WO2021113656A1

WO2021113656A1 - Cannabinoids and uses thereof

Info

Publication number: WO2021113656A1
Application number: PCT/US2020/063341
Authority: WO
Inventors: Hongfeng Deng; Clifton David LEIGH; Zhuang JIN
Original assignee: Corbus Pharmaceuticals, Inc.
Priority date: 2019-12-04
Filing date: 2020-12-04
Publication date: 2021-06-10
Also published as: WO2021113656A9

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 (CBi) 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 CBi 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 CBi 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). The disclosure is based, at least in part, on the realization that reduction of the D⁸ double bond of ajulemic acid or a structurally related analog compound produces compounds having an additional stereocenter, and that control of this stereocenter results in improved properties.

The present disclosure provides reduced ajulemic acid and structurally related cannabinoids, which 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 particular, the invention features compounds that have increased selectivity for the CB2 receptor over the CBi receptor).

In a first aspect, the invention features a composition including a compound described by formula (I) or (II):

wherein Ri is H, O, OH, F, Cl, Br, NH2, or optionally substituted C1-C3 alkoxy; R2 is H, CH3, CH2F, CHF2, CF3, CH2D, CHD2, or CDs; R3 and R4 are each independently CH3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3; R5 is CH3 OG OHSOH; Li 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; Xi and X2 are each independently H, O, Cl, or F; 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 X3 is O or NH, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (I):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IA):

(IA), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by any one of formulas (IA-1), (IA-2), and (IA- 3):

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), and (IA-3)), 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-1 A):

wherein R_a 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 some embodiments, the compound is described by formula (IA-2A):

(IA-2A), wherein R_a 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 some embodiments, the compound is described by formula (IA-3A):

(IA-3A), wherein R_a 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 some embodiments of any of the aspects described herein (e.g., any one of formulas (IA-1A), (1A-2A), and (1A-3A)), R_a is H.

In some embodiments, the compound is described by formula (IA-1B):

(IA-1 B), wherein R_a and Rb are each 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 R_a and Rb, 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, the compound is described by formula (IA-2B):

(IA-2B), wherein R_a and Rb are each 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 R_a and Rb, 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, the compound is described by formula (IA-3B):

(IA-3B), wherein R_a and Rb are each 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 R_a and Rb, 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 of any of the aspects described herein (e.g., any one of formulas (IA-1B), (IA-2B), and (IA-3B), R_a 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. In some embodiments of any of the aspects described herein (e.g., any one of formulas (IA-1 B), (IA-2B), and (IA-3B), R_a is optionally substituted C1-C20 alkyl, e.g., R_a is

In some embodiments of any of the aspects described herein (e.g., any one of formulas (IA-1 B), optionally substituted C3-C20 cycloalkyl, e.g., R_a is

In some embodiments of any of the aspects described herein (e.g., any one of formulas (IA-1 B), (IA-2B), and (IA-3B), R is H or Ci-C₄ alkyl, e.g., R_b is H.

In some embodiments of any of the aspects described herein (e.g., any one of formulas (IA-1 B), (IA-2B), and (IA-3B), R_a and R_b, 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), and (IA-3)), 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), and (IA-3)), 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),

In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), and (IA-3)), A is

In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-2), and (IA-3)), 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), and (IA-3)), 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 of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-1 A), (IA-1 B), (IA-2), (IA-2A), (IA-2B), (IA-3), (IA-3A), and (IA-3B)), Ri is OH.

In some embodiments of any of the aspects described herein (e.g., any one of formulas (I), (IA), (IA-1), (IA-1 A), (IA-1 B), (IA-2), (IA-2A), (IA-2B), (IA-3), (IA-3A), and (IA-3B)), Ri is -OCH₃ or -OCH₂CH₃.

In some embodiments of any of the aspects described herein (e.g., any one of formulas (e.g., any one of formulas (I), (IA), (IA-1), (IA-1A), (IA-1 B), (IA-2), (IA-2A), (IA-2B), (IA-3), (IA-3A), and (IA-3B)), Ri is H.

In some embodiments, the compound is described by formula (II):

or a pharmaceutically acceptable salt thereof. In some embodiments, L2 is optionally substituted C3-C8 alkylene, preferably C4 alkylene. In some embodiments, the compound is described by formula (IIA):

(I I A) , wherein R_e and R_f are each independently H, OH, Cl, Br, or F; or R_e and R_f are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IIA-1):

(HA-1), wherein R_e and R_f are each independently H, OH, Cl, Br, or F; or R_e and R_f are joined to form an epoxy;or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IIA-2):

(IIA-2), wherein R_e and R_f are each independently H, OH, Cl, Br, or F; or R_e and R_f are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.

In some embodiments of any of the aspects described herein (e.g., any one of formulas (IIA), (IIA-1), and (IIA-2)), R_e and R are each H.

In some embodiments of any of the aspects described herein (e.g., any one of formulas (IIA), (IIA-1), and (IIA-2)), R_e and R are each OH.

In some embodiments of any of the aspects described herein (e.g., any one of formulas (IIA), (IIA-1), and (IIA-2)), R_e and R_f are joined to form an epoxy.

In some embodiments, l_2 is optionally substituted C3-C8 alkenylene, preferably C4 alkenylene. In some embodiments, the compound is described by formula (MB):

(MB), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IIB-1):

(IIB-1), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IIB-2):

(IIB-2), or a pharmaceutically acceptable salt thereof.

In some embodiments, l_2 is optionally substituted Cs alkylene.

In some embodiments the compound is described by formula (IIC):

(lie), wherein R_e, R_f, and R_g are each independently H, OH, Cl, Br, or F; or R_e and R_fare joined to form an epoxy; or R_f and R_g are joined to form an epoxy; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (IIC-1):

(IIC-1), wherein R_e, R_f, and R_g are each independently H, OH, Cl, Br, or F; or R_e and R_fare joined to form an epoxy; or R_f and R_g are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IIC-2):

(IIC-2), wherein R_e, R_f, and R_g are each independently H, OH, Cl, Br, or F; or R_e and R_fare joined to form an epoxy; or R_f and R_g are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.

In some embodiments of any of the aspects described herein (e.g., any one of formulas (IIC), (IIC-1), and (IIC-2)), R_e, R_f, and R_g are each H.

In some embodiments of any of the aspects described herein (e.g., any one of formulas (IIC), (IIC-1), and (IIC-2)), R_g is H and R_e and R_f are joined to form an epoxy. In some embodiments of any of the aspects described herein (e.g., any one of formulas (IIC),

(IIC-1), and (IIC-2)), R_e is H and R_f and R_g are joined to form an epoxy.

In some embodiments, l_2 is optionally substituted Cs alkenylene.

In some embodiments, the compound is described by any one of formulas (IID, (IID-1), and (I ID-

CUD),

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by any one of formulas (ME), (IIE-1), and (IIE-

2):

(I IE-2), or a pharmaceutically acceptable salt thereof.

In some embodiments, l_2 is optionally substituted C3-C8 heteroalkylene, preferably C₄ heteroalkylene. In some embodiments, the compound is described by any one of formulas (IIF), (IIF-1), and (IIF-

2):

or a pharmaceutically acceptable salt thereof.

In some embodiments of any of the aspects described herein (e.g., any one or formulas (II), (IIA),

In some embodiments of any of the aspects described herein (e.g., any one or formulas (II), (IIA), (IIA-1), (IIA-2), (MB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF),

(IIF-1), and (IIF-2)), X₃ is NH.

In some embodiments of any of the aspects described herein (e.g., any one or formulas (I), (IA), (IA-1), (IA-1A), (IA- 1 B), (IA-2), (IA-2A), (IA-2B), (IA-3), (IA-3A), (IA-3B), (II), (IIA), (IIA-1), (IIA-2), (MB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), Rs is CH₃.

In some embodiments of any of the aspects described herein (e.g., any one or formulas (I), (IA), (IA-1), (IA-1 A), (IA-1 B), (IA-2), (IA-2A), (IA-2B), (IA-3), (IA-3A), (IA-3B), (II), (IIA), (IIA-1), (IIA-2), (MB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₄ is CH₃. In some embodiments of any of the aspects described herein (e.g., any one or formulas (I), (IA),

(IA-1), (IA-1 A), (IA-1 B), (IA-2), (IA-2A), (IA-2B), (IA-3), (IA-3A), (IA-3B), (II), (IIA), (IIA-1), (IIA-2), (MB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₄ is CD₃, CH₂D, or CHD₂. In some embodiments of any of the aspects described herein (e.g., any one or formulas (I), (IA), (IA-1), (IA-1 A), (IA-1 B), (IA-2), (IA-2A), (IA-2B), (IA-3), (IA-3A), (IA-3B), (II), (IIA), (IIA-1), (IIA-2), (MB),

(I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₄ is CH2F, CHF2, or CFs.

In some embodiments of any of the aspects described herein (e.g., any one or formulas (I), (IA), (IA-1), (IA-1 A), (IA-1 B), (IA-2), (IA-2A), (IA-2B), (IA-3), (IA-3A), (IA-3B), (II), (IIA), (IIA-1), (IIA-2), (MB),

(I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₃ is CH₃.

(I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₃ is CD₃, CH₂D, or CHD₂.

(I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₃ is CH₂F, CHF₂, or CF₃.

(I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₂ is CD₃, CH₂D, or CHD₂.

(I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₂ is CH₂F, CHF₂, or CF₃.

(I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₂ is CH₃.

(I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₂ is H.

In some embodiments of any of the aspects described herein (e.g., any one or formulas (I), (IA), (IA-1), (IA-1A), (IA- 1 B), (IA-2), (IA-2A), (IA-2B), (IA-3), (IA-3A), (IA-3B), (II), (IIA), (IIA-1), (IIA-2), (MB),

(I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), Li is optionally substituted C2-C6 alkylene. For example, Li is

, more preferably

(I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₂ is H and Li is optionally substituted C2-C6 alkylene. For example, R2 and Li form

In some embodiments of any of the aspects described herein (e.g., any one or formulas (I), (IA), (IA-1), (IA-1 A), (IA-1 B), (IA-2), (IA-2A), (IA-2B), (IA-3), (IA-3A), (IA-3B), (II), (IIA), (IIA-1), (IIA-2), (MB), (I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₂ is H and Li is optionally substituted phenylene. For example, R₂ and Li form

(I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₂ is H and Li is optionally substituted 5-membered heterocyclylene. For example, R₂ and Li 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 some embodiments of any of the aspects described herein (e.g., any one or formulas (I), (IA), (IA-1), (IA-1 A), (IA-1 B), (IA-2), (IA-2A), (IA-2B), (IA-3), (IA-3A), (IA-3B), (II), (IIA), (IIA-1), (IIA-2), (MB), (I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₂ and Li form

(I IB-1 ), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (ME), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2)), R₂ is H and Li is optionally substituted amido of formula -C(0)NHI_3-, wherein l_3 is optionally substituted Ci- 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 Li form

In some embodiments, the compound is any one of the compounds of Table 1 and Table 2:

Table 1

(Compound i: X = CH₂F; Compound ii: X = CHF₂; Compound iii: X = CF3; Compound iv: X = CH₂D;

Compound v: X = CHD₂; Compound vi: X = CD3)

Table 2

Compound v: X = CHD₂; Compound vi: X = CD3)

In another aspect, the invention provides a pharmaceutical composition including a compound of the invention (e.g., a compound of any one of formulas (l)-(ll) or any one of the compounds of Table 1 and Table 2), or a pharmaceutically acceptable 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 (e.g., at least about 500, 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 (l)-(ll) or any one of the compounds of Table 1 and Table 2), 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 (l)-(ll) or any one of the compounds of Table 1 and Table 2), 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 (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). 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 CBi 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 CBi 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 CBi receptor. Receptor selectivity may be determined by receptor binding or by functional assay (e.g., cAMP or b-arrestin), as described here, for example in Examples 2-4. 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 (l)-(ll) or any one of the compounds of Table 1 and Table 2) 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 Ci-2o alkyl group (e.g., Ci-e or CMO 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 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, 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-membered 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 nonaromatic 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 .Jheptyl 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 -Nhh group. An optionally substituted amine includes, for example, a -NHR or a -NR1R2 group, wherein R, Ri, and R2 are each independently H or any substituent group described herein. In some embodiments, Ri and R2form 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(=0)NH₂ group. An optionally substituted amide includes, for example, a -C(=0)NHR or a -C(=0)NR_IR₂ group, wherein R, Ri, and R2 are each independently H or any substituent group described herein.

