METHODS AND MATERIALS FOR INHIBITING CB1 ACTIVITY

TECHNICAL FIELD

This document relates to methods and materials for inhibiting cannabinoid receptor type 1 (CB1) activity. For example, this document provides compounds (e.g., organic compounds) having the ability to inhibit CB1 activity, formulations containing one or more compounds having the ability to inhibit CB1 activity, methods for making one or more compounds having the ability to inhibit CB1 activity, methods for inhibiting CB1 activity, and methods for treating mammals (e.g., humans) having a condition responsive to inhibition of CB1 activity.

BACKGROUND

The CB1 is a G protein-coupled cannabinoid receptor that is expressed in the peripheral nervous system and the central nervous system. Inhibitors of CB1 activity can decrease food intake, regulate body-weight gain, and be used to treat obesity. Inhibitors of CB1 activity also can be used to help people stop smoking.

SUMMARY

This document provides methods and materials for inhibiting CB1 activity. For example, the document provides compounds (e.g., organic compounds) having the ability to inhibit CB1 activity within a mammal, formulations containing one or more compounds having the ability to inhibit CB1 activity within a mammal, methods for making one or more compounds having the ability to inhibit CB1 activity within a mammal, methods for making formulations containing one or more compounds having the ability to inhibit CB1 activity within a mammal, methods for inhibiting CB1 activity within a mammal, and methods for treating mammals (e.g., humans) having a condition responsive to inhibition of CB1 activity within a mammal. Suitable examples of conditions responsive to inhibition of CB1 activity that can be treated as described herein include, without limitation, obesity, fear, metabolic-related disorders, diabetes, dyslipidaemia, and atherosclerosis. In some cases, a CB1 inhibitor described herein can be used to reduce food intake of a mammal (e.g., a human), to reduce the body weight gain of a mammal (e.g., a human), to improve lipid profiles within a mammal (e.g., a human), to improve glycemic profiles within a mammal (e.g., a human), to assist a mammal (e.g., a human) in stopping tobacco use (e.g., cigarette smoking) and/or cannabis use, to treat liver disorders (e.g., fatty liver disease, nonalcoholic steatohepatitis (NASH), cirrhosis, and/or liver cancer), to reduce the symptoms or progression of idiopathic pulmonary fibrosis or related fibrotic conditions in the lung, to ameliorate the end-organ damage induced by chronic alcohol usuage (e.g., heart failure, pancreatitis, and/or liver disease), and/or to limit or reduce the complications of chronic renal disease characterized by renal fibrosis (e.g., diabetic nephropathy, inherited glomerular diseases, and/or acquired glomerular diseases).

In some cases, a CB1 inhibitor described herein can be used to inhibit CB1 activity within the peripheral nervous system of a mammal (e.g., a human) with little or no inhibition of CB1 activity within the central nervous system of that mammal. For example, a CB1 inhibitor described herein can be used to reduce food intake of a mammal (e.g., a human), to reduce the body weight gain of a mammal (e.g., a human), to improve lipid profiles within a mammal (e.g., a human), to improve glycemic profiles within a mammal (e.g., a human), and/or to assist a mammal (e.g., a human) in stopping tobacco use (e.g., cigarette smoking), with reduced side effects associated with inhibition of CB1 within the central nervous system such as psychiatric disorder side effects.

In general, one aspect of this document features a method of inhibiting CB-1 activity within a mammal. The method comprises (or consists essentially of or consists of) administering, to the mammal, an effective amount of a compound of Formula (I):

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- or a pharmaceutically acceptable salt thereof, wherein:
- X¹is selected from O and NR¹;
- X²is selected from NR⁴and C(═O);
- X³is selected from CHR³, NR⁴and C(═O),
- provided that:
  - (i) X²is NR⁴and X³is C(═O); or
  - (ii) X²is C(═O) and X³is selected from CHR³and NR⁴;
- n is 0 or 1;
- R²is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
- each R³is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, wherein the C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
- R¹and R⁴are each independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein the C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹; or
- R¹and R², together with N atom to which R¹is attached and C atom to which R²is attached, form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R⁹;
- R⁵, R⁶, R⁷and R⁸are each independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, S(O)₂NR^c1R^d1; and a group of formula (i):

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- wherein the C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
- R¹¹is selected from C_1-6alkyl and ring A, wherein the C_1-6alkyl is optionally substituted with ring A;
- R^Nis selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl; wherein the C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹; or
- R¹¹and R^N, together with the N atom to which they are attached, for a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
- each R⁹is independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;
- ring A is selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from R^A;
- each R^Ais independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein the C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰;
- each R¹⁰is independently selected from CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;
- each R^a1, R^b1, R^c1, and R^d1is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-4alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^g;
- or any R^c1and R^d1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g; and
- each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, cyano-C_1-3alkylene, HO—C_1-3alkylene, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, thio, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, carboxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, aminosulfonyl, C_1-6alkylaminosulfonyl, di(C_1-6alkyl)aminosulfonyl, aminosulfonylamino, C_1-6alkylaminosulfonylamino, di(C_1-6alkyl)aminosulfonylamino, aminocarbonylamino, C_1-6alkylaminocarbonylamino, and di(C_1-6alkyl)aminocarbonylamino.

At least one of R⁵, R⁶, R⁷and R⁸can be a group of formula (i). At least one of R⁷and R⁸can be a group of formula (i). The compound of Formula (I) can have formula:

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- or a pharmaceutically acceptable salt thereof.

The compound of Formula (I) can have formula:

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or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can have formula:

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or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can have formula:

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or a pharmaceutically acceptable salt thereof. R²of any of the above can be selected from H and C_1-6alkyl; R¹can be selected from H, C_1-6alkyl, C_1-6haloalkyl, C(O)R^b1, and C(O)NR^c1R^d1; and the C_1-6alkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from R⁹. The R¹can be selected from C_1-6alkyl, C(O)R^b1, and C(O)NR^c1R^d1.

The compound of Formula (I) can be selected from:

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or a pharmaceutically acceptable salt thereof.

The compound of Formula (I) can be selected from:

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or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can have formula:

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or a pharmaceutically acceptable salt thereof.

The compound of Formula (I) can have formula:

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or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can have formula:

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or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can have formula:

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or a pharmaceutically acceptable salt thereof.

The compound of Formula (I) can have formula:

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or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can have formula:

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or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can have formula:

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or a pharmaceutically acceptable salt thereof. R²of any of the above can be selected from H and C_1-6alkyl. R³of any of the above can be selected from H and C_1-6alkyl. R⁴of any of the above can be selected from H, C_1-6alkyl, and C_1-6haloalkyl, wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹. In some cases, R⁴can be H. R⁵and R⁶of any of the above can be each independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, OR^a1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹. R⁵and R⁶of any of the above can be each independently selected from H, halo, C_1-6alkyl, and S(O)₂R^b1, wherein the C_1-6alkyl is optionally substituted with R⁹. In some cases, R⁵is H, and R⁶is C_1-6alkyl, optionally substituted with NR^c1R^d1. In some cases, R⁵is H, and R⁶is halo. In some cases, R⁵is H, and R⁶is S(O)₂R^b1. R⁷of any of the above can be selected from H and C_1-6alkyl. R⁸of any of the above can be selected from H and C_1-6alkyl. R^Nof any of the above can be selected from H and C_1-6alkyl. R¹¹of any of the above can be ring A. R¹¹of any of the above can be C_1-6alkyl, optionally substituted with ring A. R^Nand R¹¹, together with the N atom to which they are attached, can form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹. Ring A of any of the above can be selected from any one of the following moieties:

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Each R^Aof any of the above can be independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. Each R^Aof any of the above can be independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)OR^a1, NR^c1R^d1and NR^c1C(O)R^b1, wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. Each R¹⁰of any of the above can be independently selected from OR^a1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1S(O)₂R^b1, and S(O)₂NR^c1R^d1. Each R^Aof any of the above can be independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)OR^a1, NR^c1R^d1, and NR^c1C(O)R^b1, wherein the C_1-6alkyl is optionally substituted with C(O)OR^a1. Each R^a1, R^b1, R^c1, and R^d1of any of the above can be independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g. Each R^gof any of the above can be independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, and carboxy. In some cases, R²can be selected from H and C_1-6alkyl; R³can be selected from H and C_1-6alkyl; R¹can be selected from H, C_1-6alkyl, C_1-6haloalkyl, C(O)R^b1, and C(O)NR^c1R^d1; wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹(or R¹and R², together with N atom to which R¹is attached and C atom to which R²is attached, can form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R⁹); R⁴can be selected from H, C_1-6alkyl, and C_1-6haloalkyl, wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹; R⁵and R⁶can be each independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, OR^a1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹; R⁷and R⁸can be independently selected from H, C_1-6alkyl, and a moiety of formula (i); R^Ncan be selected from H and C_1-6alkyl (or R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹); each R^Acan be independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^d1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹¹; R¹¹can be independently selected from OR^a1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1S(O)₂R^b1, and S(O)₂NR^c1R^d1; each R^a1, R^b1, R^c1, and R^d1can be independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g; and each R^gcan be independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, and carboxy. In some cases, R²can be selected from H and C_1-6alkyl; R³can be selected from H and C_1-6alkyl; R¹can be selected from C_1-6alkyl, C(O)R^b1, and C(O)NR^c1R^d1(or R¹and R², together with N atom to which R¹is attached and C atom to which R²is attached, can form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R⁹); R⁴can be H; R⁵and R⁶can be each independently selected from H, halo, C_1-6alkyl, and S(O)₂R^b1, wherein the C_1-6alkyl is optionally substituted with R⁹; R⁷and R⁸can be independently selected from H, C_1-6alkyl, and a moiety of formula (i); R^Ncan be selected from H and C_1-6alkyl (or R^Nand R¹¹, together with the N atom to which they are attached, can form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹); each R^Acan be independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)OR^a1, NR^c1R^d1and NR^c1C(O)R^b1, wherein the C_1-6alkyl is optionally substituted with C(O)OR^a1; each R^a1, R^b1, R^c1, and R^d1can be independently selected from H and C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R^g; and each R^gcan be independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, and carboxy.

