted or unsubstituted alkyl; R 3 is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; R 4 is H; R 5is H or substituted or unsubstituted alkyl; n is 0, 1, or 2; and q is 0 or 1, In the formula, R 3 is substituted or unsubstituted phenyl, R 1 is phenyl substituted with at least one substituent other than methyl or methoxy, or a pharmaceutically acceptable salt thereof.

[0020] In another embodiment, a compound of formula (Ik-1) or a pharmaceutically acceptable salt thereof: [ka] (Ik-1) During the ceremony: R 2A is H or substituted or unsubstituted alkyl; R 2B is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; m is 0, 1, or 2; p is 0, 1, or 2; Each R 1a is independently selected from the group consisting of halo and substituted or unsubstituted alkyl; Each R 3a is independently selected from the group consisting of halo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkoxy; and R 4 is H, or a pharmaceutically acceptable salt thereof.

[0021] In another embodiment, a compound of formula (Ik-2) or a pharmaceutically acceptable salt thereof: [ka] (Ik-2) During the ceremony: G1 is selected from the group consisting of substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; Each R 1a is independently selected from the group consisting of halo and substituted or unsubstituted alkyl; Each R 2a is independently selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminothionyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl; Each R 3a is independently selected from the group consisting of halo, cyano, and substituted or unsubstituted alkyl; R 4 is H; R 5 is H or substituted or unsubstituted alkyl; m is 0, 1, or 2; n is 0, 1, or 2; and The compound of formula (Ik-2) or a pharmaceutically acceptable salt thereof is provided, wherein p is 0, 1, or 2.

[0022] In another embodiment, a compound of formula (II) or a pharmaceutically acceptable salt thereof: [ka] (Il) During the ceremony: R 2A is H or substituted or unsubstituted alkyl; R 2b is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, and hydroxy; m is 0, 1, or 2; p is 0, 1, or 2; Each R 1ais independently selected from the group consisting of halo and substituted or unsubstituted alkyl; Each R 3a are independently halo; and R 4 is H, or a pharmaceutically acceptable salt thereof.

[0023] In another embodiment, a compound of formula (Im) or a pharmaceutically acceptable salt thereof: [ka] (Im) During the ceremony: Q is -O- or -N(R 2b )-and; R 2b is selected from the group consisting of H and substituted or unsubstituted acyl; m is 0, 1, or 2; p is 0, 1, or 2; Each R 1a is independently selected from the group consisting of halo and substituted or unsubstituted alkyl; Each R 3a are independently halo; and R 4 is H, or a pharmaceutically acceptable salt thereof.

[0024] In another embodiment, a compound of formula (In-1) or a pharmaceutically acceptable salt thereof: [ka] (In-1) During the ceremony: R 1 is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted pyridyl; R 2A , R 2B , and R 3 is defined by one of (i) to (iii): (i) R 2A is H or substituted or unsubstituted alkyl; R 2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and R 3 is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; or (ii)R 2A is H or substituted or unsubstituted alkyl; R 2B is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; and R 3 is substituted or unsubstituted alkyl; or (iii)R 2A and R 2B together with the carbon atoms to which they are attached, form G 1 wherein G 1 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl ring, each of which is optionally fused to a phenyl ring; and R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 4 is H or substituted or unsubstituted alkyl; and R 5 is H or substituted or unsubstituted alkyl; where, when one or more of provisions (a) to (c) apply, R 1 is a substituted or unsubstituted pyridyl or a phenyl substituted with at least one substituent other than methyl or methoxy; (a)R 2A and R 2B is defined by (i) and R 3 is a substituted or unsubstituted phenyl; (b)R 2A and R 3 is defined by (ii) and R 2B is 4-methoxyphenyl; (c)R 2A , and R 2B is defined by (iii) and R 3 provides a compound of formula (In-1), or a pharmaceutically acceptable salt thereof, wherein:

[0025] In another embodiment, a compound of formula (In-2) ​​or a pharmaceutically acceptable salt thereof: [ka] (In-2) During the ceremony: R 1 is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted pyridyl; R 2A , R 2B , and R 3 is defined by one of (i) to (iii): (i) R 2A is H or substituted or unsubstituted alkyl; R 2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and R3 is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; or (ii)R 2A is H or substituted or unsubstituted alkyl; R 2B is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; and R 3 is substituted or unsubstituted alkyl; or (iii)R 2A and R 2B together with the carbon atoms to which they are attached, form G 1 wherein G 1 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl ring, each of which is optionally fused to a phenyl ring; and R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 4 is H or substituted or unsubstituted alkyl; and R 5 is H or substituted or unsubstituted alkyl; where, when one or more of provisions (a) to (c) apply, R 1 is a substituted or unsubstituted pyridyl or a phenyl substituted with at least one substituent other than methyl or methoxy; (a)R 2A and R 2B is defined by (i) and R 3 is a substituted or unsubstituted phenyl; (b)R2A and R 3 is defined by (ii) and R 2B is 4-methoxyphenyl; (c)R 2A , and R 2B is defined by (iii) and R 3 provides a compound of formula (In-2), or a pharmaceutically acceptable salt thereof, wherein:

[0026] In some embodiments, a compound selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof, is provided.

[0027] In some aspects, there is provided a pharmaceutical composition comprising a compound of formula (I) or any variation thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0028] In some aspects, provided are methods for treating a cardiac disease in a subject in need thereof, 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 or a pharmaceutically acceptable salt thereof. In some embodiments, the cardiac disease is hypertrophic cardiomyopathy (HCM). In some embodiments, the HCM is obstructive or non-obstructive, or is caused by sarcomeric and / or non-sarcomeric mutations. In some embodiments, the cardiac disease is heart failure with preserved left ventricular ejection fraction (HFpEF). In some embodiments, the cardiac disease is selected from the group consisting of diastolic dysfunction, primary or secondary restrictive cardiomyopathy, myocardial infarction, angina pectoris, and obstructive hypertrophic cardiomyopathy. In some embodiments, the cardiac disease is hypertensive heart disease, congenital heart disease, cardiac ischemia, coronary heart disease, diabetic heart disease, congestive heart failure, right heart failure, cardiorenal syndrome, or infiltrative cardiomyopathy. In some embodiments, the cardiac disease is or is a condition associated with cardiac aging and / or age-related diastolic dysfunction, hi some embodiments, the cardiac disease is or is a condition associated with left ventricular hypertrophy and concentric left ventricular remodeling.

[0029] In another aspect, there is provided a method of treating a disease or condition associated with HCM in a subject in need thereof, 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, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is selected from the group consisting of Fabry disease, Danon disease, mitochondrial cardiomyopathy, and Noonan syndrome.

[0030] In some aspects, there are provided methods for treating a disease or condition associated with secondary left ventricular wall thickening in a subject in need thereof, comprising administering to the subject a compound of Formula (I) or any variant thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula (I) or any variant thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is selected from the group consisting of hypertension, valvular heart disease (e.g., aortic stenosis and mitral regurgitation), metabolic syndrome (e.g., diabetes and obesity), end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich's ataxia, Danon disease, Noonan syndrome, and Pompe disease.

[0031] In another aspect, the present invention provides a method for treating a disease or condition associated with small left ventricular lumen and lumen obstruction, left ventricular hypercontractility, myocardial ischemia, or myocardial fibrosis. Also provided is a method for treating muscular dystrophy (e.g., Duchenne muscular dystrophy) or glycogen storage disease.

[0032] Also provided is a method for inhibiting cardiac sarcomeres, comprising contacting cardiac sarcomeres 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 or a pharmaceutically acceptable salt thereof. In certain embodiments, for example, the following are provided: (Item 1) Compounds of formula (I): [ka] (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted pyridyl; R 2A , R 2B , and R 3 is defined by one of (i) to (iii): (i)R 2A is H or substituted or unsubstituted alkyl; R 2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and R 3 is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; or (ii)R 2A is H or substituted or unsubstituted alkyl; R 2B is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; and R 3 is substituted or unsubstituted alkyl; or (iii)R 2A and R 2B together with the carbon atoms to which they are attached, form G 1 wherein G 1 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl ring, each of which is optionally fused to a phenyl ring; and R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 4 is H or substituted or unsubstituted alkyl; and R 5 is H or substituted or unsubstituted alkyl; where, when one or more of provisions (a) to (c) apply, R 1 is a substituted or unsubstituted pyridyl or a phenyl substituted with at least one substituent other than methyl or methoxy; (a)R 2A and R 2B is defined by (i) and R 3 is a substituted or unsubstituted phenyl; (b)R 2A and R 3 is defined by (ii) and R 2B is 4-methoxyphenyl; (c)R 2A and R 2B is defined by (iii) and R 3 is 4-methoxyphenylmethyl, or a pharmaceutically acceptable salt thereof. (Item 2) R 2A is H or substituted or unsubstituted alkyl; R 2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and R3 is substituted or unsubstituted phenyl, or substituted or unsubstituted pyridyl, or a pharmaceutically acceptable salt thereof. (Item 3) R 3 3. The compound according to item 2, or a pharmaceutically acceptable salt thereof, wherein is substituted or unsubstituted phenyl. (Item 4) R 3 3. The compound according to item 2, or a pharmaceutically acceptable salt thereof, wherein is substituted or unsubstituted pyridyl. (Item 5) R 3 is phenyl substituted with one or more halo substituents selected from the group consisting of F and Cl, or a pharmaceutically acceptable salt thereof. (Item 6) R 3 is further substituted with one, two, or three -CN substituents, or a pharmaceutically acceptable salt thereof. (Item 7) R 2A 7. The compound according to any one of items 2 to 6, or a pharmaceutically acceptable salt thereof, wherein is substituted or unsubstituted alkyl. (Item 8) R 2A 7. The compound according to any one of items 2 to 6, wherein is H, or a pharmaceutically acceptable salt thereof. (Item 9) R 2B 9. The compound according to any one of items 2 to 8, or a pharmaceutically acceptable salt thereof, wherein is substituted or unsubstituted alkyl. (Item 10) R 2B is selected from the group consisting of methyl, hydroxymethyl, and isopropyl, or a pharmaceutically acceptable salt thereof. (Item 11) R 2B 10. The compound according to any one of items 2 to 9, or a pharmaceutically acceptable salt thereof, wherein is alkyl substituted with substituted or unsubstituted alkoxy. (Item 12) R 2B 10. The compound according to any one of items 2 to 9, or a pharmaceutically acceptable salt thereof, wherein is alkyl substituted with a substituted or unsubstituted oxetanyl. (Item 13) R 2B 13. The compound according to item 12, or a pharmaceutically acceptable salt thereof, wherein is methyl substituted with unsubstituted 3-oxetanyl. (Item 14) R 2B 9. The compound according to any one of items 2 to 8, or a pharmaceutically acceptable salt thereof, wherein is substituted or unsubstituted cycloalkyl. (Item 15) R 2B 15. The compound according to item 14, or a pharmaceutically acceptable salt thereof, wherein is cyclobutanyl. (Item 16) R 2B 9. The compound according to any one of items 2 to 8, or a pharmaceutically acceptable salt thereof, wherein is substituted or unsubstituted heterocyclyl. (Item 17) R 2B 17. The compound according to item 16, or a pharmaceutically acceptable salt thereof, wherein is oxetanyl. (Item 18) R 2B 18. The compound according to item 17, or a pharmaceutically acceptable salt thereof, wherein is 3-oxetanyl. (Item 19) R 2A is H or substituted or unsubstituted alkyl; R 2B is substituted or unsubstituted phenyl, or substituted or unsubstituted pyridyl; and R 3 is substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof. (Item 20) R 2A 20. The compound according to item 19, or a pharmaceutically acceptable salt thereof, wherein is unsubstituted alkyl. (Item 21) R 2A20. The compound according to item 19, wherein is H, or a pharmaceutically acceptable salt thereof. (Item 22) R 2B 22. The compound according to any one of items 19 to 21, or a pharmaceutically acceptable salt thereof, wherein is substituted phenyl or substituted pyridyl. (Item 23) R 2B is phenyl or pyridyl, each of which is substituted with one or more substituents independently selected from the group consisting of halo, alkoxy, and substituted alkyl, or a pharmaceutically acceptable salt thereof. (Item 24) R 2B is phenyl or pyridyl, each of which is substituted with -CF3, or a pharmaceutically acceptable salt thereof. (Item 25) R 2B is phenyl or pyridyl, each of which is substituted with methoxy, or a pharmaceutically acceptable salt thereof. (Item 26) R 3 26. The compound according to any one of items 19 to 25, or a pharmaceutically acceptable salt thereof, wherein is unsubstituted alkyl. (Item 27) R 3 27. The compound according to any one of items 19 to 26, or a pharmaceutically acceptable salt thereof, wherein is isopropyl. (Item 28) R 2A and R 2B together with the carbon atoms to which they are attached, form G 1 and forming , G 1 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl ring, each of which is optionally fused to a phenyl ring; and R 3is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or a pharmaceutically acceptable salt thereof. (Item 29) G 1 29. The compound according to item 28, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted 2,3-dihydro-1H-indene. (Item 30) G 1 but, [ka] 30. The compound according to item 28 or 29, or a pharmaceutically acceptable salt thereof, wherein * indicates the point of attachment to the parent structure. (Item 31) G 1 is substituted or unsubstituted [ka] 31. The compound according to any one of items 28 to 30, or a pharmaceutically acceptable salt thereof, wherein (Item 32) G 1 is substituted with one, two, or three substituents selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof. (Item 33) G 1 but, [ka] 33. The compound according to any one of items 28 to 32, wherein: (Item 34) R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl, or a pharmaceutically acceptable salt thereof. (Item 35) R 3 is phenyl substituted with one or more substituents selected from the group consisting of nitro, alkoxy, halo, cycloalkyl, cyano, alkenyl, alkoxycarbonyl, phenylcarbonyl, and alkyl, or a pharmaceutically acceptable salt thereof. (Item 36) R 3 36. The compound according to any one of items 28 to 35, or a pharmaceutically acceptable salt thereof, wherein is phenyl substituted with F and CN. (Item 37) R 3 is cycloalkyl substituted with one or more substituents selected from the group consisting of alkyl, cyano, and halo, or a pharmaceutically acceptable salt thereof. (Item 38) R 3 is alkyl substituted with one or more substituents selected from the group consisting of alkoxy, cyano, and halo, or a pharmaceutically acceptable salt thereof. (Item 39) R 4 39. The compound according to any one of items 1 to 38, or a pharmaceutically acceptable salt thereof, wherein (Item 40) R 439. The compound according to any one of items 1 to 38, or a pharmaceutically acceptable salt thereof, wherein is alkyl substituted with a substituted or unsubstituted alkoxy. (Item 41) R 5 41. The compound according to any one of items 1 to 40, wherein is H, or a pharmaceutically acceptable salt thereof. (Item 42) R 1 is phenyl or pyridinyl, each of which is substituted with one or more substituents independently selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl, or a pharmaceutically acceptable salt thereof. (Item 43) R 1 43. The compound according to any one of items 1 to 42, or a pharmaceutically acceptable salt thereof, wherein is phenyl substituted with trifluoromethyl. (Item 44) A compound selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof. (Item 45) 45. A pharmaceutical composition comprising the compound according to any one of items 1 to 44 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (Item 46) 1. A method for treating a cardiac disease in a subject in need thereof, comprising: The method comprises administering to the subject the compound according to any one of items 11 to 44 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 45. (Item 47) Item 47. The method of item 46, wherein the cardiac disease is hypertrophic cardiomyopathy. (Item 48) 48. The method of item 47, wherein the hypertrophic cardiomyopathy is obstructive or non-obstructive, or is caused by sarcomeric and / or non-sarcomeric mutations. (Item 49) Item 47. The method according to item 46, wherein the heart disease is heart failure with preserved left ventricular ejection fraction. (Item 50) Item 47. The method according to item 46, wherein the cardiac disease is selected from the group consisting of diastolic dysfunction, primary or secondary restrictive cardiomyopathy, myocardial infarction and angina pectoris, hypertrophic obstructive cardiomyopathy, hypertensive heart disease, congenital heart disease, cardiac ischemia, coronary heart disease, diabetic heart disease, congestive heart failure, right heart failure, cardiorenal syndrome, and infiltrative cardiomyopathy. (Item 51) Item 47. The method of item 46, wherein the cardiac disease is or is associated with one or more conditions selected from the group consisting of cardiac aging, age-related diastolic dysfunction, left ventricular hypertrophy, and concentric left ventricular remodeling. (Item 52) 1. A method for treating a disease or condition associated with hypertrophic cardiomyopathy in a subject in need thereof, comprising: The method comprises administering to the subject the compound according to any one of items 1 to 44 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 45. (Item 53) 53. The method of item 52, wherein the disease or condition is selected from the group consisting of Fabry disease, Danon disease, mitochondrial cardiomyopathy, and Noonan syndrome. (Item 54) 1. A method for treating a disease or condition associated with secondary left ventricular wall thickening in a subject in need thereof, comprising: The method comprises administering to the subject the compound according to any one of items 1 to 44 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 45. (Item 55) 55. The method of item 54, wherein the disease or condition is selected from the group consisting of hypertension, valvular heart disease, aortic stenosis, mitral regurgitation, metabolic syndrome, diabetes, obesity, end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich's ataxia, Danon disease, Noonan syndrome, and Pompe disease. (Item 56) 1. A method for treating a disease or condition associated with small left ventricular lumen and lumen obstruction, left ventricular hypercontraction, myocardial ischemia, or myocardial fibrosis in a subject in need thereof, comprising: The method comprises administering to the subject the compound according to any one of items 1 to 44 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 45. (Item 57) 1. A method for treating a disease or condition selected from muscular dystrophy and glycogen storage disease in a subject in need thereof, comprising: The method comprises administering to the subject the compound according to any one of items 1 to 44 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 45. (Item 58) A method for inhibiting cardiac sarcomere, comprising: The method comprises contacting the cardiac sarcomere with the compound according to any one of items 1 to 44 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 45. DETAILED DESCRIPTION OF THE INVENTION

[0033] definition As used in the present specification, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0034] Throughout this application, unless the context indicates otherwise, reference to compounds of formula (I) is and (Im), (In-1), and (In-2), including all subgroups of formula (I) defined above, for example, formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2), including all substructures, subgenera, preferences, embodiments, examples, and specific compounds defined and / or described herein. References to compounds of formula (I) and sub-groups thereof, such as formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2) ​​include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and / or protected forms thereof. In some embodiments, references to compounds of Formula (I) and subgroups thereof, such as Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2) ​​include polymorphs, solvates, co-crystals, isomers, tautomers, and / or oxides thereof. In some embodiments, references to compounds of Formula (I) and subgroups thereof, such as Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2) ​​include polymorphs, salts, solvates, and / or co-crystals thereof. In some embodiments, references to compounds of Formula (I) and subgroups thereof, such as formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2) ​​include isomers, tautomers and / or oxides thereof.In some embodiments, references to compounds of Formula (I) and subgroups thereof, such as formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2) ​​include solvates thereof.

[0035] "Alkyl" includes straight and branched carbon chains having the indicated number of carbon atoms, e.g., 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, C 1-6 Alkyl includes both straight-chain and branched alkyls of 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbon atoms is named, all branched and straight-chain versions having 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 t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0036] Given a set of values ​​(e.g., C 1-6 alkyl), including each value within the range and all intervening ranges. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 , and C 1-2 Contains alkyl.

[0037] "Alkenyl" refers to an unsaturated, branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s). Alkenyl groups include ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl). 1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl).

[0038] "Alkynyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl), and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl).

[0039] "Cycloalkyl" refers to a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10, or 3 to 8, or 3 to 6 carbon ring atoms. Cycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged and caged ring groups (e.g., norbornane, bicyclo[2.2.2]octane). Furthermore, one ring of a polycyclic cycloalkyl group can be aromatic, provided that the polycyclic cycloalkyl group is attached to the parent structure through a non-aromatic carbon atom. For example, 1,2,3,4-tetrahydronaphthalen-1-yl (wherein the moiety is attached to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (wherein the moiety is attached to the parent structure through an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are set forth below.

[0040] "Cycloalkenyl" refers to a non-aromatic carbocyclic ring containing the indicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 carbon ring 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 bridged and caged ring groups (e.g., bicyclo[2.2.2]octene). Furthermore, one ring of a polycyclic cycloalkenyl group can be aromatic, provided that the polycyclic alkenyl group is attached to the parent structure through a non-aromatic carbon atom. For example, inden-1-yl, where the moiety is attached to the parent structure through a non-aromatic carbon atom, is considered a cycloalkenyl group, while inden-4-yl, where the moiety is attached to the parent structure through an aromatic carbon atom, is not considered a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused to an aromatic ring are set forth below.

[0041] "Cycloalkynyl" refers to an unsaturated hydrocarbon group within a cycloalkyl group having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C). A cycloalkynyl can consist of one ring, such as cyclooctyne, or multiple rings. A cycloalkynyl moiety is an unsaturated cyclic hydrocarbon having 5 to 10 ring carbon atoms ("C5-C 10 Examples include cyclopentyne, cyclohexyne, cycloheptyne, cyclooctyne, cyclononyne, and the like.

[0042] "Aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon atoms, e.g., 6 to 12 or 6 to 10 carbon atoms. 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., (e.g., naphthyl). In other cases, a polycyclic aryl group may contain a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is attached to the parent structure through an atom in the aromatic ring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (where the moiety is attached to the parent structure through an aromatic carbon atom) would be considered an aryl group, while a 1,2,3,4-tetrahydronaphthalen-1-yl group (where the moiety is attached to the parent structure through a non-aromatic carbon atom) would not be considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (where the moiety is attached to the parent structure through an aromatic carbon atom) would be considered an aryl group, while a 1,2,3,4-tetrahydroquinolin-1-yl group (where the moiety is attached to the parent structure through a non-aromatic nitrogen atom) would not be considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl," as defined herein, regardless of point of attachment (e.g., quinolin-5-yl and quinolin-2-yl are both heteroaryl groups). In some cases, aryl is phenyl or naphthyl. In certain cases, aryl is phenyl. Additional examples of aryl groups that include an aromatic carbocyclic ring fused to a non-aromatic ring are described below.

[0043] "Heteroaryl" refers to an aromatic ring (e.g., a 5- to 12- or 5- to 10-membered heteroaryl) containing the indicated number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon. A heteroaryl group does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in a heteroaryl group is 1 or less. Unless otherwise specified, a heteroaryl group may be attached to the parent structure by a carbon or a nitrogen atom, if valence allows. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl groups, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl groups.

[0044] In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine), and tetrazine.

[0045] In some cases, both rings of a polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[3,4 ... Pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine Lysine, Isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, Furo[3,2-b]pyridine, Oxazolo[4,5-b]pyridine, Isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, Furo[2,3-c]pyridine, Oxazolo[5,4-c]pyridine, Isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5, 4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, iso Thiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinolinol quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole.

[0046] In other cases, polycyclic heteroaryl groups may contain non-aromatic rings fused to the heteroaryl ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl), provided that the polycyclic heteroaryl group is attached to the parent structure through an atom in the aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (which is attached to the parent structure through an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (which is attached to the parent structure through a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of heteroaryl rings fused to non-aromatic rings are provided below.

[0047] "Heterocycloalkyl" refers to a non-aromatic, fully saturated ring (e.g., 3- to 10-, or 3- to 7-membered heterocycloalkyl) having the indicated number of atoms, consisting of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Furthermore, one ring of a polycyclic heterocycloalkyl group can be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2,3,4-tetrahydroquinolin-1-yl group (which is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while a 1,2,3,4-tetrahydroquinolin-8-yl group (which is attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are provided below.

[0048] "Heterocycloalkenyl" refers to a group consisting of one or more heteroatoms (e.g., cyclohexyl ...) selected from N, O, and S. "Heterocycloalkenyl" refers to a non-aromatic ring (e.g., 3- to 10-, or 3- to 7-membered heterocycloalkyl) having the indicated number of atoms, composed of 1, 2, 3, or 4 heteroatoms, with the remaining ring atoms being carbon, and at least one double bond being obtained by removal of one hydrogen atom from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. Heterocycloalkenyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). Additionally, one ring of a polycyclic heterocycloalkenyl group can be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkenyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2-dihydroquinolin-1-yl group (which is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while a 1,2-dihydroquinolin-8-yl group (which is attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are provided below.

[0049] Examples of polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-Dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydrobenzo 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one, 1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran-3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)-one, benzo [d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one, benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazolin-2,4(1H,3H)-dione, quinoxalin-2(1H)-one, quinoxalin-2,3(1H,4H, )-dione, cinnolin-4(3H)-one, pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one and 4,5-dihydropyrrolo[3,4-d]thiazol-6-one. As discussed herein, whether each ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group is determined by the atom through which the moiety is attached to the parent structure.

[0050] The terms "heterocycle," "heterocyclyl," or "heterocyclic" refer to a saturated, partially saturated, or unsaturated 4- to 12-membered ring containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, the heteroatom may be carbon- or nitrogen-bonded, a -CH- group may be optionally replaced by C(O)-, and a ring sulfur atom may be optionally oxidized to form a sulfinyl or sulfonyl group. A heterocycle may be aromatic (heteroaryl) or non-aromatic. Furthermore, not all rings in a polycyclic heterocyclyl group may be aromatic (e.g., aryl or heteroaryl). For example, both 1,2,3,4-tetrahydroquinolin-1-yl and 1,2,3,4-tetrahydroquinolin-8-yl groups are considered heterocyclyl groups.

[0051] "Heterocycle," "heterocyclyl," or "heterocyclic" also includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryl, cycloalkyl, and heterocycle. Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, Examples include oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl, and triazolyl.

[0052] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0053] Unless otherwise indicated, the compounds disclosed and / or described herein include all such possible enantiomers, diastereomers, mesoisomers, and other stereoisomeric forms, including racemic mixtures, optically pure forms, and mixtures of intermediates. Enantiomers, diastereomers, mesoisomers, and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless otherwise specified, when a compound disclosed and / or described herein contains an olefinic double bond or other center of geometric asymmetry, the compound is intended to include both the E and Z isomers. When a compound described herein contains moieties capable of tautomerization, unless otherwise specified, the compound is intended to include all possible tautomers.

[0054] "Protecting group" has the meaning commonly associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a polyfunctional compound so that a chemical reaction can be selectively carried out on another unprotected reactive site, and that can be easily removed after the selective reaction is complete. Various protecting groups are disclosed, for example, in T.H. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a "hydroxy-protected form" contains at least one hydroxy group protected with a hydroxy-protecting group. Similarly, amines and other reactive groups can be similarly protected.

[0055] The term "pharmaceutically acceptable salt" refers to any salt of the compounds herein that is known to be non-toxic and commonly used in pharmaceutical literature. In some embodiments, a pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and is not biologically or otherwise unsuitable. 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 embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0056] When the compound described herein is obtained as an acid addition salt, its free base can be obtained by basifying the solution of the acid salt.On the other hand, when the compound is a free base, addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating this solution with an acid according to the conventional procedure for preparing an acid addition salt from a base compound (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19).Those skilled in the art will be aware of various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0057] 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 any ratio of compound to water, such as monohydrates, dihydrates, and hemihydrates.

[0058] The term "substituted" refers to the fact that a particular group or moiety is substituted with an alkoxy, acyl, acylo The term "unsubstituted" means that a particular group has no substituents, including, but not limited to, substituents such as oxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocyclyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, and oxo. The term "unsubstituted" means that the particular group has no substituents. When the term "substituted" is used to describe a structural system, substitution is intended to occur at any valence-allowed position on the system. When a group or moiety has two or more substituents, it is understood that the substituents can be the same or different from one another. In some embodiments, a substituent or moiety has 1 to 5 substituents. In some embodiments, a substituent or moiety has 1 substituent. In some embodiments, a substituent or moiety has 2 substituents. In some embodiments, a substituent or moiety has 3 substituents. In some embodiments, the substituent or moiety has 4 substituents, hi some embodiments, the substituent or moiety has 5 substituents.

