C7 substituted oxysterols and methods as NMDA modulators

Abstract

The present application relates to C7 substituted oxysterols and methods thereof as NMDA modulators. In particular, provided herein are compounds of Formula (A) and pharmaceutically acceptable salts and pharmaceutical compositions thereof; wherein R1A, R1B, n, R2A, R2B, R3 and R4 are as defined herein. The compounds of the invention are intended for the prevention and treatment of various disorders.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511041222.2 (22) Application Date 2017.09.30 (30) Priority Data 62 / 402,789 2016.09.30 US 62 / 402,797 2016.09.30 US (62) Divisional Application Data 201780072617.6 2017.09.30 (71) Applicant Sachs Therapeutics Inc. Address Massachusetts, USA (72) Inventors F.G. Salituro A.J. Robichod G. Martinez Botra A.G. Griffin B.L. Harrison D. La (74) Patent Agency Beijing Liu Shen Law Firm 11105 Patent Attorney He Wei (51) Int.Cl. C07J 9 / 00(2006.01) C07D 301 / 02(2006.01) C07D 303 / 04(2006.01) C07J 31 / 00(2006.01) A61P 35 / 00(2006.01) A61P 3 / 10(2006.01) A61P 1 / 04(2006.01) A61P 1 / 00(2006.01) A61P 29 / 00(2006.01) A61P 1 / 10(2006.01) A61P 9 / 14(2006.01) A61P 25 / 28(2006.01) A61P 25 / 16(2006.01) A61P 25 / 24(2006.01) A61P 25 / 20(2006.01) A61P 25 / 22(2006.01) A61P 25 / 04(2006.01) A61P 25 / 08(2006.01) A61P 23 / 00(2006.01) A61P 25 / 00(2006.01) A61P 27 / 16(2006.01) A61P 25 / 14(2006.01) A61P 21 / 00(2006.01) A61P 21 / 02(2006.01) A61P 25 / 30(2006.01) A61K 31 / 575(2006.01) (54) Invention Title: C7-substituted oxosterols and methods thereof as NMDA modifiers (57) Abstract: This application relates to C7-substituted oxosterols and methods thereof as NMDA modifiers. Specifically, compounds of formula (A) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof are provided herein; wherein R1A, R1B, n, R2A, R2B, R3, and R4 are as defined herein. The compounds of the present invention are intended for the prevention and treatment of various conditions. Claims: 13 pagesInstructions for Use, page 92, CN 121085986 A, 2025.12.09, CN 1 21 08 59 86 A. 1. Compound of formula (A): or a pharmaceutically acceptable salt thereof, wherein: R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atom to which they are attached form a 3-8 membered ring; n is 1 or 2; R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein RC is hydrogen or alkyl, or R2A and R2B together with the carbon atom to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen; R3 is hydrogen, alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl; R4 is absent or is hydrogen; and represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is a compound of formula (A-I): 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is a compound of formula (A-II): 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is a compound of formula (A-III): Claims 1 / 13 Page 2 CN 121085986 A 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is a compound of formula (A-IV), (A-V), or (A-VI): wherein R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl. 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is a compound of formula (A-VII), (A-VIII), or (A-IX): wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, and RA is alkyl. 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is a compound of formula (A-X): [Claims 2 / 13 page 3 CN 121085986 A] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, and RA is alkyl. 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is a compound of formula (A-XII): wherein R' is alkyl or –ORA, and RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3. 9. Compound of formula (B): or a pharmaceutically acceptable salt thereof, wherein: R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1AR1B and the carbon atoms they are attached to form a 3-8 membered ring; n is 1 or 2; R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, where RC is hydrogen or alkyl, or R2A and R2B together with the carbon atoms they are attached to form an oxo group, where R2A and R2B are not both hydrogen; R3 is alkyl, alkenyl, alkynyl, or –ORA, where RA is alkyl; R4 is absent or hydrogen; and represent a single bond or a double bond, where when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent. 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is: a) a compound of formula (B-I): Claims 3 / 13 Page 4 CN 121085986 A 11. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is a compound of formula (B-II): 12. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is a compound of formula (B-III): 13. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is a compound of formula (B-IV), (B-V), or (B-VI): wherein R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl. 14. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is a compound of formula (B-VII), (B-VIII), or (B-IX): Claims 4 / 13 Page 5 CN 121085986 A Wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl. 15. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is a compound of formula (B-X): Wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl. 16. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is a compound of formula (B-XII): Wherein R' is alkyl or –ORA, wherein RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3. 17. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Claims 5 / 13 pages 6 CN 121085986 A R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring; R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein RC is hydrogen or alkylR1A, R2A, and R2B together with the carbon atoms to which they are attached form an oxo group, wherein R2A and R2B are not both hydrogen; R3 is hydrogen, alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl; R4 is absent or is hydrogen; and represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent; provided that when R1A, R3, and R4 are hydrogen and R1B is unsubstituted isopropyl, then R2A and R2B together with the carbon atoms to which they are attached do not form an oxo group; and when R4 is absent, R3 is hydrogen, and R1A and R1B are –CH3, then R2A is not –CH3 and R2B is not –OH. 18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R1A, R3, and R4 are hydrogen, R1B is an unsubstituted isopropyl group, and R2a and R2b, together with the carbon atoms to which they are attached, do not form oxo groups. 19. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R4 is absent, R3 is hydrogen, R1A and R1B are –CH3, R2A is not –CH3, and R2B is not –OH. 20. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-A): 21. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-B): 22. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-C): Claims 6 / 13 Page 7 CN 121085986 A 23. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-E), (I-F), or (I-G): wherein R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl. 24. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-H), (I-I), or (I-J): wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, and RA is alkyl. 25. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-K): [Claims 7 / 13, page 8, CN 121085986 A] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, and RA is alkyl. 26. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-M): wherein R' is alkyl or –ORA, and RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.27. Compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atom to which they are attached form a 3-8 membered ring; R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, ynyl, aryl or heteroaryl, wherein RC is hydrogen or alkyl, or R2A and R2B together with the carbon atom to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen; R3 is hydrogen, alkyl, alkenyl, ynyl or –ORA, wherein RA is alkyl; R4 is absent or is hydrogen; and represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent; The premise is that when R4 is absent, R2A is –OH, R2B is hydrogen or –CF3 and R1A and R1B are –CH3, then R3 is not hydrogen; and when R1A and R1B are –CH3 and R3 is hydrogen, then R2A and R2B together with the carbon atoms they are attached to do not form oxo groups. 28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-A): Claims 8 / 13 pages 9 CN 121085986 A 29. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-B): 30. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-C): 31. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-D): 32. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-E), (II-F), or (II-G): Claims 9 / 13 pages 10 CN 121085986 A Wherein R2C is hydrogen or a substituted or unsubstituted alkyl group and R3 is an alkyl group, substituted or unsubstituted alkyl group. 33. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-H), (II-I), or (II-J): wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, and RA is alkyl. 34. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-K): wherein R' is alkyl or –ORA, and RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.35. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is absent, one of R2A and R2B is -OH, and R3 is not hydrogen. 36. The compound of any one of claims 1, 9, 17, or 27 or a pharmaceutically acceptable salt thereof, wherein R1A and R1B are each independently an unsubstituted or substituted alkyl group. 37. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R1A and R1B are each independently a substituted alkyl group. 38. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein R1A and R1B are each independently a haloalkyl or alkoxyalkyl group. 39. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R1A is –CF3 or –CH2OCH3. 40. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R1A and R1B are –CH3, –CH2CH3, or –CH(CH3)2. Claims 10 / 13 pages 11 CN 121085986 A 41. A compound according to any one of claims 1, 9, 17 and 27, or a pharmaceutically acceptable salt thereof, wherein R2A and R2B are each independently substituted or unsubstituted alkyl groups. 42. A compound according to any one of claims 1, 9, 17 and 27, or a pharmaceutically acceptable salt thereof, wherein R2A and R2B are –CH3 and R3 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or –ORA, wherein RA is a substituted or unsubstituted alkyl group. 44. The compound of any one of claims 1, 9, 17, and 27, or a pharmaceutically acceptable salt thereof, wherein R3 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or –ORA, wherein RA is a substituted or unsubstituted alkyl. 45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein R3 is a substituted or unsubstituted alkyl. 46. ​​A compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein: R1A and R1B are each substituted or unsubstituted alkyl groups; R2A and R2B are each independently hydrogen, ORC, or alkyl, wherein RC is hydrogen or alkyl, or R2A and R2B together with the carbon atoms to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen; R3 is alkyl; R4 is absent or is hydrogen; and represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent. 47. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R1A and R1B are each –CH3.48. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R2A and R2B together with the carbon atom to which they are attached form an oxo group. 49. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R3 is –CH2CH3. 50. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R2A is –OH and R2B is H. 51. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R2A is CH3 and R1B is H. 52. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R2A is –OH and R1B is –CH3. 53. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R1A is –CF3. 54. A pharmaceutical composition comprising the compound of any one of claims 1-53 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 55. Use of the compound of any one of claims 1-52 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing sedation or anesthesia. 56. Use of any compound of claims 1-52 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of the following conditions: gastrointestinal (GI) conditions, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, structural conditions affecting the gastrointestinal tract, anal conditions, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colonic polyps, cancer or colitis, diabetes or sterol synthesis disorders, metabolic disorders, autoimmune diseases, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis. 57. Use of any compound of claims 1-52 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of CNS-related disorders, wherein the CNS-related disorders are selected from: adaptive disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, affective disorders (including depression and postpartum depression), bipolar disorder, dysphoric disorder, suicidal ideation, schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (Shank3)), neurodevelopmental disorders (including Rett syndrome, complex tuberous sclerosis), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), and encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-inflammatory encephalopathy).58. The use of claim 57, wherein the CNS-related condition is schizophrenia, Alzheimer's disease, autism spectrum disorder, Huntington's disease, or Parkinson's disease. 59. A method for synthesizing compound 22, comprising the following steps: a) adding Me3SI (4.18 g, 20.5 mmol) to a suspension of t-BuOK (3.53 g, 31.6 mmol) in THF (30 mL) at N2 and 15 °C; b) stirring the suspension at 15 °C for 30 min; c) adding dropwise a solution of 21 (2 g, 15.8 mmol) in 10 mL THF to the mixture at 15 °C; d) stirring the mixture at 15 °C for 16 h; e) quenching the mixture with saturated NH4Cl (100 mL) and extracting with EtOAc (3 x 150 mL); and f) drying the combined organic phase with Na2SO4, filtering and concentrating under vacuum to give 22 (1.8 g, 81%), which is a liquid. 60. Compound 2, which is: 61. A method for synthesizing compound 2, comprising the following steps: Claims 12 / 13 pages 13 CN 121085986 A a) at 35°C, adding DMP (2.14 kg, 5.08 mol) in portions to a solution of 1 (800 g, 2.54 mol) in DCM (8 L); b) stirring the reaction mixture at 35°C for 20 minutes; c) filtering the reaction mixture; d) washing the filter cake with DCM (3 x 1 L); and e) washing the combined organic phase with a saturated aqueous solution of Na2S2O3 / saturated NaHCO3 (3:1, 2 x 1.5 L) and brine (1.5 L), drying with Na2SO4, filtering and concentrating under vacuum to give 2 (794 g, crude), which is a solid. Claims 13 / 13 Page 14 CN 121085986 A C7-substituted oxosterol and method thereof as NMDA modifier

[0001] This application is a divisional application of Chinese invention patent application (filed on September 30, 2017; application number: 2022112266693; invention title: C7-substituted oxosterol and method thereof as NMDA modifier).

[0002] Related Applications

[0003] This application claims priority and benefit to U.S. Provisional Application No. 62 / 402,789 and U.S. Provisional Application No. 62 / 402,797, filed on September 30, 2016, each of which is incorporated herein by reference. Background Art

[0004] NMDA receptors are heteropolymeric complexes composed of NR1, NR2, and / or NR3 subunits and have different recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine and glutamate agonists and modulators. NMDA receptors are expressed in peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. Activation of these receptors contributes to synaptic plasticity in some cases and excitatory toxicity in others. These receptors are ligand-gated ion channels that allow Ca2+ upon binding to glutamate and glycine and are fundamental to excitatory neurotransmission and normal CNS function. Positive modulators can be used as therapeutic agents with potential clinical applications, as cognitive enhancers, and for the treatment of mental disorders with reduced or deficient glutamatergic transmission (see, for example, Horak et al., J. of Neuroscience, 2004, 24(46), 10318–10325). Conversely, negative modulators can be used as therapeutic agents with potential clinical applications for the treatment of mental disorders in which glutamatergic transmission is pathologically increased (e.g., for the treatment of resistant depression).

[0005] Oxosterols are cholesterol analogs that are regulators of NMDA receptor function. New oxosterols are needed to modulate NMDA receptors for the prevention and treatment of conditions associated with NMDA expression and function. The compounds, compositions, and methods described herein are intended for this purpose. Summary of the Invention

[0006] This invention provides substituted oxosterols that can be used for the prevention and / or treatment of a variety of diseases, including but not limited to NMDA-mediated diseases. Pharmaceutical compositions comprising the compounds of the present invention are also provided, as well as their use and treatment methods.

[0007] In one aspect, this document provides a compound of formula (A):

[0008] (A)

[0009] or a pharmaceutically acceptable salt thereof, wherein:

[0010] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atom to which they are attached form a 3-8 membered ring;

[0011] n is 1 or 2;

[0012] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, ynyl, aryl or heteroaryl, wherein RC is hydrogen or alkyl, or R2A and R2B together with the carbon atom to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen;

[0013] R3 is hydrogen, alkyl, alkenyl, ynyl or –ORA, wherein RA is alkyl; Specification 1 / 92 pages 15 CN 121085986 A

[0014] R4 is absent or is hydrogen; and

[0015] represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent.

[0016] In some embodiments, n is 1. In other embodiments, n is 2.

[0017] In some embodiments, when R1A, R3, and R4 are hydrogen and R1B is unsubstituted isopropyl, then R2A and R2B together with the carbon atom to which they are attached do not form oxo groups; and when R4 is absent, R3 is hydrogen, and R1A and R1B are –CH3, then R2A is not –CH3 and R2B is not –OH. In other embodiments, n is 1.

[0018] In some embodiments, when R4 is absent, R2A is –OH, R2B is hydrogen or –CF3, and R1A and R1B are –CH3, then R3 is not hydrogen; and when R1A and R1B are –CH3 and R3 is hydrogen, then R2A and R2B together with the carbon atom to which they are attached do not form oxo groups. In other embodiments, n is 2.

[0019] In some embodiments, wherein the compound of formula (A) is a compound of formula (A-I):

[0020] (A-I).

[0021] In some embodiments, the compound of formula (A) is a compound of formula (A-II):

[0022] (A-II).

[0023] In some embodiments, the compound of formula (A) is a compound of formula (A-III):

[0024] (A-III).

[0025] In some embodiments, the compound of formula (A) is a compound of formula (A-IV), (A-V), or (A-VI):

[0026] (A-IV), (A-V), or (A-VI)

[0027] (A-VI)

[0028] wherein R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0029] In some embodiments, the compound of formula (A) is a compound of formula (A-VII), (A-VIII), or (A-IX):

[0030] (A-VII), (A-VIII), or

[0031] (A-IX)

[0032] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0033] In some embodiments, the compound of formula (A) is a compound of formula (A-X):

[0034] (A-X)

[0035] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0036] In some embodiments, the compound of formula (A) is a compound of formula (A-XII)

[0037] (A-XII)

[0038] wherein R' is alkyl or –ORA, wherein RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.

[0039] In some embodiments, R4 is absent, one of R2A and R2B is –OH, and R3 is not hydrogen.

[0040] In some embodiments, R1A and R1B are each independently an unsubstituted or substituted alkyl group (e.g., haloalkane specification 3 / 92).Page 17 CN 121085986 A alkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0041] In other embodiments, R1A and R1B are each independently substituted alkyl (e.g., haloalkyl). In some embodiments, R1A and R1B are alkyl (e.g., unsubstituted or substituted alkyl (e.g., –CH3)). In some embodiments, R1A and R1B are –CH3.

[0042] In some aspects, R1A is –CF3 or –CH2OCH3.

[0043] In other aspects, R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aryl or heteroaryl.

[0044] In some embodiments, R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring.

[0045] In some aspects, R1A is a substituted alkyl or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[0046] In some embodiments, R2A and R2B are each independently alkyl (e.g., substituted or unsubstituted alkyl). In some aspects, R2A and R2B are each independently –F.

[0047] In other embodiments, R2A and R2B are –CH3 and R3 is alkyl, alkenyl, ynyl, or –ORA, wherein RA is alkyl. In some other embodiments, R2A and R2B are each independently hydrogen and R3 is alkyl (e.g., substituted or unsubstituted alkyl).

[0048] In some embodiments, R3 is alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, ynyl, or –ORA, wherein RA is alkyl. In other embodiments, R3 is alkyl (e.g., substituted or unsubstituted alkyl).

[0049] In one aspect, compounds of formula (B) are provided herein:

[0050] (B)

[0051] or a pharmaceutically acceptable salt thereof, wherein:

[0052] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring;

[0053] n is 1 or 2;

[0054] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, ynyl, aryl or heteroaryl, wherein RC is hydrogen or alkyl, or R2A and R2B together with the carbon atoms to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen;

[0055] R3 is alkyl, alkenyl, ynyl or –ORA, wherein RA is alkyl;

[0056] R4 is absent or is hydrogen; and

[0057] R4 represents a single or double bond, where if one is a double bond, the other is a single bond; if both are single bonds, R4 is hydrogen; and if one is a double bond, R4 does not exist.

[0058] In some embodiments, n is 1. In other embodiments, n is 2.

[0059] In some embodiments, the compound of formula (B) is a compound of formula (B-I):

[0060] (B-I). Specification 4 / 92 pages 18 CN 121085986 A

[0061] In some embodiments, the compound of formula (B) is a compound of formula (B-II):

[0062] (B-II).

[0063] In some embodiments, the compound of formula (B) is a compound of formula (B-III):

[0064] (B-III).

[0065] In some embodiments, the compound of formula (B) is a compound of formula (B-IV), (B-V) or (B-VI):

[0066] (B-IV), (B-V) or

[0067] (B-VI)

[0068] wherein R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[0069] In some embodiments, the compound of formula (B) is a compound of formula (B-VII), (B-VIII), or (B-IX):

[0070] (B-VII), (B-VIII), or

[0071] (B-IX)

[0072] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl. Specification 5 / 92 pages 19 CN 121085986 A

[0073] In some embodiments, the compound of formula (B) is a compound of formula (B-X):

[0074] (B-X)

[0075] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0076] In some embodiments, the compound of formula (B) is a compound of formula (B-XII)

[0077] (B-XII)

[0078] wherein R' is an alkyl or –ORA, wherein RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0079] In some embodiments, R1A and R1B are each independently unsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0080] In other embodiments, R1A and R1B are each independently substituted alkyl (e.g., haloalkyl). In some embodiments, R1A and R1B are alkyl (e.g., unsubstituted or substituted alkyl (e.g., –CH3)). In some embodiments, R1A and R1B are –CH3.

[0081] In some aspects, R1A is –CF3 or –CH2OCH3.

[0082] In other aspects, R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0083] In some embodiments, R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring.

[0084] In some aspects, R1A is a substituted alkyl or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[0085] In some embodiments, R2A and R2B are each independently alkyl (e.g., substituted or unsubstituted alkyl). In some aspects, R2A and R2B are each independently –F.

[0086] In other embodiments, R2A and R2B are –CH3 and R3 is alkyl, alkenyl, ynyl or –ORA, wherein RA is alkyl. In some other embodiments, R2A and R2B are each independently hydrogen and R3 is alkyl (e.g., substituted or unsubstituted alkyl).

[0087] In some embodiments, R3 is alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, ynyl or –ORA, wherein RA is alkyl. In other embodiments, R3 is an alkyl group (e.g., a substituted or unsubstituted alkyl group).

[0088] In one aspect, compounds of formula (I) are provided herein:

[0089] (I) Specification 6 / 92 pages 20 CN 121085986 A

[0090] or a pharmaceutically acceptable salt thereof, wherein:

[0091] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring;

[0092] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, ynyl, aryl or heteroaryl, wherein RC is hydrogen or alkyl, or R2A and R2B together with the carbon atoms to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen;

[0093] R3 is hydrogen, alkyl, alkenyl, ynyl or –ORA, wherein RA is alkyl;

[0094] R4 is absent or is hydrogen; and

[0095] represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent;

[0096] wherein when R1A, R3, and R4 are hydrogen and R1B is unsubstituted isopropyl, then R2A and R2B together with the carbon atoms to which they are attached do not form oxo groups; and

[0097] when R4 is absent, R3 is hydrogen, and R1A and R1B are –CH3, then R2A is not –CH3 and R2B is not –OH.

[0098] In some embodiments, R1A, R3, and R4 are hydrogen, R1B is unsubstituted isopropyl, and R2A and R2B together with the carbon atoms to which they are attached do not form oxo groups.

[0099] In some embodiments, R4 is absent, R3 is hydrogen, R1A and R1B are –CH3, R2A is not –CH3 and R2B is not –OH.

[0100] In some embodiments, the compound of formula (I) is a compound of formula (I-A):

[0101] (I-A).

[0102] In some embodiments, the compound of formula (I) is a compound of formula (I-B):

[0103] (I-B).

[0104] In some embodiments, the compound of formula (I) is a compound of formula (I-C): Specification 7 / 92 page 21 CN 121085986 A

[0105] (I-C).

[0106] In some embodiments, the compound of formula (I) is a compound of formula (I-E), (I-F), or (I-G):

[0107] (I-E), (I-F), or

[0108] (I-G)

[0109] wherein R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0110] In some embodiments, the compound of formula (I) is a compound of formula (I-H), (I-I), or (I-J):

[0111] (I-H), (I-I), or

[0112] (I-J)

[0113] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0114] In some embodiments, the compound of formula (I) is a compound of formula (I-K): Specification 8 / 92 pages 22 CN 121085986 A

[0115] (I-K)

[0116] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0117] In some embodiments, the compound of formula (I) is a compound of formula (I-M):

[0118] (I-M)

[0119] wherein R' is an alkyl or –ORA, wherein RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0120] In some embodiments, R1A and R1B are each independently unsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0121] In some embodiments, R1A and R1B are each independently substituted alkyl (e.g., haloalkyl).

[0122] In some embodiments, R1A is –CF3 or –CH2OCH3.

[0123] In some embodiments, R1A and R1B are alkyl (e.g., unsubstituted or substituted alkyl (e.g., –CH3)).

[0124] In some embodiments, R1A and R1B are –CH3.

[0125] In some embodiments, R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring.

[0126] In some embodiments, R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0127] In some embodiments, R1A is a substituted alkyl or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[0128] In some embodiments, R2A and R2B are each independently alkyl (e.g., substituted or unsubstituted alkyl).

[0129] In some embodiments, R2A and R2B are each independently –F.

[0130] In some embodiments, R2A and R2B are –CH3 and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0131] In some embodiments, R2A and R2B are –F.

[0132] In some embodiments, R3 is alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0133] In some embodiments, R3 is alkyl (e.g., substituted or unsubstituted alkyl).

[0134] In some embodiments, R2A and R2B are each independently hydrogen and R3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0135] In one aspect, compounds of formula (II) are provided herein: Specification 9 / 92 pages 23 CN 121085986 A

[0136] (II)

[0137] or a pharmaceutically acceptable salt thereof, wherein:

[0138] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atom to which they are attached form a 3-8 membered ring;

[0139] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein RC is hydrogen or alkyl, or R2A and R2B together with the carbon atom to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen;

[0140] R3 is hydrogen, alkyl, alkenyl, alkynyl or –ORA, wherein

[0141] RA is alkyl;

[0142] R4 is absent or is hydrogen; and

[0143] represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent;

[0144] provided that when R4 is absent, R2A is –OH, R2B is hydrogen or –CF3 and R1A and R1B are –CH3, then R3 is not hydrogen; and

[0145] when R1A and R1B are –CH3 and R3 is hydrogen, then R2A and R2B together with the carbon atoms to which they are attached do not form oxo groups.

[0146] In some embodiments, R4 is absent, one of R2A and R2B is –OH and R3 is not hydrogen.

[0147] In some embodiments, the compound of formula (II) is a compound of formula (II-A):

[0148] (II-A).

[0149] In some embodiments, the compound of formula (II) is a compound of formula (II-B):

[0150] (II-B).

[0151] In some embodiments, the compound of formula (II) is a compound of formula (II-C):

[0152] (II-C).

[0153] In some embodiments, the compound of formula (II) is a compound of formula (II-D): Specification 10 / 92 pages 24 CN 121085986 A

[0154] (II-D).

[0155] In some embodiments, the compound of formula (II) is a compound of formula (II-E), (II-F), or (II-G):

[0156] (II-E), (II-F), or

[0157] (II-G)

[0158] wherein R2C is hydrogen or alkyl (e.g., substituted or unsubstituted alkyl) and R3 is alkyl (e.g., substituted or unsubstituted alkyl).

[0159] In some embodiments, the compound of formula (II) is a compound of formula (II-H), (II-I), or (II-J):

[0160] (II-H), (II-I), or

[0161] (II-J)

[0162] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0163] In some embodiments, the compound of formula (II) is a compound of formula (II-K): Specification 11 / 92 pages 25 CN 121085986 A

[0164] (II-K)

[0165] wherein R' is alkyl or –ORA, wherein RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.