The term “imino” as used herein, represents a -C(=NR_I)R2 group. An optionally substituted imino includes, for example, a -C(=NR_I)R2 group, wherein each of Ri and R2 are independently selected from H or any substituted group described herein.

The term “thioester,” as used herein, represents a -C(=0)SH group. An optionally substituted thioester includes, for example, a -C(=0)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)NR_IR2 group, wherein R, Ri, and R2 are each independently H or any substituent group described herein.

The term “sulfonamide,” as used herein, represents a -S(=0)₂NH₂ group. An optionally substituted sulfonamide includes, for example, a -S(=0)₂NHR or a -S(=0)₂NR_IR₂ group, wherein R, Ri, and R2 are each independently H or any substituent group described herein.

The term “sulfonyl,” as used herein, represents a -S(=0)₂R group. An optionally substituted sulfonyl includes, for example, a S(=0)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 =0, 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, S02NR₂, 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 Descriptions of the Drawings

FIG. 1 shows a ¹H NMR spectrum of Compound 1a.

FIG. 2 shows a two-dimensional nuclear Overhauser effect spectrum of Compound 1 a. FIG. 3 shows a ¹H NMR spectrum of Compound 1 b.

FIG. 4 shows a two-dimensional nuclear Overhauser effect spectrum of Compound 1 b.

Detailed Description of the Invention

The invention relates 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, the disclosure is based, at least in part, on the realization that reduction of the D⁸ double bond of ajulemic acid or a structurally related analog compound produces compounds having an additional stereocenter, and that control of this stereocenter results in improved properties. The present disclosure provides reduced ajulemic acid and structurally related cannabinoids, which provide advantageous properties, such as increased metabolic stability, improved pharmacokinetic properties (e.g., increased serum half- life, maximum serum concentration and/or oral bioavailability), and/or receptor selectivity (e.g., increased CB2 receptor selectivity), for example, as compared to ajulemic acid or structurally-related cannabinoids.

Compounds

The disclosure provides cannabinoid compounds (e.g., a cannabinoid compound described by any one of formulas (l)-(ll), or any one of the compounds of Table 1 and Table 2) useful for the treatment of disease (e.g., a fibrotic disease or an inflammatory disease).

In particular, the invention features reduced 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 compounds structurally-related to reduced ajulemic acid. Ajulemic acid has been investigated for the treatment of inflammatory disease and fibrotic disease. The structure of ajulemic acid (AJA) is:

In particular, the invention features ajulemic acid in which the D⁸ double bond is reduced:

Reduced AJA).

The invention also feature cannabinoids structurally related to reduced AJA, such as cannabinoids described by any one of formulas (l)-(ll) and (G)-(IIG) or any one of the compounds of Table 1 and Table 2.

The present disclosure recognizes that reduction of the D⁸ double bond of AJA produces a stereocenter. Accordingly, the reduced AJA and AJA analog compound stereoisomers can be separated and may have different binding properties from each other or from the parent compound (e.g., AJA). For example, D⁸ Reduced AJA can be separated into the following stereoisomers:

-Reduced AJA).

In some embodiments, a compound of the disclosure has a stereoisomeric purity of at least 60%, 70%, 80%, 90%, 95%, 98%, or 99%.

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, a stereoisomer has increased CB2 selectivity as compared to another stereoisomer.

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 CBi-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, deja 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 improved stability (e.g., improved pharmacokinetic properties or improved stability as compared to ajulemic acid).

In some embodiments, a compound of the invention is described by any one of formulas (I), (IA), (IA-1 (IA-1 A), (IA-1B), (IA-2), (IA-2A), (IA-2B), (IA-3), (IA-3A), (IA-3B), (II), (IIA), (IIA-1), (IIA-2), (MB), (IIB- 1), (I IB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), (IID-2), (HE), (IIE-1), (IIE-2), (IIF), (IIF-1), and (IIF-2).

In some embodiments, the compound of the invention is a compound of Table 1 or Table 2.

Pharmaceutical compositions

Compounds of the invention (e.g., a cannabinoid compound, such as a compound described by any one of formulas (l)-(ll) or any one of the compounds of Table 1 and Table 2) 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. Nonlimiting 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 semipermeable 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 biopolymer microspheres that contains the therapeutically active agent. The biocompatible matrix and biopolymer 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 Gl 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 ingredients), 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^).

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 antiinflammatory 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 200-500mg 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 (l)-(ll) or any one of the compounds of Table 1 and Table 2 prepared 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 formulas (l)-(ll) or any one of the compounds of Table 1 and Table 2) may be used to treat or prevent inflammatory disease.

Inflammatory diseases include, for example, schlerodoma (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 (l)-(ll) or any one of the compounds of Table 1 and Table 2). 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 (l)-(ll) or any one of the compounds of Table 1 and Table 2) 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 (l)-(ll) or any one of the compounds of Table 1 and Table 2 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 compound described by formula (I) or (II):

wherein Ri is H, O, OH, F, Cl, Br, NH2, or optionally substituted C₁-C3 alkoxy;

R₂ is H, CH₃, CH2F, CHF₂, CF₃, CH₂D, CHD₂, or CD₃;

R₃ and R4 are each independently CH₃, CH₂F, CHF₂, CF₃, CH₂D, CHD₂, or CD₃;

Rs is CH₃ or CH₂OH;

LI is optionally substituted Ci-C₂o alkylene, optionally substituted Ci-C₂o heteroalkylene, optionally substituted C₂-C₂o alkenylene, optionally substituted C₂-C₂o heteroalkenylene, optionally substituted C₂-C₂o alkynylene, optionally substituted C₂-C₂o heteroalkynylene, optionally substituted C5- C₁₅ arylene, optionally substituted C₃-C₂o cycloalkylene, optionally substituted C₂-Cis 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;

Xi and X₂ are each independently H, O, Cl, or F; l_2 is optionally substituted C₃-C8 alkylene, optionally substituted C₃-C8 heteroalkylene, optionally substituted C₃-Cs alkenylene, optionally substituted C₃-Cs heteroalkenylene, optionally substituted C₃-Cs alkynylene, or optionally substituted C₃-Cs heteroalkynylene; and

X₃ is O or NH, or a pharmaceutically acceptable salt thereof. 2. The compound of embodiment 1 , wherein the compound is described by formula (I):

or a pharmaceutically acceptable salt thereof.

3. The compound of embodiment 2, wherein the compound is described by formula (IA):

(IA), or a pharmaceutically acceptable salt thereof.

4. The compound of embodiment 3, wherein the compound is described by formula (IA-1):

(IA-1), or a pharmaceutically acceptable salt thereof.

5. The compound of embodiment 4, wherein the compound is described by formula (IA-2):

(IA-2), or a pharmaceutically acceptable salt thereof. 6. The compound of embodiment 4, wherein the compound is described by formula (IA-3):

(IA-3), or a pharmaceutically acceptable salt thereof.

7. The compound of any one of embodiments 1-6, wherein A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, or cyano.

8. The compound of embodiment 7, wherein the compound is described by formula (IA-1 A):

(IA-1A), wherein R_a 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.

9. The compound of embodiment 8, wherein the compound is described by formula (IA-2A):

(IA-2A), wherein R_a 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 compound of embodiment 8, wherein the compound is described by formula (IA-3A):

(IA-3A), wherein R_a 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.

11. The compound of any one of embodiments 8-10, wherein R_a is H.

12. The compound of embodiment 7, wherein the compound is described by formula (IA-1B):

(IA-1 B), wherein R_a and Rb are each 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

R_a and Rb, 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.

13. The compound of embodiment 12, wherein the compound is described by formula (IA-2B):

(IA-2B), wherein R_a and Rb are each 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

14. The compound of embodiment 12, wherein the compound is described by formula (IA-3B):

(IA-3B), wherein R_a and Rb are each 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

15. The compound of any one of embodiments 12-14, wherein R_a is H, optionally substituted Ci- 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.

16. The compound of any one of embodiments 12-15, wherein R_a is optionally substituted C1-C20 alkyl.

17. The compound of any one of embodiments 12-16, wherein R_a is selected from:

18. The compound of any one of embodiments 12-15, wherein R_a is optionally substituted C3-C20 cycloalkyl.

19. The compound of any one of embodiments 12-15 and 18, wherein

20. The compound of any one of embodiments 12-19 wherein Rb is H or C1-C4 alkyl.

21 . The compound of any one of embodiments 12-20, wherein Rb is H.

22. The compound of any one of embodiments 12-14, wherein R_a and Rb, together with the nitrogen atom to which they are attached, combine to form an optionally substituted C3-C20 heterocyclyl.

23. The compound of any one of embodiments 1-6, wherein A is optionally substituted 3-to-8 membered heterocyclyl.

24. The compound of embodiment 23, wherein A is optionally substituted 5-membered heterocyclyl.

25. The compound of embodiment 24, 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.

26. The compound of embodiment 25, wherein A is

27. The compound of embodiment 26, wherein A is

/=\

28. The compound of embodiment 27, wherein A is

29. The compound of embodiment 25, wherein A is

30. The compound of embodiment 23, wherein A is optionally substituted 6-membered heterocyclyl.

31 . The compound of embodiment 30, 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. 32. The compound of embodiment 31 , wherein A is

33. The compound of embodiment 32, wherein A is

34. The compound of embodiment 31 , wherein A is

35. The compound of embodiment 23, wherein A is optionally substituted 7-membered heterocyclyl.

36. The compound of embodiment 35, wherein A is optionally substituted azepine, optionally substituted 1 ,4-diazepine, optionally substituted thiepine, or optionally substituted 1 ,4-thiazepine.

