Opioid receptor modulators

Abstract

This article provides opioid receptor modulators and pharmaceutical compositions comprising such compounds.

Description

[Previous Technology]

[0001] Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands, which have long been used to treat pain. Opioids generally act on these receptors as agonists, antagonists, or partial agonists. There are three typical opioid receptors, originally named μ (after morphine, its most common exogenous ligand), δ (after the vas deferens, a tissue in which the receptor is first isolated), and κ (after the first ligand acting on this receptor, ketocyclazocine). These opioid receptors are widely distributed in the central nervous system and to a lesser extent throughout the periphery. Whether naturally occurring or synthetic, opioids exhibit numerous intractable side effects, such as constipation, addiction, and respiratory depression, and efforts to eliminate these properties have yielded limited success. Therefore, there is still a need in this technology for agents that can modulate opioid receptors in a manner that limits the side effects typically associated with the drug. [Summary of the Invention]

[0002] This invention provides, for example, opioid receptor modulators, methods of their preparation, their use as medicaments for treating neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcohol addiction, gambling addiction, pain, opioid overdose, opioid use disorder, and addiction, as well as pharmaceutical compositions comprising compounds of this invention as at least one active ingredient. This invention also provides the use of the compounds described herein as medicaments and / or in the manufacture of medicaments for treating neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcohol addiction, gambling addiction, pain, opioid overdose, opioid use disorder, and addiction.

[0003] In one state, there is a compound of formula (I): Formula (I); wherein: R1 is selected from C6-10 aryl and C1-9 heteroaryl, wherein the C6-10 aryl and C1-9 heteroaryl are substituted by one, two, three, four or five R7 as appropriate; R2 is selected from C6-10 aryl and C1-9 heteroaryl, wherein the C6-10 aryl and C1-9 heteroaryl are substituted by one, two, three, four or five R8 as appropriate; R3 is -X-R3a, C2-C8 alkyl, C2-C8 haloalkyl or C2-C8 alkenyl; X is a bond or C1-6 alkenyl; R3a is a C3-8 cycloalkyl substituted by one, two, three, four or five R9 as appropriate; R4 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; R5 and R6 are each independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; or R5 and R6 are combined to form a nitrogen-containing heterocyclic butyl, pyrrolidinyl, piperidinyl, or piperidine ring; each R7 is independently selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocyclic alkyl, C6-10 aryl, C1-9 heteroaryl, -OR10, -SR10, -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)R13, ​​-N(R12)C(O)OR 13. -N(R12)S(O)2R13, -C(O)R13, ​​-OC(O)R13, ​​-C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -S(O)R13, ​​-S(O)2R13 and -S(O)2N(R10)(R11), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl and C1-9 heteroaryl As appropriate, it may be substituted with one, two, or three groups selected from the following: halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, C1-9 heteroaryl, -OR14, -SR14, -C(O)OR14, -OC(O)N(R14)(R15), -N(R16)C(O)N(R14)(R15), -N(R16)C(O)R17 -N(R16)C(O)OR17, -N(R16)S(O)2R17, -C(O)R17, -OC(O)R17, -C(O)N(R14)(R15), -C(O)C(O)N(R14)(R15), -S(O)R17, -S(O)2R17 and -S(O)2N(R14)(R15); or two R7s combined to form a heterocyclic alkyl ring substituted with a side-oxygen group as appropriate; or R7 and R6 combined to form a heterocyclic alkyl ring;Each R8 and each R9 is independently selected from halogens, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, C1-9 heteroaryl, -OR10, -SR10, -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)R1 3. -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, ​​-OC(O)R13, ​​-C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -S(O)R13, ​​-S(O)2R13 and -S(O)2N(R10)(R11), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocyclic alkyl, C6-10 aryl, and C1-9 heteroaryl groups are substituted, as appropriate, with one, two, or three groups selected from the following: halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocyclic alkyl, C6-10 aryl, C1-9 heteroaryl, -OR14, -SR14, -C(O)OR14, -OC(O)N(R14)(R15), -N(R 16)C(O)N(R14)(R15), -N(R16)C(O)R17, -N(R16)C(O)OR17, -N(R16)S(O)2R17, -C(O)R17, -OC(O )R17, -C(O)N(R14)(R15), -C(O)C(O)N(R14)(R15), -S(O)R17, -S(O)2R17 and -S(O)2N(R14)(R15); Each R10 group is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl groups are substituted by one, two, or three groups selected from the following: halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl; Each R11 group is independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; Each R12 group is independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl.Each R13 group is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl and C1-9 heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl and C1-9 heteroaryl groups are substituted by one, two or three groups selected from the following groups: halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl and C1-9 heteroaryl; Each R14 group is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl groups are, as appropriate, substituted by one, two, or three groups selected from the following: halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl; Each R15 group is independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; Each R16 group is independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; and each R17 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl groups are, as appropriate, substituted by one, two, or three groups selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl; or a pharmaceutically acceptable salt or solvate thereof.

[0004] In one embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Ia): formula (Ia); wherein n is 0, 1, 2, 3 or 4.

[0005] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Ib): formula (Ib); wherein n is 0, 1, 2, 3 or 4.

[0006] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Ic): formula (Ic); wherein n is 0, 1, 2, 3 or 4.

[0007] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Id): formula (Id); wherein n is 0, 1, 2 or 3.

[0008] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Ie): formula (Ie); wherein n is 0, 1, 2 or 3.

[0009] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (If): formula (If); where n is 0, 1, 2 or 3.

[0010] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Ig): formula (Ig); wherein n is 0, 1, 2 or 3.

[0011] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Ih): formula (Ih); wherein n is 0, 1, 2 or 3.

[0012] In another embodiment, it refers to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein R10 is independently selected from hydrogen and C1-6 alkyl groups. In another embodiment, it refers to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or a pharmaceutically acceptable salt thereof, wherein R11 is hydrogen. In another embodiment, it refers to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In another embodiment, the series consists of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein n is 1. In another embodiment, the series consists of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein n is 0. In another embodiment, the series consists of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein each R7 is independently selected from halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, -OR10, and -C(O)N(R10)(R11). In another embodiment, the compounds are of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein each R10 is independently selected from hydrogen and C1-6 alkyl groups. In another embodiment, the compounds are of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein each R7 is independently selected from halogens and C1-6 alkyl groups. In another embodiment, the compounds are of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3 is -X-R3a. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein X is a bond. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein X is a C1-6 alkyl group.In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein X is -CH2-. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3a is a C3-8 cycloalkyl group substituted with one, two, or three R9s, as appropriate. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3a is a C3-8 cycloalkyl group substituted with one, two, or three R9s. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3a is a C3-8 cyclopropyl group substituted with one, two, or three R9s. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein each R9 is independently selected from halogens, -CN, C1-6 alkyl groups, and C1-6 haloalkyl groups. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3a is a cyclopropyl group substituted with one R9. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein R3a is a C1-6 haloalkyl-substituted cyclopropyl group. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein R3a is a -CF3-substituted cyclopropyl group. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein R3a is an unsubstituted C3-8 cycloalkyl group. In another embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are used, wherein R3a is an unsubstituted cyclopropyl group.In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3 is a C2-C8 alkyl group. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3 is -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, or -CH2CH2CH2CH3. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3 is a C2-C8 alkenyl group. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein R3 is -CH2CH2CH=CH. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein R3 is a C2-C8 haloalkyl group. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein R2 is a C6-10 aryl group substituted with one, two, three, four, or five R8 groups, as appropriate. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R2 is a phenyl group substituted with one, two, three, four, or five R8 groups, as appropriate. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R2 is a phenyl group substituted with one, two, or three R8 groups, as appropriate. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R2 is a C1-9 heteroaryl group substituted with one, two, three, four, or five R8 groups, as appropriate. In another embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are provided, wherein R2 is a C1-9 heteroaryl group substituted with one, two, or three R8 groups.In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein R2 is pyridinyl, pyrimidinyl, or thiazolyl, wherein the pyridinyl, pyrimidinyl, or thiazolyl group is substituted with one, two, or three R8 groups. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein each R8 group is independently selected from halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, and -OR10. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein each R10 group is a C1-6 alkyl group. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein R2 is an unsubstituted phenyl group. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein R2 is an unsubstituted C1-9 heteroaryl group. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein R2 is an unsubstituted pyridyl group, an unsubstituted pyrimidinyl group, or an unsubstituted thiazolyl group. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R5 and R6 are each independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R5 is selected from hydrogen and C1-C6 alkyl. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R6 is selected from hydrogen and C1-C6 alkyl. In another embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are used, wherein R5 and R6 are C1-C6 alkyl groups.In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are formed, wherein R5 and R6 combine to form an azahexacyclic butyl, pyrrolidyl, piperidinyl, or piperidine ring. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are formed, wherein R4 is hydrogen.

[0013] In another embodiment, it is a pharmaceutical composition comprising a compound of formula (I) described herein or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0014] In another embodiment, it is a method for treating a disease or condition in an individual in need, the disease or condition being selected from neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcoholism, gambling addiction, pain, opioid overdose, opioid use disorder and addiction, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I) described herein or a medically acceptable salt thereof.

Implementation Method

[0015] Cross-reference

[0016] This application claims priority to U.S. Provisional Application No. 63 / 171,008, filed April 5, 2021, and U.S. Provisional Application No. 63 / 318,486, filed March 10, 2022, each of which is incorporated herein by reference in its entirety. Declaration Regarding Federally Funded Research

[0017] This invention was made with the support of the U.S. government and under contract numbers 1UG3DA049598-01 and 1R43DA047723-01 of the National Institutes of Health (“NIH”).

[0018] The compounds disclosed herein regulate one, two, or all three of the μ-opioid receptor (MOR), κ-opioid receptor (KOR), and / or δ-opioid receptor (DOR). As used herein, a “modulator” of MOR and / or KOR and / or DOR is a compound that provides the desired modulation of the target receptor when administered to an individual. For example, the compound may act as a complete or partial antagonist or agonist of the receptor by interacting directly or indirectly with the target receptor.

[0019] Unless the context clearly indicates otherwise, as used herein and in the appended claims, the singular forms "a / an" and "the" include a plurality of indicators. Thus, for example, reference to "a reagent" includes a plurality of such reagents, and reference to "the cell" includes reference to one or more cells (or a plurality of cells) and their equivalents. When the scope used herein refers to physical properties such as molecular weight or chemical properties such as chemical formula, it is intended to include all combinations and sub-combinations of the scope and specific embodiments herein. The term "about" when referring to a numerical value or range of values ​​means that the value or range mentioned is an approximation within experimental variability (or within experimental statistical error), and therefore the value or range of values ​​may vary between 1% and 15% of said value or range of values. The term "comprising" (and related terms such as "comprise / comprises," "having," or "including") is not intended to exclude terms used in other embodiments, for example, embodiments of any composition of the substance, composition, method, or process described herein or the like may be "composed of" or "substantially composed of" the described features. Definitions

[0020] Unless otherwise stated, as used in the specification and the accompanying claims, the following terms shall have the meanings indicated below.

[0021] As used herein, C1-Cx includes C1-C2, C1-C3...C1-Cx. C1-Cx refers to the number of carbon atoms constituting the portion it represents (excluding substituents present where applicable).

[0022] "Amino group" refers to the -NH2 group.

[0023] "Cyano" refers to the -CN group.

[0024] "Nitro" refers to the -NO2 group.

[0025] "O-" refers to the -O- group.

[0026] "Side oxygen group" refers to the =O group.

[0027] "Thionone group" refers to the =S group.

[0028] "Imine group" refers to the =NH group.

[0029] "Oxime group" refers to the =N-OH group.

[0030] "alkyl" or "alkylene" refers to a straight-chain or branched-chain hydrocarbon chain group (e.g., C1-C18 alkyl) consisting only of carbon and hydrogen atoms, containing no unsaturated groups, and having one to eighteen carbon atoms. In some embodiments, the alkyl group comprises three to eighteen carbon atoms (e.g., C3-C18 alkyl). In some embodiments, the alkyl group comprises one to fifteen carbon atoms (e.g., C1-C15 alkyl). In some embodiments, the alkyl group comprises one to twelve carbon atoms (e.g., C1-C12 alkyl). In some embodiments, the alkyl group comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises one to six carbon atoms (e.g., C1-C6 alkyl). In other embodiments, the alkyl group comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group comprises one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, the alkyl group comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (secondary butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tertiary butyl), and 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise specified in this specification, alkyl groups may be substituted with one or more of the following substituents, as appropriate: halogen, cyano, nitro, syloxy, thionyl, imino, oxime, trimethylsilyl, -ORa, -SRa, -OC(O)-Rf, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-NRaRf, -N(Ra)C(O)Rf, - N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2), wherein each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0031] "Alkoxy" refers to a group in the formula -O-alkyl that is bonded by an oxygen atom, wherein the alkyl group is an alkyl chain as defined above.

[0032] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing at least one carbon-carbon double bond, and having two to eighteen carbon atoms. In some embodiments, the alkenyl group contains three to eighteen carbon atoms. In some embodiments, the alkenyl group contains three to twelve carbon atoms. In some embodiments, the alkenyl group contains six to twelve carbon atoms. In some embodiments, the alkenyl group contains six to ten carbon atoms. In some embodiments, the alkenyl group contains eight to ten carbon atoms. In some embodiments, the alkenyl group contains two to eight carbon atoms. In other embodiments, the alkenyl group contains two to four carbon atoms. The alkenyl group is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentenyl, 1,4-dienyl, and similar groups. Unless otherwise specified in this specification, the alkenyl group may be substituted with one or more of the following substituents as appropriate: halogen, cyano, nitro, syloxy, thionyl, imino, oxime, trimethylsilyl, -ORa, -SRa, -OC(O)-Rf, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-NRaRf, -N(Ra)C(O)Rf, - N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2), wherein each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0033] "Alynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon bond, and having two to eighteen carbon atoms. In some embodiments, the alkynyl group contains three to eighteen carbon atoms. In some embodiments, the alkynyl group contains three to twelve carbon atoms. In some embodiments, the alkynyl group contains six to twelve carbon atoms. In some embodiments, the alkynyl group contains six to ten carbon atoms. In some embodiments, the alkynyl group contains eight to ten carbon atoms. In some embodiments, the alkynyl group contains two to eight carbon atoms. In other embodiments, the alkynyl group has two to four carbon atoms. The alkynyl group is connected to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentyynyl, hexynyl, and similar groups. Unless otherwise specified in this specification, the alkynyl group may be substituted with one or more of the following substituents as appropriate: halogen, cyano, nitro, syloxy, thionyl, imino, oxime, trimethylsilyl, -ORa, -SRa, -OC(O)-Rf, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-NRaRf, -N(Ra)C(O)Rf, - N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2), wherein each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0034] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a carbon atom in the ring. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon (six to eighteen carbon atoms), wherein at least one ring in the ring system is completely unsaturated, that is, it contains a cyclic, non-localized (4n+2) π-electron system according to Hückel theory. Ring systems that derive aryl groups include, but are not limited to, groups such as benzene, indane, indene, naphthalene, and naphthalene. Unless otherwise specified in this specification, the term "aryl" or the prefix "aromatic-" (such as in "arylalkyl") means, where applicable, an aryl group substituted with one or more substituents selected from: alkyl, alkenyl, ynyl, haloyl, haloalkyl, cyano, nitro, aryl, aralkyl, aryl-alkenyl, arylynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), wherein each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight-chain or branched alkyl or alkenyl chain, and Rc is a straight-chain or branched alkyl or alkenyl chain.

[0035] "Aryloxy group" refers to a group of the formula -O-aryl bonded by an oxygen atom, wherein the aryl group is as defined above.

[0036] "Aryl" refers to a group of the formula -Rc-aryl, wherein Rc is an alkyl chain as defined above, such as methylene, ethyl, and similar groups. The alkyl chain portion of the aryl group is substituted as described above for the alkyl chain, as appropriate. The aryl portion of the aryl group is substituted as described above for the aryl group, as appropriate.

[0037] "Arylalkoxy" refers to a group of the formula -O-aryl group bonded by an oxygen atom, wherein the aryl group is as defined above.

[0038] "Aryl" refers to a group of the formula -Rd-aryl, wherein Rd is an alkenyl chain as defined above. The aryl portion of the aryl group is substituted as described above for the aryl group. The alkenyl chain portion of the aryl group is substituted as described above for the alkenyl group.

[0039] "Arynyl" refers to a group of the formula -Re-aryl, wherein Re is an arynyl chain as defined above. The aryl portion of the arynyl group is substituted as described above for the aryl group, as appropriate. The arynyl chain portion of the arynyl group is substituted as defined above for the arynyl chain, as appropriate.

[0040] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused ring or bridged ring systems having three to fifteen carbon atoms. In some embodiments, the cycloalkyl group contains three to ten carbon atoms. In other embodiments, the cycloalkyl group contains five to seven carbon atoms. The cycloalkyl group is connected to the rest of the molecule by a single bond. The cycloalkyl group is saturated (i.e., containing only C-C single bonds) or partially unsaturated (i.e., containing one or more double bonds or triple bonds). Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group contains three to eight carbon atoms (e.g., C3-C8 cycloalkyl). In other embodiments, the cycloalkyl group contains three to seven carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, the cycloalkyl group contains three to six carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, the cycloalkyl group contains three to five carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, the cycloalkyl group comprises three to four carbon atoms (e.g., C3-C4 cycloalkyl). Partially unsaturated cycloalkyl groups are also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclic groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and similar groups. Unless otherwise specified in this specification, the term "cycloalkyl" means cycloalkyl substituted with one or more substituents selected from the following: alkyl, alkenyl, ynyl, haloyl, haloalkyl, syloxy, thionyl, cyano, nitro, aryl, aralkyl, aryl-alkenyl, arylynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O) N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), wherein each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight-chain or branched alkyl or alkenyl chain, and Rc is a straight-chain or branched alkyl or alkenyl chain.

[0041] "Halogen" or "halogen" refers to bromine, chlorine, fluorine or iodine substituents.

[0042] "Haloalkyl" means an alkyl group as defined above that has been substituted with one or more halogen groups as defined above.

[0043] "Haloalkoxy" refers to an alkoxy group as defined above that has been substituted with one or more halogen groups as defined above.

[0044] "Fluoroalkyl" means an alkyl group as defined above that has been substituted with one or more fluorine groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl and similar groups. The alkyl portion of a fluoroalkyl group is substituted as defined above for alkyl groups, as appropriate.

[0045] "Heterocyclic alkyl" refers to a stable 3- to 18-membered non-aromatic ring group comprising two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in this specification, heterocyclic alkyl is a monocyclic, bicyclic, tricyclic, or tetracyclic system, including fused, spirocyclic, or bridged ring systems. The heteroatoms in the heterocyclic alkyl are oxidized as appropriate. If one or more nitrogen atoms are present, they are quaternarily ammonized as appropriate. The heterocyclic alkyl is partially or fully saturated. In some embodiments, the heterocyclic alkyl is attached to the remainder of the molecule via any ring atom. Examples of such heterocyclic alkyl groups include (but are not limited to) dioxolane, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazodinyl, isothiazolinyl, isothiazolinyl, succinyl, octahydroindolyl, octahydroisoindolyl, 2-side-oxypiperidyl, 2-side-oxypiperidinyl, 2-side-oxypyrrolidinyl, succinyl, piperidinyl, piperidyl, 4-piperidinoneyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazodinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropiperidyl, thiosuccinyl, thiasuccinyl, 1-side-oxy-thiosuccinyl and 1,1-diside-oxy-thiosuccinyl. Unless otherwise specified in this specification, the term "heterocyclic alkyl" is intended to include, where applicable, heterocyclic alkyl groups as defined above that are substituted with one or more substituents selected from the following: alkyl, alkenyl, ynyl, haloyl, haloalkyl, thioketyl, cyano, nitro, aryl, aralkyl, aryl-alkenyl, arylynyl, cycloalkyl, heterocyclic alkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), wherein each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight-chain or branched alkyl or alkenyl chain, and Rc is a straight-chain or branched alkyl or alkenyl chain.

[0046] "Heteroaryl" refers to a group derived from an aromatic ring group of 3 to 18 members, containing one to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is completely unsaturated, i.e., it contains a cyclic, nonlocal (4n+2) π-electron system according to Hückel's theory. Heteroaryl includes fused ring or bridged ring systems. The heteroatoms in a heteroaryl are oxidized as appropriate. If one or more nitrogen atoms are present, they are quaternarily ammonized as appropriate. The heteroaryl is attached to the rest of the molecule via any ring atom. Unless otherwise specified in this specification, the term "heteroaryl" means including, as applicable, a heteroaryl group as defined above that has been substituted with one or more substituents selected from the following: alkyl, alkenyl, ynyl, haloyl, haloalkyl, syloxy, thionyl, cyano, nitro, aryl, aralkyl, aryl-alkenyl, arylynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C (O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), wherein each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight-chain or branched alkyl or alkenyl chain, and Rc is a straight-chain or branched alkyl or alkenyl chain.

[0047] "N-heteroaryl" means a heteroaryl as defined above, which contains at least one nitrogen atom and wherein the connection point between the heteroaryl and the rest of the molecule passes through the nitrogen atom in the heteroaryl. N-heteroaryl is substituted as described above for heteroaryl.

[0048] "C-heteroaryl" refers to a heteroaryl group as defined above, wherein the connection point between the heteroaryl group and the rest of the molecule is through a carbon atom in the heteroaryl group. C-heteroaryl groups are substituted as described above for heteroaryl groups, as appropriate.

[0049] "Heteroaryl group" refers to a group of the formula -O-heteroaryl bonded by an oxygen atom, wherein the heteroaryl group is as defined above.

[0050] “Heteroarylalkyl” refers to a group of the formula -Rc-heteroaryl, wherein Rc is an alkyl chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, then the heteroaryl is attached to an alkyl group at the nitrogen atom as appropriate. The alkyl chain of the heteroarylalkyl is substituted as defined above for the alkyl chain as appropriate. The heteroaryl portion of the heteroarylalkyl is substituted as defined above for the heteroaryl.

[0051] “Heteroarylalkoxy” refers to a group of the formula -O-Rc-heteroaryl bonded by an oxygen atom, wherein Rc is an alkyl chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is attached to an alkyl group at the nitrogen atom as appropriate. The alkyl chain of the heteroarylalkoxy group is substituted as defined above for the alkyl chain as appropriate. The heteroaryl portion of the heteroarylalkoxy group is substituted as defined above for the heteroaryl group as appropriate.

[0052] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomers, which, in absolute stereochemistry, may be defined as (R)- or (S)-. Unless otherwise stated, the present invention is intended to cover all stereoisomers of the compounds disclosed herein. When the compounds described herein contain an alkene double bond, the present invention is intended to include both E and Z geometric isomers (e.g., cis or trans) unless otherwise stated. Similarly, it is intended to include all possible isomers as well as their racemic and optically pure forms, and all tautomers. The term "geometric isomer" refers to the E or Z geometric isomer of the alkene double bond (e.g., cis or trans). The term "positional isomer" refers to a structural isomer with respect to the central ring, such as ortho, meta, and para isomers with respect to the benzene ring.

[0053] "Tautomer" refers to a molecule in which a proton may translocate from one atom of the molecule to another atom of the same molecule. In some embodiments, the compounds presented herein exist in tautomer form. In cases where tautomerization may occur, a chemical equilibrium of tautomers will exist. The precise ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include:

[0054] "Optional" means that the event or condition described below may or may not occur, and the specification includes the circumstances under which the event or condition occurs and the circumstances under which the event or condition does not occur. For example, "substituted aryl" means that the aryl group is substituted or unsubstituted, and this specification includes substituted aryl and unsubstituted aryl groups.

[0055] "Medically acceptable salts" include acid addition salts and base addition salts.

[0056] "Pharmaceutical-acceptable acid addition salts" refers to salts that retain the bioavailability and properties of the free base, are biologically or otherwise desirable, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. It also includes salts formed from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl alkanoates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, transbutenedioic acid salts, maleic acid salts, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Salts of amino acids, such as arginine, gluconates, and galacturons, are also included (see, for example, Berge SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt.