[0059] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that such description encompasses instances in which said event or circumstance occurs and instances in which said event or circumstance occurs. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. Those of skill in the art will understand that with respect to any group containing one or more substituents, it is not intended that such groups introduce any substitution or substitution pattern that is sterically impractical, synthetically impractical, and / or inherently unstable. When a group or moiety is referred to as optionally substituted, it is also understood that the present disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is not substituted.

[0060] The compounds disclosed and / or described herein may be present in isotopic enriched forms, e.g. 2 H, 3 H, 11 C. 13 C and / or 14 In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be made, for example, by the procedures described in U.S. Pat. Nos. 5,846,514 and 6,334,997. Such deuterated compounds can improve the efficacy and duration of action of the compounds disclosed and / or described herein. Deuterium-substituted compounds can be prepared by a variety of methods, for example, by the procedures described in Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32, etc.

[0061] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in pharmaceutical compositions is contemplated. Supplementary active ingredients may also be incorporated into pharmaceutical compositions. can.

[0062] The terms "patient," "individual," and "subject" refer to an animal, such as a mammal, bird, or fish. In some embodiments, a patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, a patient or subject is a human, e.g., a human who has been or will be the subject of treatment, observation, or experimentation. The compounds, compositions, and methods described herein can be useful for both human treatment and veterinary applications.

[0063] As used herein, the term "therapeutic" refers to the ability to modulate cardiac sarcomeres. As used herein, "modulation" refers to a change in activity, as compared to activity in the absence of a compound entity, as a direct or indirect response to the presence of a compound entity described herein. The change may be an increase in activity or a decrease in activity, and may be due to a direct interaction of the compound entity with the target, or due to the interaction of the compound entity with one or more other factors that, in turn, affect the activity of the target. For example, the presence of a compound entity may increase or decrease target activity by directly binding to the target, by introducing (directly or indirectly) another factor that increases or decreases target activity, or by increasing or decreasing (directly or indirectly) the amount of target present in a cell or organism.

[0064] The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound disclosed and / or described herein that, when administered to a patient in need of such treatment, is sufficient to affect treatment, as defined herein. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation of cardiac sarcomeres. A therapeutically effective amount will vary depending, for example, on the subject and disease state being treated, the subject's weight and age, the severity of the disease state, the particular compound, the dosing regimen to be followed, the timing of administration, and the method of administration, all of which can be readily determined by one of ordinary skill in the art. A therapeutically effective amount can be determined experimentally, for example, by assaying the blood concentration of the compound entity, or theoretically, for example, by calculating bioavailability.

[0065] "Treatment" (and related terms, such as "treat," "treated," "treating," etc.) includes one or more of the following: inhibiting a disease or disorder; delaying or halting the onset of clinical symptoms of a disease or disorder; and / or alleviating a disease or disorder (i.e., causing relief from or regression of clinical symptoms). The term covers both complete and partial reduction or prevention of a condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, the compounds described and / or disclosed herein may prevent an existing disease or disorder from getting worse, aid in the management of a disease or disorder, or reduce or eliminate a disease or disorder.

[0066] "ATPase" refers to an enzyme that hydrolyzes ATP. ATPases include proteins that comprise molecular motors such as myosin.

[0067] As used herein, "selective binding" or "selectively binds" refers to preferential binding to a target protein in one type of muscle or muscle fiber over other types. For example, a compound selectively binds to fast skeletal muscle troponin C if it preferentially binds to troponin C in fast skeletal muscle fibers or sarcomere troponin complexes compared to troponin C in slow muscle fibers or sarcomere troponin complexes, or compared to troponin C in cardiac muscle sarcomere troponin complexes.

[0068] Embodiments described herein as "comprising" include It should be understood that this includes the embodiments "consisting of" and "consisting essentially of."

[0069] compound The compounds and their salts (e.g., pharmaceutically acceptable salts) are described in detail herein, including in the Summary of the Invention and the accompanying claims. All compounds described herein, including all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and mixtures thereof in any ratio, including racemic mixtures, salts and solvates of the compounds described herein, and methods for preparing such compounds are also provided. Any compound described herein may also be referred to as a drug.

[0070] In one embodiment, the compound of formula (I): [ka] (I) or a pharmaceutically acceptable salt thereof, During the ceremony: R 1 is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted pyridyl; R 2A , R 2B , and R 3is defined by one of (i) to (iii): (i) R 2A is H or substituted or unsubstituted alkyl; R 2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and R 3 is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; or (ii)R 2A is H or substituted or unsubstituted alkyl; R 2B is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; and R 3 is substituted or unsubstituted alkyl; or (iii)R 2A and R 2B together with the carbon atoms to which they are attached, form G 1 wherein G 1 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl ring, each of which is optionally fused to a phenyl ring; and R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 4 is H or substituted or unsubstituted alkyl; and R 5 is H or substituted or unsubstituted alkyl; where, when one or more of provisions (a) to (c) apply, R 1 is a substituted or unsubstituted pyridyl or a phenyl substituted with at least one substituent other than methyl or methoxy; (a)R 2A and R 2B is defined by (i) and R 3 is a substituted or unsubstituted phenyl; (b)R 2A and R 3 is defined by (ii) and R 2B is 4-methoxyphenyl; (c)R 2A and R 2B is defined by (iii) and R 3 provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0071] In some embodiments of Formula (I), R 4 and R 5 are each independently H. In some embodiments of Formula (I), R 4 and R 5 At least one of is other than H. In some embodiments of Formula (I), R 4 is a substituted or unsubstituted alkyl. In some embodiments of Formula (I), R 4 is methyl. In some embodiments of Formula (I), R 4 is alkyl substituted with alkoxy. In some embodiments of Formula (I), R 4 In some embodiments of Formula (I), R 5 is a substituted or unsubstituted alkyl. In some embodiments of Formula (I), R 5 is methyl. In some embodiments of Formula (I), R 5 is substituted alkyl. In some embodiments of Formula (I), R 5is hydroxymethyl.

[0072] In some embodiments of Formula (I), R 1 is unsubstituted pyridyl or unsubstituted phenyl. In some embodiments of Formula (I), R 1 is 2-pyridyl. In some embodiments of Formula (I), R 1 is phenyl or pyridinyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents independently selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted diazirinyl. In some embodiments of Formula (I), R 1 is pyridyl substituted with one or two halo selected from the group consisting of F and Cl. In some embodiments of Formula (I), R 1 is pyridyl substituted with -CF. In some embodiments of Formula (I), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo selected from the group consisting of F and Cl. In some embodiments of Formula (I), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methyl. In some embodiments of Formula (I), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) cyano. In some embodiments of Formula (I), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) —CF3. In some embodiments of Formula (I), R 1 is phenyl substituted with one halo and one cyano. In some embodiments of Formula (I), R 1 is phenyl substituted with one Cl and one F. In some embodiments of Formula (I), R 1is phenyl substituted with one halo and one -CF. In some embodiments of Formula (I), R 1 is phenyl substituted with diazirinyl. In some embodiments of Formula (I), R 1 is a phenyl substituted with a diazirinyl substituted with a trifluoromethyl.

[0073] In some embodiments of Formula (I), R 2A and R 2B The carbon bearing the moiety is in the "S" stereochemical configuration. 2A and R 2B For any of the embodiments of Formula (I) and subformulas thereof provided herein, the present disclosure provides that the R 2A and R 2B Embodiments in which the carbon bearing the moiety is in the "S" stereochemical configuration, and 2A and R 2B It is to be understood that this includes embodiments in which the carbon bearing the moiety is in the "R" stereochemical configuration.

[0074] It is understood that each of the variables described herein may be combined with other variables to the same extent as if each and every combination were specifically and independently listed. For example, each R 1 are either individually or collectively R 2A , R 2B , R 3 , R 4 , and R 5 It is to be understood that this also applies to each of formula (I) and subgroups thereof described herein: formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2).

[0075] In another embodiment, the compound of formula (I) is a compound of formula (Ia): [ka] (Ia) or a pharmaceutically acceptable salt thereof; In the formula, R 1 is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl; R 2A is H or substituted or unsubstituted alkyl; R 2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 3 is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl; R 4 is H, or substituted or unsubstituted alkyl; and R 5 is H or substituted or unsubstituted alkyl; 3 is substituted or unsubstituted phenyl, R 1 is a substituted or unsubstituted pyridyl, or a phenyl substituted with at least one substituent other than methyl or methoxy.

[0076] In some embodiments of Formula (Ia), R 4 and R 5 are each independently H. In some embodiments of Formula (Ia), R 4 and R 5 At least one of is other than H.

[0077] In some embodiments of Formula (Ia), R 3 is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ia), R 3 is 2-pyridyl. In some embodiments of Formula (Ia), R 3 is unsubstituted phenyl. In some embodiments of Formula (Ia), R 3is phenyl or pyridyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo substituents selected from the group consisting of F and Cl. In some embodiments of Formula (Ia), R 3 is phenyl or pyridyl, each of which is substituted with two halo substituents selected from the group consisting of F and Cl. In some embodiments of Formula (Ia), R 3 is phenyl or pyridyl, each of which is substituted with two F. In some embodiments of Formula (Ia), R 3 is phenyl or pyridyl, each of which is substituted with two Cl. In some embodiments of Formula (Ia), R 3 is phenyl or pyridyl, each of which is substituted with one F and one Cl. In some embodiments of Formula (Ia), R 3 is phenyl or pyridyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) CN substituents. In some embodiments of Formula (Ia), R 3 is phenyl or pyridyl, each of which is substituted with two CN substituents. In this state, R 3 is phenyl or pyridyl, each of which is substituted with one halo and one CN substituent. In some embodiments of Formula (Ia), R 3 is phenyl or pyridyl, each of which is substituted with one Cl and one CN. In some embodiments of Formula (Ia), R 3 is phenyl or pyridyl, each of which is substituted with one F and one CN.

[0078] In some embodiments of Formula (Ia), R 2A is H. In some embodiments of Formula (Ia), R 2A is substituted or unsubstituted alkyl. In some embodiments of Formula (Ia), R 2Ais a substituted or unsubstituted methyl. In some embodiments of Formula (Ia), R 2A is methyl.

[0079] In some embodiments of Formula (Ia), R 2B is H. In some embodiments of Formula (Ia), R 2B is substituted or unsubstituted alkyl. In some embodiments of Formula (Ia), R 2B is selected from the group consisting of methyl, isopropyl, and propyl. In some embodiments of Formula (Ia), R 2B is alkyl substituted with hydroxyl, or substituted or unsubstituted alkoxy. In some embodiments of Formula (Ia), R 2B In some embodiments of Formula (Ia), R 2B is a substituted alkoxyalkyl. In some embodiments of Formula (Ia), R 2B In some embodiments of Formula (Ia), R 2B is a substituted or unsubstituted cycloalkyl. In some embodiments of Formula (Ia), R 2B is a substituted or unsubstituted C3-C7 cycloalkyl. In some embodiments of Formula (Ia), R 2B In some embodiments of Formula (Ia), R 2B is a substituted or unsubstituted heterocyclyl. In some embodiments of Formula (Ia), R 2B is a substituted or unsubstituted C3-C7 heterocyclyl. In some embodiments of Formula (Ia), R 2B is a substituted or unsubstituted C3-C7 heterocyclyl containing one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) N or O ring atoms. In some embodiments of Formula (Ia), R 2B is oxetanyl. In some embodiments of Formula (Ia), R 2B is 3-oxetanyl.

[0080] In some embodiments of Formula (Ia), R 1 is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ia), R 1 is 2-pyridyl. In some embodiments of Formula (Ia), R 1 is unsubstituted phenyl. In some embodiments of Formula (Ia), R 1 is phenyl or pyridyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents independently selected from the group consisting of cyano, halo, alkoxy, —CF3, alkyl, and diazirinyl. In some embodiments of Formula (Ia), R 1 In some embodiments of Formula (Ia), R is phenyl or pyridyl, each of which is substituted with substituted alkyl. 1 is phenyl or pyridyl, each of which is substituted with -CF. In some embodiments of Formula (Ia), R 1 is a phenyl substituted with 4-CF3.

[0081] In some embodiments of Formula (Ia), R 1 is phenyl substituted with -CF3, and R 3 is phenyl substituted with two halo substituents. In some embodiments of Formula (Ia), R 1 is phenyl substituted with -CF3, and R 3 is phenyl substituted with one halo and one CN. In some embodiments of Formula (Ia), R 1 is a substituted or unsubstituted pyridyl, and R 3 is phenyl substituted with two halo. In some embodiments of Formula (Ia), R 1 is a substituted or unsubstituted pyridyl, and R 3 is phenyl substituted with one halo and one CN. In some embodiments of Formula (Ia), R 1 is 2-pyridyl and R 3 is phenyl substituted with two halo. In some embodiments of Formula (Ia), R 1is 2-pyridyl and R 3 is one halo and and phenyl substituted with one CN. In some embodiments of Formula (Ia), R 1 is phenyl substituted with -CF3, and R 3 is phenyl.

[0082] In some embodiments of Formula (Ia), R 1 is phenyl substituted with -CF3, and R 2A is H and R 2B is 3-oxetanyl, and R 3 is phenyl substituted with one or more substituents selected from the group consisting of F and Cl, and R 4 is H and R 5 is H. In some embodiments of Formula (Ia), R 1 is phenyl substituted with -CF3, and R 2A is H and R 2B is 3-oxetanyl, and R 3 is pyridyl substituted with one or more substituents selected from the group consisting of F and Cl, and R 4 is H and R 5 is H. In some embodiments of Formula (Ia), R 1 is phenyl substituted with -CF3, and R 2A is H and R 2B is isopropyl, and R 3 is phenyl substituted with one or more substituents selected from the group consisting of F and Cl, and R 4 is H and R 5 is H. In some embodiments of Formula (Ia), R 1 is phenyl substituted with -CF3, and R 2A is H and R 2B is isopropyl, and R 3 is pyridyl substituted with one or more substituents selected from the group consisting of F and Cl, and R 4 is H and R 5 is H.

[0083] In some embodiments of Formula (Ia): R 4 and R 5 are each independently H; R 3 is phenyl or pyridyl, each of which is substituted with two halo substituents selected from the group consisting of F and Cl; R 2A is H or methyl; R 2B is selected from the group consisting of methyl, isopropyl, propyl, hydroxymethyl, trifluoromethoxymethyl, cyclobutanyl, and 3-oxetanyl; and R 1 is phenyl or pyridyl, each of which is substituted with -CF3.

[0084] In another embodiment, the compound of formula (I) is a compound of formula (Ib): [ka] (Ib) or a pharmaceutically acceptable salt thereof; In the formula, R 1 is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl; R 2A is H or substituted or unsubstituted alkyl; R 2B is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl; R 3 is a substituted or unsubstituted alkyl; R 4 is H, or substituted or unsubstituted alkyl; and R 5 is H or substituted or unsubstituted alkyl; 2B is 4-methoxyphenyl, R 1 is a substituted or unsubstituted pyridyl, or a phenyl substituted with at least one substituent other than methyl or methoxy.

[0085] In some embodiments of Formula (Ib), R 4 and R 5 are each independently H. In some embodiments of Formula (Ib), R 4 and R 5At least one of is other than H.

[0086] In some embodiments of Formula (Ib), R 2A is H. In some embodiments of Formula (Ib), R 2A is substituted or unsubstituted alkyl. In some embodiments of Formula (Ib), R 2A is a substituted or unsubstituted methyl. In some embodiments of Formula (Ia), R 2A is methyl.

[0087] In some embodiments of Formula (Ib), R 2B is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ib), R 2B is 2-pyridyl. In some embodiments, R 2B is a substituted or unsubstituted phenyl. In some embodiments of Formula (Ib), R 2B is phenyl or pyridyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents independently selected from the group consisting of halo, substituted or unsubstituted alkoxy, and substituted or unsubstituted alkyl. In some embodiments of Formula (Ib), R 2B is pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halo and substituted or unsubstituted alkyl. In some embodiments of Formula (Ib), R 2B is pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ib), R 2B is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ib), R 2B is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) —CF3. In some embodiments of Formula (Ib), R 2Bis phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) alkoxy. In some embodiments of Formula (Ib), R 2B is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methoxy.

[0088] In some embodiments of Formula (Ib), R 3 is a substituted or unsubstituted C1-C 10 In some embodiments of Formula (Ib), R 3 is unsubstituted C1-C 10 In some embodiments of Formula (Ib), R 3 is unsubstituted C2-C6 alkyl. In some embodiments of Formula (Ib), R 3 is unsubstituted C3-C5 alkyl. In some embodiments of Formula (Ib), R 3 is an unsubstituted C alkyl. In some embodiments of Formula (Ib), R 3 is unsubstituted isopropyl.

[0089] In some embodiments of Formula (Ib), R 1 is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ib), R 1 is 2-pyridyl. In some embodiments of Formula (Ib), R 1 is a substituted or unsubstituted phenyl. In some embodiments of Formula (Ib), R 1 is phenyl or pyridinyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents independently selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted diazirinyl. In some embodiments of Formula (Ib), R 1 is pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ib), R 1is pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) —CF3. In some embodiments of Formula (Ib), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ib), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) —CF3. In some embodiments of Formula (Ib), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) —CN. In some embodiments of Formula (Ib), R 1 is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methyl.

[0090] In some embodiments of Formula (Ib), R 2B is 4-methoxyphenyl, and R 1 is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ib), R 2 B is 4-methoxyphenyl, and R 1 is 2-pyridyl. In some embodiments of Formula (Ib), R 2B is 4-methoxyphenyl, and R 1 is 2-pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ib), R 2B is 4-methoxyphenyl, and R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ib), R 2B is 4-methoxyphenyl, and R 1 is phenyl substituted with 4-Cl.

[0091] In some embodiments of Formula (Ib), R 1 is pyridyl substituted with one or more substituents independently selected from the group consisting of halo and -CF3; R 2A is H and R 2B is pyridyl substituted with one or more substituents selected from the group consisting of F and Cl, and R 3 is isopropyl, and R 4 is H and R 5 is H. In some embodiments of Formula (Ib), R 1 is phenyl substituted with one or more substituents independently selected from the group consisting of halo, -CF, -CN, and methyl; R 2A is H and R 2B is pyridyl substituted with one or more substituents selected from the group consisting of F and Cl, and R 3 is isopropyl, and R 4 is H and R 5 is H. In some embodiments of Formula (Ib), R 1 is pyridyl substituted with one or more substituents independently selected from the group consisting of halo and -CF3; R 2A is methyl and R 2B is pyridyl substituted with one or more substituents selected from the group consisting of F and Cl, and R 3 is isopropyl, and R 4 is H and R 5 is H. In some embodiments of Formula (Ib), R 1 is phenyl substituted with one or more substituents independently selected from the group consisting of halo, -CF, -CN, and methyl; R 2A is methyl and R 2B is pyridyl substituted with one or more substituents selected from the group consisting of F and Cl, and R 3 is isopropyl, and R 4 is H and R 5 is H.

[0092] In another embodiment, the compound of formula (I) is a compound of formula (Ic): [ka] (I C) or a pharmaceutically acceptable salt thereof; In the formula, R 1 is selected from the group consisting of substituted or unsubstituted pyridyl, and substituted or unsubstituted phenyl; R 2A and R 2B together with the carbon atoms to which they are attached, form G 1 wherein G 1 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl ring, each of which is optionally fused to a phenyl ring; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 4 is H, or substituted or unsubstituted alkyl; and R 5 is H or substituted or unsubstituted alkyl; 3 is 4-methoxyphenylmethyl, R 1 is a substituted or unsubstituted pyridyl, or a phenyl substituted with at least one substituent other than methyl or methoxy.

[0093] In some embodiments of Formula (Ic), R 4 and R 5 are each independently H. In some embodiments of Formula (Ic), R 4 and R 5 At least one of them is not H. In some embodiments of Formula (Ic), R 4 is substituted or unsubstituted alkyl. In some embodiments of Formula (Ic), R 4is methyl. In some embodiments of Formula (Ic), R 4 is alkyl substituted with alkoxy. In some embodiments of Formula (Ic), R 4 In some embodiments of Formula (Ic), R 5 is substituted or unsubstituted alkyl. In some embodiments of Formula (Ic), R 5 is methyl. In some embodiments of Formula (Ic), R 5 is substituted alkyl. In some embodiments of Formula (Ic), R 5 is hydroxymethyl.

[0094] In some embodiments of Formula (Ic), G 1 is selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted 2,3-dihydro-1H-indene. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted C3-C6 heterocyclyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted cyclopropyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted cyclobutanyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted azetidinyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted tetrahydrofuranyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted pyrrolidinyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted pyrrolidin-2-one-yl.

[0095] In some embodiments of Formula (Ic), G 1is heterocyclyl or cycloalkyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1 to 4 or 1 to 3 or 2 to 4) substituents selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminothionyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl. In some embodiments of Formula (Ic), G 1 is a heterocyclyl substituted with a substituted or unsubstituted phenyl. In some embodiments of Formula (Ic), G 1 is heterocyclyl substituted with phenyl, which is substituted with halo. In some embodiments of Formula (Ic), G 1 is a heterocyclyl substituted with a substituted or unsubstituted heteroaryl. In some embodiments of Formula (Ic), G 1 is a heterocyclyl substituted with a substituted or unsubstituted pyridyl. In some embodiments of Formula (Ic), G 1 is heterocyclyl substituted with pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, CN, hydroxyl, alkoxycarbonyl, methoxycarbonyl, alkoxy, carboxyl, cycloalkyl, halo, and aminoacyl. In some embodiments of Formula (Ic), G 1 is a heterocyclyl substituted with a substituted or unsubstituted pyrimidyl. In some embodiments of Formula (Ic), G 1 is a heterocyclyl substituted with a substituted or unsubstituted pyrazolyl. In some embodiments of Formula (Ic), G 1 is a heterocyclyl substituted with a pyrazolyl substituted with an alkyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted thiazolyl-substituted heterocyclyl. In some embodiments of Formula (Ic), G 1is a thiazolyl-substituted heterocyclyl that is substituted with an aminoacyl. In some embodiments of Formula (Ic), G 1 is a heterocyclyl substituted with a substituted or unsubstituted alkoxycarbonyl. In some embodiments of Formula (Ic), G 1 is heterocyclyl substituted with methoxycarbonyl. In some embodiments of Formula (Ic), G 1 is a heterocyclyl substituted with a substituted or unsubstituted aminoacyl. In some embodiments of Formula (Ic), G 1 is heterocyclyl substituted with methylaminoacyl. In some embodiments of Formula (Ic), G 1 is an aryl, cycloalkyl, pyridyl, pyrazolyl, and alkoxyalkyl; In some embodiments of Formula (Ic), G is a heterocyclyl substituted with an aminoacyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of: 1 is a heterocyclyl substituted with a substituted or unsubstituted pyridin-on-yl. In some embodiments of Formula (Ic), G 1 is heterocyclyl substituted with pyridin-on-yl, which is substituted with alkyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted oxadiazolyl-substituted heterocyclyl. In some embodiments of Formula (Ic), G 1 is heterocyclyl substituted with oxadiazolyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl and phenyl. In some embodiments of Formula (Ic), G 1 is a heterocyclyl substituted with a substituted or unsubstituted 9-membered bicyclic heterocyclyl. In some embodiments of Formula (Ic), G 1 is heterocyclyl substituted with —C(O)H. In some embodiments of Formula (Ic), G 1 is a heterocyclyl substituted with a substituted or unsubstituted pyridazinyl. In some embodiments of Formula (Ic), G1 is heterocyclyl substituted with pyridazinyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halo, alkoxy, alkyl, and aminoacyl. In some embodiments of Formula (Ic), G 1 is a heterocyclyl substituted with a substituted or unsubstituted aminothionyl. In some embodiments of Formula (Ic), G 1 is heterocyclyl substituted with aminothionyl substituted with alkyl. In some embodiments of Formula (Ic), G 1 is a heterocyclyl substituted with a substituted or unsubstituted acyl. In some embodiments of Formula (Ic), G 1 is heterocyclyl substituted with acyl, which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl, alkyl, and heterocyclyl. In some embodiments of Formula (Ic), G 1 is an acyl-substituted heterocyclyl that is substituted with morpholinyl. In some embodiments of Formula (Ic), G 1 is a heterocyclyl substituted with a substituted or unsubstituted aminocarbonylamino. In some embodiments of Formula (Ic), G 1 is heterocyclyl substituted with aminocarbonylamino, which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl and heterocyclyl.

[0096] In some embodiments of Formula (Ic), G 1 is a cycloalkyl substituted with a substituted or unsubstituted phenyl. In some embodiments of Formula (Ic), G 1 is a cycloalkyl substituted with a substituted or unsubstituted thiazolyl. In some embodiments of Formula (Ic), G 1 is a cycloalkyl substituted with thiazolyl, which is substituted with alkyl. In some embodiments of Formula (Ic), G 1is a cycloalkyl substituted with a substituted or unsubstituted oxazolyl. In some embodiments of Formula (Ic), G 1 is a cycloalkyl substituted with an oxazolyl substituted with an alkyl. In some embodiments of Formula (Ic), G 1 is a cycloalkyl substituted with a substituted or unsubstituted aminoacyl. In some embodiments of Formula (Ic), G 1 is cycloalkyl substituted with aminoacyl, which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl. In some embodiments of Formula (Ic), G 1 is a cycloalkyl substituted with a substituted or unsubstituted oxadiazolyl. In some embodiments of Formula (Ic), G 1 is cycloalkyl substituted with oxadiazolyl, which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl and alkyl. In some embodiments of Formula (Ic), G 1 is a cycloalkyl substituted with a substituted or unsubstituted acyl. In some embodiments of Formula (Ic), G 1 is a cycloalkyl substituted with an acyl substituted with a heterocyclyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted amino In some embodiments of Formula (Ic), G is a cycloalkyl substituted with carbonylamino. 1 is cycloalkyl substituted with aminocarbonylamino, which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl. In some embodiments of Formula (Ic), G 1 is a cycloalkyl substituted with a substituted or unsubstituted alkoxycarbonyl. In some embodiments of Formula (Ic), G 1is a cycloalkyl substituted with an alkoxycarbonyl substituted with an alkyl. In some embodiments of Formula (Ic), G 1 is cycloalkyl substituted with substituted or unsubstituted alkyl. In some embodiments of Formula (Ic), G 1 is a cycloalkyl substituted with an alkyl substituted with a hydroxyl. In some embodiments of Formula (Ic), G 1 is a cycloalkyl substituted with a hydroxyl.

[0097] In some embodiments of Formula (Ic), R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl. In some embodiments of Formula (Ic), R 3 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of nitro, alkoxy, halo, cycloalkyl, cyano, alkenyl, alkoxycarbonyl, phenylcarbonyl, and alkyl. In some embodiments of Formula (Ic), R 3 is cycloalkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cyano, and halo. In some embodiments of Formula (Ic), R 3 is alkyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkoxy, cyano, and halo.

[0098] In some embodiments of Formula (Ic), R 1 is a substituted or unsubstituted pyridyl. In some embodiments of Formula (Ic), R 1 is 2-pyridyl. In some embodiments of Formula (Ic), R 1 is a substituted or unsubstituted phenyl. In some embodiments of Formula (Ic), R 1is phenyl or pyridinyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents independently selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted diazirinyl. In some embodiments of Formula (Ic), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ic), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) —CF3. In some embodiments of Formula (Ic), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methyl. In some embodiments of Formula (Ic), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) diazirinyls. In some embodiments of Formula (Ic), R 1 is phenyl substituted with trifluoromethyldiazirinyl.