37. The compound of any one of embodiments 1-36, where Ri is OH.

38. The compound of any one of embodiments 1 -36, where Ri is -OCH3 or -OCH₂CH3.

39. The compound of any one of embodiments 1-36, where Ri is H.

40. The compound of embodiment 1 , wherein the compound is described by formula (II):

or a pharmaceutically acceptable salt thereof.

41 . The compound of embodiment 40, wherein L2 is optionally substituted C3-C8 alkylene.

42. The compound of embodiment 41 , wherein L2 is optionally substituted C4 alkylene.

43. The compound of embodiment 42, wherein the compound is described by formula (IIA):

44. The compound of embodiment 43, wherein the compound is described by formula (IIA-1):

(IIA-1), wherein R_e and R_f are each independently H, OH, Cl, Br, or F; or R_e and R_f are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.

45. The compound of embodiment 43, wherein the compound is described by formula (IIA-2):

(HA-2), wherein R_e and R_f are each independently H, OH, Cl, Br, or F; or R_e and R_f are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.

46. The compound of any one of embodiments 43-45, wherein R_e and R_f are each H.

47. The compound of any one of embodiments 43-45, wherein R_e and R_f are each OH.

48. The compound of any one of embodiments 43-45, wherein R_e and R_f are joined to form an epoxy.

49. The compound of embodiment 40, wherein l_2 is optionally substituted C3-C8 alkenylene.

50. The compound of embodiment 49, wherein L2 is optionally substituted C4 alkenylene.

51 . The compound of embodiment 50, wherein the compound is described by formula (MB):

(MB), or a pharmaceutically acceptable salt thereof. 52. The compound of embodiment 51 , wherein the compound is described by formula (I IB-1 ):

(IIB-1), or a pharmaceutically acceptable salt thereof.

53. The compound of embodiment 41 , wherein the compound is described by formula (IIB-2):

(IIB-2), or a pharmaceutically acceptable salt thereof.

54. The compound of embodiment 40, wherein l_2 is optionally substituted Cs alkylene.

55. The compound of embodiment 54, wherein the compound is described by formula (IIC):

(IIC), wherein R_e, R_f, and R_g are each independently H, OH, Cl, Br, or F; or R_e and R_f are joined to form an epoxy; or R_f and R_g are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.

56. The compound of embodiment 54, wherein the compound is described by formula (IIC-1):

(IIC-1), wherein R_e, R_f, and R_g are each independently H, OH, Cl, Br, or F; or R_e and R_f are joined to form an epoxy; or R_f and R_g are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.

57. The compound of embodiment 54, wherein the compound is described by formula (IIC-2):

(IIC-2), wherein R_e, R_f, and R_g are each independently H, OH, Cl, Br, or F; or R_e and R_f are joined to form an epoxy; or R_f and R_g are joined to form an epoxy; or a pharmaceutically acceptable salt thereof.

58. The compound of any one of embodiments 55-57, wherein R_e, R_f, and R_g are each H.

59. The compound of any one of embodiments 55-57, wherein R_g is H and R_e and R_f are joined n epoxy.

60. The compound of any one of embodiments 55-57, wherein R_e is H and R_f and R_g are joined n epoxy.

61 . The compound of embodiment 40, wherein l_2 is optionally substituted Cs alkenylene.

62. The compound of embodiment 61 , wherein the compound is described by formula (I ID):

(HD), or a pharmaceutically acceptable salt thereof.

63. The compound of embodiment 62, wherein the compound is described by formula (IID-1):

(IID-1), or a pharmaceutically acceptable salt thereof. 64. The compound of embodiment 62, wherein the compound is described by formula (IID-2):

(I ID-2), or a pharmaceutically acceptable salt thereof.

65. The compound of embodiment 61 , wherein the compound is described by formula (ME):

(HE), or a pharmaceutically acceptable salt thereof.

66. The compound of embodiment 65, wherein the compound is described by formula (I IE-1 ):

(IIE-1), or a pharmaceutically acceptable salt thereof.

67. The compound of embodiment 65, wherein the compound is described by formula (I IE-2):

(I IE-2), or a pharmaceutically acceptable salt thereof.

68. The compound of embodiment 40, wherein l_2 is optionally substituted C3-C8 heteroalkylene.

69. The compound of embodiment 68, wherein L2 is optionally substituted C4 heteroalkylene. 70. The compound of embodiment 68, wherein the compound is described by formula (I IF):

or a pharmaceutically acceptable salt thereof.

71 . The compound of embodiment 70, wherein the compound is described by formula (IIF-1):

or a pharmaceutically acceptable salt thereof.

72. The compound of embodiment 70, wherein the compound is described by formula (IIF-2):

(IIF-2), or a pharmaceutically acceptable salt thereof.

73. The compound of any one of embodiments 40-72, wherein X3 is O.

74. The compound of any one of embodiments 40-72, wherein X3 is NH.

75. The compound of any one of embodiments 1 -74, wherein Rs is CH3.

76. The compound of any one of embodiments 1-75, wherein R4 is CH3.

77. The compound of any one of embodiments 1-75, wherein R4 is CD3, CH₂D, or CHD₂.

78. The compound of any one of embodiments 1-75, wherein R4 is CH₂F, CHF₂, or CF3.

79. The compound of any one of embodiments 1-78, wherein R3 is CH3.

80. The compound of any one of embodiments 1-78, wherein R3 is CD3, CH₂D, or CHD₂.

81 . The compound of any one of embodiments 1-78, wherein R3 is CH₂F, CHF₂, or CF3.

82. The compound of any one of embodiments 1-81 , wherein R₂ is CD3, CH₂D, or CHD₂.

83. The compound of any one of embodiments 1-81 , wherein R₂ is CH₂F, CHF₂, or CF3.

84. The compound of any one of embodiments 1-81 , wherein R₂ is CH3.

85. The compound of any one of embodiments 1-81 , wherein R2 is H.

86. The compound of any one of embodiments 1-84, wherein Li is optionally substituted C2-C6 alkylene. 87. The compound of embodiment 86, wherein Li is

88. The compound of embodiment 87, wherein Li is

89. The compound of embodiment 85, wherein Li is optionally substituted C2-C6 alkylene.

90. The compound of embodiment 89, wherein R2 and Li form

91 . The compound of embodiment 90, wherein R2 and Li form

92. The compound of any one of embodiments 1-85, wherein Li is optionally substituted C1-C6 heteroalkylene.

93. The compound of embodiment 92, wherein Li is

94. The compound of embodiment 93, wherein Li is

95. The compound of any one of embodiments 1-85, wherein Li is optionally substituted C2-C6 alkenylene. 96. The compound of embodiment 95, wherein Li is

97. The compound of embodiment 85, wherein Li is optionally substituted phenylene.

98. The compound of embodiment 97, wherein

Li form

99. The compound of embodiment 85, wherein Li is optionally substituted 5-membered heterocyclylene.

100. The compound of embodiment 99, wherein

and Li 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 compound of embodiment 100, wherein

and Li form

102. The compound of embodiment 85, wherein Li is optionally substituted amido of formula - C(0)NHI_3-, wherein l_3 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 compound of embodiment 102, wherein R2 and Li form

104. The compound of embodiment 1 , wherein the compound is any one of the compounds of Table 1 and Table 2 or a pharmaceutically acceptable salt thereof.

105. A pharmaceutical composition comprising the compound of any one of embodiments 1-104 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

106. The pharmaceutical composition of embodiment 105, 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.

107. The pharmaceutical composition of embodiment 106, wherein the composition has an isotopic enrichment factor for deuterium of at least about 500.

108. The pharmaceutical composition of embodiment 107, wherein the composition has an isotopic enrichment factor for deuterium of at least about 1000.

109. The pharmaceutical composition of embodiment 108, wherein the composition has an isotopic enrichment factor for deuterium of at least about 3000.

110. The pharmaceutical composition of embodiment 109, wherein the composition has an isotopic enrichment factor for deuterium of at least about 4000, 5000, or 6000.

111 . 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 104-109 in an amount sufficient to treat the condition.

112. The method of embodiment 111 , 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.

113. The method of embodiment 112, wherein the inflammatory disease is scleroderma.

114. The method of embodiment 113, wherein the scleroderma is systemic sclerosis, localized scleroderma, or sine scleroderma.

115. 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 105-110 in an amount sufficient to treat the condition. 116. The method of embodiment 115, 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.

117. The method of embodiment 116, wherein the fibrotic disease is scleroderma.

118. The method of embodiment 117, wherein the scleroderma is systemic sclerosis, localized scleroderma, or sine scleroderma.

119. The method of embodiment 116, wherein the fibrotic disease is organ fibrosis.

120. The method of embodiment 119, where the organ fibrosis is dermal fibrosis, lung fibrosis, liver fibrosis, kidney fibrosis, or heart fibrosis.

121. The method of embodiment 116, 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

LC-MS methods

General mass spec condition for different LC-MS methods: 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 electrospray 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 nebulisergas, at a pressure of 35 psig. Data acquisition was performed with Agilent Chemstation software.

HPLC condition for LC-MS 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 x4.6 mm I.D..; 3 pm 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 forthe MS detector. HPLC condition for LC-MS 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 pm 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 NH40Ac)/95% Acetonitrile in 1 .5 min; the resulting composition was held for 0.9 min; from 5% (Water + 50 mM NH40Ac)/95% Acetonitrile to 95% (Water + 50 mM NH40Ac)/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 LC-MS 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 pm 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 pL. MS acquisition range and DAD detector were set to 100-1000 m/z and 200-400 nm respectively.

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. Synthesis of reduced AJA and reduced AJA analogs

The synthetic procedures for non-A⁸-reduced AJA analogs are reported in International Patent Application Nos. PCT/US2019/034965 and PCT/US2020/057985, each of which is hereby incorporated by reference in its entirety. Representative synthetic procedures for reduced AJA and analogs thereof are as described below.