In another embodiment, the compound of Formula (I) can have formula (Ib):

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or a pharmaceutically acceptable salt thereof, wherein Hal is halogen. The R⁴, R⁵, and R⁸can be each H. R^Ncan be H. Ring A can be selected from C_6-10aryl and C_3-10cycloalkyl, each of which is optionally substituted with 1-10 substituents independently selected from R^A. Each R^Acan be independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, and C(O)R^b1, wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. Each R^Acan be independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, and C(O)R^b1, wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. In some cases, R²can be selected from H and C_1-6alkyl; R⁴, R⁵, and R⁸can be each H; R^Ncan be H (or R^Nand R¹¹, together with the N atom to which they are attached, can form a ring selected from pyrrolidinyl, morpholinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹); ring A can be selected from C_6-10aryl and C_3-10cycloalkyl, each of which is optionally substituted with 1-10 substituents independently selected from R^A; and each R^Acan be independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, and C(O)R^b1, wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. In some cases, R^Acan be independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, and C(O)R^b1, wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In another embodiment, the compound of Formula (I) can have Formula (Ic):

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or a pharmaceutically acceptable salt thereof, wherein R^Bis selected from halogen and S(O)₂R^b1. R^Bcan be a halogen. R^Bcan be a S(O)₂R^b1. R²can be selected H and C_1-6alkyl. R⁴can be H. R⁵can be H. R⁷can be selected H and C_1-6alkyl. R^Ncan be H. R^Nand R¹¹, together with the N atom to which they are attached, can form a ring selected from morpholinyl and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹. Ring A can be selected from C_6-10aryl and C_3-10cycloalkyl, optionally substituted with 1-10 substituents independently selected from R^A. Each R^Acan be independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, and OR^a1; wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. In some cases, R²can be selected H and C_1-6alkyl; R⁴can be H; R⁵can be H; R⁷can be selected H and C_1-6alkyl; R^Ncan be H (or R^Nand R¹¹, together with the N atom to which they are attached, can form a ring selected from morpholinyl and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹); ring A can be selected from C_6-10aryl and C_3-10cycloalkyl, optionally substituted with 1-10 substituents independently selected from R^A; and each R^Acan be independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, and OR^a1; wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In another embodiment, the compound of Formula (I) has Formula (Id):

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or a pharmaceutically acceptable salt thereof. R²can be selected from H and C_1-6alkyl. R⁴can be H. R⁵, R⁶, and R⁸can be each H. R¹can be selected from H, C_1-6alkyl, C(O)R^b1, and C(O)NR^c1R^d1, wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹. Each R^Acan be H. In some cases, R²can be selected from H and C_1-6alkyl; R⁴can be H; R⁵, R⁶, and R⁸can be each H; R¹can be selected from H, C_1-6alkyl, C(O)R^b1, and C(O)NR^c1R^d1, wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹; each R⁹can be independently selected from OH, C_1-6alkoxy, carboxy, C(O)NH₂, amino, C_1-6alkylamino, and di(C_1-6alkyl)amino; and each R^Acan be H.

In another embodiment, the compound of Formula (I) can have Formula (Ie):

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or a pharmaceutically acceptable salt thereof, wherein R^Bis selected from halogen and S(O)₂R^b1.

In another embodiment, the compound of Formula (I) can have Formula (If):

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or a pharmaceutically acceptable salt thereof, wherein R is selected from halogen and S(O)₂R^b1. R^Bcan be a halogen. R^Bcan be S(O)₂R^b1. R²and R³can be each independently selected from H and C_1-6alkyl. R⁴can be H. R⁵can be H. R⁸can be selected H and C_1-6alkyl. R^Ncan be H. Ring A can be C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A. Each R^Acan be independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, and OR^a1; wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. In some cases, R²and R³can be each independently selected H and C_1-6alkyl; R⁴can be H; R⁵can be H; R⁸can be selected H and C_1-6alkyl; R^Ncan be H; R¹¹can be C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A; and each R^Acan be independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, and C_1-6haloalkoxy.

In another embodiment, the compound of Formula (I) can have Formula (Ig):

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or a pharmaceutically acceptable salt thereof, wherein R^Bis selected from halogen and S(O)₂R^b1. R^Bcan be a halogen. R^Bcan be S(O)₂R^b1. R²and R³can be each independently selected from H and C_1-6alkyl. R⁴can be H. R⁵can be H. R⁷can be selected H and C_1-6alkyl. R^Ncan be H. Ring A can be C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A. Each R^Acan be independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, and OR^a1; wherein the C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. In some cases, R²and R³can be each independently selected H and C_1-6alkyl; R⁴can be H; R⁵can be H; R⁷can be selected H and C_1-6alkyl; R^Ncan be H; R¹¹can be C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A; and each R^Acan be independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, and C_1-6haloalkoxy.

In some embodiments, the compound of Formula (I) can be selected from any one of the compounds listed in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, and Table 10, or a pharmaceutically acceptable salt thereof.

In some cases, the method can comprise identifying the mammal as being in need of inhibited CB1 activity. The method can be a method for treating obesity. The method can be a method for treating fear. The method can be a method for treating a metabolic-related disorder. The method can be a method for treating diabetes. The method can be a method for treating dyslipidaemia. The method can be a method for treating atherosclerosis. The method can be a method for reducing food intake of the mammal. The method can be a method for reducing body weight gain of the mammal. The method can be a method for improving lipid profiles within the mammal. The method can be a method for improving glycemic profiles within the mammal. The method can be a method for assisting the mammal in stopping tobacco use and/or cannabis use. The method can be a method for treating a liver disorder. The liver disorder can be fatty liver disease, nonalcoholic steatohepatitis (NASH), cirrhosis, or liver cancer. The method can be a method for reducing a symptom or the progression of idiopathic pulmonary fibrosis or a fibrotic condition in the lung. The method can be a method for reducing the severity of or occurrence of end-organ damage induced by chronic alcohol usuage. The end-organ damage can be heart failure, pancreatitis, or liver disease. The method can be a method for reducing a complication of chronic renal disease characterized by renal fibrosis. The chronic renal disease can be diabetic nephropathy or inherited or acquired glomerular diseases. The administering step can reduce CB1 activity within the peripheral nervous system of the mammal. The administering step can reduce little if any CB1 activity within the central nervous system of the mammal. The administering step can be an administering step that does not reduce CB1 activity within the central nervous system of the mammal.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims.

DETAILED DESCRIPTION

This document provides methods and materials for inhibiting CB1 activity.

For example, the document provides compounds (e.g., organic compounds) having the ability to inhibit CB1 activity within a mammal (e.g., a human), formulations containing one or more compounds having the ability to inhibit CB1 activity within a mammal (e.g., a human), methods for making one or more compounds having the ability to inhibit CB1 activity within a mammal (e.g., a human), methods for making formulations containing one or more compounds having the ability to inhibit CB1 activity within a mammal (e.g., a human), methods for inhibiting CB1 activity within a mammal (e.g., a human), and methods for treating mammals (e.g., humans) having a condition responsive to inhibition of CB1 activity. Suitable examples of conditions responsive to inhibition of CB1 activity within a mammal include, without limitation, obesity, fear, metabolic-related disorders, diabetes, dyslipidaemia, atherosclerosis, pulmonary fibrosis, renal fibrosis, NASH, and alcohol-induced organ dysfunction.

In some cases, a CB1 inhibitor described herein can be used to reduce food intake of a mammal (e.g., a human), to reduce the body weight gain of a mammal (e.g., a human), to improve lipid profiles within a mammal (e.g., a human), to improve glycemic profiles within a mammal (e.g., a human), and/or to assist a mammal (e.g., a human) in stopping tobacco use (e.g., cigarette smoking).

Methods of Treatment Using One or More Inhibitors of CB1 Activity

In some cases, this document provides methods for inhibiting CB1 activity within a mammal by contacting a cell with a compound of Formula (I):

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or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, n, R², R³, R⁵, R⁶, R⁷, and R⁸are as described herein.

In one general aspect, this document provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable a carrier.

In some cases, methods for inhibiting CB1 activity of a cell can be performed in vivo. For example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to inhibit CB1 activity within that mammal. In some cases, methods for inhibiting CB1 activity of cells can be performed in vitro. For example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) can be added to a cell culture containing cells (e.g., human cells) to inhibit CB1 activity within those cells. In some cases, such intervention can improve the quality of the cell while in culture or subsequently.

This document also provides methods for treating diseases, disorders, and conditions in a mammal by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof. In some cases, the disease, disorder, or condition being treated can be a disease, disorder, or condition that is responsive to inhibiting CB1 activity within the mammal (e.g., a human). In some cases, the disease, disorder, or condition being treated can be a disease, disorder, or condition that is associated with CB1 activity within the mammal. Examples of diseases, disorders, and conditions that can be treated with one or more compounds provided herein include, without limitation, obesity, fear, metabolic-related disorders, diabetes, dyslipidaemia, atherosclerosis, NASH, idiopathic pulmonary fibrosis, alcohol-induced end-organ damage (e.g., heart failure, pancreatitis, and/or liver disease), and chronic renal disease characterized by renal fibrosis. Examples of metabolic-related disorders that can be treated with one or more compounds provided herein include, without limitation, fatty liver, diabetic nephropathy, and defects of insulin secretion or sensitivity.

In some cases, provided herein are methods for treating obesity in a mammal (e.g., human) by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for treating fear in a mammal (e.g., human) by administering one or more compounds provided herein (e.g., a compound set forth Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for treating a metabolic-related disorder (e.g., any one of the metabolic-related disorders described herein) in a mammal (e.g., human) by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for treating diabetes in a mammal (e.g., human) by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for treating dyslipidaemia in a mammal (e.g., human) by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for treating atherosclerosis in a mammal (e.g., human) by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

This document also provides methods for reducing food intake of a mammal (e.g., a human), reducing body weight gain of a mammal (e.g., a human), improving lipid profiles within a mammal (e.g., a human), improving glycemic profiles within a mammal (e.g., a human), and/or assisting a mammal (e.g., a human) in stopping tobacco use (e.g., cigarette smoking).

In some cases, provided herein are methods for reducing food intake of a mammal (e.g., a human) by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for reducing body weight gain of a mammal (e.g., a human) by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for improving lipid profiles within a mammal (e.g., a human) by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for improving glycemic profiles within a mammal (e.g., a human) by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for assisting a mammal (e.g., a human) in stopping tobacco use (e.g., cigarette smoking) by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

As described herein, one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to inhibit CB1 activity within the peripheral nervous system with little or no inhibition within the central nervous system of the mammal. For example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to treat obesity, fear, metabolic-related disorders, diabetes, dyslipidaemia, and/or atherosclerosis, or to assist in stopping tobacco use (e.g., cigarette smoking), cannabis use, or the unwanted use of other addictive agents with reduced side effects associated with inhibition of CB1 within the central nervous system such as psychiatric disorder side effects. As another example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to reduce food intake of a mammal (e.g., a human), to reduce body weight gain of a mammal (e.g., a human), to improve lipid profiles within a mammal (e.g., a human), to improve glycemic profiles within a mammal (e.g., a human), and/or to assist a mammal (e.g., a human) in stopping tobacco use (e.g., cigarette smoking) with reduced side effects associated with inhibition of CB1 within the central nervous system such as psychiatric disorder side effects.

In some cases, one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) can be used as described herein (e.g., to inhibit CB1 activity within a mammal and/or to treat a disease, disorder, or condition as described herein) as the sole active ingredient(s). For example, a composition containing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can lack any other active ingredients that inhibit CB1 activity within cells. In some cases, a composition containing a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof, can lack any other active ingredients that are effective to treat a disease, disorder, or condition as described herein.

Therapeutic Compounds

As described herein, any one or more of the compounds provided herein can be used to inhibit CB1 activity within a mammal and/or can be used to treat (or prevent) a disease, disorder, and condition in a mammal (e.g., a human) as described herein.

