WO2021113669A1 - Cannabinoids and uses thereof - Google Patents

Cannabinoids and uses thereof Download PDF

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Publication number
WO2021113669A1
WO2021113669A1 PCT/US2020/063356 US2020063356W WO2021113669A1 WO 2021113669 A1 WO2021113669 A1 WO 2021113669A1 US 2020063356 W US2020063356 W US 2020063356W WO 2021113669 A1 WO2021113669 A1 WO 2021113669A1
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Prior art keywords
optionally substituted
compound
pharmaceutical composition
pharmaceutically acceptable
acceptable salt
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Application number
PCT/US2020/063356
Other languages
French (fr)
Inventor
Hongfeng Deng
Robert Paul Discordia
Xiao Feng
Zhuang JIN
Clifton David LEIGH
Kristos Adrian MOSHOS
Gang Sun
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Corbus Pharmaceuticals, Inc.
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Publication of WO2021113669A1 publication Critical patent/WO2021113669A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans

Definitions

  • Cannabinoids are a class of chemicals found in Cannabis sativa L (Cannabis) and related derivatives that have been shown to exhibit various pharmacologic activities. Tetrahydrocannabinol (THC) is the major psychoactive cannabinoid of cannabis. In addition to mood-altering effects, THC has been reported to exhibit other activities, some of which may have therapeutic value. The potential therapeutic value of THC has led to a search for related compounds which minimize the psychoactive effects, while retaining the activities of potential medicinal value. Cannabinoids in current therapeutic use, such as nabilone, activate both the cannabinoid type 1 receptor (CB1) and the cannabinoid type 2 receptor (CB2).
  • CBD1 cannabinoid type 1 receptor
  • CB2 cannabinoid type 2 receptor
  • Selective CB2 modulation or peripherally restricted CB2 modulation may provide some of the therapeutic effects of cannabinoids, such as their immuno-modulatory properties, without the psychoactive effects of CB 1 activation associated with central neuron system. Therefore, cannabinoid CB2 receptors represent an attractive target for drug development.
  • the invention relates to cannabinoid compounds, pharmaceutical compositions including one or more cannabinoid compounds, and the use of pharmaceutical compositions including one or more cannabinoid compounds for the treatment of a disease or condition (e.g., a fibrotic disease or an inflammatory disease) in a subject in need thereof.
  • a disease or condition e.g., a fibrotic disease or an inflammatory disease
  • the invention features compounds sharing structural features with (6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyl-2-octanyl)-6a,7,10,10a- tetrahydro-6H-benzo[c]chromene-9-carboxylic acid (ajulemic acid).
  • ajulemic acid is based, at least in part, on the identification and analysis of metabolic products of ajulemic acid.
  • the present disclosure provides deuterated and/or fluorinated analogs of ajulemic acid and structurally related cannabinoids.
  • Compounds disclosed herein are deuterated and/or fluorinated to provide advantageous properties (e.g., as compared to other cannabinoids such as ajulemic acid), for example, increased metabolic stability, improved pharmacokinetic properties (e.g., increased serum half-life), and/or increased receptor selectivity (e.g., increased CB2 receptor selectivity).
  • the invention features compounds with an increased safety or efficacy profile in the treatment of a disease or condition (e.g., a fibrotic disease or an inflammatory disease), as compared to other cannabinoids, such as ajulemic acid.
  • the invention features a composition including a compound described by formula (I), (II), or (III): , wherein R1 is H, O, OH, F, Cl, Br, NH2, or optionally substituted C 1 -C 3 alkoxy; R 2 is H, CH 3 , CH2D, CHD2, or CD3; R 3 and R4 are each independently CH 3 , CH2D, CHD2, or CD3; R5 is CH 3 or CH2OH; L1 is optionally substituted C 1 -C 20 alkylene, optionally substituted C 1 -C 20 heteroalkylene, optionally substituted C 2 -C 20 alkenylene, optionally substituted C 2 -C 20 heteroalkenylene, optionally substituted C 2 -C 20 alkynylene, optionally substituted C 2 -C 20 heteroalkynylene, optionally substituted C5-C15 arylene, optionally substituted C 3 -C 20 cycloalkylene, optionally substituted C 2 -C 15 ary
  • the compound is not .
  • the compound is described by formula (I): , or a pharmaceutically acceptable salt thereof.
  • the compound is described by any one of formulas (1A-1), (1A-2), (1A-3), and (1A-4): (IA-4), or a pharmaceutically acceptable salt thereof.
  • A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, or cyano.
  • the compound is described by formula (IA-2A): (IA-2A), wherein Ra is H, optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 alkenyl, optionally substituted C 1 -C 20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C 3 -C 20 cycloalkyl, optionally substituted C 1 -C 20 heteroalkyl, optionally substituted C 3 -C 20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or a pharmaceutically acceptable salt thereof.
  • Ra is H.
  • the compound is described by formula (IA-2B): (IA-2B), wherein each of Ra and Ra′ is independently H, optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 alkenyl, optionally substituted C 1 -C 20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C 3 -C 20 cycloalkyl, optionally substituted C 1 -C 20 heteroalkyl, optionally substituted C 3 -C 20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or Ra and Ra′, together with the nitrogen atom to which they are attached, combine to form an optionally substituted C 3 -C 20 heterocyclyl; or a pharmaceutically acceptable salt thereof
  • Ra is optionally substituted C 1 -C 20 alkyl. In some embodiments, Ra is optionally substituted C 3 -C 20 cycloalkyl. In some embodiments, Ra′ is H. In some embodiments, Ra and R a′, together with the nitrogen atom to which they are attached, combine to form an optionally substituted C 3 -C 20 heterocyclyl. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), and (IA-4)), A is optionally substituted 3-to-8 membered heterocyclyl.
  • A is optionally substituted 5-membered heterocyclyl.
  • A is optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4-oxatriazole, or optionally substituted 1,2,3,4-thiatriazole.
  • A is optionally substituted 6-membered heterocyclyl.
  • A is optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, or optionally substituted tetrahydropyran.
  • A is In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), and (IA-4)), A is In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), ), and (IA-4)), A is some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), and (IA-4)), A is optionally substituted 7-membered heterocyclyl.
  • A is optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted thiepine, or optionally substituted 1,4-thiazepine.
  • the compound is described by formula (II): , or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (IIA): (IIA), wherein Q1, Q2, and Q3 are each independently C, O, or N; Rb H, alkyl, or absent; and Rc, and Rd are each independently H, optionally substituted C 1 -C 6 alkyl, or absent; or a pharmaceutically acceptable salt thereof.
  • Rb, Rc, and Rd are each independently H, alkyl, or absent.
  • the compound is described by formula (IIA-1): (IIA-1), wherein Q1 and Q2 are each independently O or N; and Rb and Rc are each independently H, C 1 -C 6 alkyl, or absent; or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (IIA-2): (IIA-2), wherein Q2 and Q3 are each independently O or N; and Rc and Rd are each independently H, optionally substituted C 1 -C 6 alkyl, or absent; or a pharmaceutically acceptable salt thereof.
  • Rc is H, C 1 -C 6 alkyl, or absent; and Rd is H, optionally substituted C 1 -C 6 alkyl, or absent. In some embodiments, Rc and Rd are each independently H, C 1 -C 6 alkyl, or absent. In some embodiments, the compound is described by formula (IIA-2A): wherein Rc is H or optionally substituted C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof. In some embodiments, Rc is H or C 1 -C 6 alkyl.
  • Rc is C 1 -C 6 alkyl substituted with ORh or NRiRj, wherein Rh is H or C 1 -C 6 alkyl, and each of Ri and Rj is independently H or alkyl, or Ri and Rj, together with the nitrogen atom to which they are attached form an optionally substituted 3- to 6- membered saturated ring.
  • Rc is , , In preferred embodiments, Rc is H. In other preferred embodiments, Rc is CH 3 .
  • the compound is described by formula (IIA-2B): wherein Rd is H or optionally substituted C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • Rd is H or C 1 -C 6 alkyl. In some embodiments, Rd is C 1 -C 6 alkyl substituted with ORh or NRiRj, wherein Rh is H or C 1 -C 6 alkyl, and each of Ri and Rj is independently H or alkyl, or Ri and Rj, together with the nitrogen atom to which they are attached form an optionally substituted 3- to 6- membered saturated ring. In some embodiments, Rd is , , In preferred embodiments, Rd is H. In other preferred embodiments, Rd is CH 3 . In some embodiments, the compound is described by formula (IIA-2C): (IIA-2C), or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (IIA-3): (IIA-3), wherein Rd is H or C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • Rd is H.
  • Rd is CH 3 .
  • any of the aspects described herein e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), and (IIA- 3)
  • R1 is OH.
  • R1 is OCH 3 .
  • the compound is described by formula (III): , or a pharmaceutically acceptable salt thereof.
  • L2 is optionally substituted C 3 -C 8 alkylene, preferably optionally substituted C4 alkylene.
  • the compound is described by formula (IIIA): (IIIA), wherein Re and Rf are each independently H, OH, Cl, Br, or F; or Re and Rf are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.
  • Re and Rf are each H.
  • Re and Rf are joined to form an epoxy.
  • L2 is optionally substituted C 3 -C 8 alkenylene, preferably optionally substituted C4 alkenylene.
  • the compound is described by formula (IIIB): (IIIB), or a pharmaceutically acceptable salt thereof.
  • L2 is optionally substituted C5 alkylene.
  • the compound is described by formula (IIIC): (IIIC), wherein Re, Rf, and Rg are each independently H, OH, Cl, Br, or F; or Re and Rf are joined to form an epoxy; or Rf and Rg are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.
  • Re, Rf, and Rg are each H.
  • Rg is H and Re and Rf are joined to form an epoxy.
  • Re is H and Rf and Rg are joined to form an epoxy.
  • L2 is optionally substituted C5 alkenylene.
  • the compound is described by formula (IIID): (IIID), or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (IIIE): (IIIE), or a pharmaceutically acceptable salt thereof.
  • L2 is optionally substituted C 3 -C 8 heteroalkylene, preferably optionally substituted C4 heteroalkylene.
  • the compound is described by formula (IIIF): (IIIF), or a pharmaceutically acceptable salt thereof.
  • X5 is O.
  • X5 is NH.
  • R 2 is CH2D. In other preferred embodiments, R 2 is CHD2. In further preferred embodiments, R 2 is CD3. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA), (IIA-1), (IIA-2), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), R 2 is H or CH 3 .
  • R 3 is CH 3 and R4 is CH2D, CHD2, or CD3. In other preferred embodiments, R 3 and R4 are each CH2D, CHD2, or CD3. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), L1 is optionally substituted C2-C6 alkylene.
  • L1 is preferably .
  • L1 is optionally substituted C2-C6 alkenylene.
  • L1 is .
  • R 2 is H and L1 is optionally substituted C2-C6 alkylene.
  • R 2 and L1 form In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), R 2 is H and L1 is optionally substituted 5-membered heterocyclylene.
  • R 2 and L 1 form optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, optionally substituted tetrahydropyran, optionally substituted thiepine, or optionally substituted 1,4- thiazepine.
  • R 2 and L1 form In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), R 2 is H and L1 is optionally substituted amido of formula - C(O)NHL3-, wherein L3 is optionally substituted C 1 -C 20 alkylene, optionally substituted C 1 -C 20 heteroalkylene, optionally substituted C 1 -C 20 alkenylene, optionally substituted C 1 -C 20 heteroalkenylene, optionally substituted C 1 -C 20 alky
  • R 2 and L1 form In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA), (IIA-1), (IIA-2), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), R5 is CH 3 .
  • R5 is CH2OH.
  • the compound is a compound of Table 1 (e.g., any one of compounds 1- 530, 534-689, 1389-1433, and 1485-1490): Table 1.
  • the invention relates to a compound described by formula (I′), (II′), or (III′): , wherein R1 is H, O, OH, F, Cl, Br, NH2, or optionally substituted C 1 -C 3 alkoxy; R 2 is H, CH 3 , CH2F, CHF2, or CF3; R 3 and R 4 are each independently CH 3 , CH2F, CHF2, or CF3; R5 is CH 3 or CH2OH; L1 is optionally substituted C 1 -C 20 alkylene, optionally substituted C 1 -C 20 heteroalkylene, optionally substituted C 2 -C 20 alkenylene, optionally substituted C 2 -C 20 heteroalkenylene, optionally substituted C 2 -C 20 alkynylene, optionally substituted C 2 -C 20 heteroalkynylene, optionally substituted C5-C15 arylene, optionally substituted C 3 -C
  • the compound is not In some embodiments, the compound is described by formula (I′): , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by any one of formulas (1′A-1), (1′A-2), (1′A- 3), and (1′A-4): (I′A-4), or a pharmaceutically acceptable salt thereof.
  • A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, or cyano.
  • the compound is described by formula (I′A-2A):
  • R a is H, optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 alkenyl, optionally substituted C 1 -C 20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C 3 -C 20 cycloalkyl, optionally substituted C 1 -C 20 heteroalkyl, optionally substituted C 3 -C 20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or a pharmaceutically acceptable salt thereof.
  • R a is H.
  • the compound is described by formula (GA-2B):
  • each of R a and R a ' is independently H, optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 alkenyl, optionally substituted C 1 -C 20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C 3 -C 20 cycloalkyl, optionally substituted C 1 -C 20 heteroalkyl, optionally substituted C 3 -C 20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or R a and R a ', together with the nitrogen atom to which they are attached, combine to form an optionally substituted C 3 -C 20 heterocyclyl; or a pharmaceutically acceptable salt thereof.
  • R a is optionally substituted C 1 -C 20 alkyl. In some embodiments, R a is optionally substituted C 3 -C 20 cycloalkyl. In some embodiments, R a ' is H. In some embodiments, R a and R a ', together with the nitrogen atom to which they are attached, combine to form an optionally substituted C 3 -C 20 heterocyclyl.
  • A is optionally substituted 3-to-8 membered heterocyclyl.
  • A is optionally substituted 5-membered heterocyclyl.
  • A is optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1 ,3,4-oxadiazole, optionally substituted 1 ,3,4-thiadiazole, optionally substituted 1 ,2,3,4-oxatriazole, or optionally substituted 1 pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazo
  • A is optionally substituted 6-membered heterocyclyl.
  • A is optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, or optionally substituted tetrahydropyran.
  • A is .g., any one of (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), and (I′A-4)
  • A is optionally substituted 7-membered heterocyclyl.
  • A is optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted thiepine, or optionally substituted 1,4-thiazepine.
  • the compound is described by formula (II′): , or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (II′A): (II′A), wherein Q1, Q2, and Q3 are each independently C, O, or N; and Rb is H, C 1 -C 6 alkyl, or absent; and Rc, and Rd are each independently H, optionally substituted C 1 -C 6 alkyl, or absent; or a pharmaceutically acceptable salt thereof.
  • Rb, Rc, and Rd are each independently H, C 1 -C 6 alkyl, or absent.
  • the compound is described by formula (II′A-1): (II′A-1), wherein Q1 and Q2 are each independently O or N; and Rb and Rc are each independently H, C 1 -C 6 alkyl, or absent; or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (II′A-2): (II′A-2), wherein Q2 and Q3 are each independently O or N; and Rc and Rd are each independently H, optionally substituted C 1 -C 6 alkyl, or absent; or a pharmaceutically acceptable salt thereof.
  • Rc is H, C 1 -C 6 alkyl, or absent; and Rd is H, optionally substituted C 1 -C 6 alkyl, or absent. In some embodiments R and Rd are each independently H C1 C6 alkyl or absent. In some embodiments, the compound is described by formula (II′A-2A): (II′A-2A), wherein Rc is H or optionally substituted C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof. In preferred embodiments, Rc is H. In some embodiments, Rc is H or C 1 -C 6 alkyl.
  • Rc is C 1 -C 6 alkyl substituted with ORh or NRiRj, wherein Rh is H or C 1 -C 6 alkyl, and each of Ri and Rj is independently H or alkyl, or Ri and Rj, together with the nitrogen atom to which they are attached form an optionally substituted 3- to 6-membered saturated ring.
  • Rc is , , , .
  • Rc is CH 3 .
  • the compound is described by formula (II′A-2B): (II′A-2B), wherein Rd is H or optionally substituted C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • Rd is H or C 1 -C 6 alkyl. In some embodiments, Rd is C 1 -C 6 alkyl substituted with ORh or NRiRj, wherein Rh is H or C 1 -C 6 alkyl, and each of Ri and Rj is independently H or alkyl, or Ri and Rj, together with the nitrogen atom to which they are attached form an optionally substituted 3- to 6- membered saturated ring. In some embodiments, R d is , , . In preferred embodiments, Rd is H. In other preferred embodiments, Rd is CH 3 . In some embodiments, the compound is described by formula (II′A-2C): (II′A-2C), or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (II′A-3): (II′A-3), wherein Rd is H or C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • Rd is H.
  • Rd is CH 3 .
  • R1 is OH.
  • R1 is OCH 3 .
  • the compound is described by formula (III′): , or a pharmaceutically acceptable salt thereof.
  • L2 is optionally substituted C 3 -C 8 alkylene, preferably optionally substituted C4 alkylene.
  • the compound is described by formula (III′A): wherein Re and Rf are each independently H, OH, Cl, Br, or F; or Re and Rf are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.
  • Re and Rf are each H.
  • Re and Rf are joined to form an epoxy.
  • L2 is optionally substituted C 3 -C 8 alkenylene, preferably optionally substituted C4 alkenylene.
  • the compound is described by formula (III′B): or a pharmaceutically acceptable salt thereof.
  • L2 is optionally substituted C5 alkylene.
  • the compound is described by formula (III′C): wherein Re, Rf, and Rg are each independently H, OH, Cl, Br, or F; or Re and Rf are joined to form an epoxy; or Rf and Rg are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.
  • Re, Rf, and Rg are each H.
  • Rg is H and Re and Rf are joined to form an epoxy.
  • Re is H and Rf and Rg are joined to form an epoxy.
  • L2 is optionally substituted C5 alkenylene.
  • the compound is described by formula (III′D):
  • the compound is described by formula (III′E):
  • L2 is optionally substituted C 3 -C 8 heteroalkylene, preferably optionally substituted C4 heteroalkylene.
  • the compound is described by formula (III′F): In some embodiments of any of the aspects described herein (e.g., any one of formulas (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), X5 is O.
  • X5 is NH.
  • R 3 and R4 are each CH 3 .
  • R 2 is CH2D.
  • R 2 is CHD2. In further preferred embodiments, R 2 is CD3. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A), (II′A-1), (II′A-2), (II′A-2B), (II′A-2C), (II′A-3), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), R 2 is H or CH 3 .
  • R 3 is CH 3 and R4 is CH2D, CHD2, or CD3. In other preferred embodiments, R 3 and R4 are each CH2D, CHD2, or CD3. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (II′A-3), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), L1 is optionally substituted C2-C6 alkylene.
  • L1 is In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (II′A-3), (II′A-2C), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), L1 is optionally substituted C2-C6 alkenylene.
  • L1 is .
  • R 2 is H and L1 is optionally substituted C2-C6 alkylene.
  • R 2 and L1 form In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (II′A-3), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), R 2 is H and L1 is optionally substituted 5- membered heterocyclylene.
  • R 2 and L1 form optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, optionally substituted tetrahydropyran, optionally substituted thiepine, or optionally substituted 1,4-thiazepine.
  • R 2 and L1 form In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A), (II′A-1), (II′A-2), (II′A-2B), (II′A-2C), (II′A-3), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), R 2 is H and L1 is optionally substituted amido of formula -C(O)NHL3-, wherein L3 is optionally substituted C 1 -C 20 alkylene, optionally substituted C 1 -C 20 heteroalkylene, optionally substituted C 1 -C 20 alkenylene, optionally substituted C 1
  • R 2 and L1 form In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A), (II′A-1), (II′A-2), (II′A-2B), (II′A-2C), (II′A-3), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), R5 is CH 3 .
  • R5 is CH2OH.
  • the compound is a compound of Table 2 (e.g., any one of compounds 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b, 1233b-1388b, 1434b-1484b, 690c-1229c, 1233c- 1388c, and 1434c-1484c):
  • the invention provides a pharmaceutical composition including a compound of the invention (e.g., a compound of any one of formulas (I′)-(III′) or any one of compounds 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b, 1233b-1388b, 1434b-1484b, 690c-1229c-1388c, and 1434c- 1484c), or a salt thereof, and a pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition including Compound 1491, or a salt thereof, and a pharmaceutically acceptable excipient.
  • At least one of R 2 , R 3 , and R4 is deuterium-enriched, and the composition has an isotopic enrichment factor for deuterium of at least 5.
  • the composition has an isotopic enrichment factor for deuterium of at least about 500 (e.g., at least about 1000, at least about 3000, and at least about 4000, 5000, or 6000).
  • the invention provides a method of treating an inflammatory disease in a subject in need thereof.
  • the method includes administering to the subject a pharmaceutical composition including a compound of the invention (e.g., a compound of any one of formulas (I)-(III) and (I′)-(III′) or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491), or a salt thereof, and a pharmaceutically acceptable excipient, in an amount sufficient to treat the condition.
  • a compound of the invention e.g., a compound of any one of formulas (I)-(III) and (I′)-(III′) or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233
  • the inflammatory disease is selected from the group consisting of scleroderma, dermatomyositis, systemic lupus erythematosus, acquired immune deficiency syndrome (AIDS), multiple sclerosis, rheumatoid arthritis, psoriasis, diabetes, cancer, asthma, atopic dermatitis, an autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, stroke, ischemia, a neurodegenerative disease, amyotrophic lateral sclerosis (ALS), chronic traumatic encephalopathy (CTE), chronic inflammatory demyelinating polyneuropathy, an autoimmune inner ear disease, uveitis, ulceris, and peritonitis.
  • AIDS acquired immune deficiency syndrome
  • multiple sclerosis rheumatoid arthritis
  • psoriasis psoriasis
  • diabetes cancer
  • asthma atopic dermatitis
  • an autoimmune thyroid disorders ulcerative colitis, Crohn’s disease
  • the inflammatory disease is scleroderma (e.g., systemic sclerosis, localized scleroderma, or sine scleroderma).
  • the inflammatory disease is cancer.
  • the invention provides a method of treating a fibrotic disease in a subject in need thereof.
  • the method includes administering to the subject the pharmaceutical composition including a compound of the invention (e.g., a compound of any one of formulas (I)-(III) and (I′)-(III′) or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491), or a salt thereof, and a pharmaceutically acceptable excipient, in an amount sufficient to treat the condition.
  • a compound of the invention e.g., a compound of any one of formulas (I)-(III) and (I′)-(III′) or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 14
  • the fibrotic disease is selected from the group consisting of scleroderma, cystic fibrosis, liver cirrhosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, Dupuytren’s contracture, keloids, chronic kidney disease, chronic graft rejection, scarring, wound healing, post- operative adhesions, reactive fibrosis, polymyositis, ANCA vasculitis, Behcet's disease, anti-phospholipid syndrome, relapsing polychondritis, Familial Mediterranean Fever, giant cell arteritis, Graves ophthalmopathy, discoid lupus, pemphigus, bullous pemphigoid, hydradenitis suppuritiva, sarcoidosis, bronchiolitis obliterans, primary sclerosing cholangitis, primary biliary cirrhosis, and organ fibrosis (e.g., s
  • the fibrotic disease is scleroderma (e.g., systemic sclerosis, localized scleroderma, or sine scleroderma).
  • the fibrotic disease is organ fibrosis (e.g., dermal fibrosis, lung fibrosis, liver fibrosis, kidney fibrosis, or heart fibrosis).
  • the fibrotic disease is cystic fibrosis.
  • the compound has increased affinity for the CB2 receptor compared to affinity for the CB1 receptor.
  • the compound has 10%, 20%, 30% 40%, 50%, 60% 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% or more greater affinity for the CB2 receptor compared to the CB1 receptor.
  • the compound has 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15- fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 25-fold, 30-fold, 40-fold, or 50-fold or more greater affinity for the CB2 receptor compared to the CB1 receptor.
  • Receptor selectivity may be determined by receptor binding or by functional assay (e.g., cAMP or ⁇ -arrestin), as described here, for example in Examples 5-8.
  • the compound has greater CB2 receptor selectivity compared to the CB2 receptor selectivity of ajulemic acid.
  • the term “deuterium-enriched” or “deuterated,“ refers to a compound of the inventions (e.g., ajulemic acid or an analog thereof) with a level of deuterium (D or 2 H) that has been enriched to be greater than 0.015%, the natural abundance of deuterium.
  • a composition of the invention has a minimum isotopic enrichment factor of at least 5 (0.075% deuterium incorporation), e.g., at least 10 (0.15% deuterium incorporation). In other embodiments, a composition has an isotopic enrichment factor of at least 50 (0.75% deuterium incorporation), at least 500 (7.5% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), or at least 6600 (99% deuterium incorporation).
  • the term "treat” or “treatment” includes administration of a compound to a subject, e.g., by any route, e.g., orally, topically, by inhalation, by ex-vivo contact with one or more cells of the subject.
  • the compound can be administered alone or in combination with one or more additional compounds. Treatments may be sequential, with the present compound being administered before or after the administration of other agents. Alternatively, compounds may be administered concurrently.
  • the subject e.g., a patient, can be one having a disorder (e.g., a disease or condition described herein), a symptom of a disorder, or a predisposition toward a disorder.
  • Treatment is not limited to curing or complete healing, but can result in one or more of alleviating, relieving, altering, partially remedying, ameliorating, improving or affecting the disorder, reducing one or more symptoms of the disorder or the predisposition toward the disorder.
  • the treatment at least partially
  • the treatment at least partially
  • the treatment reduces at least one symptom of the disorder or delays onset of at least one symptom of the disorder. The effect is beyond what is seen in the absence of treatment.
  • terapéuticaally effective amount refers to an amount, e.g., pharmaceutical dose, effective in inducing a desired effect in a subject or in treating a subject having a condition or disorder described herein (e.g., a fibrotic disease of an inflammatory disease). It is also to be understood herein that a “therapeutically effective amount” may be interpreted as an amount giving a desired therapeutic and/or preventative effect, taken in one or more doses or in any dosage or route, and/or taken alone or in combination with other therapeutic agents.
  • subject can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, turkey, goat, fish, monkey, chicken, rat, mouse, and sheep.
  • pharmaceutical composition refers to the combination of an active agent with an excipient, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • a “pharmaceutically acceptable excipient,” after being administered to or upon a subject, does not cause undesirable physiological effects.
  • the excipient in the pharmaceutical composition must be “acceptable” also in the sense that it is compatible with the active ingredient.
  • the excipient may also be capable of stabilizing the active ingredient.
  • One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an active compound.
  • pharmaceutically acceptable excipients include, but are not limited to, biocompatible vehicles, adjuvants, additives, and diluents to achieve a composition usable as a dosage form.
  • excipients include colloidal silicon oxide, magnesium stearate, cellulose, and sodium lauryl sulfate.
  • excipient refers to a diluent, adjuvant, carrier, or vehicle with which the active compound is administered.
  • Such pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
  • auxiliary, stabilizing, thickening, lubricating and coloring agents can be used.
  • the pharmaceutically acceptable vehicles are preferably sterile.
  • Water can be the vehicle when the active compound is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions.
  • Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, sodium stearate, glycerol monostearate, talc, sodium chloride, glycerol, propylene glycol, water, and ethanol.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, sodium stearate, glycerol monostearate, talc, sodium chloride, glycerol, propylene glycol, water, and ethanol.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • the term “pharmaceutically acceptable salt” represents a salt of a compound of the invention (e.g., a compound of any one of formulas (I)-(III) and (I′)-(III′) or any one of compounds 1- 530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491) that is within the scope of sound medical judgment, suitable for use in methods described herein without undue toxicity, irritation, and/or allergic response.
  • Pharmaceutically acceptable salts are well known in the art.
  • salts are described in: Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of a compound described herein or separately by reacting the free base group with a suitable organic acid.
  • alkyl alkenyl
  • alkynyl straight-chain and branched- chain monovalent substituents, as well as combinations of these, containing only C and H when unsubstituted.
  • the alkyl group can be referred to as an “alkenyl” or “alkynyl” group respectively.
  • the monovalency of an alkyl, alkenyl, or alkynyl group does not include the optional substituents on the alkyl, alkenyl, or alkynyl group.
  • monovalency of the alkyl, alkenyl, or alkynyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl, alkenyl, or alkynyl group.
  • the alkyl group may contain, e.g., 1-20.1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1- C2).
  • 1-20.1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4 or 1-2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1- C2).
  • the alkenyl or alkynyl group may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2 C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4).
  • Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2- propenyl, and 3-butynyl.
  • heteroalkyl examples include alkyl, alkenyl, or alkynyl groups, as defined above, but which include one or more heteroatoms (e.g., oxygen, nitrogen, and/or sulfur atoms) in the alkyl, alkenyl, or alkynyl main chain.
  • heteroatoms e.g., oxygen, nitrogen, and/or sulfur atoms
  • the heteroalkyl, heteroalkenyl, or heteroalknyl group may contain, e.g., 1-20.1-18, 1-16, 1-14, 1-12, 1-10, 1- 8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1- C6, C1-C4, or C1-C2) and one or more (e.g., one, two, three, four, or five) heteroatoms atoms.
  • alkylene refers to divalent groups having a specified size. Alkylene groups are exemplified by methylene, ethylene, isopropylene, and the like. Alkylene, alkenylene, and/or alkynylene includes straight-chain and branched-chain forms, as well as combinations of these. The divalency of an alkylene, alkenylene, or alkynylene group does not include the optional substituents on the alkylene, alkenylene, or alkynylene group.
  • alkoxy represents a chemical substituent of formula –OR, where R is a C1-20 alkyl group (e.g., C1-6 or C1-10 alkyl), unless otherwise specified.
  • alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • the alkyl group can be further substituted with 1, 2, 3, 4, or more substituent groups as defined herein (e.g., hydroxy or alkoxy).
  • aryl refers to any monocyclic or fused ring bicyclic or tricyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system, e.g., phenyl, naphthyl, or phenanthrene.
  • a ring system contains 5-15 ring member atoms or 5-10 ring member atoms.
  • An aryl group may have, e.g., five to fifteen carbons (e.g., a C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C11, C5-C12, C5-C13, C5-C14, or C5-C15 aryl).
  • heteroaryl also refers to such monocyclic or fused bicyclic ring systems containing one or more, e.g., 1- 4, 1-3, 1, 2, 3, or 4, heteroatoms selected from O, S and N.
  • a heteroaryl group may have, e.g., two to fifteen carbons (e.g., a C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9.
  • the inclusion of a heteroatom permits inclusion of 5 membered rings to be considered aromatic as well as 6 membered rings.
  • heteroaryl systems include, e.g., pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl, and imidazolyl. Because tautomers are possible, a group such as phthalimido is also considered heteroaryl.
  • the aryl or heteroaryl group is a 5- or 6-membered aromatic ring system optionally containing 1-2 nitrogen atoms.
  • the aryl or heteroaryl group is an optionally substituted phenyl, pyridyl, indolyl, pyrimidyl, pyridazinyl, benzothiazolyl, benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, or imidazopyridinyl.
  • the aryl group is phenyl.
  • an aryl group may be optionally substituted with a substituent such an aryl substituent, e.g., biphenyl.
  • a substituent such an aryl substituent, e.g., biphenyl.
  • heterocyclyl represents a ring have 2 or more carbon atoms and at least one heteroatom.
  • a heterocyclyl ring may have, e.g., two to fifteen carbons ring atoms (e.g., a C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9.
  • heterocyclyl groups include both non-aromatic and aromatic rings (e.g., includes heteroaryl groups, as previously defined).
  • a heterocyclyl group is a 3- to 8-membered ring, a 3- to 6- membered ring, a 4- to 6-membered ring, most preferably a 5-membered ring or a 6-membered ring.
  • Heterocyclyls include aromatic and non-aromatic rings.
  • Exemplary 5-membered heterocyclyl groups may have zero to two double bonds, and exemplary 6-membered heterocyclyl groups may have zero to three double bonds.
  • Exemplary 5-membered groups include, for example, optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiofene, optionally substituted thiolane, optionally substituted furan, optionally substituted terahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4-oxatriazole, and optionally substituted 1,2,3,4
  • Exemplary 6-membered heterocyclyl groups include, for example, optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, and optionally substituted tetrahydropyran.
  • Exemplary 7-memebered heterocyclyl groups include, for example, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted thiepine, and optionally substituted 1,4-thiazepine.
  • cycloalkyl represents a monovalent saturated or unsaturated non- aromatic cyclic alkyl group.
  • a cycloalkyl may have, e.g., three to twenty carbons (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl).
  • Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • the cycloalkyl group can be referred to as a “cycloalkenyl” group.
  • a cycloalkenyl may have, e.g., four to twenty carbons (e.g., a C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenyl).
  • Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • the cycloalkyl group when the cycloalkyl group includes at least one carbon-carbon triple bond, the cycloalkyl group can be referred to as a “cycloalkynyl” group.
  • a cycloalkynyl may have, e.g., eight to twenty carbons (e.g., a C8-C9, C8-C10, C8-C11, C8-C12, C8-C14, C8-C16, C8-C18, or C8-C20 cycloalkynyl).
  • cycloalkyl also includes a cyclic compound having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1.]heptyl and adamantyl.
  • cycloalkyl also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spiro-cyclic compounds.
  • alkaryl refers to an aryl group that is connected to an alkylene, alkenylene, or alkynylene group.
  • an alkaryl is C6- C35 alkaryl (e.g., C6-C16, C6-C14, C6-C12, C6-C10, C6-C9, C6-C8, C7, or C6 alkaryl), in which the number of carbons indicates the total number of carbons in both the aryl portion and the alkylene, alkenylene, or alkynylene portion of the alkaryl.
  • alkaryls include, but are not limited to, (C1- C8)alkylene(C6-C12)aryl, (C2-C8)alkenylene(C6-C12)aryl, or (C2 C8)alkynylene(C6-C12)aryl.
  • an alkaryl is benzyl or phenethyl.
  • one or more heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the alkaryl group and/or may be present in the aryl portion of the alkaryl group.
  • the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkaryl group and/or may be present on the aryl portion of the alkaryl group.