[0057] "Pharmaceutically acceptable base addition salts" refer to salts that retain the bioavailability and properties of the free base and are biologically or otherwise desirable. These salts are prepared by the addition of an inorganic or organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed from metals or amines, such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include (but are not limited to) sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and similar salts. Salts derived from organic bases include (but are not limited to) salts of the following: primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-diphenylmethylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethyldiphenylamine, N-methylreduced glucosamine, glucosamine, methylreduced glucosamine, theobromine, purines, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., above.

[0058] The terms "individual" or "patient" encompass mammals. Examples of mammals include (but are not limited to) any member of the mammal class: humans, non-human primates such as chimpanzees and other ape and monkey species; livestock such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents (such as rats, mice, and guinea pigs) and the like. In one instance, the mammal is human.

[0059] As used herein, the terms "treatment / treating," "palliating," or "ameliorating" are used interchangeably. These terms refer to methods for obtaining beneficial or desired results, including (but not limited to) therapeutic and / or preventive benefits. "Therapeutic benefit" means the eradication or improvement of the underlying condition being treated. Furthermore, therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition, resulting in observed improvement in a patient, even though the patient still suffers from the underlying condition. Regarding preventive benefit, the composition is administered to a patient at risk of developing a specific disease or to a patient reported to have one or more physiological symptoms of a disease, even if the disease has not yet been diagnosed.

[0060] The compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein are opioid receptor modulators. In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein are μ-class opioid receptor antagonists. In some embodiments, the compound of formula (I) described herein is a δ-class opioid receptor antagonist. In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein are κ-class opioid receptor antagonists. In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein are selective opioid receptor antagonists. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, and compositions comprising such compounds, are suitable for treating one or more conditions selected from the following: neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcoholism, gambling addiction, pain, opioid overdose, opioid use disorder, and addiction.

[0061] In some embodiments, the series compounds are of formula (I): Formula (I); wherein: R1 is selected from C6-10 aryl and C1-9 heteroaryl, wherein the C6-10 aryl and C1-9 heteroaryl are substituted by one, two, three, four or five R7 as appropriate; R2 is selected from C6-10 aryl and C1-9 heteroaryl, wherein the C6-10 aryl and C1-9 heteroaryl are substituted by one, two, three, four or five R8 as appropriate; R3 is -X-R3a, C2-C8 alkyl, C2-C8 haloalkyl or C2-C8 alkenyl; X is a bond or C1-6 alkenyl; R3a is a C3-8 cycloalkyl substituted by one, two, three, four or five R9 as appropriate; R4 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; R5 and R6 are each independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; or R5 and R6 are combined to form a nitrogen-containing heterocyclic butyl, pyrrolidinyl, piperidinyl, or piperidine ring; each R7 is independently selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocyclic alkyl, C6-10 aryl, C1-9 heteroaryl, -OR10, -SR10, -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)R13, ​​-N(R12)C(O)OR 13. -N(R12)S(O)2R13, -C(O)R13, ​​-OC(O)R13, ​​-C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -S(O)R13, ​​-S(O)2R13 and -S(O)2N(R10)(R11), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl and C1-9 heteroaryl As appropriate, it may be substituted with one, two, or three groups selected from the following: halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, C1-9 heteroaryl, -OR14, -SR14, -C(O)OR14, -OC(O)N(R14)(R15), -N(R16)C(O)N(R14)(R15), -N(R16)C(O)R17 -N(R16)C(O)OR17, -N(R16)S(O)2R17, -C(O)R17, -OC(O)R17, -C(O)N(R14)(R15), -C(O)C(O)N(R14)(R15), -S(O)R17, -S(O)2R17 and -S(O)2N(R14)(R15); or two R7s combined to form a heterocyclic alkyl ring substituted with a side-oxygen group as appropriate; or R7 and R6 combined to form a heterocyclic alkyl ring;Each R8 and each R9 is independently selected from halogens, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, C1-9 heteroaryl, -OR10, -SR10, -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)R1 3. -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, ​​-OC(O)R13, ​​-C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -S(O)R13, ​​-S(O)2R13 and -S(O)2N(R10)(R11), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocyclic alkyl, C6-10 aryl, and C1-9 heteroaryl groups are substituted, as appropriate, with one, two, or three groups selected from the following: halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocyclic alkyl, C6-10 aryl, C1-9 heteroaryl, -OR14, -SR14, -C(O)OR14, -OC(O)N(R14)(R15), -N(R 16)C(O)N(R14)(R15), -N(R16)C(O)R17, -N(R16)C(O)OR17, -N(R16)S(O)2R17, -C(O)R17, -OC(O )R17, -C(O)N(R14)(R15), -C(O)C(O)N(R14)(R15), -S(O)R17, -S(O)2R17 and -S(O)2N(R14)(R15); Each R10 group is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl groups are substituted by one, two, or three groups selected from the following: halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl; Each R11 group is independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; Each R12 group is independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl.Each R13 group is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl and C1-9 heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl and C1-9 heteroaryl groups are substituted by one, two or three groups selected from the following groups: halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl and C1-9 heteroaryl; Each R14 group is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl groups are, as appropriate, substituted by one, two, or three groups selected from the following: halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl; Each R15 group is independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; Each R16 group is independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; and each R17 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl groups are, as appropriate, substituted by one, two, or three groups selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl; or a pharmaceutically acceptable salt or solvate thereof.

[0062] In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a C6-10 aryl group substituted with one, two, three, four, or five R7 groups, depending on the situation. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a phenyl group substituted with one, two, three, four, or five R7 groups, depending on the situation. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a phenyl group substituted with one, two, or three R7 groups, depending on the situation. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a C1-9 heteroaryl group substituted with one, two, three, four, or five R7 groups, depending on the situation. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a C1-9 heteroaryl group substituted with one, two, three, four, or five R7 groups. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a C1-9 heteroaryl group substituted with one, two, or three R7 groups. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is an unsubstituted C1-9 heteroaryl group.

[0063] In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Ia): formula (Ia); wherein n is 0, 1, 2, 3 or 4.

[0064] In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R10 is independently selected from hydrogen and C1-6 alkyl. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R10 is hydrogen. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R10 is C1-6 alkyl. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R10 is hydrogen and R11 is hydrogen. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R7 substituent is present at the ortho position of -C(O)N(R10)(R11), R10 is hydrogen, R11 is hydrogen, and at least one ortho R7 substituent is fluorine. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R10 is C1-6 alkyl and R11 is hydrogen.

[0065] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Ib): formula (Ib); wherein n is 0, 1, 2, 3 or 4.

[0066] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Ic): formula (Ic); wherein n is 0, 1, 2, 3 or 4.

[0067] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Id): formula (Id); where n is 0, 1, 2 or 3.

[0068] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Ie): formula (Ie); wherein n is 0, 1, 2 or 3.

[0069] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (If): formula (If); where n is 0, 1, 2 or 3.

[0070] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Ig): formula (Ig); wherein n is 0, 1, 2 or 3.

[0071] In some embodiments, it is a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein R10 is independently selected from hydrogen and C1-6 alkyl. In some embodiments, it is a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein R10 is hydrogen. In some embodiments, it is a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein R10 is C1-6 alkyl. In some embodiments, it is a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein R10 is hydrogen and R11 is hydrogen. In some embodiments, it is a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R7 substituent is present at the ortho position of -C(O)N(R10)(R11), R10 is hydrogen, R11 is hydrogen and at least one ortho R7 substituent is fluorine. In some embodiments, it is a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein R10 is C1-6 alkyl and R11 is hydrogen.

[0072] In another embodiment, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (Ih): formula (Ih); wherein n is 0, 1, 2 or 3.

[0073] In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or pharmaceutically acceptable salts or solvates thereof, wherein R10 is independently selected from hydrogen and C1-6 alkyl groups. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or pharmaceutically acceptable salts or solvates thereof, wherein R10 is hydrogen. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or pharmaceutically acceptable salts or solvates thereof, wherein R10 is C1-6 alkyl groups. In another embodiment, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein R11 is hydrogen. In another embodiment, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In another embodiment, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In another embodiment, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein n is 0. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein n is 1 and R7 is selected from halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, -OR10, and -C(O)N(R10)(R11). In another embodiment, the series are compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein n is 1, R7 is selected from halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, -OR10, and -C(O)N(R10)(R11), and each R10 and each R11 is independently selected from hydrogen and C1-6 alkyl groups.In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein n is 1 and R7 is selected from halogens and C1-6 alkyl groups. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein n is 1 and R7 is a halogen. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein n is 1 and R7 is a C1-6 alkyl group. In another embodiment, the series comprises compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein n is 2 and each R7 is independently selected from halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, -OR10, and -C(O)N(R10)(R11). In another embodiment, the series comprises compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein n is 2, each R7 is independently selected from halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, -OR10, and -C(O)N(R10)(R11), and each R10 and each R11 is independently selected from hydrogen and C1-6 alkyl groups. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein n is 2 and each R7 is independently selected from halogens and C1-6 alkyl groups. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein n is 2 and each R7 is a halogen. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein n is 2 and each R7 is a C1-6 alkyl group. In another embodiment, the series of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are provided, wherein n is 3 and each R7 is independently selected from halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, -OR10, and -C(O)N(R10)(R11).In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are used, wherein n is 3, each R7 is independently selected from halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, -OR10, and -C(O)N(R10)(R11), and each R10 and each R11 is independently selected from hydrogen and C1-6 alkyl groups. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are used, wherein n is 3 and each R7 is independently selected from halogens and C1-6 alkyl groups. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein n is 3 and each R7 is a halogen. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein n is 3 and each R7 is a C1-6 alkyl group.

[0074] In another embodiment, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -X-R3a. In another embodiment, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond. In another embodiment, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein X is a C1-6 alkyl group. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein X is -CH2-. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3a is a C3-8 cycloalkyl group substituted with one, two, or three R9s, as appropriate. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3a is a C3-8 cycloalkyl group substituted with one, two, or three R9s. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3a is a C3-8 cyclopropyl group substituted with one, two, or three R9s. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein each R9 is independently selected from halogens, -CN, C1-6 alkyl groups, and C1-6 haloalkyl groups. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3a is a cyclopropyl group substituted with one R9. In another embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are provided, wherein R3a is a cyclopropyl group substituted with a C1-6 haloalkyl group.In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3a is a -CF3-substituted cyclopropyl group. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3a is an unsubstituted C3-8 cycloalkyl group. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3a is an unsubstituted cyclopropyl group.

[0075] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3a is a -CF3-substituted cyclopropyl group, one or more pharmacokinetic properties are enhanced compared to embodiments wherein R3a is an unsubstituted cyclopropyl group. In some embodiments wherein R3a is a -CF3-substituted cyclopropyl group, CNS exposure (i.e., brain:plasma ratio) is enhanced compared to embodiments wherein R3a is an unsubstituted cyclopropyl group. In some embodiments, the enhanced pharmacokinetic property is an increase in permeability (e.g., cell permeability, tissue permeability, blood-brain barrier permeability, CNS permeability, etc.). In some embodiments, the enhanced pharmacokinetic property is an increase in lipophilicity or logP. In some embodiments, the enhanced pharmacokinetic property is an increase in bioavailability (e.g., oral bioavailability). In some embodiments, the enhanced pharmacokinetic property is an increase in metabolic stability. In some embodiments, the enhanced pharmacokinetic property is a decrease in efflux. In some embodiments, the enhanced pharmacokinetic property is a decrease in clearance. In some embodiments, the enhanced pharmacokinetic property is a reduction in non-specific binding (e.g., plasma protein binding). In some embodiments, the enhanced pharmacokinetic property is a reduction in off-target binding (e.g., cytochrome P450 enzymes or other metabolic enzymes).

[0076] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein R3a is a -CF3-substituted cyclopropyl group, one or more pharmacological properties are enhanced compared to embodiments wherein R3a is an unsubstituted cyclopropyl group. In some embodiments, the enhanced pharmacological property is increased binding to μ-type opioid receptors. In some embodiments, the enhanced pharmacological property is decreased binding to μ-type opioid receptors. In some embodiments, the enhanced pharmacological property is increased binding to δ-type opioid receptors. In some embodiments, the enhanced pharmacological property is decreased binding to δ-type opioid receptors. In some embodiments, the enhanced pharmacological property is increased binding to κ-type opioid receptors. In some embodiments, the enhanced pharmacological property is decreased binding to κ-type opioid receptors. In some embodiments, the enhanced pharmacological property is increased selectivity of μ-type opioid receptors relative to δ and / or κ-type opioid receptors. In some embodiments, the enhanced pharmacological property is the regulatory effect on μ-opioid receptors (e.g., increased or decreased activation (e.g., β-inhibitor protein activation, G protein activation)). In some embodiments, the enhanced pharmacological property is increased μ-opioid receptor activity. In some embodiments, the enhanced pharmacological property is decreased μ-opioid receptor activity (e.g., G protein activation).

[0077] In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or pharmaceutically acceptable salts or solvates thereof, wherein R3 is a C2-C8 alkyl group. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or pharmaceutically acceptable salts or solvates thereof, wherein R3 is -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, or -CH2CH2CH2CH3. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, or -CH2CH2CH2CH3. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CH2CH3. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CH(CH3)2. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3 is -C(CH3)3. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3 is -CH2CH(CH3)2. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3 is -CH2CH2CH2CH3. In another embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein R3 is -CH2CH2CH3.

[0078] In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3 is a C2-C8 alkenyl group. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R3 is -CH2CH2CH=CH.

[0079] In another embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are provided, wherein R3 is a C2-C8 haloalkyl group.

[0080] In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is a C6-10 aryl group substituted with one, two, three, four, or five R8 groups, as appropriate. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is a phenyl group substituted with one, two, three, four, or five R8 groups, as appropriate. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is a phenyl group substituted with one, two, or three R8 groups. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein R2 is a C1-9 heteroaryl group substituted with one, two, three, four, or five R8 groups, as appropriate. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein R2 is a C1-9 heteroaryl group substituted with one, two, or three R8 groups. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein R2 is pyridinyl, pyrimidinyl, or thiazolyl, wherein the pyridinyl, pyrimidinyl, or thiazolyl group is substituted with one, two, or three R8 groups. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein each R8 group is independently selected from halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, and -OR10. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein each R10 group is a C1-6 alkyl group. In another embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are used, wherein R2 is an unsubstituted phenyl group.In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein R2 is an unsubstituted C1-9 heteroaryl group. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are present, wherein R2 is an unsubstituted pyridyl, unsubstituted pyrimidinyl, or unsubstituted thiazolyl group.

[0081] In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or pharmaceutically acceptable salts or solvates thereof, wherein R5 and R6 are each independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is selected from hydrogen and C1-C6 alkyl. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or pharmaceutically acceptable salts or solvates thereof, wherein R6 is selected from hydrogen and C1-C6 alkyl. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R5 and R6 are each hydrogen. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R5 and R6 are each C1-C6 alkyl. In another embodiment, the compounds are of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their pharmaceutically acceptable salts or solvates, wherein R5 and R6 are C1-C6 alkyl. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein R5 and R6 combine to form an azahexacyclic butyl, pyrrolidyl, piperidinyl, or piperidine ring. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein R5 and R6 combine to form an azahexacyclic butyl ring. In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein R5 and R6 combine to form a pyrrolidyl ring. In another embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are used, wherein R5 and R6 combine to form a piperidinyl ring.In another embodiment, the compounds are of the formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates, wherein R5 and R6 combine to form a piperidine ring.

[0082] In another embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their pharmaceutically acceptable salts or solvates are used, wherein R4 is hydrogen.

[0083] Other embodiments provided herein include combinations of one or more of the specific embodiments described above.

[0084] In some embodiments, it is a compound selected from:; or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, it is a compound selected from:; or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein are μ-opioid receptor modulators. In some embodiments, the compounds described herein are μ-opioid receptor super-activators. In some embodiments, the compounds described herein are μ-opioid receptor activators. In some embodiments, the compounds described herein are μ-opioid receptor partial activators. In some embodiments, the compounds described herein are μ-opioid receptor weak partial activators. In some embodiments, the compounds described herein are μ-opioid receptor weak partial activators / antagonists. In some embodiments, the compounds described herein are μ-opioid receptor antagonists.

[0087] In some embodiments, the compounds described herein are partial agonists of μ-opioid receptors having at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater cAMP activation compared to a standard full agonist (e.g., DAMGO). In some embodiments, the compounds described herein are weak partial agonists of μ-opioid receptors having about 10% to about 50% (e.g., about 10% to about 30%) cAMP activation compared to a standard full agonist (e.g., DAMGO). In some embodiments, the compounds described herein are partial agonists of μ-opioid receptors having about 30% to about 70% cAMP activation compared to a standard full agonist (e.g., DAMGO). In some embodiments, the compounds described herein are partial agonists of μ-opioid receptors having about 50% to about 70% cAMP activation compared to a standard full agonist (e.g., DAMGO). In some embodiments, the compounds described herein are partial tropons of μ-opioid receptors with approximately 40% cAMP activation compared to a standard full troponin (e.g., DAMGO). In some embodiments, the compounds described herein are μ-opioid receptor tropons with approximately 50% cAMP activation compared to a standard full troponin (e.g., DAMGO). In some embodiments, the compounds described herein are μ-opioid receptor tropons with approximately 60% cAMP activation compared to a standard full troponin (e.g., DAMGO). In some embodiments, the compounds described herein are μ-opioid receptor tropons with approximately 70% cAMP activation compared to a standard full troponin (e.g., DAMGO). In some embodiments, the compounds described herein are μ-opioid receptor tropons with approximately 80% cAMP activation compared to a standard full troponin (e.g., DAMGO).

[0088] In some embodiments, the compounds described herein are μ-opioid receptor antagonists / weak partial agonists with efficacy less than buprenorphine. In some embodiments, the compounds described herein are μ-opioid receptor antagonists / weak partial agonists with efficacy greater than naltrexone. In some embodiments, the compounds described herein are μ-opioid receptor antagonists / weak partial agonists with efficacy less than buprenorphine and more than naltrexone. In some embodiments, the compounds described herein are μ-opioid receptor antagonists / weak partial agonists with efficacy less than morphine and more than buprenorphine.

[0089] In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein are μ-type opioid receptor modulators (e.g., agonists, partial agonists, weak partial agonists, antagonists, etc.). In some embodiments, the compounds described herein are G protein μ-type opioid receptor modulators. In some embodiments, the compounds described herein are β-repressor protein opioid receptor modulators.

[0090] In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein are delta-opioid receptor modulators. In some embodiments, the compounds described herein are delta-opioid receptor agonists. In some embodiments, the compounds described herein are partial delta-opioid receptor agonists. In some embodiments, the compounds described herein are weak partial delta-opioid receptor agonists / antagonists. In some embodiments, the compounds described herein are delta-opioid receptor antagonists.

[0091] In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein are κ-opioid receptor modulators. In some embodiments, the compounds described herein are κ-opioid receptor agonists. In some embodiments, the compounds described herein are partial κ-opioid receptor agonists. In some embodiments, the compounds described herein are weak partial κ-opioid receptor agonists / antagonists. In some embodiments, the compounds described herein are κ-opioid receptor antagonists.

[0092] In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein are selective opioid receptor modulators. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein are selective μ-opioid receptor modulators.

[0093] In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, and compositions comprising such compounds, are suitable for treating one or more conditions selected from: neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcoholism, gambling addiction, pain, opioid overdose, opioid use disorder, and addiction. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, and compositions comprising such compounds, are suitable for treating one or more diseases or conditions without substantial respiratory depression (i.e., less than about 75%, less than about 50%, less than about 25%, less than about 20%, less than about 10%, or less than about 5% compared to standard care opiates (e.g., fentanyl, morphine, oxycodone, or similar). In some embodiments, the compounds described herein do not suppress respiration (e.g., at doses effective in treating one or more of the diseases or conditions described herein). In some embodiments, the compounds described herein do not substantially suppress respiration at doses effective in treating one or more conditions selected from neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcoholism, gambling addiction, pain, opioid overdose, opioid use disorder, and addiction.

[0094] In some embodiments, the compounds described herein are not self-administered. In some embodiments, the compounds described herein are not self-administered at doses effective in treating one or more of the diseases or conditions described herein (e.g., neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcoholism, gambling addiction, pain, opioid overdose, opioid use disorder, addiction, or any combination thereof). In some embodiments, the compounds described herein are not likely to induce dependence. In some embodiments, the compounds described herein do not provide positive reinforcement. In some embodiments, the compounds described herein are not self-administered. In some embodiments, the compounds described herein are not addictive. In some embodiments, the compounds described herein are not addictive at doses effective in treating one or more of the diseases or conditions described herein (e.g., neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcoholism, gambling addiction, pain, opioid overdose, opioid use disorder, addiction, or any combination thereof). In some embodiments, the compounds described herein are less addictive than standard care opiates (e.g., morphine, oxycodone, and their analogues).

[0095] In some embodiments, the compounds described herein have a low tendency to cause respiratory depression (e.g., relative to standard care) (e.g., at doses that are effective in treating one or more of the diseases or conditions described herein (e.g., neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcoholism, gambling addiction, pain, opioid overdose, opioid use disorder, addiction, or any combination thereof)). In some embodiments, the compounds described herein have a low tendency to cause addiction (e.g., relative to standard care) (e.g., at doses that are effective in treating one or more of the diseases or conditions described herein (e.g., neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcoholism, gambling addiction, pain, opioid overdose, opioid use disorder, addiction, or any combination thereof)). In some embodiments, the compounds described herein have a low tolerance tendency (e.g., relative to standard care products) (e.g., at doses that are effective in treating one or more of the diseases or conditions described herein (e.g., neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcoholism, gambling addiction, pain, opioid overdose, opioid use disorder, addiction, or any combination thereof)). In some embodiments, the compounds described herein have a low sedative tendency (e.g., relative to standard care products) (e.g., at doses that are effective in treating one or more of the diseases or conditions described herein (e.g., neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcoholism, gambling addiction, pain, opioid overdose, opioid use disorder, addiction, or any combination thereof)). In some embodiments, the compounds described herein are analgesics that have reduced respiratory depression, tolerance, addiction, and / or sedation tendencies (e.g., relative to standard care products) (e.g., at doses that are effective in treating one or more of the diseases or conditions described herein (e.g., neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcoholism, gambling addiction, pain, opioid overdose, opioid use disorder, addiction, or any combination thereof)).

[0096] In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein have high CNS exposure. In some embodiments, the compounds described herein have oral bioavailability. In some embodiments, the compounds described herein have 3 or fewer H bond donors (e.g., 2 or fewer H bond donors (e.g., 1 or fewer H bond donor)). In some embodiments, the compounds described herein have high permeability (e.g., cell permeability, tissue permeability, blood-brain barrier permeability). In some embodiments, the compounds described herein have high stability (e.g., thermal stability, storage stability, solution stability, plasma stability, lysosomal stability, liver stability, etc.). In some embodiments, the compounds described herein have high metabolic stability. In some embodiments, the compounds described herein have low efflux. Preparation of Compounds

[0097] The compounds used in the reactions described herein are prepared using commercially available chemicals and / or compounds described in chemical literature as starting materials, according to organic synthesis techniques. "Commercially available chemicals" are sourced from standard commercial sources, including Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, IL), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Combi-blocks (San Diego, CA), Crescent Chemical Co. (Hauppauge, NY), eMolecules (San Diego, CA), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Matrix Scientific, (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc.(Mount Pleasant, SC), Spectrum Chemicals (Gardena, CA), Sundia Meditech, (Shanghai, China), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and WuXi (Shanghai, China).

[0098] Suitable references and papers detailing the synthesis of reactants applicable to the preparation of the compounds described herein or referring to articles describing such preparations include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations", 2nd ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions", 2nd ed., WA Benjamin, Inc., Menlo Park, Calif. 1972; TL Gilchrist, "Heterocyclic Chemistry", 2nd ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., Wiley-Interscience, New York, 1992. Other suitable references and papers that detail the synthesis of reactants applicable to the preparation of the compounds described herein or refer to articles describing such preparations include, for example, Fuhrhop, J. and Penzlin G., "Organic Synthesis: Concepts, Methods, Starting Materials", Second Revised and Expanded Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV., "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC., "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4th Edition (1992), John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (Editor), "Modern Carbonyl Chemistry" (2000), Wiley-VCH, ISBN: 3-527-29871-1; Patai, S., "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992), Interscience, ISBN: 0-471-93022-9; Solomons, T. W. G., "Organic Chemistry", 7th Edition (2000), John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry", 2nd Edition (1993), Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999), John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942 - 2000), John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups", John Wiley & Sons, 73 volumes.

