AKT3 Modulators

Abstract

Compounds of formula Ia, Ib, or Ic are described and the various substituents are defined herein. TIFF2024540107000788.tif76139 The compounds can modulate the properties or effects of Akt3 in vitro or in vivo, and can also be used individually or in combination with other agents in the prevention or treatment of various conditions. Methods for synthesizing the compounds are described. Pharmaceutical compositions and methods for using these compounds or compositions individually or in combination with other agents or compositions in the prevention or treatment of various conditions are also described.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 276,218, filed November 5, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] Incorporation by Reference Any patents, patent publications, scientific publications or other documents cited herein are expressly incorporated herein by reference in their entirety.

[0003] The present invention relates generally to Akt3 modulators and methods for treating and preventing disease by modulating Akt3 signaling. [Background technology]

[0004] Chronic illnesses and diseases are long-lasting conditions that require ongoing medical attention and usually negatively impact a patient's quality of life. Chronic diseases are the leading cause of disability and death in the United States. Common chronic diseases include, but are not limited to, heart disease, cancer, neurodegenerative diseases, diabetes, obesity, eating disorders, and arthritis. It is estimated that 6 in 10 adults in the United States have a chronic disease, and 4 in 10 have two or more chronic diseases. Chronic diseases are also the leading cause of annual health care costs in the United States, amounting to $3.3 trillion (see "About Chronic Disease," National Center for Chronic Disease Prevention, Centers for Disease Control and Prevention; updated October 23, 2019). These statistics highlight the need for new and improved treatments and preventative interventions for diseases such as cancer, inflammatory diseases, neurodegenerative diseases, pathogenic infections, immunodeficiency disorders, weight gain disorders, weight loss disorders, hormone imbalances, tuberous sclerosis, retinitis pigmentosa, and congestive heart failure.

[0005] Neurodegenerative diseases are debilitating conditions characterized by the progressive degeneration and death of nerve cells, also called neurons. Neurons are components of the nervous system and do not normally self-replenish after injury or death. In patients with neurodegenerative diseases, the loss or dysfunction of neurons can affect physical movement and brain function. Neurodegenerative diseases include, but are not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, multiple sclerosis, prion disease, motor neuron disease, spinocerebellar degeneration, and spinal muscular atrophy. The symptoms of advanced neurodegenerative diseases can be severe, causing patients to lose memory, motor control, and personality. Existing treatments for neurodegenerative diseases can address symptoms but generally cannot prevent or cure the disease. These existing treatments usually have negative side effects that further deteriorate patients' quality of life.

[0006] A serious complication of chronic diseases, such as neurodegenerative diseases and cancer, is cachexia, also known as wasting syndrome. Cachexia is defined as a loss of more than 5% of body weight in 12 months or less in the presence of a chronic disease. Other symptoms of cachexia include muscle atrophy, fatigue, weakness, and often loss of appetite. Weight loss associated with cachexia is due to loss of not only fat but also muscle mass. Patients with cachexia often lose weight even if they eat a normal diet. There is currently no effective treatment for cachexia, which is the cause of death associated with many chronic diseases, such as neurodegenerative diseases. Summary of the Invention [Problem to be solved by the invention]

[0007] Thus, there is an unmet need for more effective and acceptable therapeutic and prophylactic interventions for these diseases and other diseases and complications associated with these diseases. [Means for solving the problem]

[0008] As used herein, Akt3 is a RAC-gammaserine / threonine-protein kinase, an enzyme that in humans is encoded by the Akt3 gene. In one embodiment, the Akt3 protein is represented by Formula Ia, Ib, or Ic. [ka] or a salt thereof, wherein the various substituents are defined herein. In certain embodiments, the compounds can modulate the properties or effects of Akt3 in vitro or in vivo and / or can be used, individually or in combination with other agents, in the prevention or treatment of various conditions. In other embodiments, methods for synthesizing the compounds are provided. In another aspect, pharmaceutical compositions comprising the compounds and methods for using these compositions, individually or in combination with other agents or compositions, in the prevention or treatment of various conditions are also described herein.

[0009] In one embodiment, a compound of formula Ia, Ib or Ic [ka] [During the ceremony, [ka] teeth, [ka] each occurrence of X1, X2, X3, X4, X5, X6, X7, X8, and X9 is independently CR1 or N; Each occurrence of R is independently selected from H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C4-C 14 )tricycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 14 ) heterotricycloalkyl, (C4-C 10 ) heterospiroalkyl, (C3-C7) cycloalkenyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 14 ) tricycloalkenyl, (C4-C 14 ) Heterotricycloalkenyl, aryl, heteroaryl, -ORa, -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] and one or more of (C1-C6) alkyl, halogenated (C1-C6) alkyl, -SO2R a or -SO2N(R a ) a partially saturated bicyclic heteroaryl optionally substituted with 2; R1 is (C3-C7)cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C4-C 14 )tricycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 14 ) heterotricycloalkyl, (C4-C 10 ) heterospiroalkyl, (C3-C7) cycloalkenyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 14 ) tricycloalkenyl, (C4-C 14 ) Heterotricycloalkenyl, aryl and heteroaryl are each selected from the group consisting of one or more of (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2, each of which is appropriately replaced, n is an integer of 0 to 4 allowed by the valence; Q is C(R a )2, O, NR a , N(C=O)R a or NSO2R a and Y1, Y2, Y3, Y4, and Y5 are each independently N or CR2, as allowed by valence; R2 is H, halogen, D, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C10 )bicycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] is selected from the group consisting of -EG- is -(C=O)NR x -, -NR x (C=O)-, -N(R x )(C=O)N(R x )-, -O(C=O)N(R x )-, -N(R x )(C=O)O-, -SO2NR x -, -NR x SO2- or [ka] and R x Each occurrence of is independently H, (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl or R x and Y3, R x and Y4, R x and Z1, or R x and Z4 together, one or more R z and R z each occurrence is independently H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen, or two R ztogether form a 4- to 6-membered ring optionally substituted with halogen or (C1-C6) alkyl; W1, W2, W3, W4 and W5 are each independently CR6, N or NR6, as allowed by valences; each occurrence of R6 is independently selected from the group consisting of H, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl; Each occurrence of T is independently O, N, NR as allowed by valence. a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a and Each occurrence of U may independently be O, N, or NR as allowed by valence. a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a and R b each occurrence is independently H or (C1-C6) alkyl; Z1, Z2, Z3, Z4, and Z5 are each independently N or CR3, as allowed by valences; R3 is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl, heteroaryl, -ORa, -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(Ra )2, -N(R a )SO2R a , [ka] is selected from the group consisting of V is absent or C(R a )2, NR a , N(C=O)R a , NSO2R a or O, R4 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) selected from the group consisting of heterospiroalkyl, aryl, and heteroaryl, each of which is optionally substituted with one or more R5; or alternatively, V and R4 together represent (C3-C7)heterocycloalkyl or (C4-C 10 ) forming a heterospiroalkyl, Each occurrence of R5 is independently selected from H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2Ra , N(R a )COR a [ka] is selected from the group consisting of R a each occurrence is independently H, (C1-C6) alkyl, (C2-C6) alkenyl, (C3-C7) cycloalkyl, aryl, or heteroaryl, or two R a together form a 4- to 6-membered ring optionally substituted with halogen or (C1-C6) alkyl. or a pharmaceutically acceptable salt thereof is described.

[0010] In any one of the embodiments disclosed herein, Q, T, and U are each independently, as allowed by valences, O, NH, NCH, N(C=O)H, N(C=O)CH, N(C=O)CHCH, NSOCH, or NSOCHCH. In any one of the embodiments disclosed herein, T and U are each independently, as allowed by valences, O, N, NH, NCH, N(C=O)H, N(C=O)CH, N(C=O)CHCH, NSOCH, or NSOCHCH.

[0011] In any one of the embodiments disclosed herein, X1, X2, X3, X4, X5, X6, X7, X8, X9, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4 and Z5 are each independently CH, C (halogen) or N.

[0012] In any one of the embodiments disclosed herein, [ka] teeth, [ka] is.

[0013] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0014] In any one of the embodiments disclosed herein, n is 0, 1, or 2.

[0015] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0016] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0017] In any one of the embodiments disclosed herein, [ka] teeth, [ka] is.

[0018] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0019] In any one of the embodiments disclosed herein, n is 0, 1, or 2.

[0020] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] [ka] It has the following structure.

[0021] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0022] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0023] In any one of the embodiments disclosed herein, [ka] teeth, [ka] is.

[0024] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0025] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0026] In any one of the embodiments disclosed herein, Q is O.

[0027] In any one of the embodiments disclosed herein, Q is NR a , N(C=O)R a or NSO2R a is.

[0028] In any one of the embodiments disclosed herein, each occurrence of R is independently selected from H, D, halogen, OR a , N(R a )2, (C1-C6) alkyl, (C1-C6) alkynyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, (C4-C 10 ) Bicycloalkyl, -CN, -NC, N3, NO2, CORa , CO2R a , CON(R a )2, -SO2R a or -SO2N(R a ), wherein the (C3-C7)heterocycloalkyl is optionally substituted with one or more (C1-C6)alkyl.

[0029] In any one of the embodiments disclosed herein, each occurrence of R is independently selected from H, halogen, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, N(R a )2 or —CN, and the (C3-C7)heterocycloalkyl is optionally substituted with one or more (C1-C6)alkyl.

[0030] In any one of the embodiments disclosed herein, each occurrence of R is independently H, halogen, (C1-C6)alkyl, (C1-C6)alkyl, halogenated (C3-C7)heterocycloalkyl, or (C3-C7)heterocycloalkyl, wherein the (C3-C7)heterocycloalkyl is optionally substituted with one or more (C1-C6)alkyl.

[0031] In any one of the embodiments disclosed herein, each occurrence of R is independently H, D, F, Cl, Br, CH, OCH, NH, NHCH, N(CH), [ka] -CN, -NC, N3, NO2, [ka] is.

[0032] In any one of the embodiments disclosed herein, each occurrence of R is independently H, D, F, CH, NH, NHCH, N(CH), [ka] is.

[0033] In any one of the embodiments disclosed herein, at least one occurrence of R is [ka] is.

[0034] In any one of the embodiments disclosed herein, at least one occurrence of R is [ka] and X is CR 15 , O, N.R. 14 or S, and each occurrence of R is independently H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2 and R 14 is H, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, aryl, or heteroaryl, and R 15 each occurrence is independently selected from H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2 and q is 0, 1, 2 or 3.

[0035] In any one of the embodiments disclosed herein, X is O.

[0036] In any one of the embodiments disclosed herein, each occurrence of R9 is independently H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, or halogen.

[0037] In any one of the embodiments disclosed herein, each occurrence of R9 is independently H, F, Cl, Br, CH3, CF3, OH, NH2, -NHCH3, or -N(CH3)2.

[0038] In any one of the embodiments disclosed herein, each occurrence of R9 is independently H, F, Cl, Br, or CH3.

[0039] In any one of the embodiments disclosed herein, R 15 Each occurrence of is independently H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, or halogen.

[0040] In any one of the embodiments disclosed herein, R 15 Each occurrence of is independently H, F, Cl, Br, or CH3.

[0041] In any one of the embodiments disclosed herein, q is 0.

[0042] In any one of the embodiments disclosed herein, q is 1.

[0043] In any one of the embodiments disclosed herein, q is 2 or 3.

[0044] In any one of the embodiments disclosed herein, X is NR 14 and R 14 is H or (C1-C6) alkyl.

[0045] In any one of the embodiments disclosed herein, at least one occurrence of R is [ka] and X is O or NR 14 and R 14 is H or (C1-C6) alkyl.

[0046] In any one of the embodiments disclosed herein, at least one occurrence of R is [ka] is.

[0047] In any one of the embodiments disclosed herein, [ka] teeth, [ka] and R 12 is (C3-C7) cycloalkenyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 14 ) tricycloalkenyl or (C4-C 14 ) heterotricycloalkenyl, each of which may be selected from one or more of (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2 as appropriate.

[0048] In any one of the embodiments disclosed herein, R 12 teeth, [ka] and X is CR 15 , O, N.R. 14 or S, and each occurrence of R is independently H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2 and R 14 is H, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, aryl, or heteroaryl, and R 15 each occurrence is independently selected from H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a)2 and q is 0, 1, 2 or 3.

[0049] In any one of the embodiments disclosed herein, R 12 teeth, [ka] and X is O or NR 14 and R 14 is H or (C1-C6) alkyl.

[0050] In any one of the embodiments disclosed herein, R 12 teeth, [ka] is.

[0051] In any one of the embodiments disclosed herein, [ka] teeth, [ka] is.

[0052] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] [ka] [ka] wherein Q is O or NH.

[0053] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] [ka] [ka] [ka] wherein Q is O or NH.

[0054] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] wherein Q is O or NH, and R1 is H, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, halogenated (C3-C7) heterocycloalkyl, or halogen.

[0055] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] wherein Q is O or NH.

[0056] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] wherein Q is O or NH.

[0057] In any one of the embodiments disclosed herein, the compound has the formula of Formula Ia:

[0058] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0059] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0060] In any one of the embodiments disclosed herein, each occurrence of R2 is independently H, halogen, CH3, CF3, OH, NH2, -NHCH3, or -N(CH3)2.

[0061] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has a structure.

[0062] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0063] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0064] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0065] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0066] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0067] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0068] In any one of the embodiments disclosed herein, each occurrence of R3 is H, halogen, CH3, CF3, OH, NH2, -NHCH3, or -N(CH3)2.

[0069] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0070] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] wherein R3 is H, CH3, OH, halogen, or NH2, and R x is H, CH3 or CH2CH3.

[0071] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] wherein each occurrence of m is independently 1 or 2, and J is C(R y )2 and R y each occurrence is independently H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen, or any two R y The groups, together with the carbon atom(s) to which they are attached, form a (C3-C7)cycloalkyl or a (C3-C7)heterocycloalkyl.

[0072] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] [ka] wherein Y1, Y2, Y3, and Y4 are each independently N, CH, CCH3, or CF.

[0073] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka]

[0074] wherein each occurrence of m is independently 1 or 2, and J is C(R z )2 and R z each occurrence is independently H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen, or any two R zThe groups, together with the carbon atom(s) to which they are attached, form a (C3-C7)cycloalkyl or a (C3-C7)heterocycloalkyl.

[0075] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] wherein Z1, Z2, Z3, and Z4 are each independently N, CH, CCH3, or CF.

[0076] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0077] In any one of the embodiments disclosed herein, the compound has the formula of Formula Ib:

[0078] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] wherein each occurrence of T and U is independently O, N, NR, as allowed by valence. a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a is.

[0079] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] wherein R3 is H, CH3, OH, halogen, or NH2, and R a is H, CH3 or CH2CH3.

[0080] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0081] In any one of the embodiments disclosed herein, R b Each occurrence of is independently H or (C1-C6) alkyl.

[0082] In any one of the embodiments disclosed herein, R b Each occurrence is independently H, CH3, CH2CH3, or CH(CH3)2.

[0083] In any one of the embodiments disclosed herein, the compound has the formula of Formula Ic:

[0084] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] wherein each occurrence of T and U is independently O, N, NR, as allowed by valence. a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a is.

[0085] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] wherein R2 is H, CH3, OH, halogen, or NH2, and R a is H, CH3 or CH2CH3.

[0086] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0087] In any one of the embodiments disclosed herein, R b Each occurrence of is independently H or (C1-C6) alkyl.

[0088] In any one of the embodiments disclosed herein, R b Each occurrence is independently H, CH3, CH2CH3, or CH(CH3)2.

[0089] In any one of the embodiments disclosed herein, each occurrence of R2 is independently H, CH3, OH, NH2, or halogen.

[0090] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0091] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0092] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0093] In any one of the embodiments disclosed herein, the structural moiety [ka] V and R4 together form (C4~C 10 ) forming a heterospiroalkyl.

[0094] In any one of the embodiments disclosed herein, V is absent.

[0095] In any one of the embodiments disclosed herein, R4 is (C1-C6) alkyl, [ka] and m is an integer of 0 to 3.

[0096] In any one of the embodiments disclosed herein, each occurrence of R5 is independently selected from H, (C1-C6) alkyl, halogen, OR a , OH, NH2, N(R a )COR a , CN, CF3, (C1-C6) haloalkyl or [ka] and R a Each occurrence of is independently H, (C2-C6)alkenyl, or (C1-C6)alkyl.

[0097] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] V has the structure of C(R a )2, O, NR a , N(C=O)R a or NSO2R a and V' is CR a Or N.

[0098] In any one of the embodiments disclosed herein, each occurrence of R5 is independently H, CH3, halogen, OH, CN, [ka] CF3, (C1-C6)haloalkyl or NH2.

[0099] In any one of the embodiments disclosed herein, R a Each occurrence of is independently H, (C2-C6)alkenyl, or (C1-C6)alkyl.

[0100] In any one of the embodiments disclosed herein, R a Each occurrence of is H, CH3, or CH2CH3.

[0101] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0102] In any one of the embodiments disclosed herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0103] In any one of the embodiments disclosed herein, the compound of formula Ia is [ka] [ka] and R1 is H, (C1-C6) alkyl, N(R a )2, (C3-C7)heterocycloalkyl or halogen, and R5 and R 11 are each independently H or CH; Y, Y, Y, Y, Z, Z, Z, L, and L are each independently CH or N; and V is NH or O.

[0104] In any one of the embodiments disclosed herein, R1 is H, F, Cl, Br, CH3, CH2CH3, CH(CH3)2, NH2, NMe2, [ka] is.

[0105] In any one of the embodiments disclosed herein, the compound of formula Ib has the structure [ka] and R 11 and R5 are each independently H or CH3, and Y1, Y2, Y3, Y4, Z2, Z3 and Z4 are each independently CH or N.

[0106] In any one of the embodiments disclosed herein, the compound of formula Ib has the structure [ka] and R1, R5 and R 11 are each independently H, halogen, or CH3, and Y1, Y2, Y3, Y4, Z2, Z3, and Z4 are each independently CH or N.

[0107] In any one of the embodiments disclosed herein, the compound of formula Ic has the structure [ka] and R1, R5 and R 11 are each independently H, halogen, or CH3, and Y1, Y2, Y4, Z1, Z2, Z3, and Z4 are each independently CH or N.

[0108] In any one of the embodiments disclosed herein, the compound of formula Ia is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is.

[0109] In any one of the embodiments disclosed herein, the compound of formula Ib is [ka] [ka] [ka] is.

[0110] In any one of the embodiments disclosed herein, the compound of formula Ic is [ka] is.

[0111] In any one of the embodiments disclosed herein, the compound is [ka] is.

[0112] In any one of the embodiments disclosed herein, the compound is [ka] is.

[0113] In any one of the embodiments disclosed herein, the compound is selected from the group consisting of compounds 2-45 in Examples 2-45, respectively.

[0114] In another aspect, a method of treating a disease in a subject in need thereof is described, comprising administering to the subject an effective amount of a compound of any one of the embodiments disclosed herein.

[0115] In any one of the embodiments described herein, the disease is selected from the group consisting of neurodegenerative diseases, cachexia, anorexia, obesity, complications of obesity, inflammatory diseases, virally induced inflammatory responses, Gulf War syndrome, tuberous sclerosis, retinitis pigmentosa, transplant rejection, cancer, autoimmune diseases, ischemic tissue injury, traumatic tissue injury, and combinations thereof.

[0116] In any one of the embodiments described herein, the disease is a neurodegenerative disease.

[0117] In any one of the embodiments described herein, the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, motor neuron disease, Huntington's disease, HIV-induced neurodegeneration, Lewy body disease, spinal muscular atrophy, prion disease, spinocerebellar degeneration, familial amyloid polyneuropathy, multiple sclerosis, and combinations thereof.

[0118] In any one of the embodiments described herein, the disease is cachexia or anorexia.

[0119] In any one of the embodiments described herein, the disease is obesity or a complication of obesity.

[0120] In any one of the embodiments described herein, the complication of obesity is selected from the group consisting of impaired glucose tolerance, fatty liver, dyslipidemia, and combinations thereof.

[0121] In any one of the embodiments described herein, the disease is an inflammatory disease.

[0122] In any one of the embodiments described herein, the inflammatory disease is selected from the group consisting of atopic dermatitis, allergies, asthma, and combinations thereof.

[0123] In any one of the embodiments described herein, the disease is a virus-induced inflammatory response.

[0124] In any one of the embodiments described herein, the virus-induced inflammatory response is SARS-induced inflammatory pneumonia, coronavirus disease 2019, or a combination thereof.

[0125] In any one of the embodiments described herein, the disease is Gulf War syndrome or tuberous sclerosis complex.

[0126] In any one of the embodiments described herein, the disease is retinitis pigmentosa or graft rejection.

[0127] In any one of the embodiments described herein, the disease is ischemic tissue injury or traumatic tissue injury.

[0128] In any one of the embodiments described herein, the disease is cancer.

[0129] In any one of the embodiments described herein, the cancer is selected from the group consisting of adult T-cell leukemia / lymphoma, bladder, brain, breast, cervical, colorectal, esophageal, kidney, liver, lung, nasopharyngeal, pancreatic, prostate, skin, stomach, uterine, ovarian, and testicular cancer.

[0130] In any one of the embodiments described herein, the cancer is leukemia.

[0131] In any one of the embodiments described herein, the leukemia is adult T-cell leukemia / lymphoma.

[0132] In any one of the embodiments described herein, the adult T-cell leukemia / lymphoma is caused by a human T-cell lymphotropic virus.

[0133] In any one of the embodiments described herein, the disease is an autoimmune disease.

[0134] In any one of the embodiments described herein, the autoimmune disease is selected from the group consisting of achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-renal glomerular basement membrane disease, anti-tubular basement membrane antibody nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy, Barrow's disease, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease, celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multiple osteomyelitis, Churg-Strauss syndrome, eosinophilic granulomatosis, cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie-myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Eva Symptoms include: fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, herpes gestationis, hidradenitis suppurativa (acne suppurativa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki disease, Ran's disease, Bart-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear IgA disease, lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Muscha-Haberman disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular pemphigoid, optic neuritis, relapsing rheumatoid arthritis, pediatric autoimmune neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, pars planitis (peripheral uveitis),Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs impotence syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-body syndrome, subacute bacterial endocarditis, Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and combinations thereof.

[0135] In any one of the embodiments described herein, the compound modulates Akt3 in immune cells.

[0136] In any one of the embodiments described herein, the immune cell is selected from the group consisting of a T cell, a B cell, a macrophage, and a glial cell.

[0137] In any one of the embodiments described herein, the glial cells are astrocytes, microglia, or oligodendrocytes.

[0138] In any one of the embodiments described herein, the T cells are regulatory T cells.

[0139] In any one of the embodiments described herein, the compound activates Akt3 signaling.

[0140] In any one of the embodiments described herein, the compound inhibits Akt3 signaling.

[0141] In any one of the embodiments described herein, the compound increases the activity or production of regulatory T cells.

[0142] In any one of the embodiments described herein, the compound reduces the activity or production of regulatory T cells.

[0143] In any one of the embodiments described herein, the method further comprises administering a second therapeutic agent to the subject.

[0144] In any one of the embodiments described herein, the second therapeutic agent is selected from the group consisting of a nutritional supplement, a chemotherapeutic agent, an anti-inflammatory agent, an immunosuppressant, a cholinesterase inhibitor, an antidepressant, an anxiolytic, an antipsychotic, riluzole, edavarone, a dopamine agonist, an MAO B inhibitor, a catechol O-methyltransferase inhibitor, an anticholinergic, an anticonvulsant, tetrabenazine, carbidopa-levodopa, an antispasmodic, an antibody, a fusion protein, an enzyme, a nucleic acid, a ribonucleic acid, an antiproliferative agent, a cytotoxic agent, an appetite stimulant, a 5-HT3 antagonist, a Cox-2 inhibitor, and combinations thereof.

[0145] In any one of the embodiments described herein, the method further comprises treating the subject with an immunotherapeutic agent, an immune modulator, a costimulatory activating agonist, a cytokine, a chemokine, a chemokine factor, an oncolytic virus, a biologic, a vaccine, a small molecule, a targeted therapy, an anti-inflammatory agent, a cell therapy, chemotherapy, or radiation therapy.

[0146] Any one of the embodiments disclosed herein can be appropriately combined with any other embodiment disclosed herein. The combination of any one of the embodiments disclosed herein with any other embodiment disclosed herein is expressly contemplated. Specifically, the selection of one or more embodiments for one substituent can be appropriately combined with the selection of one or more specific embodiments for any other substituent. Such combinations can be made with any one or more embodiments of the application described herein or any formula described herein.

[0147] The present application is described with reference to the following figures, which are presented for illustrative purposes only and are not intended to be limiting. [Brief explanation of the drawings]

[0148] [Figure 1] 1 shows an assessment of iTreg induction (FoxP3) from human CD4 T cells treated with Compound 22 in the presence of anti-CD3 / anti-CD28 / IL-2 / TGFβ, according to one or more embodiments described herein. [Figure 2] 1 shows an assessment of iTreg induction (FoxP3) from human CD4 T cells treated with compounds 31 and 39-43, according to one or more embodiments described herein. [Figure 3] 1 shows an evaluation of iTreg induction in human CD4 T cells treated with compounds 44-45 according to one or more embodiments described herein. DETAILED DESCRIPTION OF THE INVENTION

[0149] definition It is to be appreciated that the present disclosure is not limited to the compositions and methods described herein and the experimental conditions described, and thus may vary. It is also to be understood that the terminology used herein is for the purpose of describing certain embodiments only, and is not intended to be limiting, since the scope of the present disclosure is limited only by the appended claims.

[0150] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Any compositions, methods, and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.

[0151] In the context of describing the invention claimed herein (particularly in the context of the claims), the use of the singular and similar descriptions shall be construed to cover both the singular and the plural, unless otherwise indicated herein or the context clearly contradicts.

[0152] The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within that range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.

[0153] The use of the term "about" is intended to describe values ​​within approximately ±10% of any stated value. In some embodiments, values ​​may range approximately ±5% above or below any stated value. In some embodiments, values ​​may range approximately ±2% above or below any stated value. In other embodiments, values ​​may range approximately ±1% above or below any stated value. The preceding ranges are intended to be made clear by context, and no further limitations are implied. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language provided herein (e.g., "exemplary," "e.g., such as," "for example," "including but not limited to") is intended merely to better clarify the invention and does not impose limitations on the scope of the invention unless otherwise indicated.

[0154] The following are definitions of terms used in the specification of the present invention. The first definition provided for a group or term herein applies to that group or term individually or as part of another group throughout the specification, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0155] The terms "alkyl" and "alk" refer to straight or branched chain alkane (hydrocarbon) groups containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutylpentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. 1~The term "C4) alkyl" refers to a straight or branched chain alkane (hydrocarbon) group containing 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. "Substituted alkyl" refers to an alkyl group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a group such as, for example, an alkyl group bearing a CF3 group or CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , -N=S(=O)(R a ), S(=O)(=NR a )(=N(R a )2) (connected to the molecule via S or N), P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. dS(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c may form a heterocycle together with the N to which they are attached, and R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.) In some embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl may themselves be optionally substituted.

[0156] The term "heteroalkyl" refers to a straight- or branched-chain alkyl group, preferably having 2 to 12 carbons in the chain, more preferably 2 to 10 carbons, in which one or more of the carbons has been replaced with a heteroatom selected from the group consisting of S, O, P, and N. Exemplary heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, alkyl sulfides, and the like. The group may be a terminal group or a bridging group. In some embodiments, heteroalkyls are optionally substituted.

[0157] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. The term "C2-C6 alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methyl(E)-but-2-enyl, 2-methyl(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, and the like. "Alkenyl" refers to alkenyl groups substituted at any available point of attachment with one or more substituents, preferably one to four substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, halogenated alkyl (i.e., an alkyl group bearing a single halogen substituent or multiple halogen substituents, e.g., CF3 or CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or N), P(=O)R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R.b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c may form a heterocycle together with the N to which they are attached, and R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.) The exemplary substituents may themselves be optionally substituted.

[0158] The term "alkynyl" refers to a straight- or branched-chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Exemplary groups include ethynyl. The term "C2-C6 alkynyl" refers to a straight- or branched-chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl. "Substituted alkynyl" refers to an alkynyl substituted with one or more substituents, preferably one to four substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a group such as, for example, a CF3 group or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or N), P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d, C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c may form a heterocycle together with the N to which they are attached, and R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.) The exemplary substituents may themselves be optionally substituted.

[0159] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing one to four rings and three to eight carbons per ring. "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substituted cycloalkyl" refers to a cycloalkyl group substituted at any available point of attachment with one or more substituents, preferably one to four substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a group such as, for example, a CF3 group or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or N), P(=O)R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. bC(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c may form a heterocycle together with the N to which they are attached, and R e (each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, and the aforementioned substituents, e.g., cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents, may themselves be optionally substituted.