  • carboxyl represents a -COOH group.
  • An optionally substituted carboxyl includes, for example, a -COOR group, wherein R is H or any substituent group described herein.
  • amine represents an -NH2 group.
  • An optionally substituted amine includes, for example, a -NHR or a -NR1R 2 group, wherein R, R1, and R 2 are each independently H or any substituent group described herein.
  • R1 and R 2 form cyclic ring (e.g., a 5- or 6- membered ring), such that –NR1R 2 is an optionally substituted heterocycle or heteroaryl.
  • the term “thioamide,” as used herein, represents a -C( S)NH2 group.
  • cyano as used herein, represents a -CN group.
  • hydroxyl as used herein, represents an -OH group.
  • optionally substituted refers to having 0, 1, or more substituents, such as 0-25, 0-20, 0-10 or 0-5 substituents.
  • Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, alkaryl, acyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkaryl, halogen, oxo, cyano, nitro, amino, alkamino, hydroxy, alkoxy, alkanoyl, carbonyl, carbamoyl, guanidinyl, ureido, amidinyl, any of the groups or moieties described above, and hetero versions of any of the groups or moieties described above.
  • Substituents include, but are not limited to, F, Cl, Br, methyl, ethyl, propyl, butyl, phenyl, benzyl, OR, NR 2 , SR, SOR, SO2R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO2NR 2 , NRSO 2 NR 2 , CN, CF 3 , OCF 3 , SiR 3 , and NO 2 , wherein each R is, independently, H, alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl, or heteroaryl, and wherein two of the optional substituents on the same or adjacent atoms can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3–8 members, or two of the optional substituents on the same
  • an optionally substituted group or moiety refers to a group or moiety (e.g., any one of the groups or moieties described above) in which one of the atoms (e.g., a hydrogen atom) is optionally replaced with another substituent.
  • an optionally substituted alkyl may be an optionally substituted methyl, in which a hydrogen atom of the methyl group is replaced by, e.g., OH.
  • a substituent on a heteroalkyl or its divalent counterpart, heteroalkylene may replace a hydrogen on a carbon or a hydrogen on a heteroatom such as N.
  • FIG.1 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met5 from the analysis of a 4 hour plasma sample following oral administration of ajulemic acid (AJA).
  • FIG.2 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met6 from the analysis of a 4 hour plasma sample following oral administration of AJA.
  • FIG.3 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met7 from the analysis of a 4 hour plasma sample following oral administration of AJA.
  • FIG.4 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met8 from the analysis of a 1 hour plasma sample following oral administration of AJA.
  • FIG.5 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met1 from the analysis of a 4 hour plasma sample following oral administration of AJA.
  • FIG.6 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met2 from the analysis of a solid phase feces sample following oral administration of AJA.
  • FIG.7 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met3 from the analysis of a solid phase feces sample following oral administration of AJA.
  • FIG.8 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met4 from the analysis of a 4 hour plasma sample following oral administration of AJA.
  • the invention relates to deuterium-enriched and/or fluorinated cannabinoid compounds, pharmaceutical compositions including one or more such cannabinoid compounds, and the use of pharmaceutical compositions including such one or more cannabinoid compounds for the treatment of a disease or condition (e.g., a fibrotic disease or an inflammatory disease) in a subject in need thereof.
  • a disease or condition e.g., a fibrotic disease or an inflammatory disease
  • the present disclosure is based, at least in part, on the identification and analysis of metabolic products of ajulemic acid.
  • the present disclosure provides deuterated and/or fluorinated analogs of ajulemic acid and structurally related cannabinoids.
  • Compounds disclosed herein are deuterated and/or fluorinated to provide advantageous properties, for example, increased metabolic stability, improved pharmacokinetic properties (e.g., increased serum half-life), and/or receptor selectivity (e.g., increased CB2 receptor selectivity), for example, as compared to ajulemic Compounds
  • deuterium-enriched and/or fluorinated compounds e.g., a cannabinoid compound described by any one of formulas (l)-(lll) and (l')-(lll'), or any one of compounds 1-530, 534- 689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, and 1434c-1484c) useful for the treatment of disease (e.g., a fibrotic disease or an inflammatory disease).
  • disease e.g., a fibrotic disease or an inflammatory disease.
  • the invention features deuterium-enriched and/or fluorinated analogs of (6aR,10aR)- 1-hydroxy-6,6-dimethyl-3-(2-methyl-2-octanyl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylic acid (ajulemic acid), and deuterium-enriched and/or fluorinated analogs of compounds structurally-related to ajulemic acid.
  • Ajulemic acid has been investigated for the treatment of inflammatory disease and fibrotic disease.
  • the structure of ajulemic acid (AJA) is:
  • a deuterium-enriched and/or fluorinated compound has an increased serum half-life (T 1/2), oral bioavailability (%F), and/or exposure as determined by maximum serum concentration (Cmax) relative to the corresponding compound that is not deuterium-enriched or fluorinated.
  • a deuterium-enriched and/or fluorinated compound may be administered at a lower dose and/or with decreased frequency relative to the parent compound, e.g., as a result of increased pharmacokinetic performance.
  • the invention features compounds which are modulators (e.g., agonists, inverse agonists, or antagonists) of the CB2 receptor.
  • the invention features compounds that have increased affinity for the CB2 receptor (e.g., increased affinity for the CB2 receptor compared to ajulemic acid), increased selectivity for the CB2 receptor (e.g., increased selectivity for the CB2 receptor over the CBi receptor compared to ajulemic acid), or both increased affinity and increased selectivity for the CB2 receptor.
  • the invention features compounds with an increased safety or efficacy profile in the treatment of a disease or condition (e.g., a fibrotic disease or an inflammatory disease), as compared to other cannabinoids, such as ajulemic acid.
  • a disease or condition e.g., a fibrotic disease or an inflammatory disease
  • administration of a compound of the invention to a subject results in a decrease in treatment-associated adverse events relative to treatment with one or more other cannabinoids (e.g., treatment with an equivalent dose and method of administration of ajulemic acid).
  • administration of a compound of the invention to a subject results in a decrease in CB1-associated adverse events relative to treatment with one or more other cannabinoids (e.g., ajulemic acid).
  • administration of a compound of the invention to a subject results in a decrease in the rate of occurrence, severity, or risk of one or more of the following adverse events: dizziness, dry mouth, disorientation, euphoria, headache, nausea, pallor, somnolence, vomiting, tremor, abnormal feeling, tachycardia, fatigue, feeling drunk, paraesthesia, muscle spasms, muscle tightness, disturbance in attention, déjà vu, altered mood, anorexia, and cardiovascular events such as orthostatic hypotension, or QTc prolongation.
  • adverse events dizziness, dry mouth, disorientation, euphoria, headache, nausea, pallor, somnolence, vomiting, tremor, abnormal feeling, tachycardia, fatigue, feeling drunk, paraesthesia, muscle spasms, muscle tightness, disturbance in attention, déjà vu, altered mood, anorexia, and cardiovascular events such as orthostatic hypotension, or QTc prolongation.
  • the reduction in adverse events may be a reduction of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more in the occurrence or severity of any one of the above-described adverse events (e.g., compared to a subject or subjects treated with an equivalent dose and method of administration of another cannabinoid, such as ajulemic acid).
  • the invention features compounds having improved pharmacokinetic properties or metabolic stability (e.g., improved pharmacokinetic properties or improved stability as compared to ajulemic acid).
  • a deuterated or fluorinated compound of the present invention has an increased serum half-life (T1/2) (e.g., increased by at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 3-fold, 4-fold, 5-fold, or 10-fold as compared to the corresponding cannabinoid compound that is not deuterated or fluorinated).
  • T1/2 serum half-life
  • a compound of the invention is described by any one of formulas (I), (IA- 1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (III′B), (IIIC), (IIID), (IIIE), (IIIF), (I′), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A), (II′A- 1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (III′), (III′A), (III′B), (III′C), (III′D), (
  • the compound of the invention is a compound of Table 1 or Table 2 (e.g., a compound selected from any one of compounds 1-530, 534-689, 1389-1433, and 1485-1490 of Table 1 and compounds 690a-1229a, 1232a-1388a, 1434a-1484a, 690b-1229b, 1233b-388b, 1434b-1484b, 690c-1229c, 1233c-1388c, and 1434c-1484c of Table 2), or Compound 1491.
  • Table 1 or Table 2 e.g., a compound selected from any one of compounds 1-530, 534-689, 1389-1433, and 1485-1490 of Table 1 and compounds 690a-1229a, 1232a-1388a, 1434a-1484a, 690b-1229b, 1233b-388b, 1434b-1484b, 690c-1229c, 1233c-1388c, and 1434c-1484c of Table 2
  • compositions Compounds of the invention (e.g., a cannabinoid compound, such as a compound described by any one of formulas (I′)-(III′) and (I′)-(III′), or any one of compounds 1-530, 534-689,1389-1433, 1485- 1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c- 1388c, 1434c-1484c, and 1491) may be formulated as a pharmaceutical composition for the treatment of disease.
  • a cannabinoid compound such as a compound described by any one of formulas (I′)-(III′) and (I′)-(III′)
  • the pharmaceutical compositions of the invention additionally include a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable excipient includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired.
  • Remington s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
  • materials which can serve as pharmaceutically acceptable excipients include, but are not limited to, sugars such as lactose, glucose, mannitol, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; natural and synthetic phospholipids, such as soybean and egg yolk phosphatides, lecithin, hydrogenated soy lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecit
  • lecithin which are preferred include those which are available under the trade name Phosal® or Phospholipon® and include Phosal 53 MCT, Phosal 50 PG, Phosal 75 SA, Phospholipon 90H, Phospholipon 90G and Phospholipon 90 NG; soy- phosphatidylcholine (SoyPC) and DSPE-PEG2000 are particularly preferred; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • buffering agents such as magnesium hydroxide and aluminum hydro
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention also include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), self- microemulsifying drug delivery systems (SMEDDS), such as d-E-tocopherol polyethylene-glycol 1000 succinate; surfactants used in pharmaceutical pharmaceutical compositions such as Tweens or other similar polymeric delivery matrices; serum proteins such as human serum albumin; buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts; or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxmethylcellulose
  • Cyclodextrins such as alpha, beta and .gamma.-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-beta cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein that can be used in the methods of the invention for preventing and/or treating fibrotic conditions.
  • unit dosage formulations are compounded for immediate release, though unit dosage formulations compounded for delayed or prolonged release of one or both agents are also disclosed.
  • Viscosity modifiers that may be used in pharmaceutical compositions of the present invention include, but are not limited to, caprylic/capric triglyceride (Migliol 810), isopropyl myristate (IPM), ethyl oleate, triethyl citrate, dimethyl phthalate, benzyl benzoate and various grades of polyethylene oxide.
  • High viscosity liquid carriers used in sustained release pharmaceutical compositions include, but are not limited to, sucrose acetate isobutyrate (SAIB) and cellulose acetate butyrate (CAB 381-20).
  • Non-limiting examples of binding agents that may be used in pharmaceutical compositions of the present invention include but are not limited to hydroxyalkyl cellulose, a hydroxyalkylalkyl cellulose, hydroxypropyl methyl cellulose, or a polyvinylpyrrolidone.
  • Non-limiting examples of osmotic agents that may be used in pharmaceutical compositions of the present invention include, but are not limited to, sorbitol, mannitol, sodium chloride, or other salts.
  • biocompatible polymers employed in the contemplated pharmaceutical compositions include but are not limited to poly(hydroxy acids), polyanhydrides, polyorthoesters, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polysiloxanes, poly(vinyl alcohols), poly (vinyl acetate), polystyrene, polyurethanes and co-polymers thereof, synthetic celluloses, polyacrylic acids, poly(butyric acid), poly(valeric acid), and poly(lactide-co-caprolactone), ethylene vinyl acetate, copolymers and blends thereof.
  • Non-limiting examples of hygroscopic polymers that may be employed in the contemplated pharmaceutical compositions include, but are not limited to, polyethylene oxide (e.g., Polyox® with MWs from 4,000,000 to 10,000,000), cellulose, hydroxymethylcellulose, hydroxyethylcellulose, crosslinked polyacrylic acids, and xanthan gum.
  • Non-limiting examples of rate-controlling polymers the may be employed in the contemplated pharmaceutical compositions include but are not limited to polymeric acrylate, methacrylate lacquer or mixtures thereof, polymeric acrylate lacquer, methacrylate lacquer, an acrylic resin including a copolymer of acrylic and methacrylic acid esters, or an ammonium methacrylate lacquer with a plasticizer.
  • compositions in any of the forms described herein, can be used for treating disease (e.g., fibrotic disease, inflammatory disease, or any other disease or condition described herein).
  • An effective amount refers to the amount of an active compound/agent that is required to confer a therapeutic effect on a treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment.
  • a pharmaceutical composition of this invention can be administered by any suitable route, e.g., parenterally, orally, nasally, rectally, topically, buccally, by ophthalmic administration, or by inhalation.
  • a sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • solutions include, but are not limited to, 1,3-butanediol, mannitol, water, Ringer’s solution, and isotonic sodium chloride solution.
  • fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides).
  • Fatty acids such as, but not limited to, oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as, but not limited to, olive oil or castor oil, or polyoxyethylated versions thereof.
  • oils such as, but not limited to, olive oil or castor oil, or polyoxyethylated versions thereof.
  • These oil solutions or suspensions also can contain a long chain alcohol diluent or dispersant such as, but not limited to, carboxymethyl cellulose, or similar dispersing agents.
  • Other commonly used surfactants such as, but not limited to, Tweens or Spans or other similar emulsifying agents or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other pharmaceutical compositions also can be used for the purpose of formulation.
  • a composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions.
  • the dosage form is an oral dosage form such as a pressed tablet, hard or soft gel capsule, enteric coated tablet, osmotic release capsule, or unique combination of excipients.
  • excipients include, but are not limited to, lactose, mannitol, and corn starch.
  • Lubricating agents such as, but not limited to, magnesium stearate, also are typically added.
  • useful diluents include, but are not limited to, lactose, mannitol, glucose, sucrose, corn starch, potato starch, or cellulose.
  • the dosage form includes a capsule wherein the capsule contains a mixture of materials to provide a desired sustained release formulation.
  • the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.
  • the pharmaceutical compositions can include a tablet coated with a semipermeable coating.
  • the tablet includes two layers, a layer containing a compound of the invention and a second layer referred to as a "push" layer.
  • the semi-permeable coating is used to allow a fluid (e.g., water) to enter the tablet and erode a layer or layers.
  • this sustained release dosage form further includes a laser hole drilled in the center of the coated tablet.
  • the compound containing layer may include a compound described herein, a disintegrant, a viscosity enhancing agent, a binding agent, and an osmotic agent.
  • the push layer includes a disintegrant, a binding agent, an osmotic agent, and a viscosity enhancing agent.
  • Non-limiting examples of materials that make up preferred semi- permeable layers include, but are not limited to cellulosic polymers such as cellulose acetate, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose diacetate, cellulose triacetate or any mixtures thereof; ethylene vinyl acetate copolymers, polyethylene, copolymers of ethylene, polyolefins including ethylene oxide copolymers (e.g., Engage® Dupont Dow Elastomers), polyamides, cellulosic materials, polyurethanes, polyether blocked amides, and copolymers (e.g., PEBAX®, cellulosic acetate butyrate and polyvinyl acetate).
  • cellulosic polymers such as cellulose acetate, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose diacetate, cellulose triacetate or any mixtures thereof
  • ethylene vinyl acetate copolymers polyethylene, cop
  • Non-limiting examples of disintegrants that may be employed in the above sustained release pharmaceutical compositions include but are not limited to croscarmellose sodium, crospovidone, sodium alginate or similar excipients.
  • the dosage form includes a tablet including a biocompatible matrix and a compound described herein.
  • the dosage form may also include a hard-shell capsule containing bio- polymer microspheres that contains the therapeutically active agent.
  • the biocompatible matrix and bio- polymer microspheres each contain pores for drug release and delivery. These pores are formed by mixing the biocompatible matrix of bio-polymer microsphere with a pore forming agent.
  • Each biocompatible matrix or bio-polymer microsphere is made up of a biocompatible polymer or mixture of biocompatible polymers.
  • the matrix and microspheres can be formed by dissolving the biocompatible polymer and active agent (compound described herein) in a solvent and adding a pore-forming agent (e.g., a volatile salt). Evaporation of the solvent and pore forming agent provides a matrix or microsphere containing the active compound.
  • the dosage form includes a tablet, wherein the tablet contains a compound of the invention and one or more polymers and wherein the tablet can be prepared by compressing the compound and one or more polymers.
  • the one or more polymers may include a hygroscopic polymer formulated with a compound of the invention. Upon exposure to moisture, the tablet dissolves and swells.
  • compositions for topical administration according to the described invention can be formulated as solutions, ointments, creams, suspensions, lotions, powders, pastes, gels, sprays, aerosols, or oils.
  • topical formulations can be in the form of patches or dressings impregnated with active ingredient(s), which can optionally include one or more excipients or diluents.
  • the topical formulations include a material that would enhance absorption or penetration of the active agent(s) through the skin or other affected areas.
  • a topical composition contains a safe and effective amount of a dermatologically acceptable excipient suitable for application to the skin.
  • a “cosmetically acceptable” or “dermatologically-acceptable” composition or component refers a composition or component that is suitable for use in contact with human skin without undue toxicity, incompatibility, instability, or allergic response.
  • the excipient enables an active agent and optional component to be delivered to the skin at an appropriate concentration(s).
  • the excipient thus can act as a diluent, dispersant, solvent, or the like to ensure that the active materials are applied to and distributed evenly over the selected target at an appropriate concentration.
  • the excipient can be solid, semi-solid, or liquid.
  • the excipient can be in the form of a lotion, a cream, or a gel, in particular one that has a sufficient thickness or yield point to prevent the active materials from sedimenting.
  • the excipient can be inert or possess dermatological benefits. It also should be physically and chemically compatible with the active components described herein, and should not unduly impair stability, efficacy, or other use benefits associated with the composition.
  • the present compositions may be formulated for sustained release (e.g., over a 6 hour period, over a 12 hour period, over a 24 hour period, or over a 48 hour period).
  • the sustained release dosage form includes a tablet or a capsule including particle cores coated with a suspension of active agent and a binding agent which is subsequently coated with a polymer.
  • the polymer may be a rate-controlling polymer.
  • the delivery rate of the rate-controlling polymer is determined by the rate at which the active agent is dissolved.
  • the composition is formulated to provide extended release.
  • the agent is formulated with an enteric coating.
  • the agent is formulated using a biphasic controlled release delivery system, thereby providing prolonged gastric residence.
  • the delivery system includes (1) an inner solid particulate phase formed of substantially uniform granules containing a pharmaceutical having a high water solubility, and one or more hydrophilic polymers, one or more hydrophobic polymers and/or one or more hydrophobic materials such as one or more waxes, fatty alcohols and/or fatty acid esters, and (2) an outer solid continuous phase in which the above granules of inner solid particulate phase are embedded and dispersed throughout, the outer solid continuous phase including one or more hydrophobic polymers, one or more hydrophobic polymers and/or one or more hydrophobic materials such as one or more waxes, fatty alcohols and/or fatty acid esters, which may be compressed into tablets or filled into capsules.
  • an inner solid particulate phase formed of substantially uniform granules containing a pharmaceutical having a high water solubility, and one or more hydrophilic polymers, one or more hydrophobic polymers and/or one or more hydrophobic materials such as one or more waxes, fatty
  • the agent is incorporated into polymeric matrices included of hydrophilic polymers that swell upon imbibition of water to a size that is large enough to promote retention of the dosage form in the stomach during the fed mode.
  • the active compound in the formulation may be formulated as a combination of fast-acting and controlled release forms.
  • the active compound is formulated with a single release property.
  • it is present in a modified release form, e.g., a controlled release form.
  • the pharmaceutical composition can be administered alone or in combination with one or more additional compounds. Treatments may be sequential, with the present compound being administered before or after the administration of other agents. Alternatively, compounds may be administered concurrently.
  • Exemplary additional agents include an analgesic agent such as an opiate, an anti- inflammatory agent, or a natural agent such as a triglyceride containing unsaturated fatty acid, or isolated pure fatty acids such as eicosapentaenoic acid (EPA), dihomogamma linolenic acid (DGLA), docosahexaenoic acid (DHA) and others.
  • analgesic agent such as an opiate
  • an anti- inflammatory agent such as a natural agent such as a triglyceride containing unsaturated fatty acid, or isolated pure fatty acids such as eicosapentaenoic acid (EPA), dihomogamma linolenic acid (DGLA), docosahexaenoic acid (DHA) and others.
  • EPA eicosapentaenoic acid
  • DGLA dihomogamma linolenic acid
  • DHA docosahexaen
  • composition including a compound of the present invention can be administered at a dose of 0.001-0.01 mg/kg, 0.01-0.5 mg/kg, 0.5-2 mg/kg, 2-5 mg/kg, 5-10 mg/kg, 10-20 mg/kg, 20-40 mg/kg, 40-60 mg/kg, 60-80 mg/kg, 80-100 mg/kg, 100-200 mg/kg or 200-500mg/kg.
  • a unit of a pharmaceutical dosage form may include, for example, 0.001-0.01 mg, 0.01-0.5 mg, 0.5-2 mg, 2-5 mg, 5- 10 mg, 10-20 mg, 20-40 mg, 40-60 mg, 60-80 mg, 80-100 mg, 100-200 mg or 200-500 mg of a compound of the invention.
  • any of the above-described compositions may be administered to a subject (e.g., a mammal, such as a human, cat, dog, horse, cow, or pig) having a disease (e.g., a fibrotic disease or an inflammatory disease) in order to treat, prevent, or ameliorate the disease.
  • a subject e.g., a mammal, such as a human, cat, dog, horse, cow, or pig
  • a disease e.g., a fibrotic disease or an inflammatory disease
  • a therapeutically effective amount of any of the compositions described herein e.g. a pharmaceutical composition comprising a compound described by any one of formulas (I′)-(III′) and (I′)- (III′), or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491) may be used to treat or prevent inflammatory disease.
  • a pharmaceutical composition comprising a compound described by any one of formulas (I′)-(III′) and (I′)- (III′), or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c,
  • Inflammatory diseases include, for example, scleroderma (e.g., systemic sclerosis, localized scleroderma, or sine scleroderma), dermatomyositis, systemic lupus erythematosus, acquired immune deficiency syndrome (AIDS), multiple sclerosis, rheumatoid arthritis, psoriasis, diabetes, cancer, asthma, atopic dermatitis, an autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, stroke, ischemia, a neurodegenerative disease, amyotrophic lateral sclerosis (ALS), chronic traumatic encephalopathy (CTE), chronic inflammatory demyelinating polyneuropathy, an autoimmune inner ear disease, uveitis, ulceris, and peritonitis.
  • scleroderma e.g., systemic sclerosis, localized scleroderma, or sine scleroderma
  • dermatomyositis
  • inflammation can be assayed by measuring the chemotaxis and activation state of inflammatory cells.
  • inflammation can be measured by examining the production of specific inflammatory mediators such as interleukins, cytokines and eicosanoids.
  • in vivo inflammation is measured by swelling and edema of a localized tissue or migration of leukocytes. Inflammation may also be measured by organ function such as in the lung or kidneys and by the production of pro-inflammatory factors. Inflammation may also be assessed by other suitable methods.
  • a cannabinoid compound a compound described by any one of formulas (I′)-(III′) and (I′)-(III′), or any one of compounds 1-530, 534- 689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491).
  • a cannabinoid compound a compound described by any one of formulas (I′)-(III′) and (I′)-(III′)
  • compounds 1-530 534- 689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491).
  • a therapeutically effective amount of any of the compositions described herein e.g. a pharmaceutical composition comprising a compound described by any one of formulas (I′)-(III′) and (I′)- (III′), or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491) may be used to treat or prevent inflammatory disease.
  • a pharmaceutical composition comprising a compound described by any one of formulas (I′)-(III′) and (I′)- (III′), or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c,
  • Fibrotic diseases include, for example, scleroderma (e.g., systemic sclerosis, localized scleroderma, or sine scleroderma), cystic fibrosis, liver cirrhosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, Dupuytren’s contracture, keloids, chronic kidney disease, chronic graft rejection, scarring, wound healing, post-operative adhesions, reactive fibrosis, polymyositis, ANCA vasculitis, Behcet's disease, anti-phospholipid syndrome, relapsing polychondritis, Familial Mediterranean Fever, giant cell arteritis, Graves ophthalmopathy, discoid lupus, pemphigus, bullous pemphigoid, hydradenitis suppuritiva, sarcoidosis, bronchiolitis obliterans, primary sclerosing cholangitis, primary
  • Non-limiting examples of fibrosis include liver fibrosis, lung fibrosis (e.g., silicosis, asbestosis, idiopathic pulmonary fibrosis), oral fibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, deltoid fibrosis, kidney fibrosis (including diabetic nephropathy), cystic fibrosis, and glomerulosclerosis.
  • Liver fibrosis for example, occurs as a part of the wound-healing response to chronic liver injury.
  • Fibrosis can occur as a complication of haemochromatosis, Wilson's disease, alcoholism, schistosomiasis, viral hepatitis, bile duct obstruction, exposure to toxins, and metabolic disorders.
  • Endomyocardial fibrosis is an idiopathic disorder that is characterized by the development of restrictive cardiomyopathy.
  • endomyocardial fibrosis the underlying process produces patchy fibrosis of the endocardial surface of the heart, leading to reduced compliance and, ultimately, restrictive physiology as the endomyocardial surface becomes more generally involved.
  • Oral submucous fibrosis is a chronic, debilitating disease of the oral cavity characterized by inflammation and progressive fibrosis of the submucosal tissues (lamina basement and deeper connective tissues).
  • the buccal mucosa is the most commonly involved site, but any part of the oral cavity can be involved, even the pharynx.
  • Retroperitoneal fibrosis is characterized by the development of extensive fibrosis throughout the retroperitoneum, typically centered over the anterior surface of the fourth and fifth lumbar vertebrae. Treatment of fibrosis may be assessed by suitable methods known to one of skill in the art including the improvement, amelioration, or slowing the progression of one or more symptoms associated with the particular fibrotic disease being treated.
  • Scleroderma Scleroderma is a disease of the connective tissue characterized by inflammation and fibrosis of the skin and internal organs. Scleroderma has a spectrum of manifestations and a variety of therapeutic implications. It includes localized scleroderma, systemic sclerosis, scleroderma-like disorders, and sine scleroderma. Systemic sclerosis can be diffuse or limited. Limited systemic sclerosis is also called CREST (calcinosis, Raynaud's esophageal dysfunction, sclerodactyly, telangiectasia).
  • Systemic sclerosis includes: scleroderma lung disease, scleroderma renal crisis, cardiac manifestations, muscular weakness including fatigue or limited CREST, gastrointestinal dysmotility and spasm, and abnormalities in the central, peripheral and autonomic nervous system.
  • the major symptoms or manifestations of scleroderma, and in particular of systemic sclerosis, are inappropriate excessive collagen synthesis and deposition, endothelial dysfunction, vasospasm, collapse and obliteration of vessels by fibrosis.
  • an important clinical parameter may be skin thickening proximal to the metacarpophalangeal joints. Raynaud's phenomenon may be a component of scleroderma.
  • Raynaud’s may be diagnosed by color changes of the skin upon cold exposure. Ischemia and skin thickening may also be symptoms of Raynaud's disease.
  • a therapeutically effective amount of any of the compositions described herein e.g. a cannabinoid compound, a compound described by any one of formulas (I′)-(III′) and (I′)-(III′), or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b- 1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491 prepared by any of the methods described herein) may be used to treat or prevent fibrosis.
  • a pharmaceutical composition comprising a compound described by formula (I), (II), or (III): , wherein R1 is H, O, OH, F, Cl, Br, NH2, or optionally substituted C 1 -C 3 alkoxy; R 2 is H, CH 3 , CH2D, CHD2, or CD3; R 3 and R4 are each independently CH 3 , CH2D, CHD2, or CD3; R5 is CH 3 or CH2OH; L1 is optionally substituted C 1 -C 20 alkylene, optionally substituted C 1 -C 20 heteroalkylene, optionally substituted C 2 -C 20 alkenylene, optionally substituted C 2 -C 20 heteroalkenylene, optionally substituted C 2 -C 20 alkynylene, optionally substituted C 2 -C 20 heteroalkynylene, optionally substituted C5- C15 arylene, optionally substituted C
  • Ra is H, optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 alkenyl, optionally substituted C 1 -C 20 alkynyl
  • each of Ra and Ra′ is independently H, optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 alkenyl, optionally substituted C 1 -C 20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C 3 -C 20 cycloalkyl, optionally substituted C1- C20 heteroalkyl, optionally substituted C 3 -C 20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or Ra and Ra′, together with the nitrogen atom to which they are attached, combine to form an optionally substituted C 3 -C 20 heterocyclyl; or
  • A is optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4-oxatriazole, or optionally substituted 1,2,3,4-thiatriazole.
  • A is 20.
  • the pharmaceutical composition of embodiment 18, wherein A is 23.
  • 24. The pharmaceutical composition of embodiment 23, wherein A is optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, or optionally substituted tetrahydropyran. 25.
  • 30. The pharmaceutical composition of embodiment 1, wherein the compound is described by , or a pharmaceutically acceptable salt thereof.
  • composition of embodiment 30 wherein the compound is described by formula (IIA): wherein Q1, Q2, and Q3 are each independently C, O, or N; and Rb and Rc are each independently H, C 1 -C 6 alkyl, or absent; and Rd is H, optionally substituted C 1 -C 6 alkyl, or absent; or a pharmaceutically acceptable salt thereof.
  • Q1, Q2, and Q3 are each independently C, O, or N; and Rb and Rc are each independently H, C 1 -C 6 alkyl, or absent; and Rd is H, optionally substituted C 1 -C 6 alkyl, or absent; or a pharmaceutically acceptable salt thereof.
  • Rd is H, optionally substituted C 1 -C 6 alkyl, or absent; or a pharmaceutically acceptable salt thereof.
  • Rc is H, C 1 -C 6 alkyl, or absent; Rd is H, optionally substituted C 1 -C 6 alkyl, or absent; or a pharmaceutically acceptable salt thereof.
  • Rc is H.
  • Rc is CH 3 . 37.
  • Rd is C 1 -C 6 alkyl substituted with ORh or NRiRj, wherein Rh is H or C 1 -C 6 alkyl, and each of Ri and Rj is independently H or alkyl, or Ri and Rj, together with the nitrogen atom to which they are attached form an optionally substituted 3- to 6- membered saturated ring.
  • Rd is , 43.
  • 44. The pharmaceutical composition of embodiment 31, wherein the compound is described by formula (IIA-3): or a pharmaceutically acceptable salt thereof. 45.
  • the pharmaceutical composition of embodiment 57 wherein the compound is described by formula (IIIB): (IIIB), or a pharmaceutically acceptable salt thereof.
  • 59. The pharmaceutical composition of embodiment 50, wherein L2 is optionally substituted C5 alkylene.
  • 60. The pharmaceutical composition of embodiment 59, wherein the compound is described by formula (IIIC): (IIIC) wherein Re, Rf, and Rg are each independently H, OH, Cl, Br, or F; or Re and Rf are joined to form an epoxy; or Rf and Rg are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.
  • 61. The pharmaceutical composition of embodiment 60, wherein Re, Rf, and Rg are each H. 62.
  • the pharmaceutical composition of any one of embodiments 1-71, wherein R 3 and R4 are each CH 3 . 73.
  • the pharmaceutical composition of embodiment 72, wherein R 2 is CH2D.
  • the pharmaceutical composition of embodiment 72, wherein R 2 is CHD2.
  • the pharmaceutical composition of embodiment 81, wherein R 3 and R4 are each CD3.
  • the pharmaceutical composition of embodiment 90, wherein R 2 and L1 form . 92.
  • composition of any one of embodiments 76-84, wherein is H and L1 is optionally substituted 5-membered heterocyclylene.
  • 100. The pharmaceutical composition of embodiment 99, wherein and L 1 form optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, optionally substituted tetrahydropyran, optionally substituted thiepine, or optionally substituted 1,4-thiazepine.
  • each of Ra and Ra′ is independently H, optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 alkenyl, optionally substituted C 1 -C 20 alkynyl, optionally substituted C 5 -C 15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C 3 -C 20 cycloalkyl, optionally substituted C1- C20 heteroalkyl, optionally substituted C 3 -C 20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or Ra and Ra′, together with the nitrogen atom to which they are attached, combine to form an optionally substituted C 3
  • A is optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4-oxatriazole, or optionally substituted 1,2,3,4-thiatriazole.
  • the compound of embodiment 131, wherein A is 133.
  • the compound of embodiment 132, wherein A is . 134.
  • the compound of embodiment 131, wherein A is . 135.
  • the compound of embodiment 108, wherein the compound is described by formula (II′): , or a pharmaceutically acceptable salt thereof. 138.
  • the compound of embodiment 137 wherein the compound is described by formula (II′A): wherein Q1, Q2, and Q3 are each independently C, O, or N; and Rb and Rc are each independently H, C 1 -C 6 alkyl, or absent; and Rd is H, optionally substituted C 1 -C 6 alkyl, or absent; or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 138 wherein the compound is described by formula (II′A-2): wherein Q2 and Q3 are each independently O or N; and Rc is H, C 1 -C 6 alkyl, or absent; Rd is H, optionally substituted C 1 -C 6 alkyl, or absent; or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 158 wherein the compound is described by formula (III′A): wherein R and Rf are each independently H OH Cl Br or F; or Re and Rf are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 159, wherein Re and Rf are joined to form an epoxy. 163.
  • the compound of embodiment 156, wherein L2 is optionally substituted C 3 -C 8 alkenylene.
  • Re, Rf, and Rg are each H.
  • R 2 is H and L1 is optionally substituted phenylene.
  • 205 The compound of embodiment 204, wherein R 2 and L1 form substituted 5-membered heterocyclylene.
  • R 2 and L1 form optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, optionally substituted tetrahydropyran, optionally substituted thiepine, or optionally substituted 1,4-thiazepine.
