AKT3 Modulators

Abstract

Formula Ia or Ib Compounds of TIFF2024541975000616.tif51130 are described, with various substituents defined herein. 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 of 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 / 276,073, 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 refers to RAC-gamma serine / threonine-protein kinase, which in humans is the enzyme encoded by the Akt3 gene. In one embodiment, the compound of formula Ia or Ib [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 or Ib: [ka] [During the ceremony, [ka] teeth, [ka] and n is an integer of 0 to 4, as allowed by the valence of the atom. 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, -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(Ra )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, Q is C(R a )2, O, NR a , N(C=O)R a or NSO2R a and Y, Y, Y, Y, and Y are each independently N or CR as allowed by valence, provided that when Y or Y is attached to -EG, then Y or Y is C; 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, (C3-C7) cycloalkenyl, (C4-C 10 ) Bicycloalkyl, (C4-C 10 )bicycloalkenyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) heterospiroalkyl, (C4-C 10 ) tricycloalkyl, (C4-C 10 ) Tricycloalkenyl, 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 connected to Y3 or Y4, and -(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 xEach 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 y and R y each occurrence is independently H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen, or two R y may be joined together to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring; W1, W2, W3, W4, and W5 are each independently CR6, N, or NR6, as allowed by valence; each occurrence of R6 is independently selected from the group consisting of H, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl; Z1, Z2, Z3, and Z4 are each independently N or CR3 where valence allows; 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, (C3-C7) cycloalkenyl, (C4-C 10 ) Bicycloalkyl, (C4-C 10 )bicycloalkenyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) heterospiroalkyl, (C4-C 10 ) tricycloalkyl, (C4-C 10 ) Tricycloalkenyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -CORa , -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 T is O, S or NR a and Each occurrence of L is independently O, S, or NR a or C(R a )2, m is an integer of 0 to 3, and when m is 0, the structural moiety [ka] teeth, [ka] Each of them has the structure U1, U2, U3, and U4 are each independently N or CR4, as allowed by valence; R4 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, (C3-C7) cycloalkenyl, (C4-C 10 ) Bicycloalkyl, (C4-C 10 )bicycloalkenyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) heterospiroalkyl, (C4-C 10 ) tricycloalkyl, (C4-C 10) Tricycloalkenyl, 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 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 described herein, X1, X2, X3, X4, X5, X6, X7, X8, X9, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4, U1, U2, U3 and U4 are each independently CH, C(halogen), C(C1-C6(alkyl)) or N.

[0011] In any one of the embodiments described herein, X1, X2, X3, X4, X5, X6, X7, X8, X9, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4, U1, U2, U3 and U4 are each independently CH or N.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0028] In any one of the embodiments described 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) cycloalkenyl, (C3-C7) heterocycloalkyl, (C4-C 10) heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, (C3-C7) heterocycloalkenyl, aryl, (C4-C 10 ) Bicycloalkyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) tricycloalkenyl, (C4-C 10 ) Heterotricycloalkenyl, -CN, N3, NO2, COR a , CO2R a , CON(R a )2, -SO2R a or -SO2N(R a )2, and is (C3-C7)cycloalkenyl, (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) tricycloalkenyl and (C4-C 10 )Heterotricycloalkenyls are each optionally substituted with one or more (C1-C6) alkyl.

[0029] In any one of the embodiments described 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 described herein, each occurrence of R is independently H, (C-C) alkyl, (C-C) heterocyclohaloalkyl, or (C-C) heterocycloalkyl, wherein the (C-C) heterocycloalkyl is optionally substituted with one or more (C-C) alkyl.

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

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

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

[0034] In any one of the embodiments described 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 described herein, X is O.

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

[0037] In any one of the embodiments described 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 described herein, each occurrence of R9 is independently H, F, Cl, Br, or CH3.

[0039] In any one of the embodiments described 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 described herein, R 15 Each occurrence of is independently H, F, Cl, Br, or CH3.

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

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

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

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

[0045] In any one of the embodiments described 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 described herein, at least one occurrence of R is [ka] is.

[0047] In any one of the embodiments described 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 described herein, R 12 teeth, [ka] and X is CR 15 , O, N.R. 14or 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 described 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 described herein, R 12 teeth, [ka] is.

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

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

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

[0054] In any one of the embodiments described 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 described herein, the structural moiety [ka] teeth, [ka] wherein Q is O or NH.

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

[0057] In any one of the embodiments described herein, the structural moiety [ka] teeth, [ka] It has the following structure.

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

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

[0060] In any one of the embodiments described herein, the structural moiety [ka] teeth, [ka] It has the following structure.

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

[0062] In any one of the embodiments described herein, each occurrence of R2 is independently H, halogen, CH3, CF3, OH, NH2, -NHCH3, or -N(CH3)2.

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

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

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

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

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

[0068] In any one of the embodiments described herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0069] In any one of the embodiments described herein, the structural moiety [ka] teeth, [ka] wherein each occurrence of o 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 two R y may be joined together to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring.

[0070] In any one of the embodiments described herein, the structural moiety [ka] teeth, [ka] wherein Y1, Y2, and Y5 are each independently N, CH, CCH3, or CF.

[0071] In any one of the embodiments described herein, the structural moiety [ka] teeth, [ka] wherein each occurrence of o 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 two R y may be joined together to form a 3- to 7-membered cycloalkyl or heterocycloalkyl ring.

[0072] In any one of the embodiments described herein, the structural moiety [ka] teeth, [ka] wherein Y1, Y2, Y3, and Y5 are each independently N, CH, CCH3, or CF.

[0073] In any one of the embodiments described herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0074] In any one of the embodiments described herein, the compound has the structure of Formula Ia:

[0075] In any one of the embodiments described herein, the structural moiety [ka] teeth, [ka] wherein each occurrence of R and R is independently H, halogen, or (C-C) alkyl; T is O, S, NH, or N((C-C) alkyl); and each occurrence of L is independently O, S, NH, N((C-C) alkyl), or C(R a )2 and R a Each occurrence of is independently H, OH, OCH3, halogen, or (C1-C6) alkyl.

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

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

[0078] In any one of the embodiments described herein, the structural moiety [ka] teeth, [ka] wherein each occurrence of R and R is independently H, halogen, or (C-C) alkyl; T is O, S, NH, or N((C-C) alkyl); and each occurrence of L is independently O, S, NH, N((C-C) alkyl), or C(R a )2 and R a Each occurrence of is independently H, OH, OCH3, halogen, or (C1-C6) alkyl.

[0079] In any one of the embodiments described herein, the structural moiety [ka] teeth, [ka] It has the following structure.

[0080] In any one of the embodiments described herein, the compound of formula Ia is [ka] wherein Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z4, U1, U2, U3 and U4 are each independently CH, CCH3, CF or N; a is H or CH3.