Formula (I)

In one general aspect, the present disclosure provides a compound of Formula (I):

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or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, n, R², R³, R⁵, R⁶, R⁷, and R⁸are as described herein.

In some embodiments:

- X¹is selected from O and NR¹;
- X²is selected from NR⁴and C(═O);
- X³is selected from CHR³, NR⁴and C(═O), provided that:
  - (i) X²is NR⁴and X³is C(═O); or
  - (ii) X²is C(═O) and X³is selected from CHR³and NR⁴;
- n is 0 or 1;
- R²is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
- each R³is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
- each R¹and R⁴is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹; or
- R¹and R², together with N atom to which R¹is attached and C atom to which R²is attached, form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R⁹;
- R⁵, R⁶, R⁷and R⁸are each independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NRIRl, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, S(O)₂NR^c1R^d1; and a group of formula (i):

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- wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
- R¹¹is selected from C_1-6alkyl and ring A, wherein said C_1-6alkyl is optionally substituted with ring A;
- R^Nis selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹; or
- R¹¹and R^N, together with the N atom to which they are attached, for a −10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
- each R⁹is independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;
- ring A is selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1-10 substituents independently selected from R^A;
- each R^Ais independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰;
- each R¹⁰is independently selected from CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;
- each R^a1, R^b1, R^c1, and R^d1is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-4alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^g;
- or any R^c1and R^d1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g; and
- each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, cyano-C_1-3alkylene, HO—C_1-3alkylene, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, thio, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, carboxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, aminosulfonyl, C_1-6alkylaminosulfonyl, di(C_1-6alkyl)aminosulfonyl, aminosulfonylamino, C_1-6alkylaminosulfonylamino, di(C_1-6alkyl)aminosulfonylamino, aminocarbonylamino, C_1-6alkylaminocarbonylamino, and di(C_1-6alkyl)aminocarbonylamino.

In some embodiments, X¹is 0.

In some embodiments, X¹is NR¹.

In some embodiments, X²is NR⁴.

In some embodiments, X²is C(═O).

In some embodiments, X²is NR⁴.

In some embodiments, X²is CHR³.

In some embodiments, X²is C(═O).

In some embodiments, X²is NR⁴and X³is C(═O).

In some embodiments, X²is NR⁴and X³is CHR³.

In some embodiments, X²is C(═O) and X³is selected from CHR³and NR⁴.

In some embodiments, X²is C(═O) and X³is CHR³.

In some embodiments, X²is C(═O) and X³is NR⁴.

In some embodiments, n is 1.

In some embodiments, n is 0 (i.e., there is a bond between X³and a carbon atom to which R²is attached).

In some embodiments, at least one of R⁵, R⁶, R⁷, and R⁸is a group of formula (i).

In some embodiments, at least one of R⁷and R⁸is a group of formula (i).

In some embodiments, R⁷is a group of formula (i).

In some embodiments, R⁸is a group of formula (i).

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments:

R²is selected from H and C_1-6alkyl;

R¹is selected from H, C_1-6alkyl, C_1-6haloalkyl, C(O)R^b1, and C(O)NR^c1R^d1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.

In some embodiments:

R²is selected from H and C_1-6alkyl;

R¹is selected from C_1-6alkyl, C(O)R^b1, and C(O)NR^c1R^d1.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R²is selected from H and C_1-6alkyl. In some embodiments, R²is H. In some embodiments, R²is C_1-6alkyl.

In some embodiments, R³is selected from H and C_1-6alkyl. In some embodiments, R³is H. In some embodiments, R³is C_1-6alkyl.

In some embodiments, R⁴is selected from H, C_1-6alkyl, and C_1-6haloalkyl, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹. In some embodiments, R⁴is H. In some embodiments, R⁴is C_1-6alkyl.

In some embodiments, R⁵and R⁶are each independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, OR^a1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.

In some embodiments, R⁵and R⁶are each independently selected from H, halo, C_1-6alkyl, and S(O)₂R^b1, wherein said C_1-6alkyl is optionally substituted with R⁹.

In some embodiments, R⁵is H and R⁶is C_1-6alkyl, optionally substituted with NR^c1R^d1. In some embodiments, R⁵is H and R⁶is halo. In some embodiments, R⁵is H and R⁶is S(O)₂R^b1.

In some embodiments, R⁷is selected from H and C_1-6alkyl (and R⁸is a moiety of formula (i)). In some embodiments, R⁸is selected from H and C_1-6alkyl (and R⁷is a moiety of formula (i)).

In some embodiments, R^Nis selected from H and C_1-6alkyl. In some embodiments, R^Nis H. In some embodiments, R^Nis C_1-6alkyl.

In some embodiments, R¹¹is ring A.

In some embodiments, R¹¹is C_1-6alkyl, optionally substituted with ring A.

In some embodiments, R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.

In some embodiments, ring A is selected from C_6-10aryl and C_3-10cycloalkyl, each of which is optionally substituted with 1-10 substituents independently selected from R^A.

In some embodiments, ring A is 4-10 membered heterocycloalkyl, optionally substituted with 1-10 substituents independently selected from R^A.

In some embodiments, ring A is C_6-10aryl, optionally substituted with 1-10 substituents independently selected from R^A.

In some embodiments, ring A is C_3-10cycloalkyl, optionally substituted with 1-10 substituents independently selected from R^A.

In some embodiments, ring A is 5-10 membered heteroaryl, optionally substituted with 1-10 substituents independently selected from R^A.

In some embodiments, ring A is selected from any one of the following moieties:

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In some embodiments, each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1; NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹¹.

In some embodiments, each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)OR^a1, NR^c1R^d1and NR^c1C(O)R^b1, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹¹.

In some embodiments, each R¹¹is independently selected from OR^a1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1S(O)₂R^b1, and S(O)₂NR^c1R^d1.

In some embodiments, each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, and C(O)R^b1, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In some embodiments, each R^Ais independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, and C(O)R^b1, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In some embodiments, each R⁹is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, halo, CN, OH, C_1-6alkoxy, carboxy, amino, C(O)NH₂, C_1-6alkylamino, di(C_1-6alkyl)amino, and C_1-6haloalkoxy. In some embodiments, each R⁹is independently selected from OH, C_1-6alkoxy, carboxy, C(O)NH₂, amino, C_1-6alkylamino, and di(C_1-6alkyl)amino.

In some embodiments, each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, C(O)NH₂, and carboxy.

In some embodiments, each R^a1, R^b1, R^c1, and R^d1is independently selected from H and C_1-6alkyl, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R^g; and

In some embodiments, each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, and carboxy.

In some embodiments:

each R³is independently selected from H and C_1-6alkyl;

R¹is selected from H, C_1-6alkyl, C_1-6haloalkyl, C(O)R^b1, and C(O)NR^c1R^d1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

R²is selected from H and C_1-6alkyl; or

R¹and R², together with N atom to which R¹is attached and C atom to which R²is attached, form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R⁹;

each R⁴is independently selected from H, C_1-6alkyl, and C_1-6haloalkyl, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

R⁵and R⁶are each independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, OR^a1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

R⁷and R⁸are independently selected from H, C_1-6alkyl, and a moiety of formula (i);

R^Nis selected from H and C_1-6alkyl; or

R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰;

each R¹⁰is independently selected from OR^a1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1S(O)₂R^b1, and S(O)₂NR^c1R^d1;

each R^a1, R^b1, R^c1, and R^d1is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g; and

each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, and carboxy.

In some embodiments:

each R³is independently selected from H and C_1-6alkyl;

R¹is selected from C_1-6alkyl, C(O)R^b1, and C(O)NR^c1R^d1;

R²is selected from H and C_1-6alkyl; or

each R⁴is H;

R⁵and R⁶are each independently selected from H, halo, C_1-6alkyl, and S(O)₂R^b1, wherein said C_1-6alkyl is optionally substituted with R⁹;

R⁷and R⁸are independently selected from H, C_1-6alkyl, and a moiety of formula (i);

R^Nis selected from H and C_1-6alkyl; or

each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)OR^a1NR^c1R^d1, and NR^c1C(O)R^b1, wherein said C_1-6alkyl is optionally substituted with C(O)OR^a1;

each R^a1, R^b1, R^c1, and R^d1is independently selected from H and C_1-6alkyl, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R^g; and

each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, and carboxy.

In some embodiments, each R^a1, R^b1, R^c1, and R^d1is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-4alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g.

In some embodiments, each R^a1, R^b1, R^c1, and R^d1is independently selected from H, C_1-6alkyl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and C_6-10aryl-C_1-4alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g.

In some embodiments, each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, and carboxy.

In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, and Table 10, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 3, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 6, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 7, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 8, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 9, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 10, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has Formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) has Formula (Ic), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) has Formula (Id), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) has Formula (Ie), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) has Formula (If), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) has Formula (Ig), or a pharmaceutically acceptable salt thereof.

Formula (Ib)

In one general aspect, the present disclosure provides a compound of Formula (Ib):

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or a pharmaceutically acceptable salt thereof, wherein:

Hal is halogen, and

R², R⁴, R⁵, R⁸, R^N, and R¹¹are as described herein for Formula (I).

In some embodiments:

Hal is a halogen;

R²is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

R⁴is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

R⁵and R⁸are each independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

R¹¹is selected from C_1-6alkyl and ring A, wherein said C_1-6alkyl is optionally substituted with ring A;

R^Nis selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹; or

R¹¹and R^N, together with the N atom to which they are attached, for a −10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

each R⁹is independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

ring A is selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from R^A;

each R^Ais independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰;

each R¹⁰is independently selected from CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

each R^a1, R^b1, R^c1, and R^d1is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-4alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^g;

or any R^c1and R^d1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g; and

each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, cyano-C_1-3alkylene, HO—C_1-3alkylene, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, thio, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, carboxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, aminosulfonyl, C_1-6alkylaminosulfonyl, di(C_1-6alkyl)aminosulfonyl, aminosulfonylamino, C_1-6alkylaminosulfonylamino, di(C_1-6alkyl)aminosulfonylamino, aminocarbonylamino, C_1-6alkylaminocarbonylamino, and di(C_1-6alkyl)aminocarbonylamino.

In some embodiments, R²is H or C_1-6alkyl.

In some embodiments, R⁴is H or C_1-6alkyl.

In some embodiments, R⁵is H or C_1-6alkyl.

In some embodiments, R⁸is H or C_1-6alkyl.

In some embodiments, R⁴, R⁵, and R⁸are each H.

In some embodiments, R^Nis H.

In some embodiments, R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from pyrrolidinyl, morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.

In some embodiments, R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from pyrrolidinyl, morpholinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.

In some embodiments, R¹¹is ring A. In some embodiments, R¹¹is C_1-6alkyl, optionally substituted with ring A.

In some embodiments, ring A is selected from C_6-10aryl and C_3-10cycloalkyl, each of which is optionally substituted with 1-10 substituents independently selected from R^A.

In some embodiments, ring A is C_6-10aryl, optionally substituted with 1-10 substituents independently selected from R^A.

