AKT3 Modulator

Abstract

Formula Ia, Ib or Ic Compounds of formula (I) are described, and various substituents are defined herein. The compounds can modify the properties or effects of Akt3 in vitro or in vivo and can also be used alone or in combination with other agents to prevent or treat a variety of conditions. Methods for synthesizing the compounds are described. Pharmaceutical compositions and methods for using these compounds or compositions alone or in combination with other agents or compositions to prevent or treat a variety of conditions are also described.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits and priority of U.S. Provisional Application 63 / 021,981 filed 8 May 2020 and U.S. Provisional Application 63 / 121,000 filed 3 December 2020, and incorporates the contents of each of these applications in whole by reference herein.

[0002] Inclusion by citation Any patents, patent publications, publications, or other documents cited herein are expressly incorporated herein by their entirety.

[0003] Field of Invention The present invention generally relates to Akt3 modulators and methods for treating and preventing diseases by regulating Akt3 signaling. [Background technology]

[0004] Background of the Invention Chronic diseases and illnesses are persistent conditions that require ongoing treatment and generally negatively impact a patient's quality of life. Chronic diseases are the leading causes 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. Roughly six out of ten adults in the United States have a chronic disease, and four out of ten have two or more chronic diseases. Chronic diseases are also a leading driver of $3.3 trillion in annual healthcare spending in the United States (see “About Chronic Diseases”, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention; updated October 23, 2019). These statistics highlight the need for new and improved treatments and preventive interventions for conditions such as cancer, inflammatory diseases, neurodegenerative diseases, pathogenic infections, immunodeficiency disorders, weight gain disorders, weight loss disorders, hormonal 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 known as neurons. Neurons are components of the nervous system and are not normally replaced after damage or death. Neuronal loss or dysfunction in patients with neurodegenerative diseases can affect body 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 diseases, motor neuron disorders, spinocerebellar ataxia, and spinal muscular atrophy. Symptoms of advanced neurodegenerative diseases can be devastating, causing patients to lose memory, motor control, and personality. Existing treatments for neurodegenerative diseases can manage symptoms but generally cannot prevent or cure the disease. Such existing treatments typically have negative side effects that further worsen the patient's quality of life.

[0006] Severe complications of chronic diseases such as neurodegenerative diseases and cancer are cachexia or wasting syndrome. Cachexia is defined as a weight loss of more than 5% of body weight within 12 months in the presence of a chronic disease. Other symptoms of cachexia include muscle atrophy, fatigue, weakness, and often loss of appetite. The weight loss associated with cachexia is due to a decrease in muscle mass as well as fat. Patients with cachexia often lose weight even if they are still eating a normal diet. As with neurodegenerative diseases, there is currently no effective treatment for cachexia, which leads to many chronic disease-related deaths. [Overview of the project] [Problems that the invention aims to solve]

[0007] Therefore, there is an unmet need for more effective and acceptable treatments and preventive interventions for these and other diseases and their associated complications. [Means for solving the problem]

[0008] Summary of the Invention The Akt3 used herein is the RAC-gammaserine / threonine-protein kinase, an enzyme encoded by the Akt3 gene in humans. In one embodiment, formula Ia, Ib, or Ic [ka] Compounds having the structure or salts thereof are described, where various substituents are defined herein. In some embodiments, the compounds can modulate the properties or effects of Akt3 in vitro or in vivo and / or can be used alone or in combination with other agents for the prevention or treatment of a variety of conditions. In other embodiments, methods for synthesizing the compounds are provided. In other embodiments, pharmaceutical compositions comprising the compounds and methods for using these compositions alone or in combination with other agents or compositions for the prevention or treatment of a variety of conditions are also described herein.

[0009] In one embodiment, formulas Ia, Ib, or Ic: [Chemical formula] a compound or a pharmaceutically acceptable salt thereof is described, where: [Chemical formula] is [Chemical formula] and each of X1, X2, X3, X4, X5, X6, X7, X8 and X9 is independently CR1 or N; R1 is H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 )heterospiroalkyl, aryl, heteroaryl, -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 , [Chemical formula] and optionally one or more (C1-C6)alkyl, halogenated (C1-C6)alkyl, -SO2R a or -SO2N(R a )2 substituted partially saturated bicyclic heteroaryl selected from the group consisting of; Here, R1 is a (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl, and heteroaryl each may contain one or more (C1-C6)alkyl, halogenated (C1-C6)alkyl, halogen, -OR a -CN or -N(R a ) is replaced with 2; n is an integer between 0 and 4, depending on the valence; Q is C(R a )2, O, NR a , N(C=O)R a Or NSO2R a and; Y1, Y2, Y3, Y4, and Y5 are independently possible N or CR2 depending on their valence; R2 is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] Selected from the group consisting of; -EG- is -(C=O)NR x -, -NR x (C=O)-, -N(R) x )(C=O)N(R x )-, -O(C=O)N(R x )-,-N(R x )(C=O)O-, -SO2NR x -, -NR x SO2- or [ka] And here R x In each case, is independently H, (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl; or R x and Y3, R x and Y4, R x and Z1 or R x And Z4 together form a 5-6 member heteroring which may be substituted; W1, W2, W3, W4, and W5 are each independently possible as CR6, N, or NR6 depending on their valence; In each case, R6 is independently selected from the group consisting of H, halogens, (C1-C6) alkyls, and (C1-C6) haloalkyls; T is possible in each case independently by valence for O, N, and NR. a , N(C=O)R a NC(R b )2OP(=O)(OR b )2 or NSO2R a and; U is possible in each case independently by valence: O, N, NR a , N(C=O)R a NC(R b )2OP(=O)(OR b )2 or NSO2R a and; R b In each case, is independently H or (C1-C6) alkyl; Z1, Z2, Z3, Z4, and Z5 are each independently possible as N or CR3 depending on their valence; R3 is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] Selected from the group consisting of; V is absent, C(R a )2, NR a , N(C=O)R a NSO2R a or O; R4 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Selected from the group consisting of heterospiroalkyl, aryl, and heteroaryl molecules, each possibly substituted with one or more R5 groups; Alternatively, V and R4 together form a (C3-C7) heterocycloalkyl or (C4-C 10 ) form heterospiroalkyl groups; R5 is independently in each case H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 )heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , N(R a )COR a ,

Chem.

Chem.

[0010] In any of the embodiments disclosed herein, Q, T and U are each independently O, NH, NCH3, N(C=O)H, N(C=O)CH3, N(C=O)CH2CH((END]]

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

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

[0013] In any of the embodiments disclosed herein, the structural part [ka] teeth [ka] It has the structure of [the object].

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

[0015] In any of the embodiments disclosed herein, the structural part [ka] teeth, [ka] It has the structure of [the object].

[0016] In any of the embodiments disclosed herein, the structural part [ka] teeth [ka] It has the structure of [the object].

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

[0018] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

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

[0020] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0021] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0022] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

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

[0024] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0025] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

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

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

[0028] In any of the embodiments disclosed herein, R1 is independently H, D, halogen, OR in each case.a , N(R a )2, (C1-C6) alkyl, (C1-C6) alkynyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, (C4-C 10 ) Bicycloalkyl, -CN, N3, NO2, COR a CO2R a CON(R a )2, -SO2R a or -SO2N(R a )2; where the (C3-C7) heterocycloalkyl group is optionally substituted with one or more (C1-C6) alkyl groups.

[0029] In any of the embodiments disclosed herein, R1 is independently H, halogen, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, N(R a )2 or -CN; where the (C3-C7) heterocycloalkyl group is optionally substituted with one or more (C1-C6) alkyl groups.

[0030] In any of the embodiments disclosed herein, R1 is independently in each case H, (C1-C6) alkyl, (C3-C7) heterocyclohaloalkyl, or (C3-C7) heterocycloalkyl; where the (C3-C7) heterocycloalkyl is optionally substituted with one or more (C1-C6) alkyl groups.

[0031] In any of the embodiments disclosed herein, R1 is independently H, D, F, Cl, Br, CH3, OCH3, NH2, NHCH3, N(CH3)2 in each case. [ka] That is the case.

[0032] In any of the embodiments disclosed herein, at least one of R1 is [ka] In any of the embodiments disclosed herein, [ka] teeth [ka] That is the case.

[0033] In any of the embodiments disclosed herein, R1 is independently H, D, F, CH3, NH2, NHCH3, N(CH3)2 in each case. [ka] That is the case.

[0034] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] [ka] It has the structure, where Q is O or NH.

[0035] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH.

[0036] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] The structure is such that Q is O or NH, and R1 is H, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, halogenated (C3-C7) heterocycloalkyl, or halogen.

[0037] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH.

[0038] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH.

[0039] In any of the embodiments disclosed herein, the compound has the formula Ia.

[0040] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0041] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0042] In any of the embodiments disclosed herein, R2 is independently H, halogen, CH3, CF3, OH, NH2, -NHCH3, or -N(CH3)2 in each case.

[0043] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0044] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0045] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0046] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0047] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0048] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0049] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0050] In any of the embodiments disclosed herein, each case of R3 is H, halogen, CH3, CF3, OH, NH2, -NHCH3, or -N(CH3)2.

[0051] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0052] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure, where R3 is H, CH3, OH, halogen or NH2; and R x The group is H, CH3, or CH2CH3.

[0053] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure, where m is independently 1 or 2 in each case, and J is C(R y )2, R y In each case, independently, is H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen.

[0054] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the following structure, where Y1, Y2, Y3, and Y4 are each independently N, CH, CCH3, or CF.

[0055] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure, where m is independently 1 or 2 in each case, and J is C(R z )2, R z In each case, independently, is H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen.

[0056] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the following structure, where Z1, Z2, Z3, and Z4 are each independently N, CH, CCH3, or CF.

[0057] In any of the embodiments disclosed herein, the compound has the formula Ib.

[0058] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure, where T and U are independently possible by valence in each case: O, N, NR a , N(C=O)R a NC(R b )2OP(=O)(OR b )2 or NSO2R a That is the case.

[0059] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure, where R3 is H, CH3, OH, halogen or NH2; and R a The group is H, CH3, or CH2CH3.

[0060] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0061] In any of the embodiments disclosed herein, R b In each case, is independently H or (C1-C6) alkyl.

[0062] In any of the embodiments disclosed herein, R b In each case, the constituents are independently H, CH3, CH2CH3, or CH(CH3)2.

[0063] In any of the embodiments disclosed herein, the compound has the formula Ic.

[0064] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure, where T and U are independently possible by valence in each case: O, N, NR a , N(C=O)R a NC(R b )2OP(=O)(OR b )2 or NSO2R a That is the case.

[0065] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure, where R2 is H, CH3, OH, halogen or NH2; and R a The group is H, CH3, or CH2CH3.

[0066] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0067] In any of the embodiments disclosed herein, R b In each case, is independently H or (C1-C6) alkyl.

[0068] In any of the embodiments disclosed herein, R b In each case, the constituents are independently H, CH3, CH2CH3, or CH(CH3)2.

[0069] In any of the embodiments disclosed herein, R2 is independently H, CH3, OH, NH2, or a halogen in each case.

[0070] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0071] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0072] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0073] In any of the embodiments disclosed herein, the structural part [ka] V and R4 are integrated into (C4-C 10 ) Forms heterospiroalkyl groups.

[0074] In any of the embodiments disclosed herein, V is absent.

[0075] In any of the embodiments disclosed herein, R4 is [ka] Here, m is an integer between 0 and 3.

[0076] In any of the embodiments disclosed herein, R5 is independently H, (C1-C6) alkyl, halogen, OR in each case. a OH, NH2, N(R a )COR a , CN, CF3, (C1-C6) haloalkyl or [ka] And R a In each case, is independently H, (C2-C6) alkenyl, or (C1-C6) alkyl.

[0077] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure, where V is C(R a )2, O, NR a , N(C=O)R a Or NSO2R a And V' is CR a Or it is N.

[0078] In any of the embodiments disclosed herein, R5 is independently in each case [ka] That is the case.

[0079] In any of the embodiments disclosed herein, R a In each case, is independently H, (C2-C6) alkenyl, or (C1-C6) alkyl.

[0080] In any of the embodiments disclosed herein, R a In each case, is H, CH3, or CH2CH3.

[0081] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0082] In any of the embodiments disclosed herein, a substructure [ka] teeth [ka] It has the structure of [the object].

[0083] In any of the embodiments disclosed herein, the compound of formula Ia [ka] [ka] It has the structure, where R1 is H, (C1-C6) alkyl, N(R a )2, (C3-C7) heterocycloalkyl or halogen; R5 and R 11 Each of the following is independently H or CH3; Y1, Y2, Y3, Y4, Z1, Z2, Z3, Z4, L1 and L2 are each independently CH or N; and V is NH or O.

[0084] In any of the embodiments disclosed herein, R1 is H, F, Cl, Br, CH3, CH2CH3, CH(CH3)2, NH2, N(CH3)2, [ka] That is the case.

[0085] In any of the embodiments disclosed herein, the compound of formula Ib has a structure [ka] It has, and here, R 11 And R5 are each independently H or CH3; and Y1, Y2, Y3, Y4, Z2, Z3 and Z4 are each independently CH or N.

[0086] In any of the embodiments disclosed herein, the compound of formula Ia [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] That is the case.

[0087] In any of the embodiments disclosed herein, the compound of formula Ib [ka] [ka] [ka] [ka] That is the case.

[0088] In any of the embodiments disclosed herein, the compound of formula Ic [ka] That is the case.

[0089] In any of the embodiments disclosed herein, the compound [ka] [ka] That is the case.

[0090] In any of the embodiments disclosed herein, the compound is selected from the group consisting of compounds 2-5, 7-30, 32-101, and 105-136 in Examples 2-5, 7-30, 32-101, and 105-136, respectively.

[0091] In other embodiments, a method for treating a disease in a subject requiring treatment is described, comprising administering to the subject an effective amount of any of the compounds of the embodiments disclosed herein.

[0092] In any of the embodiments described herein, the disease is selected from the group consisting of neurodegenerative diseases, cachexia, eating disorders, obesity, complications of obesity, inflammatory diseases, virus-induced inflammatory responses, Gulf War syndrome, tuberous sclerosis, retinitis pigmentosa, graft rejection, cancer, autoimmune diseases, ischemic tissue injury, traumatic tissue injury, and combinations thereof.

[0093] In any of the embodiments described herein, the disease is a neurodegenerative disease.

[0094] In any 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 disorders, Huntington's disease, HIV-induced neurodegeneration, Lewy body disease, spinal muscular atrophy, prion disease, spinocerebellar ataxia, familial amyloid polyneuropathy, multiple sclerosis, and combinations thereof.

[0095] In any of the embodiments described herein, the disorder is cachexia or an eating disorder.

[0096] In any of the embodiments described herein, the disease is obesity or a complication of obesity.

[0097] In any of the embodiments described herein, the complications of obesity are selected from the group consisting of glucose intolerance, fatty liver, dyslipidemia, and combinations thereof.

[0098] In any of the embodiments described herein, the disease is an inflammatory disease.

[0099] In any of the embodiments described herein, the inflammatory disease is selected from the group consisting of atopic dermatitis, allergies, asthma, and combinations thereof.

[0100] In any of the embodiments described herein, the disease is a virus-induced inflammatory response.

[0101] In any of the embodiments described herein, the virus-induced inflammatory response is SARS-induced inflammatory pneumonia, coronavirus disease 2019, or a combination thereof.

[0102] In any of the embodiments described herein, the disease is Gulf War Syndrome or tuberous sclerosis.

[0103] In any of the embodiments described herein, the disease is retinitis pigmentosa or graft rejection.

[0104] In any of the embodiments described herein, the disease is ischemic tissue injury or traumatic tissue injury.

[0105] In any of the embodiments described herein, the disease is cancer.

[0106] In any of the embodiments described herein, cancer is selected from the group consisting of adult T-cell leukemia / lymphoma, bladder, brain, breast, cervix, colorectal, esophagus, kidney, liver, lung, nasopharynx, pancreas, prostate, skin, stomach, uterus, ovaries, and testes.

[0107] In any of the embodiments described herein, cancer is leukemia.

[0108] In any of the embodiments described herein, leukemia is adult T-cell leukemia / lymphoma.

[0109] In any of the embodiments described herein, adult T-cell leukemia / lymphoma is caused by a human T-cell lymphotropic virus.

[0110] In any of the embodiments described herein, the disease is an autoimmune disease.

[0111] In any of the embodiments described herein, the autoimmune disease is 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 antibody 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, Barlow's disease, Behçet's disease, benign mucosa. Bullous pemphigoid, Castleman disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing polymyelitis, Churg-Strauss syndrome, eosinophilic granulomatosis, scarring bullous pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, Crest syndrome, Crohn's disease, herpetiform dermatitis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrotic lung Alveolar inflammation, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, pemphigoid of pregnancy, sweat gland abscess (reverse acne), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immunothrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes (type 1 diabetes), juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing, woody conjunctivitis, linear IgA disease, lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mohlen's ulcer, Mukka-Habermann disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular scarring pemphigoid, optic neuritis, relapsing rheumatoid arthritis, childhood autoimmune neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, squamous cellulitis (peripheral uveitis), Personage-Turner syndrome, pemphigus, peripheral neuropathy, perineal encephalomyelitis, pernicious anemia,POEMS syndrome, polyarteritis nodosa, polymyalgia syndrome type I, polymyalgia syndrome type II, polymyalgia syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone 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, joint The group consists of rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, generalized rigidus syndrome, subacute bacterial endocarditis, Suzac syndrome, sympathetic ophthalmitis, Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, leukoplakia, Vogt-Koyanagi-Harada disease, and combinations thereof.

[0112] In any of the embodiments described herein, the compound modulates Akt3 in immune cells.

[0113] In any of the embodiments described herein, the immune cells are selected from the group consisting of T cells, B cells, macrophages, and glial cells.

[0114] In any of the embodiments described herein, the glial cell is an astrocyte, microglia, or oligodendrocyte.

[0115] In any of the embodiments described herein, the T cell is a T regulatory cell.

[0116] In any of the embodiments described herein, the compound activates Akt3 signaling.

[0117] In any of the embodiments described herein, the compound inhibits Akt3 signaling.

[0118] In any of the embodiments described herein, the compound increases T regulatory cell activity or production.

[0119] In any of the embodiments described herein, the compound reduces T regulatory cell activity or production.

[0120] In any of the embodiments described herein, the method further comprises administering a second therapeutic agent to a subject.

[0121] In any of the embodiments described herein, the second therapeutic agent is selected from the group consisting of nutritional supplements, chemotherapy 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.

[0122] In any of the embodiments described herein, the method further comprises treating the subject with an immunotherapeutic agent, an immunomodulator, a costimulatory activating agonist, a cytokine, a chemokine, a chemokine factor, an oncolytic virus, a biologic, a vaccine, a small molecule, targeted therapy, an anti-inflammatory agent, a cell therapy, a chemotherapeutic agent, radiotherapy, or a combination thereof.

[0123] Any of the embodiments disclosed herein can be appropriately combined with any of the other embodiments disclosed herein. Any combination of any of the embodiments disclosed herein and any of the other embodiments disclosed herein is explicitly intended. 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 some other substituent. Such combinations can be implemented in any of the one or more embodiments of the present application described herein or in any of the formulas described herein. [Brief explanation of the drawing]

[0124] This application is described with reference to the following drawings, which are provided for illustrative purposes only and are not intended to be limiting. The drawings depict the following:

[0125] [Figure 1] The evaluation of iTreg induction (FoxP3) from human CD4 T cells treated with compounds 137, 38, and 67 in the presence of anti-CD3 / anti-CD28 / IL-2 / TGFβ is shown herein, according to one or more embodiments described.

[0126] [Figure 2] The evaluation of iTreg induction (FoxP3) from human CD4 T cells treated with compounds 97 and 99 in the presence of anti-CD3 / anti-CD28 / IL-2 / TGFβ is shown here, according to one or more embodiments described herein.

[0127] [Figure 3] The evaluation of IL-10 in the supernatant from human nTreg cells treated with 1 μM compound 137 for 24 and 48 hours in the presence of anti-CD3 / anti-CD28 / IL-2 stimulation is shown here, according to one or more embodiments described herein.

[0128] [Figure 4] The in vivo changes in Treg, TME, and spleen on day 2 after IP treatment (1 mg / kg and 5 mg / kg) with compound 137 (*, p<0.05; **, p<0.01; ***p<0.001) according to one or more embodiments described herein are shown.

[0129] [Figure 5] The evaluation of iTreg induction (FoxP3) from human CD4 T cells treated with compound 31 in the presence of anti-CD3 / anti-CD28 / IL-2 / TGFβ is shown here, according to one or more embodiments described herein.

[0130] [Figure 6]The evaluation of iTreg induction (FoxP3) from human CD4 T cells treated with compounds 59 and 106 in the presence of anti-CD3 / anti-CD28 / IL-2 / TGFβ is shown here, according to one or more embodiments described herein.

[0131] [Figure 7] The evaluation of iTreg induction (FoxP3) from human CD4 T cells treated with compounds 64 and 65 in the presence of anti-CD3 / anti-CD28 / IL-2 / TGFβ is shown herein, according to one or more embodiments described therein.

[0132] [Figure 8] The following describes the evaluation of Treg inhibition (normalized to untreated control; measured by flow cytometry) in isolated spleens of TC-1 tumor-bearing mice two days after treatment with a single forced oral administration of compounds 137, 110, 99, and 114 using one or more embodiments.

[0133] [Figure 9] The following describes the evaluation of Treg inhibition (normalized to untreated control; measured by flow cytometry) in isolated spleens of TC-1 tumor-bearing mice two days after treatment with a single forced oral administration of compounds 137, 126, and 120, according to one or more embodiments described herein. [Modes for carrying out the invention]

[0134] Detailed description of the invention definition It should be recognized that the present invention is not limited to the compositions and methods and experimental conditions described herein, and that they may be modified. Since the scope of the present invention is limited only by the appended claims, it should also be understood that the terms used herein are for illustrative purposes only and are not intended to limit any particular embodiment.

[0135] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. Any composition, method, and substance similar to or equivalent to those described herein may be used in carrying out or testing this invention.

[0136] The use of singular expressions in the description of the claimed invention herein (particularly in the claims) should be interpreted as encompassing both singular and plural forms unless otherwise specifically stated herein or unless it is clearly contrary to the context.

[0137] Unless otherwise specified herein, the ranges of values ​​described herein are intended as an abbreviation to refer simply to each individual value that falls within that range, and each separate value is incorporated herein to the same extent as if it were mentioned individually.

[0138] The use of the term "approximately" is intended to refer to values ​​within a range of approximately ±10% above or below the stated value. In one embodiment, the value may be within a range of approximately ±5% above or below the stated value. In one embodiment, the value may be within a range of approximately ±2% above or below the stated value. In another embodiment, the value may be within a range of approximately ±1% above or below the stated value. The aforementioned ranges are intended to be apparent from the context and do not imply further limitation. All methods described herein may be performed in any appropriate order unless otherwise specifically noted or unless it is clearly contrary to the context. Any and all examples or illustrative terms provided herein (e.g., "exemplary," "etc.," "for example," "including, but not limited to") are intended solely to facilitate the understanding of the invention and do not impose limitations on the scope of the invention unless otherwise specifically noted.

[0139] The following are definitions of terms used herein. The first definition provided for a given base or term applies throughout this specification, individually or as part of another base, unless otherwise specified. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0140] The terms "alkyl" and "alk" refer to linear or branched alkane (hydrocarbon) radicals containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc. 1- "C4) alkyl" refers to a linear or branched alkane (hydrocarbon) radical containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. "Substitutive alkyl" refers to an alkyl group that is substituted with one or more substituents, preferably 1 to 4 substituents, at any of the available bonding sites. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., single halogen substituent or multiple halo substituent, in the latter case forming a CF3 or CCl3-supported alkyl group), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a , SR 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) (bonded to the molecule via S or N), P(=O)2OR e , NR b R c , NR b S(=O)2R e , NR 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 , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a or NR b P(=O)2R e , here, R a In each case, R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b , R c and R d In each case, R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or b and R c They combine with the N to which they are bound, sometimes forming a heteroring, R e In each case, independently, the group is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. In some embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclic, and aryl may themselves be substituted as needed.

[0141] The term "heteroalkyl" refers to a linear or branched alkyl group having preferably 2 to 12 carbon atoms, more preferably 2 to 10 carbon atoms, in which one or more are replaced by heteroatoms selected from the group consisting of S, O, P, and N. Examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkylamines, and alkyl sulfides. The group may be a terminal group or a bridging group.

[0142] The term "alkenyl" refers to a linear or branched hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Examples of such groups include ethenyl or allyl. The term "C2-C6 alkenyl" includes etylene, propenyl, 2-propenyl, (E)-buto-2-enyl, (Z)-buto-2-enyl, 2-methi(E)-buto-2-enyl, 2-methi(Z)-buto-2-enyl, 2,3-dimethyl-buto-2-enyl, (Z)-pento-2-enyl, (E)-pento-1-enyl, (Z)-hexy-1-enyl, (E)-pento- "Substitutable alkenyl" refers to a linear or branched hydrocarbon radical containing 2 to 6 carbon atoms and at least 1 carbon-carbon double bond, such as 2-enyl, (Z)-hexy-2-enyl, (E)-hexy-2-enyl, (Z)-hexy-1-enyl, (E)-hexy-1-enyl, (Z)-hexy-3-enyl, (E)-hexy-3-enyl, and (E)-hexy-1,3-dienyl. "Substitutable alkenyl" refers to an alkenyl group that is substituted with one or more substituents, preferably 1 to 4 substituents, at any of its available bonding sites. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, alkyl halide (i.e., single halogen substituent or alkyl group supporting multiple halogen substituents such as CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a , SR 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 bonded to the molecule via N), P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c, NR b S(=O)2R e , NR 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 , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a or NR b P(=O)2R e , here, R a In each case, R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b , R c and R d In each case, R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or b and R c They may form a heteroring together with the N to which they are bound; and R e Each of these substituents is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents may themselves be substituted by choice.

[0143] The term "alkynyl" refers to a linear or branched hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. An example of the group is ethynyl. The term "C2-C6 alkynyl" refers to a linear or branched hydrocarbon radical containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-inyl, prop-2-inyl, buto-1-inyl, buto-2-inyl, pento-1-inyl, pento-2-inyl, hexy-1-inyl, hexy-2-inyl, or hexy-3-inyl. "Substitutive alkynyl" refers to an alkynyl that is substituted with one or more substituents, preferably 1 to 4 substituents, at any of the available bonding sites. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., single halogen substituent or multiple halo substituent, in the latter case forming CF3 or CCl3-supported alkyl groups), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a , SR 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 bonded to the molecule via N), P(=O)2OR e , NR b R c , NR b S(=O)2R e , NR 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)NRb R c ,OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a or NR b P(=O)2R e , here, R a In each case, R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b , R c and R d In each case, R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or b and R c They may form a heteroring together with the N to which they are bound; and R e Each of these substituents is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents may themselves be substituted by choice.

[0144] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbon atoms per ring. "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substitutive cycloalkyl" refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any of the available bonding sites. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., single halogen substituent or multiple halo substituent, in the latter case forming CF3 or CCl3-supported alkyl groups), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a , SR 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 bonded to the molecule via N), P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NR b S(=O)2R e , NR 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 , NR b C(=O)OR e , NR dC(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a or NR b P(=O)2R e , here, R a In each case, R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b , R c and R d In each case, R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or b and R c They may form a heteroring together with the N to which they are bound; and R e Each substituent is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents may be substituted themselves as appropriate. Examples of substituents include spirobonded or fused cyclic substituents, in particular spirobonded cycloalkyl, spirobonded cycloalkenyl, spirobonded heterocyclic (except heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl substituents, where the cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents may be substituted themselves as appropriate.

[0145] The terms "bicycloalkyl" or "spiroalkyl" refer to a compound comprising at least one cycloalkyl ring that shares one or more ring atoms with at least one other cycloalkyl ring. The terms "heterobicycloalkyl" or "heterospiroalkyl" refer to a bicycloalkyl group in which at least one, preferably 1 to 3, carbon atoms of at least one ring are replaced by heteroatoms selected from the group consisting of N, S, O, or P. Examples of bicycloalkyl groups in which the heteroatom may be at the terminal position or the bridging position (i.e., the bond point of the two rings) include adamantyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.1.1]hexyl, octahydropentarenyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecanyl, decahydronaphthalenyl, bicyclo[3.2.0]heptyl, octahydro-1H-indenyl, bicyclo[4.2.1]nonanyl, etc. Examples of spirobicycloalkyl groups include spiro[4.4]nonyl, spiro[3.3]heptyl, spiro[5.5]undecyl, spiro[3.5]nonyl, spiro[4.5]decyl, etc. "Substituted bicycloalkyl," "substituted spiroalkyl," "substituted heterobicycloalkyl," and "substituted heterospiroalkyl" refer to bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl groups that are substituted with one or more substituents, preferably 1 to 4 substituents, at any of the available bond sites. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., single halogen substituent or multiple halo substituent, in the latter case forming CF3 or CCl3-supported alkyl groups), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a , SR a , S(=O)R e , S(=O)2R e -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NRa )(=N(R a )2)(R a (or bonded to the molecule via N), P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NR b S(=O)2R e , NR 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 , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a or NR b P(=O)2R e , here, R a In each case, R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b , R c and R d In each case, R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or b and R c They may form a heteroring together with the N to which they are bound; and R eEach substituent is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents may be substituted themselves as appropriate. Examples of substituents include spirobonded or fused cyclic substituents, in particular spirobonded cycloalkyl, spirobonded cycloalkenyl, spirobonded heterocyclic (except heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl substituents, where the cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents may be substituted themselves as appropriate.

[0146] The term "heterocycloalkyl" or "cycloheteroalkyl" refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from the group consisting of at least one nitrogen, sulfur, and oxygen, preferably 1 to 3 heteroatoms, in at least one ring. Each ring is preferably 3 to 10 members, more preferably 4 to 7 members. Suitable heterocycloalkyl substituents include, but are not limited to, azetidinyl, oxetanyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranil, piperidyl, piperadyl, tetrahydropyranil, morpholino, 1,3-diazepanyl, 1,4-diazepanyl, 1,4-oxazepanyl, and 1,4-oxathiopanyl. The groups may be terminal groups or bridging groups.