[0081] In any one of the embodiments described herein, the compound of formula Ib is [ka] wherein Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, U1, U2, U3 and U4 are each independently CH, CCH3, CF or N; and R a is H or CH3.

[0082] In any one of the embodiments described herein, the compound of formula Ia is [ka] is.

[0083] In any one of the embodiments described herein, the compound of formula Ia is [ka] is.

[0084] In any one of the embodiments described herein, the compound of formula Ia is [ka] is.

[0085] In any one of the embodiments described herein, the compound of formula Ib is [ka] is.

[0086] In any one of the embodiments described herein, the compound of formula Ib is [ka] is.

[0087] In any one of the embodiments described herein, the compound of formula Ib is [ka] is.

[0088] 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.

[0089] 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.

[0090] In any one of the embodiments described herein, the disease is a neurodegenerative disease.

[0091] 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.

[0092] In any one of the embodiments described herein, the disease is cachexia or anorexia.

[0093] In any one of the embodiments described herein, the disease is obesity or a complication of obesity.

[0094] 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.

[0095] In any one of the embodiments described herein, the disease is an inflammatory disease.

[0096] 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.

[0097] In any one of the embodiments described herein, the disease is a virus-induced inflammatory response.

[0098] 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.

[0099] In any one of the embodiments described herein, the disease is Gulf War syndrome or tuberous sclerosis complex.

[0100] In any one of the embodiments described herein, the disease is retinitis pigmentosa or graft rejection.

[0101] In any one of the embodiments described herein, the disease is ischemic tissue injury or traumatic tissue injury.

[0102] In any one of the embodiments described herein, the disease is cancer.

[0103] 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.

[0104] In any one of the embodiments described herein, the cancer is leukemia.

[0105] In any one of the embodiments described herein, the leukemia is adult T-cell leukemia / lymphoma.

[0106] In any one of the embodiments described herein, the adult T-cell leukemia / lymphoma is caused by a human T-cell lymphotropic virus.

[0107] In any one of the embodiments described herein, the disease is an autoimmune disease.

[0108] 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.

[0109] In any one of the embodiments described herein, the compound modulates Akt3 in immune cells.

[0110] 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.

[0111] In any one of the embodiments described herein, the glial cells are astrocytes, microglia, or oligodendrocytes.

[0112] In any one of the embodiments described herein, the T cells are regulatory T cells.

[0113] In any one of the embodiments described herein, the compound activates Akt3 signaling.

[0114] In any one of the embodiments described herein, the compound inhibits Akt3 signaling.

[0115] In any one of the embodiments described herein, the compound increases the activity or production of regulatory T cells.

[0116] In any one of the embodiments described herein, the compound reduces the activity or production of regulatory T cells.

[0117] In any one of the embodiments described herein, the method further comprises administering a second therapeutic agent to the subject.

[0118] 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.

[0119] 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.

[0120] 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. DETAILED DESCRIPTION OF THE INVENTION

[0121] Detailed Description of the Invention 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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)ORd , 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 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.

[0128] 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.

[0129] 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 band 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 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 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, 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] "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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.

[0144] 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.

[0145] Unless otherwise noted, any heteroatom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] Throughout the specification, groups and substituents may be chosen to provide stable moieties and compounds.

[0155] 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).

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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). 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.

[0166] 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.

[0167] 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.

[0168] 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).

[0169] 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.

[0170] 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.

[0171] "Suppressive immune response" and "immunosuppressive response" refer to a response that reduces or prevents the activation or efficiency of innate or adaptive immunity.

[0172] 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)).

[0173] 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.

[0174] compound In one embodiment, compounds of formula Ia or Ib 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.

[0175] In one embodiment, a compound of formula Ia or Ib: [ka] [During the ceremony, [ka] teeth, [ka] and n is an integer of 0 to 4, as allowed by the valence of the atom. 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-C10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 14 ) tricycloalkenyl, (C4-C 14 ) Heterotricycloalkenyl, 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] 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, 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, provided that when Y3 or Y4 is connected to -EG-, then Y3 or Y4 is each C; 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, (C3-C7) cycloalkenyl, (C4-C 10 ) Bicycloalkyl, (C4-C 10 )bicycloalkenyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) heterospiroalkyl, (C4-C 10 ) tricycloalkyl, (C4-C 10 ) Tricycloalkenyl, 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 connected to Y3 or Y4, and -(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 y and R y each occurrence is independently H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen, or two R y may be joined together to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring; W1, W2, W3, W4, and W5 are each independently CR6, N, or NR6, as allowed by valence; each occurrence of R6 is independently selected from the group consisting of H, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl; Z1, Z2, Z3, and Z4 are each independently N or CR3 where valence allows; 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, (C3-C7) cycloalkenyl, (C4-C 10 ) Bicycloalkyl, (C4-C 10)bicycloalkenyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) heterospiroalkyl, (C4-C 10 ) tricycloalkyl, (C4-C 10 ) Tricycloalkenyl, 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 T is O, S or NR a and Each occurrence of L is independently O, S, or NR a or C(R a )2, m is an integer of 0 to 3, and when m is 0, the structural moiety [ka] teeth, [ka] Each of them has the structure U1, U2, U3, and U4 are each independently N or CR4, as allowed by valence; R4 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, (C3-C7) cycloalkenyl, (C4-C 10 ) Bicycloalkyl, (C4-C 10 )bicycloalkenyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) heterospiroalkyl, (C4-C 10 ) tricycloalkyl, (C4-C 10 ) Tricycloalkenyl, 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 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.

[0176] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] is.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0181] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0182] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0183] 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 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 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 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 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 or CCH3. In some embodiments, X2 is N, X7 is CR, and X1, X3, X4, X5, and X6 are each independently CH or CCH3. In some embodiments, X2 is N, X7 is CR1, X3 is 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 or CCH3.

[0184] In some embodiments, X1, X2, X3, X4, X5, X6, and X7 are each independently CH, C(halogen), C(C1-C6(alkyl)), or N. In some embodiments, at least one of X1, X2, X3, X4, X5, X6, and X7 is CH. In some embodiments, at least one of X1, X2, X3, X4, X5, X6, and X7 is C(halogen). In some embodiments, at least one of X1, X2, X3, X4, X5, X6, and X7 is independently CF, CCl, CBr, or CI. In some embodiments, at least one of X1, X2, X3, X4, X5, X6, and X7 is C(C1-C6(alkyl)). In some embodiments, at least one of X1, X2, X3, X4, X5, X6, and X7 is independently CCH3 or CCH2CH3. In some embodiments, at least one of X1, X2, X3, X4, X5, X6, and X7 is N. In some embodiments, at least one of X1, X2, X3, X4, X5, X6, and X7 is independently CH, CF, CCH3, or N.