  • 208 The compound of embodiment 207, wherein R 2 and L1 form ,
  • a pharmaceutical composition comprising a compound of any one of embodiments 108-214 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • 216 The pharmaceutical composition of embodiment 207, wherein at least one of R 2 , R 3 , and R4 is deuterium-enriched, and the composition has an isotopic enrichment factor for deuterium of at least 5.
  • the inflammatory disease is selected from the group consisting of scleroderma, dermatomyositis, systemic lupus erythematosus, acquired immune deficiency syndrome (AIDS), multiple sclerosis, rheumatoid arthritis, psoriasis, diabetes, cancer, asthma, atopic dermatitis, an autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, stroke, ischemia, a neurodegenerative disease, amyotrophic lateral sclerosis (ALS), chronic traumatic encephalopathy (CTE), chronic inflammatory demyelinating polyneuropathy, an autoimmune inner ear disease, uveitis, ulceris, and peritonitis. 223.
  • AIDS acquired immune deficiency syndrome
  • scleroderma is systemic sclerosis, localized scleroderma, or sine scleroderma.
  • 225 A method of treating a fibrotic disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of embodiments 1-107 and 215- 220 in an amount sufficient to treat the condition. 226.
  • fibrotic disease is selected from the group consisting of scleroderma, cystic fibrosis, liver cirrhosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, Dupuytren’s contracture, keloids, chronic kidney disease, chronic graft rejection, scarring, wound healing, post-operative adhesions, reactive fibrosis, polymyositis, ANCA vasculitis, Behcet's disease, anti-phospholipid syndrome, relapsing polychondritis, Familial Mediterranean Fever, giant cell arteritis, Graves ophthalmopathy, discoid lupus, pemphigus, bullous pemphigoid, hydradenitis suppuritiva, sarcoidosis, bronchiolitis obliterans, primary sclerosing cholangitis, primary biliary cirrhosis, or organ fibrosis.
  • fibrotic disease is scleroderma. 228.
  • the method of embodiment 227 wherein the scleroderma is systemic sclerosis, localized scleroderma, or sine scleroderma. 229.
  • the method of embodiment 226, wherein the fibrotic disease is organ fibrosis.
  • the method of embodiment 229, wherein the organ fibrosis is dermal fibrosis, lung fibrosis, liver fibrosis, kidney fibrosis, or heart fibrosis. 231.
  • the method of embodiment 226, wherein the fibrotic disease is cystic fibrosis.
  • the mass spectrometer was operated with an atmospheric pressure electro-spray ionization (API-ES) source in positive ion mode.
  • the capillary voltage was set to 3000 V, the fragmentor voltage to 70 V and the quadrupole temperature was maintained at 100°C.
  • the drying gas flow and temperature values were 12.0 L/min and 350 °C, respectively. Nitrogen was used as the nebuliser gas, at a pressure of 35 psig. Data acquisition was performed with Agilent Chemstation software.
  • HPLC condition for method Tacc50-6 Analyses were carried out on a Thermo Scientific Accucore aQ C18 column (50 mm long x 4.6 mm I.D.; 2.6 ⁇ m particles) at 35 °C, with a flow rate of 3 mL/min. A gradient elution was performed from 90% (Water + 0.1% Formic acid) / 10% Acetonitrile to 5% (Water + 0.1% Formic acid) / 95% Acetonitrile in 1.50 minutes; the resulting composition was held for 0.90 min; then the final mobile phase composition; from 10% (Water + 0.1% Formic acid) / 90% Acetonitrile to 90% (Water + 0.1% Formic acid) / 10% Acetonitrile in 0.10 minutes.
  • the injection volume was 2 ⁇ L.
  • MS acquisition range and DAD detector were set to 100-1000 m/z and 200-400 nm respectively.
  • HPLC condition for method Tacc50-6_AP_AMAC Analyses were carried out on a Thermo Scientific Accucore aQ C18 column (50 mm long x 4.6 mm I.D.; 2.6 ⁇ m particle size) at 35 °C, with a flow rate of 3 mL/min.
  • a gradient elution was performed from 50% (Water + 50 mM NH4OAc)/50% Acetonitrile to 5% (Water + 50 mM NH4OAc)/95% Acetonitrile in 1.5 min; the resulting composition was held for 0.9 min; from 5% (Water + 50 mM NH4OAc)/95% Acetonitrile to 95% (Water + 50 mM NH4OAc)/5% Acetonitrile in 0.2 min. Acquisition ranges were set to 190-400 nm for the UV-PDA detector and 100-1400 m/z for the MS detector.
  • Method VILLA and Method ZVilla_amonico_21 The analyses were performed using an Agilent G1956A LC/MSD quadrupole coupled to an Agilent 1100 series liquid chromatography (LC) system consisting of a binary pump with degasser, autosampler, thermostat column compartment and diode array detector.
  • the mass spectrometer (MS) was operated with an atmospheric pressure electro-spray ionization (API-ES) source in positive ion mode.
  • API-ES atmospheric pressure electro-spray ionization
  • the capillary voltage was set to 3000 V, the fragmentor voltage to 70 V and the quadrupole temperature was maintained at 100°C.
  • the drying gas flow and temperature values were 12.0 L/min and 350 °C, respectively.
  • Nitrogen was used as the nebuliser gas, at a pressure of 35 psig.
  • Data acquisition was performed with Agilent Chemstation software.
  • HPLC condition for method VILLA It is a long routine analysis for Quality Control of final compounds. Analyses were carried out on a YMC pack ODS-AQ C18 column (50 mm long x 4.6 mm I.D..; 3 ⁇ m particle size) at 35 °C, with a flow rate of 2.6 mL/min.
  • a gradient elution was performed from 95% (Water + 0.1% Formic acid)/5% Acetonitrile to 5% (Water + 0.1% Formic acid)/95% Acetonitrile in 4.8 min; the resulting composition was held for 1.0 min; from 5% (Water + 0.1% formic acid)/95% Acetonitrile to 95% (Water + 0.1% formic acid)/5% Acetonitrile in 0.2 min. Acquisition ranges were set to 190-400 nm for the UV-PDA detector and 100-1400 m/z for the MS detector.
  • HPLC condition for method ZVilla_amonico_21 Analyses were carried out on a Phenomenex Kinetex C18 column (50 mm long x 2.1 mm; 2.6 ⁇ m particle size) at 35 °C, with a flow rate of 0.7 mL/min. A gradient elution was performed from 95% (Water, 50 mM NH4OAc)/5% Acetonitrile to 5% (Water, 50 mM NH4OAc)/95% Acetonitrile in 4.8 min; the resulting composition was held for 1.0 min and to 95% (Water, 50 mM NH4OAc)/5% Acetonitrile in 0.2 min.
  • Method VILLA_2T It is a long routine analysis for Quality Control of final compounds. Analyses were carried out on a YMC pack ODS-AQ C18 column (50 mm long x 4.6 mm I.D.; 3 ⁇ m particle size) at 35 °C, with a flow rate of 2.6 mL/min.
  • a gradient elution was performed using ISET 2V1.0 Emulated Agilent Pump G1312A V1.0 from 95% (Water + 0.1% Formic acid)/5% Acetonitrile to 5% (Water + 0.1% Formic acid)/95% Acetonitrile in 4.8 min; the resulting composition was held for 1.0 min; from 5% (Water + 0.1% formic acid)/95% Acetonitrile to 95% (Water + 0.1% formic acid)/5% Acetonitrile in 0.2 min. Acquisition ranges were set to 190-400 nm for the UV-PDA detector and 100-1000 m/z for the TOF-MS detector. Synthesis of ajulemic acid Ajulemic acid (AJA) may be synthesized as known in the art.
  • ajulemic acid is an ultrapure formulation of ajulemic acid including more than 99% ajulemic acid and less than 1% highly-active CB-1 impurities, e.g., HU-210.
  • Ajulemic acid may be synthesized as described in U.S. Patent Publication No. 2015/0141501, which is incorporated herein by reference.
  • Example 1 Metabolic study of AJA A study was conducted to determine the profile of AJA and its metabolites in plasma, urine, and feces samples obtained following oral administration of 14 C-labeled AJA to 6 healthy male subjects, and to elucidate the chemical structures of selected metabolites using high resolution LC-MS(/MS).
  • TDR total drug related * unknown peaks assigned across matrices based on peak retention time data only Xh faeces pooled over differing time-periods to generate samples with 90% of total radioactivity ms detected by LC-MS but peak below limit of quantification in radio-chromatogram NC relative exposure not calculated. Insufficient data points to calculate AUC Table 4. Structures of major metabolites of AJA
  • the mixture was acidified to pH 5 with 2 M aqueous HCl, then extracted with dichloromethane.
  • the combined organic extracts were dried over MgSO4, filtered, concentrated and passed through a silica gel plug. eluting with heptane/ethyl acetate.
  • Fractions containing the desired product were combined and repurified by prep- HPLC (Gemini C18 column, 100 x 30 mm, 5 ⁇ m, mobile phase A: 25mM aq. ammonium bicarbonate, mobile phase B: ACN, gradient: 41% B to 83% B over 30 min).
  • the product-containing fractions were lyophilized to provide the product as a white powder (42 mg, 40%).
  • 6-(3,5-Dihydroxyphenyl)-6-methylheptanoic acid Boron tribromide (3.4 mL, 35.3 mmol, 2.2 eq) was added dropwise to a solution of 6-(3,5- dimethoxyphenyl)-6-methylheptanoic acid (4.5 g, 16.0 mmol, 1 eq) in anhydrous dichloromethane (30 mL) at -78 °C. The mixture was allowed to warm to room temperature and stirred 1 hour before quenching it with ice water.
  • 6-((6aR,10aR)-9-Formyl-6,6-dimethyl-1-(pivaloyloxy)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)- 6-methylheptyl pivalate A solution of selenium dioxide (1.182 g, 10.65 mmol, 2.4 eq.) in EtOH (20 mL) and water (2 mL) was added dropwise over 30 min to a solution of 6-methyl-6-((6aR,10aR)-6,6,9-trimethyl-1-(pivaloyloxy)- 6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)heptyl pivalate (2.4 g, 4.45 mmol, 1 eq) in EtOH (20 mL) and the resulting mixture was heated to reflux for 16 hours.
  • CB1 Radioligand Binding Assay Cell membrane homogenates (5 ⁇ g protein) prepared from Chem cells expressing human recombinant CB1 receptor were incubated for 30 min at 22°C with 2 nM [ 3 H]CP 55940 (CB1/CB2 radioligand) in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 2.5 mM EDTA and 0.3% BSA.. Nonspecific binding is determined in the presence of 10 ⁇ M WIN 55212-2. Each compound was tested in 8 concentrations (1.58 – 5000 nM).
  • CB2 Radioligand Binding Assay Cell membrane homogenates (12 ⁇ g protein) prepared from CHO cells expressing human recombinant CB2 receptor were incubated for 120 min at 37°C with 0.8 nM [ 3 H]WIN 55212-2 (CB1/CB2 radioligand) in the absence or presence of the test compound in a buffer containing 50 mM Hepes/Tris (pH 7.4), 5 mM MgCl2, 2.5 mM EGTA and 0.1% BSA.
  • Nonspecific binding was determined in the presence of 5 ⁇ M WIN 55212-2. Each compound was tested in 8 concentrations (0.95 – 3000 nM). For each concentration, % Inhibition was determined as a function of radioligand specific binding to the CB2 receptor. Inhibition constant (Ki) was determined from the concentration-response curve of each tested compound. Table 5. Affinity for CB1 and CB2 Receptors as determined by a radioligand binding assay Example 5.
  • CB 1 - and CB 2 -mediated activity as determined by cyclic adenosine monophosphate (cAMP) agonist assay Compounds of the invention were assayed in the Hit Hunter® cAMP assay to determine Gi- coupled agonist activity on the CB1 and CB2 receptors, the results of which are provided in Table 6.
  • the Hit Hunter® cAMP assay monitors the activation of a GPCR via Gi and Gs secondary messenger signaling in a homogenous, non-imaging assay format using a technology developed by DiscoverX called Enzyme Fragment Complementation (EFC) with ⁇ -galactosidase ( ⁇ -Gal) as the functional reporter.
  • EFC Enzyme Fragment Complementation
  • the enzyme is split into two inactive complementary portions: EA for Enzyme Acceptor and ED for Enzyme Donor.
  • ED is fused to cAMP and in the assay competes with cAMP generated by cells for binding to a cAMP-specific antibody.
  • Active ⁇ -Gal is formed by complementation of exogenous EA to any unbound ED cAMP. Active enzymes can then convert a chemiluminescent substrate, generating an output signal detectable on a standard microplate reader.
  • cAMP Hunter cell lines were expanded from freezer stocks according to standard procedures. Cells were seeded in a total volume of 20 ⁇ L into white walled, 384-well microplates and incubated at 37°C for the appropriate time prior to testing.
  • cAMP modulation was determined using the DiscoverX Hit Hunter cAMP XS+ assay.
  • Gi agonist activity determination cells were incubated with sample in the presence of EC80 forskolin to induce response (20 ⁇ M and 25 ⁇ M in the CB1 and CB2 assays, respectively).
  • Media was aspirated from cells and replaced with 15 ⁇ L 2:1 HBSS/10 mM HEPES : cAMP XS+ Ab reagent.
  • Intermediate dilution of sample stocks was performed to generate 4X sample in assay buffer. 5 ⁇ L of 4X compound was added to cells and incubated at 37°C or room temperature for 30 or 60 minutes. Final vehicle concentration was 1%.
  • CB1- and CB2-mediated activity as determined by ⁇ -Arrestin assay Compounds of the invention were assayed in the PathHunter® ⁇ -Arrestin assay to determine agonist activity on the CB1 and CB2 receptors, the results of which are provided in Table 7.
  • the PathHunter® ⁇ -Arrestin assay monitors the activation of a GPCR in a homogenous, non-imaging assay format using a technology developed by DiscoverX called Enzyme Fragment Complementation (EFC) with ⁇ -galactosidase ( ⁇ -Gal) as the functional reporter.
  • EFC Enzyme Fragment Complementation
  • ⁇ -Gal ⁇ -galactosidase
  • EA Enzyme Acceptor
  • PK ProLink
  • PathHunter cell lines were expanded from freezer stocks according to standard procedures. Cells were seeded in a total volume of 20 ⁇ L into white walled, 384-well microplates and incubated at 37°C for the appropriate time prior to testing. For agonist activity determination, cells were incubated with sample to induce response. Intermediate dilution of sample stocks was performed to generate 5X sample in assay buffer. 5 ⁇ L of 5X sample was added to cells and incubated at 37°C or room temperature for 90 to 180 minutes. Vehicle concentration was 1%.
  • Microsomal stability study A microsomal stability study was performed in order to determine the metabolic stability of compounds described herein. Experimental Procedure 1) The following buffers were prepared as follows: Buffer A: 1.0 L of 0.1 M monobasic Potassium Phosphate buffer containing 1.0 mM EDTA; Buffer B: 1.0 L of 0.1 M Dibasic Potassium Phosphate buffer containing 1.0 mM EDTA; Buffer C: 0.1 M Potassium Phosphate buffer, 1.0 mM EDTA, pH 7.4 by titrating 700 mL of buffer B with buffer A while monitoring with the pH meter.
  • Reference compound (Ketanserin) and test compound spiking solutions were prepared as follows: 500 ⁇ M spiking solution: add 10 ⁇ L of 10 mM DMSO stock solution into 190 ⁇ L CAN; 1.5 ⁇ M spiking solution in microsomes (0.75 mg/mL): add 1.5 ⁇ L of 500 ⁇ M spiking solution and 18.75 ⁇ L of 20 mg/mL liver microsomes into 479.75 ⁇ L of Buffer C on ice. 3) NADPH stock solution (6 mM) was prepared by dissolving NADPH into Buffer C.
  • the animals were fasted overnight prior to dosing with free access to water, the food was resumed 4 hours post-dose.
  • Dosing and Sampling The IV dose was administered via tail vein injection.
  • the PO dose was administered via oral gavage.
  • the animals were restrained manually at the designated time points (Table 9). Approx.110 ⁇ L blood/time point was taken from facial vein for semi-serial bleeding or cardiac puncture for terminal bleeding into K2EDTA tubes.
  • the blood samples were centrifuged to obtain plasma samples (2000 g, 5 min at 4 o C) within 15 minutes. All samples were stored at approximately -70 o C until analysis. The backup samples were discarded after 3 weeks.
  • 18 male CD1 mice approximately 29-31 g of body weight, originally purchased from Shanghai Jihui Laboratory Animal Co.
  • the area under the curve from time 0 to last time point (AUClast), from time 0 to infinity (AUCINF), and from 0 to 24 hr (AUC0-24hr) were 2625 hr*ng/mL, 2756 hr*ng/mL and 2975 hr*ng/mL, respectively.
  • Compound 2 demonstrated increased exposure, prolonged-half-life, and increased oral bioavailability in a mouse pharmacokinetics study.

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Abstract

The invention relates to cannabinoid compounds, pharmaceutical compositions including one or more cannabinoid compounds, and the use of pharmaceutical compositions including one or more cannabinoid compounds for the treatment of a disease or condition (e.g., a fibrotic disease or an inflammatory disease) in a subject in need thereof.

Description

CANNABINOIDS AND USES THEREOF Background of the Invention Cannabinoids are a class of chemicals found in Cannabis sativa L (Cannabis) and related derivatives that have been shown to exhibit various pharmacologic activities. Tetrahydrocannabinol (THC) is the major psychoactive cannabinoid of cannabis. In addition to mood-altering effects, THC has been reported to exhibit other activities, some of which may have therapeutic value. The potential therapeutic value of THC has led to a search for related compounds which minimize the psychoactive effects, while retaining the activities of potential medicinal value. Cannabinoids in current therapeutic use, such as nabilone, activate both the cannabinoid type 1 receptor (CB1) and the cannabinoid type 2 receptor (CB2). Selective CB2 modulation or peripherally restricted CB2 modulation may provide some of the therapeutic effects of cannabinoids, such as their immuno-modulatory properties, without the psychoactive effects of CB1 activation associated with central neuron system. Therefore, cannabinoid CB2 receptors represent an attractive target for drug development. (6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyl-2-octanyl)-6a,7,10,10a-tetrahydro-6H- benzo[c]chromene-9-carboxylic acid (also known as ajulemic acid, AJA, JBT-101, resunab, anabasum, or lenabasum) has been investigated for its potential therapeutic benefits in a number of diseases, including fibrotic diseases and inflammatory diseases, for which there is a need for new therapies with improved safety and efficacy profiles. Ajulemic acid has been shown to exhibit receptor selectivity for CB2 over CB1 as well as preferential peripheral distribution. There is a continued need for the development of cannabinoids with improved safety and efficacy profiles, including improved pharmacokinetic performance, potency, peripheral distribution, and CB2 selectivity. Summary of the Invention The invention relates to cannabinoid compounds, pharmaceutical compositions including one or more cannabinoid compounds, and the use of pharmaceutical compositions including one or more cannabinoid compounds for the treatment of a disease or condition (e.g., a fibrotic disease or an inflammatory disease) in a subject in need thereof. In particular, the invention features compounds sharing structural features with (6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyl-2-octanyl)-6a,7,10,10a- tetrahydro-6H-benzo[c]chromene-9-carboxylic acid (ajulemic acid). Without wishing to be bound by theory, the present disclosure is based, at least in part, on the identification and analysis of metabolic products of ajulemic acid. The present disclosure provides deuterated and/or fluorinated analogs of ajulemic acid and structurally related cannabinoids. Compounds disclosed herein are deuterated and/or fluorinated to provide advantageous properties (e.g., as compared to other cannabinoids such as ajulemic acid), for example, increased metabolic stability, improved pharmacokinetic properties (e.g., increased serum half-life), and/or increased receptor selectivity (e.g., increased CB2 receptor selectivity). In some embodiments, the invention features compounds with an increased safety or efficacy profile in the treatment of a disease or condition (e.g., a fibrotic disease or an inflammatory disease), as compared to other cannabinoids, such as ajulemic acid. In a first aspect, the invention features a composition including a compound described by formula (I), (II), or (III):
Figure imgf000004_0001
, wherein R1 is H, O, OH, F, Cl, Br, NH2, or optionally substituted C1-C3 alkoxy; R2 is H, CH3, CH2D, CHD2, or CD3; R3 and R4 are each independently CH3, CH2D, CHD2, or CD3; R5 is CH3 or CH2OH; L1 is optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C5-C15 arylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C2-C15 heterocyclylene, or optionally substituted amido; each dashed line is optionally a double bond; A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, optionally substituted 3-to-8 membered heterocyclyl, or cyano; X1 and X2 are each independently H, O, Cl, or F; X3 and X4 are each independently H or absent; Q is an optionally substituted 5-to-8 membered heterocyclyl fused ring; L2 is optionally substituted C3-C8 alkylene, optionally substituted C3-C8 heteroalkylene, optionally substituted C3-C8 alkenylene, optionally substituted C3-C8 heteroalkenylene, optionally substituted C3-C8 alkynylene, or optionally substituted C3-C8 heteroalkynylene; and X5 is O or NH, wherein at least one of R2, R3, and R4 is CH2D, CHD2, or CD3, and the composition has an isotopic enrichment factor for deuterium of at least 5; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. In some embodiments, the compound is not
Figure imgf000004_0002
. In some embodiments, the compound is described by formula (I):
Figure imgf000004_0003
, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by any one of formulas (1A-1), (1A-2), (1A-3), and (1A-4):
Figure imgf000005_0001
(IA-4), or a pharmaceutically acceptable salt thereof. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), and (IA-4)), A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, or cyano. In some embodiments, the compound is described by formula (IA-2A):
Figure imgf000005_0002
(IA-2A), wherein Ra is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C3-C20 cycloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C3-C20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or a pharmaceutically acceptable salt thereof. In preferred embodiments, Ra is H. In some embodiments, the compound is described by formula (IA-2B):
Figure imgf000006_0001
(IA-2B), wherein each of Ra and Ra′ is independently H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C3-C20 cycloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C3-C20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or Ra and Ra′, together with the nitrogen atom to which they are attached, combine to form an optionally substituted C3-C20 heterocyclyl; or a pharmaceutically acceptable salt thereof. In some embodiments, Ra is optionally substituted C1-C20 alkyl. In some embodiments, Ra is optionally substituted C3-C20 cycloalkyl. In some embodiments, Ra′ is H. In some embodiments, Ra and R a′, together with the nitrogen atom to which they are attached, combine to form an optionally substituted C3-C20 heterocyclyl. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), and (IA-4)), A is optionally substituted 3-to-8 membered heterocyclyl. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), and (IA-4)), A is optionally substituted 5-membered heterocyclyl. For example, A is optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4-oxatriazole, or optionally substituted 1,2,3,4-thiatriazole. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA),
Figure imgf000007_0001
In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA),
Figure imgf000007_0002
In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), and (IA-4)), A is optionally substituted 6-membered heterocyclyl. For example, A is optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, or optionally substituted tetrahydropyran. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), and (IA-4)), A is
Figure imgf000007_0003
In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), ), and (IA-4)), A is
Figure imgf000007_0004
some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), and (IA-4)), A is optionally substituted 7-membered heterocyclyl. For example, A is optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted thiepine, or optionally substituted 1,4-thiazepine. In some embodiments, the compound is described by formula (II):
Figure imgf000008_0001
, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (IIA):
Figure imgf000008_0002
(IIA), wherein Q1, Q2, and Q3 are each independently C, O, or N; Rb H,
Figure imgf000008_0003
alkyl, or absent; and Rc, and Rd are each independently H, optionally substituted C
Figure imgf000008_0004
1-C6 alkyl, or absent; or a pharmaceutically acceptable salt thereof. In some embodiments, Rb, Rc, and Rd are each independently H,
Figure imgf000008_0005
alkyl, or absent. In some embodiments, the compound is described by formula (IIA-1):
Figure imgf000008_0006
(IIA-1), wherein Q1 and Q2 are each independently O or N; and Rb and Rc are each independently H, C1-C6 alkyl, or absent; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (IIA-2):
Figure imgf000008_0007
(IIA-2), wherein Q2 and Q3 are each independently O or N; and Rc and Rd are each independently H, optionally substituted C1-C6 alkyl, or absent; or a pharmaceutically acceptable salt thereof. In some embodiments, Rc is H, C1-C6 alkyl, or absent; and Rd is H, optionally substituted C1-C6 alkyl, or absent. In some embodiments, Rc and Rd are each independently H, C1-C6 alkyl, or absent. In some embodiments, the compound is described by formula (IIA-2A):
Figure imgf000009_0001
wherein Rc is H or optionally substituted C1-C6 alkyl; or a pharmaceutically acceptable salt thereof. In some embodiments, Rc is H or C1-C6 alkyl. In some embodiments, Rc is C1-C6 alkyl substituted with ORh or NRiRj, wherein Rh is H or C1-C6 alkyl, and each of Ri and Rj is independently H or alkyl, or Ri and Rj, together with the nitrogen atom to which they are attached form an optionally substituted 3- to 6- membered saturated ring. In some embodiments, Rc is
Figure imgf000009_0002
, ,
Figure imgf000009_0003
In preferred embodiments, Rc is H. In other preferred embodiments, Rc is CH3. In some embodiments, the compound is described by formula (IIA-2B):
Figure imgf000009_0004
wherein Rd is H or optionally substituted C1-C6 alkyl; or a pharmaceutically acceptable salt thereof. In some embodiments, Rd is H or C1-C6 alkyl. In some embodiments, Rd is C1-C6 alkyl substituted with ORh or NRiRj, wherein Rh is H or C1-C6 alkyl, and each of Ri and Rj is independently H or alkyl, or Ri and Rj, together with the nitrogen atom to which they are attached form an optionally substituted 3- to 6- membered saturated ring. In some embodiments, Rd is
Figure imgf000009_0005
, ,
Figure imgf000009_0006
In preferred embodiments, Rd is H. In other preferred embodiments, Rd is CH3. In some embodiments, the compound is described by formula (IIA-2C):
Figure imgf000010_0001
(IIA-2C), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (IIA-3):
Figure imgf000010_0002
(IIA-3), wherein Rd is H or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof. In preferred embodiments, Rd is H. In other preferred embodiments, Rd is CH3. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), and (IIA- 3)), R1 is OH. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), and (IIA- 3)), R1 is OCH3. In some embodiments, the compound is described by formula (III):
Figure imgf000010_0003
, or a pharmaceutically acceptable salt thereof. In some embodiments, L2 is optionally substituted C3-C8 alkylene, preferably optionally substituted C4 alkylene. In some embodiments, the compound is described by formula (IIIA):
Figure imgf000011_0001
(IIIA), wherein Re and Rf are each independently H, OH, Cl, Br, or F; or Re and Rf are joined to form an epoxy; or a pharmaceutically acceptable salt thereof. In preferred embodiments, Re and Rf are each H. In other preferred embodiments, Re and Rf and each OH. In further preferred embodiments, Re and Rf are joined to form an epoxy. In some embodiments, L2 is optionally substituted C3-C8 alkenylene, preferably optionally substituted C4 alkenylene. In some embodiments the compound is described by formula (IIIB):
Figure imgf000011_0002
(IIIB), or a pharmaceutically acceptable salt thereof. In some embodiments, L2 is optionally substituted C5 alkylene. In some embodiments, the compound is described by formula (IIIC):
Figure imgf000011_0003
(IIIC), wherein Re, Rf, and Rg are each independently H, OH, Cl, Br, or F; or Re and Rf are joined to form an epoxy; or Rf and Rg are joined to form an epoxy; or a pharmaceutically acceptable salt thereof. In preferred embodiments, Re, Rf, and Rg are each H. In other preferred embodiments, Rg is H and Re and Rf are joined to form an epoxy. In further preferred embodiments, Re is H and Rf and Rg are joined to form an epoxy. In some embodiments, L2 is optionally substituted C5 alkenylene. In some embodiments, the compound is described by formula (IIID):
Figure imgf000012_0001
(IIID), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (IIIE):
Figure imgf000012_0002
(IIIE), or a pharmaceutically acceptable salt thereof. In some embodiments, L2 is optionally substituted C3-C8 heteroalkylene, preferably optionally substituted C4 heteroalkylene. In some embodiments, the compound is described by formula (IIIF):
Figure imgf000012_0003
(IIIF), or a pharmaceutically acceptable salt thereof. In some embodiments of any of the aspects described herein (e.g., any one of formulas (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), X5 is O. In some embodiments of any of the aspects described herein (e.g., any one of formulas (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), X5 is NH. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), R3 and R4 are each CH3. In preferred embodiments, R2 is CH2D. In other preferred embodiments, R2 is CHD2. In further preferred embodiments, R2 is CD3. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), R2 is H or CH3. In preferred embodiments, R3 is CH3 and R4 is CH2D, CHD2, or CD3. In other preferred embodiments, R3 and R4 are each CH2D, CHD2, or CD3. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), L1 is optionally substituted C2-C6 alkylene. For example, L1 is
Figure imgf000013_0001
preferably . In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), L1 is optionally substituted C2-C6 alkenylene. For example, L1 is
Figure imgf000014_0001
. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), R2 is H and L1 is optionally substituted C2-C6 alkylene. For example, R2 and L1 form
Figure imgf000014_0002
In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), R2 is H and L1 is optionally substituted 5-membered heterocyclylene. For example, R2 and L1 form optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, optionally substituted tetrahydropyran, optionally substituted thiepine, or optionally substituted 1,4- thiazepine. In preferred embodiments, R2 and L1 form
Figure imgf000014_0003
Figure imgf000015_0001
In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), R2 is H and L1 is optionally substituted amido of formula - C(O)NHL3-, wherein L3 is optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C1-C20 alkenylene, optionally substituted C1-C20 heteroalkenylene, optionally substituted C1-C20 alkynylene, optionally substituted C1-C20 heteroalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heterocyclylene, or optionally substituted C3-C20 cycloalkylene. For example, R2 and L1 form
Figure imgf000015_0002
In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), R5 is CH3. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), and (IIIF)), R5 is CH2OH. In some embodiments, the compound is a compound of Table 1 (e.g., any one of compounds 1- 530, 534-689, 1389-1433, and 1485-1490): Table 1. Deuterium-enriched ajulemic acid and analogs thereof
Figure imgf000015_0003
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0003
In another aspect, the invention relates to a compound described by formula (I′), (II′), or (III′):
Figure imgf000033_0001
, wherein R1 is H, O, OH, F, Cl, Br, NH2, or optionally substituted C1-C3 alkoxy; R2 is H, CH3, CH2F, CHF2, or CF3; R3 and R4 are each independently CH3, CH2F, CHF2, or CF3; R5 is CH3 or CH2OH; L1 is optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C5-C15 arylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C2-C15 heterocyclylene, or optionally substituted amido; each dashed line is optionally a double bond; A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, optionally substituted 3-to-8 membered heterocyclyl, or cyano; X1 and X2 are each independently H, O, Cl, or F; X3 and X4 are each independently H or absent; Q is an optionally substituted 5-to-8 membered heterocyclyl fused ring; L2 is optionally substituted C3-C8 alkylene, optionally substituted C3-C8 heteroalkylene, optionally substituted C3-C8 alkenylene, optionally substituted C3-C8 heteroalkenylene, optionally substituted C3-C8 alkynylene, or optionally substituted C3-C8 heteroalkynylene; and X5 is O or NH, wherein at least one of R2, R3, and R4 is CH2F, CHF2, or CF3; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is not
Figure imgf000033_0002
In some embodiments, the compound is described by formula (I′):
Figure imgf000034_0001
, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by any one of formulas (1′A-1), (1′A-2), (1′A- 3), and (1′A-4):
Figure imgf000034_0002
(I′A-4), or a pharmaceutically acceptable salt thereof. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′ A), (I′A-1), (I′A-2), (I′A-3), and (I′A-4)), A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, or cyano. In some embodiments, the compound is described by formula (I′A-2A):
Figure imgf000035_0001
(GA-2A), wherein Ra is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C3-C20 cycloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C3-C20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or a pharmaceutically acceptable salt thereof. In preferred embodiments, Ra is H.
In some embodiments, the compound is described by formula (GA-2B):
Figure imgf000035_0002
(GA-2B), wherein each of Ra and Ra' is independently H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C3-C20 cycloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C3-C20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or Ra and Ra', together with the nitrogen atom to which they are attached, combine to form an optionally substituted C3-C20 heterocyclyl; or a pharmaceutically acceptable salt thereof. In some embodiments, Ra is optionally substituted C1-C20 alkyl. In some embodiments, Ra is optionally substituted C3-C20 cycloalkyl. In some embodiments, Ra' is H. In some embodiments, Ra and Ra', together with the nitrogen atom to which they are attached, combine to form an optionally substituted C3-C20 heterocyclyl.
In some embodiments of any of the aspects described herein (e.g., any one of formulas (G), (G A), (GA-1), (GA-2), (GA-3), and (GA-4)), A is optionally substituted 3-to-8 membered heterocyclyl.