[0099] Specific and similar reactants were also identified using an index of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, which is available in most public and university libraries as well as through online databases (the American Chemical Society, Washington, DC). Known but not listed in the commercial catalogues were prepared, as appropriate, by conventional chemical synthesis facilities, many of which provide conventional synthesis services (such as those listed above). References regarding the preparation and selection of pharmaceutical salts of the compounds described herein are PH Stahl and CG Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0100] In some embodiments, the following synthesis method may be used. General Process I

[0101] The synthesis of compounds containing amide-substituted aryl groups (such as those described in formula (Ia)) can be performed according to general procedure I. Generally, a suitable aryl halide (e.g., an aryl bromide) is subjected to conditions sufficient to couple with the functionalized amino acid indicated in step (a). This can be achieved by means known to those skilled in the art, including (but not limited to) root-bank coupling. In some embodiments, the reagent suitable for step (a) includes Zn, I2, Pd2(dba)3, and S-Phos in a suitable solvent (e.g., DMF) and at a certain temperature (e.g., about 80°C). Subsequently, the methyl ester can be reduced to The alcohol, and nitrile, are hydrolyzed (preferably in that order), as indicated in step (b). Reduction can be carried out using various hydride reagents, including, for example, LiBH4. Hydrolysis can be carried out using suitable bases and aqueous solvents (e.g., NaOH and H2O). In step (c) of General Process I, the alcohol functional group can be substituted with a suitable nucleophile (e.g., phthalimide) under various conditions. In some cases, these conditions include photoelectrophoresis conditions (e.g., PPh3 and DIAD in THF at 0 to room temperature). This conversion can be achieved using a variety of suitable reagents, solvents, and temperatures known to those skilled in the art. In step (d), for example, 4N... The Boc group on nitrogen is removed under acidic conditions using HCl dialkyl. Following Boc deprotection, the amine can be further functionalized to introduce R5 and R6 substituents. In some embodiments, formaldehyde, acetic acid, and sodium cyanoborohydride are used to functionalize the nitrogen. In other embodiments, the nitrogen is functionalized using a dibromide (e.g., Br-(CH2)n-Br, where n is an integer between 2 and 10, preferably 4 or 5 and the nitrogen forms pyrrolidine or piperidine). Such dibromide functionalization is typically carried out with a suitable base (e.g., potassium carbonate) and a suitable solvent system (e.g., DMF). In some embodiments, the phthalimide group can be removed using a hydrazine reagent (e.g., N2H4) in a suitable solution (e.g., H2O), diluted as needed in another solvent (e.g., EtOH). General Process II

[0102] In addition to General Process I, compounds of formula (Ia) can also be synthesized using, as appropriate, substituted benzoic acid as outlined in General Process II. In step (a) of General Process II, bromobenzoic acid can be converted to a amide (e.g., a primary amide) by reaction with a suitable amine, NHR10R11, or its cation (e.g., NH4OH, NH2CH3, NH(CH3)2, and the like). In some embodiments, such conversion is preceded by an activation step, wherein the acid forms an activated ester upon coupling with a suitable coupling agent (e.g., CDI). Other coupling agents (e.g., peptide coupling agents) are commercially available and can be exchanged to optimize yield or kinetics. As is known to those skilled in the art, alternative amines can also be used in step (a). In some embodiments, the amide coupling in step (a) may also include the use of a base (e.g., triethylamine and the like) in a suitable solvent (e.g., dichloromethane). Steps (b)-(f) of General Process II can be performed using methods similar to those previously described in General Process I or other suitable methods known to those skilled in the art. The steps described herein can be implemented to produce primary, secondary, or tertiary amides, depending on the amine used in step (a). Alternatively, the primary amide may be further substituted at a later stage. General Process III

[0103] Compounds of formula (Ib) can be prepared using a method similar to that described above, using suitable phenolic starting materials. For example, root-bank coupling conditions (e.g., Zn, I2, Pd2(dba)3, and S-Phos in DMF at 80°C) can be used in step (a) to introduce the modified amino acid as previously described. In some cases, it is advantageous or necessary to protect the phenol to prevent side reactions. In some embodiments, step (b) includes protecting the phenol (e.g., with TBSCl and imidazole) before ester reduction to prevent undesirable coupling with various alcohols. In some embodiments, the TBS protecting group is removed after the photoelectrophoresis in step (c). In other embodiments of General Process III (not shown), the phenolic alcohol can be functionalized with other substituents. In some embodiments, the phenol is unsubstituted and the -OH group participates in the relevant acceptor-ligand interactions. General Process IV

[0104] In the preparation of compound (Ic), steps such as those described in General Process IV can be performed to obtain the desired chemical skeleton and substituents. For example, in the preparation of compound (Ic), the substituted aniline may be functionalized (e.g., cyclized) in an initial step. Such cyclization conditions may include t-Bu nitrile and acetic anhydride in combination with a suitable base (e.g., potassium acetate). Step (a) may additionally include the use of a crown ether (e.g., 18-C-6). In some embodiments, step (a) further includes the use of a base or hydride reagent (e.g., NaH) and a sulfonyl chloride (e.g., toluenesulfonyl chloride) in a suitable solvent (e.g., DMF), which produces toluenesulfonyl chloride as shown in General Process IV. The starting material may be further substituted with an additional R7 group. After cyclizing the indazole as described in step (a), the compound (Ic) may be prepared according to steps similar to those described herein. General Process V

[0105] In the preparation of the compound of formula (Id), the nitrophenol, such as that indicated in General Process V, may be functionalized using reagents and conditions known to those skilled in the art. In some embodiments, prior to root-bank coupling, the phenolic moiety of the nitrophenol starting agent is first protected (e.g., with TBSCl), the root-bank coupling occurring in step (b) of General Process V (as described herein). Subsequent steps (c) through (e) are as described herein, having appropriate modifications as understood by those skilled in the art. After nitro reduction, the resulting amine is treated with 2-chloroacetyl chloride, followed by deprotection as previously described. General Process VI or

[0106] In some embodiments, the compounds of the present invention have an antipodal center at the position corresponding to R3 of formula (I). In some embodiments, antipodality is established by using an antipodal azolidinone commonly known as an Evans auxiliary. In some embodiments, antipodality is known and specified. In other embodiments, antipodality is known as a monoisomer, but the exact (R) or (S) stereochemical specification is unknown. In some embodiments, the compounds disclosed herein are monodiameric or enantiomers. As outlined in General Procedure VI, aldehydes can be converted to α-β-unsaturated carbonyl compounds as described in step (a). In some embodiments, step (a) comprises a Horner-Wadsworth-Emmons or Wittig-type reaction. For example, in some cases, step (a) includes treatment with a phosphonoacetate (e.g., trimethyl phosphonoacetate) and a suitable base (e.g., sodium hydride) in a suitable solvent (e.g., THF). The α-β-unsaturated ester of General Process VI may be hydrolyzed to the corresponding carboxylic acid (e.g., using THF / H2O containing LiOH), and subsequently coupled with a synergistic agent using appropriate amide coupling conditions. (R) or (S) the synergistic agent may be used according to General Process VI. Suitable amide coupling conditions for step (b) may include the use of coupling agents (e.g., DIC and DMAP) in a suitable solvent (e.g., dichloromethane). The α-β-unsaturated amide may then be alkylated using any suitable alkylation conditions, including conjugate addition (e.g., via Grinner or magnesium bromide reagents). In some embodiments, the alkylation reaction also includes the use of copper halide (I) (e.g., CuI). In some embodiments, the alkylation reaction further includes dimethyl sulfide. Such reactions can be carried out at low temperatures (e.g., -40°C) and in suitable solvents (e.g., THF). In step (d) of General Process VI, the antagonistic auxiliary is cleaved under conditions that produce a terminal carboxylic acid (e.g., THF containing LiOH / H2O2). General Process VII

[0107] In some embodiments, the chamomile of R3 is established using a suitable carboxylic acid as a starting material, as shown in General Procedure VII. In some embodiments, chamomile is known and specified. In other embodiments, chamomile is known as a monomeric isomer, but the exact (R) or (S) stereochemical specification is unknown. In some embodiments, the compound disclosed herein is a monomeric diastereomer or an enantiomer. In some embodiments, the carboxylic acid (e.g., via CDI) is activated to form an activated ester to promote amide coupling. Such activation reactions are carried out in a suitable solvent system (e.g., dichloromethane). Subsequently, the activated acid can be converted to Weinreb amide, as shown in step (a) of General Procedure VII. Step (b) involves alkylating Weinreb amide with the R3 group. In some embodiments, R3 is added via an organolithium or organomagnesium substance. Step (c) of General Procedure VII includes an addition reaction to a ketone, such as the Horner-Watsworth-Emmons or Witt-type reaction as previously described. In some embodiments, the reaction is facilitated by the use of trimethylphosphonic acetate. In some embodiments, a suitable base (e.g., NaH or KHMDS) is also used. In some embodiments, the reaction further comprises the use of a crown ether (e.g., 18-C-6). The configuration of the double bond (e.g., E or Z and subsequent stereochemical orientation) can be controlled using techniques known to those skilled in the art. Step (d) provides the stereochemistry indicated in formula (I) by using an anticlinal ligand (e.g., R-DTBM-SEGPHOS or S-DTBM-SEGPHOS). Referring to general procedure VII, in rows (i) and (iii), reagent R-DTBM SEGPHOS is used, and in rows (ii) and (iv), S-DTBM SEGPHOS is used, to produce the specific enantiomers shown above. In some embodiments, step (d) further comprises the use of a copper substance (e.g., Cu(OAc)2). In some embodiments, step (d) further comprises DMMS, tert-BuOH, and / or toluene. In some embodiments, the olefin produced in step (c) of General Process VII is reduced with hydrogen (H2) via a catalyst (e.g., Pd / C) in a suitable solvent (e.g., EtOH). In some embodiments, the resulting ester is a mixture of R and S isomers. In some embodiments, the mixture of isomers is not resolved. In some embodiments, the mixture of isomers is resolved by diametric chromatography in a subsequent step. The final step of General Process VII, step (e), involves ester cleavage to obtain a specified carboxylic acid. In some embodiments, the ester is cleaved under basic conditions (e.g., with LiOH) in a suitable solvent or solvent system (e.g., MeOH / THF / H2O).

[0108] The amines and acids disclosed herein can be combined in any combination to produce a wide range of compounds belonging to the class of formula (I). The methods described herein are merely examples. Other methods may be used to provide other compounds disclosed herein. Other isomers of the compounds disclosed herein.

[0109] Furthermore, in some embodiments, the compounds described herein are present in geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, isolateral, trans-lateral, engegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some cases, the compounds are present in tautomer forms. The compounds described herein include all possible tautomers within the chemical formulas described herein. In some cases, the compounds described herein have one or more palmar centers, each center being present in an R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms and their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or interconversion are suitable for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by palmar chromatography resolution of racemic mixtures. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form diastereomeric compound pairs, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated using these differences. In some embodiments, the diastereomers are separated by palmar chromatography or preferably by separation / resolving techniques based on solubility differences. In some embodiments, the optically pure enantiomers are then recovered along with the resolving agent by any practical means that do not cause racemization. Labeled Compounds

[0110] In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds in the form of a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to the compounds listed herein, except that one or more atoms have undergone atomic substitutions with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein containing other atoms of the aforementioned isotopes and / or other isotopes, and their pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives, are within the scope of this invention. Certain isotopically labeled compounds, such as those containing radioactive isotopes such as 3H and 14C, are suitable for pharmaceutical and / or recipient tissue distribution analysis. Tritium (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, substitution with heavy isotopes such as deuterium (i.e., 2H) produces certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirement. In some embodiments, the isotopically labeled compounds, their pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives, are prepared by any suitable method.

[0111] In some embodiments, the compounds described herein are labeled in other ways, including but not limited to the use of chromophores or fluorescent portions, bioluminescent labeling, or chemiluminescent labeling. Pharmaceutically acceptable salts

[0112] In some embodiments, the compounds described herein are present in their pharmaceutically acceptable salt form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0113] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, such salts are prepared in situ during the final separation and purification of the compounds described herein, or by reacting the purified compound in its free form with a suitable acid or base alone and separating the resulting salt. Solvents

[0114] In some embodiments, the compounds described herein are present in the form of solvates. In some embodiments, methods of treating diseases are described by administering such solvates. Methods of treating diseases by administering such solvates in the form of pharmaceutical compositions are further described herein.

[0115] Solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during crystallization with a pharmaceutically acceptable solvent such as water, ethanol, and the like. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholic compound is formed. Solvates of the compounds described herein are preferably prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are preferably prepared by recrystallization from an aqueous / organic solvent mixture using an organic solvent, including but not limited to dialkyl, tetrahydrofuran, or MeOH. Furthermore, the compounds provided herein exist in both non-solvated and solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form. Pharmaceutical Compositions

[0116] In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) as described herein are administered in the form of pure chemicals. In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) as described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected based on the chosen route of administration and standard pharmaceutical practice, such as as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition. Mack Pub. Co., Easton, PA (2005)).

[0117] Therefore, this document provides a pharmaceutical composition comprising at least one compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide, and one or more pharmaceutically acceptable carriers. A carrier is acceptable or suitable if it is compatible with the other components of the composition and is harmless to the recipient (i.e., the individual) of the composition.

[0118] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (Id) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (Ie) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (If) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (Ih) or a pharmaceutically acceptable salt or solvate thereof.

[0119] Another embodiment provides a pharmaceutical composition substantially composed of a pharmaceutically acceptable excipient and a compound of formula (I) or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition substantially composed of a pharmaceutically acceptable excipient and a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition substantially composed of a pharmaceutically acceptable excipient and a compound of formula (Ib) or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition substantially composed of a pharmaceutically acceptable excipient and a compound of formula (Ic) or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition substantially composed of a pharmaceutically acceptable excipient and a compound of formula (Id) or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition substantially composed of a pharmaceutically acceptable excipient and a compound of formula (Ie) or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition substantially composed of a pharmaceutically acceptable excipient and a compound of formula (If) or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition substantially composed of a pharmaceutically acceptable excipient and a compound of formula (Ig) or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition substantially composed of a pharmaceutically acceptable excipient and a compound of formula (Ih) or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) as described herein are substantially pure because they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as contaminating intermediates or byproducts generated in one or more steps of the synthetic method.

[0121] In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein are formulated for oral, rectal, topical, buccal, non-intestinal (e.g., subcutaneous, intramuscular, intradermal, or intravenous), vaginal, ocular, or aerosol administration, but the most suitable form of administration in any given case will depend on the extent and severity of the condition being treated and the nature of the particular compound used. For example, the disclosed compositions are formulated as unit doses and / or formulated for oral or subcutaneous administration.

[0122] Exemplary pharmaceutical compositions are used in pharmaceutical formulations, such as in solid, semi-solid, or liquid form, comprising one or more of the disclosed compounds as active ingredients, in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral, or non-enterogonal administration. In some embodiments, the active ingredient is, for example, formulated with a commonly used, non-toxic, pharmaceutically acceptable carrier for use in tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable form. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or symptoms of a disease.

[0123] In some embodiments, for the preparation of solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier and other pharmaceutical diluents (e.g., water) to form a solid preformed composition containing a homogeneous mixture of the disclosed compound or a non-toxic, pharmaceutically acceptable salt thereof. The pharmaceutical carrier may be, for example, a known tablet-making ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum. When it is mentioned that such preformed compositions are homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, making the composition easily reclassified into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0124] In the oral administration of solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules and the like), the compositions of the present invention are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol and / or silica; (2) binders, such as carboxymethyl cellulose, hydroxyl group monophosphate ... The composition comprises: (1) cellulose methyl ester, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (2) humectants, such as glycerol; (3) disintegrants, such as crospovidone, sodium crospovidone carboxymethyl cellulose, sodium glycolate starch, agar-agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; (4) dissolution inhibitors, such as paraffin; (5) absorption promoters, such as quaternary ammonium compounds; (6) humectants, such as docusate sodium, cetyl alcohol, and glycerol monostearate; (7) absorbents, such as kaolin and bentonite; (8) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (9) colorants. In the case of capsules, tablets, and pills, in some embodiments, the composition includes a buffer. In some embodiments, similar solid compositions are also used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or tartrate and high molecular weight polyethylene glycol and the like.

[0125] In some embodiments, the tablets are prepared by compression or molding, as appropriate, together with one or more adjunct ingredients. In some embodiments, compressed tablets are prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. In some embodiments, molded tablets are prepared by molding a mixture of the compositions of the present invention moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets and other solid dosage forms such as sugar-coated pills, capsules, pellets, and granules are prepared by coating and shelling with coatings such as enteric coatings and other coatings.

[0126] Compositions for inhalation or insufflation include solutions, suspensions, and powders in pharmaceutically acceptable aqueous solutions or organic solvents or mixtures thereof. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the compositions of the present invention, in some embodiments, the liquid dosage form contains an inert diluent, such as water or other solvents; a solubilizer and emulsifier, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol; oils (where applicable, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil); glycerin; tetrahydrofuranol; fatty acid esters of polyethylene glycol and sorbitol; cyclodextrins and mixtures thereof.

[0127] In some embodiments, in addition to the composition of the present invention, the suspension may also contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar, tragali and mixtures thereof.

[0128] In some embodiments, the preparation for transrectal or transvaginal administration may be presented in suppository form, which is prepared by mixing the composition of the present invention with one or more suitable non-irritating excipients or carriers, such excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, which are solid at room temperature but liquid at body temperature, and thus will melt in the body cavity and release the active agent.

[0129] Dosage forms for transdermal administration of the compositions of the present invention include powders, sprays, ointments, pastes, creams, emulsions, gels, solutions, patches, and inhalers. In some embodiments, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0130] In some embodiments, in addition to the compositions of the present invention, ointments, pastes, creams and gels also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragali, cellulose derivatives, polyethylene glycol, polysiloxane, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0131] In some embodiments, in addition to the compositions of the present invention, the powders and sprays also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder or mixtures thereof. In some embodiments, the sprays further contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0132] In some embodiments, the compounds described herein are formulated as ophthalmic drops.

[0133] Alternatively, the compositions and compounds disclosed herein are administered via aerosols. This is achieved by preparing aqueous aerosols, liposome formulations, or solid particles containing the compounds. In some embodiments, non-aqueous (e.g., fluorocarbon propellants) suspensions are used. In some embodiments, sonic atomizers are used because they minimize the reagent's exposure to shear, which can lead to degradation of the compounds contained in the compositions of the present invention. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the compositions of the present invention with a known pharmaceutically acceptable carrier and stabilizer. The carrier and stabilizer vary depending on the specific requirements of the compositions of the present invention, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol); sorbitol esters; oleic acid; lecithin; amino acids, such as glycine; buffers; salts; sugars or sugar alcohols. Aerosols are typically prepared from isotonic solutions.

[0134] Pharmaceutical compositions applicable to non-enteral administration include the compositions of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use. In some embodiments, they contain antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0135] Examples of suitable aqueous and non-aqueous carriers for use in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate) and cyclodextrins. For example, by using a coating material such as lecithin, the desired particle size can be maintained in the case of a dispersion, and by using a surfactant, appropriate flowability can be maintained.

[0136] Also encompasses enteric pharmaceutical preparations, including the disclosed compounds and enteric-coated materials; and their pharmaceutically acceptable carriers or excipients. Enteric-coated materials refer to polymers that are substantially insoluble in the acidic environment of the stomach and are primarily soluble in intestinal fluid at a specific pH. The small intestine is part of the gastrointestinal tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the distal ileum is approximately 7.5. Therefore, enteric materials are soluble only at the following pH values, such as about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Examples of enteric-coated materials include cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); hydroxypropyl methylcellulose acetate succinate (HPMCAS); cellulose acetate benzotriacyl acetate; hydroxypropyl methylcellulose succinate; cellulose acetate succinate; cellulose hexahydrophthalic acid cellulose; cellulose propionate phthalate; cellulose maleate cellulose; cellulose butyrate cellulose; cellulose propionate cellulose; copolymers of methyl methacrylate and methyl methacrylate; copolymers of methyl acrylate, methyl methacrylate, and methacrylate; copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series); copolymers of ethyl methacrylate-methyl methacrylate-trimethylammonium chloride acrylate; and natural resins such as corn gluten, shellac, and copal rosin. (collophorium); and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is known or readily measurable in vitro.

[0137] The dosage of a composition comprising at least one compound of formula (I) as described herein varies depending on the patient’s condition (i.e., stage of disease, general health, age and other factors).

[0138] The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dose, duration, and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, an appropriate dose and treatment regimen provide an amount of the composition sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free survival and / or overall survival, or reduced symptom severity). Optimal doses are generally determined using experimental models and / or clinical trials. In some embodiments, the optimal dose is determined based on the patient's body mass, weight, or blood volume. Method

[0139] In another embodiment, this document describes a method of using, for example, a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, or a pharmaceutically acceptable salt thereof, in a method of treating a disease or condition. In some embodiments, this is a method of treating a disease or condition in a patient in need, selected from neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcoholism, gambling addiction, pain, opioid overdose, opioid use disorder, and addiction, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, this is a method of treating a neuropsychiatric disorder in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, this is a method of treating depression in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, this is a method of treating obsessive-compulsive disorder in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, this is a method of treating alcohol addiction in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, or a medically acceptable salt thereof. In some embodiments, this is a method of treating gambling addiction in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, or a medically acceptable salt thereof. In some embodiments, this is a method of treating pain in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, or a medically acceptable salt thereof.In some embodiments, this is a method for treating opioid overdose in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, this is a method for treating opioid use disorder in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, this is a method for treating addiction in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) described herein, or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, the disclosed compound used by one or more of the foregoing methods is one of the general, subgenus or specific compounds described herein, such as compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih).

[0141] The disclosed compounds are administered to patients (animals and humans) requiring this treatment at a dose that provides optimal efficacy. It should be understood that the dose required for any particular application varies from patient to patient, depending not only on the specific compound or composition chosen, but also on the route of administration, the nature of the condition to be treated, the patient's age and condition, concurrent medications, the patient's subsequent diet, and other factors. The appropriate dose is ultimately determined by the attending physician. The compounds disclosed herein are administered orally, subcutaneously, topically, non-enterally, by inhalation spray, or rectally in the form of dosage units containing known, non-toxic, and pharmaceutically acceptable carriers, adjuvants, and mediators for the treatment of the clinical conditions and diseases mentioned above. Non-enteral administration includes subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0142] The following examples are provided merely to illustrate various embodiments and should not be construed as limiting the invention in any way. Example Chemical Synthesis

[0143] Unless otherwise specified, reagents and solvents were used as is from the commercial supplier. For synthetic transformations sensitive to moisture and / or oxygen, anhydrous solvents and dried glassware were used. Yields were not optimized. Reaction times were approximate and not optimized. Unless otherwise specified, column chromatography and thin-layer chromatography (TLC) were performed on silicone. Spectra are given in ppm (δ) and coupling constant J is reported in Hertz. For proton spectra, the solvent peak was used as a reference peak. Synthetic Example A: Intermediate

[0144] Example A1: Preparation of (S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluorobenzoamide (1G, "Intermediate 1"):

[0145] Preparation of methyl (S)-2-((tributoxycarbonyl)amino)-3-(4-cyano-3-fluorophenyl)propionate (1B): Zinc (2.29 g, 35 mmol) and anhydrous DMF (4 mL) were added to 100 mL of dried RBF. A solution of iodine (159 mg, 1.25 mmol) in DMF (0.5 mL) was added to the reaction mixture. The reaction mixture was stirred for 10 min, and then a solution of methyl (2R)-2-{[(tributoxy)carbonyl]amino}-3-iodopropionate (3.95 g, 12 mmol) in DMF (10 mL) and a solution of iodine (159 mg, 1.25 mmol) in DMF (0.5 mL) were added, which resulted in exothermic reaction. The reaction mixture was stirred and cooled to room temperature for 20 minutes, and 4-bromo-2-fluorobenzonitrile (2.00 g, 10 mmol), Pd2(dba)3 (458 mg, 0.50 mmol), and SPhos (411 mg, 1 mmol) were added to the reaction mixture. The reaction mixture was stirred at 70 °C for 16 h. The crude reaction mixture was cooled to room temperature, quenched with water, diluted with EtOAc, and filtered through diatomaceous earth. The organic layer was then washed with brine (5×), dried over MgSO4, and concentrated. The resulting residue was adsorbed onto silica and purified by column chromatography (100 g silica, 0-30% EtOAc / hex) to give the title compound (2.75 g, 85%) as a white solid. MS (m / z) = 345.1 [M+H].