[0166] In some embodiments, R1A and R1B are each independently an unsubstituted or substituted alkyl group (e.g., haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3, or –CH2OCH3).

[0167] In some embodiments, R1A and R1B are each independently a substituted alkyl group (e.g., haloalkyl).

[0168] In some embodiments, R1A is –CF3 or –CH2OCH3.

[0169] In some embodiments, R1A and R1B are alkyl groups (e.g., unsubstituted or substituted alkyl groups (e.g., –CH3)).

[0170] In some embodiments, R1A and R1B are –CH3.

[0171] In some embodiments, R1A and R1B form a ring together with the carbon atom to which they are attached.

[0172] In some embodiments, R1A is hydrogen and R1B is an alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl group.

[0173] In some embodiments, R2A and R2B are each independently an alkyl group (e.g., substituted or unsubstituted alkyl groups).

[0174] In some embodiments, R3 is an alkyl group (e.g., a substituted or unsubstituted alkyl group).

[0175] In some embodiments, R2A and R2B are each independently hydrogen and R3 is an alkyl group (e.g., a substituted or unsubstituted alkyl group).

[0176] In some embodiments, R2A and R2B are each independently –F.

[0177] In some embodiments, R2A and R2B are –CH3 and R3 is an alkyl, alkenyl, alkynyl, or –ORA, wherein RA is an alkyl group.

[0178] In some embodiments, R2A and R2B are –F.

[0179] In some embodiments, R1A is a substituted or unsubstituted C2-C6 alkyl group and R1B is a substituted or unsubstituted C1-C6 alkyl group.

[0180] In some aspects, the compound is a compound of formula (III):

[0181] (III)

[0182] or a pharmaceutically acceptable salt thereof, wherein:

[0183] R1A and R1B are each substituted or unsubstituted alkyl groups;

[0184] R2A and R2B are each independently hydrogen, –ORC or alkyl, wherein RC is hydrogen or alkyl, or

[0185] R2A and R2B together with the carbon atom to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen;

[0186] R3 is alkyl;

[0187] R4 is absent or is hydrogen; and

[0188] represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent.

[0189] In some embodiments, R1A and R1B are each –CH3. Instructions for Use, Page 12 / 92, 26 CN 121085986 A

[0190] In some embodiments, R2A and R2B together with the carbon atom to which they are attached form an oxo group.

[0191] In some embodiments, R3 is –CH2CH3.

[0192] In some embodiments, R2A is –OH and R2B is H.

[0193] In some embodiments, R2A is –CH3 and R2B is H.

[0194] In some embodiments, R2A is –OH and R2B is –CH3.

[0195] In some embodiments, R1A is –CF3.

[0196] In one aspect, pharmaceutical compositions are provided herein comprising the compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0197] In one aspect, methods for inducing sedation or anesthesia are provided herein, comprising administering to a subject an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0198] In one aspect, this document provides methods for treating or preventing the conditions described herein, including providing treatment to a recipient in need of such treatment.The test subject is given an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0199] In some embodiments, the condition is an autoimmune disease.

[0200] In some embodiments, the condition is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[0201] In some embodiments, the condition is a metabolic disorder.

[0202] In some embodiments, the condition is a gastrointestinal (GI) condition, such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural conditions affecting the gastrointestinal tract, anal conditions (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colonic polyps, cancer, or colitis.

[0203] In some embodiments, the condition is inflammatory bowel disease.

[0204] In some embodiments, the condition is cancer, diabetes, or a sterol synthesis disorder.

[0205] In one aspect, this document provides a method for treating or preventing CNS-related disorders, comprising administering to a subject in need an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the CNS-related disorders are adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia (e.g., frontotemporal dementia), dissociative disorders, eating disorders, affective disorders (including depression (e.g., postpartum depression), bipolar disorder, dysphoric disorder, and suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis, etc.). Complex), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain; headache, e.g., migraine), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss, or tinnitus.

[0206] In some embodiments, the condition is Huntington's disease. In some embodiments, the condition is Parkinson's disease. In some embodiments, the condition is an inflammatory disease (e.g., lupus).

[0207] In some embodiments, the condition is a sterol synthesis disorder.

[0208] In some embodiments, the condition is Smith-Lemli-Opitz Syndrome (SLOS). In some embodiments, the condition is desmosterolosis. In some embodiments, the condition is hypersitosterinemia. In some embodiments, the condition is cerebral tendon xanthomatosis (CTX). Specification 13 / 92 pages 27 CN 121085986 A In some embodiments, the condition is mevalonate kinase deficiency (MKD). In some embodiments, the condition is SC4MOL gene mutation (SMO deficiency). In some embodiments, the condition is Niemann-Pick disease. In some embodiments, the condition is autism spectrum disorder (ASD). In some embodiments, the condition is associated with phenylketonuria.

[0209] Other objects and advantages will become apparent to those skilled in the art in consideration of the following detailed description of the invention, embodiments, and claims.

[0210] Definitions

[0211] Chemical Definitions

[0212] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the periodic table, CAS edition, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry, as well as specific functional parts and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0213] Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See also,For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This invention also includes compounds described herein as single isomers substantially free of other isomers, or as mixtures of various isomers.

[0214] “Enantiomer excess” (“ee”) or “% enantiomer excess” (“%ee”) of a composition means an excess of one enantiomer relative to another enantiomer present in the composition. For example, a composition may contain 90% of one enantiomer, such as the S enantiomer, and 10% of another enantiomer, namely the R enantiomer.

[0215] ee = (90-10) / 100 = 80%.

[0216] Therefore, a composition containing 90% of one enantiomer and 10% of another enantiomer has an enantiomer excess of 80%.

[0217] “Diasteromer excess” (“d.e.”) or “%diasteromer excess” (“%d.e.”) of a composition means that one diastereomer is in excess relative to one or more different diastereomers present in the composition. For example, a composition may contain 90% of one diastereomer and 10% of one or more different diastereomers.

[0218] de = (90-10) / 100 = 80%.

[0219] Therefore, a composition containing 90% of one diastereomer and 10% of one or more different diastereomers has an 80% diastereomer excess.

[0220] When a range value is listed, it is intended to include each value and subrange within that range. For example, “C1–6 alkyl” is intended to include C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl. Specification 14 / 92 pages 28 CN 121085986 A

[0221] The following terms are intended to have the meanings described below and are used to understand the description and intended scope of the invention.When describing the present invention, it may include compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds and compositions, and unless otherwise stated, the following terms (if present) shall have the following meanings. It should also be understood that, when described herein, any portion defined below may be substituted with various substituents, and the various definitions are intended to include such substituted portions within their scope, as described below. Unless otherwise stated, the term “substituted” is defined as follows. It should be further understood that, when used herein, the terms “group” and “portion” may be considered interchangeable. The articles “a” and “an” may be used herein to refer to one or more (i.e., at least one) grammatical object of the article. For example, “an analog” means one or more analogs.

[0222] “Aliphatic” means alkyl, alkenyl, alkynyl, or carbocyclic as defined herein.

[0223] “Alkyl” means a group having a straight-chain or branched saturated hydrocarbon group having 1-20 carbon atoms (“C1–20 alkyl”). In some embodiments, the alkyl group has 1-12 carbon atoms (“C1–12 alkyl”). In some embodiments, the alkyl group has 1-10 carbon atoms (“C1–10 alkyl”). In some embodiments, the alkyl group has 1-9 carbon atoms (“C1–9 alkyl”). In some embodiments, the alkyl group has 1-8 carbon atoms (“C1–8 alkyl”). In some embodiments, the alkyl group has 1-7 carbon atoms (“C1–7 alkyl”). In some embodiments, the alkyl group has 1-6 carbon atoms (“C1–6 alkyl”, also referred to herein as “lower alkyl”). In some embodiments, the alkyl group has 1-5 carbon atoms (“C1–5 alkyl”). In some embodiments, the alkyl group has 1-4 carbon atoms (“C1–4 alkyl”). In some embodiments, the alkyl group has 1-3 carbon atoms (“C1–3 alkyl”). In some embodiments, the alkyl group has 1-2 carbon atoms (“C1–2 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2–6 carbon atoms (“C2–6 alkyl”). Examples of C1–6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, each example of an alkyl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted alkyl”) or substituted.One or more substituents are substituted (“substituted alkyl”); for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkyl group is an unsubstituted C1–10 alkyl group (e.g., –CH3). In some embodiments, the alkyl group is a substituted C1–10 alkyl group. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3) or i-Bu (-CH2CH(CH3)2).

[0224] “Alkylene” refers to an alkyl group in which two hydrogens are removed to provide a divalent group, and it may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Exemplary substituted alkylene groups, such as those substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc. When a range or number of carbons is provided for a particular alkylene group, it should be understood that the range or number refers to the range or number of carbons in a straight-chain divalent carbon chain. Alkylene groups may be substituted or unsubstituted with one or more substituents as described herein.

[0225] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C2–20 alkenyl"). In some embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C2–10 alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C2–9 alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C2–8 alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms.The alkenyl group has 2-6 carbon atoms (“C2-6 alkenyl”). In some embodiments, the alkenyl group has 2-5 carbon atoms (“C2-5 alkenyl”). In some embodiments, the alkenyl group has 2-4 carbon atoms (“C2-4 alkenyl”). In some embodiments, the alkenyl group has 2-3 carbon atoms (“C2-3 alkenyl”). In some embodiments, the alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of C2-4 alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. Examples of C2–6 alkenyl groups include the aforementioned C2–4 alkenyl groups, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octtrienyl (C8), and the like. Unless otherwise stated, each example of an alkenyl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted with one or more substituents (“substituted alkenyl”), for example, 1–5 substituents, 1–3 substituents, or 1 substituent. In some embodiments, the alkenyl group is an unsubstituted C2–10 alkenyl group. In some embodiments, the alkenyl group is a substituted C2–10 alkenyl group.

[0226] “Alynyl” refers to a straight-chain or branched hydrocarbon group having 2-20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2–20 ynyl”). In some embodiments, the ynyl group does not contain any double bonds. In some embodiments, the ynyl group has 2-10 carbon atoms (“C2–10 ynyl”). In some embodiments, the ynyl group has 2-9 carbon atoms (“C2–9 ynyl”). In some embodiments, the ynyl group has 2-8 carbon atoms (“C2–8 ynyl”). In some embodiments, the ynyl group has 2-7 carbon atoms (“C2–7 ynyl”). In some embodiments, the ynyl group has 2-6 carbon atoms (“C2–6 ynyl”). In some embodiments, the ynyl group has 2-5 carbon atoms (“C2–5 ynyl”). In some embodiments, the alkynyl group has 2-4 carbon atoms (“C2–4 alkynyl”). In some embodiments, the alkynyl group has 2-3 carbon atoms (“C2–3 alkynyl”). In some embodiments, the alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butyne) or terminal (e.g., in 1-butyne). Examples of C2–4 alkynyl groups include, but are not limited to, acetylene.(C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. Examples of C2–6 alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentyynyl (C5), hexynyl (C6), etc. Other examples of alkenyl groups include heptyynyl (C7), octyynyl (C8), etc. Unless otherwise stated, each example of an alkenyl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted with one or more substituents (substituted alkenyl); for example, 1–5 substituents, 1–3 substituents, or 1 substituent. In some embodiments, the alkenyl group is an unsubstituted C2–10 alkenyl group. In some embodiments, the alkenyl group is a substituted C2–10 alkenyl group.

[0227] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein, whose parent chain further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or one or more heteroatoms are inserted between carbon atoms and the parent molecule, i.e., between connection points. In some embodiments, a heteroalkyl group refers to a saturated group having 1-10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero-C1–10 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1-9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero-C1–9 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1-8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero-C1–8 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 1-7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“hetero-C1–7 alkyl”). In some embodiments, the heteroalkyl group is a group having 1-6 carbon atoms and 1, 2, or 3 heteroatoms (“hetero-C1–6 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-5 carbon atoms and 1 or 2 heteroatoms (“hetero-C1–5 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-4 carbon atoms and 1 or 2 heteroatoms (“hetero-C1–4 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-3 carbon atoms and 1 heteroatom (“hetero-C1–3 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-2 carbon atoms and 1 heteroatom (“hetero-C1–2 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having one carbon atom and one heteroatom (“hetero-C1 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 2-6 carbon atoms and one or two heteroatoms (“hetero-C2–6 alkyl”). Unless otherwise stated, each example of a heteroalkyl group is independently unrepresented.The heteroalkyl group is either substituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”). In some embodiments, the heteroalkyl group is an unsubstituted heteroC1–10 alkyl group. In some embodiments, the heteroalkyl group is a substituted heteroC1–10 alkyl group.

[0228] “Aryl” refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., enjoying 6, 10, or 14 π electrons in the ring array) (“C6–14 aryl”) that provides 6–14 ring carbon atoms and zero heteroatoms in the aromatic ring system. In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C10 aryl”; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (“C14 aryl”; for example, anthracene). "Aryl" also includes ring systems in which the aromatic ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the radical or linker is on the aryl ring, and in this case, the number of carbon atoms continues to represent the number of carbon atoms in the aromatic ring system. Typical aryl groups include, but are not limited to, those derived from the following groups: aceanthrylene, acenaphthene, acephenanthrylene, anthracene, azurite, benzene, benzo[a]benzene, hexabenzo[b]benzene, fluorene, hexabenzo[a]benzene, hexaphene, hexalene, asymmetric indole, symmetric indole, indole, naphthalene, octacene, octaphene, octalene, ovalene, pentylene-2, 4-Diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Specifically, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise stated, each example of an aryl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted aryl”) or substituted with one or more substituents (“substituted aryl”). In some embodiments, the aryl group is an unsubstituted C6–14 aryl. In some embodiments, the aryl group is a substituted C6–14 aryl.

[0229] In some embodiments, the aryl group is substituted by one or more groups selected from: halogen, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0230] Representative examples of substituted aryl groups include the following:

[0231]

[0232] wherein one of R56 and R57 may be hydrogen and at least one of R56 and R57 may be independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclic, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59, NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R56 and R57 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, which optionally contains one or more heteroatoms selected from N, O or S. R60 and R61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 heterocyclic group, C6-C10 aryl, substituted C6-C10 aryl, 5-10 heterocyclic group or substituted 5-10 heterocyclic group.

[0233] "Fused aryl" refers to an aryl group whose two ring carbons are shared with a second aryl or heteroaryl ring or with a carbocyclic or heterocyclic ring. Specification 17 / 92 pages 31 CN 121085986 A

[0234] "Heteroaryl" refers to a group in a 5-10 member monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms (e.g., having 6 or 10 π electrons shared in a cyclic array), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 member heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the linkage point can be either a carbon atom or a nitrogen atom, provided the valence allows it. A heteroaryl bicyclic system may contain one or more heteroatoms in one or both rings. "Hyperaryl" includes ring systems where a heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linkage point is on the heteroaryl ring, and in this case, the number of ring members continues to represent the number of ring members in the heteroaryl ring system. "Hyperaryl" also includes ring systems where a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the linkage point is on the aryl or heteroaryl ring, and in this case, the number of ring members represents the number of ring members in the fused (aryl / heteraryl) ring system. In bicyclic heteroaryl groups, where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazoyl, etc.), the linkage point can be on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0235] In some embodiments, the heteroaryl group is provided in the aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms.The heteroaryl group is a 5-10-membered aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6-membered heteroaryl”). In some embodiments, the 5-6-membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6-membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6-membered heteroaryl group has 1 cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise stated, each instance of a heteroaryl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0236] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and thiopheneyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirrocycloheptatrienyl, oxacycloheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzooxazolyl, benzoisooxazolyl, benzooxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinel. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, piperidinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0237] Representative examples of heteroaryl groups include the following: Specification 18 / 92 pages 32 CN 121085986 A

[0238]

[0239] Each Z is selected from carbonyl, N, NR65, O, and S; and R65 is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclic, C6-C10 aryl, and 5-10 membered heteroaryl.

[0240] “Carbocyclic” or “carbocyclic” refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 cyclic carbon atoms (“C3–10 carbocyclic”) and 0 heteroatoms in a non-aromatic ring system. In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C3–8 carbocyclic”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C3–6 carbocyclic”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C3–6 carbocyclic”). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C5–10 carbocyclic”). Exemplary C3–6 carbon cyclogroups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C3–8 carbon cyclogroups include, but are not limited to, the above-mentioned C3–6 carbon cyclogroups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Exemplary C3–10 carbocyclic groups include, but are not limited to, the aforementioned C3–8 carbocyclic groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthyl (C10), spiro[4.5]decyl (C10), etc. As shown in the foregoing embodiments, in some embodiments, the carbocyclic group is a monocyclic (“monocyclic carbocyclic”) or contains a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic carbocyclic”), and may be saturated or may be partially unsaturated. “Carbocyclic” also includes a ring system in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclic ring, and in this case, the number of carbons continues to represent the number of carbons in the carbocyclic system. Unless otherwise stated, each instance of a carbocyclic group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted carbocyclic group”) or substituted by one or more substituents (“substituted carbocyclic group”). In some embodiments, the carbocyclic group is an unsubstituted C3–10 carbocyclic group. In some embodiments, the carbocyclic group is a substituted C3–10 carbocyclic group.

[0241] In some embodiments, “carbocyclic group” is a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms (“C3–10”).Cycloalkyl. In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C3–8 cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C3–6 cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C5–6 cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C5–10 cycloalkyl”). Examples of C5–6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3–6 cycloalkyl groups include the aforementioned C5–6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). C3–8 cycloalkyl groups include the aforementioned C3–6 cycloalkyl groups as well as cycloheptyl (C7) and specification 19 / 92 pages 33 CN 121085986 A Cyclooctyl (C8). Unless otherwise stated, each instance of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C3–10 cycloalkyl group. In some embodiments, the cycloalkyl group is a substituted C3–10 cycloalkyl group.

[0242] “Heterocyclic group” or “heterocyclic” refers to a group having a cyclic carbon atom and 1 to 4 cyclic heteroatoms in a 3 to 10-membered non-aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (3–10-membered heterocyclic groups). In heterocyclic groups containing one or more nitrogen atoms, the linkage may be a carbon or nitrogen atom, provided that the valence allows it. Heterocyclic groups may be monocyclic (“monocyclic heterocyclic group”) or fused, bridged, or spirocyclic systems, such as bicyclic systems (“bicyclic heterocyclic group”), and may be saturated or may be partially unsaturated. Heterocyclic bicyclic systems may contain one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems in which the heterocyclic group ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic group or the heterocyclic group ring, or includes ring systems in which the heterocyclic group ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic group ring, and in this case, the number of ring members continues to represent the number of ring members in the heterocyclic group ring system. Unless otherwise stated, each instance of a heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclic group") or substituted by one or more substituents ("substituted heterocyclic group"). In some embodiments, the heterocyclic group is an unsubstituted 3-10 member heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3-10 member heterocyclic group.

[0243] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclic group”). In some embodimentsIn this context, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1 cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0244] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azircyclopropane, oxacyclopropane, and thiocyclopropane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azahexacyclobutane, oxacyclobutane, and thiohexacyclobutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiohexane. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiocyclohexyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, [1,3,5]triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aromatic ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused with an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. Instruction manual, 20 / 92 pages, 34 CN 121085986 A

[0245] "Nitrogen-containing heterocyclic group" refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azacyclic butane, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine such as N-methylpiperazine. Specific examples include azacyclic butane, piperidinone, and piperazone.

[0246] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen, or sulfur heteroatoms. Heteroatoms can be applied to any of the above-mentioned hydrocarbon groups, such as alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocyclic), aryl (e.g., heteroaryl), cycloalkenyl (e.g., heterocyclic heteroalkenyl), etc., which have 1 to 5, particularly 1 to 3, heteroatoms.

[0247] “Acyl” means the group -C(O)R20, wherein R20 is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic, a substituted or unsubstituted heterocyclic, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, as defined herein. “Alkyl” is an acyl group, wherein R20 is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), C(O)-C1-C8 alkyl, –C(O)-(CH2)t (C6-C10 aryl), –C(O)-(CH2)t (5-10 membered heteroaryl), –C(O)-(CH2)t (C3-C10 cycloalkyl), and –C(O)-(CH2)t (4-10 membered heterocyclic), where t is an integer from 0 to 4. In some embodiments, R21 is a C1-C8 alkyl group substituted with a halogen or hydroxyl group; or a C3-C10 cycloalkyl group, a 4-10 membered heterocyclic group, a C6-C10 aryl group, an arylalkyl group, a 5-10 membered heteroaryl group, or a heteroarylalkyl group, each substituted with: an unsubstituted C1-C4 alkyl group, a halogen, an unsubstituted C1-C4 alkoxy group, an unsubstituted C1-C4 haloalkyl group, an unsubstituted C1-C4 hydroxyalkyl group, or an unsubstituted C1-C4 haloalkoxy group or a hydroxyl group.

[0248] "Alkoxy" refers to the group – OR29, wherein R29 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxyAlkoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, i.e., having 1 to 6 carbon atoms. Other specific alkoxy groups have 1 to 4 carbon atoms.

[0249] In some embodiments, R29 is a group having one or more substituents, for example, 1 to 5 substituents, particularly 1 to 3 substituents, particularly a group with 1 substituent, said substituent being selected from amino, substituted amino, C6-C10 aryl, aryloxy, carboxyl, cyano, C3-C10 cycloalkyl, 4-10 heterocyclic, halogen, 5-10 heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-. Exemplary 'substituted alkoxy' groups include, but are not limited to, O-(CH2)t (C6-C10 aryl), –O-(CH2)t (5-10 membered heteroaryl), –O-(CH2)t (C3-C10 cycloalkyl), and –O-(CH2)t (4-10 membered heterocyclic), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclic group present may be substituted by: unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl. Specific exemplary 'substituted alkoxy' groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0250] "Amino" refers to the group -NH2.

[0251] "Oxy group" refers to -C(=O)-.

[0252] "Substituted amino" refers to an amino group of the formula -N(R38)2, wherein R38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or amino protecting group, wherein at least one of R38 is not hydrogen. In some embodiments, each R38 is independently selected from hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 ynyl, C6-C10 aryl, 5-10 heteroaryl, 4-10 heterocyclic or C3-C10 cycloalkyl; or C1-C8 alkyl substituted with halogen or hydroxyl; C3-C8 alkenyl substituted with halogen or hydroxyl; C3-C8 ynyl or -(CH2)t(C6-C10 aryl), -(CH2)t(5-10 heterocyclic)Aryl), -(CH2)t (C3-C10 cycloalkyl) or -(CH2)t (4-10 heterocyclic group), where t is an integer between 0 and 8, each of which is substituted by: unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; or two R38 groups linked together to form an alkylene group.

[0253] Exemplary “substituted amino” groups include, but are not limited to, –NR39-C1-C8 alkyl, –NR39-(CH2)t (C6-C10 aryl), –NR39-(CH2)t (5-10 heteroaryl), –NR39-(CH2)t (C3-C10 cycloalkyl), and –NR39-(CH2)t (4-10 heterocyclic), where t is an integer from 0 to 4, such as 1 or 2, and each R39 independently represents H or C1-C8 alkyl; and any alkyl group present may itself be substituted with a halogen, substituted or unsubstituted amino or hydroxyl group; and any aryl, heteroaryl, cycloalkyl or heterocyclic group present may itself be substituted with an unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxyl group. For the avoidance of ambiguity, the term “substituted amino” includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino, as defined below. Substituted amino includes monosubstituted amino and disubstituted amino.

[0254] “Carboxyl” refers to the group -C(O)OH.

[0255] “Cyano” refers to the group -CN.

[0256] “Halo” or “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen group is fluorine or chlorine.

[0257] “Haloalkyl” refers to an alkyl group in which the alkyl group is substituted by one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, etc.

[0258] “Hydroxy” refers to the group -OH.

[0259] “Nitro” refers to the group –NO2.

[0260] “Thioketone” refers to the group =S.

[0261] Alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups as defined herein may optionally be substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” ynyl, “substituted” or “unsubstituted” carbocyclic, “substituted” or “unsubstituted” heterocyclic, “substituted” or “unsubstituted”).Aryl or “substituted” or “unsubstituted” heteroaryl). Generally, the term “substituted,” whether or not preceded by the term “optionally,” means that at least one hydrogen atom (e.g., a carbon or nitrogen atom) present on the group is substituted by a permissible substituent, such as a substituent that, upon substitution, yields a stable compound, such as a compound that does not spontaneously undergo transformation, for example by rearrangement, cyclization, elimination, or other reactions. Unless otherwise stated, a “substituted” group has a substituent at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. The term “substituted” includes substitution with all permissible substituents of an organic compound, any substituent described herein resulting in the formation of a stable compound. The invention contemplates any and all such combinations to obtain a stable compound. For the purposes of the invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any suitable substituent as described herein, which satisfies the valence of the heteroatom and results in the formation of a stable moiety.