[0160] The term "bicycloalkyl" or "spiroalkyl" refers to a group containing at least one cycloalkyl ring that shares one or more ring atoms with at least one other cycloalkyl ring. The term "heterobicycloalkyl" or "heterospiroalkyl" refers to a bicycloalkyl group in which at least one, preferably 1 to 3, carbon atoms in at least one ring are replaced with a heteroatom selected from the group consisting of N, S, O, or P. The heteroatom can occupy a terminal position or a bridging position (i.e., a connection point between two rings). Exemplary bicycloalkyl groups include adamantyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.1.1]hexyl, octahydropentalenyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecanyl, decahydronaphthalenyl, bicyclo[3.2.0]heptyl, octahydro-1H-indenyl, bicyclo[4.2.1]nonanyl, and the like. Exemplary spiro bicycloalkyl groups include spiro[4.4]nonyl, spiro[3.3]heptyl, spiro[5.5]undecyl, spiro[3.5]nonyl, spiro[4.5]decyl, and the like. "Substituted bicycloalkyl," "substituted spiroalkyl," "substituted heterobicycloalkyl," and "substituted heterospiroalkyl" refer to a bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl group that is substituted at any available point of attachment with one or more substituents, preferably one to four substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a group such as, for example, a CF3 group or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , -N=S(=O)(R a ), -Ra S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or N), P(=O)R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c may form a heterocycle together with the N to which they are attached, and R e(each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, and the aforementioned substituents, e.g., cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents, may themselves be optionally substituted.

[0161] The term "heterocycloalkyl" or "cycloheteroalkyl" refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing, in at least one ring, at least one heteroatom, preferably 1 to 3 heteroatoms, selected from the group consisting of nitrogen, sulfur, and oxygen. Each ring preferably has 3 to 10 members, more preferably 4 to 7 members. In some embodiments, a heterocycloalkyl or cycloheteroalkyl is optionally substituted. Examples of suitable heterocycloalkyl substituents include, but are not limited to, azetidinyl, oxetanyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazepanyl, 1,4-diazepanyl, 1,4-oxazepanyl, and 1,4-oxathiapanyl. The group may be a terminal group or a bridging group.

[0162] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing one to four rings and three to eight carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted at any available attachment point with one or more substituents, preferably one to four substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a group such as, for example, a CF3 group or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or N), P(=O)R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)ORe , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R cおよび R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c may form a heterocycle together with the N to which they are attached, and R e (each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, and the aforementioned substituents, e.g., cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents, may themselves be optionally substituted.

[0163] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one to five aromatic rings, particularly a monocyclic or bicyclic group, such as phenyl, biphenyl, or naphthyl. When containing two or more aromatic rings (such as bicyclic rings), the aromatic rings of the aryl group may be bonded at a single point (e.g., biphenyl) or fused (e.g., naphthyl, phenanthrenyl, etc.). The term "fused aromatic ring" refers to a molecular structure having two or more aromatic rings in which two adjacent aromatic rings share two carbon atoms. "Substituted aryl" refers to an aryl group substituted with one or more substituents, preferably one to three substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a group such as, for example, a CF3 group or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or N), P(=O)R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)Ra , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c may form a heterocycle together with the N to which they are attached, and R e (each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include fused ring groups, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, and the aforementioned substituents, e.g., cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents, may themselves be optionally substituted.

[0164] The term "biaryl" refers to two aryl groups linked by a single bond. The term "biheteroaryl" refers to two heteroaryl groups linked by a single bond. Similarly, the term "heteroaryl-aryl" refers to a heteroaryl group and an aryl group linked by a single bond, and the term "aryl-heteroaryl" refers to an aryl group and a heteroaryl group linked by a single bond. In certain embodiments, the number of ring atoms in the heteroaryl and / or aryl rings is used to specify the aryl or heteroaryl ring size of the substituent. For example, 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is linked to a 6-membered aryl group. Other combinations and ring sizes can be similarly specified.

[0165] The term "carbocycle" or "carbocycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing one to four rings and three to eight carbons per ring, or a cyclic, aromatic hydrocarbon group having one to five aromatic rings, particularly a monocyclic or bicyclic group, such as phenyl, biphenyl, or naphthyl. The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl as defined hereinabove. The term "substituted carbocycle" refers to a carbocycle or carbocyclic group substituted at any available attachment point with one or more substituents, preferably one to four substituents. Exemplary substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl. Exemplary substituents also include spiro-linked or fused ring substituents at any available point or attachment point, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, and the aforementioned substituents, e.g., cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents, may themselves be optionally substituted.

[0166] The terms "heterocycle" and "heterocyclic" refer to fully saturated or partially or fully unsaturated ring groups (e.g., 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring systems), including aromatic (i.e., "heteroaryl") rings, having at least one heteroatom in at least one carbon atom-containing ring. Each ring of a heterocyclic group can be independently saturated or partially or fully unsaturated. Each ring of a heteroatom-containing heterocyclic group can have 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms; the nitrogen and sulfur heteroatoms can be oxidized, and the nitrogen heteroatom can be quaternized. (The term "heteroarylium" refers to a heteroaryl group that carries a quaternary nitrogen atom, thus carrying a positive charge.) A heterocyclic group can be attached to the remainder of the molecule at any heteroatom or carbon atom in the ring or ring system. Exemplary monocyclic heterocyclic groups are azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, Examples of aryl include 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl.Exemplary bicyclic heterocyclic groups are indolyl, indolinyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][1,3]dioxolyl, dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzyl, benzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzo[b][1,4]dioxinyl, benzo[b][1,4]dioxinyl, benzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzo[b][1,4]diox ... Exemplary tricyclic heterocyclic groups include benzofurazanyl, dihydrobenzo[d]oxazole, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (e.g., furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (e.g., 3,4-dihydro-4-oxoquinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like. The term "partially saturated bicyclic heteroaryl" refers to a bicyclic heteroaryl having a partially saturated, e.g., saturated, cycloalkyl or heterocyclic alkyl ring.

[0167] "Substituted heterocycle" and "substituted heterocyclic" (e.g., "substituted heteroaryl") refer to a heterocycle or heterocyclic group that is substituted at any available point of attachment with one or more substituents, preferably one to four substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a group such as, for example, a CF3 group or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , -N=S(=O)(Ra ), -R a S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or N), P(=O)R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c may form a heterocycle together with the N to which they are attached, and Re (each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents at any available point or attachment point, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, and the aforementioned substituents, e.g., cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents, may themselves be optionally substituted.

[0168] The term "oxo" [ka] This refers to a substituent of the formula: which may be attached to a carbon ring atom on a carbocyclic or heterocyclic ring. When the oxo substituent is attached to a carbon ring atom on an aromatic group, e.g., an aryl or heteroaryl, the bonds on the aromatic ring may be rearranged to meet valence requirements. For example, a pyridine with a 2-oxo substituent has the structure [ka] which structure can also have its tautomeric form [ka] Also includes.

[0169] The term "alkylamino" refers to a group having the structure -NHR', where R' is hydrogen, alkyl or substituted alkyl, cycloalkyl, or substituted cycloalkyl, as defined herein. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.

[0170] The term "dialkylamino" refers to a group having the structure -NRR', where R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined herein. R and R' can be the same or different dialkylamino moieties. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In certain embodiments, R and R' are linked to form a cyclic structure. The resulting cyclic structure may be aromatic or non-aromatic. Examples of the resulting cyclic structures include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0171] The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.

[0172] The term "substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group, or any other group disclosed herein) is substituted at any available point of attachment with one or more substituents, preferably 1 to 6 substituents, as allowed by valence. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a group such as, for example, a CF3 group or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, alkyl, halogen-substituted alkyl, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or N), P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)ORe , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c may form a heterocycle together with the N to which they are attached, and R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). In the above exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl may themselves be optionally substituted. The term "optionally substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein) may or may not be substituted with one or more of the substituents described above.

[0173] Unless otherwise noted, any heteroatom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0174] The compounds of the present invention can form salts that are also within the scope of the present invention. Reference to a compound of the present invention is considered to include reference to its salts, unless otherwise indicated. The term "salt," as used herein, refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, when a compound of the present invention contains both a basic moiety, such as, but not limited to, pyridine or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("internal salts") may be formed, and these are included in the term "salt" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts that can be utilized during preparation are also useful, for example, in isolation or purification steps. Salts of the compounds of the present invention can be formed, for example, by reacting a compound described herein with an amount of an acid or base, e.g., an equivalent amount of an acid or base, in a medium, e.g., a medium in which the salt precipitates or an aqueous medium, followed by lyophilization.

[0175] The compounds of the present invention containing a basic moiety, such as, but not limited to, an amine or a pyridine or imidazole ring, can form salts with various organic and inorganic acids. Exemplary acid addition salts include acetate (e.g., formed with acetic acid or trihaloacetic acid; e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate ... Included are sulfonates (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate, e.g., tosylate, undecanoate, and the like.

[0176] The compounds of the present invention that contain an acidic moiety, for example, but not limited to, carboxylic acid, can form salts with various organic and inorganic bases.Exemplary base salts include ammonium salts, alkali metal salts, for example, sodium salts, lithium salts and potassium salts, alkaline earth metal salts, for example, calcium salts and magnesium salts, salts with organic bases (for example, organic amines), for example, benzathine, dicyclohexylamine, hydrabamine (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glycamide, t-butylamine salts, and salts with amino acids, for example, arginine, lysine, etc. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0177] Prodrugs and solvates of the compounds of the present invention are also contemplated herein. The term "prodrug" as used herein refers to a compound that, when administered to a subject, undergoes chemical conversion by metabolic or chemical processes to produce the compounds of the present invention or their salts and / or solvates. Solvates of the compounds of the present invention include, for example, hydrates.

[0178] The compounds of the present invention and their salts or solvates can exist in their tautomeric forms (e.g., amides or iminols). All such tautomeric forms are contemplated herein as part of the present invention. As used herein, any depicted structure of a compound includes its tautomeric forms.

[0179] All stereoisomers of the compounds described herein, including enantiomeric and diastereomeric forms (e.g., those that may exist due to asymmetric carbon atoms on various substituents), are contemplated within the scope of the present invention. Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers (e.g., as pure or substantially pure optical isomers having the specified activity), or may be, for example, racemic or mixed with all other stereoisomers, or with other selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the 1974 Recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemates can be resolved by physical methods, for example, fractional crystallization, separation, or crystallization of diastereomeric derivatives or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemates by any suitable method, including, but not limited to, conventional methods, for example, salt formation with an optically active acid followed by crystallization.

[0180] The compounds of the present invention are preferably isolated and purified after their preparation to obtain compositions containing greater than or equal to 90% by weight, e.g., greater than or equal to 95% by weight, greater than or equal to 99% by weight of the compound (a "substantially pure" compound), which are then used or formulated as described herein. Such "substantially pure" compounds of the present invention are also contemplated herein as part of the present invention.

[0181] All configurational isomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of the compounds of the present invention encompasses both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

[0182] Throughout the specification, groups and substituents may be chosen to provide stable moieties and compounds.

[0183] Definitions of certain functional groups and chemical terms are described in more detail herein. For purposes of the present invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry, as well as specific functional group moieties and reactivities, are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito (1999), the entire contents of which are incorporated herein by reference.

[0184] Certain compounds of the present invention can exist in particular geometric or stereoisomeric forms. The present invention contemplates that all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0185] Mixtures of isomers containing any of a variety of isomeric ratios can be utilized in accordance with the present invention. For example, when combining only two isomers, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomeric ratios are all contemplated by the present invention. Those skilled in the art will readily recognize that similar ratios are contemplated for more complex isomeric mixtures.

[0186] The present invention also includes isotopically labeled compounds that are identical to the compounds disclosed herein except for the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H (or D), 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 The compounds of the present invention, or their enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates, which contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, radioactive isotopes, e.g., 3 H and 14 Compounds incorporating C are useful in drug and / or substrate tissue distribution assays. Tritiated isotopes, i.e., 3 H and carbon-14 isotopes, i.e., 14 C is particularly preferred due to its ease of preparation and detectability. Additionally, heavier isotopes such as deuterium, i.e., 2 Substitution with H may confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the following schemes and / or examples, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0187] For example, if a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to yield the desired pure enantiomer. Alternatively, if the molecule contains a basic functional group, e.g., amino, or an acidic functional group, e.g., carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers so formed by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomers.

[0188] It should be recognized that the compounds described herein may be substituted with any number of substituents or functional moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, and whether the substituent is included in the formula of the invention, refers to the replacement of a hydrogen radical in a given structure with a specified substituent radical. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatom. Furthermore, this invention is not intended to limit in any manner the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in therapy, for example, in the treatment of proliferative disorders. The term "stable," as used herein, refers to a compound that preferably possesses sufficient stability to permit manufacture and maintains its integrity for a period of time sufficient for the compound to be detected, preferably for a period of time sufficient to be useful for the purposes detailed herein.

[0189] As used herein, the terms "cancer" and, equivalently, "tumor" refer to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a subject. Cancer may be malignant or non-malignant. Cancers or tumors include, but are not limited to, adult T-cell leukemia / lymphoma (including those caused by human T-cell lymphotropic virus (HTLV-1)), bile duct cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (stomach) cancer; intraepithelial neoplasia; leukemia; lymphoma; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastoma; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcoma; skin cancer; testicular cancer; thyroid cancer; and other carcinomas and sarcomas. As used herein, the term "lymphoma" refers to cancer of the lymphatic system or blood cancers that develop from lymphocytes. Cancer can be primary or metastatic. Diseases other than cancer can also be associated with mutational changes in components of the Ras signaling pathway, and the compounds disclosed herein can be used to treat these non-cancer diseases. Such non-cancer diseases can include: neurofibromatosis; Leopard syndrome; Noonan syndrome; Regius syndrome; Costello syndrome; cardiofaciocutaneous syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndrome; and capillary malformation-cerebral arteriovenous malformation.

[0190] As used herein, "effective amount" refers to any amount necessary or sufficient to achieve or promote a desired result. In some cases, an effective amount is a therapeutically effective amount. A therapeutically effective amount is any amount necessary or sufficient to promote or achieve a desired biological response in a subject. The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the specific drug being administered, the size of the subject, or the severity of the disease or condition. Those skilled in the art can empirically determine the effective amount of a particular drug without undue experimentation.

[0191] As used herein, the term "subject" refers to a vertebrate. In one embodiment, the subject is a mammal or mammalian species. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human vertebrate, including, but not limited to, non-human primates, laboratory animals, farm animals, racehorses, domestic animals, and non-domestic animals.

[0192] The term "immune cells," as used herein, refers to cells of the innate and acquired immune system, including, but not limited to, neutrophils, eosinophils, basophils, glial cells (e.g., astrocytes, microglia, and oligodendrocytes), monocytes, macrophages, dendritic cells, lymphocytes, including B cells, T cells, and NK cells.

[0193] As used herein, "conventional T cells" are T lymphocytes that express the αβ T cell receptor ("TCR") and the co-receptors CD4 or CD8. Conventional T cells are present in peripheral blood, lymph nodes, and tissues. See Roberts and Girardi, "Conventional and Unconventional T Cells," Clinical and Basic Immunodermatology, pp. 85-104, (Gaspari and Tyring (ed.)), Springer London (2008), the entire contents of which are incorporated herein by reference. As used herein, "unconventional T cells" are lymphocytes that express the γδ TCR and can typically reside in epithelial environments, such as the skin, gastrointestinal tract, or urogenital tract. Another subset of unconventional T cells is invariant natural killer T ("NKT") cells, which have the phenotype and functional capabilities of conventional T cells and the characteristics of natural killer cells (e.g., cytotoxic activity). See ibid. As used herein, regulatory T cells ("Tregs") are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, reverse autoimmune diseases, and suppress otherwise immune stimulation or activate other cellular responses. Tregs take many forms, but the best understood are those that express CD4, CD25, and Foxp3. As used herein, "natural Tregs" or "nTregs" refer to Tregs or cells that develop in the thymus. As used herein, "inducible Tregs" or "iTregs" refer to Tregs or cells that develop from mature CD4+ conventional T cells outside the thymus.

[0194] The "activity" of Akt3 refers to the biological function of the Akt3 protein. Biological activity can be increased or decreased by increasing or decreasing the basal level activity of the protein, increasing or decreasing the basal level avidity of the protein, the amount of the protein, the ratio of Akt3 to one or more other isoforms of Akt protein (e.g., Akt1 or Akt2), increasing or decreasing the expression level of the protein (including increasing or decreasing the mRNA expression of Akt3), or a combination thereof. For example, a biologically available Akt3 protein is one that has kinase activity and can bind to and phosphorylate Akt3 substrates. An Akt3 protein that is not biologically available includes an Akt3 protein that is mislocalized or cannot bind to and phosphorylate Akt substrates.

[0195] In some embodiments, the disclosed compounds selectively modulate Akt3 relative to Akt1 and Akt2. In some embodiments, any one of the disclosed compounds does not modulate Akt1 and Akt2 to a statistically significant degree. In other embodiments, modulation of Akt3 by the disclosed compounds is about 5-fold, about 10-fold, about 15-fold, about 50-fold, about 100-fold, about 1000-fold, or about 5000-fold greater than their modulation of Akt1 and / or Akt2.

[0196] As used herein, the term "peptide" or "polypeptide" refers to a chain of amino acids of any length, regardless of modification (e.g., phosphorylation or glycosylation). The term includes proteins and fragments thereof. A polypeptide may be "exogenous," meaning that the polypeptide is "heterologous," i.e., foreign to the host cell utilized, e.g., a human polypeptide produced by a bacterial cell. Polypeptides are disclosed herein as amino acid residue sequences. The sequences are written from amino to carboxy terminus, left to right. In accordance with standard nomenclature, amino acid residue sequences are designated by either the three-letter or one-letter code shown as follows: alanine (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine ​​(Cys, C), glutamine (Gln, Q), glutamic acid (Glu, E), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V).

[0197] The term "stimulate expression of" means to affect the expression of, for example, to induce expression or activity or to induce increased / greater expression or activity compared to normal, healthy controls.

[0198] The terms "immunostimulatory response," "activating an immune response," and "immunostimulatory response" refer to a response that initiates, induces, enhances, or increases the activation or efficiency of innate or adaptive immunity. Such immune responses include, for example, the generation of beneficial humoral (antibody-mediated) and / or cellular (mediated by antigen-specific T cells or their secretions) responses directed against a peptide in a recipient patient. Such responses can be active responses elicited by administration of an immunogen or passive responses elicited by administration of antibodies or primed T cells. Cellular immune responses are elicited by presenting polypeptide epitopes in conjunction with class I or class II major histocompatibility complex ("MHC") molecules to activate antigen-specific CD4+ T helper cells and / or CD8+ cytotoxic T cells. Responses can also include activation of monocytes, macrophages, NK cells, basophils, dendritic cells, astrocytes, microglial cells, eosinophils, or activation or recruitment of neutrophils or other components of innate immunity. The presence of a cell-mediated immunological response can be determined by proliferation assays (CD4+ T cells) or cytotoxic T lymphocyte ("CTL") assays. The relative contributions of humoral and cellular responses to the protective or therapeutic effect of an immunogen can be distinguished by isolating antibodies and T cells separately from an immunized syngeneic animal and measuring the protective or therapeutic effect in a second subject.

[0199] "Suppressive immune response" and "immunosuppressive response" refer to a response that reduces or prevents the activation or efficiency of innate or adaptive immunity.

[0200] The term "immune tolerance" refers to any mechanism that prevents, suppresses, or shifts a potentially harmful immune response toward a non-harmful immune response (see Bach, et al., N. Eng. J. Med., 347:911-920 (2002)).

[0201] The term "immunogenic agent" or "immunogen" refers to an agent that is capable of eliciting an immunological response upon administration to a mammal, optionally in combination with an adjuvant.

[0202] compound In one embodiment, compounds of Formula Ia, Ib, or Ic are described as Akt3 modulators. Applicants have surprisingly discovered that the compounds disclosed herein modulate Akt3 activity, e.g., activate or inhibit Akt3 activity and / or downstream events, depending on their structure and substitution.

[0203] In one embodiment, a compound of formula Ia, Ib or Ic [ka] [During the ceremony, [ka] teeth, [ka] and each occurrence of X1, X2, X3, X4, X5, X6, X7, X8, and X9 is independently CR1 or N; Each occurrence of R is independently selected from H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C4-C 14 )tricycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 14 ) heterotricycloalkyl, (C4-C 10 ) heterospiroalkyl, (C3-C7) cycloalkenyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C10 ) heterobicycloalkenyl, (C4-C 14 ) tricycloalkenyl, (C4-C 14 ) Heterotricycloalkenyl, aryl, heteroaryl, -ORa, -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] and one or more of (C1-C6) alkyl, halogenated (C1-C6) alkyl, -SO2R a or -SO2N(R a ) a partially saturated bicyclic heteroaryl optionally substituted with 2; R1 is (C3-C7)cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C4-C 14 )tricycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 14 ) heterotricycloalkyl, (C4-C 10 ) heterospiroalkyl, (C3-C7) cycloalkenyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 14 ) tricycloalkenyl, (C4-C 14 ) Heterotricycloalkenyl, aryl and heteroaryl are each selected from the group consisting of one or more of (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2, each of which is appropriately replaced, n is an integer of 0 to 4 allowed by the valence; Q is C(R a )2, O, NR a , N(C=O)R a or NSO2R a and Y1, Y2, Y3, Y4, and Y5 are each independently N or CR2, as allowed by valence; R2 is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] is selected from the group consisting of -EG- is -(C=O)NR x -, -NR x (C=O)-, -N(R x )(C=O)N(R x )-, -O(C=O)N(R x )-, -N(R x )(C=O)O-, -SO2NR x -, -NR x SO2- or [ka] and R x Each occurrence of is independently H, (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl or R x and Y3, R x and Y4, R x and Z1, or R x and Z4 together, one or more R z and R z each occurrence is independently H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen, or two R z together form a 4- to 6-membered ring optionally substituted with halogen or (C1-C6) alkyl; W1, W2, W3, W4 and W5 are each independently CR6, N or NR6, as allowed by valences; each occurrence of R6 is independently selected from the group consisting of H, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl; Each occurrence of T is independently O, N, NR as allowed by valence. a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a and Each occurrence of U may independently be O, N, or NR as allowed by valence. a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a and R b each occurrence is independently H or (C1-C6) alkyl; Z1, Z2, Z3, Z4, and Z5 are each independently N or CR3, as allowed by valences; R3 is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] is selected from the group consisting of V is absent or C(R a )2, NR a , N(C=O)R a , NSO2R a or O, R4 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) selected from the group consisting of heterospiroalkyl, aryl, and heteroaryl, each of which is optionally substituted with one or more R5; or alternatively, V and R4 together represent (C3-C7)heterocycloalkyl or (C4-C 10 ) forming a heterospiroalkyl, Each occurrence of R5 is independently selected from H, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , N(R a )COR a , [ka] is selected from the group consisting of R a each occurrence is independently H, (C1-C6) alkyl, (C2-C6) alkenyl, (C3-C7) cycloalkyl, aryl, or heteroaryl, or two R a together form a 4- to 6-membered ring optionally substituted with halogen or (C1-C6) alkyl. or a pharmaceutically acceptable salt thereof is described.

[0204] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] is.

[0205] In some embodiments, Q is C(R a )2, O or NR a In some embodiments, Q is O. In some embodiments, Q is NR a In some embodiments, Q is NH. In some embodiments, Q is NCH or NCHCH. In some embodiments, Q is N(C=O)R a or NSO2R a In some embodiments, Q is N(C=O)H. In some embodiments, Q is N(C=O)CH3 or N(C=O)CH2CH3. In some embodiments, Q is NSO2H. In some embodiments, Q is NSO2CH3 or NSO2CH2CH3.

[0206] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0207] In some embodiments, [ka] teeth [ka] In some embodiments, X2, X3, and X4 are each independently CR1 or N. In some embodiments, X2, X3, and X4 are CR1. In some embodiments, X2, X3, and X4 are CH. In some embodiments, one of X2, X3, and X4 is N, and the rest are CR1. In some embodiments, one of X2, X3, and X4 is N, and the rest are CH. In some embodiments, two of X2, X3, and X4 are N, and the rest are CR1. In some embodiments, two of X2, X3, and X4 are N, and the rest are CH.

[0208] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0209] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0210] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0211] In some embodiments, X1, X2, X3, X4, X5, X6, and X7 are each independently CR1 or N. In some embodiments, X1, X2, X3, X4, X5, X6, and X7 are each independently CR1. In some embodiments, X1, X2, X3, X4, X5, X6, and X7 are each independently CH, C(halogen), or CCH3. In some embodiments, one of X1, X2, X3, X4, X5, X6, and X7 is N, and the rest are CR1. In some embodiments, one of X1, X2, X3, X4, X5, X6, and X7 is N, and the rest are each independently CH, C(halogen), or CCH3. In some embodiments, two of X1, X2, X3, X4, X5, X6, and X7 are N, and the rest are CR1. In some embodiments, two of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining are each independently CH, C(halogen), or CCH3. In some embodiments, three of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining are CR1. In some embodiments, three of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining are each independently CH, C(halogen), or CCH3. In some embodiments, four of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining are CR1. In some embodiments, four of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining are each independently CH, C(halogen), or CCH3. In some embodiments, X2 is N, X7 is CR1, and X1, X3, X4, X5, and X6 are each independently CH, C(halogen), or CCH3. In some embodiments, X2 is N, X7 is CR1, X3 is C(halogen) or CCH3, and X1, X4, X5, and X6 are CH. In some embodiments, X2 and X7 are N, and X1, X3, X4, X5, and X6 are CR1. In some embodiments, X2 and X7 are N, and X1, X3, X4, X5, and X6 are each independently CH, C(halogen), or CCH3. In some embodiments, the halogen is F, Cl, Br, or I. In some embodiments, the halogen is F.

[0212] In some embodiments, X2, X3, X4, X8, and X9 are each independently CR1 or N. In some embodiments, X2, X3, X4, X8, and X9 are CR1. In some embodiments, X2, X3, X4, X8, and X9 are each independently CH, C(halogen), or CCH3. In some embodiments, one of X2, X3, X4, X8, and X9 is N, and the rest are CR1. In some embodiments, one of X2, X3, X4, X8, and X9 is N, and the rest are each independently CH, C(halogen), or CCH3. In some embodiments, two of X2, X3, X4, X8, and X9 are N, and the rest are CR1. In some embodiments, two of X2, X3, X4, X8, and X9 are N, and the rest are each independently CH, C(halogen), or CCH3. In some embodiments, three of X2, X3, X4, X8, and X9 are N, and the remainder are CR1. In some embodiments, three of X2, X3, X4, X8, and X9 are N, and the remainder are each independently CH, C(halogen), or CCH3. In some embodiments, four of X2, X3, X4, X8, and X9 are N, and one is CR1. In some embodiments, four of X2, X3, X4, X8, and X9 are N, and one is CH, C(halogen), or CCH3. In some embodiments, the halogen is F, Cl, Br, or I. In some embodiments, the halogen is F.

[0213] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0214] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, Q is O. In some embodiments, Q is NR a , N(C=O)R a or NSO2R a In some embodiments, Q is NH. In some embodiments, Q is NCH3 or NCH2CH3.

[0215] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, Q is O. In some embodiments, Q is NR a , N(C=O)R a or NSO2R a In some embodiments, Q is NH. In some embodiments, Q is NCH3 or NCH2CH3.

[0216] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0217] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0218] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, Q is O. In some embodiments, Q is NR a , N(C=O)R a or NSO2R a In some embodiments, Q is NH. In some embodiments, Q is NCH3 or NCH2CH3.