[0147] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbon atoms per ring. Examples of such groups include cyclobutenyl, cyclopentenyl, and cyclohexenyl. A "substituted cycloalkenyl" refers to a cycloalkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any of the available bonding sites. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., single halogen substituent or multiple halo substituent, in the latter case forming CF3 or CCl3-supported alkyl groups), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a , SR 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 bonded to the molecule via N), P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NR b S(=O)2R e , NR 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 , NR b C(=O)OR e , NR d C(=O)NRb R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a or NR b P(=O)2R e , here, R a In each case, R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b , R c and R d In each case, R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or b and R c They may form a heteroring together with the N to which they are bound; and R e Each substituent is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents may be substituted themselves as appropriate. Examples of substituents include spirobonded or fused cyclic substituents, in particular spirobonded cycloalkyl, spirobonded cycloalkenyl, spirobonded heterocyclic (except heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl substituents, where the cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents may be substituted themselves as appropriate.

[0148] The term "aryl" refers to a cyclic, aromatic hydrocarbon group having 1 to 5 aromatic rings, particularly monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When it contains two or more aromatic rings (such as bicyclic), the aromatic rings of the aryl group may be bonded at one point (e.g., biphenyl) or condensed (e.g., naphthyl, phenantrenyl). The term "condensed aromatic ring" refers to a molecular structure having two or more aromatic rings, where two adjacent aromatic rings share two carbon atoms. "Substitutive aryl" refers to an aryl group that is substituted with one or more substituents, preferably 1 to 3 substituents, at any of the available bonding sites. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., single halogen substituent or multiple halo substituent, in the latter case forming CF3 or CCl3-supported alkyl groups), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a , SR 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 bonded to the molecule via N), P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NR b S(=O)2R e , NR 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)Ra , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a or NR b P(=O)2R e , here, R a In each case, R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b , R c and R d In each case, R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or b and R c They may form a heteroring together with the N to which they are bound; and R e Each of these substituents is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents may be substituted themselves as they may be. Examples of substituents also include fused cyclic groups, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl, where the cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents may be substituted themselves as they may be.

[0149] The term "biaryl" refers to two aryl groups joined by a single bond. The term "biheteroaryl" refers to two heteroaryl groups joined by a single bond. Similarly, the term "heteroaryl-aryl" refers to a heteroaryl group and an aryl group joined by a single bond, and the term "aryl-heteroaryl" refers to an aryl group and a heteroaryl group joined by a single bond. In some embodiments, the number of ring atoms in the heteroaryl and / or aryl ring is used to specify the size of the aryl or heteroaryl ring in the substituent. For example, 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is bonded to a 6-membered aryl group. Other combinations and ring sizes can be specified in a similar manner.

[0150] The term "carbocyclic" or "carbon ring" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbon atoms per ring, or a cyclic, aromatic hydrocarbon group having 1 to 5 aromatic rings, particularly monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. The term "carbocyclic" includes the cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl groups defined above. The term "substituted carbocyclic" refers to a carbocyclic or carbocyclic group that is substituted with one or more substituents, preferably 1 to 4 substituents, at any of the available bonding sites. Examples of substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl groups. Examples of substituents include spirobonds or condensed cyclic substituents at one or more available bond sites, in particular spirobonded cycloalkyls, spirobonded cycloalkenyls, spirobonded heterocycles (except heteroaryls), condensed cycloalkyls, condensed cycloalkenyls, condensed heterocycles, or condensed aryls, where the cycloalkyls, cycloalkenyls, heterocycles, and aryl substituents may themselves be substituted as appropriate.

[0151] The terms "heterocyclic" and "heterocyclic formula" refer to fully unsaturated cyclic groups (e.g., 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring systems) containing at least one heteroatom in at least one carbon-carbon ring. Each ring in a heterocyclic group can independently be saturated, partially, or fully unsaturated. Each ring in a heterocyclic group containing a heteroatom may have one, two, three, or four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms, where the nitrogen and sulfur heteroatoms may be oxidized, and the nitrogen heteroatom may be quaternized. (The term "heteroarylium" refers to a quaternary nitrogen atom, and therefore a positively charged heteroaryl group.) A heterocyclic group may be bonded to the rest of the molecule by any heteroatom or carbon atom in the ring or ring system. Examples of monocyclic and heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, and 2-oxopiperazinyl. This includes 2-oxopiperidinyl, 2-oxopyrrodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranil, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl.Examples of bicyclic heterocyclic groups include 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]dioxynyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranil, indolidinyl, benzofuryl, and be This includes lenzoflazanil, dihydrobenzo[d]oxazole, chromonyl, coumalinyl, benzopyranil, synnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, flupyridinyl (e.g., flu[2,3-c]pyridinyl, flu[3,2-b]pyridinyl, or flu[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (e.g., 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, etc. Examples of tricyclic heterocyclic groups include carbazolyl, benzidyl, phenanthrolinyl, acridinyl, phenanthridine, xanthenyl, etc. The term "partially saturated bicyclic heteroaryl" refers to a partially saturated bicyclic heteroaryl having, for example, a saturated cycloalkyl or heterocyclic alkyl ring.

[0152] A "substituted heterocycle" and a "substituted heterocyclic formula" (e.g., "substituted heteroaryl") refer to a heterocycle or heterocyclic group that is substituted with one or more substituents, preferably 1 to 4 substituents, at any of the available bonding sites. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., single halogen substituent or multiple halo substituent, in the latter case forming CF3 or CCl3-supported alkyl groups), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O)2R e -N=S(=O)(R a ), -R aS(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a (or bonded to the molecule via N), P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NR b S(=O)2R e , NR 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 , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a or NR b P(=O)2R e , here, R a In each case, R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b , R c and R d In each case, R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or b and R c They may form a heteroring together with the N to which they are bound; and R eEach substituent is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents may be substituted by themselves. Examples of substituents include spirobonded or condensed cyclic substituents at any of the one or more available bonding sites, in particular spirobonded cycloalkyl, spirobonded cycloalkenyl, spirobonded heterocyclic (except heteroaryl), condensed cycloalkyl, condensed cycloalkenyl, condensed heterocyclic, or condensed aryl, where the cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents may be substituted by themselves by themselves.

[0153] The term "oxo" refers to a group of carbon ring atoms in a carbocyclic or heterocyclic structure that can bond to a carbon ring atom. [ka] This refers to a substituent. When an oxo substituent is bonded to a carbocyclic atom of an aromatic group, such as an aryl or heteroaryl group, the bonds in the aromatic ring can be rearranged to satisfy the valence requirement. For example, a pyridine having a 2-oxo substituent [ka] When it can have a structure, it also [ka] This includes its tautomerized forms.

[0154] The term "alkylamino" refers to a group having the structure -NHR' (wherein R' is a hydrogen atom, 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, isopropylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, and cyclohexylamino.

[0155] The term "dialkylamino" refers to a group having the structure -NRR' (wherein R and R' are each independently an alkyl or substituted alkyl, a cycloalkyl or substituted cycloalkyl, a cycloalkenyl or substituted cycloalkenyl, an aryl or substituted aryl, a heterocycle or substituted heterocycle, as defined above). R and R' may 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, and di(cyclohexyl)amino. In some embodiments, R and R' are bonded 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.

[0156] The term "halogen" refers to chlorine, bromine, fluorine, or iodine.

[0157] The term “substitution” means an embodiment in which a molecule, molecular moiety, or substituent (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aryl group or any other group disclosed herein) is substituted with one or more substituents, preferably 1 to 6 substituents, at any of the available bonding sites, which is possible by valence. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., single halogen substituent or multiple halo substituent, in the latter case forming CF3 or CCl3-supported alkyl groups), cyano, nitro, oxo (i.e., =O), CF3, OCF3, alkyl, halogen-substituted alkyl, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a , SR 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 bonded to the molecule via N), P(=O)2OR e , NR b R c , NR b S(=O)2R e , NR 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 , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a or NR b P(=O)2R e , here, R a In each case, R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b , R c and R d In each case, R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or b and Rc They may form a heteroring together with the N to which they are bound; and R e Each of these substituents is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. In the examples of substituents above, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclic, and aryl may themselves be optionally substituted. The term "optionally substituted" means embodiments in which the molecule, molecular moiety, or substituent (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl group or any other group disclosed herein) may or may not be substituted with one or more of the substituents.

[0158] Unless otherwise specified, any heteroatom whose valence is not satisfied is presumed to have enough hydrogen atoms to satisfy its valence.

[0159] The compounds of the present invention can form salts, which are also within the scope of the invention. Unless otherwise specified, references to the compounds of the present invention are understood to include references to their salts. The term “salt” as used herein refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Furthermore, when the compounds of the present invention include both a basic moiety, such as but not limited to pyridine or imidazole, and an acidic moiety, such but not limited to a carboxylic acid, zwitterions ("intramolecular salts") may be formed, which are within the scope of the term “salt” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, but other salts may also be useful, for example, in isolation or purification steps and may be used during production. Salts of the compounds of the present invention can be obtained, for example, by reacting the compounds described herein with a fixed amount, such as an equivalent, of acid or base in a medium such as a salt precipitate or an aqueous medium, followed by freeze-drying.

[0160] Compounds of the present invention, comprising a basic moiety such as, but not limited to, an amine, pyridine, or imidazole ring, can form salts with a variety of organic and inorganic acids. Examples of acid addition salts include acetates (e.g., acetic acid or trihaloacetic acid; e.g., those formed with trifluoroacetic acid), adipines, alginates, ascorbicates, aspartates, benzoates, benzenesulfons, bisulfates, borates, acetates, citrates, camphorates, camphorsulfons, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfons, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobroms, hydroiodides, and hydroxyethanesulfates. This includes sulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propions, salicylates, succinates, sulfates (e.g., those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates, toluenesulfonates, undecanoates, and others.

[0161] Compounds of the present invention, which include an acidic moiety such as a carboxylic acid, can form salts with a variety of organic and inorganic bases. Examples of basic salts include alkali metal salts such as ammonium salts, sodium salts, lithium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydravamin (formed with N,N-bis(dehydroabiethyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, and t-butylamine, and salts with amino acids such as arginine and lysine. 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.

[0162] Prodrugs and solvates of the compounds of the present invention are also intended herein. The term "prodrug" as used herein means a compound that, upon administration to a subject, undergoes a metabolic chemical transformation or chemical process to produce the compound of the present invention or its salts and / or solvates. Solvates of the compounds of the present invention include, for example, hydrates.

[0163] The compounds of the present invention and their salts or solvates may exist in tautomeristic forms (e.g., as amides or iminols). All such tautomeristic forms are intended herein as part of the present invention. Any structure described herein of the compounds includes its tautomeristic form.

[0164] All stereoisomers of the compound, including enantiomers and diastereomers (e.g., those that may exist due to various substituent chiral carbons), are intended within the scope of the present invention. Individual stereoisomers of the compound of the present invention may, for example, be substantially free of other isomers (e.g., pure or substantially pure optical isomers having specific activity) or may be, for example, as a racemate or mixed with all other or other selected stereoisomers. The chiral centers of the present invention may have S or R configurations as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. Racemates can be decomposed by physical methods such as fractional crystallization, separation or crystallization of the diastereomer derivatives, or by separation by chiral column chromatography. Individual optical isomers may be obtained from the racemate by any suitable method, including, but not limited to, conventional methods such as salt formation with an optically active acid followed by crystallization.

[0165] The compounds of the present invention are, following their preparation, preferably isolated and purified to obtain a composition containing 90% or more by weight of the compound (for example, 95% or more, or 99% or more) ("substantially pure" compounds), which is then used or formulated as described herein. Such "substantially pure" compounds of the present invention are also intended to be part of the present invention.

[0166] The total configurational isomers of the compounds of the present invention are intended to be in mixed, pure, or substantially pure forms. The definition of the compounds of the present invention includes cis(Z) and trans(E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbons or heterocyclic rings.

[0167] Throughout this specification, groups and their substituents may be selected to provide stable moieties and compounds.

[0168] Definitions of specific functional groups and chemical terms are described in more detail here. For the purposes of this invention, chemical elements are defined in the periodic table, CAS version, Handbook of Chemistry and Physics, 75 th Definitions are made according to the ed. and the inside cover, and specific functional groups are generally defined as described therein. Furthermore, the general principles of organic chemistry, as well as specific functional parts and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito (1999), the entire content of which is incorporated herein by reference.

[0169] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. 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. Further chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0170] Isomer mixtures containing any of a variety of isomer ratios can be used in accordance with the present invention. For example, when combining only two isomers, mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are all intended by the present invention. Those skilled in the art will readily recognize that similar ratios are intended for more complex isomer mixtures.

[0171] The present invention also includes isotope-labeled compounds that are identical to the compounds disclosed herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively. 2 H, 3H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Contains Cl. Compounds of the present invention containing the above isotopes and / or other isotopes of other atoms, or their enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates, are within the scope of the present invention. A compound of the present invention labeled with a certain isotope, for example, 3 H and 14 Tritimination, i.e., the incorporation of radioactive isotopes such as 13C, is useful in drug and / or substrate tissue distribution assays. 3 H and carbon-14, that is, 14 C, isotopes are particularly preferred due to their ease of production and detectability. Furthermore, deuterium, i.e., 2 Substitution with heavier isotopes such as 1H can provide therapeutic advantages due to greater metabolic stability, such as extended in vivo half-life or reduced required dose, and is therefore preferable in certain situations. Isotope-labeled compounds can generally be produced by replacing unlabeled reactants with readily available isotope-labeled reactants and carrying out the methods described in the scheme and / or examples below.

[0172] For example, if a specific enantiomer of the compound of the present invention is desired, it can be produced by asymmetric synthesis or derivatization with a chiral auxiliary agent, separation of the resulting diastereomer mixture, and cleavage of the auxiliary group to obtain the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, a diastereomer salt is formed with a suitable optically active acid or base, and subsequently, the diastereomer thus formed is separated by fractional crystallization or chromatographic means known in the art to recover the pure enantiomer.

[0173] It is recognized that the compounds described herein may be substituted with a number of substituents or functional moieties. In general, the term “substitution” means the replacement of a hydrogen radical in a structure with a radical of a particular substituent, whether or not the substituents included in the term “optionally” and the formula of the present invention are described before or after. When one or more locations in a structure can be substituted with more than one substituent selected from a particular group, the substituents may be identical or different at all positions. The term “substitution” as used herein is intended to include all permissible substituents of an organic compound. In a broad embodiment, permissible substituents include cyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of the organic compound. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents that satisfy the valence of the heteroatom and / or any permissible substituent of the organic compound described herein. Furthermore, the present invention is intended not to be limited in any way by the permissible substituents of the organic compound. The combinations of substituents and variable groups conceived by the present invention preferably result in the formation of stable compounds useful, for example, for treating growth disorders. The term "stable" as used herein preferably means a compound that is stable enough to enable manufacturing and maintains its integrity for a sufficient period to be detected, preferably a sufficient period useful for the purposes detailed herein.

[0174] As used herein, the terms “cancer” and, similarly, “tumor” refer to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a subject. Cancer can be malignant or non-malignant. Cancer or tumors include, but are not limited to, adult T-cell leukemia / lymphoma (including those caused by human T-cell lymphotropic virus (HTLV-1)), cholangiocarcinoma; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (body) cancer; neoplasia in situ; 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; kidney cancer; sarcoma; skin cancer; testicular cancer; thyroid cancer; and other carcinomas and sarcomas. As used herein, the term “lymphoma” refers to cancers of the lymphatic system or blood cancers that develop from lymphocytes. Cancer can be primary or metastatic. Non-cancerous diseases may be associated with mutational alterations of elements of the Ras signaling pathway, and the compounds disclosed herein may be used to treat these non-cancerous diseases. Such non-cancerous diseases include neurofibromatosis; Leopard syndrome; Noonan syndrome; Regius syndrome; Costello syndrome; cardiac-facial-cutaneous syndromes; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndromes; and capillary malformations-arteriovenous malformations.

[0175] As used herein, "effective dose" refers to any amount necessary or sufficient to achieve or promote a desired outcome. In some cases, the effective dose is the therapeutic effective dose. The therapeutic effective dose is any amount necessary or sufficient to achieve or promote a desired biological response in a subject. The effective dose for a particular application may vary depending on factors such as the disease or condition being treated, the specific drug being administered, the subject's physique, or the severity of the disease or condition. A person skilled in the art can determine the effective dose of a particular drug by experience without the need for excessive experimentation.

[0176] The term "subject" as used herein refers to a vertebrate. In some embodiments, the subject is a mammal or a mammalian species. In some embodiments, 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, livestock, racehorses, domesticated animals, and undomesticated animals.

[0177] The term "immune cells" as used herein refers to cells of the innate and adaptive immune systems, including, but not limited to, lymphocytes such as neutrophils, eosinophils, basophils, glial cells (e.g., astrocytes, microglia, and oligodendrocytes), monocytes, macrophages, dendritic cells, B cells, T cells, and NK cells.

[0178] The term "conventional T cells" used herein refers to T lymphocytes that express the αβ T cell receptor ("TCR") and the co-receptor CD4 or CD8. Conventional T cells are found in peripheral blood, lymph nodes, and tissues. See Roberts and Girardi, “Conventional and Unconventional T Cells”, Clinical and Basic Immunodermatology, pp. 85-104, (Gaspari and Tyring (ed.)), Springer London (2008). The term "unconventional T cells" used herein refers to lymphocytes that express the γδ TCR and can commonly be found 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 possess the phenotype and functional capabilities of conventional T cells as well as the characteristics of natural killer cells (e.g., cytolytic activity). See the same literature. The regulatory T cells ("Treg") used herein are a subpopulation of T cells that modulate the immune system, maintain tolerance to autoantigens, suppress autoimmune diseases, and otherwise inhibit the immune stimuli or activation responses of other cells. Tregs exist in many forms, the most well understood being those expressing CD4, CD25, and Foxp3. The terms "native Treg" or "nTreg" used herein refer to Tregs or cells that develop in the thymus. The terms "inducible Treg" or "iTreg" used herein refer to Tregs or cells that develop outside the thymus from mature CD4+ conventional T cells.

[0179] The "activity" of Akt3 refers to the biological function of the Akt3 protein. Biological activity can be increased or decreased by changes in the basal level activity of the protein, changes in the basal level avidity of the protein, the amount of protein, the ratio of Akt3 to one or more other isoforms of Akt (e.g., Akt1 or Akt2) proteins, changes in the level of protein expression (including changes in the mRNA expression of Akt3), or a combination thereof. For example, a bioavailable Akt3 protein is a protein that has kinase activity, can bind to Akt3 substrates, and can be phosphorylated. A non-biovatable Akt3 protein is an Akt3 protein that is mislocalized or cannot bind to Akt substrates and cannot be phosphorylated.

[0180] In one embodiment, the disclosed compounds selectively modulate Akt3 compared to Akt1 and Akt2. In one embodiment, none of the disclosed compounds modulate Akt1 and Akt2 to a statistically significant degree. In another embodiment, the modification of Akt3 by the disclosed compounds is about 5, 10, 15, 50, 100, 1000, or 5000 times greater than the modification of Akt1 and / or Akt2.

[0181] The terms "peptide" and "polypeptide" used herein refer to amino acid chains of any length, regardless of modifications (e.g., phosphorylation or glucosylation). This term includes proteins and their fragments. Polypeptides are "exogenous," meaning they are foreign to the host cell from which they are utilized, such as human polypeptides produced by bacterial cells. Polypeptides are described here as amino acid residue sequences. These sequences are written from left to right, from the amino terminus to the carboxyl terminus. According to standard nomenclature, amino acid residue sequences are named with three-letter or one-letter codes, 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).

[0182] The term "stimulate expression" means, for example, inducing expression or activity, or influencing expression to induce increased / greater expression or activity compared to a normal, healthy control.

[0183] The terms “immunoactivating response,” “activated immune response,” and “immunostimulated response” refer to responses that initiate, induce, enhance, increase, or facilitate the activation of innate or adaptive immunity. Such immune responses include, for example, the development of beneficial humoral (antibody-mediated) and / or cellular (antigen-specific T cell or secretory product-mediated) responses to peptides in a recipient patient. Such responses may be active responses induced by immunogen administration or passive responses induced by antibody or sensitized T cell administration. Cellular immune responses are triggered by the presentation of polypeptide epitopes conjugated to 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 may also include the activation of monocytes, macrophages, NK cells, basophils, dendritic cells, astrocytes, microglia, eosinophils, neutrophils, or other components of innate immunity. The presence of a cell-mediated immunological response can be determined by a proliferation assay (CD4+ T cells) or a cytotoxic T lymphocyte ("CTL") assay. The relative contributions of humoral and cellular responses to the protective or therapeutic effect of an immunogen can be distinguished by separately isolating antibodies and T cells from immunized syngenes and measuring their protective or therapeutic effects in a second subject.

[0184] The terms "suppressive immune response" and "immunosuppressive response" refer to responses that reduce or prevent the activation or efficiency of innate or adaptive immunity.

[0185] The term "immune tolerance" refers to any mechanism that prevents, suppresses, or shifts a potentially harmful immune response to a non-harmful immune response (see Bach, et al., N. Eng. J. Med., 347:911-920 (2002)).

[0186] The term "immunogenic agent" or "immunogen" refers to a drug that, when administered to a mammal, can induce an immunological response, preferably in combination with an adjuvant.

[0187] compound In one embodiment, compounds of formula Ia, Ib, or Ic are described as Akt3 modulators. The applicant has surprisingly discovered that the compounds disclosed herein, depending on their structure and substitutions, modulate Akt3 activity, for example, by activating or inhibiting Akt3 activity and / or downstream events.

[0188] In one embodiment, formulas Ia, Ib, or Ic [ka] Compounds or pharmaceutically acceptable salts thereof are described. Here, [ka] teeth [ka] And, Each of X1, X2, X3, X4, X5, X6, X7, X8, and X9 is independently CR1 or N; R1 is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] and, if applicable, one or more (C1-C6) alkyl, halogenated (C1-C6) alkyl, -SO2R a or -SO2N(R a Selected from the group consisting of partially saturated bicyclic heteroaryls substituted with )2; Here, R1 is a (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl, and heteroaryl each may contain one or more (C1-C6)alkyl, halogenated (C1-C6)alkyl, halogen, -OR a -CN or -N(R a ) is replaced with 2; n is an integer between 0 and 4, depending on the valence; Q is C(R a )2, O, NR a , N(C=O)R a Or NSO2R a and; Y1, Y2, Y3, Y4, and Y5 are independently possible N or CR2 depending on their valence; R2 is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a CON(R a)2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] Selected from the group consisting of; -EG- is -(C=O)NR x -, -NR x (C=O)-, -N(R) x )(C=O)N(R x )-, -O(C=O)N(R x )-,-N(R x )(C=O)O-, -SO2NR x -, -NR x SO2- or [ka] And here R x In each case, is independently H, (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl; or R x and Y3, R x and Y4, R x and Z1 or R x And Z4 together form a 5-6 member heteroring which may be substituted; W1, W2, W3, W4, and W5 are each independently possible as CR6, N, or NR6 depending on their valence; In each case, R6 is independently selected from the group consisting of H, halogens, (C1-C6) alkyls, and (C1-C6) haloalkyls; T is possible in each case independently by valence for O, N, and NR. a , N(C=O)R a NC(R b )2OP(=O)(OR b )2 or NSO2R a and; U is possible in each case independently by valence: O, N, NR a , N(C=O)R aNC(R b )2OP(=O)(OR b )2 or NSO2R a and; R b In each case, is independently H or (C1-C6) alkyl; Z1, Z2, Z3, Z4, and Z5 are each independently possible as N or CR3 depending on their valence; R3 is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] Selected from the group consisting of; V is absent, C(R a )2, NR a , N(C=O)R a NSO2R a or O; R4 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10) Selected from the group consisting of heterospiroalkyl, aryl, and heteroaryl molecules, each possibly substituted with one or more R5 groups; Alternatively, V and R4 together form a (C3-C7) heterocycloalkyl or (C4-C 10 ) form heterospiroalkyl groups; R5 is independently H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , N(R a )COR a , [ka] Selected from the group consisting of; and R a In each case, H is independently of (C1-C6) alkyl, (C2-C6) alkenyl, (C3-C7) cycloalkyl, aryl, or heteroaryl, or two R a These together form a 4-6 membered ring, which may be substituted with a halogen or (C1-C6)alkyl group; However, compounds [ka] isn't it.

[0189] One explanation, [ka] teeth [ka] In one example, [ka] teeth [ka] In one example, [ka] teeth [ka] That is the case.

[0190] For one reason, Q is C(R a )2, O or NR a In one embodiment, Q is O. In another embodiment, Q is NR a In one embodiment, Q is NH. In one embodiment, Q is NCH3 or NCH2CH3. In one embodiment, Q is N(C=O)R a Or NSO2R a In one embodiment, Q is N(C=O)H. In one embodiment, Q is N(C=O)CH3 or N(C=O)CH2CH3. In one embodiment, Q is NSO2H. In one embodiment, Q is NSO2CH3 or NSO2CH2CH3.

[0191] In one embodiment, n is 0, 1, 2, 3, or 4. In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. In one embodiment, n is 4.

[0192] One explanation, [ka] teeth [ka] In one embodiment, X2, X3, and X4 are each independently CR1 or N. In one embodiment, X2, X3, and X4 are CR1. In one embodiment, X2, X3, and X4 are CH. In one embodiment, one of X2, X3, and X4 is N and the rest are CR1. In one embodiment, one of X2, X3, and X4 is N and the rest are CH. In one embodiment, two of X2, X3, and X4 are N and the rest are CR1. In one embodiment, two of X2, X3, and X4 are N and the rest are CH.

[0193] In one embodiment, substructure [ka] teeth [ka] It has the structure of [the object].

[0194] In one embodiment, substructure [ka] teeth [ka] It has the structure of [the object].

[0195] In one embodiment, substructure [ka] teeth [ka] It has the structure of [the object].

[0196] In one embodiment, X1, X2, X3, X4, X5, X6, and X7 are each independently CR1 or N. In one embodiment, X1, X2, X3, X4, X5, X6, and X7 are CR1. In one embodiment, X1, X2, X3, X4, X5, X6, and X7 are each independently CH or CCH3. In one embodiment, one of X1, X2, X3, X4, X5, X6, and X7 is N and the rest are CR1. In one embodiment, one of X1, X2, X3, X4, X5, X6, and X7 is N and the rest are each independently CH or CCH3. In one embodiment, two of X1, X2, X3, X4, X5, X6, and X7 are N and the rest are CR1. In one embodiment, two of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining ones are each independently CH or CCH3. In one embodiment, three of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining ones are CR1. In one embodiment, three of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining ones are each independently CH or CCH3. In one embodiment, four of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining ones are CR1. In one embodiment, four of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining ones are each independently CH or CCH3. In one embodiment, X2 is N, X7 is CR1, and X1, X3, X4, X5, and X6 are each independently CH or CCH3. In one embodiment, X2 is N, X7 is CR1, X3 is CCH3 and X1, X4, X5, and X6 are CH. In another embodiment, X2 and X7 are N and X1, X3, X4, X5, and X6 are CR1. In yet another embodiment, X2 and X7 are N and X1, X3, X4, X5, and X6 are each independently CH or CCH3.

[0197] In one embodiment, X2, X3, X4, X8, and X9 are each independently CR1 or N. In one embodiment, X2, X3, X4, X8, and X9 are CR1. In one embodiment, X2, X3, X4, X8, and X9 are each independently CH or CCH3. In one embodiment, one of X2, X3, X4, X8, and X9 is N and the rest are CR1. In one embodiment, one of X2, X3, X4, X8, and X9 is N and the rest are each independently CH or CCH3. In one embodiment, two of X2, X3, X4, X8, and X9 are N and the rest are CR1. In one embodiment, two of X2, X3, X4, X8, and X9 are N and the rest are each independently CH or CCH3. In one embodiment, three of X2, X3, X4, X8, and X9 are N and the rest are CR1. In one embodiment, three of X2, X3, X4, X8, and X9 are N, and the remaining ones are each independently CH or CCH3. In another embodiment, four of X2, X3, X4, X8, and X9 are N, and one is CR1. In yet another embodiment, four of X2, X3, X4, X8, and X9 are N, and one is CH or CCH3.

[0198] In one embodiment, substructure [ka] teeth [ka] It has the structure of [the object].

[0199] In one embodiment, substructure [ka] teeth [ka] It has the structure of . In one embodiment, Q is O. In one embodiment, Q is NR a , N(C=O)R aOr NSO2R a In one embodiment, Q is NH. In another embodiment, Q is NCH3 or NCH2CH3.

[0200] In one embodiment, substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the structure of . In one embodiment, Q is O. In one embodiment, Q is NR a , N(C=O)R a Or NSO2R a In one embodiment, Q is NH. In another embodiment, Q is NCH3 or NCH2CH3.

[0201] In one embodiment, substructure [ka] teeth [ka] It has the structure of [the object].

[0202] In one embodiment, substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the structure of [the object].

[0203] In one embodiment, substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the structure of . In one embodiment, Q is O. In one embodiment, Q is NR a , N(C=O)R a Or NSO2R a In one embodiment, Q is NH. In another embodiment, Q is NCH3 or NCH2CH3.