In some embodiments, ring A is C_3-10cycloalkyl, optionally substituted with 1-substituents independently selected from R^A.

In some embodiments:

R²is selected from H and C_1-6alkyl;

R⁴, R⁵, and R⁸are each H;

R^Nis H; or

R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from pyrrolidinyl, morpholinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

ring A is selected from C_6-10aryl and C_3-10cycloalkyl, each of which is optionally substituted with 1-10 substituents independently selected from R^A; and

each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, and C(O)R^b1, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In some embodiments, R^Ais independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, and C(O)R^b1, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In some embodiments, each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, and carboxy.

In some embodiments, the compound of Formula (Ib) is selected from any one of the compounds of Table 2 or Table 3, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (Ib) is selected from any one of the compounds of Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ib) is selected from any one of the compounds of Table 3, or a pharmaceutically acceptable salt thereof.

Formula (Ic)

In one general aspect, the present disclosure provides a compound of Formula (Ic):

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or a pharmaceutically acceptable salt thereof, wherein:

R^Bis selected from halogen and S(O)₂R^b1; and

R², R⁴, R⁵, R⁷, R^N, and R¹¹are as described herein for Formula (I).

In some embodiments:

R^Bis selected from halogen and S(O)₂R^b1;

R²is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

R⁴are each independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

R⁵and R⁷are each independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

R¹¹is selected from C_1-6alkyl and ring A, wherein said C_1-6alkyl is optionally substituted with ring A;

R¹¹and R^N, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

each R¹⁰is independently selected from CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

In some embodiments, R^Bis a halogen (e.g., Cl, F, or Br). In some embodiments, R^Bis Cl. In some embodiments, R^Bis S(O)₂R^b1(e.g., R^b1is C_1-6alkyl).

In some embodiments, R^Bis ethylsulfonyl.

In some embodiments, R²is selected H and C_1-6alkyl.

In some embodiments, R⁴is H.

In some embodiments, R⁵is H.

In some embodiments, R⁷is selected H and C_1-6alkyl.

In some embodiments, R^Nis H.

In some embodiments, R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from morpholinyl and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.

In some embodiments, R¹¹is ring A. In some embodiments, R¹¹is C_1-6alkyl, optionally substituted with ring A.

In some embodiments, ring A is selected from C_6-10aryl and C_3-10cycloalkyl, optionally substituted with 1-10 substituents independently selected from R^A.

In some embodiments, ring A is C_6-10aryl, optionally substituted with 1-10 substituents independently selected from R^A.

In some embodiments, ring A is C_3-10cycloalkyl, optionally substituted with 1-10 substituents independently selected from R^A.

In some embodiments, each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, and OR^a1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In some embodiments:

R²is selected H and C_1-6alkyl;

R⁴is H;

R⁵is H;

R⁷is selected H and C_1-6alkyl;

R^Nis H; or

R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from morpholinyl and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

ring A is selected from C_6-10aryl and C_3-10cycloalkyl, optionally substituted with 1-10 substituents independently selected from R^A; and

each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, and OR^a1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In some embodiments, each R⁹is independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, and carboxy.

In some embodiments, the compound of Formula (Ic) is selected from any one of the compounds of Table 4 or Table 5, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (Ic) is selected from any one of the compounds of Table 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ic) is selected from any one of the compounds of Table 5, or a pharmaceutically acceptable salt thereof.

Formula (Id)

In one general aspect, the present disclosure provides a compound of Formula (Id):

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or a pharmaceutically acceptable salt thereof, wherein R¹, R², R⁴, R⁵, R⁶, R⁸, and R^Aare as described herein for Formula (I).

In some embodiments:

R¹and R⁴are each independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

R²is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

R⁵, R⁶, and R⁸are each independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

each R¹⁰is independently selected from CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

In some embodiments, R²is selected from H and C_1-6alkyl.

In some embodiments, R⁴is H.

In some embodiments, R¹is selected from H, C_1-6alkyl, C(O)R^b1, and C(O)NR^c1R^d1, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.

In some embodiments, each R⁹is independently selected from OH, C_1-6alkoxy, carboxy, C(O)NH₂, amino, C_1-6alkylamino, and di(C_1-6alkyl)amino.

In some embodiments, R⁵, R⁶, and R⁸are each independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, and C_1-6alkoxy. In some embodiments, R⁵, R⁶, and R⁸are each H.

In some embodiments, each R^Ais independently selected from H, C_1-6alkyl, C_1-6haloalkyl, halo, CN, OH, C_1-6alkoxy, carboxy, amino, C(O)NH₂, C_1-6alkylamino, di(C_1-6alkyl)amino, and C_1-6haloalkoxy. In some embodiments, each R^Ais independently selected from H, C_1-6alkyl, C_1-6haloalkyl, halo, and C_1-6alkoxy. In some embodiments, each R^Ais independently selected from H and C_1-6alkyl. In some embodiments, each R^Ais H.

In some embodiments:

R²is selected from H and C_1-6alkyl;

R⁴is H;

R⁵, R⁶, and R⁸are each H;

R¹is selected from H, C_1-6alkyl, C(O)R^b1, and C(O)NR^c1R^d1, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

each R⁹is independently selected from OH, C_1-6alkoxy, carboxy, C(O)NH₂, amino, C_1-6alkylamino, and di(C_1-6alkyl)amino; and

each R^Ais H.

In some embodiments, each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, and carboxy.

In some embodiments, the compound of Formula (Id) is selected from any one of the compounds of Table 6, or a pharmaceutically acceptable salt thereof.

Formula (Ie)

In one general aspect, the present disclosure provides a compound of Formula (Ie):

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or a pharmaceutically acceptable salt thereof, wherein:

R^Bis selected from halogen and S(O)₂R^b1; and

R², R³, R⁴, R⁵, R⁷, R^N, and R¹¹are as described herein for Formula (I).

In some embodiments:

R²and R³are each independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

R¹¹is selected from C_1-6alkyl and ring A, wherein said C_1-6alkyl is optionally substituted with ring A;

R¹¹and R^N, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

each R¹⁰is independently selected from CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

In some embodiments, R^Bis a halogen.

In some embodiments, R^Bis S(O)₂R^b1.

In some embodiments, R²and R³are each independently selected from H and C_1-6alkyl.

In some embodiments, R⁴is H.

In some embodiments, R⁵is H.

In some embodiments, R⁷is selected H and C_1-6alkyl.

In some embodiments, R^Nis H.

In some embodiments, ring A is C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A.

In some embodiments:

R²and R³are each independently selected H and C_1-6alkyl;

R⁴is H;

R⁵is H;

R⁷is selected H and C_1-6alkyl;

R^Nis H;

R¹¹is C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A; and each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, and C_1-6haloalkoxy.

In some embodiments, the compound of Formula (Ie) is selected from any one of the compounds of Table 8, or a pharmaceutically acceptable salt thereof.

Formula (If)

In one general aspect, the present disclosure provides a compound of Formula (If):

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or a pharmaceutically acceptable salt thereof, wherein:

R^Bis selected from halogen and S(O)₂R^b1;

and R², R³, R⁴, R⁵, R⁸, R^N, and R¹¹are as described herein for Formula (I).

In some embodiments:

R¹¹is selected from C_1-6alkyl and ring A, wherein said C_1-6alkyl is optionally substituted with ring A;

R¹¹and R^N, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

each R⁹is independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1; NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

each R¹⁰is independently selected from CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

In some embodiments, R^Bis a halogen.

In some embodiments, R^Bis S(O)₂R^b1.

In some embodiments, R²and R³are each independently selected from H and C_1-6alkyl.

In some embodiments, R⁴is H.

In some embodiments, R⁵is H.

In some embodiments, R⁸is selected H and C_1-6alkyl.

In some embodiments, R^Nis H.

In some embodiments, ring A is C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A.

In some embodiments:

R²and R³are each independently selected H and C_1-6alkyl;

R⁴is H;

R⁵is H;

R⁸is selected H and C_1-6alkyl;

R^Nis H;

R¹¹is C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A; and

each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, and C_1-6haloalkoxy.

In some embodiments, the compound of Formula (If) is selected from any one of the compounds of Table 9, or a pharmaceutically acceptable salt thereof.

Formula (Ig)

In one general aspect, the present disclosure provides a compound of Formula (Ig):

embedded image

or a pharmaceutically acceptable salt thereof, wherein:

R^Bis selected from halogen and S(O)₂R^b1; and

R², R³, R⁴, R⁵, R⁷, R^N, and R¹¹are as described herein.

In some embodiments:

R¹¹is selected from C_1-6alkyl and ring A, wherein said C_1-6alkyl is optionally substituted with ring A;

R¹¹and R^N, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;

each R¹⁰is independently selected from CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

In some embodiments, R^Bis a halogen.

In some embodiments, R^Bis S(O)₂R^b1.

In some embodiments, R²and R³are each independently selected from H and C_1-6alkyl.

In some embodiments, R⁴is H.

In some embodiments, R⁵is H.

In some embodiments, R⁷is selected H and C_1-6alkyl.

In some embodiments, R^Nis H.

In some embodiments, ring A is C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A.

In some embodiments:

R²and R³are each independently selected H and C_1-6alkyl;

R⁴is H;

R⁵is H;

R⁷is selected H and C_1-6alkyl;

R^Nis H;

R¹¹is C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A; and

each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, and C_1-6haloalkoxy.

In some embodiments, the compound of Formula (Ig) is selected from any one of the compounds of Table 10, or a pharmaceutically acceptable salt thereof.

In some embodiments, a salt of any one of the compounds disclosed herein is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds disclosed herein include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds disclosed herein include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH—(C1-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

In some embodiments, any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, is substantially isolated.

Methods of Making Therapeutic Compounds

Compounds as set forth in any one of the Formulae disclosed herein, including salts thereof, can be prepared using organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. A person skilled in the art knows how to select and implement appropriate synthetic protocols, and appreciates that a broad repertoire of synthetic organic reactions is available to be potentially employed in synthesizing compounds provided herein.

Suitable synthetic methods of starting materials, intermediates, and products can be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49 (J. Heterocyclic Chemistry, 1964-2012); Carreira et al., (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge Updates KU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky et al., (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al., (Ed.) Comprehensive Organic Functional Group Transformations II (Elsevier, 2^ndEdition, 2004); Katritzky et al., (Ed.) Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6^thEd. (Wiley, 2007); Trost et al. (Ed.) Comprehensive Organic Synthesis (Pergamon Press, 1991).

The reactions for preparing the compounds provided herein can be carried out in suitable solvents that can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, 4^thEd., Wiley & Sons, Inc., New York (2006).

Pharmaceutical Compositions and Formulations

This document also provides pharmaceutical compositions comprising an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition also can comprise any one of the additional therapeutic agents and/or therapeutic molecules described herein. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions provided herein include, without limitation, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., 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, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

The compositions or dosage forms can contain any one or more of the compounds or therapeutic agents described herein in the range of 0.005 percent to 100 percent with the balance made up from the suitable pharmaceutically acceptable carriers or excipients. The contemplated compositions can contain from about 0.001 percent to about 100 percent (e.g., from about 0.1 percent to about 95 percent, from about 75 percent to about 85 percent, or from about 20 percent to about 80 percent) of any one or more of the compounds or therapeutic agents provided herein, wherein the balance can be made up of any pharmaceutically acceptable carrier or excipient described herein, or any combination of these carriers or excipients.