[0262] Exemplary carbon atom substituents include, but are not limited to, halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –ORaa, –ON(Rbb)2, –N(Rbb)2, –N(Rbb)3+X–, –N(ORcc)Rbb, –SH, –SRaa, –SSRcc, –C(=O)Raa, –CO2H, –CHO, –C(ORcc)2, –CO2Raa, –OC(=O)Raa, –OCO2Raa, –C(=O)N(Rbb)2, –OC(=O)N(Rbb)2, –NRbbC(=O)Raa, –NRbbCO2Raa, –NRbbC(=O)N(Rbb)2, –C(=NR bb)Raa, –C(=NRbb)ORaa, –OC(=NRbb)Raa, –OC(=NRbb) Instructions 22 / 92 Page 36 CN 121085986 A ORaa, –C(=NRbb)N(Rbb)2, –OC(=NR bb)N(Rbb)2, –NR bbC(=NRbb)N(Rbb)2, –C(=O)NR bbSO2R aa, – NRbbSO2R aa, –SO2N(R bb)2, –SO2R aa, –SO2OR aa, –OSO2R aa, –S(=O)Raa, –OS(=O)Raa, –Si(Raa)3, –OSi (Raa)3 –C(=S)N(Rbb)2, –C(=O)SR aa, –C(=S)SRaa, –SC(=S)SRaa, –SC(=O)SRaa, –OC(=O)SRaa, –SC (=O)ORaa, –SC(=O)Raa, –P(=O)2Raa, –OP(=O)2R aa, –P(=O)(Raa)2, –OP(=O)(R aa)2, –OP(=O) (ORcc)2, –P(=O)2N(R bb)2, –OP(=O)2N(R bb)2, –P(=O)(NR bb)2, –OP(=O)(NR bb)2, –NR bbP(=O) (ORcc)2, –NR bbP(=O)(NRbb)2, –P(R cc)2, –P(R cc)3, –OP(R cc)2, –OP(R cc)3, –B(R aa)2, –B(OR cc)2, – BRaa(ORcc), C1–10 alkyl, C1–10 haloalkyl, C2–10 alkenyl, C2–10 ynyl, C3–10 carbocyclic, 3–14 heterocyclic, C6–14 aryl and 5–14 heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 Rdd groups; or the two twin hydrogens on the carbon atom are replaced by the groups =O, =S, =NN(Rbb)2, =NNR bbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raaa, =NRbb or =NORcc;

[0263] Each instance of Raa is independently selected from C1–10 alkyl, C1–10 haloalkyl, C2–10 alkenyl, C2–10 ynyl, C3–10 carbocyclic, 3–14-membered heterocyclic, C6–14 aryl, and 5–14-membered heteroaryl, or two Raa groups together forming a 3–14-membered heterocyclic ring or a 5–14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 Rdd groups;

[0264] Each instance of Rbb is independently selected from hydrogen, –OH, –ORaa, –N(Rcc)2, –CN, –C(=O)Raaa, –C(=O)N(Rcc)2, –CO2Raaa, –SO2R aa, –C(=NRcc)ORaa, –C(=NRcc)N(Rcc)2, –SO2N(R cc)2, –SO2R cc, –SO2OR cc, –SORaa, –C(= S)N(Rcc)2, –C(=O)SR cc, –C(=S)SRcc, –P(=O)2R aa, –P(=O)(Raa)2, –P(=O)2N(R cc)2, –P(=O)(NRcc)2, C1–10 alkyl, C1–10 haloalkyl, C2–10 alkenyl, C2–10 ynyl, C3–10 carbocyclic, 3–14 membered heterocyclic, C6–14 aryl and 5–14 membered heteroaryl or two Rbb groups together to form a 3–14 membered heterocyclic ring or a 5–14 membered heteroaryl ring, wherein each alkyl,Alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups are independently substituted by 0, 1, 2, 3, 4, or 5 Rdd groups;

[0265] Examples of Rcc are independently selected from hydrogen, C1–10 alkyl, C1–10 haloalkyl, C2–10 alkenyl, C2–10 ynyl, C3–10 carbocyclic, 3–14-membered heterocyclic, C6–14 aryl, and 5–14-membered heteroaryl, or two Rcc groups together to form a 3–14-membered heterocyclic ring or a 5–14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 Rdd groups;

[0266] Examples of Rdd are independently selected from halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OR ee, –ON(Rff)2, –N (Rff)2, –N(R ff)3 +X–, –N(ORee)Rff, –SH, –SRee, –SSRee, –C(=O)Ree, –CO2H, –CO2R ee, –OC(=O)Ree, –OCO2R ee, –C(=O)N(Rff)2, –OC(=O)N(R ff)2, –NR ffC(=O)Ree, –NRffCO2R ee, –NRffC(=O)N(Rff)2, –C(= NRff)ORee, –OC(=NRff)Ree, –OC(=NRff)ORee, –C(=NRff)N(Rff)2, –OC(=NR ff)N(Rff)2, –NR ffC(= NRff)N(Rff)2, –NR ffSO2R ee, –SO2N(R ff)2, –SO2R ee, –SO2OR ee, –OSO2R ee, –S(=O)Ree, –Si(Ree)3, –OSi(Ree)3, –C(=S)N(R ff)2, –C(=O)SR ee, –C(=S)SRee, –SC(=S)SRee, –P(=O)2R ee, –P(=O)(Ree)2, –OP(=O)(Ree)2, –OP(=O)(OR ee)2, C1–6 alkyl, C1–6 haloalkyl, C2–6 alkenyl, C2–6 ynyl, C3–10 carbocyclic, 3–10 C1–10 aryl, C6–10 heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 Rgg groups or two twin Rdd substituents can be combined to form =O or =S;

[0267] Examples of Ree are independently selected from C1–6 alkyl, C1–6 haloalkyl, C2–6 alkenyl, C2–6 ynyl, C3–10 carbocyclic,C6–10 aryl, 3–10 heterocyclic and 3–10 heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 Rgg groups;

[0268] Examples of Rff are independently selected from hydrogen, C1–6 alkyl, C1–6 haloalkyl, C2–6 alkenyl, C2–6 ynyl, C3–10 carbocyclic, 3–10 heterocyclic, C6–10 aryl and 5–10 heteroaryl or two Rff groups together to form a 3–14 heterocyclic ring or a 5–14 heteroaryl ring, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 Rgg groups. Specification 23 / 92 pages 37 CN 121085986 A Or 5 Rgg groups are substituted; and

[0269] Examples of Rgg are independently halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OC1–6 alkyl, –ON(C1–6 alkyl)2, –N(C1–6 alkyl)2, –N(C1–6 alkyl)3 +X–, –NH(C1–6 alkyl)2 +X–, –NH2(C1–6 alkyl)+X–, –NH3 +X–, –N (OC1–6 alkyl)(C1–6 alkyl), –N(OH)(C1–6 alkyl), –NH(OH), –SH, –SC1–6 alkyl, –SS(C1–6 alkyl), –C(=O) (C1–6 alkyl), –CO2H, –CO2(C1–6 alkyl), –OC(=O)(C1–6 alkyl), –OCO2(C1–6 alkyl), –C(=O)NH2, –C(=O) N(C1–6 alkyl)2, –OC(=O)NH(C1–6 alkyl), –NHC(=O)(C1–6 alkyl), –N(C1–6 alkyl)C(=O)(C1–6 alkyl), –NHCO2(C1–6 alkyl), –NHC(=O)N(C1–6 alkyl)2, –NHC(=O)NH(C1–6 alkyl), –NHC(=O)NH2, –C(=NH)O (C1–6 alkyl), –OC(=NH)(C1–6 alkyl), –OC(=NH)OC1–6 alkyl, –C(=NH)N(C1–6 alkyl)2, –C(=NH)NH(C1–6 alkyl), –C(=NH)NH2, –OC(=NH)N(C1–6 alkyl)2, –OC(NH)NH(C1–6 alkyl), –OC(NH)NH2, –NHC(NH)N (C1–6 alkyl)2, –NHC(=NH)NH2, –NHSO2(C1–6 alkyl), –SO2N(C1–6 alkyl)2, –SO2NH(C1–6 alkyl), –SO2NH2, –SO2C1–6alkyl, –SO2OC1–6alkyl, –OSO2C1–6alkyl, –SOC1–6alkyl, –Si(C1–6alkyl)3, –OSi(C1–6alkyl)3, –C(=S)N(C1–6alkyl)2, C(=S)NH(C1–6alkyl), C(=S)NH2, –C(=O)S(C1–6alkyl), –C(=S)SC1–6alkyl, –SC(=S)SC1–6alkyl, –P(=O)2(C1–6alkyl), –P(=O)(C1–6alkyl)2, –OP(=O)(C1–6alkyl)2, –OP(= O)(OC1–6alkyl)2, C1–6alkyl, C1–6 haloalkyl, C2–6 alkenyl, C2–6 alkynyl, C3–10 carbocyclic, C6–10 aryl, 3–10 heterocyclic, 5–10 heteroaryl; or two twin Rgg substituents can be combined to form =O or =S; wherein X– is a counterion.

[0270] “Counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group to maintain electroneutrality. Exemplary counterions include halide ions (e.g., F-, Cl-, Br-, I-), NO3-, ClO4-, OH-, H2PO4-, HSO4-, SO4-2-sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonate-5-sulfonate, acetyl-1-sulfonate-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanoate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0271] When valence permits, the nitrogen atom may be substituted or unsubstituted, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, –OH, –ORaa, –N(Rcc)2, –CN, –C(=O)R aa, –C(=O)N(Rcc)2, –CO2R aa, –SO2R aa, –C(=NRbb)Raa, –C(=NRcc)ORaa, –C(=NRcc)N(Rcc)2, –SO2N(R cc)2, –SO2R cc, –SO2OR cc, –SORaa, –C(=S)N(Rcc)2, –C(=O)SR cc, –C(=S)SRcc, –P(=O)2R aa, –P(=O)(Raa)2, –P(=O)2N(R cc)2, –P(=O)(NR cc)2, C1–10 alkyl, C1–10 haloalkyl, C2–10 alkenyl, C2–10 ynyl, C3–10 carbocyclic, 3–14-membered heterocyclic, C6–14 aryl, and 5–14-membered heteroaryl, or two Rcc groups attached to the nitrogen atom together to form 3–14-membered heterocyclic compounds.Cyclocyclic ring or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 Rdd groups and wherein Raa, Rbb, Rcc, and Rdd are as defined above.

[0272] These and other exemplary substituents are described in more detail in the detailed description of the invention, examples, and claims. The invention is not limited in any way to the substituents exemplified above.

[0273] Other Definitions

[0274] The term “pharmaceuticalally acceptable salt” means those salts that are suitable for contact with tissues of humans and lower animals within the limits of reasonable medical judgment without excessive toxicity, irritation, anaphylactic reactions, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1–19. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with amino groups of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconate, glyceryl phosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pyrate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, p-valerate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N+(C1–4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0275] The term "subject" to be considered includes, but is not limited to, humans (i.e., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0276] Disease, disorder, and symptom are used interchangeably herein.

[0277] As used herein, and unless otherwise stated, the term "treatment" refers to an effect that occurs when a subject has a particular disease, disorder, or symptom, which reduces the severity of said disease, disorder, or symptom or delays or slows the progression of said disease, disorder, or symptom ("therapeutic treatment"), and also to an effect that occurs before the subject begins to have a particular disease, disorder, or symptom ("preventive treatment").

[0278] Generally, an “effective amount” of a compound refers to an amount sufficient to elicit a desired biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, health, and condition of the subject. Effective amounts include therapeutic and preventative treatments.

[0279] As used herein, and unless otherwise stated, a “therapeutic effective amount” of a compound is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with said disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeutic effective amount” can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0280] As used herein, and unless otherwise stated, a “preventively effective amount” of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent its recurrence. A preventively effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a preventive benefit in preventing a disease, disorder, or condition. The term “preventively effective amount” may include an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent.

[0281] Detailed Description of Specific Embodiments of the Invention

[0282] As generally described herein, the present invention provides substituted oxosterols for the prevention and / or treatment of a variety of diseases, including but not limited to NMDA-mediated diseases.

[0283] Compounds

[0284] In one aspect, compounds of formula (A) are provided herein: Description25 / 92 Page 39 CN 121085986 A

[0285] (A)

[0286] or a pharmaceutically acceptable salt thereof, wherein:

[0287] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atom to which they are attached form a 3-8 membered ring;

[0288] n is 1 or 2;

[0289] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein RC is hydrogen or alkyl, or R2A and R2B together with the carbon atom to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen;

[0290] R3 is hydrogen, alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl;

[0291] R4 is absent or is hydrogen; and

[0292] represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent.

[0293] In some embodiments, n is 1. In other embodiments, n is 2.

[0294] In some embodiments, when R1A, R3, and R4 are hydrogen and R1B is an unsubstituted isopropyl group, then R2A and R2B do not form oxo groups with the carbon atoms to which they are attached; and when R4 is absent, R3 is hydrogen, and R1A and R1B are –CH3, then R2A is not –CH3 and R2B is not –OH.

[0295] In some embodiments, when R4 is absent, R2A is –OH, R2B is hydrogen or –CF3 and R1A and R1B are –CH3, then R3 is not hydrogen; and when R1A and R1B are –CH3 and R3 is hydrogen, then R2A and R2B together with the carbon atoms to which they are attached do not form oxo groups.

[0296] In some embodiments, the compound of formula (A) is a compound of formula (A-I):

[0297] (A-I).

[0298] In some embodiments, the compound of formula (A) is a compound of formula (A-II):

[0299] (A-II). Specification 26 / 92 pages 40 CN 121085986 A

[0300] In some embodiments, the compound of formula (A) is a compound of formula (A-III):

[0301] (A-III).

[0302] In some embodiments, the compound of formula (A) is a compound of formula (A-IV), (A-V), or (A-VI):

[0303] (A-IV), (A-V)

[0304] or (A-VI)

[0305] wherein R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, ynyl, or –ORA, wherein RA is alkyl.

[0306] In some embodiments, the compound of formula (A) is a compound of formula (A-VII), (A-VIII), or (A-IX):

[0307] (A-VII), (A-VIII)

[0308] or (A-IX)

[0309] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0310] In some embodiments, the compound of formula (A) is a compound of formula (A-X): Specification 27 / 92 pages 41 CN 121085986 A

[0311] (A-X)

[0312] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0313] In some embodiments, the compound of formula (A) is a compound of formula (A-XII)

[0314] (A-XII)

[0315] wherein R' is an alkyl or –ORA, wherein RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0316] In some embodiments, R4 is absent, one of R2A and R2B is –OH and R3 is not hydrogen.

[0317] In some embodiments, R1A and R1B are each independently unsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0318] In other embodiments, R1A and R1B are each independently substituted alkyl (e.g., haloalkyl). In some embodiments, R1A and R1B are alkyl (e.g., unsubstituted or substituted alkyl (e.g., –CH3)). In some embodiments, R1A and R1B are –CH3.

[0319] In some aspects, R1A is –CF3 or –CH2OCH3.

[0320] In other aspects, R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0321] In some embodiments, R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring.

[0322] In some aspects, R1A is a substituted alkyl or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[0323] In some embodiments, R2A and R2B are each independently alkyl (e.g., substituted or unsubstituted alkyl). In some aspects, R2A and R2B are each independently –F.

[0324] In other embodiments, R2A and R2B are –CH3 and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl. In some other embodiments, R2A and R2B are each independently hydrogen and R3 is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0325] In some embodiments, R3 is an alkyl group (e.g., substituted or unsubstituted alkyl), alkenyl, alkynyl, or –ORA, where RA is an alkyl group. In other embodiments, R3 is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0326] In one aspect, this document provides a compound of formula (B): Specification 28 / 92 pages 42 CN 121085986 A

[0327] (B)

[0328] or a pharmaceutically acceptable salt thereof, wherein:

[0329] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atom to which they are attached form a 3-8 membered ring;

[0330] n is 1 or 2;

[0331] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein RC is hydrogen or alkyl, or R2A and R2B together with the carbon atom to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen;

[0332] R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl;

[0333] R4 is absent or is hydrogen; and

[0334] represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent.

[0335] In some embodiments, n is 1. In other embodiments, n is 2.

[0336] In some embodiments, the compound of formula (B) is a compound of formula (B-I):

[0337] (B-I).

[0338] In some embodiments, the compound of formula (B) is a compound of formula (B-II):

[0339] (B-II).

[0340] In some embodiments, the compound of formula (B) is a compound of formula (B-III):

[0341] (B-III).

[0342] In some embodiments, the compound of formula (B) is a compound of formula (B-IV), (B-V), or (B-VI): Specification 29 / 92 pages 43 CN 121085986 A

[0343] (B-IV), (B-V)

[0344] or (B-VI)

[0345] wherein R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0346] In some embodiments, the compound of formula (B) is a compound of formula (B-VII), (B-VIII), or (B-IX):

[0347] (B-VII), (B-VIII)

[0348] or (B-IX)

[0349] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0350] In some embodiments, the compound of formula (B) is a compound of formula (B-X):

[0351] (B-X)

[0352] Wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0353] In some embodiments, the compound of formula (B) is a compound of formula (B-XII)

[0354] (B-XII)

[0355] wherein R' is alkyl or –ORA, wherein RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.

[0356] In some embodiments, R1A and R1B are each independently unsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3, or –CH2OCH3).

[0357] In other embodiments, R1A and R1B are each independently substituted alkyl (e.g., haloalkyl). In some embodiments, R1A and R1B are alkyl (e.g., unsubstituted or substituted alkyl (e.g., –CH3)). In some embodiments, R1A and R1B are –CH3.

[0358] In some aspects, R1A is –CF3 or –CH2OCH3.

[0359] In other aspects, R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0360] In some embodiments, R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring.

[0361] In some aspects, R1A is a substituted or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[0362] In some embodiments, R2A and R2B are each independently alkyl (e.g., substituted or unsubstituted alkyl). In some aspects, R2A and R2B are each independently –F.

[0363] In other embodiments, R2A and R2B are –CH3 and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl. In some other embodiments, R2A and R2B are each independently hydrogen and R3 is alkyl (e.g., substituted or unsubstituted alkyl).

[0364] In some embodiments, R3 is alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, alkynyl, or –ORA, wherein RA is alkyl. In other embodiments, R3 is alkyl (e.g., substituted or unsubstituted alkyl).

[0365] In one aspect, compounds of formula (I) are provided herein:

[0366] (I)

[0367] or a pharmaceutically acceptable salt thereof, wherein:

[0368] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring; R2A and R2B are each independently hydrogen, halogen, –ORC, alkylR1A, R2B, R3, R4, R3, R4, R5, R6, R7, R8, R9, R1A, R2B, R1B, R2A, R2B, R3, R4, R3, R4, R5, R6, R7, R8, R1A, R2B, R1B, R2A, R2B, R3, R4, R1B, R2A, R2 ...

[0369] In some embodiments, R1A, R3, and R4 are hydrogen, R1B is unsubstituted isopropyl, and R2A and R2B do not form oxo groups with the carbon atoms to which they are attached.

[0370] In some embodiments, R4 is absent, R3 is hydrogen, R1A and R1B are –CH3, R2A is not –CH3, and R2B is not –OH.

[0371] In some embodiments, the compound of formula (I) is a compound of formula (I-A): Specification 31 / 92 pages 45 CN 121085986 A

[0372] (I-A).

[0373] In some embodiments, the compound of formula (I) is a compound of formula (I-B):

[0374] (I-B).

[0375] In some embodiments, the compound of formula (I) is a compound of formula (I-C):

[0376] (I-C).

[0377] In some embodiments, the compound of formula (I) is a compound of formula (I-E), (I-F), or (I-G):

[0378] (I-E), (I-F), or

[0379] (I-G)

[0380] wherein R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0381] In some embodiments, the compound of formula (I) is a compound of formula (I-H), (I-I), or (I-J):

[0382] (I-H), (I-I)

[0383] or (I-J)

[0384] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0385] In some embodiments, the compound of formula (I) is a compound of formula (I-K):

[0386] (I-K)

[0387] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, and RA is alkyl.

[0388] In some embodiments, the compound of formula (I) is a compound of formula (I-M):

[0389] (I-M)

[0390] Wherein R' is an alkyl or –ORA, where RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0391] In some embodiments, R1A and R1B are each independently unsubstituted or substituted alkyl (e.g., substituted or unsubstituted –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0392] In some embodiments, R1A and R1B are each independently substituted alkyl (e.g., haloalkyl).

[0393] In some embodiments, R1A is –CF3 or –CH2OCH3.

[0394] In some embodiments, R1A and R1B are alkyl (e.g., unsubstituted or substituted alkyl (e.g., –CH3)).

[0395] In some embodiments, R1A and R1B are –CH3.

[0396] In some embodiments, R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring.

[0397] In some embodiments, R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0398] In some embodiments, R1A is a substituted alkyl or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[0399] In some embodiments, R2A and R2B are each independently alkyl (e.g., substituted or unsubstituted alkyl).

[0400] In some embodiments, R2A and R2B are each independently –F.

[0401] In some embodiments, R2A and R2B are –CH3 and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0402] In some embodiments, R2A and R2B are –F.

[0403] In some embodiments, R3 is an alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, ynyl, or –ORA, wherein RA is an alkyl. Specification 33 / 92 pages 47 CN 121085986 A

[0404] In some embodiments, R3 is an alkyl (e.g., substituted or unsubstituted alkyl).

[0405] In some embodiments, R2A and R2B are each independently hydrogen and R3 is an alkyl (e.g., substituted or unsubstituted alkyl).

[0406] In one aspect, compounds of formula (II) are provided herein:

[0407] (II)

[0408] or a pharmaceutically acceptable salt thereof, wherein:

[0409] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl, or R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring;

[0410] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein RC is hydrogen or alkyl, or R2A and R2B together with the carbon atom to which they are attached form an oxo group, wherein R2A and R2B are not both hydrogen;

[0411] R3 is hydrogen, alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl;

[0412] R4 is absent or is hydrogen; and

[0413] represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent;

[0414] The premise is that when R4 is absent, R2A is –OH, R2B is hydrogen or –CF3 and R1A and R1B are –CH3, then R3 is not hydrogen; and when R1A and R1B are –CH3 and R3 is hydrogen, then R2A and R2B together with the carbon atoms to which they are attached do not form oxo groups.

[0415] In some embodiments, R4 is absent, one of R2A and R2B is –OH and R3 is not hydrogen.

[0416] In some embodiments, the compound of formula (II) is a compound of formula (II-A):

[0417] (II-A).

[0418] In some embodiments, the compound of formula (II) is a compound of formula (II-B):

[0419] (II-B).

[0420] In some embodiments, the compound of formula (II) is a compound of formula (II-C): Specification 34 / 92 pages 48 CN 121085986 A

[0421] (II-C).

[0422] In some embodiments, the compound of formula (II) is a compound of formula (II-D):

[0423] (II-D).

[0424] In some embodiments, the compound of formula (II) is a compound of formula (II-E), (II-F) or (II-G):

[0425] (II-E), (II-F)

[0426] or (II-G)

[0427] wherein R2C is hydrogen or alkyl (e.g., substituted or unsubstituted alkyl) and R3 is alkyl (e.g., substituted or unsubstituted alkyl).

[0428] In some embodiments, the compound of formula (II) is a compound of formula (II-H), (II-I), or (II-J):

[0429] (II-H), (II-I)

[0430] or (II-J)

[0431] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0432] In some embodiments, the compound of formula (II) is a compound of formula (II-K):

[0433] (II-K) Specification 35 / 92 pages 49 CN 121085986 A

[0434] Wherein R' is an alkyl or –ORA, where RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0435] In some embodiments, R1A and R1B are each independently unsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0436] In some embodiments, R1A and R1B are each independently substituted alkyl (e.g., haloalkyl).

[0437] In some embodiments, R1A is –CF3 or –CH2OCH3.

[0438] In some embodiments, R1A and R1B are alkyl (e.g., unsubstituted or substituted alkyl (e.g., –CH3)).

[0439] In some embodiments, R1A and R1B are –CH3.

[0440] In some embodiments, R1A and R1B form a ring together with the carbon atom to which they are attached.

[0441] In some embodiments, R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0442] In some embodiments, R2A and R2B are each independently alkyl (e.g., substituted or unsubstituted alkyl).

[0443] In some embodiments, R3 is alkyl (e.g., substituted or unsubstituted alkyl).

[0444] In some embodiments, R2A and R2B are each independently hydrogen and R3 is alkyl (e.g., substituted or unsubstituted alkyl).

[0445] In some embodiments, R2A and R2B are each independently –F.

[0446] In some embodiments, R2A and R2B are –CH3 and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0447] In some embodiments, R2A and R2B are –F.

[0448] In some embodiments, R1A is a substituted alkyl or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[0449] In some aspects, the compound is a compound of formula (III):

[0450] (III)

[0451] or a pharmaceutically acceptable salt thereof, wherein:

[0452] each of R1A and R1B is alkyl;

[0453] R2A and R2B are each independently hydrogen, –ORC or alkyl, wherein RC is hydrogen or alkyl, or

[0454] R2A and R2B together with the carbon atom to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen;

[0455] R3 is alkyl;

[0456] R4 is absent or is hydrogen; and

[0457] represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent.

[0458] In some aspects, R1A and R1B are each –CH3.

[0459] In some aspects, R2A and R2B together with the carbon atom to which they are attached form an oxo group.

[0460] In some aspects, R3 is –CH2CH3.

[0461] In some aspects, R2A is –OH and R2B is H.

[0462] In some aspects, R2A is –CH3 and R2B is H.

[0463] In some aspects, R2A is –OH and R2B is –CH3. Specification 36 / 92 pages 50 CN 121085986 A

[0464] In some aspects, R1A is –CF3.

[0465] In an alternative embodiment, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen can be 2H (D or deuterium) or 3H (T or tritium); carbon can be, for example, 13C or 14C; oxygen can be, for example, 18O; nitrogen can be, for example, 15N, etc. In other embodiments, a particular isotope (e.g., 3H, 13C, 14C, 18O, or 15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site of the compound.

[0466] Pharmaceutical Composition

[0467] In another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula (A), formula (B), formula (I), formula (II), or formula (III).

[0468] When used as a pharmaceutical, the compounds provided herein are typically administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner known in the pharmaceutical industry and contain at least one active compound.