Synthesis of (6aR,9S,10aR)-1 -hydroxy-6, 6-dimethyl-3-(2-methyloctan-2-yl)-6a, 7, 8, 9,10,10a- hexahydro-6H-benzo[c]chromene-9-carboxylic acid (Compound 1a) and (6aR,9R,10aR)-1 -hydroxy- 6, 6-dimethyl-3-(2-methyloctan-2-yl)-6a, 7, 8, 9, 10,10a-hexahydro-6H-benzo[c]chromene-9-carboxylic acid (Compound 1b):

AJA Compound 1a Compound 1b AJA (0.5 g, 1 .25 mmol, 1 eq) was dissolved in EtOH (12.5 ml_), Pd on C (10% wet) (50 mg) was added and the mixture was degassed in vacuum and saturated with H2 (g). The reaction mixture was stirred at room temperature overnight under H2 (g) atmosphere at 1 atm of pressure. The mixture was filtered across a plug of Celite and rinsed with EtOH, the solvent was removed under reduced pressure. The products were purified by reverse phase (Method: MAP5AC) to yield Compound 1a and Compound 1b as white solids (Compound 1a; 155 mg, 31%and Compound 1 b; 45 mg, 8.8%). The stereochemistry at C9 for both compounds was determined by NOESY NMR. For Compound 1a: ¹H NMR (400 MHz, DMSO-de; see FIG. 1) 6 12.02 (bs, 1 H), 9.14 (s, 1 H), 6.27 (d, J = 1.80 Hz, 1 H), 6.09 (d, J = 1.76 Hz, 1 H), 3.43 (m, 1 H), 2.41 - 2.31 (m, 2H), 1 .99 (d, J = 11 .08 Hz, 1 H), 1 .93 (d, J = 10.24 Hz), 1 .44 (m, 3H), 1 .34 (m, 2H), 1 .28 (s, 3H), 1 .23 - 1 .10 (m, 15H), 1 .05 - 0.97 (m, 6H), 0.81 (t, J = 7.04 Hz, 3H). LC-MS (ESI+): 403.3 (M+H⁺); R.T.: 4.805 min (LC-MS Method Villa). For Compound 1b: ¹H NMR (400 MHz, DMSO-de; see FIG. 3) 6 11.97 (bs, 1 H), 9.14 (bs, 1 H), 6.24 (s, J = 1.76 Hz, 1 H), 6.07 (s, J = 1.72 Hz, 1 H), 3.61 (d, J = 12.1 Hz, 1 H), 2.65 (s, 1 H), 2.39 (dt, J = 11 .2 - 2.21 Hz, 1 H), 2.10 (d, J = 13.04 Hz, 1 H), 1.65 (d, J = 11.36 Hz, 1H), 1.52 - 1.41 (m, 3H), 1.36 (m, 1 H), 1.27 (s, 3H), 1.23 - 1.09 (m, 14H), 1.00 (bs, 2H), 0.94 (s, 3H), 0.81 (t, J = 7.04 Hz, 3H). LC-MS (ESI+): 403.3 (M+H⁺); R.T.: 4.856 min (LC-MS Method Villa). Method MAP5AC: GILSON Semi-Preparative System, operated by Unipoint software, equipped with a Phenomenex Gemini C18 100A column (100 mm long x 21.2 mm I.D.; 5 pm particles) at RT °C.

Solvents: Organic phase: MeOH:ACN (1 :1); Aqueous phase: water (65mM NH40Ac). Gradient elution was performance: 2 min at 32% [AP] - 68% [OP] (flow 5 mL/min), from 32% [AP] - 68% [OP] to 4% [AP] - 96% [OP] in 20 minutes (flow 40 mL/min), and 10 min at 100 % [OP] (flow 40 mL/min). Two-dimensional nuclear Overhauser effect spectra of Compounds 1a and 1b are shown in FIGs. 2 and 4, respectively.

Synthesis of (9R)-9-(1 H-imidazol-2-yl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,8,9,10,10a- hexahydro-6H-benzo[c]chromen-1-ol (Compound 558a); (9S)-9-(1H-imidazol-2-yl)-6,6-dimethyl-3- (2-methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1 -ol (Compound 558b):

AJA

Pyridine (10.5 mL, 131 .07 mmol, 2.1 eq) and n-heptane (225 mL) were charged to round bottom flask, and the solution was heated at 50°C, then AJA (25 g, 62.41 mmol, 1eq) was added to the stirred solution, followed by acetic anhydride (10.62 mL, 112.34 mmol, 1 .8 eq) added dropwise. The reaction was stirred at 50° C for 18 hours. Water (35 mL) was added and the mixture was stirred at 50°C for 5 hours. The product was extracted with EtOAc (3x50 mL), the combined organic layers were washed with brine and water, dried over anhydrous MgS0₄, filtered and concentrated under reduced pressure. The product was purified by chromatography on silica gel (Heptane: EtOAc; from 100:0 to 75:25) to yield the desired product as a white solid. (20.14 g; 72.9%). ¹H NMR (300 MHz, DMSO-de) 6 12.22 (s, 1 H), 6.89 (s, 1H), 6.59 (s, 1 H), 6.55 (s, 1 H), 3.26 (d, J = 17.53 Hz, 1 H), 2.47 - 2.31 (m, 2H), 2.24 (s, 3H), 2.08 - 1.95 (m, 1 H), 1.84 - 1.67 (m, 2H), 1.52 - 1.45 (m, 2H), 1.34 (s, 3H), 1.17 (s, 12H), 1.03 (s, 5H), 0.81 (t, J = 6.84 Hz, 3H). LC-MS (ESI+): 443.3 (M+H⁺); R.T.: 1.563 min (LC-MS Method Tacc50-6_AP_AMAC).

Step b. ( 6aR, 10aR)-6, 6-dimethyl-3-(2-methyloctan-2-yl)-9-oxo-6a, 7, 8, 9, 10,10a-hexahydro-6H- benzo[c]chromen-1-yl acetate

Diphenylphosphorylazide (1.07 mL, 4.97 mmol, 1.1 eq) and triethylamine (0.92 mL, 6.78 mmol, 1.5 eq) were added to a stirred solution of the product from step a. (2.0 g, 4.52 mmol, 1 eq) in THF under nitrogen. The reaction mixture was stirred at 70°C for 2 hours. The solvent was removed under reduced pressure. The yellow oil was diluted in dioxane (10 mL), then 10 mL of citric acid aqueous solution (10%) was added and the resulted mixture was stirred at 60°C for 2 hours. The dioxane was distilled under reduced pressure, and the product was extracted with EtOAc (3x 15 mL). The combined organic layers were dried over anhydrous MgS04, filtered and concentrated under reduced pressure. The product was purified by chromatography on silica gel (Heptane: EtOAc: from 100: 0 to 90:10) to yield the product as a light yellow solid. (1 .24 g; 66.2%). 1 H NMR (300 MHz, CDCI3) d 6.69 (s, 1 H), 6.51 (s, 1 H), 3.27 (d, J = 14.34 Hz, 1H), 2.71 (t, J = 12.39 Hz, 1 H), 2.57 (d, J = 15.36 Hz, 1 H), 2.47 - 2-40 (m, 1 H), 2.32 (s, 3H), 2.26 (d, J = 14.43 Hz, 1 H), 2.19 - 2.13 (m, 2H), 1.95 (t, J = 11.34 Hz, 1 H), 1.57 (s, 1 H), 1.47 (s, 6H), 1.21 (s, 12H), 1.11 (s, 3H), 1.06 (bs, 2H), 0.84 (s, 3H). LC-MS (ESI+): 415.1 (M+H+); R.T.: 1.915 min (LC-MS Method Tacc50-6_AP_AMAC).

Lithium bis(trimethylsilyl)amide solution [1.0 M] in THF (2.47 mL, 2.47 mmol, 1.2 eq) was added to a stirred solution of the product from step b. (0.86 g, 2.06 mmol, 1 eq) in dry THF (7.0 mL) under nitrogen at -78° C. The mixture was stirred at -78°C for 1 h, then a solution of A/-Phenyl-bis(trifluomethansulfonimide) (1 .03 g, 2.89 mmol, 1 .4 eq) in dry THF (6.5 mL) was added dropwise. The mixture reaction was allowed to warm up to room temperature over a period of 4 hours and stirred at room temperature for 12 hours more. The solution was treated with an aqueous saturated solution of NH4CI and extracted with Et₂0. The combined organic layers were dried over anhydrous MgS0₄, filtered and concentrated under reduced pressure. The product was purified by chromatography on silica gel (Heptane: EtOAc) to yield the product as an oil. (0.52 g; 46.1%).¹H NMR (300 MHz, CDCh) <56.69 (s, 1 H), 6.54 (s, 1 H), 5.82 (s, 1 H), 3.21 (d, J = 17.55 Hz, 1H), 2.78 (m, 1H), 2.31 (s, 5H), 1.99 (t, J = 14.94 Hz, 1 H), 1.84 (dt, J = 11 .28 - 3.2 Hz, 1 H), 1.56 - 1.48 (m, 3H), 1.42 (s, 3H), 1.22 (s, 12H), 1.13 (s, 3H), 1.05 (bs, 2H), 0.84 (t, J = 5.61 Hz, 3H). LC- MS (ESI+): 547.2 (M+H⁺); R.T.: 2.172 min (LC-MS Method Tacc50-6_AP_AMAC).

Step d. ( 6aR, 10aR)-6, 6-dimethyl-3-(2-methyloctan-2-yl)-9-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)- 6a, 7, 10, 10a-tetrahydro-6H-benzo[c]chromen-1 -yl acetate

The product from step c. (0.5 g, 0.92 mmol, 1 eq), bis(pinacolato)diboron (0.28 g, 1.10 mmol, 1.2 eq), Pd(dppf) (38 mg, 0.046 mmol, 0.05 eq) and potassium acetate (0.27 g, 2.75 mmol, 3.0 eq) were dissolved in dioxane (12-5 ml_) in a sealed tube under nitrogen atmosphere. The reaction mixture was stirred at 90°C for 14 hours. The mixture was diluted with EtOAc and washed with a saturated aqueous solution of NaHCOs, the organic layer was dried over MgS0₄, filtered and concentrated under reduced pressure. The product was purified by chromatography on silica gel (Heptane: EtOAc; from 100:0 to 95:5) to yield the product as a white solid. (0.198 g; 41 .2 %). ¹H NMR CDCI₃ 6.69 (m, 1 H), 6.52 (m, 2H), 3.12 (dd, J = 15.60 - 3.24 Hz, 1 H), 2.50 (dt, J = 10.92 - 3.84 Hz, 1 H), 2.29 (s, 3H), 2.25 (s, 2H), 1.95 - 1 .79 (m, 3H), 1.52 - 1.46 (m, 2H), 1.40 (s, 1 H), 1.37 (s, 2H), 1 .25 - 1 .13 (m, 24H), 1.11 (s, 3H), 1.03 (bs, 2H), 0.84 (t, J = 6.90 Hz, 3H) LC-MS (ESI+): 525.4 (M+H⁺); R.T.: 2.343 min (LC-MS Method Tacc50- 6_AP_AMAC).