[0099] In some embodiments of Formula (Ic), R 1 is phenyl substituted with Cl, and R 3 is substituted with 4-methoxyphenylmethyl. In some embodiments of Formula (Ic), R 1 is phenyl substituted with F, and R 3 is substituted with 4-methoxyphenylmethyl. In some embodiments of Formula (Ic), R 1 is phenyl substituted with -CF3, and R 3 is substituted with 4-methoxyphenylmethyl. In some embodiments of Formula (Ic), R 1 is phenyl substituted with trifluoromethyldiazirinyl, and R 3 is substituted with 4-methoxyphenylmethyl.

[0100] In another embodiment, the compound of formula (I) is a compound of formula (Id): [ka] (Id) or a pharmaceutically acceptable salt thereof; In the formula, R 2A is H or substituted or unsubstituted alkyl; R 2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; n is 0, 1, or 2; and each R 3a is independently selected from the group consisting of halo and cyano; and R 4 is H.

[0101] In some embodiments of Formula (Id), R 2A is H. In some embodiments of Formula (Id), R 2A is a substituted or unsubstituted alkyl. In some embodiments of Formula (Id), R 2A is a substituted or unsubstituted methyl. In some embodiments of Formula (Id), R 2A is methyl.

[0102] In some embodiments of Formula (Id), R 2B is H. In some embodiments of Formula (Id), R 2B is a substituted or unsubstituted alkyl. In some embodiments of Formula (Id), R 2B is selected from the group consisting of methyl, isopropyl, and propyl. In some embodiments of Formula (Id), R 2B is alkyl substituted with hydroxyl, or substituted or unsubstituted alkoxy. In some embodiments of Formula (Id), R 2Bis hydroxymethyl. In some embodiments of Formula (Id), R 2B is a substituted alkoxyalkyl. In some embodiments of Formula (Id), R 2B In some embodiments of Formula (Id), R 2B is a substituted or unsubstituted cycloalkyl. In some embodiments of Formula (Id), R 2B is a substituted or unsubstituted C3-C7 cycloalkyl. In some embodiments of Formula (Id), R 2B In some embodiments of Formula (Id), R 2B is a substituted or unsubstituted heterocyclyl. In some embodiments of Formula (Id), R 2B is a substituted or unsubstituted C-C heterocyclyl. In some embodiments of Formula (Id), R 2B is a substituted or unsubstituted C3-C7 heterocyclyl containing one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) S, N, or O atoms. In some embodiments of Formula (Id), R 2B is oxetanyl. In some embodiments of Formula (Id), R 2B is 3-oxetanyl.

[0103] In some embodiments of Formula (Id), n is 0. In some embodiments of Formula (Id), n is 1. In some embodiments of Formula (Id), n is 2. In some embodiments of Formula (Id), each R 3a is halo, e.g., Cl or F. In some embodiments of Formula (Id), each R 3a In some embodiments of Formula (Id), n is 2 and one R 3a is a halo and one R 3a Is, Shi In some embodiments of Formula (Id), n is 2 and both R 3a In some embodiments of Formula (Id), n is 2 and both R 3aIn some embodiments of Formula (Id), n is 2 and R 3a In some embodiments of Formula (Id), n is 2 and R 3a In some embodiments of Formula (Id), n is 2 and R 3a In some embodiments of Formula (Id), n is 2 and R 3a In some embodiments of Formula (Id), n is 2 and R 3a In some embodiments of Formula (Id), n is 2 and R 3a In some embodiments of Formula (Id), n is 2 and R 3a In some embodiments of Formula (Id), n is 2 and R 3a are 2-CN and 4-CN.

[0104] In some embodiments of Formula (Id), R 2A is H and R 2B is trifluoromethoxymethyl, n is 1, and R 3a is cyano or halo. In some embodiments of Formula (Id), R 2A is H and R 2B is 3-oxetanyl, n is 1, and R 3a is cyano or halo. In some embodiments of Formula (Id), R 2A is H and R 2B is cyclobutanyl, n is 1, and R 3a is cyano or halo. In some embodiments of Formula (Id), R 2A is H and R 2B is trifluoromethoxymethyl, n is 2, and each R 3a is independently cyano or halo. In some embodiments of Formula (Id), R 2A is H and R 2B is 3-oxetanyl, n is 2, and each R3a is independently cyano or halo. In some embodiments of Formula (Id), R 2A is H and R 2B is cyclobutanyl, n is 2, and each R 3a are independently cyano or halo.

[0105] In another embodiment, the compound of formula (I) is a compound of formula (Ie): [ka] (Ie) or a pharmaceutically acceptable salt thereof; In the formula, R 1 is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl; R 2A is H or substituted or unsubstituted alkyl; R 2B is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; and R 4 is H; 2B is 4-methoxyphenyl, R 1 is a substituted or unsubstituted pyridyl, or a phenyl substituted with at least one substituent other than methyl or methoxy.

[0106] In some embodiments of Formula (Ie), R 2A is H. In some embodiments of Formula (Ie), R 2A is a substituted or unsubstituted alkyl. In some embodiments of Formula (Ie), R 2A is a substituted or unsubstituted methyl. In some embodiments of Formula (Ie), R 2A is methyl.

[0107] In some embodiments of Formula (Ie), R 2B is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ie), R 2B is 2-pyridyl. In some embodiments, R 2Bis a substituted or unsubstituted phenyl. In an embodiment of the present invention, R 2B is phenyl or pyridyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents independently selected from the group consisting of halo, substituted or unsubstituted alkoxy, and substituted or unsubstituted alkyl. In some embodiments of Formula (Ie), R 2B is pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halo and substituted or unsubstituted alkyl. In some embodiments of Formula (Ie), R 2B is pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ie), R 2B is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ie), R 2B is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) —CF3. In some embodiments of Formula (Ie), R 2B is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) alkoxy. In some embodiments of Formula (Ie), R 2B is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methoxy.

[0108] In some embodiments of Formula (Ie), R 1 is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ie), R 1 is 2-pyridyl. In some embodiments of Formula (Ie), R 1 is unsubstituted phenyl. In some embodiments of Formula (Ie), R 1is phenyl or pyridinyl, each of which is substituted with one or more substituents independently selected from the group consisting of cyano, halo, and substituted or unsubstituted alkyl. In some embodiments of Formula (Ie), R 1 is pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ie), R 1 is pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) —CF3. In some embodiments of Formula (Ie), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ie), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) —CF3. In some embodiments of Formula (Ie), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) CN. In some embodiments of Formula (Ie), R 1 is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methyl.

[0109] In some embodiments of Formula (Ie), R 2B is 4-methoxyphenyl, and R 1 is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ie), R 2B is 4-methoxyphenyl, and R 1 is 2-pyridyl. In some embodiments of Formula (Ie), R 2B is 4-methoxyphenyl, and R 1 is 2-pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ie), R 2B is 4-methoxyphenyl, and R 1is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ie), R 2B is 4-methoxyphenyl, and R 1 is phenyl substituted with 4-Cl.

[0110] In another embodiment, the compound of formula (I) is a compound of formula (If): [ka] (If) or a pharmaceutically acceptable salt thereof; In the formula, G 1 is selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, and substituted or unsubstituted heterocyclyl rings, each of which is optionally fused to a phenyl ring; R 1a is selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl; each R 2a is independently selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl; n is 0, 1, 2, or 3; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl; and R 4 is H; 3 is 4-methoxyphenylmethyl, R 1a is not methyl or methoxy.

[0111] G 1It is understood that the group is a ring that includes a carbon atom that is shared with the piperazinedione ring.

[0112] In some embodiments of formula (If), G 1 is selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted 2,3-dihydro-1H-indene. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted C3-C6 heterocyclyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted cyclopropyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted cyclobutanyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted azetidinyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted tetrahydrofuranyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted pyrrolidinyl. In some embodiments of Formula (Ic), G 1 is a substituted or unsubstituted pyrrolidin-2-one-yl.

[0113] In some embodiments of formula (If), G 1 is one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) R 2a Each R is a heterocyclyl substituted with 2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminothionyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl. In some embodiments of Formula (If), R 2ais a substituted or unsubstituted phenyl. In some embodiments of formula (If), R 2a is phenyl substituted with halo. In some embodiments of formula (If), R 2a is a substituted or unsubstituted heteroaryl In some embodiments of formula (If), R 2a is a substituted or unsubstituted pyridyl. In some embodiments of formula (If), R 2a is pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, CN, hydroxyl, alkoxycarbonyl, methoxycarbonyl, alkoxy, carboxyl, cycloalkyl, halo, and aminoacyl. In some embodiments of Formula (If), R 2a is substituted or unsubstituted pyrimidyl. In some embodiments of formula (If), R 2a is a substituted or unsubstituted pyrazolyl. In some embodiments of formula (If), R 2a is pyrazolyl substituted with alkyl. In some embodiments of formula (If), R 2a is a substituted or unsubstituted thiazolyl. In some embodiments of formula (If), R 2a is thiazolyl substituted with aminoacyl. In some embodiments of formula (If), R 2a is a substituted or unsubstituted alkoxycarbonyl. In some embodiments of formula (If), R 2a is methoxycarbonyl. In some embodiments of Formula (If), R 2a is a substituted or unsubstituted aminoacyl. In some embodiments of formula (If), R 2a is methylaminoacyl. In some embodiments of formula (If), R 2a is aminoacyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of aryl, cycloalkyl, pyridyl, pyrazolyl, and alkoxyalkyl. In some embodiments of Formula (If), R 2ais a substituted or unsubstituted pyridin-on-yl. In some embodiments of formula (If), R 2a is alkyl-substituted pyridin-on-yl. In some embodiments of formula (If), R 2a is a substituted or unsubstituted oxadiazolyl. In some embodiments of formula (If), R 2a is oxadiazolyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl and phenyl. In some embodiments of Formula (If), R 2a is a substituted or unsubstituted 9-membered bicyclic heterocyclyl. In some embodiments of formula (If), R 2a is —C(O)H. In some embodiments of formula (If), R 2a is a substituted or unsubstituted pyridazinyl. In some embodiments of formula (If), R 2a is pyridazinyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halo, alkoxy, alkyl, and aminoacyl. In some embodiments of Formula (If), R 2a is a substituted or unsubstituted aminothionyl. In some embodiments of formula (If), R 2a is aminothionyl substituted with alkyl. In some embodiments of formula (If), R 2a is substituted or unsubstituted acyl. In some embodiments of formula (If), R 2a is acyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl, alkyl, and heterocyclyl. In some embodiments of Formula (If), R 2a is acyl substituted with morpholinyl. In some embodiments of formula (If), R 2a is a substituted or unsubstituted aminocarbonylamino. In some embodiments of formula (If), R 2ais aminocarbonylamino substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl and heterocyclyl.

[0114] In some embodiments of formula (If), G 1 is one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) R 2a In some embodiments of formula (If), R 2a is a substituted or unsubstituted phenyl. In some embodiments of formula (If), R 2a is a substituted or unsubstituted thiazolyl. In some embodiments of formula (If), R 2a is thiazolyl substituted with alkyl. In some embodiments of formula (If), R 2a is a substituted or unsubstituted oxazolyl. In some embodiments of formula (If), R 2a is oxazolyl substituted with alkyl. In some embodiments of formula (If), R 2a is replaced or unreplaced. In some embodiments of formula (If), R 2a is aminoacyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl. In some embodiments of Formula (If), R 2a is a substituted or unsubstituted oxadiazolyl. In some embodiments of formula (If), R 2a is oxadiazolyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl and alkyl. In some embodiments of Formula (If), R 2a is substituted or unsubstituted acyl. In some embodiments of formula (If), R 2a is acyl substituted with heterocyclyl. In some embodiments of formula (If), R 2ais a substituted or unsubstituted aminocarbonylamino. In some embodiments of formula (If), R 2a is aminocarbonylamino substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl. In some embodiments of Formula (If), R 2a is a substituted or unsubstituted alkoxycarbonyl. In some embodiments of formula (If), R 2a is an alkoxycarbonyl substituted with alkyl. In some embodiments of formula (If), R 2a is a substituted or unsubstituted alkyl. In some embodiments of formula (If), R 2a is alkyl substituted with hydroxyl. In some embodiments of formula (If), R 2a is a hydroxyl.

[0115] In some embodiments of formula (If), R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl. In some embodiments of formula (If), R 3 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of nitro, alkoxy, halo, cycloalkyl, cyano, alkenyl, alkoxycarbonyl, phenylcarbonyl, and alkyl. In some embodiments of Formula (If), R 3 is cycloalkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cyano, and halo. In some embodiments of Formula (If), R 3 is alkyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkoxy, cyano, and halo.

[0116] In some embodiments of formula (If), R 1a is selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted diazirinyl. 1a is halo. In some embodiments of formula (If), R 1a is -CF3. In some embodiments of formula (If), R 1a is methyl. In some embodiments of Formula (If), R 1a In some embodiments of formula (If), R 1a is trifluoromethyldiazirinyl.

[0117] In some embodiments of formula (If), R 1a is Cl and R 3 is substituted with 4-methoxyphenylmethyl. In some embodiments of Formula (If), R 1a is F and R 3 is substituted with 4-methoxyphenylmethyl. In some embodiments of Formula (If), R 1a is -CF3, and R 3 is substituted with 4-methoxyphenylmethyl. In some embodiments of Formula (If), R 1a is trifluoromethyldiazirinyl and R 3 is substituted with 4-methoxyphenylmethyl.

[0118] In some embodiments of Formula (I), Formula (Ic), and Formula (If), G 1 teeth, [ka] [ka] is selected from the group consisting of where * indicates the point of attachment to the parent structure; R 2ais selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl; and n is 0, 1, 2, or 3.

[0119] In some embodiments of Formula (I), Formula (Ic), and Formula (If), G 1 teeth, [ka] one or more (e.g., 1 or 2 or 3 or 1 to 4 or 1 to 3 or 2 to 4) R independently selected from the group consisting of 2a is replaced by wherein n is 0 to 3, and each X is independently selected from the group consisting of H, halo, alkyl, cyano, hydroxyl, cycloalkyl, alkoxycarbonyl, carboxyl, aminoacyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, aminothionyl, and heterocyclyl.

[0120] In another embodiment, the compound of formula (Ig): [ka] (Ig) or a pharmaceutically acceptable salt thereof, In the formula, R 1a is cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted R is selected from the group consisting of substituted alkyl, and substituted or unsubstituted heterocyclyl; 2ais selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl; n is 0, 1, 2, or 3; and each R 3a is independently selected from the group consisting of substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, halo, nitro, and cyano; and R 4 is H.

[0121] In some embodiments of Formula (Ig), R 1a is selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted diazirinyl. 1a is halo. In some embodiments of Formula (Ig), R 1a is —CF. In some embodiments of Formula (Ig), R 1a is methyl. In some embodiments of Formula (Ig), R 1a In some embodiments of Formula (Ig), R 1a is trifluoromethyldiazirinyl.

[0122] In some embodiments of Formula (Ig), n is 0. In some embodiments of Formula (Ig), n is 1. In some embodiments of Formula (Ig), n is 2. In some embodiments of Formula (Ig), each R 3a is halo, e.g., Cl or F. In some embodiments of Formula (Ig), each R 3a In some embodiments of Formula (Ig), n is 2 and one R 3a is a halo and one R 3a In some embodiments of Formula (If), n is 2 and both R 3aIn some embodiments of formula (If), n is 2 and both R 3a In some embodiments of Formula (If), n is 2 and R 3a In some embodiments of Formula (Ig), n is 2 and R 3a In some embodiments of Formula (Ig), n is 2 and R 3a In some embodiments of Formula (Ig), n is 2 and R 3a In some embodiments of Formula (Ig), n is 2 and R 3a In some embodiments of Formula (Ig), n is 2 and R 3a In some embodiments of Formula (Ig), n is 2 and R 3a In some embodiments of Formula (Ig), n is 2 and R 3a In some embodiments of Formula (Ig), n is 2 and R 3a In some embodiments of Formula (Ig), n is 2 and R 3a In some embodiments of Formula (Ig), n is 2 and R 3a is 2-CN and 4-CN. In some embodiments of Formula (Ig), R 3a In some embodiments of Formula (Ig), n is 1 and R 3a In some embodiments of Formula (Ig), n is 1 and R 3a is 4-Cl or 3-Cl. In some embodiments of Formula (Ig), n is 1 and R 3a is 4-F or 3-F. In some embodiments of Formula (Ig), n is 1 and R 3a is 4-CN or 3-CN. In some embodiments of Formula (Ig), R 3a In some embodiments of Formula (Ig), R3a is propenyl. In some embodiments of Formula (Ig), R 3a In some embodiments of Formula (Ig), n is 2 and R 3a In some embodiments of Formula (Ig), n is 2 and R 3a In some embodiments of Formula (Ig), n is 2 and R 3a is 3-F and 4-difluoromethoxy.

[0123] In some embodiments of Formula (Ig), R 2a is a substituted or unsubstituted phenyl In some embodiments of Formula (Ig), R 2a is a substituted or unsubstituted aminoacyl. In some embodiments of Formula (Ig), R 2a is aminoacyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl. In some embodiments of Formula (Ig), R 2a is a substituted or unsubstituted oxadiazolyl. In some embodiments of Formula (Ig), R 2a is oxadiazolyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl and alkyl. In some embodiments of Formula (Ig), R 2a is substituted or unsubstituted acyl. In some embodiments of Formula (Ig), R 2a is acyl substituted with heterocyclyl. In some embodiments of Formula (Ig), R 2a is aryl-substituted acyl. In some embodiments of Formula (Ig), R 2a is acyl substituted with phenyl. In some embodiments of Formula (Ig), R 2a is an acyl substituted with alkyl. In some embodiments of Formula (Ig), R 2ais substituted or unsubstituted pyridyl. In some embodiments of Formula (Ig), R 2a is pyridyl substituted with CN or halo. In some embodiments of Formula (Ig), R 2a is a substituted or unsubstituted aminocarbonylamino. In some embodiments of Formula (Ig), R 2a is aminocarbonylamino substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl. In some embodiments of Formula (Ig), R 2a is a substituted or unsubstituted alkoxycarbonyl. In some embodiments of Formula (Ig), R 2a is an alkoxycarbonyl substituted with alkyl. In some embodiments of Formula (Ig), R 2a is a substituted or unsubstituted alkyl. In some embodiments of Formula (Ig), R 2a is alkyl substituted with hydroxyl. In some embodiments of Formula (Ig), R 2a is alkyl substituted with halo. In some embodiments of Formula (Ig), R 2a is hydroxyl. In some embodiments of Formula (Ig), R 2a is a substituted or unsubstituted aminosulfonyl. In some embodiments of Formula (Ig), R 2a is an aminosulfonyl substituted with alkyl.

[0124] In another embodiment, the compound of formula (Ih): [ka] (Ih) or a pharmaceutically acceptable salt thereof, In the formula, R 1a is selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl; R 2ais selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl; and R 4 is H; 3 is 4-methoxyphenylmethyl, R 1a is not methyl or methoxy.

[0125] In some embodiments of Formula (Ih), R 1a is selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted diazirinyl. 1a is halo. In some embodiments of Formula (Ih), R 1a is —CF. In some embodiments of Formula (Ih), R 1a is methyl. In some embodiments of Formula (Ih), R 1a In some embodiments of Formula (Ih), R 1a is trifluoromethyldiazirinyl.

[0126] In some embodiments of Formula (Ih), R 2a is a substituted or unsubstituted phenyl. In some embodiments of Formula (Ih), R 2a is a substituted or unsubstituted aminoacyl. In some embodiments of Formula (Ih), R 2ais aminoacyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl. In some embodiments of Formula (Ih), R 2a is a substituted or unsubstituted oxadiazolyl. In some embodiments of Formula (Ih), R 2a is oxadiazolyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl and alkyl. In some embodiments of Formula (Ih), R 2a is substituted or unsubstituted acyl. In some embodiments of Formula (Ih), R 2a is acyl substituted with heterocyclyl. In some embodiments of Formula (Ih), R 2a is aryl-substituted acyl. In some embodiments of Formula (Ih), R 2a is acyl substituted with phenyl. In some embodiments of Formula (Ih), R 2a is an acyl substituted with alkyl. In some embodiments of Formula (Ih), R 2a is a substituted or unsubstituted pyridyl. In some embodiments of Formula (Ih), R 2a is pyridyl substituted with CN or halo. In some embodiments of Formula (Ih), R 2a is a substituted or unsubstituted aminocarbonylamino. In some embodiments of Formula (Ih), R 2a is aminocarbonylamino substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl. In some embodiments of Formula (Ih), R 2a is a substituted or unsubstituted alkoxycarbonyl. In some embodiments of Formula (Ih), R 2a is an alkoxycarbonyl substituted with alkyl. In some embodiments of Formula (Ih), R 2a is a substituted or unsubstituted alkyl. In some embodiments of Formula (Ih), R2a is alkyl substituted with hydroxyl. In some embodiments of Formula (Ih), R 2a is alkyl substituted with halo. In some embodiments of Formula (Ih), R 2a is hydroxyl. In some embodiments of Formula (Ih), R 2a is a substituted or unsubstituted aminosulfonyl. In some embodiments of Formula (Ih), R 2a is aminosulfonyl substituted with alkyl. In some embodiments of Formula (Ih), R 2a is a substituted or unsubstituted thiazolyl. In some embodiments of Formula (Ih), R 2a is thiazolyl substituted with alkyl. In some embodiments of Formula (Ih), R 2a is a substituted or unsubstituted oxazolyl. In some embodiments of Formula (Ih), R 2a is an alkyl-substituted oxazolyl.

[0127] In some embodiments of Formula (Ih), R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl. In some embodiments of Formula (Ih), R 3 is substituted with one or more (e.g., 1 or 2 or 3 or 1 to 4 or 1 to 3 or 2 to 4) substituents selected from the group consisting of nitro, alkoxy, halo, cycloalkyl, cyano, alkenyl, alkoxycarbonyl, phenylcarbonyl, and alkyl. In some embodiments, R 3 is phenyl substituted with CN and F. In some embodiments of Formula (Ih), R 3 is alkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkoxy, cyano, and halo. In some embodiments, R 3 is isopropyl.

[0128] In another embodiment, the compound of formula (Ii): [ka] (II) or a pharmaceutically acceptable salt thereof, In the formula, R 1a is selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl; R 2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl; R 4 is H;R 5 is H, or substituted or unsubstituted alkyl; and X and Y are independently —CH— or —C(O)—; where R 3 is 4-methoxyphenylmethyl, R 1a is not methyl or methoxy.

[0129] In some embodiments of Formula (Ii), R 1a is selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted diazirinyl. 1a In some embodiments of Formula (Ii), R 1a is —CF. In some embodiments of Formula (Ii), R 1a is methyl. In some embodiments of Formula (Ii), R 1a is Cl. In some embodiments of Formula (Ih), R 1ais trifluoromethyldiazirinyl.

[0130] In some embodiments of Formula (Ii), R 2a is a substituted or unsubstituted phenyl. In some embodiments of Formula (Ii), R 2a is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ii), R 2a is pyridyl substituted with alkyl, CN, or halo. In some embodiments of Formula (Ii), R 2a is substituted or unsubstituted pyrimidyl. In some embodiments of Formula (Ii), R 2a is a substituted or unsubstituted pyridazinyl. In some embodiments of Formula (Ii), R 2a is pyridazinyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halo, alkoxy, alkyl, and aminoacyl. In some embodiments of Formula (Ii), R 2a is a substituted or unsubstituted aminoacyl. In some embodiments of Formula (Ii), R 2a is selected from the group consisting of alkyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl. In some embodiments of Formula (Ii), R is an aminoacyl substituted with one or more (e.g., 1 or 2 or 3 or 1 to 4 or 1 to 3 or 2 to 4) substituents. 2a is a substituted or unsubstituted pyrazolyl. In some embodiments of Formula (Ii), R 2a In some embodiments of Formula (Ii), R 2a is a substituted or unsubstituted oxadiazolyl. In some embodiments of Formula (Ii), R 2a is oxadiazolyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl and alkyl. In some embodiments of Formula (Ii), R 2ais substituted or unsubstituted acyl. In some embodiments of Formula (Ii), R 2a is acyl substituted with heterocyclyl. In some embodiments of Formula (Ii), R 2a is aryl-substituted acyl. In some embodiments of Formula (Ii), R 2a is acyl substituted with phenyl. In some embodiments of Formula (Ii), R 2a is an acyl substituted with alkyl. In some embodiments of Formula (Ii), R 2a is a substituted or unsubstituted aminocarbonylamino. In some embodiments of Formula (Ii), R 2a is aminocarbonylamino substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl. In some embodiments of Formula (Ii), R 2a is a substituted or unsubstituted alkoxycarbonyl. In some embodiments of Formula (Ii), R 2a is an alkoxycarbonyl substituted with alkyl. In some embodiments of Formula (Ii), R 2a is a substituted or unsubstituted alkyl. In some embodiments of Formula (Ii), R 2a is alkyl substituted with hydroxyl. In some embodiments of Formula (Ii), R 2a is alkyl substituted with halo. In some embodiments of Formula (Ii), R 2a is hydroxyl. In some embodiments of Formula (Ii), R 2a is a substituted or unsubstituted aminosulfonyl. In some embodiments of Formula (Ii), R 2a is aminosulfonyl substituted with alkyl. In some embodiments of Formula (Ii), R 2a is a substituted or unsubstituted thiazolyl. In some embodiments of Formula (Ii), R 2a is thiazolyl substituted with alkyl. In some embodiments of Formula (Ii), R 2ais a substituted or unsubstituted oxazolyl. In some embodiments of Formula (Ii), R 2a is an alkyl-substituted oxazolyl.

[0131] In some embodiments of Formula (Ii), R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl. In some embodiments of Formula (Ii), R 3 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of nitro, alkoxy, halo, cycloalkyl, cyano, alkenyl, alkoxycarbonyl, phenylcarbonyl, and alkyl. In some embodiments of Formula (Ii), R 3 is phenyl substituted with CN and F. In some embodiments of Formula (Ii), R 3 is phenyl substituted with CN or Cl. In some embodiments of Formula (Ii), R 3 is cycloalkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cyano, and halo. In some embodiments of Formula (Ii), R 3 is cyclopropyl substituted with alkyl. In some embodiments of Formula (Ii), R 3 is alkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkoxy, cyano, and halo. In some embodiments of Formula (Ii), R 3 is isopropyl, methyl, or ethyl. In some embodiments of Formula (Ii), R 3 is a substituted or unsubstituted heterocyclyl. In some embodiments of Formula (Ii), R 3 is furanyl.

[0132] In some embodiments of Formula (Ii), R 5is a substituted or unsubstituted alkyl. In some embodiments of Formula (Ii), R 5 is methyl. In some embodiments of Formula (Ii), R 5 is substituted alkyl. In some embodiments of Formula (Ii), R 5 is hydroxymethyl. In some embodiments of Formula (Ii), R 5 is H.

[0133] In some embodiments of Formula (Ii), X and Y are independently -CH2- or -C(O)-. In some embodiments of Formula (Ii), X and Y are both -CH2-. In some embodiments of Formula (Ii), X is -CH2- and Y is -C(O)-. In some embodiments of Formula (Ii), Y is -CH2- and X is -C(O)-.

[0134] In another embodiment, the compound of formula (I) is a compound of formula (Ij): [ka] (Ij) or a pharmaceutically acceptable salt thereof; In the formula, R 1 is a substituted or unsubstituted phenyl; 2b are independently substituted or unsubstituted alkyl; R 3 is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl; R 4 is H;R 5 is H or substituted or unsubstituted alkyl; n is 0, 1, or 2; and q is 0 or 1; where R 3 is substituted or unsubstituted phenyl, R 1 is a substituted or unsubstituted pyridyl, or a phenyl substituted with at least one substituent other than methyl or methoxy.