[0146] Preparation of (S)-(1-(4-cyano-3-fluorophenyl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (1C): Methyl (2S)-2-{[(tributyloxy)carbonyl]amino}-3-(4-cyano-3-fluorophenyl)propionate (2.75 g, 8.53 mmol) and THF (30 mL) were added to a 250 mL round-bottom flask. The reaction mixture was cooled to 0 °C, and a solution of lithium borohydride (4 M in THF, 5.0 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min, and then heated to room temperature for 16 h. The reaction mixture was then cooled to 0 °C and quenched by adding water dropwise. The crude reaction mixture was diluted with brine, and the (3×) product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated. The residue was purified by column chromatography (80 g silicon dioxide, 10-70% EtOAc / hex) to give the title compound (1.77 g, 60%) as a white solid. MS (m / z) = 317.1 [M+Na].

[0147] Preparation of (S)-(1-(4-aminomethoxy-3-fluorophenyl)-3-hydroxypropyl-2-yl)tributyl aminocarboxylate (1D): N-[(2S)-1-(4-cyano-3-fluorophenyl)-3-hydroxypropyl-2-yl]tributyl aminocarboxylate (1.45 g, 4.93 mL), MeOH (30 mL), 10 M NaOH aqueous solution (1.45 mL), and 27% H2O2 aqueous solution (4.8 mL) were added to a 250 mL round-bottom flask. The reaction mixture was stirred at 50 °C for 1 h, followed by the addition of another 10 M NaOH aqueous solution (0.64 mL) and 27% H2O2 aqueous solution (1.9 mL). The crude reaction mixture was neutralized with saturated NH4Cl (aqueous solution), and the MeOH was removed under reduced pressure. The product was extracted with EtOAc (3×), and the combined organic layers were washed with brine, dried over MgSO4, and then concentrated. The product was further dried by toluene azeotrope to give the title compound (1.35 g, 88%) as a white solid.

[0148] Preparation of (S)-(1-(4-aminomethoxy-3-fluorophenyl)-3-(1,3-di-dioxyisoindoline-2-yl)propyl-2-yl)aminocarboxylic acid tributyl ester (1E): N-[(2S)-1-(4-aminomethoxy-3-fluorophenyl)-3-hydroxypropyl-2-yl]aminocarboxylic acid tributyl ester (1.35 g, 4.32 mmol), triphenylphosphine (1.25 g, 4.75 mmol), phthalimide (0.70 g, 4.75 mmol), and anhydrous THF (30 mL) were added to a 250 mL round-bottom flask. The reaction mixture was cooled to 0 °C, and DIAD (0.94 mL, 4.75 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h, followed by stirring at room temperature for 16 h. This resulted in the formation of a white precipitate. The precipitate was filtered, washed with THF and dried to give the title compound (2.03 g, 106%) as a white solid. MS (m / z) = 442.1 [M+H].

[0149] Preparation of (S)-4-(2-(dimethylamino)-3-(1,3-di-dioxyisoindoline-2-yl)propyl)-2-fluorobenzamide (1F): Step 1: Add N-[(2S)-1-(4-aminomethoxy-3-fluorophenyl)-3-(1,3-di-dioxy-2,3-dihydro-1H-isoindoline-2-yl)propyl-2-yl]aminoformate tributyl ester (2.03 g, 4.6 mmol), MeOH (25 mL), and formic acid (50 mL) to a 250 mL round-bottom flask. Stir the reaction mixture at 500 °C for 1 h. Concentrate the reaction mixture, and use the resulting residue directly in the next step. MS (m / z) = 342.1 [M+H]. Step 2: The crude reaction mixture was dissolved in MeCN / H2O (5:1, 22 mL), followed by the addition of 37 wt% formaldehyde aqueous solution (1.03 mL, 13.8 mmol). The reaction mixture was stirred for 30 minutes, then NaB(CN)H3 (1.03 g, 16.1 mmol) was added to the reaction mixture in one go, and stirring was continued for another 30 minutes. The reaction mixture was cooled to 0°C and quenched with saturated sodium bicarbonate aqueous solution (approximately 50 mL). The product was extracted with EtOAc (7×), and the combined organic layers were dried over MgSO4 and then concentrated. The resulting residue was used in the next step without further purification. MS (m / z) = 370.1 [M+H].

[0150] Preparation of (S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluorobenzamide (1G): Anhydrous EtOH (50 mL) and 80 wt% aqueous hydrazine hydrate (1.40 mL, 23 mmol) were added to the crude product of (S)-4-(2-(dimethylamino)-3-(1,3-di-dioxyisoindoline-2-yl)propyl)-2-fluorobenzamide (1F). The reaction mixture was stirred at 75 °C for 3 h. The crude reaction mixture was then concentrated, adsorbed onto silica, and subsequently purified by column chromatography (40 g silica, 0-20% MeOH / DCM + 1% NH4OH) to give the title compound (0.46 g, 42%) as a white solid. MS (m / z): 240.2 [M+H].

[0151] Example A2: Preparation of (S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluorobenzoamide (2H, "Intermediate 2"):

[0152] Preparation of 4-bromo-2-fluorobenzoic acid (2B): 4-bromo-2-fluorobenzoic acid (44 g, 200 mmol) was dissolved in dichloromethane (500 ml), and carbonyl diimidazole (65 g, 200 mmol) was added in small amounts over 15 minutes. The suspension became a viscous solid and then gradually clarified over 45 minutes. Ammonium hydroxide solution (150 ml) was then added very slowly over 15 minutes. The two phases were then stirred for 14 hours. The two layers were separated, and the organic layer was washed with 2 N HCl solution, followed by washing with water. The organic layer was then filtered through magnesium sulfate, and the filtrate was concentrated to give a product as a white powder (40.9 g, 94%). MS (m / z): 218, 220 [M+H].

[0153] Preparation of (S)-2-((tributoxycarbonyl)amino)-3-(4-aminomethoxy-3-fluorophenyl)propionate (2C): Particulate zinc (37 g, 560 mmol, 20 mesh) was dissolved in DMF (190 ml) under nitrogen atmosphere, and iodine (1.2 g, 9.4 mmol) was added. The suspension was stirred for 15 min, during which time the initial brown color dissipated. Then, (2R)-2-{[(tributoxy)carbonyl]amino}-3-iodopropionate methyl ester (93 g, 281 mmol) and iodine (1.2 g, 9.4 mmol) were added. The suspension turned brown and subsequently darkened with increasing temperature. When the temperature returned to room temperature and the color disappeared, it was stirred for 1 hour. In separate flasks, 4-bromo-2-fluorobenzamide (40.9 g, 188 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (8.0 g, 11.3 mmol) were dissolved together in 1,4-dimethylbenzane (190 ml). The solution of "N-Boc-β-Zn-Ala-OMe" generated in the first flask was transferred to the second flask via a sleeve, and the solution was bubbled with nitrogen for 15 min. The solution was then heated at 100 °C for 18 h. TLC and LCMS indicated that the reaction was complete. The solution was cooled to room temperature, and then a saturated solution of ammonium hydroxide (6 × 60 ml) was added. This resulted in a white solid precipitate. Water (3 × 60 ml) was added, and the suspension was stirred for 30 min. The solid was then collected by filtration and washed with hexane to give a product as a grayish-white powder (47.1 g, 74%). MS (m / z): 363 [M+Na].

[0154] Preparation of (S)-(1-(4-aminomethoxy-3-fluorophenyl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (2D): Methyl (2S)-2-{[(tributyloxy)carbonyl]amino}-3-(4-aminomethoxy-3-fluorophenyl)propionate (47.1 g, 138 mmol) was dissolved in THF (500 ml) under nitrogen atmosphere and cooled in an ice bath. A solution of lithium borohydride (70 ml, 4 M in THF, 280 mmol) was then added dropwise over 20 minutes. After 30 minutes, the ice bath was removed and the solution was stirred overnight at room temperature. TLC and LCMS indicated the reaction was complete. The flask was cooled in an ice bath and the reactants were quenched by slow addition of a saturated ammonium chloride solution. The reaction mixture was filtered to remove the black insoluble substance. The solution was extracted into ethyl acetate (4 × 150 mL). The organic layer was dried with magnesium sulfate, and the filtrate was concentrated. The product was then dried under high vacuum to obtain a light brown powder (41.9 g, 97%). MS (m / z): 335 [M+Na].

[0155] Preparation of (S)-(1-(1,3-di-di-oxyisoindoline-2-yl)-3-(3-fluoro-4-((di-oxy-13-methyl)-14-azalkyl)phenyl)prop-2-yl)aminocarboxylate (2E): N-[(2S)-1-(4-aminomethoxy-3-fluorophenyl)-3-hydroxyprop-2-yl]aminocarboxylate (41.9 g, 134 mmol) was dissolved together with phthalimide (23.7 g, 161 mmol) and triphenylphosphine (42.2 g, 161 mmol) in THF (700 ml). The solution was cooled in an ice bath and then diisopropyl azodicarbonate (31.7 ml, 161 mmol) was added dropwise. The ice bath was removed and the solution was stirred for 24 hours. The product was diluted with MTBE (500 ml) and the precipitated solid was collected by filtration. The solid was washed with a 1:1 mixture of MTBE and ethyl acetate to give a white solid product (41.1 g, 70%). MS (m / z): 464 [M+Na].

[0156] Preparation of (S)-4-(2-amino-3-(1,3-di-dioxyisoindoline-2-yl)propyl)-2-fluorobenzoamide formic acid (2F): N-[(2S)-1-(4-aminomethoxy-3-fluorophenyl)-3-(1,3-di-dioxy-2,3-dihydro-1H-isoindoline-2-yl)propyl-2-yl]aminoformate tributyl ester (41.1 g, 93 mmol) was dissolved in 1,4-dimethylethane (500 ml), and formic acid (200 ml) was added to the solution. The solution was stirred for 18 hours. Acetonitrile (500 ml) was slowly added, and the precipitated solid was collected by filtration to give a product as a white powder (28.1 g, 78%). MS (m / z): 342 [M+H].

[0157] Preparation of (S)-4-(2-(dimethylamino)-3-(1,3-dioxyisoindolin-2-yl)propyl)-2-fluorobenzamide (2G): Formic acid 4-[(2S)-2-amino-3-(1,3-dioxy-2,3-dihydro-1H-isoindolin-2-yl)propyl]-2-fluorobenzamide (28.1, 72.7 mmol) was dissolved in acetonitrile / water (50 ml / 10 ml). Formaldehyde aqueous solution (6.0 ml, 37% solution, 218 mmol) was then added and the solution was stirred at room temperature for 1 hour. Next, sodium triacetoxyborohydride (61 g, 291 mmol) was added, which caused foaming. The solution was stirred for another 45 minutes. LCMS indicated the reaction was complete. The solution was quenched by slow addition of sodium bicarbonate solution, followed by extraction into ethyl acetate (3 times). The combined organic layers were filtered through magnesium sulfate and the filtrate was concentrated to give the product (23.6 g, 88%). MS (m / z): 370.2 [M+H].

[0158] Preparation of (S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluorobenzamide (2H): 4-[(2S)-2-(dimethylamino)-3-(1,3-dioxy-2,3-dihydro-1H-isoindol-2-yl)propyl]-2-fluorobenzamide (23.6 g, 64 mmol) was dissolved in ethanol (500 ml), and hydrazine hydrate solution (11.7 ml, 35% solution, 128 mmol) was added. The solution was heated under reflux for 3 hours. The reaction was indicated by LCMS. The solution was diluted with ethyl acetate and the precipitated solid was removed by filtration. The filtrate was concentrated and the residue was purified on a Combiflash using a dichloromethane / methanol / ammonium hydroxide gradient to give the product (13.6 g, 89%). MS (m / z): 240.2 [M+H].

[0159] The following intermediates are synthesized using a method similar to that described in Example A2: Int. 2 and General Process II: Intermediate item (Int.) number structure LC / MS (m / z) name Int. 13 274.1 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-3-chloro-2-fluorobenzoamide Int. 16 256.3 (M+H) 4-[(2S)-3-amino-2-(dimethylamino)propyl]-3-chlorobenzamide Int. 17 270.0 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-3-chloro-N-methylbenzamide Int. 30 254.1 (M+H) 4-[(2S)-3-amino-2-(dimethylamino)propyl]-2-fluoro-3-methylbenzamide Int. 31 271.9 (M+H) 4-[(2S)-3-amino-2-(dimethylamino)propyl]-2,6-difluoro-3-methylbenzamide Int. 32 286.1 (M+H) 4-[(2S)-3-amino-2-(dimethylamino)propyl]-2,6-difluoro-3,5-dimethylbenzamide Int. 33 4-[(2S)-3-amino-2-(dimethylamino)propyl]-2-fluoro-3,5-dimethylbenzamide Int. 35 258.1 (M+H) 4-[(2S)-3-amino-2-(dimethylamino)propyl]-2,6-difluorobenzoamide Int. 41 258.1 (M+H) 4-[(2S)-3-amino-2-(dimethylamino)propyl]-2,3-difluorobenzoamide Int. 53 298.2 (M+H) 4-[(2S)-3-amino-2-[benzyl(methyl)amino]propyl]benzamide Int. 73 222.2 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)benzamide Int. 74 250.2 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-3,5-dimethylbenzamide Int. 94 194.1 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-2,5-difluoro-N-methylbenzamide Int. 95 272.1 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-3,5-difluoro-N-methylbenzamide Int. 96 264.2 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-N,3,5-trimethylbenzamide Int. 97 254.2 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide Int. 99 288.2 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide Int. 102 270.3 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-3-chloro-N-methylbenzamide Int. 110 254.3 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-3-fluoro-N-methylbenzamide Int. 111 268.3 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N,3-dimethylbenzamide Int. 112 250.2 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-N,3-dimethylbenzamide Int. 122 268.2 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N,5-dimethylbenzamide Int. 123 270.2 (M+H) (S)-4-(3-amino-2-(dimethylamino)propyl)-2-chloro-N-methylbenzamide Int. 128 282.2 (M+H) (S)-4-(3-amino-2-(diethylamino)propyl)-2-fluoro-N-methylbenzamide Int. 129 282.2 (M+H) (S)-3-(aminomethyl)-N,2-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-methylamine Int. 131 280.2 (M+H) 4-[(2S)-3-amino-2-(pyrrolidin-1-yl)propyl]-2-fluoro-N-methylbenzamide

[0160] Example A3: Preparation of (R)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionic acid (3F, "intermediate 3"):

[0161] Preparation of N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropane-1-methylamine (3B): 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (25 g, 162 mmol) was dissolved in dichloromethane (250 ml), and carbonyl diimidazole (32 g, 200 mmol) was added in portions, resulting in rapid foaming. The solution was then stirred at room temperature for 30 minutes. Triethylamine (45 ml, 324 mmol) was then added, followed by N,O-dimethylhydroxylamine hydrochloride (17.4 g, 180 mmol), and the solution was stirred for 24 hours. The reaction was indicated by TLC to be complete. The reactants were quenched by adding 2 N HCl solution. After stirring for 15 minutes, the two layers were separated. The organic layer was then washed with a saturated sodium bicarbonate layer and then with brine. The organic layer was filtered through magnesium sulfate and the filtrate was concentrated to give the title compound (30 g, 94%) as an oil.

[0162] Preparation of phenyl(1-(trifluoromethyl)cyclopropyl methyl ketone (3C): Under a N2 balloon atmosphere, THF (200 mL) was added to a dried 500 mL RBF and an egg-shaped stir bar containing N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropane-1-methylamine (20.6 g, 104 mmol). The resulting mixture was cooled to -78°C for about 15 minutes in a dry ice acetone bath. A pale yellow solution was observed. Phenyl magnesium bromide (41.8 mL, 3M in diethyl ether, 125 mmol) was added dropwise over 10 minutes with vigorous shaking to prevent gelation of the stir bar. The reaction mixture was maintained at -78°C for 20 minutes, followed by stirring at 0°C for 30 minutes. The mixture was then stirred overnight at room temperature. Most of the volatiles were then evaporated, and the resulting crude product was cooled to 0°C and NH4Cl (80 mL) and water (100 mL) were added. The sample was then extracted twice with EtOAc, washed three times with water, and washed with brine. After drying and concentration with MgSO4, a crude product (27.7 g, approximately 80% purity) was obtained as a pale yellow oil. The crude product was used directly in the next step without further purification.

[0163] Preparation of (Z)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)acrylate (3D): Anhydrous THF (200 mL) was added to 500 mL of RBF containing methyl 2-(dimethoxyphosphatidyl)acetate (13.3 g, 73.2 mmol) and 18-crown-6 (19.3 g, 73.2 mmol). The reaction mixture was then cooled to 0 °C, and bis(trimethylsilyl)amidine potassium (73.2 mL, 1 M in THF) was added dropwise over 10 minutes. After the addition (a clear yellow solution), the reaction mixture was heated and stirred at room temperature for 40 minutes. Then, a solution of phenyl[1-(trifluoromethyl)cyclopropyl] ketone (14.0 g) in THF (25 mL) was added dropwise over 2 minutes at room temperature. After the addition, THF (30 mL) was added. The reaction mixture was stirred overnight at room temperature and ¹H-NMR showed complete conversion (Z / E ratio approximately 5 / 1 in CDCl₃). The crude product was then evaporated to remove approximately half of the THF, and the residue was treated with EtOAc and water, followed by three extractions of the aqueous layer with EtOAc. The combined organic layers were dried over MgSO₄, concentrated, and purified by a 220 g silica gel column (sample mixed with silica gel and centrifuged in hexane / hexane with 0–25% 10% EtOAc) to give a top spot (major product) of a colorless oil (methyl (2Z)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]prop-2-enoate (10.6 g, 75%, for both steps). MS (m / z): 271.2 (M+H). NOE between the olefin CH and the benzene ring H confirmed the double bond geometry.

[0164] Preparation of (R)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionate (3E): Under N2 balloon conditions, at 0°C, (dimethoxymethyl)silane (9.7 mL, 79 mmol) was added to a stirred mixture of (R)-DTBM-SEGPHOS® (375 mg, 0.32 mmol) and Cu(OAc)2 (173 mg, 0.955 mmol) in toluene (40 mL), followed by the addition of t-BuOH (6 mL, 63 mmol). Subsequently, a solution of (2Z)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]prop-2-enoate (8.6 g, 31.8 mmol) in toluene (15 mL) was added dropwise over 5 minutes. The mixture was stirred at 0°C for 45 minutes, followed by stirring at room temperature for another 45 minutes. LC-MS and H-NMR showed complete conversion. Add saturated ammonium chloride solution (100 mL). After stirring for 30 minutes, extract with EtOAc (2×). Wash the combined extracts with water, 1 N HCl, water, saturated NaHCO3 solution, and brine. After drying with MgSO4, concentrate and purify using ESLD detection combi-flash via a 220 g silicone column (0-100% 10% EtOAc in hexane / hexane) to give methyl (3R)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionate (6 g, 69%) as a colorless oil. MS (m / z): 273.2 (M+H).

[0165] Preparation of (R)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionic acid (3F): Lithium hydroxide monohydrate (2.78 g, 66 mmol) was added to a solution of methyl (3S)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionate (6.0 g, 22 mmol) in THF-MeOH-water (v / v / v 1:1:1; 75 mL) at room temperature. The mixture was stirred overnight at room temperature. Complete conversion was observed by LC-MS. Most of the volatiles were removed by rotary evaporation. Water (30 mL) was added to the crude product. After cooling in an ice-water bath, 1 N HCl (approximately 72 mL) was added dropwise to adjust the pH to 5. The mixture was extracted four times with EtOAc, and the combined extract layers were washed with brine. After drying with anhydrous Na₂SO₄, the solution was filtered and concentrated to obtain (3R)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid (5.65 g, 99%) as a colorless oil. MS (m / z): 259.1 M+H.

[0166] Example A4: Preparation of (S)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionic acid (4D, "Intermediate 4"):

[0167] Preparation of (Z)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)acrylate (4A): Ethyl 2-(diethoxyphosphatidyl)acrylate (9.68 g, 43.2 mmol) was added dropwise to a stirred suspension of NaH (60%, 1.51 g, 37.8 mmol) in THF (50 mL) at 0 °C. After the addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 1 h. 20 mL of THF containing phenyl[1-(trifluoromethyl)cyclopropyl]methyl ketone (5.64 g, 21.6 mmol) was added. The reaction mixture was then heated to reflux over 16 h. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of NH4Cl was added. Extraction was performed with EtOAc (3×). The combined extracts were dried over MgSO4, concentrated, and purified by rapid chromatography (0-5% EtOAc / hexane) to give ethyl (2Z)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]prop-2-enoate (4A, 2.41 g, 39%) and ethyl (2E)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]prop-2-enoate (4B, 2.27 g, 37%). MS (m / z): 285.1 (M+H).

[0168] Preparation of ethyl (3S)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionate (4C): Under N2 balloon conditions, at 0°C, (dimethoxymethyl)silane (0.645 mL, 5.28 mmol) was added to a stirred mixture of (S)-DTBM-SEGPHOS® (20.7 mg, 0.017 mmol) and Cu(OAc)2 (16 mg, 0.088 mmol) in toluene (4 mL), followed by the addition of t-BuOH (0.334 mL, 3.52 mmol). Subsequently, a solution of ethyl (2Z)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]prop-2-enoate (0.5 g, 1.76 mmol, compound 4A) in toluene (4 mL) was added dropwise over 5 minutes. The mixture was stirred at 0°C for 45 min, followed by stirring at room temperature for another 45 min. Complete conversion was then observed by LC-MS and 1H-NMR. A saturated ammonium chloride solution (10 mL) was added. After stirring for 30 min, extraction with EtOAc (2×) was performed. The combined extracts were washed with water, 1 N HCl, water, saturated NaHCO3 solution, and brine. After drying over MgSO4, the extracts were concentrated and purified using a silicone column (0-100% 10% EtOAc in hexane / hexane) with ESLD detection combi-flash to give ethyl (3S)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionate (0.546 g, 87%) as a colorless oil. MS (m / z): 287.1 (M+H).

[0169] Preparation of (3S)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid (4D): Lithium hydroxide monohydrate (2.78 g, 66 mmol) was added to a solution of ethyl (3R)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid (0.5 g, 1.41 mmol) in EtOHCl-water (1:1; 4 mL) at room temperature. The mixture was stirred overnight at room temperature. Complete conversion was observed by LC-MS. Most of the volatiles were removed by rotary evaporation. Water (5 mL) was added to the crude product. After cooling in an ice-water bath, 1N HCl (approximately 72 mL) was added dropwise to adjust the pH to 5. The mixture was extracted four times with EtOAc, and the combined extract layers were washed with brine. After drying with anhydrous Na2SO4, the solution was filtered and concentrated to obtain (3S)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid (0.354 g, 96%) as a colorless oil. MS (m / z): 259.1 (M+H).

[0170] Example A5: Preparation of (S)-4-(3-amino-2-(dimethylamino)propyl)-2,3-difluorobenzoamide (5E, "Intermediate 5"):

[0171] Preparation of (S)-4-(3-amino-2-(dimethylamino)propyl)-2,3-difluorobenzoamide (5E): The title compound (670 mg, 67%) was prepared by the same method as intermediate 1 described in Example A1. MS (m / z): 258.1 (M +H).

[0172] Example A6: Preparation of (S)-3-(2-methylthiazolyl-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid (6D, "Intermediate 6"):

[0173] Preparation of (2-methylthiazol-5-yl)(1-(trifluoromethyl)cyclopropyl)methyl ketone (6A): A solution of n-BuLi / hexane (2.5 M, 19.0 mL, 47.4 mmol) in THF (30 mL) was added dropwise (over 20 minutes) at -78 °C to a solution of n-BuLi / hexane (2.5 M, 19.0 mL, 47.4 mmol) in THF (30 mL). The reactants turned a pale brown turbidity. Intermediate 3B (9.34 g, 47.4 mmol) was added dropwise, and the mixture was stirred at -78 °C for 2 hours. The reactants were quenched with saturated NH4Cl (aqueous solution) (150 mL), extracted with EtOAc (3×), dried over MgSO4, filtered, concentrated, and purified on a 330 g gold-silicone column with 0–50% EtOAc / hexane to give the title compound (6.47 g, 63%) as a brown oil. MS (m / z): 236.0 (M+H).