Routes of Administration and Dosage Forms

The therapeutic compounds and/or pharmaceutical compositions provided herein (e.g., a composition containing one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof) can include those suitable for any acceptable route of administration. Acceptable routes of administration include, without limitation, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, vaginal, intravitreal, subretinal or other intraocular routes of administrations.

Compositions and formulations described herein can conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and can be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000). Such preparative methods include, without limitation, the step of bringing into association with the molecule to be administered ingredients such as a carrier that constitutes one or more accessory ingredients. In general, the compositions can be prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

In some embodiments, any one or more of the compounds or therapeutic agents described herein can be administered orally. Compositions described herein that are suitable for oral administration can be presented as discrete units such as capsules, sachets, granules, or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient(s); a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus. Soft gelatin capsules can be useful for containing such suspensions, which can beneficially increase the rate of compound absorption. In the case of tablets for oral use, carriers that are commonly used include, without limitation, lactose, sucrose, glucose, mannitol, silicic acid, and starches. Other acceptable excipients can include, without limitation, (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in a capsule form, useful diluents include, without limitation, lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient(s) can be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents can be added. Compositions suitable for oral administration include, without limitation, lozenges comprising ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient(s) in an inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include, without limitation, aqueous and non-aqueous sterile injection solutions or infusion solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injections, saline (e.g., 0.9% saline solution), or 5% dextrose solution, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The injection solutions can be in the form of, for example, a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation also can be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils can be used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used including, without limitation, synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used to prepare injectables. In some cases, natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions, can be used to prepare injectables. These oil solutions or suspensions also can contain a long-chain alcohol diluent or dispersant.

In some cases, a therapeutic compound and/or pharmaceutical composition provided herein can be administered in the form of suppository for rectal administration. These compositions can be prepared by mixing a compound described herein (e.g., any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof) with a suitable non-irritating excipient that is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active component(s). Such materials include, without limitation, cocoa butter, beeswax, and polyethylene glycols.

In some cases, a therapeutic compounds and/or pharmaceutical composition provided herein can be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, for example, U.S. Pat. No. 6,803,031. Additional formulations and methods for intranasal administration are found in Ilium, L., J. Pharm. Pharmacol., 56:3-17 (2004); and Ilium, L., Eur. J. Pharm. Sci., 11:1-18 (2000).

In some cases, a therapeutic compounds and/or pharmaceutical composition provided herein can be prepared as a topical composition and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and/or cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of a therapeutic compounds and/or pharmaceutical composition provided herein can be useful when the desired treatment involves areas or organs readily accessible by topical application. In some cases, a topical composition can include a combination of any one or more of the compounds or therapeutic agents described herein (e.g., a compound set forth in any one of Formulae herein, or a pharmaceutically acceptable salt thereof), and one or more additional ingredients, carriers, excipients, or diluents including, without limitation, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents/pigments, emollients (moisturizers), emulsifiers, film-forming/holding agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin-identical/repairing agents, slip agents, sunscreen actives, surfactants/detergent cleansing agents, penetration enhancers, and thickeners.

In some cases, one or more compounds or therapeutic agent described herein (e.g., any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof) can be incorporated into a composition for coating an implantable medical device such as a prosthesis, artificial valve, vascular graft, stent, or catheter. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings can be biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, or mixture thereof. In some cases, the coating can optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

In some cases, this document provides an implantable drug release device impregnated with or containing one or more compounds or therapeutic agents described herein (e.g., any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof) such that the compound(s) or therapeutic agent(s) are released from the device and are therapeutically active.

Dosages and Regimens

A composition (e.g., pharmaceutical compositions provided herein) containing a compound provided herein, or a pharmaceutically acceptable salt thereof, can include that compound in an effective amount (e.g., a therapeutically effective amount).

Effective doses can vary, depending on the diseases being treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents, and the judgment of the treating physician.

In some embodiments, an effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, can range, for example, from about 0.1 mg to about 1000 mg. In some cases, the effective amount can be from about 0.5 mg to about 500 mg of a compound disclosed herein, or any amount in between these two values, for example, one of about 0.5 mg, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. The effective amount can be an amount sufficient to alleviate or reduce one or more of the symptoms associated with a disease, disorder, or condition being treated as described herein.

In some cases, an effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, can range, for example, from about 0.001 mg/kg to about 500 mg/kg (e.g., from about 0.001 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 150 mg/kg; from about 0.01 mg/kg to about 100 mg/kg; from about 0.01 mg/kg to about 50 mg/kg; from about 0.01 mg/kg to about 10 mg/kg; from about 0.01 mg/kg to about 5 mg/kg; from about 0.01 mg/kg to about 1 mg/kg; from about 0.01 mg/kg to about 0.5 mg/kg; from about 0.01 mg/kg to about 0.1 mg/kg; from about 0. 1 mg/kg to about 200 mg/kg; from about 0.1 mg/kg to about 150 mg/kg; from about 0. 1 mg/kg to about 100 mg/kg; from about 0.1 mg/kg to about 50 mg/kg; from about 0. 1 mg/kg to about 10 mg/kg; from about 0.1 mg/kg to about 5 mg/kg; from about 0.1 mg/kg to about 2 mg/kg; from about 0.1 mg/kg to about 1 mg/kg; from about 0.1 mg/kg to about 0.5 mg/kg, or from about 0.5 mg/kg to about 500 mg/kg).

In some cases, an effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, can be about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, or about 5 mg/kg.

The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, thrice daily) or on a non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, or once a month). In some cases, the dosages can be administered every 4 hours, 6 hours, 8 hours, 12 hours, or 24 hours.

Kits

This document also provides pharmaceutical kits useful, for example, to inhibit CB1 within a mammal (e.g., a human). In some cases, this document provides pharmaceutical kits useful, for example, to treat diseases, disorders, and conditions referred to herein. Such pharmaceutical kits can include one or more containers containing a pharmaceutical composition that includes a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some cases, such kits can further include, if desired, one or more of various conventional pharmaceutical kit components such as containers with one or more pharmaceutically acceptable carriers. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components also can be included in a kit provided herein.

Combination Therapies

In some cases, one or more compounds provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one or more therapeutic molecules. Examples of therapeutic molecules that can be used in combination with one or more compounds provided herein, or a pharmaceutically acceptable salt thereof, include, without limitation, nicotine-replacement therapy, varenicline or bupropion, anti-fibrotic agents (e.g., nintedanib or pirfenidone), and anti-inflammatory agents (e.g., hydrocortisone or mycophenolic acid).

One or more compounds provided herein, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic molecules can be administered in any order or simultaneously. If simultaneously administered, they can be provided in a single, unified, form or in multiple forms (e.g., either as a single pill or as two separate pills). One of the items can be given in multiple doses, or both can be given as multiple doses. If not simultaneous, the timing between the multiple doses can vary from more than zero weeks to less than four weeks.

Definitions

As used herein, the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).

At various places in this document, substituents of compounds provided herein are disclosed in groups or in ranges. It is specifically intended that these groups and ranges include each and every individual subcombination of the members of such groups and ranges. For example, the term “C_1-6alkyl” is specifically intended to individually disclose methyl, ethyl, C₃alkyl, C₄alkyl, C₅alkyl, and C₆alkyl.

At various places in this document various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

It is further appreciated that certain features described herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features described herein which are, for brevity, described in the context of a single embodiment, also can be provided separately or in any suitable subcombination.

The term “aromatic” refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n+2) delocalized π (pi) electrons where n is an integer).

The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution can be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.

Throughout the definitions, the term “C_n-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C_1-4, C_1-6, and the like.

As used herein, the term “C_n-malkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, without limitation, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

As used herein, the term “C_n-mhaloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms that may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “C_n-malkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, without limitation, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_n-malkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, without limitation, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_n-malkylene”, employed alone or in combination with other terms, refers to a divalent alkyl-linking group having n to m carbons. Examples of alkylene groups include, without limitation, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

As used herein, the term “C_n-malkoxy”, employed alone or in combination with other terms, refers to a group of formula —O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, without limitation, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “C_n-mhaloalkoxy” refers to a group of formula —O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF₃. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “C_n-malkylamino” refers to a group of formula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, without limitation, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(n-butyl)amino and N-(tert-butyl)amino), and the like.

As used herein, the term “di(C_n-m-alkyl)amino” refers to a group of formula —N(alkyl)₂, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkoxycarbonyl” refers to a group of formula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl groups include, without limitation, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g., n-butoxycarbonyl and tert-butoxycarbonyl), and the like.

As used herein, the term “C_n-malkylcarbonyl” refers to a group of formula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylcarbonyl groups include, without limitation, methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n-propylcarbonyl and isopropylcarbonyl), butylcarbonyl (e.g., n-butylcarbonyl and tert-butylcarbonyl), and the like.

As used herein, the term “C_n-malkylcarbonylamino” refers to a group of formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylsulfonylamino” refers to a group of formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula —S(O)₂NH₂.

As used herein, the term “C_n-malkylaminosulfonyl” refers to a group of formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-malkyl)aminosulfonyl” refers to a group of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group of formula —NHS(O)₂NH₂.

As used herein, the term “C_n-malkylaminosulfonylamino” refers to a group of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-malkyl)aminosulfonylamino” refers to a group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or in combination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_n-malkylaminocarbonylamino” refers to a group of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-malkyl)aminocarbonylamino” refers to a group of formula —NHC(O)N(alkyl)₂, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “C_n-malkylcarbamyl” refers to a group of formula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-m-alkyl)carbamyl” refers to a group of formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_n-malkylthio” refers to a group of formula —S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylsulfinyl” refers to a group of formula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylsulfonyl” refers to a group of formula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a —C(═O)— group, which may also be written as C(O).

As used herein, the term “carboxy” refers to a —C(O)OH group. In some embodiments, the “carboxy” group also refers to a bioisostere replacement group selected from the group consisting of:

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and the like, where R refers to a hydrogen, (C₁-C₈) alkyl, or C₆aryl.

As used herein, the term “cyano-C_1-3alkyl” refers to a group of formula —(C_1-3alkylene)-CN.

As used herein, the term “HO—C_1-3alkyl” refers to a group of formula —(C_1-3alkylene)-OH.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br.

As used herein, the term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). The term “C_n-maryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups can have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C_3-10). In some embodiments, the cycloalkyl is a C_3-10monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C_3-7monocyclic cycloalkyl. Example cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls include, without limitation, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls include, without limitation, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl. Ring-forming carbon atoms of a heteroaryl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)).

As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include, without limitation, pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)₂, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.

At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring can be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position.

As used herein, the term “oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C═O), or attached to a heteroatom forming a sulfoxide or sulfone group.