[0185] 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 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 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 or CCH3. In some embodiments, three of X2, X3, X4, X8, and X9 are N, and the rest are CR1. In some embodiments, three of X2, X3, X4, X8, and X9 are N, and the remaining are each independently CH 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 or CCH3.

[0186] In some embodiments, X2, X3, X4, X8, and X9 are each independently CH, C(halogen), C(C1-C6(alkyl)), or N. In some embodiments, at least one of X2, X3, X4, X8, and X9 is CH. In some embodiments, at least one of X2, X3, X4, X8, and X9 is C(halogen). In some embodiments, at least one of X2, X3, X4, X8, and X9 is independently CF, CCl, CBr, or CI. In some embodiments, at least one of X2, X3, X4, X8, and X9 is C(C1-C6(alkyl)). In some embodiments, at least one of X2, X3, X4, X8, and X9 is independently CCH3 or CCH2CH3. In some embodiments, at least one of X2, X3, X4, X8, and X9 is N. In some embodiments, at least one of X2, X3, X4, X8, and X9 is independently CH, CF, CCH3, or N.

[0187] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0188] 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.

[0189] 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.

[0190] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0191] 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.

[0192] 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 aIn some embodiments, Q is NH. In some embodiments, Q is NCH3 or NCH2CH3.

[0193] In some embodiments, each occurrence of R is independently selected from H, D, halogen, OR a , N(R a )2, (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, -CN, N3, NO2, COR a , CO2R a , CON(R a )2, -SO2R a or -SO2N(R a )2, (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, and heteroaryl are each optionally substituted with one or more (C1-C6)alkyl or halogen. In some embodiments, each occurrence of R is independently selected from (C1-C6)alkyl, (C3-C7)cycloalkenyl, (C3-C7)heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) tricycloalkenyl and (C4-C 10 )heterotricycloalkenyl, (C1-C6) alkyl, (C3-C7) cycloalkenyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) tricycloalkenyl and (C4-C 10 )heterotricycloalkenyl is optionally substituted with one or more (C1-C6)alkyl or halogen. In some embodiments, each occurrence of R 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 or halogen. In some embodiments, each occurrence of R is independently selected from the group consisting of (C4-C 10) selected from the group consisting of heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, aryl, and heteroaryl; (C4-C 10 ) heterospiroalkyl, aryl, and heteroaryl are each optionally substituted with one or more (C1-C6) alkyl or halogen. In some embodiments, each occurrence of R is independently selected from (C3-C7) cycloalkenyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) bicycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 14 ) tricycloalkenyl, (C4-C 14 ) tricycloalkyl, (C4-C 14 ) heterotricycloalkyl or (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 an optionally substituted (C3-C7)cycloalkenyl or an optionally substituted (C3-C7)heterocycloalkenyl. In some embodiments, each occurrence of R 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 ) heterotricycloalkyl. In some embodiments, each occurrence of R is independently [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, 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 or halogen. In some embodiments, each occurrence of R is independently 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 or halogen. 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 or halogen. In some embodiments, at least one occurrence of R is optionally substituted with one or more (C4-C6)alkyl or halogen. 10 )heterospiroalkyl. In some embodiments, at least one occurrence of R is halogenated (C3-C7)heterocycloalkyl optionally substituted with one or more (C1-C6)alkyl or halogen. In some embodiments, each occurrence of R is independently H, D, F, Cl, Br, CH3, OCH3, NH2, NHCH3, N(CH3)2, [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.

[0194] 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 replaced appropriately.

[0195] In some embodiments, at least one occurrence of R is [ka] In some embodiments, [ka] teeth, [ka] is.

[0196] 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 )2. 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 [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 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] In some embodiments, at least one occurrence of R is [ka] (In the formula, R a 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 -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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

[0202] In some embodiments, R 14is 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.

[0203] 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.

[0204] In some embodiments, [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. In some embodiments, [ka] teeth, [ka] wherein X2 is N, X3 is CH or CMe, 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, 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 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.

[0205] In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is CR 15 In some embodiments, X is NR14 is.

[0206] 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.

[0207] 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.

[0208] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

[0209] In some embodiments, R 14 is H, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, aryl, or heteroaryl. 14is 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.

[0210] 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.

[0211] In some embodiments, the structural moiety [ka] teeth, [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.

[0212] 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.

[0213] In some embodiments, 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. [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. [ka] teeth, [ka] wherein Q is O or NH and R1 is methyl or Cl.

[0214] 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.

[0215] In some embodiments, the structural moiety [ka] teeth, [ka] and Q is O or NH. 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.

[0216] 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 independently CR2. In some embodiments, Y1, Y2, Y3, Y4, and Y5 are each independently CH, CF, or CCH3. 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, CF, or CCH3, 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, CF, or CCH3, 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, CF, or CCH3, and two of Y1, Y2, Y3, Y4, and Y5 are N.

[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] 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, the structural moiety [ka] teeth, [ka] It has the following structure.

[0219] 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.

[0220] 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, (C3-C7) cycloalkenyl, (C4-C 10 ) Bicycloalkyl, (C4-C 10 ) bicycloalkenyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) tricycloalkyl, (C4-C 10 ) Tricycloalkenyl, 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 R2 is independently selected from the group consisting of (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, (C4-C 10 ) Bicycloalkyl, (C4-C 10 )bicycloalkenyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) heterospiroalkyl, (C4-C 10 ) tricycloalkyl and (C4-C 10 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-C 10 ) heterospiroalkyl, halogenated (C-C) heterocycloalkyl, 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, 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 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] In some embodiments, each occurrence of R is independently H, D, F, CH, N(CH), [ka] is.

[0221] 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.

[0222] 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.

[0223] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0224] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0225] 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.

[0226] 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, one or more R y and R y each occurrence is independently H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen, or two R y may be joined together to form a 3-6 membered cycloalkyl or heterocycloalkyl ring. In some embodiments, R x Each occurrence of is independently H, (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl. x Each occurrence of is independently H or (C1-C6) alkyl. x Each occurrence of is independently H, CH, or CHCH. In some embodiments, R x and Y3 together form an R of 1 or more. y In some embodiments, R x and Y4 together form an R y In some embodiments, R x and Z1 together form an R greater than or equal to 1. y In some embodiments, R x and Z4 together, R more than 1 y In some embodiments, R y Each occurrence of is independently H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen. yEach occurrence of is independently H or (C1-C6) alkyl. y Each occurrence of R is independently CH or CHCH. In some embodiments, two R y may be joined together to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring. In some embodiments, two R y may be joined together to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring. In some embodiments, two R y may be joined together to form a cyclopropyl ring.

[0227] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0228] 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.

[0229] 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.