[0135] In some embodiments of Formula (Ij), R 1is a substituted or unsubstituted phenyl. In some embodiments of Formula (Ij), R 1 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halo, unsubstituted alkyl, and alkyl substituted with one or more halo groups. In some embodiments of Formula (Ij), R 1 is phenyl substituted with halo. In some embodiments of Formula (Ij), R 1 is phenyl substituted with F or Cl. In some embodiments of Formula (Ij), R 1 is phenyl substituted with unsubstituted alkyl. In some embodiments of Formula (Ij), R 1 is phenyl substituted with methyl or ethyl. In some embodiments of Formula (Ij), R 1 is phenyl substituted with alkyl substituted with one or more halo groups. In some embodiments of Formula (Ij), R 1 is phenyl substituted with -CHF2 or -CF3. In some embodiments of Formula (Ij), R 1 is phenyl substituted with 4-Cl. In some embodiments of Formula (Ij), R 1 is phenyl substituted with 4-CF. In some embodiments of Formula (Ij), R 1 is phenyl substituted with two or more groups selected from the group consisting of F, Cl, methyl, and —CF. In some embodiments of Formula (Ij), R 1 is phenyl substituted with two F groups. In some embodiments of Formula (Ij), R 1 is phenyl substituted with F and Cl. In some embodiments of Formula (Ij), R 1 is phenyl substituted with F and methyl. In some embodiments of Formula (Ij), R 1 is phenyl substituted with F and -CF3.

[0136] In some embodiments of Formula (Ij), n is 0, 1, or 2. In some embodiments of Formula (Ij), n is 0. In some embodiments of Formula (Ij), n is 1. In some embodiments of Formula (Ij), n is 1 and R 2b is a substituted or unsubstituted alkyl. In some embodiments of Formula (Ij), n is 1 and R 2b is unsubstituted alkyl. In some embodiments of Formula (Ij), n is 1 and R 2b is methyl.

[0137] In some embodiments of Formula (Ij), R 3 is a substituted or unsubstituted phenyl. In some embodiments of Formula (Ij), R 3 is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halo and cyano. In some embodiments of Formula (Ij), R 3 is phenyl substituted with halo. In some embodiments of Formula (Ij), R 3 is phenyl substituted with F, Cl, or Br. In some embodiments of Formula (Ij), R 3 is phenyl substituted with cyano. In some embodiments of Formula (Ij), R 3 is phenyl substituted with two or more groups selected from the group consisting of F, Cl, Br, and cyano. In some embodiments of Formula (Ij), R 3 is phenyl substituted with F and Cl. In some embodiments of Formula (Ij), R 3 is phenyl substituted with F and Br. In some embodiments of the embodiment of Formula (Ij), R 3 is phenyl substituted with F and cyano.

[0138] In some embodiments of Formula (Ij), R 3 is a substituted or unsubstituted pyridinyl. In some embodiments of Formula (Ij), R 3is pyridinyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkoxy. In some embodiments of Formula (Ij), R 3 is pyridinyl substituted with halo. In some embodiments of Formula (Ij), R 3 is pyridinyl substituted with F or Cl. In some embodiments of Formula (Ij), R 3 is pyridinyl substituted with unsubstituted alkyl. In some embodiments of Formula (Ij), R 3 is pyridinyl substituted with methyl. In some embodiments of Formula (Ij), R 3 is pyridinyl substituted with unsubstituted alkenyl. In some embodiments of Formula (Ij), R 3 is pyridinyl substituted with -CH=CH2. In some embodiments of Formula (Ij), R 3 In some embodiments of Formula (Ij), R is pyridinyl substituted with alkoxy optionally substituted with halo. 3 is pyridinyl substituted with methoxy or -OCHF. In some embodiments of Formula (Ij), R 3 is pyridinyl substituted with two or more groups selected from the group consisting of halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkoxy. In some embodiments of Formula (Ij), R 3 is pyridinyl substituted with F and Cl. In some embodiments of Formula (Ij), R 3 is pyridinyl substituted with Cl and methyl. In some embodiments of Formula (Ij), R 3 is pyridinyl substituted with F and methoxy. In some embodiments of Formula (Ij), R 3 is pyridinyl substituted with F and -OCHF. In some embodiments of Formula (Ij), R 3 is pyridinyl substituted with F and -CH=CH2. In some embodiments of Formula (Ij), R 3is a substituted or unsubstituted pyridin-2-yl.

[0139] In some embodiments of Formula (Ij), R 5 is H. In some embodiments of Formula (Ij), R 5 is substituted or unsubstituted alkyl. In some embodiments of Formula (Ij), R 5 is methyl.

[0140] In some embodiments of Formula (Ij), q is 0. In the embodiment, q is 1.

[0141] In some embodiments of Formula (Ij), R 1 is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2, and -CF3, n is 0, and R 3 is pyridinyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CH=CH2, methoxy, and -OCHF2; R 5 is H and q is 0. In some embodiments of Formula (Ij), R 1 is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2, and -CF3, n is 0, and R 3 is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, Br, and cyano; R 5 is H and q is 0. In some embodiments of Formula (Ij), R 1 is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2, and -CF3, n is 1, and R 2b is methyl and R 3 is pyridinyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CH=CH2, methoxy, and -OCHF2; R 5 is H and q is 0. In some embodiments of Formula (Ij), R 1is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2, and -CF3, n is 1, and R 2b is methyl and R 3 is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, Br, and cyano; R 5 is H and q is 0. In some embodiments of Formula (Ij), R 1 is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2, and -CF3, n is 0, and R 3 is pyridinyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CH=CH2, methoxy, and -OCHF2; R 5 is H and q is 1. In some embodiments of Formula (Ij), R 1 is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2, and -CF3, n is 0, and R 3 is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, Br, and cyano; R 5 is H and q is 1. In some embodiments of Formula (Ij), R 1 is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2, and -CF3, n is 1, and R 2b is methyl and R 3 is pyridinyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CH=CH2, methoxy, and -OCHF2; R 5 is H and q is 1. In some embodiments of Formula (Ij), R 1 is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2, and -CF3, n is 1, and R 2b is methyl and R 3 is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, Br, and cyano; R 5is H and q is 1.

[0142] In some embodiments of Formula (Ij): R 1 is phenyl substituted with one substituent selected from the group consisting of F, Cl, methyl, ethyl, -CHF2, or -CF3; n is 0 or n is 1, and R 2b is methyl; R 3 is pyridinyl substituted with two substituents selected from the group consisting of F, Cl, methyl, -CH=CH2, methoxy, and -OCHF2; R 5 is H; and q is 0 or 1.

[0143] In another embodiment, the compound of formula (I) is a compound of formula (Ik-1): [ka] (Ik-1) or a pharmaceutically acceptable salt thereof; In the formula, R 2A is H or substituted or unsubstituted alkyl; R 2B is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; m is 0, 1, or 2; p is 0, 1, or 2; and each R 1a is independently selected from the group consisting of halo and substituted or unsubstituted alkyl; each R 3a is independently selected from the group consisting of halo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkoxy; and R 4 is H.

[0144] In some embodiments of Formula (Ik-1), R 2A is H. In some embodiments of formula (Ik-1), R 2A is a substituted or unsubstituted alkyl. In some embodiments of Formula (Ik-1), R 2Ais a substituted or unsubstituted methyl. In some embodiments of Formula (Ik-1), R 2A is methyl.

[0145] In some embodiments of Formula (Ik-1), R 2B is a substituted or unsubstituted alkyl. In some embodiments of Formula (Ik-1), R 2B In some embodiments of Formula (Ik-1), R 2B is substituted alkyl. In some embodiments of Formula (Ik-1), R 2B is alkyl substituted with halo. In some embodiments of Formula (Ik-1), R 2B is -CHF2. In some embodiments of Formula (Ik-1), R 2B is alkyl substituted with —OH. In some embodiments of Formula (Ik-1), R 2B is —CH(OH)CH. In some embodiments of Formula (Ik-1), R 2B In some embodiments of Formula (Ik-1), R 2B is —CH2CH2SCH3. In some embodiments of Formula (Ik-1), R 2B is —CH 2 CH 2 S(O) 2 CH 3 . In some embodiments of Formula (Ik-1), R 2B is —CHN(H)C(O)CH. In some embodiments of Formula (Ik-1), R 2B is —CH2CH2C(O)NH2. In some embodiments of Formula (Ik-1), R 2B is alkyl substituted with heterocyclyl. In some embodiments of Formula (Ik-1), R 2B is C1-C2 alkyl substituted with heterocyclyl. In some embodiments of Formula (Ik-1), R 2B is methyl substituted with oxetanyl. In some embodiments of Formula (Ik-1), R 2B is methyl substituted with azetidinyl.

[0146] In some embodiments of Formula (Ik-1), R2B is a substituted or unsubstituted cycloalkyl. In some embodiments of Formula (Ik-1), R 2B is a substituted or unsubstituted C-C cycloalkyl. In some embodiments of Formula (Ik-1), R 2B is unsubstituted cyclopropyl. In some embodiments of Formula (Ik-1), R 2B is unsubstituted cyclobutyl. In some embodiments of Formula (Ik-1), R 2B is cyclobutyl substituted with hydroxyl. In some embodiments of Formula (Ik-1), R 2B is cyclobutyl substituted with methoxy. In some embodiments of Formula (Ik-1), R 2B is a polycyclic cycloalkyl. Some embodiments of formula (Ik-1) In this state, R 2B is a substituted or unsubstituted bicyclo[1.1.1]pentanyl. In some embodiments of Formula (Ik-1), R 2B is bicyclo[1.1.1]pentanyl substituted by a group selected from the group consisting of hydroxy, alkoxycarbonyl, carbamoyl, and hydroxymethyl.

[0147] In some embodiments of Formula (Ik-1), R 2B is a substituted or unsubstituted heterocyclyl. In some embodiments of formula (Ik-1), R 2B is a substituted or unsubstituted 4- to 7-membered heterocyclyl. In some embodiments of Formula (Ik-1), R 2B is a substituted or unsubstituted 4- to 7-membered heterocyclyl containing one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) N, O, or S atoms. In some embodiments of Formula (Ik-1), R 2B is a substituted or unsubstituted 4-6 membered heterocyclyl containing one N atom. In some embodiments of Formula (Ik-1), R 2B is a substituted or unsubstituted azetidinyl. In some embodiments of Formula (Ik-1), R 2Bis 3-azetidinyl substituted with aminoacyl or acyl. In some embodiments of Formula (Ik-1), R 2B is a substituted or unsubstituted 4-6 membered heterocyclyl containing one O atom. In some embodiments of formula (Ik-1), R 2B is a substituted or unsubstituted oxetanyl. In some embodiments of formula (Ik-1), R 2B is unsubstituted 3-oxetanyl. In some embodiments of Formula (Ik-1), R 2B is 3-oxetanyl substituted with methyl. In some embodiments of Formula (Ik-1), R 2B is a substituted or unsubstituted tetrahydro-2H-pyranyl. In some embodiments of Formula (Ik-1), R 2B is unsubstituted tetrahydro-2H-pyranyl. In some embodiments of Formula (Ik-1), R 2B is a substituted or unsubstituted 4-6 membered heterocyclyl containing one S atom. In some embodiments of formula (Ik-1), R 2B is a substituted or unsubstituted 4-tetrahydro-2H-thiopyranyl.

[0148] In some embodiments of Formula (Ik-1), both R 2A and R 2B is methyl. In some embodiments of Formula (Ik-1), R 2A is methyl and R 2B is a substituted methyl. In some embodiments of Formula (Ik-1), R 2A is methyl and R 2B In some embodiments of Formula (Ik-1), R 2A is methyl and R 2B is —CHN(H)C(O)CH. In some embodiments of Formula (Ik-1), R 2A is methyl and R 2B is -CHF2.

[0149] In some embodiments of Formula (Ik-1), m is 0. In some embodiments of Formula (Ik-1), m is 1. In some embodiments of Formula (Ik-1), m is 2. In some embodiments of Formula (Ik-1), each R 1a is independently selected from the group consisting of halo and substituted or unsubstituted alkyl. In some embodiments of Formula (Ik-1), m is 1 and R 1a is at the 4-position of the phenyl moiety. In some embodiments of Formula (Ik-1), m is 1 and R 1a In some embodiments of Formula (Ik-1), m is 1 and R 1a In some embodiments of Formula (Ik-1), m is 1 and R 1a In some embodiments of Formula (Ik-1), m is 1 and R 1a is a substituted or unsubstituted C1-C3 alkyl. In some embodiments of Formula (Ik-1), m is 1 and R 1a In some embodiments of Formula (Ik-1), m is 1 and R 1a In some embodiments of Formula (Ik-1), m is 1 and R 1a In some embodiments of Formula (Ik-1), m is 1 and R 1a In some embodiments of Formula (Ik-1), m is 2 and two R 1a In some embodiments of Formula (Ik-1), m is 2 and R 1a In some embodiments of Formula (Ik-1), m is 2 and R 1a are 3-F and 4-Cl In some embodiments of Formula (Ik-1), m is 2 and R 1a In some embodiments of Formula (Ik-1), m is 2 and R 1a In some embodiments of Formula (Ik-1), m is 2 and R 1aIn some embodiments of Formula (Ik-1), m is 2 and R 1a are 3-methyl and 4-F.

[0150] In some embodiments of Formula (Ik-1), p is 0. In some embodiments of Formula (Ik-1), p is 1. In some embodiments of Formula (Ik-1), p is 2. In some embodiments of Formula (Ik-1), p is 2 and each R 3a is independently selected from the group consisting of halo, cyano, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C3 alkenyl, and substituted or unsubstituted C1-C3 alkoxy. In some embodiments of Formula (Ik-1), p is 2 and each R 3a is independently F, Cl, Br, cyano, methyl, -CH=CH2, -OCH3, or -OCHF2. In some embodiments of Formula (Ik-1), p is 2 and at least one R 3a is F. In some embodiments of Formula (Ik-1), p is 2 and at least one R 3a In some embodiments of Formula (Ik-1), p is 2 and one R 3a is 3-F and one R 3a is at the 5-position of the pyridinyl moiety and is selected from the group consisting of halo, cyano, unsubstituted C1-C3 alkyl, unsubstituted C2-C3 alkenyl, and substituted or unsubstituted C1-C3 alkoxy. In some embodiments of Formula (Ik-1), p is 2 and R 3a In some embodiments of Formula (Ik-1), p is 2 and R 3a In some embodiments of Formula (Ik-1), p is 2 and R 3a In some embodiments of Formula (Ik-1), p is 2 and R 3a In some embodiments of Formula (Ik-1), p is 2 and R 3aIn some embodiments of Formula (Ik-1), p is 2 and R 3a In some embodiments of Formula (Ik-1), p is 2 and R 3a In some embodiments of Formula (Ik-1), p is 2 and R 3a In some embodiments of Formula (Ik-1), p is 2 and R 3a are 3-methyl and 5-Cl.

[0151] In some embodiments of Formula (Ik-1), R 2A is H and R 2B is isopropyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano. In some embodiments of Formula (Ik-1), R 2A is H and R 2B is 3-oxetanyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano. In some embodiments of Formula (Ik-1), R 2A is methyl and R 2B is methyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano.

[0152] In some embodiments of Formula (Ik-1), R 2A is H and R 2B is isopropyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, p is 2, and each R 3ais independently selected from the group consisting of F, Cl, and cyano. In some embodiments of Formula (Ik-1), R 2A is H and R 2B is 3-oxetanyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, p is 2, and each R 3a is independently selected from the group consisting of F, Cl, and cyano. In some embodiments of Formula (Ik-1), R 2A is methyl and R 2B is methyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, p is 2, and each R 3a are independently a group consisting of F, Cl, and cyano is selected from.

[0153] In some embodiments of Formula (Ik-1), R 2A is H and R 2B is isopropyl, m is 2, and each R 1a is independently selected from the group consisting of F, Cl, and —CF3, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano. In some embodiments of Formula (Ik-1), R 2A is H and R 2B is 3-oxetanyl, m is 2, and each R 1a is independently selected from the group consisting of F, Cl, and —CF3, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano. In some embodiments of Formula (Ik-1), R 2A is methyl and R 2B is methyl, m is 2, and each R 1a is independently selected from the group consisting of F, Cl, and —CF3, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano.

[0154] In some embodiments of Formula (Ik-1), R 2A is H and R2B is isopropyl, m is 2, and each R 1a is independently selected from the group consisting of F, Cl, and —CF; p is 2; and each R 3a is independently selected from the group consisting of F, Cl, and cyano. In some embodiments of Formula (Ik-1), R 2A is H and R 2B is 3-oxetanyl, m is 2, and each R 1a is independently selected from the group consisting of F, Cl, and —CF; p is 2; and each R 3a is independently selected from the group consisting of F, Cl, and cyano. In some embodiments of Formula (Ik-1), R 2A is methyl and R 2B is methyl, m is 2, and each R 1a is independently selected from the group consisting of F, Cl, and —CF; p is 2; and each R 3a is independently selected from the group consisting of F, Cl, and cyano.

[0155] In some embodiments of formula (Ik-1): R 2A is H or methyl; R 2B is selected from the group consisting of isopropyl, -CHF2, -CH(OH)CH3, -CH2OH, -CH2CH2SCH3, -CH2CH2S(O)2CH3, -CH2N(H)C(O)CH3, -CH2CH2C(O)NH2, oxetanyl or azetidinyl substituted methyl, cyclopropyl, cyclobutyl, aminoacyl or acyl substituted 3-azetidinyl, 3-oxetanyl, methyl substituted 3-oxetanyl, tetrahydro-2H-pyranyl, and 4-tetrahydro-2H-thiopyranyl; m is 1; R 1a are 4-F, 4-Cl, 4-methyl, 4-CHF2, and 4-CF3; p is 2; and two R 3aThe group is selected from the group consisting of 3-F and 5-Cl, 3-F and 5-Br, 3-F and 5-cyano, 3-F and 5-methyl, 3-F and 5-ethenyl, 3-F and 5-methoxy, 3-F and 5-OCH, 3-F and 5-OCHF, and 3-methyl and 5-Cl.

[0156] In another embodiment, the compound of formula (I) is a compound of formula (Ik-2): [ka] (Ik-2) or a pharmaceutically acceptable salt thereof; In the formula, G 1 is a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclic group. each R is selected from the group consisting of: 1a is independently selected from the group consisting of halo and substituted or unsubstituted alkyl; each R 2a is independently selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminothionyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl; each R 3a is independently selected from the group consisting of halo, cyano, and substituted or unsubstituted alkyl; R 4 is H;R 5 is H or substituted or unsubstituted alkyl; m is 0, 1, or 2; n is 0, 1, or 2; and p is 0, 1, or 2.

[0157] In some embodiments of formula (Ik-2), G 1 is a substituted or unsubstituted cycloalkyl. In some embodiments of formula (Ik-2), G 1 is a substituted or unsubstituted cyclopropyl. In some embodiments of formula (Ik-2), G 1is a substituted or unsubstituted cyclobutanyl. In some embodiments of formula (Ik-2), G 1 is a substituted or unsubstituted 4- to 6-membered heterocyclyl containing one or more (e.g., 1 or 2 or 3 or 1 to 4 or 1 to 3 or 2 to 4) N or O atoms. In some embodiments of formula (Ik-2), G 1 is a substituted or unsubstituted 4- to 6-membered heterocyclyl containing one N atom. In some embodiments of formula (Ik-2), G 1 is a substituted or unsubstituted azetidinyl. In some embodiments of formula (Ik-2), G 1 is a substituted or unsubstituted piperidinyl. In some embodiments of formula (Ik-2), G 1 is a substituted or unsubstituted 4- to 6-membered heterocyclyl containing one O atom. In some embodiments of formula (Ik-2), G 1 is a substituted or unsubstituted oxetanyl. In some embodiments of formula (Ik-2), G 1 is a substituted or unsubstituted tetrahydrofuranyl.

[0158] In some embodiments of Formula (Ik-2), m is 0. In some embodiments of Formula (Ik-2), m is 1 and R 1a In some embodiments of Formula (Ik-2), m is 1 and R 1a is at the 4-position of the phenyl moiety. In some embodiments of Formula (Ik-2), m is 1 and R 1a In some embodiments of Formula (Ik-2), m is 1 and R 1a In some embodiments of Formula (Ik-2), m is 1 and R 1a is C1-C3 alkyl optionally substituted with halo. In some embodiments of Formula (Ik-2), m is 1 and R 1a In some embodiments of Formula (Ik-2), m is 1 and R 1aIn some embodiments of Formula (Ik-2), m is 1 and R 1a is 4-CF3.

[0159] In some embodiments of Formula (Ik-2), n is 0. In some embodiments of Formula (Ik-2), n is 1. In some embodiments of Formula (Ik-2), n is 2.

[0160] In some embodiments of Formula (Ik-2), each R 2a is independently selected from the group consisting of halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, and hydroxy. In some embodiments of Formula (Ik-2), R 2a is halo, for example, fluoro. In some embodiments of formula (Ik-2), R 2a is a substituted or unsubstituted aryl. In some embodiments of formula (Ik-2), R 2a is a substituted or unsubstituted phenyl. In some embodiments of formula (Ik-2), R 2a is selected from the group consisting of halo, alkoxycarbonyl, substituted or unsubstituted amino, and substituted or unsubstituted aminoacyl; In some embodiments of Formula (Ik-2), R is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents. 2a is phenyl substituted with halo. In some embodiments of formula (Ik-2), R 2a is phenyl substituted with alkoxycarbonyl. In some embodiments of formula (Ik-2), R 2a is phenyl substituted with methoxycarbonyl. In some embodiments of Formula (Ik-2), R 2a is phenyl substituted with a substituted or unsubstituted amino. In some embodiments of formula (Ik-2), R 2ais phenyl substituted with methylamino. In some embodiments of Formula (Ik-2), R 2a is phenyl substituted with a substituted or unsubstituted aminoacyl. In some embodiments of formula (Ik-2), R 2a is phenyl substituted with methylaminoacyl. In some embodiments of Formula (Ik-2), R 2a is phenyl substituted with two substituents selected from the group consisting of methoxycarbonyl, methylamino, and methylaminoacyl. In some embodiments of Formula (Ik-2), R 2a is a substituted or unsubstituted heteroaryl. In some embodiments of formula (Ik-2), R 2a is a substituted or unsubstituted oxadiazolyl. In some embodiments of formula (Ik-2), R 2a is unsubstituted oxadiazolyl. In some embodiments of Formula (Ik-2), R 2a In some embodiments of formula (Ik-2), R is oxadiazolyl substituted with cycloalkyl. 2a is oxadiazolyl substituted with cyclopropyl. In some embodiments of formula (Ik-2), R 2a is a substituted or unsubstituted pyridinyl. In some embodiments of formula (Ik-2), R 2a is unsubstituted pyridinyl. In some embodiments of Formula (Ik-2), R 2a is pyridinyl substituted with halo, e.g., F. In some embodiments of formula (Ik-2), R 2a is pyridinyl substituted with cyano. In some embodiments of formula (Ik-2), R 2a is a substituted or unsubstituted pyridin-2-yl. In some embodiments of Formula (Ik-2), R 2a is a substituted or unsubstituted alkoxycarbonyl. In some embodiments of formula (Ik-2), R 2a In some embodiments of Formula (Ik-2), R 2a is ethoxycarbonyl. In some embodiments of Formula (Ik-2), R 2ais a substituted or unsubstituted aminoacyl. In some embodiments of formula (Ik-2), R 2a is unsubstituted aminoacyl. In some embodiments of formula (Ik-2), R 2a is aminoacyl substituted with one or more (e.g., 1 or 2 or 3 or 1 to 4 or 1 to 3 or 2 to 4) substituents selected from the group consisting of C1-C3 alkyl, C3-C6 cycloalkyl, and 4- to 7-membered heterocyclyl. In some embodiments of Formula (Ik-2), R 2a is aminoacyl substituted with C1-C3 alkyl. In some embodiments of formula (Ik-2), R 2a is methylaminoacyl, ethylaminoacyl, or isopropylaminoacyl. In some embodiments of Formula (Ik-2), R 2a is dimethylaminoacyl. In some embodiments of Formula (Ik-2), R 2a is cyclopropylaminoacyl. In some embodiments of Formula (Ik-2), R 2a is tetrahydropyranylaminoacyl. In some embodiments of Formula (Ik-2), R 2a is substituted or unsubstituted acyl. In some embodiments of formula (Ik-2), R 2a is unsubstituted acyl. In some embodiments of formula (Ik-2), R 2a is acyl substituted with one or more (e.g., 1 or 2 or 3 or 1 to 4 or 1 to 3 or 2 to 4) substituents selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted aryl. In some embodiments of Formula (Ik-2), R 2a is acyl substituted with methyl. In some embodiments of formula (Ik-2), R 2a is acyl substituted with phenyl, wherein the phenyl is optionally substituted with amino. In some embodiments of Formula (Ik-2), R 2a is a substituted or unsubstituted alkyl. In some embodiments of formula (Ik-2), R 2a is C1-C3 alkyl substituted with halo. In some embodiments of formula (Ik-2), R2a is ethyl substituted with two fluoro groups, e.g., —CHCHF. In some embodiments of Formula (Ik-2), R 2a is hydroxy.

[0161] In some embodiments of Formula (Ik-2), p is 0. In some embodiments of Formula (Ik-2), p is 1. In some embodiments of Formula (Ik-2), p is 1 and R 3a In some embodiments of Formula (Ik-2), p is 1 and R 3a is 5-Cl. In some embodiments of Formula (Ik-2), p is 2. In some embodiments of Formula (Ik-2), p is 2 and each R 3a is independently halo, cyano, or substituted or unsubstituted C-C alkyl. In some embodiments of Formula (Ik-2), p is 2 and each R 3a is independently F, Cl, Br, cyano, or methyl. In some embodiments of Formula (Ik-2), p is 2 and at least one R 3a is F or methyl. In some embodiments of Formula (Ik-2), p is 2 and at least one R 3a In some embodiments of Formula (Ik-2), p is 2 and one R 3a is at the 3-position of the pyridinyl moiety and is selected from the group consisting of F and methyl, and one R 3a is at the 5-position of the pyridinyl moiety and is selected from the group consisting of halo, cyano, and unsubstituted C1-C3 alkyl. In some embodiments of Formula (Ik-2), p is 2 and R 3a In some embodiments of Formula (Ik-2), p is 2 and R 3a In some embodiments of Formula (Ik-1), p is 2 and R 3a In some embodiments of Formula (Ik-2), p is 2 and R 3aIn some embodiments of Formula (Ik-2), p is 2 and R 3a are 3-methyl and 5-cyano.

[0162] In some embodiments of formula (Ik-2), R 5 is H. In some embodiments of formula (Ik-2), R 5 is a substituted or unsubstituted alkyl. In some embodiments of formula (Ik-2), R 5 is methyl.

[0163] In some embodiments of formula (Ik-2), G 1 is cyclobutanyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, n is 0, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano; R 5 is H. In some embodiments of formula (Ik-2), G 1 is azetidinyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, n is 0, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano; R 5 is H. In some embodiments of formula (Ik-2), G 1 is oxetanyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, n is 0, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano; R 5 is H. In some embodiments of formula (Ik-2), G 1 is cyclobutanyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, n is 0, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano; R 5 is methyl. In some embodiments of formula (Ik-2), G 1is azetidinyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, n is 0, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano; R 5 is methyl. In some embodiments of formula (Ik-2), G 1 is oxetanyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, n is 0, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano; R 5 is methyl.