In some embodiments of any of the aspects described herein (e.g., any one of formulas (G), (G A), (GA-1), (GA-2), (GA-3), and (GA-4)), A is optionally substituted 5-membered heterocyclyl. For example, A is optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1 ,3,4-oxadiazole, optionally substituted 1 ,3,4-thiadiazole, optionally substituted 1 ,2,3,4-oxatriazole, or optionally substituted 1 ,2,3,4-thiatriazole. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A),
Figure imgf000036_0004
In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A),
Figure imgf000036_0001
In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), and (I′A-4)), A is optionally substituted 6-membered heterocyclyl. For example, A is optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, or optionally substituted tetrahydropyran. In some embodiments of any of the aspects described herein (e.g., any one of (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), and (I′A-4)), A is
Figure imgf000036_0002
. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A),
Figure imgf000036_0003
In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′ A), (I′A-1), (I′A-2), (I′A-3), and (I′A-4))), A is optionally substituted 7-membered heterocyclyl. For example, A is optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted thiepine, or optionally substituted 1,4-thiazepine. In some embodiments, the compound is described by formula (II′):
Figure imgf000037_0001
, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (II′A):
Figure imgf000037_0002
(II′A), wherein Q1, Q2, and Q3 are each independently C, O, or N; and Rb is H, C1-C6 alkyl, or absent; and Rc, and Rd are each independently H, optionally substituted C1-C6 alkyl, or absent; or a pharmaceutically acceptable salt thereof. In some embodiments, Rb, Rc, and Rd are each independently H, C1-C6 alkyl, or absent. In some embodiments, the compound is described by formula (II′A-1):
Figure imgf000037_0003
(II′A-1), wherein Q1 and Q2 are each independently O or N; and Rb and Rc are each independently H, C1-C6 alkyl, or absent; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (II′A-2):
Figure imgf000037_0004
(II′A-2), wherein Q2 and Q3 are each independently O or N; and Rc and Rd are each independently H, optionally substituted C1-C6 alkyl, or absent; or a pharmaceutically acceptable salt thereof. In some embodiments, Rc is H, C1-C6 alkyl, or absent; and Rd is H, optionally substituted C1-C6 alkyl, or absent. In some embodiments R and Rd are each independently H C1 C6 alkyl or absent In some embodiments, the compound is described by formula (II′A-2A):
Figure imgf000038_0001
(II′A-2A), wherein Rc is H or optionally substituted C1-C6 alkyl; or a pharmaceutically acceptable salt thereof. In preferred embodiments, Rc is H. In some embodiments, Rc is H or C1-C6 alkyl. In some embodiments, Rc is C1-C6 alkyl substituted with ORh or NRiRj, wherein Rh is H or C1-C6 alkyl, and each of Ri and Rj is independently H or alkyl, or Ri and Rj, together with the nitrogen atom to which they are attached form an optionally substituted 3- to 6-membered saturated ring. In some embodiments, Rc is ,
Figure imgf000038_0002
, , . In other preferred embodiments, Rc is CH3. In some embodiments, the compound is described by formula (II′A-2B):
Figure imgf000038_0003
(II′A-2B), wherein Rd is H or optionally substituted C1-C6 alkyl; or a pharmaceutically acceptable salt thereof. In some embodiments, Rd is H or C1-C6 alkyl. In some embodiments, Rd is C1-C6 alkyl substituted with ORh or NRiRj, wherein Rh is H or C1-C6 alkyl, and each of Ri and Rj is independently H or alkyl, or Ri and Rj, together with the nitrogen atom to which they are attached form an optionally substituted 3- to 6- membered saturated ring. In some embodiments, Rd is
Figure imgf000038_0004
, ,
Figure imgf000038_0005
. In preferred embodiments, Rd is H. In other preferred embodiments, Rd is CH3. In some embodiments, the compound is described by formula (II′A-2C):
Figure imgf000039_0001
(II′A-2C), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (II′A-3):
Figure imgf000039_0002
(II′A-3), wherein Rd is H or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof. In preferred embodiments, Rd is H. In other preferred embodiments, Rd is CH3. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), and (II′A-3)), R1 is OH. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), and (II′A-3)), R1 is OCH3. In some embodiments, the compound is described by formula (III′):
Figure imgf000039_0003
, or a pharmaceutically acceptable salt thereof. In some embodiments, L2 is optionally substituted C3-C8 alkylene, preferably optionally substituted C4 alkylene. In some embodiments, the compound is described by formula (III′A):
Figure imgf000040_0001
wherein Re and Rf are each independently H, OH, Cl, Br, or F; or Re and Rf are joined to form an epoxy; or a pharmaceutically acceptable salt thereof. In preferred embodiments, Re and Rf are each H. In other preferred embodiments, Re and Rf and each OH. In further preferred embodiments, Re and Rf are joined to form an epoxy. In some embodiments, L2 is optionally substituted C3-C8 alkenylene, preferably optionally substituted C4 alkenylene. In some embodiments the compound is described by formula (III′B):
Figure imgf000040_0002
or a pharmaceutically acceptable salt thereof. In some embodiments, L2 is optionally substituted C5 alkylene. In some embodiments, the compound is described by formula (III′C):
Figure imgf000040_0003
wherein Re, Rf, and Rg are each independently H, OH, Cl, Br, or F; or Re and Rf are joined to form an epoxy; or Rf and Rg are joined to form an epoxy; or a pharmaceutically acceptable salt thereof. In preferred embodiments, Re, Rf, and Rg are each H. In other preferred embodiments, Rg is H and Re and Rf are joined to form an epoxy. In further preferred embodiments, Re is H and Rf and Rg are joined to form an epoxy. In some embodiments, L2 is optionally substituted C5 alkenylene. In some embodiments, the compound is described by formula (III′D):
Figure imgf000041_0001
In some embodiments, the compound is described by formula (III′E):
Figure imgf000041_0002
In some embodiments, L2 is optionally substituted C3-C8 heteroalkylene, preferably optionally substituted C4 heteroalkylene. In some embodiments, the compound is described by formula (III′F):
Figure imgf000041_0003
In some embodiments of any of the aspects described herein (e.g., any one of formulas (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), X5 is O. In some embodiments of any of the aspects described herein (e.g., any one of formulas (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), X5 is NH. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (II′A-3), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), R3 and R4 are each CH3. In preferred embodiments, R2 is CH2D. In other preferred embodiments, R2 is CHD2. In further preferred embodiments, R2 is CD3. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (II′A-3), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), R2 is H or CH3. In preferred embodiments, R3 is CH3 and R4 is CH2D, CHD2, or CD3. In other preferred embodiments, R3 and R4 are each CH2D, CHD2, or CD3. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (II′A-3), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), L1 is optionally substituted C2-C6 alkylene. For example, L1 is
Figure imgf000042_0001
In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (II′A-3), (II′A-2C), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), L1 is optionally substituted C2-C6 alkenylene. For example, L1 is
Figure imgf000043_0001
. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (II′A-3), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), R2 is H and L1 is optionally substituted C2-C6 alkylene. For example, R2 and L1 form
Figure imgf000043_0002
In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (II′A-3), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), R2 is H and L1 is optionally substituted 5- membered heterocyclylene. For example, R2 and L1 form optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, optionally substituted tetrahydropyran, optionally substituted thiepine, or optionally substituted 1,4-thiazepine. In preferred embodiments, R2 and L1 form
Figure imgf000043_0003
Figure imgf000044_0001
In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (II′A-3), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), R2 is H and L1 is optionally substituted amido of formula -C(O)NHL3-, wherein L3 is optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C1-C20 alkenylene, optionally substituted C1-C20 heteroalkenylene, optionally substituted C1-C20 alkynylene, optionally substituted C1-C20 heteroalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heterocyclylene, or optionally substituted C3-C20 cycloalkylene. For example, R2 and L1 form
Figure imgf000044_0002
In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (II′A-3), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), R5 is CH3. In some embodiments of any of the aspects described herein (e.g., any one of formulas (I′), (I′A), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A-1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (II′A-3), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), and (III′F)), R5 is CH2OH. In some embodiments, the compound is a compound of Table 2 (e.g., any one of compounds 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b, 1233b-1388b, 1434b-1484b, 690c-1229c, 1233c- 1388c, and 1434c-1484c):
Table 2. Fluorinated ajulemic acid and analogs thereof (Compound a: X = CH2F; Compound b: X = CHF2; Compound c:X = CF3)
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Structure # R2 R3 R4 Structure # R2 R3 R4 865 868 CH3 X CH3 CH3 X CH3 a-c a-c 866 869 CH3 X X CH3 X X a-c a-c 867 870 X CH3 CH3 X CH3 CH3 a-c a-c 871 874 CH3 X CH3 CH3 X CH3 a-c a-c 872 875 CH3 X X CH3 X X a-c a-c 873 876 X CH3 CH3 X CH3 CH3 a-c a-c 877 880 CH3 X CH3 CH3 X CH3 a-c a-c 878 881 CH3 X X CH3 X X a-c a-c 879 882 X CH3 CH3 X CH3 CH3 a-c a-c 883 886 CH3 X CH3 CH3 X CH3 a-c a-c 884 887 CH3 X X CH3 X X a-c a-c 885 888 X CH3 CH3 X CH3 CH3 a-c a-c 889 892 CH3 X CH3 CH3 X CH3 a-c a-c 890 893 CH3 X X CH3 X X a-c a-c 891 894 X CH3 CH3 X CH3 CH3 a-c a-c 895 898 CH3 X CH3 CH3 X CH3 a-c a-c 896 899 CH3 X X CH3 X X a-c a-c 897 900 X CH3 CH3 X CH3 CH3 a-c a-c 901 904 CH3 X CH3 CH3 X CH3 a-c a-c 902 905 CH3 X X CH3 X X a-c a-c 903 906 X CH3 CH3 X CH3 CH3 a-c a-c 907 910 CH3 X CH3 CH3 X CH3 a-c a-c 908 911 CH3 X X CH3 X X a-c a-c 909 912 X CH3 CH3 X CH3 CH3 a-c a-c 913 916 CH3 X CH3 CH3 X CH3 a-c a-c 914 917 CH3 X X CH3 X X a-c a-c 915 918 X CH3 CH3 X CH3 CH3 a-c a-c
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Structure # R2 R3 R4 Structure # R2 R3 R4 1219 1221 CH3 X CH3 CH3 X CH3 a-c a-c 1220 1222 CH3 X X CH3 X X a-c a-c 1221 1223 X CH3 CH3 X CH3 CH3 a-c a-c 1224 1227 CH3 X CH3 CH3 X CH3 a-c a-c 1225 1228 CH3 X X CH3 X X a-c a-c 1226 1229 X CH3 CH3 X CH3 CH3 a-c a-c 1233 CH3 X CH3 a-c 1234 CH3 X X a-c 1235 X CH3 CH3 a-c 1236 1239 CH3 X CH3 CH3 X CH3 a-c a-c 1237 1240 CH3 X X CH3 X X a-c a-c 1238 1241 X CH3 CH3 X CH3 CH3 a-c a-c 1242 1245 CH3 X CH3 CH3 X CH3 a-c a-c 1243 1246 CH3 X X CH3 X X a-c a-c 1244 1247 X CH3 CH3 X CH3 CH3 a-c a-c 1248 1251 CH3 X CH3 CH3 X CH3 a-c a-c 1249 1252 CH3 X X CH3 X X a-c a-c 1250 1253 X CH3 CH3 X CH3 CH3 a-c a-c 1254 1257 CH3 X CH3 CH3 X CH3 a-c a-c 1255 1258 CH3 X X CH3 X X a-c a-c 1256 1259 X CH3 CH3 X CH3 CH3 a-c a-c 1260 1263 CH3 X CH3 CH3 X CH3 a-c a-c 1261 1264 CH3 X X CH3 X X a-c a-c 1262 1265 X CH3 CH3 X CH3 CH3 a-c a-c 1266 1269 CH3 X CH3 CH3 X CH3 a-c a-c 1267 1270 CH3 X X CH3 X X a-c a-c 1268 1271 X CH3 CH3 X CH3 CH3 a-c a-c
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0002
Figure imgf000061_0001
or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides a pharmaceutical composition including a compound of the invention (e.g., a compound of any one of formulas (I′)-(III′) or any one of compounds 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b, 1233b-1388b, 1434b-1484b, 690c-1229c-1388c, and 1434c- 1484c), or a salt thereof, and a pharmaceutically acceptable excipient. In another aspect, the invention provides a pharmaceutical composition including Compound 1491, or a salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, at least one of R2, R3, and R4 is deuterium-enriched, and the composition has an isotopic enrichment factor for deuterium of at least 5. In some embodiments of any of the aspects described herein (e.g., a composition containing a compound of any one of formulas (I)-(III) and (I′)-(III′) or any one of compounds 1-530, 534-689,1389- 1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491) or a salt thereof, the composition has an isotopic enrichment factor for deuterium of at least about 500 (e.g., at least about 1000, at least about 3000, and at least about 4000, 5000, or 6000). In another aspect, the invention provides a method of treating an inflammatory disease in a subject in need thereof. The method includes administering to the subject a pharmaceutical composition including a compound of the invention (e.g., a compound of any one of formulas (I)-(III) and (I′)-(III′) or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491), or a salt thereof, and a pharmaceutically acceptable excipient, in an amount sufficient to treat the condition. In some embodiments, the inflammatory disease is selected from the group consisting of scleroderma, dermatomyositis, systemic lupus erythematosus, acquired immune deficiency syndrome (AIDS), multiple sclerosis, rheumatoid arthritis, psoriasis, diabetes, cancer, asthma, atopic dermatitis, an autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, stroke, ischemia, a neurodegenerative disease, amyotrophic lateral sclerosis (ALS), chronic traumatic encephalopathy (CTE), chronic inflammatory demyelinating polyneuropathy, an autoimmune inner ear disease, uveitis, iritis, and peritonitis. In some embodiments, the inflammatory disease is scleroderma (e.g., systemic sclerosis, localized scleroderma, or sine scleroderma). In some embodiments, the inflammatory disease is cancer. In another aspect, the invention provides a method of treating a fibrotic disease in a subject in need thereof. The method includes administering to the subject the pharmaceutical composition including a compound of the invention (e.g., a compound of any one of formulas (I)-(III) and (I′)-(III′) or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491), or a salt thereof, and a pharmaceutically acceptable excipient, in an amount sufficient to treat the condition. In some embodiments, the fibrotic disease is selected from the group consisting of scleroderma, cystic fibrosis, liver cirrhosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, Dupuytren’s contracture, keloids, chronic kidney disease, chronic graft rejection, scarring, wound healing, post- operative adhesions, reactive fibrosis, polymyositis, ANCA vasculitis, Behcet's disease, anti-phospholipid syndrome, relapsing polychondritis, Familial Mediterranean Fever, giant cell arteritis, Graves ophthalmopathy, discoid lupus, pemphigus, bullous pemphigoid, hydradenitis suppuritiva, sarcoidosis, bronchiolitis obliterans, primary sclerosing cholangitis, primary biliary cirrhosis, and organ fibrosis (e.g., dermal fibrosis, lung fibrosis, liver fibrosis, kidney fibrosis, or heart fibrosis). In some embodiments, the fibrotic disease is scleroderma (e.g., systemic sclerosis, localized scleroderma, or sine scleroderma). In some embodiments, the fibrotic disease is organ fibrosis (e.g., dermal fibrosis, lung fibrosis, liver fibrosis, kidney fibrosis, or heart fibrosis). In some embodiments, the fibrotic disease is cystic fibrosis. In some embodiments, the compound has increased affinity for the CB2 receptor compared to affinity for the CB1 receptor. In some embodiments, the compound has 10%, 20%, 30% 40%, 50%, 60% 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% or more greater affinity for the CB2 receptor compared to the CB1 receptor. In some embodiments, the compound has 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15- fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 25-fold, 30-fold, 40-fold, or 50-fold or more greater affinity for the CB2 receptor compared to the CB1 receptor. Receptor selectivity may be determined by receptor binding or by functional assay (e.g., cAMP or β-arrestin), as described here, for example in Examples 5-8. In some embodiments, the compound has greater CB2 receptor selectivity compared to the CB2 receptor selectivity of ajulemic acid. Definitions To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the invention. Terms such as "a", "an," and "the" are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not limit the invention, except as outlined in the claims. As used herein, the term “about” refers to a value that is within 10% above or below the value being described. As used herein, any values provided in a range of values include both the upper and lower bounds, and any values contained within the upper and lower bounds. As used interchangeably herein, the term “deuterium-enriched” or “deuterated,“ refers to a compound of the inventions (e.g., ajulemic acid or an analog thereof) with a level of deuterium (D or 2H) that has been enriched to be greater than 0.015%, the natural abundance of deuterium. In certain embodiments, a composition of the invention has a minimum isotopic enrichment factor of at least 5 (0.075% deuterium incorporation), e.g., at least 10 (0.15% deuterium incorporation). In other embodiments, a composition has an isotopic enrichment factor of at least 50 (0.75% deuterium incorporation), at least 500 (7.5% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), or at least 6600 (99% deuterium incorporation). As used herein, the term "treat" or "treatment" includes administration of a compound to a subject, e.g., by any route, e.g., orally, topically, by inhalation, by ex-vivo contact with one or more cells of the subject. The compound can be administered alone or in combination with one or more additional compounds. Treatments may be sequential, with the present compound being administered before or after the administration of other agents. Alternatively, compounds may be administered concurrently. The subject, e.g., a patient, can be one having a disorder (e.g., a disease or condition described herein), a symptom of a disorder, or a predisposition toward a disorder. Treatment is not limited to curing or complete healing, but can result in one or more of alleviating, relieving, altering, partially remedying, ameliorating, improving or affecting the disorder, reducing one or more symptoms of the disorder or the predisposition toward the disorder. In an embodiment the treatment (at least partially) alleviates or relieves symptoms related to a fibrotic disease. In an embodiment the treatment (at least partially) alleviates or relieves symptoms related to an inflammatory disease. In one embodiment, the treatment reduces at least one symptom of the disorder or delays onset of at least one symptom of the disorder. The effect is beyond what is seen in the absence of treatment. The terms “therapeutically effective amount” or “amount sufficient to treat” as used interchangeably herein, refer to an amount, e.g., pharmaceutical dose, effective in inducing a desired effect in a subject or in treating a subject having a condition or disorder described herein (e.g., a fibrotic disease of an inflammatory disease). It is also to be understood herein that a “therapeutically effective amount” may be interpreted as an amount giving a desired therapeutic and/or preventative effect, taken in one or more doses or in any dosage or route, and/or taken alone or in combination with other therapeutic agents. The term “subject,” as used herein, can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, turkey, goat, fish, monkey, chicken, rat, mouse, and sheep. The term “pharmaceutical composition” refers to the combination of an active agent with an excipient, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo. A “pharmaceutically acceptable excipient,” after being administered to or upon a subject, does not cause undesirable physiological effects. The excipient in the pharmaceutical composition must be “acceptable” also in the sense that it is compatible with the active ingredient. The excipient may also be capable of stabilizing the active ingredient. One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an active compound. Examples of pharmaceutically acceptable excipients include, but are not limited to, biocompatible vehicles, adjuvants, additives, and diluents to achieve a composition usable as a dosage form. Examples of other excipients include colloidal silicon oxide, magnesium stearate, cellulose, and sodium lauryl sulfate. As used herein, the term "excipient" refers to a diluent, adjuvant, carrier, or vehicle with which the active compound is administered. Such pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used. When administered to a subject, the pharmaceutically acceptable vehicles are preferably sterile. Water can be the vehicle when the active compound is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, sodium stearate, glycerol monostearate, talc, sodium chloride, glycerol, propylene glycol, water, and ethanol. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. As used herein, the term “pharmaceutically acceptable salt” represents a salt of a compound of the invention (e.g., a compound of any one of formulas (I)-(III) and (I′)-(III′) or any one of compounds 1- 530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491) that is within the scope of sound medical judgment, suitable for use in methods described herein without undue toxicity, irritation, and/or allergic response. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of a compound described herein or separately by reacting the free base group with a suitable organic acid. The terms “alkyl,” “alkenyl,” and “alkynyl,” as used herein, include straight-chain and branched- chain monovalent substituents, as well as combinations of these, containing only C and H when unsubstituted. When the alkyl group includes at least one carbon-carbon double bond or carbon-carbon triple bond, the alkyl group can be referred to as an “alkenyl” or “alkynyl” group respectively. The monovalency of an alkyl, alkenyl, or alkynyl group does not include the optional substituents on the alkyl, alkenyl, or alkynyl group. For example, if an alkyl, alkenyl, or alkynyl group is attached to a compound, monovalency of the alkyl, alkenyl, or alkynyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl, alkenyl, or alkynyl group. In some embodiments, the alkyl group may contain, e.g., 1-20.1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1- C2). In some embodiments, the alkenyl or alkynyl group may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2 C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2- propenyl, and 3-butynyl. The terms “heteroalkyl,” “heteroalkenyl,” and “heteroalkynyl,” as used herein, include alkyl, alkenyl, or alkynyl groups, as defined above, but which include one or more heteroatoms (e.g., oxygen, nitrogen, and/or sulfur atoms) in the alkyl, alkenyl, or alkynyl main chain. In some embodiments, the heteroalkyl, heteroalkenyl, or heteroalknyl group may contain, e.g., 1-20.1-18, 1-16, 1-14, 1-12, 1-10, 1- 8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1- C6, C1-C4, or C1-C2) and one or more (e.g., one, two, three, four, or five) heteroatoms atoms. The terms “alkylene,” “alkenylene,” and “alkynylene,” as used herein, refer to divalent groups having a specified size. Alkylene groups are exemplified by methylene, ethylene, isopropylene, and the like. Alkylene, alkenylene, and/or alkynylene includes straight-chain and branched-chain forms, as well as combinations of these. The divalency of an alkylene, alkenylene, or alkynylene group does not include the optional substituents on the alkylene, alkenylene, or alkynylene group. The term “alkoxy,” as used herein, represents a chemical substituent of formula –OR, where R is a C1-20 alkyl group (e.g., C1-6 or C1-10 alkyl), unless otherwise specified. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group can be further substituted with 1, 2, 3, 4, or more substituent groups as defined herein (e.g., hydroxy or alkoxy). The term “aryl,” as used herein, refers to any monocyclic or fused ring bicyclic or tricyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system, e.g., phenyl, naphthyl, or phenanthrene. In some embodiments, a ring system contains 5-15 ring member atoms or 5-10 ring member atoms. An aryl group may have, e.g., five to fifteen carbons (e.g., a C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C11, C5-C12, C5-C13, C5-C14, or C5-C15 aryl). The term “heteroaryl” also refers to such monocyclic or fused bicyclic ring systems containing one or more, e.g., 1- 4, 1-3, 1, 2, 3, or 4, heteroatoms selected from O, S and N. A heteroaryl group may have, e.g., two to fifteen carbons (e.g., a C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9. C2-C10, C2-C11, C2-C12, C2-C13, C2-C14, or C2-C15 heteroaryl). The inclusion of a heteroatom permits inclusion of 5 membered rings to be considered aromatic as well as 6 membered rings. Thus, typical heteroaryl systems include, e.g., pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl, and imidazolyl. Because tautomers are possible, a group such as phthalimido is also considered heteroaryl. In some embodiments, the aryl or heteroaryl group is a 5- or 6-membered aromatic ring system optionally containing 1-2 nitrogen atoms. In some embodiments, the aryl or heteroaryl group is an optionally substituted phenyl, pyridyl, indolyl, pyrimidyl, pyridazinyl, benzothiazolyl, benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, or imidazopyridinyl. In some embodiments, the aryl group is phenyl. In some embodiments, an aryl group may be optionally substituted with a substituent such an aryl substituent, e.g., biphenyl. The term “heterocyclyl,” as used herein, represents a ring have 2 or more carbon atoms and at least one heteroatom. For example, a heterocyclyl ring may have, e.g., two to fifteen carbons ring atoms (e.g., a C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9. C2-C10, C2-C11, C2-C12, C2-C13, C2- C14, or C2-C15 heterocyclyl) and one or more (e.g., one, two, three, four, or five) ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclyl groups include both non-aromatic and aromatic rings (e.g., includes heteroaryl groups, as previously defined). In preferred embodiments of the invention, a heterocyclyl group is a 3- to 8-membered ring, a 3- to 6- membered ring, a 4- to 6-membered ring, most preferably a 5-membered ring or a 6-membered ring. Heterocyclyls include aromatic and non-aromatic rings. Exemplary 5-membered heterocyclyl groups may have zero to two double bonds, and exemplary 6-membered heterocyclyl groups may have zero to three double bonds. Exemplary 5-membered groups include, for example, optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiofene, optionally substituted thiolane, optionally substituted furan, optionally substituted terahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4-oxatriazole, and optionally substituted 1,2,3,4-thiatriazole. Exemplary 6-membered heterocyclyl groups include, for example, optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, and optionally substituted tetrahydropyran. Exemplary 7-memebered heterocyclyl groups include, for example, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted thiepine, and optionally substituted 1,4-thiazepine. The term “cycloalkyl,” as used herein, represents a monovalent saturated or unsaturated non- aromatic cyclic alkyl group. A cycloalkyl may have, e.g., three to twenty carbons (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl). Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. When the cycloalkyl group includes at least one carbon-carbon double bond, the cycloalkyl group can be referred to as a “cycloalkenyl” group. A cycloalkenyl may have, e.g., four to twenty carbons (e.g., a C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenyl). Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. When the cycloalkyl group includes at least one carbon-carbon triple bond, the cycloalkyl group can be referred to as a “cycloalkynyl” group. A cycloalkynyl may have, e.g., eight to twenty carbons (e.g., a C8-C9, C8-C10, C8-C11, C8-C12, C8-C14, C8-C16, C8-C18, or C8-C20 cycloalkynyl). The term “cycloalkyl” also includes a cyclic compound having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1.]heptyl and adamantyl. The term “cycloalkyl” also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spiro-cyclic compounds. The term “alkaryl,” refers to an aryl group that is connected to an alkylene, alkenylene, or alkynylene group. In general, if a compound is attached to an alkaryl group, the alkylene, alkenylene, or alkynylene portion of the alkaryl is attached to the compound. In some embodiments, an alkaryl is C6- C35 alkaryl (e.g., C6-C16, C6-C14, C6-C12, C6-C10, C6-C9, C6-C8, C7, or C6 alkaryl), in which the number of carbons indicates the total number of carbons in both the aryl portion and the alkylene, alkenylene, or alkynylene portion of the alkaryl. Examples of alkaryls include, but are not limited to, (C1- C8)alkylene(C6-C12)aryl, (C2-C8)alkenylene(C6-C12)aryl, or (C2 C8)alkynylene(C6-C12)aryl. In some embodiments, an alkaryl is benzyl or phenethyl. In a heteroalkaryl, one or more heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the alkaryl group and/or may be present in the aryl portion of the alkaryl group. In an optionally substituted alkaryl, the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkaryl group and/or may be present on the aryl portion of the alkaryl group. The terms “heteroalkylene”, “heteroalkenylene”, “heteroalkynylene”, “arylene”, “cycloalkylene”, and “heterocyclylene”, as used herein, each represent a divalent radical respectively derived from “heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”, “aryl”, “cycloalkyl”, and “heterocyclyl”, as defined above. The term “carboxyl,” as used herein, represents a -COOH group. An optionally substituted carboxyl includes, for example, a -COOR group, wherein R is H or any substituent group described herein. The term “amine,” as used herein, represents an -NH2 group. An optionally substituted amine includes, for example, a -NHR or a -NR1R2 group, wherein R, R1, and R2 are each independently H or any substituent group described herein. In some embodiments, R1 and R2 form cyclic ring (e.g., a 5- or 6- membered ring), such that –NR1R2 is an optionally substituted heterocycle or heteroaryl. The term “amide,” as used herein, represents a -C(=O)NH2 group. An optionally substituted amide includes, for example, a -C(=O)NHR or a –C(=O)NR1R2 group, wherein R, R1, and R2 are each independently H or any substituent group described herein. The term “imino” as used herein, represents a -C(=NR1)R2 group. An optionally substituted imino includes, for example, a -C(=NR1)R2 group, wherein each of R1 and R2 are independently selected from H or any substituted group described herein. The term “thioester,” as used herein, represents a -C(=O)SH group. An optionally substituted thioester includes, for example, a -C(=O)SR group, wherein R is H or any substituent group described herein. The term “thioamide,” as used herein, represents a -C(=S)NH2 group. An optionally substituted thioamide includes, for example, a -C(=S)NHR or a –C(=S)NR1R2 group, wherein R, R1, and R2 are each independently H or any substituent group described herein. The term “sulfonamide,” as used herein, represents a -S(=O)2NH2 group. An optionally substituted sulfonamide includes, for example, a -S(=O)2NHR or a -S(=O)2NR1R2 group, wherein R, R1, and R2 are each independently H or any substituent group described herein. The term “sulfonyl,” as used herein, represents a -S(=O)2R group. An optionally substituted sulfonyl includes, for example, a S(=O)2R, wherein R is an H or any substituent group described herein. The term “cyano,” as used herein, represents a -CN group. The term “hydroxyl,” as used herein, represents an -OH group. The term “oxo,” as used herein, refers to a substituent having the structure =O, where there is a double bond between an atom and an oxygen atom. The term “optionally substituted,” as used herein, refers to having 0, 1, or more substituents, such as 0-25, 0-20, 0-10 or 0-5 substituents. Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, alkaryl, acyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkaryl, halogen, oxo, cyano, nitro, amino, alkamino, hydroxy, alkoxy, alkanoyl, carbonyl, carbamoyl, guanidinyl, ureido, amidinyl, any of the groups or moieties described above, and hetero versions of any of the groups or moieties described above. Substituents include, but are not limited to, F, Cl, Br, methyl, ethyl, propyl, butyl, phenyl, benzyl, OR, NR2, SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOCR, SO3R, CONR2, SO2NR2, NRSO2NR2, CN, CF3, OCF3, SiR3, and NO2, wherein each R is, independently, H, alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl, or heteroaryl, and wherein two of the optional substituents on the same or adjacent atoms can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3–8 members, or two of the optional substituents on the same atom can be joined to form an optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3–8 members. An optionally substituted group or moiety refers to a group or moiety (e.g., any one of the groups or moieties described above) in which one of the atoms (e.g., a hydrogen atom) is optionally replaced with another substituent. For example, an optionally substituted alkyl may be an optionally substituted methyl, in which a hydrogen atom of the methyl group is replaced by, e.g., OH. As another example, a substituent on a heteroalkyl or its divalent counterpart, heteroalkylene, may replace a hydrogen on a carbon or a hydrogen on a heteroatom such as N. Brief Description of the Figures FIG.1 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met5 from the analysis of a 4 hour plasma sample following oral administration of ajulemic acid (AJA). FIG.2 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met6 from the analysis of a 4 hour plasma sample following oral administration of AJA. FIG.3 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met7 from the analysis of a 4 hour plasma sample following oral administration of AJA. FIG.4 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met8 from the analysis of a 1 hour plasma sample following oral administration of AJA. FIG.5 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met1 from the analysis of a 4 hour plasma sample following oral administration of AJA. FIG.6 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met2 from the analysis of a solid phase feces sample following oral administration of AJA. FIG.7 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met3 from the analysis of a solid phase feces sample following oral administration of AJA. FIG.8 illustrates full scan and product ion mass spectra, structure, and proposed fragmentation pattern of metabolite Met4 from the analysis of a 4 hour plasma sample following oral administration of AJA. FIG.9 is a graph showing the mean plasma concentration-time profiles of Compound 2 after IV dose of 1 mg/kg and PO dose at 10 mg/kg in fasted male C57BL/6 mice (N=3/time point). FIG.10 is a graph showing the mean plasma concentration-time profiles of AJA after IV dose of 1 mg/kg and PO dose of 10 mg/kg in fasted male CD1 mice (N=3/time point). Detailed Description of the Invention The invention relates to deuterium-enriched and/or fluorinated cannabinoid compounds, pharmaceutical compositions including one or more such cannabinoid compounds, and the use of pharmaceutical compositions including such one or more cannabinoid compounds for the treatment of a disease or condition (e.g., a fibrotic disease or an inflammatory disease) in a subject in need thereof. Without wishing to be bound by theory, the present disclosure is based, at least in part, on the identification and analysis of metabolic products of ajulemic acid. The present disclosure provides deuterated and/or fluorinated analogs of ajulemic acid and structurally related cannabinoids. Compounds disclosed herein are deuterated and/or fluorinated to provide advantageous properties, for example, increased metabolic stability, improved pharmacokinetic properties (e.g., increased serum half-life), and/or receptor selectivity (e.g., increased CB2 receptor selectivity), for example, as compared to ajulemic Compounds
The disclosure provides deuterium-enriched and/or fluorinated compounds (e.g., a cannabinoid compound described by any one of formulas (l)-(lll) and (l')-(lll'), or any one of compounds 1-530, 534- 689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, and 1434c-1484c) useful for the treatment of disease (e.g., a fibrotic disease or an inflammatory disease).
In particular, the invention features deuterium-enriched and/or fluorinated analogs of (6aR,10aR)- 1-hydroxy-6,6-dimethyl-3-(2-methyl-2-octanyl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylic acid (ajulemic acid), and deuterium-enriched and/or fluorinated analogs of compounds structurally-related to ajulemic acid. Ajulemic acid has been investigated for the treatment of inflammatory disease and fibrotic disease. The structure of ajulemic acid (AJA) is:
Figure imgf000070_0001
Metabolic studies to identify metabolites of ajulemic acid were performed as described in Example 1. Based on the metabolites analyzed, the inventors identified chemical substituents of ajulemic acid and structurally-related analogs for modification by deuterium enrichment and/or fluorination (e.g.,
R2, R3, or R4 of a compound described by Formula (I), (II), or (III)). Deuterium-enrichment and/or fluorination of the identified metabolically labile groups can improve the pharmacokinetic properties of the compounds by increasing metabolic stability (e.g., decreasing the rate of conversion to an inactive metabolite). In preferred embodiments, a deuterium-enriched and/or fluorinated compound has an increased serum half-life (T 1/2), oral bioavailability (%F), and/or exposure as determined by maximum serum concentration (Cmax) relative to the corresponding compound that is not deuterium-enriched or fluorinated. In preferred embodiments, a deuterium-enriched and/or fluorinated compound may be administered at a lower dose and/or with decreased frequency relative to the parent compound, e.g., as a result of increased pharmacokinetic performance.
In some embodiments, the invention features compounds which are modulators (e.g., agonists, inverse agonists, or antagonists) of the CB2 receptor. In preferred embodiments of the invention, the invention features compounds that have increased affinity for the CB2 receptor (e.g., increased affinity for the CB2 receptor compared to ajulemic acid), increased selectivity for the CB2 receptor (e.g., increased selectivity for the CB2 receptor over the CBi receptor compared to ajulemic acid), or both increased affinity and increased selectivity for the CB2 receptor.