[0230] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0231] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, each occurrence of o 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 two R y may be joined together to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, R y Each occurrence of is independently H or (C1-C6) alkyl. yEach occurrence of is independently OH, O(C1-C6)alkyl, or halogen. y Each occurrence of is H. In some embodiments, R y Each occurrence of is CH. In some embodiments, two R y may be joined together to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring. In some embodiments, two R y are joined together to form a cyclopropyl, cyclobutyl, or cyclopentyl ring. In some embodiments, two R y are joined together to form a cyclopropyl ring.

[0232] 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, Y, Y, and Y are each independently N, CH, CCH, or CF.

[0233] 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, each occurrence of o 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 two R y may be joined together to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, R y Each occurrence of is independently H or (C1-C6) alkyl. y Each occurrence of is independently OH, O(C1-C6)alkyl, or halogen. y Each occurrence of is H. In some embodiments, R y Each occurrence of is CH. In some embodiments, two Ry may be joined together to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring. In some embodiments, two R y are joined together to form a cyclopropyl, cyclobutyl, or cyclopentyl ring. In some embodiments, two R y are joined together to form a cyclopropyl ring.

[0234] 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, Y, Y, Y, and Y are each independently N, CH, CCH, or CF.

[0235] In some embodiments, m is an integer from 0 to 3. In some embodiments, m is 0, and the structural moiety [ka] teeth, [ka] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0236] In some embodiments, T is O, S, or NR a In some embodiments, T is O. In some embodiments, T is S. In some embodiments, T is NR a In some embodiments, R a is H or (C1-C6) alkyl. In some embodiments, T is NH. In some embodiments, T is NCH3.

[0237] In some embodiments, each occurrence of L is independently O, S, NR a or C(R a)2. In some embodiments, at least one occurrence of L is O, S, or NR a In some embodiments, at least one occurrence of L is O, S, or NR a and the remainder is C(R a )2. In some embodiments, R a is H, halogen, CF, or (C-C) alkyl. In some embodiments, at least one occurrence of L is O, S, NH, or NCH. In some embodiments, at least one occurrence of L is O, S, NH, or NCH, and the remainder are CH, CHCH, or C(CH), CHF, or CCF.

[0238] 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.

[0239] 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, (C3-C7) cycloalkenyl, (C4-C 10 ) Bicycloalkyl, (C4-C 10 ) bicycloalkenyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) tricycloalkyl, (C4-C 10 ) Tricycloalkenyl, 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 R is independently selected from the group consisting of (C-C)cycloalkyl, (C-C)cycloalkenyl, (C-C 10 ) Bicycloalkyl, (C4-C 10 )bicycloalkenyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) heterospiroalkyl, (C4-C 10 ) tricycloalkyl and (C4-C 10In 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-C 10 ) heterospiroalkyl, halogenated (C-C) heterocycloalkyl, 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, 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] In some embodiments, each occurrence of R is independently H, D, F, CH, N(CH), [ka] is.

[0240] 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 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.

[0241] 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.

[0242] In some embodiments, U1, U2, U3, and U4 are each independently CR4 or N. In some embodiments, U1, U2, U3, and U4 are each independently CR4. In some embodiments, U1, U2, U3, and U4 are each independently CH, CF, or CCH3. In some embodiments, U1, U2, U3, and U4 are each N. In some embodiments, one of U1, U2, U3, and U4 is CR4, and the rest are N. In some embodiments, one of U1, U2, U3, and U4 is CH, CF, or CCH3, and the rest are N. In some embodiments, two of U1, U2, U3, and U4 are CR4, and the rest are N. In some embodiments, two of U1, U2, U3, and U4 are CH, CF, or CCH3, and the rest are N. In some embodiments, three of U1, U2, U3, and U4 are CR4, and two of U1, U2, U3, and U4 are N. In some embodiments, three of U1, U2, U3, and U4 are CH, CF, or CCH3, and two of U1, U2, U3, and U4 are N.

[0243] In some embodiments, the structural moiety [ka] teeth, [ka] It has the following structure.

[0244] 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, (C3-C7) cycloalkenyl, (C4-C 10 ) Bicycloalkyl, (C4-C 10 ) bicycloalkenyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10) heterobicycloalkenyl, (C4-C 10 ) heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, (C3-C7) heterocycloalkenyl, (C4-C 10 ) tricycloalkyl, (C4-C 10 ) Tricycloalkenyl, 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 R is independently selected from the group consisting of (C-C)cycloalkyl, (C-C)cycloalkenyl, (C-C 10 ) Bicycloalkyl, (C4-C 10 )bicycloalkenyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C 10 ) heterobicycloalkyl, (C4-C 10 ) heterobicycloalkenyl, (C4-C 10 ) heterospiroalkyl, (C4-C 10 ) tricycloalkyl and (C4-C 10 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-C 10) heterospiroalkyl, halogenated (C-C) heterocycloalkyl, 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, N3, NO2, COR a , CO2R a , CON(R a )2, -SO2R a or -SO2N(R a )2. In some embodiments, each occurrence of R4 is independently H, D, halogen, (C1-C6)alkyl, (C3-C7)heterocycloalkyl, N(R a )2 or -CN. In some embodiments, each occurrence of R4 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] In some embodiments, each occurrence of R is independently H, D, F, CH, N(CH), [ka] is.

[0245] In some embodiments, at least one occurrence of R4 is H, D, or halogen. In some embodiments, at least one occurrence of R4 is H. In some embodiments, at least one occurrence of R4 is D. In some embodiments, at least one occurrence of R4 is F. In some embodiments, at least one occurrence of R4 is CH3. In some embodiments, at least one occurrence of R4 is OCH3. In some embodiments, at least one occurrence of R4 is NH2. In some embodiments, at least one occurrence of R4 is N(CH3)2. In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] [In the formula, R a ' is H or (C1-C6) alkyl. In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] [In the formula, R a ' is H or (C1-C6) alkyl. In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is -CN. In some embodiments, at least one occurrence of R4 is -NC. In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is NO2. In some embodiments, at least one occurrence of R4 is N3. In some embodiments, at least one occurrence of R4 is [ka] In some embodiments, at least one occurrence of R4 is [ka] is.

[0246] 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 R4 is selected from the group consisting of: In some embodiments, at least one occurrence of R4 is H, CH3, OH, NH2, or halogen. In some embodiments, at least one occurrence of R4 is H or CH3. In some embodiments, at least one occurrence of R4 is OH or NH2. In some embodiments, at least one occurrence of R4 is halogen. In some embodiments, at least one occurrence of R4 is H. In some embodiments, at least one occurrence of R4 is CF3. In some embodiments, R4 is H or CH3.

[0247] In some embodiments, the compound has the structure of Formula Ia.