[0219] In some embodiments, each occurrence of R is independently selected from H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C4-C 14 )tricycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 14 ) heterotricycloalkyl, (C4-C 10 ) heterospiroalkyl, (C3-C7) cycloalkenyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 14 ) tricycloalkenyl, (C4-C 14 ) Heterotricycloalkenyl, aryl, heteroaryl, -OR a , -N(R a )2, -CORa , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a (C3-C7)cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C4-C 14 )tricycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 14 ) heterotricycloalkyl, (C4-C 10 ) heterospiroalkyl, (C3-C7) cycloalkenyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 14 ) tricycloalkenyl, (C4-C 14 )heterotricycloalkenyl, aryl, and heteroaryl are each optionally substituted with one or more (C1-C6)alkyl. In some embodiments, each occurrence of R1 is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl and (C4-C 10 )heterobicycloalkyl, (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl and (C4-C 10 )heterobicycloalkyl is optionally substituted with one or more (C1-C6)alkyl. In some embodiments, each occurrence of R is independently selected from the group consisting of aryl and heteroaryl, and is optionally substituted with one or more (C4-C 10) heterospiroalkyl, aryl, and heteroaryl are each optionally substituted with one or more (C1-C6) alkyl. In some embodiments, each occurrence of R1 is independently an optionally substituted (C3-C7) cycloalkenyl or an optionally substituted (C3-C7) heterocycloalkenyl. In some embodiments, each occurrence of R1 is independently an optionally substituted (C4-C 10 ) bicycloalkenyl or optionally substituted (C4-C 10 In some embodiments, each occurrence of R is independently an optionally substituted (C4-C 14 )tricycloalkenyl or optionally substituted (C4-C 14 In some embodiments, each occurrence of R is independently an optionally substituted (C4-C 14 ) tricycloalkyl or optionally substituted (C4-C 14 In some embodiments, each occurrence of R is independently -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a In some embodiments, each occurrence of R is independently selected from the group consisting of: [ka] In some embodiments, each occurrence of R is independently selected from the group consisting of H, D, halogen, OR a , N(R a )2, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, (C1-C6) alkynyl, aryl, (C4-C 10) Bicycloalkyl, -CN, -NC, N3, NO2, COR a , CO2R a , CON(R a )2, -SO2R a or -SO2N(R a )2, (C3-C7)heterocycloalkyl, (C4-C 10 ) heterospiroalkyl, aryl and (C4-C 10 )bicycloalkyl is optionally substituted with one or more (C1-C6)alkyl. In some embodiments, each occurrence of R is independently selected from H, D, halogen, (C1-C6)alkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, N(R a )2 or -CN, (C3-C7)heterocycloalkyl and (C4-C 10 )heterospiroalkyl is optionally substituted with one or more (C1-C6)alkyl. In some embodiments, at least one occurrence of R1 is optionally substituted with one or more (C4-C 10 )heterospiroalkyl. In some embodiments, at least one occurrence of R is a halogenated (C3-C7)heterocycloalkyl. In some embodiments, each occurrence of R is independently H, (C1-C6)alkyl, (C1-C6)alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -SO2R a or -SO2N(R a )2, and aryl and (C4-C 10 )bicycloalkyl is optionally substituted with one or more (C1-C6)alkyl. In some embodiments, at least one occurrence of R1 is (C4-C 10 )heterospiroalkyl, optionally substituted with one or more (C1-C6)alkyl. In some embodiments, at least one occurrence of R1 is a halogenated (C3-C7)heterocycloalkyl, optionally substituted with one or more (C1-C6)alkyl. In some embodiments, each occurrence of R1 is independently H, D, F, Cl, Br, CH3, OCH3, NH2, NHCH3, N(CH3)2, [ka] -CN, N3, NO2, [ka] [In the formula, R a In some embodiments, each occurrence of R is independently H, D, F, CH, N(CH), [ka] [In the formula, R a ' is H or (C1-C6) alkyl. In some embodiments, each occurrence of R1 is independently [ka] is.

[0220] In some embodiments, R is (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) heterospiroalkyl, (C3-C7) cycloalkenyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 14 ) tricycloalkenyl, (C4-C 14 ) heterotricycloalkenyl, (C4-C 14 ) tricycloalkyl, (C4-C 14 ) Heterotricycloalkyl, aryl and heteroaryl are each selected from the group consisting of one or more halogens, (C1-C6) alkyl, -OR a , -CN or -N(R a )2, each of which is substituted as appropriate.

[0221] In some embodiments, at least one occurrence of R is selected from one or more of (C1-C6) alkyl, halogenated (C1-C6) alkyl, —SO2R a or -SO2N(R a In some embodiments, at least one occurrence of R is optionally substituted with [ka] In some embodiments, [ka] teeth, [ka] is.

[0222] In some embodiments, at least one occurrence of R1 is H, D, or halogen. In some embodiments, at least one occurrence of R1 is H. In some embodiments, at least one occurrence of R1 is D. In some embodiments, at least one occurrence of R1 is F. In some embodiments, at least one occurrence of R1 is CH3. In some embodiments, at least one occurrence of R1 is OCH3. In some embodiments, at least one occurrence of R1 is NH2. In some embodiments, at least one occurrence of R1 is NHCH3. In some embodiments, at least one occurrence of R1 is N(CH3)2. In some embodiments, at least one occurrence of R1 is F. In some embodiments, at least one occurrence of R1 is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] and R a ' is H or (C1-C6) alkyl. In some embodiments, at least one occurrence of R1 is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] and R a ' is H or (C1-C6) alkyl. In some embodiments, at least one occurrence of R1 is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is -CN. In some embodiments, at least one occurrence of R is -NC. In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is NO. In some embodiments, at least one occurrence of R is N. In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] is.

[0223] In some embodiments, at least one occurrence of R is [ka] and X is CR 15 , O, N.R. 14 or S, and each occurrence of R is independently H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2 and R 14 is H, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, aryl, or heteroaryl, and R 15 each occurrence is independently selected from H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2 and q is 0, 1, 2 or 3.

[0224] In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is CR 15 In some embodiments, X is NR 15 is.

[0225] In some embodiments, each occurrence of R is independently selected from H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(Ra )2. In some embodiments, each occurrence of R9 is independently H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, or halogen. In some embodiments, each occurrence of R9 is independently H, F, Cl, Br, CH3, CF3, OH, NH2, —NHCH3, or —N(CH3)2. In some embodiments, each occurrence of R9 is independently H, F, Cl, Br, or CH3.

[0226] In some embodiments, R 15 each occurrence is independently selected from H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2. In some embodiments, R 15 Each occurrence of is independently H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, or halogen. 15 Each occurrence of is independently H, F, Cl, Br, CH, CF, OH, NH, —NHCH, or —N(CH). 15 Each occurrence of is independently H, F, Cl, Br, or CH3.

[0227] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

[0228] In some embodiments, R 14 is H, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, aryl, or heteroaryl. 14 is H, (C1-C6) alkyl, or (C3-C7) cycloalkyl. In some embodiments, R 14 is H or (C1-C6) alkyl. In some embodiments, R 14 is H or CH3.

[0229] In some embodiments, at least one occurrence of R is [ka] and X is O or NR 14 and R 14 is H or (C1-C6) alkyl. In some embodiments, at least one occurrence of R1 is [ka] is.

[0230] In some embodiments, [ka] teeth, [ka] [In the formula, R 12 is (C3-C7) cycloalkenyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 14 ) tricycloalkenyl or (C4-C 14 ) heterotricycloalkenyl, each of which may be selected from one or more of (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2, optionally substituted. 12 teeth, [ka] and X is CR 15 , O, N.R. 14 or S, and each occurrence of R is independently H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2 and R 14is H, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, aryl, or heteroaryl, and R 15 each occurrence is independently selected from H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2 and q is 0, 1, 2, or 3. In some embodiments, X2 is N. In some embodiments, X3 is CH or CCH3. In some embodiments, [ka] teeth, [ka] X2 is N, X3 is CH or CCH3, and R 12 is (C3-C7) cycloalkenyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 14 ) tricycloalkenyl or (C4-C 14 ) heterotricycloalkenyl, each of which may be selected from one or more of (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2 as appropriate.

[0231] In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is CR 15 In some embodiments, X is NR 14 is.

[0232] In some embodiments, each occurrence of R is independently selected from H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a)2. In some embodiments, each occurrence of R9 is independently H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, or halogen. In some embodiments, each occurrence of R9 is independently H, F, Cl, Br, CH3, CF3, OH, NH2, —NHCH3, or —N(CH3)2. In some embodiments, each occurrence of R9 is independently H, F, Cl, Br, or CH3.

[0233] In some embodiments, R 15 each occurrence is independently selected from H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2. In some embodiments, R 15 Each occurrence of is independently H, (C1-C6) alkyl, halogenated (C1-C6) alkyl, or halogen. 15 Each occurrence of is independently H, F, Cl, Br, CH, CF, OH, NH, —NHCH, or —N(CH). 15 Each occurrence of is independently H, F, Cl, Br, or CH3.

[0234] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

[0235] In some embodiments, R 14 is H, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, aryl, or heteroaryl. 14 is H, (C1-C6) alkyl, or (C3-C7) cycloalkyl. In some embodiments, R 14 is H or (C1-C6) alkyl. In some embodiments, R 14 is H or CH3.

[0236] In some embodiments, R 12 At least one occurrence of [ka] and X is O or NR 14 and R 14 is H or (C1-C6) alkyl. In some embodiments, R 12 At least one occurrence of [ka] is.

[0237] In some embodiments, the structural moiety [ka] teeth, [ka] [ka] [ka] [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0238] In some embodiments, the structural moiety [ka] teeth, [ka] [ka] [ka] and Q is O or NH. In some embodiments, the structural moiety [ka] teeth, [ka] and Q is O or NH. In some embodiments, the structural moiety [ka] teeth, [ka] and Q is O or NH. In some embodiments, the structural moiety [ka] teeth, [ka] and Q is O or NH. In some embodiments, the structural moiety [ka] teeth, [ka] and Q is O or NH. In some embodiments, the structural moiety [ka] teeth, [ka] and Q is O or NH. In some embodiments, the structural moiety [ka] teeth, [ka] and Q is O or NH. In some embodiments, the structural moiety [ka] teeth, [ka] and Q is O or NH. In some embodiments, the structural moiety [ka] teeth, [ka] and Q is O or NH. In some embodiments, the structural moiety [ka] teeth, [ka] wherein Q is O or NH.

[0239] In some embodiments, the structural moiety [ka] teeth, [ka] wherein Q is O or NH and R1 is H, D, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, halogenated (C3-C7) heterocycloalkyl, or halogen. [ka] teeth, [ka] wherein Q is O or NH and R1 is H, D, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, F, Cl, or Br.

[0240] In some embodiments, the structural moiety [ka] teeth, [ka] and Q is O or NH. In some embodiments, the structural moiety [ka] teeth, [ka] and Q is O or NH. In some embodiments, the structural moiety [ka] teeth, [ka] and Q is O or NH. In some embodiments, the structural moiety [ka] teeth, [ka] wherein Q is O or NH.

[0241] In some embodiments, the structural moiety [ka] teeth, [ka] wherein Q is O or NH.

[0242] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, Q is O or NH.

[0243] In some embodiments, the compound has the structure of Formula Ia.

[0244] In some embodiments, Y1, Y2, Y3, Y4, and Y5 are each independently CR2 or N. In some embodiments, Y1, Y2, Y3, Y4, and Y5 are each CR2. In some embodiments, Y1, Y2, Y3, Y4, and Y5 are each CH. In some embodiments, Y1, Y2, Y3, Y4, and Y5 are each N. In some embodiments, one of Y1, Y2, Y3, Y4, and Y5 is CR2, and the rest are N. In some embodiments, one of Y1, Y2, Y3, Y4, and Y5 is CH, and the rest are N. In some embodiments, two of Y1, Y2, Y3, Y4, and Y5 are CR2, and the rest are N. In some embodiments, two of Y1, Y2, Y3, Y4, and Y5 are CH, and the rest are N. In some embodiments, three of Y1, Y2, Y3, Y4, and Y5 are CR2 and two of Y1, Y2, Y3, Y4, and Y5 are N. In some embodiments, three of Y1, Y2, Y3, Y4, and Y5 are CH and two of Y1, Y2, Y3, Y4, and Y5 are N.

[0245] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0246] In some embodiments, each occurrence of R is independently selected from H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C4-C 10 )heterobicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, aryl, heteroaryl, -ORa, -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a In some embodiments, each occurrence of R2 is independently selected from the group consisting of (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl and (C4-C 10 In some embodiments, each occurrence of R is independently selected from the group consisting of aryl and heteroaryl. In some embodiments, each occurrence of R is independently selected from the group consisting of -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a In some embodiments, each occurrence of R is independently selected from the group consisting of: [ka] In some embodiments, each occurrence of R is independently selected from the group consisting of H, D, halogen, OR a , N(R a )2, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, (C1-C6) alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -CN, -NC, N3, NO2, COR a , CO2R a , CON(R a )2, -SO2R a or -SO2N(R a )2. In some embodiments, each occurrence of R2 is independently H, D, halogen, (C1-C6)alkyl, (C3-C7)heterocycloalkyl, N(R a )2 or —CN. In some embodiments, each occurrence of R2 is independently (C4-C 10 )heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each occurrence of R2 is independently H, (C1-C6)alkyl, (C1-C6)alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -SO2R a or -SO2N(R a In some embodiments, each occurrence of R is independently H, D, F, Cl, Br, CH, OCH, NH, N(CH), [ka] -CN, -NC, N3, NO2, [ka] In some embodiments, each occurrence of R is independently H, D, F, CH, N(CH), [ka] is.

[0247] In some embodiments, at least one occurrence of R2 is H, D, or halogen. In some embodiments, at least one occurrence of R2 is H. In some embodiments, at least one occurrence of R2 is D. In some embodiments, at least one occurrence of R2 is F. In some embodiments, at least one occurrence of R2 is CH3. In some embodiments, at least one occurrence of R2 is OCH3. In some embodiments, at least one occurrence of R2 is NH2. In some embodiments, at least one occurrence of R2 is N(CH3)2. In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] [In the formula, R a ' is H or (C1-C6) alkyl. In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] [In the formula, R a ' is H or (C1-C6) alkyl. In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is -CN. In some embodiments, at least one occurrence of R2 is -NC. In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is NO2. In some embodiments, at least one occurrence of R2 is N3. In some embodiments, at least one occurrence of R2 is [ka] In some embodiments, at least one occurrence of R2 is [ka] is.

[0248] In some embodiments, each occurrence of R is independently selected from H, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, —N(R a )2, NO2 and -OR a In some embodiments, each occurrence of R2 is independently H, halogen, CH3, CF3, OH, NH2, -NHCH3, or -N(CH3)2. In some embodiments, at least one occurrence of R2 is H. In some embodiments, at least one occurrence of R2 is (C1-C6) alkyl. In some embodiments, at least one occurrence of R2 is -N(R a )2, NO2 or -OR a In some embodiments, at least one occurrence of R2 is H, CH3, OH, NH2, or halogen. In some embodiments, at least one occurrence of R2 is H. In some embodiments, at least one occurrence of R2 is CF3. In some embodiments, R2 is H or CH3.

[0249] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0250] In some embodiments, Z1, Z2, Z3, Z4, and Z5 are each independently CR3 or N. In some embodiments, Z1, Z2, Z3, Z4, and Z5 are each independently CR3. In some embodiments, Z1, Z2, Z3, Z4, and Z5 are each independently CH. In some embodiments, Z1, Z2, Z3, Z4, and Z5 are each N. In some embodiments, one of Z1, Z2, Z3, Z4, and Z5 is CR3, and the rest are N. In some embodiments, one of Z1, Z2, Z3, Z4, and Z5 is CH, and the rest are N. In some embodiments, two of Z1, Z2, Z3, Z4, and Z5 are CR3, and the rest are N. In some embodiments, two of Z1, Z2, Z3, Z4, and Z5 are CH, and the rest are N. In some embodiments, three of Z1, Z2, Z3, Z4, and Z5 are CR3 and two are N. In some embodiments, three of Z1, Z2, Z3, Z4, and Z5 are CH and two are N. In some embodiments, Z4 is N and Z1, Z2, Z3, and Z5 are CR3.

[0251] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0252] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0253] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In these embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0254] In some embodiments, R x Each occurrence of is independently H, (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl or R x and Y3, R x and Y4, R x and Z1, or R x and Z4 together form an optionally substituted 5- to 6-membered heterocycle. x Each occurrence of is independently H, (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl. x Each occurrence of is independently H, CH, or CHCH. In some embodiments, R x and Y4 together form an optionally substituted 5-6 membered heterocycle. x and Y3 together form an optionally substituted 5- to 6-membered heterocycle. x and Z1 together form an optionally substituted 5- to 6-membered heterocycle. x and Z4 together form an optionally substituted 5- to 6-membered heterocycle.

[0255] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0256] In some embodiments, W1, W2, W3, W4, and W5 are each independently CR6, N, or NR6, where valence allows. In some embodiments, one of W1, W2, W3, W4, and W5, where valence allows, is N or NR6, and the remainder are C or CR6. In some embodiments, two of W1, W2, W3, W4, and W5, where valence allows, are N or NR6, and the remainder are C or CR6. In some embodiments, three of W1, W2, W3, W4, and W5, where valence allows, are N or NR6, and two are C or CR6. In some embodiments, one of W1, W2, W3, W4, and W5, where valence allows, is N, and the remainder are C or CR6. In some embodiments, two of W1, W2, W3, W4, and W5, where valence allows, are N, and the remainder are C or CR6. In some embodiments, three of W1, W2, W3, W4 and W5, as allowed by valences, are N and two are C or CR6.

[0257] In some embodiments, each occurrence of R6 is independently selected from the group consisting of H, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl. In some embodiments, each occurrence of R6 is independently selected from the group consisting of H, F, CH3, and CH2CH3.

[0258] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0259] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, R3 is H, CH3, OH, halogen, or NH2. In some embodiments, R x is H, CH3 or CH2CH3.

[0260] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In these embodiments, each occurrence of m is independently 1 or 2, and J is C(R y )2 and R y each occurrence is independently H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen, or any two R y The groups, taken together with the carbon atom(s) to which they are attached, form a (C-C)cycloalkyl or a (C-C)heterocycloalkyl. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R y Each occurrence of is independently H or (C1-C6) alkyl. In some embodiments, R y Each occurrence of is independently OH, O(C1-C6)alkyl, or halogen. y Each occurrence of is H. In some embodiments, any two R y The groups, together with the carbon atom(s) to which they are attached, form a (C3-C7)cycloalkyl or a (C3-C7)heterocycloalkyl.

[0261] In some embodiments, the structural moiety [ka] teeth, [ka] [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, Y1, Y2, Y3, and Y4 are each independently N, CH, CCH3, or CF. In some embodiments, Y1, Y2, Y3, and Y4 are each independently N or CH.

[0262] In some embodiments, the structural moiety [ka] teeth, [ka] wherein each occurrence of m is independently 1 or 2, and J is C(R z )2 and R z each occurrence is independently H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen, or any two R z The groups, taken together with the carbon atom(s) to which they are attached, form a (C3-C7)cycloalkyl or a (C3-C7)heterocycloalkyl. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R zEach occurrence of is independently H or (C1-C6) alkyl. In some embodiments, R z Each occurrence of is independently OH, O(C1-C6)alkyl, or halogen. z Each occurrence of is H. In some embodiments, R z Each occurrence of is CH. In some embodiments, two R z The groups, taken together with the carbon atom(s) to which they are attached, form a (C-C)cycloalkyl. In some embodiments, two R z The groups, taken together with the carbon atom(s) to which they are attached, form a (C-C)heterocycloalkyl. In some embodiments, two R z The groups together with the carbon atom to which they are attached form a cyclopropyl.

[0263] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, Z1, Z2, Z3, and Z4 are each independently N, CH, CCH3, or CF. In some embodiments, Z1, Z2, Z3, and Z4 are each independently N or CH. In some embodiments, R z Each occurrence of is independently H or CH. In some embodiments, two R z The groups, taken together with the carbon atom(s) to which they are attached, form a (C-C)cycloalkyl. In some embodiments, two R z The groups, taken together with the carbon atom(s) to which they are attached, form a (C-C)heterocycloalkyl. In some embodiments, two R z The groups, taken together with the carbon atom to which they are attached, form a cyclopropyl. In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0264] In some embodiments, the compound has the structure of Formula Ib.

[0265] In some embodiments, T is N(C=O)R a or NSO2R a In some embodiments, T is N(C=O)Me or N(C=O)Et. In some embodiments, T is NSO2Me or NSO2Et. In some embodiments, T is O or NR a In some embodiments, T is O. In some embodiments, T is NR a In some embodiments, T is NH. In some embodiments, T is NCH3 or NCH2CH3. In some embodiments, T is NC(R b )2OP(=O)(OR b )2. In some embodiments, T is N or O where valence allows.

[0266] In some embodiments, U is N(C=O)R a or NSO2R a In some embodiments, U is N(C=O)Me or N(C=O)Et. In some embodiments, U is NSO2Me or NSO2Et. In some embodiments, U is O or NR a In some embodiments, U is O. In some embodiments, U is NR a In some embodiments, U is NH. In some embodiments, U is NCH3 or NCH2CH3. In some embodiments, U is NC(R b )2OP(=O)(OR b )2. In some embodiments, U is N or O where valence allows.

[0267] In some embodiments, R b Each occurrence of is independently H or (C1-C6) alkyl. b Each occurrence of R is independently H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl. b Each occurrence of is independently H or CH. In some embodiments, R bEach occurrence of is H.

[0268] In some embodiments, the structural moiety [ka] teeth, [ka] wherein each occurrence of T and U is independently O, N, NR, as allowed by valence. a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a is.

[0269] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0270] In some embodiments, the structural moiety [ka] teeth, [ka] and R b Each occurrence of is independently H or CH. In some embodiments, the structural moiety [ka] teeth, [ka] and R b Each occurrence of is independently H or CH. In some embodiments, the structural moiety [ka] teeth, [ka] and R b Each occurrence of is independently H or CH3.

[0271] In some embodiments, the compound has the structure of Formula Ic.

[0272] In some embodiments, the structural moiety [ka] teeth, [ka] wherein each occurrence of T and U is independently O, N, NR, as allowed by valence. a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a is.

[0273] In some embodiments, the structural moiety [ka] teeth, [ka] wherein R2 is H, CH3, OH, halogen, or NH2, and R a is H, CH, or CHCH. In some embodiments, R is H, CH, OH, halogen, or NH. In some embodiments, R a is H, CH3 or CH2CH3.

[0274] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, R b Each occurrence of is independently H or CH3.

[0275] In some embodiments, each occurrence of R is independently selected from H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, aryl, heteroaryl, -OR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a In some embodiments, each occurrence of R3 is independently selected from the group consisting of (C4-C 10)heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each occurrence of R3 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl and (C4-C 10 In some embodiments, each occurrence of R is independently selected from the group consisting of aryl and heteroaryl. In some embodiments, each occurrence of R is independently selected from the group consisting of -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a In some embodiments, each occurrence of R is independently selected from the group consisting of: [ka] In some embodiments, each occurrence of R is independently selected from the group consisting of H, D, halogen, OR a , N(R a )2, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, (C1-C6) alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -CN, -NC, N3, NO2, COR a , CO2R a , CON(R a )2, -SO2R a or -SO2N(R a )2. In some embodiments, each occurrence of R3 is independently H, D, halogen, (C1-C6)alkyl, (C3-C7)heterocycloalkyl, N(R a)2 or -CN. In some embodiments, each occurrence of R3 is independently H, (C1-C6) alkyl, (C1-C6) alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -SO2R a or -SO2N(R a In some embodiments, each occurrence of R is independently H, D, F, Cl, Br, CH, OCH, NH, N(CH), [ka] -CN, -NC, N3, NO2, [ka] In some embodiments, each occurrence of R is independently H, D, F, CH, N(CH), [ka] is.

[0276] In some embodiments, at least one occurrence of R3 is H, D, or halogen. In some embodiments, at least one occurrence of R3 is H. In some embodiments, at least one occurrence of R3 is D. In some embodiments, at least one occurrence of R3 is F. In some embodiments, at least one occurrence of R3 is CH3. In some embodiments, at least one occurrence of R3 is OCH3. In some embodiments, at least one occurrence of R3 is NH2. In some embodiments, at least one occurrence of R3 is N(CH3)2. In some embodiments, at least one occurrence of R3 is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] [In the formula, R a ' is H or (C1-C6) alkyl. In some embodiments, at least one occurrence of R3 is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R3 is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] [In the formula, R a ' is H or (C1-C6) alkyl. In some embodiments, at least one occurrence of R3 is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R3 is -CN. In some embodiments, at least one occurrence of R3 is -NC. In some embodiments, at least one occurrence of R3 is [ka] In some embodiments, at least one occurrence of R3 is [ka] In some embodiments, at least one occurrence of R3 is [ka] In some embodiments, at least one occurrence of R is -NC. In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is NO. In some embodiments, at least one occurrence of R is N. In some embodiments, at least one occurrence of R is [ka] In some embodiments, at least one occurrence of R is [ka] is.

[0277] In some embodiments, each occurrence of R is independently H, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, —N(R a )2, NO2 and -OR a In some embodiments, at least one occurrence of R3 is H, CH3, OH, NH2, or halogen. In some embodiments, at least one occurrence of R3 is H or CH3. In some embodiments, at least one occurrence of R3 is OH or NH2. In some embodiments, at least one occurrence of R3 is halogen. In some embodiments, at least one occurrence of R3 is H. In some embodiments, at least one occurrence of R3 is CF3. In some embodiments, R3 is H or CH3.

[0278] In some embodiments, V is absent, O, or NR a In some embodiments, V is absent. In some embodiments, V is O. In some embodiments, V is NR aIn some embodiments, V is NH. In some embodiments, V is NCH3 or NCH2CH3.

[0279] In some embodiments, V is N(C=O)R a or NSO2R a In some embodiments, V is N(C=O)H. In some embodiments, V is N(C=O)CH3 or N(C=O)CH2CH3. In some embodiments, V is NSO2H. In some embodiments, V is NSO2CH3 or NSO2CH2CH3.

[0280] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0281] In some embodiments, the structural moiety [ka] V and R4 together form (C4~C 10 ) forming a heterospiroalkyl.

[0282] In some embodiments, R4 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more R5. In some embodiments, R4 is substituted with 0, 1, 2, 3, 4, 5, or 6 R5 substituents, and each R5 is independently selected from the group consisting of H, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C6) 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, N(R a )COR a , -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] In some embodiments, each occurrence of R5 is independently selected from the group consisting of (C4 to C 10 ) heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, or heteroaryl. In some embodiments, R4 is [ka] and [ka] wherein R5 may be attached to any position of the bicycloalkyl or heterobicycloalkyl, including the bridgehead carbon; [ka] In some embodiments, R4 is: [ka] In some embodiments, R4 is [ka] In some embodiments, R4 is [ka] In some embodiments, R4 is [ka] In some embodiments, R4 is [ka] In some embodiments, R4 is [ka] In some embodiments, R4 is [ka] In some embodiments, R4 is [ka] In some embodiments, m is an integer from 0 to 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0283] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, V has the structure: a )2, O, NR a , N(C=O)R a or NSO2R a In some embodiments, V' is CR a Or N.

[0284] In some embodiments, each occurrence of R is independently selected from H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, aryl, heteroaryl, -OR a , -N(R a )2, -COR a , -CO2R a , N(R a )COR a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a In some embodiments, each occurrence of R is independently selected from the group consisting of (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl and (C4-C 10 In some embodiments, each occurrence of R is independently selected from the group consisting of (C4-C10 ) heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, and heteroaryl. In some embodiments, each occurrence of R5 is independently selected from the group consisting of -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , N(R a )COR a , -SO2N(R a )2 and -N(R a )SO2R a In some embodiments, each occurrence of R5 is independently selected from the group consisting of: [ka] In some embodiments, each occurrence of R is independently selected from the group consisting of H, D, halogen, OR a , N(R a )2, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, (C1-C6) alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -CN, -NC, N3, NO2, COR a , CO2R a , CON(R a )2, -SO2R a , N(R a )COR a or -SO2N(R a )2. In some embodiments, each occurrence of R5 is independently H, D, halogen, (C1-C6)alkyl, (C3-C7)heterocycloalkyl, N(R a )COR a , N(R a )2 or -CN. In some embodiments, each occurrence of R5 is independently H, (C1-C6) alkyl, (C1-C6) alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -SO2R a or -SO2N(R aIn some embodiments, each occurrence of R is independently H, D, F, Cl, Br, CH, CF, OCH, NH, N(CH), [ka] -CN, -NC, N3, NO2, [ka] In some embodiments, each occurrence of R is independently H, D, F, CH, N(CH), [ka] is.

[0285] In some embodiments, at least one occurrence of R5 is H, D, or halogen. In some embodiments, at least one occurrence of R5 is H. In some embodiments, at least one occurrence of R5 is D. In some embodiments, at least one occurrence of R5 is F. In some embodiments, at least one occurrence of R5 is CH3. In some embodiments, at least one occurrence of R5 is OCH3. In some embodiments, at least one occurrence of R5 is NH2. In some embodiments, at least one occurrence of R5 is N(CH3)2. In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] and R a ' is H or (C1-C6) alkyl. In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] and R a ' is H or (C1-C6) alkyl. In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is -CN. In some embodiments, at least one occurrence of R5 is -NC. In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is NO2. In some embodiments, at least one occurrence of R5 is N3. In some embodiments, at least one occurrence of R5 is [ka] In some embodiments, at least one occurrence of R5 is [ka] is.

[0286] In some embodiments, each occurrence of R5 is independently selected from halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, OR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, N(R a )COR a , -CN, NO2, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] In some embodiments, at least one occurrence of R5 is selected from the group consisting of (C1-C6) alkyl, halogen, OH, NH2, or [ka] In some embodiments, at least one occurrence of R5 is CH3, halogen, OH, or NH2. In some embodiments, at least one occurrence of R5 is OH. In some embodiments, at least one occurrence of R5 is CH3. In some embodiments, at least one occurrence of R5 is [ka] is.

[0287] In any one of the embodiments described herein, R a Each occurrence of R is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C3-C7) cycloalkyl, aryl, or heteroaryl. In any one of the embodiments described herein, R a At least one occurrence of R is aryl or heteroaryl. In any one of the embodiments described herein, R a each occurrence is independently H, (C1-C6) alkyl, (C2-C6) alkenyl, or (C3-C7) cycloalkyl, or two R a taken together form a 5- or 6-membered ring optionally substituted with halogen or (C1-C6) alkyl. In some embodiments, R a Each occurrence of is independently H or (C1-C6) alkyl. a Each occurrence of is independently (C-C) alkenyl. a Each occurrence of is independently H, CH, or CHCH. In some embodiments, R a At least one occurrence of is H or CH. In some embodiments, R a Each occurrence of is H. In some embodiments, R a Each occurrence of R is CH. a At least one occurrence of is (C-C)cycloalkyl optionally substituted with halogen or (C-C)alkyl. a At least one occurrence of is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with halogen or (C1-C6) alkyl.