[0469] In one embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, an oral carrier, or a topical carrier.

[0470] The present invention also relates to compounds of formula (A), (B), (I), (II), or (III) or pharmaceutical compositions thereof used as pharmaceuticals or medicaments.

[0471] Generally, the compounds provided herein are administered in a therapeutically effective amount. The amount of compound actually administered is usually determined by a physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the age, weight, and response of each patient, the severity of the patient's symptoms, etc.

[0472] The pharmaceutical compositions provided herein can be administered via various routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the desired route of delivery, the compounds provided herein are preferably formulated as injectable compositions or oral.Compositions for oral administration, or formulated as ointments, lotions, or patches for transdermal application.

[0473] Compositions for oral administration may be in the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, the composition is present in unit dosage forms to aid in precise administration. The term "unit dosage form" refers to a physically dispersed unit suitable for a single dose in human subjects and other mammals, each unit containing a predetermined amount of active substance and suitable pharmaceutical excipients, wherein the amount of active substance is calculated to produce the desired therapeutic effect. Typical unit dosage forms include pre-filled liquid compositions, ampoules or syringes of predicted amounts, or, in the case of solid compositions, pills, tablets, or capsules, etc. In such compositions, the compound is typically a small component (about 0.1 to 50% by weight or preferably about 1 to about 40% by weight), with the remainder being various media or carriers, and processing aids that help form the desired dosage form.

[0474] Suitable liquid forms for oral administration may include appropriate aqueous or non-aqueous media, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components or compounds having similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginate, Primogel, or corn starch; lubricants such as magnesium stearate; flow aids such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavorings.

[0475] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As described above, the active compound in the composition is typically a minority component, usually about 0.05 to 10% by weight, with the remainder being injectable carriers, etc.

[0476] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient, typically in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is typically combined with paraffin or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. This transdermal formulation is known in the art and typically contains other ingredients to increase the transdermal permeation stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope described herein.

[0477] The compounds provided herein can also be administered via transdermal devices. Thus, transdermal administration can be accomplished by using reservoir-type or porous membrane-type patches or by using solid matrix types.

[0478] The ingredients described above for oral, injectable, or topical application of the compositions are merely representative. At Remington'sOther materials and processing techniques are listed in Part 8 of Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0479] The ingredients described above for oral, injectable, or topical applications are only representative. Other materials and processing techniques are listed in Part 8 of Remington's The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins, which is incorporated herein by reference.

[0480] The compounds of the present invention can be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found in Remington's Pharmaceutical Sciences.

[0481] The present invention also relates to pharmaceutically acceptable formulations of compounds of formula (A), (B), (I), (II), or (III). In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α–, β–, and γ–cyclodextrins, which consist of 6, 7, and 8 α–1,4– linked glucose units, respectively, optionally containing one or more substitutions on the linked sugar moieties, including but not limited to methylation, hydroxyalkylation, acylation, and sulfonyl alkyl ether substituents. In some embodiments, the cyclodextrin is a sulfonyl alkyl ether β–cyclodextrin, for example, sulfobutyl ether β–cyclodextrin, also known as Captisol®. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In a more specific embodiment, the formulation comprises hexapropyl-β-cyclodextrin (10–50% in water).

[0482] The present invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula (A), (B), (I), (II), or (III). Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, namely salts containing pharmaceutically acceptable anions, such as hydrochlorides, hydroiodates, hydrobromates, nitrates, sulfates, hydrogen sulfates, phosphates, acetates, lactates, citrates, tartrates, succinates, maleates, fumarates, benzoates, p-toluenesulfonates, etc.

[0483] The following formulation examples illustrate representative pharmaceutical compositions that can be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0484] Exemplary Formulation 1 –Tablets: Compounds of formula (A), (B), (I), (II), or (III) or pharmaceutically acceptable salts thereof may be mixed as dry powders with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is formed into tablets of 240 to 270 mg in a tableting machine (each tablet containing 80 to 90 mg of the active compound).

[0485] Exemplary Formulation 2 – Capsules: Compounds of formula (A), (B), (I), (II), or (III) or pharmaceutically acceptable salts thereof may be mixed as dry powders with a starch diluent at a weight ratio of about 1:1. The mixture is filled into 250 mg capsules (each capsule containing 125 mg of the active compound).

[0486] Exemplary Formulation 3 – Liquid: A compound of formula (A), formula (B), formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof (125 mg) may be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture may be blended, sieved through a 10-mesh US sieve, and then mixed with a previously prepared aqueous solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavoring agent and coloring agent are diluted with water and added with stirring. Sufficient water may then be added to produce a total volume of 5 mL.

[0487] Exemplary Formulation 4 – Tablet: A compound of formula (A), formula (B), formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is then compressed in a tableting machine to form tablets of 450 to 900 mg (150 to 300 mg of the active compound).

[0488] Exemplary Formulation 5 – Injection: A compound of formula (A), formula (B), formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof is soluble in or suspended in a buffered sterile saline injectable aqueous medium at a concentration of about 5 mg / mL.

[0489] Exemplary Formulation 6 – Tablet: A compound of formula (A), formula (B), formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof is mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is then compressed in a tableting machine to form tablets of 90 to 150 mg (30 to 50 mg of the active compound per tablet).

[0490] Exemplary Formulation 7 – Tablet: A compound of formula (A), formula (B), formula (I), formula (II) or formula (III) or pharmaceutically acceptable thereof.An acceptable salt may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is then compressed in a tableting machine to form tablets of 30 to 90 mg (each tablet containing 10 to 30 mg of the active compound).

[0491] Exemplary Formulation 8 – Tablet: A compound of formula (A), formula (B), formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is then compressed in a tableting machine to form tablets of 0.3 to 30 mg (each tablet containing 0.1 to 10 mg of the active compound).

[0492] Exemplary Formulation 9 – Tablet: A compound of formula (A), formula (B), formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is then compressed in a tableting machine to form tablets of 150 to 240 mg (50 to 80 mg of active compound per tablet).

[0493] Exemplary Formulation 10 – Tablets: Compounds of formula (A), (B), (I), (II), or (III) or pharmaceutically acceptable salts thereof may be mixed as dry powders with dry gelatin binders at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is then compressed in a tableting machine to form tablets of 270 to 450 mg (90 to 150 mg of active compound per tablet).

[0494] The injection dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour over a period of about 1 hour to 120 hours, particularly over 24 to 96 hours. A preload bolus of about 0.1 mg / kg to about 10 mg / kg or greater may also be administered to achieve a sufficiently stable state level. For human patients weighing 40 to 80 kg, the total maximum dose is not expected to exceed about 2 g / day.

[0495] For the prevention and / or treatment of long-term conditions, treatment regimens are often extended over many months or years, and therefore oral administration is preferred in consideration of patient convenience and tolerability. For oral administration, 1 to 5 times daily, especially 2 to 4 times daily, and typically 3 times daily are representative regimens. Using these administration regimens, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, with preferred doses providing about 0.1 to about 10 mg / kg, and especially about 1 to about 5 mg / kg.

[0496] Transdermal doses are generally chosen to provide similar or lower blood levels compared to injectable doses.

[0497] When used to avoid CNS disorders, subjects at risk of developing the condition are given the above-described dose levels. (Pages 39 / 92, 53 CN)121085986 A Administration of the compounds provided herein is generally performed under the advice and supervision of a physician. Subjects at risk of developing a specific condition generally include those with a family history of the condition or those identified by genetic testing or screening as particularly susceptible to developing the condition.

[0498] Methods of Treatment and Use

[0499] The compounds of the present invention, such as those of formula (A), (B), (I), (II), or (III) and their pharmaceutically acceptable salts as described herein, are generally designed to modulate NMDA function and thus act as oxidosterols for the treatment and prevention, for example, of CNS-related conditions in subjects. In some embodiments, the compounds described herein, such as those of formula (A), (B), (I), (II), or (III) and their pharmaceutically acceptable salts as described herein, are generally designed to penetrate the blood-brain barrier (e.g., designed to be transported across the blood-brain barrier). As used herein, modulation refers, for example, the inhibition or enhancement of NMDA receptor function. In some embodiments, compounds of formula (A), (B), (I), (II), or (III), or pharmaceutically acceptable salts thereof, act as negative allosteric modulators (NAMs) of NMDA and inhibit NMDA receptor function. In some embodiments of the invention, for example, compounds of formula (A), (B), (I), (II), or (III), or pharmaceutically acceptable salts thereof, act as positive allosteric modulators (PAMs) of NMDA and enhance NMDA receptor function. In some embodiments, compounds of formula (A), (B), (I), (II), or (III), or pharmaceutically acceptable salts thereof, block or reduce the enhancement or inhibition of NMDA receptor function via naturally occurring substrates. These compounds do not act as negative allosteric modulators (NAMs) or positive allosteric modulators (PAMs) of NMDA. In some embodiments, the condition is cancer. In some embodiments, the condition is diabetes. In some embodiments, the condition is a sterol synthesis disorder. In some embodiments, the condition is a gastrointestinal (GI) condition, such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural conditions affecting the gastrointestinal tract, anal conditions (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colonic polyps, cancer, or colitis. In some embodiments, the condition is inflammatory bowel disease.

[0500] Exemplary conditions associated with NMDA regulation include, but are not limited to, gastrointestinal (GI) conditions, such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural conditions affecting the gastrointestinal tract, anal conditions (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colonic polyps, cancer, colitis, and CNS diseases.Disorders, such as diseases as described herein.

[0501] Exemplary disorders associated with NMDA regulation (e.g., CNS disorders) include, but are not limited to, adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia, including cortical-basal dementia-progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's dementia, and Lewy body dementia), dissociative disorders, eating disorders, affective disorders (including depression (e.g., postpartum depression), bipolar disorder, dysphoric disorder, suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (e.g., Shank3), neurodevelopmental disorders (including Rett syndrome). Syndrome (including multiple sclerosis, sterol synthesis disorders, Schlumberger-Lonzo-Oxley syndrome), pain (including acute pain, chronic pain, and neuropathic pain), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease, complex tuberous sclerosis (TSC), and infantile spasms), stroke, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral ischemia, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), attention deficit disorder, attention deficit hyperactivity disorder, metabolic encephalopathy (including phenylketonuria), postpartum psychosis, syndromes associated with high titers of anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis), neurodegenerative diseases, neuroinflammation, neuropsychiatric lupus, Niemann-Pick C disorder, and tinnitus.

[0502] In some embodiments, the compounds of the present invention, for example, compounds of formula (A), (B), (I), (II), or (III) (see specification 40 / 92 pages 54 CN 121085986 A), or pharmaceutically acceptable salts thereof, can be used to induce sedation or anesthesia.

[0503] In some embodiments, compounds of formula (A), (B), (I), (II), or (III), or pharmaceutically acceptable salts thereof, are used to treat or prevent adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia, including cortical-basal dementia-progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's dementia, and Lewy body dementia), dissociative disorders, eating disorders, affective disorders (including depression (e.g., postpartum depression, bipolar disorder, dysphoric disorder, suicide), schizophrenia, or other psychosis).(Including affective schizophrenia), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, Schlumberger-Oxley syndrome, pain (including acute pain, chronic pain, and neuropathic pain), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease, complex tuberous sclerosis (TSC), and infantile spasms), stroke, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral ischemia, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), attention deficit, attention deficit hyperactivity disorder, metabolic encephalopathy (including phenylketonuria), postpartum psychosis, syndromes associated with high titers of anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis), neurodegenerative diseases, neuroinflammation, neuropsychiatric lupus, Niemann-Pick type C disorder, and tinnitus.

[0504] In some embodiments, compounds of formula (A), formula (B), formula (I), formula (II) or formula (III) or pharmaceutically acceptable salts thereof are used to treat or prevent adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia, including cortical-basal dementia-progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's dementia and Lewy body dementia), substance abuse-related disorders, dissociative disorders, eating disorders, affective disorders (including depression (e.g., postpartum depression), bipolar disorder, dysphoric disorder, suicide), schizophrenia or other psychosis (including affective schizophrenia), personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (e.g., Shank3)) or postpartum psychosis.

[0505] In some embodiments, compounds of formula (A), (B), (I), (II), or (III), or pharmaceutically acceptable salts thereof, are used to treat or prevent neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, Schlumberger-Oxley syndrome, pain (including acute pain, chronic pain, and neuropathic pain), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease, complex tuberous sclerosis (TSC), and infantile spasms), stroke, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral ischemia, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), attention deficit, attention deficit hyperactivity disorder, metabolic encephalopathy (including phenylketonuria), and syndromes associated with high titers of anti-NMDA receptor antibodies.(Including anti-NMDA receptor encephalitis), neurodegenerative diseases, neuroinflammation, neuropsychiatric lupus, Niemann-Pick type C disorder, or tinnitus.

[0506] In some embodiments, the compounds of the present invention, such as compounds of formula (A), (B), (I), (II), or (III), which act as PAM or NAMs that function as NMDA receptors, can be used to treat or prevent conditions (e.g., CNS-related conditions), including schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), autism spectrum disorders (including those involving mutations in the Shank proteome (e.g., Shank3), multiple sclerosis, movement disorders (including Huntington's disease and Parkinson's disease), attention deficit, attention deficit hyperactivity disorder, metabolic encephalopathy (including phenylketonuria), postpartum psychosis, and syndromes associated with high titers or anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis).

[0507] In some embodiments, the compounds of the present invention, for example, compounds of formula (A), formula (B), formula (I), formula (II) or formula (III), which act as NAMs that function as NMDA receptors, can be used to treat or prevent conditions (e.g., CNS-related conditions), including anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), affective disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymia, suicide), personality disorders (including obsessive-compulsive personality disorder), neurodevelopmental disorders (including Rett syndrome), pain (including acute and chronic pain), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease and complex tuberous sclerosis (TSC)), stroke, traumatic brain injury, adjustment disorder, neuropsychiatric lupus, and tinnitus.

[0508] In some embodiments, the compounds of the present invention, for example, compounds of formula (A), (B), (I), (II), or (III), which act as PAM or NAMs functioning as NMDA receptors, can be used to treat or prevent conditions (e.g., CNS-related conditions), including cognitive impairments (including Alzheimer's disease and other forms of dementia, including cortical-basal dementia-progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's dementia, and Lewy body dementia), sterol synthesis disorders, and eating disorders.

[0509] In another aspect, a method is provided for treating or preventing brain excitability in a subject who is susceptible to or suffers from conditions related to brain excitability, comprising administering to the subject an effective amount of a compound of the present invention, for example, a compound of formula (A), (B), (I), (II), or (III), or a pharmaceutically acceptable salt thereof.

[0510] In another aspect, the present invention provides combinations of the compounds of the invention, such as compounds of formula (A), formula (B), formula (I), formula (II) or formula (III) or pharmaceutically acceptable salts thereof and another pharmacologically active agent. The compounds provided herein may be administered as individual active agents or they may be administered in combination with other agents. Combination administration may be performed by any technique readily apparent to those skilled in the art, including, for example, separate, sequential, simultaneous and alternating administration.

[0511] Movement Disorders

[0512] Methods for treating movement disorders are also described herein. As used herein, “movement disorder” refers to a variety of diseases and disorders associated with hyperactivity disorders and related abnormalities in muscle control. Exemplary movement disorders include, but are not limited to, Parkinson’s disease and Parkinson’s syndrome (particularly defined by bradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and panic, tics and Tourette syndrome, restless legs syndrome, stiff-person syndrome and gait disorders.

[0513] Tremor is an involuntary, irregular, rhythmic contraction and relaxation of muscles that may involve vibration or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs). Tremors include hereditary, degenerative, and primary diseases such as Wilson's disease, Parkinson's disease, and essential tremor; metabolic diseases (e.g., thyroid-parathyroid disorders, liver diseases, and hypoglycemia); peripheral neuropathy (associated with Charcot-Marie-Tooth disease, Roussy-Levy syndrome, diabetes, and complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced diseases (episodic anesthetics, tricyclic antidepressants, lithium, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic diseases. Clinical tremors can be classified into physiological tremors, aggravated physiological tremors, essential tremor syndromes (including typical essential tremor, essential orthostatic tremor, task and position-specific tremor), dystonia tremor, Parkinson's disease tremor, cerebellar tremor, Holmes' tremor (i.e., red nucleus tremor), palatal tremor, neurogenic tremor, toxic or drug-induced tremor, and psychogenic tremor. Other forms of tremor include cerebellar tremor or intention tremor, dystonia tremor, essential tremor, orthostatic tremor, Parkinson's disease tremor, physiological tremor, psychogenic tremor, or red nucleus tremor.

[0514] Cerebellar tremor or intention tremor is a slow, widespread tremor of the limbs that occurs after purposeful movement. Cerebellar tremor is caused by cerebellar damage due to conditions such as tumors, stroke, or diseases (e.g., multiple sclerosis, hereditary degenerative diseases).Caused by injury or damage.

[0515] Dystonia tremor occurs in individuals affected by dystonia, a movement disorder in which persistent, involuntary muscle contractions cause twisting and repetitive movements and / or pain and abnormal postures or positions. Dystonia tremor may affect any muscle in the body. Dystonia tremor occurs irregularly and is usually relieved by complete rest.

[0516] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor may be mild and non-progressive in some cases, and may be slowly progressive, starting on one side of the body but affecting both sides within 3 years. The hands are most commonly affected, but the head, voice, tongue, legs, and trunk may also be involved. As a person ages, the frequency of tremor may decrease, but the severity may increase. Elevated mood, stress, fever, physical fatigue, or hypoglycemia may trigger tremors and / or increase their severity. Symptoms typically develop over time and can be visible and persistent after onset.

[0517] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions that occur immediately after standing in the legs and trunk. Spasms are felt in the thighs and legs, and the patient may sway uncontrollably when asked to stand in one position. Orthostatic tremor may occur in patients with essential tremor.

[0518] Parkinson's disease tremor is caused by damage to the brain structures that control movement. Parkinson's disease tremor is often a precursor to Parkinson's disease and is usually thought of as a "pill-rolling" motion of the hands, but may also affect the jaw, lips, legs, and trunk. Onset of Parkinson's disease tremor usually begins after age 60. The movement begins in one limb or one side of the body and can progress to include the other side.

[0519] Physiological tremor can occur in normal individuals and is not clinically significant. It can be seen in all voluntary muscle groups. Physiological tremors can be caused by certain medications, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia. Tremors typically have a frequency of about 10 Hz.

[0520] Psychogenic tremors, or hysterical tremors, can occur at rest or during postural or dynamic movements. Patients with psychogenic tremors may have conversion disorder or other mental illnesses.

[0521] Red nucleus tremor is characterized by a coarse, slow tremor that can be present at rest, in posture, and during intention. The tremor is associated with a condition affecting the red nucleus in the midbrain, namely classic atypical stroke.

[0522] Parkinson's disease affects nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremor, and changes in speech and gait. Parkinson's disease is characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinson's disease presents with symptoms of Parkinson's disease, but the symptoms are complex and not a progressive neurodegenerative disease.

[0523] Dystonia is a movement disorder characterized by persistent or intermittent muscle contractions that result in abnormal and often repetitive movements or postures. Dystonia movements can be patterned, distorted, and may be trembling. Dystonia is usually triggered or exacerbated by voluntary movements and is accompanied by spillover muscle activation.

[0524] Chorea is a neurological disorder characterized by twitching involuntary movements that typically affect the shoulders, hips, and face.

[0525] Huntington's disease is a genetic disorder that causes the wastage of nerve cells in the brain. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington's disease can impair walking, talking, and swallowing.

[0526] Ataxia is the loss of complete control over body movements and may affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0527] Myoclonus and panic are reactions to sudden and unexpected stimuli, which can be acoustic, tactile, visual, or vestibular.

[0528] A tic is an involuntary movement that is usually sudden, brief, and repetitive, but non-rhythmic, often mimicking normal behavior and frequently occurring in the context of normal activity. Tics can be classified as motor or vocal, with motor tic being associated with motor tic and vocal tic with vocal tic, as described on pages 43 / 92 of the specification, 57 CN 121085986 A. Tics can be characterized as simple or complex. For example, a simple motor tic involves only a few muscles limited to a specific body part.

[0529] Tourette syndrome is a hereditary neuropsychiatric disorder that occurs in childhood and is characterized by multiple motor tic and at least one vocal tic.

[0530] Restless legs syndrome is a neurosensory-motor disorder characterized by an overwhelming urge to move the legs at rest.

[0531] Stiff-person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle stiffness, usually involving the lower back and legs. It usually results in a stiff gait with exaggerated lumbar lordosis. Characteristic abnormalities are typically observed in EMG recordings of continuous motor unit activity involving paravertebral muscles. Variants include “stiff limb syndrome,” which produces focal stiffness that typically affects the distal leg and foot.

[0532] Gait disturbances refer to abnormalities in the manner or type of walking caused by neuromuscular, arthritis, or other bodily changes. Gait is classified according to the system responsible for abnormal movement, including hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, Parkinson's gait, chorea-like gait, ataxia-like gait, and sensory gait.

[0533] Emotional Disorders

[0534] This article also provides methods for treating mood disorders such as clinical depression, postpartum depression or postpartum melancholia, atypical depression, melancholic depression, psychotic major depression, and catatonic depression.Clinical depression, also known as major depressive disorder, seasonal affective disorder, dysphoric mood, dual depression, depressive personality disorder, recurrent transient depression, mild depression, bipolar disorder or manic depression, depression caused by chronic medical conditions, treatment-resistant depression, treatment-resistant depression, suicide, suicidal ideation or suicidal behavior.

[0535] Clinical depression is also known as major depressive disorder, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder and recurrent depression, and is a mental disorder characterized by a generalized and persistent low mood, accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression have difficulty sleeping, losing weight, and often feel anxious and irritable. Clinical depression can affect an individual’s feelings, thoughts and behaviors and can lead to a variety of emotional and physical problems. People with clinical depression may have difficulty with daily activities and feel that life is not worth living.

[0536] Postpartum depression (PND), also known as postpartum melancholia (PPD), is a clinical depression that affects women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased libido, crying episodes, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant depression (e.g., a treatment-resistant depression as described herein). In some embodiments, the PND is a treatment-resistant depression (e.g., a treatment-resistant depression as described herein).

[0537] In some embodiments, the subject with the PND also experiences symptoms of depression or depressive disorder during pregnancy. This depression is referred to herein as perinatal depression. In one embodiment, the subject experiencing perinatal depression has an increased risk of developing PND.

[0538] Atypical depression (AD) is characterized by mood responsiveness (e.g., anomalous lack of interest) and positivity, significant weight gain, or increased appetite. Patients with AD may also have excessive sleep or somnolence (hypersomnia), heaviness in the limbs, and significant social impairment due to hypersensitivity to perceived interpersonal rejection.

[0539] Melancholic depression is characterized by loss of pleasure (loss of interest) in most or all activities, inability to respond to pleasant stimuli, more pronounced depressive mood than sadness or loss, excessive weight loss, or excessive guilt.

[0540] Psychotic major depressive disorder (PMD) or psychotic depression refers to a major depressive episode, particularly a melancholic episode, in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0541] Catatonic depression refers to a disorder involving motor behavior and other symptoms.Severe depression. Individuals may become mute and comatose, and either be immobile or exhibit aimless or strange movements.

[0542] Seasonal affective disorder (SAD) is a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that occur in the fall or winter.

[0543] Dysthymia is a condition associated with unipolar depression in which the same physical and cognitive problems are present. They are less severe and tend to last longer (e.g., at least 2 years).

[0544] Dual depression is a condition of fairly depressed mood (dysthymia) that lasts for at least 2 years and occasionally includes major depressive disorder.

[0545] Depressive personality disorder (DPD) is a personality disorder characterized by depressive features.

[0546] Recurrent transient depression (RBD) is a condition in which an individual experiences depressive episodes approximately once a month, each lasting 2 weeks or less, usually less than 2-3 days.

[0547] Mild depressive disorder or mild depression is a depression in which at least two symptoms last for 2 weeks.

[0548] Bipolar disorder or manic-depressive illness causes extreme mood swings, including high mood (mania or hypomania) and low mood (depression). During a manic episode, an individual may feel or behave abnormally happy, energetic, or irritable. They often make ill-considered decisions without regard for consequences. They typically have a reduced need for sleep. During a depressive episode, crying, poor eye contact, and negative views of life may occur. People with this disorder have a greater than 6% risk of suicide over 20 years, while the incidence of self-harm is 30-40%. Other mental health problems, such as anxiety disorders and substance use disorders, are often associated with bipolar disorder.

[0549] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, or chronic stress.

[0550] Treatment-resistant depression refers to a condition in which an individual has been treated for depression but whose symptoms have not improved. For example, antidepressants or psychotherapy (psychotherapy) do not alleviate the depressive symptoms of a person with treatment-resistant depression. In some cases, individuals with treatment-resistant depression may experience symptom improvement but relapse. Treatment-resistant depression occurs in patients with the following types of depression who are resistant to standard medications, including tricyclic antidepressants, MAOIs, SSRIs, dual and triple uptake inhibitors and / or anxiolytics, as well as nonpharmacological treatments (such as psychotherapy, electroconvulsive therapy, vagus nerve stimulation and / or transcranial magnetic stimulation).

[0551] Suicide, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation involves thoughts or abnormal focus on suicide. The range of suicidal ideation varies greatly, from brief thoughts to broad thoughts, detailed plans, and more.Role-playing, incomplete attempts. Symptoms include talking about suicide, acquiring means of suicide, withdrawing from social contact, focusing on death, feeling confused or hopeless about the situation, increased alcohol use, doing risky or self-destructive things, saying goodbye to people in a farewell manner.