Step e. (6aR,10aR)-9-(1/-/-imidazol-2-yl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydro-6/-/- benzo[c]chromen-1-ol (Compound 558¹)

Compound 558'

The product from step d. (0.593 g, 1.13 mmol, 1 eq), 2-Bromo-1/-/-imidazole (0.199 g, 1 .356 mmol, 1 .2 eq), Pd(Pph3)₄ (66 mg, 0.057 mmol, 0.05 eq), xPhos (54 mg, 0.113 mmol, 0.1 eq) and potassium carbonate (0.625 g, 4.52 mmol, 4.0 eq) were dissolved in a mixture dioxane: water (4:1) (22 ml_) in a sealed tube under nitrogen atmosphere. The reaction mixture was stirred at 100°C for overnight. The mixture was diluted with EtOAc and washed with a saturated aqueous solution of NaHCC>3, the organic layer was dried over MgSC , filtered and concentrated under reduced pressure. The product was purified by chromatography on silica gel (Heptane: EtOAc; from 100:0 to 70:30) to yield Compound 558' as a white solid. (53 mg; 11.2 %). ¹H NMR (300 MHz, DMSO-de) d 11.96 (s, 1 H), 9.25 (s, 1 H), 6.95 (s, 2H), 6.39 (s, 1 H), 6.33 (s, 1 H), 6.14 (s, 1H), 4.06 (d, J = 14.85 Hz, 1 H), 2.57 (dt, J = 13.20 - 4.08 Hz, 1 H), 2.37 - 2.27 (m, 1H), 2.07 - 1.79 (m, 3H), 1.72 (dt, J = 11 .28 - 4.20, 1 H, 1.49 - 1.43 (m, 2H), 1.33 (s, 3H), 1.17 (bs, 5H), 1.15 (s, 7H), 1.04 (s, 5H), 0.81 (t, J = 6.78 Hz, 3H). LC-MS (ESI+): 423.3 (M+H⁺); R.T.: 3.155 min (LC-MS Method Villa).

Step f. (9R)-9-(1 H-imidazol-2-yl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H- benzo[c]chromen-1-ol (Compound 558a); (9S)-9-(1 H-imidazol-2-yl)-6,6-dimethyl-3-(2-methyloctan-2-yl)- 6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ol (Compound 558b)

Compound 558' Compound 558a Compound 558b

Compound 558' (30 mg, 0.071 mmol, 1 eq) was dissolved in EtOH (1.0 ml_), Pd on C (10% wet) (3 mg) was added and the mixture was degassed in vacuum and saturated with hh (g). The reaction mixture was stirred at room temperature overnight under H2 (g) atmosphere at 1 atm of pressure. The mixture was filtered across a plug of Celite and rinsed with EtOH, the solvent was removed under reduced pressure. The products were purified by reverse phase (Method: MAP5BIC) to yield Compound 558a and Compound 558b as white solids (Compound 558a; 18 mg, 59 % and Compound 558b; 7 mg, 23%). The stereochemistry at C9 for both compounds was determined analogously to compounds 1 a and 1 b. For Compound 558a: ¹H NMR (400 MHz, DMSO-de) d 6.94 (s, 1 H), 6.41 (d, J = 1 .60 Hz, 1 H), 6.28 (d, J = 1.60 Hz, 1 H), 3, 79 (d, J = 12.52 Hz, 1 H), 3.10 (m, 1H), 2.66 (dt, J = 10.37 - 2.10 Hz, 1 H), 2.20 (m, 1 H), 1.97 (m, 1 H), 1.70-1.51 (m, 2H), 1.45 (m, 2H), 1.38 (s, 3H), 1.28 - 1.14 (m, 16H), 1.09 (s, 3H), 1.05 (bs, 2H), 0.83 (t, J = 7.08 Hz, 3H). LC-MS (ESI+): 425.3 (M+H⁺); R.T.: 3.478 min (LC-MS Method Villa). For Compound 558b: ¹H NMR (400 MHz, DMSO-de) d 7.03 (s, 1 H), 6.44 (d, J = 1.76 Hz, 1 H), 6.34 (d, J = 1.76 Hz, 1 H), 3.45 (d, J = 13. 60 Hz, 1H), 3.32 (m, 1 H), 2.73 (t, J = 10.44 Hz, 1 H), 2.37 (m, 1 H), 2.12 - 2.02 (m, 1 H), 1.82 - 1 .69 (m, 2H), 1 .64 - 1 .47 (m, 10H), 1 .35 (s, 3H), 1 .21 (m, 13H), 1 .07 (m, 2H), 0.91 (s, 3H), 0.83 (t, J = 7.04 Hz, 3H). LC-MS (ESI+): 425.3 (M+H⁺); R.T.: 3.404 min (LC-MS Method Villa). Method MAP5BIC: GILSON Semi-Preparative System, operated by Unipoint software, equipped with a Phenomenex Gemini C18 100A column (100 mm long x 21.2 mm I.D.; 5 pm particles) at RT °C. Solvents: Organic phase: MeOH:ACN (1 :1); Aqueous phase: water (25mM NH4HC03). Gradient elution was performance: 2 min at 32% [AP] - 68% [OP] (flow 5 mL/min), from 32% [AP] - 68% [OP] to 4% [AP] - 96% [OP] in 20 minutes (flow 40 mL/min), and 10 min at 100 % [OP] (flow 40 mL/min).

Other 9-heterocyclic-substituted compounds, e.g., 550a-557avi, 550b-557bvi, 559ai-665avi, 559bi- 665bvi, 853a-892avi, and 853b-892bvi, and their non-A⁸-reduced precursors, can be prepared based on the procedure above. Synthesis of (6aR,9R,10aR)-1 -hydroxy-6, 6-dimethyl-3-(2-methylheptan-2-yl)-N-(1 - (trifluoromethyl)cyclobutyl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-9-carboxamide (Compound 371a); (6aR,9S,10aR)-1 -hydroxy-6, 6-dimethyl-3-(2-methylheptan-2-yl)-N-(1 - (trifluoromethyl)cyclobutyl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-9-carboxamide (Compound 371b):

DIPEA (0.135 mL, 0.777 mmol, 3.0 eq) and HATU (0.109 g, 0.285 mmol, 1.1 eq) were added to a solution of (6aR, 10aR)-1 -hydroxy-6, 6-dimethyl-3-(2-methylheptan-2-yl)-6a, 7, 10,10a-tatrahydro-6H- benzo[c]chromene-9-carboxylic acid (0.1 g, 0.259 mmol) in dry DMF (2.8 mL) under nitrogen atmosphere. The mixture was stirred for 10 minutes. Then, 1-(trifluoromethyl)cyclobutan-1 -amine hydrochloride (0.055 g, 0.311 mmol, 1.2 eq) was added. The reaction mixture was stirred at 100 °C for 45 minutes under microwave irradiation. The solution was diluted with EtOAc and washed with a saturated aqueous solution of NaHCC>3 (x3) and an aqueous solution of HCI (10%) (x3). The organic layer was dried over anhydrous MgSC , filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Heptane: EtOAc, from 100:0 to 80:20) to yield (6aR,10aR)-1-hydroxy-6,6- dimethyl-3-(2-methylheptan-2-yl)-A/-(1-(trifluoromethyl)cyclobutyl)-6a,7,10,10a-tetrahydro-6/-/- benzo[c]chromene-9-carboxamide as a solid (Compound 371'; 0.016 g, 12.2 %). ¹H NMR (400 MHz, CDCh) d 6.69 (d, J = 5.36 Hz, 1 H), 6.37 (d, J = 1 .76 Hz, 1 H), 6.24 (d, J = 1 .80 Hz, 1 H), 5.76 (s, 1 H), 5.17 (s, 1 H), 3.75 (dd, J = 15.2 - 4.12 Hz, 1 H), 2.69 (dt, J = 10.44 - 4.56 Hz, 1 H), 2.55 (t, J = 8.52 Hz, 4H), 2.40 - 2.32 (m, 1 H), 2.05 - 1 .92 (m, 4H), 1 .81 (dt, J = 11 .9 - 4.20 Hz, 1 H), 1 .47 (m, 2H), 1 .38 (s, 3H),

1.24 - 1.13 (m, 10H), 1.10 (s, 3 H), 1.04 (m, 2H), 0.80 (t, J = 6.88 Hz, 3H). LC-MS (ESI+): 508.2 (M+H⁺); R.T.: 4.961 min (LC-MS Method VILLA).

Compound 371' (30 mg, 0.059 mmol, 1 eq) was dissolved in EtOH (0.8 mL), Pd on C (10% wet) (3 mg) was added and the mixture was degassed in vacuum and saturated with H2 (g). The reaction mixture was stirred at room temperature overnight under H2 (g) atmosphere at 1 atm of pressure. The mixture was filtered across a plug of Celite and rinsed with EtOH, the solvent was removed under reduced pressure. The products were purified by reverse phase (Method: MAP5AF) to yield Compound 371a and Compound 371b as white solids (Compound 371a; 10 mg, 34 % and Compound 371b; 7 mg, 24%). The stereochemistry at C9 for both compounds was determined analogously to compounds 1 a and 1 b. For Compound 371a: ¹H NMR (400 MHz, DMSO-de) d 6.35 (s, 1 H), 6.20 (s, 1 H), 5.55 (s, 1 H), 5.03 (s,

1 H), 3.37 (d, J = 16.97 Hz, 1 H), 2.52 (m, 4H), 2.36 (m, 1 H), 2.09-1 .94 (m, 4 H), 1.64 (m, 1 H), 1 .53 - 1 .44 (m, 2H), 1.38 (s, 3H), 1.31 - 1.11 (m, 13H), 0.82 (t, J = 9.48 Hz, 3H). LC-MS (ESI+): 510.3 (M+H⁺); R.T.: 4.501 min (LC-MS Method Villa). For Compound 371 b: ¹H NMR (400 MHz, DMSO-de) d 6.38 (s, 1 H), 6.34 (s, 1 H), 6.27 (s, 1 H), 5.33 (s, 1 H), 3.22 (d, J = 19.36 Hz, 1 H), 2.72 (bs, 1 H), 2.56 (m, 4H), 2.44 (m, 2H), 2.02 (m, 2H), 1.77 (d, J = 17.17 Hz, 1 H), 1.66 - 1.39 (m, 6H), 1.37 (s, 3H), 1.31-1.06 (m, 15 H), 1.02 (s, 3H), 0.82 (t, J = 9.48 Hz, 3H). LC-MS (ESI+): 510.3 (M+H⁺); R.T.: 4.738 min (LC-MS Method Villa). Method MAP5AF: GILSON Semi-Preparative System, operated by Unipoint software, equipped with a Phenomenex Gemini C18 100A column (100 mm long x 21.2 mm I.D.; 5 pm particles) at RT °C. Solvents: Organic phase: MeOH:ACN (1 :1); Aqueous phase: water (0.1% HCOOH). Gradient elution was performance: 2 min at 32% [AP] - 68% [OP] (flow 5 mL/min), from 32% [AP] - 68% [OP] to 4% [AP] - 96% [OP] in 20 minutes (flow 40 mL/min), and 10 min at 100 % [OP] (flow 40 mL/min).