The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds provided herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Any appropriate method can be used to prepare optically active forms from, for example, optically inactive starting materials. For example, techniques such as resolution of racemic mixtures or stereoselective synthesis can be used to prepare optically active forms of a compound provided herein. Many geometric isomers of olefins, C═N double bonds, N═N double bonds, and the like also can be present in a compound described herein, and all such stable isomers are contemplated herein. Cis and trans geometric isomers of the compounds provided herein are described and can be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, a compound provided herein has the (R)-configuration. In some embodiments, a compound provided herein has the (S)-configuration.

Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers that are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include, without limitation, ketone—enol pairs, amide—imidic acid pairs, lactam—lactim pairs, enamine—imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. For example, in aqueous solution, pyrazoles can exhibit the following isomeric forms, which are referred to as tautomers of each other:

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As readily understood by one skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of compounds as described herein are within the scope provided herein.

As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal (e.g., a human). In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal (e.g., a human).

As used herein, the term “contacting” refers to the bringing together of indicated moieties or items in an in vitro system, an ex vivo system, or an in vivo system. For example, “contacting” a cell with a compound provided herein includes the act of administering that compound to a mammal (e.g., a human) containing that cell as well as, for example, introducing that compound into a cell culture containing that cell.

As used herein, the term “mammal” includes, without limitation, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, elephants, deer, non-human primates (e.g., monkeys and apes), house pets, and humans.

As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, mammal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.

As used herein, the term “treating” or “treatment” refers to (a) inhibiting a disease, disorder, or condition, for example, inhibiting a disease, disorder, or condition in a mammal (e.g., human) that is experiencing or displaying the pathology or symptomatology of the disease, disorder, or condition (e.g., arresting further development of the pathology and/or symptomatology), or (b) ameliorating the disease, disorder, or condition, for example, ameliorating a disease, disorder, or condition in a mammal (e.g., a human) that is experiencing or displaying the pathology or symptomatology of the disease, disorder, or condition (e.g., reversing the pathology and/or symptomatology).

As used herein, the term “preventing” or “prevention” of a disease, disorder, or condition refers to decreasing the risk of occurrence of the disease, disorder, or condition in a mammal or group of mammals (e.g., a mammal or group of mammals predisposed to or susceptible to the disease, disorder, or condition). In some embodiments, preventing a disease, disorder, or condition refers to decreasing the possibility of acquiring the disease, disorder, or condition and/or its associated symptoms. In some embodiments, preventing a disease, disorder, or condition refers to completely or almost completely stopping the disease, disorder, or condition from occurring.

EXAMPLES
Methods

cAMP CNR1 Hunter cell line (Eurofins DiscoveryX) were expanded from freezer stocks and seeded in a total volume of 20 μL into white walled, 384-well microplates and incubated at 37° C. for the appropriate time prior to testing. For antagonist determination, cell media was aspirated from cells and replaced with 10 μL 1:1 HBSS/Hepes:cAMP XS+Ab reagent. 5 μL of 4× compound was added to the cells and incubated at 37° C. for 30 minutes. 5 μL of 4× EC80 agonist was added to cells and incubated at 37° C. for 30 minutes. After appropriate compound incubation, assay signal was generated through incubation with 20 μL cAMP XS+ED/CL lysis cocktail for one hour followed by incubation with 20 μL cAMP XS+EA reagent for three hours at room temperature. Microplates were read following signal generation with a PerkinElmer Envision™ instrument for chemiluminescent signal detection. Compound activity (IC₅₀) was analyzed using CBIS data analysis suite (ChemInnovation, CA).

Efficacy (IC₅₀): “+” ≥25 μM, “++” ≥1 μM and <25 μM, and “+++”<1 μM.