[0248] 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, each occurrence of R3 and R4 is independently H, halogen, or (C1-C6) alkyl, T is O, S, NH, or N((C1-C6) alkyl), and each occurrence of L is independently O, S, NH, N((C1-C6) alkyl), or C(R a )2 and R a is independently H, OH, OCH3, halogen, or (C1-C6) alkyl. In some embodiments, each occurrence of R3 and R4 is independently H, F, or CH3. In some embodiments, T is O or S. In some embodiments, T is NH or N((C1-C6) alkyl). In some embodiments, T is NH. In some embodiments, T is N((C1-C6) alkyl). In some embodiments, T is NCH3. In some embodiments, L is O or S. In some embodiments, L is NH or N((C1-C6) alkyl). In some embodiments, L is NH. In some embodiments, L is N((C1-C6) alkyl). In some embodiments, L is NCH3. In some embodiments, L is C(R a )2 and R a Each occurrence of is independently H or (C1-C6) alkyl. In some embodiments, L is C(R a )2 and R a Each occurrence of is independently H. In some embodiments, L is C(Ra )2 and R a Each occurrence is independently CH.

[0249] 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.

[0250] In some embodiments, the compound has the structure of Formula Ib.

[0251] 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, each occurrence of R3 and R4 is independently H, halogen, or (C1-C6) alkyl, T is O, S, NH, or N((C1-C6) alkyl), and each occurrence of L is independently O, S, NH, N((C1-C6) alkyl), or C(R a )2 and R ais independently H, OH, OCH3, halogen, or (C1-C6) alkyl. In some embodiments, each occurrence of R3 and R4 is independently H, F, or CH3. In some embodiments, T is O or S. In some embodiments, T is NH or N((C1-C6) alkyl). In some embodiments, T is NH. In some embodiments, T is N((C1-C6) alkyl). In some embodiments, T is NCH3. In some embodiments, L is O or S. In some embodiments, L is NH or N((C1-C6) alkyl). In some embodiments, L is NH. In some embodiments, L is N((C1-C6) alkyl). In some embodiments, L is NCH3. In some embodiments, L is C(R a )2 and R a Each occurrence of is independently H or (C1-C6) alkyl. In some embodiments, L is C(R a )2 and R a Each occurrence of is independently H. In some embodiments, L is C(R a )2 and R a Each occurrence is independently CH.

[0252] 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.

[0253] In some embodiments, the compound of formula Ia is [ka] In some embodiments, the compound of formula Ia has the structure: [ka] In some embodiments, the compound of formula Ia has the structure: [ka] In some embodiments, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z4, U1, U2, U3, and U4 are each independently CH, CCH3, CF, or N; a is H or CH3.

[0254] In some embodiments, the compound of formula Ib is [ka] In some embodiments, the compound of formula Ib has the structure: [ka] In some embodiments, the compound of formula Ib has the structure: [ka] In some embodiments, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, U1, U2, U3, and U4 are each independently CH, CCH3, CF, or N; a is H or CH3.

[0255] In some embodiments, the compound of formula Ia is [ka] is.

[0256] In some embodiments, the compound of formula Ia is [ka] is.

[0257] In some embodiments, the compound of formula Ia is [ka] is.

[0258] In some embodiments, the compound of formula Ib is [ka] is.

[0259] In some embodiments, the compound of formula Ib is [ka] is.

[0260] In some embodiments, the compound of formula Ib is [ka] is.

[0261] 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").

[0262] 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).

[0263] 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).

[0264] 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.

[0265] 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).

[0266] 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.

[0267] In some embodiments, the compounds of Formula Ia or Ib described herein are inhibitors of Akt3. In other embodiments, the compounds of Formula Ia or Ib described herein are activators of Akt3.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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).

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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 or Ib described herein.

[0282] 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.

[0283] In some embodiments, compounds of Formula Ia or Ib modulate 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 cells are Tregs. In some embodiments, compounds of Formula Ia or Ib activate Akt3 signaling. In other embodiments, compounds of Formula Ia or Ib inhibit Akt3 signaling. In some embodiments, compounds of Formula Ia or Ib modulate Akt3 in Tregs. The inventors surprisingly found that in some embodiments, compounds of Formula Ia or Ib increase Treg activity or production, while in other embodiments, the compounds reduce Treg activity or production. The inventors also surprisingly found that in some embodiments, compounds of Formula Ia or Ib activate Akt3 signaling, while in other embodiments, the compounds inhibit Akt3 signaling.

[0284] 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 or Ib 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.

[0285] 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.

[0286] 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.

[0287] 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 or Ib 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.

[0288] 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 of Formula Ia or Ib described herein in an amount effective to inhibit an immunosuppressive response and treat or prevent progression of the disease. In some embodiments, the Akt3 inhibitor of Formula Ia or Ib 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.

[0289] In one embodiment, a compound of Formula Ia or Ib 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.

[0290] In some embodiments, administration of an Akt3 activator of Formula Ia or Ib described herein to a subject with ALS slows disease progression and increases the subject's survival time.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] In some embodiments, the disclosed Akt3 activators of Formula Ia or Ib 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.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] 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 or Ib 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.

[0301] 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).

[0302] 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.

[0303] One embodiment provides a method of treating SMA in a subject by administering to the subject an Akt3 modulator of Formula Ia or Ib described herein in an amount effective to allow survival of motor neurons. In another embodiment, the subject is administered an effective amount of an Akt3 modulator to reduce or eliminate symptoms of SMA or slow disease progression.

[0304] 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.

[0305] One embodiment provides a method of treating MS in a subject by administering to the subject an Akt3 modulator of Formula Ia or Ib 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.

[0306] 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 or Ib 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.

[0307] 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, hormone 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 or Ib, 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, a compound of Formula Ia or Ib, 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.

[0308] 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 or Ib 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 or Ib disclosed herein can be used to treat anorexia. In one embodiment, the disclosed Akt3 inhibitor compounds of formula Ia or Ib can be administered to subjects diagnosed with anorexia in an amount effective to promote adipogenesis and reverse extreme weight loss.

[0309] 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.

[0310] 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.

[0311] 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.

[0312] Non-limiting examples of inflammatory diseases include atopic dermatitis, allergies, asthma, and combinations thereof.

[0313] 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.

[0314] cancer In some embodiments, provided are methods for treating or preventing cancer in a subject in need thereof, comprising modulating Akt3 signaling by administering to the subject an effective amount of a compound of Formula Ia or Ib described herein. In some embodiments, the compound of Formula Ia or Ib inhibits Akt3 signaling and / or reduces Treg activity or production, resulting in an immune response activation effect.

[0315] 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.

[0316] 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).

[0317] 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).

[0318] 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.

[0319] 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).

[0320] 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.

[0321] 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.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] 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.

[0327] 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.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] 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.

[0340] 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.

[0341] In some embodiments, the additional therapeutic agent comprises a nucleic acid. In some embodiments, the additional therapeutic agent comprises a ribonucleic acid.

[0342] 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.

[0343] 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.