[0204] In one embodiment, R1 is independently H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR a , -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 Selected from the group consisting of; where (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl, and heteroaryl are each optionally substituted with one or more (C1-C6)alkyl groups. In one embodiment, R1 is independently in each case (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 ) Selected from the group consisting of heterobicycloalkyl groups; where (C3-C7)cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl and (C4-C 10 )Heterobicycloalkyls are each substituted with one or more (C1-C6)alkyl groups, depending on the case.In one embodiment, R1 is independently (C4-C 10 ) Selected from the group consisting of heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, and heteroaryl; where (C4-C 10 ) Heterospiroalkyl, aryl, and heteroaryl are each optionally substituted with one or more (C1-C6) alkyl groups. In one embodiment, R1 is independently -OR in each case. 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 Selected from the group consisting of. In one embodiment, R1 is independently in each case [ka] 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, -SO2Ra or -SO2N(R a )2; where (C3-C7) heterocycloalkyl, (C4-C 10 )heterospiroalkyl, aryl and (C4-C 10 Each bicycloalkyl is optionally substituted with one or more (C1-C6)alkyl groups. In one embodiment, R1 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; where (C3-C7) heterocycloalkyl and (C4-C 10 Each heterospiroalkyl is optionally substituted with one or more (C1-C6)alkyl groups. In one embodiment, R1 is independently H, (C1-C6)alkyl, (C1-C6)alkynyl, aryl, or (C4-C 10 ) Bicycloalkyl, -SO2R a or -SO2N(R a )2; where aryl and (C4-C 10 Each bicycloalkyl is optionally substituted with one or more (C1-C6)alkyl groups. In one embodiment, at least one of R1 is optionally substituted with one or more (C1-C6)alkyl groups (C4-C 10 ) is a heterospiroalkyl. In one embodiment, at least one of R1 is optionally substituted with one or more (C1-C6) alkyl groups, and is a halogenated (C3-C7) heterocycloalkyl. In one embodiment, R1 is independently H, D, F, Cl, Br, CH3, OCH3, NH2, NHCH3, N(CH3)2, [ka] And here, R a ' is H or (C1-C6) alkyl. In one embodiment, R1 is independently H, D, F, CH3, N(CH3)2 in each case. [ka] And here, R a ' is H or (C1-C6) alkyl. In one embodiment, R1 is independently in each case [ka] That is the case.

[0205] In one embodiment, R1 is a (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl, and heteroaryl each may contain one or more halogens, -OR a -CN or -N(R a ) is replaced with 2.

[0206] In one embodiment, at least one of R1 is [ka] In one example, [ka] teeth [ka] That is the case.

[0207] In one embodiment, at least one of R1 is optionally one or more (C1-C6) alkyl, halogenated (C1-C6) alkyl, -SO2R a or -SO2N(R aIt is a partially saturated bicyclic heteroaryl substituted with )2. In one embodiment, at least one of R1 is H, D or a halogen. In one embodiment, at least one of R1 is H. In one embodiment, at least one of R1 is D. In one embodiment, at least one of R1 is F. In one embodiment, at least one of R1 is CH3. In one embodiment, at least one of R1 is OCH3. In one embodiment, at least one of R1 is NH2. In one embodiment, at least one of R1 is NHCH3. In one embodiment, at least one of R1 is N(CH3)2. In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] And here, R a ' is H or (C1-C6) alkyl. In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] And here, R a ' is H or (C1-C6) alkyl. In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is -CN. In one embodiment, at least one of R1 is -NC. In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is NO2. In one embodiment, at least one of R1 is N3. In one embodiment, at least one of R1 is [ka] In one embodiment, at least one of R1 is [ka] That is the case.

[0208] In one embodiment, substructure [ka] teeth [ka] [ka] [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the structure of [the object].

[0209] In one embodiment, substructure [ka] teeth [ka] It has the structure, where Q is O or NH. In one embodiment, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH. In one embodiment, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH. In one embodiment, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH. In one embodiment, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH. In one embodiment, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH. In one embodiment, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH. In one embodiment, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH. In one embodiment, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH. In one embodiment, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH.

[0210] In one embodiment, substructure [ka] teeth [ka] The structure is such that Q is O or NH, and R1 is H, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, halogenated (C3-C7) heterocycloalkyl, or halogen. In one embodiment, the substructure [ka] teeth [ka] The structure is such that Q is O or NH and R1 is H, D, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, F, Cl, or Br. In one embodiment, the substructure [ka] teeth [ka] It has the structure shown, where Q is O or NH and R1 is methyl or Cl.

[0211] In one embodiment, substructure [ka] teeth [ka] It has the structure, where Q is O or NH. In one embodiment, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH. In one embodiment, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH. In one embodiment, a substructure [ka] teeth [ka] It has the structure, where Q is O or NH.

[0212] In one embodiment, substructure [ka] teeth [ka] It has the structure, where Q is O or NH. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the following structure. In one embodiment, Q is O or NH.

[0213] In one embodiment, the compound has the structure of formula Ia.

[0214] In one embodiment, Y1, Y2, Y3, Y4, and Y5 are each independently CR2 or N. In one embodiment, Y1, Y2, Y3, Y4, and Y5 are each CR2. In one embodiment, Y1, Y2, Y3, Y4, and Y5 are each CH. In one embodiment, Y1, Y2, Y3, Y4, and Y5 are each N. In one embodiment, one of Y1, Y2, Y3, Y4, and Y5 is CR2 and the rest are N. In one embodiment, one of Y1, Y2, Y3, Y4, and Y5 is CH and the rest are N. In one embodiment, two of Y1, Y2, Y3, Y4, and Y5 are CR2 and the rest are N. In one embodiment, two of Y1, Y2, Y3, Y4, and Y5 are CH and the rest are N. In one embodiment, three of the elements Y1, Y2, Y3, Y4, and Y5 are CR2, and two of the elements Y1, Y2, Y3, Y4, and Y5 are N. In another embodiment, three of the elements Y1, Y2, Y3, Y4, and Y5 are CH, and two of the elements Y1, Y2, Y3, Y4, and Y5 are N.

[0215] In one embodiment, substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the structure of [the object].

[0216] In one embodiment, R2 is independently H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR a , -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 The group consisting of the following is selected. In one embodiment, R2 is independently selected in each case 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 ) Selected from the group consisting of heterobicycloalkyl groups. In one embodiment, R2 is independently (C4-C 10 ) Selected from the group consisting of heterospiroalkyls, halogenated (C3-C7) heterocycloalkyls, aryls, and heteroaryls. In one embodiment, R2 is independently -OR in each case. 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 Selected from the group consisting of. In one embodiment, R2 is independently in each case [ka] 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 one embodiment, R2 is independently H, D, halogen, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, N(R a )2 or -CN. In one embodiment, R2 is independently H, (C1-C6)alkyl, (C1-C6)alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -SO2R a or -SO2N(R a )2. In one embodiment, R2 is independently H, D, F, Cl, Br, CH3, OCH3, NH2, N(CH3)2 in each case. [ka] In one embodiment, R2 is independently H, D, F, CH3, N(CH3)2 in each case. [ka] That is the case.

[0217] In one embodiment, at least one of R2 is H, D or halogen. In one embodiment, at least one of R2 is H. In one embodiment, at least one of R2 is D. In one embodiment, at least one of R2 is F. In one embodiment, at least one of R2 is CH3. In one embodiment, at least one of R2 is OCH3. In one embodiment, at least one of R2 is NH2. In one embodiment, at least one of R2 is N(CH3)2. In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] And here, Ra ' is H or (C1-C6) alkyl. In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] , here, R a ' is H or (C1-C6) alkyl. In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is -CN. In one embodiment, at least one of R2 is -NC. In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is NO2. In one embodiment, at least one of R2 is N3. In one embodiment, at least one of R2 is [ka] In one embodiment, at least one of R2 is [ka] That is the case.

[0218] In one embodiment, R2 is independently H, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, -N(R) a )2, NO2 and -OR aSelected from the group consisting of the following. In one embodiment, R2 is independently H, halogen, CH3, CF3, OH, NH2, -NHCH3 or -N(CH3)2 in each case. In one embodiment, at least one of R2 is H. In one embodiment, at least one of R2 is (C1-C6)alkyl. In one embodiment, at least one of R2 is -N(R a )2, NO2 or -OR a In one embodiment, at least one of R2 is H, CH3, OH, NH2, or a halogen. In one embodiment, at least one of R2 is H. In one embodiment, at least one of R2 is CF3. In one embodiment, R2 is H or CH3.

[0219] In one embodiment, substructure [ka] teeth [ka] It has the structure of [the object].

[0220] In one embodiment, Z1, Z2, Z3, Z4, and Z5 are each independently CR3 or N. In one embodiment, Z1, Z2, Z3, Z4, and Z5 are each independently CR3. In one embodiment, Z1, Z2, Z3, Z4, and Z5 are each independently CH. In one embodiment, Z1, Z2, Z3, Z4, and Z5 are each N. In one embodiment, one of Z1, Z2, Z3, Z4, and Z5 is CR3 and the rest are N. In one embodiment, one of Z1, Z2, Z3, Z4, and Z5 is CH and the rest are N. In one embodiment, two of Z1, Z2, Z3, Z4, and Z5 are CR3 and the rest are N. In one embodiment, two of Z1, Z2, Z3, Z4, and Z5 are CH and the rest are N. In one embodiment, three of Z1, Z2, Z3, Z4, and Z5 are CR3 and two are N. In another embodiment, three of Z1, Z2, Z3, Z4, and Z5 are CH and two are N. In yet another embodiment, Z4 is N and Z1, Z2, Z3, and Z5 are CR3.

[0221] In one embodiment, substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the structure of [the object].

[0222] In one embodiment, substructure [ka] teeth [ka] It has the structure of [the object].

[0223] In one embodiment, substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the structure of these embodiments. [ka] teeth [ka] It has the structure of [the object].

[0224] One reason, R x In each case, is independently H, (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl; or R x and Y2, R x and Y3, R x and Z1 or R x And Z4 together form a 5-6 member heteroring which may be substituted. In one embodiment, R x In each case, R is independently H, (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl. In one embodiment, R x In each case, R is independently H, CH3, or CH2CH3. In one embodiment, R x And Y2 together form a 5-6 membered heteroring which may be substituted. In one embodiment, R x And Y3 together form a 5-6 membered heteroring which may be substituted. In one embodiment, R x And Z1 together form a 5-6 member heteroring which may be substituted. In one embodiment, R x And Z4 together form a 5-6 member heteroring, which may be substituted in some cases.

[0225] In one embodiment, substructure [ka] teeth [ka] It has the structure of [the object].

[0226] In one embodiment, W1, W2, W3, W4, and W5 are each independently possible CR6, N, or NR6 depending on their valence. In one embodiment, one of W1, W2, W3, W4, and W5 is possible N or NR6 depending on its valence, and the rest are C or CR6. In one embodiment, two of W1, W2, W3, W4, and W5 are possible N or NR6 depending on their valence, and the rest are C or CR6. In one embodiment, three of W1, W2, W3, W4, and W5 are possible N or NR6 depending on their valence, and two are C or CR6. In one embodiment, one of W1, W2, W3, W4, and W5 is possible N depending on its valence, and the rest are C or CR6. In one embodiment, two of W1, W2, W3, W4, and W5 are possible N depending on their valence, and the rest are C or CR6. In one embodiment, three of W1, W2, W3, W4, and W5 are N, which is possible by valence, and two are C or CR6.

[0227] In one embodiment, R6 is independently selected in each case from the group consisting of H, halogens, (C1-C6)alkyls and (C1-C6)haloalkyls. In another embodiment, R6 is independently selected in each case from the group consisting of H, F, CH3 and CH2CH3.

[0228] In one embodiment, substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the structure of [the object].

[0229] In one embodiment, substructure [ka] teeth [ka] It has the structure of [the object].

[0230] In one embodiment, substructure [ka] teeth [ka] It has the following structure. In one embodiment, R3 is H, CH3, OH, halogen or NH2. In one embodiment, R x The group is H, CH3, or CH2CH3.

[0231] In one embodiment, substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the structure of . In one embodiment, m is independently 1 or 2 in each case, and J is C(R y )2, R y In each case, m is independently H, (C1-C6) alkyl, OH, O(C1-C6) alkyl, or halogen. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, R y In each case, R is independently H or (C1-C6) alkyl. In one embodiment, R y In each case, R is independently OH, O(C1-C6) alkyl, or halogen. In one embodiment, R y In each case, H is the case.

[0232] In one embodiment, substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the following structure. In one embodiment, Y1, Y2, Y3, and Y4 are each independently N, CH, CCH3, or CF. In another embodiment, Y1, Y2, Y3, and Y4 are each independently N or CH.

[0233] In one embodiment, substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the structure of . In one embodiment, m is independently 1 or 2 in each case, and J is C(R z )2, R zIn each case, m is independently H, (C1-C6) alkyl, OH, O(C1-C6) alkyl, or halogen. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, R z In each case, R is independently H or (C1-C6) alkyl. In one embodiment, R z In each case, R is independently OH, O(C1-C6) alkyl, or halogen. In one embodiment, R z In each case, H is the case.

[0234] In one embodiment, substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the following structure. In one embodiment, Z1, Z2, Z3, and Z4 are each independently N, CH, CCH3, or CF. In another embodiment, Z1, Z2, Z3, and Z4 are each independently N or CH.

[0235] In one embodiment, the compound has the structure of formula Ib.

[0236] In one embodiment, T is N(C=O)R a Or NSO2R a In one embodiment, T is N(C=O)Me or N(C=O)Et. In another embodiment, T is NSO2Me or NSO2Et. In another embodiment, T is O or NR a In one embodiment, T is O. In another embodiment, T is NR a In one embodiment, T is NH. In one embodiment, T is NCH3 or NCH2CH3. In one embodiment, T is NC(R b )2OP(=O)(OR b )2.

[0237] In one embodiment, U is N(C=O)R a Or NSO2R a In one embodiment, U is N(C=O)Me or N(C=O)Et. In one embodiment, U is NSO2Me or NSO2Et. In one embodiment, U is O or NR a In one embodiment, U is O. In one embodiment, U is NR a In one embodiment, U is NH. In one embodiment, U is NCH3 or NCH2CH3. In one embodiment, U is NC(R b )2OP(=O)(OR b )2.

[0238] One reason, R b In each case, R is independently H or (C1-C6) alkyl. In one embodiment, R b In each case, independently is H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl. In one embodiment, R b In each case, R is independently either H or CH3. In one embodiment, R b In each case, H is the case.

[0239] In one embodiment, substructure [ka] teeth [ka] It has the structure, where T and U are independently possible by valence in each case: O, N, NR a , N(C=O)R a NC(R b )2OP(=O)(OR b )2 or NSO2R a That is the case.

[0240] In one embodiment, substructure [ka] teeth [ka] It has the structure of . In one embodiment, R3 is H, CH3, OH, halogen or NH2; and R a The group is H, CH3, or CH2CH3.

[0241] In one embodiment, substructure [ka] teeth [ka] has the structure of. In certain embodiments, the substructure

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

[0242] In certain embodiments, the compound has the structure of Formula Ic.

[0243] In certain embodiments, the substructure

Chemical Formula

Chemical Formula

[0244] In certain embodiments, the substructure

Chemical Formula

Chemical Formula

[0245] In certain embodiments, the partial structure

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0246] In certain embodiments, R3 is independently H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR a , -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 The group consisting of the following is selected. In one embodiment, R3 is independently selected in each case 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 ) Selected from the group consisting of heterobicycloalkyl groups. In one embodiment, R3 is independently (C4-C 10 ) Selected from the group consisting of heterospiroalkyls, halogenated (C3-C7) heterocycloalkyls, aryls, and heteroaryls. In one embodiment, R3 is independently -OR in each case. 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 Selected from the group consisting of. In one embodiment, R3 is independently in each case [ka] 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 one embodiment, R3 is independently H, D, halogen, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, N(R a )2 or -CN. In one embodiment, R3 is independently H, (C1-C6)alkyl, (C1-C6)alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -SO2R a or -SO2N(R a )2. In one embodiment, R3 is independently H, D, F, Cl, Br, CH3, OCH3, NH2, N(CH3)2 in each case. [ka] In one embodiment, R3 is independently H, D, F, CH3, N(CH3)2 in each case. [ka] That is the case.

[0247] In one embodiment, at least one of R3 is H, D or halogen. In one embodiment, at least one of R3 is H. In one embodiment, at least one of R3 is D. In one embodiment, at least one of R3 is F. In one embodiment, at least one of R3 is CH3. In one embodiment, at least one of R3 is OCH3. In one embodiment, at least one of R3 is NH2. In one embodiment, at least one of R3 is N(CH3)2. In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] And here, R a ' is H or (C1-C6) alkyl. In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] And here, R a ' is H or (C1-C6) alkyl. In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is -CN. In one embodiment, at least one of R3 is -NC. In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is NO2. In one embodiment, at least one of R3 is N3. In one embodiment, at least one of R3 is [ka] In one embodiment, at least one of R3 is [ka] That is the case.

[0248] In one embodiment, R3 is independently H, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, -N(R) a )2, NO2 and -OR a Selected from the group consisting of: In one embodiment, at least one of R3 is H, CH3, OH, NH2, or a halogen. In one embodiment, at least one of R3 is H or CH3. In one embodiment, at least one of R3 is OH or NH2. In one embodiment, at least one of R3 is a halogen. In one embodiment, at least one of R3 is H. In one embodiment, at least one of R3 is CF3. In one embodiment, R3 is H or CH3.

[0249] In one embodiment, V is absent, O or NR a In one instance, V is absent. In one instance, V is O. In one instance, V is NR aIn one embodiment, V is NH. In another embodiment, V is NCH3 or NCH2CH3.

[0250] In one embodiment, V is N(C=O)R a Or NSO2R a In one embodiment, V is N(C=O)H. In one embodiment, V is N(C=O)CH3 or N(C=O)CH2CH3. In one embodiment, V is NSO2H. In one embodiment, V is NSO2CH3 or NSO2CH2CH3.

[0251] In one embodiment, substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the structure of [the object].

[0252] In one embodiment, the structural part [ka] V and R4 are integrated into (C4-C 10 ) Forms heterospiroalkyl groups.

[0253] In one embodiment, R4 is optionally substituted with one or more R5 atoms: (C1-C6) alkyl, (C3-C7) cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) is selected from the group consisting of heterobicycloalkyl, aryl, and heteroaryl. In one embodiment, R4 is substituted with 0, 1, 2, 3, 4, 5, or 6 R5 substituents, where each R5 is independently H, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 ) Bicycloalkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, N(R a )COR a , -COR a , -CO2R a CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] Selected from the group consisting of. In one embodiment, R4 is [ka] And here, [ka] In this, R5 may be bonded to any position of the bicycloalkyl or heterobicycloalkyl group containing the bridgehead carbon. [ka] In this configuration, R5 may be bonded to any ring, such as in an available position. In one embodiment, R4 [ka] In one example, R4 is [ka] In one example, R4 is [ka] In one example, R4 is [ka] In one example, R4 is [ka] In one example, R4 is [ka] In one example, R4 is [ka] In one example, R4 is [ka] In one embodiment, m is an integer between 0 and 3. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 3.

[0254] In one embodiment, substructure [Chemical] is [Chemical] has the structure of. In certain embodiments, V is C(R a )2, O, NR a , N(C=O)R a or NSO2R a . In certain embodiments, V’ is CR a or N.

[0255] In certain embodiments, R5 is independently in each case H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 )heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, aryl, heteroaryl, -OR a , -N(R a )2, -COR a , -CO2R a , N(R a )COR a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a is selected from the group consisting of. In certain embodiments, R5 is independently in each case (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) Selected from the group consisting of heterobicycloalkyl groups. In one embodiment, R5 is independently (C4-C 10 ) Selected from the group consisting of heterospiroalkyls, halogenated (C3-C7) heterocycloalkyls, aryls, and heteroaryls. In one embodiment, R5 is independently -OR in each case. a , -SR a , -N(R a )2, -COR a , -CO2R a CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , N(R a )COR a , -SO2N(R a )2 and -N(R a )SO2R a Selected from the group consisting of. In one embodiment, R5 is independently in each case [ka] 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 , N(R a )COR a or -SO2N(R a )2. In one embodiment, R5 is independently H, D, halogen, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, N(R a )COR a , N(R a )2 or -CN. In one embodiment, R5 is independently H, (C1-C6)alkyl, (C1-C6)alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -SO2Ra or -SO2N(R a )2. In one embodiment, R5 is independently H, D, F, Cl, Br, CH3, CF3, OCH3, NH2, N(CH3)2 in each case. [ka] In one embodiment, R5 is independently H, D, F, CH3, N(CH3)2 in each case. [ka] That is the case.

[0256] In one embodiment, at least one of R5 is H, D or halogen. In one embodiment, at least one of R5 is H. In one embodiment, at least one of R5 is D. In one embodiment, at least one of R5 is F. In one embodiment, at least one of R5 is CH3. In one embodiment, at least one of R5 is OCH3. In one embodiment, at least one of R5 is NH2. In one embodiment, at least one of R5 is N(CH3)2. In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] And here, R a ' is H or (C1-C6) alkyl. In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] And here, R a ' is H or (C1-C6) alkyl. In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is -CN. In one embodiment, at least one of R5 is -NC. In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is NO2. In one embodiment, at least one of R5 is N3. In one embodiment, at least one of R5 is [ka] In one embodiment, at least one of R5 is [ka] That is the case.

[0257] In one embodiment, R5 is independently a halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, OR a , -N(R a )2, -COR a , -CO2R a CON(R a )2, -N(R a )COR a -CN, NO2, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] Selected from the group consisting of the following. In one embodiment, at least one of R5 is (C1-C6) alkyl, halogen, OH, NH2 or [ka] In one embodiment, at least one of R5 is CH3, halogen, OH or NH2. In one embodiment, at least one of R5 is OH. In one embodiment, at least one of R5 is CH3. In one embodiment, at least one of R5 is [ka] That is the case.

[0258] In any of the embodiments described herein, R a In each case, is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C7)cycloalkyl, aryl, or heteroaryl. In any of the embodiments described herein, R a At least one of them is aryl or heteroaryl. In any of the embodiments described herein, R a In each case, is independently H, (C1-C6) alkyl, (C2-C6) alkenyl or (C3-C7) cycloalkyl or two R a These together form a 5-membered or 6-membered ring which may be substituted with a halogen or (C1-C6)alkyl group. In one embodiment, R a In each case, R is independently H or (C1-C6) alkyl. In one embodiment, R a In each case, R is independently a (C2-C6) alkenyl. In one embodiment, R a In each case, R is independently H, CH3, or CH2CH3. In one embodiment, R a At least one of them is H or CH3. In one embodiment, R a In each case, H is the case. In one embodiment, R a In each case, is CH3. In one embodiment, R a At least one of them is a (C3-C7) cycloalkyl which is optionally substituted with a halogen or a (C1-C6) alkyl. In one embodiment, R a At least one of them is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which may be substituted with a halogen or (C1-C6) alkyl group.

[0259] In one embodiment, substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has a structure. In one embodiment, a substructure [ka] teeth [ka] It has the structure of [the object].

[0260] In one embodiment, the compound of formula Ia [ka] [ka] [ka] It has the structure, where R1 is H, (C1-C6) alkyl, N(R a )2, (C3-C7) heterocycloalkyl or halogen; R5 and R 11 Each is independently H or CH3; Y1, Y2, Y3, Y4, Z1, Z2, Z3, Z4, L1 and L2 are each independently CH or N; and V is NH or O. In one embodiment, the compound of formula Ia [ka] [ka] It has the structure, where R1 is H, (C1-C6) alkyl, N(R a )2, (C3-C7) heterocycloalkyl or halogen; R5 and R 11Each is independently H or CH3; Y1, Y2, Y3, Y4, Z1, Z2, Z3, Z4, L1 and L2 are each independently CH or N; and V is NH or O. In one embodiment, the compound of formula Ia [ka] [ka] It has the structure, where R1 is H, (C1-C6) alkyl, N(R a )2, (C3-C7) heterocycloalkyl or halogen; R5 and R 11 Each is independently H or CH3; Y1, Y2, Y3, Y4, Z1, Z2, Z3, Z4, L1 and L2 are each independently CH or N; and V is NH or O. In one embodiment, R1 is H, F, Cl, Br, CH3, CH2CH3, CH(CH3)2, NH2, NMe2, [ka] In one embodiment, R1 is [ka] In one embodiment, R1 is [ka] That is the case.

[0261] In one embodiment, the compound of formula Ib has structure [ka] It has, and here, R 11 And R5 are each independently H or CH3; and Y1, Y2, Y3, Y4, Z2, Z3 and Z4 are each independently CH or N. In one embodiment, the compound of formula Ib has structure [ka] It has, and here, R 11 And R5 are each independently H or CH3; and Y1, Y2, Y3, Y4, Z2, Z3 and Z4 are each independently CH or N. In one embodiment, the compound of formula Ib has structure [ka] It has, and here, R 11 And R5 are each independently H or CH3; and Y1, Y2, Y3, Y4, Z2, Z3 and Z4 are each independently CH or N.

[0262] In one embodiment, compounds of formula Ia, Ib, or Ic activate Akt3, [ka] A compound is selected from the group consisting of the following. In one embodiment, a compound of formula Ia, Ib, or Ic activates Akt3 and is selected from the group consisting of compounds 3, 6, 26, 31, 59, 61, 65, and 106 shown in Table 2.

[0263] In one embodiment, compounds of formula Ia, Ib, or Ic inhibit Akt3, [ka] Selected from the group consisting of; where R1 and R5 are independently H, (C1-C6) alkyl, or halogen; R 11 is H or CH3; Y1, Y2, Y3, Y4, Z1, Z2, Z3, Z4, L1 and L2 are each independently CH or N; and V is NH or O. In one embodiment, the compounds of formula Ia, Ib or Ic inhibit Akt3 and are selected from the group consisting of compounds 4-5, 10, 21, 38, 67, 97, 99, 107-114, 118-120 and 125-132 shown in Table 1. In one embodiment, the compounds of formula Ia, Ib or Ic inhibit Akt3, [ka] [ka] [ka] [ka] It is selected from the group consisting of the following.

[0264] In one embodiment, the compound of formula Ia [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] That is the case.

[0265] In one embodiment, the compound of formula Ia [ka] Here, R1 is -CONH2, -SO2NH2, -SO2CH3 or [ka] That is the case.

[0266] In one embodiment, the compound of formula Ia [ka] Here, R1 is -CN or -F, and G1 and G2 are -N- and -CH- or -CH- and -N-.

[0267] In one embodiment, the compound of formula Ia [ka] Here, R1 is -CONH2, -SO2NH2, -SO2CH3 or [ka] Thus, each of J1, J2, J3, J4, J5, and J6 is independently -N- or -CF.

[0268] In one embodiment, the compound of formula Ib [ka] [ka] [ka] [ka] That is the case.

[0269] In one embodiment, the compound of formula Ic is [ka] That is the case.

[0270] In one embodiment, the compound [ka] [ka] [ka] That is the case.

[0271] In one embodiment, each compound is selected from the group consisting of compounds 2-5, 7-30, 32-101, and 105-136 in Examples 2-5, 7-30, 32-101, and 105-136.

[0272] In one embodiment, the compound is selected from the group consisting of compounds 4-5, 10, 21, 38, 67, 97, 99, 107-114, 118-120, and 125-132 shown in Table 1.

[0273] In one embodiment, the compound is selected from the group consisting of compounds 3, 6, 26, 31, 59, 61, 65, and 106 shown in Table 2.

[0274] Prodrug In some embodiments, any of the compounds described herein can be made into a prodrug by attaching a cleavable moiety to one or more of its functional groups. See, for example, J. Med. Chem., Vol. 61, pp. 62-80 (2018); J. Med. Chem., Vol. 61, pp. 6308-6327 (2018); and J. Med. Chem., Vol. 61, pp. 3918-3929 (2018). In some embodiments, the moiety is cleavable by exposure to an irritant. Non-limiting examples of such irritants include temperature, electromagnetic radiation, sonic vibration, pH, solvents, and processes observed on or within substances and living organisms. In some embodiments, the cleavable moiety is removed by contact with living organisms. In some embodiments, the cleavable moiety is removed by contact with enzymes. In some embodiments, the cleavable moiety is removed by contact with alkaline phosphatase. In one embodiment, the cleavable portion is a phosphonooxymethyl portion that is cleaved as described in Scheme A below. [ka]

[0275] How to adjust Akt3 Akt3, also known as RAC-gammaserine / threonine-protein kinase, is an enzyme encoded by the Akt3 gene in humans. Akt kinases are regulators of insulin and growth factor-responsive cell signaling and are known to be involved in a wide range of biological processes, including but not limited to cell proliferation, differentiation, apoptosis, tumorigenesis, 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").

[0276] Akt3 kinase activity mediates serine and / or threonine phosphorylation of a range of downstream substrates. The nucleic acid sequence of Akt3 is known in this field. For example, see Genbank accession no. AF124141.1: Homo sapiens protein kinase B gamma mRNA, complete cds, which includes the entire sequence by reference: 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 TGCTGTTGCTGCTACT GTCTTACTATTA (Sequence ID 1).

[0277] The amino acid sequence of Akt3 is also known in this field. For example, see UniProtKB / Swiss-Prot accession no. Q9Y243 (Akt3_HUMAN), which includes the entire sequence by citation and provides the following amino acid sequence: MSDVTIVKEGWVQKRGEYIKNWRPRYFLLKTDGSFIGYKEKPQDVDLPYPLNNFSVAKCQ LMKTERPKPNTFIIRCLQWTTVIERTFHVDTPEEREEWTEAIQAVADRLQRQEEERMNCS PTSQIDNIGEEEMDASTTHHKRKTMNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILK KEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNGGELFFHLSRE RVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLKLENLMLDKDGHIKITDFGLCKEGITDA ATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILM EDIKFPRTLSSDAKSLLSGLLIKDPNKRLGGGPDDAKEIMRHSFFSGVNWQDVYDKKLVP PFKPQVTSETDTRYFDEEFTAQTITITPPEKYDEDGMDCMDNERRPHFPQFSYSASGRE (Sequence ID 2).