In some embodiments, the invention features compounds with an increased safety or efficacy profile in the treatment of a disease or condition (e.g., a fibrotic disease or an inflammatory disease), as compared to other cannabinoids, such as ajulemic acid. In some embodiments, administration of a compound of the invention to a subject (e.g., a subject having a disease or condition described herein) results in a decrease in treatment-associated adverse events relative to treatment with one or more other cannabinoids (e.g., treatment with an equivalent dose and method of administration of ajulemic acid). In some embodiments, administration of a compound of the invention to a subject (e.g., a subject having a disease or condition described herein) results in a decrease in CB1-associated adverse events relative to treatment with one or more other cannabinoids (e.g., ajulemic acid). In some embodiments, administration of a compound of the invention to a subject (e.g., a subject having a disease or condition described herein) results in a decrease in the rate of occurrence, severity, or risk of one or more of the following adverse events: dizziness, dry mouth, disorientation, euphoria, headache, nausea, pallor, somnolence, vomiting, tremor, abnormal feeling, tachycardia, fatigue, feeling drunk, paraesthesia, muscle spasms, muscle tightness, disturbance in attention, déjà vu, altered mood, anorexia, and cardiovascular events such as orthostatic hypotension, or QTc prolongation. The reduction in adverse events may be a reduction of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more in the occurrence or severity of any one of the above-described adverse events (e.g., compared to a subject or subjects treated with an equivalent dose and method of administration of another cannabinoid, such as ajulemic acid). In some embodiments, the invention features compounds having improved pharmacokinetic properties or metabolic stability (e.g., improved pharmacokinetic properties or improved stability as compared to ajulemic acid). In some embodiments, a deuterated or fluorinated compound of the present invention has an increased serum half-life (T1/2) (e.g., increased by at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 3-fold, 4-fold, 5-fold, or 10-fold as compared to the corresponding cannabinoid compound that is not deuterated or fluorinated). In some embodiments, a compound of the invention is described by any one of formulas (I), (IA- 1), (IA-2), (IA-3), (IA-4), (IA-2A), (IA-2B), (II), (IIA), (IIA-1), (IIA-2), (IIA-2A), (IIA-2B), (IIA-2C), (IIA-3), (III), (IIIA), (III′B), (IIIC), (IIID), (IIIE), (IIIF), (I′), (I′A-1), (I′A-2), (I′A-3), (I′A-4), (I′A-2A), (I′A-2B), (II′), (II′A), (II′A- 1), (II′A-2), (II′A-2A), (II′A-2B), (II′A-2C), (III′), (III′A), (III′B), (III′C), (III′D), (III′E), or (III′F). In some embodiments, the compound of the invention is a compound of Table 1 or Table 2 (e.g., a compound selected from any one of compounds 1-530, 534-689, 1389-1433, and 1485-1490 of Table 1 and compounds 690a-1229a, 1232a-1388a, 1434a-1484a, 690b-1229b, 1233b-388b, 1434b-1484b, 690c-1229c, 1233c-1388c, and 1434c-1484c of Table 2), or Compound 1491. Pharmaceutical compositions Compounds of the invention (e.g., a cannabinoid compound, such as a compound described by any one of formulas (I′)-(III′) and (I′)-(III′), or any one of compounds 1-530, 534-689,1389-1433, 1485- 1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c- 1388c, 1434c-1484c, and 1491) may be formulated as a pharmaceutical composition for the treatment of disease. As described above, the pharmaceutical compositions of the invention additionally include a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Some examples of materials which can serve as pharmaceutically acceptable excipients include, but are not limited to, sugars such as lactose, glucose, mannitol, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; natural and synthetic phospholipids, such as soybean and egg yolk phosphatides, lecithin, hydrogenated soy lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, dioleoyl lecithin, hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine, diastearoyl phosphatidylethanolamine (DSPE) and its pegylated esters, such as DSPE-PEG750 and, DSPE-PEG2000, phosphatidic acid, phosphatidyl glycerol and phosphatidyl serine. Commercial grades of lecithin which are preferred include those which are available under the trade name Phosal® or Phospholipon® and include Phosal 53 MCT, Phosal 50 PG, Phosal 75 SA, Phospholipon 90H, Phospholipon 90G and Phospholipon 90 NG; soy- phosphatidylcholine (SoyPC) and DSPE-PEG2000 are particularly preferred; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention also include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), self- microemulsifying drug delivery systems (SMEDDS), such as d-E-tocopherol polyethylene-glycol 1000 succinate; surfactants used in pharmaceutical pharmaceutical compositions such as Tweens or other similar polymeric delivery matrices; serum proteins such as human serum albumin; buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts; or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxmethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as alpha, beta and .gamma.-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-beta cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein that can be used in the methods of the invention for preventing and/or treating fibrotic conditions. In certain embodiments, unit dosage formulations are compounded for immediate release, though unit dosage formulations compounded for delayed or prolonged release of one or both agents are also disclosed. Viscosity modifiers that may be used in pharmaceutical compositions of the present invention include, but are not limited to, caprylic/capric triglyceride (Migliol 810), isopropyl myristate (IPM), ethyl oleate, triethyl citrate, dimethyl phthalate, benzyl benzoate and various grades of polyethylene oxide. High viscosity liquid carriers used in sustained release pharmaceutical compositions include, but are not limited to, sucrose acetate isobutyrate (SAIB) and cellulose acetate butyrate (CAB 381-20). Non-limiting examples of binding agents that may be used in pharmaceutical compositions of the present invention include but are not limited to hydroxyalkyl cellulose, a hydroxyalkylalkyl cellulose, hydroxypropyl methyl cellulose, or a polyvinylpyrrolidone. Non-limiting examples of osmotic agents that may be used in pharmaceutical compositions of the present invention include, but are not limited to, sorbitol, mannitol, sodium chloride, or other salts. Non- limiting examples of biocompatible polymers employed in the contemplated pharmaceutical compositions include but are not limited to poly(hydroxy acids), polyanhydrides, polyorthoesters, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polysiloxanes, poly(vinyl alcohols), poly (vinyl acetate), polystyrene, polyurethanes and co-polymers thereof, synthetic celluloses, polyacrylic acids, poly(butyric acid), poly(valeric acid), and poly(lactide-co-caprolactone), ethylene vinyl acetate, copolymers and blends thereof. Non-limiting examples of hygroscopic polymers that may be employed in the contemplated pharmaceutical compositions include, but are not limited to, polyethylene oxide (e.g., Polyox® with MWs from 4,000,000 to 10,000,000), cellulose, hydroxymethylcellulose, hydroxyethylcellulose, crosslinked polyacrylic acids, and xanthan gum. Non-limiting examples of rate-controlling polymers the may be employed in the contemplated pharmaceutical compositions include but are not limited to polymeric acrylate, methacrylate lacquer or mixtures thereof, polymeric acrylate lacquer, methacrylate lacquer, an acrylic resin including a copolymer of acrylic and methacrylic acid esters, or an ammonium methacrylate lacquer with a plasticizer. The above-described compositions, in any of the forms described herein, can be used for treating disease (e.g., fibrotic disease, inflammatory disease, or any other disease or condition described herein). An effective amount refers to the amount of an active compound/agent that is required to confer a therapeutic effect on a treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment. A pharmaceutical composition of this invention can be administered by any suitable route, e.g., parenterally, orally, nasally, rectally, topically, buccally, by ophthalmic administration, or by inhalation. The term “parenteral” as used herein refers to subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique. A sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Such solutions include, but are not limited to, 1,3-butanediol, mannitol, water, Ringer’s solution, and isotonic sodium chloride solution. In addition, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides). Fatty acids, such as, but not limited to, oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as, but not limited to, olive oil or castor oil, or polyoxyethylated versions thereof. These oil solutions or suspensions also can contain a long chain alcohol diluent or dispersant such as, but not limited to, carboxymethyl cellulose, or similar dispersing agents. Other commonly used surfactants, such as, but not limited to, Tweens or Spans or other similar emulsifying agents or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other pharmaceutical compositions also can be used for the purpose of formulation. A composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. In some embodiments, the dosage form is an oral dosage form such as a pressed tablet, hard or soft gel capsule, enteric coated tablet, osmotic release capsule, or unique combination of excipients. In the case of tablets, commonly used excipients include, but are not limited to, lactose, mannitol, and corn starch. Lubricating agents, such as, but not limited to, magnesium stearate, also are typically added. For oral administration in a capsule form, useful diluents include, but are not limited to, lactose, mannitol, glucose, sucrose, corn starch, potato starch, or cellulose. In additional embodiments, the dosage form includes a capsule wherein the capsule contains a mixture of materials to provide a desired sustained release formulation. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added. The pharmaceutical compositions can include a tablet coated with a semipermeable coating. In certain embodiments, the tablet includes two layers, a layer containing a compound of the invention and a second layer referred to as a "push" layer. The semi-permeable coating is used to allow a fluid (e.g., water) to enter the tablet and erode a layer or layers. In certain embodiments, this sustained release dosage form further includes a laser hole drilled in the center of the coated tablet. The compound containing layer may include a compound described herein, a disintegrant, a viscosity enhancing agent, a binding agent, and an osmotic agent. The push layer includes a disintegrant, a binding agent, an osmotic agent, and a viscosity enhancing agent. Non-limiting examples of materials that make up preferred semi- permeable layers include, but are not limited to cellulosic polymers such as cellulose acetate, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose diacetate, cellulose triacetate or any mixtures thereof; ethylene vinyl acetate copolymers, polyethylene, copolymers of ethylene, polyolefins including ethylene oxide copolymers (e.g., Engage® Dupont Dow Elastomers), polyamides, cellulosic materials, polyurethanes, polyether blocked amides, and copolymers (e.g., PEBAX®, cellulosic acetate butyrate and polyvinyl acetate). Non-limiting examples of disintegrants that may be employed in the above sustained release pharmaceutical compositions include but are not limited to croscarmellose sodium, crospovidone, sodium alginate or similar excipients. In further embodiments, the dosage form includes a tablet including a biocompatible matrix and a compound described herein. The dosage form may also include a hard-shell capsule containing bio- polymer microspheres that contains the therapeutically active agent. The biocompatible matrix and bio- polymer microspheres each contain pores for drug release and delivery. These pores are formed by mixing the biocompatible matrix of bio-polymer microsphere with a pore forming agent. Each biocompatible matrix or bio-polymer microsphere is made up of a biocompatible polymer or mixture of biocompatible polymers. The matrix and microspheres can be formed by dissolving the biocompatible polymer and active agent (compound described herein) in a solvent and adding a pore-forming agent (e.g., a volatile salt). Evaporation of the solvent and pore forming agent provides a matrix or microsphere containing the active compound. In additional embodiments, the dosage form includes a tablet, wherein the tablet contains a compound of the invention and one or more polymers and wherein the tablet can be prepared by compressing the compound and one or more polymers. In some embodiments, the one or more polymers may include a hygroscopic polymer formulated with a compound of the invention. Upon exposure to moisture, the tablet dissolves and swells. This swelling allows the sustained release dosage form to remain in the upper GI tract. The swelling rate of the polymer mixture can be varied using different grades of polyethylene oxide. Pharmaceutical compositions for topical administration according to the described invention can be formulated as solutions, ointments, creams, suspensions, lotions, powders, pastes, gels, sprays, aerosols, or oils. Alternatively, topical formulations can be in the form of patches or dressings impregnated with active ingredient(s), which can optionally include one or more excipients or diluents. In some preferred embodiments, the topical formulations include a material that would enhance absorption or penetration of the active agent(s) through the skin or other affected areas. A topical composition contains a safe and effective amount of a dermatologically acceptable excipient suitable for application to the skin. A “cosmetically acceptable” or “dermatologically-acceptable” composition or component refers a composition or component that is suitable for use in contact with human skin without undue toxicity, incompatibility, instability, or allergic response. The excipient enables an active agent and optional component to be delivered to the skin at an appropriate concentration(s). The excipient thus can act as a diluent, dispersant, solvent, or the like to ensure that the active materials are applied to and distributed evenly over the selected target at an appropriate concentration. The excipient can be solid, semi-solid, or liquid. The excipient can be in the form of a lotion, a cream, or a gel, in particular one that has a sufficient thickness or yield point to prevent the active materials from sedimenting. The excipient can be inert or possess dermatological benefits. It also should be physically and chemically compatible with the active components described herein, and should not unduly impair stability, efficacy, or other use benefits associated with the composition. The present compositions may be formulated for sustained release (e.g., over a 6 hour period, over a 12 hour period, over a 24 hour period, or over a 48 hour period). In some embodiments, the sustained release dosage form includes a tablet or a capsule including particle cores coated with a suspension of active agent and a binding agent which is subsequently coated with a polymer. The polymer may be a rate-controlling polymer. In general, the delivery rate of the rate-controlling polymer is determined by the rate at which the active agent is dissolved. In another embodiment, the composition is formulated to provide extended release. For example, the agent is formulated with an enteric coating. In an alternative embodiment, the agent is formulated using a biphasic controlled release delivery system, thereby providing prolonged gastric residence. For example, in some embodiments, the delivery system includes (1) an inner solid particulate phase formed of substantially uniform granules containing a pharmaceutical having a high water solubility, and one or more hydrophilic polymers, one or more hydrophobic polymers and/or one or more hydrophobic materials such as one or more waxes, fatty alcohols and/or fatty acid esters, and (2) an outer solid continuous phase in which the above granules of inner solid particulate phase are embedded and dispersed throughout, the outer solid continuous phase including one or more hydrophobic polymers, one or more hydrophobic polymers and/or one or more hydrophobic materials such as one or more waxes, fatty alcohols and/or fatty acid esters, which may be compressed into tablets or filled into capsules. In some embodiments, the agent is incorporated into polymeric matrices included of hydrophilic polymers that swell upon imbibition of water to a size that is large enough to promote retention of the dosage form in the stomach during the fed mode. The active compound in the formulation may be formulated as a combination of fast-acting and controlled release forms. For example, the active compound is formulated with a single release property. For example, it is present in a modified release form, e.g., a controlled release form. The pharmaceutical composition can be administered alone or in combination with one or more additional compounds. Treatments may be sequential, with the present compound being administered before or after the administration of other agents. Alternatively, compounds may be administered concurrently. Exemplary additional agents include an analgesic agent such as an opiate, an anti- inflammatory agent, or a natural agent such as a triglyceride containing unsaturated fatty acid, or isolated pure fatty acids such as eicosapentaenoic acid (EPA), dihomogamma linolenic acid (DGLA), docosahexaenoic acid (DHA) and others. In some embodiments, the therapeutic agents that can be used in the present methods are formulated in a single unit dose such that the agents are released from the dosage at different times. The pharmaceutical composition can be administered at a dose determined by one of skill in the art (e.g., an effective therapeutic dose, for example, to treat a disorder described herein). For example, pharmaceutical composition including a compound of the present invention can be administered at a dose of 0.001-0.01 mg/kg, 0.01-0.5 mg/kg, 0.5-2 mg/kg, 2-5 mg/kg, 5-10 mg/kg, 10-20 mg/kg, 20-40 mg/kg, 40-60 mg/kg, 60-80 mg/kg, 80-100 mg/kg, 100-200 mg/kg or 200-500mg/kg. A unit of a pharmaceutical dosage form may include, for example, 0.001-0.01 mg, 0.01-0.5 mg, 0.5-2 mg, 2-5 mg, 5- 10 mg, 10-20 mg, 20-40 mg, 40-60 mg, 60-80 mg, 80-100 mg, 100-200 mg or 200-500 mg of a compound of the invention. Methods of treatment In some embodiments of the invention, any of the above-described compositions (e.g., compositions including a cannabinoid compound, a compound described by any one of formulas (I′)-(III′) and (I′)-(III′), or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a- 1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491prepared according to the methods of the invention), including any of the above-described pharmaceutical compositions, may be administered to a subject (e.g., a mammal, such as a human, cat, dog, horse, cow, or pig) having a disease (e.g., a fibrotic disease or an inflammatory disease) in order to treat, prevent, or ameliorate the disease. Inflammation A therapeutically effective amount of any of the compositions described herein (e.g. a pharmaceutical composition comprising a compound described by any one of formulas (I′)-(III′) and (I′)- (III′), or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491) may be used to treat or prevent inflammatory disease. Inflammatory diseases include, for example, scleroderma (e.g., systemic sclerosis, localized scleroderma, or sine scleroderma), dermatomyositis, systemic lupus erythematosus, acquired immune deficiency syndrome (AIDS), multiple sclerosis, rheumatoid arthritis, psoriasis, diabetes, cancer, asthma, atopic dermatitis, an autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, stroke, ischemia, a neurodegenerative disease, amyotrophic lateral sclerosis (ALS), chronic traumatic encephalopathy (CTE), chronic inflammatory demyelinating polyneuropathy, an autoimmune inner ear disease, uveitis, iritis, and peritonitis. In some embodiments, inflammation can be assayed by measuring the chemotaxis and activation state of inflammatory cells. In some embodiments, inflammation can be measured by examining the production of specific inflammatory mediators such as interleukins, cytokines and eicosanoids. In some embodiments, in vivo inflammation is measured by swelling and edema of a localized tissue or migration of leukocytes. Inflammation may also be measured by organ function such as in the lung or kidneys and by the production of pro-inflammatory factors. Inflammation may also be assessed by other suitable methods. Other methods known to one skilled in the art may also be suitable methods for the assessment of inflammation and may be used to evaluate or score the response of the subject to treatment with one or more therapeutic agents of the invention (e.g., a cannabinoid compound, a compound described by any one of formulas (I′)-(III′) and (I′)-(III′), or any one of compounds 1-530, 534- 689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491). Fibrotic diseases A therapeutically effective amount of any of the compositions described herein (e.g. a pharmaceutical composition comprising a compound described by any one of formulas (I′)-(III′) and (I′)- (III′), or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b-1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491) may be used to treat or prevent inflammatory disease. Fibrotic diseases include, for example, scleroderma (e.g., systemic sclerosis, localized scleroderma, or sine scleroderma), cystic fibrosis, liver cirrhosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, Dupuytren’s contracture, keloids, chronic kidney disease, chronic graft rejection, scarring, wound healing, post-operative adhesions, reactive fibrosis, polymyositis, ANCA vasculitis, Behcet's disease, anti-phospholipid syndrome, relapsing polychondritis, Familial Mediterranean Fever, giant cell arteritis, Graves ophthalmopathy, discoid lupus, pemphigus, bullous pemphigoid, hydradenitis suppuritiva, sarcoidosis, bronchiolitis obliterans, primary sclerosing cholangitis, primary biliary cirrhosis, and organ fibrosis (e.g., dermal fibrosis, lung fibrosis, liver fibrosis, kidney fibrosis, or heart fibrosis). Non-limiting examples of fibrosis include liver fibrosis, lung fibrosis (e.g., silicosis, asbestosis, idiopathic pulmonary fibrosis), oral fibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, deltoid fibrosis, kidney fibrosis (including diabetic nephropathy), cystic fibrosis, and glomerulosclerosis. Liver fibrosis, for example, occurs as a part of the wound-healing response to chronic liver injury. Fibrosis can occur as a complication of haemochromatosis, Wilson's disease, alcoholism, schistosomiasis, viral hepatitis, bile duct obstruction, exposure to toxins, and metabolic disorders. Endomyocardial fibrosis is an idiopathic disorder that is characterized by the development of restrictive cardiomyopathy. In endomyocardial fibrosis, the underlying process produces patchy fibrosis of the endocardial surface of the heart, leading to reduced compliance and, ultimately, restrictive physiology as the endomyocardial surface becomes more generally involved. Oral submucous fibrosis is a chronic, debilitating disease of the oral cavity characterized by inflammation and progressive fibrosis of the submucosal tissues (lamina propria and deeper connective tissues). The buccal mucosa is the most commonly involved site, but any part of the oral cavity can be involved, even the pharynx. Retroperitoneal fibrosis is characterized by the development of extensive fibrosis throughout the retroperitoneum, typically centered over the anterior surface of the fourth and fifth lumbar vertebrae. Treatment of fibrosis may be assessed by suitable methods known to one of skill in the art including the improvement, amelioration, or slowing the progression of one or more symptoms associated with the particular fibrotic disease being treated. Scleroderma Scleroderma is a disease of the connective tissue characterized by inflammation and fibrosis of the skin and internal organs. Scleroderma has a spectrum of manifestations and a variety of therapeutic implications. It includes localized scleroderma, systemic sclerosis, scleroderma-like disorders, and sine scleroderma. Systemic sclerosis can be diffuse or limited. Limited systemic sclerosis is also called CREST (calcinosis, Raynaud's esophageal dysfunction, sclerodactyly, telangiectasia). Systemic sclerosis includes: scleroderma lung disease, scleroderma renal crisis, cardiac manifestations, muscular weakness including fatigue or limited CREST, gastrointestinal dysmotility and spasm, and abnormalities in the central, peripheral and autonomic nervous system. The major symptoms or manifestations of scleroderma, and in particular of systemic sclerosis, are inappropriate excessive collagen synthesis and deposition, endothelial dysfunction, vasospasm, collapse and obliteration of vessels by fibrosis. In terms of diagnosis, an important clinical parameter may be skin thickening proximal to the metacarpophalangeal joints. Raynaud's phenomenon may be a component of scleroderma. Raynaud’s may be diagnosed by color changes of the skin upon cold exposure. Ischemia and skin thickening may also be symptoms of Raynaud's disease. A therapeutically effective amount of any of the compositions described herein (e.g. a cannabinoid compound, a compound described by any one of formulas (I′)-(III′) and (I′)-(III′), or any one of compounds 1-530, 534-689,1389-1433, 1485-1490, 690a-1229a, 1233a-1388a, 1434a-1484a, 690b- 1229b-1388b, 1434b-1484b, 690c1229c, 1233c-1388c, 1434c-1484c, and 1491 prepared by any of the methods described herein) may be used to treat or prevent fibrosis. Fibrosis may be assessed by suitable methods known to one of skill in the art. Numbered Embodiments 1. A pharmaceutical composition comprising a compound described by formula (I), (II), or (III):
Figure imgf000078_0001
, wherein R1 is H, O, OH, F, Cl, Br, NH2, or optionally substituted C1-C3 alkoxy; R2 is H, CH3, CH2D, CHD2, or CD3; R3 and R4 are each independently CH3, CH2D, CHD2, or CD3; R5 is CH3 or CH2OH; L1 is optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C5- C15 arylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C2-C15 heterocyclylene, or optionally substituted amido; each dashed line is optionally a double bond; A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, optionally substituted 3-to-8 membered heterocyclyl, or cyano; X1 and X2 are each independently H, O, Cl, or F; X3 and X4 are each independently H or absent; Q is an optionally substituted 5-to-8 membered heterocyclyl fused ring; L2 is optionally substituted C3-C8 alkylene, optionally substituted C3-C8 heteroalkylene, optionally substituted C3-C8 alkenylene, optionally substituted C3-C8 heteroalkenylene, optionally substituted C3-C8 alkynylene, or optionally substituted C3-C8 heteroalkynylene; and X5 is O or NH, wherein at least one of R2, R3, and R4 is CH2D, CHD2, or CD3, and the composition has an isotopic enrichment factor for deuterium of at least 5; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. 2. The pharmaceutical composition of embodiment 1, wherein the compound is described by formula (I):
Figure imgf000079_0001
, or a pharmaceutically acceptable salt thereof. 3. The pharmaceutical composition of embodiment 2, wherein the compound is described by formula (IA):
Figure imgf000080_0001
or a pharmaceutically acceptable salt thereof. 4. The pharmaceutical composition of embodiment 3, wherein the compound is described by formula (IA-1):
Figure imgf000080_0002
or a pharmaceutically acceptable salt thereof. 5. The pharmaceutical composition of embodiment 4, wherein the compound is described by formula (IA-2):
Figure imgf000080_0003
or a pharmaceutically acceptable salt thereof. 6. The pharmaceutical composition of embodiment 4, wherein the compound is described by formula (IA-3):
Figure imgf000080_0004
or a pharmaceutically acceptable salt thereof. 7. The pharmaceutical composition of embodiment 3, wherein the compound is described by formula (1A-4):
Figure imgf000081_0001
(IA-4), or a pharmaceutically acceptable salt thereof. 8. The pharmaceutical composition of any one of embodiments 2-7, wherein A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, or cyano. 9. The pharmaceutical composition of embodiment 8, wherein the compound is described by formula (IA-2A):
Figure imgf000081_0002
(IA-2A), wherein Ra is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C3-C20 cycloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C3-C20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or a pharmaceutically acceptable salt thereof. 10. The pharmaceutical composition of embodiment 9, wherein Ra is H. 11. The pharmaceutical composition of embodiment 8, wherein the compound is described by formula (IA-2B):
Figure imgf000081_0003
(IA-2B), wherein each of Ra and Ra′ is independently H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C3-C20 cycloalkyl, optionally substituted C1- C20 heteroalkyl, optionally substituted C3-C20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or Ra and Ra′, together with the nitrogen atom to which they are attached, combine to form an optionally substituted C3-C20 heterocyclyl; or a pharmaceutically acceptable salt thereof. 12. The pharmaceutical composition of embodiment 11, wherein Ra is optionally substituted C1- C20 alkyl. 13. The pharmaceutical composition of embodiment 11, wherein Ra is optionally substituted C3- C20 cycloalkyl. 14. The pharmaceutical composition of any one of embodiments 11-13, wherein Ra′ is H. 15. The pharmaceutical composition of embodiment 11, wherein Ra and R a′, together with the nitrogen atom to which they are attached, combine to form an optionally substituted C3-C20 heterocyclyl. 16. The pharmaceutical composition of any one of embodiments 2-7, wherein A is optionally substituted 3-to-8 membered heterocyclyl. 17. The pharmaceutical composition of embodiment 16, wherein A is optionally substituted 5- membered heterocyclyl. 18. The pharmaceutical composition of embodiment 17, wherein A is optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4-oxatriazole, or optionally substituted 1,2,3,4-thiatriazole. 19. The pharmaceutical composition of embodiment 18, wherein A is
Figure imgf000082_0001
20. The pharmaceutical composition of embodiment 19, wherein A is
Figure imgf000082_0002
21. The pharmaceutical composition of embodiment 20, wherein A is
Figure imgf000082_0003
. 22. The pharmaceutical composition of embodiment 18, wherein A is
Figure imgf000083_0001
23. The pharmaceutical composition of embodiment 16, wherein A is optionally substituted 6- membered heterocyclyl. 24. The pharmaceutical composition of embodiment 23, wherein A is optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, or optionally substituted tetrahydropyran. 25. The pharmaceutical composition of embodiment 24, wherein A is
Figure imgf000083_0002
26. The pharmaceutical composition of embodiment 25, wherein A is
Figure imgf000083_0003
. 27. The pharmaceutical composition of embodiment 26, wherein A is
Figure imgf000083_0004
. 28. The pharmaceutical composition of embodiment 16, wherein A is optionally substituted 7- membered heterocyclyl. 29. The pharmaceutical composition of embodiment 28, wherein A is optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted thiepine, or optionally substituted 1,4- thiazepine. 30. The pharmaceutical composition of embodiment 1, wherein the compound is described by
Figure imgf000083_0005
, or a pharmaceutically acceptable salt thereof. 31. The pharmaceutical composition of embodiment 30, wherein the compound is described by formula (IIA):
Figure imgf000084_0001
wherein Q1, Q2, and Q3 are each independently C, O, or N; and Rb and Rc are each independently H, C1-C6 alkyl, or absent; and Rd is H, optionally substituted C1-C6 alkyl, or absent; or a pharmaceutically acceptable salt thereof. 32. The pharmaceutical composition of embodiment 31, wherein the compound is described by formula (IIA-1):
Figure imgf000084_0002
(IIA-1), wherein Q1 and Q2 are each independently O or N; and Rb and Rc are each independently H, C1-C6 alkyl, or absent; or a pharmaceutically acceptable salt thereof. 33. The pharmaceutical composition of embodiment 31, wherein the compound is described by formula (IIA-2):
Figure imgf000084_0003
wherein Q2 and Q3 are each independently O or N; and Rc is H, C1-C6 alkyl, or absent; Rd is H, optionally substituted C1-C6 alkyl, or absent; or a pharmaceutically acceptable salt thereof. 34. The pharmaceutical composition of embodiment 33, wherein the compound is described by formula (IIA-2A):
Figure imgf000085_0001
(IIA-2A), wherein Rc is H or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof. 35. The pharmaceutical composition of embodiment 34, wherein Rc is H. 36. The pharmaceutical composition of embodiment 34, wherein Rc is CH3. 37. The pharmaceutical composition of embodiment 33, wherein the compound is described by formula (IIA-2B):
Figure imgf000085_0002
(IIA-2B), wherein Rd is H or optionally substituted C1-C6 alkyl; or a pharmaceutically acceptable salt thereof. 38. The pharmaceutical composition of embodiment 37, wherein Rd is H or C1-C6 alkyl. 39. The pharmaceutical composition of embodiment 38, wherein Rd is H. 40. The pharmaceutical composition of embodiment 38, wherein Rd is CH3. 41. The pharmaceutical composition of embodiment 37, wherein Rd is C1-C6 alkyl substituted with ORh or NRiRj, wherein Rh is H or C1-C6 alkyl, and each of Ri and Rj is independently H or alkyl, or Ri and Rj, together with the nitrogen atom to which they are attached form an optionally substituted 3- to 6- membered saturated ring. 42. The pharmaceutical composition of embodiment 41, wherein Rd is
Figure imgf000085_0003
,
Figure imgf000085_0004
43. The pharmaceutical composition of embodiment 33, wherein the compound is described by formula (IIA-2C):
Figure imgf000086_0001
or a pharmaceutically acceptable salt thereof. 44. The pharmaceutical composition of embodiment 31, wherein the compound is described by formula (IIA-3):
Figure imgf000086_0002
or a pharmaceutically acceptable salt thereof. 45. The pharmaceutical composition of embodiment 44, wherein Rd is H. 46. The pharmaceutical composition of embodiment 45, wherein Rd is CH3. 47. The pharmaceutical composition of any one of embodiments 1-46, wherein R1 is OH. 48. The pharmaceutical composition of any one of embodiments 1-46, wherein R1 is OCH3. 49. The pharmaceutical composition of embodiment 1, wherein the compound is a described by formula (III):
Figure imgf000086_0003
, or a pharmaceutically acceptable salt thereof. 50. The pharmaceutical composition of embodiment 49, wherein L2 is optionally substituted C3- C8 alkylene. 51. The pharmaceutical composition of embodiment 50, wherein L2 is optionally substituted C4 alkylene. 52. The pharmaceutical composition of embodiment 51, wherein the compound is described by formula (IIIA):
Figure imgf000087_0001
(IIIA), wherein Re and Rf are each independently H, OH, Cl, Br, or F; or Re and Rf are joined to form an epoxy; or a pharmaceutically acceptable salt thereof. 53. The pharmaceutical composition of embodiment 52, wherein Re and Rf are each H. 54. The pharmaceutical composition of embodiment 52, wherein Re and Rf are each OH. 55. The pharmaceutical composition of embodiment 52, wherein Re and Rf are joined to form an epoxy. 56. The pharmaceutical composition of embodiment 49, wherein L2 is optionally substituted C3- C8 alkenylene. 57. The pharmaceutical composition of embodiment 56, wherein L2 is optionally substituted C4 alkenylene. 58. The pharmaceutical composition of embodiment 57, wherein the compound is described by formula (IIIB):