[0344] 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.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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]

[0349] Example 1: Compound 1 (N-(10,11-dihydro-5H-benzo[b]pyrido[3,4-f]azepin-7-yl)-4-(pyridin-4-ylamino)benzamide) [ka] [ka] [ka] Substrates and reagents were commercially available and used without further purification. Reactions were monitored by liquid chromatography-mass spectrometry (LC-MS) or thin-layer chromatography (TLC) using precoated glass plates. Column chromatography was performed using silica gel (200-300 mesh) or a Biotage instrument (normal-phase HPLC). The preparative high-performance liquid chromatography (HPLC) method used a Gilson 281 (PHG012) apparatus, a Welch 10 μm 150A 21.2*250 mm column, A: water (12 mM NH4HCO3), B: acetonitrile, a mobile phase consisting of 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 nuclear magnetic resonance ("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. Mass spectrometry ("MS") data was obtained on an LC-MS instrument equipped with an electrospray source.

[0350] Step a: To a solution of compound 1-1 (5.00 g, 33.1 mmol, 1.00 equiv.) and 4-bromopyridine (6.27 g, 39.7 mmol, 1.20 equiv.) in t-BuOH (200 mL), Pd(dba) (6.06 g, 6.62 mmol, 0.200 equiv.), XPhos (3.15 g, 6.62 mmol, 0.200 equiv.), and t-BuONa (9.54 g, 99.2 mmol, 3.00 equiv.) were added at 15 °C. The mixture was stirred at 80 °C under N for 12 h. LC-MS indicated that compound 1-1 was completely consumed and the desired mass was detected. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 1-2 (11.2 g, crude) as a brown solid.

[0351] Step b: To a solution of compound 1-2 (10.7 g, 39.6 mmol, 1.00 equiv.) in MeOH (120 mL) and HO (40 mL) was added NaOH (3.17 g, 79.2 mmol, 2.00 equiv.) at 15 °C. The mixture was stirred at 40 °C for 2 h. LC-MS showed that compound 1-2 remained and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with HO (50 mL) and washed with EtOAc (2 × 50 mL). The aqueous layer was adjusted to pH 5 with HCl (2 M), washed with EtOAc (2 × 50 mL), and concentrated under reduced pressure. The crude product was purified by reverse-phase medium-pressure liquid chromatography ("MPLC") (formic acid conditions). Compound 1-3 (3.10 g, 14.5 mmol, 36.6% yield) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (d, J = 6.8 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 6.8 Hz, 2H).

[0352] Process c: To a solution of compound 1-4 (5.00 g, 23.1 mmol, 1.00 equiv.) and N-bromosuccinimide (“NBS”) (4.12 g, 23.2 mmol, 1.00 equiv.) in CCl4 (60 mL) was added azobisisobutyronitrile (“AIBN”) (380 mg, 2.31 mmol, 0.100 equiv.) at 20 °C under N2. The mixture was stirred at 70 °C for 12 h. TLC (SiO2, petroleum ether (“PE”) / EtOAc = 10 / 1) showed that compound 1-4 remained and two new spots had formed. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 10 / 1) to give compound 1-5 (2.80 g, 9.49 mmol, 41.0% yield) as a brown oil. 1 H NMR (400 MHz, CDCl3) δ ppm 8.47 (d, J = 2.4 Hz, 1H), 8.18 (dd, J = 8.4, 2.3 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 4.63 (s, 2H).

[0353] Process d: To a solution of compound 1-5 (2.80 g, 9.49 mmol, 1.00 equiv.) in MeCN (50 mL) was added PPh3 (2.49 g, 9.49 mmol, 1.00 equiv.) at 20 °C. The mixture was stirred at 80 °C for 12 h. LC-MS showed that compound 1-5 was completely consumed and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give compound 1-6 (5.40 g, crude product) as a yellow gum.

[0354] Process e: To a solution of compound 1-6 (3.80 g, 6.82 mmol, 1.00 equiv.) in DMF (40 mL) was added NaH (355 mg, 8.88 mmol, 60% purity, 1.30 equiv.) at 20 °C. The mixture was stirred at 20 °C for 0.5 h. 4-Chloropyridine-3-carbaldehyde (1.06 g, 7.52 mmol, 1.10 equiv.) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 12 h. LC-MS showed that compound 1-6 was completely consumed and one major peak with the desired mass was detected. Water (150 mL) was added to the mixture, which was then filtered. The filter cake was dried under vacuum to give compound 1-7 (1.93 g, crude product) as a brown solid.

[0355] Process f: The reactions were arranged in 10 parallel batches. To a solution of compound 1-7 (100 mg, 295 μmol, 1.00 equiv.) and (4-methoxyphenyl)methanamine (48.6 mg, 354 μmol, 45.9 μL, 1.20 equiv.) in dioxane (5 mL) was added t-BuONa (56.6 mg, 589 μmol, 2.00 equiv.), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (28.2 mg, 59.2 μmol, 0.200 equiv.), and [2-(2-aminophenyl)phenyl]palladium(1+); dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane; methanesulfonate salt (49.8 mg, 58.8 μmol, 0.200 equiv.) at 20 °C under N2. The mixture was stirred at 100 °C for 12 h under N2. TLC (SiO2, PE / THF = 1 / 2) showed that compound 1-7 was completely consumed and four new spots were formed. The four batches were combined, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / THF = 1 / 2) to give compound 1-8 (240 mg, 668 μmol, 22.7% yield) as a yellow oil.

[0356] Process g: To a mixture of 10% Pd / C (60.0 mg, 50% water) in EtOAc (10 mL) was added compound 1-8 (150 mg, 417 μmol, 1.00 equiv) at 20 °C under a N atmosphere. The suspension was degassed and purged with H five times. The mixture was stirred under H (50 Psi) at 30 °C for 12 h. LC-MS showed the reaction was incomplete. The mixture was stirred under H (50 Psi) at 30 °C for another 12 h. LC-MS showed the reaction was still incomplete. The mixture was stirred under H (50 Psi) at 50 °C for another 12 h. LC-MS showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 1-9 (120 mg, crude product) as a yellow oil.

[0357] Process h: To a solution of compound 1-9 (50.0 mg, 151 μmol, 1.00 equiv.) in DMF (4 mL), compound 1-3 (35.6 mg, 166 μmol, 1.10 equiv.), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate ("PyAOP") (86.5 mg, 166 μmol, 1.10 equiv.), and N,N-diisopropylethylamine ("DIPEA") (48.8 mg, 378 μmol, 65.8 μL, 2.50 equiv.) were added at 20° C. The mixture was stirred at 20° C. for 12 hours. LC-MS indicated that compound 1-9 remained, with one major peak having the desired mass being detected. Water (10 mL) was added to the mixture, which was then filtered, and the filter cake was dried under vacuum. Compound I-10 (53.0 mg, crude product) was obtained as a yellow oil.