[0278] The domain structure of Akt3 was reviewed in Romano, Scientifica, Volume 2013 (2013), Article ID 317186, p. 12, and includes an N-terminal plextrin homology domain ("PH"), followed by a catalytic kinase domain ("KD") and a C-terminal regulatory hydrophobic region. Both the KD and regulatory domains are important for the biological actions mediated by Akt protein kinases and exhibit the highest degree of homology among the three Akt isoforms. The PH domain binds to lipid substrates such as phosphatidylinositol (3,4) diphosphate ("PIP2") and phosphatidylinositol (3,4,5) triphosphate ("PIP3"). The ATP-binding site is located almost in the center of the catalytic kinase domain and exhibits a considerable degree of homology with other elements of the AGC kinase family, such as p70 S6 kinase ("S6K"), p90 ribosomal S6 kinase ("RSK"), protein kinase A ("PKA"), and protein kinase B ("PKB"). The hydrophobic regulatory moiety is a typical characteristic of the AGC kinase family. Sequence ID No. 2, Akt 3 is generally thought to have the molecular processing and domain structure outlined below. [Table 1]

[0279] The initiation methionine in SEQ ID NO: 2 is disposable in Akt3 function. Therefore, in one embodiment, the compound directly or indirectly regulates the expression or bioavailability of Akt3 having the following amino acid sequence: SDVTIVKEGWVQKRGEYIKNWRPRYFLLKTDGSFIGYKEKPQDVDLPYPLNNFSVAKCQ LMKTERPKPNTFIIRCLQWTTVIERTFHVDTPEEREEWTEAIQAVADRLQRQEEERMNCS PTSQIDNIGEEEMDASTTHHKRKTMNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILK KEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNGGELFFHLSRE RVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLKLENLMLDKDGHIKITDFGLCKEGITDA ATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILM EDIKFPRTLSSDAKSLLSGLLIKDPNKRLGGGPDDAKEIMRHSFFSGVNWQDVYDKKLVP PFKPQVTSETDTRYFDEEFTAQTITITPPEKYDEDGMDCMDNERRPHFPQFSYSASGRE (Sequence ID 3).

[0280] Two specific sites, one in the kinase domain (Thr-305, see SEQ ID NO: 2) and the other in the C-terminal regulatory region (Ser-472, see SEQ ID NO: 2), need to be phosphorylated for Akt3 to be fully activated. The interaction between the PH domain of Akt3 and TCL1A enhances Akt3 phosphorylation and activation. IGF-1 leads to the activation of Akt3, which may play a role in regulating cell survival.

[0281] In one embodiment, the compounds of formula Ia, Ib, or Ic described herein are inhibitors of Akt3. In another embodiment, the compounds of formula Ia, Ib, or Ic described herein are activators of Akt3.

[0282] Pharmaceutical composition Some aspects of the present invention involve administering an effective amount of a composition to a subject in order to achieve a specific outcome. Small molecule compositions useful by the method of the present invention can therefore be formulated by any method suitable for pharmaceutical use.

[0283] The formulation of the present invention is administered in a pharmaceutically acceptable solution that may contain a salt, buffer, preservative, compatible carrier, adjuvant, and optionally other therapeutic components at concentrations conventionally accepted in the pharmaceutical field.

[0284] For therapeutic use, an effective amount of the compound may be administered to the subject by any method that allows the compound to be taken up by appropriate target cells. “Administration” of 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 patch), non-enteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, intrarectal, vaginal, etc.). Injections may be bolus or continuous infusions.

[0285] For example, the pharmaceutical compositions of the present invention may be administered intravenously, intramuscularly, or by other non-enteral means. They may also be administered intranasally, by inhalation, topically, orally, or by implantation; rectal or vaginal use is also possible. Suitable liquid or solid pharmaceutical formulations may be, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, spiral-shaped, coated on microscopic gold particles, liposome-encapsulated, sprayed, aerosol, pellets for skin implantation, or dried on a sharp instrument for skin application. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, droplets, or formulations that release active compounds over a long period, in which additives and excipients and / or auxiliary agents such as disintegrants, binders, coatings, leavening agents, lubricants, flavoring agents, sweeteners, or solubilizers are conventionally used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of this method for drug delivery, see Langer R (1990) Science 249:1527-33.

[0286] The concentration of the compound in the composition used in the method of the present invention may be in the range of about 1 nM to about 100 μM. The effective dose is thought to be in the range of about 10 picomoles / kg to about 100 micromoles / kg.

[0287] Pharmaceutical compositions are preferably prepared and administered in dose units. Liquid dose units are vials or ampoules for injection or other non-enteral administration. Solid dose units are tablets, capsules, powders, and suppositories. Different doses may be required for the treatment of a patient, depending on the activity of the compound, the method of administration, the purpose of administration (i.e., prevention or treatment), the nature and severity of the disorder, and the patient's age and weight. Administration of a certain dose may be carried out by both single doses in the form of individual dose units or by several small dose units. Multiple repetitions and multiple doses at specific intervals separated by several days, weeks, or months are also intended by the present invention.

[0288] The composition may be administered either in its own form (undiluted) or in the form of a pharmaceutically acceptable salt. When used in medicine, the salt must be pharmaceutically acceptable, but a pharmaceutically unacceptable salt may be conveniently used to prepare a pharmaceutically acceptable salt. 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-sulfone, and benzenesulfonic acid. Such salts may also be prepared as alkali metal salts or alkaline earth salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[0289] 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).

[0290] Compositions suitable for non-enteral administration include sterile aqueous formulations that are conveniently isotonic with the recipient's blood. Particularly acceptable media and solvents are water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. Furthermore, sterile, fixed oils are conveniently used as solvents or suspension 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 useful in injectable formulations. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, and intravenous administration can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.

[0291] Compounds useful in the present invention can be delivered as a mixture of two or more such compounds. The mixture may further contain one or more adjuvants in addition to the combination of compounds.

[0292] A variety of administration routes are available. The specific method selected naturally depends on the specific compound selected, the age and overall health of the subject, the specific condition being treated, and the dosage required for therapeutic efficacy. The methods of the present invention can be carried out using any medically acceptable method of administration, meaning any method that produces an effective level of response without causing clinically unacceptable adverse effects. Preferred methods of administration are described above.

[0293] The composition is conveniently presented in unit dose form and can be manufactured using any method well known in the pharmaceutical field. All methods involve mixing the compound with a carrier constituting one or more auxiliary components. Generally, the composition is prepared by homogeneously and closely mixing the compound with a liquid carrier, a micronized solid carrier, or both, and then, if necessary, molding the product.

[0294] Other delivery systems may include sequential, delayed, or sustained-release delivery systems. Such systems avoid repeated administration of the compound and are more convenient for the patient and the physician. Many types of delivery systems are available and known to those skilled in the art. These include polymer-based systems such as poly(lactide-glycolides), coprooxalates, polycaprolactonic acids, polyesteramides, polyorthoesters, polyhydroxybutyrates, and polyanhydrides. Microcapsules of the polymers containing the drug are described, for example, in U.S. Patent 5,075,109. Delivery systems also include non-polymeric systems, which include: lipids such as sterols such as cholesterol and cholesterol esters, and fatty acids or neutral fats such as mono, di, and triglycerides; hydrogel-release systems; cylastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and additives; and partial condensation implants. Specific examples include, but are not limited to, (a) erosion systems in which the agent of the present invention is contained in a matrix form, such as those described in U.S. Patents 4,452,775, 4,675,189 and 5,736,152, and (b) diffusion systems in which the active ingredient penetrates from the polymer at a controlled rate, such as those described in U.S. Patents 3,854,480, 5,133,974 and 5,407,686. Furthermore, pump-based metal delivery systems can be used, some of which are suitable for implantation.

[0295] Disease treatment methods In another embodiment, a method for treating a disease in a subject requiring treatment includes administering to the subject an effective amount of a compound of formula Ia, Ib, or Ic described herein.

[0296] In one embodiment, the disease is selected from the group consisting of neurodegenerative diseases, cachexia, eating disorders, obesity, complications of obesity, inflammatory diseases, virus-induced inflammatory responses, Gulf War Syndrome, tuberous sclerosis, retinitis pigmentosa, graft rejection, cancer, autoimmune diseases, ischemic tissue injury, traumatic tissue injury, and combinations thereof.

[0297] In one embodiment, compounds of formula Ia, Ib, or Ic modulate Akt3 in immune cells. Non-limiting examples of immune cells include T cells (e.g., T regulatory cells ("Treg")), B cells, macrophages, and glial cells (e.g., astrocytes, microglia, or oligodendrocytes). In one embodiment, the immune cell is a Treg. In one embodiment, compounds of formula Ia, Ib, or Ic activate Akt3 signaling. In another embodiment, compounds of formula Ia, Ib, or Ic inhibit Akt3 signaling. In one embodiment, compounds of formula Ia, Ib, or Ic modulate Akt3 in Tregs. Surprisingly, the inventors have found that in one embodiment, compounds of formula Ia, Ib, or Ic increase Treg activity or production, while in another embodiment, the compounds decrease Treg activity or production. The inventors also surprisingly discovered that in one embodiment, compounds of formula Ia, Ib, or Ic activate Akt3 signaling, while in other embodiments, the compounds inhibit Akt3 signaling.

[0298] Neurodegenerative diseases In one embodiment, a method is described for treating or preventing a neurodegenerative disease in a subject requiring such treatment, comprising the modulation of Akt3 signaling by administering an effective amount of a compound of formula Ia, Ib, or Ic described herein to the subject. In one embodiment, the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, motor neuron disorders, Huntington's disease, HIV-induced neurodegeneration, Lewy body disease, spinal muscular atrophy, prion diseases, spinocerebellar ataxia, familial amyloid polyneuropathy, multiple sclerosis, and combinations thereof.

[0299] 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 contributes to disease progression. Current treatments help alleviate some of the physical or mental symptoms associated with neurodegenerative diseases, but there is currently no way to slow disease progression, and no cure is known.

[0300] Although the mechanisms that cause neurodegenerative processes are unknown, there is growing evidence suggesting 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 the immune response and are essential mediators of self-tolerance and immune homeostasis, CD4 + Tregs are a subset of T cells (see Sakaguchi, et al., Cell, 133, 775-787 (2008)). There is evidence suggesting that Tregs play a crucial role in the progression of neurodegenerative diseases. For example, Akt3 can regulate the inhibitory function of native Tregs and the polarization of induced Tregs; therefore, Akt3 regulation in immune cells can regulate the immune response. More specifically, Akt3 in activated immune cells can induce an immunosuppressive response, while Akt3 inhibition in immune cells can induce an immunosuppressive response. Although not bound by either theory, it is thought that regulating Akt3 signaling in immune cells could be used to treat and prevent neurodegenerative diseases.

[0301] In one embodiment, a method for treating or preventing neurodegenerative diseases in a subject requiring such treatment is described, comprising administering an Akt3 activator of a compound of formula Ia, Ib, or Ic described herein to the subject in an effective amount that induces an immunosuppressive response and treats or delays the progression of the disease. In one embodiment, the Akt3 activator modulates the immune response by increasing the suppressive function of immunosuppressive cells. In one embodiment, Akt3 is selectively activated in immune cells. Examples of 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 one embodiment, the Akt3 activator may also be used to increase or promote the activity or production of Tregs, increase the production of cytokines such as IL-10 from Tregs, increase Treg differentiation, increase Treg number, or increase Treg survival.

[0302] In one embodiment, a method for treating or preventing neurodegenerative disease in a subject requiring such treatment is described, comprising administering an Akt3 inhibitor of a compound of formula Ia, Ib, or Ic described herein to the subject in an effective dose that inhibits the immunosuppressive response and treats or prevents the progression of the disease. In one embodiment, the Akt3 inhibitor of a compound of formula Ia, Ib, or Ic described herein modulates the immune response by reducing the immunosuppressive response or increasing the immunostimulatory response. In one embodiment, Akt3 is selectively inhibited in immune cells. Examples of 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.

[0303] In one embodiment, compounds of formula Ia, Ib, or Ic can treat or prevent ALS. ALS, also known as Lou Gehrig's disease, is a progressive neurodegenerative disease affecting the motor nerves of 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 distinct types of ALS: sporadic and familial. Sporadic ALS, the most common form of the disease in the United States, accounts for 90–95 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 neuron-glia interactions, and apoptosis have all been shown to contribute to motor nerve damage in the presence of mutant OD1. While not bound by any one theory, it is believed that Treg dysfunction plays a role in the progression of ALS, and that Akt3 modulator administration may 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 inhibitory function. One embodiment provides a method for treating ALS in subjects in need, comprising administering an Akt3 activator to a subject in need in an effective amount that activates Akt3 in immune cells and induces an immunosuppressive response. In a preferred embodiment, Akt3 is activated in Tregs.

[0304] In one embodiment, administration of the Akt3 activator of formula Ia, Ib, or Ic described herein to subjects with ALS slows disease progression and prolongs the subjects' survival.

[0305] For example, other motor neurological disorders, including progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis, spinal muscular atrophy, and post-polio syndrome, can be treated or prevented using the Akt3 modulator of the disclosure.

[0306] Parkinson's disease is a neurodegenerative disorder that primarily affects dopamine-producing neurons in a specific area of ​​the brain called the substantia nigra. Parkinson's disease is a progressive disorder that worsens over time due to the increasing number of damaged or dying neurons. The cause of neuronal cell death in Parkinson's disease is unknown. Symptoms of Parkinson's disease include, but are not limited to, tremors of the hands, arms, legs, jaw, or head; stiffness of the limbs and torso; bradykinesia (slowness of movement); and impairment of balance and coordination.

[0307] One embodiment provides a method for treating Parkinson's disease, comprising administering an Akt3 modulator to a subject in need in an effective amount that activates or inhibits Akt3 in immune cells and induces an immunosuppressive response. In one embodiment, administration of the Akt3 activator to a subject with Parkinson's disease slows or halts disease progression to unaffected areas of the brain.

[0308] In one embodiment, an Akt3 activator of formula Ia, Ib, or Ic disclosed herein may be administered prophylactically to a subject if the subject has a family history of Parkinson's disease or other neurodegenerative disease. In one embodiment, the Akt3 activator protects neurons from disease induction or slows disease induction.

[0309] Huntington's disease is a progressive neurodegenerative disease characterized by the progressive decay of nerve cells in the brain. Symptoms of Huntington's disease include, but are not limited to, involuntary motor problems and dysfunctions in voluntary movements, e.g., involuntary spasms, muscle rigidity, oculomotor hypertrichosis or abnormalities, gait, posture and balance disorders, difficulty with the physical output of speech or swallowing; cognitive impairments, e.g., difficulty organizing, prioritizing or consolidating tasks, lack of flexibility or tendency to stick to thoughts, actions or activities, lack of impulse control, lack of awareness of one's own actions and abilities, slowness of thinking or word-finding and difficulty learning new information; and mental disorders, e.g., depression. In one embodiment, the disclosed Akt3 modulator reduces or slows the progression of Huntington's disease.

[0310] One embodiment provides a method for treating Huntington's disease in a subject requiring it, by administering an Akt3 modulator in an effective amount that activates or inhibits Akt3 in immune cells and induces an immunosuppressive response. In one embodiment, the Akt3 modulator slows or halts the progression of disease symptoms in a subject with Huntington's disease. In another embodiment, the Akt3 modulator can alter the Treg / Th17 equilibrium.

[0311] Huntington's disease is largely hereditary; all children of parents with Huntington's disease have a 50 / 50 chance of inheriting the disease. In one embodiment, subjects with a family history of Huntington's disease may be prophylactically administered the disclosed Akt3 modulator before the onset of disease symptoms to prevent or slow the manifestation of disease symptoms.

[0312] Alzheimer's disease is a progressive disorder that leads to the degeneration and eventual death of brain cells. It is the leading cause of dementia and is characterized by a progressive decline in thinking, behavior, and social skills that impair a person's ability to function independently. Symptoms of Alzheimer's disease include, but are not limited to, memory loss, impaired thinking and reasoning abilities, difficulty in 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 dysfunction in brain proteins that interfere with neuronal function, unleashing a series of toxic events. Damage most often begins in areas of the brain that control memory, but this process begins several years before the first symptoms appear. Neuronal loss spreads to other areas of the brain in a somewhat predictable pattern. In the later stages of the disease, the brain undergoes significant atrophy. Beta-amyloid plaques and tau protein concentrates most frequently contribute to the majority of neuronal damage and dysfunction in Alzheimer's disease.

[0313] One embodiment provides a method for treating Alzheimer's disease in a subject by administering an effective dose of an Akt3 activator to the subject, which hyperpolarizes Akt3 in Tregs and activates downstream neuroprotective pathways in the brain. In another embodiment, the subject is administered an effective dose of an Akt3 activator that reduces or eliminates the symptoms of Alzheimer's disease or slows disease progression.

[0314] Other embodiments provide a method for treating or preventing the progression of Alzheimer's disease in a subject by administering an Akt3 inhibitor of formula Ia, Ib, or Ic described herein to the subject in an effective dose that inhibits Akt3 in Tregs and induces an immune response or reduces an immunosuppressive response. In one embodiment, inhibition of Akt3 in Tregs leads to beta-amyloid plaque clearance, mitigation of neuroinflammatory responses, and recovery of cognitive decline.

[0315] Spinal muscular atrophy ("SMA") is a group of chronic neuromuscular diseases characterized by progressive loss of motor nerves and muscle wasting. SMA is generally classified into four types, differing in severity and the life stage at which the disease manifests. These types are: SMA1 or Werdnig-Hoffmann disease ("pediatric" SMA) that manifests between 0 and 6 months of age; SMA2 or Dubovitz disease ("intermediate" SMA) that manifests between 6 and 18 months of age; SMA3 or Kugelberg-Wellander disease ("juvenile" SMA) that manifests after the age of one; and SMA4, which develops during adulthood ("adult-onset" SMA). The most severe form of SMA1 is sometimes referred to as SMA0 ("severe childhood" SMA). Signs and symptoms of SMA vary by type, but most commonly include, but are not limited to, body instability or a tendency to fall, difficulty sitting, standing, or walking, loss of strength in respiratory muscles, spasms, and difficulty eating and swallowing. All types of SMA are associated with exon deletions and / or point mutations in the SMN1 gene, which block the expression of the SMN protein. Depending on the type, SMA can be treated with various gene therapies, nutrition and respiratory support, orthopedics, and combinations thereof. Neuroprotective drugs are promising as a way to stabilize motor nerve loss, but currently available candidates have not yet achieved full progress in clinical trials. Therefore, further candidate neuroprotective drugs are needed for the treatment of SMA.

[0316] One embodiment provides a method for treating SMA in a subject by administering to the subject an effective amount of the Akt3 modulator of formula Ia, Ib, or Ic described herein, which allows for motor neuron survival. In another embodiment, the subject is administered an effective amount of the Akt3 modulator that reduces or eliminates the symptoms of SMA or slows disease progression.

[0317] Multiple sclerosis ("MS") is a disease characterized by demyelination of nerve cells in the brain and spinal cord, leading to nerve cell damage and signaling disruptions throughout the nervous system. Individuals with MS may experience almost all neurological signs / symptoms, with autonomic, visual, motor, and sensory dysfunction being the most common. The exact cause of MS is unknown, but it 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. Treatment for MS, including but not limited to medication and physiotherapy, attempts to restore function in the affected area after an acute attack and prevent the occurrence of new attacks. There is no known cure for MS, and many current medications, while moderately effective, have severe side effects and can be poorly tolerated. Therefore, novel medications are needed for safe, effective, reversible, and prophylactic treatment of MS.

[0318] One embodiment provides a method for treating MS in a subject by administering to the subject an effective dose of an Akt3 modulator of formula Ia, Ib, or Ic described herein, which restores post-seizure loss of function and / or prevents seizures from occurring. In another embodiment, the subject is administered an effective dose of an Akt3 activator which reduces or eliminates the symptoms of MS or slows disease progression.

[0319] weight loss In one embodiment, a method for treating or preventing extreme weight loss is disclosed herein, comprising administering the compounds disclosed herein to a subject in need thereof. Non-limited examples of weight loss disorders include cachexia, eating disorders, and anorexia nervosa. An exemplary method involves inhibiting Akt3 in a subject in need thereof by administering a compound of formula Ia, Ib, or Ic described herein. Not bound by any one theory, Akt3 is thought to play a crucial role in adipogenesis. White adipogenesis requires activation of a transcriptional cascade involving the sequential induction of several transcription factors, including but not limited to FOXO1, several members of the C / EBP family, and PPARγ. FOXO1 is an essential negative regulator of adipogenesis and is primarily regulated by the phosphorylation / acetylation of multiple residues by enzymes containing 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 adipogenesis via phosphorylation of WNK1, leading to downregulation of SGK1 activity and SGK-1-mediated inhibition of FOXO1. In some embodiments, inhibition of Akt3 in Tregs can promote adipogenesis and reverse disease derivative weight loss.

[0320] Cahexi, or wasting syndrome, is a multifactorial syndrome characterized by progressive skeletal muscle loss that cannot be fully recovered with conventional nutritional support and leads to progressive dysfunction. Cahexi is destructive to the extent that the body utilizes other energy sources, namely skeletal muscle and adipose tissue, when it senses nutritional deficiency. It affects most patients with advanced cancer and is associated with the ability to fight infection, treatment tolerance, response to treatment, quality of life, and life expectancy. In some embodiments, cachexy is caused by chronic diseases including, but not limited to, cancer, inflammatory diseases, neurodegenerative diseases, pathogenic infections, immunodeficiency disorders, weight gain disorders, weight loss disorders, hormonal imbalances, tuberous sclerosis, retinitis pigmentosa, congestive heart failure, and combinations thereof. One embodiment provides a method for treating cachexy in a subject in need by administering to the subject an Akt3 inhibitor of a compound of formula Ia, Ib, or Ic described herein in an effective amount that reduces the symptoms of cachexy. Other embodiments provide a method for promoting weight gain in subjects in need by administering to a subject an effective amount of an Akt3 inhibitor of a compound of formula Ia, Ib, or Ic described herein to promote adipogenesis in the subject. In one embodiment, an Akt3 inhibitor may be prophylactically administered to a subject suspected of being susceptible to cachexia (e.g., a subject diagnosed with cancer or other disease) to prevent or slow the onset of cachexia syndrome. In one embodiment, the compounds disclosed herein are used to treat cachexia by modulating Akt3 rather than by modulating T regulatory cells.

[0321] Anorexia nervosa is an eating disorder characterized by weight loss or, in growing children, failure to gain weight, difficulty maintaining a weight appropriate for height, age, and stature, and often a distorted body image. One of the primary goals of treating eating disorders is the restoration of normal weight. In some embodiments, the compounds disclosed herein of formula Ia, Ib, or Ic inhibit Akt3, which is hyperactivated by elevated estradiol levels in subjects with eating disorders. In some embodiments, the compounds disclosed herein of formula Ia, Ib, or Ic may be used in the treatment of eating disorders. In some embodiments, an Akt3 inhibitor of the disclosed compounds of formula Ia, Ib, or Ic is administered to a subject diagnosed with an eating disorder in an effective dose that promotes lipogenesis and reverses extreme weight loss.

[0322] Obesity and its complications Diseases characterized by significant weight gain (e.g., obesity) affect 40% of adults and 20% of children and adolescents in the United States alone, and these numbers are increasing. (See “Overweight & Obesity: Data & Statistics”, US Centers for Disease Control and Prevention, accessed April 3, 2020.) >30kg / m 2 Obesity, characterized by the body mass index, increases the probability 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 includes administering an Akt3 activator to an obese or obese subject in an effective dose that reverses or prevents the effects of the disease.

[0323] In one embodiment, the compounds disclosed herein that modulate Akt3 are used to treat obesity and / or complications of obesity. In one embodiment, complications of obesity are selected from the group consisting of glucose intolerance, fatty liver, dyslipidemia, and combinations thereof. In one embodiment, the compounds disclosed herein are used to treat obesity and / or complications of obesity by modulating Akt3 rather than by modulating T regulatory cells.

[0324] inflammatory diseases Akt3 signaling is associated with chronic or acute inflammation contributing to inflammatory diseases. One embodiment provides a method for treating or preventing inflammatory diseases in a subject in need, comprising administering to the subject a composition comprising an Akt3 modulator in an effective amount that modulates Akt3 signaling and treats or delays the progression of the disease. In one embodiment, the Akt3 modulator activates Akt3 signaling and / or increases Treg activity or production, resulting in an immunosuppressive effect.

[0325] Non-exclusive examples of inflammatory diseases include atopic dermatitis, allergies, asthma, and combinations thereof.

[0326] Virus-induced inflammatory response Akt3 signaling is associated with acute immune responses resulting from virus-induced inflammatory diseases such as severe acute respiratory syndrome ("SARS") and coronavirus disease 2019 ("COVID-19"). Therefore, in one embodiment, a method for treating a virus-induced inflammatory disease in a subject requiring it comprises administering to the subject an effective dose of an Akt3 modulator that reverses or slows disease progression.

[0327] cancer In one embodiment, a method is provided for treating or preventing cancer in a subject requiring such treatment, comprising modulating Akt3 signaling by administering an effective amount of one of the compounds of formula Ia, Ib, or Ic described herein to the subject. In one embodiment, the compound of formula Ia, Ib, or Ic inhibits Akt3 signaling and / or reduces Treg activity or production, resulting in an immune response activating effect.

[0328] In one embodiment, 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, stomach cancer, uterine cancer, ovarian cancer, testicular cancer, adult T-cell leukemia / lymphoma, and combinations thereof.

[0329] In some embodiments, the compounds and compositions disclosed herein are useful for the treatment of leukemia. In some embodiments, the compounds and compositions disclosed herein that inhibit Akt3 are useful for the treatment of leukemia. In these embodiments, the compounds and compositions disclosed herein that inhibit Akt3 are useful in vivo and ex vivo as immune response stimulating therapies. The ability to inhibit Akt3 and therefore inhibit or reduce Treg-mediated immunosuppression enables a more robust immune response. In some embodiments, the compounds and compositions disclosed herein are also useful for stimulating or enhancing immune stimuli or activation responses involving T cells. In some embodiments, the compounds and compositions disclosed herein are useful for stimulating or enhancing the immune response in the host for the treatment of leukemia by selectively inhibiting Akt3. In these embodiments, the compounds and compositions disclosed herein may be administered to a subject in an effective amount that stimulates T cells in the subject. The 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 lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), adult T-cell leukemia / lymphoma (ATLL), and chronic myelomonocytic leukemia (CMML).

[0330] In one embodiment, ATLL is diagnosed almost exclusively in adults, with a median age of mid-60s. In one embodiment, there are four types of ATLL: (1) acute, (2) chronic, (3) smoldering, and (4) lymphomatous. In one embodiment, acute ATLL is the most common form, characterized by high white blood cell count, hypercalcemia, organ enlargement, and high lactose dehydrogenase. In one embodiment, lymphomatous ATLL manifests in the lymph nodes and accounts for less than 1% of circulating lymphocytes. In one embodiment, chronic and smoldering ATLL are characterized by a less aggressive clinical course and the possibility of long-term survival. In one embodiment, the 4-year survival rate for acute and lymphomatous ATLL is less than 5%. In one embodiment, the 4-year survival rates for chronic and smoldering forms of ATLL are 26.9% and 62%, respectively. In one embodiment, adult T-cell leukemia / lymphoma is caused by human T-cell lymphotropic virus (HTLV-1).

[0331] In one embodiment, the compounds and compositions disclosed herein are useful for treating ATLL. In one embodiment, the compounds and compositions disclosed herein that inhibit Akt3 are useful for treating ATLL. In one embodiment, Tregs expressing CD25 and FoxP3 become cancerous in ATLL cells. In one embodiment, ATLL cells exhibit an activated helper / inducer T cell phenotype but show strong immunosuppressive activity. In one embodiment, the compounds and compositions disclosed herein that inhibit Akt3 reduce the immunosuppressive response of ATLL cells. In another embodiment, the compounds and compositions disclosed herein that inhibit Akt3 enhance the immune-stimulating response and overcome the strong immunosuppressive activity of ATLL cells.

[0332] In some embodiments, the compounds and compositions disclosed herein, useful for the treatment of leukemia or ATLL, reduce or inhibit immunosuppressive responses, including but not limited to the immunosuppressive function of innate Treg (nTreg) cells and the induction of conventional T cells into inducible Treg (iTreg) cells. In these embodiments, the immunosuppressive function in 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 comprises administering to the subject a secondary activator, such as, but not limited to, an anti-nausea drug, a chemotherapy drug, or an enhancer (e.g., cyclophosphamide).

[0333] autoimmune diseases In one embodiment, 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 antibody 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, Barlow's disease, Behçet's disease, benign mucosal pemphigoid, etc. Pemphigus, Castleman disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing polymyelitis, Churg-Strauss syndrome, eosinophilic granulomatosis, scarring pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, Crest syndrome, Crohn's disease, herpetiform dermatitis, dermatomyositis, Devic's disease (neuromyelitis optica), lupus discoid, Dressler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosis Alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, bullous pemphigoid of pregnancy, sweat gland abscess (reverse acne), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immunothrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes (type 1 diabetes), juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing, woody tissue Conjunctivitis, linear IgA disease, lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mohlen's ulcer, Mukka-Habermann disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular scarring pemphigoid, optic neuritis, relapsing rheumatoid arthritis, childhood autoimmune neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, squamous cellulitis (peripheral uveitis), Personage-Turner syndrome, pemphigus, peripheral neuropathy,Perivenromal encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polymyalgia syndrome type I, polymyalgia syndrome type II, polymyalgia syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone-induced dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome This group includes retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, generalized rigidus syndrome, subacute bacterial endocarditis, Suzak syndrome, sympathetic ophthalmitis, Takayasu arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, leukoplakia, and Vogt-Koyanagi-Harada disease.

[0334] Other indications In one embodiment, the compounds disclosed herein modulate Akt3 and are used to treat Gulf War Syndrome, tuberous sclerosis, retinitis pigmentosa, graft rejection, ischemic tissue injury, or traumatic tissue injury. In one embodiment, graft rejection is graft-versus-host disease. In one embodiment, the compounds disclosed herein are used to treat retinitis pigmentosa by modulating Akt3, rather than by modulating T regulatory cells. In one embodiment, the compounds disclosed herein are used to treat ischemic tissue injury or traumatic tissue injury. In one embodiment, ischemic tissue injury or traumatic tissue injury is ischemic tissue injury or traumatic tissue injury of the brain.

[0335] Combination therapy methods In some embodiments, the disclosed compound may be administered alone or in combination with one or more further therapeutic agents to a subject requiring it. In some embodiments, the compound and the further therapeutic agents are administered separately but simultaneously. In some embodiments, the compound and the further therapeutic agents are administered as part of the same composition. In other embodiments, the compound and the second therapeutic agent are administered separately at different time points but as part of the same treatment regimen.