Figure imgf000087_0002
(IIIB), or a pharmaceutically acceptable salt thereof. 59. The pharmaceutical composition of embodiment 50, wherein L2 is optionally substituted C5 alkylene. 60. The pharmaceutical composition of embodiment 59, wherein the compound is described by formula (IIIC):
Figure imgf000087_0003
(IIIC) wherein Re, Rf, and Rg are each independently H, OH, Cl, Br, or F; or Re and Rf are joined to form an epoxy; or Rf and Rg are joined to form an epoxy; or a pharmaceutically acceptable salt thereof. 61. The pharmaceutical composition of embodiment 60, wherein Re, Rf, and Rg are each H. 62. The pharmaceutical composition of embodiment 60, wherein Rg is H and Re and Rf are joined to form an epoxy. 63. The pharmaceutical composition of embodiment 60, wherein Re is H and Rf and Rg are joined to form an epoxy. 64. The pharmaceutical composition of embodiment 49, wherein L2 is optionally substituted C5 alkenylene. 65. The pharmaceutical composition of embodiment 64, wherein the compound is described by formula (IIID):
Figure imgf000088_0001
or a pharmaceutically acceptable salt thereof. 66. The pharmaceutical composition of embodiment 64, wherein the compound is described by formula (IIIE):
Figure imgf000088_0002
(IIIE), or a pharmaceutically acceptable salt thereof. 67. The pharmaceutical composition of embodiment 49, wherein L2 is optionally substituted C3- C8 heteroalkylene. 68. The pharmaceutical composition of embodiment 67, wherein L2 is optionally substituted C4 heteroalkylene. 69. The pharmaceutical composition of embodiment 68, wherein the compound is described by formula (IIIF):
Figure imgf000089_0001
(IIIF), or a pharmaceutically acceptable salt thereof. 70. The pharmaceutical composition of any one of embodiments 49-69, wherein X5 is O. 71. The pharmaceutical composition of any one of embodiments 49-69, wherein X5 is NH. 72. The pharmaceutical composition of any one of embodiments 1-71, wherein R3 and R4 are each CH3. 73. The pharmaceutical composition of embodiment 72, wherein R2 is CH2D. 74. The pharmaceutical composition of embodiment 72, wherein R2 is CHD2. 75. The pharmaceutical composition of embodiment 72, wherein R2 is CD3. 76. The pharmaceutical composition of any one of embodiments 1-71, wherein R2 is H or CH3. 77. The pharmaceutical composition of embodiment 76, wherein R3 is CH3. 78. The pharmaceutical composition of embodiment 77, wherein R4 is CH2D. 79. The pharmaceutical composition of embodiment 77, wherein R4 is CHD2. 80. The pharmaceutical composition of embodiment 77, wherein R4 is CD3. 81. The pharmaceutical composition of embodiment 76, wherein R3 and R4 are each CH2D, CHD2, or CD3. 82. The pharmaceutical composition of embodiment 81, wherein R3 and R4 are each CH2D. 83. The pharmaceutical composition of embodiment 81, wherein R3 and R4 are each CHD2. 84. The pharmaceutical composition of embodiment 81, wherein R3 and R4 are each CD3. 85. The pharmaceutical composition of any one of embodiments 72-75, wherein L1 is optionally substituted C2-C6 alkylene. 86. The pharmaceutical composition of embodiment 85, wherein L1 is
Figure imgf000089_0002
. 87. The pharmaceutical composition of embodiment 86, wherein L1 is
Figure imgf000089_0003
88. The pharmaceutical composition of embodiment 87, wherein L1 is
Figure imgf000089_0004
. 89. The pharmaceutical composition of embodiment 87, wherein L1 is
Figure imgf000090_0001
. 90. The pharmaceutical composition of any one of embodiments 76-84, wherein
Figure imgf000090_0002
is H and L1 is optionally substituted C2-C6 alkylene. 91. The pharmaceutical composition of embodiment 90, wherein R2 and L1 form
Figure imgf000090_0003
. 92. The pharmaceutical composition of any one of embodiments 72-84, wherein L1 is optionally substituted C1-C6 heteroalkylene. 93. The pharmaceutical composition of embodiment 92, wherein L1 is
Figure imgf000090_0004
94. The pharmaceutical composition of embodiment 93, wherein R1 is
Figure imgf000090_0005
. 95. The pharmaceutical composition of any one of embodiments 72-84, wherein L1 is optionally substituted C2-C6 alkenylene. 96. The pharmaceutical composition of embodiment 95, wherein L1 is
Figure imgf000090_0006
. 97. The pharmaceutical composition of any one of embodiments 76-84, wherein R2 is H and L1 is optionally substituted phenylene. 98. The pharmaceutical composition of embodiment 97, wherein R2 and L1 form
Figure imgf000091_0001
99. The pharmaceutical composition of any one of embodiments 76-84, wherein
Figure imgf000091_0002
is H and L1 is optionally substituted 5-membered heterocyclylene. 100. The pharmaceutical composition of embodiment 99, wherein
Figure imgf000091_0003
and L1 form optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, optionally substituted tetrahydropyran, optionally substituted thiepine, or optionally substituted 1,4-thiazepine. 101. The pharmaceutical composition of embodiment 100, wherein
Figure imgf000091_0004
and L1 form
Figure imgf000091_0005
Figure imgf000091_0007
102. The pharmaceutical composition of any one of embodiments 76-84, wherein
Figure imgf000091_0006
is H and L1 is optionally substituted amido of formula -C(O)NHL3-, wherein L3 is optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C1-C20 alkenylene, optionally substituted C1-C20 heteroalkenylene, optionally substituted C1-C20 alkynylene, optionally substituted C1- C20 heteroalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heterocyclylene, or optionally substituted C3-C20 cycloalkylene. 103. The pharmaceutical composition of embodiment 102, wherein R2 and L1 form
Figure imgf000092_0001
104. The pharmaceutical composition of any one of embodiments 1-103, wherein R5 is CH3. 105. The pharmaceutical composition of any one of embodiments 1-103, wherein R5 is CH2OH. 106. The pharmaceutical composition of embodiment 1, wherein the compound is any one of compounds 1-531 and 534-689, or a pharmaceutically acceptable salt thereof. 107. The pharmaceutical composition of embodiment 1, wherein the compound is any one of compounds 1389-1433 and 1485-1490, or a pharmaceutically acceptable salt thereof. 108. A compound described by formula (I′), (II′), or (III′):
Figure imgf000092_0002
, wherein R1 is H, O, OH, F, Cl, Br, NH2, or optionally substituted C1-C3 alkoxy; R2 is H, CH3, CH2F, CHF2, or CF3; R3 and R4 are each independently CH3, CH2F, CHF2, or CF3; R5 is CH3 or CH2OH; L1 is optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C5- C15 arylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C2-C15 heterocyclylene, or optionally substituted amido; each dashed line is optionally a double bond; A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, optionally substituted 3-to-8 membered heterocyclyl, or cyano; X1 and X2 are each independently H, O, Cl, or F; X3 and X4 are each independently H or absent; Q is an optionally substituted 5-to-8 membered heterocyclyl fused ring; L2 is optionally substituted C3-C8 alkylene, optionally substituted C3-C8 heteroalkylene, optionally substituted C3-C8 alkenylene, optionally substituted C3-C8 heteroalkenylene, optionally substituted C3-C8 alkynylene, or optionally substituted C3-C8 heteroalkynylene; and X5 is O or NH, wherein at least one of R2, R3, and R4 is CH2F, CHF2, or CF3; or a pharmaceutically acceptable salt thereof. 109. The compound of embodiment 108, where the compound is described by formula (I′):
Figure imgf000093_0001
, or a pharmaceutically acceptable salt thereof. 110. The compound of embodiment 109, wherein the compound is described by formula (I′A):
Figure imgf000093_0002
(I′A), or a pharmaceutically acceptable salt thereof. 111. The compound of embodiment 110, wherein the compound is described by formula (I′A-1):
Figure imgf000093_0003
(I′A), or a pharmaceutically acceptable salt thereof. 112. The compound of embodiment 111, wherein the compound is described by formula (I′A-2):
Figure imgf000093_0004
(I′A-2), or a pharmaceutically acceptable salt thereof. 113. The compound of embodiment 111, wherein the compound is described by formula (I′A-3):
Figure imgf000093_0005
(I′A-3), or a pharmaceutically acceptable salt thereof. 114. The compound of embodiment 109, wherein the compound is described by formula (1′A-4):
Figure imgf000094_0001
(I′A-4), or a pharmaceutically acceptable salt thereof. 115. The compound of any one of embodiments 109-114, wherein A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, or cyano. 116. The compound of embodiment 115, wherein the compound is described by formula (I′A- 2A):
Figure imgf000094_0002
(I′A-2A), wherein Ra is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C3-C20 cycloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C3-C20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or a pharmaceutically acceptable salt thereof. 117. The compound of embodiment 116, wherein Ra is H. 118. The compound of embodiment 115, wherein the compound is described by formula (I′A- 2B):
Figure imgf000094_0003
(I′A-2B), wherein each of Ra and Ra′ is independently H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C3-C20 cycloalkyl, optionally substituted C1- C20 heteroalkyl, optionally substituted C3-C20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or Ra and Ra′, together with the nitrogen atom to which they are attached, combine to form an optionally substituted C3-C20 heterocyclyl; or a pharmaceutically acceptable salt thereof. 119. The compound of embodiment 118, wherein Ra is optionally substituted C1-C20 alkyl. 120. The compound of embodiment 118, wherein Ra is optionally substituted C3-C20 cycloalkyl. 121. The compound of any one of embodiments 118-120, wherein Ra′ is H. 122. The compound of embodiment 118, wherein Ra and Ra′, together with the nitrogen atom to which they are attached, combine to form an optionally substituted C3-C20 heterocyclyl. 123. The compound of any one of embodiments 109-114, wherein A is optionally substituted 3- to-8 membered heterocyclyl. 124. The compound of embodiment 123, wherein A is optionally substituted 5-membered heterocyclyl. 125. The compound of embodiment 124, wherein A is optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4-oxatriazole, or optionally substituted 1,2,3,4-thiatriazole. 126. The compound of embodiment 125, wherein A is
Figure imgf000095_0001
127. The compound of embodiment 126, wherein A is
Figure imgf000095_0002
. 129. The compound of embodiment 125, wherein A is
Figure imgf000096_0001
130. The compound of embodiment 123, wherein A is optionally substituted 6-membered heterocyclyl. 131. The compound of embodiment 130, wherein A is optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, or optionally substituted tetrahydropyran. 132. The compound of embodiment 131, wherein A is
Figure imgf000096_0002
133. The compound of embodiment 132, wherein A is
Figure imgf000096_0003
. 134. The compound of embodiment 131, wherein A is
Figure imgf000096_0004
. 135. The compound of embodiment 123, wherein A is optionally substituted 7-membered heterocyclyl. 136. The compound of embodiment 135, wherein A is optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted thiepine, or optionally substituted 1,4-thiazepine. 137. The compound of embodiment 108, wherein the compound is described by formula (II′):
Figure imgf000096_0005
, or a pharmaceutically acceptable salt thereof. 138. The compound of embodiment 137, wherein the compound is described by formula (II′A):
Figure imgf000097_0001
wherein Q1, Q2, and Q3 are each independently C, O, or N; and Rb and Rc are each independently H, C1-C6 alkyl, or absent; and Rd is H, optionally substituted C1-C6 alkyl, or absent; or a pharmaceutically acceptable salt thereof. 139. The compound of embodiment 138, wherein the compound is described by formula (II′A-1):
Figure imgf000097_0002
(II′A-1), wherein Q1 and Q2 are each independently O or N; and Rb and Rc are each independently H, C1-C6 alkyl, or absent; or a pharmaceutically acceptable salt thereof. 140. The compound of embodiment 138, wherein the compound is described by formula (II′A-2):
Figure imgf000097_0003
wherein Q2 and Q3 are each independently O or N; and Rc is H, C1-C6 alkyl, or absent; Rd is H, optionally substituted C1-C6 alkyl, or absent; or a pharmaceutically acceptable salt thereof. 141. The compound of embodiment 140, wherein the compound is described by formula (II′A- 2A):
Figure imgf000098_0001
(II′A-2A), wherein Rc is H or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof. 142. The compound of embodiment 141, wherein Rc is H. 143. The compound of embodiment 141, wherein Rc is CH3. 144. The compound of embodiment 140, wherein the compound is described by formula (II′A- 2B):
Figure imgf000098_0002
(II′A-2B), wherein Rd is H or optionally substituted C1-C6 alkyl; or a pharmaceutically acceptable salt thereof. 145. The compound of embodiment 144, wherein Rd is H or C1-C6 alkyl. 146. The compound of embodiment 145, wherein Rd is H. 147. The compound of embodiment 145, wherein Rd is CH3. 148. The compound of embodiment 144, wherein Rd is C1-C6 alkyl substituted with ORh or NRiRj, wherein Rh is H or C1-C6 alkyl, and each of Ri and Rj is independently H or alkyl, or Ri and Rj, together with the nitrogen atom to which they are attached form an optionally substituted 3- to 6-membered saturated ring. 149. The compound of embodiment 148, wherein Rd is
Figure imgf000098_0003
, ,
Figure imgf000098_0004
150. The compound of embodiment 140, wherein the compound is described by formula (II′A- 2C):
Figure imgf000099_0001
or a pharmaceutically acceptable salt thereof. 151. The compound of embodiment 138, wherein the compound is described by formula (II′A-3):
Figure imgf000099_0002
or a pharmaceutically acceptable salt thereof. 152. The compound of embodiment 151, wherein Rd is H. 153. The compound of embodiment 151, wherein Rd is CH3. 154. The compound of any one of embodiments 108-153, wherein R1 is OH. 155. The compound of any one of embodiments 108-153, wherein R1 is OCH3. 156. The compound of embodiment 108, wherein the compound is described by formula (III′):
Figure imgf000099_0003
, or a pharmaceutically acceptable salt thereof. 157. The compound of embodiment 156, wherein L2 is optionally substituted C3-C8 alkylene. 158. The compound of embodiment 157, wherein L2 is optionally substituted C4 alkylene. 159. The compound of embodiment 158, wherein the compound is described by formula (III′A):
Figure imgf000099_0004
wherein R and Rf are each independently H OH Cl Br or F; or Re and Rf are joined to form an epoxy; or a pharmaceutically acceptable salt thereof. 160. The compound of embodiment 159, wherein Re and Rf are each H. 161. The compound of embodiment 159, wherein Re and Rf are each OH. 162. The compound of embodiment 159, wherein Re and Rf are joined to form an epoxy. 163. The compound of embodiment 156, wherein L2 is optionally substituted C3-C8 alkenylene. 164. The compound of embodiment 163, wherein L2 is optionally substituted C4 alkenylene. 165. The compound of embodiment 164, wherein the compound is described by formula (III′B):
Figure imgf000100_0001
or a pharmaceutically acceptable salt thereof. 166. The compound of embodiment 157, wherein L2 is optionally substituted C5 alkylene. 167. The compound of embodiment 166, wherein the compound is described by formula (III′C):
Figure imgf000100_0002
wherein Re, Rf, and Rg are each independently H, OH, Cl, Br, or F; or Re and Rf are joined to form an epoxy; or Rf and Rg are joined to form an epoxy; or a pharmaceutically acceptable salt thereof. 168. The compound of embodiment 167, wherein Re, Rf, and Rg are each H. 169. The compound of embodiment 167, wherein Rg is H and Re and Rf are joined to form an epoxy. 170. The compound of embodiment 167, wherein Re is H and Rf and Rg are joined to form an epoxy. 171. The compound of embodiment 156, wherein L2 is optionally substituted C5 alkenylene. 172. The compound of embodiment 171 , wherein the compound is described by formula (I I I'D):
Figure imgf000101_0001
or a pharmaceutically acceptable salt thereof.
173. The compound of embodiment 171 , wherein the compound is described by formula (IIIΈ):
Figure imgf000101_0002
or a pharmaceutically acceptable salt thereof.
174. The compound of embodiment 156, wherein l_2 is optionally substituted C3-C8 heteroalkylene.
175. The compound of embodiment 174, wherein L2 is optionally substituted C4 heteroalkylene.
176. The compound of embodiment 175, wherein the compound is described by formula (lll'F):
Figure imgf000101_0003
(IM F), or a pharmaceutically acceptable salt thereof.
177. The compound of any one of embodiments 156-176, wherein X5 is O.
178. The compound of any one of embodiments 156-176, wherein X5 is NH.
179. The compound of any one of embodiments 108-178, wherein R3 and R4 are each CH3.
180. The compound of embodiment 179, wherein R2 is CH2F.
181. The compound of embodiment 179, wherein R2 is CHF2.
182. The compound of embodiment 179, wherein R2 is CF3.
183. The compound of any one of embodiments 108-178, wherein R2 is H or CH3.
184. The compound of embodiment 183, wherein R3 is CH3.
185. The compound of embodiment 183, wherein R4 is CH2F.
186. The compound of embodiment 183, wherein R4 is CHF2.
187. The compound of embodiment 183, wherein R4 is CF3.
188. The compound of embodiment 183, wherein R3 and R4 are each CH2F, CHF2, or CF3. 189. The compound of embodiment 188, wherein R3 and R4 are each CH2F. 190. The compound of embodiment 188, wherein R3 and R4 are each CHF2. 191. The compound of embodiment 188, wherein R3 and R4 are each CF3. 192. The compound of any one of embodiments 179-182, wherein L1 is optionally substituted C2- C6 alkylene. 193. The compound of embodiment 192, wherein L1 is
Figure imgf000102_0004
194. The compound of embodiment 193, wherein L1 is
Figure imgf000102_0001
195. The compound of embodiment 194, wherein L1 is f embodiment 194, wherein L1 is
Figure imgf000102_0002
. 197. The compound of any one of embodiments 183-191, wherein R2 is H and L1 is optionally substituted C2-C6 alkylene. 198. The compound of embodiment 197, wherein R2 and L1 form
Figure imgf000102_0003
199. The compound of any one of embodiments 179-191, wherein L1 is optionally substituted C1- C6 heteroalkylene. 200. The compound of embodiment 199, wherein L1 is
Figure imgf000103_0001
. 201. The compound of embodiment 200, wherein R1 is
Figure imgf000103_0002
. 202. The compound of any one of embodiments 179-191, wherein L1 is optionally substituted C2- C6 alkenylene. 203. The compound of embodiment 202, wherein L1 is
Figure imgf000103_0003
. 204. The compound of any one of embodiments 183-191, wherein R2 is H and L1 is optionally substituted phenylene. 205. The compound of embodiment 204, wherein R2 and L1 form
Figure imgf000103_0004
substituted 5-membered heterocyclylene. 207. The compound of embodiment 206, wherein R2 and L1 form optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, optionally substituted tetrahydropyran, optionally substituted thiepine, or optionally substituted 1,4-thiazepine. 208. The compound of embodiment 207, wherein R2 and L1 form ,
Figure imgf000103_0005
,
Figure imgf000104_0003
209. The compound of any one of embodiments 183-191, wherein
Figure imgf000104_0001
is H and L1 is optionally substituted amido of formula -C(O)NHL3-, wherein L3 is optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C1-C20 alkenylene, optionally substituted C1-C20 heteroalkenylene, optionally substituted C1-C20 alkynylene, optionally substituted C1-C20 heteroalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heterocyclylene, or optionally substituted C3-C20 cycloalkylene. 210. The compound of embodiment 209, wherein R2 and L1 form
Figure imgf000104_0002
211. The compound of any one of embodiments 108-210, wherein R5 is CH3. 212. The compound of any one of embodiments 108-210, wherein R5 is CH2OH. 213. The compound of claim 108, wherein the compound is any one of embodiments 690a- 1229a, 1233a-1388a, 690b-1229b, 1233b-1388b, 690c-1229c, and 1233c-1388c, or a pharmaceutically acceptable salt thereof. 214. The compound of claim 108, wherein the compound is any one of embodiments 1434a- 1484a, 1434b-1484b, and 1434c-1484c, or a pharmaceutically acceptable salt thereof. 215. A pharmaceutical composition comprising a compound of any one of embodiments 108-214 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 216. The pharmaceutical composition of embodiment 207, wherein at least one of R2, R3, and R4 is deuterium-enriched, and the composition has an isotopic enrichment factor for deuterium of at least 5. 217. The pharmaceutical composition of any one of embodiments 1-107 and 216, wherein the composition has an isotopic enrichment factor for deuterium of at least about 500. 218. The pharmaceutical composition of embodiment 217, wherein the composition has an isotopic enrichment factor for deuterium of at least about 1000. 219. The pharmaceutical composition of embodiment 218, wherein the composition has an isotopic enrichment factor for deuterium of at least about 3000. 220. The pharmaceutical composition of embodiment 219, wherein the composition has an isotopic enrichment factor for deuterium of at least about 4000, 5000, or 6000. 221. A method of treating an inflammatory disease in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of any one of embodiments 1-107 and 215-220 in an amount sufficient to treat the condition. 222. The method of embodiment 221, wherein the inflammatory disease is selected from the group consisting of scleroderma, dermatomyositis, systemic lupus erythematosus, acquired immune deficiency syndrome (AIDS), multiple sclerosis, rheumatoid arthritis, psoriasis, diabetes, cancer, asthma, atopic dermatitis, an autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, stroke, ischemia, a neurodegenerative disease, amyotrophic lateral sclerosis (ALS), chronic traumatic encephalopathy (CTE), chronic inflammatory demyelinating polyneuropathy, an autoimmune inner ear disease, uveitis, iritis, and peritonitis. 223. The method of embodiment 222, wherein the inflammatory disease is scleroderma. 224. The method of embodiment 223, wherein the scleroderma is systemic sclerosis, localized scleroderma, or sine scleroderma. 225. A method of treating a fibrotic disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of embodiments 1-107 and 215- 220 in an amount sufficient to treat the condition. 226. The method of embodiment 225, wherein the fibrotic disease is selected from the group consisting of scleroderma, cystic fibrosis, liver cirrhosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, Dupuytren’s contracture, keloids, chronic kidney disease, chronic graft rejection, scarring, wound healing, post-operative adhesions, reactive fibrosis, polymyositis, ANCA vasculitis, Behcet's disease, anti-phospholipid syndrome, relapsing polychondritis, Familial Mediterranean Fever, giant cell arteritis, Graves ophthalmopathy, discoid lupus, pemphigus, bullous pemphigoid, hydradenitis suppuritiva, sarcoidosis, bronchiolitis obliterans, primary sclerosing cholangitis, primary biliary cirrhosis, or organ fibrosis. 227. The method of embodiment 226, wherein the fibrotic disease is scleroderma. 228. The method of embodiment 227, wherein the scleroderma is systemic sclerosis, localized scleroderma, or sine scleroderma. 229. The method of embodiment 226, wherein the fibrotic disease is organ fibrosis. 230. The method of embodiment 229, wherein the organ fibrosis is dermal fibrosis, lung fibrosis, liver fibrosis, kidney fibrosis, or heart fibrosis. 231. The method of embodiment 226, wherein the fibrotic disease is cystic fibrosis. Examples The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. General Methods Liquid Chromatography-Mass Spectrometry (LCMS) Methods Method Tacc50-6 and Method Tacc50-6_AP_AMAC: The analyses were performed using an Agilent Technology 6120 LC/MSD quadrupole coupled to an Agilent 1260 Infinity series liquid chromatography (LC) system consisting of a binary pump with degasser, autosampler, thermostat column compartment and diode array detector. The mass spectrometer (MS) was operated with an atmospheric pressure electro-spray ionization (API-ES) source in positive ion mode. The capillary voltage was set to 3000 V, the fragmentor voltage to 70 V and the quadrupole temperature was maintained at 100°C. The drying gas flow and temperature values were 12.0 L/min and 350 °C, respectively. Nitrogen was used as the nebuliser gas, at a pressure of 35 psig. Data acquisition was performed with Agilent Chemstation software. HPLC condition for method Tacc50-6: Analyses were carried out on a Thermo Scientific Accucore aQ C18 column (50 mm long x 4.6 mm I.D.; 2.6 μm particles) at 35 °C, with a flow rate of 3 mL/min. A gradient elution was performed from 90% (Water + 0.1% Formic acid) / 10% Acetonitrile to 5% (Water + 0.1% Formic acid) / 95% Acetonitrile in 1.50 minutes; the resulting composition was held for 0.90 min; then the final mobile phase composition; from 10% (Water + 0.1% Formic acid) / 90% Acetonitrile to 90% (Water + 0.1% Formic acid) / 10% Acetonitrile in 0.10 minutes. The injection volume was 2 μL. MS acquisition range and DAD detector were set to 100-1000 m/z and 200-400 nm respectively. HPLC condition for method Tacc50-6_AP_AMAC: Analyses were carried out on a Thermo Scientific Accucore aQ C18 column (50 mm long x 4.6 mm I.D.; 2.6 μm particle size) at 35 °C, with a flow rate of 3 mL/min. A gradient elution was performed from 50% (Water + 50 mM NH4OAc)/50% Acetonitrile to 5% (Water + 50 mM NH4OAc)/95% Acetonitrile in 1.5 min; the resulting composition was held for 0.9 min; from 5% (Water + 50 mM NH4OAc)/95% Acetonitrile to 95% (Water + 50 mM NH4OAc)/5% Acetonitrile in 0.2 min. Acquisition ranges were set to 190-400 nm for the UV-PDA detector and 100-1400 m/z for the MS detector. Method VILLA and Method ZVilla_amonico_21: The analyses were performed using an Agilent G1956A LC/MSD quadrupole coupled to an Agilent 1100 series liquid chromatography (LC) system consisting of a binary pump with degasser, autosampler, thermostat column compartment and diode array detector. The mass spectrometer (MS) was operated with an atmospheric pressure electro-spray ionization (API-ES) source in positive ion mode. The capillary voltage was set to 3000 V, the fragmentor voltage to 70 V and the quadrupole temperature was maintained at 100°C. The drying gas flow and temperature values were 12.0 L/min and 350 °C, respectively. Nitrogen was used as the nebuliser gas, at a pressure of 35 psig. Data acquisition was performed with Agilent Chemstation software. HPLC condition for method VILLA: It is a long routine analysis for Quality Control of final compounds. Analyses were carried out on a YMC pack ODS-AQ C18 column (50 mm long x 4.6 mm I.D..; 3 μm particle size) at 35 °C, with a flow rate of 2.6 mL/min. A gradient elution was performed from 95% (Water + 0.1% Formic acid)/5% Acetonitrile to 5% (Water + 0.1% Formic acid)/95% Acetonitrile in 4.8 min; the resulting composition was held for 1.0 min; from 5% (Water + 0.1% formic acid)/95% Acetonitrile to 95% (Water + 0.1% formic acid)/5% Acetonitrile in 0.2 min. Acquisition ranges were set to 190-400 nm for the UV-PDA detector and 100-1400 m/z for the MS detector. HPLC condition for method ZVilla_amonico_21: Analyses were carried out on a Phenomenex Kinetex C18 column (50 mm long x 2.1 mm; 2.6 μm particle size) at 35 °C, with a flow rate of 0.7 mL/min. A gradient elution was performed from 95% (Water, 50 mM NH4OAc)/5% Acetonitrile to 5% (Water, 50 mM NH4OAc)/95% Acetonitrile in 4.8 min; the resulting composition was held for 1.0 min and to 95% (Water, 50 mM NH4OAc)/5% Acetonitrile in 0.2 min. Acquisition ranges were set to 190-400 nm for the UV-PDA detector and 100-1400 m/z for the MS detector. Method VILLA_2T: It is a long routine analysis for Quality Control of final compounds. Analyses were carried out on a YMC pack ODS-AQ C18 column (50 mm long x 4.6 mm I.D.; 3 μm particle size) at 35 °C, with a flow rate of 2.6 mL/min. A gradient elution was performed using ISET 2V1.0 Emulated Agilent Pump G1312A V1.0 from 95% (Water + 0.1% Formic acid)/5% Acetonitrile to 5% (Water + 0.1% Formic acid)/95% Acetonitrile in 4.8 min; the resulting composition was held for 1.0 min; from 5% (Water + 0.1% formic acid)/95% Acetonitrile to 95% (Water + 0.1% formic acid)/5% Acetonitrile in 0.2 min. Acquisition ranges were set to 190-400 nm for the UV-PDA detector and 100-1000 m/z for the TOF-MS detector. Synthesis of ajulemic acid Ajulemic acid (AJA) may be synthesized as known in the art. Preferably, ajulemic acid is an ultrapure formulation of ajulemic acid including more than 99% ajulemic acid and less than 1% highly-active CB-1 impurities, e.g., HU-210. Ajulemic acid may be synthesized as described in U.S. Patent Publication No. 2015/0141501, which is incorporated herein by reference. Example 1. Metabolic study of AJA A study was conducted to determine the profile of AJA and its metabolites in plasma, urine, and feces samples obtained following oral administration of 14C-labeled AJA to 6 healthy male subjects, and to elucidate the chemical structures of selected metabolites using high resolution LC-MS(/MS). Pooled plasma and feces samples were prepared for analysis using sequential extraction with ca.3 volumes of 1% formic acid in acetonitrile. The sample extracts were concentrated by evaporation at room temperature. Where necessary, sample extracts were diluted with mobile phase and centrifuged to remove particulate material. Pooled urine samples were centrifuged to remove particulate matter prior to LC-MS(/MS) analysis. The recovery of radioactivity in the final samples was determined by liquid scintillation counting (LSC) and found to be acceptable for each matrix. The profiles of the radiolabeled components in each sample extract were determined by radio-HPLC analysis with off-line radio-detection. Selected samples from each matrix were then further analyzed by high resolution mass spectrometry to investigate the identity of the highly abundant metabolites. The major metabolic pathway was oxidation plus glucuronidation (Table 3). Overall eight metabolites were identified (Table 4 and FIGs.1-8). Other minor metabolites were quantified in the radio-analysis, but no identification was obtained due to the low abundance of these metabolites and/or significant suppression of the LC-MS response which resulted from endogenous material. Table 3. Notable metabolites detected by radio-HPLC following single oral administration of [14C]- AJA to 6 healthy male subjects.
Figure imgf000108_0001
TDR = total drug related * unknown peaks assigned across matrices based on peak retention time data only Xh faeces pooled over differing time-periods to generate samples with 90% of total radioactivity ms detected by LC-MS but peak below limit of quantification in radio-chromatogram NC relative exposure not calculated. Insufficient data points to calculate AUC Table 4. Structures of major metabolites of AJA
Figure imgf000108_0002
Figure imgf000109_0001
*Met1 has been previously characterized in Batista et al. Determination of ajulemic acid and its glucuronide in human plasma by gas chromatography–mass spectrometry, Journal of Chromatography B 820:77-82 (2005). In plasma, unchanged AJA was the major circulating component, accounting for 36% of the total drug related exposure (based on mean AUC(0-inf) values). The most notable metabolite, characterized as the hydroxy AJA acylglucuronide (Met6), accounted for 14% of the total drug related exposure (mean value). The other hydroxy AJA acylglucuronide, (Met5), accounted for ca 6%. All other plasma metabolites were considered to be minor as each accounted for 5% or less of the total drug related exposure (AUC(0-inf)). Met 5 and Met 6 and corresponding precursors (such as Met7) were only observed as metabolites of AJA in humans. Met 5 and Met 6 and corresponding precursors (such as Met7) were not observed in analogous metabolism studies performed in mouse, rat, dog, and monkey animal models. In the excreta, a dihydroxy acylglucuronide metabolite accounted for 13% of the total administered radioactive dose (via urine and feces). For all other metabolites, each accounted for less than 10% of the total excreted dose. No significant differences were observed in the metabolism of [14C]-lenabasum by the six study subjects; with the metabolite profiles of plasma and the excreta comparable between the individuals. Example 2. Synthesis of deuterated AJA analogs Synthesis of Compound 2
Figure imgf000110_0001
To a stirred suspension of NaH (60% in mineral oil, 6.78 g, 169.3 mmol, 3 eq.) in DMF (30 mL) was added 2-(3,5-dimethoxyphenyl)acetonitrile (10.0 g, 56.4 mmol, 1.0 eq.) in DMF (10 mL) dropwise at 0 ºC under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 0 ºC. Then CD3I (24.54 g, 169.3 mmol, 3.0 eq.) in DMF (10 mL) was added to the mixture dropwise over 0.5 h at 0 ºC. The resulting mixture was stirred for additional 2~3 h at room temperature. The reaction was quenched with sat. NH4Cl (aq.100 mL) at room temperature. The reaction mixture was extracted with EtOAc (3 ^100 mL). The combined organic layer was concentrated in vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum either (PE) / EtOAc (98:2) to afford the title compound as a colorless oil in 88.1% yield (10.5 g). ESI-MS m/z: 212.20 [M+H]+. 1H NMR (400 MHz, CDCl3, ppm): δ 6.62 (s, 2H), 6.42 (s, 1H), 3.84 (s, 6H).
Figure imgf000111_0001
To a stirred solution of 2-(3,5-dimethoxyphenyl)-2-(methyl-d3)propanenitrile-3,3,3-d3 (10.50 g, 49.7 mmol, 1.0 equiv) in DCM (100 mL) was added DIBAl-H (1 M, 124 mL, 124.2 mmol, 2.5 equiv) dropwise at -78 oC under nitrogen atmosphere. The resulting mixture was stirred for 1~2 h at -78 oC under nitrogen atmosphere. The reaction was quenched by the addition of water (200 mL) at -78 oC. The aqueous layer was extracted with EtOAc (3 ^200 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (98:2) to afford the title compound (10 g, 93.9%) as a colorless oil. ESI-MS m/z: 215.15 [M+H]+. 1H NMR (400 MHz, CDCl3, ppm): δ 9.47 (s, 1H), 6.41-6.43 (m, 3H), 3.81 (s, 6H).
Figure imgf000111_0002
To a stirred suspension of pentyltriphenylphosphanium bromide (96.44 g, 233.3 mmol, 5.0 equiv) in THF (150 mL) was added LiHMDS (1 M in THF, 233mL, 233.3 mmol, 5 equiv) dropwise at 0 oC under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 0 oC ~room temperature under nitrogen atmosphere. To the above mixture was added 2-(3,5-dimethoxyphenyl)-2-(methyl-d3)propanal-3,3,3-d3 (10.00 g, 46.7 mmol, 1.0 equiv) in THF (50 mL) dropwise at 0 oC. The resulting mixture was stirred for additional overnight at room temperature. The reaction was quenched with sat. NH4Cl (aq.) at 0 oC. The aqueous layer was extracted with EtOAc (3 ^200 mL). The organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (99:1) to afford the title compound (5.1 g, 40.7%) as a colorless oil. ESI-MS m/z: 269.15 [M+H]+. 1H NMR (400 MHz, CDCl3, ppm): δ 6.57 (s, 2H), 6.31 (s, 1H), 5.61-5.64 (m, 1H), 5.29-5.34 (m, 1H), 3.81 (s, 6H), 1.67- 1.69 (m, 2H), 1.13-1.17 (m, 4H), 0.75-0.79 (m, 3H).
Figure imgf000112_0001
To a 100 mL round-bottom flask were added 1,3-dimethoxy-5-(2-(methyl-d3)oct-3-en-2-yl-1,1,1- d3)benzene (5.10 g, 19 mmol, 1.0 equiv) and Pd/C (510 mg) in EtOAc (30 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The resulting mixture was filtrated through Celite, the filtrate was concentrated under reduced pressure to afford the title compound (5.1 g, crude) as a colorless oil. ESI-MS m/z: 271.25 [M+H]+. 1H NMR (400 MHz, CDCl3, ppm): δ 6.51 (s, 2H), 6.33 (m, 6H), 3.82 (s, 6H), 1.56-1.60 (m, 2H), 1.20-1.27 (m, 6H),1.08-1.10 (m, 2H), 0.86-0.89 (m, 3H).