[0164] In some embodiments of formula (Ik-2), G 1 is cyclobutanyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, n is 0, p is 2, and each R 3a are independently selected from the group consisting of F, Cl, and cyano; R 5 is H. In some embodiments of formula (Ik-2), G 1 is azetidinyl where m is 1 and R 1a is selected from the group consisting of F, Cl, and —CF3, n is 0, p is 2, and each R 3a are independently selected from the group consisting of F, Cl, and cyano; R 5 is H. In some embodiments of formula (Ik-2), G 1 is oxetanyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, n is 0, p is 2, and each R 3a are independently selected from the group consisting of F, Cl, and cyano; R 5 is H. In some embodiments of formula (Ik-2), G 1 is cyclobutanyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, n is 0, p is 2, and each R 3aare independently selected from the group consisting of F, Cl, and cyano; R 5 is methyl. In some embodiments of formula (Ik-2), G 1 is azetidinyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, n is 0, p is 2, and each R 3a are independently selected from the group consisting of F, Cl, and cyano; R 5 is methyl. In some embodiments of formula (Ik-2), G 1 is oxetanyl, m is 1, and R 1a is selected from the group consisting of F, Cl, and —CF3, n is 0, p is 2, and each R 3a are independently selected from the group consisting of F, Cl, and cyano; R 5 is methyl.

[0165] In some embodiments of formula (Ik-2), G 1 is cyclobutanyl, m is 2, and each R 1a are independently selected from the group consisting of F, Cl, and —CF3, n is 0, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano; R 5 is H. In some embodiments of formula (Ik-2), G 1 is azetidinyl, m is 2, and each R 1a are independently selected from the group consisting of F, Cl, and —CF3, n is 0, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano; R 5 is H. In some embodiments of formula (Ik-2), G 1 is oxetanyl, m is 2, and each R 1a are independently selected from the group consisting of F, Cl, and —CF3, n is 0, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano; R 5 is H. In some embodiments of formula (Ik-2), G 1is cyclobutanyl, m is 2, and each R 1a are independently selected from the group consisting of F, Cl, and —CF3, n is 0, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano; R 5 is methyl. In some embodiments of formula (Ik-2), G 1 is azetidinyl, m is 2, and each R 1a are independently selected from the group consisting of F, Cl, and —CF3, n is 0, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano; R 5 is methyl. In some embodiments of formula (Ik-2), G 1 is oxetanyl, m is 2, and each R 1a are independently selected from the group consisting of F, Cl, and —CF3, n is 0, p is 1, and R 3a is selected from the group consisting of F, Cl, and cyano; R 5 is methyl.

[0166] In some embodiments of formula (Ik-2), G 1 is cyclobutanyl, m is 2, and each R 1a are independently selected from the group consisting of F, Cl, and —CF; n is 0; p is 2; and each R 3a are independently selected from the group consisting of F, Cl, and cyano; R 5 is H. In some embodiments of formula (Ik-2), G 1 is azetidinyl, m is 2, and each R 1a are independently selected from the group consisting of F, Cl, and —CF; n is 0; p is 2; and each R 3a are independently selected from the group consisting of F, Cl, and cyano; R 5 is H. In some embodiments of formula (Ik-2), G 1 is oxetanyl, m is 2, and each R 1aare independently selected from the group consisting of F, Cl, and —CF; n is 0; p is 2; and each R 3a are independently selected from the group consisting of F, Cl, and cyano; R 5 is H. In some embodiments of formula (Ik-2), G 1 is cyclobutanyl, m is 2, and each R 1a is independently selected from the group consisting of F, Cl, and -CF3, and n is 0. p is 2, and each R 3a are independently selected from the group consisting of F, Cl, and cyano; R 5 is methyl. In some embodiments of formula (Ik-2), G 1 is azetidinyl, m is 2, and each R 1a are independently selected from the group consisting of F, Cl, and —CF; n is 0; p is 2; and each R 3a are independently selected from the group consisting of F, Cl, and cyano; R 5 is methyl. In some embodiments of formula (Ik-2), G 1 is oxetanyl, m is 2, and each R 1a are independently selected from the group consisting of F, Cl, and —CF; n is 0; p is 2; and each R 3a are independently selected from the group consisting of F, Cl, and cyano; R 5 is methyl.

[0167] In another embodiment, the compound of formula (I) is a compound of formula (II): [ka] (Il) or a pharmaceutically acceptable salt thereof; In the formula, R 2A is H or substituted or unsubstituted alkyl; R 2bis selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, and hydroxy; m is 0, 1, or 2; p is 0, 1, or 2; and each R 1a is independently selected from the group consisting of halo and substituted or unsubstituted alkyl; each R 3a are independently halo; and R 4 is H.

[0168] In some embodiments of Formula (II), R 2A is H.

[0169] In some embodiments of Formula (II), R 2b is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, and hydroxy. In some embodiments of Formula (II), R 2b is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, and hydroxy. In some embodiments of Formula (II), R 2b is selected from the group consisting of substituted C1-C3 alkyl, unsubstituted C1-C3 alkoxycarbonyl, unsubstituted aminoacyl, and hydroxy. In some embodiments of Formula (II), R 2b is a C1-C3 alkyl substituted with hydroxy. In some embodiments of Formula (II), R 2b is —CHOH. In some embodiments of Formula (II), R 2b is methoxycarbonyl. In some embodiments of Formula (II), R 2b is ethoxycarbonyl. In some embodiments of Formula (II), R 2b is unsubstituted aminoacyl. In some embodiments of Formula (II), R 2b is hydroxy.

[0170] In some embodiments of Formula (II), m is 1 and R 1aIn some embodiments of Formula (II), m is 1 and R 1a is at the 4-position of the phenyl moiety. In some embodiments of Formula (II), m is 1 and R 1a In some embodiments of Formula (II), m is 1 and R 1a is 4-Cl. In some embodiments of Formula (II), where m is 1 and R 1a is C1-C3 alkyl optionally substituted with halo. In some embodiments of Formula (II), m is 1 and R 1a In some embodiments of Formula (II), m is 1 and R 1a In some embodiments of Formula (II), m is 1 and R 1a is 4-CF3.

[0171] In some embodiments of Formula (II), p is 2 and each R 3a is independently halo. In some embodiments of Formula (II), p is 2 and each R 3a is independently F or Cl. In some embodiments of Formula (II), p is 2 and one R 3a is a 3-halo with one R 3a In some embodiments of Formula (II), p is 2 and R 3a are 3-F and 5-Cl.

[0172] In another embodiment, the compound of formula (I) is a compound of formula (Im): [ka] (Im) or a pharmaceutically acceptable salt thereof; In the formula, Q is -O- or -N(R 2b )-and;R 2b is selected from the group consisting of H and substituted or unsubstituted acyl; m is 0, 1, or 2; p is 0, 1, or 2; and each R1a is independently selected from the group consisting of halo and substituted or unsubstituted alkyl; each R 3a are independently halo; and R 4 is H.

[0173] In some embodiments of Formula (Im), Q is -O-. In some embodiments of Formula (Im), Q is -N(R 2b )-.

[0174] In some embodiments of Formula (Im), R 2b is substituted or unsubstituted acyl. In some embodiments of Formula (Im), R 2b is unsubstituted acyl. In some embodiments of Formula (Im), R 2b is an acyl substituted with alkyl. In some embodiments of Formula (Im), R 2b is a methyl-substituted acyl.

[0175] In some embodiments of Formula (Im), m is 1 and R 1a is selected from the group consisting of halo and substituted or unsubstituted alkyl. In some embodiments of Formula (Im), m is 1 and R 1a is at the 4-position of the phenyl moiety. In some embodiments of Formula (Im), m is 1 and R 1a In some embodiments of Formula (Im), m is 1 and R 1a In some embodiments of Formula (Im), m is 1 and R 1a is C1-C3 alkyl optionally substituted with halo. In some embodiments of Formula (Im), m is 1 and R 1a In some embodiments of Formula (Im), m is 1 and R 1a In some embodiments of Formula (Im), m is 1 and R 1a is 4-CF3.

[0176] In some embodiments of Formula (Im), p is 2 and each R3a is independently halo. In some embodiments of Formula (Im), p is 2 and each R 3a is independently F or Cl. In some embodiments of Formula (Im), p is 2 and one R 3 a is a 3-halo with one R 3a In some embodiments of Formula (Im), p is 2 and R 3a are 3-F and 5-Cl.

[0177] In another embodiment, the compound of formula (I) is a compound of formula (In-1) or formula (In-2): [ka] or a pharmaceutically acceptable salt thereof; During the ceremony: R 1 is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted pyridyl; R 2A , R 2B , and R 3 is defined by one of (i) to (iii): (i)R 2A is H or substituted or unsubstituted alkyl; R 2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and R 3 is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; or (ii)R 2A is H or substituted or unsubstituted alkyl; R 2Bis a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl; and R 3 is substituted or unsubstituted alkyl; or (iii)R 2A and R 2B together with the carbon atoms to which they are attached, form G 1 wherein G 1 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl ring, each of which is optionally fused to a phenyl ring; and R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 4 is H or substituted or unsubstituted alkyl; and R 5 is H or substituted or unsubstituted alkyl; where, when one or more of provisions (a) to (c) apply, R 1 is a substituted or unsubstituted pyridyl or a phenyl substituted with at least one substituent other than methyl or methoxy; (a)R 2A and R 2B is defined by (i) and R 3 is a substituted or unsubstituted phenyl; (b)R 2A and R 3 is defined by (ii) and R 2B is 4-methoxyphenyl; (c)R 2A , and R 2B is defined by (iii) and R 3is 4-methoxyphenylmethyl.

[0178] In some embodiments, provided herein are compounds set forth in Table 1 and salts thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66

Table 1-67

Table 1-69

Table 1-90

Table 1-97

Table 1-110

Table 1-120

Table 1-150

[0179] In some variations, any of the compounds described herein, e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or any variation thereof, or a compound in Table 1, can be deuterated (e.g., a hydrogen atom is replaced with a deuterium atom). 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 non-deuterated compounds. Hydrogen atoms can also be replaced with deuterium atoms using other methods known in the art.

[0180] Any formula provided herein, for example, formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), is intended to represent compounds having the structure depicted by the structural formula, as well as certain variations or forms. In particular, compounds of any formula provided herein may also have asymmetric centers and therefore may exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of compounds of the general formula, and mixtures thereof in any proportion, are considered to be within the scope of the formula. Thus, any formula provided herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any proportion. When a compound in Table 1 is depicted in a particular stereochemical configuration, any alternative stereochemical configuration of the compound, as well as mixtures of the compound's stereoisomers in any ratio, are also provided herein. For example, if a compound in Table 1 has a stereocenter that is in the "S" stereochemical configuration, then enantiomers of the compound where that stereocenter is in the "R" stereochemical configuration are also provided herein. Similarly, when a compound in Table 1 has a stereocenter that is in the "R" stereochemical configuration, then enantiomers of the compound where that stereocenter is in the "S" stereochemical configuration are also provided herein. Also provided are mixtures of compounds having both the "S" and "R" stereochemical configurations. Furthermore, when a compound in Table 1 has more than one stereocenter, then any enantiomers or diastereomers of the compound are 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, also provides stereoisomers of the compound having the first and second stereocenters having "S" and "S" stereochemical configurations, respectively, having "S" and "R" stereochemical configurations, respectively, and having "R" and "S" stereochemical configurations, respectively.When a compound of Table 1 contains a first stereocenter and a second stereocenter having "S" and "S" stereochemical configurations, respectively, stereoisomers of the compound having the first and second stereocenters having "R" and "R" stereochemical configurations, respectively, and having "R" and "S" stereochemical configurations, respectively, are also provided. When a compound of Table 1 contains a first stereocenter and a second stereocenter having "S" and "R" stereochemical configurations, respectively, stereoisomers of the compound having the first and second stereocenters having "R" and "S" stereochemical configurations, respectively, and having "R" and "R" stereochemical configurations, respectively, are also provided. Similarly, if a compound in Table 1 contains a first stereocenter and a second stereocenter having "R" and "S" stereochemical configurations, respectively, stereoisomers of the compound having the first and second stereocenters having "S" and "R" stereochemical configurations, respectively, and having "S" and "S" stereochemical configurations, respectively, are also provided. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Furthermore, any formula given herein is intended to refer to any one of the hydrates, solvates, and amorphous and polymorphic forms of such a compound, and mixtures thereof, even if such forms are not explicitly recited. In some embodiments, the solvent is water and the solvate is a hydrate.

[0181] Representative examples of compounds detailed herein, including intermediate and final compounds, are shown in the Tables and elsewhere herein. It is understood that any compound may be used in the methods detailed herein, including intermediate compounds, where available, which may be isolated and administered to an individual or subject.

[0182] The compounds provided herein may be presented as salts, even if not shown, and it is understood that the compositions and methods provided herein encompass all salts and solvates of the compounds provided herein, as well as non-salt and non-solvated forms of the compounds, as will be appreciated by one of ordinary skill in the art. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0183] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual or subject. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, pharmaceutical compositions are provided comprising the compounds detailed herein and a pharmaceutically acceptable carrier. In another variation, methods for administering the compounds are provided. The pure forms, pharmaceutical compositions, and methods for administering the compounds are suitable for any of the compounds or forms thereof detailed herein.

[0184] G as provided herein 1 , R 1 , R 2A , R 2B , R 3 , R 4 , and R 5 Any variation or embodiment of G is treated as if each combination were individually and specifically described. 1 , R 1 , R 2A , R 2B , R 3 , R 4 , and R 5 can be combined with any other variant or embodiment of the present invention.

[0185] G as provided herein 1 , R 1 , R 2A , R 2B , R 3 , R 4 , R 5 , R 1a , R 2a , R 2b , R 3aAny variation or embodiment of m, n, p, q, X, and Q is understood to be within the meaning of the formula G as if each combination were individually and specifically described. 1 , R 1 , R 2A , R 2B , R 3 , R 4 , R 5 , R 1a , R 2a , R 2b , R 3a , m, n, p, q, X, and Q can be combined with any other variations or embodiments of m, n, p, q, X, and Q.

[0186] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0187] Formula (I) includes all subformulas thereof, for example, formula (I) includes compounds of formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2).

[0188] Certain compound names provided herein, including in Table 1, are listed in ChemBioDraw Professional 15.0.0.106. Those skilled in the art will appreciate that compounds can be named or identified using a variety of generally recognized nomenclature systems and symbols. By way of example, compounds can be named or identified using common names, systematic or non-systematic names. Nomenclature systems and symbols generally recognized in the chemical arts include, for example, Chemical Abstract Service (CAS), ChemBioDraw Ultra, and International Union of Pure and Applied Chemistry. Chemistry (IUPAC) is one example.

[0189] composition Also provided are compositions, eg, pharmaceutical compositions, comprising a compound disclosed and / or described herein and one or more additional medicinal agents, pharmacological agents, adjuvants, carriers, excipients, etc. Suitable drugs and pharmacological agents include those described herein. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient or adjuvant and at least one compound entity described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, saccharin sodium, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, a composition is provided, such as a pharmaceutical composition containing one or more compounds described herein, or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, provided are pharmaceutically acceptable compositions comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound in Table 1, or a pharmaceutically acceptable salt thereof. In some aspects, the compositions may include synthetic intermediates that can be used in the preparation of the compounds described herein. The compositions described herein may also include any other suitable active or inactive agents.

[0191] Any of the compositions described herein may be sterile or may contain sterile components. Sterility can be achieved by methods known in the art. Any of the compositions described herein may contain one or more substantially pure compounds or conjugates.

[0192] Also provided is a packaged pharmaceutical composition comprising a pharmaceutical composition described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.

[0193] How to use The compounds and pharmaceutical compositions herein can be used to treat or prevent a disease or condition in an individual or subject.

[0194] When used for prophylactic purposes, the compounds disclosed and / or described herein can prevent the onset of a disease or disorder or reduce the extent of the disease or disorder that may develop in an individual or subject at risk of developing the disease or disorder.

[0195] Without being bound by theory, it is believed that the compounds and pharmaceutical compositions disclosed herein act to inhibit myosin. This inhibition potentially reduces the number of independent myosin heads that interact with actin filaments, reducing the amount of contraction. Reducing myocardial contractility may be important in treating cardiac diseases in which excessive contractility is a problem. In some embodiments, methods are provided for treating or preventing cardiac disease in an individual or subject in need thereof, comprising administering to the individual or subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, methods are provided for treating or preventing cardiac disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound entity described herein. In some embodiments, there is provided a method for treating cardiac disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound entity described herein. In some embodiments, there is provided a method for treating established or diagnosed cardiac disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound entity described herein. In some embodiments, there is provided a method for treating established or diagnosed cardiac disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound entity described herein. The present invention provides a method for preventing heart disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound entity selected from the group consisting of benzodiazepines, ...

[0196] Also provided herein is the use of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cardiac disease in a subject. In some embodiments, provided is a compound or composition described herein for use in a method of treatment of the human or animal body by therapy. In some embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy. In some embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of cardiac disease. In some embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiac disease. In some embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of established or diagnosed cardiac disease. In other embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in the prevention of cardiovascular disease.In some embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition associated with HCM. In some embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition associated with secondary left ventricular wall thickening. In some embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in ameliorating symptoms associated with heart disease. In other embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in reducing the risk of symptoms associated with heart disease. In other embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases or conditions associated with a small left ventricular cavity and cavity obstruction, left ventricular hypercontractility, obstruction of blood flow from the left ventricle, cardiac hypertrophy, small cardiac stroke volume, impaired left ventricular relaxation, high left ventricular filling pressure, myocardial ischemia, or myocardial fibrosis. In certain embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases or conditions associated with a small left ventricular cavity and cavity obstruction, left ventricular hypercontractility, myocardial ischemia, or myocardial fibrosis. Provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of muscular dystrophy. In some embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in treating glycogen storage diseases. In other embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in modulating cardiac sarcomeres, e.g., inhibiting cardiac sarcomeres. In yet other embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in enhancing cardiac myosin.

[0197] 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 established or diagnosed heart disease. In some embodiments, the subject has 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 in myosin heavy chain beta (MHC-β), cardiac troponin T (cTnT), tropomyosin alpha 1 chain (TPM1), cardiac myosin-binding protein C (MYBPC3), cardiac troponin I (cTnI), myosin essential light chain (ELC), titin (TTN), myosin regulatory light chain 2 ventricular / cardiac isoform (MLC-2), cardiac alpha actin, muscle LIM protein (MLP), or protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2). In some embodiments, the mutation is in MHC-β. In some embodiments, the subject has established or diagnosed hypertrophic cardiomyopathy without a confirmed genetic etiology.

[0198] In some embodiments, the subject has a high risk of a progressive condition. In some embodiments, the subject has a high risk of atrial fibrillation, ventricular tachyarrhythmia, stroke, and / or sudden death. In some embodiments, the subject has a decrease in exercise capacity. In some embodiments, the decrease in exercise capacity is compared to an age-matched control population. In some embodiments, the subject is eligible for surgical intervention or percutaneous ablation to treat cardiac disease.

[0199] In some embodiments, the cardiac disease is hypertrophic cardiomyopathy (HCM). In some embodiments, the cardiac disease is obstructive HCM. In some embodiments, the cardiac disease is non-obstructive HCM. In some embodiments, the HCM is associated with a sarcomere mutation. In some embodiments, the HCM is associated with a non-sarcomere mutation. In some embodiments, the cardiac disease is obstructive or non-obstructive HCM caused by a sarcomere and / or non-sarcomere mutation. In some embodiments, the sarcomere mutation is associated with myosin heavy chain beta (MHC-β), cardiac troponin T (cTnT), tropomyosin alpha 1 chain (TPM1), cardiac myosin-binding protein C (MYBPC3), cardiac troponin I (cTnI), The mutation is in myosin essential light chain (ELC), titin (TTN), myosin regulatory light chain 2 ventricular / cardiac isoform (MLC-2), cardiac alpha actin, or muscle LIM protein (MLP). In some embodiments, the sarcomeric mutation is in MHC-β. In some embodiments, the non-sarcomeric mutation is in protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2).

[0200] In some embodiments, provided herein are methods for treating a disease or condition associated with HCM, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound in Table 1, or a pharmaceutically acceptable salt thereof, to an individual or subject in need thereof. In some embodiments, the disease or condition is Fabry disease, Danon disease, mitochondrial cardiomyopathy, or Noonan syndrome.

[0201] Also provided herein is the use of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with HCM.

[0202] In some embodiments, the cardiac disease is heart failure with preserved left ventricular ejection fraction (HFpEF). In some embodiments, the cardiac disease is diastolic dysfunction. In some embodiments, the cardiac disease is cardiomyopathy. In some embodiments, the cardiac disease is primary or secondary restrictive cardiomyopathy. In some embodiments, the cardiac disease is a condition or symptom caused by ischemic heart disease. In some embodiments, the cardiac disease is myocardial infarction or angina pectoris. In some embodiments, the cardiac disease is hypertrophic obstructive cardiomyopathy. In some embodiments, the cardiac disease is hypertensive heart disease. In some embodiments, the cardiac disease is congenital heart disease. In some embodiments, the cardiac disease is cardiac ischemia and / or coronary heart disease. In some embodiments, the cardiac disease is diabetic heart disease. In other embodiments, the cardiac disease is congestive heart failure. In some embodiments, the cardiac disease is right heart failure. In other embodiments, the cardiac disease is cardiorenal syndrome. In some embodiments, the cardiac disease is infiltrative cardiomyopathy. In some embodiments, the cardiac disease is or is a condition associated with cardiac aging or age-related diastolic dysfunction, hi some embodiments, the cardiac disease is or is a condition associated with left ventricular hypertrophy and / or concentric left ventricular remodeling.

[0203] In some embodiments, provided are methods for treating a disease or condition associated with secondary left ventricular wall thickening in an individual or subject in need thereof, comprising administering to the individual or subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is hypertension, valvular heart disease (aortic stenosis, mitral regurgitation), metabolic syndrome (diabetes, obesity), end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich's ataxia, Danon disease, Noonan syndrome, or Pompe disease.

[0204] Also, a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with secondary left ventricular wall thickening. The use of acceptable salts is provided herein.

[0205] In some embodiments, there is provided a method of ameliorating symptoms associated with cardiac disease in a subject, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, to an individual or subject in need thereof, wherein the symptoms include poor or decreased cardiac elasticity, poor or decreased diastolic left ventricular relaxation. is one or more of: decreased left atrial pressure (e.g., abnormal left atrial pressure), paroxysmal or persistent atrial fibrillation, increased left atrial and pulmonary capillary wedge pressure, elevated left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular myocardial mass, increased left ventricular wall thickness, mid-left ventricular obstruction, increased mitral valve systolic anterior motion, hypertrophic obstructive cardiomyopathy, chest pain, exertional dyspnea, presyncope, abnormal exercise capacity, and fatigue.

[0206] In some embodiments, a method of reducing the risk of a symptom associated with cardiac disease in a subject comprises administering to an individual or subject in need thereof a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the symptom is sudden cardiac death, poor or decreased cardiac elasticity, decreased diastolic left ventricular relaxation, or a combination thereof. the symptoms are one or more selected from: poor or decreased left atrial pressure (e.g., abnormally high left atrial pressure), paroxysmal or persistent atrial fibrillation, increased left atrial and pulmonary capillary wedge pressure, elevated left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular myocardial mass, increased left ventricular wall thickness, mid-left ventricular obstruction, increased mitral valve systolic anterior motion, hypertrophic obstructive cardiomyopathy, chest pain, exertional dyspnea, presyncope, abnormal exercise capacity, and fatigue.

[0207] In some embodiments, provided are methods for treating a disease or condition associated with a small left ventricular lumen, lumen occlusion, left ventricular hypercontraction, obstruction of blood flow from the left ventricle, cardiac hypertrophy, small cardiac stroke volume, impaired left ventricular relaxation, high left ventricular filling pressure, myocardial ischemia, or myocardial fibrosis in an individual or subject in need thereof, comprising administering to the individual or subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, provided are methods for treating a disease or condition associated with small left ventricular lumen and lumen obstruction, left ventricular hypercontractility, myocardial ischemia, or myocardial fibrosis in an individual or subject in need thereof, comprising administering to the individual or subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound in Table 1, or a pharmaceutically acceptable salt thereof.

[0209] Also provided herein is the use of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with small left ventricular lumen and lumen obstruction, left ventricular hypercontractility, myocardial ischemia, or myocardial fibrosis.

[0210] In some embodiments, a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1 Also provided herein is the use of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of muscular dystrophy (e.g., Duchenne muscular dystrophy).

[0211] In some embodiments, there is provided a method of treating glycogen storage disease in an individual or subject in need thereof, comprising administering to the individual or subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of glycogen storage disease.

[0212] Also provided are methods for modulating cardiac sarcomeres in an individual or subject in need thereof, comprising administering to the individual or subject a therapeutically effective amount of at least one compound entity described herein. In some embodiments, provided are methods for inhibiting cardiac sarcomeres, comprising contacting cardiac sarcomeres with at least one compound entity described herein, e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Further provided herein is the use of at least one compound entity described herein, e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of cardiac muscle sarcomeres in an individual or subject.

[0213] Also provided is a method of enhancing cardiac myosin in an individual or subject in need thereof, comprising administering to the individual or subject a therapeutically effective amount of at least one compound entity described herein, e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound in Table 1, or a pharmaceutically acceptable salt thereof. Further provided herein is the use of at least one compound entity described herein, e.g., a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for enhancing cardiac myosin in an individual or subject.

[0214] In some embodiments, the methods provided herein further comprise monitoring the effectiveness of the treatment. Exemplary indicators include, but are not limited to, improvements in one or more of the following: New York Heart Association (NYHA) functional class, exercise capacity, myocardial elasticity, left ventricular diastolic relaxation, left atrial pressure, paroxysmal or persistent atrial fibrillation, left atrial and pulmonary capillary wedge pressure, left ventricular diastolic pressure, syncope, ventricular relaxation in diastole, ventricular fibrosis, left ventricular hypertrophy, and the like. The following indicators may be monitored: left ventricular mass, left ventricular wall thickness, left ventricular mid-obstruction, mitral systolic anterior motion, hypertrophic obstructive cardiomyopathy, chest pain, exertional dyspnea, presyncope, abnormal exercise capacity, and fatigue. These indicators can be monitored by techniques known in the art, including self-reporting; ECG, e.g., ambulatory ECG; echocardiography; cardiac MRI; CT; biopsy; cardiopulmonary exercise testing (CPET); and actigraphy.

[0215] In some embodiments, the compound reduces cardiomyocyte contractility. In some embodiments, the compound reduces cardiomyocyte contractility by more than 40%, e.g., 45%, 50%, 60%, 70%, 80%, or more than 90%. In some embodiments, the compound reduces cardiomyocyte contractility by 40% to 90%, e.g., 40% to 80%, 40% to 70%, 50% to 90%, 50% to 80%, or 50% to 70%. In some embodiments, the compound does not significantly alter calcium transport in cardiomyocytes. In some embodiments, the compound reduces ATPase activity in cardiomyocytes. Methods for measuring contractility, ATPase activity, and calcium transport are known in the art, for example, by calcium labeling, electrophysiological recording, and microscopic imaging. In some embodiments, the compound does not significantly inhibit or induce cytochrome P450 (CYP) proteins.

[0216] I'm not interested in theory, but R 2A and R 2BA stereoisomer of a compound of formula (I) or any variation thereof, in which the carbon bearing the moiety is in the "S" stereochemical configuration, has an R 2A and R 2B It is believed that the more active stereoisomer is the one in which the carbon bearing the moiety is in the "R" stereochemical configuration than the corresponding stereoisomer. Crystal structures have been obtained for representative compounds of formula (I), and as between the "S" and "R" isomers, the more active stereoisomer is the one in the "R" stereochemical configuration as measured by the myofibrillar assay described in Example B-1. 2A and R 2B The carbon bearing the moiety is in the "S" stereochemical configuration, indicating that the stereoisomer is one.