[0174] Preparation of (E)-3-(2-methylthiazolyl-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)methyl acrylate (6B): A stirred solution of trimethyl phosphonoacetate (6.49 g, 35.6 mmol) and 18-crown-6-ether (Combi-Blocks, SS-7385, B43822, FW 264.3, 9.41 g, 35.6 mmol) in THF (40 mL) was added dropwise to THF containing KHMDS (Oakwood Chemical, batch 104258M05H, 1.0 M, 35.6 mL). The reaction mixture was heated to room temperature for 30 minutes. A solution of ketone (6A, 6.45 g, 27.4 mmol) in THF (20 mL) was added dropwise. After the addition was complete, the mixture was kept at 0°C to room temperature for 16 hours. The reaction mixture was cooled, and NaHCO3 (30 mL) was added. Extraction was performed with EtOAc (3×). The combined extracts were washed with water (1×) and brine (1×), dried over MgSO4, concentrated, and purified by column chromatography (0-100% MTBE / hexane) using a 220 g silica gel column to give the title compound (3.67 g, 45%). MS (m / z): 292.0 (M+H).

[0175] Preparation of (3S)-3-(2-methyl-1,3-thiazolyl-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionate (6C): Under N2 balloon, at 0°C, DMHS (508 mg, 4.83 mmol, 2.5 eq) was added to a stirred mixture of (R)-DTBM-SEGPHOS® (MW 1180, 22.8 mg, 0.0193 mmol, 0.01 eq) and Cu(OAc)2 (MW 181.6, 10.5 mg, 0.0580 mmol, 0.03 eq) in toluene (5 mL), followed by the addition of t-BuOH (MW 74.12, d = 0.781, 0.367 mL, 3.87 mmol, 2.0 eq). The solution of 6B (563 mg, 1.93 mmol) was then added dropwise to toluene (5 mL) over 3 minutes. The mixture was stirred from 0°C to room temperature for 30 minutes. The color changed from pale blue to green to dark brown. Saturated NaHCO3 (5 mL) was added and the mixture was stirred at room temperature for 30 minutes, followed by extraction with EtOAc (2×). The combined extracts were washed with water and brine, dried over MgSO4, concentrated, and purified by a 40 g silicone column (0-50% EtOAc / hexane) to give the title compound (491 mg, 87%). MS (m / z): 294.0 (M+H).

[0176] Preparation of (S)-3-(2-methylthiazolyl-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid (6D): A solution of 6C (486 mg, 1.66 mmol) in MeOH (3 mL) / THF (3 mL) was treated with LiOH (2 N, 2.6 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature. LCMS: The reaction was complete. The solvent was removed by rotary evaporation. Water (3 mL) was added, the mixture was cooled in an ice-water bath, and the pH was adjusted to approximately 4 by adding 1 N HCl. The mixture was extracted with DCM (3×). The combined extracts were dried over MgSO4, filtered, and concentrated to give the title compound (360 mg, 78%). MS (m / z): 280.0 (M+H).

[0177] The following intermediates are synthesized using a method similar to that described in Example A6: Int. 6 and General Process VII: Intermediate item (Int.) number structure LC / MS (m / z) name Int. 9 303.1 (M+H) (R)-3-(2-methylpyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 10 288.1 (M+H) (R)-3-(6-methylpyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 11 288.1 (M+H) (S)-3-(6-methylpyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 12 260.1 (M+H) 3-(pyridin-4-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 14 295.0 (M+H) (3S)-3-(5-chloropyrimidin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 15 260.1 (M+H) (R)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 18 207.1 (M+H) (3S)-3-Cyclopropyl-3-(2-methylpyrimidin-5-yl)propionic acid Int. 19 260.1 (M+H) (3R)-3-(pyrimidin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 20 304.1 (M+H) 3-[2-(dimethylamino)pyrimidin-5-yl]-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 21 261.0 (M+H) 3-(pyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 22 328.1 (M+H) 3-[1-(trifluoromethyl)cyclopropyl]-3-[6-(trifluoromethyl)pyridin-3-yl]propionic acid Int. 23 291.1 (M+H) 3-(2-Methoxypyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 24 275.1 (M+H) 3-(2-methylpyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 25 290.1 ​​(M+H) 3-(6-methoxypyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 26 278.1 (M+H) 3-(5-Fluoropyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 27 294.1 (M+H) 3-(5-chloropyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 28 260.1 (M+H) 3-(pyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 29 260.1 (M+H) (3S)-3-(pyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 34 226.1 (M+H) (3R)-3-(5-Fluoropyridin-3-yl)-4,4-Dimethylvaleric acid Int. 36 249.1 (M+H) (R)-3-(furan-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 37 279.0 (M+H) (3S)-3-(5-methylthiophen-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 38 279.0 (M+H) (S)-3-(5-methylthiophen-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 39 265.1 (M+H) (3S)-3-(thien-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 40 266.0 (M+H) (3S)-3-(1,3-thiazo-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 42 280.0 (M+H) (3R)-3-(2-methyl-1,3-thiazo-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 43 280.0 (M+H) (3S)-3-(5-methyl-1,3-thiazo-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 44 208.1 (M+H) (3S)-5-methyl-3-(pyridin-3-yl)hexanoic acid Int. 45 208.1 (M+H) (3S)-5-methyl-3-(pyridin-3-yl)hexanoic acid Int. 46 206.1 (M+H) (S)-4-Cyclopropyl-3-(pyridin-4-yl)butyric acid Int. 47 278.2 (M+H) (3R)-3-(3-Fluoropyridin-4-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 48 207.1 (M+H) (3R)-4-Cyclopropyl-3-(pyrimidin-5-yl)butyric acid Int. 49 206.1 (M+H) (3R)-4-Cyclopropyl-3-(pyridin-3-yl)butyric acid Int. 50 194.1 (M+H) (3S)-4-methyl-3-(pyridin-3-yl)valeric acid Int. 51 327.1 (M+H) (3R)-3-(3,4-dichlorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 52 260.1 (M+H) (3S)-3-(pyridin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 54 315.0 (M+Na) (3R)-3-(4-chlorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 55 260.1 (M+H) (3R)-3-(pyridin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 56 259.2 (M+H) (3S)-3-Pheny-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 59 260.1 (M+H) (3R)-3-(pyridin-4-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 71 165.1 (M+H) (R)-3-(3-fluorophenyl)butyric acid Int. 72 261.1 (M+H) 3-(pyrimidin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 77 205.1 (M+H) (3S)-3-(1-methylcyclopropyl)-3-(pyridin-3-yl)propionic acid Int. 89 274.1 (M+H) (3R)-3-(2-methylpyridin-4-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 90 274.1 (M+H) (3R)-3-(5-methylpyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 91 192.1 (M+H) (3S)-3-Cyclopropyl-3-(pyridin-3-yl)propionic acid Int. 93 260.1 (M+H) (3S)-3-(pyridin-4-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid Int. 98 208.2 (M+H) (R)-5-methyl-3-(pyridin-2-yl)hexanoic acid Int. 100 260.2 (M+H) (S)-3-(pyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 101 294.2 (M+H) 3-(5-chloropyrimidin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 103 294.2 (M+H) (R)-3-(5-chloropyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 104 290.2 (M+H) 3-(5-methoxypyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 105 274.2 (M+H) 3-(4-methylpyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 106 260.2 (M+H) 3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 107 278.2 (M+H) 3-(3-Fluoropyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 108 278.2 (M+H) 3-(5-Fluoropyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 109 294.2 (M+H) 3-(5-chloropyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 113 208.2 (M+H) (R)-5-methyl-3-(pyridin-3-yl)hexanoic acid Int. 114 278.2 (M+H) (R)-5-methyl-3-(pyridin-3-yl)hexanoic acid Int. 115 277.2 (M+H) ((R)-3-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 116 208.2 (M+H) (S)-4,4-Dimethyl-3-(pyridin-3-yl)valeric acid Int. 117 295.2 (M+H) (R)-3-(3,5-difluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 118 294.2 (M+H) (R)-3-(5-chloropyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 119 294.2 (M+H) (S)-3-(5-chloropyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 121 260.2 (M+H) 3-(pyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 130 303.1 (M+H) (S)-3-(2-methylpyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid Int. 145 192.2 [M+H] (S)-3-Cyclopropyl-3-(pyridin-4-yl)propionic acid Int. 146 200.1 [M+H] (R)-3-(2-methylthiazo-5-yl)valeric acid Int. 147 212.2 [M+H] (S)-3-Cyclopropyl-3-(2-methylthiazo-5-yl)propionic acid Int. 148 212.2 [M+H] (R)-3-Cyclopropyl-3-(2-methylthiazo-5-yl)propionic acid Int. 149 206.1 (M+H) (3S)-4-Cyclopropyl-3-(pyridin-3-yl)butyric acid Int. 150 206.1 (M+H) (S)-4-Cyclopropyl-3-(pyridin-4-yl)butyric acid Int. 151 198.1 [M+H] (3S)-3-Cyclopropyl-3-(1,3-Thiazolyl-5-yl)propionic acid Int. 152 263.1 (M+H) (S)-3-(5-methylfuran-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid

[0178] Example A7: Preparation of 2-(pyrimidin-2-yl)cyclopropane-1-carboxylic acid (7D, "Intermediate 7"):

[0179] Preparation of (2E)-3-(pyrimidin-2-yl)prop-2-enoic acid tributyl ester (7B). 2-(diethoxyphosphatidyl)acetic acid tributyl ester (9.75 g, 38.7 mmol) was added dropwise to a stirred suspension of NaH (1.69 g, 42.2 mmol) in THF (50 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for 30 min. Pyrimidin-2-carboxaldehyde (3.8 g, 35.2 mmol) was then added, and stirring continued at room temperature for 2 h. The reaction mixture was diluted with EtOAc and quenched with saturated NH4Cl. The organic layer was separated, dried over MgSO4, concentrated, and purified by rapid chromatography (0-60% EtOAc / hexane) to give 7B, (2E)-3-(pyrimidin-2-yl)prop-2-enoic acid tributyl ester (5.5 g, 75.9%). MS (m / z): 207.1 (M+H).

[0180] Preparation of 2-(pyrimidin-2-yl)cyclopropane-1-carboxylic acid tributyl ester (7C). KOt-Bu was added in a single addition to a stirred solution of trimethylsilyl iodide (3.07 g, 14.0 mmol) in DMSO (20 mL). Stirring was continued for 30 min, followed by a single addition of (2E)-3-(pyrimidin-2-yl)propane-2-enoic acid tributyl ester (2.40 g, 11.6 mmol). The reaction mixture was stirred at room temperature for 2 h. A saturated aqueous solution of NH4Cl was added, and the mixture was extracted with EtOAc (3×). The extract was dried over MgSO4, concentrated, and purified by rapid chromatography (0–40% EtOAc / hexane) to give 2-(pyrimidin-2-yl)cyclopropane-1-carboxylic acid tributyl ester (1.1 g, 42.9%). MS (m / z): 221.2 (M+H).

[0181] Preparation of 2-(pyrimidin-2-yl)cyclopropane-1-carboxylic acid (7D). A solution of 1.1 g (4.99 mmol) of tributyl 2-(pyrimidin-2-yl)cyclopropane-1-carboxylic acid in 10 mL of 4 M HCl and 0.3 mL of H₂O was stirred at room temperature for 3 h. The mixture was concentrated to dryness to give 1.2 g (100%) of 2-(pyrimidin-2-yl)cyclopropane-1-carboxylic acid hydrochloride. MS (m / z): 165.1 (M+H).

[0182] Example A8: Preparation of (S)-3-cyclopropyl-3-phenylpropionic acid (8D, "Intermediate 8"):

[0183] Preparation of (2E)-3-cyclopropyl-3-phenylprop-2-enoic acid tributyl ester (8B). 2-(diethoxyphosphatidyl)acetic acid tributyl ester (12 mL, 51.3 mmol) was added to a stirred suspension of NaH (60%, 2.05 g, 51.3 mmol) in THF (50 mL) at 0 °C. The mixture was stirred for 30 min after the addition. Cyclopropyl(phenyl) ketone (5 g, 34.2 mmol) was added, and the reaction mixture was stirred at 50 °C for 16 h. The mixture was cooled to room temperature, and saturated NH4Cl was added. Extraction was performed with EtOAc (3×). The combined extracts were washed with H2O and brine, dried over MgSO4, concentrated, and purified by rapid chromatography (0-20% MTBE / hexane) to give (2E)-3-cyclopropyl-3-phenylprop-2-enoic acid tributyl ester (1.76 g, 21%).

[0184] Preparation of (3R)-3-cyclopropyl-3-phenylpropionic acid tributyl ester (8C). PMHS (1.6 g, 139 mmol) was added to a stirred mixture of (S)-DTBM-SEGPHOS® (164 mg, 6.96 mmol) and (triphenylphosphine) copper hydride hexamer (95.5 mg, 0.139 mmol) in toluene (8 mL) at 0 °C, followed by dropwise addition of a solution of t-BuOH (567 mg, 7.76 mmol) and (2E)-3-cyclopropyl-3-phenylprop-2-enoic acid tributyl ester (1.7 g, 6.96 mmol) in toluene (5 mL). The mixture was then stirred at 0 °C for 16 h. LC / MS showed only 50% conversion. At this point, the same amounts of catalyst and solvent were added, and the temperature was gradually raised to room temperature. After the second addition was complete, the reaction mixture was stirred for 4 h. Saturated NH4Cl was slowly added and stirred for 1 h, followed by extraction with EtOAc (3×). The combined extracts were dried over MgSO4, filtered, concentrated, and purified by rapid chromatography (0-20% EtOAc / hexane) to give tributyl (3R)-3-cyclopropyl-3-phenylpropionate (1.7 g, 99%). MS (m / z): 247.1 (M+H).

[0185] Preparation of (3R)-3-cyclopropyl-3-phenylpropionic acid (8D). TFA (7.9 g, 69.6 mmol) was added to a stirred solution of tributyl (3R)-3-cyclopropyl-3-phenylpropionic acid (1.7 g, 6.9 mmol) in DCM (10 mL). Stirring was continued for 4 h. The mixture was concentrated to dryness to give (3R)-3-cyclopropyl-3-phenylpropionic acid (1.15 g, 86%).

[0186] Example A9: Preparation of (3S)-4-cyclobutyl-3-phenylbutyric acid (57C, "Intermediate 57"):

[0187] Preparation of (4S)-4-phenyl-3-[(2E)-3-phenylprop-2-enyl]-1,3-azolidin-2-one (57A). N,N′-diisopropylcarbodiimide (6.39 g, 50.6 mmol) was added dropwise to a stirred mixture of (2E)-3-phenylprop-2-enoic acid (5 g, 33.7 mmol), DMAP (412 mg, 3.37 mmol), and (S)-4-phenylazolidin-2-one (5.5 g, 33.7 mmol) in DCM (80 mL) at 0 °C. Stirring was continued for 16 h, and the precipitated solid was filtered off. The filtrate was washed with 2N HCl, saturated NaHCO3, and brine, dried over Na2SO4, and concentrated to dryness. The crude product was wet-milled in i-PrOH. The precipitated solid was collected and dried to give (4S)-4-phenyl-3-[(2E)-3-phenylprop-2-enyl]-1,3-azolidin-2-one (8.01 g, 80.9%). MS (m / z): 294.2 (M+H).

[0188] Preparation of (4S)-3-[(3S)-4-cyclobutyl-3-phenylbutyryl]-4-phenyl-1,3-azolidin-2-one (57B). Iodine (382 mg, 1.5 mmol) was added to a stirred suspension of Mg (1.1 g, 45.1 mmol) in THF (20 mL) in a condenser-equipped 2-necked RBF. After the addition was complete, the mixture was stirred for 10 min, followed by the addition of (bromomethyl)cyclobutane (2.69 g, 18 mmol), and then another iodine (382 mg, 1.5 mmol). Stirring was continued for 1 h. Subsequently, the mixture was added dropwise at -40 °C to a stirred portion of the suspension of copper(I) dimethyl sulfide (4.02 g, 19.5 mmol) in THF (20 mL). After the addition, the mixture was stirred at -40 °C for 1 h. Finally, a solution of (4S)-4-phenyl-3-[(2E)-3-phenylprop-2-enyl]-1,3-azolidin-2-one (4.41 g, 15 mmol) in THF (40 mL) was added dropwise to the stirred mixture at -40 °C using a self-dropping funnel. After the addition was complete, the reaction mixture was stirred at -40 °C for 1 h, then gradually heated to room temperature and stirred overnight. A saturated aqueous solution of NH4Cl was added and stirred for 15 min. Extraction was performed with EtOAc (3×). The combined extracts were dried over MgSO4, concentrated, and purified by rapid chromatography (0-20% EtOAc / hexane) to give (4S)-3-[(3S)-4-cyclobutyl-3-phenylbutyryl]-4-phenyl-1,3-azolidin-2-one (354 mg, 6.5%). MS (m / z): 364.2 (M+H).

[0189] Preparation of (3S)-4-cyclobutyl-3-phenylbutyric acid (57C). Lithium hydroxide monohydrate (2.64 mL, 1.6 eq., 5.28 mmol) was added to a stirred solution of (4S)-3-[(3S)-4-cyclobutyl-3-phenylbutyryl]-4-phenyl-1,3-azolidin-2-one (1.20 g, 3.30 mmol) in THF (20 mL), followed by the addition of H2O2 (1.51 mL, 4 eq., 13.2 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 3 h, diluted with MTBE and water, and the layers were separated. The aqueous layer was cooled in an ice bath, acidified with 2N HCl, and extracted with DCM (3×). The combined extracts were dried over Na2SO4, concentrated and purified by rapid chromatography (0-50% EtOAc / DCM) to give (3S)-4-cyclobutyl-3-phenylbutyric acid (650 mg, 90 mg).

[0190] The following intermediates are synthesized using a method similar to that described in Example A9: Int. 57 and General Process VI: Intermediate item (Int.) number structure LC / MS (m / z) name Int. 60 193.2 (M+H) (R)-4-methyl-3-phenylpentanoic acid Int. 61 165.1 (M+H) (R)-3-Phenylacetic acid Int. 62 165.1 (M+H) (S)-3-Phenylobutyric acid Int. 63 191.2 (M+H) (S)-3-Cyclopropyl-3-phenylpropionic acid Int. 64 191.2 (M+H) (R)-3-Cyclopropyl-3-phenylpropionic acid Int. 65 193.2 (M+H) (S)-4-methyl-3-phenylpentanoic acid Int. 66 193.2 (M+H) (R)-4-methyl-3-phenylpentanoic acid Int. 67 207.2 (M+H) (R)-5-methyl-3-phenylhexanoic acid Int. 68 207.2 (M+H) (S)-5-methyl-3-phenylhexanoic acid Int. 69 207.2 (M+H) (R)-4,4-Dimethyl-3-phenylpentanoic acid Int. 70 207.2 (M+H) (S)-4,4-Dimethyl-3-phenylpentanoic acid Int. 120 206.2 (M+H) (S)-4-Cyclopropyl-3-(pyridin-2-yl)butyric acid Int. 124 199.1 (M+H) (R)-3-(4-chlorophenyl)butyric acid Int. 125 199.1 (M+H) (S)-3-(4-chlorophenyl)butyric acid Int. 126 166.1 (M+H) (S)-3-(4-chlorophenyl)butyric acid Int. 127 205.2 (M+H) (S)-3-Phenylhept-6-enoic acid Int. 132 166.1 (M+H) (S)-3-(pyridin-2-yl)butyric acid

[0191] Example A10: [(2S)-1-amino-3-(2-methoxyquinoline-6-yl)propyl-2-yl]dimethylamine (58H, "intermediate 58"):

[0192] Preparation of 6-bromo-2-methoxyquinoline (58B): A mixture of 6-bromo-2-chloroquinoline (5.00 g, 20.6 mmol) and sodium methoxide (1.34 g, 1.2 eq., 24.7 mmol) in MeOH (50 mL) was heated under reflux for 24 h. The reaction mixture was cooled to room temperature and poured onto an ice-water beaker. The precipitated solid was collected, washed with H2O, and dried to give the title compound (4.5 g, 92%), which was used in the next step.

[0193] Preparation of methyl (2S)-2-{[(tributoxy)carbonyl]amino}-3-(2-methoxyquinoline-6-yl)propionate (58C). Step 1: Iodine (480 mg, 0.1 eq., 1.89 mmol) was added to a stirred suspension of zinc (3.71 g, 3 eq., 56.7 mmol) in DMF (20 mL). Stirring was continued for 15 minutes until the mixture became clear. Then, methyl (2R)-2-{[(tributoxy)carbonyl]amino}-3-iodopropionate (7.47 g, 1.2 eq., 22.7 mmol) was added all at once, followed by the addition of iodine (480 mg, 0.1 eq., 1.89 mmol). The mixture was heated and stirred at room temperature for 1 h. Step 2: The mixture from Step 1 was added to a stirred mixture of 6-bromo-2-methoxyquinoline (4.50 g, 18.9 mmol), S-Phos (543 mg, 0.07 eq., 1.32 mmol), and Pd2(dba)3 (519 mg, 0.03 eq., 567 µmol) in DMF (20 mL). After the addition was complete, the reaction mixture was degassed for 5 minutes, then heated to 70 °C over 24 hours. The reaction mixture was cooled to room temperature, saturated NH4Cl was added, and the mixture was stirred for 15 minutes. The mixture was then diluted with EtOAc. The layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined extracts were dried over MgSO4, concentrated, and purified by rapid chromatography (0-30% EtOAc / hexane) to give methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(2-methoxyquinoline-6-yl)propionate (2.50 g, 36%).

[0194] Preparation of N-[(2S)-1-hydroxy-3-(2-methoxyquinoline-6-yl)prop-2-yl]aminoformate tributyl ester (58D). Lithium borohydride (2.60 mL, 1.5 eq., 10.4 mmol) was added dropwise to a stirred solution of methyl (2S)-2-{[(tributyloxy)carbonyl]amino}-3-(2-methoxyquinoline-6-yl)propionate (2.50 g, 6.94 mmol) in THF (20 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for 1 h, followed by stirring at room temperature for 2 h. The reaction mixture was cooled in an ice bath and slowly quenched with saturated NH4Cl, then extracted with EtOAc (3×). The combined extracts were dried over MgSO4 and concentrated to obtain N-[(2S)-1-hydroxy-3-(2-methoxyquinoline-6-yl)propyl-2-yl]aminoformate tributyl ester (2.01 g, 87%), which was used in the next step.

[0195] Preparation of N-[(2S)-1-(1,3-dioxy-2,3-dihydro-1H-isoindol-2-yl)-3-(2-methoxyquinoline-6-yl)propyl-2-yl]aminocarbamate tributyl ester (58E). N-[(2S)-1-hydroxy-3-(2-methoxyquinoline-6-yl)propyl-2-yl]aminocarbamate tributyl ester (1.99 g, 5.99 mmol), triphenylphosphine (1.88 g, 1.2 eq., 7.18 mmol), and phthalimide (1.06 g, 1.2 eq., 7.18 mmol) were added dropwise to a stirred mixture in THF (30 mL). DIAD (1.42 mL, 1.2 eq., 7.18 mmol) was then added dropwise. After addition, the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated to dryness and purified by rapid chromatography (40% EtOAc / hexane) to give N-[(2S)-1-(1,3-dioxy-2,3-dihydro-1H-isoindol-2-yl)-3-(2-methoxyquinolin-6-yl)propyl-2-yl]tributyl aminocarboxylate (1.50 g, 54%). MS (m / z): 462.2.

[0196] Preparation of 2-[(2S)-2-amino-3-(2-methoxyquinoline-6-yl)propyl]-2,3-dihydro-1H-isoindole-1,3-dione (58F). A solution of N-[(2S)-1-(1,3-dioxy-2,3-dihydro-1H-isoindole-2-yl)-3-(2-methoxyquinoline-6-yl)propyl-2-yl]aminoformate tributyl ester (1.50 g, 3.25 mmol) in formic acid (20 mL) was stirred for 16 h at room temperature. The reaction mixture was concentrated to dryness to give the title compound (1.1 g, 100%), which was used in the next step. MS (m / z): 362.1 (M+H).