Bioassay Results for Tested Compounds

TABLE 1

BC No.
Compound
CB1 assay

BC19132

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+

BC19131

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+++

BC19134

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+++

TABLE 2

BC No.
Structure
CB1 assay

BC19133

embedded image

+++

BC19135

embedded image

++

BC19136

embedded image

+++

BC19137

embedded image

+++

BC19138

embedded image

+++

BC19161

embedded image

+++

BC19162

embedded image

+++

BC19163

embedded image

+++

BC19164

embedded image

+++

BC19165

embedded image

++

BC19166

embedded image

+++

BC19167

embedded image

+++

BC19206

embedded image

+

BC19207

embedded image

+

BC19208

embedded image

+

BC19209

embedded image

+

BC19210

embedded image

+++

BC19211

embedded image

++

BC19212

embedded image

++

BC19213

embedded image

+

BC19214

embedded image

+

BC19215

embedded image

+

BC19216

embedded image

+++

BC19217

embedded image

+

BC19218

embedded image

++

BC19219

embedded image

+

BC19220

embedded image

+

BC19221

embedded image

++

BC19222

embedded image

++

BC19223

embedded image

++

BC19224

embedded image

+

BC19280

embedded image

++

BC19281

embedded image

+

BC19282

embedded image

++

BC19283

embedded image

++

BC19284

embedded image

+

BC19285

embedded image

++

BC19286

embedded image

+

BC19287

embedded image

++

BC19354

embedded image

+

BC19356

embedded image

+

BC19357

embedded image

++

BC19358

embedded image

++

BC19359

embedded image

++

BC19360

embedded image

+

BC19361

embedded image

++

BC19368

embedded image

+

BC19369

embedded image

+

BC19370

embedded image

+

BC19371

embedded image

+

BC19372

embedded image

+

BC19373

embedded image

+

BC19387

embedded image

+

BC19388

embedded image

+

BC19389

embedded image

+

BC19390

embedded image

+

BC19391

embedded image

+

BC19392

embedded image

+

BC19393

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TABLE 3

BC No.
Structure
CB1 assay

BC19696

embedded image

++

BC19698

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+

BC19700

embedded image

++

BC19702

embedded image

+

BC19704

embedded image

+

BC19706

embedded image

+

BC19708

embedded image

+

BC19709

embedded image

++

BC19711

embedded image

+

BC19713

embedded image

++

BC19715

embedded image

+++

BC19717

embedded image

+

BC19719

embedded image

++

BC19721

embedded image

+++

BC19729

embedded image

+++

BC19731

embedded image

++

BC19733

embedded image

++

BC19735

embedded image

+

BC19737

embedded image

++

BC19739

embedded image

++

BC19741

embedded image

++

BC19743

embedded image

+

BC19745

embedded image

++

BC19747

embedded image

++

BC19749

embedded image

++

BC19751

embedded image

+++

BC19753

embedded image

++

BC19755

embedded image

++

BC19758

embedded image

+

BC19760

embedded image

++

BC19762

embedded image

+

BC19764

embedded image

++

BC19766

embedded image

+

BC19768

embedded image

++

BC19770

embedded image

+

BC19772

embedded image

++

BC19774

embedded image

+

BC19776

embedded image

+

BC19778

embedded image

+

BC19780

embedded image

++

BC19782

embedded image

+

BC19784

embedded image

+

BC19786

embedded image

+

BC19788

embedded image

++

BC19790

embedded image

++

BC19792

embedded image

+

BC19794

embedded image

+

BC19795

embedded image

+

BC19797

embedded image

+

BC19799

embedded image

+

BC19901

embedded image

+

BC19903

embedded image

++

BC19905

embedded image

+

BC19907

embedded image

+

BC19910

embedded image

+

BC19912

embedded image

+

BC19914

embedded image

++

BC19916

embedded image

++

BC19919

embedded image

+

BC19920

embedded image

++

BC19922

embedded image

+

BC19924

embedded image

++

BC19926

embedded image

+

BC19928

embedded image

+

BC19930

embedded image

+

BC19932

embedded image

+

BC19934

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+

BC19936

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+

BC19938

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TABLE 4

CB1

BC No.
Structure
assay

BC19168

embedded image

++

BC19169

embedded image

+++

BC19170

embedded image

++

BC19171

embedded image

++

BC19172

embedded image

+

BC19173

embedded image

+

BC19174

embedded image

+

BC19175

embedded image

+

BC19176

embedded image

+++

BC19177

embedded image

++

BC19178

embedded image

+++

BC19179

embedded image

++

BC19180

embedded image

+

BC19225

embedded image

+

BC19226

embedded image

+

BC19227

embedded image

+

BC19228

embedded image

++

BC19229

embedded image

+

BC19230

embedded image

+

BC19231

embedded image

+

BC19232

embedded image

+

BC19233

embedded image

+

BC19234

embedded image

+

BC19288

embedded image

++

BC19289

embedded image

+

BC19290

embedded image

+

BC19291

embedded image

+

BC19292

embedded image

++

BC19293

embedded image

+

BC19294

embedded image

++

BC19355

embedded image

++

BC19362

embedded image

+

BC19363

embedded image

++

BC19364

embedded image

++

BC19365

embedded image

++

BC19366

embedded image

+

BC19367

embedded image

+

BC19374

embedded image

+

BC19375

embedded image

++

BC19376

embedded image

++

BC19377

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+

BC19378

embedded image

++

BC19379

embedded image

++

BC19380

embedded image

+

BC19381

embedded image

+

BC19382

embedded image

++

BC19383

embedded image

+

BC19384

embedded image

+

BC19385

embedded image

+

BC19386

embedded image

+

BC19394

embedded image

+

BC19421

embedded image

+

BC19422

embedded image

+

BC19423

embedded image

+

BC19424

embedded image

+

BC19425

embedded image

+

BC19426

embedded image

+

BC19427

embedded image

+

BC19428

embedded image

+

BC19429

embedded image

+

BC19430

embedded image

+

BC19431

embedded image

+

BC19432

embedded image

+

BC19433

embedded image

+

BC19434

embedded image

+

BC19435

embedded image

+

BC19436

embedded image

+

BC19437

embedded image

+

BC19438

embedded image

+

BC19439

embedded image

+

BC19440

embedded image

+

BC19441

embedded image

+

BC19442

embedded image

+

BC19443

embedded image

TABLE 5

BC No.
Structure
CB1 assay

BC19481

embedded image

+

BC19482

embedded image

+

BC19483

embedded image

+

BC19484

embedded image

+

BC19485

embedded image

+

BC19486

embedded image

+

BC19487

embedded image

+

BC19488

embedded image

+

BC19489

embedded image

+

BC19490

embedded image

+

BC19491

embedded image

+

BC19492

embedded image

+

BC19493

embedded image

+

BC19544

embedded image

+

BC19545

embedded image

+

BC19546

embedded image

+

BC19547

embedded image

+

BC19548

embedded image

+

BC19697

embedded image

+

BC19699

embedded image

++

BC19701

embedded image

++

BC19703

embedded image

++

BC19705

embedded image

++

BC19707

embedded image

+

BC19710

embedded image

+

BC19712

embedded image

+

BC19714

embedded image

+

BC19716

embedded image

++

BC19718

embedded image

+

BC19720

embedded image

+

BC19722

embedded image

++

BC19730

embedded image

++

BC19732

embedded image

++

BC19734

embedded image

++

BC19736

embedded image

+

BC19738

embedded image

+++

BC19740

embedded image

++

BC19742

embedded image

++

BC19744

embedded image

+

BC19746

embedded image

++

BC19748

embedded image

+

BC19750

embedded image

+

BC19752

embedded image

++

BC19754

embedded image

++

BC19756

embedded image

++

BC19757

embedded image

+

BC19759

embedded image

++

BC19761

embedded image

++

BC19763

embedded image

++

BC19765

embedded image

+

BC19767

embedded image

++

BC19769

embedded image

++

BC19771

embedded image

++

BC19773

embedded image

++

BC19775

embedded image

+

BC19777

embedded image

+

BC19779

embedded image

+

BC19781

embedded image

++

BC19783

embedded image

++

BC19785

embedded image

+

BC19787

embedded image

+

BC19789

embedded image

+

BC19791

embedded image

+

BC19793

embedded image

+

BC19796

embedded image

++

BC19798

embedded image

+

BC19900

embedded image

+

BC19902

embedded image

+

BC19904

embedded image

++

BC19906

embedded image

+

BC19908

embedded image

+

BC19909

embedded image

+

BC19911

embedded image

+

BC19913

embedded image

++

BC19915

embedded image

++

BC19921

embedded image

++

BC19923

embedded image

+

BC19925

embedded image

++

BC19927

embedded image

+

BC19929

embedded image

+

BC19931

embedded image

+

BC19933

embedded image

+

BC19935

embedded image

+

BC19937

embedded image

TABLE 6

BC No.
Structure
CB1 assay

BC19181

embedded image

+

BC19182

embedded image

+++

BC19183

embedded image

++

BC19184

embedded image

++

BC19235

embedded image

+

BC19236

embedded image

+

BC19295

embedded image

+

BC19296

embedded image

++

BC19297

embedded image

+

BC19298

embedded image

+

BC19299

embedded image

++

BC19300

embedded image

TABLE 7

BC No.
Structure
CB1 assay

BC19917

embedded image

TABLE 8

BC No.
Structure
CB1 assay

BC19549

embedded image

+

BC19550

embedded image

+

BC19551

embedded image

+

BC19552

embedded image

+

BC19553

embedded image

+

BC19603

embedded image

+

BC19604

embedded image

++

BC19605

embedded image

+

BC19606

embedded image

+

BC19607

embedded image

++

BC19608

embedded image

+

BC19609

embedded image

++

BC19610

embedded image

++

BC19611

embedded image

+

BC19612

embedded image

+

BC19613

embedded image

+

BC19614

embedded image

+

BC19615

embedded image

TABLE 9

BC No.
Structure
CB1 assay

BC19652

embedded image

+

BC19653

embedded image

+

BC19654

embedded image

+

BC19655

embedded image

+

BC19656

embedded image

+

BC19657

embedded image

+

BC19658

embedded image

+

BC19659

embedded image

+

BC19660

embedded image

+

BC19661

embedded image

+++

BC19689

embedded image

+

BC19690

embedded image

+++

BC19691

embedded image

++

BC19692

embedded image

+++

BC19693

embedded image

++

BC19694

embedded image

++

BC19695

embedded image

TABLE 10

BC No.
Structure
CB1 assay

BC19648

embedded image

+

BC19649

embedded image

+

BC19650

embedded image

+

BC19651

embedded image

+

BC19685

embedded image

+

BC19686

embedded image

++

BC19687

embedded image

+

BC19688

embedded image

Numbered Paragraphs

- 1. A method of inhibiting CB-1 activity within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (I):

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- - or a pharmaceutically acceptable salt thereof, wherein:
  - X¹is selected from 0 and NR¹;
  - X²is selected from NR⁴and C(═O);
  - X³is selected from CHR³, NR⁴and C(═O), provided that:
- (i) X²is NR⁴and X³is C(═O); or
- (ii) X²is C(═O) and X³is selected from CHR³and NR⁴;
  - n is 0 or 1;
    - R²is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
    - each R³is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
    - each R¹and R⁴is each independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹; or
    - R¹and R², together with N atom to which R¹is attached and C atom to which R²is attached, form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R⁹;
    - R⁵, R⁶, R⁷and R⁸are each independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, S(O)₂NR^c1R^d1; and a group of formula (i):

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- - - wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
    - R¹¹is selected from C_1-6alkyl and ring A, wherein said C_1-6alkyl is optionally substituted with ring A;
    - R^Nis selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R⁹; or
    - R¹¹and R^N, together with the N atom to which they are attached, for a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
    - each R⁹is independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;
    - ring A is selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from R^A.
    - each R^Ais independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰;
    - each R¹⁰is independently selected from CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;
    - each R^a1, R^b1, R^c1, and R^d1is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-4alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^g;
    - or any R^c1and R^d1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g; and
    - each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, cyano-C_1-3alkylene, HO—C_1-3alkylene, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, thio, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, carboxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, aminosulfonyl, C_1-6alkylaminosulfonyl, di(C_1-6alkyl)aminosulfonyl, aminosulfonylamino, C_1-6alkylaminosulfonylamino, di(C_1-6alkyl)aminosulfonylamino, aminocarbonylamino, C_1-6alkylaminocarbonylamino, and di(C_1-6alkyl)aminocarbonylamino.
- 2. The method of paragraph 1, wherein at least one of R⁵, R⁶, R⁷and R⁸is a group of formula (i).
- 3. The method of paragraph 2, wherein at least one of R⁷and R⁸is a group of formula (i).
- 4. The method of paragraph 1, wherein the compound of Formula (I) has formula:

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- - or a pharmaceutically acceptable salt thereof.
- 5. The method of paragraph 1, wherein the compound of Formula (I) has formula:

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- - or a pharmaceutically acceptable salt thereof.
- 6. The method of paragraph 1, wherein the compound of Formula (I) has formula:

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- - or a pharmaceutically acceptable salt thereof.
- 7. The method of paragraph 1, wherein the compound of Formula (I) has formula:

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- - or a pharmaceutically acceptable salt thereof.
- 8. The method of any one of paragraphs 4-7, wherein:
  - R²is selected from H and C_1-6alkyl;
  - R¹is selected from H, C_1-6alkyl, C_1-6haloalkyl, C(O)R^b1, and C(O)NR^c1R^d1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.
- 9. The method of paragraph 8, wherein R¹is selected from C_1-6alkyl, C(O)R^b1, and C(O)NR^c1R^d1.
- 10. The method of paragraph 1, wherein the compound of Formula (I) is selected from:

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- - or a pharmaceutically acceptable salt thereof.
- 11. The method of paragraph 1, wherein the compound of Formula (I) is selected from:

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- - or a pharmaceutically acceptable salt thereof.
- 12. The method of paragraph 1, wherein the compound of Formula (I) has formula:

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- - or a pharmaceutically acceptable salt thereof.
- 13. The method of paragraph 1, wherein the compound of Formula (I) has formula:

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- - or a pharmaceutically acceptable salt thereof.
- 14. The method of paragraph 1, wherein the compound of Formula (I) has formula:

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- - or a pharmaceutically acceptable salt thereof.
- 15. The method of paragraph 1, wherein the compound of Formula (I) has formula:

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- - or a pharmaceutically acceptable salt thereof.
- 16. The method of paragraph 1, wherein the compound of Formula (I) has formula:

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- - or a pharmaceutically acceptable salt thereof.
- 17. The method of paragraph 1, wherein the compound of Formula (I) has formula:

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- - or a pharmaceutically acceptable salt thereof.
- 18. The method of paragraph 1, wherein the compound of Formula (I) has formula:

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- - or a pharmaceutically acceptable salt thereof.
- 19. The method of any one of paragraphs 1-18, wherein R²is selected from H and C_1-6alkyl.
- 20. The method of any one of paragraphs 1-19, wherein R³is selected from H and C_1-6alkyl.
- 21. The method of any one of paragraphs 1-20, wherein R⁴is selected from H, C_1-6alkyl, and C_1-6haloalkyl, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.
- 22. The method of paragraph 21, wherein R⁴is H.
- 23. The method of any one of paragraphs 1-22, wherein R⁵and R⁶are each independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, OR^a1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.
- 24. The method of any one of paragraphs 1-22, wherein R⁵and R⁶are each independently selected from H, halo, C_1-6alkyl, and S(O)₂R^b1, wherein said C_1-6alkyl is optionally substituted with R⁹.
- 25. The method of paragraph 24, wherein R⁵is H and R⁶is C_1-6alkyl, optionally substituted with NR^c1R^d1.
- 26. The method of paragraph 24, wherein R⁵is H and R⁶is halo.
- 27. The method of paragraph 24, wherein R⁵is H and R⁶is S(O)₂R^b1.
- 28. The method of any one of paragraphs 1-27, wherein R⁷is selected from H and C_1-6alkyl.
- 29. The method of any one of paragraphs 1-27, wherein R⁸is selected from H and C_1-6alkyl.
- 30. The method of any one of paragraphs 1-29, wherein R^Nis selected from H and C_1-6alkyl.
- 31. The method of any one of paragraphs 1-30, wherein R¹¹is ring A.
- 32. The method of any one of paragraphs 1-30, wherein R¹¹is C_1-6alkyl, optionally substituted with ring A.
- 33. The method of any one of paragraphs 1-32, wherein R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.
- 34. The method of any one of paragraphs 1-33, wherein ring A is selected from any one of the following moieties:

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- 35. The method of any one of paragraphs 1-34, wherein each R is independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.
- 36. The method of any one of paragraphs 1-34, wherein each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)OR^a1, NR^c1R^d1and NR^c1C(O)R^b1, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.
- 37. The method of any one of paragraphs 1-36, wherein each R¹⁰is independently selected from OR^a1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1S(O)₂R^b1, and S(O)₂NR^c1R^d1.
- 38. The method of any one of paragraphs 1-34, wherein each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)OR^a1, NR^c1R^d1and NR^c1C(O)R^b1, wherein said C_1-6alkyl is optionally substituted with C(O)OR^a1.
- 39. The method of any one of paragraphs 1-38, wherein each R^a1, R^b1, R^c1, and R^d1is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.
- 40. The method of any one of paragraph 1-39, wherein each R⁹is independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, and carboxy.
- 41. The method of paragraph 1, wherein:
  - each R³is independently selected from H and C_1-6alkyl;
  - R¹is selected from H, C_1-6alkyl, C_1-6haloalkyl, C(O)R^b1, and C(O)NR^c1R^d1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
  - R²is selected from H and C_1-6alkyl; or
  - R¹and R², together with N atom to which R¹is attached and C atom to which R²is attached, form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R⁹;
  - each R⁴is independently selected from H, C_1-6alkyl, and C_1-6haloalkyl, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
  - R⁵and R⁶are each independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, OR^a1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
  - R⁷and R⁸are independently selected from H, C_1-6alkyl, and a moiety of formula (i);
  - R^Nis selected from H and C_1-6alkyl; or
  - R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
  - each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰;
  - each R¹⁰is independently selected from OR^a1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1S(O)₂R^b1, and S(O)₂NR^c1R^d1;
  - each R^a1, R^b1, R^c1, and R^d1is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g; and
  - each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, and carboxy.
- 42. The method of paragraph 1, wherein:
  - each R³is independently selected from H and C_1-6alkyl;
  - R¹is selected from C_1-6alkyl, C(O)R^b1, and C(O)NR^c1R^d1;
  - R²is selected from H and C_1-6alkyl; or
  - R¹and R², together with N atom to which R¹is attached and C atom to which R²is attached, form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R⁹;
  - each R⁴is H;
  - R⁵and R⁶are each independently selected from H, halo, C_1-6alkyl, and S(O)₂R^b1, wherein said C_1-6alkyl is optionally substituted with R⁹;
  - R⁷and R⁸are independently selected from H, C_1-6alkyl, and a moiety of formula (i);
  - R^Nis selected from H and C_1-6alkyl; or
  - R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
  - each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, C(O)R^b1, C(O)OR^a1, NR^c1R^d1, and NR^c1C(O)R^b1, wherein said C_1-6alkyl is optionally substituted with C(O)OR^a1;
  - each R^a1, R^b1, R^c1, and R^d1is independently selected from H and C_1-6alkyl, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R^g; and
  - each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, and carboxy.
- 43. The method of paragraph 1, wherein the compound of Formula (I) has formula (Ib):