[0552] Symptoms of depression include persistent anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, physical challenge, loss of interest in pleasant activities or hobbies, inability to concentrate, decreased energy, poor self-esteem, lack of positive thoughts or plans, excessive sleep, binge eating, decreased appetite, insomnia, self-harm, suicidal thoughts and suicide attempts. The presence, severity, frequency and duration of symptoms may vary from person to person. Symptoms of depression and symptom relief can be determined by a physician or psychologist (e.g., through a mental status examination).

[0553] Anxiety Disorders Manual 45 / 92 pages 59 CN 121085986 A

[0554] This document provides methods for treating anxiety disorders. Anxiety disorder is a broad term that encompasses several different forms of abnormal and pathological fear and anxiety. Current diagnostic criteria for mental illness identify a wide variety of anxiety disorders.

[0555] Generalized anxiety disorder is a common chronic condition characterized by persistent anxiety that is not focused on any particular object or situation. People with generalized anxiety disorder experience nonspecific, persistent fear and worry and become overly focused on everyday matters. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0556] In panic disorder, a person suffers brief attacks of intense terror and anxiety, typically characterized by tremors, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks, defined by the APA as sudden onset of fear or discomfort that peaks in less than ten minutes and can last for hours, can be triggered by stress, fear, or even exercise; however, the specific cause is not well understood. In addition to recurrent, unexpected panic attacks, a diagnosis of panic disorder requires that the attacks have chronic consequences: either worry about the potential effects of the attack or persistent worry about future attacks or significant changes in behavior related to the attack. Therefore, people with panic disorder may experience symptoms even outside of specific panic attacks. Typically, panic disorder sufferers notice normal changes in their heart rate, leading them to believe there is something wrong with their heart or that they are about to have another panic attack. In some cases, an elevated cognitive state of bodily functioning (hypervigilance) occurs during a panic attack, where any perceived physiological changes are interpreted as potentially life-threatening illness (i.e., extreme hypochondria).

[0557] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder characterized by repetitive obsessive thoughts (distressing, persistent, and intrusive thoughts or images) and compulsive behaviors (causing the performance of specific behaviors or rituals). The thoughts of obsessive-compulsive disorder (OCD)Patterns can be likened to superstition because they involve a belief in causality that, in reality, does not exist. This process is often completely illogical; for example, the compulsive adoption of walking in a certain pattern can be used to alleviate obsessive thoughts of impending harm. In many cases, the compulsion is completely inexplicable and is simply an impulse to complete a ritual triggered by tension. In a minority of cases, obsessive-compulsive disorder sufferers may only have obsessive thoughts without overt compulsive behaviors; even fewer sufferers may only experience compulsive behaviors.

[0558] The single largest category of anxiety disorders is phobias, which include all situations of fear and anxiety triggered by specific stimuli or circumstances. Sufferers typically anticipate terrible consequences of encountering the object they fear, which can be anything from animals to places to bodily fluids.

[0559] Post-traumatic stress disorder, or PTSD, is an anxiety disorder caused by a traumatic experience. Post-traumatic stress can be caused by extreme situations such as combat, rape, hostage situations, or even serious accidents. It can also be due to prolonged (chronic) exposure to severe stressors, such as a soldier who endures an individual battle but is unable to cope with sustained combat. Common symptoms include flashback, avoidance behavior, and depression.

[0560] Epilepsy

[0561] Epilepsy is a brain disorder characterized by recurrent seizures over time. Types of epilepsy may include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures while awake, West syndrome, Lennox-Gastaut syndrome, and partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy in children.

[0562] Epileptiformation

[0563] Epileptiformation is the gradual process by which a normal brain develops into epilepsy (a chronic condition in which seizures occur). Epileptiformation is caused by neuronal damage resulting from an initial injury (e.g., status epilepticus).

[0564] Status Epilepticus (SE)

[0565] Status epilepticus (SE) may include, for example, convulsive status epilepticus, such as early status epilepticus, definitive status epilepticus, refractory status epilepticus, and ultra-refractory status epilepticus; nonconvulsive status epilepticus, such as generalized status epilepticus and complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus seizures.This condition can include early status epilepticus, confirmed status epilepticus, refractory status epilepticus, and ultra-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Confirmed status epilepticus is characterized by status epileptic seizures that persist despite first-line therapy and second-line therapy. Refractory status epilepticus is characterized by status epileptic seizures that persist despite first-line and second-line therapy and is usually treated with general anesthetics. Ultra-refractory status epilepticus is characterized by status epileptic seizures that persist for 24 hours or longer despite first-line, second-line, and general anesthesia.

[0566] Nonconvulsive status epilepticus may include, for example, focal nonconvulsive status epilepticus, such as complex partial nonconvulsive status epilepticus, simple partial nonconvulsive status epilepticus, minimal nonconvulsive status epilepticus; generalized nonconvulsive status epilepticus, such as delayed absence nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical absence nonconvulsive status epilepticus.

[0567] Seizure

[0568] A seizure is a physical finding or behavioral change that occurs after an abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” A spasm refers to a rapid and uncontrolled shaking of the body. During a convulsion, the body’s muscles repeatedly contract and relax.

[0569] Based on behavioral type and brain activity, seizures are classified into two main categories: generalized and partial (also called focal or lesion). Classifying the type of seizure helps doctors diagnose whether a patient has epilepsy.

[0570] Generalized seizures are produced by electrical impulses from the entire brain, while partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain that produces a seizure is sometimes referred to as a lesion.

[0571] There are six types of generalized seizures. The most common and most noticeable, and also the most well-known, is the generalized tonic-clonic seizure, also known as a grand mal seizure. In this type of seizure, the patient loses consciousness and usually falls down. After the loss of consciousness comes a generalized rigidity (called the “tonic” phase of a seizure) for 30 to 60 seconds, followed by violent convulsions (the “clonic” phase) lasting 30 to 60 seconds, after which the patient enters a deep sleep (“postictal” or post-ictal phase). During a grand mal seizure, injuries and accidents such as biting the tongue and urinary incontinence can occur.

[0572] Absence seizures result in a brief loss of consciousness (only a few seconds), with few or no symptoms. The patient (usually a child) will typically stop moving and stare blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually unaware that they are having a seizure unless they become aware of “losing time.”

[0573] Myoclonic seizures consist of sporadic twitches, usually on both sides of the body. Patients sometimes describe the twitches as brief electric shocks. In the event of violence, these seizures may cause falls or involuntary throwing of objects.

[0574] Clonic seizures are repetitive, rhythmic twitches that involve both sides of the body simultaneously.

[0575] Tonic seizures are characterized by muscle stiffness.

[0576] Atonic seizures involve a sudden and generalized loss of muscle tone, particularly in the arms and legs, which often leads to falls.

[0577] The epileptic seizures described herein may include: epileptic seizures; acute repetitive seizures; clustered seizures; continuous seizures; uninterrupted seizures; prolonged seizures; recurrent seizures; status epilepticus, such as refractory convulsive status epilepticus, nonconvulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized tonic-clonic seizures; infantile spasms; Jacksonian seizures. seizures; massive bilateral myoclonic seizures; multifocal seizures; neonatal paroxysmal seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; minimal seizures; Sylvan seizures; visual reflex seizures; or seizures following drug withdrawal. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Rengoir syndrome, complex tuberous sclerosis, Rett syndrome, or PCDH19 female pediatric epilepsy.

[0578] Example 1: Synthesis 61

[0579]

[0580] Overview:

[0581]

[0582] Synthesis 1

[0583]

[0584] t-BuOK (404 g, 3.6 mol) was added to a mixture of MePPh3Br (1.28 kg, 3.6 mol) in THF (4.5 L) at 15°C and N2. The resulting mixture was stirred at 50°C for 30 minutes. Pregnenolone (950 g, 2.9 mol) was added in portions at below 65°C. The reaction mixture was stirred at 50°C for 1 hour. The combined mixture was quenched at 15°C with a saturated aqueous solution of NH4Cl (1 L). The THF layer was separated. The aqueous solution was extracted with EtOAc (2 x 2 L). The combined mixture...The solid was concentrated under vacuum. The solid was further purified by grinding with MeOH / H2O (1:1, 15 L) and refluxed to obtain 1 (940 g, 99%), which was a solid. Specification 48 / 92 pages 62 CN 121085986 A

[0585] 1H NMR (400 MHz, CDCl3) δ 5.40-5.32 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 3.58-3.46 (m, 1H), 2.36-2.16 (m, 2H), 2.08-1.94 (m, 2H), 1.92-1.62 (m, 9H), 1.61-1.39 (m, 6H), 1.29-1.03 (m, 4H), 1.01 (s, 3H), 0.99-0.91 (m, 1H), 0.59 (s, 3H).

[0586] Synthesis 2

[0587]

[0588] At 35°C, DMP (2.14 kg, 5.08 mol) was added in portions to a solution of 1 (800 g, 2.54 mol) in DCM (8 L). The reaction mixture was stirred at 35°C for 20 minutes. The reaction mixture was filtered. The filter cake was washed with DCM (3 x 1 L). The combined organic phase was washed with a saturated Na2S2O3 / saturated NaHCO3 aqueous solution (3:1, 2 x 1.5 L) and brine (1.5 L), dried with Na2SO4, filtered and concentrated under vacuum to give 2 (794 g, crude), which was a solid and used directly in the next step.

[0589] Synthesis 3

[0590]

[0591] Under a N2 atmosphere below 25°C, AlMe3 (2.14 L, 4.28 mol in 2.0 M toluene solution) was added dropwise to a solution of BHT (1.97 kg, 8.94 mol) in toluene (1 L). The resulting mixture was stirred at 25°C for 1 hour. 2 (794 g, 85% by weight, 2.16 mol) in DCM (3 L) was added at -70°C. The mixture was stirred at -70°C for 1 hour. MeMgBr (862 mL, 2.59 mol in 3.0 M diethyl ether solution) was added at -70°C. The reaction mixture was stirred at -70°C for 10 minutes. The mixture was quenched with saturated citric acid (3 L) and extracted with EtOAc (2 x 2 L). The combined organic phase was washed with brine (2 L), dried with Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which was then ground with MeCN (3 L) at 25 °C to obtain 3 (340 g, 43%), which was a solid.

[0592] 1H NMR (400 MHz, CDCl3) δ 5.34–5.261 .27‑1 .13 (m, 3H), 1 .12 (s, 3H), 1 .10‑1 .05 (m, 1H), 1 .02 (s, 3H), 1 .00‑0.92 (m, 1H), 0.58 (s, 3H).

[0593] Synthesis 4 Specification 49 / 92 pages 63 CN 121085986 A

[0594]

[0595] At 0°C and N2, 3 (100 g, 304 mmol) was dissolved in 9-BBN (1.21 L, 0.5 M in THF, 608 mmol). The solution was stirred at 65°C for 1 hour and then cooled again to 10°C. A large amount of solid precipitated. Ethanol (279 g, 6080 mmol) and NaOH aqueous solution (304 mL, 5 M, 1520 mmol) were added dropwise to the mixture at below 10°C to obtain a clear solution. Then, hydrogen peroxide (343 g, 30% in water, 3040 mmol) was added dropwise at below 10°C. The reaction mixture was stirred at 75°C for 1 hour. After cooling again to 20°C, the solid precipitated and was collected by filtration. The filter cake was washed with water (3 x 500 mL), dried under vacuum, and a solid was obtained. The solid was then ground in ethanol (1.5 L) under reflux to obtain 4 (92 g, 87.6%), which was a solid.

[0596] 1H NMR (400 MHz, CDCl3) δ 5.31–5.29 (m, 1H), 3.65–3.63 (m, 1H), 3.38–3.37 (m, 1H), 2.42 (d, J = 12.4, 1H), 2.05–1.92 (m, 3H), 1.88–1.63 (m, 4H), 1.63–1.40 (m, 8H), 1.40–0.90 (m, 16H), 0.70 (s, 3H).

[0597] Synthesis 5

[0598]

[0599] At 15°C, TsCl (204 g, 1071 mmol) was added to a solution of 4 (124.5 g, 357 mmol) in chloroform (1 L) and pyridine (700 mL). The mixture was stirred at 15°C for 2 hours. The mixture was concentrated under vacuum to remove most of the chloroform. The pyridine mixture was added to water (6 L). The solid was obtained and collected by filtration, and washed with water (6 x 1 L). The solid was dissolved in DCM (3.5 g / mL).The solution was dried with Na2SO4, filtered, and concentrated under vacuum to obtain 5 (163 g, 92%), which was a solid. H NMR (400 MHz, CDCl ) δ 7.78 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 5.29-5.28 (m, 1H), 3.96 (dd, J = 3.2, 9.6 Hz, 1H), 3.79 (dd, J = 6.4, 9.2 Hz, 1H), 2.45 (s, 3H), 2.41 (d, J = 13.6 Hz, 1H), 1.99‑1.91 (m, 3H), 1.77‑1.39 (m, 11H), 1.26‑ 0.86 (m, 16H), 0.64 (s, 3H).

[0601] Synthesis 61

[0602]

[0603] At 15°C, KI (258 g, 1560 mmol) was added to a solution of 5 (163 g, 325 mmol) in DMF (1.7 L). The mixture was stirred at 60°C for 2 hours. Then, sodium benzenesulfinate (195 g, 975 mmol) was added and the mixture was stirred at 60°C for 2 hours. The reaction mixture was cooled to 25°C and combined with another batch obtained from 83 g of 5. The combined mixture was poured into water (20 L) and some solids were obtained. The mixture was filtered and the filter cake was washed with water (3 x 2 L). The obtained filter cake was dissolved in DCM (5 L), washed with water (2 x 1 L) and brine (2 x 1 L), dried with Na2SO4, filtered, and concentrated under vacuum to obtain a crude product, which was a solid. This product was recrystallized in toluene (2.5 L) to obtain 61 (150 g, 65%), which was a solid. The recrystallized filtrate was concentrated under vacuum to obtain crude 61 (30 g), which was a solid. H NMR (400 MHz, CDCl ) δ 7.91 (d, J = 7.2 Hz, 2H), 7.69-7.61 (m, 1H), 7.60-7.50 (m, 2H), 5.28-5.27 (m, 1H), 3.14 (d, J = 14.0 Hz, 1H), 2.85 (dd, J = 9.6, 14.0 Hz, 1H), 2.41 (d, J = 12.8 Hz, 1H), 2.17-2.03 (m, 1H), 2.02-1.87 (m, 3H), 1.81-1.65 (m, 3H), 1.60-1.32 (m, 8H), 1.25-0.85 (m, 16H), 0.65(s, 3H).

[0605] LCMS Rt = 2.057 min in 3.0 min chromatogram, 30-90 AB, purity 100%, MS ESI C29H41O2S [M+H-H2O]+ calculated value 453, measured value 453.

[0606] Example 2: Synthesis of epoxides

[0607]

[0608] Me3SI (4.18 g, 20.5 mmol) was added to a suspension of t-BuOK (3.53 g, 31.6 mmol) in THF (30 mL) at N2, 15 °C. The suspension was stirred at 15 °C for 30 min. At 15 °C, a solution of 21 (2 g, 15.8 mmol) in 10 mL THF was added dropwise to the mixture. The mixture was stirred at 15 °C for 16 hours. The mixture was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic phases were dried with Na2SO4, filtered, and concentrated under vacuum to give 22 (1.8 g, 81%), which was a liquid.

[0609] 1H NMR (400 MHz, CDCl3) δ 2.58 (s, 2H), 1.90–1.80 (m, 1H), 1.70–1.55 (m, 2H), 1.54–1.45 (m, 3H), 1.40–1.30 (m, 2H), 1.00–0.90 (m, 6H).

[0610] Example 3: Synthesis of 71

[0611]

[0612] Overview: Specification 51 / 92 pages 65 CN 121085986 A

[0613]

[0614]

[0615] Compound 4-2 was synthesized. At room temperature, HATU (46.3 g, 121.8 mmol) and DIPEA (45.9 g, 355.2 mmol) were added to a solution of 4-1 (38 g, 101.5 mmol) in THF (400 mL). The mixture was stirred for 1 h and N,O-dimethylhydroxylamine hydrochloride (19.8 g, 203 mmol) was added. The mixture was stirred again at room temperature for 6 h. The reaction mixture was concentrated, poured into water, extracted with EtOAc, washed with water, dried and concentrated with Na2SO4 to give crude product. The crude product was purified by silica gel column chromatography (elution buffer: PE:EA = 3:1) to obtain the desired product 4-2 (24 g, 57%), which was a solid.

[0616] 1H NMR: (300 MHz, CDCl3) δ: ppm 5.25 (d, J = 5.2 Hz, 1H), 3.59 (s, 3H), 3.46–3.37 (m, 1H), 3.07(s, 3H), 2.70 (s, 1H), 2.40–2.09 (m, 4H), 1.92–1.63 (m, 6H), 1.44–1.33 (m, 6H), 1.29–1.15 (m, 3H), 1.11–0.93 (m, 5H), 0.90 (s, 3H), 0.85 (d, J = 6.4 Hz, 3H), 0.82–0.78 (m, 1H), 0.58 (s, 3H).

[0617] Synthesized compounds 4–3. At 0 °C, Dess-Martin reagent (28 g, 67.04 mmol, 2.0 eq) was added fractionally to a solution of compound 4-2 (14 g, 33.52 mmol, 1.0 eq) in anhydrous CH2Cl2 (600 mL). The reaction mixture was then stirred at room temperature for 6.5 h. TLC (PE:EA = 3:1) showed complete depletion of the starting material. The mixture was quenched with a saturated aqueous solution of NaHCO3 / Na2S2O3 = 1:3 (800 mL). The organic phase was washed with brine (500 mL), dried over Na2SO4, and the solvent was evaporated to give crude product 4-3 (14.0 g, 100%).

[0618] Compound 4-4 was synthesized. At -78 °C under nitrogen, a solution of 4-3 (14.0 g, 33.7 mmol, 1.0 eq) in toluene was added dropwise to a solution of MAD (101 mmol, 3.0 eq) in toluene (10 mL). The toluene solution of MAD was freshly prepared by adding a Me3Al solution (50.5 mL, 101.00 mmol, 2 M hexane solution) to a stirred solution of 2,6-di-tert-butyl-4-methylphenol (44.4 g, 202 mmol) in toluene (200 mL) and stirring at room temperature for 1 h. The reaction mixture was then stirred for 30 min, and a MeMgBr solution (33.7 mL, 101 mmol, 3.0 eq, 3 M in diethyl ether) was added dropwise at -78 °C. The reaction mixture was then warmed to 25 °C and stirred at that temperature for 12 h. TLC (PE:EA = 3:1) showed complete depletion of the starting material. The mixture was poured into a saturated NH4Cl aqueous solution (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic phases were dried over Na2SO4 and the solvent was evaporated to obtain a crude product. The crude product was purified by silica gel column chromatography (elution: PE:EA = 3:1) to obtain a pure target substance (7.5 g, 52%) as a powder.

[0619] 1H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2Hz, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.50–2.30 (m, 3H), 2.05–1.70 (m, 7H), 1.52–1.30 (m, 9H), 1.20–0.90 (m, 15H), 0.68 (s, 3H).

[0620] Synthesize compound 3-1. Under nitrogen atmosphere at room temperature, MeMgBr solution (29 mL, 87 mmol, 5.0 eq, 3 M THF solution) was added dropwise to a solution of compound 4-4 (7.5 g, 17.4 mmol, 1.0 eq) in THF (150 mL) over a period of 30 minutes. The reaction mixture was then stirred at room temperature for 12 h. TLC (PE:EA = 1:1) showed complete depletion of the starting material. The mixture was poured into a saturated NH4Cl aqueous solution (200 mL) and extracted with EtOAc (150 mL x 2). The combined organic phases were dried over Na2SO4 and the solvent was evaporated to give a crude product. The crude product was purified by silica gel column chromatography (elution: PE:EA = 4:1) to give product 3-1 (5.2 g, 77%) as a powder. H NMR: (400 MHz, CDCl) δ 5.30 (d, J=5.2Hz, 1H), 2.50-2.30 (m, 3H), 2.14 (s, 3H) 2.03-1.93 (m, 3H), 1.87-1.68 (m, 4H), 1.60-1.18 (m, 12H), 1.12 (s, 3H), 1.11- 1.03 (m, 1H), 1.01 (s, 3H), 1.00-0.94 (m, 1H), 0.91 (d, J=6.4Hz, 3H), 0.68 (s, 3H).

[0622] Synthesis of 3-2. TMSCF3 (1.53 mL, 10.35 mmol) was added to a suspension of 3-1 (400 mg, 1.035 mmol) and CsF (76 mg) in toluene / THF (20 mL, 8 / 1), and the mixture was stirred at room temperature under nitrogen for 20 min. TLC (petroleum ether: ethyl acetate = 3 / 1) showed complete depletion of the starting material. TBAF solution (6.8 mL, 1 M in THF) was added, and the mixture was stirred at room temperature for 4 h. The mixture was diluted with MTBE (200 mL), washed with saturated NaHCO3 aqueous solution (30 mL x 3), and concentrated under vacuum. The residue was purified by silica gel column chromatography (elution: petroleum ether: ethyl acetate = 20:1) to give 3-2 (220 mg, 46 mg).%), which is a solid.

[0623] 1H NMR: (400 MHz, CDCl3) δ 5.31 (d, J=2.0 Hz, 1H), 2.44-2.41 (m, 1H), 2.04-1.96 (m, 3H), 1.81-1.67 (m, 5H), 1.65-1.39 (m, 11H), 1.34-1.32 (m, 3H), 1.31-1.25 (m, 1H), 1.21-1.10 (m, 3H), 1.12-0.98 (m, 4H), 0.96 (s, 3H), 0.98-0.90 (m, 4H), 0.68 (s, 3H.)

[0624] Synthesis 71. Compound 3-2 (1.2 g, 2.63 mmol) was separated by SFC to give product 71 (400 mg).

[0625] 1H NMR (71): (400 MHz, CDCl3) δ 5.32 (d, J=4.0 Hz, 1H), 2.50-2.40 (m, 1H), 2.08-1.95 (m, 3H), 1.90-0.90 (m, 35H), 0.70 (s, 3H).

[0626] Example 4: Synthesis of 1201

[0627]

[0628]

[0629] DMP (108 g, 256 mmol) was added to a solution of 001-4 (50 g, 128 mmol) in DCM (800 mL) at 30 °C. The reaction mixture was stirred at 30 °C for 10 min. Add H₂O (2.3 g, 128 mmol) dropwise. Quench the reaction mixture with saturated NaHCO₃ aqueous solution (500 mL) until the pH of the aqueous layer becomes approximately 9. Filter the mixture. Separate the DCM layer and extract the aqueous layer with DCM (100 mL). Wash the combined organic phases with saturated Na₂S₂O₃ aqueous solution (600 mL) and brine (500 mL), dry with Na₂SO₄, filter, and concentrate to give 55 (108 g, crude), which is an oil. This reaction is described in the instruction manual, page 53 / 92, 67 CN 121085986 A. The reaction was performed in duplicate. 1H NMR (400 MHz, CDCl) δ 5.30-5.26 (m, 1H), 3.67 (s, 3H), 3.30-3.22 (m, 1H), 2.85-2.79 (m, 1H), 2.50-2.15 (m, 4H), 2.08-1.96 (m, 3H), 1.90‑1.71 (m, 2H), 1.56‑ 1.45 (m, 6H), 1.44‑1.19 (m, 3H), 1.17 (s, 3H), 1.15‑0.97(m, 5H), 0.96–0.88 (m, 3H), 0.70 (s, 3H).

[0631]

[0632] Under nitrogen atmosphere at 0°C, trimethylaluminum (2 M in toluene, 418 mL, 837 mmol) was added dropwise to a solution of BHT (367 g, 1.67 mmol) in toluene (1000 mL). The mixture was stirred at 0°C for 30 min and used directly as a solution of MAD (0.59 M in toluene) without further purification. Under nitrogen atmosphere at -78°C, a solution of 55 (108 g, 279 mmol) in toluene (500 mL) was added dropwise to a solution of MAD (0.59 M in toluene, 1410 mL, 837 mmol). The mixture was stirred at -78°C for 30 min. EtMgBr (3 M in diethyl ether, 278 mL, 837 mmol, 3 M in diethyl ether) was added dropwise. The resulting mixture was stirred at -78 °C for 1 hour. The reaction mixture was poured into ice-cooled aqueous citric acid solution (1000 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (0–20% EtOAc in PE) to give 1201 (95 g, impure), which was an oil. The reaction was performed in duplicate. 1H (400 MHz, CDCl) δ 5.30-5.26 (m, 1H), 3.65 (s, 3H), 2.48-2.18 (m, 4H), 2.08-1.91 (m, 2H), 1.90-1.76 (m, 4H), 1.75-1.61 (m, 4H), 1.60‑1.48 (m, 5H), 1.47‑1.22 (m, 5H), 1.17 (s, 1H), 1.16‑1.02 (m, 3H), 1.01‑0.96 (m, 2H), 0.95‑0.90 (m, 1H), 0.89‑ 0.82 (m, 4H), 0.81-0.76 (m, 2H), 0.67 (s, 3H).

[0634] Example 5: Synthesis of U6477, U6478

[0635]

[0636] Overview: Specification 54 / 92 pages 68 CN 121085986 A

[0637]

[0638] The experiment of intermediate 61 can be seen in Example 1 of this document. The synthesis of this epoxide can be seen in Example 2 of this document.