Synthesis of (6aR,9R,10aR)-N-((R)-2,3-dihydroxypropyl)-1 -hydroxy-6,6-dimethyl-3-(2-methyloctan- 2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-9-carboxamide (97a) and (6aR,9S,10aR)-N- ((R)-2,3-dihydroxypropyl)-1 -hydroxy-6, 6-dimethyl-3-(2-methyloctan-2-yl)-6a, 7, 8, 9,10,10a- hexahydro-6H-benzo[c]chromene-9-carboxamide (97b)

Palladium on carbon (10% loading, wet support, 1 mg, 0.006 mmol, 0.1 eq) was added to a solution of Compound 97' (30 mg, 0.06 mmol, 1 eq) in EtOH (2 ml_) and the mixture was stirred at room temperature under hydrogen atmosphere (1 atm) for 12 hours. The black suspension was filtered through a pad of Celite and the cake was washed with ethanol (5 ml_). The filtrates were concentrated in vacuo and the residue was purified by reverse phase preparative HPLC (Gemini C18 column (100 x 30 mm, 5 pm)) using the following gradient: from 49% [0.1% formic acid(aq.)] - 51% [acetonitrile] to 6%

[0.1% formic acid(aq.)] - 94% [acetonitrile] (run time: 30 min). All the fractions containing the products were directly lyophilized to give Compound 97a as a white solid (9.6 mg, 16%) and Compound 97b as a white solid (7.6 mg, 10%). The stereochemistry at C9 for both compounds was determined analogously to compounds 1a and 1 b. Compound 97a: ¹H NMR (300 MHz, CDCI₃) d 6.77 (s, 1 H), 6.34 (d, J = 16.0 Hz, 2H), 3.83 (s, 1 H), 3.58 (d, J = 3.7 Hz, 3H), 3.38 (d, J = 13.6 Hz, 1 H), 3.25 (d, J = 13.7 Hz, 1 H), 2.73

(s, 1 H), 2.45 (dd, J = 23.9, 12.5 Hz, 3H), 2.07 (s, 1 H), 1.77 (d, J = 11.9 Hz, 1 H), 1.69 - 1.41 (m, 3H), 1.36 (s, 3H), 1.33 (d, J = 17.6 Hz, 3H), 1.22 (d, J = 19.8 Hz, 13H), 1.01 (s, 5H), 0.84 (t, J = 6.4 Hz, 3H); LC-MS (ESI+): 476.3 (M+H+); HPLC RT: 4.311 min (LC-MS Method: VILLA). Compound 97b: ¹H NMR (400 MHz, CDCb) d 6.92 (bp, 1 H), 6.67 (s, 1 H), 6.30 (d, J = 17.0 Hz, 2H), 3.60 (dd, J = 11 .6, 3.7 Hz, 2H), 3.48 (ddd, J = 19.8, 12.6, 5.4 Hz, 2H), 3.38 - 3.21 (m, 2H), 2.43 (q, J = 12.8 Hz, 2H), 2.15 - 1.96 (m, 1 H), 1.90 (d, J = 7.7 Hz, 1 H), 1 .81 (s, 1 H), 1 .65 - 1 .40 (m, 4H), 1 .35 (s, 3H), 1 .30 - 0.96 (m, 18H), 0.83 (t, J = 6.9 Hz, 3H); LC-MS (ESI+): 476.1 (M+H+); HPLC RT: 4.160 min (LC-MS Method: VILLA).

Synthesis of (9aR,10R)-11,11 -dimethyl-14-(2-methyloctan-2-yl)-3,4,5,6,9,9a,10,11 -octahydro-2H- 8,10-ethanochromeno[4,5-jk][1]oxa[6]azacyclododecin-7(8H)-one (Compounds 666a/b)

Step a. Methyl (6aR,10aR)-1 -hydroxy-6, 6-dimethyl-3-(2-methyloctan-2-yl)-6a, 7, 10,10a-tetrahydro-6H- benzo[c]chromene-9-carboxylate

4-Dimethylaminopyridine (0.763 g, 6.24 mmol, 0.5 eq) and EDC HCI (2.63 g, 13.731 mmol, 1.10 eq) were added to a solution of AJA (5.0 g, 12.48 mmol) in CH2CI2 (125 mL) under nitrogen atmosphere. The mixture was stirred for 5 minutes. Then, methanol (5.0 mL, 124.83 mmol, 10.0 eq) was added and the reaction mixture was stirred at rt for overnight. The solution was diluted with EtOAc and washed with a saturated aqueous solution of NaHCC>3 (x3) and an aqueous solution of HCI (10%). The organic layer was dried over anhydrous MgSC , filtered and concentrated under reduced pressure. The product was purified by chromatography on silica gel (Heptane: EtOAc, from 100:0 to 80:20) to afford the product as a foam (2.74 g, 52.9 %). ¹H NMR (300 MHz, CDCI3) 57.01 (s, 1 H), 6.38 (s, 1 H), 6.25 (s, 1 H), 5.06 (bs,

1 H), 3.87 - 3.71 (m, 1 H), 3.75 (s, 3H), 2.66 (dt, J = 10.80 - 4.02 Hz, 1 H), 2.40 (dt, J = 16.53 - 4.80 Hz,

1 H), 2.00 (m, 2H), 1 .83 (dt, J = 10.77 - 3.45 Hz, 1 H), 1 .56 (bs, 2H), 1 .49 (m, 2H), 1 .40 (s, 3H), 1 .25 (s, 14H), 1.2 (s, 3H), 1.05 (bs, 2H), 0.84 (m, 3H). LC-MS (ESI+): 415.2 (M+H⁺); R.T.: 1.988 min (LC-MS Method Tacc50-6).

Step b. 4-((tert-butoxycarbonyl)amino)butyl methanesulfonate

Methanesulfonyl chloride (1 .34 g, 17.38 mmol, 1 .3 eq) and triethylamine (2.79 mL, 20.05 mmol, 1 .5 eq) were added to a stirred solution of (5-Hydroxy-pentyl)-carbamic acid fe/f-butyl ester (2.53 g, 13.36 mmol,

1 eq) in CH2CI2 (40 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at rt for 1 day. The solution was concentrated under reduced pressure. The crude product was used without purification. (6.39 g, 178.8 %). LC-MS (ESI+): 212.0 (M-56⁺); R.T.: 1.106 min (LC-MS Method Tacc50-6). Step c. Methyl (6aR,10aR)-1-(4-((tert-butoxycarbonyl)amino)butoxy)-6,6-dimethyl-3-(2-methyloctan-2-yl)- 6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylate

A solution of 5-((tert-butoxycarbonyl)amino)butyl methanesulfonate (2.55 g, 9.55 mmol, 5.0 eq) in dry DMF (6.0 ml_) was added dropwise to a stirred suspension of methyl (6aR,10aR)-1 -hydroxy-6, 6-dimethyl- 3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydro-6/-/-benzo[c]chromene-9-carboxylate (0.792 g, 1.91 mmol,

1 eq) and cesium carbonate (5.00 g, 15.3 mmol, 8 eq) in dry DMF (6.0 ml_) under nitrogen. The reaction mixture was stirred at 50°C for 16 hours. The solution was diluted with EtOAc and water, the organic layer was separated and washed with brine. The organic layer was dried over anhydrous MgSCU, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel (Heptane/EtOAc; from 100:0 to 90:10) to yield the product as a foam. (0.672 g, 60.1 %). ¹H NMR (300 MHz, CDCI₃) 6.99 (s, 1 H), .6.41 (s, 1 H), 6.36 (s, 1H), 5.02 (bs, 1 H), 3.98 (bs, 1 H), 3.86 (d, J = 17.13 Hz, 1H), 3.19 (bs, 1 H), 2.61 (dt, J = 10.62 -3.69 Hz, 1 H), 2.40 (d, J = 17.79 Hz, 1 H), 2.04 - 1.67 (m, 8H), 1.60 (s, 1 H), 1.52 (m, 2H), 1.43 (s, 12H), 1.22 (s, 13H), 1.11 (s, 3H), 1.05 (bs, 2H), 0.84 (t, J = 5.34 Hz, 3H). LC-MS (ESI+): 486.3 (M-100⁺); R.T.: 2.345 min (LC-MS Method Tacc50-6_AP_AMAC).

Step d. (6aR,10aR)-1-(4-((tert-butoxycarbonyl)amino)butoxy)-6,6-dimethyl-3-(2-methyloctan-2-yl)- 6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylic acid

A solution of NaOH [1 M] in water (8.98 ml_) was added dropwise to a solution of the product of step c. (0.658 g, 1.12 mmol) in methanol (11 .0 ml_) at 0 °C. The reaction mixture was stirred at room temperature for 20 hours. The solution was diluted with water, acidified to pH=3 with an aqueous solution of HCI [1 M] and the product was extracted with EtOAc. The combined organic layers were dried over anhydrous MgS0₄, filtered and concentrated under reduced pressure. The product was purified by chromatography on silica gel (Heptane/EtOAc; from 100:0 to 70:30) to yield (6aR,10aR)-1-((5-((fe/f- butoxycarbonyl)amino)pentyl)oxy)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydro-6/-/- benzo[c]chromene-9-carboxylic acid as a yellow oil. (0.41 g, 63.8 %). ¹H NMR (300 MHz, CDC ) £7.11 (s, 1 H), 6.41 (s, 1 H), 6.35 (s, 1 H), 4.83 (bs, 1 H), 3.98 (s, 2H), 3.88 (d, J = 17.67 Hz, 1 H) 3.17 (s, 2H),

2.62 (dt, J = 10.74 - 3.57 Hz, 1 H), 2.44 (d, J = 27.58 Hz, 1 H), 2.08 - 1 .79 (m, 6H), 1 .68 (m, 1 H), 1 .52 (s, 3H), 1.43 (s, 12H), 1.22 (s, 12H), 1.11 (s, 3H), 1.06 (bs, 2H), 0.84 (t, J = 6.18 Hz, 3H). LC-MS (ESI+): 472.3 (M+H⁺); R.T.: 1.995 min (LC-MS Method Tacc50-6_AP_AMAC). Step e. 4-(((6aR,10aR)-9-carboxy-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydro-6H- benzo[c]chromen-1 -yl)oxy)butan-1 -aminium chloride

HCI [4M] in dioxane (5.0 ml_) was added to a stirred solution of the product from step d. (0.352 g, 0.616 mmol, 1 eq) in dioxane (1 .8 ml_) at rt. The mixture was stirred at rt for 20 hours. The solvent was removed under reduced pressure; the white solid was used without purification. (0.30 g, 100%). ¹H NMR (300 MHz, CDCb) 7.95 (2H), 6.99 (s, 1 H), 6.41 (s, 1H), 6.31 (s, 1 H), 4.01 - 3.63 (m, 5H), 3.12 (bs, 2H), 2.56 (t, J = 10.11 Hz, 1H), 2.32 (d, J = 14.52 Hz, 2H), 2.00 (m, 2H), 1.82 (bs, 4H), 1.50 (bs, 2H), 1.37 (s, 3H), 1.22 (s, 12H), 1.08 (s, 5H), 0.84 (s, 3H) LC-MS (ESI+): 472.3 (M+H⁺); R.T.: 1.445 min (LC-MS Method T acc50-6_AP_AM AC) .