[0336] In one embodiment, the subject may be administered the first 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 the administration of the second agent. In one embodiment, the subject may be administered the first agent once or more every 1, 2, 3, 4, 5, 6, 7, 14, 21, 28, 35, or 48 days before a single dose of the second agent. The compounds disclosed herein may be either the first or second agent.

[0337] In one embodiment, the compound and further therapeutic agents may be administered as part of a treatment regimen. For example, if the first therapeutic agent can be administered to the subject every four days, the second therapeutic agent may be administered on the first, second, third, or fourth day, or a combination thereof. The first or second therapeutic agent may be administered repeatedly throughout the entire treatment regimen.

[0338] Further examples of therapeutic agents include, but are not limited to, cytokines, chemotherapeutic agents, radioisotopes, other immunotherapies, enzymes, antibiotics, antivirals (e.g., protease inhibitors alone or in combination with nucleosides for HIV or hepatitis B or C), antiparasitic agents (e.g., helminths or protozoa), growth factors, growth inhibitors, hormones, hormone antagonists, antibodies and their bioactive fragments (including humanized, single-stranded and chimeric antibodies), antigens and vaccine preparations (including adjuvants), peptide drugs, anti-inflammatory agents, ligands that bind to Toll-like receptors to activate the innate immune system (including, but not limited to, CpG oligonucleotides), molecules that mobilize 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.

[0339] Further therapeutic agents are selected based on the condition, disorder, or disease being treated. For example, the compounds of the present invention are co-administered with one or more further agents that function to enhance or promote the immune response or to reduce or inhibit the immune response.

[0340] Chemotherapy agents In one embodiment, the compounds of the present invention may be combined with one or more chemotherapeutic agents or apoptosis promoters. Typical chemotherapeutic agents include amsacrin, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clofarabine, chrysanthanspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxycarbamide, idarubicin, ifosfamide, irinotecan, leucovorin, liposomal doxorubicin, Liposomal daunorubicin, lomustine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, pentostatin, procarbazine, larcitrexed, satoraplatin, streptozocin, tegafur-uracil, temozolomide, teniposide, thiotepa, thioguanine, topotecan, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, or combinations thereof. Representative apoptosis promoters include, but are not limited to, fludarabine, staurosporine, cycloheximide, actinomycin D, lactosylceramide, 15d-PGJ(2), and combinations thereof.

[0341] Anti-inflammatory drugs Other suitable further 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 the anti-inflammatory agent. Representative examples of nonsteroidal anti-inflammatory drugs (NSAIDs) include oxicam, e.g., piroxicam, isoxicam, tenoxicam, sudoxicam; salicylic acids, e.g., aspirin, disalside, benolilate, trilysart, sappapyrine, sorprin, diflunisal, and fendosal; acetic acid derivatives, e.g., diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, flofenac, thiopinac, zidomethacin, acemetacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; and fenamete, e.g., mefenam. This includes, but is not limited to, meclofenum, flufenum, niflum, and tolfenamic acid; propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, thioxaprofen, suprofen, aluminoprofen, and thiaprofen; and pyrazoles, such as phenylbutazone, oxyfenbutazone, feprazone, azapropazone, and trimethazone. In some embodiments, mixtures of these nonsteroidal anti-inflammatory agents may also be used.

[0342] Representative examples of steroidal anti-inflammatory drugs include corticosteroids, such as hydrocortisone, hydroxyl-triamcinolone, alpha-methyldexamethasone, dexamethasone phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorizone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluchlorolone acetonide, fludrocortisone, flumetasone pivalate, fluocinolone acetonide, fluocinonide, flucortin butyl ester, fluocortolone, fluprednilidene acetate, fludrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, and triamcinolone acetate. This includes, but is not limited to, nide, cortisone, cortodoxone, flucetonide, fludrocortisone, diflorazone diacetate, fluradrenolon, fludrocortisone, diflorazone diacetate, fluradrenolon acetonide, medrisone, amsinafel, amsinafid, betamethasone and its esters in balance, chloroprednisone, chloroprednisone acetate, crocoltrone, crescinolone, dichlorizone, difluprednate, fluchloronide, flunisolide, fluoromethalone, fluperolon, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone and mixtures thereof.

[0343] 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 immunotherapies, immunomodulators, costimulatory activating agonists, other cytokines and chemokines and factors, vaccines, oncolytic viruses, cell therapies, small molecule and targeted therapies, chemotherapy and radiotherapy. In some embodiments, the immunomodulators include checkpoint inhibitors such as anti-PD1, anti-CTLA4, anti-TIM3, and anti-LAG3. In some embodiments, the costimulatory activating agonists include anti-OX40 and anti-GITR. In some embodiments, the cell therapies include engineered T cells, CAR-T cells, TCR-T cells, and others.

[0344] In one embodiment, the compounds disclosed herein are used in combination with other immunotherapies, immunomodulators, biological agents (e.g., antibodies), vaccines, small molecule and targeted therapies, anti-inflammatory agents, cell therapies (e.g., engineered Treg and other types of cells), chemotherapy and radiotherapy.

[0345] In one embodiment, the compounds disclosed herein are administered in vivo to a patient by intravenous, intramuscular, or other non-enteral means, either alone or in combination with other agents. They may also be administered intranasally, by inhalation, rectally, vaginally, topically, orally, or by implantation. In another embodiment, the compounds disclosed herein are applied ex vivo, either alone or in combination with other agents, to enhance the function of inhibitory Tregs, including native Tregs, induced Tregs, engineered Tregs, and other types of inhibitory T cells, which may then be used for treatment of the patient as desired.

[0346] In one embodiment, a further therapeutic agent is an immunosuppressant. The immunosuppressant is an antibody against other lymphocyte surface markers (e.g., CD40, alpha-4 integrin) or cytokines, or a fusion protein (e.g., CTLA-4-Ig(Orencia)). (登録商標)), TNFR-Ig(Enbrel (登録商標) )), TNF-α blockers, e.g., Enbrel, Remicade, Cimzia and Humira, cyclophosphamide ("CTX") (e.g., Endoxan) (登録商標) , Citoxane (登録商標) Neosar (登録商標) Procytox (登録商標) and Revimmune TM ), methotrexate ("MTX") (for example, Rheumatrex) (登録商標) and Trexall (登録商標) ), belimumab (e.g., Benlysta (登録商標) This includes, but is not limited to, other immunosuppressive drugs (e.g., cyclosporine A, FK506-like compounds, rapamycin compounds, and steroids), antiproliferative agents, cytotoxic agents, and other compounds that may aid in immunosuppression.

[0347] In one embodiment, a further therapeutic agent may be a checkpoint inhibitor. In one embodiment, a further therapeutic agent may be a CTLA-4 fusion protein such as CTLA-4-Ig (abatacept). The CTLA-4-Ig fusion protein may compete with the T cell co-stimulatory receptor, CD28, for binding to CD80 / CD86 (B7-1 / B7-2) in antigen-presenting cells, and therefore may function to inhibit T cell activation. In another embodiment, a further therapeutic agent is a CTLA-4-Ig fusion protein known as beratacept. Beratacept contains two amino acid substitutions (L104E and A29Y) that can significantly increase avidity to CD86 in vivo. In yet another embodiment, a further therapeutic agent is Maxy-4.

[0348] In another embodiment, a further therapeutic agent is CTX (Endoxan). (登録商標) , Citoxane (登録商標) Neosar (登録商標) Procytox (登録商標) and Revimmune TMCTX (the generic name for CTX), also known as cytophosphan, is a nitrogen mustard alkylating agent of the oxazofolin group. It can be used to treat various types of cancer and some autoimmune disorders. CTX is a first-line drug used for generalized proliferative glomerulonephritis in patients with renal lupus.

[0349] In one embodiment, a further therapeutic agent may be administered to a patient in need in an effective amount that reduces blood or serum levels of anti-double-stranded DNA ("anti-ds DNA") autoantibodies and / or reduces proteinuria.

[0350] In other embodiments, further therapeutic agents may increase the amount of adenosine in the serum (see, for example, WO08 / 147482). For example, the second therapeutic agent may be CD73-Ig, recombinant CD73, or other agents that increase the expression of CD73 (e.g., cytokines, monoclonal antibodies, or small molecules) (see, for example, WO04 / 084933). In other embodiments, further therapeutic agents may be interferon-beta.

[0351] In one embodiment, further therapeutic agents may be small molecules that inhibit or reduce differentiation, proliferation, activity, cytokine production, and / or cytokine secretion by other cells, including but not limited to Th1, Th17, Th22, and / or IL-1β, TNF-α, TGF-beta, IFN-γ, IL-18, IL-17, IL-6, IL-23, IL-22, IL-21, and MMPs, or that cause other cells to secrete inflammatory molecules. In another embodiment, further therapeutic agents are small molecules that interact with Tregs, enhance Treg activity, promote or enhance IL-10 secretion by Tregs, increase Treg numbers, increase Treg inhibitory performance, or a combination thereof.

[0352] In one embodiment, the composition increases Treg activity or production. Examples of Treg enhancers include, but are not limited to, the glucocorticoid fluticasone, salmeterol, antibodies against IL-12, IFN-γ, and IL-4; vitamin D3 and dexamethasone and combinations thereof.

[0353] In one embodiment, further therapeutic agents include antibodies against pro-inflammatory molecules such as IL-6, IL-23, IL-22, or IL-21, for example, functional blockade antibodies.

[0354] In one embodiment, the further therapeutic agent comprises nucleic acid. In another embodiment, the further therapeutic agent comprises ribonucleic acid.

[0355] Combination treatments for neurodegenerative diseases In one embodiment, the compounds disclosed herein may be administered in conjunction with a second treatment selected based on the disease condition of the subject. In one embodiment, the second treatment may be a treatment for Alzheimer's disease. Current treatments for Alzheimer's disease include, but are not limited to, cholinesterase inhibitors, e.g., donepezil, rivastigmine, and galantamine; memantine; antidepressants, e.g., citalopram, fluoxetine, paroxetine, sertraline, and trazodone; anxiolytics, e.g., lorazepam and oxazepam; and antipsychotics, e.g., aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone.

[0356] In other embodiments, further therapeutic agents may be used to treat ALS. There are currently 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 may also be treated with drugs that target specific symptoms of the disease. Examples of such drugs include, but are not limited to, drugs that reduce spasticity, such as antispasmodics (e.g., baclofen, dantrolene, and diazepam); drugs that help manage neuropathic pain, such as amitriptyline, carbamazepine, duloxetine, gabapentin, lamotrigine, milnacipran, nortriptyline, pregabalin, and venlafexine; and drugs that help patients swallow, such as trihexyphenidyl or amitriptyline.

[0357] In one embodiment, further therapeutic agents may be used for the treatment of 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; MAO B inhibitors such as selegiline, rasagiline, and safinamide; catechol O-methyltransferase inhibitors such as entacapone and tolcapone; anticholinergics such as benztropine and trihexyphenidyl; and amantadine.

[0358] In one embodiment, the second therapeutic agent may be for the treatment of Huntington's disease. Current treatments for Huntington's disease include, but are not limited to, tetrabenazine; antipsychotics such as haloperidol, chlorpromazine, risperidone, and quetiapine; antidepressants such as amantadine; levetiracetam; clonazepam; citalopram, escitalopram, fluoxetine, and sertraline; and anticonvulsants such as valoproate, carbamazepine, and lamotrigine.

[0359] Combination treatments for weight loss In one embodiment, the compounds disclosed herein may be administered to a subject together with further therapeutic agents used to treat cachexia or extreme weight loss. The current strategy for treating cachexia and extreme weight loss is appetite enhancement using appetite stimulants to ensure adequate nutritional intake. Pharmacological interventions with appetite stimulants, nutritional supplements, 5-HT3 antagonists, and Cox-2 inhibitors have been used to treat cancer cachexia.

[0360] In one embodiment, the appetite stimulant is a vitamin, mineral, or herb, including, but not limited to, zinc, thiamine, or fish oil. In another embodiment, the appetite stimulant is a pharmaceutical, including, but not limited to, dronabinol, megestrol, and oxandrolone.

[0361] Equivalents The following representative examples are intended to aid in the explanation of the present invention and should not be intended to limit the scope of the invention, nor should they be construed as limiting it. In fact, in addition to what is shown and described herein, various modifications of the invention and many further embodiments will be apparent to those skilled in the art from the entirety of this document, including the following examples and the scientific and patent documents cited herein. Furthermore, the contents of the cited documents are incorporated herein by reference to help explain the advanced art. The following examples include important additional information, examples and guidance that may be adapted to the implementation of the invention in its various embodiments and equivalents. [Examples]

[0362] Example 1: Compound 1(3-((6-nitroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] As shown in Scheme 1, meta-nitrobenzoic acid was coupled with 1,3-phenylenediamine using EDCI in the presence of HOBt and DIPEA. The resulting intermediate was coupled with 4-chloropyridine, and the nitro group was subsequently reduced to an amino group using Sn / HCl. The resulting amino intermediate was then reacted under reflux for 3 hours with an EtOH solution of 4-chloro-6-nitro-quinoline and 2-3 drops of TEA to obtain meta-substituted product compound 1. The final product was precipitated from the reaction mixture as soon as it reached room temperature, then filtered and purified by recrystallization from EtOH:diethyl ether in a 1:1 ratio.

[0363] The compounds shown in the following examples were prepared by a similar method based on the procedure described in Example 1 and / or by the methods described below and / or known in the art.

[0364] The following abbreviations used in the following examples have the following definitions: DCE = dichloroethane; DCM = dichloromethane; DIEPA or DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; EA or Depositphotos = ethyl acetate; EDC or EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HPLC = high-performance liquid chromatography; PE = petroleum ether; RT = retention time (e.g., HPLC retention time); TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; and TsOH or TosOH = p-toluenesulfonic acid. These abbreviations and definitions are not intended to limit other abbreviations and definitions herein.

[0365] Example 2: Compound 2(4-((3-((3-((pyridine-4-ylamino)phenyl)carbamoyl)phenyl)amino)quinoline-6-carboxamide) [ka] [ka] [ka] [ka] Compound 2 was prepared by the method shown in Schemes 2-4. Compound 2 (4-((3-((3-((pyridine-4-ylamino)phenyl)carbamoyl)phenyl)amino)quinoline-6-carboxamide)) was prepared as shown in Schemes 2-4:C 28 H 22 N6O2;474.52g / mol;30mg;yellow solid;ESI-LCMS m / z=475[M+H] + LCMS RT=1.451 min, 100% (214nm and 254nm).

[0366] Example 3: Compound 3(3-((6-(methylsulfonyl)quinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] [ka] Compound 3 was prepared by the method shown in Scheme 5-6. Compound 3 (3-((6-(methylsulfonyl)quinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 5-6:C 28 H 23 N5O3S;509.58g / mol;4mg;yellow solid;ESI-LCMS m / z=510[M+H] + LCMS RT=1.517 mins, 100% (214nm and 254nm).

[0367] Example 4: Compound 4(3-((6-ethynylquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] [ka] Compound 4 was prepared by the method shown in Scheme 7-8. Compound 4 (3-((6-ethinylquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 7-8:C 29 H 21 N5O;455.52g / mol;30mg;yellow solid;ESI-LCMS m / z=456[M+H] + LCMS RT=1.665 min, 100% (214nm and 254nm).

[0368] Example 5: Compound 5(3-((6-azidoquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] [ka] Compound 5 was prepared by the method shown in Scheme 9-10. Compound 5 (3-((6-azidoquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 9-10:C 27 H 20 N8O;472.51g / mol;30mg;yellow solid;ESI-LCMS m / z=473[M+H] + LCMS RT=1.696 min, 100% (214nm and 254nm).

[0369] Example 6: Compound 6(3-((6-cyanoquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 6 was prepared by the method shown in Scheme 11. Compound 6 (3-((6-cyanoquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 11:C 28 H 20 N6O;456.51g / mol;28mg;yellow solid;ESI-LCMS m / z=457[M+H] + ;LCMS RT=1.76 min, >95%(214nm).

[0370] Example 7: Compound 7(3-((6-cyanoquinoline-4-yl)oxy)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 7 was prepared by the method shown in Scheme 12. Compound 7 (3-((6-cyanoquinoline-4-yl)oxy)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 12:C 28 H 19 N5O2;457.49g / mol;ESI-LCMS m / z=458.1[M+H] + ;LCMS RT=2.825 min, >95%(210nm).

[0371] Example 8: Compound 8(3-((6-cyanoquinoline-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) [ka] [ka] Compound 8 was prepared by the method shown in Scheme 13. Compound 8 (3-((6-cyanoquinoline-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) was prepared as shown in Scheme 13:C 28 H 19 N5O2;457.49g / mol;ESI-LCMS m / z=458.1[M+H] + ;LCMS RT=2.531 min, >97%(210nm).

[0372] Example 9: Compound 9(3-((6-fluoroquinoline-4-yl)oxy)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 9 was prepared by the method shown in Scheme 14. Compound 9 (3-((6-fluoroquinoline-4-yl)oxy)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 14:C 27 H 19 FN4O2;450.47g / mol;ESI-LCMS m / z=451.1[M+H] + ;LCMS RT=2.784 min, >98%(210nm).

[0373] Example 10: Compound 10 (3-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) [ka] [ka] Compound 10 was prepared by the method shown in Scheme 15. Compound 10 (3-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) was prepared as shown in Scheme 15:C 27 H 19 FN4O2;450.47g / mol;ESI-LCMS m / z=450.8[M+H] + ;LCMS RT=2.582 min, >99%(210nm).

[0374] Example 11: Compound 11(3-((6-(prop-1-in-1-yl)quinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 11 was prepared by the method shown in Scheme 16. Compound 11 (3-((6-(prop-1-in-1-yl)quinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 16:C 30 H 23 N5O;469.55g / mol;ESI-LCMS m / z=470.2[M+H] + ;LCMS RT=2.833 min, >99%(210nm).

[0375] Example 12: Compound 12(3-((6-phenylquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 12 was prepared by the method shown in Scheme 17. Compound 12 (3-((6-phenylquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 17:C 33 H 25 N5O;507.60g / mol;ESI-LCMS m / z=508.2[M+H] + ;LCMS RT=3.192 min, >98%(210nm).

[0376] Example 13: Compound 13 (2-((6-cyanoquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)isonicotinamide) [ka] [ka] Compound 13 was prepared by the method shown in Scheme 18. Compound 13 (2-((6-cyanoquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)isonicotinamide) was prepared as shown in Scheme 18:C 27 H 19 N7O;457.50g / mol;ESI-LCMS m / z=458.2[M+H] + ;LCMS RT=2.588 min, >98%(210nm).

[0377] Example 14: Compound 14 (5-((6-cyanoquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)nicotinamide) [ka] [ka] Compound 14 was prepared by the method shown in Scheme 19. Compound 14 (5-((6-cyanoquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)nicotinamide) was prepared as shown in Scheme 19:C27 H 19 N7O;457.50g / mol;10mg;white solid;ESI-LCMS m / z=458[M+H] + ;LCMS RT=1.37 min, >95%(214nm).

[0378] Example 15: Compound 15 (5-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)nicotinamide) [ka] [ka] Compound 15 was prepared by the method shown in Scheme 20. Compound 15 (5-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)nicotinamide) was prepared as shown in Scheme 20:C 26 H 19 FN6O;450.48g / mol;ESI-LCMS m / z=451.1[M+H] + ;LCMS RT=2.437 min, >96%(210nm).

[0379] Example 16: Compound 16(4-((6-cyanoquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)picolinamide) [ka] [ka] Compound 16 was prepared by the method shown in Scheme 21. Compound 16 (4-((6-cyanoquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)picolinamide) was prepared as shown in Scheme 21:C 27 H 19 N7O;457.50g / mol;ESI-LCMS m / z=458.2[M+H] +;LCMS RT=2.571 min, >95%(210nm).

[0380] Example 17: Compound 17(4-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)picolinamide) [ka] [ka] Compound 17 was prepared by the method shown in Scheme 22. Compound 17 (4-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)picolinamide) was prepared as shown in Scheme 22:C 26 H 19 FN6O;450.48g / mol;ESI-LCMS m / z=451.1[M+H] + ;LCMS RT=2.615 min, >97%(210nm).

[0381] Example 18: Compound 18 (6-((6-cyanoquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)picolinamide) [ka] [ka] Compound 18 was prepared by the method shown in Scheme 23. Compound 18 (6-((6-cyanoquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)picolinamide) was prepared as shown in Scheme 23:C 27 H 19 N7O;457.50g / mol;ESI-LCMS m / z=458.2[M+H] + ;LCMS RT=2.638 min, >99%(210nm).

[0382] Example 19: Compound 19 (6-((6-Fluoroquinolin-4-yl)amino)-N-(3-(pyridin-4-ylamino)phenyl)picolylamide)

Chem.

Chem.

[0383] Example 20: Compound 20 (3-((6-Cyanoquinolin-4-yl)amino)-N-(6-(pyridin-4-ylamino)pyridin-2-yl)benzamide)

Chem.

Chem.

[0384] Example 21: Compound 21 (3-((6-Fluoroquinolin-4-yl)amino)-N-(6-(pyridin-4-ylamino)pyridin-2-yl)benzamide)

Chem.

[0385] Example 22: Compound 22(3-((6-cyanoquinoline-4-yl)amino)-N-(2-(pyridine-4-ylamino)pyridine-4-yl)benzamide) [ka] [ka] Compound 22 was prepared by the method shown in Scheme 27. Compound 22 (3-((6-cyanoquinoline-4-yl)amino)-N-(2-(pyridine-4-ylamino)pyridine-4-yl)benzamide) was prepared as shown in Scheme 27:C 27 H 19 N7O;457.50g / mol;ESI-LCMS m / z=458.2[M+H] + ;LCMS RT=5.950 min, >96%(210nm).

[0386] Example 23: Compound 23(3-((6-fluoroquinoline-4-yl)amino)-N-(2-(pyridine-4-ylamino)pyridine-4-yl)benzamide) [ka] [ka] Compound 23 was prepared by the method shown in Scheme 28. Compound 23 (3-((6-Fluoroquinolin-4-yl)amino)-N-(2-(pyridin-4-ylamino)pyridin-4-yl)benzamide) was prepared as shown in Scheme 28:C 26 H 19 FN6O; 450.48 g / mol; ESI-LCMS m / z = 451.0 [M+H] + ; LCMS RT = 6.052 min, >96% (210 nm).

[0387] Example 24: Compound 24 (3-((6-Cyanoquinolin-4-yl)amino)-N-(5-(pyridin-4-ylamino)pyridin-3-yl)benzamide)

Chem.

Chem.

[0388] Example 25: Compound 25 (3-((6-Fluoroquinolin-4-yl)amino)-N-(5-(pyridin-4-ylamino)pyridin-3-yl)benzamide)

Chem.

[0389] Example 26: Compound 26(3-((6-cyanoquinoline-4-yl)amino)-N-(4-(pyridine-4-ylamino)pyridine-2-yl)benzamide) [ka] [ka] Compound 26 was prepared by the method shown in Scheme 31. Compound 26 (3-((6-cyanoquinoline-4-yl)amino)-N-(4-(pyridine-4-ylamino)pyridine-2-yl)benzamide) was prepared as shown in Scheme 31:C 27 H 19 N7O;457.50g / mol;ESI-LCMS m / z=458.2[M+H] + ;LCMS RT=6.075 min, >95%(210nm).

[0390] Example 27: Compound 27 (3-((6-fluoroquinoline-4-yl)amino)-N-(4-(pyridine-4-ylamino)pyridine-2-yl)benzamide 2,2,2-trifluoroacetate) [ka] [ka] Compound 27 was prepared by the method shown in Scheme 32. Compound 27 (3-((6-fluoroquinoline-4-yl)amino)-N-(4-(pyridine-4-ylamino)pyridine-2-yl)benzamide 2,2,2-trifluoroacetate) was prepared as shown in Scheme 32:C 28 H 20 F4N6O3;564.50g / mol;ESI-LCMS m / z=451.1[M+H] + ;LCMS RT=6.236 min, >95%(210nm).

[0391] Example 28: Compound 28(3-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridazine-4-ylamino)phenyl)benzamide) [ka] Compound 28 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 28 (3-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridazine-4-ylamino)phenyl)benzamide) C 26 H 19 FN6O;450.48g / mol;45mg;white solid;ESI-LCMS m / z=451.2[M+H] + ;LCMS RT=1.621 min, 98.91% (214 nm).

[0392] Example 29: Compound 29(3-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyrimidine-4-ylamino)phenyl)benzamide) [ka] Compound 29 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 29 (3-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyrimidine-4-ylamino)phenyl)benzamide): C 26 H 19FN6O;450.48g / mol;50mg;white solid;ESI-LCMS m / z=451[M+H] + ;LCMS RT=1.604 min, 100% (214 nm).

[0393] Example 30: Compound 30 (4-((3-(6-(pyridine-4-ylamino)-1H-benzo[d]imidazole-2-yl)phenyl)amino)quinoline-6-carbonitrile) [ka] [ka] Compound 30 was prepared by the method shown in Scheme 33. Compound 30 (4-((3-(6-(pyridine-4-ylamino)-1H-benzo[d]imidazole-2-yl)phenyl)amino)quinoline-6-carbonitrile) was prepared as shown in Scheme 33:C 28 H 19 N7;453.51g / mol;22mg;yellow solid;ESI-LCMS m / z=454[M+H] + ;LCMS RT=1.634 min, 100% (214 nm).

[0394] Example 31: Compound 31 (3-((6-(dimethylamino)quinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 31 was prepared by the method shown in Scheme 34. Compound 31 (3-((6-(dimethylamino)quinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 34:C 29 H 26 N6O;474.57g / mol;12mg;pale yellow solid;ESI-LCMS m / z=475[M+H] +;LCMS RT=1.48 min, >95.00%(214nm).

[0395] Example 32: Compound 32 (3-((6-fluoroquinoline-4-yl)amino)-N-methyl-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 32 was prepared by the method shown in Scheme 35. Compound 32 (3-((6-fluoroquinoline-4-yl)amino)-N-methyl-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 35, where step a comprises MeI, Cs2CO3 or HCHO, NaBH(OAc)3, and step b comprises PyBOP, Et3N or EDCI or HATU;C 28 H 22 FN5O;463.52g / mol;16mg;white solid;ESI-LCMS m / z=464[M+H] + ;LCMS RT=1.38 min, >95.00%(214nm).

[0396] Example 33: Compound 33(N-(3-(pyridine-4-ylamino)phenyl)-3-((6-(3,3,3-trifluoroprop-1-in-1-yl)quinoline-4-yl)amino)benzamide) [ka] [ka] [ka] [ka] Compound 33 was prepared by the methods shown in Schemes 36, 36a and 36b. Compound 33 (N-(3-(pyridin-4-ylamino)phenyl)-3-((6-(3,3,3-trifluoroprop-1-yn-1-yl)quinolin-4-yl)amino)benzamide) was prepared as shown in Scheme 36, 36a or 36b:C 30 H 20 F3N5O; 523.52 g / mol; 12 mg; pale yellow solid; ESI-LCMS m / z = 524 [M+H] + ; LCMS RT = 1.80 minutes, >95.00% (214 nm).

[0397] Example 34: Compound 34 (3-((6-fluoroquinolin-4-yl)amino)-N-(3-((2-methylpyridin-4-yl)oxy)phenyl)benzamide)

Chem.

[0398] Example 35: Compound 35 (3-((6-fluoroquinolin-4-yl)amino)-N-(3-(pyridin-4-ylamino)phenyl)benzenesulfonamide)

Chem.

Chem.

[0399] Example 36: Compound 36 (N-(3-((6-fluoroquinoline-4-yl)amino)phenyl)-3-(pyridine-4-ylamino)benzamide) [ka] [ka] Compound 36 was prepared by the method shown in Scheme 38. Compound 36 (N-(3-((6-fluoroquinoline-4-yl)amino)phenyl)-3-(pyridine-4-ylamino)benzamide) was prepared as shown in Scheme 38:C 27 H 20 FN5O;449.49g / mol;12mg;white solid, ESI-LCMS m / z=450[M+H] + ;LCMS RT=1.53 min, >95.00%(214nm).

[0400] Example 37: Compound 37(3-((6-cyanoquinoline-4-yl)amino)-N-(4-(phenylamino)pyridine-2-yl)benzamide) [ka] Compound 37 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 37 (3-((6-cyanoquinoline-4-yl)amino)-N-(4-(phenylamino)pyridine-2-yl)benzamide);C 28 H 20N6O;456.51g / mol;15mg;Pale yellow solid;ESI-LCMS m / z=457[M+H] + ;RT=1.68min, >95.00%(214nm).

[0401] Example 38: Compound 38 (N-(4-(pyridine-4-ylamino)pyridine-2-yl)-3-(quinoline-4-ylamino)benzamide) [ka] [ka] Compound 38 was prepared by the method shown in Scheme 39. Compound 38 (N-(4-(pyridine-4-ylamino)pyridine-2-yl)-3-(quinoline-4-ylamino)benzamide) was prepared as shown in Scheme 39:C 26 H 20 N6O;432.49g / mol;20mg;pale yellow solid, ESI-LCMS m / z=433[M+H] + ;LCMS RT=1.36 min, >95.00%(214nm).

[0402] Example 39: Compound 39 (3-((6-fluoroquinoline-4-yl)amino)-2-methyl-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 39 was prepared by the method shown in Scheme 40. Compound 39 (3-((6-fluoroquinoline-4-yl)amino)-2-methyl-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 40:C 28 H 22 FN5O;463.51g / mol;12mg;white solid, ESI-LCMS m / z=464[M+H] +;LCMS RT=1.41 min, >95.00%(214nm).

[0403] Example 40: Compound 40 (3-((6-fluoroquinoline-4-yl)amino)-4-methyl-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 40 was prepared by the method shown in Scheme 41. Compound 40 (3-((6-fluoroquinoline-4-yl)amino)-4-methyl-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 41:C 28 H 22 FN5O;463.51g / mol;20mg;white solid, ESI-LCMS m / z=464[M+H] + ;LCMS RT=1.45 min, >95.00% (214 nm).