[0288] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0289] In some embodiments, the compound of formula Ia is [ka] [ka] and R1 is H, (C1-C6) alkyl, N(R a )2, (C3-C7)heterocycloalkyl or halogen, and R5 and R 11 are each independently H or CH, Y, Y, Y, Y, Z, Z, Z, L, and L are each independently CH or N, and V is NH or O. In some embodiments, the compound of formula Ia is [ka] [ka] and R1 is H, (C1-C6) alkyl, N(R a)2, (C3-C7)heterocycloalkyl or halogen, and R5 and R 11 are each independently H or CH, Y, Y, Y, Y, Z, Z, Z, L, and L are each independently CH or N, and V is NH or O. In some embodiments, the compound of formula Ia is [ka] and R1 is H, (C1-C6) alkyl, N(R a )2, (C3-C7)heterocycloalkyl or halogen, and R5 and R 11 are each independently H or CH, Y, Y, Y, Y, Z, Z, Z, L, and L are each independently CH or N, and V is NH or O. In some embodiments, R is H, F, Cl, Br, CH, CHCH, or CH(CH), [ka] In some embodiments, R is [ka] In some embodiments, R is [ka] is.

[0290] In some embodiments, the compound of formula Ib is [ka] and R 11 and R5 are each independently H or CH3, and Y1, Y2, Y3, Y4, Z2, Z3, and Z4 are each independently CH or N. In some embodiments, the compound of formula Ib is [ka] and R11 and R5 are each independently H or CH3, and Y1, Y2, Y3, Y4, Z2, Z3, and Z4 are each independently CH or N. In some embodiments, the compound of formula Ib is [ka] and R 11 and R5 are each independently H or CH3, and Y1, Y2, Y3, Y4, Z2, Z3 and Z4 are each independently CH or N.

[0291] In some embodiments, the compound of formula Ib is [ka] and R1, R5 and R 11 are each independently H, halogen, or CH3, and Y1, Y2, Y3, Y4, Z2, Z3, and Z4 are each independently CH or N.

[0292] In some embodiments, the compound of formula Ic is [ka] and R1, R5 and R 11 are each independently H, halogen, or CH3, and Y1, Y2, Y4, Z1, Z2, Z3, and Z4 are each independently CH or N.

[0293] In some embodiments, the compound of formula Ia, Ib, or Ic activates Akt3, and the compound [ka] In some embodiments, the compound of Formula Ia, Ib, or Ic activates Akt3 and is compound 2 shown in Table 2.

[0294] In some embodiments, the compound of Formula Ia, Ib, or Ic inhibits Akt3, [ka] In some embodiments, the compound of formula Ia, Ib, or Ic inhibits Akt3 and is selected from the group consisting of: [ka] In some embodiments, the compound of Formula Ia, Ib, or Ic inhibits Akt3 and is selected from the group consisting of compounds 3, 18-21, 26, 27, 30, 32-34, and 37-45 shown in Table 1.

[0295] In some embodiments, the compound of formula Ia is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is.

[0296] In some embodiments, the compound of formula Ia is [ka] and R1 is -CONH2, -SO2NH2, -SO2CH3 or [ka] is.

[0297] In some embodiments, the compound of formula Ia is [ka] wherein R1 is -CN or -F, and G1 and G2 are -N- and -CH- or -CH- and -N-.

[0298] In some embodiments, the compound of formula Ia is [ka] and R1 is -CONH2, -SO2NH2, -SO2CH3 or [ka] and each of J1, J2, J3, J4, J5 and J6 is independently -N- or -CF.

[0299] In some embodiments, the compound of formula Ia is [ka] and R1 is -CONH2, -SO2NH2, -SO2CH3, [ka] is.

[0300] In some embodiments, the compound of formula Ia is [ka] and R1 is [ka] and G1 and G2 are either -N- and -CH- or -CH- and -N-.

[0301] In some embodiments, the compound of formula Ia is [ka] and R1 is [ka] and each of J1, J2, J3, J4, J5, J6 and J7 is independently -N- or -CF.

[0302] In some embodiments, the compound of formula Ib is [ka] [ka] [ka] [ka] is.

[0303] In some embodiments, the compound of formula Ic is [ka] is.

[0304] In some embodiments, the compound is [ka] is.

[0305] In some embodiments, the compound is [ka] is.

[0306] In any one of the embodiments disclosed herein, the compound is selected from the group consisting of compounds 2-45 in Examples 2-45, respectively.

[0307] In any one of the embodiments disclosed herein, the compound is selected from the group consisting of compounds 22, 31, and 39-45 in Examples 22, 31, and 39-45, respectively.

[0308] In any one of the embodiments disclosed herein, the compound is selected from the group consisting of compounds 3, 18-21, 26, 27, 30, 32-34, and 37-45 shown in Table 1.

[0309] In any one of the embodiments disclosed herein, the compound is Compound 2 shown in Table 2.

[0310] Prodrug In some embodiments, any one of the compounds described herein can be modified into a prodrug by attaching one or more functional groups therein to a cleavable moiety. See, for example, J. Med. Chem., Vol. 61, pp. 62-80 (2018); J. Med. Chem., Vol. 61, pp. 6308-6327 (2018); and J. Med. Chem., Vol. 61, pp. 3918-3929 (2018). In some embodiments, the moiety is cleavable upon exposure to a stimulus. Non-limiting examples of such stimuli include temperature, electromagnetic radiation, sound vibration, pH, solvents, and substances and processes found on or within living organisms. In some embodiments, the cleavable moiety is removed by contact with a living organism. In some embodiments, the cleavable moiety is removed by contact with an enzyme. In some embodiments, the cleavable moiety is removed by contact with alkaline phosphatase. In some embodiments, the cleavable moiety is a phosphonooxymethyl moiety that is cleaved as illustrated in Scheme A below. [ka]

[0311] How to Modulate Akt3 Akt3, also known as RAC-γ serine / threonine-protein kinase, is an enzyme encoded by the Akt3 gene in humans. Akt kinase is known to be a regulator of cell signaling in response to insulin and growth factors, and is involved in a wide range of biological processes, including but not limited to cell proliferation, differentiation, apoptosis and tumorigenesis, as well as glycogen synthesis and glucose uptake. Akt3 has been shown to be stimulated by platelet-derived growth factor ("PDGF"), insulin and insulin-like growth factor 1 ("IGF1").

[0312] Akt3 kinase activity mediates the serine and / or threonine phosphorylation of a series of downstream substrates. The nucleic acid sequence for Akt3 is known in the art. See, for example, Genbank Accession No. AF124141.1: Homo sapiens protein kinase B gamma mRNA (complete cds), which is specifically incorporated by reference in its entirety and provides the following nucleic acid sequence: AGGGGAGTCATCATGAGCGATGTTACCATTGTGAAGGAAGGTTGGGTTCAGAAGAGGGGA GAATATATAAAAAACTGGAGGCCAAGATACTTCCTTTTGAAGACAGATGGCTCATTCATA GGATATAAAGAGAAACCTCAAGATGTGGATTTACCTTATCCCCTCAACAACTTTTCAGTG GCAAAAATGCCAGTTAATGAAAACAGAACGACCAAAGCCAAACACATTTATAATCAGATGT CTCCAGTGGACTACTGTTATAGAGAGAACATTTCATGTAGATACTCCAGAGGAAAGGGAA GAATGGACAGAAGCTATCCAGGCTGTAGCAGACAGACTGCAGAGGCAAGAAGAGGAGAGA ATGAATTGTAGTCCAACTTCACAAATTGATAATATAGGAGAGGAAGAGATGGATGCCTCT ACAACCCATCATAAAAGAAAGACAATGAATGATTTTGACTATTTGAAACTACTAGGTAAA GGCACTTTTGGGAAAGTTATTTTGGTTCGAGAGAAGGCAAGTGGAAAATACTATGCTATG AAGATTCTGAAGAAAGAAGTCATTATTGCAAAGGATGAAGTGGCACACACTCTAACTGAA AGCAGAGTATTAAAGAACACTAGACATCCCTTTTTAACATCCTTGAAATATTCCTTCCAG ACAAAAGACCGTTTGTGTTTTGTGATGGAATATGTTAATGGGGGCGAGCTGTTTTTCCAT TTGTCGAGAGAGCGGGTGTTCTCTGAGGACCGCACACGTTTCTATGGTGCAGAAATTGTC TCTGCCTTGGACTATCTACATTCCGGAAAGATTGTGTACCGTGATCTCAAGTTGGAGAAT CTAATGCTGGACAAAGATGGCCACATAAAAATTACAGATTTTGGACTTTGCAAAGAAGGG ATCACAGATGCAGCCACCATGAAGACATTCTGTGGCACTCCAGAATATCTGGCACCAGAG GTGTTAGAAGATAATGACTATGGCCGAGCAGTAGACTGGTGGGGCCTAGGGGTTGTCATG TATGAAATGATGTGTGGGAGGTTACCTTTCTACAACCAGGACCATGAGAAACTTTTTGAA TTAATATTAATGGAAGACATTAAATTTCCTCGAACACTCTCTTCAGATGCAAAATCATTG CTTTCAGGGCTCTTGATAAAGGATCCAAATAAACGCCTTGGTGGAGGACCAGATGATGCA AAAGAAATTATGAGACACAGTTTCTTCTCTGGAGTAAACTGGCAAGATGTATATGATAAA AAGCTTGTACCTCCTTTTAAACCTCAAGTAACATCTGAGACAGATACTAGATATTTTGAT GAAGAATTTACAGCTCAGACTATTACAATAACACCACCTGAAAAATATGATGAGGATGGT ATGGACTGCATGGACAATGAGAGGCGGCCGCATTTCCCTCAATTTTCCTACTCTGCAAGT GGACGAGAATAAGTCTCTTTCATTCTGCTACTTCACTGTCATCTTCAATTTATTACTGAA AATGATTCCTGGACATCACCAGTCCTAGCTCTTACACATAGCAGGGGCACCTTCCGACAT CCCAGACCAGCCAAGGGTCCTCACCCCTCGCCACCTTTCACCCTCATGAAAACACACATA CACGCAAATACACTCCAGTTTTTGTTTTTGCATGAAATTGTATCTCAGTCTAAGGTCTCA TGCTGTTGCTGCTACTGTCTTACTATTA (SEQ ID NO: 1).

[0313] The amino acid sequence for Akt3 is also known in the art. See, e.g., UniProtKB / Swiss-Prot Accession No. Q9Y243 (Akt3_HUMAN), which is specifically incorporated by reference in its entirety and provides the following amino acid sequence: MSDVTIVKEGWVQKRGEYIKNWRPRYFLLKTDGSFIGYKEKPQDVDLPYPLNNFSVAKCQ LMKTERPKPNTFIIRCLQWTTVIERTFHVDTPEEREEWTEAIQAVADRLQRQEEERMNCS PTSQIDNIGEEEMDASTTHHKRKTMNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILK KEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNGGELFFHLSRE RVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLKLENLMLDKDGHIKITDFGLCKEGITDA ATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILM EDIKFPRTLSSDAKSLLSGLLIKDPNKRLGGGPDDAKEIMRHSFFSGVNWQDVYDKKLVP PFKPQVTSETDTRYFDEEFTAQTITITPPEKYDEDGMDCMDNERRPHFPQFSYSASGRE (SEQ ID NO: 2).

[0314] The domain structure of Akt3 is outlined in Romano, Scientifica, Volume 2013 (2013), Article ID 317186, page 12, and includes an N-terminal pleckstrin homology domain ("PH") followed by a catalytic kinase domain ("KD") and a C-terminal regulatory hydrophobic region. The KD and regulatory domains are important for the biological actions mediated by Akt protein kinases and show the greatest homology among the three Akt isoforms. The PH domain binds lipid substrates, such as phosphatidylinositol (3,4) diphosphate ("PIP2") and phosphatidylinositol (3,4,5) triphosphate ("PIP3"). The ATP-binding site is located approximately in the center of the catalytic kinase domain, which has a significant degree of homology to other members of the AGC kinase family, e.g., p70 S6 kinase ("S6K") and p90 ribosomal S6 kinase ("RSK"), protein kinase A ("PKA"), and protein kinase B ("PKB"). A hydrophobic regulatory moiety is a typical feature of the AGC kinase family. With reference to SEQ ID NO: 2, Akt3 is generally believed to have the molecular processing and domain structure outlined below.

[0315] Molecular Processing: Main features Position(s) Length Type Initiator methionine 1 1 removal Chain 2-479 478 Akt3 region: Main features Position(s) Length Type Domain 5~107 103 PH Domains 148-405 258 Protein Kinases Domain 406–479 74 AGC-kinase, C-terminus Nucleotide binding 154-162 9 ATP Part: Main features Position(s) Length Type Active site 271 1 Proton acceptor Binding site 177 1 ATP The initiator methionine of SEQ ID NO: 2 is disposable for Akt3 function. Thus, in some embodiments, the compound directly or indirectly modulates the expression or bioavailability of Akt3 having the following amino acid sequence: SDVTIVKEGWVQKRGEYIKNWRPRYFLLKTDGSFIGYKEKPQDVDLPYPLNNFSVAKCQ LMKTERPKPNTFIIRCLQWTTVIERTFHVDTPEEREEWTEAIQAVADRLQRQEEERMNCS PTSQIDNIGEEEMDASTTHHKRKTMNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILK KEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNGGELFFHLSRE RVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLKLENLMLDKDGHIKITDFGLCKEGITDA ATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILM EDIKFPRTLSSDAKSLLSGLLIKDPNKRLGGGPDDAKEIMRHSFFSGVNWQDVYDKKLVP PFKPQVTSETDTRYFDEEFTAQTITITPPEKYDEDGMDCMDNERRPHFPQFSYSASGRE (SEQ ID NO: 3).

[0316] Two specific sites must be phosphorylated for full activation of Akt3: one in the kinase domain (Thr-305, per SEQ ID NO: 2) and the other in the C-terminal regulatory region (Ser-472, per SEQ ID NO: 2). Interaction between the PH domain of Akt3 and TCL1A enhances Akt3 phosphorylation and activation. IGF-1 leads to activation of Akt3, which may play a role in regulating cell survival.

[0317] In some embodiments, the compounds of Formula Ia, Ib, or Ic described herein are inhibitors of Akt3. In other embodiments, the compounds of Formula Ia, Ib, or Ic described herein are activators of Akt3.

[0318] Pharmaceutical Composition Some aspects of the invention involve administering an effective amount of a composition to a subject to achieve a particular result. Thus, small molecule compositions useful in accordance with the methods of the invention can be formulated in any manner suitable for pharmaceutical use.

[0319] The formulations of the present invention are administered in pharmaceutically acceptable solutions, which may conventionally contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and other therapeutic ingredients as appropriate.

[0320] For use in therapy, an effective amount of the compound can be administered to a subject in any mode that allows the compound to be absorbed by the appropriate target cells. "Administering" the pharmaceutical composition of the present invention can be achieved by any means known to those skilled in the art. Specific routes of administration include, but are not limited to, oral, transdermal (e.g., via a patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.) or mucosal (intranasal, intratracheal, inhalation, rectal, intravaginal, etc.). Injection can be by bolus or continuous infusion.

[0321] For example, pharmaceutical compositions according to the present invention are often administered intravenously, intramuscularly, or by other parenteral means. They can also be administered intranasally, by inhalation, topically, orally, or as an implant, or even rectally or vaginally. Suitable liquid or solid pharmaceutical preparations include, for example, aqueous solutions or saline solutions for injection or inhalation, microencapsulated, cochleated, coated on fine gold particles, contained in liposomes, nebulized, aerosolized, as pellets for skin implantation, or dried on sharp objects that scratch the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with delayed release of the active compound, which typically contain excipients and additives and / or auxiliaries, such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers, as described above. The pharmaceutical compositions are suitable for use in various drug delivery systems. For a brief review of current methods for drug delivery, see Langer R (1990) Science 249:1527-33.

[0322] The concentration of the compound in the composition used in the method of the present invention can range from about 1 nM to about 100 μM. Effective doses are believed to be in the range of about 10 picomoles / kg to about 100 micromoles / kg.

[0323] Pharmaceutical compositions are preferably prepared and administered in dosage units. Liquid dosage units are vials or ampoules for injection or other parenteral administration. Solid dosage units are tablets, capsules, powders and suppositories. For the treatment of patients, different dosages may be required depending on the activity of the compound, the mode of administration, the purpose of administration (i.e., prophylactic or therapeutic), the nature and severity of the disorder, and the age and weight of the patient. The administration of a given dose can be carried out as a single administration in the form of individual dosage units or in the form of several smaller dosage units. Repeated and multiple administration of the dose at specific daily, weekly or monthly intervals is also contemplated by the present invention.

[0324] The composition can be administered as it is (pure) or in the form of a pharmaceutically acceptable salt. When used in medicine, the salt must be pharmaceutically acceptable, but non-pharmaceutically acceptable salts can also be conveniently used to prepare pharmaceutically acceptable salts. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, TsOH (p-toluenesulfonic acid), tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Such salts can also be prepared as alkali metal or alkaline earth salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[0325] Suitable buffering agents include acetic acid and salts (1-2% w / v), citric acid and salts (1-3% w / v), boric acid and salts (0.5-2.5% w / v), and phosphoric acid and salts (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v), chlorobutanol (0.3-0.9% w / v), parabens (0.01-0.25% w / v), and thimerosal (0.004-0.02% w / v).

[0326] Compositions suitable for parenteral administration advantageously include sterile aqueous preparations that can be isotonic with the recipient's blood. Acceptable vehicles and solvents include water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as solvents or suspending media. For this purpose, any non-irritating, fixed mineral oil or non-mineral oil, including synthetic mono- or diglycerides, may be used. In addition, fatty acids, such as oleic acid, are found to be used in injectable preparations. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous, etc. administration can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.

[0327] The compounds useful in the present invention can be delivered as a mixture of more than two such compounds, which can further include one or more adjuvants in addition to the combination of compounds.

[0328] A variety of administration routes are available.The specific mode selected will naturally depend on the specific compound selected, the age and general health of the subject, the specific condition being treated, and the dosage required for therapeutic effect.The method of the present invention can be carried out using any medically acceptable administration mode, which means any mode that produces an effective response level without causing clinically unacceptable adverse effects.Preferred administration modes have been discussed above.

[0329] Composition can be conveniently presented in unit dosage form, and can be prepared by any method known in the art of pharmacy.All methods comprise the step of combining compound with carrier that constitutes one or more accessory components.Generally, composition is prepared by uniformly and intimately combining compound with liquid carrier, finely divided solid carrier or both, and then, if necessary, shaping product.

[0330] Other delivery systems include sustained-release, delayed-release, or sustained-release delivery systems. Such systems can avoid repeated administration of the compound, increasing convenience for both the patient and the physician. Many types of release delivery systems are available and known to those skilled in the art. These include polymer-based systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Drug-containing microcapsules of the aforementioned polymers are described, for example, in U.S. Pat. No. 5,075,109. Delivery systems also include non-polymeric systems, such as lipids or neutral lipids containing sterols, such as cholesterol, cholesterol esters, and fatty acids, e.g., mono-, di-, and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; and partially condensed implants. Specific examples include, but are not limited to: (a) erosion systems, in which the agent of the invention is contained in a matrix, such as those described in U.S. Patent Nos. 4,452,775, 4,675,189, and 5,736,152, and (b) diffusion systems, in which the active ingredient permeates through a polymer at a controlled rate, such as those described in U.S. Patent Nos. 3,854,480, 5,133,974, and 5,407,686. In addition, pump-based hardware delivery systems can be used, some of which are adapted for implantation.

[0331] How to Treat a Disease In another aspect, a method of treating a disease in a subject in need thereof comprises administering to the subject an effective amount of a compound of Formula Ia, Ib, or Ic described herein.

[0332] In some embodiments, the disease is selected from the group consisting of neurodegenerative diseases, cachexia, anorexia, obesity, complications of obesity, inflammatory diseases, virally induced inflammatory responses, Gulf War syndrome, tuberous sclerosis, retinitis pigmentosa, transplant rejection, cancer, autoimmune diseases, ischemic tissue injury, traumatic tissue injury, and combinations thereof.

[0333] In some embodiments, a compound of Formula Ia, Ib, or Ic modulates Akt3 in immune cells. Non-limiting examples of immune cells include T cells (e.g., regulatory T cells ("Tregs")), B cells, macrophages, and glial cells (e.g., astrocytes, microglia, or oligodendrocytes). In some embodiments, the immune cell is a Treg. In some embodiments, a compound of Formula Ia, Ib, or Ic activates Akt3 signaling. In other embodiments, a compound of Formula Ia, Ib, or Ic inhibits Akt3 signaling. In some embodiments, a compound of Formula Ia, Ib, or Ic modulates Akt3 in Tregs. The inventors surprisingly found that in some embodiments, a compound of Formula Ia, Ib, or Ic increases Treg activity or production, while in other embodiments, the compound reduces Treg activity or production. The inventors have also surprisingly found that in some embodiments, compounds of Formula Ia, Ib, or Ic activate Akt3 signaling, while in other embodiments, the compounds inhibit Akt3 signaling.

[0334] Neurodegenerative diseases In some embodiments, methods are described for treating or preventing a neurodegenerative disease in a subject in need thereof, comprising modulating Akt3 signaling by administering to the subject an effective amount of a compound of Formula Ia, Ib, or Ic described herein. In some embodiments, the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, motor neuron disease, Huntington's disease, HIV-induced neurodegeneration, Lewy body disease, spinal muscular atrophy, prion disease, spinocerebellar degeneration, familial amyloid polyneuropathy, multiple sclerosis, and combinations thereof.

[0335] Neurodegenerative diseases occur when nerve cells in the brain or peripheral nervous system lose function over time and eventually die.In many neurodegenerative diseases, chronic neuroinflammation is the cause of disease progression.Current treatments can help alleviate some of the physical or mental symptoms associated with neurodegenerative diseases, but there is currently no way to slow the progression of the disease, and there is no known cure.

[0336] Although the mechanisms that trigger neurodegenerative processes are unknown, increasing evidence suggests a crucial role for immunity and the immune system in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, spinal muscular atrophy, familial amyloid polyneuropathy, and ALS. Tregs suppress immune responses and mediate self-tolerance and immune homeostasis through the CD4 + Tregs are a subset of T cells (see Sakaguchi, et al., Cell, 133, 775-787 (2008)). Evidence suggests that Tregs play an important role in the progression of neurodegenerative diseases. For example, Akt3 can modulate the suppressive function of natural Tregs and the polarization of inducible Tregs, and thus, modulating Akt3 in immune cells can modulate immune responses. More specifically, activation of Akt3 in immune cells can result in an increased immunosuppressive response, while inhibition of Akt3 in immune cells can result in a decreased immunosuppressive response. Without being bound by any one theory, it is believed that modulating Akt3 signaling in immune cells can be used to treat and prevent neurodegenerative diseases.

[0337] In some embodiments, a method for treating or preventing a neurodegenerative disease in a subject in need thereof is described, comprising administering to the subject an Akt3 activator of a compound of Formula Ia, Ib, or Ic described herein in an amount effective to induce an immunosuppressive response and treat or slow the progression of the disease. In some embodiments, the Akt3 activator modulates the immune response by increasing the suppressive function of immunosuppressive cells. In some embodiments, Akt3 is selectively activated in immune cells. Exemplary immune cells include, but are not limited to, T cells, B cells, macrophages, and glial cells, such as astrocytes, microglia, and oligodendrocytes. In a preferred embodiment, Akt3 is activated in Tregs. In some embodiments, the Akt3 activator can be used to increase or promote the activity or production of Tregs, increase the production of cytokines, such as IL-10, from Tregs, increase the differentiation of Tregs, increase the number of Tregs, or increase the survival time of Tregs.

[0338] In some embodiments, a method for treating or preventing a neurodegenerative disease in a subject in need thereof is described, comprising administering to the subject an Akt3 inhibitor compound of Formula Ia, Ib, or Ic described herein in an amount effective to inhibit the immunosuppressive response and treat or prevent the progression of the disease. In some embodiments, the Akt3 inhibitor compound of Formula Ia, Ib, or Ic described herein modulates the immune response by reducing the immunosuppressive response or increasing the immunostimulatory response. In some embodiments, Akt3 is selectively inhibited in immune cells. Exemplary immune cells include, but are not limited to, T cells, B cells, macrophages, and glial cells, such as astrocytes, microglia, and oligodendrocytes. In a preferred embodiment, Akt3 is inhibited in Tregs.

[0339] In one embodiment, a compound of Formula Ia, Ib, or Ic can treat or prevent ALS. ALS, also known as Lou Gehrig's disease, is a progressive neurodegenerative disease that affects motor neurons in the brain and spinal cord. Symptoms of ALS include, but are not limited to, difficulty speaking, swallowing, walking, moving, and breathing. ALS typically affects men and women between the ages of 40 and 70. There are two different types of ALS: sporadic and familial. Sporadic ALS is the most common form of the disease in the United States, accounting for 90 to 95 percent of all cases. Familial ALS is associated with mutations in Cu / Zn superoxide dismutase (SOD1). Oxidative stress, mitochondrial dysfunction, excitotoxicity, protein aggregation, endoplasmic reticulum stress, axonal transport dysfunction, dysregulation of neuronal-glial interactions, and apoptosis have all been demonstrated to contribute to motor neuron damage in the presence of mutant SOD1. Without being bound by any one theory, it is believed that Treg dysfunction plays a role in the development of ALS, and that administering an Akt3 modulator can treat or prevent the progression of ALS. Some subjects with rapidly progressing ALS have a deficiency in the Treg master transcription factor FOXP3, which leads to dysfunction of Treg suppressive function. One embodiment provides a method for treating ALS in a subject in need of treatment by administering to the subject in need of treatment an Akt3 activator in an amount effective to activate Akt3 in immune cells and induce an immunosuppressive response. In a preferred embodiment, Akt3 is activated in Treg.

[0340] In some embodiments, administration of an Akt3 activator of Formula Ia, Ib, or Ic described herein to a subject with ALS slows disease progression and increases the subject's survival time.

[0341] For example, other motor neuron diseases including progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis, spinal muscular atrophy, and post-polio syndrome can be treated or prevented using the disclosed Akt3 modulators.

[0342] Parkinson's disease is a neurodegenerative disorder that mainly affects dopamine-producing neurons in a specific area of ​​the brain called the substantia nigra.Parkinson's disease is a progressive disease that worsens over time as neurons are damaged or disappear.The cause of neuronal death in Parkinson's disease is unknown.Symptoms of Parkinson's disease include, but are not limited to, tremors in hands, arms, legs, jaw or head, stiffness of limbs and trunk, slowness of movement and impaired balance and coordination.

[0343] One embodiment provides a method of treating Parkinson's disease by administering to a subject in need of treatment an Akt3 modulator in an amount effective to activate or inhibit Akt3 in immune cells and induce an immunosuppressive response. In some embodiments, administration of an Akt3 activator to a subject with Parkinson's disease slows or halts disease progression to unaffected areas of the brain.

[0344] In some embodiments, the disclosed Akt3 activators of Formula Ia, Ib, or Ic described herein can be administered prophylactically to a subject with a family history of Parkinson's disease or other neurodegenerative diseases. In some embodiments, the Akt3 activators can protect neurons from or delay the onset of the disease.

[0345] Huntington's disease is a progressive neurodegenerative disease.The disease is characterized by the progressive degeneration of nerve cells in the brain.Symptoms of Huntington's disease include, but are not limited to, problems with involuntary movement and dysfunction in voluntary movement, such as involuntary spasms, muscle rigidity, slow or abnormal eye movements, walking, loss of posture and balance, physical disorders of speech or swallowing; cognitive dysfunction, such as difficulty in organizing, prioritizing or concentrating on tasks, lack of flexibility or tendency to get stuck in thinking, behavior or actions, lack of impulse control, lack of awareness of one's own behavior and abilities, slowness in processing thoughts or specific words and difficulty in learning new information, and psychiatric disorders, such as depression.In one embodiment, the disclosed Akt3 modulator can reduce or slow the progression of the symptoms of Huntington's disease.

[0346] One embodiment provides a method of treating Huntington's disease in a subject in need thereof by administering to the subject an Akt3 modulator in an amount effective to activate or inhibit Akt3 in immune cells and induce an immunosuppressive response. In some embodiments, the Akt3 modulator can slow or halt the progression of disease symptoms in a subject with Huntington's disease. In another embodiment, the Akt3 modulator can alter the balance of Treg / Th17.

[0347] Huntington's disease is primarily hereditary. All children of parents with Huntington's disease have a 50 / 50 chance of inheriting the disease. In one embodiment, subjects with a familial history of Huntington's disease can prevent or delay the onset of disease symptoms by prophylactically administering one of the disclosed Akt3 modulators before the onset of disease symptoms.

[0348] Alzheimer's disease is a progressive disorder that causes brain cells to degenerate and eventually disappear. Alzheimer's disease is the most common cause of dementia and is characterized by a progressive decline in thinking, behavior, and social skills that disrupts a person's ability to function independently. Symptoms of Alzheimer's disease include, but are not limited to, memory loss, impairments in thinking and reasoning abilities, difficulty making judgments and decisions, and changes in personality and behavior. While the exact cause of Alzheimer's disease is not fully understood, the core problem is thought to be a malfunction in brain proteins that disrupts neuronal function and triggers a series of toxic events. Damage most often begins in the brain area that controls memory, but this process begins several years before the first symptoms. Neuronal loss spreads to other areas of the brain in a somewhat predictable pattern. By the later stages of the disease, the brain has significantly shrunk. Beta-amyloid plaques and tau protein tangles are most often responsible for the massive neuronal damage and dysfunction in Alzheimer's disease.