[0639] Synthesis of 62

[0640]

[0641] n-BuLi (6.60 mL, 2.5 M in hexane, 16.5 mmol) was added to THF (5 mL). Then, at -70°C, 61 was addedA solution of 6,6-dimethyl-1-oxaspiro[2.5]octane (3.00 g, 6.37 mmol) in THF (30 mL) was prepared. The mixture was stirred at -70 °C for 1 h. 6,6-Dimethyl-1-oxaspiro[2.5]octane (1.78 g, 12.7 mmol) was added at -70 °C. After stirring at -70 °C for another 1 h, the mixture was heated to 25 °C and stirred for 16 h, then treated with NH4Cl (50 mL, saturated aqueous solution). The mixture was extracted with EtOAc (2 x 30 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to give 62 (4.00 g, crude), which was a solid.

[0642] Synthesis of 63

[0643]

[0644] NiCl2 (61.5 mg, 0.654 mmol) was added to a solution of 62 (4.00 g, 6.54 mmol) in MeOH (200 mL) and heated to 60 °C. Magnesium powder (6.34 g, 261 mmol) was added in portions at 60 °C. The mixture was stirred at 60 °C for 1 h. The mixture was quenched with HCl (200 mL, 2 M) until the reaction became clear and extracted with EtOAc (3 x 200 mL). The combined organic phases were dried with Na2SO4, filtered, concentrated and purified by rapid column chromatography (0-15% EtOAc in PE) to give 63 (1.20 g, 39%) as a solid. Specification 55 / 92 pages 69 CN 121085986 A

[0645] 1H NMR 63 (400 MHz, CDCl3) δ 5.32-5.28 (m, 1H), 2.43-2.38 (m, 1H), 2.05-1.56 (m, 9H), 1.50-1.41 (m, 8H), 1.41-1.26 (m, 5H), 1.26-0.94 (m, 15H), 0.94-0.83 (m, 12H), 0.68 (s, 3H).

[0646] Synthesis of 64

[0647]

[0648] Molecular sieve (200 mg) and tert-butyl hydroperoxide (4.23 mL, 25.4 mmol, 6 M in decane) were added to a solution of 63 (2.00 g, 4.24 mmol) in ethyl acetate (120 mL). The suspension was stirred at 25 °C under a nitrogen atmosphere for 30 min, and then manganese(III) acetate dihydrate (340 mg, 1.27 mmol) was added in one go. The reaction mixture was stirred at 25 °C for 48 h. The solid was filtered off and the filtrate was washed with Na2SO3 (200 mL), brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography.(0-15% EtOAc in DCM), yielding 64 (1.10 g, 54%), which was a solid.

[0649] 1H NMR 64 (400 MHz, CDCl3) δ 5.66 (s, 1H), 2.61-2.55 (m, 1H), 2.45-2.34 (m, 1H), 2.28-2.19 (m, 2H), 2.08-1.78 (m, 5H), 1.68-1.50 (m, 9H), 1.50-1.08 (m, 21H), 0.98-0.83 (m, 9H), 0.68 (s, 3H).

[0650] Synthesis of 65

[0651]

[0652] Under nitrogen atmosphere at -40°C, a solution of 64 (500 mg, 1.03 mmol) was added dropwise to a solution of TMSCH2Li (0.56 M in hexane, 9.19 mL, 5.15 mmol) in anhydrous THF (25 mL). The mixture was stirred at -40°C for 4 hours and gradually heated to 20°C and stirred again at 20°C for 16 hours. The reaction mixture was quenched with saturated NH4Cl (20 mL), acidified with 10% HCl (8 mL), and stirred for 2 hours. The mixture was combined with another batch (prepared from 100 mg of 64) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (0–20% EtOAc in PE) to give 65 (220 mg, 44%) as a solid. 1H NMR 65 (400 MHz, CDCl ) δ 5.79 (s, 1H), 4.93 (s, 1H), 4.74 (s, 1H), 2.51-2.42 (m, 1H), 2.19-2.00 (m, 4H), 1.97-1.85 (m, 1H), 1.82-1.70 (m, 2H), 1.63-1.58 (m, 2H), 1.52-1.37 (m, 12H), 1.36-1.14 (m, 11H), 1.13 (s, 3H), 1.09 (s, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.93 (s, 3H), 0.87 (s, 3H), 0.71 (s, 3H).

[0654] Synthesis 66 Specification 56 / 92 pages 70 CN 121085986 A

[0655]

[0656] 10% Pd / C (wet weight, 300 mg) was added to a solution of 65 (220 mg, 0.455 mmol) in THF (15 mL). The mixture was degassed and purged three times with H2. The mixture was then placed under a hydrogen balloon.The mixture was stirred at 15°C for 18 hours (15 psi). The reaction mixture was filtered through a Celite pad and the pad was washed with THF (4 x 5 mL). The combined organic solution was concentrated to give 66 (210 mg, crude), which was a solid.

[0657] LCMS 66 Rt = 5.692 min in 7.0 min chromatogram, 30-90AB_7MIN_220&254_E, (column: Ultimate C18 2.1*30mm, 3um; mobile phase: A: water (4L) + TFA (1.5mL) B: acetonitrile (4L) + TFA (0.75mL); gradient: 30%-90% B over 6 min, with 90% for 0.5 min, then 30% B for 0.5 min; flow rate: 0.8mL / min; wavelength: UV 220nm, 254nm; oven temperature: 50℃; MS ionization: ESI; detector: PDA, ELSD), purity 100%, MS ESI calculated value C33H53 [M+H-2H2O] + 449, measured value 449.

[0658] SFC 66 Peak 1: Rt = 6.184 min and Peak 2 Rt = 6.969 min in 10 min chromatogram, AD_3_EtOH_DEA_5_40_25ML ("Column: Chiralpak AD-3 150×4.6mm ID, 3um Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: 5%-40% B, within 5 min, and 40% for 2.5 min, then 5% B for 2.5 min Flow rate: 2.5 mL / min Column temperature: 35°C").

[0659] Synthesis of U6477 and U6478

[0660]

[0661] 66 (210 mg, 0.433 mmol) was purified by SFC (column: AD (250 mm * 30 mm, 5 μm); conditions: 0.1% NH3H2O ​​EtOH; start B: 40%; end B: 40%; gradient time (min): 100% B; hold time (min); flow rate (ml / min): 60 mL / min; injection: 200) to obtain U6477 (peak 1, 56 mg, 27%), which was a solid, and U6478 (peak 2, 30 mg, 14%), which was a solid. Based on the characteristic HNMR of compounds 82 and U6429, the stereochemistry of C7 was assigned as: a) 7-α-H isomer, where H-6 is a singlet in the high field; b) 7-β-H isomer, where H-6 is a doublet in the low field.

[0662] U6477 Specification 57 / 92 pages 71 CN121085986 A

[0663] 1H NMR (400 MHz, CDCl3) δ 5.79 (s, 1H), 2.50-2.42 (m, 1H), 2.05-1.65 (m, 7H), 1.55-1.35 (m, 13H), 1.34-1.05 (m, 16H), 1.03-0.85 (m, 7H), 0.84-0.75 (m, 7H), 0.70-0.60 (m, 4H).

[0664] LCMS Rt = 1.490 min in 2.0 min chromatogram, 30-90AB_2MIN_E, purity 98.839%, MS ESI calculated value C33H53 [M+H-2H2O] + 449, measured value 449.

[0665] SFC Rt = 6.292 min in 10 min chromatogram, AD_3_EtOH_DEA_5_40_25ML, 100%de. U6478 H NMR (400 MHz, CDCl) δ 5.03 (s, 1H), 2.50-2.42 (m, 1H), 2.05-1.95 (m, 2H), 1.94-1.60 (m, 6H), 1.55-1.25 (m, 15H), 1.24-1.05 (m, 12H), 1.03-0.85 (m, 16H), 0.68 (s, 3H).

[0668] LCMS Rt = 1.568 min in 2.0 min chromatogram, 30-90AB_2MIN_E, purity 100%, MS ESI calculated value C33H53 [M+H-2H2O] + 449, measured value 449.

[0669] SFC Rt = 7.066 min in 10 min chromatogram, AD_3_EtOH_DEA_5_40_25ML, 95% de.

[0670] Example 6: Synthesis of U6472, U6473

[0671]

[0672] Overview: Specification 58 / 92 pages 72 CN 121085986 A

[0673]

[0674] The synthesis of 71 can be found in Example 3 of this document.

[0675] Synthesis of 72

[0676]

[0677] Tert-butyl hydroperoxide (8.74 mL, 52.5 mmol, 6 M in decane) was added to a solution of 71 (4 g, 8.76 mmol) in ethyl acetate (200 mL). The suspension was stirred under a nitrogen atmosphere for 30 min, and then manganese(III) acetate dihydrate (702 mg, 2.62 mg) was added in one go.After stirring at 30°C for 48 hours, the mixture was quenched with Na₂SO₃ (200 mL) and extracted with THF (2 x 100 mL). The combined organic matter was washed with Na₂SO₃ (200 mL) and brine (200 mL), dried with Na₂SO₄, filtered and concentrated to obtain a residue, which was then ground with MeCN (60 mL) to give pure 72 (800 mg) as a solid. 1H NMR 72 (400 MHz, CDCl ) δ 5.69-5.64 (m, 1H), 2.64-2.53 (m, 1H), 2.51-2.36 (m, 1H), 2.29-2.18 (m, 2H), 2.07-1.99 (m, 1H), 1.95-1.64 (m, 6H), 1.63-1.58 (m, 3H), 1.54-1.47 (m, 3H), 1.45-1.25 (m, 8H), 1.20 (s, 3H), 1.18-1.02 (m, 6H), 0.99-0.90 (m, 3H), 0.69 (s, 3H).

[0679] Synthesis of 73

[0680]

[0681] At -40°C, a solution of 72 (800 mg, 1.69 mmol) in THF (50 mL) was added dropwise to a solution of TMSCH2Li (18.3 mL, 8.45 mmol, 0.46 M in hexane) in THF (20 mL). After addition, the resulting mixture was heated to 30°C and stirred for 16 hours. The mixture was quenched with HCl (2 M, 100 mL) and extracted with EtOAc (2 x 80 mL). The combined organic phase was washed with saturated NaHCO3 (100 mL), dried with Na2SO4, filtered, concentrated, and purified by combi-flash (0-20% EtOAc in PE) to give 73 (350 mg, 44%) as a solid. 1H NMR 73 (400 MHz, CDCl ) δ 5.81-5.76 (m, 1H), 4.95-4.89 (m, 1H), 4.77-4.70 (m, 1H), 2.50-2.41 (m, 1H), 2.18-2.06 (m, 2H), 2.04-2.00 (m, 1H), 1.94-1.68 (m, 5H), 1.55-1.47 (m, 4H), 1.44-1.37 (m, 4H), 1.32 (s, 3H), 1.30-1.11 (m, 10H), 1.09 (s, 3H), 0.99-0.94(m, 3H), 0.89–0.81 (m, 1H), 0.71 (s, 3H).

[0683] Synthesis of 74

[0684]

[0685] Pd / C (350 mg, wet weight) was added to a solution of 73 (350 mg, 0.746 mmol) in THF (30 mL). The mixture was hydrogenated at 15 Psi, 30 °C for 16 hours. The mixture was filtered. The filter cake was washed with THF (2 x 10 mL). The combined filtrate was concentrated and purified by combi-flash (0–20% EtOAc in PE) to give pure 74 (200 mg, 57%) as a solid.

[0686] SFC 74- Peak 1: Rt = 3.343 min and Peak 2 Rt = 4.297 min in 10 min chromatogram, AD_3_ EtOH_DEA_5_40_25ML ("Column: Chiralpak AD-3 150×4.6mm ID, 3um Mobile phase: A: CO2 B: Methanol (0.05% DEA) Gradient: 5%-40% B, in 5 min and 40% for 2.5 min, then 5% B for 2.5 min Flow rate: 2.5mL / min Column temperature: 35oC "

[0687] Synthesis of U6472, U6473

[0688]

[0689] Separation of racemic sample 200 mg by SFC (Column: AD (250mm*30mm, 5um), gradient: 35-35% B (A= Using 0.05% NH3 / H2O (B = MeOH), at a flow rate of 50 mL / min, we obtained U6472 (57 mg, 29% yield, peak 1) and U6473 (43 mg, 22% yield, peak 2), both in solid form. Based on the characteristic HNMR of compounds 82 and U6429, the stereochemistry of C7 was assigned to: a) the 7-α-H isomer, with H-6 as a singlet in the high field; b) the 7-β-H isomer, with H-6 as a doublet in the low field.

[0690] U6472 Specification 60 / 92 pages 74 CN 121085986 A

[0691] 1H NMR (400 MHz, CDCl3) δ 5.35–5.30 (m, 1H), 2.49–2.39 (m, 1H), 2.06–1.90 (m, 3H), 1.87–1.66 (m, 5H), 1.56–1.40 (m, 8H), 1.35–1.24 (m, 5H), 1.18–1.06 (m, 10H), 1.01 (s, 3H), 0.97–0.91 (m, 3H), 0.86–0.79(m, 3H), 0.68 (s, 3H).

[0692] LCMS Rt = 1.240 min in 2.0 min chromatographic medium, 30-90AB_E, purity 100%, MS ESI calculated value C28H44F3O [M+H-H2O] + 453, measured value 453.

[0693] SFC Rt = 3.357 min in 10 min chromatographic medium, AD_3_EtOH_DEA_5_40_25ML, 99.72% de.

[0694] U6473

[0695] 1H NMR (400 MHz, CDCl3) δ 5.06-5.00 (m, 1H), 2.42-2.34 (m, 1H), 2.03-1.95 (m, 2H), 1.87-1.65 (m, 7H), 1.56-1.35 (m, 6H), 1.34–1.26 (m, 5H), 1.22–1.03 (m, 10H), 1.00–0.91 (m, 10H), 0.69 (s, 3H).

[0696] LCMS Rt = 1.246 min in 2.0 min chromatogram, 30–90 AB_E, purity 100%, MS ESI calculated value C28H44F3O [M+H-H2O] + 453, measured value 453.

[0697] SFC Rt = 4.300 min in 10 min chromatogram, AD_3_EtOH_DEA_5_40_25ML, 99.52%de.

[0698] Example 7: Synthesis of U6450

[0699]

[0700] The synthesis of U6461 can be found in Example 11 of this document.

[0701] Synthesis of 82

[0702]

[0703] At -70°C, K-selectride (1.16 mL, 1.16 mmol 1M in THF) was added dropwise to a solution of U6461 (100 mg, 0.232 mmol) in THF (5 mL). After addition, the mixture was warmed to 0°C and stirred at that temperature for 1 h. The mixture was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (2 x 20 mL), dried with Na2SO4, filtered and concentrated, and purified by combi-flash (0-60% EtOAc in PE) to give 60 mg of impure 82, which was a solid and used directly in the next step. The stereochemistry of C7 was assigned according to the literature (Synthesis, 1987, 1002) and compared with compound U6429, based on α) .7-α-Ha) 7-β-H isomer, wherein H-6 is a single peak in the high field; b) 7-β-H isomer, wherein H-6 is a double peak in the low field.

[0704] Synthesis of U6450 Specification 61 / 92 pages 75 CN 121085986 A

[0705]

[0706] 140 mg of impure 82 was separated by SFC (column: AD (250mm*30mm, 5um), gradient: 50-50% B (A= ​​0.05%NH3 / H2O, B= MeOH), flow rate: 60 mL / min) to obtain 82 (70 mg, 50%), which is a solid. 1H NMR U6450 (400 MHz, CDCl) δ 5.58-5.52 (m, 1H), 3.87-3.79 (m, 1H), 2.46-2.38 (m, 1H), 2.14-1.84 (m, 3H), 1.80-1.57 (m, 4H), 1.55‑1.38 (m, 9H), 1.37‑1.22 (m, 4H), 1.21‑1.06 (m, 12H), 1.04‑0.97 (m, 4H), 0.96‑0.91 (m, 3H), 0.88‑0.82 (m, 3H), 0.68 (s, 3H).

[0708] LCMS U6450 Rt = 1.108 min in 2.0 min chromatogram, 30-90AB_E, purity 100%, MS ESI calculated value C28H45O [M+H-2H2O] + 397, measured value 397.

[0709] Example 8: Synthesis of U6437, U6438

[0710]

[0711] Overview:

[0712] Specification 62 / 92 pages 76 CN 121085986 A

[0713] The synthesis of U6461 can be found in Example 11 of this document.

[0714] Synthesis of 91

[0715]

[0716] At 0°C, N2, MeLi (2.17 mL, 3.48 mmol) was added to a solution of U6461 (300 mg, 0.696 mmol) in THF (20 mL). The mixture was stirred at 15°C for 10 min and quenched with saturated NH4Cl (30 mL). The reaction mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with saturated NH4Cl (50 mL), dried with Na2SO4, filtered, concentrated and purified by combi-flash (0-50% EtOAc in PE) to give 91 (250 mg, 81%) as a solid.

[0717] Synthesis of U6437, U6438

[0718]

[0719] 16091 mg was purified by SFC (column: AD (250mm*30mm, 5um)), gradient: 50-50% B (A= ​​0.05%NH3 / H2O, B= MeOH), yielding U6437 (peak 1, 80 mg, 50%) and U6438 (peak 2, 60 mg, 38%), which were in solid form.

[0720] U6437

[0721] 1H NMR (400 MHz, CDCl3) δ 5.16-5.13 (m, 1H), 2.43-2.34 (m, 1H), 2.07-1.96 (m, 2H), 1.91-1.61 (m, 5H), 1.58-1.46 (m, 5H), 1.45-1.29 (m, 7H), 1.26-1.18 (m, 9H), 1.18-1.10 (m, 6H), 1.09-1.00 (m, 5H), 0.98-0.93 (m, 3H), 0.88-0.82 (m, 3H), 0.69 (s, 3H).

[0722] LCMS Rt = 1.161 min in 2.0 min chromatogram, 30-90AB_E, purity 100%, MS ESI calculated value C29H47O [M+H-2H2O] + 411, measured value 411.

[0723] SFC Rt = 4.266 min in 8 min chromatogram, AD_ETOH(DEA)_5_40_2, 8ML_8MIN (Column: Chiralpak AD-3 100×4.6mm ID, 3um Mobile phase: A: CO2 B: Ethanol (0.05% DEA).

[0724] Gradient: 5%-40% B in 4.5 min, and at 40% for 2.5 min, then at 5% B for 1 min

[0725] Flow rate: 2.8mL / min column temperature: 40 oC), 100% de.

[0726] U6438

[0727] 1H NMR (400 MHz, CDCl3) δ 5.19-5.16 (m, 1H), 2.40-2.32 (m, 1H), 2.08-1.98 (m, 2H), 1.94-1.85 (m, 2H), 1.77-1.59 (m, 4H), 1.52‑1.29 (m, 13H), 1.24 (s, 3H), 1.22‑ 1.19 (m, 6H), 1.17‑1.03 (m, 6H), 0.99‑0.92 (m, 6H), 0.88‑0.82 (m, 3H), 0.70 (s, 3H).

[0728] LCMS Rt = 1.162In a 2.0 min chromatogram, 30-90AB_E, purity 99.5%, MS ESI calculated value C29H47O [M+H-2H2O] + 411, measured value 411.

[0729] SFC Rt = 5.815 min in an 8 min chromatogram, AD_ETOH(DEA)_5_40_2, 8ML_8MIN (Column: Chiralpak AD-3 100×4.6mm ID, 3um Mobile phase: A: CO2 B: Ethanol (0.05% DEA)

[0730] Gradient: 5%-40% B, within 4.5 min, and at 40% for 2.5 min, then at 5% B for 1 min

[0731] Flow rate: 2.8mL / min Column temperature: 40 oC), 98% de.

[0732] The structure of this compound was confirmed by X-ray diffraction.

[0733] ​​Example 9: Synthesis of U6410

[0734]

[0735] Overview:

[0736]

[0737] The synthesis of U6461 can be found in Example 11 of this document.

[0738] Synthesis of U6410

[0739]

[0740] Pd(OH)2 (600 mg, anhydrous) was added to a solution of U6461 (300 mg, 0.696 mmol) in MeOH (50 mL). The mixture was stirred at 50 Psi, 50 °C for 48 hours. The mixture was filtered, concentrated, and purified by combi-flash (0-50% EtOAc in PE) to give U6410 (35 mg, 12%) as a solid. Specification page 64 / 92 78 CN 121085986 A

[0741] 1H NMR (400 MHz, CDCl3) δ 2.39-2.29 (m, 2H), 2.26-2.15 (m, 1H), 2.03-1.87 (m, 3H), 1.70-1.56 (m, 5H), 1.53-1.37 (m, 8H), 1.36-1.24 (m, 4H), 1.23-1.16 (m, 7H), 1.15-1.04 (m, 7H), 1.02-0.90 (m, 5H), 0.89-0.83 (m, 3H), 0.65 (s, 3H).

[0742] LCMS - Rt = 1.029 min in 2.0 min chromatogram, 30-90AB_E, purity 100%, MS ESI calculated value C28H47O2 [M+H-H2O] + 415, measured value 415.

[0743] Example 10: Synthesis of U6408, U6409

[0744]

[0745] Summary:

[0746]

[0747] The synthesis of U6461 can be found in Example 11 of this document.

[0748] Synthesis 1101

[0749]

[0750] t-BuOK (389 mg, 3.48 mmol) was added to a suspension of bromo(methyl)triphenylphosphine (1.24 g, 3.48 mmol) in THF (45 mL). The mixture was stirred at 50 °C under N2 for 30 min. Then a solution of U6461 (300 mg, 0.696 mmol) in THF (5 mL) was added and the mixture was stirred at 50 °C for 1 h. The mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phase was dried with Na2SO4, filtered, concentrated, and purified by combi-flash (0-30% EtOAc in PE) to obtain the desired product (72 mg, 24%), which was a solid. 1H NMR (400 MHz, CDCl) δ 5.80-5.75 (m, 1H), 4.93 (s, 1H), 4.73 (s, 1H), 2.43-2.36 (m, 1H), 2.20-2.01 (m, 4H), 1.99-1.86 (m, 1H), 1.80‑1.62 (m, 3H), 1.61‑1.58 (m, 2H), 1.56‑1.46 (m, 1H), 1.45‑1.22 (m, 9H), 1.21‑1.18 (m, 7H), 1.16‑ 1.05 (m, 8H), 0.99‑0.91 (m, 3H), 0.88‑0.82 (m, 3H), 0.71 (s, 3H).

[0752] Synthesis of 1102

[0753]

[0754] Pd / C (wet weight, 150 mg) was added to a solution of 1101 (72 mg, 0.167 mmol) in THF (5 mL). The mixture was stirred at 15°C, 15 Psi for 12 hours. The mixture was filtered, concentrated and purified by combi-flash (0-10% EtOAc in PE) to give impure 1102 (50 mg, 69%) as a solid.

[0755] Synthesis of U6408 and U6409

[0756]

[0757] 50 mg of impure 1102 was separated by SFC (column: AD (250 mm * 30 mm, 10 μm), gradient: 30–30% B (A = 0.05% NH3 / H2O, B = MeOH), flow rate: 60 mL / min) to obtain U6408 (peaks 1 and 5).Compound 82 (10 mg) and U6409 (peak 2, 7 mg, 14%), both solids, were assigned stereochemically to C7 based on the characteristic HNMR of compounds 82 and U6429 as: a) 7-α-H isomer, with H-6 as a singlet in the high field; b) 7-β-H isomer, with H-6 as a doublet in the low field.

[0758] U6408

[0759] 1H NMR (400 MHz, CDCl3) δ 5.33–5.28 (m, 1H), 2.43–2.34 (m, 1H), 2.05–1.94 (m, 3H), 1.91–1.80 (m, 1H), 1.77–1.67 (m, 2H), 1.65–1.61 (m, 2H), 1.52–1.42 (m, 6H), 1.38–1.23 (m, 6H), 1.19 (s, 6H), 1.15–1.07 (m, 6H), 1.03 (s, 3H), 0.98–0.91 (m, 4H), 0.87–0.79 (m, 6H), 0.67 (s, 3H).

[0760] LCMS Rt = 1.245 min in 2.0 min chromatogram, 30–90 AB_E, purity 100%, MS ESI calculated value C29H47 [M+H-2H2O] + 395, measured value 395.

[0761] SFC Rt = 4.245 min in 10 min chromatogram, column: ChiralPak AD-3 150×4.6mm ID, 3um mobile phase: A: CO2 B: ethanol (0.05% DEA) gradient: 5%–40% B in 5.5 min, and 40% for 3 min, then 5% B for 1.5 min flow rate: 2.5 mL / min column temperature: 40°C, 100% DEA.

[0762] U6409

[0763] 1H NMR (400 MHz, CDCl3) δ 5.04-4.99 (m, 1H), 2.38-2.28 (m, 1H), 2.07-1.96 (m, 2H), 1.92-1.78 (m, 2H), 1.72-1.62 (m, 4H), 1.53-1.44 (m, 4H), 1.43-1.25 (m, 8H), 1.19 (s, 6H), 1.16-1.05 (m, 6H), 0.99-0.91 (m, 10H), 0.88-0.81 (m, 3H), 0.68 (s, 3H). LCMS Rt=1.253 min at 2.0 minIn the chromatogram, 30-90AB_E, purity 100%, MS ESI calculated value C29H47 [M+H-2H2O] + 395, measured value 395.

[0765] SFC Rt = 4.967 min, in 10 min chromatogram, column: ChiralPak AD-3 150×4.6mm ID, 3um mobile phase: A: CO2 B: ethanol (0.05% DEA) gradient: 5%-40% B, in 5.5 min, and at 40% for 3 min, then at 5% B for 1.5 min, flow rate: 2.5 mL / min column temperature: 40°C, 100% DEA.