[0404] Example 41: Compound 41 (3-((6-fluoroquinoline-4-yl)amino)-N-(2-methyl-3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 41 was prepared by the method shown in Scheme 42. Compound 41 (3-((6-fluoroquinoline-4-yl)amino)-N-(2-methyl-3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 42:C 28 H 22 FN5O;463.51g / mol;19mg;white solid, ESI-LCMS m / z=464[M+H] + ;LCMS RT=1.42 min, >95.00%(214nm).

[0405] Example 42: Compound 42(3-((6-fluoroquinoline-4-yl)amino)-N-(4-methyl-3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 42 was prepared by the method shown in Scheme 43. Compound 42 (3-((6-fluoroquinoline-4-yl)amino)-N-(4-methyl-3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 43:C 28 H 22 FN5O;463.51g / mol;12mg;white solid, ESI-LCMS m / z=464[M+H] + ;LCMS RT=1.46 min, >95.00%(214nm).

[0406] Example 43: Compound 43 (3-((6-fluoroquinoline-4-yl)amino)-5-methyl-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 43 was prepared by the method shown in Scheme 44. Compound 43 (3-((6-fluoroquinoline-4-yl)amino)-5-methyl-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 44, where step a comprises HCl, then NaOH, and step b comprises EDCI, DMAP;C 28 H 22 FN5O;463.52g / mol;19mg;pale yellow solid, ESI-LCMS m / z=464[M+H] + ;LCMS RT=1.44 min, >95.00%(214nm).

[0407] Example 44: Compound 44 (5-((6-fluoroquinoline-4-yl)amino)-2-methyl-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 44 was prepared by the method shown in Scheme 45. Compound 44 (5-((6-fluoroquinoline-4-yl)amino)-2-methyl-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 39, where step a comprises HCl, then NaOH, and step b comprises EDCI, DMAP;C 28 H 22 FN5O;463.52g / mol;19mg;pale yellow solid, ESI-LCMS m / z=464[M+H] + ;LCMS RT=1.41 min, >95.00%(214nm).

[0408] Example 45: Compound 45(3-((6-fluoroquinoline-4-yl)amino)-N-(3-methyl-5-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 45 was prepared by the method shown in Scheme 46. Compound 45 (3-((6-fluoroquinoline-4-yl)amino)-N-(3-methyl-5-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 46, where step a comprises Pd(OAc)2, Xant-Phos; step b comprises H2, Pd / C; and step c comprises EDCI, DMAP; C 28 H 22 FN5O;463.52g / mol;17mg;pale yellow solid, ESI-LCMS m / z=464[M+H] + ;LCMS RT=1.44 min, >95.00%(214nm).

[0409] Example 46: Compound 46(3-((6-fluoroquinoline-4-yl)amino)-N-(2-methyl-5-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 46 was prepared by the method shown in Scheme 47. Compound 46 (3-((6-fluoroquinoline-4-yl)amino)-N-(2-methyl-5-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 47:C 28 H 22 FN5O;463.52g / mol;15mg;pale yellow solid, ESI-LCMS m / z=464[M+H] + ;LCMS RT=1.42 min, >95.00%(214nm).

[0410] Example 47: Compound 47(2-fluoro-3-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 47 was prepared by the method shown in Scheme 48. Compound 47 (2-fluoro-3-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 48:C 27 H 19 F2N5O;467.48g / mol;13mg;pale yellow solid, ESI-LCMS m / z=468[M+H] + ;LCMS RT=1.39 min, >95.00%(214nm).

[0411] Example 48: Compound 48 (4-fluoro-3-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 48 was prepared by the method shown in Scheme 49. Compound 48 (4-fluoro-3-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 49:C 27 H 19 F2N5O;467.48g / mol;26mg;white solid, ESI-LCMS m / z=468[M+H] + ;LCMS RT=1.75 min, >95.00%(214nm).

[0412] Example 49: Compound 49(N-(2-fluoro-3-(pyridine-4-ylamino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide) [ka] [ka] Compound 49 was prepared by the method shown in Scheme 50. Compound 49 (N-(2-fluoro-3-(pyridine-4-ylamino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide) was prepared as shown in Scheme 50:C 27 H 19 F2N5O;467.48g / mol;11mg;white solid, ESI-LCMS m / z=468[M+H] + ;LCMS RT=1.75 min, >95.00%(214nm).

[0413] Example 50: Compound 50 (N-(4-fluoro-3-(pyridine-4-ylamino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide) [ka] [ka] Compound 50 was prepared by the method shown in Scheme 51. Compound 50 (N-(4-fluoro-3-(pyridine-4-ylamino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide) was prepared as shown in Scheme 51:C 27 H 19 F2N5O;467.48g / mol;14mg;pale yellow solid, ESI-LCMS m / z=468[M+H] + ;LCMS RT=1.42 min, >95.00%(214nm).

[0414] Example 51: Compound 51 (3-fluoro-5-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 51 was prepared by the method shown in Scheme 52. Compound 51 (3-fluoro-5-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 52:C 27 H 19 F2N5O;467.47g / mol;18mg;pale yellow solid, ESI-LCMS m / z=468[M+H] + ;LCMS RT=1.47 min, >95.00%(214nm).

[0415] Example 52: Compound 52 (2-Fluoro-5-((6-Fluoroquinoline-4-yl)amino)-N-(3-(Pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 52 was prepared by the method shown in Scheme 53. Compound 52 (2-fluoro-5-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 53:C 27 H 19 F2N5O;467.47g / mol;26mg;white solid, ESI-LCMS m / z=468[M+H] + ;LCMS RT=1.81 min, >95.00%(214nm).

[0416] Example 53: Compound 53 (N-(3-fluoro-5-(pyridine-4-ylamino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide) [ka] [ka] Compound 53 was prepared by the method shown in Scheme 54. Compound 53 (N-(3-fluoro-5-(pyridine-4-ylamino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide) was prepared as shown in Scheme 54:C 27 H 19 F2N5O;467.47g / mol;12mg;white solid, ESI-LCMS m / z=468[M+H] + ;LCMS RT=1.85 min, >95.00%(214nm).

[0417] Example 54: Compound 54 (N-(2-fluoro-5-(pyridine-4-ylamino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide) [ka] [ka] Compound 54 was prepared by the method shown in Scheme 55. Compound 54 (N-(2-fluoro-5-(pyridine-4-ylamino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide) was prepared as shown in Scheme 55:C 27 H 19 F2N5O;467.47g / mol;12mg;white solid, ESI-LCMS m / z=468[M+H] + ;LCMS RT=1.80 min, >95.00%(214nm).

[0418] Example 55: Compound 55 (N-(3-((2-aminopyridine-4-yl)amino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide) [ka] [ka] Compound 55 was prepared by the method shown in Scheme 56. Compound 55 (N-(3-((2-aminopyridine-4-yl)amino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide) was prepared as shown in Scheme 56:C 27 H 21 FN6O;464.50g / mol;15mg;white solid, ESI-LCMS m / z=465[M+H] + ;LCMS RT=1.02 min, >95.00%(214nm).

[0419] Example 56: Compound 56 (3-((5-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 56 was prepared by the method shown in Scheme 57. Compound 56 (3-((5-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 57:C 27 H 20 FN5O;449.49g / mol;14mg;white solid, ESI-LCMS m / z=450[M+H] + ;LCMS RT=1.37 min, >95.00%(214nm).

[0420] Example 57: Compound 57 (3-((7-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 57 was prepared by the method shown in Scheme 58. Compound 57 (3-((7-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 58:C 27 H 20 FN5O;449.49g / mol;15mg;pale yellow solid, ESI-LCMS m / z=450[M+H] + ;LCMS RT=1.45 min, >95.00% (214 nm).

[0421] Example 58: Compound 58 (6-fluoro-N-(3-(1-(3-(phenylamino)phenyl)-1H-1,2,3-triazole-4-yl)phenyl)quinoline-4-amine) [ka] [ka] Compound 58 was prepared by the method shown in Scheme 59. Compound 58 (6-fluoro-N-(3-(1-(3-(phenylamino)phenyl)-1H-1,2,3-triazole-4-yl)phenyl)quinoline-4-amine) was prepared as shown in Scheme 59:C 29 H 21 FN6;472.53g / mol;20mg;Pale yellow solid, ESI-LCMS m / z=473[M+H] + ;LCMS RT=2.08 min, >95.00%(214nm).

[0422] Example 59: Compound 59(3-((6-(dimethylamino)quinoline-4-yl)amino)-N-(3-((2-methylpyridine-4-yl)amino)phenyl)benzamide) [ka] [ka] [ka] Compound 59 was prepared by the method shown in Schemes 60-61. Compound 59 (3-((6-(dimethylamino)quinoline-4-yl)amino)-N-(3-((2-methylpyridine-4-yl)amino)phenyl)benzamide) was prepared as shown in Scheme 60 or Scheme 61, where step a comprises DMAP and step b comprises Pd2(dba)3, XantPhos;C 30 H 28 N6O;488.60g / mol;13mg;Pale yellow solid;ESI-LCMS m / z=489[M+H] + ;LCMS RT=1.70 min, >95.00%(214nm).

[0423] Example 60: Compound 60 (3-((6-cyanoquinoline-4-yl)amino)-N-(4-(m-tolylamino)pyridine-2-yl)benzamide) [ka] Compound 60 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 60 (3-((6-cyanoquinoline-4-yl)amino)-N-(4-(m-tolylamino)pyridine-2-yl)benzamide);C 29 H 22 N6O;470.54g / mol;11mg;pale yellow solid;ESI-LCMS m / z=471[M+H] + ;RT=1.75min, >95.00%(214nm).

[0424] Example 61: Compound 61(3-((6-(dimethylamino)quinoline-4-yl)amino)-N-(4-((2-methylpyridine-4-yl)amino)pyridine-2-yl)benzamide) [ka] [ka] Compound 61 was prepared by the method shown in Scheme 62. Compound 61 (3-((6-(dimethylamino)quinoline-4-yl)amino)-N-(4-((2-methylpyridine-4-yl)amino)pyridine-2-yl)benzamide) was prepared as shown in Scheme 62; C 29 H 27 N7O;489.58g / mol;14mg;Pale yellow solid;ESI-LCMS m / z=490[M+H] + ;LCMS RT=1.56 min, >95.00%(214nm).

[0425] Example 62: Compound 62(3-((6-cyanoquinoline-4-yl)amino)-N-(4-((2-methylpyridine-4-yl)amino)pyridine-2-yl)benzamide) [ka] Compound 62 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 62(3-((6-cyanoquinoline-4-yl)amino)-N-(4-((2-methylpyridine-4-yl)amino)pyridine-2-yl)benzamide);C 28 H 21 N7O;471.52g / mol;13mg;pale yellow solid;ESI-LCMS m / z=472[M+H] + ;RT=1.49min, >95.00%(214nm).

[0426] Example 63: Compound 63(2-((6-(dimethylamino)quinoline-4-yl)amino)-N-(3-((2-methylpyridine-4-yl)amino)phenyl)isonicotinamide) [ka] [ka] Compound 63 was prepared by the method shown in Scheme 63. Compound 63 (2-((6-(dimethylamino)quinoline-4-yl)amino)-N-(3-((2-methylpyridine-4-yl)amino)phenyl)isonicotinamide) was prepared as shown in Scheme 63; C 29 H 27 N7O;489.58g / mol;15mg;yellow solid;ESI-LCMS m / z=490[M+H] + ;LCMS RT=1.60 min, >95.00%(214nm).

[0427] Example 64: Compound 64(5-((6-(dimethylamino)quinoline-4-yl)amino)-N-(3-((2-methylpyridine-4-yl)amino)phenyl)nicotinamide) [ka] [ka] Compound 64 was prepared by the method shown in Scheme 64. Compound 64 (5-((6-(dimethylamino)quinoline-4-yl)amino)-N-(3-((2-methylpyridine-4-yl)amino)phenyl)nicotinamide) was prepared as shown in Scheme 64:C 29 H 27 N7O;489.58g / mol;10mg;yellow solid;ESI-LCMS m / z=490[M+H] + ;LCMS RT=1.61 min, >95.00%(214nm).

[0428] Example 65: Compound 65(5-((6-(dimethylamino)quinoline-4-yl)amino)-N-(3-((2-methylpyridine-4-yl)oxy)phenyl)nicotinamide) [ka] [ka] Compound 65 was prepared by the method shown in Scheme 65. Compound 65 (5-((6-(dimethylamino)quinoline-4-yl)amino)-N-(3-((2-methylpyridine-4-yl)oxy)phenyl)nicotinamide) was prepared as shown in Scheme 65:C 29 H 26 N6O2;490.57g / mol;12mg;yellow solid;ESI-LCMS m / z=491[M+H] + ;LCMS RT=1.53 min, >95.00%(214nm).

[0429] Example 66: Compound 66 (4-((3-((3-((2-methylpyridine-4-yl)amino)phenyl)carbamoyl)phenyl)amino)quinoline-6-carboxylic acid) [ka] [ka] Compound 66 was prepared by the method shown in Scheme 66. Compound 66 (4-((3-((3-((2-methylpyridine-4-yl)amino)phenyl)carbamoyl)phenyl)amino)quinoline-6-carboxylic acid) was prepared as shown in Scheme 66:C 29 H 23 N5O3;489.54g / mol;11mg;light yellow solid;ESI-LCMS m / z=490[M+H] + ;LCMS RT=1.13 min, >95.00%(214nm).

[0430] Example 67: Compound 67 ((3-((6-fluoroquinoline-4-yl)amino)phenyl)(4-(pyridine-4-ylamino)indoline-1-yl)methanone) [ka] [ka] Compound 67 was prepared by the method shown in Scheme 67. Compound 67 ((3-((6-fluoroquinoline-4-yl)amino)phenyl)(4-(pyridine-4-ylamino)indoline-1-yl)methanone) was prepared as shown in Scheme 67:C 29 H 22 FN5O;475.53g / mol;12mg;light yellow solid;ESI-LCMS m / z=476[M+H] + ;LCMS RT=1.51 min, >95.00%(214nm).

[0431] Example 68: Compound 68 ((3-((6-fluoroquinoline-4-yl)amino)phenyl)(6-(pyridine-4-ylamino)indoline-1-yl)methanone) [ka] [ka] Compound 68 was prepared by the method shown in Scheme 68. Compound 68 ((3-((6-fluoroquinoline-4-yl)amino)phenyl)(6-(pyridine-4-ylamino)indoline-1-yl)methanone) was prepared as shown in Scheme 68:C 29 H 22 FN5O;475.53g / mol;10mg;light yellow solid;ESI-LCMS m / z=476[M+H] + ;LCMS RT=1.50 min, >95.00%(214nm).

[0432] Example 69: Compound 69(3-((1,6-naphthyridine-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) [ka] [ka] Compound 69 was prepared by the method shown in Scheme 69. Compound 69 (3-((1,6-naphthyridine-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) was prepared as shown in Scheme 69:C 26 H 19 N5O2;433.47g / mol;12mg;light yellow solid;ESI-LCMS m / z=434[M+H] + ;LCMS RT=1.39 min, >95.00%(214nm).

[0433] Example 70: Compound 70 (3-((1,6-naphthyridine-4-yl)amino)-N-(4-(pyridine-4-yloxy)pyridine-2-yl)benzamide) [ka] [ka] Compound 70 was prepared by the method shown in Scheme 70. Compound 70(3-((1,6-naphthyridine-4-yl)amino)-N-(4-(pyridine-4-yloxy)pyridine-2-yl)benzamide);C 25 H 18 N6O2 was prepared as shown in Scheme 70: 434.46 g / mol; 12 mg; pale yellow solid; ESI-LCMS m / z = 435 [M + H] + ;LCMS RT=1.13 min, >95.00%(214nm).

[0434] Example 71: Compound 71 (3-(pyridine-4-ylamino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) [ka] [ka] Compound 71 was prepared by the method shown in Scheme 71. Compound 71(3-(pyridine-4-ylamino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide);C 23 H 18 N4O2 was prepared as shown in Scheme 71: 382.42 g / mol; 11 mg; pale yellow solid; ESI-LCMS m / z = 383 [M + H] + ;LCMS RT=1.19 min, >95.00%(214nm).

[0435] Example 72: Compound 72(3-((1,6-naphthyridine-4-yl)amino)-N-(4-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 72 was prepared by the method shown in Scheme 72. Compound 72 (3-((1,6-naphthyridine-4-yl)amino)-N-(4-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 72:C 26 H 20 N6O;432.49g / mol;16mg;pale yellow solid;ESI-LCMS m / z=433[M+H] + ;LCMS RT=1.34 min, >95.00%(214nm).

[0436] Example 73: Compound 73 (3-(6-fluoroquinoline-4-ylamino)-N-(3-phenoxyphenyl)benzamide) [ka] Compound 73 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 73 (3-(6-fluoroquinoline-4-ylamino)-N-(3-phenoxyphenyl)benzamide); C 28 H 20 FN3O2;449.49g / mol;14mg;white solid;ESI-LCMS m / z=450[M+H] + ;RT=1.77min, >95.00%(214nm).

[0437] Example 74: Compound 74 (N-(4-(pyridine-4-yloxy)pyridine-2-yl)-3-(quinoline-4-ylamino)benzamide) [ka] [ka] Compound 74 was prepared by the method shown in Scheme 73. Compound 74 (N-(4-(pyridine-4-yloxy)pyridine-2-yl)-3-(quinoline-4-ylamino)benzamide) was prepared as shown in Scheme 73:C 26 H 19N5O2;433.47g / mol;10mg;light yellow solid;ESI-LCMS m / z=434[M+H] + ;RT=1.26min, >95.00%(214nm).

[0438] Example 75: Compound 75 (N-(3-(pyridine-4-yloxy)phenyl)-3-(quinoline-4-ylamino)benzamide) [ka] [ka] Compound 75 was prepared by the method shown in Scheme 74. Compound 75 (N-(3-(pyridine-4-yloxy)phenyl)-3-(quinoline-4-ylamino)benzamide); C 27 H 20 N4O2 was prepared as shown in Scheme 74: 432.48 g / mol; 15 mg; pale yellow solid; ESI-LCMS m / z = 433 [M + H] + ;RT=1.33min, >95.00%(214nm).

[0439] Example 76: Compound 76(3-((2-methylpyridine-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) [ka] [ka] Compound 76 was prepared by the method shown in Scheme 75. Compound 76 (3-((2-methylpyridine-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) was prepared as shown in Scheme 75:C 24 H 20 N4O2;396.45g / mol;11mg;light yellow solid;ESI-LCMS m / z=397[M+H] + ;RT=1.23min, >95.00%(214nm).

[0440] Example 77: Compound 77(3-((3-methylquinoline-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) [ka] [ka] Compound 77 was prepared by the method shown in Scheme 76. Compound 77 (3-((3-methylquinoline-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) was prepared as shown in Scheme 76:C 28 H 22 N4O2;446.51g / mol;20mg;light yellow solid;ESI-LCMS m / z=447[M+H] + ;RT=1.37min, >95.00%(214nm).

[0441] Example 78: Compound 78 (3-((2-methylquinoline-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) [ka] [ka] Compound 78 was prepared by the method shown in Scheme 77. Compound 78 (3-((2-methylquinoline-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) was prepared as shown in Scheme 77:C 28 H 22 N4O2;446.51g / mol;23mg;light yellow solid;ESI-LCMS m / z=447[M+H] + ;RT=1.36min, >95.00%(214nm).

[0442] Example 79: Compound 79(3-((6-chloroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] Compound 79 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 79 (3-((6-chloroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide);C 27 H 20 ClN5O;465.93g / mol;13mg;pale yellow solid;ESI-LCMS m / z=466[M+H] + ;RT=1.50min, >95.00%(214nm).

[0443] Example 80: Compound 80 (3-((6-methoxyquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] Compound 80 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 80 (3-((6-methoxyquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide); C 28 H 23 N5O2;461.53g / mol;18mg;light yellow solid;ESI-LCMS m / z=462[M+H] + ;RT=1.47min, >95.00%(214nm).

[0444] Example 81: Compound 81 (3-((6-methylquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] Compound 81 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 81(3-((6-methylquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide);C 28 H 23N5O;445.53g / mol;13mg;pale yellow solid;ESI-LCMS m / z=446[M+H] + ;RT=1.57min, >95.00%(214nm).

[0445] Example 82: Compound 82 (N-(3-(pyridine-4-ylamino)phenyl)-3-(quinoline-4-ylamino)benzamide) [ka] [ka] Compound 82 was prepared by the method shown in Scheme 78. Compound 82(N-(3-(pyridine-4-ylamino)phenyl)-3-(quinoline-4-ylamino)benzamide);C 27 H 21 N5O was prepared as shown in Scheme 78: 431.50 g / mol; 12 mg; white solid; ESI-LCMS m / z=432[M+H] + ;RT=1.45min, >95.00%(214nm).

[0446] Example 83: Compound 83(3-((3-methylpyridine-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) [ka] [ka] Compound 83 was prepared by the method shown in Scheme 79. Compound 83 (3-((3-methylpyridine-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) was prepared as shown in Scheme 79:C 24 H 20 N4O2;396.45g / mol;12mg;white solid;ESI-LCMS m / z=397[M+H] + ;RT=1.25min, >95.00%(214nm).

[0447] Example 84: Compound 84 (3-((2,3-dimethylpyridine-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) [ka] [ka] Compound 84 was prepared by the method shown in Scheme 80. Compound 84 (3-((2,3-dimethylpyridine-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) was prepared as shown in Scheme 80:C 25 H 22 N4O2;410.48g / mol;12mg;white solid;ESI-LCMS m / z=411[M+H] + ;RT=1.29min, >95.00%(214nm).

[0448] Example 85: Compound 85 (3-((3-chloro-2-methylpyridine-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) [ka] [ka] Compound 85 was prepared by the method shown in Scheme 81. Compound 85 (3-((3-chloro-2-methylpyridine-4-yl)amino)-N-(3-(pyridine-4-yloxy)phenyl)benzamide) was prepared as shown in Scheme 81:C 24 H 19 ClN4O2;430.89g / mol;10mg;white solid;ESI-LCMS m / z=431[M+H] + ;RT=1.35min, >95.00%(214nm).

[0449] Example 86: Compound 86 (3-(pyridine-4-ylamino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 86 was prepared by the method shown in Scheme 82. Compound 86(3-(pyridine-4-ylamino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide);C 23 H 19 N5O was prepared as shown in Scheme 82: 381.44 g / mol; 13 mg; white solid; ESI-LCMS m / z = 382 [M + H] + ;RT=1.71min, >95.00%(214nm).

[0450] Example 87: Compound 87 (3-((2-methylpyridine-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 87 was prepared by the method shown in Scheme 83. Compound 87 (3-((2-methylpyridine-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 83:C 24 H 21 N5O;395.47g / mol;15mg;white solid;ESI-LCMS m / z=396[M+H] + ;RT=1.27min, >95.00%(214nm).

[0451] Example 88: Compound 88 (N-(3-((2-methylpyridine-4-yl)amino)phenyl)-3-(pyridine-4-ylamino)benzamide) [ka] [ka] Compound 88 was prepared by the method shown in Scheme 84. Compound 88 (N-(3-((2-methylpyridine-4-yl)amino)phenyl)-3-(pyridine-4-ylamino)benzamide) was prepared as shown in Scheme 84:C 24 H 21 N5O;395.47g / mol;12mg;white solid;ESI-LCMS m / z=396[M+H] + ;RT=1.73min, >95.00%(214nm).

[0452] Example 89: Compound 89(3-((2-methylpyridine-4-yl)amino)-N-(3-((2-methylpyridine-4-yl)amino)phenyl)benzamide) [ka] [ka] Compound 89 was prepared by the method shown in Scheme 85. Compound 89 (3-((2-methylpyridine-4-yl)amino)-N-(3-((2-methylpyridine-4-yl)amino)phenyl)benzamide) was prepared as shown in Scheme 85:C 25 H 23 N5O;409.49g / mol;21mg;white solid;ESI-LCMS m / z=410[M+H] + ;RT=1.35min, >95.00%(214nm).

[0453] Example 90: Compound 90 (N-(4-((2-methylpyridine-4-yl)oxy)pyridine-2-yl)-3-(pyridine-4-ylamino)benzamide) [ka] [ka] Compound 90 was prepared by the method shown in Scheme 86. Compound 90 (N-(4-((2-methylpyridine-4-yl)oxy)pyridine-2-yl)-3-(pyridine-4-ylamino)benzamide) was prepared as shown in Scheme 86:C 23 H 19 N5O2;397.44g / mol;10mg;white solid;ESI-LCMS m / z=398[M+H] + ;RT=1.44min, >95.00%(214nm).

[0454] Example 91: Compound 91 (N-(4-(pyridazine-4-yloxy)pyridin-2-yl)-3-(pyridin-4-ylamino)benzamide) [ka] [ka] Compound 91 was prepared by the method shown in Scheme 87. Compound 91 (N-(4-((2-methylpyridine-4-yl)oxy)pyridine-2-yl)-3-(pyridine-4-ylamino)benzamide) was prepared as shown in Scheme 87:C 21 H 16 N6O2;384.40g / mol;16mg;white solid;ESI-LCMS m / z=385[M+H] + ;RT=1.34min, >95.00%(214nm).

[0455] Example 92: Compound 92 (N-(4-phenoxypyridine-2-yl)-3-(pyridine-4-ylamino)benzamide) [ka] [ka] Compound 92 was prepared by the method shown in Scheme 88. Compound 92 (N-(4-phenoxypyridine-2-yl)-3-(pyridine-4-ylamino)benzamide); C 23 H 18N4O2 was prepared as shown in Scheme 88: 382.42 g / mol; 11 mg; white solid; ESI-LCMS m / z = 383 [M + H] + ;RT=1.52min, >95.00%(214nm).

[0456] Example 93: Compound 93(3-(pyridine-4-ylamino)-N-(4-(pyridine-4-yloxy)pyridine-2-yl)benzamide) [ka] [ka] Compound 93 was prepared by the method shown in Scheme 89. Compound 93 (3-(pyridine-4-ylamino)-N-(4-(pyridine-4-yloxy)pyridine-2-yl)benzamide) was prepared as shown in Scheme 89:C 22 H 17 N5O2;383.41g / mol;12mg;white solid;ESI-LCMS m / z=384[M+H] + ;RT=1.16 min, >95.00%(214nm).

[0457] Example 94: Compound 94(N-(3-(azetidine-3-ylamino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide) [ka] Compound 94 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 94 (N-(3-(azetidine-3-ylamino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide); C 25 H 22 FN5O;427.48g / mol;18mg;Pale yellow solid;ESI-LCMS m / z=428[M+H] + ;RT=0.98min, >95.00%(214nm).

[0458] Example 95: Compound 95(3-((6-fluoroquinoline-4-yl)amino)-N-(3-(phenylamino)phenyl)benzamide) [ka] Compound 95 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 95 (3-((6-fluoroquinoline-4-yl)amino)-N-(3-(phenylamino)phenyl)benzamide);C 28 H 21 FN4O;448.49g / mol;18mg;Pale yellow solid;ESI-LCMS m / z=449[M+H] + ;RT=1.98min, >95.00%(214nm).

[0459] Example 96: Compound 96(3-(pyridine-4-ylamino)-N-(6-(pyridine-4-ylamino)pyridine-2-yl)benzamide) [ka] [ka] Compound 96 was prepared by the method shown in Scheme 90. Compound 96 (3-(pyridine-4-ylamino)-N-(6-(pyridine-4-ylamino)pyridine-2-yl)benzamide) was prepared as shown in Scheme 90:C 22 H 18 N6O;382.43g / mol;10mg;white solid;ESI-LCMS m / z=383[M+H] + ;RT=1.69min, >95.00%(214nm).

[0460] Example 97: Compound 97 (N-(3-(phenylamino)phenyl)-3-(pyridine-4-ylamino)benzamide) [ka] [ka] Compound 97 was prepared by the method shown in Scheme 91. Compound 97 (N-(3-(phenylamino)phenyl)-3-(pyridine-4-ylamino)benzamide); C 24 H 20 N4O was prepared as shown in Scheme 91: 380.45 g / mol; 16 mg; white solid; ESI-LCMS m / z = 381 [M + H] + ;RT=1.90min, >95.00%(214nm).

[0461] Example 98: Compound 98 (N-(3-(pyridazine-4-ylamino)phenyl)-3-(pyridine-4-ylamino)benzamide) [ka] [ka] Compound 98 was prepared by the method shown in Scheme 92. Compound 98 (N-(3-(pyridazine-4-ylamino)phenyl)-3-(pyridine-4-ylamino)benzamide) was prepared as shown in Scheme 92:C 22 H 18 N6O;382.43g / mol;11mg;white solid;ESI-LCMS m / z=383[M+H] + ;RT=1.56 min, >95.00%(214nm).

[0462] Example 99: Compound 99(3-((2-methylpyridine-4-yl)amino)-N-(3-(phenylamino)phenyl)benzamide) [ka] [ka] Compound 99 was prepared by the method shown in Scheme 93. Compound 99 (3-((2-methylpyridine-4-yl)amino)-N-(3-(phenylamino)phenyl)benzamide) was prepared as shown in Scheme 93:C 25 H22 N4O;394.48g / mol;11mg;white solid;ESI-LCMS m / z=395[M+H] + ;RT=1.93min, >95.00%(214nm).

[0463] Example 100: Compound 100 (3-((2-methylpyridine-4-yl)amino)-N-(3-(pyridazine-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 100 was prepared by the method shown in Scheme 94. Compound 100 (3-((2-methylpyridine-4-yl)amino)-N-(3-(pyridazine-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 94:C 23 H 20 N6O;396.45g / mol;11mg;white solid;ESI-LCMS m / z=397[M+H] + ;RT=1.58min, >95.00%(214nm).

[0464] Example 101: Compound 101 (N-(3-((2-fluoropyridine-4-yl)amino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide) [ka] [ka] Compound 101 was prepared by the method shown in Scheme 95. Compound 101 (N-(3-((2-fluoropyridine-4-yl)amino)phenyl)-3-((6-fluoroquinoline-4-yl)amino)benzamide) was prepared as shown in Scheme 95:C 27 H 19 F2N5O;467.47g / mol;17mg;light yellow solid;ESI-LCMS m / z=468[M+H] +;RT=1.50min, >95.00%(214nm).