[0349] One embodiment provides a method of treating Alzheimer's disease in a subject by administering to the subject an Akt3 activator in an amount effective to activate Akt3 in Tregs and activate downstream neuroprotective pathways in the brain. In another embodiment, the subject is administered an effective amount of an Akt3 activator to reduce or eliminate symptoms of Alzheimer's disease or slow disease progression.

[0350] Another embodiment provides a method of treating or preventing the progression of Alzheimer's disease in a subject by administering to the subject an Akt3 inhibitor of Formula Ia, Ib, or Ic described herein in an amount effective to inhibit Akt3 in Tregs and induce an immune response or reduce an immunosuppressive response. In some embodiments, inhibition of Akt3 in Tregs results in clearance of beta-amyloid plaques, attenuation of neuroinflammatory responses, and reversal of cognitive decline.

[0351] Spinal muscular atrophy ("SMA") is a group of chronic neuromuscular disorders characterized by the progressive loss of motor neurons and muscle wasting. SMA is generally classified into four types that differ in severity and life stage during which the disease manifests. These types are: SMA1 or Werdnig-Hoffmann disease, which appears between 0 and 6 months of age ("infantile" SMA); SMA2 or Dubowitz disease, which appears between 6 and 18 months of age ("intermediate" SMA); SMA3 or Kugelberg-Welander disease, which appears after age 1 year ("juvenile" SMA); and SMA4, which appears during adulthood ("adult-onset" SMA).

[0352] The most severe form, SMA1, is sometimes referred to as SMA0 ("infantile severe" SMA). Signs and symptoms of SMA vary depending on the type, but the most common include, but are not limited to, a tendency to slump or collapse, difficulty sitting, standing, or walking, loss of respiratory muscle strength, twitching, and difficulty eating and swallowing. All types of SMA are linked to exon deletions and / or point mutations in the SMN1 gene that prevent expression of the SMN protein. Depending on the type, SMA can be treated using various gene therapies, nutritional and respiratory support, orthopedic surgery, or a combination of these. Neuroprotective drugs hold promise as a way to stabilize motor neuron loss, but currently available candidates are still progressing successfully through clinical trials. Therefore, additional neuroprotective drug candidates are needed for the treatment of SMA.

[0353] One embodiment provides a method of treating SMA in a subject by administering to the subject an Akt3 modulator of Formula Ia, Ib, or Ic described herein in an amount effective to allow survival of motor neurons. In another embodiment, the subject receives an effective amount of an Akt3 modulator to reduce or eliminate symptoms of SMA or slow disease progression.

[0354] Multiple sclerosis ("MS") is a disease in which nerve cells in the brain and spinal cord demyelinate, leading to nerve cell damage and disruption of signal transmission throughout the nervous system. People with MS can experience almost any neurological sign / symptom, with autonomic, visual, motor, and sensory dysfunction being the most common. The exact cause of MS is unknown but is thought to be a combination of genetic factors, such as chromosomal abnormalities in the major histocompatibility complex, and environmental factors, such as exposure to infectious agents and toxins. Treatments for MS include, but are not limited to, drug and physical therapy, attempts to restore function in affected areas after an acute attack, and attempts to prevent new attacks. There is no known cure for MS, and many current drugs, while somewhat effective, have serious side effects and can be poorly tolerated. Therefore, new drugs are needed for safe, effective, reversible, and preventative treatment of MS.

[0355] One embodiment provides a method of treating MS in a subject by administering to the subject an Akt3 modulator of Formula Ia, Ib, or Ic described herein in an amount effective to restore function after a seizure and / or prevent a seizure from occurring. In another embodiment, the subject receives an effective amount of an Akt3 modulator to reduce or eliminate symptoms of MS or slow disease progression.

[0356] weight loss In some embodiments, disclosed herein are methods for treating or preventing extreme weight loss, comprising administering a compound disclosed herein to a subject in need thereof. Non-limiting examples of weight loss disorders include cachexia, anorexia nervosa, and anorexia nervosa. An exemplary method comprises inhibiting Akt3 in a subject in need thereof by administering a compound of Formula Ia, Ib, or Ic described herein. Without being bound by any one theory, Akt3 is believed to play a key role in adipogenesis. White adipogenesis requires the activation of a transcriptional cascade involving the sequential induction of several transcription factors, including, but not limited to, FOXO1, some members of the C / EBP family, and PPARγ. FOXO1 is a major negative regulator of adipogenesis and is primarily regulated through phosphorylation / acetylation on multiple residues by enzymes, including Akt. FOXO1 can also be regulated by the serine / threonine protein kinase SGK1. SGK1 is downstream of PI3K and can inhibit FOXO1 by phosphorylation. SGK1 is regulated by the serine / threonine protein kinase WNK1, which can also be regulated by Akt and SGK1. Akt3 suppresses lipogenesis through phosphorylation of WNK1, resulting in downregulation of SGK1 activity and SGK-1-mediated inhibition of FOXO1. In one embodiment, inhibition of Akt3 in Tregs can promote lipogenesis and reverse disease-induced weight loss.

[0357] Cachexia, or wasting syndrome, is a multifactorial syndrome characterized by the ongoing loss of skeletal muscle, which cannot be fully reversed by conventional nutritional supplementation and leads to progressive functional impairment. Cachexia is so destructive that when the body senses a lack of nutrients, it turns to other sources of energy, namely skeletal muscle and adipose tissue. Cachexia affects a large proportion of patients with advanced cancer and is associated with a decrease in infection-fighting ability, resistance to treatment, response to therapy, quality of life, and survival. In one embodiment, cachexia is caused by a chronic disease, such as, but not limited to, cancer, inflammatory disease, neurodegenerative disease, pathogenic infection, immunodeficiency disorder, weight gain disorder, weight loss disorder, hormonal imbalance, tuberous sclerosis, retinitis pigmentosa, congestive heart failure, and combinations thereof. One embodiment provides a method for treating cachexia in a subject in need of treatment by administering to the subject an Akt3 inhibitor, a compound of Formula Ia, Ib, or Ic, described herein, in an amount effective to reduce the symptoms of cachexia. Another embodiment provides a method for promoting weight gain in a subject in need of treatment by administering to the subject an Akt3 inhibitor, such as a compound of Formula Ia, Ib, or Ic, described herein, in an amount effective to promote adipogenesis in the subject. In one embodiment, a subject suspected of being susceptible to cachexia (e.g., a subject diagnosed with cancer or other disease) can be administered an Akt3 inhibitor prophylactically to prevent or delay the onset of cachexia syndrome. In some embodiments, the compounds disclosed herein are used to treat cachexia by modulating Akt3, rather than by modulating regulatory T cells.

[0358] Anorexia nervosa is an eating disorder characterized by weight loss or lack of weight gain in growing children, difficulty maintaining an appropriate weight for height, age, and stature, and often a distorted body image. One of the primary goals of treatment for anorexia is to restore normal body weight. In some embodiments, the compounds of formula Ia, Ib, or Ic disclosed herein inhibit Akt3, which is overactivated by estradiol and whose levels are increased in subjects with anorexia. In some embodiments, the compounds of formula Ia, Ib, or Ic disclosed herein can be used to treat anorexia. In one embodiment, the disclosed Akt3 inhibitor compounds of formula Ia, Ib, or Ic can be administered to subjects diagnosed with anorexia in an amount effective to promote adipogenesis and reverse excessive weight loss.

[0359] Obesity and its complications Disorders characterized by weight gain (e.g., obesity) are estimated to occur in 40% of adults and 20% of children and adolescents in the United States alone, and these numbers are trending upward. See "Overweight & Obesity: Data & Statistics," US Centers for Disease Control and Prevention, accessed April 3, 2020. Obesity is defined as a body mass index >30 kg / m 2 Akt3 activation is characterized by increased risk of various diseases (e.g., cardiovascular disease and type 2 diabetes). Akt3 activation has been shown to protect against obesity. In one embodiment, a method for treating obesity comprises administering an Akt3 activator to a subject with obesity or at risk of developing obesity in an amount effective to reverse or prevent the effects of the disease.

[0360] In some embodiments, the compounds disclosed herein that modulate Akt3 are used to treat obesity and / or obesity complications. In some embodiments, the obesity complications are selected from the group consisting of impaired glucose tolerance, fatty liver, dyslipidemia, and combinations thereof. In some embodiments, the compounds disclosed herein are used to treat obesity and / or obesity complications by modulating Akt3, rather than by modulating regulatory T cells.

[0361] inflammatory diseases Akt3 signaling is linked to chronic or acute inflammation, which leads to inflammatory diseases. One embodiment provides a method for treating or preventing an inflammatory disease in a subject in need thereof, comprising administering to the subject a composition comprising an Akt3 modulator in an amount effective to modulate Akt3 signaling and treat or delay the progression of the disease. In some embodiments, the Akt3 modulator activates Akt3 signaling and / or increases the activity or production of Tregs, resulting in an immunosuppressive effect.

[0362] Non-limiting examples of inflammatory diseases include atopic dermatitis, allergies, asthma, and combinations thereof.

[0363] Virus-induced inflammatory response Akt3 signaling is linked to the acute immune response that contributes to virally induced inflammatory diseases, such as severe acute respiratory syndrome ("SARS") and coronavirus disease 2019 ("COVID-19"). Thus, in one embodiment, a method of treating a virally induced inflammatory disease in a subject in need thereof comprises administering to the subject an Akt3 modulator in an amount effective to reverse or slow the progression of the disease.

[0364] cancer In some embodiments, there is provided a method of treating or preventing cancer in a subject in need thereof, comprising modulating Akt3 signaling via administering to the subject an effective amount of a compound of Formula Ia, Ib, or Ic described herein. In some embodiments, the compound of Formula Ia, Ib, or Ic inhibits Akt3 signaling and / or reduces Treg activity or production, resulting in an immune response activation effect.

[0365] In some embodiments, the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, uterine cancer, ovarian cancer, testicular cancer, adult T-cell leukemia / lymphoma, and combinations thereof.

[0366] In some embodiments, the compounds and compositions disclosed herein are useful for treating leukemia. In some embodiments, the compounds and compositions disclosed herein that inhibit Akt3 are useful for treating leukemia. In these embodiments, the compounds and compositions disclosed herein that inhibit Akt3 are useful in vivo and ex vivo as therapeutic agents that stimulate immune responses. The ability to inhibit Akt3, and thus inhibit or reduce Treg-mediated immunosuppression, allows for a more robust immune response. In some embodiments, the compounds and compositions disclosed herein are also useful for stimulating or enhancing immune stimulatory or activation responses involving T cells. In some embodiments, the compounds and compositions disclosed herein are useful for stimulating or enhancing immune responses in a host to treat leukemia by selectively inhibiting Akt3. In these embodiments, the compounds and compositions disclosed herein can be administered to a subject in an amount effective to stimulate T cells in the subject. Types of leukemia that can be treated with the compounds and compositions disclosed herein include, but are not limited to, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), adult T-cell leukemia / lymphoma (ATLL), and chronic myelomonocytic leukemia (CMML).

[0367] In some embodiments, ATLL is diagnosed almost exclusively in adults with a mean age in the mid-60s. In some embodiments, there are four types of ATLL: (1) acute, (2) chronic, (3) smoldering, and (4) lymphomatous. In some embodiments, acute ATLL is the most common form and is characterized by high white blood cell counts, hypercalcemia, organomegaly, and elevated lactose dehydrogenase activity. In some embodiments, lymphomatous ATLL manifests in lymph nodes and contains less than 1% circulating lymphocytes. In some embodiments, chronic and smoldering ATLL are characterized by a less aggressive clinical course and allow for prolonged survival. In some embodiments, the four-year survival rate for acute and lymphomatous ATLL is less than 5%. In some embodiments, the four-year survival rates for chronic and smoldering forms of ATLL are 26.9% and 62%, respectively. In some embodiments, adult T-cell leukemia / lymphoma is caused by human T-cell lymphotropic virus 1 (HTLV-1).

[0368] In some embodiments, the compounds and compositions disclosed herein are useful for treating ATLL. In some embodiments, the compounds and compositions disclosed herein that inhibit Akt3 are useful for treating ATLL. In some embodiments, Tregs that express CD25 and FoxP3 can be converted into ATLL cells. In some embodiments, ATLL cells exhibit an activated helper / inducer T cell phenotype but strong immunosuppressive activity. In some embodiments, the compounds and compositions disclosed herein that inhibit Akt3 reduce the immunosuppressive response of ATLL cells. In other embodiments, the compounds and compositions disclosed herein that inhibit Akt3 increase the immunostimulatory response to overcome the strong immunosuppressive activity of ATLL cells.

[0369] In some embodiments, the compounds and compositions disclosed herein useful for treating leukemia or ATLL reduce or inhibit immunosuppressive responses, such as, but not limited to, the immunosuppressive function of natural Treg (nTreg) cells and the induction of conventional T cells into inducible Treg (iTreg). In these embodiments, the immunosuppressive function of nTreg cells that is reduced or inhibited is the secretion of one or more anti-inflammatory cytokines, such as, but not limited to, IL10, TGFβ, or a combination thereof. In some embodiments, a method for treating leukemia or adult T-cell leukemia / lymphoma includes administering to a subject a second active agent, such as, but not limited to, an antiemetic, a chemotherapeutic, or a potentiating agent (e.g., cyclophosphamide).

[0370] autoimmune disease In some embodiments, the disease is an autoimmune disease. Non-limiting examples of autoimmune diseases include achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-glomerular basement membrane disease, anti-tubular basement membrane antibody nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathies, Barrow's disease, Behcet's disease, and benign mucous membrane pemphigoid. , bullous pemphigoid, Castleman's disease, celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome, eosinophilic granulomatosis, cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie-myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans' syndrome, fibromyalgia, Fibrotic alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, herpes gestationis, hidradenitis suppurativa (acne suppurativa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus Scabies, lignified conjunctivitis, linear IgA disease, lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Muscha-Haberman disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular pemphigoid, optic neuritis, relapsing rheumatism, pediatric autoimmune neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathyPerivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome These include: retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-body syndrome, subacute bacterial endocarditis, Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, and Vogt-Koyanagi-Harada disease.

[0371] Other indications In some embodiments, the compounds disclosed herein modulate Akt3 and are used to treat Gulf War syndrome, tuberous sclerosis, retinitis pigmentosa, transplant rejection, ischemic tissue injury, or traumatic tissue injury. In some embodiments, the transplant rejection is graft-versus-host disease. In some embodiments, the compounds disclosed herein are used to treat retinitis pigmentosa by modulating Akt3, but not by modulating regulatory T cells. In some embodiments, the compounds disclosed herein are used to treat ischemic or traumatic tissue injury. In some embodiments, the ischemic or traumatic tissue injury is cerebral ischemic or traumatic tissue injury.

[0372] Combination therapy methods In some embodiments, the disclosed compound can be administered alone or in combination with one or more additional therapeutic agents to a subject in need of treatment.In some embodiments, the compound and the additional therapeutic agent are administered separately but simultaneously.In some embodiments, the compound and the additional therapeutic agent are administered as part of the same composition.In other embodiments, the compound and the second therapeutic agent are administered separately and at different times but as part of the same treatment regimen.

[0373] In some embodiments, a subject can receive a first therapeutic agent 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, or more, or 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more, before receiving a second therapeutic agent. In some embodiments, a subject can receive one or more doses of a first agent every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 28 days, 35 days, or 48 days before receiving the first dose of a second agent. A compound disclosed herein can be a first or second therapeutic agent.

[0374] In some embodiments, compound and additional therapeutic agent can be administered as part of a treatment regimen.For example, the first therapeutic agent can be administered to the subject every 4 days, and the second therapeutic agent can be administered on the 1st, 2nd, 3rd or 4th day or a combination thereof.The first therapeutic agent or the second therapeutic agent can be repeatedly administered throughout the entire treatment regimen.

[0375] Exemplary additional therapeutic agents include, but are not limited to, cytokines, chemotherapeutic agents, radionuclides, other immunotherapies, enzymes, antibiotics, antiviral agents (e.g., protease inhibitors alone or in combination with nucleosides for the treatment of HIV or hepatitis B or C), antiparasitic agents (e.g., helminths or protozoans), growth factors, growth inhibitory agents, hormones, hormone antagonists, antibodies and bioactive fragments thereof (including humanized, single chain, and chimeric antibodies), antigen and vaccine formulations (including adjuvants), peptide drugs, anti-inflammatory drugs, ligands that bind to Toll-like receptors to activate the innate immune system (including, but not limited to, CpG oligonucleotides), molecules that recruit and optimize the adaptive immune system, other molecules that activate or upregulate the action of cytotoxic T lymphocytes, NK cells, and helper T cells, and other molecules that inactivate or downregulate suppressor or regulatory T cells.

[0376] The additional therapeutic agent is selected based on the condition, disorder, or disease to be treated. For example, the compounds of the present invention can be co-administered with one or more additional agents that function to enhance or promote the immune response, or to decrease or inhibit the immune response.

[0377] chemotherapy drugs In some embodiments, the compounds of the invention can be combined with one or more chemotherapeutic or pro-apoptotic agents. Representative chemotherapeutic agents include amsacrine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clofarabine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxycarbamide, idarubicin, ifosfamide, irinotecan, leucovorin, and liposomal doxorubicin. Representative pro-apoptotic agents include, but are not limited to, liposomal daunorubicin, lomustine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, pentostatin, procarbazine, raltitrexed, satraplatin, streptozocin, tegafur-uracil, temozolomide, teniposide, thiotepa, thioguanine, topotecan, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, or combinations thereof. Representative pro-apoptotic agents include, but are not limited to, fludarabine, staurosporine, cycloheximide, actinomycin D, lactosylceramide, 15d-PGJ(2), and combinations thereof.

[0378] Anti-inflammatory drugs Other suitable additional therapeutic agents include, but are not limited to, anti-inflammatory agents. In some embodiments, the anti-inflammatory agent may be non-steroidal, steroidal, or a combination thereof. One embodiment provides an oral composition containing about 1% (w / w) to about 5% (w / w), typically about 2.5% (w / w), of an anti-inflammatory agent. Representative examples of nonsteroidal anti-inflammatory agents include, but are not limited to, oxicams such as piroxicam, isoxicam, tenoxicam, sudoxicam; salicylates such as aspirin, disalcid, benorylate, trilisate, safaprin, solprin, diflunisal, and fendosal; acetic acid derivatives such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; Fenamic acids, such as mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and tolfenamic acid; propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic acid; pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethasone. In some embodiments, mixtures of these nonsteroidal anti-inflammatory agents can also be utilized.

[0379] Representative examples of steroidal anti-inflammatory drugs include, but are not limited to, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyldexamethasone, dexamethasone phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoximetasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluchlorolone acetonide, fludrocortisone, flumethasone pivalate, fluocinolone acetonide, fluocinonide, flucortine butyl ester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, thiaminumab ... Includes liamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafide, amcinafide, betamethasone and its ester counterbalance, chloroprednisone, chloroprednisone acetate, clocortelone, clesinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures thereof.

[0380] immunosuppressants In some embodiments, the compounds disclosed herein reduce Treg activity or production. In some embodiments, the compounds disclosed herein are used in induction therapy for cancer. In some embodiments, the compounds disclosed herein are used in combination with other immunotherapeutics, immune modulators, costimulatory activating agonists, other cytokines and chemokines and factors, vaccines, oncolytic viruses, cell therapy, small molecule and targeted therapy, chemotherapy, and radiation therapy. In some embodiments, immune modulators include checkpoint inhibitors, such as anti-PD1, anti-CTLA4, anti-TIM3, and anti-LAG3. In some embodiments, costimulatory activating agonists include anti-OX40, anti-GITR, and the like. In some embodiments, cell therapy includes genetically engineered T cells, CAR-T, TCR-T cells, and the like.

[0381] In some embodiments, the compounds disclosed herein are used in combination with other immunotherapeutics, immune modulators, biologics (e.g., antibodies), vaccines, small molecule and targeted therapies, anti-inflammatory drugs, cell therapies (e.g., genetically engineered Tregs and other types of cells), chemotherapy, and radiation therapy.

[0382] In some embodiments, the compounds disclosed herein, used alone or in combination with other agents, are administered to a patient in vivo by intravenous, intramuscular, or other parenteral means. These compounds can also be administered intranasally, by inhalation, rectally, vaginally, topically, orally, or as an implant. In other embodiments, the compounds disclosed herein, used alone or in combination with other agents, are applied ex vivo to enhance the function of suppressor Tregs and other types of suppressor T cells, including natural Tregs, induced Tregs, and genetically engineered Tregs, and can then be used appropriately to treat a patient.

[0383] In some embodiments, the additional therapeutic agent is an immunosuppressant. Immunosuppressants include, but are not limited to, antibodies against other lymphocyte surface markers (e.g., CD40, alpha-4 integrin) or against cytokines, fusion proteins (e.g., CTLA-4-Ig (Orencia®), TNFR-Ig (Enbrel®)), TNF-α blockers such as Enbrel, Remicade, Cimzia, and Humira, cyclophosphamide ("CTX") (e.g., Endoxan®, Cytoxan®, Neosar®, Procytox®, and Revimmune™), methotrexate ("MTX") (e.g., Rheumatrex® and Trexall®), belimumab (e.g., Benlysta®), other immunosuppressive drugs (e.g., cyclosporin A, FK506-like compounds, rapamycin compounds, and steroids), antiproliferative agents, cytotoxic agents, and other compounds that can aid in immunosuppression.

[0384] In some embodiments, the additional therapeutic agent can be a checkpoint inhibitor. In some embodiments, the additional therapeutic agent can be a CTLA-4 fusion protein, e.g., CTLA-4-Ig (abatacept). CTLA-4-Ig fusion proteins can function on T cells to compete with the costimulatory receptor, CD28, for binding to CD80 / CD86 (B7-1 / B7-2) on antigen-presenting cells, thereby inhibiting T cell activation. In another embodiment, the additional therapeutic agent is the CTLA-4-Ig fusion protein known as belatacept. Belatacept contains two amino acid substitutions (L104E and A29Y) that can significantly increase its avidity with CD86 in vivo. In another embodiment, the additional therapeutic agent is Maxy-4.

[0385] In another embodiment, the additional therapeutic agent is CTX. CTX (the generic name for Endoxan®, Cytoxan®, Neosar®, Procytox®, and Revimmune™), also known as cytophosphan, is a nitrogen mustard alkylating agent derived from the oxazofurin family. It can be used to treat various types of cancer and some autoimmune disorders. CTX is the first-line drug used to treat diffuse proliferative glomerulonephritis in patients with lupus nephritis.

[0386] In some embodiments, the additional therapeutic agent can be administered in an amount effective to reduce blood or serum levels of anti-double-stranded DNA ("anti-dsDNA") autoantibodies and / or to reduce proteinuria in a patient in need thereof.

[0387] In another embodiment, the additional therapeutic agent can increase the amount of adenosine in serum (see, e.g., WO08 / 147482). For example, the second therapeutic agent can be CD73-Ig, recombinant CD73, or another agent (e.g., a cytokine, monoclonal antibody, or small molecule) that increases expression of CD73 (see, e.g., WO04 / 084933). In another embodiment, the additional therapeutic agent is interferon-beta.

[0388] In some embodiments, the additional therapeutic agent may be a small molecule that inhibits or reduces differentiation, proliferation, activity, cytokine production and / or cytokine secretion by Th1, Th17, Th22 and / or other cells that secrete, or cause other cells to secrete, proinflammatory molecules including, but not limited to, IL-1β, TNF-α, TGF-beta, IFN-γ, IL-18, IL-17, IL-6, IL-23, IL-22, IL-21 and MMPs. In another embodiment, the additional therapeutic agent is a small molecule that interacts with Tregs, enhances Treg activity, promotes or enhances IL-10 secretion by Tregs, increases the number of Tregs, increases the suppressive capacity of Tregs, or a combination thereof.

[0389] In some embodiments, the composition increases the activity or production of Tregs. Exemplary Treg enhancers include, but are not limited to, glucocorticoid fluticasone, salmeteroal, antibodies against IL-12, IFN-γ, and IL-4; vitamin D3 and dexamethasone, and combinations thereof.

[0390] In some embodiments, the additional therapeutic agent is an antibody, eg, a function-blocking antibody against a pro-inflammatory molecule such as IL-6, IL-23, IL-22, or IL-21.

[0391] In some embodiments, the additional therapeutic agent comprises a nucleic acid. In some embodiments, the additional therapeutic agent comprises a ribonucleic acid.

[0392] Combination Therapies for Neurodegenerative Diseases In some embodiments, the compound disclosed herein can be administered with a second therapeutic agent that is selected based on the condition of the patient.In some embodiments, the second therapeutic agent can be a treatment for Alzheimer's disease.Current treatments for Alzheimer's disease include but are not limited to: cholinesterase inhibitors, such as donepezil, rivastigmine and galantamine; memantine; antidepressants, such as citalopram, fluoxetine, paroxetine, sertraline and trazadone; antianxiety drugs, such as lorazepam and oxazepam; and antipsychotics, such as aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone and ziprasidone.

[0393] In another embodiment, the additional therapeutic agent can be a treatment for ALS. Currently, there are two US FDA-approved treatments for ALS: riluzole and edaravone. Both drugs have been shown to slow the progression of ALS. In addition to riluzole and edaravone, subjects with ALS can also be treated with drugs that target specific symptoms of the disease. Exemplary such drugs include, but are not limited to, drugs that reduce spasticity, such as anticonvulsants (e.g., baclofen, dantrolene, and diazepam); drugs that help control nerve pain, such as amitriptyline, carbamazepine, duloxetine, gabapentin, lamotrigine, milnacipran, nortriptyline, pregabalin, and venlafaxine; and drugs that help patients swallow, such as trihexyphenidyl or amitriptyline.

[0394] In one embodiment, the additional therapeutic agent can be a treatment for Parkinson's disease.Current treatments for Parkinson's disease include but are not limited to: carbidopa-levodopa; dopamine agonists, such as pramipexole, ropinirole and rotigotine; MAOB inhibitors, such as selegiline, rasagiline and safinamide; catechol O-methyltransferase inhibitors, such as entacapone and tolcapone; anticholinergics, such as benztropine and trihexyphenidyl; and amantadine.

[0395] In some embodiments, the second therapeutic agent can be the treatment for Huntington's disease.Current treatment for Huntington's disease includes but is not limited to: tetrabenazine; antipsychotics, such as haloperidol, chlorpromazine, risperidone and quetiapine; amantadine; levetiracetam; clonazepam; antidepressants, such as citalopram, escitalopram, fluoxetine and sertraline; and anticonvulsants, such as valproate, carbamazepine and lamotrigine.

[0396] Combination treatment for weight loss In some embodiments, the compounds disclosed herein can be administered to subjects with additional therapeutic agents that are used to treat cachexia or extreme weight loss.The current strategy for treating cachexia and extreme weight loss is to improve appetite by using appetite stimulants to ensure sufficient intake of nutrients.Pharmacological interventions using appetite stimulants, nutrient supplementation, 5-HT3 antagonists and Cox-2 inhibitors are used to treat cancer cachexia.

[0397] In some embodiments, the appetite stimulant is a vitamin, mineral, or herb, including, but not limited to, zinc, thiamine, or fish oil, hi other embodiments, the appetite stimulant is a medication, including, but not limited to, dronabinol, megestrol, and oxandrolone.

[0398] equivalent The following representative examples are intended to help illustrate the present invention and are not intended to, and should not be construed as, limiting the scope of the present invention. Indeed, in addition to the embodiments shown and described herein, various variations of the present invention and many further embodiments thereof will be apparent to those skilled in the art from the following examples and the complete contents of this document, including references to the scientific and patent literature cited herein. It should be further recognized that the contents of these cited references are incorporated herein by reference to help illustrate the state of the art. The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof. [Example]

[0399] Example 1: Compound 1 (3-((6-nitroquinolin-4-yl)amino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0400] As shown in Scheme 1, meta-nitrobenzoic acid was coupled with 1,3-phenylenediamine using EDCI in the presence of HOBt and DIPEA. The resulting intermediate was coupled with 4-chloropyridine, followed by reduction of the nitro group to an amino group using Sn / HCl. The resulting amino intermediate was then reacted with 4-chloro-6-nitroquinoline in EtOH under reflux for 3 hours with the addition of 2-3 drops of TEA to afford the meta-substituted product compound 1. The final product precipitated from the reaction mixture upon reaching room temperature, then was filtered off and purified via recrystallization from 1:1 EtOH:diethyl ether.

[0401] The compounds shown in the following examples were made based on the experimental procedures described in Example 1 and / or as described below and / or by methods known in the art.