[0766] Example 11: Synthesis of U6461, U6429, U6479

[0767]

[0768] Overview: Specification 67 / 92 pages 81 CN 121085986 A

[0769]

[0770] The synthesis of 1201 can be found in Example 4 of this document.

[0771] Synthesis of 1202

[0772]

[0773] At 0°C, MeLi (111 mL, 178 mmol, 1.6 M in diethyl ether) was added dropwise to a solution of impure 1201 (14.9 g, 35.7 mmol) in THF (600 mL). After stirring at 15°C for 30 minutes, the mixture was quenched with saturated NH4Cl (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic phases were dried with Na2SO4, filtered, and concentrated to obtain a crude residue, which was then ground with MeCN (300 mL) to give 11 g of crude product, which was a solid. The crude product was recrystallized from EtOAc (300 mL) to give 1202 (9 g, 80% purity, 49%), which was a solid. 1H NMR 1202 (400 MHz, CDCl) δ 5.28-5.25 (m, 1H), 2.40-2.32 (m, 1H), 2.05-1.92 (m, 3H), 1.90-1.80 (m, 1H), 1.79-1.58 (m, 3H), 1.56‑1.51 (m, 5H), 1.50‑1.39 (m, 7H), 1.38‑1.28 (m, 2H), 1.27‑1.16 (m, 6H), 1.15‑1.04 (m, 5H), 1.02 (s, 3H), 1.00‑0.96 (m, 1H), 0.95-0.88 (m, 4H), 0.87-0.77 (m, 3H), 0.68 (s, 3H).

[0775] Synthesis of U6461

[0776]

[0777] To 1202 (5 g, 11.9 g)Molecular sieve (10 g) and tert-butyl hydroperoxide (11.9 mL, 71.4 mmol, 6 M in decane) were added to a solution in ethyl acetate (300 mL). The suspension was stirred under nitrogen atmosphere for 30 min, and then manganese(III) acetate dihydrate (956 mg, 3.57 mmol) was added in one batch. The reaction mixture was stirred at 15 °C for 48 h. The solid was filtered off. The filtrate was washed with Na₂SO₃ (200 mL) and brine (200 mL) and dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–15% EtOAc in DCM) to give impure U6461 (2 g, 40%) as a solid. 100 mg of this solid was recrystallized from MeCN (30 mL) at 90 °C to give pure U6461 (34 mg, 34%) as a solid. Specification page 68 / 92 82 CN 121085986 A

[0778] 1H NMR (400 MHz, CDCl3) δ 5.67–5.64 (m, 1H), 2.58–2.49 (m, 1H), 2.47–2.36 (m, 1H), 2.31–2.20 (m, 2H), 2.06–1.81 (m, 3H), 1.79–1.68 (m, 2H), 1.55–1.49 (m, 3H), 1.48–1.37 (m, 5H), 1.36–1.24 (m, 5H), 1.23–1.16 (m, 11H), 1.15–1.05 (m, 3H), 0.92–0.92 (m, 3H), 0.90–0.83 (m, 3H), 0.68 (s, 3H).

[0779] LCMS Rt = 1.059 min at 2.0 min, 30–90 AB, purity 100%, MS ESI calculated value C28H47O3 [M+H] + 431, measured value 431.

[0780] Synthesis of U6429

[0781]

[0782] CeCl3 (857 mg, 3.48 mmol) was added to a solution of U6461 (500 mg, 1.16 mmol) in MeOH (30 mL). After stirring at 15°C for 30 min, NaBH4 (197 mg, 5.80 mmol) was added in portions. The reaction mixture was stirred at 15°C for 30 min. The mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated to give 470.mg of the crude product was recrystallized from MeCN (100 mL) to give U6429 (370 mg, 74%), which was a solid. The stereochemistry of C7 was assigned according to the literature (Synthesis, 1987, 1002) and compared with compound 82, which was based on a) the .7-α-H isomer, in which H-6 is a singlet in the high field; b) the .7-β-H isomer, in which H-6 is a doublet in the low field. 1H NMR (400 MHz, CDCl ) δ 5.25-5.22 (m, 1H), 3.89-3.82 (m, 1H), 2.43-2.35 (m, 1H), 2.13-1.97 (m, 2H), 1.96-1.77 (m, 2H), 1.76-1.60 (m, 3H), 1.53‑1.40 (m, 8H), 1.39‑1.28 (m, 5H), 1.24‑1.18 (m, 7H), 1.16‑0.99 (m, 9H), 0.97‑0.91 (m, 3H), 0.88‑0.82 (m, 3H), 0.69 (s, 3H).

[0784] LCMS Rt = 0.999 min, 30-90AB_E in 2.0 min chromatogram, purity 100%, MS ESI calculated value C28H45O[M+H-2H2O] + 397, measured value 397. The structure of this compound was confirmed by X-ray diffraction.

[0785] Synthesis of U6479

[0786]

[0787] Pd(OH)2 (200 mg, anhydrous) was added to a solution of U6429 (100 mg, 0.231 mmol) in MeOH (30 mL). The mixture was stirred at 50°C in H2 (50 Psi) for 48 hours. The mixture was filtered, concentrated and purified by combi-flash (0-50% EtOAc in PE) to give U6479 (23 mg, 23%) as a solid.

[0788] 1H NMR (400 MHz, CDCl3) δ 3.44–3.29 (m, 1H), 2.03–1.95 (m, 1H), 1.94–1.76 (m, 2H), 1.67–1.58 (m, 4H), 1.53–1.42 (m, 6H), 1.42–1.33 (m, 5H), 1.32–1.24 (m, 4H), 1.23–1.11 (m, 11H), 1.10–1.04 (m, 2H), 0.97–0.91 (m, 4H), 0.90–0.82 (m, 6H), 0.75–0.63 (m, 4H). (See specification pages 69 / 92, CN 121085986 A)

[0789] LCMS Rt = 1.010 min, in 2.0 min chromatogram, 30-90AB_E, purity 100%, MS ESI calculated value C28H45 [M+H-3H2O] + 381, measured value 381.

[0790] Example 12: EC50 and EMax data

[0791] Automated patch-clamp system (QPatch HTX)

[0792] In this study, HEK 293 cells stably transfected with glutamate-activated GRINI / 2A subtype channels were used to study the negative allosteric regulation of the test compounds with the second-maximum NMDA concentration (300 µM NMDA, co-administered with 8 µM glycine).

[0793] Cell culture

[0794] Typically, cells were passaged at approximately 80% to approximately 90% confluence. For electrophysiological measurements, cells were harvested from sterile culture flasks containing complete culture medium at approximately 80% to 90% confluence. Cells were transferred as a PBS suspension to a QPatch 16X or QPatch HTX system and then directly to a centrifuge / washer.

[0795] Standard laboratory conditions: Cells were cultured at 37°C in a humidified atmosphere containing 5% CO2 (approximately 95% relative humidity).

[0796] Culture medium: Cells were continuously maintained and passaged in sterile culture flasks containing a 1:1 mixture of Dulbecco modified Eagle medium and nutrient mixture F-12 (D-MEM / F-12 1x, liquid, containing L-glutamine), supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin solution and 50 µM AP-5 inhibitor.

[0797] Antibiotics: The complete culture medium as described above was supplemented with 100 µg / mL hygromycin, 15 µg / mL cyprodinil, and 1 µg / mL puromycin.

[0798] Induction of expression: 2.5 µg / mL tetracycline was added 24 hours before the start of the experiment.

[0799] Dosage formulation

[0800] Dosage levels were based on the test compound provided. A medium was added to achieve a stock concentration of 10 mM (stored at -10°C to 30°C). Another stock solution of 1.0 mM was prepared in DMSO. Details of stock solution use (thawing, dosage formulation) are recorded in the raw data. The time period of stock solution use is detailed in the report.

[0801] Test compound concentration

[0802] Dosage levels were based on the test compound provided. A medium was added to achieve a stock concentration of 10 mM (stored at -10°C to 30°C). Another stock solution of 1.0 mM was prepared in DMSO. The raw data records detailed information on the use of the stock solution (thawing, dosage formulation). The time period for stock solution use is detailed in the report.

[0803] One test concentration tested was 1.0 µM.

[0804] All test solutions were prepared as follows: stock solutions were diluted shortly before electrophysiological experiments with either a Mg-free bath or a Mg-free bath containing NMDA (300 µM) and glycine (8.0 µM) and maintained at room temperature (19°C–30°C) when used. 0.1% DMSO was used as the medium.

[0805] Preparation frequency: Fresh test compound solutions were prepared daily for each test concentration.

[0806] Stability of dosing formulations: All preparation times were recorded in the raw data. Any observations of instability of the test compounds were mentioned in the raw data.

[0807] Storage of dosing formulations: On the day of the experiment, the dosing formulations were maintained at room temperature (19°C–30°C) when used.

[0808] Bath Solution

[0809] To prepare for the experiment and to form the giga-ohm seal, the following standard bath solutions were used:

[0810] Sodium chloride: 137 mM; Potassium chloride: 4 mM; Calcium chloride: 1.8 mM; Magnesium chloride: 1 mM; HEPES: 10 mM; D-glucose: 10 mM; Cremophor: 0.02%; pH (NaOH): 7.4 (Instructions for Use, 70 / 92 pages, 84 CN 121085986 A)

[0811] The 1x bath solution was prepared by diluting a 10x bath solution without glucose and a solution containing 100x glucose with water at least every 7 days. Both stock solutions were prepared prior to the start of the experiments in this study and stored at 1°C to 9°C (10x bath solution) or 10°C to -30°C (100x glucose solution). The batch numbers of the bath solutions used in the experiments are recorded in the raw data. When in use, the 1x bath solution is kept at room temperature (19°C to 30°C). When not in use, the 1x bath solution is stored at 1°C to 9°C.

[0812] After forming a gigabit seal, the following magnesium-free bath solution is used:

[0813] Sodium chloride: 137 mM; Potassium chloride: 4 mM; Calcium chloride: 2.8 mM; HEPES: 10 mM; D-glucose: 10 mM; Cremophor: 0.02%; pH (NaOH): 7.4

[0814] The Mg-free bath solution is prepared into a 1x solution and stored at 1°C to 9°C. The solution is freshly prepared at least every 10 days.

[0815] Intracellular solution

[0816] The 1x intracellular solution is thawed daily from a frozen 1x intracellular solution that was prepared, aliquoted and stored at -10°C to -30°C prior to the start of the experiments in this study. When used, the 1x intracellular solution is maintained at room temperature (19°C to 30°C). Remaining 1x intracellular solution is stored in a refrigerator (1°C to 9°C). The 1x intracellular solution comprises the following components:

[0817] Potassium chloride: 130 mM; Magnesium chloride: 1 mM; Mg-ATP: 5 mM; HEPES: 10 mMmM; EGTA: 5 mM; pH (KOH): 7.2

[0818] Cell Treatment

[0819] For this study, cells were continuously perfused with NMDA / glycine, the test compound, or the test compound / NMDA / glycine.

[0820] In each case, a pre-wash step with the test compound for at least 30 seconds was performed between applications. See Table A below for details.

[0821] Each experimental type was analyzed in at least n = 3 isolated cells. NMDA and glycine stock solutions were prepared prior to the start of the experiments in this study and stored frozen (-10°C to -30°C) until the day of the experiment. The frozen stock solutions were thawed and diluted shortly before the start of the electrophysiological experiments.

[0822] Controls: The effects of the mediator (0.1% DMSO) and D-(-)-2-amino-5-phosphatidylvaleric acid (AP-5) (100 µM) were measured in three cells every week to ensure successful expression of the NMDA receptor.

[0823] Prior to the start of the experiments in this study, a 50 mM AP-5 stock solution was prepared, aliquoted, and frozen (-10°C to -30°C) until the day of the experiments. Shortly before the start of the electrophysiological experiments, the frozen stock solution was thawed and then diluted in a Mg-free bath containing NMDA (300 µM) and glycine (8.0 µM) to obtain a final perfusion concentration of 100 µM.

[0824] Experimental Procedure

[0825] Cells were transferred as a suspension in serum-free medium to the QPatch HTX system and kept in the cell storage tank / stirrer during the experiments. All solutions applied to the cells, including intracellular solutions, were kept at room temperature (19°C to 30°C).

[0826] The standard bath described above was used during the sealing process. All solutions applied to the cells, including pipette solutions, were kept at room temperature (19°C to 30°C). After a gigaohmic seal was formed between the patch electrode and the transfected single HEK293 cells, only a Mg-free bath was infused and the cell membrane was ruptured to ensure electrical ingress into the cells (whole-cell patch configuration). The inward current was measured 5 seconds after applying 300 μM NMDA (and 8.0 μM glycine) to the patch-clamp cells. Throughout the experiment, the cell was voltage-clamped at a holding potential of -80 mV.

[0827] To analyze the test compound, NMDA receptors were stimulated with 300 μM NMDA and 8.0 μM glycine and the test compound described below. A thirty-second pre-wash step was performed between the two applications using the test compound. Instructions for Use, pages 71 / 92, 85 CN 121085986 A

[0828] Table A: Application scheme; test compound use dependence

[0829]

[0830] Table B: Application scheme; control experiment

[0831]

[0832] Results are recorded in Table 1:

[0833] Table 1 Instructions for UsePages 72 / 92, 86 CN 121085986 A

[0834] Specification Pages 73 / 92, 87 CN 121085986 A

[0835] Specification Pages 74 / 92, 88 CN 121085986 A

[0836]

[0837] Abbreviations

[0838] PCC: Pyridinium chlorochromate; t-BuOK: Potassium tert-butoxide; 9-BBN: 9-Borobicyclo[3.3.1]nonane; Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium(O); AcCl: Acetyl chloride; i-PrMgCl: Isopropyl magnesium chloride; TBSCl: Tert-butyl(chloro)dimethylsilane; (i-PrO)4Ti: Tetraisopropoxide titanium; BHT: 2,6-Di-tert-butyl-4-methylphenol salt; Me: Methyl; i- Pr: Isopropyl; t-Bu: Tert-Butyl; Ph: Phenyl; Et: Ethyl; Bz: Benzoyl; BzCl: Benzoyl chloride; CsF: Cesium fluoride; DCC: Dicyclohexylcarbodiimide; DCM: Dichloromethane; DMAP: 4-Dimethylaminopyridine; DMP: Dys-Martin reagent; EtMgBr: Ethyl magnesium bromide; EtOAc: Ethyl acetate; TEA: Triethylamine; AlaOH: Alanine; Boc: Tert-Butylcarbonyl. Py: Pyridine; TBAF: Tetra-n-butylammonium fluoride; THF: Tetrahydrofuran; TBS: Tert-butyldimethylsilyl; TMS: Trimethylsilyl; TMSCF3: (Trifluoromethyl)trimethylsilane; Ts: p-Toluenesulfonyl; Bu: Butyl; Ti(OiPr)4: Tetraisopropoxytitanium; LAH: Lithium aluminum hydride; LDA: Lithium diisopropylaminodimethyl; LiOH.H2O: Lithium hydroxide hydrate; MAD: Methylaluminum bis(2,6-di-tert-butyl-4-methylphenol); MeCN: Acetonitrile; NBS: N-bromosuccinimide; Na2SO4: Sodium sulfate; Na2S2O3: Sodium thiosulfate; PE: Petroleum ether; MeCN: Acetonitrile; MeOH: Methanol; Boc: Tert-butoxycarbonyl; MTBE: Methyl tert-butyl ether; K-selectride: Potassium tris(sec-butyl)borohydride.

[0839] The present invention relates to the following schemes:

[0840] 1. Compound of formula (A):

[0841] (A)

[0842] or a pharmaceutically acceptable salt thereof, wherein:

[0843] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring;

[0844] n is 1 or 2;

[0845] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein RC is specified in the specification 75 / 92 pages 89 CN 121085986 AHydrogen or alkyl or R2A and R2B together with the carbon atoms to which they are attached form an oxo group, wherein R2A and R2B are not both hydrogen;

[0846] R3 is hydrogen, alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl;

[0847] R4 is absent or is hydrogen; and

[0848] represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent.

[0849] 2. The compound according to 1, wherein n is 1.

[0850] 3. The compound according to 1, wherein n is 2.

[0851] 4. According to the compound of 1, when R1A, R3, and R4 are hydrogen and R1B is unsubstituted isopropyl, then R2A and R2B together with the carbon atoms to which they are attached do not form oxo groups; and

[0852] when R4 is absent, R3 is hydrogen, and R1A and R1B are –CH3, then R2A is not –CH3 and R2B is not –OH.

[0853] 5. According to the compound of 1, when R4 is absent, R2A is –OH, R2B is hydrogen or –CF3, and R1A and R1B are –CH3, then R3 is not hydrogen; and

[0854] when R1A and R1B are –CH3 and R3 is hydrogen, then R2A and R2B together with the carbon atoms to which they are attached do not form oxo groups.

[0855] 6. The compound according to 1, wherein the compound of formula (A) is a compound of formula (A-I):

[0856] (A-I).

[0857] 7. The compound according to 1, wherein the compound of formula (A) is a compound of formula (A-II):

[0858] (A-II).

[0859] 8. The compound according to 1, wherein the compound of formula (A) is a compound of formula (A-III):

[0860] (A-III).

[0861] 9. The compound according to 1, wherein the compound of formula (A) is a compound of formula (A-IV), (A-V) or (A-VI): Specification 76 / 92 pages 90 CN 121085986 A

[0862] (A-IV), (A-V) or

[0863] (A-VI)

[0864] wherein R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[0865] 10. The compound according to 1, wherein the compound of formula (A) is a compound of formula (A-VII), (A-VIII) or (A-IX):

[0866] (A-VII), (A-VIII) or

[0867] (A-IX)

[0868] wherein R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[0869] 11. The compound according to 1, wherein the compound of formula (A) is a compound of formula (A-X):

[0870] (A-X)

[0871] Wherein R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[0872] 12. The compound according to 1, wherein the compound of formula (A) is the compound of formula (A-XII) specification 77 / 92 pages 91 CN 121085986 A

[0873] (A-XII)

[0874] wherein R` is alkyl or –ORA, wherein RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0875] 13. The compound of any one of 1-12, wherein R4 is absent, one of R2A and R2B is –OH and R3 is not hydrogen.

[0876] 14. The compound of any one of 1-11, wherein R1A and R1B are each independently unsubstituted or substituted alkyl.

[0877] 15. The compound of claim 14, wherein R1A and R1B are each independently selected from haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 and –CH2OCH3.

[0878] 16. The compound of any one of 1-11, wherein R1A and R1B are each independently substituted alkyl.

[0879] 17. The compound of claim 16, wherein R1A and R1B are each independently haloalkyl.

[0880] 18. The compound of any one of 1-11, wherein R1A is –CF3 or –CH2OCH3.

[0881] 19. The compound of any one of 1-11, wherein R1A and R1B are unsubstituted or substituted alkyl.

[0882] 20. The compound of any one of 1-11, wherein R1A and R1B are –CH3.

[0883] A compound of any one of 21.1-11, wherein R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring.

[0884] A compound of any one of 22.1-11, wherein R1A is hydrogen and R1B is an alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl group.

[0885] A compound of any one of 23.1-11, wherein R1A is a substituted alkyl or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[0886] A compound of any one of 24.1-8 or 13, wherein R2A and R2B are each independently substituted or unsubstituted alkyl groups.

[0887] A compound of any one of 25.1-8 or 12, wherein R2A and R2B are each independently –F.

[0888] 26. A compound of any one of 1 to 8 or 12, wherein R2A and R2B are –CH3 and R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[0889] 27. A compound of any one of 1 to 12, wherein R3 is a substituted or unsubstituted alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[0890] 28. A compound of any one of 1-12, wherein R3 is a substituted or unsubstituted alkyl group.

[0891] 29. A compound of any one of 1-8 or 12, wherein R2A and R2B are each independently hydrogen and R3 is a substituted or unsubstituted alkyl group.

[0892] 30. A pharmaceutical composition comprising the compound of 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

[0893] 31. A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of the compound of 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0894] 32. A method of treating or preventing the condition described herein, comprising administering to a subject in need an effective amount of the compound of 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Instruction manual 78 / 92 pages 92 CN 121085986 A

[0895] 33. According to the method of 32, the condition is a gastrointestinal (GI) condition, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, structural conditions affecting the gastrointestinal tract, anal conditions, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colonic polyps, cancer, or colitis.

[0896] 34. According to the method of 32, the condition is inflammatory bowel disease.

[0897] 35. According to the method of 32, the condition is cancer, diabetes, or sterol synthesis disorders.

[0898] 36. According to the method of 32, the condition is a metabolic disorder.

[0899] 37. According to the method of 32, the condition is an autoimmune disease.

[0900] 38. The method according to 32, wherein the condition is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[0901] 39. A method of treating or preventing a CNS-related condition, comprising administering to a subject in need an effective amount of the compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0902] 40. According to the method of 39, wherein the CNS-related disorders are adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, affective disorders (including depression and postpartum depression, bipolar disorder, dysthymia, and suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (Shank3), neurodevelopmental disorders (including Rett syndrome and complex tuberous sclerosis), multiple sclerosis, sterol synthesis disorders, and pain.(including acute and chronic pain), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss, or tinnitus.

[0903] 41. The method according to 32, wherein said condition is a sterol synthesis condition.

[0904] 42. Compound of formula (B):

[0905] (B)

[0906] or a pharmaceutically acceptable salt thereof, wherein:

[0907] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atom to which they are attached form a 3-8 membered ring;

[0908] n is 1 or 2;

[0909] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, ynyl, aryl or heteroaryl, wherein RC is hydrogen or alkyl, or R2A and R2B together with the carbon atom to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen;

[0910] R3 is alkyl, alkenyl, ynyl or –ORA, wherein RA is alkyl;

[0911] R4 is absent or is hydrogen; and

[0912] Represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 does not exist.

[0913] 43. The compound according to 42, wherein n is 1.

[0914] 44. The compound according to 42, wherein n is 2.

[0915] 45. The compound according to 42, wherein the compound of formula (B) is a compound of formula (B-I):

[0916] (B-I).

[0917] 46. The compound according to 42, wherein the compound of formula (B) is a compound of formula (B-II):

[0918] (B-II).

[0919] 47. The compound according to 42, wherein the compound of formula (B) is a compound of formula (B-III):

[0920] (B-III).

[0921] 48. The compound according to 42, wherein the compound of formula (B) is a compound of formula (B-IV), (B-V), or (B-VI):

[0922] (B-IV), (B-V), or

[0923] (B-VI)

[0924] wherein R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, ynyl, or –ORA, wherein RA is alkyl.

[0925] 49. The compound according to 42, wherein the compound of formula (B) is a compound of formula (B-VII), (B-VIII), or (B-IX): Specification 80 / 92 pages 94 CN 121085986A

[0926] (B-VII), (B-VIII) or

[0927] (B-IX)

[0928] wherein R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[0929] 50. According to the compound of 42, wherein the compound of formula (B) is a compound of formula (B-X):

[0930] (B-X)

[0931] wherein R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[0932] 51. According to the compound of 42, wherein the compound of formula (B) is a compound of formula (B-XII)

[0933] (B-XII)

[0934] wherein R' is alkyl or –ORA, wherein RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0935] 52. The compound according to any one of 42-50, wherein R1A and R1B are each independently unsubstituted or substituted alkyl groups.

[0936] 53. The compound according to 52, wherein R1A and R1B are each independently selected from haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 and –CH2OCH3.

[0937] 54. The compound according to any one of 42-50, wherein R1A and R1B are each independently substituted alkyl groups.

[0938] 55. The compound according to any one of 42-50, wherein R1A and R1B are each independently haloalkyl.

[0939] 56. The compound according to any one of 42-50, wherein R1A is –CF3 or –CH2OCH3.

[0940] 57. A compound according to any one of 42-50, wherein R1A and R1B are –CH3.

[0941] 58. A compound according to any one of 42-50, wherein R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring.

[0942] 59. A compound according to any one of 42-50, wherein R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aromatic, or heteroaryl.

[0943] 60. A compound according to any one of 42-50, wherein R1A is a substituted alkyl or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[0944] 61. A compound according to any one of 42-50, wherein R2A and R2B are each independently substituted or unsubstituted alkyl groups.

[0945] 62. A compound according to any one of 42-51, wherein R2A and R2B are each independently –F.

[0946] 63. A compound according to any one of 42-51, wherein R2A and R2B are –CH3 and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0947] 64. A compound according to any one of 42-51, wherein R3 is a substituted or unsubstituted alkyl, alkenyl, alkynyl, or –ORA, wherein RA is an alkyl group.

[0948] 65. A compound according to any one of 42-51, wherein R3 is a substituted or unsubstituted alkyl group.

[0949] 66. A compound according to any one of 42-51, wherein R2A and R2B are each independently hydrogen and R3 is a substituted or unsubstituted alkyl group.

[0950] 67. A pharmaceutical composition comprising the compound of 42 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

[0951] 68. A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of the compound of 42 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0952] 69. A method of treating or preventing the conditions described herein, comprising administering to a subject in need an effective amount of the compound of 42 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0953] 70. According to the method of 69, wherein the condition is a gastrointestinal (GI) condition, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, a structural condition affecting the gastrointestinal tract, anal condition, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colonic polyps, cancer, or colitis.

[0954] 71. According to the method of 69, wherein the condition is inflammatory bowel disease.

[0955] 72. According to the method of 69, wherein the condition is cancer, diabetes, or a sterol synthesis disorder.