[0217] In some embodiments, the subject has a thicker-than-normal left ventricular wall before treatment. In some embodiments, the subject has a left ventricular wall thickness of more than 15 mm, for example, more than 18 mm, 20 mm, 22 mm, 25 mm, or 30 mm, before treatment. In some embodiments, the left ventricular wall thickness decreases by more than 5%, for example, more than 8%, 10%, 12%, 15%, 20%, or 30% after treatment. Left ventricular wall thickness can be measured by methods known in the art, such as echocardiography, CT scan, or cardiac MRI.

[0218] In some embodiments, the subject has abnormal myocardial fibrosis before treatment. In some embodiments, the abnormal myocardial fibrosis is reduced by more than 5%, for example, 8%, 10%, 12%, 15%, 20%, or more than 30% after treatment. Myocardial fibrosis can be measured by methods known in the art, such as biopsy or cardiac MRI.

[0219] In some embodiments, the subject has reduced exercise capacity prior to treatment. In some embodiments, the subject's exercise capacity increases by more than 5%, e.g., more than 8%, 10%, 12%, 15%, 20%, or 30%, after treatment. In some embodiments, exercise capacity is measured by cardiopulmonary exercise testing (CPET). CPET measures changes in oxygen consumption (VO2max). Methods for measuring CPET and VO2max are well known in the art (Malhotra et al., JACC: Heart Failure, 2016, 4(8):607-616; Guazzi et al., J Amer College Cardiol, 2017, 70(13):1618-1636; Rowin et al., J Amer College Cardiol, 2017, 70(13):1618-1636). al., JACC: Cariovasc Imaging, 2017, 10(11):1374-1386). In some embodiments, the VO2max is greater than or equal to 1 mL / kg / m after treatment. 2 greater than, for example, 1.2 mL / kg / m 2 , 1.4 mL / kg / m 2 , 1.5mL / kg / m 2 , 1.7 mL / kg / m 2 , 2 mL / kg / m 2 , 2.2 mL / kg / m 2 , 2.5 mL / kg / m 2 , 3 mL / kg / m 2 , 3.2 mL / kg / m 2 , or 3.5 mL / kg / m 2 Super improved.

[0220] In some embodiments, the subject has a New York Heart Association (NYHA) functional class of II, III, or IV before treatment. In some embodiments, the subject has a New York Heart Association (NYHA) functional class of III or IV before treatment. In some embodiments, the subject has a New York Heart Association (NYHA) functional class of IV before treatment. In some embodiments, the subject remains in the same NYHA functional class or has a decrease in NYHA functional class after treatment.

[0221] In some embodiments, the VO2max is greater than or equal to 1 mL / kg / m after treatment. 2 greater than, for example, 1.2 mL / kg / m 2 , 1.4 mL / kg / m 2 , 1.5 mL / kg / m 2 , 1.7 mL / kg / m 2 , or 2 mL / kg / m 2 In some embodiments, the VO2max is greater than or equal to 2.5 mL / kg / m after treatment. 2 , 3 mL / kg / m 2 , 3.2 mL / kg / m 2 , or 3.5 mL / kg / m 2 Super-improved, subjects are in the same NYHA functional class or have a decline in NYHA functional class.

[0222] In some embodiments, the subject's daily function and / or activity level improves after treatment. The improvement in daily function and / or activity level can be measured by journaling or actigraphy, e.g., a FitBit or FitBit-like monitor.

[0223] In some embodiments, the subject has one or more of reduced shortness of breath, reduced chest pain, reduced arrhythmia burden, e.g., atrial fibrillation and ventricular arrhythmias, reduced incidence of heart failure, and reduced ventricular outflow tract obstruction after treatment.

[0224] Dosage The compounds and compositions disclosed and / or described herein are administered at a therapeutically effective dose, e.g., a dose sufficient to provide treatment for a disease condition. While human dosage levels have not yet been optimized for the chemical entities described herein, generally, daily doses range from about 0.01 to 100 mg / kg body weight; in some embodiments, from about 0.05 to 10.0 mg / kg body weight, and in some embodiments, from about 0.10 to 1.4 mg / kg body weight. Thus, for a 70 kg human, in some embodiments, the dosage range is from about 0.7 to 7000 mg / day; in some embodiments, from about 3.5 to 700.0 mg / day, and in some embodiments, from about 7 to 100.0 mg / day. The amount of the chemical entity administered will depend, for example, on the subject and disease condition being treated, the severity of the affliction, the method and schedule of administration, and the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is about 5 mg to about 500 mg per day, and an exemplary dosage range for intravenous administration is about 5 mg to about 500 mg per day, each depending on the pharmacokinetics of the compound.

[0225] A daily dose is the total amount administered in one day. A daily dose may be administered, but is not limited to, every day, every other day, every week, every two weeks, every month, or at various intervals. In some embodiments, a daily dose is administered for a period ranging from one day to the subject's lifetime. In some embodiments, a daily dose is administered once a day. In some embodiments, a daily dose is administered in multiple divided doses, for example, 2, 3, or 4 divided doses. In some embodiments, a daily dose is administered in two divided doses.

[0226] Administration of the compounds and compositions disclosed and / or described herein can include, but is not limited to, oral administration. The compound or composition may be administered by any of the accepted modes of administration of a therapeutic agent, including intravenous, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and / or described herein is administered orally.

[0227] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms, such as tablets, capsules, powders, liquids, suspensions, suppositories, and aerosol forms. The compounds disclosed and / or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled / sustained release pills, depot injections, osmotic pumps, or transdermal (including electrotransport) patch forms) for prolonged and / or pulsatile administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of precise doses.

[0228] The compounds disclosed and / or described herein can be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical compositions can also contain minor amounts of nontoxic auxiliary substances, such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like). Generally, depending on the intended mode of administration, pharmaceutical compositions contain from about 0.005% to 95% by weight, or from about 0.5% to 50% by weight, of the compounds disclosed and / or described herein. Actual methods for preparing such 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.

[0229] In some embodiments, the compositions take the form of a pill or tablet, and thus the compositions may include one or more diluents (e.g., lactose, sucrose, dicalcium phosphate), lubricants (e.g., magnesium stearate), and / or binders (e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives) along with a compound disclosed and / or described herein. Alternative solid dosage forms include powders, marume, solutions, or suspensions (e.g., in propylene carbonate, vegetable oils, or triglycerides) encapsulated in a gelatin capsule.

[0230] Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving, dispersing, or suspending a compound disclosed and / or described herein and optional excipients in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of compound included in such parenteral compositions depends, for example, on the physical properties of the compound, the activity of the compound, and the needs of the subject. However, percentages of active ingredient ranging from 0.01% to 10% in solution are usable, and may be higher if the composition is a solid that is subsequently diluted to another concentration. In some embodiments, the composition contains about 0.2% to about 2% of a compound disclosed and / or described herein in solution.

[0231] Pharmaceutical compositions of the compounds disclosed and / or described herein may also be used alone or in combination with an inert carrier. It may be administered to the respiratory tract, for example, in combination with lactose, as an aerosol or solution for nebulizer, or as an ultrafine powder for insufflation.In such cases, the particles of the pharmaceutical composition may have a diameter of less than 50 microns, or in some embodiments, less than 10 microns.

[0232] Additionally, pharmaceutical compositions may include a compound disclosed and / or described herein and one or more additional drugs, pharmacological agents, adjuvants, etc. Suitable drugs and pharmacological agents include those described herein.

[0233] kit Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The articles of manufacture may include a labeled container. Suitable containers include, for example, bottles, vials, and test tubes. The container may be formed from a variety of materials, such as glass or plastic. The container may hold a pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used for the prevention, treatment, or suppression of a condition described herein, and may also indicate instructions for either in vivo or in vitro use. In one aspect, the present invention provides a kit comprising the compound or composition described herein and instructions for use.The kit may also include instructions for use in treating cardiac disease in an individual or subject in need thereof.The kit may further include any material or device that can be used to administer the compound or composition, such as a vial, a syringe, or an IV bag.The kit may also include a sterile package.

[0234] combination The compounds and compositions described and / or disclosed herein can be administered alone or in combination with other treatments and / or therapeutic agents useful in the treatment of the aforementioned disorders, diseases, or conditions.

[0235] The compounds and compositions described and / or disclosed herein can be combined with one or more other therapies to treat cardiac diseases, such as HCM or HFpEF. In some embodiments, the one or more therapies include a therapy that slows the progression of heart failure and prevents cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor). In some embodiments, the one or more therapies include a therapy that improves cardiac function by stimulating myocardial contraction (e.g., a positive inotropic agent such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone). In other embodiments, the one or more therapies include a therapy that reduces cardiac preload (e.g., a diuretic such as furosemide) or cardiac afterload (a vasodilator of any class, including, but not limited to, a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator).

[0236] The compounds and compositions described and / or disclosed herein can be combined with one or more other treatments to treat HCM or HFpEF, hi some embodiments, the compounds and compositions may be combined with a beta-blocker, verapamil, and / or disopyramide.

[0237] General synthesis method By reference to the exemplary synthetic schemes below for the general preparation and specific examples that follow, it is possible to provide compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), The compounds (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2) ​​are described. To obtain the various compounds herein, those skilled in the art will recognize that starting materials may be appropriately selected so that the ultimately desired substituents are carried through the reaction scheme, with or without protection, as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, an appropriate group that can be carried through the reaction scheme and replaced with the desired substituent as needed. Furthermore, those skilled in the art will recognize that protecting groups may be used to protect certain functional groups (amino, carboxy, or side chain groups) from reaction conditions, and that such groups are removed under standard conditions as needed. Unless otherwise indicated, the variables are as defined above with respect to formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2).

[0238] If it is desired to obtain a specific enantiomer of a compound, any conventional procedure suitable for separating or resolving enantiomers can be used to achieve this from the corresponding enantiomeric mixture.Thus, for example, diastereomeric derivatives can be produced by reacting an enantiomeric mixture, for example, a racemate, with a suitable chiral compound.The diastereomers can be separated by any conventional means, for example, by crystallization, and the desired enantiomer can be recovered.In another resolution process, chiral high performance liquid chromatography can be used to separate the racemate.Alternatively, if desired, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the above processes.

[0239] Where it is desired to obtain a particular isomer of a compound or alternatively purify the product of a reaction, chromatography, recrystallization, and other conventional separation procedures may be employed on intermediates or final products.

[0240] General methods for preparing the compounds described herein are illustrated in the following exemplary methods. The variables in the schemes provided herein are defined as formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2), or any variation thereof. Other compounds described herein can be prepared by similar methods.

[0241] In some embodiments, the compounds provided herein can be synthesized according to Scheme 1. Scheme 1 [ka] In the formula, R 1 , R 2A , R 2B , R 3 , R 4 , and R 5 is as defined in formula (I) or any variation thereof detailed herein.

[0242] An exemplary embodiment of the preparation method in Scheme 1 is shown in Scheme 1a. Scheme 1a [ka] In the formula, R 2A and R 2B is as defined in formula (I) or any variation thereof detailed herein; and wherein R 1a is as defined in formula (If) or any variation thereof detailed herein.

[0243] Another exemplary embodiment of the preparation method in Scheme 1 is shown in Scheme 1b. Scheme 1b [ka] In the formula, R1 , R 3 , R 4 , and R 5 is as defined in formula (I) or any variation thereof detailed herein, and wherein R 2a is as defined in formula (If) or any variation thereof detailed herein.

[0244] Another exemplary embodiment of the preparation method in Scheme 1 is shown in Scheme 1c. Scheme 1c [ka] In the formula, R 1a and R 2a is as defined in formula (If) or any variation thereof detailed herein.

[0245] In some embodiments, the compounds provided herein can be synthesized according to Scheme 2.

[0246] Scheme 2 [ka] In the formula, R 1 , R 2A , R 2B , R 3 , R 4 , and R 5 is as defined in formula (I) or any variation thereof detailed herein.

[0247] Another exemplary embodiment of the preparation method in Scheme 2 is shown in Scheme 2a. Scheme 2a [ka] In the formula, R 2A and R 2B is as defined in formula (I) or any variation thereof detailed herein; and wherein R 1ais as defined in formula (If) or any variation thereof detailed herein.

[0248] Another exemplary embodiment of the preparation method in Scheme 2 is shown in Scheme 2b. Scheme 2b [ka] In the formula, R 1 , R 3 , R 4 , and R 5 is as defined in formula (I) or any variation thereof detailed herein, wherein R 2a is as defined in formula (If) or any variation thereof detailed herein, and wherein X is a halogen.

[0249] Another exemplary embodiment (eg, of the preparation method in Scheme 2) is shown in Scheme 2c. Scheme 2c [ka] In the formula, R 1 , R 3 , R 4 , and R 5 is as defined in formula (I) or any variation thereof detailed herein.

[0250] Another exemplary embodiment of the preparation method in Scheme 2 is shown in Scheme 2d. Scheme 2d [ka] In the formula, R 1a and R 2a is as defined in formula (If) or any variation thereof detailed herein.

[0251] Another exemplary embodiment (eg, of the preparation method in Scheme 2) is shown in Scheme 2e. Scheme 2e [ka]

[0252] Another exemplary embodiment (eg, of the preparation method in Scheme 2) is shown in Scheme 2f. Scheme 2f [ka]

[0253] Another exemplary embodiment of the preparation method in Scheme 2 is shown in Scheme 2g. Scheme 2g [ka] wherein X is a halide; 2A and R 3 is as defined in formula (I) or any variation thereof detailed herein; and wherein R 1a and m is as defined in formula (Ik-1) or any variation thereof detailed herein.

[0254] In some embodiments, the compounds provided herein can be synthesized according to Scheme 3. Scheme 3 [ka] In the formula, R 1 , R 2A , R 2B , R 3 , R 4 , and R 5 is as defined in formula (I) or any variation thereof detailed herein.

[0255] Another exemplary embodiment of the preparation method in Scheme 3 is shown in Scheme 3a. Scheme 3a [ka] In the formula, R 1ais as defined in formula (If) or any variation thereof detailed herein; and wherein R a and R b are independently H or C1-C6 alkyl.

[0256] Another exemplary embodiment of the preparation method in Scheme 3 is shown in Scheme 3b-1. Scheme 3b-1 [ka] wherein X is CH or N; and wherein R 1a is as defined in formula (If) or any variation thereof detailed herein.

[0257] Another exemplary embodiment of the preparation method in Scheme 3 is shown in Scheme 3b-2. Scheme 3b-2 [ka] wherein X is CH or N; and wherein R 1a is as defined in formula (If) or any variation thereof detailed herein.

[0258] Another exemplary embodiment of the preparation method in Scheme 3 is shown in Scheme 3c. Scheme 3c [ka] In the formula, R 1a is as defined in formula (If) or any variation thereof detailed herein.

[0259] Another exemplary embodiment of the preparation method in Scheme 3 is shown in Scheme 3d. Scheme 3d [ka] In the formula, R 2Ais as defined in formula (I) or any variation thereof detailed herein; and wherein R 1a is selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl.

[0260] Another exemplary embodiment of the preparation method in Scheme 3 is shown in Scheme 3e. Scheme 3e [ka] In the formula, R 1a is selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl.

[0261] Another exemplary embodiment of the preparation method in Scheme 3 is shown in Scheme 3f. Scheme 3f [ka] In the formula, R 1a is selected from the group consisting of halo and substituted or unsubstituted alkyl; and wherein m is 0, 1, or 2.

[0262] Another exemplary embodiment of the preparation method in Scheme 3 is shown in Scheme 3g. Scheme 3g [ka] In the formula, R 1a and m is as defined in formula (Ik-1) or any variation thereof detailed herein.

[0263] Another exemplary preparation method is shown in Scheme 4. Scheme 4 [ka] In the formula, R 1a , R3a , m, and p are as defined in formula (Ik-1) or any variation thereof detailed herein.

[0264] Specific non-limiting examples are provided in the Examples section below. [Example]

[0265] The following examples are provided to illustrate, but not limit, the compositions, uses, and methods provided herein. Compounds are prepared using the general methods described above. In the following examples, compound designations using a particular letter followed by a compound number refer to stereoisomeric forms or mixtures of stereoisomers of such compounds, as is apparent from the context of the particular example. Thus, if a compound, e.g., compound 288, can exist as two individual stereoisomeric forms, it will be understood that the two letter designations, 288A and 288B, can be used herein to refer to the individual stereoisomeric forms. Similarly, individual diastereomers or mixtures thereof can be designated as 858A, 858B, 858C, and 858D, as will be apparent from the examples below. It will be understood that data tables presented herein, e.g., Table A, provide data associated with specific stereoisomers, where applicable, by using the designations shown in these examples. It will also be understood that, in accordance with the terminology used herein, certain compounds referred to in particular stereoisomeric forms in these examples by letter designation may find their counterparts in Table 1, where such compounds are shown by structure and name.

[0266] The following abbreviations are used throughout the examples: TEA (trimethylamine), DCM (dichloromethane), (Boc)2O (di-tert-butyl decarboxylate), EA (ethyl acetate), PE (petroleum ether, DMF (N,N-dimethylformamide), DIEA (N-ethyl-N-isopropylpropan-2-amine), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide), Hexafluorophosphate), HOAt (1-hydroxy-7-azabenzotriazole), HOBt (hydroxybenzotriazole), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), MeOH (methanol), EtOH (ethanol), IPA (iPrOH; propan-2-ol), NMP (1-methylpyrrolidin-2-one), STAB (sodium triacetoxyhydroborate), ACN (acetonitrile), TFA (trifluoroacetic acid), DPPA (diphenylphosphoryl azide), DBU (1,8-diazabicyclo(5.4.0)undec-7-ene), THF (tetrahydrofuran), PPh3 (triphenylphosphane), SM (starting material), Hex (hexane), NCS (N-chlorosuccinimide), rt (room temperature), DC E (dichloroethane), FA (formic acid), CHCl3 (chloroform), BnBr (benzyl bromide), HCl (hydrogen chloride), equiv (equivalent), RT (retention time), SFC (supercritical fluid chromatography), and DSC (bis(2,5-dioxopyrrolidin-1-yl)carbonate).

[0267] Example 1: Synthesis of Compound 288 1. Synthesis of intermediate 1-2: [ka] To a solution of methyl 2-amino-2-(4-chlorophenyl)acetate (1.5 g, 7.51 mmol, 1.0 equiv) in DCE (20 mL) at room temperature was added 4-chlorobenzaldehyde (1.05 g, 7.47 mmol, 1.00 equiv), acetic acid (900 mg, 14.99 mmol, 2.00 equiv), and STAB (2.4 g, 11.32 mmol, 1.50 equiv). The mixture was stirred at room temperature for 2 h, diluted with EA (100 mL), washed twice with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2.4 g (99%) of methyl 2-(4-chlorophenyl)-2-[[(4-chlorophenyl)methyl]amino]acetate as a brown oil.

[0268] 2. Synthesis of intermediates 1-3: [ka] To a solution of methyl 2-(4-chlorophenyl)-2-[[(4-chlorophenyl)methyl]amino]acetate (2.4 g, 7.40 mmol, 1.00 equiv.) in DCM (30 mL) at room temperature, TEA (1.5 g, 14.82 mmol, 2.00 equiv.) and 2-chloroacetyl chloride (1 g, 8.85 mmol, 1.20 equiv.) were added dropwise. The mixture was stirred at room temperature for 2 h, diluted with DCM (50 mL), washed twice with brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a silica gel column with ACN and water (3:1) to give 2 g (67%) of methyl 2-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]-2-(4-chlorophenyl)acetate as a brown oil.

[0269] 3. Synthesis of compound 288: [ka] To a solution of methyl 2-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]-2-(4-chlorophenyl)acetate (150 mg, 0.37 mmol, 1.0 equiv) in ACN (10 mL) at room temperature was added propan-2-amine (66.5 mg, 1.1 mmol, 3.0 equiv) and TEA (115 mg, 1.1 mmol, 3.0 equiv). The mixture was stirred at room temperature for 1 hour and at 80 °C for 2 hours, concentrated under reduced pressure, and purified by preparative HPLC under the following conditions (2#-Analyse HPLC-SHIMADZU (HPLC-10)): column, XBridge Shield RP18 OBD column, 5 µm, 19*150 mm; mobile phase, water (0.05% NH3HO) and ACN (48.0% to 68.0% ACN over 8 minutes); detector, UV 220 nm) to give 100 mg of 3-(4-chlorophenyl)-4-[(4-chlorophenyl)methyl]-1-(propan-2-yl)piperazine-2,5-dione. LRMS (ES) m / z 391 (M+H). 1 H NMR(DMSO-d6,300MHz)δ7.44-7.33(m,2H),7.36-7.22(m,4H),7.22-7.13(m,2H),4.95(s,1H),4.88(d,J=15.1Hz,1H),4.40(h,J= 6.9Hz,1H),4.15(d,J=17.7Hz,1H),3.98(d,J=17.8Hz,1H),3.86(d,J=15.1Hz,1H),1.07(d,J=6.8Hz,3H),0.96(d,J=6.8Hz,3H).

[0270] The following compounds were prepared by methods similar to those described for compound 288: [Table 2-1] [Table 2-2]

[0271] 4. Compound 288 Enantiomers: Separation of Enantiomers 288A and 288B [ka] Racemic compound 3-(4-chlorophenyl)-4-[(4-chlorophenyl)methyl]-1-cyclopentylpiperazine-2,5-dione (80 mg, 0.19 mmol, 1.0 equiv.) was separated by chiral HPLC under the following conditions (column: chiral ART cellulose-SB, 2*25 cm, 5 μm; mobile phase A: Hex-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 30B to 30B in 10 min; 220 / 254 nm) to give 25.4 mg (first eluting peak) of enantiomer 288A and 32 mg (second eluting peak) of enantiomer 288B. Chiral analytical data (column: chiral cellulose-SB; 0.46 cm × 15 cm; 5 micron; Hex (0.2% IP amine):EtOH = 70:30 at 1 ml / min) shows that enantiomer 288A is the first eluting peak (RT 3.3 min) and enantiomer 288B is the second eluting peak (RT 4.0 min).

[0272] Enantiomer 288A: LRMS (ES) m / z 391 (M+H). 1 H NMR(300MHz,DMSO-d6)δ7.44-7.34(m,2H),7.39-7.22(m,4H),7.27-7.13(m,2H),4.95(s,1H),4.87(d,J=15.1Hz,1H),4.39(h,J= 6.8Hz,1H),4.15(d,J=17.7Hz,1H),3.97(d,J=17.8Hz,1H),3.86(d,J=15.1Hz,1H),1.07(d,J=6.8Hz,3H),0.96(d,J=6.9Hz,3H).

[0273] Enantiomer 288B: LRMS (ES) m / z 391 (M+H). 1H NMR(300MHz,DMSO-d6)δ7.44-7.33(m,2H),7.36-7.22(m,4H),7.22-7.13(m,2H),4.95(s,1H),4.87(d,J=15.1Hz,1H),4.41(p,J= 6.8Hz,1H),4.15(d,J=17.7Hz,1H),3.97(d,J=17.8Hz,1H),3.86(d,J=15.1Hz,1H),1.07(d,J=6.8Hz,3H),0.96(d,J=6.9Hz,3H).

[0274] The following compounds were prepared by methods similar to those described for enantiomers 288A and 288B: [Table 3]

[0275] Example 2: Synthesis of Compound 20 [ka] To a solution of 5-(4-chlorobenzyl)-2-(4-fluorophenyl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione (20.5 mg, 0.049 mmol, 1.0 equiv.) in dry THF (2 mL) at -78 °C was added LHMDS (1 M in THF, 54 μL, 0.054 mmol, 1.1 equiv.). The mixture was stirred at -78 °C for 2 min, and MeI (2 M in ether, 30 μL, 0.059 mmol, 1.2 equiv.) was added to the mixture, which was stirred at -78 °C for 5 min, slowly warmed to room temperature, and diluted with water and EA. The organic layer was dried over NaSO, filtered, concentrated, and purified by silica gel chromatography (40 g column, 0-60% EtOAc in hexanes) to give 9.9 mg ( 47%) of 5-(4-chlorobenzyl)-2-(4-fluorophenyl)-8-isopropyl-7-methyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione as a white solid: LRMS (ES) m / z 430.1 (M+H). 1H-NMR (methylene chloride-d2, 400MHz, ppm) δ7.40-7.28(m,2H),7.24-7.13(m,2H),7.0 6-6.91(m,2H),6.46-6.37(m,2H),5.29(d,J=16.2Hz,1H),4.87(d,J=16.3Hz ,1H),4.72(d,J=8.6Hz,1H),4.44(Hepta,J=6.8Hz,1H),4.28-4.14(m,2H),4.0 3(dd,J=9.8,8.2Hz,2H),1.49(d,J=7.0Hz,3H),1.33(dd,J=6.9,5.0Hz,6H).

[0276] The following compounds were prepared by methods similar to those described for compound 20: [Table 4]

[0277] Example 3: Synthesis of Compound 65 1. Synthesis of intermediate 3-2 [ka] To a solution of 1-(tert-butyl) 3-methyl-3-aminoazetidine-1,3-dicarboxylate (5.0 g, 21.7 mmol, 1.0 equiv.) in MeOH (50 mL) was added 4-chlorobenzaldehyde (4.5 g, 32.6 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 1 hour. To this mixture was added NaCNBH3 (1.4 g, 21.7 mmol, 1.0 equiv.) and AcOH (1 mL). The mixture was continued to stir for 4 hours, concentrated under reduced pressure, and diluted with DCM (60 mL) and saturated aqueous sodium bicarbonate (60 mL). The aqueous layer was extracted with DCM (25 mL). The combined organic layers were dried over sodium sulfate, filtered through Celite, concentrated under reduced pressure, and purified by silica gel chromatography (80 g column, 0-100% EtOAc in hexanes) to give 6.0 g (78%) of 1-(tert-butyl)3-methyl 3-((4-chlorobenzyl)amino)azetidine-1,3-dicarboxylate. LRMS (ES) m / z 355.2 (M+H). 1H-NMR (methylene chloride-d2, 400MHz, ppm) δ7.35(s,4H),4.19(d,J=8.8Hz,2H),3.86(d,J=8.8Hz,2H),3.82(s,3H),3.68(s,2H),1.46(s,9H).

[0278] 2. Synthesis of intermediate 3-3 [ka] To a solution of 1-(tert-butyl)3-methyl 3-((4-chlorobenzyl)amino)azetidine-1,3-dicarboxylate (6.0 g, 16.9 mmol, 1.0 equiv.) in DCM (50 mL) cooled to 0 °C, TEA (7.1 mL, 50.7 mmol, 3.0 equiv.) and chloroacetyl chloride (2.7 mL, 33.8 mmol, 2.0 equiv.) were added. The ice bath was removed, and the mixture was stirred at room temperature for 3 h before being poured into saturated aqueous NH₄Cl (200 mL). The aqueous layer was extracted three times with DCM (100 mL). The combined organic layers were dried over MgSO₄ and concentrated to give the intermediate product, 1-(tert-butyl)3-methyl 3-(2-chloro-N-(4-chlorobenzyl)acetamido)azetidine-1,3-dicarboxylate. LRMS (ES) m / z 431.1 (M+H).

[0279] 3. Synthesis of intermediate 3-4 [ka] To a solution of 1-(tert-butyl)-3-methyl 3-(2-chloro-N-(4-chlorobenzyl)acetamido)azetidine-1,3-dicarboxylate (16.9 mmol, 1.0 equiv. assuming 100% yield) in ACN (300 mL) was added isopropylamine (2.9 mL, 33.9 mmol, 2.0 equiv.) and TEA (7.1 mL, 50.8 mmol, 3.0 equiv.). The mixture was heated to 80 °C for 15 h, concentrated, and purified by silica gel chromatography (80 g, 0–100% EtOAc in hexanes) to afford 6.5 g (91%) of tert-butyl 5-(4-chlorobenzyl)-8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate as a colored solid. LRMS (ES) m / z 366.1 (M+H- t Bu).