[0465] Example 102: Compound 102 (3-((6-acetylquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka] Compound 102 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 102 (3-((6-acetylquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide); C 29 H 23 N5O2;473.54g / mol;18mg;light yellow solid;ESI-LCMS m / z=474[M+H] + ;LCMS RT=0.96 min, >95.00%(214nm).

[0466] Example 103: Compound 103 (4-((3-((3-((pyridine-4-ylamino)phenyl)carbamoyl)phenyl)amino)quinoline-6-carboxylic acid) [ka] Compound 103 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 103 (4-((3-((3-((pyridine-4-ylamino)phenyl)carbamoyl)phenyl)amino)quinoline-6-carboxylic acid);C 28 H 21 N5O3;475.51g / mol;12mg;light yellow solid;ESI-LCMS m / z=476[M+H] + ;LCMS RT=1.39 min, >95.00%(214nm).

[0467] Example 104: Compound 104 (4-((3-((3-((pyridine-4-ylamino)phenyl)carbamoyl)phenyl)amino)quinoline-6-carboxylate) [ka] Compound 104 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 104 (4-((3-((3-((pyridine-4-ylamino)phenyl)carbamoyl)phenyl)amino)quinoline-6-carboxylate);C 29 H 23 N5O3;489.54g / mol;18mg;light yellow solid;ESI-LCMS m / z=490[M+H] + ;RT=1.48min, >95.00%(214nm).

[0468] Example 105: Compound 105 (2-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)isonicotinamide) [ka] Compound 105 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 105 (2-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)isonicotinamide); C 26 H 19 FN6O;450.48g / mol;14mg;Pale yellow solid;ESI-LCMS m / z=451[M+H] + ;RT=1.44min, >95.00%(214nm).

[0469] Example 106: Compound 106 (4-((3-(5-(pyridine-4-ylamino)-3H-imidazo[4,5-b]pyridine-2-yl)phenyl)amino)quinoline-6-carbonitrile) [ka] [ka] Compound 106 was prepared by the method shown in Scheme 96. Compound 106(4-((3-(5-(pyridine-4-ylamino)-3H-imidazo[4,5-b]pyridine-2-yl)phenyl)amino)quinoline-6-carbonitrile);C 27 H 18 N8;454.50g / mol;13mg;yellow solid;ESI-LCMS m / z=455[M+H] + ;RT=1.44min, >95.00%(214nm).

[0470] Example 107: Compound 107 (N-(4-phenoxypyridine-2-yl)-3-(pyridine-4-ylamino)benzamide) [ka] [ka] Process a 3-nitrobenzoic acid (1.67 g, 10 mmol), DMAP (1.83 g, 15 mmol), and EDCI (2.86 g, 15 mmol) were dissolved in DMF (20 mL), to which 4-bromopyridine-2-amine (1.72 g, 10 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction product was diluted with water (60 mL) and extracted with EA (3 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA:PE = 1:4) to obtain compound 107-1 as a solid (2.29 g, 71.6%).

[0471] Process bCompound 107-1 (640 mg, 2 mmol), phenol (188 mg, 2 mmol), and Cs2CO3 (1.3 g, 4 mmol) were dissolved in DMF (10 mL), to which KI (332 mg, 2 mmol) and CuI (38 mg, 0.2 mmol) were added. The mixture was stirred overnight at 100 °C. The reaction product was filtered, added to water (50 mL), and extracted using EA (3 × 30 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain compound 107-2 (260 mg, 38.8%).

[0472] Process c To a solution of compound 107-2 (260 mg, 0.77 mmol) in MeOH (10 ml), Pd / C (50 mg) was added. The mixture was stirred at room temperature for 3 hours and then concentrated to obtain compound 107-3 (180 mg, 76%).

[0473] Process d A mixture of compound 107-3 (100 mg, 0.32 mmol), Cs2CO3 (213 mg, 0.65 mmol), and Xantphos (38 mg, 0.065 mmol) was mixed with a solution of Pd(OAc)3 (14 mg, 0.065 mmol) in dried dioxane (8 mL); then 4-bromopyridine (50 mg, 0.32 mmol) was added. The mixture was stirred at 110°C for 4 hours, then diluted with water (10 mL). The reaction product was filtered and then purified by preparative HPLC to obtain compound 107 (N-(4-phenoxypyridine-2-yl)-3-(pyridine-4-ylamino)benzamide) as a white solid (13 mg, 11.3%). 23 H 18 N4O2;382.42g / mol;ESI-LCMS m / z=383[M+H] + ;RT=1.52min, >95.00%(214nm).

[0474] Example 108: Compound 108 (3-(pyridine-4-ylamino)-N-(6-(pyridine-4-ylamino)pyridine-2-yl)benzamide) [ka] [ka] Process a To a mixture of 3-nitrobenzoyl chloride (10 g, 54 mmol) in THF (100 mL), 6-bromopyridine-2-amine (9.3 g, 54 mmol) and TEA (10.9 g, 108 mL) were added, and the mixture was stirred at room temperature for 4 hours. The combined organic phase was concentrated to obtain compound 108-1 as a white solid (15.8 g, 91%).

[0475] Process b To a mixture of compound 108-1 (15.8 g, 49 mmol) in 1,4-dioxane (400 mL), pyridine-4-amine (4.6 g, 49 mmol), Pd2(dba)3 (457 mg, 0.05 mmol), Xantphos (289 mg, 0.05 mmol), and Cs2CO3 (31.8 g, 98 mmol) were added, and the mixture was stirred at 100 °C for 12 hours under N2. The residue was purified by flash silica gel chromatography (PE solution of 0-50% EA) to obtain compound 108-2 (13.5 g, 82.2%) as a yellow solid.

[0476] Process c Compound 108-2 (13.5 g, 40 mmol) was mixed with MeOH (500 mL) and Pd / C (986 mg, 0.92 mmol) was added. The mixture was stirred under H2 at room temperature for 4 hours. The combined organic phase was filtered through diatomaceous earth to obtain compound 108-3 as a solid (12.1 g, 90%).

[0477] Process dCompound 108-3 (50 mg, 0.164 mmol) was mixed with 1,4-dioxane (2 mL) and 4-bromopyridine (26 mg, 0.164 mmol), Pd2(dba)3 (9.1 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and Cs2CO3 (102 mg, 0.32 mmol) were added. The mixture was stirred at 100°C for 12 hours under N2. The mixture was concentrated, and the crude residue was purified by preparative HPLC to obtain compound 108 (3-(pyridine-4-ylamino)-N-(6-(pyridine-4-ylamino)pyridine-2-yl)benzamide) as a white solid (15 mg, 23.9%). 22 H 18 N6O;382.43g / mol;ESI-LCMS m / z=383[M+H] + ;RT=1.69min, >95.00%(214nm).

[0478] Example 109: Compound 109 (3-((2-methylpyridine-4-yl)amino)-N-(3-(phenylamino)phenyl)benzamide) [ka] [ka] Compound 109 was prepared by the method shown in Scheme 99. Compound 109 (3-((2-methylpyridine-4-yl)amino)-N-(3-(phenylamino)phenyl)benzamide); C 25 H 22 N4O;394.48g / mol;11mg;white solid;ESI-LCMS m / z=395[M+H] + ;RT=1.93min, >95.00%(214nm).

[0479] Example 110: Compound 110 (5-(pyridine-4-ylamino)-2-(3-(pyridine-4-ylamino)phenyl)isoindorin-1-one) [ka] [ka] Process a To a mixture of methyl 2-(bromomethyl)-4-nitrobenzoate (15 g, 55 mol) in MeOH (200 mL) while stirring, tert-butyl(3-aminophenyl)carbamate (12.6 g, 60.5 mol) and TEA (12.2 g, 121 mol) were added under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 16 hours and then filtered to obtain compound 110-1 (12.2 g, 60%) as a yellow solid.

[0480] Process b To a mixture of compound 110-1 (12.2 g, 33 mmol) in dioxane hydrochloride (1000 mL, 4 M), TFA was added, and the mixture was stirred at room temperature for 4 hours. The combined organic phase was concentrated to obtain compound 110-2 as a white solid (8.4 g, 95%).

[0481] Process c To a mixture of compound 110-2 (8.4 g, 31 mmol) in 1,4-dioxane (2 mL), 4-bromopyridine (4.87 g, 31 mmol), Pd2(dba)3 (9.1 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and Cs2CO3 (10 g, 31 mmol) were added, and the mixture was stirred at 100 °C for 12 hours under N2. The residue was purified by flash silica gel chromatography (PE solution of 0-50% EA) to obtain the title compound 110-3 (9 g, 83.2%) as a yellow solid.

[0482] Process d Compound 110-3 (9 g, 26 mmol) was mixed with MeOH (1000 mL) and Pd / C (270 mg, 0.26 mmol) was added, and the mixture was stirred at room temperature under H2 for 4 hours. The combined organic phase was filtered through diatomaceous earth to obtain compound 110-4 as a yellow solid (8.2 g, 99%).

[0483] Process eCompound 110-4 (50 mg, 0.158 mmol) was mixed with 1,4-dioxane (2 mL) and 4-bromopyridine (25 mg, 0.158 mmol), Pd(OAc)2 (10.6 mg, 0.03 mmol), Xantphos (18 mg, 0.03 mmol), and Cs2CO3 (102 mg, 0.32 mmol) were added. The mixture was stirred at 100°C for 12 hours under N2. The mixture was concentrated, and the crude residue was purified by preparative HPLC to obtain compound 110 (5-(pyridine-4-ylamino)-2-(3-(pyridine-4-ylamino)phenyl)isoindorin-1-one) as a grayish-white solid (11 mg, 17.7%). 24 H 19 N5O;393.16g / mol;ESI-LCMS m / z=394[M+H] + ;RT=1.30min, >95.00%(214nm).

[0484] Example 111: Compound 111 (N-(3-(phenylamino)phenyl)-3-(pyridine-4-ylamino)benzamide) [ka] [ka] Compound 111 was prepared by the method shown in Scheme 101. Compound 111 (N-(3-(phenylamino)phenyl)-3-(pyridine-4-ylamino)benzamide); C 24 H 20 N4O;380.45g / mol;16mg;white solid;ESI-LCMS m / z=381[M+H] + ;RT=1.90min, >95.00%(214nm).

[0485] Example 112: Compound 112 (N-(3-(2-cyano-3-(trifluoromethyl)pyridine-4-ylamino)phenyl)-3-(6-fluoroquinoline-4-ylamino)benzamide) [ka] [ka] Process a EDCI (135 mg, 0.7 mmol) and DMAP (85 mg, 0.7 mmol) were added to a 2 mL solution of compound 112-1 (95 mg, 0.47 mmol) and compound 112-2 (132 mg, 0.47 mmol) in DMF while stirring. The mixture was stirred at room temperature for 8 hours. The reaction product was purified by preparative HPLC to obtain compound 112 (N-(3-(2-cyano-3-(trifluoromethyl)pyridine-4-ylamino)phenyl)-3-(6-fluoroquinoline-4-ylamino)benzamide) as a pale yellow solid (20 mg, 7.8%). 29 H 18 F4N6O;542.15g / mol;ESI-LCMS m / z=543[M+H] + ;RT=1.69min, >95.00%(214nm).

[0486] Example 113: Compound 113 (N-(3-(2-cyanopyridine-4-ylamino)phenyl)-3-(6-fluoroquinoline-4-ylamino)benzamide) [ka] [ka] Process a EDCI (135 mg, 0.7 mmol) and DMAP (85 mg, 0.7 mmol) were added to a 2 mL solution of compound 113-1 (130 mg, 0.47 mmol) and compound 112-2 (132 mg, 0.47 mmol) in DMF while stirring. The mixture was stirred at room temperature for 8 hours. The reaction product was purified by preparative HPLC to obtain compound 113 (N-(3-(2-cyanopyridine-4-ylamino)phenyl)-3-(6-fluoroquinoline-4-ylamino)benzamide) (20 mg, 9.0%) as a pale yellow solid. 28 H 19 FN6O;474.16g / mol;ESI-LCMS m / z=475[M+H] +;RT=1.58min, >95.00%(214nm).

[0487] Example 114: Compound 114 (5-(2-methylpyridine-4-ylamino)-2-(3-(pyridine-4-ylamino)phenyl)isoindorin-1-one) [ka] [ka] Compound 110-4 was synthesized by the method described in Example 110.

[0488] Process a Compound 110-4 (50 mg, 0.158 mmol) was mixed with 1,4-dioxane (2 mL) and 4-bromo-2-methylpyridine (27 mg, 0.158 mmol), Pd(OAc)2 (10.6 mg, 0.03 mmol), Xantphos (18 mg, 0.03 mmol), and Cs2CO3 (100 mg, 0.31 mmol) were added. The mixture was stirred at 100°C for 12 hours under N2. The mixture was concentrated, and the crude residue was purified by preparative HPLC to obtain compound 114 (5-(2-methylpyridine-4-ylamino)-2-(3-(pyridine-4-ylamino)phenyl)isoindorin-1-one) as a white solid (20 mg, 31%). 25 H 21 N5O;407.47g / mol;ESI-LCMS m / z=407.9[M+H] + ;RT=1.34min, >95.00%(214nm).

[0489] Example 115: Compound 115 (5-(5-chloro-2-methylpyridine-4-ylamino)-2-(3-(pyridine-4-ylamino)phenyl)isoindorin-1-one) [ka] Compound 115 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 115 (5-(5-chloro-2-methylpyridine-4-ylamino)-2-(3-(pyridine-4-ylamino)phenyl)isoindorin-1-one); C 25 H 20 ClN5O;441.91g / mol;11mg;white solid;ESI-LCMS m / z=442[M+H] + ;RT=1.47min, >95.00%(214nm).

[0490] Example 116: Compound 116 (2-(3-(pyridine-4-ylamino)phenyl)-5-(2,3,5-trimethylpyridine-4-ylamino)isoindorin-1-one) [ka] Compound 116 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 116(2-(3-(pyridine-4-ylamino)phenyl)-5-(2,3,5-trimethylpyridine-4-ylamino)isoindorin-1-one);C 27 H 25 N5O;435.52g / mol;11mg;white solid;ESI-LCMS m / z=436[M+H] + ;RT=1.44min, >95.00%(214nm).

[0491] Example 117: Compound 117 (5-(2,3-dimethylquinoline-4-ylamino)-2-(3-(pyridine-4-ylamino)phenyl)isoindoline-1-one) [ka] Compound 117 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 117(5-(2,3-dimethylquinoline-4-ylamino)-2-(3-(pyridine-4-ylamino)phenyl)isoindoline-1-one);C 30 H 25N5O;471.55g / mol;12mg;white solid;ESI-LCMS m / z=472[M+H] + ;RT=1.83min, >95.00%(214nm).

[0492] Example 118: Compound 118 (2-(3-(3-fluorophenylamino)phenyl)-5-(2-methylpyridine-4-ylamino)isoindorin-1-one) [ka] [ka] Process a A mixture of 1-bromo-3-fluorobenzene (1.74 mg, 10 mmol), Cs2CO3 (6.5 g, 20 mmol), and Xantphos (578 g) was mixed with 30 mL of dried dioxane Pd(OAc)3 (224 mg, 1 mmol), followed by 1.38 g, 10 mmol of 3-nitroaniline. The mixture was stirred at 100°C for 8 hours and then diluted with water (80 mL). The reaction product was filtered, and the residue was purified by silica gel column (EA:PE = 1:3) to obtain compound 118-1 as a solid (1.8 g, 77.5%).

[0493] Process b A solution of compound 118-1 (1.8 g, 7.7 mmol) and Pd / C (300 mg) in MeOH (30 mL) was stirred at room temperature for 2 hours. The reaction product was filtered and concentrated under reduced pressure to obtain compound 118-2 (1.3 g, 83%).

[0494] Process c A mixture of compound 118-2 (505 mg, 2.5 mmol), methyl 2-(bromomethyl)-4-nitrobenzoate (683 mg, 2.5 mmol), and pyridine (257 mg, 3.25 mmol) in EtOH (10 mL) was stirred at 80°C for 16 hours. The reaction product was filtered to obtain compound 118-3 as a solid (600 mg, 66.1%).

[0495] Process dCompound 118-3 (600 mg, 7.7 mmol) and Pd / C (300 mg) were mixed in THF (15 mL) and MeCN (15 mL) solutions and stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain compound 118-4 (500 mg, 90%).

[0496] Process e A mixture of compound 118-4 (100 mg, 0.3 mmol), Cs2CO3 (195 mg, 0.6 mmol), and Xantphos (35 mg, 0.06 mmol) was mixed with 8 mL of dried dioxane Pd(OAc)3 (14 mg, 0.06 mmol), followed by 52 mg, 0.3 mmol, of 4-bromo-2-methylpyridine. The mixture was stirred at 100°C for 4 hours and then diluted with water (20 mL). The reaction product was filtered and purified by preparative HPLC to obtain compound 118 (2-(3-(3-fluorophenylamino)phenyl)-5-(2-methylpyridine-4-ylamino)isoindorin-1-one) as a white solid (26 mg, 19.8%). 26 H 21 FN4O;424.47g / mol;ESI-LCMS m / z=425[M+H] + ;RT=1.70min, >95.00%(214nm).

[0497] Example 119: Compound 119 (5-(3-chloro-2-methylpyridine-4-ylamino)-2-(3-(pyridine-4-ylamino)phenyl)isoindorin-1-one) [ka] [ka] Compound 110-4 was synthesized by the method described in Example 110.

[0498] Process aCompound 110-4 (50 mg, 0.158 mmol) was mixed with 1,4-dioxane (2 mL) and 4-bromo-3-chloro-2-methylpyridine (32 mg, 0.158 mmol), Pd(OAc)2 (10.6 mg, 0.03 mmol), Xantphos (18 mg, 0.03 mmol), and Cs2CO3 (100 mg, 0.31 mmol) were added. The mixture was stirred at 100°C for 12 hours under N2. The mixture was concentrated, and the crude residue was purified by preparative HPLC to obtain compound 119 (5-(3-chloro-2-methylpyridine-4-ylamino)-2-(3-(pyridine-4-ylamino)phenyl)isoindorin-1-one) as a white solid (13 mg, 18.6%). 25 H 20 ClN5O;441.91g / mol;ESI-LCMS m / z=442[M+H] + ;RT=1.66min, >95.00%(214nm).

[0499] Example 120: Compound 120 (2-(3-(4-fluorophenylamino)phenyl)-5-(2-methylpyridine-4-ylamino)isoindorin-1-one) [ka] [ka] Process a A mixture of 1-bromo-4-fluorobenzene (1.74 mg, 10 mmol), Cs2CO3 (6.5 g, 20 mmol), and Xantphos (578 g) was mixed with 30 mL of dried dioxane Pd(OAc)3 (224 mg, 1 mmol), followed by 1.38 g, 10 mmol of 3-nitroaniline. The mixture was stirred at 100°C for 8 hours and then diluted with water (80 mL). The reaction product was filtered, and the residue was purified by silica gel column (EA:PE = 1:3) to obtain compound 120-1 as a solid (1.7 g, 73.2%).

[0500] Process bA solution of compound 120-1 (1.7 g, 7.7 mmol) and Pd / C (300 mg) in MeOH (30 mL) was stirred at room temperature for 2 hours. The reaction product was filtered and concentrated under reduced pressure to obtain compound 120-2 (1.2 g, 81%).

[0501] Process c Compound 120-2 (505 mg, 2.5 mmol), methyl 2-(bromomethyl)-4-nitrobenzoate (683 mg, 2.5 mmol), and pyridine (257 mg, 3.25 mmol) were mixed in EtOH (10 mL) and stirred at 80°C for 16 hours. The reaction product was filtered to obtain compound 120-3 as a solid (600 mg, 66.1%).

[0502] Process d Compound 120-3 (600 mg, 7.7 mmol) and Pd / C (300 mg) were mixed in THF (15 mL) and MeCN (15 mL) and stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain compound 120-4 (500 g, 90%).

[0503] Process e A mixture of compound 120-4 (100 mg, 0.3 mmol), Cs2CO3 (195 mg, 0.6 mmol), and Xantphos (35 mg, 0.06 mmol) was mixed with 8 mL of dried dioxane Pd(OAc)3 (14 mg, 0.06 mmol), followed by 52 mg, 0.3 mmol, of 4-bromo-2-methylpyridine. The mixture was stirred at 100°C for 4 hours and then diluted with water (20 mL). The reaction product was filtered and purified by preparative HPLC to obtain compound 120 (2-(3-(4-fluorophenylamino)phenyl)-5-(2-methylpyridine-4-ylamino)isoindorin-1-one) as a grayish-white solid (23 mg, 18.1%). 26 H 21 FN4O;424.47g / mol;ESI-LCMS m / z=425[M+H] + ;RT=1.70min, >95.00%(214nm).

[0504] Example 121: Compound 121 (5-(2-methylpyridine-4-ylamino)-2-(3-(2,3,4-trifluorophenylamino)phenyl)isoindorin-1-one) [ka] Compound 121 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 121(5-(2-methylpyridine-4-ylamino)-2-(3-(2,3,4-trifluorophenylamino)phenyl)isoindorin-1-one);C 26 H 19 F3N4O;460.45g / mol;11mg;white solid;ESI-LCMS m / z=461[M+H] + ;RT=1.72min, >95.00%(214nm).

[0505] Example 122: Compound 122 (2-(3-(2,4-difluorophenoxy)phenyl)-5-(2-methylpyridine-4-ylamino)isoindorin-1-one) [ka] Compound 122 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 122 (2-(3-(2,4-difluorophenoxy)phenyl)-5-(2-methylpyridine-4-ylamino)isoindorin-1-one); C 26 H 19 F2N3O2;443.44g / mol;13mg;off-white solid;ESI-LCMS m / z=444[M+H] + ;RT=1.76min, >95.00%(214nm).

[0506] Example 123: Compound 123 (5-(2-methylpyridine-4-ylamino)-2-(3-(pyridine-4-yloxy)phenyl)isoindorin-1-one) [ka] Compound 123 was prepared by methods known in the art and / or by methods similar to those described herein. Compound 123 (5-(2-methylpyridine-4-ylamino)-2-(3-(pyridine-4-yloxy)phenyl)isoindorin-1-one); C 25 H 20 N4O2;408.45g / mol;14mg;off-white solid;ESI-LCMS m / z=409[M+H] + ;RT=1.22min, >95.00%(214nm).

[0507] Example 124: Compound 124 (2-(3-(4-fluorophenoxy)phenyl)-5-(2-methylpyridine-4-ylamino)isoindorin-1-one) [ka] Compound 124 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 124 (2-(3-(4-fluorophenoxy)phenyl)-5-(2-methylpyridine-4-ylamino)isoindorin-1-one); C 26 H 20 FN3O2;425.45g / mol;11mg;yellow solid;ESI-LCMS m / z=426[M+H] + ;RT=1.76min, >95.00%(214nm).

[0508] Example 125: Compound 125 (3-(2-amino-6-methylpyridine-4-ylamino)-N-(4-(pyridine-4-ylamino)pyridine-2-yl)benzamide) [ka] [ka] Compound 126-3 was synthesized by the method described in Example 126.

[0509] Process aTo a mixture of 4-bromo-6-methylpyridine-2-amine (5 g, 27 mmol) in THF (20 mL), (Boc)2 (17 g, 80.6 mmol) and TEA (8 g, 80.6 mmol) were added, and the mixture was stirred at room temperature for 6 hours. The residue was purified by flash silica gel chromatography (PE solution of 0-30% ES) to obtain compound 125-1 (6 g, 57%) as a white solid.

[0510] Process b Compound 125-1 (44 mg, 0.164 mmol), Pd2(dba)3 (9.1 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and Cs2CO3 (102 mg, 0.32 mmol) were added to a mixture of compound 126-3 (50 mg, 0.164 mmol) in 1,4-dioxane (2 mL), and the mixture was stirred at 100°C for 12 hours under N2. The mixture was concentrated to obtain compound 125-2, which was used directly in the next step without further purification.

[0511] Process c The mixture of compound 125-2 in TFA (3 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the crude residue was purified by preparative HPLC to obtain compound 125 (3-(2-amino-6-methylpyridine-4-ylamino)-N-(4-(pyridine-4-ylamino)pyridine-2-yl)benzamide) as a white solid (13 mg, 14%). 23 H 21 N7O;411.46g / mol;ESI-LCMS m / z=412[M+H] + ;RT=1.40min, >95.00%(214nm).

[0512] Example 126: Compound 126 (N-(4-(pyridine-4-ylamino)pyridine-2-yl)-3-(quinoline-5-ylamino)benzamide) [ka] [ka] Process aTo a mixture of 4-nitrobenzoyl chloride (10 g, 54 mmol) in THF (100 mL), 4-bromopyridine-2-amine (9.3 g, 54 mmol) and TEA (10.9 g, 108 mL) were added, and the mixture was stirred at room temperature for 4 hours. The combined organic phase was concentrated to obtain compound 126-1 as a white solid (16.5 g, 95%).

[0513] Process b Compound 126-1 (16.5 g, 51 mmol) was mixed with 1,4-dioxane (200 mL) and pyridine-4-amine (4.9 g, 51 mmol), Pd2(dba)3 (457 mg, 0.05 mmol), Xantphos (289 mg, 0.05 mmol), and Cs2CO3 (33 g, 102 mmol) were added. The mixture was stirred at 100°C for 12 hours under N2. The residue was purified by flash silica gel chromatography (PE solution of 0-50% EA) to obtain compound 126-2 (14.3 g, 83.6%) as a yellow solid.

[0514] Process c Compound 126-2 (14.3 g, 43 mmol) was mixed with MeOH (1000 mL) and Pd / C (986 mg, 0.92 mmol) was added. The mixture was stirred under H2 at room temperature for 4 hours. The combined organic phase was filtered through diatomaceous earth to obtain compound 126-3 as a yellow solid (12.1 g, 92%).

[0515] Process d Compound 126-3 (50 mg, 0.164 mmol) was mixed with 1,4-dioxane (2 mL) and 5-chloroquinoline (26 mg, 0.164 mmol), Pd2(dba)3 (9.1 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and Cs2CO3 (102 mg, 0.32 mmol) were added. The mixture was stirred at 100°C for 12 hours under N2. The mixture was concentrated, and the crude residue was purified by preparative HPLC to obtain compound 126 (N-(4-(pyridine-4-ylamino)pyridine-2-yl)-3-(quinoline-5-ylamino)benzamide) as a yellow solid (25 mg, 36%). 26 H 20N6O;432.48g / mol;ESI-LCMS m / z=433[M+H] + ;RT=1.73min, >95.00%(214nm).

[0516] Example 127: Compound 127 (3-(2-amino-3-methylpyridine-4-ylamino)-N-(4-(pyridine-4-ylamino)pyridine-2-yl)benzamide) [ka] [ka] Compound 126-3 was synthesized by the method described in Example 126. Compound 129-3 was synthesized by the method described in Example 129.

[0517] Process a Compound 129-3 (44 mg, 0.164 mmol), Pd2(dba)3 (9.1 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and Cs2CO3 (102 mg, 0.32 mmol) were added to a mixture of compound 126-3 (50 mg, 0.164 mmol) in 1,4-dioxane (2 mL), and the mixture was stirred at 100°C for 12 hours under N2. The mixture was concentrated to obtain compound 127-1, which was used directly in the next step without further purification.

[0518] Process b A solution of compound 127-1 in TFA (3 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the crude residue was purified by preparative HPLC to obtain compound 127 (3-(2-amino-3-methylpyridine-4-ylamino)-N-(4-(pyridine-4-ylamino)pyridine-2-yl)benzamide) as a white solid (13 mg, 14%). 23 H 21 N7O;411.46g / mol;ESI-LCMS m / z=412[M+H] + ;RT=1.39min, >95.00%(214nm).

[0519] Example 128: Compound 128 (3-(2-aminopyridine-4-ylamino)-N-(4-(pyridine-4-ylamino)pyridine-2-yl)benzamide) [ka] [ka] Compound 126-3 was synthesized by the method described in Example 126.

[0520] Process a To a mixture of compound 126-3 (50 mg, 0.164 mmol) in 1,4-dioxane (2 mL), tert-butyl(4-bromopyridine-2-yl)carbamate (44 mg, 0.164 mmol), Pd2(dba)3 (9.1 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and Cs2CO3 (102 mg, 0.32 mmol) were added, and the mixture was stirred at 100°C for 12 hours under N2. The mixture was concentrated to obtain compound 128-1, which was used directly in the next step without further purification.

[0521] Process b A solution of compound 128-1 in TFA (3 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the crude residue was purified by preparative HPLC to obtain compound 128 (3-(2-aminopyridine-4-ylamino)-N-(4-(pyridine-4-ylamino)pyridine-2-yl)benzamide) as a white solid (10 mg, 15%). 22 H 19 N7O;397.43g / mol;ESI-LCMS m / z=398[M+H] + ;RT=1.41min, >95.00%(214nm).

[0522] Example 129: Compound 129 (3-(2-amino-3-methylpyridine-4-ylamino)-N-(3-(phenylamino)phenyl)benzamide) [ka] [ka] Process a A solution of 4-bromo-3-methylpyridine-2-amine (558 mg, 3 mmol), di-tert-butyl dicarbonate (1.96 g, 9 mmol), and TEA (909 mg, 9 mmol) in THF (10 mL) was stirred overnight at room temperature. The reaction mixture was filtered, added to water (30 mL), and extracted using EA (3 × 30 mL). The organic layers were combined, washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 129-3 (790 mg, 68%).

[0523] Process b 4-((tert-butoxycarbonyl)amino)benzoic acid (474 ​​mg, 2 mmol), DMAP (366 mg, 3 mmol), and EDCI (573 mg, 3 mmol) were dissolved in DMF (10 mL), to which N1-phenylbenzene-1,3-diamine (368 mg, 2 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction product was diluted with water (40 mL) and then extracted with EA (3 × 30 mL). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA:PE = 1:5) to obtain compound 129-1 as a solid (650 mg, 80.6%).

[0524] Process c To a solution of compound 129-1 (650 mg, 1.6 mmol) in MeOH (30 mL), dioxane / HCl (4 M, 30 mL) was added. The mixture was stirred at room temperature for 3 hours and then concentrated to obtain compound 129-2 (450 mg, 93%).