[0197] Preparation of 2-[(2S)-2-(dimethylamino)-3-(2-methoxyquinoline-6-yl)propyl]-2,3-dihydro-1H-isoindole-1,3-dione (58 g). Formaldehyde (1.28 mL, 3 eq., 16.6 mmol) was added to a stirred solution of 2-[(2S)-2-amino-3-(2-methoxyquinoline-6-yl)propyl]-2,3-dihydro-1H-isoindole-1,3-dione (2.00 g, 5.53 mmol) in MeCN / H2O (5:1, 24 mL). Stirring was continued for 30 min, and then sodium cyanoborohydride (696 mg, 2 eq., 11.1 mmol) was added. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. Saturated NaHCO3 was added to adjust the pH to 7-8, and the mixture was extracted with EtOAc (3×). The combined extracts were dried over MgSO4 and concentrated to dryness to give the title compound (2 g, 92%), which was used in the next step. MS (m / z): 390.1 (M+H).

[0198] Preparation of [(2S)-1-amino-3-(2-methoxyquinoline-6-yl)propyl-2-yl]dimethylamine (58H). Hydrazine (1.57 mL, 5 eq., 25.7 mmol) was added to a stirred solution of 2-[(2S)-2-(dimethylamino)-3-(2-methoxyquinoline-6-yl)propyl]-2,3-dihydro-1H-isoindole-1,3-dione (2.00 g, 5.14 mmol) in EtOH (20 mL). The reaction mixture was then heated to 80 °C over 2 h, cooled to room temperature, and diluted with EtOAc. The precipitated solid was filtered off, and the filtrate was concentrated and purified by rapid chromatography (0-15% MeOH / DCM in 1% NH4OH) to give [(2S)-1-amino-3-(2-methoxyquinoline-6-yl)propyl-2-yl]dimethylamine (180 mg, 14%). MS (m / z): 260.2 (M+H).

[0199] Example A11: Preparation of 6-[(2S)-3-amino-2-(dimethylamino)propyl]-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzoxazo-2-one (75G, "Intermediate 75"):

[0200] Preparation of 6-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]acetazol-2(3H)-one (75A): 6-bromobenzo[d]acetazol-2(3H)-one (2 g, 9.34 mmol) was added to a stirred suspension of NaH (0.45 g, 11.21 mmol) in DMF (20 mL). After the addition was complete, the mixture was stirred at room temperature for 30 min, followed by dropwise addition of SEM-Cl. The reaction mixture was then stirred at room temperature for 16 h. Saturated NH4Cl was added, and the mixture was extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography (0-30% EtOAc / hexane) to give the title compound (7.85 g, 84%). MS (m / z): 345.1 (M+H).

[0201] Preparation of (S)-2-((tributoxycarbonyl)amino)-3-(2-sideoxy-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]azol-6-yl)propionate (75B). The title compound (5.0 g, 48%) was prepared by the same method described in step 1 of intermediate 1. MS (m / z): 489.3 (M+Na).

[0202] Preparation of (S)-(1-hydroxy-3-(2-sideoxy-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]azol-6-yl)propyl-2-yl)aminocarbamate tributyl ester (75C). The title compound (3.0 g, 96%) was prepared by the same method described in step 2 of intermediate 1. MS (m / z): 461.2 (M+Na).

[0203] Preparation of N-[(2S)-1-(1,3-disideloxy-2,3-dihydro-1H-isoindol-2-yl)-3-(2-sideloxy-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzodiazol-6-yl)propyl-2-yl]aminocarbamate tributyl ester (75D). The title compound (3.3 g, 84%) was prepared by the same method described in step 3 of intermediate 1. MS (m / z): 568.2 (M+H).

[0204] Preparation of 2-[(2S)-2-amino-3-(2-sideoxy-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzodiazol-6-yl)propyl]-2,3-dihydro-1H-isoindole-1,3-dione (75E). A mixture of N-[(2S)-1-(1,3-dioxy-2,3-dihydro-1H-isoindol-2-yl)-3-(2-dioxy-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzoxazo-6-yl)propyl-2-yl]aminocarbamate tributyl ester (2.05 g, 3.61 mmol) and 4-methylbenzene-1-sulfonic acid hydrate (756 mg, 1.1 eq., 3.97 mmol) in EtOH (40 ml) was heated for 2 h at 60 °C. The mixture was cooled to room temperature and concentrated to dryness to give 2-[(2S)-2-amino-3-(2-sideoxy-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzodiazol-6-yl)propyl]-2,3-dihydro-1H-isoindole-1,3-dione (2.30 g, 100%) in the form of PTSA salt.

[0205] Preparation of 2-[(2S)-2-(dimethylamino)-3-(2-sideoxy-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzodiazol-6-yl)propyl]-2,3-dihydro-1H-isoindole-1,3-dione (75F). Acetic acid (0.809 g, 13.5 mmol) and formaldehyde (0.405 mL, 13.5 mmol) were added to a stirred solution of 2-[(2S)-2-amino-3-(2-sideoxy-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzodiazol-6-yl)propyl]-2,3-dihydro-1H-isoindole-1,3-dione (2.1 g, 4.49 mmol) in MeCN / H2O (10:1, 22 mL). The mixture was stirred for 30 minutes. Sodium cyanoborohydride (0.423 g, 6.74 mmol) was added. After the addition was complete, the reaction mixture was stirred for 30 minutes. A saturated aqueous solution of NH4Cl was added, and the mixture was extracted with EtOAc (3×). The combined extracts were dried over MgSO4 and concentrated to give 2-[(2S)-2-(dimethylamino)-3-(2-sideoxy-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzodiazol-6-yl)propyl]-2,3-dihydro-1H-isoindole-1,3-dione (1.9 g, 85.3%). MS (m / z): 496.2 (M+H).

[0206] Preparation of 6-[(2S)-3-amino-2-(dimethylamino)propyl]-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzodiazol-2-one (75 G). A mixture of 2-[(2S)-2-(dimethylamino)-3-(2-toxy-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzodiazol-6-yl)propyl]-2,3-dihydro-1H-isoindole-1,3-dione (380 mg, 0.767 mmol) and hydrazine (246 mg, 3.83 mmol) in EtOH (4 mL) was heated to 70 °C over 2 h. The reaction mixture was then cooled to room temperature. Silicone was added, the mixture was concentrated to dryness, and then dry-loaded and purified by rapid chromatography (0-25% MeOH / DCM in 1% NH4OH) to give the title compound (1.15 g, 50%). MS (m / z): 366.3 (M+H).

[0207] The following intermediates are synthesized using a method similar to that described in Example A11: Int. 77: Intermediate item (Int.) number structure LC / MS (m / z) name Int. 76 380.2 (M+H) (S)-6-(3-amino-2-(dimethylamino)propyl)-7-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]azol-2(3H)-one

[0208] Example A12: Preparation of (S)-5-(3-amino-2-(dimethylamino)propyl)-4-methylindoline-2-one (78F, "Intermediate 78"):

[0209] Preparation of (2S)-2-{[(tributoxy)carbonyl]amino}-3-(4-methyl-2-sideoxy-2,3-dihydro-1H-indol-5-yl)propionate (78A): Step 1: Iodine (310 mg, 0.1 eq., 1.2 mmol) was added to a stirred suspension of zinc powder (1.4 g, 21.4 mmol, 3 eq) in DMF (20 mL). After stirring for 15 minutes, methyl (2R)-2-{[(tributoxy)carbonyl]amino}-3-iodopropionate (2.62 g, 1.3 eq., 7.95 mmol) was added in one go, followed by the addition of iodine (310 mg, 0.1 eq., 1.2 mmol). The mixture was stirred at room temperature for 1 h. Step 2: The mixture from Step 1 was added to a stirred mixture of 5-iodo-4-methyl-2,3-dihydro-1H-indol-2-one (1.67 g, 6.12 mmol), S-Phos (251 mg, 0.1 eq., 1.2 mmol), and Pd2(dba)3 (280 mg, 0.05 eq., 0.306 mmol) in DMF (20 mL). The reaction mixture was then heated to 70 °C over 16 h. The reaction mixture was cooled to room temperature and saturated NH4Cl was added, followed by extraction with EtOAc (3×). The extract was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography (0-40% EtOAc / hexane) to give methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazol-5-yl]propionate (681 mg, 31%). MS (488.2) (M+H).

[0210] Preparation of N-[(2S)-1-hydroxy-3-(4-methyl-2-sideoxy-2,3-dihydro-1H-indol-5-yl)prop-2-yl]aminocarboxylic acid tributyl ester (78B): Methyl (2S)-2-{[(tributyloxy)carbonyl]amino}-3-(4-methyl-2-sideoxy-2,3-dihydro-1H-indol-5-yl)propionate (681 mg, 1.95 mmol) was dissolved in anhydrous THF (20 mL) under nitrogen atmosphere and cooled in an ice bath. Lithium borohydride (4M in THF, 0.7 mL, 5.85 mmol) was added dropwise and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was cooled in an ice bath and quenched with a saturated aqueous solution of NH4Cl. The aqueous layer was extracted with EtOAc (3×). The combined extracts were dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (0-60% EtOAc / hexane) to give the title compound (710 mg, 110%). MS (m / z): 321.2 (M+H).

[0211] Preparation of N-[(2S)-1-(1,3-dioxy-2,3-dihydro-1H-isoindol-2-yl)-3-(4-methyl-2-dioxy-2,3-dihydro-1H-indol-5-yl)propyl-2-yl]aminocarbamate (78C): DIAD (0.52 mL, 2.67 mmol) was added dropwise to a stirred mixture of N-[(2S)-1-hydroxy-3-(4-methyl-2-dioxy-2,3-dihydro-1H-indol-5-yl)propyl-2-yl]aminocarbamate (714 mg, 2.23 mmol), triphenylphosphine (701 mg, 2.67 mmol) and phthalimide (393 mg, 2.67 mmol) in THF (20 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated to dryness and purified by rapid chromatography (0-60% EtOAc / hexane) to give the title compound (600 mg, 60%). MS (m / z): 450.2 (M+H).

[0212] Preparation of 2-[(2S)-2-amino-3-(4-methyl-2-sideoxy-2,3-dihydro-1H-indol-5-yl)propyl]-2,3-dihydro-1H-isoindol-1,3-dione (78D): A solution of N-[(2S)-1-(1,3-sideoxy-2,3-dihydro-1H-isoindol-2-yl)-3-(4-methyl-2-sideoxy-2,3-dihydro-1H-indol-5-yl)propyl-2-yl]aminoformate tributyl ester (600 mg, 1.33 mmol) in formic acid (10 mL) was heated to 50 °C over 1 h. The reaction mixture was cooled to room temperature and concentrated to dryness to give the title compound (600 mg, 100%) for use in the next step. (MS (m / z): 350.2 (M+H).

[0213] Preparation of 2-[(2S)-2-(dimethylamino)-3-(4-methyl-2-sideoxy-2,3-dihydro-1H-indole-5-yl)propyl]-2,3-dihydro-1H-isoindole-1,3-dione (78E): Formaldehyde (300 µL, 3 eq., 10.7 mmol) was added to a stirred solution of 2-[(2S)-2-amino-3-(4-methyl-2-sideoxy-2,3-dihydro-1H-indole-5-yl)propyl]-2,3-dihydro-1H-isoindole-1,3-dione (600 mg, 1.33 mmol) in MeCN / H2O (5:1, 24 mL). The mixture was stirred for 30 minutes, followed by a single addition of sodium cyanoborohydride (162 mg, 2 eq., 2.66 mmol). The mixture was stirred for another 30 minutes. A saturated aqueous solution of NaHCO3 was slowly added to adjust the pH to 7-8, followed by extraction with EtOAc (3×). The combined extracts were dried over MgSO4 and concentrated to dryness to give the title compound (360 mg, 65%), which was used in the next step without further purification. MS (m / z): 378.2 (M+H).

[0214] Preparation of (S)-5-(3-amino-2-(dimethylamino)propyl)-4-methylindoline-2-one (78F): Hydrazine (238 mL, 5 eq., 4.44 mmol) was added to a stirred solution of 2-[(2S)-2-(dimethylamino)-3-(4-methyl-2-sideoxy-2,3-dihydro-1H-indo-5-yl)propyl]-2,3-dihydro-1H-isoindo-1,3-dione (360 mg, 0.954 mmol) in EtOH (10 mL). The reaction mixture was then heated to 80 °C over 2 h. The reaction mixture was cooled to room temperature, and the precipitated solid was filtered off and washed with EtOH. The filtrate was concentrated to dryness and purified by rapid chromatography (0-15% MeOH / DCM in 1% NH4OH) to give the title compound (125 mg, 52%). MS (m / z): 248.1 (M+H).

[0215] The following intermediates are synthesized using a method similar to that described in Example A12: Int. 78: Intermediate item (Int.) number structure LC / MS (m / z) name Int. 79 234.1 (M+H) (S)-5-(3-amino-2-(dimethylamino)propyl)indololin-2-one

[0216] Example A13: Preparation of (2S)-1-amino-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazol-5-yl]propyl-2-yl]dimethylamine (81G, "Intermediate 81"):

[0217] Preparation of 5-bromo-4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole (81A): Sodium hydride (1.25 g, 1.2 eq., 31.3 mmol) was added in portions to a stirred solution of 5-bromo-4-methyl-1H-indazole (5.50 g, 26.1 mmol) in DMF (40 mL) at 0 °C. After the addition was complete, the mixture was stirred for another 30 minutes, followed by a single addition of 4-methylbenzene-1-sulfonyl chloride (5.96 g, 1.2 eq., 31.3 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled in an ice bath, and saturated NH4Cl was added. The precipitated solid was collected, washed with H2O, and purified by rapid chromatography (50% DCM / hexane) to give 5-bromo-4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole (3.00 g, 31%).

[0218] Preparation of (2S)-2-{[(tributoxy)carbonyl]amino}-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole-5-yl]propionate (81B): Step 1: Iodine (208 mg, 0.1 eq., 821 µmol) was added to a stirred suspension of zinc powder (1.61 g, 24.6 mmol, 3 eq) in DMF (20 mL). After stirring for 15 min, methyl (2R)-2-{[(tributoxy)carbonyl]amino}-3-iodopropionate (3.24 g, 1.2 eq., 9.86 mmol) was added in one go, followed by the addition of iodine (208 mg, 0.1 eq., 821 µmol). The mixture was stirred at room temperature for 1 h. Step 2: The mixture from Step 1 was added to a stirred mixture of 5-bromo-4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole (3.00 g, 8.21 mmol), S-Phos (337 mg, 0.1 eq., 821 µmol), and Pd2(dba)3 (376 mg, 0.05 eq., 411 µmol) in DMF (20 mL). The reaction mixture was then heated to 70 °C over 16 h. The reaction mixture was cooled to room temperature and saturated NH4Cl was added, followed by extraction with EtOAc (3×). The extract was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography (0-40% EtOAc / hexane) to give methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazol-5-yl]propionate (2.20 g, 55%). MS (m / z): 488.2 (M+H).

[0219] Preparation of N-[(2S)-1-hydroxy-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole-5-yl]propyl-2-yl]aminocarboxylic acid tributyl ester (81C). Lithium borohydride (1.69 mL, 1.5 eq., 6.77 mmol) was added dropwise to a stirred solution of (2S)-2-{[(tributoxy)carbonyl]amino}-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole-5-yl]propionate (2.20 g, 4.51 mmol) in THF (20 mL). After the addition was complete, the reaction mixture was stirred over 16 h, cooled in an ice bath, slowly quenched with saturated NH4Cl, stirred for 10 min, diluted with H2O, and extracted with EtOAc (3×). The combined extracts were dried over MgSO4, filtered, and concentrated to dryness to obtain N-[(2S)-1-hydroxy-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazol-5-yl]propyl-2-yl]aminocarbamate tributyl ester (2.00 g, 96%), which was used in the next step without further purification.

[0220] Preparation of N-[(2S)-1-(1,3-dioxy-2,3-dihydro-1H-isoindol-2-yl)-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole-5-yl]propyl-2-yl]aminocarbamate (81D). DIAD (1.06 g, 5.22 mmol) was added dropwise to a stirred mixture of N-[(2S)-1-hydroxy-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole-5-yl]propyl-2-yl]aminocarbamate (2 g, 4.35 mmol), triphenylphosphine (1.37 g, 5.22 mmol), and phthalimide (0.768 g, 5.22 mmol) in THF (40 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated to dryness and purified by rapid chromatography (0-60% EtOAc / hexane) to give the title compound (2.1 g, 81%).

[0221] Preparation of 2-[(2S)-2-amino-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole-5-yl]propyl]-2,3-dihydro-1H-isoindole-1,3-dione (81E). A solution of N-[(2S)-1-(1,3-dioxy-2,3-dihydro-1H-isoindole-2-yl)-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole-5-yl]propyl-2-yl]aminoformate tributyl ester (2.10 g, 3.57 mmol) in formic acid (20 mL) was heated to 50 °C over 1 h. The reaction mixture was cooled to room temperature and concentrated to dryness to give the title compound (1.74 g, 99.8%), which was used in the next step. MS (m / z): 489.2 (M+H).

[0222] Preparation of 2-[(2S)-2-(dimethylamino)-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole-5-yl]propyl]-2,3-dihydro-1H-isoindole-1,3-dione (81F). Formaldehyde (827 µL, 3 eq., 10.7 mmol) was added to a stirred solution of 2-[(2S)-2-amino-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole-5-yl]propyl]-2,3-dihydro-1H-isoindole-1,3-dione (1.74 g, 3.56 mmol) in MeCN / H2O (5:1, 24 mL). The mixture was stirred for 30 minutes, followed by a single addition of sodium cyanoborohydride (448 mg, 2 eq., 7.13 mmol). The mixture was stirred for another 30 minutes. A saturated aqueous solution of NaHCO3 was slowly added to adjust the pH to 7-8, followed by extraction with EtOAc (3×). The combined extracts were dried over MgSO4 and concentrated to dryness to give the title compound (1.84 mg, 99.8%), which was used in the next step without further purification. MS (m / z): 517.2 (M+H).

[0223] Preparation of [(2S)-1-amino-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole-5-yl]propyl-2-yl]dimethylamine (81G). Hydrazine (1.14 g, 5 eq., 17.8 mmol) was added to a stirred solution of 2-[(2S)-2-(dimethylamino)-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazole-5-yl]propyl]-2,3-dihydro-1H-isoindole-1,3-dione (1.84 g, 3.56 mmol) in EtOH (20 mL). The reaction mixture was then heated to 80 °C over 2 h. The reaction mixture was cooled to room temperature, the precipitated solid was filtered off, and washed with EtOH. The filtrate was concentrated to dryness and purified by rapid chromatography (0-15% MeOH / DCM in 1% NH4OH) to give [(2S)-1-amino-3-[4-methyl-1-(4-methylbenzenesulfonyl)-1H-indazol-5-yl]propyl-2-yl]dimethylamine (900 mg, 65%). MS (m / z): 387.1 (M+H).

[0224] The following intermediates are synthesized using a method similar to that described in Example A13: Int. 81 and General Process IV: Intermediate item (Int.) number structure LC / MS (m / z) name Int. 80 373.2 (M+H) [(2S)-1-amino-3-[1-(4-methylbenzenesulfonyl)-1H-indazol-6-yl]propyl-2-yl]dimethylamine Int. 82 407.1 (M+H) (S)-3-(4-chloro-1-toluenesulfonyl-1H-indazol-5-yl)-N2,N2-dimethylpropane-1,2-diamine Int. 83 407.1 (M+H) (S)-3-(6-chloro-1-toluenesulfonyl-1H-indazol-5-yl)-N2,N2-dimethylpropane-1,2-diamine Int. 84 373.2 (M+H) (S)-N2,N2-Dimethyl-3-(1-toluenesulfonyl-1H-indazol-5-yl)propane-1,2-diamine Int. 85 399.4 (M+H) (S)-2-(pyrrolidin-1-yl)-3-(1-toluenesulfonyl-1H-indazol-5-yl)propyl-1-amine Int. 86 413.1 (M+H) (S)-2-(piperidin-1-yl)-3-(1-toluenesulfonyl-1H-indazol-5-yl)propyl-1-amine Int. 87 531.2 (M+H) (S)-N2-Isopropyl-N2-Methyl-3-(1-Toluenesulfonyl-1H-indazol-5-yl)propane-1,2-diamine Int. 88 391.2 (M+H) (S)-3-(7-fluoro-1-toluenesulfonyl-1H-indazol-5-yl)-N2,N2-dimethylpropane-1,2-diamine Int. 92 390.1 (M+H) (S)-3-(4-fluoro-1-toluenesulfonyl-1H-indazol-5-yl)-N2,N2-dimethylpropane-1,2-diamine

[0225] Example A14: Preparation of (S)-4-(3-amino-2-(dimethylamino)propyl)phenol (133E, "Intermediate 133"):

[0226] Preparation of methyl (S)-2-((tributoxycarbonyl)amino)-3-(2,5-difluoro-4-hydroxyphenyl)propionate (133A): Zinc (26 g, 35 mmol), anhydrous DMF (140 mL), and iodine (1.8 g, 140 mmol) were added to dried RBF. The reaction mixture was stirred for 10 min, and then a solution of methyl (2R)-2-{[(tributoxy)carbonyl]amino}-3-iodopropionate (46 g, 140 mmol) and iodine (1.8 g, 140 mmol) was added, which resulted in exothermic reaction. The reaction mixture was cooled to room temperature for 20 min, and then 4-bromophenol (20 g, 116 mmol), Pd2(dba)3 (5.3 g, 5.8 mmol), and SPhos (4.8 g, 12 mmol) were added to the reaction mixture. The reaction mixture was stirred at 75 °C for 16 h. The crude reaction mixture was cooled to room temperature, quenched with water, diluted with EtOAc, and filtered through diatomaceous earth. The organic layer was then washed with brine (5×), dried over MgSO4, and concentrated. The resulting residue was adsorbed onto silica and purified by column chromatography (silica, 0-50% EtOAc / hex) to give the title compound (27 g, 78%) as a white solid. MS (m / z) = 296.1 [M+H].

[0227] Preparation of (S)-(1-(4-((tributyldimethylsilyl)oxy)-2,5-difluorophenyl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (133B): Methyl (2S)-2-{[(tributyloxy)carbonyl]amino}-3-(2,6-difluoro-4-hydroxyphenyl)propionate (29 g, 98 mmol) was dissolved together with tributyl(chloro)dimethylsilane (16 g, 107 mmol) and 1H-imidazolium (20 g, 293 mmol) in dichloromethane (600 ml). The solution was stirred at room temperature for 24 hours. The solution was diluted with dichloromethane and subsequently washed with saturated sodium bicarbonate solution. The organic layer was filtered through magnesium sulfate, and the filtrate was concentrated to give the desired product (35 g). The product was dissolved in THF (300 mL), cooled to 0 °C, and a solution of lithium borohydride (4 M in THF, 43 mL, 170 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min, then heated to room temperature for 6 h. The reaction mixture was then cooled to 0 °C and quenched by dropwise addition of ammonium chloride solution. The crude reaction mixture was diluted with brine, and the product was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated. The residue was purified by column chromatography (80 g silicon dioxide, 10% DCM / MeOH) to give the title compound (33 g, 60%) as an oil. MS (m / z) = 382.1 [M+Na].

[0228] Preparation of (S)-(1-(4-((tributyldimethylsilyl)oxy)phenyl)-3-(1,3-di-dioxyisoindoline-2-yl)propyl-2-yl)aminocarbamate tributyl ester (133C): N-[(2S)-1-(4-aminomethoxy-3-fluorophenyl)-3-hydroxypropyl-2-yl]aminocarbamate tributyl ester (32 g, 84 mmol), triphenylphosphine (24 g, 92 mmol), and phthalimide (13.6 g, 92 mmol) were dissolved in anhydrous THF (500 mL). The reaction mixture was cooled to 0 °C, and DIAD (18.2 mL, 92 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h, followed by stirring at room temperature for 16 h. This resulted in the formation of a white precipitate. The precipitate was filtered, washed with THF and dried to give the title compound (28 g, 65%) as a white solid. MS (m / z) = 511.1 [M+H].