Figure imgf000112_0002
To a 250 mL round-bottom flask were added 1,3-dimethoxy-5-(2-(methyl-d3)octan-2-yl-1,1,1-d3)benzene (5.10 g, 19 mmol, 1.0 equiv) and BBr3 (1 M, 94.3 mL, 94.3 mmol, 5.0 equiv) in DCE (50 mL) at room temperature. The resulting mixture was stirred for 2 h at 90 oC under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3x200 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (85:15) to afford 5-(2-(methyl-d3)octan-2-yl-1,1,1-d3)benzene-1,3-diol (5 g, 109.4%) as a dark brown oil. ESI-MS m/z: 243.40 [M+H]+. 1H NMR (400 MHz, CDCl3, ppm): δ 6.41 (s, 2H), 6.21 (s, 1H), 4.67 (br s, 2H), 1.50-1.54 (m, 2H), 1.20-1.30 (m, 6H), 1.06-1.08 (m, 2H), 0.85-0.88 (m, 3H). (6aR,10aR)-6,6,9-Trimethyl-3-(2-(methyl-d3)octan-2-yl-1,1,1-d3)-6a,7,10,10a-tetrahydro-6H- benzo[c]chromen-1-ol
Figure imgf000112_0003
To a stirred solution of 5-(2-(methyl-d3)octan-2-yl-1,1,1-d3)benzene-1,3-diol (5.00 g, 20.6 mmol, 1.0 equiv) and TsOH (710.4 mg, 4.13 mmol, 0.2 equiv) in toluene (300 mL) was added (4R)-1-methyl-4-(prop-1-en- 2-yl)cyclohex-2-en-1-ol (3.45 g, 22.67 mmol, 1.1 equiv) in toluene (100 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2~3 h at 80 oC under nitrogen atmosphere. The mixture was cooled down to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL). The aqueous layer was extracted with EtOAc (3x200 mL). The organic layer was concentrated in vacuo, the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (90:10) to afford the title compound (5 g, 64.4%) as a brown solid. ESI-MS m/z: 377.50 [M+H]+. 1H NMR 400 MHz, CDCl3, ppm): δ 6.46 (s, 1H), 6.25 (s, 1H), 5.45 (m, 1H), 3.20-3.25 (m, 1H), 2.70-2.75 (m, 1H), 2.14-2.19 (m, 1H), 1.81- 1.96 (m, 4H), 1.73 (s, 3H), 1.49-1.53 (m, 2H), 1.41 (s, 3H), 1.22-1.28 (m, 6H), 1.19 (s, 3H), 1.07-1.14 (m, 2H), 0.85-0.89 (m, 3H). (6aR,10aR)-6,6,9-Trimethyl-3-(2-(methyl-d3)octan-2-yl-1,1,1-d3)-6a,7,10,10a-tetrahydro-6H- benzo[c]chromen-1-yl pivalate
Figure imgf000113_0001
To a stirred solution of (6aR,10aR)-6,6,9-trimethyl-3-(2-(methyl-d3)octan-2-yl-1,1,1-d3)-6a,7,10,10a- tetrahydro-6H-benzo[c]chromen-1-ol (3.50 g, 9.3 mmol, 1.0 equiv) and Et3N (4.70 g, 46.45 mmol, 5.0 equiv) in THF (30 mL) was added 2,2-dimethylpropanoyl chloride (4.48 g, 37.15 mmol, 4.0 equiv) dropwise at room temperature under nitrogen atmosphere. The resultant was stirred overnight at room temperature under nitrogen atmosphere. The reaction was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (98:2) to afford the title compound (5 g, 116%) as a light brown oil. ESI-MS m/z: 461.40 [M+H]+. 1H NMR (400 MHz, CDCl3, ppm): δ 6.69 (s, 1H), 6.43 (s, 1H), 5.44 (br s, 1H), 2.77-2.82 (m, 1H), 2.55-2.60 (m, 1H), 2.13-2.17 (m, 1H), 1.73-1.95 (m, 4H), 1.67-1.73 (m, 2H), 1.51-1.55 (m, 2H), 1.36-1.44 (m, 3H), 1.30 (s, 9H), 1.18-1.26 (m, 6H), 1.14 (s, 3H), 1.07-1.12 (m, 2H), 0.85-0.89 (m, 3H). (6aR,10aR)-9-Formyl-6,6-dimethyl-3-(2-(methyl-d3)octan-2-yl-1,1,1-d3)-6a,7,10,10a-tetrahydro-6H- benzo[c]chromen-1-yl pivalate
Figure imgf000113_0002
To a 250 mL round-bottom flask were added (6aR,10aR)-6,6,9-trimethyl-3-(2-(methyl-d3)octan-2-yl-1,1,1- d3)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl pivalate (5.00 g, 10.85 mmol, 1.0 equiv) and SeO2 (1.57 g, 14.11 mmol, 1.3 equiv) in THF (30 mL)/H2O (2 mL) at room temperature. The resulting mixture was stirred overnight at 50 oC under nitrogen atmosphere. The mixture was cooled down to room temperature, diluted with water (50 mL), and extracted with EtOAc (3 ^100 mL). The combined organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (95:5) to afford the title compound (2.6 g, crude) as a light yellow solid, which was immediately used in next reaction. ESI-MS m/z: 475.35 [M+H]+. (6aR,10aR)-6,6-Dimethyl-3-(2-(methyl-d3)octan-2-yl-1,1,1-d3)-1-(pivaloyloxy)-6a,7,10,10a-tetrahydro-6H- benzo[c]chromene-9-carboxylic acid
Figure imgf000114_0001
To a 100 mL round-bottom flask were added (6aR,10aR)-9-formyl-6,6-dimethyl-3-(2-(methyl-d3)octan-2- yl-1,1,1-d3)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl pivalate (2.50 g, 5.23 mmol, 1.0 equiv), hydrogen peroxide (5 mL), and THF at room temperature. The reaction was stirred overnight at room temperature under nitrogen atmosphere. The reaction was then diluted with water (50 mL) and extracted with EtOAc (3 ^100 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (90:10) to afford the title compound (2 g, 77.4%) as a light-yellow oil. ESI-MS m/z: 491.35 [M+H]+.
Figure imgf000114_0002
To a 100 mL round-bottom flask were added (6aR,10aR)-6,6-dimethyl-3-(2-(methyl-d3)octan-2-yl-1,1,1- d3)-1-(pivaloyloxy)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylic acid (2.00 g, 4.07 mmol, 1.0 equiv) and NaOH (0.98 g, 24.45 mmol, 6.0 equiv) in THF(10 mL)/H2O (2 mL) at room temperature. The reaction mixture was stirred for 2 h at room temperature then was acidified to pH=4 with HCl (aq.2 M) followed by extraction with EtOAc (3 ^30 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (WelFlash Spherical C18 20-40μm column; Flow rate = 80 mL/min; Gradient:0-80% ACN/water in 20 min) followed by prep-HPLC purification (XBridge Shield RP18 OBD Column, 5 um,19*150 mm; Mobile Phase A: Water (0.05% formic acid), Mobile Phase B: ACN; Flow rate:25 mL/min; Gradient:25%B to 50%B in 11 min; detection at 220 nm) to afford the title compound (214.3 mg, 12.9%) as a white solid. ESI-MS m/z: 407.30 [M+H]+. 1H- NMR (400 MHz, DMSO-d6, ppm): δ 0.77 – 0.88 (m, 3H), 1.03 (s, 5H), 1.19 (d, J = 8.2 Hz, 6H), 1.32 (s, 3H), 1.46 (dd, J = 11.4, 5.5 Hz, 2H), 1.66 (td, J = 12.1, 5.1 Hz, 2H), 2.00 (t, J = 15.2 Hz, 1H), 2.36 (d, J = 19.0 Hz, 1H), 2.45 (d, J = 3.5 Hz, 1H), 3.76 (d, J = 17.6 Hz, 1H), 6.14 (s, 1H), 6.32 (s, 1H), 6.84 – 6.97 (m, 1H), 9.22 (s, 1H), 12.12 (s, 1H). Synthesis of Compound 3
Figure imgf000115_0001
(Pentyl-5,5,5-d3)triphenylphosphonium bromide
Figure imgf000115_0002
Triphenylphosphine (3.4 g, 13.0 mmol, 1 eq) was added to a solution of 1-bromopentane-5,5,5-d3 (2.0 g, 13.0 mmol, 1 eq) in toluene (13 mL) and the mixture heated in a sealed tube at 110 °C for 12 hours. The resulting white precipitate was filtered off, washed with toluene and dried under vacuum to yield the product as a white solid (2.6 g, 48%). ESI-MS m/z: 335.9 [M+H]+. 1H NMR (300 MHz, CDCl3) δ 7.87 – 7.57 (m, 15H), 3.79 (s, 2H), 1.56 (s, 4H), 1.21 (s, 2H). (Z)-1,3-Dimethoxy-5-(2-methyloct-3-en-2-yl-8,8,8-d3)benzene
Figure imgf000115_0003
LiHMDS (1 M in THF, 15.5 mL, 15.5 mmol, 2.5 eq) was added dropwise to a solution of (pentyl-5,5,5- d3)triphenylphosphonium bromide (2.6 g, 6.2 mmol, 1 eq) in anhydrous THF (10 mL) at 0 °C under nitrogen atmosphere and the resulting red solution was stirred at room temperature for 1 hour. A solution of 2-(3,5-dimethoxyphenyl)-2-methylpropanal (1.2 g, 6.2 mmol, 1 eq) in anhydrous THF (10 mL) was added dropwise and the mixture stirred for a further 12 hours. Water was then added, and the mixture extracted with ethyl acetate. The combined organic fractions were dried over MgSO4, concentrated under reduced pressure, and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to give the product as a thick oil (1.3 g, 77%). ESI-MS m/z: 266.0 [M+H]+.
Figure imgf000116_0001
Palladium on carbon (Degussa type, 10% loading, wet, 0.1 g) was added to a solution of (Z)-1,3- dimethoxy-5-(2-methyloct-3-en-2-yl-8,8,8-d3)benzene (0.6 g, 2.2 mmol, 1 eq) in EtOH (30 mL) and the suspension was stirred at room temperature under hydrogen atmosphere (1 atm) for 12 hours. The mixture was filtered through a pad of Celite and the cake washed with ethanol. The combined filtrates were concentrated to afford the crude product (0.6 g, 93%) as an oil. ESI-MS m/z: 268.0 [M+H]+. 5-(2-Methyloctan-2-yl-8,8,8-d3)benzene-1,3-diol
Figure imgf000116_0002
Boron tribromide (0.8 mL, 8.7 mmol, 2.2 eq) was added dropwise to a solution of 1,3-dimethoxy-5-(2- methyloctan-2-yl-8,8,8-d3)benzene (1.1 g, 3.9 mmol, 1 eq) in anhydrous dichloromethane (20 mL) at -78 °C. The mixture was allowed to warm to room temperature and stirred for 1 hour before it was cooled to 0 °C and quenched with ice. The quenched mixture was extracted with further dichloromethane and the combined organic extracts dried over MgSO4 and concentrated to afford the product as a thick oil (0.8 g, 84%). ESI-MS m/z: 240.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 6.31 (d, J = 2.2 Hz, 2H), 6.10 (t, J = 2.2 Hz, 1H), 1.49 – 1.39 (m, 2H), 1.20 – 1.04 (m, 12H), 0.98 (dd, J = 9.6, 5.2 Hz, 2H). (6aR,10aR)-6,6,9-Trimethyl-3-(2-methyloctan-2-yl-8,8,8-d3)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen- 1-ol
Figure imgf000116_0003
A solution of (4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (0.55 g, 3.6 mmol, 1.1 eq) in toluene (2 mL) was added dropwise to a stirred solution of 5-(2-methyloctan-2-yl-8,8,8-d3)benzene-1,3-diol (0.8 g, 3.3 mmol, 1 eq) and pTSA•H2O (0.1 g, 0.7 mmol, 0.2 eq) in toluene (8 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was then refluxed into a Dean-Stark trap at 70-80 ºC under partial vacuum for 6 hours. The resulting toluene solution was washed with water and brine, dried over MgSO4, concentrated and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to give the product as a white solid (1.1 g, 89%). ESI-MS m/z: 374.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 0.93 – 1.14 (m, 16H), 1.22 (s, 1H), 1.32 (s, 3H), 1.37 – 1.47 (m, 2H), 1.63 (s, 3H), 1.69 – 1.89 (m, 3H), 2.08 (dd, J = 9.1, 4.0 Hz, 1H), 2.62 (td, J = 11.0, 4.7 Hz, 1H), 3.12 (dd, J = 16.3, 4.6 Hz, 1H), 4.55 (s, 1H), 5.36 (d, J = 4.8 Hz, 1H), 6.16 (d, J = 1.8 Hz, 1H), 6.32 (d, J = 1.8 Hz, 1H). (6aR,10aR)-6,6,9-Trimethyl-3-(2-methyloctan-2-yl-8,8,8-d3)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen- 1-yl pivalate
Figure imgf000117_0001
Pivaloyl chloride (1.8 mL, 14.7 mmol, 5 eq) was added to a solution of (6aR,10aR)-6,6,9-trimethyl-3-(2- methyloctan-2-yl-8,8,8-d3)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol (1.1 g, 2.9 mmol, 1 eq) and triethylamine (4.1 mL, 29.5 mmol, 10 eq) in anhydrous THF (10 mL) at 0 °C, after which the solution was stirred at room temperature for 12 hours. The mixture was then diluted with ethyl acetate and washed with water. The organic phase was dried over MgSO4, filtered, concentrated and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to afford the product as an off-white solid (1.3 g, 96%). ESI-MS m/z: 354.9 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 6.60 (d, J = 1.9 Hz, 1H), 6.34 (d, J = 1.9 Hz, 1H), 5.37 – 5.31 (m, 1H), 2.70 (dd, J = 16.7, 4.1 Hz, 1H), 2.48 (td, J = 10.9, 4.6 Hz, 1H), 2.14 – 1.99 (m, 1H), 1.89 – 1.68 (m, 3H), 1.60 (s, 3H), 1.48 – 1.40 (m, 2H), 1.35 – 1.28 (m, 13H), 1.17 – 1.10 (m, 11H), 1.06 – 0.98 (m, 5H).
Figure imgf000117_0002
Selenium dioxide (0.2 g, 1.6 mmol 1.2 eq) was added to a stirred solution of (6aR,10aR)-6,6,9-trimethyl- 3-(2-methyloctan-2-yl-8,8,8-d3)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl pivalate (0.6 g, 1.3 mmol, 1 eq) in THF (7 mL) and water (5 µL, 0.3 mmol, 0.2 eq) and the mixture was stirred at 60 °C for 18 hours. After cooling the mixture to 0 °C, 30% hydrogen peroxide in water (0.3 mL, 7.9 mmol, 6 eq) was slowly added before allowing the mixture to warm to room temperature and stir for 3 hours. The reaction mixture was quenched with a 20% (w/w) aqueous sodium thiosulfate solution and the resulting suspension filtered through a pad of Celite and rinsed with ethyl acetate. The combined filtrates were washed with brine and the organic layer dried over anhydrous MgSO4 and concentrated to give the crude product as a dark solid (0.2 g, 30%). ESI-MS m/z: 488.0 [M+H]+.
Figure imgf000117_0003
A solution of sodium hydroxide (50 mg, 1.3 mmol, 5 eq) in water (0.5 mL) was added dropwise to a solution of (6aR,10aR)-6,6-dimethyl-3-(2-methyloctan-2-yl-8,8,8-d3)-1-(pivaloyloxy)-6a,7,10,10a- tetrahydro-6H-benzo[c]chromene-9-carboxylic acid (127 mg, 0.3 mmol, 1 eq) in MeOH (2 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 24 hours. The mixture was acidified to pH 5 with 2 M aqueous HCl, then extracted with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, concentrated and passed through a silica gel plug. eluting with heptane/ethyl acetate. Fractions containing the desired product were combined and repurified by prep- HPLC (Gemini C18 column, 100 x 30 mm, 5 µm, mobile phase A: 25mM aq. ammonium bicarbonate, mobile phase B: ACN, gradient: 41% B to 83% B over 30 min). The product-containing fractions were lyophilized to provide the product as a white powder (42 mg, 40%). ESI-MS m/z: 404.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 4.8 Hz, 1H), 6.39 (d, J = 1.5 Hz, 1H), 6.23 (d, J = 1.5 Hz, 1H), 3.83 (d, J = 19.2 Hz, 1H), 2.68 (td, J = 10.9, 4.4 Hz, 1H), 2.44 (d, J = 16.6 Hz, 1H), 2.13 – 1.94 (m, 2H), 1.85 (dt, J = 16.1, 7.9 Hz, 1H), 1.57 – 1.44 (m, 2H), 1.41 (s, 3H), 1.27 – 1.15 (m, 13H), 1.14 (s, 3H), 1.05 (d, J = 6.3 Hz, 2H). The synthetic procedures for other deuterated AJA analogs are adapted from those reported in International Patent Application Nos. PCT/US2019/034965, PCT/US2020/057985, and PCT/US2020/054103, each of which described the synthesis of analogs of ajulemic acid and is hereby incorporated by reference in its entirety. Example 3. Synthesis of fluorinated AJA analogs Synthesis of Compound 692a Methyl (6aR,10aR)-1-hydroxy-3-(8-hydroxy-2-methyloctan-2-yl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H- benzo[c]chromene-9-carboxylate
Figure imgf000118_0001
A solution 4N of HCl in dioxane (48 µL) was added to a stirred solution of (6aR,10aR)-1-hydroxy-3-(8- hydroxy-2-methyloctan-2-yl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylic acid (20 mg, 0.048 mmol) in MeOH (0.96 mL). The mixture was stirred at room temperature overnight. The solvent was removed, and the product was purified by silica gel column chromatography eluted with Heptane:EtOAc (from 100:0 to 70:30) to afford the title compound as a white solid (10 mg, 48.4 %). LC- MS (ESI+): 431.0 (M+H+), R.T.: 1.778 min (LCMS method: Tacc50-6_AP_AMAC). 1H NMR (300 MHz, CDCl3) δ 7.02 (bs, 1H), 6.38 (s, 1H), 6.25 (s, 1H), 3.81 (d, J = 18.45 Hz, 1H), 3.74 (s, 3H), 3.63 (t, J = 6.24 Hz, 1H), 2.65 (m, 1H), 2.4 (d, J = 16.50 Hz, 1H), 2.06-1.91 (m, 2H), 1.83 (m, 2H), 1.68- 1.44 (m,5H), 1.40 – 1.20 (m, 12H), 1.13 (s, 3H), 1.08 (bs, 2H). Methyl (6aR,10aR)-3-(8-fluoro-2-methyloctan-2-yl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H- benzo[c]chromene-9-carboxylate
Figure imgf000119_0001
A solution of methyl (6aR,10aR)-1-hydroxy-3-(8-hydroxy-2-methyloctan-2-yl)-6,6-dimethyl-6a,7,10,10a- tetrahydro-6H-benzo[c]chromene-9-carboxylate in dry CH2Cl2 (120 µL) was added to a stirred solution of DAST in dry CH2Cl2 (120 uL) at -45 ºC under N2 atmosphere. The solution was stirred at -45 ºC for 20 minutes. The reaction mixture was warmed up to room temperature and stirred overnight. The solution was diluted with CH2Cl2 and washed with water and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with Heptane:EtOAc (from 100:0 to 85:15) to afford the title compound (27 mg, 52.0 %). LC-MS (ESI+): 433.0 (M+H+); R.T.: 1.735 min (LCMS method: Tacc50-6_AP_AMAC). 1H NMR (300 MHz, CDCl3) δ 7.02 (bs, 1H), 6.38 (s, 1H) 6.22 (s, 1H), 4.77 (t, J = 6.12 Hz, 1H), 4.31 (t, J = 6.30, 1H), 3.74 (m, 4H), 2.68 (m, 1H), 2.41 (m, 1H), 2.10 – 1.78 (m, 6H), 1.70-1.07 (m, 20 H). (6aR,10aR)-3-(8-fluoro-2-methyloctan-2-yl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H- benzo[c]chromene-9-carboxylic acid (Compound 692a)
Figure imgf000119_0002
A solution of NaOH (12 mg) in water (129 uL) was added dropwise to a solution of methyl (6aR,10aR)-3- (8-fluoro-2-methyloctan-2-yl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9- carboxylate in MeOH (0.5 mL). The mixture was stirred at room temperature overnight. The pH of the mixture was adjusted to 4.0 with a solution of HCl (1N), then the solution was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase prep HPLC (Method: Organic phase ACN:MeOH (1:1) (OP); Aqueous phase H2O (0.1% HCO2H) (AP). Elution from 39% AP: 61% OP to 11% AP: 89% OP) to afford the title compound (17 mg, 65.5%) as a white solid. LC-MS (ESI+): 419.2486 (M+H+); R.T.: 4.237 min (Method Villa_2T). 1H NMR (400 MHz, CDCl3) δ 7.14 (bs, 1H), 6.38 (d, J = 1.2 Hz, 1H), 6.22 (s, 1H), 4.82 (bs, 1H), 4.46 (t, J = 6.20 Hz, 1H), 4.34 (t, J = 6.20 Hz, 1H), 3.82 (d, J = 18.24 Hz, 1H), 2.67 (dt, J = 10.84 – 4.40, 1H), 2.39 (m, 1H), 1.84 (dt, J = 11.36 – 4.80 Hz, 1H), 1.69 -1.55 (m, 2H), 1.50 (m, 2H), 1.41 (s, 2H), 1.32 (m, 3H), 1.26 – 1.19 (m, 10H) 1.13 (s, 2H), 1.07 (m, 2H). Synthesis of Compound 692c
Figure imgf000120_0001
LiHMDS (1 M in THF, 16.0 mL, 16 mmol, 2.5 eq) was added dropwise to a solution of triphenyl(5,5,5- trifluoropentyl)phosphonium bromide (3.0 g, 6.4 mmol, 1 eq) in anhydrous THF (11 mL) at 0 °C under nitrogen atmosphere and the resulting solution stirred at room temperature for 1 hour. A solution of 2- (3,5-dimethoxyphenyl)-2-methylpropanal (1.3 g, 6.4 mmol, 1 eq) in anhydrous THF (10 mL) was added dropwise and the mixture heated to 50 °C and stirred for 12 hours. The reaction mixture was diluted with EtOAc and washed with water. The combined organic layers were dried over MgSO4, concentrated under reduced pressure and purified by silica gel column chromatography, eluting with heptane/EtOAc, to provide the product as a colourless oil (1.4 g, 69%). ESI-MS m/z: 316.9 [M+H]+.
Figure imgf000120_0002
Palladium on carbon (Degussa type, 10% loading, wet, 0.4 g) was added to a solution of (Z)-1,3- dimethoxy-5-(8,8,8-trifluoro-2-methyloct-3-en-2-yl)benzene (1.4 g, 4.4 mmol, 1 eq) in EtOH (45 mL) and the suspension stirred under hydrogen atmosphere (1 atm) at room temperature for 72 hours. The mixture was filtered through a pad of Celite and the filtrate purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to afford the product as a colourless oil (1.1 g, 82%). ESI-MS m/z: 318.9 [M+H]+.
Figure imgf000121_0001
Boron tribromide (0.8 mL, 7.9 mmol, 2.2 eq) was added dropwise to a solution of 1,3-dimethoxy-5-(8,8,8- trifluoro-2-methyl-octan-2-yl)benzene (1.1 g, 3.6 mmol, 1 eq) in anhydrous dichloromethane (20 mL) at -78 °C. The mixture was allowed to warm to room temperature and stirred for 1 hour before quenching it with ice water. The quenched mixture was extracted with further dichloromethane and the combined organic extracts dried over MgSO4 and concentrated to provide the product as a thick oil (1.0 g, 95%). ESI-MS m/z: 290.9 [M+H]+. (6aR,10aR)-6,6,9-Trimethyl-3-(8,8,8-trifluoro-2-methyloctan-2-yl)-6a,7,10,10a-tetrahydro-6H- benzo[c]chromen-1-ol
Figure imgf000121_0002
A solution of (4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (0.6 g, 3.8 mmol, 1.1 eq.) in toluene (2 mL) was added dropwise to a stirred solution of 5-(8,8,8-trifluoro-2-methyloctan-2-yl)benzene-1,3-diol (1.0 g, 3.4 mmol, 1 eq) and pTSA•H2O (0.1 g, 0.7 mmol, 0.2 eq) in toluene (9 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was then refluxed into a Dean-Stark trap at 70-80 °C under partial vacuum for 12 hours. The resulting toluene solution was diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO4, concentrated and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to give the product as a tan solid (1.4 g, 98%). ESI-MS m/z: 424.9 [M+H]+.
Figure imgf000121_0003
Pivaloyl chloride (2.0 mL, 16.8 mmol, 5 eq) was added to a solution of (6aR,10aR)-6,6,9-trimethyl-3- (8,8,8-trifluoro-2-methyloctan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol (1.4 g, 3.3 mmol, 1 eq) and triethylamine (4.7 mL, 33.6 mmol, 10 eq) in anhydrous THF (20 mL) at 0 °C, after which the solution was stirred at room temperature for 12 hours. The mixture was then diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO4, concentrated and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to give the product as a brown solid (1.6 g, 93%) ESI-MS m/z: 5089 [M+H]+ (6aR,10aR)-9-Formyl-6,6-dimethyl-3-(8,8,8-trifluoro-2-methyloctan-2-yl)-6a,7,10,10a-tetrahydro-6H- benzo[c]chromen-1-yl
Figure imgf000122_0001
A solution of selenium dioxide (0.157 g, 1.4 mmol, 2.4 eq) in EtOH (2.5 mL) and water (0.5 mL) was added dropwise over 30 min to a solution of (6aR,10aR)-6,6,9-trimethyl-3-(8,8,8-trifluoro-2-methyloctan- 2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl pivalate (0.3 g, 0.59 mmol, 1 eq) in EtOH (2.8 mL) and the resulting mixture was heated to reflux for 16 hours. After cooling, the suspension was filtered through a pad of Celite, rinsing the cake with MeOH. The combined filtrates were concentrated and the residue dissolved in diethyl ether. The solution was washed with water and satd. aq. NaHCO3, dried over MgSO4, concentrated and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to provide the product as a thick brown oil (100 mg, 31%). ESI-MS m/z: 522.9 [M+H]+. (6aR,10aR)-6,6-Dimethyl-1-(pivaloyloxy)-3-(8,8,8-trifluoro-2-methyloctan-2-yl)-6a,7,10,10a-tetrahydro-6H- benzo[c]chromene-9-carboxylic acid
Figure imgf000122_0002
A solution of sodium hypochlorite (203 mg, 2.2 mmol, 12 eq) and monobasic potassium phosphate (220 mg, 1.7 mmol, 9 eq) in water (2 mL) was added over 0.5 hours to a solution of (6aR,10aR)-9-formyl- 6,6-dimethyl-3-(8,8,8-trifluoro-2-methyloctan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl pivalate (97 mg, 0.2 mmol, 1 eq) and 2-methyl-but-2-ene (2.9 mL, 27.0 mmol, 145 eq) in tert-butanol (3 mL) and the resulting biphasic mixture stirred vigorously for 2.5 hours at room temperature. The mixture was then acidified with 2 M aq. HCl and extracted with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated to give the crude product as a brown solid (99 mg, 99%). ESI-MS m/z: 538.9 [M+H]+. (6aR,10aR)-1-Hydroxy-6,6-dimethyl-3-(8,8,8-trifluoro-2-methyloctan-2-yl)-6a,7,10,10a-tetrahydro-6H- benzo[c]chromene-9-carboxylic acid (Compound 692c)
Figure imgf000122_0003
A solution of sodium hydroxide (37 mg, 0.9 mmol, 5 eq) in water (1 mL) was added to a solution of (6aR 10aR) 66 dimethyl 1 (pivaloyloxy) 3 (888 trifluoro 2 methyloctan 2 yl) 6a71010a tetrahydro 6H benzo[c]chromene-9-carboxylic acid (99 mg, 0.2 mmol, 1 eq) in methanol (4 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 24 hours, after which it was acidified with 2 M aq. HCl and extracted with dichloromethane. The aqueous phase was extracted three times with dichloromethane and the combined organic extracts dried over MgSO4, concentrated and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to yield the product as a white solid (71 mg, 85%). ESI-MS m/z: 455.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ.7.21 – 7.07 (m, 1H), 6.38 (d, J = 1.6 Hz, 1H), 6.23 (d, J = 1.7 Hz, 1H), 3.83 (dd, J = 15.8, 3.6 Hz, 1H), 2.68 (td, J = 11.0, 4.5 Hz, 1H), 2.44 (dd, J = 12.7, 4.1 Hz, 1H), 2.12 – 1.91 (m, 4H), 1.84 (td, J = 11.5, 4.4 Hz, 1H), 1.55 – 1.43 (m, 4H), 1.42 (s, 3H), 1.36 – 1.18 (m, 3H), 1.20 (s, 6H), 1.15 (s, 3H), 1.18 – 0.99 (m, 2H). Synthesis of Compound 1491 and Compound 695a
Figure imgf000123_0001
(3-Carboxypropyl)triphenylphosphonium bromide
Figure imgf000123_0002
Triphenylphosphine (11.4 g, 43.7 mmol, 1 eq) was added to a solution of 4-bromobutanoic acid (7.3 g, 43.7 mmol, 1 eq) in toluene (43 mL) and the mixture heated in a sealed tube at 110 °C for 12 hours. The solvent was then removed to provide the crude product (14.3 g, 76%) as an off-white solid. ESI-MS m/z: 348.8 [M+H]+. (Z)-6-(3,5-Dimethoxyphenyl)-6-methylhept-4-enoic acid
Figure imgf000124_0001
LiHMDS (1 M in THF, 28.5 mL, 28.5 mmol, 3.5 eq) was added dropwise to a solution of (3- carboxypropyl)triphenylphosphonium bromide (3.5 g, 8.1 mmol, 1 eq) in anhydrous THF (14 mL) at 0 °C under nitrogen atmosphere and the mixture was stirred at room temperature for 1 hour. A solution of 2- (3,5-dimethoxyphenyl)-2-methylpropanal (1.7 g, 8.1 mmol, 1 eq) in anhydrous THF (14 mL) was added dropwise and the resulting mixture was stirred at 50 °C for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The combined organic layers were dried over MgSO4, concentrated under reduced pressure and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to give the product as a tan solid (1.3 g, 58%). ESI-MS m/z: 278.9 [M+H]+. 6-(3,5-Dimethoxyphenyl)-6-methylheptanoic acid
Figure imgf000124_0002
Palladium on carbon (Degussa type, 10% loading, wet, 0.6 g) was added to a solution of (Z)-6-(3,5- dimethoxyphenyl)-6-methylhept-4-enoic acid (2.1 g, 7.4 mmol, 1 eq) in EtOH (50 mL) and the suspension stirred at room temperature under hydrogen atmosphere (1atm) for 12 hours. The mixture was filtered through a pad of Celite, rinsing the cake with ethanol. Concentration of the combined filtrates afforded the product (2.1 g, 99%) as a yellowish oil. ESI-MS m/z: 280.9 [M+H]+. 6-(3,5-Dihydroxyphenyl)-6-methylheptanoic acid
Figure imgf000124_0003
Boron tribromide (3.4 mL, 35.3 mmol, 2.2 eq) was added dropwise to a solution of 6-(3,5- dimethoxyphenyl)-6-methylheptanoic acid (4.5 g, 16.0 mmol, 1 eq) in anhydrous dichloromethane (30 mL) at -78 °C. The mixture was allowed to warm to room temperature and stirred 1 hour before quenching it with ice water. The quenched mixture was extracted with 3:1 chloroform/isopropanol and the combined organic extracts dried over MgSO4 and concentrated to provide the crude product as an off-white solid (4.4 g, 100%). ESI-MS m/z: 252.9 [M+H]+.
Figure imgf000125_0003
Concentrated sulfuric acid (1.9 mL, 35.6 mmol, 2 eq) was added to a solution of 6-(3,5-dihydroxyphenyl)- 6-methylheptanoic acid (4.5 g, 17.8 mmol, 1 eq) in methanol (50 mL). After heating to reflux for 2 hours, the resulting solution was concentrated under reduced pressure to remove the bulk of the methanol and the residue was slowly quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with dichloromethane and the combined organic extracts were washed brine, dried over MgSO4, concentrated and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to afford the product as a thick oil (2.4 g, 51%). ESI-MS m/z: 266.9 [M+H]+. Methyl 6-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-6- methylheptanoate
Figure imgf000125_0001
A solution of (4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (1.1 g, 9.9 mmol, 1.5 eq) in toluene (5 mL) was added dropwise to a stirred solution of methyl 6-(3,5-dihydroxyphenyl)-6-methylheptanoate (2.4 g, 9.0 mmol, 1 eq) and p-TSA•H2O (0.3 g, 1.8 mmol, 0.2 eq) in toluene (22 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was then refluxed into a Dean-Stark trap at 70-80 °C under partial vacuum for 12 hours. The resulting toluene solution was diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO4, concentrated and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to give the product as an off-white solid (2.9 g, 82%). ESI-MS m/z: 400.9 [M+H]+. (6aR,10aR)-3-(7-hydroxy-2-methylheptan-2-yl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H- benzo[c]chromen-1-ol
Figure imgf000125_0002
DIBAL-H (1 M in toluene, 18.4 mL, 18.4 mmol, 2.5 eq) was added to a solution of methyl 6-((6aR,10aR)- 1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-6-methylheptanoate (2.95 g, 7.3 mmol, 1 eq) in anhydrous dichloromethane (22 mL) under nitrogen atmosphere at -78 °C. The solution was stirred for 2 hours before 7 mL of 10% Rochelle’s salt (aq.) were added and the mixture allowed to warm to room temperature while stirring vigorously. After stirring for 12 hours at room temperature, the mixture was concentrated and the residue extracted with dichloromethane and water. The combined organic layers were dried over MgSO4, concentrated and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to provide the product as a thick oil (1.7 g, 62%). ESI-MS m/z: 373.0 [M+H]+. 1H NMR (300 MHz, CDCl3) δ 6.30 (d, J = 1.7 Hz, 1H), 6.16 (d, J = 1.8 Hz, 1H), 5.36 (d, J = 4.2 Hz, 1H), 5.23 (s, 1H), 3.52 (t, J = 6.6 Hz, 2H), 3.13 (dd, J = 16.0, 4.1 Hz, 1H), 2.62 (td, J = 10.8, 4.6 Hz, 1H), 2.08 (d, J = 12.6 Hz, 1H), 1.88 – 1.68 (m, 3H), 1.68 – 1.57 (m, 3H), 1.53 – 1.38 (m, 5H), 1.36 – 1.27 (m, 3H), 1.24 – 1.10 (m, 8H), 1.10 – 0.99 (m, 5H). 6-Methyl-6-((6aR,10aR)-6,6,9-trimethyl-1-(pivaloyloxy)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3- yl)heptyl pivalate
Figure imgf000126_0001
Pivaloyl chloride (4.2 mL, 34.2 mmol, 7.5 eq) was added to a solution of (6aR,10aR)-3-(7-hydroxy-2- methylheptan-2-yl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol (1.7 g, 4.5 mmol, 1 eq) and triethylamine (9.5 mL, 68.4 mmol, 15 eq) in anhydrous THF (30 mL) at 0 °C , after which the solution was stirred at room temperature for 12 hours. The mixture was then diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO4, concentrated and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to afford the product as a thick oil (2.4 g, 97%). ESI-MS m/z: 541.0 [M+H]+. 6-((6aR,10aR)-9-Formyl-6,6-dimethyl-1-(pivaloyloxy)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)- 6-methylheptyl pivalate
Figure imgf000126_0002
A solution of selenium dioxide (1.182 g, 10.65 mmol, 2.4 eq.) in EtOH (20 mL) and water (2 mL) was added dropwise over 30 min to a solution of 6-methyl-6-((6aR,10aR)-6,6,9-trimethyl-1-(pivaloyloxy)- 6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)heptyl pivalate (2.4 g, 4.45 mmol, 1 eq) in EtOH (20 mL) and the resulting mixture was heated to reflux for 16 hours. After cooling, the suspension was filtered through a pad of Celite, rinsing the cake with MeOH. The combined filtrates were concentrated and the residue dissolved in diethyl ether. The solution was washed with water and satd. aq. NaHCO3, dried over anhydrous MgSO4, concentrated and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to give the product as a tan oil (0.5 g, 22%). ESI-MS m/z: 555.4 [M+H]+. 1H NMR (300 MHz, CDCl3) δ 9.50 (s, 1H), 6.92 – 6.78 (m, 1H), 6.70 (d, J = 1.8 Hz, 1H), 6.47 (d, J = 1.9 Hz, 1H), 4.01 (t, J = 6.6 Hz, 2H), 3.49 – 3.33 (m, 1H), 2.67 – 2.44 (m, 2H), 2.25 – 2.08 (m, 1H), 2.00 – 1.82 (m, 2H), 1.64 – 1.49 (m, 3H), 1.46 (s, 3H), 1.43 – 1.33 (m, 9H), 1.27 (d, J = 10.2 Hz, 9H), 1.23 – 1.06 (m, 14H). (6aR,10aR)-6,6-Dimethyl-3-(2-methyl-7-(pivaloyloxy)heptan-2-yl)-1-(pivaloyloxy)-6a,7,10,10a-tetrahydro- 6H-benzo[c]chromene-9-carboxylic acid
Figure imgf000127_0001
A solution of sodium hypochlorite (1.0 g, 11.3 mmol, 12 eq) and monobasic potassium phosphate (1.1 g, 8.5 mmol, 9 eq) in water (10 mL) was added over 0.5 hours to a solution of 6-((6aR,10aR)-9-formyl-6,6- dimethyl-1-(pivaloyloxy)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-6-methylheptyl pivalate (0.5 g, 0.9 mmol, 1 eq) and 2-methyl-but-2-ene (14.5 mL, 131.7 mmol, 140 eq) in tert-butanol (10 mL) and the resulting biphasic mixture stirred vigorously for 2.5 hours at room temperature. The mixture was then acidified to pH 5-6 with 2 M HCl, concentrated to remove the bulk of the tert-butanol and the resulting slurry diluted with ethyl acetate. The organic layer was washed with water, dried over MgSO4 and concentrated to afford the product as an off-white solid (0.5 g, 99%). ESI-MS m/z: 570.9 [M+H]+.1H NMR (300 MHz, CDCl3) δ 7.15 (d, J = 4.7 Hz, 1H), 6.70 (d, J = 1.7 Hz, 1H), 6.46 (d, J = 1.7 Hz, 1H), 4.01 (t, J = 6.6 Hz, 3H), 3.44 (dd, J = 16.1, 3.7 Hz, 1H), 2.62 – 2.36 (m, 2H), 2.13 – 1.94 (m, 2H), 1.86 (td, J = 11.4, 4.2 Hz, 1H), 1.64 – 1.50 (m, 5H), 1.44 (s, 3H), 1.42 – 1.35 (m, 10H), 1.25 (s, 6H), 1.20 (s, 11H), 1.16 (s, 4H).