[0525] Process dA mixture of compound 129-2 (85 mg, 0.25 mmol), Cs2CO3 (163 mg, 0.5 mmol), and Xantphos (29 mg, 0.05 mmol) was mixed with 8 mL of dried dioxane Pd(OAc)3 (12 mg, 0.05 mmol) and compound 129-3 (96 mg, 0.25 mmol). The mixture was stirred at 110°C for 4 hours. It was diluted with water (10 mL), filtered, and compound 129-4 (150 mg, 100%) was obtained.

[0526] Process e To a solution of compound 129-4 (150 mg) in DCM (6 mL), TFA (2 mL) was added and the mixture was stirred at room temperature for 3 hours. The reaction product was concentrated, and the residue was purified by preparative HPLC to obtain compound 129 (3-(2-amino-3-methylpyridine-4-ylamino)-N-(3-(phenylamino)phenyl)benzamide) as a white solid (15 mg, 15%). 25 H 23 N5O;409.48g / mol;ESI-LCMS m / z=410[M+H] + ;RT=1.72min, >95.00%(214nm).

[0527] Example 130: Compound 130 (3-(2-aminopyridine-4-ylamino)-N-(3-(phenylamino)phenyl)benzamide) [ka] [ka] Process a To a solution of compound 130-1 (120 mg) in DCM (5 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction product was concentrated, and the residue was purified by preparative HPLC to obtain compound 130 (3-(2-aminopyridine-4-ylamino)-N-(3-(phenylamino)phenyl)benzamide) as a white solid (15 mg, 14.7%). 24 H 21 N5O;395.46g / mol;ESI-LCMS m / z=396[M+H] +;RT=1.72min, >95.00%(214nm).

[0528] Example 131: Compound 131 (3-(2-amino-6-methylpyridine-4-ylamino)-N-(3-(phenylamino)phenyl)benzamide) [ka] [ka] Compound 129-2 was synthesized by the method described in Example 129.

[0529] Process a A solution of 4-bromo-6-methylpyridine-2-amine (558 mg, 3 mmol), di-tert-butyl dicarbonate (1.96 g, 9 mmol), and TEA (909 mg, 9 mmol) in THF (10 mL) was stirred overnight at room temperature. The reaction mixture was filtered, added to water (30 mL), and extracted using EA (3 × 30 mL). The organic layers were combined, washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 131-1 (800 mg, 69%).

[0530] Process b A mixture of compound 129-2 (85 mg, 0.25 mmol), Cs2CO3 (163 mg, 0.5 mmol), and Xantphos (29 mg, 0.05 mmol) was mixed with 8 mL of dried dioxane Pd(OAc)3 (12 mg, 0.05 mmol), followed by compound 131-1 (96 mg, 0.25 mmol). The mixture was stirred at 100°C for 4 hours, then diluted with water (10 mL). The reaction product was filtered to obtain compound 131-2 (151 mg, 100%).

[0531] Process cTo a solution of compound 131-2 (151 mg) in DCM (6 mL), TFA (2 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction product was concentrated, and the residue was purified by preparative HPLC to obtain compound 131 (3-(2-amino-6-methylpyridine-4-ylamino)-N-(3-(phenylamino)phenyl)benzamide) as a white solid (18 mg, 17.6%). 25 H 23 N5O;409.48g / mol;ESI-LCMS m / z=410[M+H] + ;RT=1.75min, >95.00%(214nm).

[0532] Example 132: Compound 132 (2-(3-(cyclopentylamino)phenyl)-5-(pyridine-4-ylamino)isoindorin-1-one) [ka] [ka] Process a A solution of compound 132-1 (403 mg, 1.5 mmol) and cyclopentanone (504 mg, 6 mmol) in DCE (15 mL) was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (954 mg, 4.5 mmol) was added. The reaction mixture was filtered, added to water (50 mL), and extracted using DCM (3 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=3:1) to obtain compound 132-2 (300 mg, 59%).

[0533] Process b Compound 132-2 (300 mg, 0.89 mmol) and Pd / C (100 mg) were mixed in THF (10 mL) and MeCN (10 mL) solutions and stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain compound 132-3 (200 mg, 73%).

[0534] Process cA mixture of compound 132-3 (76 mg, 0.25 mmol), Cs2CO3 (163 mg, 0.5 mmol), and Xantphos (29 mg, 0.05 mmol) was mixed with 8 mL of dried dioxane Pd(OAc)3 (12 mg, 0.05 mmol), followed by 4-bromopyridine (40 mg, 0.25 mmol). The mixture was stirred at 100°C for 4 hours, then diluted with water (10 mL) and filtered. The residue was purified by preparative HPLC to obtain compound 132 (2-(3-(cyclopentylamino)phenyl)-5-(pyridine-4-ylamino)isoindorin-1-one) as a white solid (15 mg, 15%). 24 H 24 N4O;384.47g / mol;ESI-LCMS m / z=385[M+H] + ;RT=1.67min, >95.00%(214nm).

[0535] Example 133: Compound 133 (2-(3-(methylamino)phenyl)-5-(pyridine-4-ylamino)isoindorin-1-one) [ka] Compound 133 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 133 (2-(3-(methylamino)phenyl)-5-(pyridine-4-ylamino)isoindorin-1-one); C 20 H 18 N4O;330.38g / mol;14mg;white solid;ESI-LCMS m / z=331[M+H] + ;RT=1.40min, >95.00%(214nm).

[0536] Example 134: Compound 134 (6-(2-methylpyridine-4-ylamino)-2-(3-(pyridine-4-ylamino)phenyl)isoindorin-1-one) [ka] Compound 134 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 134 (6-(2-methylpyridine-4-ylamino)-2-(3-(pyridine-4-ylamino)phenyl)isoindorin-1-one); C 25 H 21 N5O;407.47g / mol;11mg;white solid;ESI-LCMS m / z=408[M+H] + ;RT=1.43min, >95.00%(214nm).

[0537] Example 135: Compound 135 (1-(3-(2-methylpyridine-4-ylamino)phenyl)-3-(3-(pyridine-4-ylamino)phenyl)urea) [ka] Compound 135 was prepared by methods known in the art and / or by methods similar to those described herein. Compound 135 (1-(3-(2-methylpyridine-4-ylamino)phenyl)-3-(3-(pyridine-4-ylamino)phenyl)urea); C 24 H 22 N6O;410.47g / mol;14mg;white solid;ESI-LCMS m / z=411[M+H] + ;RT=1.47min, >95.00%(214nm).

[0538] Example 136: Compound 136 (N-(3-(2-fluoropyridine-4-ylamino)phenyl)-3-(6-fluoroquinoline-4-ylamino)benzamide) [ka] Compound 136 was prepared by methods known in the art and / or by methods relating to those described herein. Compound 136 (N-(3-(2-fluoropyridine-4-ylamino)phenyl)-3-(6-fluoroquinoline-4-ylamino)benzamide); C 27 H 19 F2N5O;467.47g / mol;17mg;light yellow solid;ESI-LCMS m / z=468[M+H]+ ;RT=1.50min, >95.00%(214nm).

[0539] Example 137: Compound 137 (3-((6-fluoroquinoline-4-yl)amino)-N-(3-(pyridine-4-ylamino)phenyl)benzamide) [ka]

[0540] Example 138. Biological assay Foxp3 induction assay Conventional CD4 T cells (Tconvs-CD4+ / CD25) selected or enriched (Miltenyi magnetic separation) from C57 / Bl6 mice were used to induce iTreg cells. 10 μg / mL plate-bound anti-CD3 antibody (50 μl / well for a 96-well plate), 2.5 μg / mL soluble anti-CD28 antibody, 100 IU / mL IL2, and 5 ng / mL TGF-β were used in or without various drug concentrations (typically ranging from 0.01 μM to 10 μM). A TGF-β-free sample was used as a negative control for induction.

[0541] After 3 days of culture in the presence of stimulation, TGF-β, and the drug, cells were stained with a fixed viable / dead cell stain (Life Technologies, NY) for gating and toxic dose exclusion. Cells were fixed and permeabilized using a mouse Foxp3 buffer kit according to the manufacturer's instructions (BD Bioscience, San Jose, CA). Anti-CD4 and anti-Foxp3 antibodies were used to stain the cells. After staining, cells were acquired using a flow cytometer.

[0542] Jurkat-FoxP3 reporter assay (by BPS Bioscience, Cat # 60628) Cell culture process: Prepare a 50 ml conical tube and a T-25 culture flask containing 5 mL of preheated Thaw Medium 2 (G418-free). Thaw the cells rapidly in a 37°C water bath with constant and slow agitation. Transfer the entire contents to the conical tube containing Thaw Medium 2 (G418-free) and centrifuge the cells at 200 × g for 3 minutes. Resuspend the cells in 6 mL of preheated Thaw Medium 2 (G418-free) and transfer the entire contents to the T25 culture flask containing Thaw Medium 2 (G418-free). Incubate the cells in a humidified 37°C incubator with 5% CO2. After 48 hours of incubation, centrifuge the cells at 250 × g for 5 minutes and resuspend them in fresh Thaw Medium 2 (G418-free). Continue monitoring growth for 2-3 days and perform cell exchange to remove dead cells and debris. After multiple cell colonies (clumps) begin to appear (an indicator of healthy cell division), switch to growth medium 2B (containing G418).

[0543] Post-assay protocol: (CD3 / CD28) 1. Jurkat-FoxP3-luciferase reporter cells were cultured in white, opaque 384-well plates in assay medium (RPMI 1640 medium supplemented with 1% penicillin / streptomycin (Thermo Fisher, Cat. #A1049101)) at a concentration of approximately 2.5 × 10³ cells / well (10 μL / well) in the absence and presence (ratio: 1:5) of human T-activator CD3 / CD28 Dynabeads (Thermo Fisher, Cat. No. 11161D).

[0544] 2. The drug was serially diluted in the range of 1 to 60,000 nM, and 10 μL of the drug was added to bring the concentration to the range of 1 to 30,000 nM, and the mixture was gently mixed by sacking. In some experiments, the range was 10 to 20,000 nM. Cells were cultured at 37°C in 5% CO2 for 12 hours in the presence and absence of the drug.

[0545] 3. One-Step TMAdd the Luciferase Assay System (BPS Bioscience, Cat. #60690) to each well according to the protocol. Add equal volumes of luciferase assay working solution (component A + component B) to the culture medium in each well. For example, a 384-well plate containing 20 μl of culture medium per well requires 20 μl of luciferase assay working solution.

[0546] 4. Gently shake the plate at room temperature for ≥15 minutes. Measure the firefly luminescence using a luminometer.

[0547] Phospho-Akt isoform specificity assay Human CD4+ / CD45R a + / CD25 naive T cells were seeded for 72 hours under induction conditions (IL-2 / anti-CD3 / anti-CD28+TGFβ) in or without the compound. To determine the specificity of the compound to each phospho-AKT isoform, phospho-AKT cell HTRF kits (Cisbio catalog numbers 63ADK078PEG (pAKT1), 63ADK080PEG (p-AKT2), ​​and 63ADK082PEG (pAKT3)) were used according to the manufacturer's instructions. Briefly, after removing the supernatant for all samples, the cells were lysed, and the total protein concentration was measured and normalized. Cell lysates were transferred to 384-well plates and a mixture of Eu-cryptate antibody + d2 antibody was added. This step was the same for each isoform, but the corresponding isoform antibody from each kit was used. Positive and negative controls (included in the kit) were incorporated into each experiment. Plates were incubated overnight. Data were acquired using a Varioskan Lux reader with a TRF fluorescence protocol setup. Data are presented as a percentage change relative to the DMSO-treated control. Each test condition was duplicated, and the assay was performed at least twice.

[0548] IL-10 ELISA assay Human CD4+ / CD25+ native Treg cells were seeded under stimulating conditions (IL-2 / anti-CD3 / anti-CD28) in or out of the presence of the compound. After 24 and 48 hours of incubation, the supernatant was collected and the IL-10 concentration was determined using a human IL-10 ELISA kit (Invitrogen BMS215-2) according to the manufacturer's specifications. Briefly, the supernatant was added to a pre-coated 96-well ELISA plate, incubated, and then biotin conjugate detection antibody and streptavidin-HRP were added. After incubation, the substrate was added and the reaction was stopped with acid. Absorbance was measured at 450 nm using a Varioskan Lux reader. Calibration curves were constructed using IL-10 of known concentration (included in the kit) and the IL-10 concentration of the supernatant was calculated. Data are presented as a percentage change relative to the untreated stimulated cell control. Each test condition was performed in triplicate, and the assay was performed at least twice.

[0549] The data shown in Figure 2 were obtained using this assay protocol, at least in part.

[0550] FoxP3 ELISA assay Human CD4+ / CD45R a+ / CD25 naive T cells were seeded for 72 hours under induction conditions (IL-2 / anti-CD3 / anti-CD28+TGFβ) in or without the compound. After incubation, cells were lysed, and FoxP3 protein was measured in lysates using a human FoxP3 ELISA kit (LSBio, LS-F5047) according to the manufacturer's specifications. Briefly, the lysates were added to a pre-coated 96-well ELISA plate, incubated, and then biotin conjugate detection antibody and streptavidin-HRP were added. After incubation, substrates were added, and the reaction was stopped with acid. Absorbance was measured at 450 nm using a Varioskan Lux reader. Calibration curves were created using FoxP3 (included in the kit) with known concentrations, and the concentration of FoxP3 in the lysates was calculated. Data are presented as a percentage change for cell induction in the absence of the compound. Each test condition was performed in duplicate, and the assay was performed at least twice.

[0551] iTreg induction assay Selected human CD4 T cells were used to induce iTregs. Human T cell activation beads (Gibco Dynabeads CD3 / CD28), 100 IU / mL of IL-2, and 5 ng / mL of TGF-β were used in the absence or presence of various drug concentrations. A TGF-β-free sample was used as a negative control for induction. Three days after TGF-β stimulation and in the presence of the drug, cells were stained with fixed viable / dead cell staining (Life Technologies) for gating and toxic dose exclusion, fixed and permeable treated with a Foxp3 buffer kit according to the manufacturer's specifications (BD Bioscience), and stained with anti-Foxp3 antibody. After staining, cells were acquired using a flow cytometer. Each test condition was duplicated, and the assay was performed at least twice.

[0552] The data shown in Figures 1 and 5–7 were obtained using this assay protocol, at least in part.

[0553] Various compounds from one or more embodiments were evaluated for iTreg-inducing activity, and the results are shown in Figures 1, 2, and 5-7. Figure 3 shows the evaluation of IL-10 in the supernatant of human nTreg cells treated with 1 μM compound 137 for 24 and 48 hours in the presence of anti-CD3 / anti-CD28 / IL-2 stimulation. Figure 4 shows the in vivo changes in Tregs, TMEs, and spleens 2 days after IP treatment (1 mg / kg and 5 mg / kg) with compound 137.

[0554] In vivo effect on Tregs TC-1 tumor-bearing mice were treated with the indicated doses of the compounds by forced oral administration. Two days after single-dose treatment, the spleen was isolated and the percentage of Tregs was evaluated using flow cytometry. %Treg was normalized to the untreated control. Figure 8 shows the evaluation of Treg inhibition in isolated spleens of TC-1 tumor-bearing mice two days after single-dose forced oral administration of compounds 137, 110, 99, and 114 (normalized to the untreated control; measured by flow cytometry). Figure 9 shows the evaluation of Treg inhibition in isolated spleens of TC-1 tumor-bearing mice two days after single-dose forced oral administration of compounds 137, 126, and 120 (normalized to the untreated control; measured by flow cytometry).

[0555] The Akt3 inhibitory and activating activities of the selected compounds disclosed herein are shown in Tables 1 and 2, respectively. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 3] Furthermore, the present invention encompasses the following aspects. 1. Formula Ia, Ib, or Ic

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Claims

1. Formulas Ia, Ib, or Ic 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof Here: 【Chemistry 2】 teeth 【Transformation 3】 And, X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , X ８ and X ９ each of which is independently CR １ or N; R １ H, D, halogen, (C １ -C ６ ) alkyl, (C ２ -C ６ ) Alkinnil, (C ２ -C ６ ) Haloalkynyl, aryl, heteroaryl, -OR ａ , -N(R ａ ) ２ , -COR ａ , -CO ２ R ａ CON(R ａ ) ２ ,-CN,NO ２ , N ３ and -SO ２ R ａ Selected from the group consisting of; Q is NR ａ or O; Y １ , Y ２ , Y ３ , Y ４ and Y ５ N or CR are possible independently depending on their valence. ２ And; R ２ H, halogen and (C １ -C ６ Selected from the group consisting of alkyl groups; -E-G- is -(C=O)NR ｘ - or - NR ｘ (C=O)-, where R ｘ and Y ３ , R ｘ and Y ４ , R ｘ and Z １ or R ｘ and Z ４ They form a 5-6 member heteroring, which may be substituted in some cases; T is independently possible in each case by valence, either N or NR ａ And; U is possible in each case independently by valence as N or NR ａ And; Z １ Z ２ Z ３ Z ４ and Z ５ Each of these is possible independently depending on the valence of N or CR ３ And; R ３ is H, halogen or (C １ -C ６ Selected from the group consisting of alkyl groups; V is NR ａ or O; R ４ is aryl, heteroaryl, (C １ -C ６ ) alkyl, (C ３ -C ７ )Cycloalkyl or (C ３ -C ７ ) Selected from the group consisting of heterocycloalkyl groups, each having one or more R ５ It has been replaced with; R ５ (C) is independent in each case. １ -C ６ )alkyl, halogen, -N(R ａ ) ２ , H, (C １ -C ６ ) Selected from the group consisting of haloalkyl or -CN; and R ａ In each case, H or (C １ -C ６ A compound or a pharmaceutically acceptable salt thereof that is alkyl.

2. A compound of claim 1 having the formula Ia, or a pharmaceutically acceptable salt thereof.

3. (a) Structural part 【Chemistry 4】 but 【Transformation 5】 It has a structure, and here, depending on the case, the structural part 【Transformation 6】 but 【change】 Having a structure; or 【Transformation 7】 Having the structure; and / or (b)R ２ In each case, independently, H, halogen, or CH ３ is; and / or (c) Structural part 【Transformation 8】 but 【Chemistry 9】 It has a structure, and in some cases the structural part 【Chemistry 10】 but 【Chemistry 11】 Having a structure; or 【Chemistry 12】 Having the structure; and / or (d)R ３ In each case, H, halogen, or CH ３ That is, A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

4. (a) Structural part 【Chemistry 13】 but 【Chemistry 14】 It has the structure, where m is independently 1 or 2 in each case, and J is C(R ｙ ) ２ And R ｙ In each case, independently H or (C １ -C ６ ) Alkyl, and in some cases structural parts 【Chemistry 15】 but 【Chemistry 16】 has a structure, where Y １ , Y ２ , Y ３ and Y ４ are independently of each other N, CH, CCH ３ or CF; or (b) Structural part 【Chemistry 17】 but [Chemistry 18] has the structure, where m is independently 1 or 2 in each case, J is C(R ｚ ) ２ , and R ｚ is independently H or (C １ -C ６ )alkyl, and optionally the structural moiety 【Chemistry 19】 but 【Chemistry 20】 It has the structure, where Z １ Z ２ Z ３ and Z ４ N, CH, CCH are independent of each other. ３ Or it is CF. A compound according to any of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. A compound of claim 1 having the formula Ib, or a pharmaceutically acceptable salt thereof.

6. structural part 【Chemistry 21】 but 【Chemistry 22】 It has the structure, where T and U are independently possible by valence, N or NR ａ And in some cases, the structural parts 【Chemistry 23】 but: 【Chemistry 24】 It has a structure, where R ３ H, CH ３ or halogen; R ａ H, CH ３ or CH ２ CH ３ That is, A compound according to claim 1 or 5 or a pharmaceutically acceptable salt thereof.

7. A compound of claim 1 having the formula Ic, or a pharmaceutically acceptable salt thereof.

8. (a) Structural part 【Chemistry 25】 but 【Chemistry 26】 It has the structure, where T and U are independently possible by valence, N or NR ａ And, depending on the case: R ２ In each case, independently, is H, CH3, or halogen; or (b) Structural part 【Chemistry 27】 but 【Chemistry 28】 It has a structure, where R ２ is H, CH3, or a halogen; where R ａ H, CH ３ or CH ２ CH ３ And in some cases R ２ In each case, H and CH are independent. ３ or halogen, A compound according to claim 1 or 7 or a pharmaceutically acceptable salt thereof.

9. structural part 【Chemistry 29】 but 【Transformation 30】 A compound of claim 1 or a pharmaceutically acceptable salt thereof having the structure of [the compound of claim 1].

10. R ４ (C １ -C ６ ) alkyl, 【Chemistry 31】 Here, m is an integer from 0 to 3; and in some cases R ５ In each case, H and (C １ -C ６ ) alkyl, halogen, NH ２ ,CN,CF ３ or (C １ -C ６ ) is a haloalkyl, R ａ In each case, independently H or (C １ -C ６ ) is alkyl, A compound according to claim 1 or 9 or a pharmaceutically acceptable salt thereof.

11. structural part 【Chemistry 32】 but: 【Transformation 33】 It has the structure where V is O or NR ａ And; in some cases R ５ In each case, H and CH are independent. ３ , halogen, CN, CF ３ , (C １ -C ６ ) Haloalkyl or NH ２ is; or 【Transformation 34】 It has a structure, and in some cases the structural part 【Chemistry 35】 but 【Transformation 36】 Having a structure A compound according to any of claims 1, 9, or 10, or a pharmaceutically acceptable salt thereof.

12. R ａ In each case, H and CH are independent. ３ or CH ２ CH ３ A compound according to any of claims 1, 6, and 8-11 or a pharmaceutically acceptable salt thereof.

13. (a) Q is NR ａ or O; and / or (b) T and U are independently NH or NCH ３ is; and / or (c)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 and Z ５ They are CH or N independently of each other. The compound of claim 1 or a pharmaceutically acceptable salt thereof. 【Request Item 14】 【Chemistry 37】 but: (a) 【Transformation 38】 and; depending on the case, the structural part 【Chemistry 39】 but: 【Chemistry 40】 It has the structure, where n is 0, 1 or 2; or 【Chemistry 41】 Having a structure; or 【Chemistry 42】 Having a structure; in some cases, structural parts 【Chemistry 43】 but 【Chemistry 44】 Having a structure; or (b) 【Chemistry 45】 and; depending on the case, the structural part 【Chemistry 46】 but 【Chemistry 47】 Having a structure; in some cases, structural parts 【Chemistry 48】 but 【Chemistry 49】 A compound of claim 1 or 13 or a pharmaceutically acceptable salt thereof having the structure of [the compound of claim 1 or 13].

15. Q is NR ａ A compound according to any of claims 1 and 13 to 14 or a pharmaceutically acceptable salt thereof.

16. R １ In each case, H, halogen, OR ａ , N(R ａ ) ２ , (C ２ -C ６ )alkyl, aryl, -CN, N ３ NO ２ COR ａ CO ２ R ａ CON(R ａ ) ２ or -SO ２ R ａ And; in some cases R １ In each case: (a) H, halogen, (C １ -C ６ )alkyl, N(R ａ ) ２ or -CN; in some cases R １ In each case, independently H or (C １ -C ６ ) is alkyl; or (b) H, F, Cl, Br, CH independently ３ , OCH ３ NH ２ , NHCH ３ , N(CH ３ ) ２ , [Transformation 50] And; in some cases R １ In each case, H, F, and CH are independent. ３ NH ２ , NHCH ３ or N(CH ３ ) is; depending on the case 【Chemistry 51】 but 【Chemistry 52】 A compound of any of claims 1 and 13 to 15 or a pharmaceutically acceptable salt thereof.

17. (a) Structural part 【Chemistry 53】 but 【Chemistry 54】 It has the structure, where Q is O or NH; or (b) Structural part 【Transformation 55】 but 【Transformation 56】 It has the structure, where Q is O or NH; or (c) Structural part 【Chemistry 57】 but 【Transformation 58】 It has the structure, where Q is O or NH, and R １ H, (C １ -C ６ ) Alkyl or halogen; in some cases structural parts 【Chemistry 59】 but 【Transformation 60】 It has the structure, where Q is O or NH. A compound according to any of claims 1 and 13 to 16, or a pharmaceutically acceptable salt thereof.

18. (a) Compound of formula Ia 【Chemistry 61】 【Transformation 62】 It has a structure, where R １ H, (C １ -C ６ )alkyl, N(R ａ ) ２ or halogen; R ５ and R １１ H or CH ３ Y １ , Y ２ , Y ３ , Y ４ Z １ Z ２ Z ３ Z ４ , L １ and L ２ are independently CH or N; V is NH or O, and possibly R １ H, F, Cl, Br, CH ３ ,CH ２ CH ３ CH(CH ３ ) ２ NH ２ or NMe ２ is; or (b) Compound of formula Ia 【Transformation 63】 【Chemistry 64】 It is; or (c) The compound of formula Ib has a structure 【Transformation 65】 It has, and here, R １１ and R ５ H or CH ３ Y １ , Y ２ , Y ３ , Y ４ Z ２ Z ３ and Z ４ are CH or N independently of each other; or (d) Compound of formula Ib 【Chemical Formula 66】 【Transformation 67】 It is; or (e) Compounds of formula Ic 【Transformation 68】 It is; or (f) Compound 【Transformation 69】 It is; or (g) A compound is selected from the group consisting of the following table. Table 1 The compound of claim 1 or a pharmaceutically acceptable salt thereof.

19. structural part 【Transformation 70】 but 【Chemistry 71】 It has a structure, where R ｘ and Y ３ , R ｘ and Y ４ , R ｘ and Z １ or R ｘ and Z ４ A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compounds form a 5-6 member heterocycle which may be substituted together.

20. A pharmaceutical composition for the treatment of a disease in a subject requiring treatment, comprising any compound of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein the treatment comprises administering an effective amount of the compound to the subject, and the disease is optionally selected from the group consisting of neurodegenerative diseases, cachexia, eating disorders, obesity, complications of obesity, inflammatory diseases, virus-induced inflammatory reactions, Gulf War syndrome, tuberous sclerosis, retinitis pigmentosa, graft rejection, cancer, autoimmune diseases, ischemic tissue injury, traumatic tissue injury and combinations thereof, optionally: (a) The disease is a neurodegenerative disease, and the neurodegenerative disease may be selected from the group consisting of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, motor neuron disorders, Huntington's disease, HIV-induced neurodegeneration, Lewy body disease, spinal muscular atrophy, prion disease, spinocerebellar ataxia, familial amyloid polyneuropathy, multiple sclerosis, and combinations thereof; or (b) The disorder is cachexia or an eating disorder; or (c) The disease is obesity or a complication of obesity, and the complication of obesity may be selected from glucose intolerance, fatty liver, dyslipidemia and combinations thereof; or (d) The disease is an inflammatory disease, and the inflammatory disease may be selected from the group consisting of atopic dermatitis, allergies, asthma and combinations thereof; or (e) The disease is a virus-induced inflammatory response, and the virus-induced inflammatory response may be selected from the group consisting of SARS-induced inflammatory pneumonia, coronavirus disease 2019, or a combination thereof; or (f) The disease is Gulf War Syndrome or tuberous sclerosis; or (g) The disease is retinitis pigmentosa or graft rejection; or (h) The disease is an ischemic tissue injury or a traumatic tissue injury; or (i) The disease is cancer; in some cases the cancer is selected from the group consisting of adult T-cell leukemia / lymphoma, bladder, brain, breast, cervix, colorectal, esophageal, kidney, liver, lung, nasopharyngeal, pancreatic, prostate, skin, stomach, uterus, ovarian and testicular cancers, and in some cases the cancer is leukemia; in some cases the leukemia is adult T-cell leukemia / lymphoma, and in some cases the adult T-cell leukemia / lymphoma is caused by human T-cell lymphotropic virus; or (j) The disease is an autoimmune disease; in some cases the autoimmune disease is 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 antibody 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, Barlow's disease, Behçet's disease, benign mucosal neuropathy Membranous pemphigoid, bullous pemphigoid, Castleman disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing polymyelitis, Churg-Strauss syndrome, eosinophilic granulomatosis, scarring pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, Crest syndrome, Crohn's disease, herpetiform dermatitis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosis Alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, bullous pemphigoid of pregnancy, sweat gland abscess (reverse acne), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immunothrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes mellitus), juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing, woody conjunctivitis, linear IgA disease, lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mohlen's ulcer, Mukka-Habermann disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular scarring pemphigoid, optic neuritis, relapsing rheumatoid arthritis, childhood autoimmune neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, squamous cellulitis (peripheral uveitis), Personage-Turner syndrome, pemphigus, peripheral neuropathy, perineal encephalomyelitis, pernicious anemia,POEMS syndrome, polyarteritis nodosa, polymyalgia syndrome type III, polymyalgia syndrome type II, polymyalgia syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone 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, A selection from the group consisting of rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, generalized rigidus syndrome, subacute bacterial endocarditis, Suzac syndrome, sympathetic ophthalmitis, Takayasu arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, leukoplakia, Vogt-Koyanagi-Harada disease, and combinations thereof. Pharmaceutical composition.

21. The pharmaceutical composition of claim 20, wherein the compound modulates Akt3 in immune cells, and optionally the immune cells are selected from the group consisting of T cells, B cells, macrophages, and glial cells, and optionally the glial cells are astrocytes, microglia, or oligodendrocytes, or the T cells are T regulatory cells.

22. The compound is: (a) Activate Akt3 signaling; or (b) Inhibit Akt3 signaling; or (c) Increase regulatory cell activity or production; or (d) Reduce T regulatory cell activity or production The pharmaceutical composition according to claim 20.

23. (a) The procedure further includes administering a second therapeutic agent to the subject, and if applicable, The second therapeutic agent is selected from nutritional supplements, chemotherapy, 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 (b) Treatment further includes treating the target with an immunotherapeutic agent, immunomodulator, costimulatory activating agonist, cytokine, chemokine, chemokine factor, oncolytic virus, biologic, vaccine, small molecule, targeted therapy, anti-inflammatory agent, cell therapy, chemotherapeutic agent or therapy, A pharmaceutical composition according to any one of claims 20 to 22.

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