[0229] Preparation of (S)-2-(3-(2,5-difluoro-4-hydroxyphenyl)-2-(dimethylamino)propyl)isoindoline-1,3-dione (133D): (S)-(1-(4-((tributyldimethylsilyl)oxy)phenyl)-3-(1,3-dioxyisoindoline-2-yl)propyl-2-yl)aminocarbamate tributyl ester (1.8 g, 3.2 mmol) was dissolved in methanol (200 ml), followed by the addition of 1,4-dimethylamine (120 mL, 500 mmol) containing 4 M HCl. The reaction mixture was stirred at 50 °C for 1 h; complete conversion was achieved according to LCMS. The reaction mixture was concentrated, and the residue was wet-milled with ethyl acetate to give a product as a white solid (17 g, 94%), which was used directly in the next step. MS (m / z) = 297.1 [M+H]. The solid was dissolved in MeCN / H₂O (240 ml / 60 ml), followed by the addition of 37 wt% formaldehyde aqueous solution (15 mL, 207 mmol). The reaction mixture was stirred for 30 min, and then NaCNBH₃ (9.8 g, 156 mmol) was added to the reaction mixture in a single addition. According to LCMS, complete conversion occurred after 1 h. The reaction mixture was cooled to 0 °C and quenched with saturated sodium bicarbonate aqueous solution (500 mL). The product was extracted with EtOAc (7×), and the combined organic layers were dried over MgSO₄ and then concentrated. The residue was purified by silica gel chromatography to give the desired product (8.4 g, 50%) as an oil. MS (m / z) = 325.1 [M+H].

[0230] Preparation of (S)-4-(3-amino-2-(dimethylamino)propyl)-2,5-difluorophenol (133E): (S)-2-(3-(2,5-difluoro-4-hydroxyphenyl)-2-(dimethylamino)propyl)isoindoline-1,3-dione (8.4 g, 26 mmol) was dissolved in anhydrous EtOH (250 mL) with 50 wt% hydrazine hydrate aqueous solution (12 mL, 130 mmol). The reaction mixture was stirred at 75 °C for 3 h. The crude reaction mixture was then concentrated, adsorbed onto silica, and purified by column chromatography (40 g silica, 0-20% MeOH / DCM + 1% NH4OH) to give the title compound (3.0 g, 60%) as a white solid. MS (m / z): 195.2 [M+H].

[0231] The following intermediates are synthesized using a method similar to that described in Example A14: Int. 133 and General Process III: Intermediate item (Int.) number structure LC / MS (m / z) name Int. 134 231.2 [M+H] (S)-4-(3-amino-2-(dimethylamino)propyl)-2,5-difluorophenol Int. 135 231.2 [M+H] (S)-4-(3-amino-2-(dimethylamino)propyl)-3,5-difluorophenol Int. 136 223.2 [M+H] (S)-4-(3-amino-2-(dimethylamino)propyl)-3,5-dimethylphenol Int. 137 263.2 [M+H] (S)-4-(3-amino-2-(dimethylamino)propyl)-3-(trifluoromethyl)phenol Int. 138 247.2 [M+H] (S)-4-(3-amino-2-(dimethylamino)propyl)-3-chloro-2-fluorophenol Int. 139 261.2 [M+H] (S)-3-(2-chloro-3-fluoro-4-methoxyphenyl)-N2,N2-dimethylpropane-1,2-diamine Int. 140 230.2 [M+H] (S)-4-(3-amino-2-(dimethylamino)propyl)-3-chlorophenol Int. 141 223.2 [M+H] (S)-4-(3-amino-2-(dimethylamino)propyl)-3-methylphenol Int. 142 229.2 [M+H] (S)-4-(3-amino-2-(dimethylamino)propyl)-2-chlorophenol Int. 143 213.2 [M+H] (S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluorophenol

[0232] Example A15: Preparation of (S)-3-(aminomethyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol ("Intermediate 144"):

[0233] Intermediate 144 was synthesized as described in WO2019195634A1. Synthetic Example B: Compound

[0234] Example B1: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(2-methylthiazolyl-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2,3-difluorobenzoamide ("Compound 1"):

[0235] CDI (22 mg, 0.14 mmol) was added to a solution of acid (Int. 6) (35 mg, 0.125 mmol) in DMF (0.25 mL). The mixture was stirred at room temperature for 1 h. DIEA (0.043 mL, 0.25 mmol) and amine (Int. 41, 35 mg, 0.138 mmol) were added to the mixture, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (20 mL), saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated on a rotary evaporator. The crude material was purified on a silicone column on 0–25% MeOH / DCM (with 1% NH4OH). The purified solvent was concentrated and then wet-milled with MTBE to give the title compound (44 mg, 67%). MS (m / z): 519.2 (M+H).

[0236] Example B2: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(thiazolyl-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2,3-difluorobenzoamide (“Compound 2”):

[0237] Compound 2 (78 mg, 70%) was synthesized from Int. 41 and Int. 40 as described in Example B1. MS (m / z): 505.1 (M+H).

[0238] Example B3: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(2-methylpyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propamido)propyl)-2,3-difluorobenzoamide (“Compound 3”):

[0239] Compound 3 (19 mg, 51%) was synthesized from Int. 41 and Int. 9 as described in Example B1. MS (m / z): 514.2 (M+H).

[0240] Example B4 4-((S)-2-(dimethylamino)-3-((R)-3-(6-methylpyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)propyl)-2,3-difluorobenzoamide (“Compound 4”):

[0241] Compound 4 (38 mg, 68%) was synthesized from Int. 41 and Int. 10 as described in Example B1. MS (m / z): 513.2 (M+H).

[0242] Example B5: Preparation of 4-[(2S)-3-[(3R)-3-(5-chloropyrimidin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]-2-(dimethylamino)propyl]-2,5-difluorobenzoamide (“Compound 5”):

[0243] Dimethoxy(methyl)silane (81.0 µL, 2.5 eq., 663 µmol) was added to a stirred mixture of (R)-DTBM-SEGPHOS (3.13 mg, 0.01 eq., 2.65 µmol) and copper diacetate (2.41 mg, 0.05 eq., 13.3 µmol) in toluene (1 mL) at 0 °C, followed by the addition of 2-methylprop-2-ol (85.4 µL, 2 eq., 900 µmol). A solution of 4-[(2S)-3-[(2Z)-3-(5-chloropyrimidin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propyl-2-enylamino]-2-(dimethylamino)propyl]-2,5-difluorobenzoamide (141 mg, 265 µmol) in toluene (4 mL) was added dropwise. The reaction mixture was stirred gradually overnight at room temperature. LC / MS showed approximately 13% conversion. The mixture was cooled in an ice bath and 10 mol% S-DTBM-SEGPHOS, 10 mol% Cu(OAc)2, 5 eq DMMS, and 4 eq t-BuOH were added. (A large number of bubbles appeared at this point). The ice bath was removed and the mixture was stirred at room temperature for 3 h. LC / MS showed the expected conversion of the product >95%. Solid NH4F was added to the mixture and stirred vigorously for 15 minutes, followed by the addition of H2O and stirring for another 10 minutes. The mixture was then extracted with EtOAc (3×). The combined extracts were dried over MgSO4, concentrated to dryness, and purified by rapid chromatography (0–15% MeOH / DCM) to give 4-[(2S)-3-[(3R)-3-(5-chloropyrimidin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]-2-(dimethylamino)propyl]-2,5-difluorobenzoamide (38.5 mg, 27%). MS (m / z): 534.1 (M+H).

[0244] Example B6: Preparation of 4-((2S)-2-(dimethylamino)-3-(2-(pyrimidin-2-yl)cyclopropane-1-methamido)propyl)-3,5-dimethylbenzamide (“Compound 6”):

[0245] HATU (220 mg, 1.2 eq., 0.58 mmol) was added to a stirred mixture of (S)-4-(3-amino-2-(dimethylamino)propyl)-3,5-dimethylbenzylamine (Int. 74, 120 mg, 0.48 mmol), 2-(pyrimidin-2-yl)cyclopropane-1-carboxylic acid (Int. 7, 95 mg, 0.58 mmol) and DIEA (0.17 mL, 2.5 eq, 1.2 mmol) in DMF (2 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. H2O was added, and the precipitated solid was collected, washed with H2O, dried, and purified by rapid chromatography (0-10% MeOH / DCM) to give 4-((2S)-2-(dimethylamino)-3-(2-(pyrimidin-2-yl)cyclopropane-1-methamido)propyl)-3,5-dimethylbenzamide (108 mg, 65%). MS (m / z): 396.2 (M+H).

[0246] Example B7: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-3,5-dimethylbenzamide ("Compound 7")

[0247] HATU (103 mg, 1.2 eq., 270 µmol) was added to a stirred mixture of 4-[(2S)-3-amino-2-(dimethylamino)propyl]-3,5-dimethylbenzamide (Int. 74, 56.2 mg, 1 eq., 225 µmol), (3S)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid (Int. 4, 58.2 mg, 225 µmol), and DIEA (252 mg, 2.5 eq., 563 µmol) in DMF (2 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. H2O was added, and the precipitated solid was collected, washed with H2O, dried, and purified by rapid chromatography (0-10% MeOH / DCM) to give 4-[(2S)-2-(dimethylamino)-3-[(3R)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]-3,5-dimethylbenzamide (37.3 mg, 76.2 µmol). MS (m / z): 490.3 (M+H).

[0248] Example B8: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-3,5-dimethylbenzamide (“Compound 8”):

[0249] Compound 8 (67.5 mg, 64%) was synthesized from Int. 74 and Int. 3 as described in Example B7. MS (m / z): 490.3 (M+H).

[0250] Example B9: Preparation of 4-[(2S)-2-(dimethylamino)-3-[(3S)-5-methyl-3-phenylhexanoamino]propyl]-3,5-dimethylbenzylamine ("Compound 9"):

[0251] A solution of 4-[(2S)-3-amino-2-(dimethylamino)propyl]benzamide (Int. 74, 28.2 mg, 113 mmol) in DMF (1 ml) was added to (S)-5-methyl-3-phenylhexanoic acid (Int. 68, 25.6 mg, 124 mmol), EDC (24 mg, 124 mmol)), 1-hydroxybenzotriazole (15.3 mg, 113 mmol), and N,N'-diisopropylethylamine (16.1 mg, 124 mmol). The solution was stirred at room temperature for 3 hours. It was then diluted with ethyl acetate and washed with water. The organic layer was filtered through magnesium sulfate and then concentrated. The residue was purified by rapid chromatography (0-25% MeOH / DCM in 1% NH4OH) to give the title compound (25 mg, 52%). MS (m / z): 438.3 (M+H).

[0252] Example B10: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-4-methyl-3-phenylpentanylamino)propyl)-3,5-dimethylbenzylamine ("Compound 10"):

[0253] Compound 10 (24.6 mg, 51%) was synthesized from Int. 74 and Int. 66 as described in Example B9. MS (m / z): 424.3 (M+H).

[0254] Example B11: Preparation of 4-((S)-3-((R)-3-cyclopropyl-3-phenylpropionic acid)-2-(dimethylamino)propyl)-3,5-dimethylbenzylamine ("Compound 11"):

[0255] Compound 11 (10 mg, 21%) was synthesized from Int. 74 and Int. 64 as described in Example B9. MS (m / z): 422.3 (M+H).

[0256] Example B12: Preparation of 4-[(2S)-2-(dimethylamino)-3-[(3R)-5-methyl-3-phenylhexanoamino]propyl]-3,5-dimethylbenzylamine (“Compound 12”):

[0257] Compound 12 (5.1 mg, 7%) was synthesized from Int. 74 and Int. 67 as described in Example B9. MS (m / z): 438.5 (M+H).

[0258] Example B13: Preparation of 4-[(2S)-3-[(3S)-4,4-dimethyl-3-phenylpentanylamino]-2-(dimethylamino)propyl]-3,5-dimethylbenzylamine (“Compound 13”):

[0259] Compound 13 (25 mg, 35%) was synthesized from Int. 74 and Int. 70 as described in Example B9. MS (m / z): 438.3 (M+H).

[0260] Example B14: Preparation of 3-chloro-4-((S)-2-(dimethylamino)-3-((R)-3-phenylbutyrylamino)propyl)benzamide ("Compound 14")

[0261] Compound 14 (17.1 mg, 17%) was synthesized from Int. 16 and Int. 61 as described in Example B9. MS (m / z): 402.2 (M+H).

[0262] Example B15: Preparation of 3-chloro-4-((S)-2-(dimethylamino)-3-((S)-3-phenylbutyrylamino)propyl)benzamide ("Compound 15"):

[0263] Compound 15 (32 mg, 37%) was synthesized from Int. 16 and Int. 62 as described in Example B9. MS (m / z): 402.2 (M+H).

[0264] Example B16: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[(3S)-3-(2-methyl-1,3-thiazo-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]-2-fluorobenzamide (“Compound 16”):

[0265] Compound 16 (46 mg, 74%) was synthesized from Int. 13 and Int. 6 as described in Example B1. MS (m / z): 535.2 (M+H).

[0266] Example B17: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[(3S)-3-(6-methylpyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propamido]propyl]-2-fluorobenzamide ("Compound 17")

[0267] TSTU (25.1 mg, 0.0834 mmol) was added to a solution of Int. 11 (22.8 mg, 0.0834 mmol) and DIEA (29.1 μL, 0.167 mmol) in DMF (0.25 mL). The mixture was stirred at room temperature for 1 hour. Int. 13 (25.1 mg, 0.0918 mmol) was added in a single addition, and stirring was continued at room temperature for another hour. The reaction mixture was diluted with ethyl acetate (15 mL) and saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography (0-10% MeOH / DCM with 1% NH4OH) to give the title compound (22 mg, 50%). MS (m / z): 529.2 (M+H).

[0268] Example B18: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[(3R)-3-(pyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]-2-fluorobenzamide (“Compound 18”):

[0269] Compound 18 (20.1 mg, 53%) was synthesized from Int. 13 and Int. 15 as described in Example B9. MS (m / z): 515.2 (M+H).

[0270] Example B19: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[3-(pyridin-4-yl)-3-[1-(trifluoromethyl)cyclopropyl]propamido]propyl]-2-fluorobenzamide ("Compound 19")

[0271] Compound 19 (30 mg, 56%) was synthesized from Int. 13 and Int. 12 as described in Example B9. MS (m / z): 515.2 (M+H).

[0272] Example B20: Preparation of 3-chloro-4-((S)-2-(dimethylamino)-3-((R)-3-(6-methylpyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluorobenzamide ("Compound 20")

[0273] Compound 20 (42 mg, 77%) was synthesized from Int. 13 and Int. 10 as described in Example B17. MS (m / z): 529.1 (M+H).

[0274] Example B21: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[(3R)-3-(2-methylpyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propamido]propyl]-2-fluorobenzamide (“Compound 21”):

[0275] Compound 21 (15.8 mg, 37%) was synthesized from Int. 13 and Int. 9 as described in Example B9. MS (m / z): 530.2 (M+H).

[0276] Example B22: Preparation of 3-chloro-4-[(2S)-3-[3-(5-chloropyrimidin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]-2-(dimethylamino)propyl]-2-fluorobenzamide (“Compound 22”):

[0277] Compound 22 (25.1 mg, 55%) was synthesized from Int. 13 and Int. 14 as described in Example B9. MS (m / z): 550.1 (M+H).

[0278] Example B23: Preparation of 3-chloro-4-((S)-3-((R)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(pyrrolidin-1-yl)propyl)benzamide ("Compound 23"):

[0279] Step 1: Methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(2-chloro-4-cyanophenyl)propionate (23B) was prepared by the same method as described in intermediate 1B.

[0280] Step 2: N-[(2S)-1-(2-chloro-4-cyanophenyl)-3-hydroxypropyl-2-yl]aminocarbamate tributyl ester (23C) was prepared by the same method as described in intermediate 1C.

[0281] Step 3: N-[(2S)-1-(4-aminomethoxy-3-chlorophenyl)-3-hydroxypropyl-2-yl]aminocarbamate tributyl ester (23D) was prepared by the same method as described in intermediate 1D.

[0282] Step 4: N-[(2S)-1-(4-aminomethoxy-3-chlorophenyl)-3-(1,3-dioxy-2,3-dihydro-1H-isoindol-2-yl)propyl-2-yl]aminocarbamate tributyl ester (23E) was prepared by the same method as described in intermediate 1E.

[0283] Step 5: 3-chloro-4-[(2S)-3-(1,3-dioxy-2,3-dihydro-1H-isoindol-2-yl)-2-(pyrrolidin-1-yl)propyl]benzamide (23F) was prepared by the same method as described in intermediate 1F. MS (m / z): 412.0 (M+H).

[0284] Step 6: 4-[(2S)-3-amino-2-(pyrrolidin-1-yl)propyl]-3-chlorobenzylamine (23G) was prepared by the same method as described in intermediate 1G. MS (m / z): 282.0 (M+H).

[0285] Step 7: 3-Chloro-4-((S)-3-((R)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(pyrrolidin-1-yl)propyl)benzamide (“Compound 23”). Add (3R)-3-(2-methylpyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid (30.0 mg, 0.11 mmol), DIPEA (0.04 mL, 0.2 mmol), and DMF (0.4 mL) to a 1 duralumin vial. Add TSTU (32.9 mg, 0.11 mmol) to the reaction mixture. After stirring the reaction mixture for 40 minutes, the mixture was added to 0.4 mL of DMF containing 4-[(2S)-3-amino-2-(pyrrolidin-1-yl)propyl]-2-fluorobenzamide (31.9 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with EtOAc (10 mL), washed with saturated NaHCO3 and brine (3×), dried over MgSO4, and then concentrated. The residue was purified by column chromatography (4 g silicon dioxide, 0-25% MeOH / DCM with 1% NH4OH), and dissociated at 20% MeOH / DCM to give the title compound (30.1 mg, 53%). MS (m / z): 524.3 (M+H).

[0286] Example B24: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[(3R)-3-(2-methylpyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propamido]propyl]benzamide (“Compound 24”):

[0287] Compound 24 (74.8 mg, 21%) was synthesized from Int. 16 and Int. 9 as described in Example B9. MS (m / z): 512.3 (M+H).

[0288] Example B25: Preparation of 3-chloro-4-[(2S)-3-[(3S)-3-cyclopropyl-3-(2-methylpyrimidin-5-yl)propionic acid]-2-(dimethylamino)propyl]benzamide (“Compound 25”):

[0289] Compound 25 (35 mg, 70%) was synthesized from Int. 16 and Int. 18 as described in Example B17. MS (m / z): 444.2 (M+H).

[0290] Example B26: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[3-(pyridin-4-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]benzamide ("Compound 26")

[0291] Compound 26 (34 mg, 64%) was synthesized from Int. 16 and Int. 12 as described in Example B9. MS (m / z): 497.2 (M+H).

[0292] Example B27: Preparation of 3-chloro-4-((2S)-2-(dimethylamino)-3-(3-(pyrimidin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)benzamide ("Compound 27")

[0293] Compound 27 (26 mg, 54%) was synthesized from Int. 16 and Int. 19 as described in Example B9. MS (m / z): 498.1 (M+H).

[0294] Example B28: Preparation of 3-chloro-4-((S)-2-(dimethylamino)-3-((R)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)benzamide ("Compound 28")

[0295] Compound 28 (226 mg, 60%) was synthesized from Int. 16 and Int. 15 as described in Example B9. MS (m / z): 497.2 (M+H).

[0296] Example B29: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-{3-[2-(dimethylamino)pyrimidin-5-yl]-3-[1-(trifluoromethyl)cyclopropyl]propamido}propyl]benzamide (“Compound 29”):

[0297] Compound 29 (17.5 mg, 64%) was synthesized from Int. 16 and Int. 20 as described in Example B9. MS (m / z): 541.2 (M+H).

[0298] Example B30: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[3-(pyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propamido]propyl]benzamide (“Compound 30”):

[0299] Compound 30 (39.8 mg, 84%) was synthesized from Int. 16 and Int. 21 as described in Example B9. MS (m / z): 498.2 (M+H).

[0300] Example B31: Preparation of 3-chloro-4-[(2S)-3-[3-(5-chloropyrimidin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]-2-(dimethylamino)propyl]benzamide ("Compound 31")

[0301] Compound 31 (43.3 mg, 64%) was synthesized from Int. 16 and Int. 14 as described in Example B9. MS (m / z): 532.2 (M+H).

[0302] Example B32: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-{3-[1-(trifluoromethyl)cyclopropyl]-3-[6-(trifluoromethyl)pyridin-3-yl]propamido}propyl]benzamide (“Compound 32”):

[0303] Compound 32 (36.3, 70%) was synthesized from Int. 16 and Int. 22 as described in Example B17. MS (m / z): 565.2 (M+H).

[0304] Example B33: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[3-(2-methoxypyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]benzamide ("Compound 33")

[0305] Compound 33 (28.9 mg, 39%) was synthesized from Int. 16 and Int. 23 as described in Example B9. MS (m / z): 528.2 (M+H).

[0306] Example B34: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[3-(2-methylpyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propamido]propyl]benzamide ("Compound 34")

[0307] Compound 34 (15.7 mg, 26%) was synthesized from Int. 16 and Int. 24 as described in Example B9. MS (m / z): 512.2 (M+H).

[0308] Example B35: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[3-(6-methoxypyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]benzamide ("Compound 35")

[0309] Compound 35 (45 mg, 72%) was synthesized from Int. 16 and Int. 25 as described in Example B9. MS (m / z): 527.2 (M+H).

[0310] Example B36: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[3-(5-fluoropyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]benzamide ("Compound 36")

[0311] Compound 36 (39.9 mg, 79%) was synthesized from Int. 16 and Int. 26 as described in Example B9. MS (m / z): 515.2 (M+H).

[0312] Example B37: Preparation of 3-chloro-4-[(2S)-3-[3-(5-chloropyridin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]-2-(dimethylamino)propyl]benzamide ("Compound 37")

[0313] Compound 37 (39.9 mg, 79%) was synthesized from Int. 16 and Int. 27 as described in Example B9. MS (m / z): 531.2 (M+H).

[0314] Example B38: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[3-(pyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]benzamide ("Compound 38")

[0315] Compound 38 (90 mg, 90%) was synthesized from Int. 16 and Int. 28 as described in Example B9. MS (m / z): 497.2 (M+H).

[0316] Example B39: Preparation of 3-chloro-4-[(2S)-2-(dimethylamino)-3-[(3R)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]benzamide ("Compound 39")

[0317] Compound 39 (36.3 mg, 70%) was synthesized from Int. 16 and Int. 3 as described in Example B17. MS (m / z): 496.2 (M+H).

[0318] Example B40: Preparation of 3-chloro-4-((S)-2-(dimethylamino)-3-((R)-4-methyl-3-phenylpentaamino)propyl)benzamide ("Compound 40")

[0319] Compound 40 (10 mg, 15%) was synthesized from Int. 16 and Int. 66 as described in Example B17. MS (m / z): 430.2 (M+H).

[0320] Example B41: Preparation of 3-chloro-4-((S)-2-(dimethylamino)-3-((S)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)benzamide ("Compound 41")

[0321] Compound 41 (220 mg, 56%) was synthesized from Int. 16 and Int. 29 as described in Example B9. MS (m / z): 497.2 (M+H).

[0322] Example B42: Preparation of 4-((S)-3-((S)-3-cyclopropyl-3-(2-methylpyrimidin-5-yl)propionic acid)-2-(dimethylamino)propyl)-2-fluoro-3-methylbenzylamine ("Compound 42"):

[0323] Compound 42 (10 mg, 28%) was synthesized from Int. 30 and Int. 18 as described in Example B1. MS (m / z): 442.2 (M+H).

[0324] Example B43: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(2-methylthiazolyl-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluoro-3-methylbenzylamine ("Compound 43")

[0325] Compound 43 (38 mg, 59%) was synthesized from Int. 30 and Int. 6 as described in Example B1. MS (m / z): 515.2 (M+H).

[0326] Example B44: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(2-methylpyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propamido)propyl)-2-fluoro-3-methylbenzamide ("Compound 44")

[0327] Compound 44 (18 mg, 49%) was synthesized from Int. 30 and Int. 9 as described in Example B1. MS (m / z): 510.2 (M+H).

[0328] Example B45: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(5-fluoropyridin-3-yl)-4,4-dimethylpentylamino)propyl)-2-fluoro-3-methylbenzylamine ("Compound 45")

[0329] Compound 45 (18 mg, 36%) was synthesized from Int.30 and Int.34 as described in Example B17. MS (m / z): 461.2 (M+H).