[0402] The following abbreviations used in the examples below have the following definitions: AIBN = azobisisobutyronitrile; DCE = dichloroethane; DCM = dichloromethane; DIEPA or DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; EA or EtOAc = ethyl acetate; EDC or EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3 -triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HPLC = high performance liquid chromatography; LCMS = liquid chromatography mass spectrometry; MS = mass spectrometry; NBS = N-bromosuccinimide; NMR = nuclear magnetic resonance; PE = petroleum ether; RT = retention time (e.g., HPLC retention time); TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; and TsOH or TosOH = p-toluenesulfonic acid. These abbreviations and definitions are not intended to be limiting of other abbreviations and definitions in this application.

[0403] The following general methods were used in one or more of the following examples. Substrates and reagents were commercially available and used without further purification. Reactions were monitored by liquid LCMS or TLC using precoated glass plates. Column chromatography was performed using silica gel (200-300 mesh) or a Biotage instrument (normal phase HPLC). Preparative HPLC methods used a Gilson 281 (PHG012) apparatus, a Welch 10 μm 150A 21.2*250 mm column, a mobile phase consisting of A: water (12 mM NH4HCO3), B: acetonitrile, a flow rate of 30.00 mL / min, and detection at 214 / 254 nm. Analysis was performed on a 500 or 400 MHz Bruker NMR spectrometer using CDCl3 / MeOD / DMSO- d6 In 、1 H NMR spectra were recorded. Resonances are given in parts per million relative to tetramethylsilane. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), coupling constant (Hz) and integral. MS data were obtained on an LCMS instrument equipped with an electrospray source.

[0404] Example 2: Compound 2 (3-((6-cyanoquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0405] Compound 2 was prepared by methods known in the art and / or analogous to those described herein. Compound 2 (3-((6-cyanoquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide): C 28 H 20 NO; 456.51 g / mol; 26 mg; yellow solid; ESI-LCMS m / z=457 [M+H] + ;LCMS RT=1.594 min, 100% (214 nm).

[0406] Example 3: Compound 3 (3-((6-fluoroquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0407] Compound 3 was prepared by methods known in the art and / or analogous to those described herein. Compound 3 (3-((6-fluoroquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide): C 27 H 20 FNO; 449.49 g / mol; 34 mg; white solid; ESI-LCMS m / z=450 [M+H] + ;LCMS RT=1.614 min, 99% (214 nm).

[0408] Example 4: Compound 4 (4-((3-(6-(pyridin-4-ylamino)-1H-benzo[d]imidazol-2-yl)phenyl)amino)quinoline-6-carbonitrile) [ka]

[0409] Compound 4 was prepared by methods known in the art and / or analogous to those described herein. Compound 4 (4-((3-(6-(pyridin-4-ylamino)-1H-benzo[d]imidazol-2-yl)phenyl)amino)quinoline-6-carbonitrile): C 28 H 19 N7; 453.51 g / mol; 22 mg; yellow solid; ESI-LCMS m / z=454 [M+H] + ;LCMS RT=1.634 min, 100% (214 nm).

[0410] Example 5: Compound 5 (3-((6-fluoroquinolin-4-yl)amino)-N-(4-(pyridin-4-yloxy)phenyl)benzamide) [ka]

[0411] Compound 5 was prepared by the method shown in Scheme 2. Compound 5 (3-((6-fluoroquinolin-4-yl)amino)-N-(4-(pyridin-4-yloxy)phenyl)benzamide) was prepared as shown in Scheme 2: 27 H 19 FN4O2; 450.47 g / mol; 13 mg; white solid; ESI-LCMS m / z=451 [M+H] + ;LCMS RT=0.99 min, >95.00%(214nm).

[0412] Example 6: Compound 6 (3-((6-fluoroquinolin-4-yl)amino)-N-(4-((2-methylpyridin-4-yl)oxy)phenyl)benzamide) [ka]

[0413] Compound 6 was prepared by methods known in the art and / or analogous to those described herein. Compound 6 (3-((6-fluoroquinolin-4-yl)amino)-N-(4-((2-methylpyridin-4-yl)oxy)phenyl)benzamide): C 28 H 21 FN4O2; 464.50 g / mol; 18 mg; pale yellow solid; ESI-LCMS m / z=456 [M+H] + ;LCMS RT=1.43 min, >95.00%(214nm).

[0414] Example 7: Compound 7 (4-((6-fluoroquinolin-4-yl)amino)-N-(3-phenoxyphenyl)benzamide) [ka]

[0415] Compound 7 was prepared by methods known in the art and / or analogous to those described herein. Compound 7 (4-((6-fluoroquinolin-4-yl)amino)-N-(3-phenoxyphenyl)benzamide): C 28 H 20 FN3O2; 449.49 g / mol; 13 mg; white solid; ESI-LCMS m / z=450 [M+H] + ;LCMS RT=1.74 min, >95.00%(214nm).

[0416] Example 8: Compound 8 (3-(pyridin-4-ylamino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0417] Compound 8 was prepared by the method shown in Scheme 3. Compound 8 (3-(pyridin-4-ylamino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 3: 23 H 19 NO; 381.44 g / mol; 12 mg; pale yellow solid; ESI-LCMS m / z=382 [M+H] + ;LCMS RT=1.30 min, >95.00%(214nm).

[0418] Example 9: Compound 9 (N-(4-(pyridin-4-ylamino)phenyl)-3-(quinolin-4-ylamino)benzamide) [ka]

[0419] Compound 9 was prepared by the method shown in Scheme 4. Compound 9 (N-(4-(pyridin-4-ylamino)phenyl)-3-(quinolin-4-ylamino)benzamide) was prepared as shown in Scheme 4: 27 H 21NO; 431.50 g / mol; 24 mg; pale yellow solid; ESI-LCMS m / z=432 [M+H] + ;LCMS RT=1.46 min, >95.00%(214nm).

[0420] Example 10: Compound 10 (N-(4-(pyridin-4-yloxy)phenyl)-3-(quinolin-4-ylamino)benzamide) [ka]

[0421] Compound 10 was prepared by the method shown in Scheme 5. Compound 10 (N-(4-(pyridin-4-yloxy)phenyl)-3-(quinolin-4-ylamino)benzamide) was prepared as shown in Scheme 5: 27 H 20 N4O2; 432.48 g / mol; 29 mg; pale yellow solid; ESI-LCMS m / z=433 [M+H] + ;LCMS RT=1.43 min, >95.00%(214nm).

[0422] Example 11: Compound 11 (3-((2-methylpyridin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0423] Compound 11 was prepared by the method shown in Scheme 6. Compound 11 (3-((2-methylpyridin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 6: 24 H 21 NO; 395.47 g / mol; 16 mg; pale yellow solid; ESI-LCMS m / z=396 [M+H] + ;LCMS RT=1.32 min, >95.00%(214nm).

[0424] Example 12: Compound 12 (3-((3-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0425] Compound 12 was prepared by the method shown in Scheme 7. Compound 12 (3-((3-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 7: C 28 H 23 NO; 445.53 g / mol; 19 mg; pale yellow solid; ESI-LCMS m / z=446 [M+H] + ;LCMS RT=1.48 min, >95.00%(214nm).

[0426] Example 13: Compound 13 (3-((2-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0427] Compound 13 was prepared by the method shown in Scheme 8. Compound 13 (3-((2-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 8: C 28 H 23 NO; 445.53 g / mol; 20 mg; pale yellow solid; ESI-LCMS m / z=446 [M+H] + ;LCMS RT=1.46 min, >95.00%(214nm).

[0428] Example 14: Compound 14 (3-((8-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0429] Compound 14 was prepared by the method shown in Scheme 9. Compound 14 (3-((8-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 9: C 28 H 23 NO; 445.53 g / mol; 29 mg; pale yellow solid; ESI-LCMS m / z=446 [M+H] + ;LCMS RT=1.54 min, >95.00%(214nm).

[0430] Example 15: Compound 15 (3-((7-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0431] Compound 15 was prepared by the method shown in Scheme 10. Compound 15 (3-((7-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 10: C 28 H 23 NO; 445.53 g / mol; 24 mg; pale yellow solid; ESI-LCMS m / z=446 [M+H] + ;LCMS RT=1.48 min, >95.00%(214nm).

[0432] Example 16: Compound 16 (3-((5-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0433] Compound 16 was prepared by the method shown in Scheme 11. Compound 16 (3-((5-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 11: C 28 H 23 NO; 445.53 g / mol; 17 mg; pale yellow solid; ESI-LCMS m / z=446 [M+H] + ;LCMS RT=1.49 min, >95.00%(214nm).

[0434] Example 17: Compound 17 (4-((3-(5-(pyridin-4-ylamino)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)amino)quinoline-6-carbonitrile) [ka]

[0435] Compound 17 was prepared by the method shown in Scheme 12. Compound 17 (4-((3-(5-(pyridin-4-ylamino)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)amino)quinoline-6-carbonitrile) was prepared as shown in Scheme 12: C 27 H 18 N8; 454.50 g / mol; 13 mg; yellow solid; ESI-LCMS m / z=455 [M+H] + ;RT=1.44min, >95.00%(214nm).

[0436] Example 18: Compound 18 (3-((5-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0437] Step a: To a stirred mixture of compound 18-1 (20 g, 0.1 mol) in 1,4-dioxane (500 mL), pyridin-4-amine (compound 18-2) (9.4 g, 0.1 mol), CsCO (65 g, 0.2 mol), Pd(dba) (457 mg, 0.5 mmol), and Xantphos (457 mg, 0.8 mmol) were added under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h. The reaction was then quenched with water (500 mL) and extracted with EA (3 × 500 mL). The combined organic phases were dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0–50% EA in PE) to give compound 18-3 as a yellow solid (19.8 g, 93%).

[0438] Step b: To a mixture of compound 18-3 (19.8 g, 93 mmol) in MeOH (1000 mL), Pd / C (986 mg, 0.93 mmol) was added, and the mixture was stirred under H at room temperature for 4 h. The combined organic phase was filtered through diatomaceous earth to give compound 18-4 (16.9 g, 98.5%) as a yellow solid.

[0439] Step c: To a mixture of compound 18-4 (16.9 g, 92 mmol) in DMF (250 mL), 3-((tert-butoxycarbonyl)amino)benzoic acid (compound 18-5) (21.8 g, 92 mmol), EDCI (9.1 mg, 0.01 mmol), and DMAP (22.4 g, 184 mmol) were added, and the mixture was stirred at room temperature for 16 h. The reaction was then quenched with water (1000 mL) and extracted with EA (3 × 600 mL). The combined organic phases were dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0–50% EA in PE) to give compound 18-6 as a white solid (30.2 g, 81.2%).

[0440] Step d: A mixture of compound 18-6 (30.2 g, 74 mmol) in dioxane hydrochloride (1000 mL, 4 M) was stirred at room temperature for 4 h. The combined organic phase was concentrated to give compound 18-7 (20.2 g, 90%) as a white solid.

[0441] Step e: To a mixture of compound 18-7 (50 mg, 0.16 mmol) in DMSO (2 mL), 4-chloro-3-methylquinoline (compound 18-8) (29 mg, 0.16 mmol) and one drop of hydrochloric acid were added. The mixture was stirred at 100 °C for 1 h. The crude residue was purified by preparative HPLC to give compound 18 (3-((5-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) as a pale yellow solid (11 mg, 15.0%): C 28 H 23 NO; 445.53 g / mol; ESI-LCMS m / z=446 [M+H] + ;RT=1.49min, >95.00%(214nm).

[0442] Example 19: Compound 19 (4-(2-aminopyridin-4-ylamino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0443] Step a: To a stirred mixture of 1-bromo-3-nitrobenzene (compound 19-1) (20 g, 0.1 mol) in 1,4-dioxane (500 mL), pyridin-4-amine (compound 18-2) (9.4 g, 0.1 mol), CsCO (65 g, 0.2 mol), Pd(dba) (457 mg, 0.5 mmol), and Xantphos (457 mg, 0.8 mmol) were added under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h. The reaction was then quenched with water (500 mL) and extracted with EA (3 × 500 mL). The combined organic phases were dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0–50% EA in PE) to give compound 19-2 as a yellow solid (20 g, 93%).

[0444] Step b: To a mixture of compound 19-2 (20 g, 93 mmol) in MeOH (1000 mL), Pd / C (986 mg, 0.93 mmol) was added, and the mixture was stirred under H at room temperature for 4 h. The combined organic phase was filtered through diatomaceous earth to give compound 19-3 as a yellow solid (17.0 g, 98.7%).

[0445] Step c: To a mixture of compound 19-3 (17.0 g, 92 mmol) in DMF (250 mL), 4-((tert-butoxycarbonyl)amino)benzoic acid (compound 19-4) (21.8 g, 92 mmol), EDCI (9.1 mg, 0.01 mmol), and DMAP (22.4 g, 184 mmol) were added, and the mixture was stirred at room temperature for 16 h. The reaction was then quenched with water (1000 mL) and extracted with EA (3 × 600 mL). The combined organic phases were dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0–50% EA in PE) to give compound 19-5 as a white solid (30 g, 81%).

[0446] Step d: A mixture of compound 19-5 (30 g, 74 mmol) in dioxane hydrochloride (1000 mL, 4 M) was stirred at room temperature for 4 h. The combined organic phase was concentrated to give compound 19-6 (20.2 g, 90%) as a white solid.

[0447] Step e: To a mixture of compound 19-6 (50 mg, 0.164 mmol) in 1,4-dioxane (2 mL), tert-butyl (4-bromopyridin-2-yl)carbamate (compound 19-7) (45 mg, 0.164 mmol), Pd(dba) (9.1 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and CsCO (102 mg, 0.32 mmol) were added, and the mixture was stirred at 100 °C under N for 12 h. The mixture was concentrated to give compound 19-8, which was used directly in the next step without further purification.

[0448] Step f: A solution of compound 19-8 in TFA (3 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the crude residue was purified by preparative HPLC to give compound 19 (4-(2-aminopyridin-4-ylamino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) as a white solid (12 mg, 18.5%): C 23 H 20 NO; 396.44 g / mol; ESI-LCMS m / z=397 [M+H] + ;RT=1.44min, >95.00%(214nm).

[0449] Example 20: Compound 20 (4-(2-amino-6-methylpyridin-4-ylamino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0450] Compound 19-6 was prepared in a manner similar to the procedure described in Example 19.

[0451] Step a: To a mixture of compound 19-6 (50 mg, 0.164 mmol) in 1,4-dioxane (2 mL), tert-butyl (4-bromopyridin-2-yl)carbamate (compound 20-1) (45 mg, 0.164 mmol), Pd(dba) (9.1 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and CsCO (102 mg, 0.32 mmol) were added, and the mixture was stirred at 100 °C under N for 12 h. The mixture was concentrated to give compound 20-2, which was used directly in the next step without further purification.

[0452] Step b: A solution of compound 20-2 in TFA (3 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the crude residue was purified by preparative HPLC to give compound 20 (4-(2-amino-6-methylpyridin-4-ylamino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) as a white solid (12 mg, 18.5%): C 24 H 22NO; 410.47 g / mol; ESI-LCMS m / z=411 [M+H] + ;RT=1.47min, >95.00%(214nm).

[0453] Example 21: Compound 21 (4-(2-amino-3-methylpyridin-4-ylamino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) [ka]

[0454] Compound 19-6 was prepared in a manner similar to the procedure described in Example 19.

[0455] Step a: To a mixture of compound 19-6 (50 mg, 0.164 mmol) in 1,4-dioxane (2 mL), compound 21-1 (45 mg, 0.164 mmol), Pd(dba) (9.1 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and CsCO (102 mg, 0.32 mmol) were added, and the mixture was stirred at 100 °C under N for 12 h. The mixture was concentrated to give compound 20-2, which was used directly in the next step without further purification.

[0456] Step b: A solution of compound 21-2 in TFA (3 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the crude residue was purified by preparative HPLC to give compound 21 (4-(2-amino-3-methylpyridin-4-ylamino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) as a white solid (12 mg, 18.5%): C 24 H 22 NO; 410.47 g / mol; ESI-LCMS m / z=411 [M+H] + ;RT=1.42min, >95.00%(214nm).

[0457] Example 22: Compound 22 (4-((2-(4-(pyridin-4-ylamino)phenyl)-1H-benzo[d]imidazol-5-yl)amino)quinoline-6-carbonitrile) [ka]

[0458] Compound 22 was prepared by the method shown in Scheme 17. Compound 22 (4-((2-(4-(pyridin-4-ylamino)phenyl)-1H-benzo[d]imidazol-5-yl)amino)quinoline-6-carbonitrile) was prepared as shown in Scheme 32: C 28 H 19 N7: 453.51 g / mol; 11 mg; pale yellow solid; ESI-LCMS m / z=454 [M+H] + ;LCMS RT=1.35 min, >95.00%(214nm).

[0459] Example 23: Compound 23 (3,3-dimethyl-5-(pyridin-4-ylamino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one) [ka]

[0460] Compound 23 can be prepared by methods known in the art and / or by methods analogous to those described herein.

[0461] Example 24: Compound 24 (6'-(pyridin-4-ylamino)-2'-(3-(pyridin-4-ylamino)phenyl)spiro[cyclopropane-1,1'-isoindolin]-3'-one) [ka]

[0462] Compound 24 can be prepared by methods known in the art and / or by methods analogous to those described herein.

[0463] Example 25: Compound 25 (2-(2-methyl-5-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one) [ka]

[0464] Compound 25 was prepared by methods known in the art and / or analogous to those described herein. Compound 25 (2-(2-methyl-5-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one): C 25 H 21 NO; 407.47 g / mol; 14 mg; off-white solid; ESI-LCMS m / z=408 [M+H] + ;LCMS RT=1.48 min, >95.00%(214nm).

[0465] Example 26: Compound 26 (2-(3-methyl-5-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one) [ka]

[0466] Compound 26 was prepared by the method shown in Scheme 18.

[0467] Step a: To a stirred mixture of 1-bromo-3-methyl-5-nitrobenzene (2.15 g, 0.01 mol) in 1,4-dioxane (50 mL) under N2, pyridin-4-amine (0.94 g, 0.01 mol), Cs2CO3 (6.5 g, 0.02 mol), Pd2(dba)3 (45.7 mg, 0.05 mmol), and Xantphos (45.7 mg, 0.08 mmol) were added. The resulting mixture was stirred at 100 °C for 4 h. The reaction was then quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0–50% EtOAc in petroleum ether) to give compound 26-1 as a yellow solid (2.0 g, 90% yield).

[0468] Step b: To a mixture of compound 26-1 (2.0 g, 8.7 mmol) in MeOH (50 mL), Pd / C (200 mg, 0.87 mmol) was added, and the mixture was stirred under H at room temperature for 4 h. The combined organic phase was filtered to give compound 26-2 as a yellow solid (1.5 g, 86.7% yield).

[0469] Step c: To a mixture of compound 26-2 (1.5 g, 7.5 mmol) and methyl 2-(bromomethyl)-4-nitrobenzoate (2.05 g, 7.5 mmol) in MeOH (50 mL), TEA (2.28 g, 22.6 mmol) was added, and the mixture was stirred at 85 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0 to 80% EtOAc in petroleum ether) to give compound 26-3 as a yellow solid (500 mg, 18.5% yield).

[0470] Step d: To a mixture of compound 26-3 (300 mg, 0.83 mmol) in MeOH (10 mL) / THF (5 mL), Pd / C (50 mg) was added, and the mixture was stirred under H at 60 °C for 5 h. The combined organic phase was filtered through diatomaceous earth to give compound 26-4 as a yellow solid (150 mg, 54% yield).

[0471] Step e: To a mixture of compound 26-4 (150 mg, 0.45 mmol) in 1,4-dioxane (6 mL), 4-bromopyridine (72 mg, 0.45 mmol), Pd(dba) (18 mg, 0.02 mmol), Xantphos (12 mg, 0.02 mmol), and CsCO (293 mg, 0.9 mmol) were added, and the mixture was stirred at 100 °C under N for 12 h. The mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 26 as a yellow solid (20 mg, 10.8% yield).

[0472] Compound 26 ((2-(3-methyl-5-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one): C 25 H 21 NO; 407.47 g / mol; 20 mg; white solid; ESI-LCMS m / z=408 [M+H] + ;LCMS RT=1.67 min, >95.00%(214nm).

[0473] Example 27: Compound 27 (2-(4-methyl-3-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one) [ka]

[0474] Compound 27 was prepared by the method shown in Scheme 19.

[0475] Step a: To a stirred mixture of 2-bromo-1-methyl-4-nitrobenzene (2.15 g, 0.01 mol) in 1,4-dioxane (50 mL) under N2, pyridin-4-amine (0.94 g, 0.01 mol), Cs2CO3 (6.5 g, 0.02 mol), Pd2(dba)3 (45.7 mg, 0.05 mmol), and Xantphos (45.7 mg, 0.08 mmol) were added. The resulting mixture was stirred at 100 °C for 4 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0–50% EtOAc in petroleum ether) to give compound 27-1 as a yellow solid (1.9 g, 83% yield).

[0476] Step b: To a mixture of compound 27-1 (1.9 g, 8.3 mmol) in MeOH (30 mL), Pd / C (200 mg, 0.87 mmol) was added, and the mixture was stirred under H at room temperature for 5 h. The combined organic phase was filtered to give compound 27-2 as a yellow solid (1.5 g, 90.9% yield).

[0477] Step c: To a mixture of compound 27-2 (1.5 g, 7.5 mmol) and methyl 2-(bromomethyl)-4-nitrobenzoate (2.05 g, 7.5 mmol) in MeOH (50 mL), TEA (2.28 g, 22.6 mmol) was added, and the mixture was stirred at 85 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0-20% MeOH in DCM) to give compound 27-3 as a yellow solid (700 mg, 25.9% yield).

[0478] Step d: To a mixture of compound 27-3 (250 mg, 0.83 mmol) in MeOH (10 mL) / THF (5 mL), Pd / C (50 mg) was added, and the mixture was stirred under H at 60 °C for 5 h. The combined organic phase was filtered to give compound 27-4 as a yellow solid (170 mg, 74% yield).

[0479] Step e: To a mixture of compound 27-4 (100 mg, 0.30 mmol) in 1,4-dioxane (6 mL), 4-bromopyridine (47 mg, 0.3 mmol), Pd(dba) (18 mg, 0.02 mmol), Xantphos (12 mg, 0.02 mmol), and CsCO (195 mg, 0.6 mmol) were added, and the mixture was stirred at 100 °C under N for 12 h. The mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 27 as a yellow solid (15 mg, 12.2% yield).

[0480] Compound 27 (2-(4-methyl-3-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one): C 25 H 21 NO; 407.48 g / mol; 15 mg; white solid; ESI-LCMS m / z=408 [M+H] + ;LCMS RT=1.64 min, >95.00%(214nm).

[0481] Example 28: Compound 28 (2-(2-methyl-3-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one) [ka]

[0482] Compound 28 was prepared by methods known in the art and / or analogous to those described herein. Compound 28 (2-(2-methyl-3-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one): C 25 H 21 NO; 407.47 g / mol; 13 mg; white solid; ESI-LCMS m / z=408 [M+H] + ;LCMS RT=1.44 min, >95.00%(214nm).

[0483] Example 29: Compound 29 (4-methyl-5-(pyridin-4-ylamino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one) [ka]

[0484] Compound 29 was prepared by methods known in the art and / or analogous to those described herein. Compound 29 (4-methyl-5-(pyridin-4-ylamino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one): C 25 H 21 NO; 407.47 g / mol; 10 mg; white solid; ESI-LCMS m / z=408 [M+H] + ;LCMS RT=1.34 min, >95.00%(214nm).

[0485] Example 30: Compound 30 (7-methyl-5-(pyridin-4-ylamino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one) [ka]

[0486] Compound 30 was prepared by the method shown in Scheme 20.

[0487] Step a: To a stirred mixture of 1-bromo-3-nitrobenzene (10 g, 0.05 mol) in 1,4-dioxane (200 mL) under N2, pyridin-4-amine (4.7 g, 0.05 mol), Cs2CO3 (32.5 g, 0.1 mol), Pd2(dba)3 (230 mg, 0.25 mmol), and Xantphos (230 mg, 0.4 mmol) were added. The resulting mixture was stirred at 100 °C for 3 h. The reaction was quenched with water (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0–50% EtOAc in petroleum ether) to give compound 30-1 as a yellow solid (10 g, 93.4% yield).

[0488] Step b: To a mixture of compound 30-1 (10 g, 46.5 mmol) in MeOH (300 mL), Pd / C (1 g) was added, and the mixture was stirred under H at room temperature for 4 h. The combined organic phase was filtered through diatomaceous earth to give compound 30-2 as a yellow solid (8.5 g, 98.7% yield).

[0489] Step c: To a mixture of methyl 4-bromo-2,6-dimethylbenzoate (1.21 g, 5 mmol) and NBS (0.979 g, 5.5 mmol) in CCl4 (15 mL), AIBN (150 mg) was added, and the mixture was stirred at 80 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0-20% DCM in petroleum ether) to give compound 30-3 as a solid (1.2 g, 75% yield).

[0490] Step d: To a mixture of compound 30-3 (640 mg, 2 mmol) and 30-2 (407 mg, 2.2 mmol) in MeOH (10 mL), TEA (606 mg, 6 mmol) was added, and the mixture was stirred at 85 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0-20% MeOH in DCM) to give compound 30-4 as a solid (400 mg, 50.8% yield).

[0491] Step e: To a mixture of compound 30-4 (150 mg, 0.38 mmol) in 1,4-dioxane (6 mL), pyridin-4-amine (36 mg, 0.38 mmol), Pd(dba) (18 mg, 0.02 mmol), Xantphos (12 mg, 0.02 mmol), and CsCO (234 mg, 0.72 mmol) were added, and the mixture was stirred at 100 °C under N for 12 h. The mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 30 as a yellow solid (18 mg, 11.6% yield).

[0492] Compound 30 (2-(7-methyl-5-(pyridin-4-ylamino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one): C 25 H 21 NO; 407.47 g / mol; 18 mg; white solid; ESI-LCMS m / z=408 [M+H] + ;LCMS RT=1.37 min, >95.00%(214nm).

[0493] Example 31: Compound 31 (6-methyl-5-(pyridin-4-ylamino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one) [ka]

[0494] Compound 31 was prepared by the method shown in Scheme 21.

[0495] Step a: To a mixture of 4-bromo-2-methylbenzoic acid (2.14 g, 10 mmol) in concentrated HSO (20 mL) was added NIS (2.47 g, 11 mmol) at 0° C., and the mixture was stirred at 0° C. for 3 h. The mixture was poured onto ice and filtered to give compound 31-1 as a yellow solid (2.5 g, 73% yield).

[0496] Step b: To a mixture of compound 31-1 (1.7 g, 5 mmol) and CsCO (234 mg, 10 mmol) in DMF (10 mL), MeI (965 mg, 6.8 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0–30% EtOAc in petroleum ether) to give compound 31-2 (1.6 g, 90% yield).

[0497] Step c: To a mixture of compound 31-2 (1.5 g, 4.2 mmol) and NBS (830 mg, 4.66 mmol) in CCl4 (20 mL), AIBN (150 mg) was added, and the mixture was stirred at 80 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0-20% DCM in petroleum ether) to give compound 31-3 as a solid (1.46 g, 80% yield).

[0498] Step d: To a mixture of compound 31-3 (1.3 g, 3 mmol) and compound 30-2 (610 mg, 3.3 mmol) in MeOH (20 mL), TEA (909 mg, 9 mmol) was added, and the mixture was stirred at 85 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0-20% MeOH in DCM) to give compound 31-4 as a solid (1.1 g, 79.8% yield).

[0499] Step e: To a stirred mixture of compound 31-4 (1.1 g, 2 mmol) in 1,4-dioxane (30 mL) under N, 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (151.2 mg, 1.2 mol), KCO (552 mg, 4 mmol), and Pd(dppf)Cl (230 mg, 0.25 mmol) were added. The resulting mixture was stirred at 100 °C for 16 h, then filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-30% MeOH in DCM) to give compound 31-5 (260 mg, 33% yield).

[0500] Step f: To a mixture of compound 31-5 (250 mg, 0.63 mmol) in 1,4-dioxane (8 mL), pyridin-4-amine (60 mg, 1.26 mmol), Pd(dba) (25 mg, 0.02 mmol), Xantphos (25 mg, 0.02 mmol), and CsCO (410 mg, 0.72 mmol) were added, and the mixture was stirred under N at 100 °C for 12 h. The mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 31 as a yellow solid (25 mg, 10% yield).

[0501] Compound 31 (6-methyl-5-(pyridin-4-ylamino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one): C 25 H 21 NO; 407.47 g / mol; 25 mg; white solid; ESI-LCMS m / z=408 [M+H] + ;LCMS RT=1.48 min, >95.00%(214nm).

[0502] Example 32: Compound 32 (4-fluoro-5-(pyridin-4-ylamino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one) [ka]

[0503] Compound 32 was prepared as shown in Scheme 22.

[0504] Step a: To a mixture of 4-bromo-3-fluoro-2-methylbenzoic acid (500 mg, 2.15 mmol) and CsCO (594 mg, 4.3 mmol) in DMF (10 mL), MeI (368 mg, 2.58 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0–30% EtOAc in petroleum ether) to give compound 32-1 (500 mg, 94% yield).