Step f. (4R,19R)-5,5-dimethyl-9-(2-methyloctan-2-yl)-6,12-dioxa-16-azatetracyclo[9.6.3.0⁴,^l9.0⁷,^2O]icosa- 1 ,7(20), 8,10-tetraen-17-ol (Compound 666')

DIEA (2.02 ml_, 11.84 mmol, 20 eq) and HATU (0.675 g, 1 .776 mmol, 3.0 eq) were added to a solution of the product from step e. in dry DMF (118 ml_) under nitrogen atmosphere. The mixture was stirred at rt for 35 minutes. The solution was diluted with EtOAc and washed with a saturated aqueous solution of NaHCC>3 (x3) and a saturated aqueous solution of NH4CI (x3). The organic layer was dried over anhydrous MgSCb, filtered and concentrated under reduced pressure. The product was purified by chromatography on silica gel (Heptane: EtOAc, from 100:0 to 50:50) to afford Compound 1 as a white solid (0.015 g, 5.6 %). ¹H NMR (300 MHz, CDCIs) £ 7.24 (d, J = 8.46 Hz, 1 H), 6.39 (s, 1 H), 6.32 (s, 1H), 5.94 (s, 1 H), 4.26 (d, J = 7.77 Hz, 1 H), 3.73 (t, J = 8.07 Hz, 1 H), 3.27 (m ,1 H), 2.95 (bs, 1 H), 2.40 (d, J = 14.31 Hz, 1H), 2.01 (m, 3H), 1.87 - 1.69 (m, 2H), 1.50 (t, J = 7.86 Hz, 4H), 1.31 (s, 3H), 1.17 (s, 12H), 0.99 (s, 5H), 0.80 (t, J = 5.22 Hz, 3H). LC-MS (ESI+): 454.3 (M+H⁺); R.T.: 4.874 min (LC-MS Method ZVilla_amonico_21). Step g. (9aR,10R)-11 ,11-dimethyl-14-(2-methyloctan-2-yl)-3,4,5,6,9,9a,10,11-octahydro-2H-8,10- ethanochromeno[4,5-jk][1]oxa[6]azacyclododecin-7(8H)-one (Compounds 666a/b)

Compound 666' Compound 666a/b

Palladium on carbon (10% loading, wet support, 3 mg, 0.007 mmol, 0.1 eq) was added to a solution of Compound 666' (30 mg, 0.07 mmol, 1 eq) in EtOH (2 ml_) and the mixture was stirred at room temperature under hydrogen atmosphere (1 atm) for 12 hours. The reaction mixture (black suspension) was filtered through a pad of Celite and the cake was washed with ethanol (5 ml_). The filtrates were concentrated in vacuo and the residue was purified by reverse phase chromatography (Gemini C18 column, 100 x 30 mm, 5 pm) using the following gradient: from 59% [0.1% formic acid(aq.)] - 41% [acetonitrile] to 17% [0.1 % formic acid(aq.)] - 83% [acetonitrile] (run time: 30 min. All the fractions containing the desired product were directly lyophilized to give Compound 666a/b as a white powder (21 mg, 70%). Chiral HPLC analysis (Phenomenex Lux Amylose-1 150x4.6 mm, 5um ; mobile phase : A: C02, B: iPrOH +0.1% Diethylamine; gradient: From 5% B to 60% B in 10 min, hold 3 min; flow rate: 3 mL/min; run time: 20 min) suggests only one diastereomer (very likely R-configuration analogously to compound 1a, i.e., Compound 666a) with a purity of 94.75%. ¹H NMR (400 MHz, CDCb) d 6.45 (d, J = 1 .5 Hz, 1 H), 6.37 (d, J = 1 .5 Hz, 1 H), 4.40 (dt, J = 8.8, 3.2 Hz, 1 H), 3.88 (ddd, J = 11 .5, 7.4, 3.4 Hz, 1 H), 3.59 (ddd, J = 11.3, 8.8, 2.1 Hz, 1 H), 2.98 - 2.77 (m, 2H), 2.73 (d, J = 2.8 Hz, 1H), 2.57 (dd, J = 13.6, 2.1 Hz, 1 H), 2.41 (t, J = 10.5 Hz, 1 H), 2.25 - 2.10 (m, 1 H), 2.03 (ddd, J = 14.5, 11.5, 3.1 Hz, 1 H), 1.88 - 1.45 (m, 8H), 1 .45 - 1 .27 (m, 4H), 1.26 - 1.13 (m, 12H), 1.08 (dd, J = 18.3, 8.0 Hz, 2H), 0.96 (s, 3H), 0.90 - 0.77 (m, 3H); LC-MS-TOF (ESI+): 456.3334 (M+H⁺); HPLC RT: 4.833 min (LC-MS Method: VILLA).

Synthesis of (6aR,9R,10aR)-1 -hydroxy-N-(4-hydroxy-2-methylbutan-2-yl)-6,6-dimethyl-3-(2- methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-9-carboxamide (Compound 61a) and (6aR,9S,10aR)-1-hydroxy-N-(4-hydroxy-2-methylbutan-2-yl)-6,6-dimethyl-3-(2- methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-9-carboxamide (Compound 61b)

Compound 61 ' (0.150 mg, 0.309 mmol, 1.0 eq) was dissolved in EtOH (4.5 mL) and degassed in vacuo and inert atmosphere (three times). Then, 10% palladium on carbon 60-65% wet (0.016 mg, 0.015 mmol, 0.05 eq) was added and the mixture was degassed in vacuo and then saturated with H2, repeated three times. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered on Celite, washed with EtOH and concentrated under reduced pressure. The products were purified by reverse phase preparative HPLC (Gemini C18 column (100 x 30 mm, 5 pm), gradient: 39% [Aqueous phase] - 61% [organic phase] to 11% [Aqueous phase] - 89% [organic phase]. Aqueous phase: H2O containing 0.1% formic acid; Organic phase: 100% Acetonitrile, run time = 30 min). The desired fractions were collected and concentrated to the smallest possible volume. The residue was diluted with CH2CI2 and washed with brine. The organic layer was dried over anhydrous MgS0₄, filtered and concentrated under reduced pressure to yield Compound 61a as a white solid (0.032 g, 23 %) and Compound 61b as a white solid (0.048 g, 32 %). The stereochemistry at C9 for both compounds was determined analogously to compounds 1 a and 1 b. Compound 61a: ¹H NMR (400 MHz, CDC ) d 6.67 (s, 1 H), 6.33 (d, J = 1.7 Hz, 1 H), 6.29 (d, J = 1.7 Hz, 1 H), 3.85 - 3.78 (m, 2H), 3.40 (d, J = 12.3 Hz, 1 H), 2.52 - 2.38 (m, 2H), 2.34 - 2.17 (m, 1 H), 2.08 (d, J = 15.6 Hz, 1 H), 1 .98 - 1 .80 (m, 3H), 1 .62 - 1 .44 (m, 4H), 1.41 (s, 3H), 1.40 (s, 3H), 1.39 - 1.33 (m, 4H), 1.26 - 1.14 (m, 14H), 1.08 - 1.01 (m, 5H), 0.84 (t, J = 6.9 Hz, 3H); LC-MS (ESI+): 488.3 (M+H⁺); HPLC RT: 4.681 min (YMC-pack ODS-AQ C18 column (50 x 4.6 mm, 3 pm), 5-95% MeCN gradient in H2O containing 40mM NH4OAC, run time = 6 min). Compound 61 b: ¹H NMR (400 MHz, CDCb) d 6.49 (s, 1 H), 6.29 (d, J = 1 .7 Hz, 1 H), 6.28 (d, J = 1 .7 Hz, 1 H), 3.82 - 3.71 (m, 2H), 3.14 - 3.01 (m, 1 H), 2.59 (s, 1 H), 2.43 (t, J = 10.2 Hz, 1 H), 2.28 - 2.19 (m, 1 H), 2.00 - 1.91 (m, 1 H), 1 .87 - 1 .78 (m, 1 H), 1 .75 - 1 .65 (m, 1 H), 1 .64 - 1 .40 (m, 5H), 1.38 (s, 3H), 1 .33 (s, 3H), 1.29 (s, 3H), 1 .35 - 1 .21 (m, 3H), 1 .20 - 1 .08 (m, 12H), 1 .04 - 0.93 (m, 5H), 0.77 (t, J = 6.9 Hz, 3H); LC-MS (ESI+): 488.3 (M+H⁺); HPLC RT: 4.859 min (YMC-pack ODS-AQ C18 column (50 x 4.6 mm, 3 pm), 5- 95% MeCN gradient in H2O containing 40mM NH4OAC, run time = 6 min).

Synthesis of (6aR,9R,10aR)-N-(3,3-difluorocyclobutyl)-1 -hydroxy-6,6-dimethyl-3-(2-methyloctan-2- yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-9-carboxamide (Compound 343a) and (6aR,9S,10aR)-N-(3,3-difluorocyclobutyl)-1 -hydroxy-6, 6-dimethyl-3-(2-methyloctan-2-yl)- 6a, 7, 8, 9,10,10a-hexahydro-6H-benzo[c]chromene-9-carboxamide (Compound 343b)

Compound 343' (0.120 mg, 0.245 mmol, 1 .0 eq) was dissolved in EtOH (3.5 ml_) and degassed in vacuo and inert atmosphere (three times). Then, 10% palladium on carbon 60-65% wet (0.013mg, 0.012 mmol, 0.05 eq) was added and the mixture was degassed in vacuo and then saturated with hh (g), repeated three times. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered on Celite, washed with EtOH, and concentrated under reduced pressure. The products were purified by reverse phase (Gemini C18 column (100 x 30 mm, 5 pm), gradient: 32% [Aqueous phase] - 68% [organic phase] to 4% [Aqueous phase] - 96% [organic phase]. Aqueous phase: H2O containing 0.1% formic acid; Organic phase: 100% Acetonitrile, run time = 30 min). The desired fractions were collected and concentrated to the smallest possible volume. The residue was diluted with CH2CI2 and washed with brine. The organic layer was dried over anhydrous MgS0₄, filtered, and concentrated under reduced pressure to yield Compound 343a as a white solid (0.046 g, 38 %) and Compound 343b as a white solid (0.038 g, 32 %). The stereochemistry at C9 for both compounds was determined analogously to compounds 1a and 1 b. Compound 343a: ¹H NMR (400 MHz, CDCh) d 6.32 (d, J = 1.7 Hz, 1 H), 6.27 (d, J = 1 .8 Hz, 1 H), 6.06 (d, J = 6.7 Hz, 1 H), 4.32 - 4.20 (m, 1 H), 3.42 (d, J = 12.7 Hz, 1 H), 3.05 - 2.90 (m, 2H), 2.53 - 2.34 (m, 4H), 2.05 (d, J = 12.0 Hz, 1 H), 1.94 (dd, J = 12.4, 2.4 Hz, 1 H), 1.66 - 1.42 (m, 4H), 1.36 (s, 3H), 1.27 - 1.10 (m, 14H), 1.08 - 0.99 (m, 5H), 0.84 (t, J = 6.9 Hz, 3H). LC-MS (ESI+):

492.2 (M+H⁺); HPLC RT: 4.100 min (YMC-pack ODS-AQ C18 column (50 x 4.6 mm, 3 pm), 5-95% MeCN gradient in H2O containing 40mM NH4OAC, run time = 6 min). Compound 343b: ¹H NMR (400 MHz, CDCh) d 6.84 (d, J = 6.7 Hz, 1 H), 6.39 (d, J = 1 .7 Hz, 1 H), 6.31 (d, J = 1 .7 Hz, 1 H), 6.11 (s, 1 H), 4.46 - 4.29 (m, 1 H), 3.26 - 3.19 (m, 1 H), 3.10 - 2.95 (m, 2H), 2.74 - 2.68 (m, 1 H), 2.55 - 2.41 (m, 4H), 1.82 - 1.73 (m, 1 H), 1.70 - 1.54 (m, 2H), 1.53 - 1.41 (m, 3H), 1.37 (s, 3H), 1.28 - 1.12 (m, 13H), 1.09 - 1.00 (m, 5H), 0.84 (t, J = 6.9 Hz, 3H); LC-MS (ESI+): 492.3 (M+H⁺); HPLC RT: 4.269 min (YMC-pack ODS-AQ C18 column (50 x 4.6 mm, 3 pm), 5-95% MeCN gradient in H2O containing 40mM NH4OAC, run time = 6 min).