[0358] Process i: A solution of compound I-10 (50.0 mg, 94.8 μmol, 1.00 equiv.) in trifluoroacetic acid ("TFA") (2 mL) was stirred at 40 °C for 4 h. LC-MS showed that compound I-10 was completely consumed, with one major peak having the desired mass detected. The reaction mixture was concentrated. The residue was dissolved in MeOH (2 mL). The suspension was filtered, and the filtrate was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 5% to 30%, 8 min). The fractions were concentrated under reduced pressure to remove most of the MeCN at 30 °C, and the aqueous phase was lyophilized. Compound 1 (11.7 mg, 25.2 μmol, 26.6% yield, 99.7% purity, 1.5% HCl) was obtained as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.93 (br s, 1.5H), 11.04 (s, 1H), 10.70 (s, 1H), 10.43 (s, 1H), 8.36 (br d, J = 6.7 Hz, 2H), 8.28 (s, 1H), 8.22 (br d, J = 6.8 Hz, 1H), 8.10 (br d, J = 8.4 Hz, 2H), 8.05 (s, 1H), 7.51 (br d, J = 8.3 Hz, 2H), 7.40 (d, J = 6.8 Hz, 1H), 7.33 - 7.25 (m, 3H), 7.19 (br d, J = 8.3 Hz, 1H), 3.02 (s, 4H). LC-MS (ESI+): m / z 204.5 / 408.1 (M / 2+H) / (M+H). [Example 2]

[0359] 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.

[0360] 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.

[0361] 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).

[0362] 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.

[0363] 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.

[0364] 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.

[0365] 4. Gently rock the plate at room temperature for ≥15 minutes. Measure firefly luminescence using a luminometer.

[0366] The Akt3 inhibitory and activating activities of selected compounds disclosed herein are shown in Tables 1 and 2, respectively.

[0367] 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.

[0368] 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.

[0369] 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.

[0370] 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.

[0371] TC-1 tumor-bearing mice were treated via oral gavage with the indicated doses of small molecules. Two days after a single treatment, spleens were isolated and the % of Tregs was assessed using flow cytometry. % Tregs were normalized to untreated controls.

[0372] IC for Compound 1 as measured in the Foxp3 induction assay 50 The values ​​were <1 μM.

Claims

1. Formula Ia or Ib: 【Chemistry 1】 [During the ceremony, 【Chemistry 2】 teeth, 【Transformation 3】 and n is an integer from 0 to 4, as allowed by the valences; 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, -OR ａ , -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, 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 However, Y ３ or Y ４ If Y is connected to -E-G, ３ or Y ４ is C, R ２ 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 ３ ~C ７ ) cycloalkenyl, (C ４ ~C １０ ) bicycloalkyl, (C ４ ~C １０ ) bicycloalkenyl, (C ３ ~C ７ ) heterocycloalkyl, halogenated (C ３ ~C ７ ) heterocycloalkyl, (C ３ ~C ７ ) heterocycloalkenyl, (C ４ ~C １０ ) heterobicycloalkyl, (C ４ ~C １０ ) heterobicycloalkenyl, (C ４ ~C １０ ) heterospiroalkyl, (C ４ ~C １０ ) tricycloalkyl, (C ４ ~C １０ ) tricycloalkenyl, aryl, heteroaryl, -OR ａ , -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- is Y ３ or Y ４ is connected to -(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 ｙ and R ｙ Each occurrence of is independently H, (C １ ~C ６ ) alkyl, OH, O(C １ ~C ６ ) alkyl, or halogen, or two R ｙ may be joined together to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring; W １ , W ２ , W ３ , W ４ and W ５ are each independently a CR group allowed by the valence 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; Z １ , Z ２ , Z ３ and Z ４ 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 ３ ~C ７ ) cycloalkenyl, (C ４ ~C １０ ) bicycloalkyl, (C ４ ~C １０ ) bicycloalkenyl, (C ３ ~C ７ ) heterocycloalkyl, halogenated (C ３ ~C ７ ) heterocycloalkyl, (C ３ ~C ７ ) heterocycloalkenyl, (C ４ ~C １０ ) heterobicycloalkyl, (C ４ ~C １０ ) heterobicycloalkenyl, (C ４ ~C １０ ) heterospiroalkyl, (C ４ ~C １０ ) tricycloalkyl, (C ４ ~C １０ ) tricycloalkenyl, aryl, heteroaryl, -OR ａ , -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 T is O, S or NR ａ and Each occurrence of L is independently O, S, NR ａ or C(R ａ ) ２ and m is an integer of 0 to 3, and when m is 0, the structural moiety 【Transformation 8】 teeth, 【Chemistry 9】 Each of them has the structure U １ , U ２ , U ３ and U ４ are each independently N or CR as allowed by valence. ４ and R ４ 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 ３ ~C ７ ) cycloalkenyl, (C ４ ~C １０ ) bicycloalkyl, (C ４ ~C １０ ) bicycloalkenyl, (C ３ ~C ７ ) heterocycloalkyl, halogenated (C ３ ~C ７ ) heterocycloalkyl, (C ３ ~C ７ ) heterocycloalkenyl, (C ４ ~C １０ ) heterobicycloalkyl, (C ４ ~C １０ ) heterobicycloalkenyl, (C ４ ~C １０ ) heterospiroalkyl, (C ４ ~C １０ ) tricycloalkyl, (C ４ ~C １０ ) tricycloalkenyl, aryl, heteroaryl, -OR ａ , -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 10】 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, halogen or (C １ ~C ６ ) forming a 4- to 6-membered ring optionally substituted with alkyl. or a pharmaceutically acceptable salt thereof.