[0505] Step b: To a mixture of compound 32-1 (492 g, 2 mmol) and NBS (392 mg, 2.2 mmol) in CCl4 (10 mL), AIBN (50 mg) was added, and the mixture was stirred at 80 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0-20% DCM in petroleum ether) to give compound 32-2 as a solid (583 mg, 90% yield).

[0506] Step c: To a mixture of compound 32-2 (500 mg, 1.54 mmol) and 30-2 (314 mg, 1.69 mmol) in MeOH (10 mL), TEA (467 mg, 4.62 mmol) was added, and the mixture was stirred at 85 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0-20% MeOH in DCM) to give compound 32-3 as a solid (300 mg, 49% yield).

[0507] Step d: To a mixture of compound 32-3 (200 mg, 0.50 mmol) in 1,4-dioxane (8 mL), pyridin-4-amine (47 mg, 0.5 mmol), Pd(dba) (20 mg, 0.02 mmol), Xantphos (20 mg, 0.02 mmol), and CsCO (325 mg, 0.1 mmol) were added, and the mixture was stirred under N at 100 °C for 12 h. The mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 32 as a yellow solid (25 mg, 12% yield).

[0508] Compound 32 (4-fluoro-5-(pyridin-4-ylamino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one): C 24 H 18 FNO; 411.43 g / mol; 25 mg; off-white solid; ESI-LCMS m / z=412 [M+H] + ;LCMS RT=1.35 min, >95.00%(214nm).

[0509] Example 33: Compound 33 (6-fluoro-5-(pyridin-4-ylamino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one) [ka]

[0510] Compound 33 was prepared as shown in Scheme 23.

[0511] Step a: To a mixture of 4-bromo-5-fluoro-2-methylbenzoic acid (500 mg, 2.15 mmol) and CsCO (594 mg, 4.3 mmol) in DMF (10 mL), MeI (368 mg, 2.58 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0–30% EtOAc in petroleum ether) to give compound 33-1 (510 mg, 96% yield).

[0512] Step b: To a mixture of compound 33-1 (500 mg, 2.03 mmol) and NBS (397 mg, 2.23 mmol) in CCl4 (10 mL), AIBN (30 mg) was added, and the mixture was stirred at 80 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0-20% DCM in petroleum ether) to give compound 33-2 as a solid (450 mg, 68% yield).

[0513] Step c: To a mixture of compound 33-2 (450 mg, 1.39 mmol) and 30-2 (283 mg, 1.52 mmol) in MeOH (10 mL), TEA (418 mg, 4.14 mmol) was added, and the mixture was stirred at 85 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0-20% MeOH in DCM) to give compound 33-3 as a solid (300 mg, 54% yield).

[0514] Step d: To a mixture of compound 33-3 (200 mg, 0.50 mmol) in 1,4-dioxane (8 mL), pyridin-4-amine (47 mg, 0.5 mmol), Pd(dba) (20 mg, 0.02 mmol), Xantphos (20 mg, 0.02 mmol), and CsCO (325 mg, 0.1 mmol) were added, and the mixture was stirred under N at 100 °C for 12 h. The mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 33 as a yellow solid (20 mg, 10% yield).

[0515] Compound 33 (6-fluoro-5-(pyridin-4-ylamino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one): C 24 H 18 FNO; 411.43 g / mol; 20 mg; white solid; ESI-LCMS m / z=412 [M+H] + ;LCMS RT=1.36 min, >95.00%(214nm).

[0516] Example 34: Compound 34 (7-fluoro-5-(pyridin-4-ylamino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one) [ka]

[0517] Compound 34 was prepared by the method shown in Scheme 24.

[0518] Step a: To a mixture of 4-bromo-5-fluoro-2-methylbenzoic acid (500 mg, 2.15 mmol) and CsCO (594 mg, 4.3 mmol) in DMF (10 mL), MeI (368 mg, 2.58 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0–30% EtOAc petrol in ether) to give compound 34-1 (500 mg, 94% yield).

[0519] Step b: To a mixture of compound 34-1 (500 mg, 2.03 mmol) and NBS (398 mg, 2.23 mmol) in CCl4 (10 mL), AIBN (30 mg) was added, and the mixture was stirred at 80 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0-20% DCM in petroleum ether) to give compound 34-2 as a solid (500 mg, 76% yield).

[0520] Step c: To a mixture of compound 34-2 (500 mg, 1.54 mmol) and 30-2 (313 mg, 1.69 mmol) in MeOH (10 mL), TEA (466 mg, 4.62 mmol) was added, and the mixture was stirred at 85 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0-20% MeOH in DCM) to give compound 34-3 as a solid (250 mg, 41% yield).

[0521] Step d: To a mixture of compound 34-3 (200 mg, 0.50 mmol) in 1,4-dioxane (8 mL), pyridin-4-amine (47 mg, 0.5 mmol), Pd(dba) (20 mg, 0.02 mmol), Xantphos (20 mg, 0.02 mmol), and CsCO (325 mg, 0.1 mmol) were added, and the mixture was stirred under N at 100 °C for 12 h. The mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 34 as a yellow solid (21 mg, 10% yield).

[0522] Compound 34 (7-fluoro-5-(pyridin-4-ylamino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one): C 24 H 18 FNO; 411.43 g / mol; 21 mg; off-white solid; ESI-LCMS m / z=412 [M+H] + ;LCMS RT=1.26 min, >95.00%(214nm).

[0523] Example 35: Compound 35 (2-(2-fluoro-3-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one) [ka]

[0524] Compound 35 was prepared by methods known in the art and / or analogous to those described herein. Compound 35 (2-(2-fluoro-3-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one): C 24 H 18 FNO; 411.43 g / mol; 11 mg; off-white solid; ESI-LCMS m / z=412 [M+H] + ;LCMS RT=1.29 min, >95.00%(214nm).

[0525] Example 36: Compound 36 (2-(2-fluoro-5-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one) [ka]

[0526] Compound 36 was prepared by methods known in the art and / or analogous to those described herein. Compound 36 (2-(2-fluoro-5-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one): C 24 H 18 FNO; 411.43 g / mol; 11 mg; white solid; ESI-LCMS m / z=412 [M+H] + ;LCMS RT=1.27 min, >95.00%(214nm).

[0527] Example 37: Compound 37 (2-(3-fluoro-5-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one) [ka]

[0528] Compound 37 was prepared by the method shown in Scheme 25.

[0529] Step a: To methyl 4-bromo-2-(bromomethyl)benzoate (459 mg, 1.5 mmol) was added 3-bromo-5-fluoroaniline (283 mg, 1.5 mmol), and the mixture was stirred at 135° C. for 8 hours. The reaction was quenched with MeOH (5 mL) and filtered to give compound 37-1 as a white solid (320 mg, 55.7% yield).

[0530] Step b: To a mixture of compound 37-1 (300 mg, 0.78 mmol) in t-BuOH (5 mL) / toluene (5 mL), pyridin-4-amine (220 mg, 2.34 mmol), Pd(dba) (30 mg, 0.02 mmol), Brettphos (30 mg, 0.02 mmol), and CsCO (760 mg, 2.34 mmol) were added, and the mixture was stirred under N at 100 °C for 12 h. The mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 37 as a yellow solid (20 mg, 9% yield).

[0531] Compound 37 (2-(3-fluoro-5-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one): C 24 H 18 FNO; 411.43 g / mol; 20 mg; off-white solid; ESI-LCMS m / z=412 [M+H]; LCMS RT=1.32 min, >95.00% (214 nm).

[0532] Example 38: Compound 38 (2-(4-fluoro-3-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one) [ka]

[0533] Compound 38 was prepared by the method shown in Scheme 26.

[0534] Step a: To methyl 4-bromo-2-(bromomethyl)benzoate (459 mg, 1.5 mmol) was added 3-bromo-4-fluoroaniline (283 mg, 1.5 mmol), and the mixture was stirred at 135° C. for 8 hours. The reaction was quenched with MeOH (6 mL) and filtered to give compound 38-1 as a white solid (350 mg, 60.8% yield).

[0535] Step b: To a mixture of compound 38-1 (200 mg, 0.52 mmol) in t-BuOH (5 mL) / toluene (5 mL), pyridin-4-amine (147 mg, 1.56 mmol), Pd(dba) (30 mg, 0.02 mmol), Brettphos (30 mg, 0.02 mmol), and CsCO (510 mg, 1.56 mmol) were added, and the mixture was stirred under N at 100 °C for 12 h. The mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 38 as a yellow solid (25 mg, 11% yield).

[0536] Compound 38 (2-(4-fluoro-3-(pyridin-4-ylamino)phenyl)-5-(pyridin-4-ylamino)isoindolin-1-one): C 24 H 18 FN5O; 411.43 g / mol; 25 mg; white solid; ESI-LCMS m / z=412[M+H]; LCMS RT=1.62 min, >95.00% (214 nm).

[0537] Example 39: Compound 39 (N-(2-methylpyridin-4-yl)-2-(4-((2-methylpyridin-4-yl)amino)phenyl)benzo[d]oxazol-5-amine) [ka] Compound 39 was prepared by the method shown in Scheme 27.

[0538] Step a: To a solution of 5-nitrobenzo[d]oxazole (500 mg, 3.05 mmol) in 1,4-dioxane (20 mL), 1-iodo-4-nitrobenzene (910 mg, 3.65 mmol), lithium t-butoxide (490 mg, 6.10 mmol), and Pd(PPh3)4 (175 mg, 0.15 mmol) were added. The mixture was stirred under Ar at 100 °C overnight. Water (60 mL) was added, and the mixture was extracted with DCM (3 × 60 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product compound 139-1. The crude product (1.2 g) was used directly in the next step.

[0539] Step b: To a solution of crude compound 39-1 (1.2 g) in ethanol (15 mL), a spoonful of Raney nickel and N2H4·H2O (3 mL) were added. The mixture was stirred under N2 at room temperature for 1 hour. The mixture was filtered, and the solvent was removed in vacuo. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1, 254 nm, silica) to give compound 39-2 as a brown solid (500 mg, 35% yield).

[0540] Step c: To a solution of compound 39-2 (140 mg, 0.62 mmol) in ethanol (6 mL), 4-bromo-2-methylpyridine (0.03 mL, 0.62 mmol), Pd2dba3 (56 mg, 0.062 mmol), K2CO3 (95 mg, 0.64 mmol), and X-Phos (146 mg, 0.29 mmol) were added. The mixture was stirred at 100 °C overnight. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give compound 39 as a white solid (60 mg, 63% yield).

[0541] Compound 39 (N-(2-methylpyridin-4-yl)-2-(4-((2-methylpyridin-4-yl)amino)phenyl)benzo[d]oxazol-5-amine): C 25 H 21 NO; 407.47 g / mol; 60 mg; white solid; ESI-LCMS m / z=408 [M+H] + LCMS RT=1.67 min, >95.00% (214 and 254 nm).

[0542] Example 40: Compound 40 (N-(2-methylpyridin-4-yl)-2-(3-((2-methylpyridin-4-yl)amino)phenyl)benzo[d]oxazol-5-amine) [ka] Compound 40 was prepared by the method shown in Scheme 28.

[0543] Step a: To a solution of 5-nitrobenzo[d]oxazole (500 mg, 3.05 mmol) in 1,4-dioxane (20 mL), 1-iodo-4-nitrobenzene (910 mg, 3.65 mmol), lithium t-butoxide (490 mg, 6.10 mmol), and Pd(PPh3)4 (175 mg, 0.15 mmol) were added. The mixture was stirred under Ar at 100 °C overnight. Water (60 mL) was added, and the mixture was extracted with DCM (3 × 60 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude compound 40-1. The crude product (1.1 g) was used directly in the next step.

[0544] Step b: To a solution of crude compound 40-1 (1.1 g) in ethanol (15 mL), a spoonful of Raney nickel and N2H4·H2O (3 mL) were added. The mixture was stirred under N2 at room temperature for 1 hour. The mixture was filtered, and the solvent was removed in vacuo. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1, 254 nm, silica) to give compound 40-2 as a brown solid (475 mg, 33% yield).

[0545] Step c: To a solution of compound 40-2 (250 mg, 1.1 mmol) in ethanol (60 mL), 4-bromo-2-methylpyridine (0.06 mL, 1.1 mmol), Pd2dba3 (100 mg, 0.11 mmol), K2CO3 (170 mg, 1.2 mmol), and X-Phos (261 mg, 0.55 mmol) were added. The mixture was stirred at 100 °C overnight. Water (150 mL) was added, and the mixture was extracted with ethyl acetate (2 × 150 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give compound 40 as a white solid (80 mg, 67% yield).

[0546] Compound 40 (N-(2-methylpyridin-4-yl)-2-(3-((2-methylpyridin-4-yl)amino)phenyl)benzo[d]oxazol-5-amine): C 25 H21 NO; 407.47 g / mol; 80 mg; white solid; ESI-LCMS m / z=408 [M+H] + LCMS RT=1.75 min, >95.00% (214 and 254 nm).

[0547] Example 41: Compound 41 (N-(2-methylpyridin-4-yl)-2-(4-((2-methylpyridin-4-yl)amino)phenyl)benzo[d]oxazol-6-amine) [ka] Compound 41 was prepared by the method shown in Scheme 29.

[0548] Step a: To a solution of 6-nitrobenzo[d]oxazole (500 mg, 3.05 mmol) in 1,4-dioxane (20 mL), 1-iodo-4-nitrobenzene (910 mg, 3.65 mmol), lithium t-butoxide (490 mg, 6.10 mmol), and Pd(PPh3)4 (175 mg, 0.15 mmol) were added. The mixture was stirred under Ar at 100 °C overnight. Water (60 mL) was added, and the mixture was extracted with DCM (3 × 60 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude compound 141-1. The crude product (1.5 g) was used directly in the next step.

[0549] Step b: To a solution of crude compound 41-1 (1.5 g) in ethanol (15 mL), a spoonful of Raney nickel and N2H4·H2O (3 mL) were added. The mixture was stirred under N2 at room temperature for 1 hour. The mixture was filtered, and the solvent was removed in vacuo. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1, 254 nm, silica) to give compound 41-2 as a brown solid (321 mg, 30% yield).

[0550] Step c: To a solution of compound 41-2 (170 mg, 0.60 mmol) in ethanol (8 mL), 4-bromo-2-methylpyridine (0.04 mL, 0.60 mmol), Pd2dba3 (68 mg, 0.060 mmol), K2CO3 (116 mg, 0.71 mmol), and X-Phos (177 mg, 0.32 mmol) were added. The mixture was stirred at 100 °C overnight. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give compound 41 as a white solid (32 mg, 57% yield).

[0551] Compound 41 (N-(2-methylpyridin-4-yl)-2-(4-((2-methylpyridin-4-yl)amino)phenyl)benzo[d]oxazol-6-amine): C 25 H 21 NO; 407.47 g / mol; 32 mg; white solid; ESI-LCMS m / z=408 [M+H] + LCMS RT=1.65 min, >95.00% (214 and 254 nm).

[0552] Example 42: Compound 42 (N-(2-methylpyridin-4-yl)-2-(3-((2-methylpyridin-4-yl)amino)phenyl)benzo[d]oxazol-6-amine) [ka] Compound 42 was prepared by the method shown in Scheme 30.

[0553] Step a: To a solution of 6-nitrobenzo[d]oxazole (500 mg, 3.05 mmol) in 1,4-dioxane (20 mL), 1-iodo-4-nitrobenzene (910 mg, 3.65 mmol), lithium t-butoxide (490 mg, 6.10 mmol), and Pd(PPh3)4 (175 mg, 0.15 mmol) were added. The mixture was stirred under Ar at 100 °C overnight. Water (60 mL) was added, and the mixture was extracted with DCM (3 × 60 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product Compound 42-1. The crude product (1.2 g) was used directly in the next step.

[0554] Step b: To a solution of crude compound 42-1 (1.2 g) in ethanol (15 mL), a spoonful of Raney nickel and N2H4·H2O (3 mL) were added. The mixture was stirred under N2 at room temperature for 1 hour. The mixture was filtered, and the solvent was removed in vacuo. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1, 254 nm, silica) to give compound 42-2 as a brown solid (563 mg, 42% yield).

[0555] Step c: To a solution of compound 42-2 (250 mg, 1.1 mmol) in ethanol (60 mL), 4-bromo-2-methylpyridine (0.06 mL, 1.1 mmol), Pd2dba3 (100 mg, 0.11 mmol), K2CO3 (170 mg, 1.2 mmol), and X-Phos (261 mg, 0.55 mmol) were added. The mixture was stirred at 100 °C overnight. Water (150 mL) was added, and the mixture was extracted with ethyl acetate (2 × 150 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give compound 42 as a white solid (40 mg, 53% yield).

[0556] Compound 42 (N-(2-methylpyridin-4-yl)-2-(3-((2-methylpyridin-4-yl)amino)phenyl)benzo[d]oxazol-6-amine): C 25 H21 NO; 407.47 g / mol; 40 mg; white solid; ESI-LCMS m / z=408 [M+H] + LCMS RT=1.53 min, >95.00% (214 and 254 nm).

[0557] Example 43: Compound 43 (2-(3-((4-fluorophenyl)amino)phenyl)-N-(2-methylpyridin-4-yl)benzo[d]oxazol-5-amine) [ka] Compound 43 was prepared as shown in Scheme 31.

[0558] Step a: To a solution of 1-bromo-3-iodobenzene (200 mg, 0.7 mmol) in xylene (10 mL) under Ar, 4-fluoroaniline (40 mg, 0.36 mmol), Pd(PPh)Cl (25 mg, 0.036 mmol), PPh (10 mg, 0.07 mmol), and t-BuONa (120 mg, 1.08 mmol) were added. The mixture was stirred at 140 °C under Ar for 16 h. The mixture was concentrated, and the residue was purified with EA / PE (0% to 10%) to give compound 43-1 as a yellow solid (150 mg, 80% yield).

[0559] Step b: To a solution of compound 43-1 (160 mg, 0.6 mmol) in 1,4-dioxane (5 mL) was added 5-nitrobenzo[d]oxazole (75 mg, 0.5 mmol), Pd(Ph3)4 (57 mg, 0.05 mmol), and t-BuLi (60 mg, 1.0 mmol) at room temperature under Ar. The mixture was stirred at 100 °C under Ar overnight. The mixture was concentrated, and the residue was purified with EA / PE (0%-10%) to give compound 43-2 as a yellow solid (50 mg, 50% yield).

[0560] Step c: To a solution of compound 43-2 (50 mg, 0.28 mmol) in EtOH (6 mL) and DCM (3 mL) was added NHNH·HO (14 mg, 0.28 mmol) and Raney Ni (10 mg) under H at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was filtered. The filtrate was concentrated to give compound 43-3 as a yellow solid (50 mg, 100% yield).

[0561] Step d: To a solution of compound 43-3 (100 mg, 0.31 mmol) in EtOH (3 mL) was added 4-bromo-2-methylpyridine (100 mg, 0.6 mmol), X-phos (74 mg, 0.062 mmol), Pd(dba) (30 mg, 0.031 mmol), and KCO (200 mg, 1.55 mmol) at room temperature under Ar. The mixture was stirred at 100 °C under Ar overnight. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (NHHCO / HO / MeCN) to give compound 43 as a yellow solid (38.2 mg, 30% yield).

[0562] Compound 43 (2-(3-((4-fluorophenyl)amino)phenyl)-N-(2-methylpyridin-4-yl)benzo[d]oxazol-5-amine): C 25 H 19 FNO; 410.45 g / mol; 38.2 mg; yellow solid; ESI-LCMS m / z=411 [M+H] + LCMS RT=1.106 min, >95.00% (214 and 254 nm).

[0563] Example 44: Compound 44 (7-methyl-5-((2-methylpyridin-4-yl)amino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one) [ka]

[0564] Compound 44 was prepared as shown in Scheme 32.

[0565] Step a: To a mixture of compound 30-3 (640 mg, 2 mmol) and compound 30-2 (407 mg, 2.2 mmol) in MeOH (10 mL), TEA (606 mg, 6 mmol) was added, and the mixture was stirred at 85 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0-20% MeOH in DCM) to give compound 30-4 as a solid (400 mg, 50.8% yield).

[0566] Step b: To a mixture of compound 30-4 (150 mg, 0.38 mmol) in t-BuOH (5 mL) / toluene (5 mL), 2-methylpyridin-4-amine (50 mg, 0.45 mmol), Pd(dba) (20 mg, 0.02 mmol), Brettphos (20 mg, 0.02 mmol), and CsCO (247 mg, 0.76 mmol) were added, and the mixture was stirred under N at 100 °C for 12 h. The mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 44 as a yellow solid (15 mg, 10% yield).

[0567] Compound 44 (7-methyl-5-((2-methylpyridin-4-yl)amino)-2-(3-(pyridin-4-ylamino)phenyl)isoindolin-1-one): C 26 H 23 NO; 421.49 g / mol; 15 mg; yellow solid; ESI-LCMS m / z=422 [M+H] + LCMS RT=1.30 min, >95.00% (214 and 254 nm).

[0568] Example 45: Compound 45 (7-methyl-5-((2-methylpyridin-4-yl)amino)-2-(3-((2-methylpyridin-4-yl)amino)phenyl)isoindolin-1-one) [ka] Compound 45 was prepared by the method shown in Scheme 33.

[0569] Step a: To a stirred mixture of 3-nitroaniline (2.76 g, 0.02 mol) in 1,4-dioxane (30 mL) under N2, 4-bromo-2-methylpyridine (3.42 g, 0.02 mol), Cs2CO3 (13 g, 0.04 mol), Pd2(dba)3 (280 mg, 0.25 mmol), and Xantphos (280 mg, 0.4 mmol) were added. The resulting mixture was stirred at 100 °C for 3 h. The reaction was quenched with water (60 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0–50% EtOAc in petroleum ether) to give compound 45-1 as a yellow solid (4 g, 87% yield).

[0570] Step b: To a mixture of compound 45-1 (4 g, 17.5 mmol) in MeOH (100 mL), Pd / C (400 mg) was added, and the mixture was stirred under H at room temperature for 4 h. The combined organic phase was filtered through diatomaceous earth to give compound 45-2 as a yellow solid (3 g, 88.7% yield).

[0571] Step c: To a mixture of compound 30-3 (400 mg, 1.25 mmol) and compound 45-2 (273 mg, 1.3 mmol) in MeOH (10 mL), TEA (253 mg, 2.5 mmol) was added, and the mixture was stirred at 85 °C for 16 h. The combined organic phase was concentrated. The residue was purified by flash chromatography on silica gel (0-20% MeOH in DCM) to give compound 45-3 as a solid (300 mg, 59% yield).

[0572] Step d: To a mixture of compound 45-3 (150 mg, 0.36 mmol) in t-BuOH (5 mL) / toluene (5 mL), 2-methylpyridin-4-amine (39 mg, 0.45 mmol), Pd(dba) (20 mg, 0.02 mmol), Brettphos (20 mg, 0.02 mmol), and CsCO (234 mg, 0.72 mmol) were added, and the mixture was stirred under N at 100 °C for 12 h. The mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 45 as a yellow solid (18 mg, 11% yield).

[0573] Compound 45 (7-methyl-5-((2-methylpyridin-4-yl)amino)-2-(3-((2-methylpyridin-4-yl)amino)phenyl)isoindolin-1-one): C 27 H 25 NO; 435.53 g / mol; 18 mg; yellow solid; ESI-LCMS m / z=436 [M+H] + LCMS RT=1.41 min, >95.00% (214 and 254 nm).

[0574] Example 46: Biological Assays Foxp3 induction assay Sorted or enriched (Miltenyi magnetic separation) CD4+ conventional T cells (Tconvs-CD4+ / CD25) from C57 / Bl6 mice were used for iTreg induction. 10 μg / mL plate-bound anti-CD3 antibody (50 μl per well, 96-well plate), 2.5 μg / mL soluble anti-CD28 antibody, 100 IU / mL IL2, and 5 ng / mL TGF-β were used in the absence or presence of different drug concentrations (usually titrated from 0.01 μM to 10 μM). A sample without TGF-β was used as a negative control for induction.

[0575] After 3 days of culture in the presence of stimuli, TGF-β, and drugs, cells were stained using a fixable live / dead cell stain (Life Technologies, NY) for gating and exclusion of toxic doses. Cells were fixed and permeabilized using a mouse Foxp3 buffer kit according to the manufacturer's instructions (BD Bioscience, San Jose, CA). Cells were stained using anti-CD4 and anti-Foxp3 antibodies. After staining, cells were acquired using a flow cytometer.

[0576] Jurkat-FoxP3 reporter assay (BPS Bioscience, Cat#60628) Cell culture process: Prepare a 50 ml conical tube and a T-25 culture flask with 5 ml of pre-warmed Thaw Medium 2 (without G418). Thaw the cells quickly in a 37°C water bath with constant, slow agitation. Immediately transfer the entire contents to the conical tube containing Thaw Medium 2 (without G418) and centrifuge the cells at 200 x g for 3 minutes. Resuspend the cells in 6 ml of pre-warmed Thaw Medium 2 (without G418) and transfer the entire contents to a T25 culture flask containing Thaw Medium 2 (without G418). Incubate the cells in a humidified 37°C incubator with 5% CO2. After 48 hours of incubation, centrifuge the cells at 250 x g for 5 minutes and resuspend them in fresh Thaw Medium 2 (without G418). Continue to monitor growth for 2-3 days, changing the medium to remove dead debris. After numerous cell colonies (in clumps) begin to appear (indicating healthy cell division), switch to Growth Medium 2B (containing G418).

[0577] After assay protocol: (CD3 / CD28) 1. Jurkat-FoxP3-luciferase reporter cells (approximately 2.5 x 10 cells / well, 10 µL per well) were cultured in a white, light-proof 384-well plate in assay medium (RPMI 1640 medium (Thermo Fisher Scientific, Cat. No. A1049101) supplemented with 1% penicillin / streptomycin) in the absence and presence of Human T-Activator CD3 / CD28 Dynabeads (Thermo Fisher Scientific, Cat. No. 11161D) at a ratio of 1:5.

[0578] 2. Serial dilutions of drug were made over a range of 1-60,000 nM. 10 μL of drug was added, resulting in a range of 1-30,000 nM, and mixed by gentle suction. In some experiments, the range was 10-20,000 nM. Cells were cultured for 12 hours at 37°C with 5% CO2 in the presence and absence of drug.

[0579] 3. Add ONE-Step™ Luciferase Assay System (BPS Bioscience, Cat. #60690) to each well according to the protocol. Add an equal volume of luciferase assay working solution (component A + component B) to the medium in each well. As an example, a 384-well plate with 20 μl of medium requires 20 μl of luciferase assay working solution per well.

[0580] 4. Gently rock the plate at room temperature for ≥15 minutes. Measure firefly luminescence using a luminometer.

[0581] Phospho-Akt isoform specificity assay Human CD4+ / CD45RA+ / CD25- unstimulated T cells were plated under induction conditions (IL-2 / anti-CD3 / anti-CD28 / TGFβ) in the absence or presence of compounds for 72 hours. To determine compound specificity for each phospho-AKT isoform, a phospho-AKT cell HTRF kit (Cisbio catalog numbers 63ADK078PEG(pAKT1), 63ADK080PEG(p-AKT2), ​​and 63ADK082PEG(pAKT3)) was used according to the manufacturer's specifications. Briefly, after removal of the supernatant, cells were lysed, and total protein concentration was measured and normalized across all samples. Cell lysates were transferred to 384-well plates, and a Eu cryptate antibody + d2 antibody mix was added. This process was the same for each isoform, utilizing the corresponding isoform antibody from each kit. Positive and negative controls (supplied with the kit) were included in each experiment. Plates were incubated overnight. Data collection was performed on a Varioskan Lux reader using settings for the TRF fluorescence protocol. Data are presented as percent change relative to DMSO-treated controls. Each test condition was run in duplicate, and assays were performed at least twice.

[0582] IL-10 ELISA assay Human CD4+ / CD25+ natural Treg cells were plated under stimulation conditions (IL-2 / anti-CD3 / anti-CD28) in the absence or presence of compounds. After 24 and 48 hours of incubation, supernatants were collected, and IL-10 concentrations were determined using a human IL-10 ELISA kit according to the manufacturer's specifications (Invitrogen BMS215-2). Briefly, supernatants were added to precoated 96-well ELISA plates and incubated, followed by the addition of a biotin-conjugated detection antibody and streptavidin-HRP. After incubation, substrate was added, and the reaction was stopped by the addition of acid. Absorbance was measured at 450 nm using a Varioskan Lux reader. A standard curve was generated using known concentrations of IL-10 (provided in the kit), and the concentration of IL-10 in the supernatants was calculated. Data are presented as percent change relative to the untreated stimulated cell control. Each test condition was performed in triplicate, and the assay was performed at least twice.

[0583] FoxP3 ELISA assay Human CD4+ / CD45RA+ / CD25- unstimulated T cells were plated under induction conditions (IL-2 / anti-CD3 / anti-CD28+TGFβ) in the absence or presence of compound for 72 hours. After incubation, cells were lysed, and FoxP3 protein was measured in the lysates using a Human FoxP3 ELISA kit according to the manufacturer's specifications (LSBio, LS-F5047). Briefly, lysates were added to precoated 96-well ELISA plates and incubated, followed by incubation with a biotin-conjugated detection antibody and streptavidin-HRP. After incubation, substrate was added, and the reaction was stopped by the addition of acid. Absorbance was measured at 450 nm using a Varioskan Lux reader. A standard curve was generated using known concentrations of FoxP3 (provided in the kit), and the concentration of FoxP3 in the lysates was calculated. Data are presented as a percentage of change relative to cells induced in the absence of compound. Each test condition was performed in duplicate and the assay was performed at least twice.