[0280] 4. Synthesis of intermediates 3-5 [ka] To a solution of tert-butyl 5-(4-chlorobenzyl)-8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate (6.5 g, 15.4 mmol, 1.0 equiv.) in DCM (40 mL) was added TFA (12 mL). The mixture was stirred at room temperature for 1 h, concentrated, diluted with saturated aqueous NaHCO (200 mL), and extracted three times with DCM. The combined organic layers were dried over MgSO, concentrated, and purified by silica gel chromatography (40 g column, 0–50% MeOH in DCM) to afford 4.1 g (83%) of 5-(4-chlorobenzyl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione as an off-white solid. LRMS (ES) m / z 322.1 (M+H). 1 H-NMR (dichloromethane-d2,400MHz,ppm)δ7.36-7.32(m,2H),7.28-7.24(m,2H),5.16(s, 2H),4.85(p,J=6.9Hz,1H),4.30-4.19(m,4H),4.00(s,2H),1.24(d,J=6.8Hz,6H).

[0281] 5. Synthesis of Compound 65 [ka] To a solution of 5-(4-chlorobenzyl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione (20 mg, 0.062 mmol, 1.0 equiv) in DCM (0.2 mL) was added DIEA (22 μL, 0.12 mmol, 2.0 equiv) and methyl isocyanate (5.0 mg, 0.093 mmol, 1.5 equiv). The mixture was stirred at room temperature for 15 h, concentrated, and purified by reverse-phase HPLC (Phenomenex, gemini 5 micron C18 150 x 21.2 mm, 10–70% acetonitrile / water over 25 min, both with 0.1% formic acid gradient) to give 8.6 mg (37%) of 5-(4-chlorobenzyl)-8-isopropyl-N-methyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxamide as a white foamy solid. LRMS (ES) m / z 379.1 (M+H). 1 H-NMR: (methanol-d4,400MHz,ppm)δ7.39-7.34(m,2H),7.32-7.27(m,2H),4.98(s,2H),4.75(hepta,J= 6.9Hz,1H),4.41-4.37(m,2H),4.08(s,2H),4.07-4.04(m,2H),2.69(s,3H),1.24(d,J=6.8Hz,6H).

[0282] The following compounds were prepared by methods similar to those described for compound 65: [Table 5]

[0283] Example 4: Synthesis of Compound 373 1. Synthesis of intermediate 4-2 [ka] To a solution of 1-tert-butyl 3-methyl 3-aminopyrrolidine-1,3-dicarboxylate (1.9 g, 7.78 mmol, 1.0 equiv.) in DCE (30 mL) at room temperature, 4-chlorobenzaldehyde (1.1 g, 7.83 mmol, 1.0 equiv.) and acetic acid (934 mg, 15.55 mmol, 2.0 equiv.) were added. The mixture was stirred at room temperature for 10 minutes. To this mixture, STAB (2.5 g, 11.80 mmol, 1.50 equiv.) was added in small portions. The mixture was continued to stir for 1.5 hours, quenched with water (20 mL), and extracted twice with DCM (20 mL). The combined organic layers were washed with aqueous NaHCO (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by reverse-phase HPLC under the following conditions: (column, C18 silica gel; mobile phase, A: water (10 mmol / L NH4HCO3), B: ACN, 65% B to 75% B gradient in 20 min; detector, UV 210 / 254 nm) to afford 2.2 g (77%) of 1-tert-butyl 3-methyl 3-[[(4-chlorophenyl)methyl]amino]pyrrolidine-1,3-dicarboxylate as a brown oil. LRMS (ES) m / z 313 (M+H-56).

[0284] 2. Synthesis of intermediate 4-3 [ka] 3-[[(4-chlorophenyl)methyl]amine in DCM (30 mL) cooled to 0 °C To a solution of 1-tert-butyl 3-methyl 3-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]pyrrolidine-1,3-dicarboxylate (2.28 g, 6.18 mmol, 1.0 equiv.), 2-chloroacetyl chloride (3.12 g, 27.62 mmol, 4.50 equiv.) and TEA (5.63 g, 55.64 mmol, 9.00 equiv.) were added. The mixture was stirred overnight at room temperature, quenched with water (20 mL), and extracted twice with DCM (20 mL). The combined organic layers were washed twice with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2.9 g of 1-tert-butyl 3-methyl 3-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]pyrrolidine-1,3-dicarboxylate as a brown oil. LRMS (ES) m / z 389 (M+H −56).

[0285] 3. Synthesis of intermediate 4-4 [ka] To a solution of 1-tert-butyl 3-methyl 3-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]pyrrolidine-1,3-dicarboxylate (2.9 g, 6.51 mmol, 1.0 equiv.) in ACN (30 mL) at room temperature was added propan-2-amine (1.9 g, 32.14 mmol, 5.00 equiv.) and TEA (5.3 g, 8.00 equiv.). The mixture was stirred at room temperature for 1 hour and then heated to 80° C. overnight. The next day, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by reverse-phase HPLC using the following conditions: column, C18 silica gel; mobile phase, A: water (10 mmol / L NH4HCO3), B: ACN, 20% B to 25% B gradient in 20 min; detector, UV 210 / 254 nm to give 2.4 g (85%) of tert-butyl 6-[(4-chlorophenyl)methyl]-7,10-dioxo-9-(propan-2-yl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate as a brown solid. LRMS (ES) m / z 380 (M+H-56).

[0286] 4. Synthesis of intermediate 4-5 [ka] To a solution of tert-butyl 6-[(4-chlorophenyl)methyl]-7,10-dioxo-9-(propan-2-yl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate (2.4 g, 5.51 mmol, 1.0 equiv.) in DCM (30 mL) at room temperature, TFA (8 mL) was added. The mixture was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 9 with sodium hydroxide (6 N, approximately 3 mL). The mixture was diluted with water and washed with DCM (20 mL). The combined organic layers were washed twice with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.7 g (92%) of 6-[(4-chlorophenyl)methyl]-9-(propan-2-yl)-2,6,9-triazaspiro[4.5]decane-7,10-dione as a brown solid. LRMS (ES) m / z 336 (M+H).

[0287] 5. Synthesis of Compound 373 [ka] To a solution of 2-bromopyridine (200 mg, 1.27 mmol, 1.0 equiv) in dioxane (5 mL) was added 6-[(4-chlorophenyl)methyl]-9-(propan-2-yl)-2,6,9-triazaspiro[4.5]decane-7,10-dione (94 mg, 0.28 mmol, 1.0 equiv), Pd(dba)CHCl (62 mg, 0.06 mmol, 0.10 equiv), Xphos (57 mg, 0.12 mmol, 0.20 equiv), and CsCO (389 mg, 1.19 mmol, 2.0 equiv) under nitrogen. The mixture was stirred at 90°C overnight, cooled to room temperature, filtered to remove solids, and purified under the following conditions (2#-Analyse HPLC-SHIMADZU (HPLC-10)): column, XBridge preparative C18 OBD column, 5µm, 19*150mm; mobile phase, water (10mmol / L NH4HCO3), and ACN (39.0% to 53.0% ACN gradient over 8 min); detector, UV 254 nm, to give 15 mg (6%) of 6-[(4-chlorophenyl)methyl]-9-(propan-2-yl)-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane-7,10-dione as a white solid. LRMS (ES) m / z 413 (M+H). 1 H-NMR: (300MHz, methanol-d4, ppm): δ8.01-7.93(m, 1H), 7.50(ddd, J=8.9, 7.2, 1.9H z,1H),7.28-7.19(m,2H),7.10(d,J=8.4Hz,2H),6.61(dd,J=6.9,5.2Hz,1H),6.41 (d,J=8.6Hz,1H),4.76-4.54(m,3H),4.16(s,2H),3.97(d,J=11.9Hz,1H),3.75(d, J=11.8Hz,1H),3.66-3.42(m,2H),2.62-2.38(m,2H),1.20(dd,J=6.8,1.4Hz,6H).

[0288] 6. Separation of Compound 373 Enantiomers [ka] Racemic compound 6-[(4-chlorophenyl)methyl]-9-(propan-2-yl)-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane-7,10-dione (80 mg, 0.19 mmol, 1.0 equiv.) was separated by chiral HPLC under the following conditions (Preparative HPLC-009): Column: Chiralpak IC, 2*25 cm, 5 μm; Mobile Phase A: Hex-HPLC, Mobile Phase B: EtOH-HPLC; Flow Rate: 15 mL / min; Isocratic Elution 21 min; 220 / 254 nm) to give 28.7 mg (36%, first peak) of enantiomer 373A and 29 mg (second peak) of enantiomer 373B as white solids. Chiral analysis data (Chiralpak IC-3; 0.46 cm × 5 cm; 3 μm; 55:45 Hex (0.1% DEA):EtOH at 1 ml / min) showed that enantiomer 373A was the first eluting peak (RT 2.2 min) and enantiomer 373B was the second eluting peak (RT 3.2 min). Enantiomer 373A: LRMS (ES) m / z 413 (M+H). 1 H-NMR: (300MHz, methanol-d4, ppm) δ7.97(ddd,J=5.2,1.9,0.9Hz,1H),7.50(ddd,J=8.8,7.1 ,1.9Hz,1H),7.28-7.18(m,2H),7.10(d,J=8.4Hz,2H),6.61(ddd,J=7.2,5.1,0.9Hz,1H),6 .41(d,J=8.6Hz,1H),4.86(s,1H),4.76-4.54(m,2H),4.15(s,2H),3.97(d,J=11.8Hz,1H), 3.75(d,J=11.8Hz,1H),3.66-3.42(m,2H),2.62-2.38(m,2H),1.20(dd,J=6.8,1.4Hz,6H).

[0289] Enantiomer 373B: LRMS (ES) m / z 413 (M+H). 1H NMR:(300MHz,methanol-d4)δ8.01-7.93(m, 1H),7.50(ddd,J=8.8,7.2,1.9Hz,1H), 7.28-7.18(m,2H),7.10(d,J=8.3Hz,2H),6.61(dd,J=6.9,5.4Hz,1H),6.41(d,J =8.5Hz,1H),4.76-4.54(m,2H),4.16(s,2H),3.97(d,J=11.8Hz,1H),3.75(d,J= 11.8Hz,1H),3.66-3.42(m,2H),2.62-2.38(m,2H),1.20(dd,J=6.9,1.4Hz,6H).

[0290] The following compounds were prepared by methods similar to those described for compound 373: [Table 6-1] [Table 6-2]

[0291] Example 5: Synthesis of Compound 108 1. Synthesis of intermediate 5-2 [ka] To a solution of 3-amino-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (7.0 g, 30.4 mmol, 1.0 equiv.) in MeOH (80 mL) was added 4-(trifluoromethyl)benzaldehyde (5.6 g, 31.9 mmol, 1.05 equiv.). The mixture was stirred at room temperature for 1 h, and then NaCNBH3 (2.9 g, 45.6 mmol, 1.5 equiv.) and AcOH (0.5 mL) were added and stirred for 2 h. 1-(tert-butoxycarbonyl)-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine The mixture containing benzophenone-3-carboxylic acid was used directly in the next step. LRMS (ES) m / z 389.2(M+H).

[0292] 2. Synthesis of intermediate 5-3 [ka] To a solution containing 1-(tert-butoxycarbonyl)-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylic acid (30.4 mmol, 1.0 equiv.) from the previous reaction was added DCM (100 mL) and (trimethylsilyl)diazomethane (2 M in hexanes, 45.6 mL, 91.1 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 3 h, added AcOH (5.0 g), concentrated onto silica (30 g), and purified by silica gel chromatography (120 g, 0–100% EtOAc in hexanes) to afford 7.4 g (61% over steps) of 1-(tert-butyl)3-methyl 3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-1,3-dicarboxylate as a white solid. LRMS (ES) m / z 403.2 (M+H).

[0293] 3. Synthesis of intermediate 5-4 [ka] To a solution of 1-(tert-butyl)3-methyl 3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-1,3-dicarboxylate (7.4 g, 18.4 mmol, 1.0 equiv.) in DCM (50 mL) cooled to 0 °C, TEA (7.7 mL, 84.9 mmol, 3.0 equiv.) and chloroacetyl chloride (2.9 mL, 36.8 mmol, 2.0 equiv.) were added. The ice bath was removed, and the mixture was stirred at room temperature for 3 h before being poured into saturated aqueous NH4Cl (200 mL). The aqueous layer was extracted three times with DCM (100 mL). The combined organic layers were dried over MgSO4 and concentrated to give the intermediate product, 1-(tert-butyl)3-methyl 3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine-1,3-dicarboxylate. LRMS(ES) m / z 379.1 (M+H-Boc).

[0294] 4. Synthesis of Intermediate 5-5 [ka] To a solution of 1-(tert-butyl)-3-methyl 3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine-1,3-dicarboxylate (18.4 mmol, 1.0 equiv. assuming 100% yield) in ACN (300 mL) was added isopropylamine (4.7 mL, 55.1 mmol, 3.0 equiv.) and TEA (7.7 mL, 55.1 mmol, 3.0 equiv.). The mixture was heated at 80 °C for 15 h, concentrated, and purified by silica gel chromatography (80 g, 0–100% EtOAc in hexanes) to afford an intermediate mixture containing tert-butyl 9-isopropyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate. LRMS (ES) m / z 414.2 (M+H- t Bu).

[0295] 5. Synthesis of intermediate 5-6 [ka] To a solution of tert-butyl 9-isopropyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate (18.4 mmol, 1.0 equiv.) in DCM (40 mL) was added TFA (20 mL). The mixture was stirred at room temperature for 1 h, concentrated, diluted with saturated aqueous NaHCO (200 mL), and extracted three times with DCM. The combined organic layers were dried over MgSO, filtered, concentrated, and purified by silica gel chromatography (40 g column, 0–50% MeOH in DCM with 1% TEA) to afford 2.8 g (41% over three steps) of 9-isopropyl-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione as a solid. LRMS(ES) m / z 370.2(M+H). 1H-NMR (dichloromethane-d2,400MHz,ppm)δ7.65-7.60(m,2H),7.39-7.33(m,2H),4.93 -4.65(m,3H),4.02(s,2H),3.46-3.40(m,1H),3.16(ddd,J=11.3,8.2,5.3Hz,1 H),3.00(ddd,J=11.3,8.1,6.7Hz,1H),2.92(d,J=12.1Hz,1H),2.45(ddd,J=13 .6,8.3,6.7Hz,1H),1.98(ddd,J=13.5,8.0,5.2Hz,1H),1.23(d,J=6.8Hz,6H).

[0296] 6. Synthesis of Compound 108 [ka] To a solution of 9-isopropyl-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione (50 mg, 0.14 mmol, 1.0 equiv) in DCM (2 mL) was added TEA (27 mg, 0.27 mmol, 2.0 equiv) and methyl isocyanate (15 mg, 0.27 mmol, 2.0 equiv). The mixture was stirred at room temperature for 30 min, concentrated, and purified by reverse-phase HPLC (Phenomenex, gemini 5 micron C18 150 x 21.2 mm, 10 to 100% acetonitrile / water over 40 min, both with 0.1% formic acid gradient) to give 49 mg (85%) of 9-isopropyl-N-methyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxamide as a white foamy solid. LRMS (ES) m / z 327.2 (M+H). 1H-NMR (methanol-d4,400MHz,ppm)δ7.67-7.62(m,2H),7.43-7.36(m,2H),4.95(d,J=17.0Hz,1H),4.79-4.65(m,2H),4.18(d,J=2.1Hz, 2H),3.95(d,J=11.7Hz,1H),3.59(d,J=11.7Hz,1H),3.52-3.43(m,2H),2.69(s,3H),2.49-2.33(m,2H),1.24(dd,J=6.8,1.3Hz,6H).

[0297] The following compounds were prepared by methods similar to those described for compound 108: [Table 7-1] [Table 7-2]

[0298] Example 6: Synthesis of Compound 76 1. Synthesis of intermediate 6-2 [ka] To a solution of 3-amino-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (7.0 g, 30.4 mmol, 1.0 equiv.) in MeOH (80 mL) was added 4-(trifluoromethyl)benzaldehyde (5.6 g, 31.9 mmol, 1.05 equiv.), and the mixture was stirred at room temperature for 1 h. To this mixture was added NaCNBH (2.9 g, 45.6 mmol, 1.5 equiv.) and AcOH (0.5 mL). The mixture was stirred at room temperature for 2 h to give a solution containing 1-(tert-butoxycarbonyl)-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylic acid, which was used in the next reaction without workup. LRMS (ES) m / z 389.2 (M+H).

[0299] 2. Synthesis of intermediate 6-3 [ka] To a solution containing 1-(tert-butoxycarbonyl)-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylic acid (30.4 mmol, 1.0 equiv.) from the previous step was added DCM (100 mL) and (trimethylsilyl)diazomethane (2 M in hexanes, 45.6 mL, 91.1 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 3 h, quenched with AcOH (5 g), concentrated onto 30 g SiO. Purification by silica gel chromatography (120 g, 0-100% EtOAc in hexanes) gave 7.4 g (61% over two steps) of 1-(tert-butyl)3-methyl 3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-1,3-dicarboxylate as a white solid: LRMS (ES) m / z 403.15 (M+H).

[0300] 3. Synthesis of intermediate 6-4 [ka] To a solution of 1-(tert-butyl)3-methyl 3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-1,3-dicarboxylate (7.4 g, 18.4 mmol, 1.0 equiv.) in DCM (50 mL) at 0 °C was added TEA (7.7 mL, 84.9 mmol, 3.0 equiv.) and chloroacetyl chloride (2.9 mL, 36.8 mmol, 2.0 equiv.). The ice bath was removed, and the mixture was stirred at room temperature for 3 h. The reaction was poured into saturated aqueous NH4Cl (200 mL) solution, and the layers were separated. The aqueous layer was extracted three times with DCM (100 mL). The combined organic layers were dried over MgSO4 and concentrated to give the intermediate product, 1-(tert-butyl)3-methyl 3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine-1,3-dicarboxylate. LRMS(ES) m / z 379.1 (M+H-Boc).

[0301] 4. Synthesis of intermediate 6-5 [ka] To a solution of 1-(tert-butyl)3-methyl 3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine-1,3-dicarboxylate (18.4 mmol, 1.0 equiv. assuming 100% yield) in ACN (300 mL) was added isopropylamine (4.7 mL, 55.1 mmol, 3.0 equiv.) and TEA (7.7 mL, 55.1 mmol, 3.0 equiv.). The mixture was heated at 80 °C for 15 h, concentrated, and purified by silica gel chromatography (80 g, 0–100% EtOAc in hexanes) to give the intermediate product, tert-butyl 9-isopropyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate, as a colorless solid. LRMS (ES) m / z 414.15 (M+H- t Bu).

[0302] 5. Synthesis of intermediate 6-6 [ka] To a solution of tert-butyl 9-isopropyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate (18.4 mmol, 1.0 equiv.) from the previous step in DCM (40 mL) was added TFA (20 mL). The mixture was stirred at room temperature for 1 h, concentrated, diluted with saturated NaHCO (200 mL), and extracted three times with DCM. The combined organic layers were dried over MgSO, filtered, concentrated, and purified by silica gel chromatography (40 g column, 0–50% MeOH in DCM with 1% TEA) to afford 2.8 g (41% over three steps) of 9-isopropyl-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione as a dark sticky solid. LRMS(ES) m / z 370.2(M+H). 1H-NMR (dichloromethane-d2,400MHz,ppm)δ7.65-7.60(m,2H),7.39-7.33(m,2H),4.93 -4.65(m,3H),4.02(s,2H),3.46-3.40(m,1H),3.16(ddd,J=11.3,8.2,5.3Hz,1 H),3.00(ddd,J=11.3,8.1,6.7Hz,1H),2.92(d,J=12.1Hz,1H),2.45(ddd,J=13 .6,8.3,6.7Hz,1H),1.98(ddd,J=13.5,8.0,5.2Hz,1H),1.23(d,J=6.8Hz,6H).

[0303] 6. Synthesis of Compound 76 [ka] To a mixture of 9-isopropyl-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione (50 mg, 0.14 mmol, 1.0 equiv.), potassium tert-butoxide (61 mg, 0.54 mmol, 4.0 equiv.), Pd(dba) (12 mg, 0.014 mmol, 0.1 equiv.), and Xantphos (16 mg, 0.027 mmol, 0.2 equiv.) combined in a 5 mL microwave vial (5 mL) was added 4-bromopyridin-2(1H)-one (47 mg, 0.27 mmol, 2.0 equiv.) and dioxane (2 mL). The mixture was sealed and heated to 150°C in a microwave reactor for 30 min, filtered, and purified by reverse-phase HPLC (Phenomenex, gemini 5µm C18 150 x 21.2mm, 10-100% acetonitrile / water over 40 min, both with 0.1% formic acid gradient) to give 4.8 mg (8%) of the product. 9-Isopropyl-2-(2-oxo-1,2-dihydropyridin-4-yl)-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione was obtained as a foamy solid. LRMS (ES) m / z 463.2 (M+H). 1H-NMR (methanol-d4, 400MHz, ppm) δ 8.18 (s, 1H), 7.62 (d, J = 8.1Hz, 2H), 7.41-7.36 (m, 2H), 7.20 (d, J = 7.4Hz, 1H), 5.88 (dd, J = 7.4, 2.4Hz, 1H), 5.30 (d, J = 2.4Hz, 1H), 4.99 ( d,J=16.9Hz,1H),4.79-4.68(m,2H),4.23(d,J=2.0Hz,2H),3.88(d,J=11.8Hz,1H), 3.66(d,J=11.7Hz,1H),3.57-3.49(m,2H),2.67-2.46(m,2H),1.26(d,J=6.8Hz,6H).

[0304] The following compounds were prepared by methods similar to those described for compound 76: [Table 8-1] [Table 8-2]

[0305] Example 7: Synthesis of Compound 49 1. Synthesis of intermediate 7-2 [ka] To a solution of 1-(tert-butyl)3-methyl-3-aminoazetidine-1,3-dicarboxylic acid (5.0 g, 21.7 mmol, 1.0 equiv.) in MeOH (50 mL) was added 4-chlorobenzaldehyde (4.5 g, 32.6 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 1 hour. To the mixture was added NaCNBH3 (1.4 g, 21.7 mmol, 1.0 equiv.) and AcOH (1 mL). The mixture was continued to stir for 4 hours, concentrated under reduced pressure, and partitioned between DCM (60 mL) and saturated sodium bicarbonate (60 mL). The layers were separated, and the aqueous phase was extracted with DCM (25 mL). The combined organic layers were dried over sodium sulfate, filtered through Celite, concentrated under reduced pressure, and purified by silica gel chromatography (80 g column, 0-100% EtOAc in hexanes) to give 6.0 g (78%) of 1-(tert-butyl)3-methyl 3-((4-chlorobenzyl)amino)azetidine-1,3-dicarboxylate. LRMS (ES) m / z 355.2 (M+H). 1 H-NMR (methylene chloride-d2, 400MHz, ppm) δ7.35(s,4H),4.19(d,J=8.8Hz,2H),3.86(d,J=8.8Hz,2H),3.82(s,3H),3.68(s,2H),1.46(s,9H).

[0306] 2. Synthesis of intermediate 7-3 [ka] To a solution of 1-(tert-butyl)3-methyl 3-((4-chlorobenzyl)amino)azetidine-1,3-dicarboxylate (6.0 g, 16.9 mmol, 1.0 equiv.) in DCM (50 mL) cooled to 0 °C, TEA (7.1 mL, 50.7 mmol, 3.0 equiv.) and chloroacetyl chloride (2.7 mL, 33.8 mmol, 2.0 equiv.) were added. The mixture was stirred at room temperature for 3 h and poured into saturated aqueous NH₄Cl (200 mL) solution. The aqueous layer was extracted three times with DCM (100 mL). The combined organic layers were dried over MgSO₄ and concentrated to give the intermediate product, 1-(tert-butyl)3-methyl 3-(2-chloro-N-(4-chlorobenzyl)acetamido)azetidine-1,3-dicarboxylate. LRMS (ES) m / z 431.1 (M+H).

[0307] 3. Synthesis of intermediate 7-4 [ka] To a solution of 1-(tert-butyl)-3-methyl 3-(2-chloro-N-(4-chlorobenzyl)acetamido)azetidine-1,3-dicarboxylate (16.9 mmol, 1.0 equiv.) in ACN (300 mL) was added isopropylamine (2.9 mL, 33.9 mmol, 2.0 equiv.) and TEA (7.1 mL, 50.8 mmol, 3.0 equiv.). The mixture was heated at 80 °C for 15 h, cooled to room temperature, concentrated, and purified by silica gel chromatography (80 g, 0 to 100% EtOAc in hexanes) to afford 6.5 g (91%) of tert-butyl 5-(4-chlorobenzyl)-8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate as a colorless solid. LRMS (ES) m / z 366.1 (M+H- t Bu).

[0308] 4. Synthesis of intermediate 7-5 [ka] tert-Butyl 5-(4-chlorobenzyl)-8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate in DCM (40 mL) To a solution of 5-(4-chlorobenzyl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione (6.5 g, 15.4 mmol, 1.0 equiv.) was added TFA (12 mL). The mixture was stirred at room temperature for 1 h, concentrated, diluted with saturated NaHCO3 (200 mL), and extracted three times with DCM. The combined organic layers were dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (40 g column, 0–50% MeOH in DCM) to afford 4.1 g (83%) of 5-(4-chlorobenzyl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione as an off-white solid. LRMS (ES) m / z 322.1 (M+H). 1 H-NMR (dichloromethane-d2,400MHz,ppm)δ7.36-7.32(m,2H),7.28-7.24(m,2H),5.16(s, 2H),4.85(p,J=6.9Hz,1H),4.30-4.19(m,4H),4.00(s,2H),1.24(d,J=6.8Hz,6H).

[0309] 5. Synthesis of Compound 49 [ka] To a mixture of 5-(4-chlorobenzyl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione (50 mg, 0.16 mmol, 1.0 equiv), potassium tert-butoxide (70 mg, 0.62 mmol, 4.0 equiv), Pd(dba) (7 mg, 0.008 mmol, 0.05 equiv), and Xantphos (9 mg, 0.016 mmol, 0.1 equiv) combined in a microwave vial (5 mL) was added 4-bromo-2,6-dimethylpyridine (58 mg, 0.31 mmol, 2.0 equiv) and dioxane (2 mL). The mixture was sealed and heated to 150 °C in a microwave reactor for 10 min, filtered, and purified by reverse-phase HPLC (Phenomenex, gemini 5 μm C18 150 × 21.2 mm, 10–100% acetonitrile / water over 40 min, both with 0.1% formic acid gradient) to give 7.1 mg (10%) of 5-(4-chlorobenzyl)-2-(2,6-dimethylpyridin-4-yl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione as a white foamy solid. LRMS (ES) m / z 427.15 (M+H). 1 H-NMR (methylene chloride-d2, 400MHz, ppm) δ7.42-7.33(m,2H),7.24-7.17(m,2H),6.07(s,2H),4.95(s,2H),4.84(p,J=6.9H) z,1H),4.62(dd,J=9.5,1.1Hz,2H),4.25(dd,J=9.5,1.1Hz,2H),4.06(s,2H),2.57(s,6H),1.25(d,J=6.8Hz,6H).