Figure imgf000127_0002
A solution of sodium hydroxide (0.4 g, 9.3 mmol, 10 eq) in water (1 mL) was added dropwise to a solution of (6aR,10aR)-6,6-dimethyl-3-(2-methyl-7-(pivaloyloxy)heptan-2-yl)-1-(pivaloyloxy)-6a,7,10,10a- tetrahydro-6H-benzo[c]chromene-9-carboxylic acid (0.5 g, 0.9 mmol, 1 eq) in MeOH (5 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 16 hours, after which it was acidified with 2 M aq. HCl and extracted with dichloromethane. The combined organic layers were dried over MgSO4, concentrated under reduced pressure and purified by silica gel column chromatography, eluting with heptane/ethyl acetate, to yield Compound 1491 as a tan solid (0.1 g, 27%). ESI-MS m/z: 403.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 4.9 Hz, 1H), 6.27 (d, J = 1.4 Hz, 1H), 6.21 (d, J = 1.4 Hz, 1H), 3.92 – 3.75 (m, 1H), 3.55 (qt, J = 10.5, 6.8 Hz, 2H), 2.61 (td, J = 10.9, 4.5 Hz, 1H), 2.46 – 2.30 (m, 1H), 2.05 – 1.85 (m, 2H), 1.77 (td, J = 11.4, 4.4 Hz, 1H), 1.58 – 1.27 (m, 4H), 1.41 (s, 3H), 1.27 – 091 ( 4H) 120 ( 3H) 117 ( 3H) 110 ( 3H)
Figure imgf000128_0001
HCl (4 M in dioxane, 0.2 mL, 0.7 mmol, 4 eq) was added to a solution of Compound 1491 (68 mg, 0.2 mmol, 1 eq) in MeOH (4 mL) and the reaction was stirred at room temperature for 12 hours. The reaction mixture was then brought to pH 7-8 with satd. aq. NaHCO3 before being concentrated under reduced pressure. The residue was suspended in ethyl acetate and washed with water. The organic layer was dried over MgSO4 and concentrated to give the crude product as an off-white solid (70 mg, 98%). ESI- MS m/z: 416.9 [M+H]+.
Figure imgf000128_0002
A solution of methyl (6aR,10aR)-1-hydroxy-3-(7-hydroxy-2-methylheptan-2-yl)-6,6-dimethyl-6a,7,10,10a- tetrahydro-6H-benzo[c]chromene-9-carboxylate (60 mg, 0.1 mmol, 1 eq) in anhydrous dichloromethane (1 mL) was added to a stirred solution of DAST (40 mg, 0.3 mmol, 2 eq) in anhydrous dichloromethane (1 mL) at -45 °C under nitrogen atmosphere. The solution was stirred for 20 minutes before being allowed to warm to room temperature and stir for a further 12 hours. The mixture was then diluted with dichloromethane and washed with water and brine. The organic layer was dried over MgSO4 and concentrated to give the crude product as a brown solid (52 mg, 86%). ESI-MS m/z: 418.9 [M+H]+. (6aR,10aR)-3-(7-fluoro-2-methylheptan-2-yl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H- benzo[c]chromene-9-carboxylic acid (Compound 695a)
Figure imgf000128_0003
A solution of sodium hydroxide (25 mg, 0.6 mmol, 5 eq) in water (0.3 mL) was added dropwise to a solution of methyl (6aR,10aR)-1-hydroxy-3-(7-fluoro-2-methylheptan-2-yl)-6,6-dimethyl-6a,7,10,10a- tetrahydro-6H-benzo[c]chromene-9-carboxylate (52 mg, 0.1 mmol, 1 eq) in MeOH (0.9 mL) and the mixture was stirred at room temperature for 12 hours The mixture was then acidified with 2 M HCl and diluted with ethyl acetate. The organic layer was washed with water and brine, then dried over MgSO4 and concentrated under reduced pressure. The residue was first purified by silica gel column chromatography, eluting with heptane/ethyl acetate, then further purified by prep-HPLC (Gemini C18 column, 100 x 30 mm, 5 µm, mobile phase A: 25mM aq. ammonium bicarbonate, mobile phase B: ACN, gradient: 41% B to 83% B over 30 min). The product-containing fractions were lyophilized to provide the product as a white powder (12 mg, 24%). ESI-MS m/z: 405.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.20 – 7.12 (m, 1H), 6.39 (d, J = 1.5 Hz, 1H), 6.23 (d, J = 1.5 Hz, 1H), 4.44 (t, J = 6.2 Hz, 1H), 4.32 (t, J = 6.2 Hz, 1H), 3.83 (dd, J = 15.8, 3.8 Hz, 1H), 2.68 (td, J = 11.0, 4.5 Hz, 1H), 2.44 (d, J = 16.8 Hz, 1H), 2.11 – 1.93 (m, 2H), 1.84 (td, J = 11.4, 4.4 Hz, 1H), 1.71 – 1.56 (m, 2H), 1.56 – 1.48 (m, 2H), 1.42 (s, 3H), 1.35 – 1.25 (m, 2H), 1.21 (s, 6H), 1.17 – 1.04 (m, 2H), 1.14 (s, 3H). The synthetic procedures for other fluorinated AJA analogs are adapted from those reported in International Patent Application Nos. PCT/US2019/034965, PCT/US2020/057985, and PCT/US2020/054103, each of which described the synthesis of analogs of ajulemic acid and is hereby incorporated by reference in its entirety. Example 4. Affinity for CB1 and CB2 Receptors as determined by a radioligand binding assay The binding affinity (% inhibition, Ki) of compounds of the invention for the CB1 and CB2 receptors was determined by a competitive radioligand binding assay, the results of which are provided in Table 5. Exemplary methods for the determination of binding affinity for a cannabinoid receptor by competitive radioligand binding can be found in the literature, for example, in Rinaldi-Carmona M, et al. Characterization of two cloned human CB1 cannabinoid receptors isoform. J. Pharmacol. Exp. Ther.278: 871 (1996); and Munro S., et al. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61-65 (1993). CB1 Radioligand Binding Assay: Cell membrane homogenates (5 µg protein) prepared from Chem cells expressing human recombinant CB1 receptor were incubated for 30 min at 22°C with 2 nM [3H]CP 55940 (CB1/CB2 radioligand) in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 2.5 mM EDTA and 0.3% BSA.. Nonspecific binding is determined in the presence of 10 µM WIN 55212-2. Each compound was tested in 8 concentrations (1.58 – 5000 nM). For each concentration, % Inhibition was determined as a function of radioligand specific binding to the CB1 receptor. Inhibition constant (Ki) was determined from the concentration-response curve of each tested compound. CB2 Radioligand Binding Assay: Cell membrane homogenates (12 µg protein) prepared from CHO cells expressing human recombinant CB2 receptor were incubated for 120 min at 37°C with 0.8 nM [3H]WIN 55212-2 (CB1/CB2 radioligand) in the absence or presence of the test compound in a buffer containing 50 mM Hepes/Tris (pH 7.4), 5 mM MgCl2, 2.5 mM EGTA and 0.1% BSA. Nonspecific binding was determined in the presence of 5 µM WIN 55212-2. Each compound was tested in 8 concentrations (0.95 – 3000 nM). For each concentration, % Inhibition was determined as a function of radioligand specific binding to the CB2 receptor. Inhibition constant (Ki) was determined from the concentration-response curve of each tested compound. Table 5. Affinity for CB1 and CB2 Receptors as determined by a radioligand binding assay
Figure imgf000130_0001
Example 5. CB1- and CB2-mediated activity as determined by cyclic adenosine monophosphate (cAMP) agonist assay Compounds of the invention were assayed in the Hit Hunter® cAMP assay to determine Gi- coupled agonist activity on the CB1 and CB2 receptors, the results of which are provided in Table 6. The Hit Hunter® cAMP assay monitors the activation of a GPCR via Gi and Gs secondary messenger signaling in a homogenous, non-imaging assay format using a technology developed by DiscoverX called Enzyme Fragment Complementation (EFC) with β-galactosidase (β-Gal) as the functional reporter. The enzyme is split into two inactive complementary portions: EA for Enzyme Acceptor and ED for Enzyme Donor. ED is fused to cAMP and in the assay competes with cAMP generated by cells for binding to a cAMP-specific antibody. Active β-Gal is formed by complementation of exogenous EA to any unbound ED cAMP. Active enzymes can then convert a chemiluminescent substrate, generating an output signal detectable on a standard microplate reader. cAMP Hunter cell lines were expanded from freezer stocks according to standard procedures. Cells were seeded in a total volume of 20 μL into white walled, 384-well microplates and incubated at 37°C for the appropriate time prior to testing. cAMP modulation was determined using the DiscoverX Hit Hunter cAMP XS+ assay. For Gi agonist activity determination, cells were incubated with sample in the presence of EC80 forskolin to induce response (20 μM and 25 μM in the CB1 and CB2 assays, respectively). Media was aspirated from cells and replaced with 15 μL 2:1 HBSS/10 mM HEPES : cAMP XS+ Ab reagent. Intermediate dilution of sample stocks was performed to generate 4X sample in assay buffer. 5 μL of 4X compound was added to cells and incubated at 37°C or room temperature for 30 or 60 minutes. Final vehicle concentration was 1%. Assay signal was generated through incubation with 20 μL cAMP XS+ ED/CL lysis cocktail for one hour at room temperature. Microplates were read following signal generation with a PerkinElmer EnvisionTM instrument for chemiluminescent signal detection. Compound activity was analyzed using CBIS data analysis suite (ChemInnovation, CA). For agonist assays, percentage activity was calculated using the following formula: % Activity = 100% x (1 – (mean RLU of test sample - mean RLU of Max control ligand) / (mean RLU of vehicle control - mean RLU of Max control ligand). Control ligand was the non-selective CB1/CB2 agonist CP55,940. Table 6. CB1- and CB2-mediated activity as determined by cAMP agonist assay
Figure imgf000131_0001
Example 6. CB1- and CB2-mediated activity as determined by β-Arrestin assay Compounds of the invention were assayed in the PathHunter® β-Arrestin assay to determine agonist activity on the CB1 and CB2 receptors, the results of which are provided in Table 7. The PathHunter® β-Arrestin assay monitors the activation of a GPCR in a homogenous, non-imaging assay format using a technology developed by DiscoverX called Enzyme Fragment Complementation (EFC) with β-galactosidase (β-Gal) as the functional reporter. The enzyme is split into two inactive complementary portions (EA for Enzyme Acceptor and PK for ProLink) expressed as fusion proteins in the cell. EA is fused to β-Arrestin and PK is fused to the GPCR of interest. PathHunter cell lines were expanded from freezer stocks according to standard procedures. Cells were seeded in a total volume of 20 μL into white walled, 384-well microplates and incubated at 37°C for the appropriate time prior to testing. For agonist activity determination, cells were incubated with sample to induce response. Intermediate dilution of sample stocks was performed to generate 5X sample in assay buffer. 5 μL of 5X sample was added to cells and incubated at 37°C or room temperature for 90 to 180 minutes. Vehicle concentration was 1%. Assay signal was generated through a single addition of 12.5 or 15 μL (50% v/v) of PathHunter Detection reagent cocktail, followed by a one hour incubation at room temperature. Microplates were read following signal generation with a PerkinElmer EnvisionTM instrument for chemiluminescent signal detection. Compound activity was analyzed using CBIS data analysis suite (ChemInnovation, CA). For agonist assays, percentage activity was calculated using the following formula: % Activity = 100% x (mean RLU of test sample – mean RLU of vehicle control) / (mean MAX control ligand – mean RLU of vehicle control). Table 7. CB1- and CB2-mediated activity as determined by β-Arrestin assay
Figure imgf000132_0001
Example 7. Microsomal stability study A microsomal stability study was performed in order to determine the metabolic stability of compounds described herein. Experimental Procedure 1) The following buffers were prepared as follows: Buffer A: 1.0 L of 0.1 M monobasic Potassium Phosphate buffer containing 1.0 mM EDTA; Buffer B: 1.0 L of 0.1 M Dibasic Potassium Phosphate buffer containing 1.0 mM EDTA; Buffer C: 0.1 M Potassium Phosphate buffer, 1.0 mM EDTA, pH 7.4 by titrating 700 mL of buffer B with buffer A while monitoring with the pH meter. 2) Reference compound (Ketanserin) and test compound spiking solutions were prepared as follows: 500 µM spiking solution: add 10 µL of 10 mM DMSO stock solution into 190 µL CAN; 1.5 µM spiking solution in microsomes (0.75 mg/mL): add 1.5 µL of 500 µM spiking solution and 18.75 µL of 20 mg/mL liver microsomes into 479.75 µL of Buffer C on ice. 3) NADPH stock solution (6 mM) was prepared by dissolving NADPH into Buffer C. 4) 30 µL of 1.5 µM spiking solution containing 0.75 mg/mL microsomes solution was dispensed to the assay plates designated for different time points (0-, 5-, 15-, 30-, 45-min) on ice. 5) For 0-min, 135 µL of ACN containing internal standard (IS) was added to the wells of 0-min plate and then 15 µL of NADPH stock solution (6 mM). was added. The internal standards used were: compound 2 for AJA; AJA for compound 2; and Imipramine for Ketanserin. 6) All other plates were pre-incubated at 37 °C for 5 minutes. 7) 15 µL of NADPH stock solution (6 mM) was added to the plates to start the reaction and timing. 8) At 5-min, 15-min, 30-min, 45-min and 60-min, 135 µL of ACN containing IS was added to the wells of corresponding plates, respectively, to stop the reaction. 9) After quenching, the plates were mixed at the vibrator (IKA, MTS 2/4) for 10 min (600 rpm/min) and then centrifuged at 5594 g for 15 min (Thermo Multifuge × 3R). 10) 50 μL of the supernatant from each well was transferred into a 96-well sample plate containing 120 μL of ultra-pure water (Millipore, ZMQS50F01) for LC/MS analysis. Results As shown in Table 8, in the human microsome stability study, for compound 2, half-life (T1/2) = 34.23 min and intrinsic clearance (Clint) = 50.78 mL/min/kg while for AJA, half-life (T1/2 ) = 28.67 min and intrinsic clearance (Clint) = 60.64 mL/min/kg; in mouse microsome stability study, for compound 2, half-life (T1/2 ) = 61.58 min and intrinsic clearance (Clint) = 88.62 mL/min/kg while for AJA, half-life (T1/2) = 64.34 min and intrinsic clearance (Clint) = 84.32 mL/min/kg; and in rat microsome stability study, for compound 2, half-life (T1/2) = 71.17 min and intrinsic clearance (Clint)= 34.90 mL/min/kg while for AJA, half-life (T1/2 ) = 70.80 min and intrinsic clearance (Clint) = 35.08 mL/min/kg. Accordingly, an increased stability was observed for Compound 2 as compared to AJA in the human microsomal stability assay. No increase was observed in rat or mouse, since metabolites Met5 and Met6 were not observed in mouse and rat (see Example 1). Table 8. Microsomal stability assay
Figure imgf000133_0001
Example 8. Mouse pharmacokinetic study A study was conducted to determine the pharmacokinetics of Compound 2 following single intravenous (IV) at 1 mg/kg and oral (PO) administration at 10 mg/kg administrations in fasted male C57BL/6 mice. Formulation Preparation Preparation of IV Solution (0.2 mg/mL): 5% DMSO, 5% Solutol HS15 and 90% saline (a clear solution, colorless) 1) Added 0.295 mL of DMSO into the tube containing the 1.18 mg of Compound 2. 2) Vortexed the tube for 1-2 min. 3) Added 0.295 mL of Solutol HS15 into the tube and vortexed it for 1 min. 4) Added 5.310 mL of saline into the tube and vortexed it for 1 min. Preparation of PO Solution (2 mg/mL): 2% MC in water (a homogeneous suspension, light white) 1) Added 1.795 mL of above vehicle into the tube containing the 3.59 mg of Compound 2. 2) Sonicated it for 10 min. 3) Stirred it for 15 min Animal Acquisition and Assignment to Study 18 male C57BL/6 mice, approximately 16-19 g of body weight, originally purchased from Shanghai Jihui Laboratory Animal Co. LTD and with Qualification No. of SCXK (SH) 2018-000320180003002710 and SCXK (JH) 2017-001220170012004698 were taken from stock and given at least a 3 days acclimation before being placed on the study. The animals were fasted overnight prior to dosing with free access to water, the food was resumed 4 hours post-dose. Dosing and Sampling The IV dose was administered via tail vein injection. The PO dose was administered via oral gavage. The animals were restrained manually at the designated time points (Table 9). Approx.110 µL blood/time point was taken from facial vein for semi-serial bleeding or cardiac puncture for terminal bleeding into K2EDTA tubes. The blood samples were centrifuged to obtain plasma samples (2000 g, 5 min at 4 oC) within 15 minutes. All samples were stored at approximately -70 oC until analysis. The backup samples were discarded after 3 weeks. Using 18 male CD1 mice, approximately 29-31 g of body weight, originally purchased from Shanghai Jihui Laboratory Animal Co. LTD and with Qualification No. of SCXK (SH) 2017-001220170012004122, a similar study was conducted to determine the pharmacokinetics of AJA. Table 9. Mouse pharmacokinetic study Design
Figure imgf000134_0001
The results of the mouse pharmacokinetic study are shown in Table 10 and in FIG.9 (Compound 2) and FIG.10 (AJA).
Figure imgf000135_0001
After IV dosing of Compound 2 at 1 mg/kg in male C57BL/6 mice, a terminal half-life (T1/2) for Compound 2 of 2.06 hours was observed (compared to 1.41 for AJA). The mean residence time (MRTINF) also increased to 2.26 hour (compared to 1.89 for AJA). The total clearance (CL) and volume of distribution at steady state (Vss) were 0.363 L/hr/kg and 0.820 L/kg, respectively. The area under the curve from time 0 to last time point (AUClast), from time 0 to infinity (AUCINF), and from 0 to 24 hr (AUC0-24hr) were 2625 hr*ng/mL, 2756 hr*ng/mL and 2975 hr*ng/mL, respectively. After PO dosing of Compound 2 at 10 mg/kg in male C57BL/6 mice, a terminal half-life (T1/2) for Compound 2 of 3.06 was observed (compared to 2.19 for AJA). The maximum plasma concentration (Cmax) for Compound 2 increased to 8125 ng/mL (compared to 3857 for AJA). The oral bioavailability (F) of Compound 2 was 95.3% (compared to 70.79% for AJA). The area under the curve from time 0 to last time point (AUClast), from time 0 to infinity (AUCINF), and from 0 to 24 hr (AUC0-24hr) were 26196 hr*ng/mL, 26257 hr*ng/mL and 26196 hr*ng/mL, respectively. Accordingly, Compound 2 demonstrated increased exposure, prolonged-half-life, and increased oral bioavailability in a mouse pharmacokinetics study. Other Embodiments While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the invention that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are within the claims.

Claims

What is claimed is: CLAIMS 1. A pharmaceutical composition comprising a compound described by formula (I), (II), or (III):
Figure imgf000137_0001
, wherein R1 is H, O, OH, F, Cl, Br, NH2, or optionally substituted C1-C3 alkoxy; R2 is H, CH3, CH2D, CHD2, or CD3; R3 and R4 are each independently CH3, CH2D, CHD2, or CD3; R5 is CH3 or CH2OH; L1 is optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C5- C15 arylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C2-C15 heterocyclylene, or optionally substituted amido; each dashed line is optionally a double bond; A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, optionally substituted 3-to-8 membered heterocyclyl, or cyano; X1 and X2 are each independently H, O, Cl, or F; X3 and X4 are each independently H or absent; Q is an optionally substituted 5-to-8 membered heterocyclyl fused ring; L2 is optionally substituted C3-C8 alkylene, optionally substituted C3-C8 heteroalkylene, optionally substituted C3-C8 alkenylene, optionally substituted C3-C8 heteroalkenylene, optionally substituted C3-C8 alkynylene, or optionally substituted C3-C8 heteroalkynylene; and X5 is O or NH, wherein at least one of R2, R3, and R4 is CH2D, CHD2, or CD3, and the composition has an isotopic enrichment factor for deuterium of at least 5; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
2. The pharmaceutical composition of claim 1, wherein the compound is described by formula (I):
Figure imgf000138_0001
, or a pharmaceutically acceptable salt thereof.
3. The pharmaceutical composition of claim 2, wherein the compound is described by formula (IA-2):
Figure imgf000138_0002
(IA-2), or a pharmaceutically acceptable salt thereof.
4. The pharmaceutical composition of claim 2 or 3, wherein A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, or cyano.
5. The pharmaceutical composition of claim 4, wherein the compound is described by formula (IA-2A):
Figure imgf000138_0003
(IA-2A), wherein Ra is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C3-C20 cycloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C3-C20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or a pharmaceutically acceptable salt thereof.
6. The pharmaceutical composition of claim 5, wherein Ra is H.
7. The pharmaceutical composition of claim 4, wherein the compound is described by formula (IA-2B):
Figure imgf000139_0001
(IA-2B), wherein each of Ra and Ra′ is independently H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C3-C20 cycloalkyl, optionally substituted C1- C20 heteroalkyl, optionally substituted C3-C20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or Ra and Ra′, together with the nitrogen atom to which they are attached, combine to form an optionally substituted C3-C20 heterocyclyl; or a pharmaceutically acceptable salt thereof.
8. The pharmaceutical composition of claim 2 or 3, wherein A is optionally substituted 3-to-8 membered heterocyclyl.
9. The pharmaceutical composition of claim 8, wherein A is optionally substituted 5-membered heterocyclyl.
10. The pharmaceutical composition of claim 9, wherein A is optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4-oxatriazole, or optionally substituted 1,2,3,4-thiatriazole.
11. The pharmaceutical composition of claim 10, wherein A is
Figure imgf000139_0002
,
Figure imgf000140_0001
.
12. The pharmaceutical composition of claim 1, wherein the compound is described by formula (II):
Figure imgf000140_0002
, or a pharmaceutically acceptable salt thereof.
13. The pharmaceutical composition of any one of claims 1-12, wherein R1 is OH.
14. The pharmaceutical composition of claim 1, wherein the compound is a described by formula (III):
Figure imgf000140_0003
, or a pharmaceutically acceptable salt thereof.
15. The pharmaceutical composition of any one of claims 1-14, wherein R3 and R4 are each CH3.
16. The pharmaceutical composition of claim 15, wherein R2 is CH2D.
17. The pharmaceutical composition of claim 15, wherein R2 is CHD2.
18. The pharmaceutical composition of claim 15, wherein R2 is CD3.
19. The pharmaceutical composition of any one of claims 1-14, wherein R2 is H or CH3.
20. The pharmaceutical composition of claim 19, wherein R3 is CH3.
21. The pharmaceutical composition of claim 20, wherein R4 is CH2D.
22. The pharmaceutical composition of claim 20, wherein R4 is CHD2.
23. The pharmaceutical composition of claim 20, wherein R4 is CD3.
24. The pharmaceutical composition of claim 19, wherein R3 and R4 are each CH2D, CHD2, or CD3.
25. The pharmaceutical composition of claim 24, wherein R3 and R4 are each CH2D.
26. The pharmaceutical composition of claim 24, wherein R3 and R4 are each CHD2.
27. The pharmaceutical composition of claim 24, wherein R3 and R4 are each CD3.
28. The pharmaceutical composition of any one of claims 15-18, wherein L1 is optionally substituted C2-C6 alkylene.
29. The pharmaceutical composition of claim 28, wherein L1 is
Figure imgf000141_0001
.
30. The pharmaceutical composition of claim 29, wherein L1 is
Figure imgf000141_0002
31. The pharmaceutical composition of any one of claims 19-27, wherein R2 is H and L1 is optionally substituted C2-C6 alkylene.
32. The pharmaceutical composition of claim 31, wherein R2 and L1 form , , , , , , , , , ,
Figure imgf000142_0001
33. The pharmaceutical composition of claim 32, wherein R2 and L1 form
Figure imgf000142_0002
.
34. The pharmaceutical composition of any one of claims 1-33, wherein R5 is CH3.
35. The pharmaceutical composition of claim 1, wherein the compound is any one of compounds 1-530, 534-689, 1389-1433, and 1485-1490, or a pharmaceutically acceptable salt thereof.
36. A compound described by formula (I′), (II′), or (III′):
Figure imgf000142_0003
, wherein R1 is H, O, OH, F, Cl, Br, NH2, or optionally substituted C1-C3 alkoxy; R2 is H, CH3, CH2F, CHF2, or CF3; R3 and R4 are each independently CH3, CH2F, CHF2, or CF3; R5 is CH3 or CH2OH; L1 is optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C5- C15 arylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C2-C15 heterocyclylene, or optionally substituted amido; each dashed line is optionally a double bond; A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, optionally substituted 3-to-8 membered heterocyclyl, or cyano; X1 and X2 are each independently H, O, Cl, or F; X3 and X4 are each independently H or absent; Q is an optionally substituted 5-to-8 membered heterocyclyl fused ring; L2 is optionally substituted C3-C8 alkylene, optionally substituted C3-C8 heteroalkylene, optionally substituted C3-C8 alkenylene, optionally substituted C3-C8 heteroalkenylene, optionally substituted C3-C8 alkynylene, or optionally substituted C3-C8 heteroalkynylene; and X5 is O or NH, wherein at least one of R2, R3, and R4 is CH2F, CHF2, or CF3; or a pharmaceutically acceptable salt thereof.
37. The compound of claim 36, where the compound is described by formula (I′):
Figure imgf000143_0001
, or a pharmaceutically acceptable salt thereof.
38. The compound of claim 37, wherein the compound is described by formula (I′A-2):
Figure imgf000143_0002
or a pharmaceutically acceptable salt thereof.
39. The compound of any one of claims 36-38, wherein A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, or cyano.
40. The compound of claim 39, wherein the compound is described by formula (I′A-2A):
Figure imgf000143_0003
wherein Ra is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C3-C20 cycloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C3-C20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or a pharmaceutically acceptable salt thereof.
41. The compound of claim 40, wherein Ra is H.
42. The compound of claim 39, wherein the compound is described by formula (I′A-2B):
Figure imgf000144_0001
(I′A-2B), wherein each of Ra and Ra′ is independently H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted C5-C15 aryl, optionally substituted C2-C15 heteroaryl, optionally substituted C3-C20 cycloalkyl, optionally substituted C1- C20 heteroalkyl, optionally substituted C3-C20 heterocyclyl, optionally substituted C6-C35 alkaryl, optionally substituted C6-C35 heteroalkaryl, optionally substituted sulfonyl, or optionally substituted imino; or Ra and Ra′, together with the nitrogen atom to which they are attached, combine to form an optionally substituted C3-C20 heterocyclyl; or a pharmaceutically acceptable salt thereof.
43. The compound of any one of claims 36-38, wherein A is optionally substituted 3-to-8 membered heterocyclyl.
44. The compound of claim 43, wherein A is optionally substituted 5-membered heterocyclyl.
45. The compound of claim 44, wherein A is optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4- oxatriazole, or optionally substituted 1,2,3,4-thiatriazole.
46. The compound of claim 45 wherein A is
Figure imgf000145_0001
47. The compound of claim 36, wherein the compound is described by formula (II′):
Figure imgf000145_0002
, or a pharmaceutically acceptable salt thereof.
48. The compound of any one of claims 36-47, wherein R1 is OH.
49. The compound of claim 36, wherein the compound is described by formula (III′):
Figure imgf000145_0003
, or a pharmaceutically acceptable salt thereof.
50. The compound of any one of claims 36-49, wherein R3 and R4 are each CH3.
51. The compound of claim 50, wherein R2 is CH2F.
52. The compound of claim 50, wherein R2 is CHF2.
53. The compound of claim 50, wherein R2 is CF3.
54. The compound of any one of claims 36-49, wherein R2 is H or CH3.
55. The compound of claim 54, wherein R3 is CH3.
56. The compound of claim 55, wherein R4 is CH2F.
57. The compound of claim 55, wherein R4 is CHF2.
58. The compound of claim 55, wherein R4 is CF3.
59. The compound of claim 58, wherein R3 and R4 are each CH2F, CHF2, or CF3.
60. The compound of claim 59, wherein R3 and R4 are each CH2F.
61. The compound of claim 59, wherein R3 and R4 are each CHF2.
62. The compound of claim 59, wherein R3 and R4 are each CF3.
63. The compound of any one of claims 50-53, wherein L1 is optionally substituted C2-C6 alkylene.
64. The compound of claim 63, wherein L1 is
Figure imgf000146_0001
.
65. The compound of claim 64, wherein L1 is
Figure imgf000146_0002
66. The compound of any one of claims 54-62, wherein R2 is H and L1 is optionally substituted C2-C6 alkylene.
67. The compound of claim 66, wherein R2 and L1 form ,
Figure imgf000146_0003
Figure imgf000147_0001
68. The compound of any one of claims 36-67, wherein R5 is CH3.
69. The compound of claim 36, wherein the compound is any one of compounds 690a-1229a, 1233a-1388a, 690b-1229b, 1233b-1388b, 690c-1229c, 1233c-1388c, 1434a-1484, 1434b-1484, and 1434c-1484 or a pharmaceutically acceptable salt thereof.
70. A pharmaceutical composition comprising a compound of any one of claims 36-69 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
71. The pharmaceutical composition of claim 70, wherein at least one of R2, R3, and R4 is deuterium-enriched, and the composition has an isotopic enrichment factor for deuterium of at least 5.
72. The pharmaceutical composition of any one of claims 1-35 and 71, wherein the composition has an isotopic enrichment factor for deuterium of at least about 500.
73. A method of treating an inflammatory disease in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of any one of claims 1-35, 71, and 72 in an amount sufficient to treat the condition.
74. The method of claim 73, wherein the inflammatory disease is selected from the group consisting of scleroderma, dermatomyositis, systemic lupus erythematosus, acquired immune deficiency syndrome (AIDS), multiple sclerosis, rheumatoid arthritis, psoriasis, diabetes, cancer, asthma, atopic dermatitis, an autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, stroke, ischemia, a neurodegenerative disease, amyotrophic lateral sclerosis (ALS), chronic traumatic encephalopathy (CTE), chronic inflammatory demyelinating polyneuropathy, an autoimmune inner ear disease, uveitis, iritis, and peritonitis.
75. A method of treating a fibrotic disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of claims 1-35, 71 and 72 in an amount sufficient to treat the condition.
76. The method of claim 75, wherein the fibrotic disease is selected from the group consisting of scleroderma, cystic fibrosis, liver cirrhosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, Dupuytren’s contracture, keloids, chronic kidney disease, chronic graft rejection, scarring, wound healing, post-operative adhesions, reactive fibrosis, polymyositis, ANCA vasculitis, Behcet's disease, anti- phospholipid syndrome, relapsing polychondritis, Familial Mediterranean Fever, giant cell arteritis, Graves ophthalmopathy, discoid lupus, pemphigus, bullous pemphigoid, hydradenitis suppuritiva, sarcoidosis, bronchiolitis obliterans, primary sclerosing cholangitis, primary biliary cirrhosis, or organ fibrosis.
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