[0584] iTreg induction assay Sorted human CD4+ T cells were used for iTreg induction. Human T cell activation beads (Gibco Dynabeads CD3 / CD28), 100 IU / mL IL2, and 5 ng / mL TGF-β were used in the absence or presence of different drug concentrations. Samples without TGF-β were used as a negative control for induction. After 3 days of culture in the presence of TGF-β and drug stimulation, cells were stained with a fixable live / dead cell stain (Life Technologies) for gating and exclusion of toxic doses. They were then fixed, permeabilized, and stained with anti-Foxp3 antibody using a Foxp3 buffer kit according to the manufacturer's specifications (BD Bioscience). After staining, cells were acquired using a flow cytometer. Each test condition was performed in duplicate, and assays were performed at least twice.

[0585] This assay protocol was used, at least in part, to generate the data illustrated by Figure 1, which shows an assessment of iTreg induction (FoxP3) from human CD4 T cells treated with compound 22 in the presence of anti-CD3 / anti-CD28 / IL-2 / TGFβ.

[0586] The Akt3 inhibitory and activating activities of selected compounds disclosed herein are shown in Tables 1 and 2, respectively. [Table 1-1] [Table 1-2] [Table 1-3]

[0587] [Table 2]

Claims

1. Formula Ia, Ib or Ic 【Chemistry 1】 [During the ceremony, 【Chemistry 2】 teeth, 【Transformation 3】 and X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , X ８ and X ９ Each occurrence of １ or N, R １ Each occurrence of is independently selected from H, D, halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, (C ２ ~C ６ ) alkenyl, (C ２ ~C ６ ) haloalkenyl, (C ２ ~C ６ ) alkynyl, (C ２ ~C ６ ) haloalkynyl, (C ３ ~C ７ ) cycloalkyl, (C ４ ~C １０ ) bicycloalkyl, (C ４ ~C １４ ) tricycloalkyl, (C ３ ~C ７ ) heterocycloalkyl, halogenated (C ３ ~C ７ ) heterocycloalkyl, (C ４ ~C １０ ) heterobicycloalkyl, (C ４ ~C １４ ) heterotricycloalkyl, (C ４ ~C １０ ) heterospiroalkyl, (C ３ ~C ７ ) cycloalkenyl, (C ３ ~C ７ ) heterocycloalkenyl, (C ４ ~C １０ ) bicycloalkenyl, (C ４ ~C １０ ) heterobicycloalkenyl, (C ４ ~C １４ ) tricycloalkenyl, (C ４ ~C １４ ) heterotricycloalkenyl, aryl, heteroaryl, —ORa, —SR ａ , -N(R ａ ) ２ , -COR ａ , -CO ２ R ａ , CON(R ａ ) ２ 、-CN、-NC、NO ２ 、N ３ 、-SO ２ R ａ 、-SO ２ N(R ａ ) ２ 、-N(R ａ )SO ２ R ａ 、 【Chemistry 4】 and one or more (C １ ~C ６ ) alkyl, halogenated (C １ ~C ６ ) alkyl, -SO ２ R ａ or -SO ２ N(R ａ ) ２ partially saturated bicyclic heteroaryl, optionally substituted with R １ (C ３ ~C ７ ) cycloalkyl, (C ４ ~C １０ ) bicycloalkyl, (C ４ ~C １４ ) tricycloalkyl, (C ３ ~C ７ ) heterocycloalkyl, halogenated (C ３ ~C ７ ) heterocycloalkyl, (C ４ ~C １０ ) heterobicycloalkyl, (C ４ ~C １４ ) heterotricycloalkyl, (C ４ ~C １０ ) heterospiroalkyl, (C ３ ~C ７ ) cycloalkenyl, (C ３ ~C ７ ) heterocycloalkenyl, (C ４ ~C １０ ) bicycloalkenyl, (C ４ ~C １０ ) heterobicycloalkenyl, (C ４ ~C １４ ) tricycloalkenyl, (C ４ ~C １４ ) Heterotricycloalkenyl, aryl and heteroaryl are each selected from the group consisting of one or more (C １ ~C ６ ) alkyl, halogenated (C １ ~C ６ ) Alkyl, halogen, -OR ａ , —CN or —N(R ａ ) ２ are substituted as appropriate, n is an integer from 0 to 4, as allowed by valence; Q is C(R ａ ) ２ , O., N.R. ａ , N(C=O)R ａ or NSO ２ R ａ and Y １ , Y ２ , Y ３ , Y ４ and Y ５ are each independently N or CR as allowed by valence. ２ and R ２ is H, halogen, D, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, (C ２ ~C ６ ) alkenyl, (C ２ ~C ６ ) haloalkenyl, (C ２ ~C ６ ) alkynyl, (C ２ ~C ６ ) haloalkynyl, (C ３ ~C ７ ) cycloalkyl, (C ４ ~C １０ ) bicycloalkyl, (C ３ ~C ７ ) heterocycloalkyl, halogenated (C ３ ~C ７ ) heterocycloalkyl, (C ４ ~C １０ ) heterobicycloalkyl, (C ４ ~C １０ ) Heterospiroalkyl, aryl, heteroaryl, -ORa, -SR ａ , -N(R ａ ) ２ , -COR ａ , -CO ２ R ａ , CON(R ａ ) ２ , -CN, -NC, NO ２ , N ３ , -SO ２ R ａ , -SO ２ N(R ａ ) ２ , -N(R ａ )SO ２ R ａ , 【Transformation 5】 is selected from the group consisting of -E-G-は、-(C=O)NR ｘ -、-NR ｘ (C=O)-、-N(R ｘ )(C=O)N(R ｘ )-、-O(C=O)N(R ｘ )-、-N(R ｘ )(C=O)O-、-SO ２ NR ｘ -、-NR ｘ SO ２ - or 【Transformation 6】 and R ｘ Each occurrence of is independently H, (C １ ~C ６ ) alkyl, (C ３ ~C ７ ) cycloalkyl, aryl, or heteroaryl or R ｘ and Y ３ , R ｘ and Y ４ , R ｘ and Z １ , or R ｘ and Z ４ together form one or more R ｚ and R ｚ Each occurrence of is independently H, (C １ ~C ６ ) alkyl, OH, O(C １ ~C ６ ) alkyl, or halogen, or two R ｚ together, halogen or (C １ ~C ６ ) forming a 4- to 6-membered ring optionally substituted with alkyl, W １ , W ２ , W ３ , W ４ and W ５ are each independently, as allowed by valence, CR ６ , N or NR ６ and R ６ Each occurrence of is independently selected from H, halogen, (C １ ~C ６ ) alkyl and (C １ ~C ６ ) haloalkyl; Each occurrence of T is independently O, N, NR, as allowed by valences. ａ , N(C=O)R ａ , NC(R ｂ ) ２ OP(=O)(OR ｂ ) ２ or NSO ２ R ａ and Each occurrence of U is independently O, N, NR, as allowed by valence. ａ , N(C=O)R ａ , NC(R ｂ ) ２ OP(=O)(OR ｂ ) ２ or NSO ２ R ａ and R ｂ Each occurrence of is independently H or (C １ ~C ６ ) alkyl, Z １ , Z ２ , Z ３ , Z ４ and Z ５ are each independently N or CR as allowed by valence. ３ and R ３ H, D, halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, (C ２ ~C ６ ) alkenyl, (C ２ ~C ６ ) haloalkenyl, (C ２ ~C ６ ) alkynyl, (C ２ ~C ６ ) haloalkynyl, (C ３ ~C ７ ) cycloalkyl, (C ４ ~C １０ ) bicycloalkyl, (C ３ ~C ７ ) heterocycloalkyl, halogenated (C ３ ~C ７ ) heterocycloalkyl, (C ４ ~C １０ ) heterobicycloalkyl, (C ４ ~C １０ ) Heterospiroalkyl, aryl, heteroaryl, -ORa, -SR ａ , -N(R ａ ) ２ , -COR ａ , -CO ２ R ａ , CON(R ａ ) ２ , -CN, -NC, NO ２ , N ３ , -SO ２ R ａ , -SO ２ N(R ａ ) ２ , -N(R ａ )SO ２ R ａ , 【Transformation 7】 is selected from the group consisting of V is either absent or C(R ａ ) ２ , N.R. ａ , N(C=O)R ａ , NSO ２ R ａ or O, R ４ (C １ ~C ６ ) alkyl, (C ３ ~C ７ ) cycloalkyl, (C ４ ~C １０ ) bicycloalkyl, (C ３ ~C ７ ) heterocycloalkyl, (C ４ ~C １０ ) heterobicycloalkyl, (C ４ ~C １０ ) selected from the group consisting of heterospiroalkyl, aryl, and heteroaryl, each of which is selected from one or more R ５ or or alternatively V and R ４ Together, (C ３ ~C ７ ) heterocycloalkyl or (C ４ ~C １０ ) forming a heterospiroalkyl, R ５ Each occurrence of is independently selected from H, D, halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, (C ２ ~C ６ ) alkenyl, (C ２ ~C ６ ) haloalkenyl, (C ２ ~C ６ ) alkynyl, (C ２ ~C ６ ) haloalkynyl, (C ３ ~C ７ ) cycloalkyl, (C ４ ~C １０ ) bicycloalkyl, (C ３ ~C ７ ) heterocycloalkyl, halogenated (C ３ ~C ７ ) heterocycloalkyl, (C ４ ~C １０ ) heterobicycloalkyl, (C ４ ~C １０ ) Heterospiroalkyl, aryl, heteroaryl, -ORa, -SR ａ , -N(R ａ ) ２ , -COR ａ , -CO ２ R ａ , CON(R ａ ) ２ , -CN, -NC, NO ２ , N ３ , -SO ２ R ａ , -SO ２ N(R ａ ) ２ , -N(R ａ )SO ２ R ａ , N(R ａ )COR ａ , 【Transformation 8】 is selected from the group consisting of R ａ Each occurrence of is independently H, (C １ ~C ６ ) alkyl, (C ２ ~C ６ ) alkenyl, (C ３ ~C ７ ) cycloalkyl, aryl, or heteroaryl, or two R ａ together form a halogen or (C １ ~C ６ ) forming a 4- to 6-membered ring optionally substituted with alkyl. or a pharmaceutically acceptable salt thereof.

2. Q, T and U are each independently O, NH, NCH, as allowed by valences. ３ , N(C=O)H, N(C=O)CH ３ , N(C=O)CH ２ CH ３ , NSO ２ CH ３ or NSO ２ CH ２ CH ３ and / or X1, X2, X3, X4, X5, X6, X7, X8, X9, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4 and Z5 are each independently CH, C(halogen) or N; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. 【Request Item 3】 【Chemistry 9】 but, a) 【Chemistry 10】 is; As desired structural part 【Chemistry 11】 but, 【Chemistry 12】 and optionally having the structure n is 0, 1 or 2; or structural part 【Chemistry 13】 but, 【Chemistry 14】 and optionally having the structure structural part 【Chemistry 15】 but, 【Chemistry 16】 having the structure: b) 【Chemistry 17】 is; As desired structural part [Chemistry 18] but, 【Chemistry 19】 and optionally having the structure n is 0, 1 or 2; or structural part 【Chemistry 20】 but, 【Chemistry 21】 and optionally having the structure structural part 【Chemistry 22】 but, 【Chemistry 23】 and optionally having the structure structural part 【Chemistry 24】 but, 【Chemistry 25】 or having the structure c) 【Chemistry 26】 is; As desired structural part 【Chemistry 27】 but, 【Chemistry 28】 and optionally having the structure structural part 【Chemistry 29】 but, 【Transformation 30】 having the structure 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. a) Q is O; or Q is NR a , N(C═O)R a or NSO 2 R a ; and / or b) each occurrence of R 1 is independently H, D, halogen, OR a , N(R a ) 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkynyl, (C 3 -C 7 )heterocycloalkyl, (C 4 -C 10 )heterospiroalkyl, halogenated (C 3 -C 7 )heterocycloalkyl, aryl, (C 4 -C 10 )bicycloalkyl, —CN, —NC, N 3 , NO 2 , COR a , CO 2 R a , CON(R a ) 2 , —SO 2 R a , or —SO 2 N(R a ) 2 , wherein the (C 3 -C 7 )heterocycloalkyl is optionally substituted with one or more (C 1 -C 6 )alkyl; (i) each occurrence of R 1 is independently H, halogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )heterocycloalkyl, (C 4 -C 10 )heterospiroalkyl, halogenated (C 3 -C 7 )heterocycloalkyl, N(R a ) 2 , or —CN, wherein the (C 3 -C 7 )heterocycloalkyl is optionally substituted with one or more (C 1 -C 6 )alkyl; each occurrence of R 1 is independently H, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, halogenated (C 3 -C 7 )heterocycloalkyl, or (C 3 -C 7 )heterocycloalkyl, wherein the (C 3 -C 7 )heterocycloalkyl is optionally substituted with one or more (C 1 -C 6 )alkyl; or (ii) each occurrence of R 1 is independently H, D, F, Cl, Br, CH 3 , OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , 【Chemistry 31】 , -CN, -NC, N 3 , NO 2 , 【Chemistry 32】 is; optionally Each occurrence of R 1 is independently H, D, F, CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , 【Transformation 33】 is; and / or c) at least one occurrence of R 1 is 【Transformation 34】 is; or At least one occurrence of R 1 is 【Chemistry 35】 and X is CR 15 , O, NR 14 or S, each occurrence of R 9 is independently H, (C 1 -C 6 )alkyl, halogenated (C 1 -C 6 )alkyl, halogen, —OR a , —CN or —N(R a ) 2 , R 14 is H, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl, aryl or heteroaryl, each occurrence of R 15 is independently H, (C 1 -C 6 )alkyl, halogenated (C 1 -C 6 )alkyl, halogen, —OR a , —CN or —N(R a ) 2 , and q is 0, 1, 2 or 3; optionally (i) X is O or X is NR 14 and R 14 is H or (C 1 -C 6 )alkyl; and / or (ii) each occurrence of R 9 is independently H, (C 1 -C 6 )alkyl, halogenated (C 1 -C 6 )alkyl, or halogen; or each occurrence of R 9 is independently H, F, Cl, Br, CH 3 , CF 3 , OH, NH 2 , —NHCH 3 or —N(CH 3 ) 2 ; optionally each occurrence of R 9 is independently H, F, Cl, Br, or CH 3 ; (iii) each occurrence of R 15 is independently H, (C 1 -C 6 )alkyl, halogenated (C 1 -C 6 )alkyl, or halogen; optionally each occurrence of R 15 is independently H, F, Cl, Br, or CH 3 ; and / or (iv) q is 0; or q is 1; or q is 2 or 3; and / or (v) at least one occurrence of R 1 is 【Transformation 36】 and X is O or NR 14 , and R 14 is H or (C 1 -C 6 )alkyl; optionally At least one occurrence of R 1 is 【Chemistry 37】 That is, 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof. 【Request Item 5】 【Chemistry 38】 but, a) 【Chemistry 39】 and R １２ However, (C ３ ~C ７ ) cycloalkenyl, (C ３ ~C ７ ) heterocycloalkenyl, (C ４ ~C １０ ) bicycloalkenyl, (C ４ ~C １０ ) heterobicycloalkenyl, (C ４ ~C １４ ) tricycloalkenyl or (C ４ ~C １４ )heterotricycloalkenyl, each of which is one or more (C １ ~C ６ ) alkyl, halogenated (C １ ~C ６ ) Alkyl, halogen, -OR ａ , —CN or —N(R ａ ) ２ optionally substituted with R 12 is 【Chemistry 40】 and X is CR 15 , O, NR 14 or S, each occurrence of R 9 is independently H, (C 1 -C 6 )alkyl, halogenated (C 1 -C 6 )alkyl, halogen, —OR a , —CN or —N(R a ) 2 , R 14 is H, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl, aryl or heteroaryl, each occurrence of R 15 is independently H, (C 1 -C 6 )alkyl, halogenated (C 1 -C 6 )alkyl, halogen, —OR a , —CN or —N(R a ) 2 , and q is 0, 1, 2 or 3; optionally R 12 is 【Chemistry 41】 and X is O or NR 14 , and R 14 is H or (C 1 -C 6 )alkyl; optionally R 12 is 【Chemistry 42】 is; or b) 【Chemistry 43】 That is, 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

6. a) Structural part 【Chemistry 44】 but, 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 wherein Q is O or NH; or b) Structural part 【Chemistry 48】 but, 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 wherein Q is O or NH; or c) Structural part 【Chemistry 53】 but, 【Chemistry 54】 wherein Q is O or NH and R 1 is H, (C 1 -C 6 )alkyl, (C 3 -C 7 )heterocycloalkyl, halogenated (C 3 -C 7 )heterocycloalkyl or halogen; or d) Structural part 【Transformation 55】 but, 【Transformation 56】 wherein Q is O or NH; or e) Structural part 【Chemistry 57】 but, 【Chemistry 58】 wherein Q is O or NH; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

7. having the formula Ia; optionally structural part 【Chemistry 59】 but, 【Transformation 60】 wherein each occurrence of R 2 is independently H, halogen, CH 3 , CF 3 , OH, NH 2 , —NHCH 3 , or —N(CH 3 ) 2 ; optionally (i) Structural part 【Chemistry 61】 but, 【Transformation 62】 and optionally having the structure each occurrence of R 2 is independently H, halogen, CH 3 , CF 3 , OH, NH 2 , —NHCH 3 , or —N(CH 3 ) 2 ; or (ii) Structural part 【Transformation 63】 but, 【Chemistry 64】 having the structure 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

8. structural part 【Transformation 65】 but, a) 【Chemical Formula 66】 or having the structure b) 【Transformation 67】 and optionally having the structure 【Transformation 68】 having the structure 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

9. a) Structural part 【Transformation 69】 but, 【Transformation 70】 and optionally each occurrence of R 3 is H, halogen, CH 3 , CF 3 , OH, NH 2 , —NHCH 3 or —N(CH 3 ) 2 ; structural part 【Chemistry 71】 but, 【Chemistry 72】 and optionally having the structure each occurrence of R 3 is H, halogen, CH 3 , CF 3 , OH, NH 2 , —NHCH 3 or —N(CH 3 ) 2 ; or b) Structural part 【Transformation 73】 but, 【Chemistry 74】 or having the structure c) Structural part 【Chemistry 75】 but, 【Transformation 76】 wherein R 3 is H, CH 3 , OH, halogen, or NH 2 and R x is H, CH 3 , or CH 2 CH 3 ; or structural part 【Chemical 77】 but, 【Transformation 78】 wherein each occurrence of m is independently 1 or 2, J is C(R y ) 2 , and each occurrence of R y is independently H, (C 1 -C 6 )alkyl, OH, O(C 1 -C 6 )alkyl, or halogen, or any two R y groups together with the carbon atom(s) to which they are attached form a (C 3 -C 7 )cycloalkyl or a (C 3 -C 7 )heterocycloalkyl; optionally structural part 【Transformation 79】 but, 【Chemistry 80】 【Chemistry 81】 【Chemistry 82】 wherein each occurrence of m is independently 1 or 2, J is C(R y ) 2 , and each occurrence of R y is independently H, (C 1 -C 6 )alkyl, OH, O(C 1 -C 6 )alkyl, or halogen; or e) Structural part 【Chemistry 83】 but, 【Chemical 84】 wherein each occurrence of m is independently 1 or 2, J is C(R z ) 2 , and each occurrence of R z is independently H, (C 1 -C 6 )alkyl, OH, O(C 1 -C 6 )alkyl, or halogen, or any two R z groups together with the carbon atom(s) to which they are attached form a (C 3 -C 7 )cycloalkyl or a (C 3 -C 7 )heterocycloalkyl; optionally structural part 【Chemical 85】 but, 【Chemical 86】 wherein Z 1 , Z 2 , Z 3 and Z 4 are each independently N, CH, CCH 3 or CF; optionally structural part 【Chemistry 87】 but, 【Chemical 88】 having the structure 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

10. having the formula Ib; optionally structural part 【Chemistry 89】 but, [Chemical 90] wherein each occurrence of T and U is independently O, N, NR, N(C=O)R, NC(Rb>)2OP(=O)(ORb )2, or NSO2R, as allowed by valences; structural part 【Chemistry 91】 but, 【Chemistry 92】 wherein R 3 is H, CH 3 , OH, halogen or NH 2 and R a is H, CH 3 or CH 2 CH 3 ; optionally structural part 【Chemistry 93】 but, 【Chemical 94】 and optionally having the structure each occurrence of R b is independently H or (C 1 -C 6 )alkyl; optionally each occurrence of R b is independently H, CH 3 , CH 2 CH 3 or CH(CH 3 ) 2 ; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

11. having the formula Ic; optionally structural part 【Chemical 95】 but, 【Chemistry 96】 wherein each occurrence of T and U is independently O, N, NR, N(C=O)R, NC(Rb>)2OP(=O)(ORb )2, or NSO2R, as allowed by valences; structural part 【Chemistry 97】 but, 【Chem.98】 wherein R 3 is H, CH 3 , OH, halogen or NH 2 and R a is H, CH 3 or CH 2 CH 3 ; optionally structural part 【Chem.99】 but, 【Chemistry 100】 and optionally having the structure each occurrence of R b is independently H or (C 1 -C 6 )alkyl; optionally each occurrence of R b is independently H, CH 3 , CH 2 CH 3 or CH(CH 3 ) 2 ; or each occurrence of R 2 is independently H, CH 3 , OH, NH 2 or halogen; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

12. (a) (i) Structural part 【Chemistry 101】 but, 【Chemical Engineering 102】 or having the structure 【Chemistry 103】 or having the structure 【Chemical 104】 or having the structure structural part 【Chemistry 105】 V and R 4 together form a (C 4 -C 10 )heterospiroalkyl; or V is absent; and / or (ii) R 4 is (C 1 -C 6 ) alkyl; 【Chemistry 106】 and m is an integer from 0 to 3; optionally Each occurrence of R 5 is independently H, (C 1 -C 6 )alkyl, halogen, OR a , OH, NH 2 , N(R a )COR a , CN, CF 3 , (C 1 -C 6 )haloalkyl, or 【Chemistry 107】 and each occurrence of R a is independently H, (C 2 -C 6 )alkenyl, or (C 1 -C 6 )alkyl, and R a is H, CH 3 , or CH 2 CH 3 ; or b) Structural part 【Chemistry 108】 but, 【Chemistry 109】 wherein V is C(R a ) 2 , O, NR a , N(C═O)R a or NSO 2 R a and V′ is CR a or N; optionally Each occurrence of R 5 is independently H, CH 3 , halogen, OH, CN, 【Chemical 110】 CF 3 , (C 1 -C 6 )haloalkyl, or NH 2 ; or c) Structural part 【Chemistry 111】 but, 【Chemistry 112】 and optionally having the structure structural part 【Chemistry 113】 but, 【Chemistry 114】 having the structure 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

13. The compound of formula Ia is 【Chemical 115】 【Chemistry 116】 【Chemistry 117】 and R １ However, H, (C １ ~C ６ ) alkyl, N(R ａ ) ２ , (C ３ ~C ７ ) heterocycloalkyl or halogen, and R ５ and R １１ are each independently H or CH ３ and Y １ , Y ２ , Y ３ , Y ４ , Z １ , Z ２ , Z ３ , Z ４ , L １ and L ２ are each independently CH or N, and V is NH or O; optionally R 1 is H, F, Cl, Br, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , NH 2 , NMe 2 , 【Chemistry 118】 is; or The compound of formula Ib has the structure 【Chemical 119】 wherein R 11 and R 5 are each independently H or CH 3 , and Y 1 , Y 2 , Y 3 , Y 4 , Z 2 , Z 3 and Z 4 are each independently CH or N; or The compound of formula Ib has the structure 【Chemical 120】 wherein R 1 , R 5 and R 11 are each independently H, halogen or CH 3 , and Y 1 , Y 2 , Y 3 , Y 4 , Z 2 , Z 3 and Z 4 are each independently CH or N; or The compound of formula Ic is 【Chemistry 121】 wherein R 1 , R 5 and R 11 are each independently H, halogen or CH 3 , and Y 1 , Y 2 , Y 4 , Z 1 , Z 2 , Z 3 and Z 4 are each independently CH or N; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

14. The compound of formula Ia is 【Chemistry 122】 【Chemical 123】 【Chemistry 124】 【Chemistry 125】 【Chemistry 126】 【Chemistry 127】 【Chemistry 128】 【Chemistry 129】 【Chemistry 130】 【Chemistry 131】 【Chemistry 132】 【Chemistry 133】 【Chemistry 134】 【Chemistry 135】 【Transformation 136】 is; or The compound of formula Ib is 【Chemistry 137】 【Chemistry 138】 【Chemistry 139】 is; or The compound of formula Ic is [Chemistry 140] is; or 【Chemistry 141】 is; or 【Chemistry 142】 is; or Selected from the group consisting of compounds 2 to 45 of Examples 2 to 45, respectively; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 2, 8 and 10 to 14 or a pharmaceutically acceptable salt thereof for use in a method for treating a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound; and optionally the disease is selected from the group consisting of neurodegenerative diseases, cachexia, anorexia, obesity, complications of obesity, inflammatory diseases, virally induced inflammatory responses, Gulf War syndrome, tuberous sclerosis, retinitis pigmentosa, transplant rejection, cancer, autoimmune diseases, ischemic tissue injury, traumatic tissue injury, and combinations thereof; optionally a) the disease is a neurodegenerative disease; optionally the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, motor neuron disease, Huntington's disease, HIV-induced neurodegeneration, Lewy body disease, spinal muscular atrophy, prion disease, spinocerebellar degeneration, familial amyloid polyneuropathy, multiple sclerosis, and combinations thereof; or b) the disease is cachexia or anorexia; or c) the disorder is obesity or a complication of obesity; optionally The complications of obesity are selected from the group consisting of impaired glucose tolerance, fatty liver, dyslipidemia, and combinations thereof; or d) the disease is an inflammatory disease; optionally the inflammatory disease is selected from the group consisting of atopic dermatitis, allergies, asthma, and combinations thereof; or e) the disease is a virus-induced inflammatory response; optionally The virus-induced inflammatory response is SARS-induced inflammatory pneumonia, COVID-19 infection, or a combination thereof; or f) the disease is Gulf War syndrome or tuberous sclerosis complex; or g) the disease is retinitis pigmentosa or graft rejection; or h) the disease is ischemic or traumatic tissue injury; or i) the disease is cancer; optionally the cancer is selected from the group consisting of adult T-cell leukemia / lymphoma, bladder, brain, breast, cervical, colorectal, esophageal, kidney, liver, lung, nasopharyngeal, pancreatic, prostate, skin, stomach, uterine, ovarian, and testicular cancer; optionally The cancer is leukemia; optionally Optionally, the leukemia is adult T-cell leukemia / lymphoma; Adult T-cell leukemia / lymphoma caused by human T-cell lymphotropic virus; or j) the disease is an autoimmune disease; optionally Autoimmune diseases include achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-glomerular basement membrane disease, anti-tubular basement membrane antibody nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy, Barrow's disease, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, and Cass disease. Lehmann's disease, celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome, eosinophilic granulomatosis, cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie-myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus erythematosus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans' syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis) , giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, herpes gestationis, hidradenitis suppurativa (acne suppurativa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear IgA disease, lupus, chronic Lyme disease , Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Muscha-Habermann's disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular pemphigoid, optic neuritis, relapsing rheumatism, pediatric autoimmune neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa,Polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoid or, k) the compound modulates Akt3 in immune cells; optionally the immune cells are selected from the group consisting of T cells, B cells, macrophages and glial cells; optionally the glial cells are astrocytes, microglia, or oligodendrocytes; optionally Optionally, the T cells are regulatory T cells. The compound activates Akt3 signaling; optionally The compound inhibits Akt3 signaling; optionally wherein the compound increases the activity or production of regulatory T cells; the compound reduces the activity or production of regulatory T cells; or l) further comprising administering a second therapeutic agent to the subject; optionally the second therapeutic agent is selected from the group consisting of nutritional supplements, chemotherapeutic agents, anti-inflammatory agents, immunosuppressants, cholinesterase inhibitors, antidepressants, anxiolytics, antipsychotics, riluzole, edaravone, dopamine agonists, MAO B inhibitors, catechol O-methyltransferase inhibitors, anticholinergics, anticonvulsants, tetrabenazine, carbidopa-levodopa, antispasmodics, antibodies, fusion proteins, enzymes, nucleic acids, ribonucleic acids, antiproliferative agents, cytotoxic agents, appetite stimulants, 5-HT3 antagonists, Cox-2 inhibitors, and combinations thereof; or m) further comprising treating the subject with an immunotherapeutic agent, an immune modulator, a costimulatory activating agonist, a cytokine, a chemokine, a chemokine factor, an oncolytic virus, a biologic, a vaccine, a small molecule, a targeted therapy, an anti-inflammatory agent, a cell therapy, chemotherapy, or radiation therapy; Pharmaceutical compositions.

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