[0310] The following compounds were prepared by methods similar to those described for compound 49: [Table 9-1] [Table 9-2]

[0311] Example 8: Synthesis of Compound 142 1. Synthesis of intermediate 8-2 [ka] A mixture of azetin-3-ol hydrochloride (1.3 g, 11.9 mmol, 1.0 equiv.), L(-)-pyrroline (0.55 g, 4.8 mmol, 0.4 equiv.), copper(I) iodide (0.45 g, 2.4 mmol, 0.2 equiv.), and cesium carbonate (9.7 g, 29.7 mmol, 2.5 equiv.) was combined in a septum-capped flask and purged with nitrogen three times under vacuum. To this vessel was added iodobenzene (2.0 mL, 18 mmol, 1.5 equiv.). and dry DMSO (30 mL) were added. The mixture was heated at 90°C for 15 h, diluted with water, and extracted three times with EA. The combined organic layers were dried over magnesium sulfate, filtered, evaporated, and purified by silica gel chromatography (40 g, 60.5 μm, 0-100% ethyl acetate / hexanes gradient over 14 min) to give 1.6 g (90%) of 1-phenylazetidin-3-ol as a clear, colorless oil. LRMS (ES) m / z 150 (M+H). 1 H NMR (400MHz, methylene chloride-d2) δ7.27-7.20(m,2H),6.81-6.74(m,1H),6.55-6.49(m,2H),4.80-4.72(m,1H),4.23-4.16(m,2H),3.71-3.65(m,2H).

[0312] 2. Synthesis of intermediate 8-3 [ka] To a solution of oxalyl chloride (1.5 mL, 17 mmol, 1.7 equiv) in dry DCM (15 mL) was added DMSO (2.4 mL, 34 mmol, 3.3 equiv) dropwise at −78° C. The mixture was stirred at −78° C. for 10 minutes, and then 1-phenylazetidin-3-ol (1.5 g, 10.3 mmol, 1.0 equiv) in dry DCM (15 mL) was added dropwise and stirred for 1 hour. To this mixture at −78° C. was added TEA (10.0 mL, 71.9 mmol, 7.0 equiv). The mixture was continued to stir at −78° C. for 1 hour, diluted with saturated sodium bicarbonate, and extracted three times with DCM. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, evaporated, and purified by silica gel chromatography (40 g, 60 um, 0-10% ethyl acetate / hexanes gradient over 28 min) to give 0.96 g (63%) of 1-phenylazetidin-3-one as a clear yellow oil. LRMS (ES) m / z 148 (M+H). 1 H NMR (400MHz, methylene chloride-d2) δ7.36-7.29(m,2H),6.92-6.87(m,1H),6.69-6.63(m,2H),4.70(s,4H).

[0313] 3. Synthesis of intermediate 8-4 [ka] 1-Phenylazetidin-3-one (0.31 g, 2.1 mmol, 1.0 equiv) and (1S)-1-[4-(trifluoromethyl)phenyl]ethan-1-amine (0.44 g, 2.3 mmol, 1.1 equiv) were combined in dry MeOH (3 mL), and the mixture was heated at 60° C. for 1 h. To this mixture, cooled to 0° C., were added acetic acid (0.13 mL, 2.3 mmol, 1.1 equiv) and sodium cyanide (0.11 g, 2.3 mmol, 1.1 equiv) sequentially. The mixture was heated at 60° C. for 15 h, diluted with water, and extracted three times with EA. The combined organic layers were dried over magnesium sulfate, filtered, evaporated, and purified by silica gel chromatography (12 g, 60 μm, 0-20% ethyl acetate / hexanes gradient over 22 min) to afford 0.46 g (62%) of (S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carbonitrile as a clear, colorless oil. LRMS (ES) m / z 346 (M+H). 1 H NMR (400MHz, methylene chloride-d2) δ7.69-7.65(m,2H),7.64-7.59(m,2H),7.26-7.19(m,2H),6.85-6.79(m,1H),6.42-6.38(m,2H), 4.38-4.35(m,1H),4.26(q,J=6.6Hz,1H),3.92-3.88(m,1H),3.83-3.79(m,1H),3.38-3.34(m,1H),1.48(d,J=6.6Hz,3H).

[0314] 4. Synthesis of intermediate 8-5 [ka] To a solution of (S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carbonitrile (0.20 g, 0.58 mmol, 1.0 equiv) in dry MeOH (2 mL) was added aqueous sodium hydroxide (1 N, 1.2 mL, 1.2 mmol, 2.0 equiv). The mixture was heated at 100° C. for 15 h, cooled to room temperature, neutralized with HCl (1 M, 1.2 mL, 1.2 mmol, 2.0 equiv), and extracted twice with EA. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 89 mg (42%) of (S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carboxylic acid as a pale yellow solid.

[0315] 5. Synthesis of intermediate 8-6 [ka] To a solution of (S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carboxylic acid (89 mg, 0.24 mmol, 1.0 equiv.) in a mixture of DCM (1 mL) and methanol (1 mL) was added (trimethylsilyl)diazomethane in hexanes (2 M, 0.37 mL, 0.74 mmol, 3.0 equiv.) dropwise. The mixture was stirred at room temperature for 2 hours, concentrated, and purified by silica gel chromatography (12 g, 60 micron, 0-30% ethyl acetate / hexanes gradient over 22 minutes). Obtained 79 mg (86%) of methyl (S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carboxylate as a clear, colorless oil. LRMS (ES) m / z 379 (M+H).

[0316] 6. Synthesis of intermediate 8-7 [ka] To a solution of (S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carboxylate (79 mg, 0.21 mmol, 1.0 equiv.) in DCM (1 mL) was added TEA (0.18 mL, 1.2 mmol, 6.0 equiv.) and chloroacetyl chloride (0.067 mL, 0.84 mmol, 4.0 equiv.) dropwise. The mixture was stirred at room temperature for 30 minutes, diluted with saturated sodium bicarbonate, and extracted with DCM. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 140 mg of (S)-3-(2-chloro-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamido)-1-phenylazetidine-3-carboxylate as a red oil. LRMS (ES) m / z 455 (M+H).

[0317] 7. Synthesis of Compound 142 [ka] To a solution of (S)-methyl 3-(2-chloro-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamido)-1-phenylazetidine-3-carboxylate (0.21 mmol, 1.0 equiv) in dry ACN (7.5 mL) was added triethylamine (0.13 mL, 0.94 mmol, 4.5 equiv) and isopropylamine (0.053 mL, 0.62 mmol, 3.0 equiv). The mixture was heated at 80 °C for 15 h, concentrated, and purified by reverse-phase HPLC (Phenomenex, gemini 5 micron C18 150 x 21.2 mm, 10 to 100% acetonitrile / water over 25 min, both with 0.1% formic acid gradient) to give 19 mg (20% over two steps) of (S)-8-isopropyl-2-phenyl-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione. LRMS (ES) m / z 446 (M+H). 1 H NMR (400 MHz, methanol-d4) δ 7.67-7.62 (m, 2H), 7.60-7.55 (m, 2H), 7.22-7.16 (m, 2H), 6. 79-6.73(m,1H),6.49-6.44(m,2H),5.74-5.65(m,1H),4.73(Hepta,J=6.8Hz,1H),4.46-4.41(m,1H),4.37-4.32 (m,1H),4.27-4.21(m,1H),4.13-4.09(m,1H),4.07-3.96(m,2H),2.01(d,J=7.0Hz,3H),1.23(d,J=6.8Hz,6H).

[0318] The following compounds were prepared by methods similar to those described for compound 142: [Table 10]

[0319] Example 9: Synthesis of Compound 327 1. Synthesis of intermediate 9-2 [ka] To a solution of 1-phenyl-2-oxo-3-pyrrolidinecarboxylic acid (0.95 g, 4.6 mmol, 1.0 equiv) in a mixture of DCM (10 mL) and MeOH (10 mL) cooled to 0 °C was added (trimethylsilyl)diazomethane in hexanes (2 M, 7.0 mL, 14 mmol, 3.0 equiv) dropwise. The mixture was stirred at room temperature for 30 min, concentrated, and purified by silica gel chromatography (24 g, 0-10% ethyl acetate / hexanes gradient over 11.5 min) to afford 1.02 g (100%) of methyl 2-oxo-1-phenylpyrrolidine-3-carboxylate as a white solid. LRMS (ES) m / z 220 (M+H). 1 H NMR (400MHz, methylene chloride-d2) δ7.66-7.61(m,2H),7.45-7.38(m,2H),7.25-7.19(m,1H),4.02-3.95( m,1H),3.91-3.84(m,1H),3.81(s,3H),3.68-3.63(m,1H),2.59-2.50(m,1H),2.48-2.38(m,1H).

[0320] 2. Synthesis of intermediate 9-3 [ka] To a mixture of methyl 2-oxo-1-phenylpyrrolidine-3-carboxylate (0.30 g, 1.4 mmol, 1.0 equiv.) and ytterbium(III) trifluoromethanesulfonate (0.255 g, 0.41 mmol, 0.30 equiv.) in EA (9 mL) was added NBS (0.244 g, 1.4 mmol, 1.0 equiv) was added. The mixture was stirred at room temperature for 30 min, concentrated, and purified by silica gel chromatography (24 g, 0-30% ethyl acetate / hexanes gradient over 11.5 min) to afford 408 mg (100%) of 3-bromo-2-oxo-1-phenylpyrrolidine-3-carboxylic acid as a white solid. LRMS (ES) m / z 298 (M+H). 1H NMR (400MHz, methylene chloride-d2) δ7.68-7.62(m,2H),7.48-7.42(m,2H),7.30-7.24(m,1 H),4.04-3.97(m,1H),3.94-3.88(m,4H),3.19-3.10(m,1H),2.72-2.64(m,1H).

[0321] 3. Synthesis of intermediate 9-4 [ka] To a solution of 3-bromo-2-oxo-1-phenylpyrrolidine-3-carboxylic acid (0.113 g, 0.38 mmol, 1.0 equiv) in DMF (1 mL) was added TEA (0.21 mL, 1.5 mmol, 4.0 equiv) and 4-(trifluoromethyl)benzylamine (0.11 mL, 0.76 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 min, heated at 50° C. for 1 h, diluted with water, and extracted three times with EA. The combined organic extracts were washed once with brine, dried over magnesium sulfate, filtered, concentrated, purified by silica gel chromatography (12 g, 60 um, 0-40% ethyl acetate / hexanes gradient over 22 min), and repurified by silica gel chromatography (12 g, 60 um, 0-30% ethyl acetate / hexanes gradient over 22 min) to afford 24 mg (16%) of methyl 2-oxo-1-phenyl-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylate as a clear, colorless oil. LRMS (ES) m / z 393 (M+H). 1 H NMR (400MHz, methylene chloride-d2) δ7.59-7.54(m,2H),7.54-7.49(m,2H),7.49-7.44(m,2H),7.35-7.29(m,2 H),7.15-7.09(m,1H),3.95-3.84(m,2H),3.81-3.69(m,5H),2.68-2.61(m,1H),2.24-2.14(m,1H).

[0322] 4. Synthesis of intermediate 9-5 [ka] To a solution of methyl 2-oxo-1-phenyl-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylate (0.024 g, 0.061 mmol, 1.0 equiv) in DCM (1 mL) was added TEA (0.051 mL, 0.36 mmol, 6.0 equiv) and chloroacetyl chloride (0.022 mL, 0.24 mmol, 4.0 equiv). The mixture was stirred for 15 min. To this mixture was added two more portions of TEA (0.051 mL, 0.36 mmol, 6.0 equiv) and chloroacetyl chloride (0.022 mL, 0.24 mmol, 4.0 equiv). The mixture was stirred for 15 min, diluted with dichloroethane (2 mL), heated at 83 °C overnight, cooled to room temperature, diluted with saturated sodium bicarbonate, and extracted three times with DCM. The combined organic extracts were then washed once with brine, dried over magnesium sulfate, filtered, and concentrated to give 29 mg (quantitative) of methyl 3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-2-oxo-1-phenylpyrrolidine-3-carboxylate as a brown solid. LRMS (ES) m / z 469 (M+H).

[0323] 5. Synthesis of Compound 327 [ka] To a solution of methyl 3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-2-oxo-1-phenylpyrrolidine-3-carboxylate (29 mg, 0.079 mmol, 1.0 equiv) in ACN (4 mL) was added TEA (0.067 mL, 0.48 mmol, 7.8 equiv) and isopropylamine (0.027 mL, 0.32 mmol, 6.3 equiv). The mixture was heated at 80 °C for 1 h, concentrated, and purified by reverse-phase HPLC (Phenomenex, Gemini 5 micron C18 150 x 21.2 mm, 10 to 100% acetonitrile / water over 25 min, both with 0.1% formic acid gradient) to give 15 mg (20%) of 9-isopropyl-2-phenyl-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-1,7,10-trione as a clear, colorless oil. LRMS (ES) m / z 460 (M+H).1 H NMR (400MHz, methanol-d4) δ7.64-7.59(m,2H),7.57-7.53(m,2H),7.53-7.49(m,2H),7.42-7.36(m,2H),7.27-7.21(m,1H),4.99-4.92(m,1) H),4.76-4.67(m,2H),4.33-4.16(m,2H),4.16-4.08(m,1H),3.87-3.78(m,1H),2.86-2.77(m,1H),2.59-2.48(m,1H),1.28-1.20(m,6H).

[0324] Example 10: Synthesis of Compound 328 1. Synthesis of intermediate 10-2 [ka] Azetin-3-ol hydrochloride (1.3 g, 11.9 mmol, 1.0 equiv.), L(-)-pyrroline (0.55 g, 4.8 mmol, 0.4 equiv.), copper(I) iodide (0.45 g, 2.4 mmol, 0.2 equiv.), and cesium carbonate (9.7 g, 29.7 mmol, 2.5 equiv.) were combined in a septum-capped flask and purged with nitrogen three times under vacuum. To the vessel was added iodobenzene (2.0 mL, 18 mmol, 1.5 equiv.) and dry dimethyl sulfoxide (30 mL). The mixture was heated at 90 °C for 15 h, diluted with water, and extracted three times with EA. The combined organic layers were dried over magnesium sulfate, filtered, evaporated, and purified by silica gel chromatography (40 g, 60 μm, 0-100% ethyl acetate / hexanes gradient over 14 min) to give 1.6 g (90%) of 1-phenylazetidin-3-ol as a clear, colorless oil. LRMS (ES) m / z 150 (M+H). 1 H NMR (400MHz, methylene chloride-d2) δ7.27-7.20(m,2H),6.81-6.74(m,1H),6.55-6.49(m,2H),4.80-4.72(m,1H),4.23-4.16(m,2H),3.71-3.65(m,2H).

[0325] 2. Synthesis of intermediate 10-3 [ka] To a solution of oxalyl chloride (1.5 mL, 17 mmol, 1.7 equiv) in dry DCM (15 mL) was added DMSO (2.4 mL, 34 mmol, 3.3 equiv) dropwise at −78° C. The mixture was stirred at −78° C. for 10 min, 1-phenylazetidin-3-ol (1.5 g, 10.3 mmol, 1.0 equiv) in dry DCM (15 mL) was added dropwise and stirred for 1 h, TEA (10.0 mL, 71.9 mmol, 7.0 equiv) was added, stirring was continued at −78° C. for 1 h, diluted with saturated sodium bicarbonate, and extracted three times with DCM. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, evaporated, and purified by silica gel chromatography (40 g, 60 um, 0-10% ethyl acetate / hexanes gradient over 28 min) to give 0.96 g (63%) of 1-phenylazetidin-3-one as a clear yellow oil. LRMS (ES) m / z 148 (M+H). 1 H NMR (400MHz, methylene chloride-d2) δ7.36-7.29(m,2H),6.92-6.87(m,1H),6.69-6.63(m,2H),4.70(s,4H).

[0326] 3. Synthesis of intermediate 10-4 [ka] 1-Phenylazetidin-3-one (0.31 g, 2.1 mmol, 1.0 equiv) and (1S)-1-[4-(trifluoromethyl)phenyl]ethan-1-amine (0.44 g, 2.3 mmol, 1.1 equiv) were combined in dry MeOH (3 mL), and the mixture was heated at 60° C. for 1 h. To this mixture, cooled to 0° C., were added acetic acid (0.13 mL, 2.3 mmol, 1.1 equiv) and sodium cyanide (0.11 g, 2.3 mmol, 1.1 equiv) sequentially. The mixture was heated at 60° C. for 15 h, diluted with water, and extracted three times with EA. The combined organic layers were dried over magnesium sulfate, filtered, evaporated, and purified by silica gel chromatography (12 g, 60 um, 0-20% ethyl acetate / hexanes gradient over 22 min) to afford 0.46 g (62%) of (S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carbonitrile as a clear, colorless oil. LRMS (ES) m / z 346 (M+H). 1 H NMR (400MHz, methylene chloride-d2) δ7.69-7.65(m,2H),7.64-7.59(m,2H),7.26-7.19(m,2H),6.85-6.79(m,1H),6.42-6.38(m,2H), 4.38-4.35(m,1H),4.26(q,J=6.6Hz,1H),3.92-3.88(m,1H),3.83-3.79(m,1H),3.38-3.34(m,1H),1.48(d,J=6.6Hz,3H).

[0327] 4. Synthesis of intermediate 10-5 [ka] To a solution of (S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carbonitrile (0.272 g, 0.787 mmol, 1.0 equiv) in DCM (3 mL) was added TEA (0.33 mL, 2.4 mmol, 3.0 equiv) and chloroacetyl chloride (0.12 mL, 1.6 mmol, 2.0 equiv) dropwise. The mixture was stirred for 15 min. To this mixture was added TEA (0.33 mL, 2.4 mmol, 3.0 equiv) and chloroacetyl chloride (0.12 mL, 1.6 mmol, 2.0 equiv). The mixture was stirred for 30 min, diluted with saturated sodium bicarbonate, and extracted twice with DCM. The combined extracts were dried over magnesium sulfate, filtered, and concentrated to give 332 mg (100%) of (S)-2-chloro-N-(3-cyano-1-phenylazetidin-3-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide as a red oil. LRMS (ES) m / z 422 (M+H). 1 H NMR (400 MHz, methylene chloride-d2) δ 7.72-7.67 (m, 2H), 7.59-7. 54(m,2H),7.28-7.21(m,2H),6.89-6.84(m,1H),6.45-6.41(m,2H),5.19-5.11(m,1H),4.49- 4.45(m,1H),4.42-4.39(m,1H),4.07-3.94(m,3H),3.83-3.79(m,1H),1.96(d,J=7.1Hz,3H).

[0328] 5. Synthesis of intermediate 10-6 [ka] To a solution of (S)-2-chloro-N-(3-cyano-1-phenylazetidin-3-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide (0.332 g, 0.787 mmol, 1.0 equiv) in dry DCM (3 mL) was added isopropylamine (3.4 mL, 39 mmol, 50 equiv). The mixture was stirred at room temperature for 3 days, concentrated, and purified by silica gel chromatography (12 g, 60 μm, 0-10% methanol / dichloromethane gradient over 22 min) to afford 314 mg (90%) of (S)-N-(3-cyano-1-phenylazetidin-3-yl)-2-(isopropylamino)-N-(1-(4-(trifluoromethyl)phenyl)ethyl). The acetamide was obtained as a clear pale yellow oil: LRMS (ES) m / z 445 (M+H). 1 H NMR (400MHz, methylene chloride-d2) δ7.64-7.60(m,2H),7.43-7.38(m,2H),7.24-7.1 8(m,2H),6.82-6.77(m,1H),6.43-6.39(m,2H),5.90-5.80(m,1H),4.60-4 .46(m,1H),4.41-4.35(m,1H),4.30-4.21(m,1H),4.07-3.99(m,2H),3.90 -3.83(m,1H),3.79-3.73(m,1H),1.87(d,J=7.2Hz,3H),1.28-1.21(m,6H).

[0329] 6. Synthesis of Compound 328 [ka] A solution of (S)-N-(3-cyano-1-phenylazetidin-3-yl)-2-(isopropylamino)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide (54 mg, 0.12 mmol, 1.0 equiv.) in dry toluene (0.5 mL) was heated to 150° C. in a microwave reactor for 30 min. The mixture was concentrated and analyzed by reverse-phase HPLC ( Purification on a Phenomenex Gemini 5 micron C18 150 x 21.2 mm column (10-100% acetonitrile / water over 25 min, both with 0.1% formic acid gradient) gave 28 mg (52%) of (S)-9-imino-8-isopropyl-2-phenyl-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonan-6-one as a clear, colorless oil. LRMS (ES) m / z 445 (M+H). 1 H NMR (400MHz, methanol-d4) δ8.38(s,1H),7.69-7.63(m,2H),7.56-7.50(m,2H),7.25-7.19(m,2H),6.89-6.82(m,1H),6 .56-6.48(m,2H),5.73-5.61(m,1H),4.54-4.45(m,2H),4.32-4.14(m,5H),1.86(d,J=7.1Hz,3H),1.46-1.39(m,6H).

[0330] Example 11: Synthesis of Compound 332 1. Synthesis of intermediate 11-2 [ka] To a solution of racemic 3-amino-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.00 g, 8.69 mmol) in NaOH (1 M, 15 mL) was added di-tert-butyl dicarbonate (3.79 g, 17.37 mmol, 2.0 equiv.) in 1,4-dioxane (15 mL). The resulting mixture was stirred at room temperature for 18 h. The pH was adjusted to 3 using 3 M aqueous HCl, and the resulting mixture was extracted twice with EA (total volume = 125 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 1-(tert-butoxycarbonyl)-3-((tert-butoxycarbonyl)amino)pyrrolidine-3-carboxylic acid (2.93 g, 7.98 mmol, 92% yield) as a sticky foam, which was used in the following step without further purification. LRMS(APCI)m / z 329.1(MH). 1H NMR(400MHz,DMSO-d6)δ12.68(s,1H),7.54(s,1H),3.74-3.66(m,1H),3.51( dd,J=20.3, 11.4Hz,1H),3.34-3.26(m,2H),2.21-2.04(m,2H),1.39(s,18H).

[0331] 2. Synthesis of intermediate 11-3 [ka] To a solution of 1-(tert-butoxycarbonyl)-3-((tert-butoxycarbonyl)amino)pyrrolidine-3-carboxylic acid (2.93 g, 7.98 mmol) in a mixture of DCM (40 mL) and MeOH (20 mL) was added (diazomethyl)trimethylsilane (11.97 mL of 2.0 M in hexanes, 23.95 mmol, 3.0 equiv.) in small portions. The resulting solution was stirred at room temperature for 30 min, quenched with glacial acetic acid (1 mL) until gas evolution ceased, and concentrated under reduced pressure. The remaining residue was dissolved in DCM (100 mL) and washed with 2 M aqueous K2CO3 (25 mL). The organic phase was dried over sodium sulfate and concentrated. Purification on silica gel with 30% EA / Hex gave 2.12 g (77%) of 1-(tert-butyl)3-methyl 3-((tert-butoxycarbonyl)amino)pyrrolidine-1,3-dicarboxylate as a colorless sticky solid. LRMS (APCI) m / z 245.2 (M+H) (Boc loss). 1 H NMR (400 MHz, methanol-d₄) δ 3.84–3.75 (m, 1H), 3.64 (s, 3H), 3.57–3.44 (m, 1H), 3.43–3.30 (m, 2H), 2.24–2.13 (m, 1H), 2.12–2.02 (m, 1H), 1.41–1....

Claims

1. Compound of formula (1b-3) 【Chemistry 393】 or a salt thereof, comprising the steps of: (i) Compound of formula (1b-1) 【Chem.382】 or a salt thereof, 【Chemistry 383】 or a salt thereof It encompasses During the ceremony R １ is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted pyridyl; R ５ is H or substituted or unsubstituted alkyl; n is 1 or 2; and Alk １ is unsubstituted methyl or ethyl; method.

2. Compound of formula (1b-10) 【Chem. 394】 or a salt thereof, comprising the steps of: (i) Compound of formula (1b-1) 【Chemical 395】 or a salt thereof, 【Chemistry 396】 or a salt thereof to give a compound of formula (1b-3) 【Chemistry 397】 or a salt thereof, and (ii) converting the compound of formula (1b-3) or a salt thereof into a compound of formula (1b-10) or a salt thereof It encompasses wherein step (ii) is (ii-a) The compound of formula (1b-3) or a salt thereof is reacted with a compound of formula (1b-4) 【Chem.398】 or a salt thereof to give a compound of formula (1b-5) 【Chem.399】 or a salt thereof; (ii-c) Reacting the compound of formula (1b-5) or a salt thereof with a compound of formula (1b-6) 【Chemical 400】 or a salt thereof to give a compound of formula (1b-7) 【Chemical 401】 or a salt thereof; (ii-e) Reacting the compound of formula (1b-7) or a salt thereof with an acid to obtain a compound of formula (1b-8) 【Chemical 402】 or a salt thereof; and (ii-f) converting the compound of formula (1b-8) or a salt thereof into a compound of formula (1b-10) or a salt thereof It encompasses During the ceremony, R １ is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted pyridyl; R ２ａ is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted aminothionyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, substituted or unsubstituted alkyl, substituted or unsubstituted pyridin-one-yl, substituted or unsubstituted 9-membered bicyclic heterocyclyl, and hydroxyl; R ３ is unsubstituted C ２ -C ６ selected from the group consisting of alkyl, alkoxy, cyano, or halo-substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ４ is H or unsubstituted alkyl; R ５ is H or substituted or unsubstituted alkyl; n is 1 or 2; and Alk １ is unsubstituted methyl or ethyl; method.

3. R ３ is unsubstituted C ２ -C ６ 3. The method of claim 2, wherein the aryl is selected from the group consisting of alkyl, alkoxy, cyano, or halo-substituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl.

4. R ３ 4. The method of claim 2 or 3, wherein is cycloalkyl substituted with one or more substituents selected from the group consisting of alkyl, cyano, and halo.

5. R ２ａ is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl.

6. R ２ａ The method according to any one of claims 2 to 5, wherein is acyl substituted with methyl.

7. R １ is phenyl or pyridinyl, each of which is substituted with one or more substituents independently selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl.

8. R ４ The method of any one of claims 2 to 7, wherein is H.

9. R ５ The method of any one of claims 1 to 8, wherein is H.

10. The method of any one of claims 1 to 9, wherein n is 1.

11. The method according to any one of claims 1 to 10, wherein the reaction in step (i) is carried out in the presence of a borohydride reagent.

12. 12. The method of claim 11, wherein the borohydride reagent is sodium triacetoxyborohydride (STAB).

13. The method according to claim 2, wherein the reaction in step (ii-c) is carried out at a temperature of 80°C or higher.

14. The method according to claim 2 or 13, wherein the reaction in step (ii-c) is carried out at a temperature of 110°C or higher.

15. The method of claim 2 , wherein the acid is TFA.

16. The method according to claim 2 or 15, wherein step (ii-f) comprises (ii-g) reacting the compound of formula (1b-8) or a salt thereof with a compound of formula (1b-9) 【Chemical 390】 or a salt thereof to form a compound of formula (1b-10) or a salt thereof, wherein X is a suitable leaving group and R 2a is as defined in claim 2.

17. Compound of formula (1b-7) 【Chemistry 391】 or a salt thereof, wherein R １ is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted pyridyl; R ３ is unsubstituted C ２ -C ６ selected from the group consisting of alkyl, alkoxy, cyano, or halo-substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ４ is H or unsubstituted alkyl; R ５ is H or substituted or unsubstituted alkyl; and A compound or a salt thereof, wherein n is 1 or 2.

18. Compound of formula (1b-8) 【Chemistry 392】 or a salt thereof, wherein R １ is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted pyridyl; R ３ is unsubstituted C ２ -C ６ selected from the group consisting of alkyl, alkoxy, cyano, or halo-substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ４ is H or unsubstituted alkyl; R ５ is H or substituted or unsubstituted alkyl; and A compound or a salt thereof, wherein n is 1 or 2.

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