Synthesis of (6aR,9R,10aR)-6,6-dimethyl-3-(2-methyloctan-2-yl)-9-(pyridine-2-yl)-6a,7,8,9,10,10a- hexahydro-6H-benzo[c]chromen-1-ol (Compound 630a) and (6aR,9S,10aR)-6,6-dimethyl-3-(2- methyloctan-2-yl)-9-(pyridine-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1 -ol (Compound 630b)

Palladium on carbon (10% loading, on wet support, 20 mg, 0.02 mmol, 0.1 eq) was added to a solution of Compound 630' (75 mg, 0.2 mmol, 1 eq) in EtOH (2 ml_) and the mixture was stirred at room temperature under hydrogen atmosphere (1 atm) for 12 hours. Then, the black suspension was filtered through a pad of Celite and the cake was washed with ethanol (5 ml_). The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel eluting with heptane/ethyl acetate mixtures to afford Compound 630a and Compound 630b in pure form. Compound 630a was eluted first and was isolated as a white solid (15 mg, 20%), and Compound 630b was eluted last and was isolated as a white solid (12 mg, 16%). The stereochemistry at C9 for both compounds was determined analogously to compounds 1 a and 1 b. Compound 630a: ¹H NMR (300 MHz, CDCI3) d 8.54 (d, J = 4.3 Hz, 1 H), 7.69 (t, J = 7.7 Hz, 1 H), 7.27 (d, J = 6.2 Hz, 2H), 7.21 - 7.12 (m, 1 H), 6.34 (d, J = 3.4 Hz, 2H), 3.63 (d, J = 12.6 Hz, 1 H), 3.16 (t, J = 12.3 Hz, 1 H), 2.73 (dd, J = 11.0, 8.8 Hz, 1 H), 2.14 (d, J = 12.3 Hz, 1 H), 2.06 - 1.97 (m, 1 H), 1.76 (qd, J = 12.8, 3.9 Hz, 1 H), 1.70 - 1.60 (m, 1 H), 1.51 - 1.40 (m, 5H), 1 .33 (ddd, J = 28.5, 18.8, 6.4 Hz, 4H), 1 .17 (dd, J = 18.0, 13.2 Hz, 13H), 1 .05 (s, 2H), 0.83 (t, J = 6.9 Hz, 3H); LC-MS (ESI+): 436.3 (M+H⁺); HPLC RT: 4.429 min (XBridge C18 (50 x 4.6 mm, 3.5 pm) column, gradient: 95% (40 mM ammonium acetate)/5% Acetonitrile to 100% Acetonitrile, run time = 5.8 min). Compound 630b: ¹H NMR (400 MHz, CDCb) d 8.86 (s, 1 H), 8.61 (d, J = 4.7 Hz, 1 H), 7.74 (t, J = 7.3 Hz,

1 H), 7.50 (d, J = 7.9 Hz, 1 H), 7.24 - 7.16 (m, 1H), 6.50 (d, J = 1.5 Hz, 1 H), 6.34 (d, J = 1.5 Hz, 1 H), 3.56 - 3.36 (m, 2H), 2.64 (t, J = 10.6 Hz, 1 H), 2.49 (d, J = 13.9 Hz, 1 H), 2.25 - 2.12 (m, 1 H), 1.80 (t, J = 10.3 Hz, 2H), 1 .63 - 1 .47 (m, 3H), 1 .45 - 1 .33 (m, 3H), 1 .30 - 1 .14 (m, 12H), 1.13 - 0.90 (m, 3H), 0.85 (dd, J = 14.8, 8.1 Hz, 6H); LC-MS (ESI+): 436.3 (M+H⁺); HPLC RT: 4.696 min (XBridge C18 (50 x 4.6 mm, 3.5 pm) column, gradient: 95% (40 mM ammonium acetate)/5% Acetonitrile to 100% Acetonitrile, run time = 5.8 min).

Other compounds of the present invention can be prepared from their non- D⁸ reduced precursors based on the procedures described above.

Example 2. Affinity for CBi and CB₂ Receptors as determined by a radioligand binding assay

The binding affinity (% inhibition, Ki) of compounds of the invention for the CBi and CB₂ receptors was determined by a competitive radioligand binding assay, the results of which are provided in Table 3.

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).

CBi Radioligand Binding Assay: Cell membrane homogenates (5 pg 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-HCI (pH 7.4), 5 mM MgCI₂, 2.5 mM EDTA and 0.3% BSA.. Nonspecific binding is determined in the presence of 10 pM 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 CBi receptor. Inhibition constant (Ki) was determined from the concentration-response curve of each tested compound.

CB₂ Radioligand Binding Assay: Cell membrane homogenates (12 pg 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 MgCI₂, 2.5 mM EGTA and 0.1% BSA. Nonspecific binding was determined in the presence of 5 pM 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 3

¹ The R diastereomer, 666a, is presumed to be the major diastereomer based on chiral HPLC screening.

Example 3. CBi- 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 4 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 b-galactosidase (b-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 b-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 pL 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 pM and 25 pM in the CB1 and CB2 assays, respectively). Media was aspirated from cells and replaced with 15 pL 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 pl_ of 4X compound was added to cells and incubated at 37 °C or room temperature for 30 or 60 minutes. Final vehicle concentration is 1%. Assay signal was generated through incubation with 20 mI_ cAMP XS+ ED/CL lysis cocktail for one hour at room temperature. Microplates were read following signal generation with a PerkinElmer Envision™ instrument for chemiluminescent signal detection. Compound activity was analyzed using CBIS data analysis suite (Chemlnnovation, 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 4

Example 4. CBi- and CB₂-mediated activity as determined by b-Arrestin assay Compounds of the invention were assayed in the PathHunter® b-Arrestin assay to determine antagonist activity on the CBi and CB₂ receptors, the results of which are provided in Table 5.

The PathHunter® b-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 b-galactosidase (b-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 b-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 pL 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 pl_ 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 pL (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 Envision™ instrument for chemiluminescent signal detection. Compound activity was analyzed using CBIS data analysis suite (Chemlnnovation, 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 5

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 compound described by formula (I) or (II):

R₂ is H, CH₃, CH2F, CHF₂, CF₃, CH₂D, CHD₂, or CD₃;

Rs is CH₃ or CH₂OH;

Xi and X₂ are each independently H, O, Cl, or F;

L₂ is optionally substituted C₃-C8 alkylene, optionally substituted C₃-C8 heteroalkylene, optionally substituted C₃-Cs alkenylene, optionally substituted C₃-Cs heteroalkenylene, optionally substituted C₃-Cs alkynylene, or optionally substituted C₃-Cs heteroalkynylene; and

X₃ is O or NH, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound is described by formula (I):

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein the compound is described by formula (IA):

(IA), or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3, wherein the compound is described by formula (IA-2):

(IA-2), or a pharmaceutically acceptable salt thereof.

5. The compound of claim 3, wherein the compound is described by formula (IA-3):

(IA-3), or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-5, wherein A is optionally substituted carboxyl, optionally substituted amide, optionally substituted thioester, optionally substituted thioamide, optionally substituted sulfonamide, optionally substituted alkyl, or cyano.

7. The compound of claim 6, wherein the compound is described by formula (IA-1 A):

(IA-1A), wherein R_a 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.

8. The compound of claim 7, wherein the compound is described by formula (IA-2A):

(IA-2A), wherein R_a 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.

9. The compound of claim 7, wherein the compound is described by formula (IA-3A):

10. The compound of claim 6, wherein the compound is described by formula (IA-1 B):

11. The compound of claim 10, wherein the compound is described by formula (IA-2B):

(IA-2B), wherein R_a and Rb are each 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

12. The compound of claim 10, wherein the compound is described by formula (IA-3B):

13. The compound of any one of claims 1-5, wherein A is optionally substituted 3-to-8 membered heterocyclyl.

14. The compound of claim 13, wherein A is optionally substituted 5-membered heterocyclyl.

15. The compound of claim 14, 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.

16. The compound of claim 15, wherein A is

17. The compound of any one of claims 1-16, where Ri is OH.

18. The compound of any one of claims 1-16, where Ri is -OCH3 or -OCH₂CH3.

19. The compound of claim 1 , wherein the compound is described by formula (II):

or a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 1-19, wherein Rs is CFh.

21 . The compound of any one of claims 1-20, wherein R4 is Chh.

22. The compound of any one of claims 1 -20, wherein R4 is CD3, CH₂D, or CHD₂.

23. The compound of any one of claims 1 -20, wherein R4 is CH₂F, CHF₂, or CF3.

24. The compound of any one of claims 1-23, wherein R3 is CH3.

25. The compound of any one of claims 1 -23, wherein R3 is CD3, CH₂D, or CHD₂.

26. The compound of any one of claims 1 -23, wherein R3 is CH₂F, CHF₂, or CF3.

27. The compound of any one of claims 1-26, wherein R2 is CD3, CH2D, or CHD2.

28. The compound of any one of claims 1 -26, wherein R₂ is CH₂F, CHF₂, or CF3.

29. The compound of any one of claims 1 -26, wherein R2 is CH3.

30. The compound of any one of claims 1-26, wherein R2 is H.

31. The compound of any one of claims 1-29, wherein Li is optionally substituted C2-C6 alkylene.

32. The compound of claim 31 , wherein Li is

33. The compound of claims 32, wherein Li is

34. The compound of claim 30, wherein Li is optionally substituted C2-C6 alkylene.

35. The compound of claim 34, wherein R2 and Li form

36. The compound of claim 35, wherein R2 and Li form

37. The compound of any one of claims 1 -36, wherein R5 is Chh.

38. The compound of claim 1 , wherein the compound is any one of the compounds of Table 1 and Table 2 or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising the compound of any one of claims 1-38 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

40. The pharmaceutical composition of claim 39, 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.

41 . A method of treating an inflammatory disease in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of claim 39 or 40 in an amount sufficient to treat the condition.

42. The method of claim 41 , 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.

43. A method of treating a fibrotic disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 39 or 40 in an amount sufficient to treat the condition.

44. The method of claim 43, 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, antiphospholipid 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.