2. X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , X ８ , X ９ , Y １ , Y ２ , Y ３ , Y ４ , Y ５ , Z １ , Z ２ , Z ３ , Z ４ , U １ , U ２ , U ３ and U ４ are each independently CH, C(halogen), C(C １ ~C ６ (alkyl)) or N; optionally CH or N; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. 【Request Item 3】 【Chemistry 11】 but, a) 【Chemistry 12】 is; As desired structural part 【Chemistry 13】 but, 【Chemistry 14】 and optionally having the structure n is 0, 1 or 2; or structural part 【Chemistry 15】 but, 【Chemistry 16】 and optionally having the structure structural part 【Chemistry 17】 but, [Chemistry 18] having the structure: b) 【Chemistry 19】 is; As desired structural part 【Chemistry 20】 but, 【Chemistry 21】 and optionally having the structure n is 0, 1 or 2; or structural part 【Chemistry 22】 but, 【Chemistry 23】 and optionally having the structure 【Chemistry 24】 and optionally having the structure 【Chemistry 25】 or having the structure c) 【Chemistry 26】 is; As desired structural part 【Chemistry 27】 but, 【Chemistry 28】 and optionally having the structure 【Chemistry 29】 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 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 )cycloalkenyl, (C 3 -C 7 )heterocycloalkyl, (C 4 -C 10 )heterospiroalkyl, halogenated (C 3 -C 7 )heterocycloalkyl, (C 3 -C 7 )heterocycloalkenyl, aryl, (C 4 -C 10 )bicycloalkyl, (C 4 -C 10 )bicycloalkenyl, (C 4 -C 10 )heterobicycloalkenyl, (C 4 -C 10 )tricycloalkenyl, (C 4 -C 10 )heterotricycloalkenyl, —CN, 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 (C 3 -C 7 )cycloalkenyl, (C 3 -C 7 )heterocycloalkyl, (C 3 -C 7 )heterocycloalkenyl, (C 4 -C 10 )bicycloalkenyl, (C 4 -C 10 )heterobicycloalkenyl, (C 4 -C 10 )tricycloalkenyl, and (C 4 -C 10 )heterotricycloalkenyl are each 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, (C 1 -C 6 )alkyl, (C 3 -C 7 )heterocyclohaloalkyl, 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 , 【Transformation 30】 is; optionally Each occurrence of R 1 is independently H, D, F, CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , 【Chemistry 31】 is; and / or c) at least one occurrence of R 1 is 【Chemistry 32】 is; or At least one occurrence of R 1 is 【Transformation 33】 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; optionally 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 ; and / or (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 34】 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 35】 That is, 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof. 【Request Item 5】 【Chemistry 36】 but, a) 【Chemistry 37】 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 【Transformation 38】 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 but, 【Chemistry 39】 and X is O or NR １４ and R １４ is H or (C １ ~C ６ ) alkyl; or R １２ but, 【Chemistry 40】 is; or b) 【Chemistry 41】 That is, 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

6. a) Structural part 【Chemistry 42】 but, 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 wherein Q is O or NH; or b) Structural part 【Chemistry 46】 but, 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 wherein Q is O or NH; or c) Structural part [Transformation 50] but, 【Chemistry 51】 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 【Chemistry 52】 but, 【Chemistry 53】 wherein Q is O or NH; or e) Structural part 【Chemistry 54】 but, 【Transformation 55】 wherein Q is O or NH; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

7. a) Structural part 【Transformation 56】 but, 【Chemistry 57】 and optionally having the structure 【Transformation 58】 having the structure 【Chemistry 59】 wherein optionally each occurrence of R 2 is independently H, halogen, CH 3 , CF 3 , OH, NH 2 , —NHCH 3 , or —N(CH 3 ) 2 ; or b) Structural part 【Transformation 60】 but, 【Chemistry 61】 wherein optionally each occurrence of R 2 is independently H, halogen, CH 3 , CF 3 , OH, NH 2 , —NHCH 3 , or —N(CH 3 ) 2 ; or c) Structural part 【Transformation 62】 but, 【Transformation 63】 wherein optionally each occurrence of R 2 is independently H, halogen, CH 3 , CF 3 , OH, NH 2 , —NHCH 3 , or —N(CH 3 ) 2 ; or d) Structural part 【Chemistry 64】 but, 【Transformation 65】 or having the structure e) Structural part 【Chemical Formula 66】 but, 【Transformation 67】 having the structure 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

8. structural part 【Transformation 68】 but, a) 【Transformation 69】 b) 【Transformation 70】 and optionally having the structure 【Chemistry 71】 having the structure 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

9. a) Structural part 【Chemistry 72】 but, 【Transformation 73】 wherein each occurrence of o is independently 1 or 2, and J is C(R ｙ ) ２ and R ｙ Each occurrence of H, (C １ ~C ６ ) alkyl, OH, O(C １ ~C ６ ) alkyl, or halogen, or two R ｙ may be joined together to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring; optionally structural part 【Chemistry 74】 but, 【Chemistry 75】 wherein Y 1 , Y 2 and Y 5 are each independently N, CH, CCH 3 or CF; or b) Structural part 【Transformation 76】 but, 【Chemical 77】 wherein each occurrence of o 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 two R y s may be joined together to form a 3- to 7-membered cycloalkyl or heterocycloalkyl ring; optionally structural part 【Transformation 78】 but, 【Chemistry 79】 wherein Y 1 , Y 2 , Y 3 and Y 5 are each independently N, CH, CCH 3 or CF; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

10. structural part 【Chemistry 80】 but, 【Chemistry 81】 3. The compound of claim 1 or 2, having the structure: or a pharmaceutically acceptable salt thereof.

11. having the structure of formula Ia; and structural part 【Chemistry 82】 but, 【Chemistry 83】 wherein each occurrence of R 3 and R 4 is independently H, halogen, or (C 1 -C 6 )alkyl, T is O, S, NH, or N((C 1 -C 6 )alkyl), each occurrence of L is independently O, S, NH, N((C 1 -C 6 )alkyl) or C(R a ) 2 , and each occurrence of R a is independently H, OH, OCH 3 , halogen, or (C 1 -C 6 )alkyl; optionally structural part 【Chemical 84】 but, 【Chemical 85】 having the structure 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof.

12. having the structure of formula Ib; and structural part 【Chemical 86】 but, 【Transformation 87】 wherein each occurrence of R 3 and R 4 is independently H, halogen, or (C 1 -C 6 )alkyl, T is O, S, NH, or N((C 1 -C 6 )alkyl), each occurrence of L is independently O, S, NH, N((C 1 -C 6 )alkyl) or C(R a ) 2 , and each occurrence of R a is independently H, OH, OCH 3 , halogen, or (C 1 -C 6 )alkyl; optionally structural part 【Chemical 88】 but, 【Chemical 89】 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 【Chemistry 90】 and Y １ , Y ２ , Y ３ , Y ４ , Y ５ , Z １ , Z ２ , Z ４ , U １ , U ２ , U ３ and U ４ are each independently CH, CCH ３ , CF or N, and R ａ is H or CH ３ is; or The compound of formula Ib is 【Chemistry 91】 wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , Z 3 , U 1 , U 2 , U 3 and U 4 are each independently CH, CCH 3 , CF or N, and R a is H or CH 3 ; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

14. The compound of formula Ia is 【Chemistry 92】 is; or The compound of formula Ia is 【Chemistry 93】 is; As desired The compound of formula Ia is 【Chemical 94】 is; or The compound of formula Ib is 【Chemical 95】 is; or The compound of formula Ib is 【Chemistry 96】 is; As desired The compound of formula Ib is 【Chemistry 97】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1-2 or 13-14 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 said compound; 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 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; 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; or 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 the T cells are regulatory T cells; or the compound activates Akt3 signaling; or the compound inhibits Akt3 signaling; or the compound increases the activity or production of regulatory T cells; or 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.

Images