embedded image

- - or a pharmaceutically acceptable salt thereof, wherein Hal is halogen.
- 44. The method of paragraph 43, wherein R⁴, R⁵, and R⁸are each H.
- 45. The method of paragraph 43, wherein R^Nis H.
- 46. The method of any one of paragraphs 43-45, wherein ring A is selected from C_6-10aryl and C_3-10cycloalkyl, each of which is optionally substituted with 1-10 substituents independently selected from R^A.
- 47. The method of any one of paragraphs 43-46, wherein each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, and C(O)R^b1wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.
- 48. The method of any one of paragraphs 43-46, wherein each R^Ais independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, and C(O)R^b1, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.
- 49. The method of paragraph 43:
  - R²is selected from H and C_1-6alkyl;
  - R⁴, R⁵, and R⁸are each H;
  - R^Nis H; or
  - R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from pyrrolidinyl, morpholinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
  - ring A is selected from C_6-10aryl and C_3-10cycloalkyl, each of which is optionally substituted with 1-10 substituents independently selected from R^A; and
  - each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, and C(O)R^b1, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.
- 50. The method of paragraph 49, wherein R^Ais independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, OR^a1, SR^a1, and C(O)R^b1, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.
- 51. The method of paragraph 43, wherein the compound of Formula (I) has Formula (Ic):

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- - or a pharmaceutically acceptable salt thereof, wherein R^Bis selected from halogen and S(O)₂R^b1.
- 52. The method of paragraph 51, wherein R^Bis a halogen.
- 53. The method of paragraph 51, wherein R^Bis a S(O)₂R^b1.
- 54. The method of any one of paragraphs 51-53, wherein R²is selected H and C_1-6alkyl.
- 55. The method of any one of paragraphs 51-54, wherein R⁴is H.
- 56. The method of any one of paragraphs 51-55, wherein R⁵is H.
- 57. The method of any one of paragraphs 51-56, wherein R⁷is selected H and C_1-6alkyl.
- 58. The method of any one of paragraphs 51-57, wherein R^Nis H.
- 59. The method of any one of paragraphs 51-58, wherein R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from morpholinyl and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.
- 60. The method of any one of paragraphs 51-59, wherein ring A is selected from C_6-10aryl and C_3-10cycloalkyl, optionally substituted with 1-10 substituents independently selected from R^A.
- 61. The method of any one of paragraphs 51-60, wherein each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, and OR^a1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.
- 62. The method of paragraph 51, wherein:
  - R²is selected H and C_1-6alkyl;
  - R⁴is H;
  - R⁵is H;
  - R⁷is selected H and C_1-6alkyl;
  - R^Nis H; or
  - R^Nand R¹¹, together with the N atom to which they are attached, form a ring selected from morpholinyl and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
  - ring A is selected from C_6-10aryl and C_3-10cycloalkyl, optionally substituted with 1-10 substituents independently selected from R^A; and
  - each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, and OR^a1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.
- 63. The method of paragraph 1, wherein the compound of Formula (I) has Formula (Id):

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- - or a pharmaceutically acceptable salt thereof.
- 64. The method of paragraph 63, wherein R²is selected from H and C_1-6alkyl.
- 65. The method of paragraph 63, wherein R⁴is H.
- 66. The method of paragraph 63, wherein R⁵, R⁶, and R⁸are each H.
- 67. The method of any one of paragraphs 63-66, wherein R¹is selected from H, C_1-6alkyl, C(O)R^b1, and C(O)NR^c1R^d1, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹.
- 68. The method of any one of paragraphs 63-67, wherein each R^Ais H.
- 69. The method of paragraph 63, wherein:
  - R²is selected from H and C_1-6alkyl;
  - R⁴is H;
  - R⁵, R⁶, and R⁸are each H;
  - R¹is selected from H, C_1-6alkyl, C(O)R^b1, and C(O)NR^c1R^d1, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R⁹;
  - each R⁹is independently selected from OH, C_1-6alkoxy, carboxy, C(O)NH₂, amino, C_1-6alkylamino, and di(C_1-6alkyl)amino; and each R^Ais H.
- 70. The method of paragraph 1, wherein the compound of Formula (I) has Formula (Ie):

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- - or a pharmaceutically acceptable salt thereof, wherein R^Bis selected from halogen and S(O)₂R^b1.
- 71. The method of paragraph 1, wherein the compound of Formula (I) has Formula (Ig):

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- - or a pharmaceutically acceptable salt thereof, wherein R^Bis selected from halogen and S(O)₂R^b1.
- 72. The method of paragraph 70 or 71, wherein R^Bis a halogen.
- 73. The method of paragraph 70 or 71, wherein R^Bis S(O)₂R^b1.
- 74. The method of any one of paragraphs 70-73, wherein R²and R³are each independently selected from H and C_1-6alkyl.
- 75. The method of any one of paragraphs 70-74, wherein R⁴is H.
- 76. The method of any one of paragraphs 70-75, wherein R⁵is H.
- 77. The method of any one of paragraphs 70-76, wherein R⁷is selected H and C_1-6alkyl.
- 78. The method of any one of paragraphs 70-77, wherein R^Nis H.
- 79. The method of any one of paragraphs 70-78, wherein ring A is C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A.
- 80. The method of any one of paragraphs 70-79, wherein each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, and OR^a1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.
- 81. The method of paragraph 70 or 71, wherein:
  - R²and R³are each independently selected H and C_1-6alkyl;
  - R⁴is H;
  - R⁸is H;
  - R⁷is selected H and C_1-6alkyl;
  - R^Nis H;
  - R¹¹is C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A; and
  - each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, and C_1-6haloalkoxy.
- 82. The method of paragraph 1, wherein the compound of Formula (I) has Formula (If):

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- - or a pharmaceutically acceptable salt thereof, wherein R^Bis selected from halogen and S(O)₂R^b1.
- 83. The method of paragraph 82, wherein R^Bis a halogen.
- 84. The method of paragraph 82, wherein R^Bis S(O)₂R^b1.
- 85. The method of any one of paragraphs 82-84, wherein R²and R³are each independently selected from H and C_1-6alkyl.
- 86. The method of any one of paragraphs 82-85, wherein R⁴is H.
- 87. The method of any one of paragraphs 82-86, wherein R⁵is H.
- 88. The method of any one of paragraphs 82-87, wherein R⁸is selected H and C_1-6alkyl.
- 89. The method of any one of paragraphs 82-88, wherein R^Nis H.
- 90. The method of any one of paragraphs 82-89, wherein ring A is C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A.
- 91. The method of any one of paragraphs 82-90, wherein each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, and OR^a1; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.
- 92. The method of paragraph 82, wherein:
  - R²and R³are each independently selected H and C_1-6alkyl;
  - R⁴is H;
  - R⁵is H;
  - R⁸is selected H and C_1-6alkyl;
  - R^Nis H;
  - R¹¹is C_6-10aryl, optionally substituted with 1-5 substituents independently selected from R^A; and
  - each R^Ais independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, and C_1-6haloalkoxy.
- 93. The method of paragraph 1, wherein the compound of Formula (I) is selected from any one of the compounds listed in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, and Table 10, or a pharmaceutically acceptable salt thereof.
- 94. The method of any one of paragraphs 1-93, wherein said method comprises identifying said mammal as being in need of inhibited CB1 activity.
- 95. The method of any one of paragraphs 1-94, wherein said method is a method for treating obesity.
- 96. The method of any one of paragraphs 1-94, wherein said method is a method for treating fear.
- 97. The method of any one of paragraphs 1-94, wherein said method is a method for treating a metabolic-related disorder.
- 98. The method of any one of paragraphs 1-94, wherein said method is a method for treating diabetes.
- 99. The method of any one of paragraphs 1-94, wherein said method is a method for treating dyslipidaemia.
- 100. The method of any one of paragraphs 1-94, wherein said method is a method for treating atherosclerosis.
- 101. The method of any one of paragraphs 1-94, wherein said method is a method for reducing food intake of said mammal.
- 102. The method of any one of paragraphs 1-94, wherein said method is a method for reducing body weight gain of said mammal.
- 103. The method of any one of paragraphs 1-94, wherein said method is a method for improving lipid profiles within said mammal.
- 104. The method of any one of paragraphs 1-94, wherein said method is a method for improving glycemic profiles within said mammal.
- 105. The method of any one of paragraphs 1-94, wherein said method is a method for assisting said mammal in stopping tobacco use and/or cannabis use.
- 106. The method of any one of paragraphs 1-94, wherein said method is a method for treating a liver disorder.
- 107. The method of paragraph 106, wherein said liver disorder is fatty liver disease, nonalcoholic steatohepatitis (NASH), cirrhosis, or liver cancer.
- 108. The method of any one of paragraphs 1-94, wherein said method is a method for reducing a symptom or the progression of idiopathic pulmonary fibrosis or a fibrotic condition in the lung.
- 109. The method of any one of paragraphs 1-94, wherein said method is a method for reducing the severity of or occurrence of end-organ damage induced by chronic alcohol usuage.
- 110. The method of paragraph 106, wherein said end-organ damage is heart failure, pancreatitis, or liver disease.
- 111. The method of any one of paragraphs 1-94, wherein said method is a method for reducing a complication of chronic renal disease characterized by renal fibrosis.
- 112. The method of paragraph 111, wherein said chronic renal disease is diabetic nephropathy or inherited or acquired glomerular diseases.
- 113. The method of any one of paragraphs 1-112, wherein said administering step reduces CB1 activity within the peripheral nervous system of said mammal.
- 114. The method of paragraph 113, wherein said administering step reduces little if any CB1 activity within the central nervous system of said mammal.
- 115. The method of paragraph 113, wherein said administering step does not reduce CB1 activity within the central nervous system of said mammal.

OTHER EMBODIMENTS

It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

METHODS AND MATERIALS FOR INHIBITING CB1 ACTIVITY

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FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

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