[0956] 73. According to the method of 69, wherein the condition is a metabolic disorder.

[0957] 74. According to the method of 69, wherein the condition is an autoimmune disease.

[0958] 75. The method according to 69, wherein the condition is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[0959] 76. A method for treating or preventing CNS-related conditions, comprising administering to a subject in need an effective amount of the compound 42 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0960] 77. According to the method of 76, wherein the CNS-related disorders are adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression and postpartum depression, bipolar disorder, dysthymia, and suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (Shank3), and neurodevelopmental disorders).(including Rett syndrome, complex tuberous sclerosis), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss or tinnitus.

[0961] 78. The method according to 69, wherein said condition is a sterol synthesis disorder.

[0962] 79. Compound of formula (I):

[0963] (I)

[0964] or a pharmaceutically acceptable salt thereof, wherein:

[0965] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or

[0966] R1A and R1B together with the carbon atom to which they are attached form a 3-8 membered ring;

[0967] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, ynyl, aryl or heteroaryl, wherein RC is hydrogen or alkyl, or

[0968] R2A and R2B together with the carbon atom to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen;

[0969] R3 is hydrogen, alkyl, alkenyl, ynyl or –ORA, wherein RA is alkyl;

[0970] R4 is absent or is hydrogen; and

[0971] Represents a single or double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent;

[0972] provided that when R1A, R3, and R4 are hydrogen and R1B is an unsubstituted isopropyl group, then R2A and R2B together with the carbon atoms to which they are attached do not form oxo groups; and

[0973] when R4 is absent, R3 is hydrogen, and R1A and R1B are –CH3, then R2A is not –CH3 and R2B is not –OH.

[0974] 80. The compound according to 79, wherein R1A, R3, and R4 are hydrogen, R1B is an unsubstituted isopropyl group, and R2A and R2B together with the carbon atoms to which they are attached do not form oxo groups.

[0975] 81. The compound according to 79, wherein R4 is absent, R3 is hydrogen, R1A and R1B are –CH3, R2A is not –CH3 and R2B is not –OH.

[0976] 82. The compound according to 79, wherein the compound of formula (I) is a compound of formula (I-A):

[0977] (I-A).

[0978] 83. The compound according to 79, wherein the compound of formula (I) is a compound of formula (I-B): Specification 83 / 92 pages 97 CN 121085986 A

[0979] (I-B).

[0980] 84. The compound according to 79, wherein the compound of formula (I) is a compound of formula (I-C):

[0981] (I-C).

[0982] 85. The compound according to 79, wherein the compound of formula (I) is a compound of formula (I-E), (I-F), or (I-G):

[0983] (I-E), (I-F), or

[0984] (I-G)

[0985] wherein R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[0986] 86. The compound according to 79, wherein the compound of formula (I) is a compound of formula (I-H), (I-I), or (I-J):

[0987] (I-H), (I-I), or

[0988] (I-J)

[0989] wherein R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl. Specification 84 / 92 pages 98 CN 121085986 A

[0990] 87. The compound according to 79, wherein the compound of formula (I) is a compound of formula (I-K):

[0991] (I-K)

[0992] wherein R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[0993] 88. The compound according to 79, wherein the compound of formula (I) is a compound of formula (I-M):

[0994] (I-M)

[0995] wherein R' is alkyl or –ORA, wherein RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0996] 89. The compound according to any one of 79-87, wherein R1A and R1B are each independently unsubstituted or substituted alkyl.

[0997] 90. A compound according to any one of 79-87, wherein R1A and R1B are each independently selected from haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 and –CH2OCH3.

[0998] 91. A compound according to any one of 79-87, wherein R1A and R1B are each independently substituted alkyl.

[0999] 92. A compound according to any one of 79-87, wherein R1A and R1B are each independently haloalkyl.

[1000] 93. A compound according to any one of 79-87, wherein R1A is –CF3 or –CH2OCH3.

[1001] 94. A compound according to any one of 79-87, wherein R1A and R1B are unsubstituted or substituted alkyl.

[1002] 95. A compound according to any one of 79-87, wherein R1A and R1B are –CH3.

[1003] 96. A compound according to any one of 79-87, wherein R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring.

[1004] 97. A compound according to any one of 79-87, wherein R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[1005] 98. A compound according to any one of 79-87, wherein R1A is a substituted alkyl or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[1006] 99. A compound according to any one of 79-88, wherein R2A and R2B are each independently substituted or unsubstituted alkyl.

[1007] 100. A compound according to any one of 79-88, wherein R2A and R2B are each independently –F.

[1008] 101. A compound according to any one of 79-88, wherein R2A and R2B are –CH3 and R3 is alkyl, alkenyl, alkynyl, or –ORA, wherein RA is alkyl.

[1009] 102. A compound according to any one of 79-88, wherein R2A and R2B are –F.

[1010] 103. A compound according to any one of 79-88, wherein R3 is a substituted or unsubstituted alkyl, alkenyl, alkynyl or –ORA, wherein RA is an alkyl. Specification 85 / 92 pages 99 CN 121085986 A

[1011] 104. A compound according to any one of 79-88, wherein R3 is an alkyl, substituted or unsubstituted alkyl.

[1012] 105. A compound according to any one of 79-88, wherein R2A and R2B are each independently hydrogen and R3 is a substituted or unsubstituted alkyl.

[1013] 106. A pharmaceutical composition comprising the compound of 79 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[1014] 107. A method for inducing sedation or anesthesia, comprising administering to a subject an effective amount of the compound 79 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1015] 108. A method for treating or preventing the conditions described herein, comprising administering to a subject in need an effective amount of the compound 79 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1016] 109. The method of 108, wherein the condition is a gastrointestinal (GI) condition, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, a structural condition affecting the gastrointestinal tract, anal conditions, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colonic polyps, cancer, or colitis.

[1017] 110. The method of 108, wherein the condition is inflammatory bowel disease.

[1018] 111. The method of 108, wherein the condition is cancer, diabetes, or a sterol synthesis disorder.

[1019] 112. The method of 108, wherein the condition is a metabolic disorder.

[1020] 113. The method of 108, wherein the condition is an autoimmune disease.

[1021] 114.108. The method wherein the condition is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[1022] 115. A method for treating or preventing CNS-related conditions, comprising administering to a subject in need an effective amount of the compound 79 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1023] 116. According to the method of 115, wherein the CNS-related disorders are adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, affective disorders (including depression or postpartum depression, bipolar disorder, dysthymia, and suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (Shank3)), neurodevelopmental disorders (including Rett syndrome and complex tuberous sclerosis), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), and seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet). Diseases, stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss, or tinnitus.

[1024] 117.108 The method wherein said disease is a sterol synthesis disorder.

[1025] 118. Compound of formula (II):

[1026] (II)

[1027] or a pharmaceutically acceptable salt thereof, wherein:

[1028] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, (Pages 86 / 92, 100 CN 121085986 A) or

[1029] R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring;

[1030] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein RC is hydrogen or alkyl, or

[1031] R2A and R2B together with the carbon atoms to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen;

[1032] R3 is hydrogen, alkyl, alkenyl, alkynyl, or –ORA, where RA is alkyl;

[1033] R4 is absent or is hydrogen; and

[1034] represents a single or double bond, where if one is a double bond, the other is a single bond; if both are single bonds, R4 is hydrogen; and if one is a double bond, R4 is absent;

[1035] The premise is that when R4 is absent, R2A is –OH, R2B is hydrogen or –CF3 and R1A and R1B are –CH3, then R3 is not hydrogen; and

[1036] when R1A and R1B are –CH3 and R3 is hydrogen, then R2A and R2B together with the carbon atoms to which they are attached do not form oxo groups.

[1037] 119. The compound of 118, wherein R4 is absent, one of R2A and R2B is –OH and R3 is not hydrogen.

[1038] 120. The compound of 118, wherein the compound of formula (II) is a compound of formula (II-A):

[1039] (II-A).

[1040] 121. The compound of 118, wherein the compound of formula (II) is a compound of formula (II-B):

[1041] (II-B).

[1042] 122. According to the compound of 118, wherein the compound of formula (II) is a compound of formula (II-C):

[1043] (II-C).

[1044] 123. According to the compound of 118, wherein the compound of formula (II) is a compound of formula (II-D): Specification 87 / 92 pages 101 CN 121085986 A

[1045] (II-D).

[1046] 124. According to the compound of 118, wherein the compound of formula (II) is a compound of formula (II-E), (II-F) or (II-G):

[1047] (II-E), (II-F) or

[1048] (II-G)

[1049] wherein R2C is hydrogen or a substituted or unsubstituted alkyl group and R3 is an alkyl group, substituted or unsubstituted alkyl group.

[1050] 125. The compound of 118, wherein the compound of formula (II) is a compound of formula (II-H), (II-I) or (II-J):

[1051] (II-H), (II-I) or

[1052] (II-J)

[1053] wherein R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[1054] 126. The compound of 118, wherein the compound of formula (II) is a compound of formula (II-K): Specification 88 / 92 pages 102 CN 121085986 A

[1055] (II-K)

[1056] wherein R` is alkyl or –ORA, wherein RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[1057] 127. A compound according to any one of 118-125, wherein R1A and R1B are each independently unsubstituted or substituted alkyl groups.

[1058] 128. A compound according to any one of 118-125, wherein R1A and R1B are independently selected from haloalkyl, alkoxy...129. A compound according to any one of 118-125, wherein R1A and R1B are each independently substituted alkyl groups.

[1060] 130. A compound according to 129, wherein R1A and R1B are each haloalkyl groups.

[1061] 131. A compound according to any one of 118-125, wherein R1A is –CF3 or –CH2OCH3.

[1062] 132. A compound according to any one of 118-125, wherein R1A and R1B are unsubstituted or substituted alkyl groups.

[1063] 133. A compound according to any one of 118-125, wherein R1A and R1B are –CH3.

[1064] 134. A compound according to any one of 118-125, wherein R1A and R1B form a ring together with the carbon atoms to which they are attached.

[1065] 135. A compound according to any one of 118-125, wherein R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[1066] 136. A compound according to any one of 118-126, wherein R2A and R2B are each independently substituted or unsubstituted alkyl groups.

[1067] 137. A compound according to any one of 118-126, wherein R3 is an alkyl group, substituted or unsubstituted.

[1068] 138. A compound according to any one of 118-126, wherein R2A and R2B are each independently hydrogen and R3 is a substituted or unsubstituted alkyl group.

[1069] 139. A compound according to any one of 118-126, wherein R2A and R2B are each independently –F.

[1070] 140. A compound according to any one of 118-126, wherein R2A and R2B are –CH3 and R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[1071] 141. A compound according to any one of 118-126, wherein R2A and R2B are –F.

[1072] 142. A compound according to any one of 118-125, wherein R1A is a substituted alkyl or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[1073] 143. A pharmaceutical composition comprising the compound of 118 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[1074] 144. A method of inducing sedation or anesthesia, comprising administering to a subject an effective amount of the compound 118 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1075] 145. A method of treating or preventing the conditions described herein, comprising administering to a subject in need an effective amount of the compound 118 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1076] 146. According to the method of 145, wherein the condition is a gastrointestinal (GI) condition, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, a structural condition affecting the gastrointestinal tract, anal condition, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colonic polyps, cancer, or colitis. Specification 89 / 92 pages 103 CN 121085986 A

[1077] 147. According to the method of 145, wherein the condition is inflammatory bowel disease.

[1078] 148. According to the method of 145, wherein the condition is cancer, diabetes, or a sterol synthesis disorder.

[1079] 149. According to the method of 145, wherein the condition is a metabolic disorder.

[1080] 150. According to the method of 145, wherein the condition is an autoimmune disease.

[1081] 151. The method of 145, wherein the condition is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[1082] 152. A method for treating or preventing CNS-related conditions, comprising administering to a subject in need an effective amount of the compound of 118 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1083] 153. According to the method of 152, wherein the CNS-related disorders are adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, affective disorders (including depression and postpartum depression), bipolar disorder, dysthymia, and suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (Shank3)), neurodevelopmental disorders (including Rett syndrome and complex tuberous sclerosis), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), and seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet's disease). Stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss, or tinnitus.

[1084] 154. The method according to 145, wherein said condition is a sterol synthesis condition.

[1085] 155. Compound of formula (III):

[1086] (I)

[1087] or a pharmaceutically acceptable salt thereof, wherein:

[1088] R1A and R1B are each substituted or unsubstituted alkyl groups;

[1089] R2A and R2B are each independently hydrogen, ORC, or alkyl, wherein RC is hydrogen or alkyl, or

[1090] R2A and R2B together with the carbon atoms to which they are attached form an oxo group, wherein R2A and R2B are not simultaneously hydrogen;

[1091] R3 is alkyl;

[1092] R4 is absent or is hydrogen; and

[1093] represents a single bond or a double bond, wherein when one is a double bond, the other is a single bond; when both are single bonds, R4 is hydrogen; and when one is a double bond, R4 is absent.

[1094] 156. The compound according to 155, wherein R1A and R1B are each –CH3.

[1095] 157. The compound according to 155, wherein R2A and R2B together with the carbon atoms to which they are attached form an oxo group.

[1096] 158. The compound according to 155, wherein R3 is –CH2CH3.

[1097] 159. The compound of 155, wherein R2A is –OH and R2B is H.

[1098] 160. The compound of 155, wherein R2A is –CH3 and R2B is H. Specification 90 / 92 pages 104 CN 121085986 A

[1099] 161. The compound of 155, wherein R2A is –OH and R2B is –CH3.

[1100] 162. The compound of 155, wherein R1A is –CF3.

[1101] 163. A pharmaceutical composition comprising the compound of 155 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

[1102] 164. A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of the compound of 155 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1103] 165. A method of treating or preventing the conditions described herein, comprising administering to a subject in need an effective amount of the compound of 155 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1104] 166. The method of 165, wherein the condition is a gastrointestinal (GI) condition, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, a structural condition affecting the gastrointestinal tract, anal condition, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colonic polyps, cancer, or colitis.

[1105] 167. The method of 165, wherein the condition is inflammatory bowel disease.

[1106] 168. The method of 165, wherein the condition is cancer, diabetes, or a sterol synthesis disorder.

[1107] 169. The method of 165, wherein the condition is a metabolic disorder.

[1108] 170. The method of 165, wherein the condition is an autoimmune disease.

[1109] 171.According to the method of 165, the condition is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[1110] 172. A method for treating or preventing CNS-related conditions, comprising administering to a subject in need an effective amount of the compound of 155 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1111] 173. According to the method of 172, the CNS-related disorders are adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, affective disorders (including depression and postpartum depression), bipolar disorder, dysthymia, and suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (Shank3)), neurodevelopmental disorders (including Rett syndrome and complex tuberous sclerosis), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), and seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease). Stroke, traumatic brain injury, movement disorder (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss, or tinnitus.

[1112] 174. The method of 165, wherein said condition is a sterol synthesis condition.

[1113] Other embodiments

[1114] In the claims, articles such as “a,” “the,” and “the” may indicate one or more, unless otherwise indicated or obvious from the context. A claim or description including “or” among one or more members of the group is considered satisfied if one, more than one, or all members of the group are present, used, or otherwise associated with a given product or process, unless otherwise stated or obvious from the context. The invention includes embodiments in which exactly one member of the group is present in a given product or process, and is used or otherwise associated with the given product or process. The invention includes embodiments in which more than one or all members of the group are present, used, or associated with a given product or process.

[1115] Furthermore, the invention includes all variations, combinations, and substitutions, wherein one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are incorporated into another claim. For example, the dependency specification pages 91 / 92 105 CN 121085986 A may be modified.Any claim in another claim may include one or more limitations found in any other claim that relies on the same basic claim. Where elements are presented in list form, for example in Markush format, each subgroup of elements is also disclosed, and any element may be removed from the group. It should be understood that, in general, where the invention or an aspect of the invention is referred to as including specific elements and / or features, certain embodiments of the invention or an aspect of the invention include or are substantially composed of such elements and / or features. For the purpose of simplification, these embodiments are not specifically described herein. It should also be noted that the terms “comprising” and “containing” are intended to be open and allow for the inclusion of additional elements or steps. Where a range is given, the endpoints are included. Furthermore, unless otherwise indicated from the context and understood by one of ordinary skill in the art or otherwise apparent, values ​​expressed as ranges may present any specific value or subrange to one-tenth of the lower limit of the range in different embodiments of the invention, unless the context expressly specifies otherwise.

[1116] This application relates to various granted patents, published patent applications, journal articles and other publications, all of which are incorporated herein by reference. If any merged references conflict with this specification, this specification shall prevail. Additionally, any particular embodiment of the invention falling within the prior art may be explicitly excluded from any one or more claims. Because such embodiments are considered known to those skilled in the art, they may be excluded even if not explicitly stated herein. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[1117] Those skilled in the art will recognize or be able to determine many equivalents of the particular embodiments described herein using no more than conventional experiments. The scope of the embodiments of the invention described herein is not intended to be limited to the above description, but is set forth in the appended claims. Those skilled in the art will understand that various changes and modifications may be made to this specification without departing from the spirit or scope of the invention as defined by the following claims. Specification 92 / 92 pages 106 CN 121085986 A Abstract The present application relates to C7 substituted oxysterols and methods thereof used as NMDA modulators. Specifically, the present application provides compounds according to Formula (A): (A) andpharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1A, R1B, n, R2A, R2B, R3, and R4 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. Abstract

Claims

1. Compound of formula (A): Or its pharmaceutically acceptable salt, wherein: R 1A and R 1B Each is independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings; n is 1 or 2; R 2A and R 2B Each independently represents hydrogen, halogen, –OR C alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein R C It is hydrogen or alkyl or R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen; R 3 It can be hydrogen, alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group; R 4 It is either non-existent or is hydrogen; and Represents a single bond or a double bond, where when one When it is a double bond, then the other one... It is a single bond; When two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist.

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

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is a compound of formula (A-II):

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is a compound of formula (A-III):

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is a compound of formula (A-IV), (AV), or (A-VI): Where R 2C Hydrogen or alkyl and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is a compound of formula (A-VII), (A-VIII), or (A-IX): Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is a compound of formula (AX): Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is a compound of formula (A-XII): Where R' is an alkyl group or –OR A , where R A It is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

9. Compound of formula (B): Or its pharmaceutically acceptable salt, wherein: R 1A and R 1B Each is independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings; n is 1 or 2; R 2A and R 2B Each independently represents hydrogen, halogen, –OR C alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein R C It is hydrogen or alkyl or R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen; R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group; R 4 It is either non-existent or is hydrogen; and Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is: a) Compounds of formula (BI):

11. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is a compound of formula (B-II):

12. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is a compound of formula (B-III):

13. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is a compound of formula (B-IV), (BV), or (B-VI): Where R 2C Hydrogen or alkyl and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

14. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is a compound of formula (B-VII), (B-VIII), or (B-IX): Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

15. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is a compound of formula (BX): Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

16. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (B) is a compound of formula (B-XII): Where R' is an alkyl group or –OR A , where R A It is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

17. Compound of formula (I): Or its pharmaceutically acceptable salt, wherein: R 1A and R 1B Each is independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings; R 2A and R 2B Each independently represents hydrogen, halogen, –OR C alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein R C It is hydrogen or alkyl, or R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen; R 3 It can be hydrogen, alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group; R 4 It is either non-existent or is hydrogen; and Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist; The premise is that when R 1A R 3 and R 4 For hydrogen and R 1B When it is an unsubstituted isopropyl group, then R 2A and R 2B They do not form oxo groups together with the carbon atoms they are attached to; and When R 4 It does not exist, R 3 For hydrogen and R 1A and R 1B When it is –CH3, then R 2A Not for –CH3 and R 2B Not –OH.

18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R 1A R 3 and R 4 For hydrogen, R 1B For unsubstituted isopropyl and R 2a and R 2b They do not form oxo groups together with the carbon atoms they are attached to.

19. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R 4 It does not exist, R 3 For hydrogen, R 1A and R 1B For –CH3, R 2A Not for –CH3 and R 2B Not –OH.

20. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IA):

21. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IB):

22. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IC):

23. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IE), (IF), or (IG): Where R 2C Hydrogen or alkyl and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

24. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IH), (II), or (IJ): Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

25. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IK): Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

26. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IM): Where R' is an alkyl group or –OR A , where R A It is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

27. Compound of formula (II): Or its pharmaceutically acceptable salt, wherein: R 1A and R 1B Each is independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings; R 2A and R 2B Each independently represents hydrogen, halogen, –OR C alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein R C It is hydrogen or alkyl, or R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen; R 3 It can be hydrogen, alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group; R 4 It is either non-existent or is hydrogen; and Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist; The premise is that when R 4 It does not exist, R 2A For –OH, R 2B For hydrogen or –CF3 and R 1A and R 1B for- When CH3 is present, then R 3 Not hydrogen; and When R 1A and R 1B For –CH3 and R 3 When it is hydrogen, then R 2A and R 2B They do not form oxo groups together with the carbon atoms they are attached to.

28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-A):

29. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-B):

30. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-C):

31. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-D):

32. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-E), (II-F), or (II-G): Where R 2C Hydrogen or substituted or unsubstituted alkyl groups and R 3 It is an alkyl group, substituted or unsubstituted.

33. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-H), (II-I), or (II-J): Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

34. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (II-K): Where R' is an alkyl group or –OR A , where R A It is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

35. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It does not exist, R 2A and R 2B One of them is -OH, and R 3 It's not hydrogen.

36. The compound of any one of claims 1, 9, 17 or 27, or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each is an unsubstituted or substituted alkyl group.

37. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each is an independently substituted alkyl group.

38. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each is independently a haloalkyl or alkoxyalkyl.

39. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R 1A It can be –CF3 or –CH2OCH3.

40. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B are –CH3, –CH2CH3, –CH(CH3)2.

41. The compound of any one of claims 1, 9, 17 and 27, or a pharmaceutically acceptable salt thereof, wherein R 2A and R 2B Each can be an substituted or unsubstituted alkyl group.

42. The compound of any one of claims 1, 9, 17 and 27, or a pharmaceutically acceptable salt thereof, wherein R 2A and R 2B Each is independently represented by –F.

43. The compound of any one of claims 1, 9, 17 and 27, or a pharmaceutically acceptable salt thereof, wherein R 2A and R 2B For –CH3 and R 3 Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or –OR A , where R A It can be a substituted or unsubstituted alkyl group.

44. The compound of any one of claims 1, 9, 17 and 27, or a pharmaceutically acceptable salt thereof, wherein R 3 Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or –OR A , where R A It can be a substituted or unsubstituted alkyl group.

45. The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein R 3 It can be a substituted or unsubstituted alkyl group.

46. ​​Compound of formula (III): Or its pharmaceutically acceptable salt, wherein: R 1A and R 1B Each is a substituted or unsubstituted alkyl group; R 2A and R 2B Each independently of hydrogen, OR C or alkyl, wherein R C It is hydrogen or alkyl, or R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen; R 3 It is an alkyl group; R 4 It is either non-existent or is hydrogen; and Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist.

47. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each is –CH3.

48. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups.

49. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R 3 It is –CH2CH3.

50. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R 2A For –OH and R 2B For H.

51. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R 2A For CH3 and R 1B For H.

52. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R 2A For -OH and R 1B It is -CH3.

53. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R 1A For –CF3.

54. A pharmaceutical composition comprising a compound of any one of claims 1-53 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

55. Use of any compound of claims 1-52 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing sedation or anesthesia.

56. Use of any compound of claims 1-52 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of conditions selected from: gastrointestinal (GI) conditions, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, structural conditions affecting the gastrointestinal tract, anal conditions, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colonic polyps, cancer or colitis, diabetes or sterol synthesis disorders, metabolic disorders, autoimmune diseases, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

57. Use of any compound of claims 1-52 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of CNS-related disorders, wherein the CNS-related disorders are selected from adaptive disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression and postpartum depression), bipolar disorder, dysphoric disorder, suicidal ideation, schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, etc. Disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (Shank3),) neurodevelopmental disorders (including Rett syndrome, complex tuberous sclerosis), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss, or tinnitus.

58. The use according to claim 57, wherein the CNS-related condition is schizophrenia, Alzheimer's disease, autism spectrum disorder, Huntington's disease, or Parkinson's disease.

59. A method for synthesizing compound 22, comprising the following steps: a) Under N2 and 15°C, add Me3SI (4.18 g, 20.5 mmol) to a suspension of t-BuOK (3.53 g, 31.6 mmol) in THF (30 mL); b) Stir the suspension at 15°C for 30 min; c) At 15°C, add dropwise a solution of 21 (2 g, 15.8 mmol) in 10 ml of THF to the mixture; d) Stir the mixture at 15°C for 16 hours; e) Quench the mixture with saturated NH4Cl (100 mL) and extract with EtOAc (3 x 150 mL); and f) The combined organic phase was dried with Na2SO4, filtered and concentrated under vacuum to give 22 (1.8 g, 81%), which was a liquid.

60. Compound 2, which is:

61. A method for synthesizing compound 2, comprising the following steps: a) At 35°C, add DMP (2.14 kg, 5.08 mol) in portions to a solution of 1 (800 g, 2.54 mol) in DCM (8 L); b) Stir the reaction mixture at 35°C for 20 minutes; c) Filter the reaction mixture; d) Wash the filter cake with DCM (3 x 1 L); and e) The combined organic phase was washed with a saturated Na2S2O3 / saturated NaHCO3 aqueous solution (3:1, 2 x 1.5 L) and brine (1.5 L), dried with Na2SO4, filtered and concentrated under vacuum to obtain 2 (794 g, crude), which was a solid.