[0330] Example B46: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(6-methylpyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluoro-3-methylbenzamide ("Compound 46")

[0331] Compound 46 (33 mg, 71%) was synthesized from Int. 30 and Int. 10 as described in Example B17. MS (m / z): 509.3 (M+H).

[0332] Example B47: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(6-methylpyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2,6-difluorobenzoamide (“Compound 47”):

[0333] Compound 47 (5 mg, 10%) was synthesized from Int. 35 and Int. 10 as described in Example B9. MS (m / z): 513.2 (M+H).

[0334] Example B48: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(2-methylpyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propamido)propyl)-2,6-difluorobenzoamide (“Compound 48”):

[0335] Compound 48 (12 mg, 20%) was synthesized from Int. 35 and Int. 9 as described in Example B9. MS (m / z): 514.2 (M+H).

[0336] Example B49: Preparation of 4-[(2S)-2-(dimethylamino)-3-[3-(6-methoxypyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]-2,6-difluorobenzoamide (“Compound 49”):

[0337] Compound 49 (15 mg, 45%) was synthesized from Int. 35 and Int. 25 as described in Example B9. MS (m / z): 529.3 (M+H).

[0338] Example B50: Preparation of 4-[(2S)-2-(dimethylamino)-3-[3-(pyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]-2,6-difluorobenzoamide (“Compound 50”):

[0339] Compound 50 (30 mg, 51%) was synthesized from Int. 35 and Int. 28 as described in Example B9. MS (m / z): 499.2 (M+H).

[0340] Example B51: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(furan-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic)propyl)-2-fluorobenzamide ("Compound 51")

[0341] Compound 51 (155 mg, 69%) was synthesized from Int. 2 and Int. 36 as described in Example B1. MS (m / z): 470.2 (M+H).

[0342] Example B52: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(5-methylthiophen-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluorobenzamide ("Compound 52")

[0343] Compound 52 (155 mg, 69%) was synthesized from Int. 2 and Int. 37 as described in Example B9. MS (m / z): 500.2 (M+H).

[0344] Example B53: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(5-methylthiophen-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluorobenzamide ("Compound 53")

[0345] Compound 53 (15 mg, 34%) was synthesized from Int. 2 and Int. 38 as described in Example B9. MS (m / z): 500.2 (M+H).

[0346] Example B54: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(thiophen-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluorobenzamide ("Compound 54")

[0347] Compound 54 (40 mg, 79%) was synthesized from Int. 2 and Int. 39 as described in Example B9. MS (m / z): 486.1 (M+H).

[0348] Example B55: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(thiazolyl-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluorobenzamide ("Compound 55")

[0349] Compound 55 (34 mg, 74%) was synthesized from Int. 2 and Int. 40 as described in Example B1. MS (m / z): 487.2 (M+H).

[0350] Example B56: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(5-methylthiazo-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluorobenzamide ("Compound 56")

[0351] Compound 56 (72 mg, 81%) was synthesized from Int. 2 and Int. 43 as described in Example B1. MS (m / z): 501.1 (M+H).

[0352] Example B57: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(5-methylpyrimidin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluorobenzamide ("Compound 57")

[0353] A mixture of Int. 2 (94.8 mg, 2 eq., 396 µmol) and methyl (3S)-3-(5-methylpyrimidin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionate (57.1 mg, 198 µmol) was heated to a net 150 °C for 4 h by microwave. The mixture was cooled to room temperature, dissolved in DCM, and purified by rapid chromatography (0-15% MeOH / DCM) to give 4-[(2S)-2-(dimethylamino)-3-[(3R)-3-(5-methylpyrimidin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionamino]propyl]-2-fluorobenzamide (9.8 mg, 10%). MS (m / z): 496.2 (M+H).

[0354] Example B58: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(2-methylthiazolyl-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluorobenzamide ("Compound 58")

[0355] Compound 58 (59 mg, 68%) was synthesized from Int. 2 and Int. 42 as described in Example B1. MS (m / z): 501.2 (M+H).

[0356] Example B59: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(2-methylthiazolyl-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluorobenzamide ("Compound 59"):

[0357] Compound 59 (72 mg, 81%) was synthesized from Int. 2 and Int. 43 as described in Example B1. MS (m / z): 501.2 (M+H).

[0358] Example B60: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-5-methyl-3-(pyridin-3-yl)hexamido)propyl)-2-fluorobenzamide ("Compound 60")

[0359] Compound 60 (31 mg, 68%) was synthesized from Int. 2 and Int. 45 as described in Example B9. MS (m / z): 429.2 (M+H).

[0360] Example B61: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(3-fluoropyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic)propyl)-2-fluorobenzamide ("Compound 61")

[0361] Compound 61 (31 mg, 68%) was synthesized from Int. 2 and Int. 47 as described in Example B9. MS (m / z): 499.2 (M+H).

[0362] Example B62: Preparation of 4-((S)-3-((S)-4-cyclopropyl-3-(pyridin-4-yl)butyramine)-2-(dimethylamino)propyl)-2-fluorobenzamide ("Compound 62"):

[0363] Compound 62 (28 mg, 63%) was synthesized from Int. 2 and Int. 46 as described in Example B9. MS (m / z): 427.2 (M+H).

[0364] Example B63: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(5-fluoropyridin-3-yl)-4,4-dimethylpentylamino)propyl)-2-fluorobenzamide ("Compound 63")

[0365] Compound 63 (30 mg, 80%) was synthesized from Int. 2 and Int. 34 as described in Example B17. MS (m / z): 447.2 (M+H).

[0366] Example B64: Preparation of 4-((S)-3-((R)-4-cyclopropyl-3-(pyrimidin-5-yl)butyramine)-2-(dimethylamino)propyl)-2-fluorobenzoamide ("Compound 64"):

[0367] Compound 64 (24 mg, 54%) was synthesized from Int. 2 and Int. 48 as described in Example B9. MS (m / z): 427.2 (M+H).

[0368] Example B65: Preparation of 2-fluoro-4-((S)-3-((R)-3-(2-methylpyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(pyrrolidin-1-yl)propyl)benzamide ("Compound 65")

[0369] Compound 65 (41 mg, 71%) was synthesized from Int. 2 and 23G as described in Example B23. MS (m / z): 522.2 (M+H).

[0370] Example B66: Preparation of 4-((S)-3-((R)-4-cyclopropyl-3-(pyridin-3-yl)butyramine)-2-(dimethylamino)propyl)-2-fluorobenzamide ("Compound 66")

[0371] Compound 66 (14 mg, 43%) was synthesized from Int. 2 and Int. 49 as described in Example B9. MS (m / z): 427.3 (M+H).

[0372] Example B67: Preparation of 4-((S)-3-((S)-3-cyclopropyl-3-(2-methylpyrimidin-5-yl)propionic acid)-2-(dimethylamino)propyl)-2-fluorobenzamide ("Compound 67"):

[0373] Compound 67 (14 mg, 43%) was synthesized from Int. 2 and Int. 18 as described in Example B9. MS (m / z): 428.0 (M+H).

[0374] Example B68: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(2-methylpyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propamido)propyl)-2-fluorobenzamide ("Compound 68")

[0375] Compound 68 (14 mg, 43%) was synthesized from Int. 2 and Int. 9 as described in Example B9. MS (m / z): 496.3 (M+H).

[0376] Example B69: Preparation of 4-((2S)-3-(3-(5-chloropyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(dimethylamino)propyl)-2-fluorobenzamide ("Compound 69"):

[0377] Compound 69 (28 mg, 72%) was synthesized from Int. 2 and Int. 109 as described in Example B9. MS (m / z): 515.2 (M+H).

[0378] Example B70: Preparation of 4-[(2S)-2-(dimethylamino)-3-[3-(pyridin-4-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]-2-fluorobenzamide ("Compound 70")

[0379] Compound 70 (31 mg, 61%) was synthesized from Int. 2 and Int. 12 as described in Example B9. MS (m / z): 481.2 (M+H).

[0380] Example B71: Preparation of 4-[(2S)-2-(dimethylamino)-3-[3-(pyrimidin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propamido]propyl]-2-fluorobenzamide ("Compound 71")

[0381] Compound 71 (25 mg, 67%) was synthesized from Int. 2 and Int. 19 as described in Example B9. MS (m / z): 482.3 (M+H).

[0382] Example B72: Preparation of 4-[(2S)-2-(dimethylamino)-3-[3-(pyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]-2-fluorobenzamide ("Compound 72")

[0383] Compound 72 (17.2 mg, 43%) was synthesized from Int. 2 and Int. 21 as described in Example B9. MS (m / z): 482.2 (M+H).

[0384] Example B73: Preparation of 4-[(2S)-3-[3-(5-chloropyrimidin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]-2-(dimethylamino)propyl]-2-fluorobenzamide ("Compound 73"):

[0385] Compound 73 (10.2 mg, 17%) was synthesized from Int. 2 and Int. 101 as described in Example B9. MS (m / z): 516.2 (M+H).

[0386] Example B74: Preparation of 4-[(2S)-2-(dimethylamino)-3-[3-(pyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]-2-fluorobenzamide ("Compound 74")

[0387] Compound 74 (34 mg, 70%) was synthesized from Int. 2 and Int. 15 as described in Example B9. MS (m / z): 481.2 (M+H).

[0388] Example B75: Preparation of 4-[(2S)-2-(dimethylamino)-3-[(3R)-3-(6-methylpyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]-2-fluorobenzamide ("Compound 75")

[0389] Compound 75 (34 mg, 70%) was synthesized from Int. 2 and Int. 10 as described in Example B17. MS (m / z): 495.2 (M+H).

[0390] Example B76: Preparation of 4-[(2S)-2-(dimethylamino)-3-[3-(5-fluoropyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]-2-fluorobenzamide ("Compound 76")

[0391] Compound 76 (36.4 mg, 67%) was synthesized from Int. 2 and Int. 26 as described in Example B9. MS (m / z): 499.2 (M+H).

[0392] Example B77: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionic)propyl)-2-fluorobenzamide ("Compound 77")

[0393] Compound 77 (27 mg, 58%) was synthesized from Int. 2 and Int. 3 as described in Example B17. MS (m / z): 480.3 (M+H).

[0394] Example B78: Preparation of 4-[(2S)-2-(dimethylamino)-3-[(3S)-4-methyl-3-(pyridin-3-yl)pentylamino]propyl]-2-fluorobenzamide ("Compound 78")

[0395] Compound 78 (20 mg, 32%) was synthesized from Int. 2 and Int. 50 as described in Example B17. MS (m / z): 415.2 (M+H).

[0396] Example B79: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(2-methylpyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)benzamide ("Compound 79")

[0397] Compound 79 (20 mg, 32%) was synthesized from Int. 73 and Int. 9 as described in Example B9. MS (m / z): 478.2 (M+H).

[0398] Example B80: Preparation of 4-((S)-3-((R)-3-(3,4-dichlorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(dimethylamino)propyl)benzamide ("Compound 80"):

[0399] Compound 80 (23.1 mg, 46%) was synthesized from Int. 73 and Int. 51 as described in Example B9. MS (m / z): 530.1 (M+H).

[0400] Example B81: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(pyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)benzamide ("Compound 81")

[0401] Compound 81 (20 mg, 32%) was synthesized from Int. 73 and Int. 52 as described in Example B9. MS (m / z): 463.2 (M+H).

[0402] Example B82: Preparation of 4-((S)-2-(methylamino)-3-((S)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propylamino)propyl)benzamide ("Compound 82")

[0403] Step 1: Preparation of 4-((S)-2-(benzyl(methyl)amino)-3-((S)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)benzylamine. TSTU (36.1 mg, 0.120 mmol) was added in a single dose to a solution of (3S)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid (Int. 56, 31.0 mg, 0.120 mmol) and DIEA (31.4 μL, 0.180 mmol) in DMF (0.45 mL). The mixture was stirred at room temperature for one hour. 4-[(2S)-3-amino-2-[benzyl(methyl)amino]propyl]benzylamine (Int. 53, 35.4 mg, 0.120 mmol) was then added to the reaction mixture, and stirring was continued for another hour. The reaction mixture was diluted with ethyl acetate and saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography (0-10% MeOH / DCM with 1% NH4OH) to give the title compound (49 mg, 77%). MS (m / z): 538.2 (M+H).

[0404] Step 2: Preparation of 4-((S)-2-(methylamino)-3-((S)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propylamino)propyl)benzamide. EtOH (10 mL) containing compound 82A (44 mg, 0.0818 mmol) and 20% Pd(OH)2 / carbon (44 mg) was treated with H2 at 55 psi for 6 hours. The catalyst was removed by filtration, and the product was washed with EtOH and concentrated. The crude product was purified by reverse-phase preparative HPLC on a C-18 column (0-100% ACN / 0.1% TFA aqueous solution with 0.1% TFA). The purified fractions were combined, pH adjusted to 9 by adding saturated NaHCO3 (aqueous solution), extracted with DCM (3×), dried over MgSO4, filtered, and concentrated to give the title compound (9 mg, 24%). MS (m / z): 448.2 (M+H).

[0405] Example B83: Preparation of 4-((S)-3-((R)-3-(4-chlorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(dimethylamino)propyl)benzamide ("Compound 83"):

[0406] Compound 83 (51 mg, 84%) was synthesized from Int. 73 and Int. 54 as described in Example B17. MS (m / z): 496.2 (M+H).

[0407] Example B84: Preparation of 4-[(2S)-2-(dimethylamino)-3-[(3R)-3-(pyridin-2-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]benzamide ("Compound 84")

[0408] Compound 84 (151 mg, 54%) was synthesized from Int. 73 and Int. 55 as described in Example B9. MS (m / z): 463.2 (M+H).

[0409] Example B85: Preparation of 4-[(2S)-2-(methylamino)-3-[(3R)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]benzamide ("Compound 85")

[0410] Compound 85 (9 mg, 24%) was synthesized as described in Example B82. MS (m / z): 448.2 (M+H).

[0411] Example B86: Preparation of 4-[(2S)-2-[benzyl(methyl)amino]-3-[(3R)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]benzylamine ("Compound 86")

[0412] Compound 86 (49 mg, 77%) was synthesized as described in Example B82. MS (m / z): 538.2 (M+H).

[0413] Example B87: Preparation of 4-[(2S)-2-amino-3-[(3R)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]benzamide ("Compound 87")

[0414] Step 1: Preparation of N-[(2S)-1-(4-aminomethoxyphenyl)-3-[(3R)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl-2-yl]aminocarbamate (87A). TSTU (36.1 mg, 0.120 mmol) was added in a single dose to a solution of acid (Int. 3, 31.0 mg, 0.120 mmol) and DIEA (31.4 μL, 0.180 mmol) in DMF (0.45 mL). The mixture was stirred at room temperature for one hour. Then, amine (35.2 mg, 0.120 mmol) was added to the reaction mixture, and stirring was continued for another hour. The reaction mixture was diluted with ethyl acetate (15 mL) and saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was purified by a silicone column (0-10% MeOH / DCM with 1% NH4OH) to give the title compound (52 mg, 81%). MS (m / z): 556.3 (M+H).

[0415] Step 2: Preparation of 4-[(2S)-2-amino-3-[(3R)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]benzamide (compound 87). MeOH (0.5 mL) containing compound 87A (50 mg, 0.0937 mmol) was treated with dialkyl containing 4N HCl for 2 hours at room temperature. The solvent was removed by rotary evaporation, the solid was wet-milled with ethyl ether, filtered, washed with ether, and dried under vacuum to give the title compound (48 mg, 100%) in HCl salt form. MS (m / z): 434.2 (M+H).

[0416] Example B88: Preparation of 4-[(2S)-2-(dimethylamino)-3-[(3S)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]benzamide ("Compound 88")

[0417] Compound 88 (77.2 mg, 41%) was synthesized from Int. 73 and Int. 56 as described in Example B9. MS (m / z): 462.2 (M+H).

[0418] Example B89: Preparation of 4-[(2S)-2-(dimethylamino)-3-[(3R)-3-phenyl-3-[1-(trifluoromethyl)cyclopropyl]propionic acid]propyl]benzamide ("Compound 89")

[0419] Compound 89 (377 mg, 86%) was synthesized from Int. 73 and Int. 3 as described in Example B9. MS (m / z): 462.2 (M+H).

[0420] Example B90: Preparation of 4-[(2S)-3-[(3S)-4-cyclobutyl-3-phenylbutyramine]-2-(dimethylamino)propyl]benzamide ("Compound 90"):

[0421] Compound 90 (89.9 mg, 27%) was synthesized from Int. 73 and Int. 57 as described in Example B9. MS (m / z): 422.2 (M+H).

[0422] Example B91: Preparation of 4-[(2S)-2-(dimethylamino)-3-[(3S)-5-methyl-3-phenylhexanoamino]propyl]benzamide ("Compound 91"):

[0423] Compound 91 (620 mg, 60%) was synthesized from Int. 73 and Int. 68 as described in Example B9. MS (m / z): 410.3 (M+H).

[0424] Example B92: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-4-methyl-3-phenylpentanylamino)propyl)benzamide ("Compound 92")

[0425] Compound 92 (26 mg, 58%) was synthesized from Int. 73 and Int. 66 as described in Example B9. MS (m / z): 396.3 (M+H).

[0426] Example B93: Preparation of 4-[(2S)-3-[(3R)-4,4-dimethyl-3-phenylpentanylamino]-2-(dimethylamino)propyl]benzamide ("Compound 93")

[0427] Compound 93 (49 mg, 66%) was synthesized from Int. 73 and Int. 69 as described in Example B9. MS (m / z): 410.2 (M+H).

[0428] Example B94: Preparation of 4-[(2S)-2-(dimethylamino)-3-[(3S)-4-methyl-3-phenylpentaamino]propyl]benzamide ("Compound 94")

[0429] Compound 94 (45 mg, 72%) was synthesized from Int. 73 and Int. 94 as described in Example B9. MS (m / z): 396.5 (M+H).

[0430] Example B95: Preparation of 4-((S)-3-((R)-4,4-dimethyl-3-phenylpentanylamino)-2-(dimethylamino)propyl)benzamide ("Compound 95")

[0431] Compound 95 (51 mg, 69%) was synthesized from Int. 73 and Int. 69 as described in Example B9. MS (m / z): 410.3 (M+H).

[0432] Example B96: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-5-methyl-3-phenylhexanoamino)propyl)benzamide ("Compound 96")

[0433] Compound 96 (48 mg, 74%) was synthesized from Int. 73 and Int. 67 as described in Example B9. MS (m / z): 410.3 (M+H).

[0434] Example B97: Preparation of 4-((S)-3-((R)-3-cyclopropyl-3-phenylpropionic acid)-2-(dimethylamino)propyl)benzamide ("Compound 97"):

[0435] Compound 97 (10 mg, 21%) was synthesized from Int. 73 and Int. 64 as described in Example B9. MS (m / z): 394.3 (M+H).

[0436] Example B98: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-phenylbutyrylamino)propyl)benzamide ("Compound 98"):

[0437] Compound 98 (152 mg, 55%) was synthesized from Int. 73 and Int. 61 as described in Example B9. MS (m / z): 368.2 (M+H).

[0438] Example B99: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-phenylbutyrylamino)propyl)benzamide ("Compound 99"):

[0439] Compound 99 (118 mg, 65%) was synthesized from Int. 73 and Int. 62 as described in Example B9. MS (m / z): 368.2 (M+H).

[0440] Example B100: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-phenylbutyrylamino)propyl)-3,5-dimethylbenzylamine (“Compound 100”):

[0441] Compound 100 (190 mg, 52%) was synthesized from Int. 74 and Int. 62 as described in Example B9. MS (m / z): 396.3 (M+H).

[0442] Example B101: Preparation of 4-((S)-3-((S)-4,4-dimethyl-3-phenylpentanylamino)-2-(dimethylamino)propyl)-2-fluoro-N-(2,2,2-trifluoroethyl)benzylamine ("Compound 101"):

[0443] Compound 101 (59 mg, 45%) was synthesized as described in Example B17. MS (m / z): 510.3 (M+H).

[0444] Example B102: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(2-sideoxy-1,2-dihydroquinolin-6-yl)propyl)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 102"):

[0445] Step 1: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(2-methoxyquinoline-6-yl)propyl)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid (102A). HATU (51.5 mg, 1.2 eq., 136 µmol) was added to a stirred mixture of [(2S)-1-amino-3-(2-methoxyquinoline-6-yl)propyl-2-yl]dimethylamine (29.3 mg, 113 µmol), (3S)-3-(pyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid (30.8 mg, 1.1 eq., 119 µmol) and DIEA (30.0 µL, 1.5 eq., 169 µmol) in DMF (1 mL). The reaction mixture was then stirred at room temperature for 1 h. H₂O was added, and the mixture was extracted with EtOAc (3×). The combined extracts were dried over MgSO₄, concentrated, and purified by rapid chromatography (0–10% MeOH / DCM) to give (3S)-N-[(2S)-2-(dimethylamino)-3-(2-methoxyquinoline-6-yl)propyl]-3-(pyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid (56.0 mg, 99%). MS (m / z). 501.1 (M+H).

[0446] Step 2: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(2-methoxy-1,2-dihydroquinoline-6-yl)propyl)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid (compound 102): Hydrogen chloride (186 µL, 10 eq., 1.12 mmol) was added to a stirred solution of (3S)-N-[(2S)-2-(dimethylamino)-3-(2-methoxyquinoline-6-yl)propyl]-3-(pyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid (56.0 mg, 112 µmol) in p-dioxane (2 mL). The reaction mixture was then stirred at 60 °C for 16 h, followed by an increase to 100 °C over 4 h. LC / MS showed no SM residue. The mixture was cooled, concentrated to dryness, diluted with H2O, alkalized with 10N NaOH until pH 5-6, and extracted with DCM (3×). The combined extracts were dried over MgSO4, concentrated, and purified by rapid chromatography (0-15% MeOH / DCM) to give compound 102 (18.9 mg, 35%). MS (m / z): 487.2 (M+H).

[0447] Example B103: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(2-sideoxy-1,2-dihydroquinolin-6-yl)propyl)-3-(pyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 103"):

[0448] Compound 103 (23.7 mg, 32%) was synthesized as described in Example B102. MS (m / z): 487.2 (M+H).

[0449] Example B104: Preparation of 4-((S)-3-((S)-4,4-dimethyl-3-phenylpentanylamino)-2-(dimethylamino)propyl)-2,5-difluoro-N-methylbenzylamine ("Compound 104"):

[0450] Compound 104 (226 mg, 60%) was synthesized from Int. 94 and Int. 70 as described in Example B9. MS (m / z): 460.2 (M+H).

[0451] Example B105: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(2-methylpyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propamido)propyl)-3,5-difluoro-N-methylbenzamide ("Compound 105")

[0452] Compound 105 (226 mg, 60%) was synthesized from Int. 95 and Int. 9 as described in Example B9. MS (m / z): 528.2 (M+H).

[0453] Example B106: Preparation of 4-((S)-3-((R)-3-(4-chlorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(dimethylamino)propyl)-N,3,5-trimethylbenzylamine ("Compound 106"):

[0454] Compound 106 (36 mg, 78%) was synthesized from Int. 96 and Int. 54 as described in Example B9. MS (m / z): 539.2 (M+H).

[0455] Example B107: Preparation of 4-((S)-3-((R)-3-(4-chlorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzylamine ("Compound 107"):

[0456] Compound 107 (33 mg, 75%) was synthesized from Int. 97 and Int. 54 as described in Example B9. MS (m / z): 529.2 (M+H).

[0457] Example B108: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-5-methyl-3-(pyridin-2-yl)hexamido)propyl)-N,3,5-trimethylbenzamide ("Compound 108")

[0458] Compound 108 (9 mg, 18%) was synthesized from Int. 96 and Int. 98 as described in Example B9. MS (m / z): 453.2 (M+H).

[0459] Example B109: Preparation of 3-chloro-4-((S)-2-(dimethylamino)-3-((S)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propamido)propyl)-2-fluoro-N-methylbenzamide ("Compound 109"):

[0460] Compound 109 (15 mg, 45%) was synthesized from Int. 99 and Int. 15 as described in Example B9. MS (m / z): 529.2 (M+H).

[0461] Example B110: Preparation of 3-chloro-4-((S)-2-(dimethylamino)-3-((S)-3-(pyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propamido)propyl)-2-fluoro-N-methylbenzamide ("Compound 110")

[0462] Compound 110 (15 mg, 63%) was synthesized from Int. 99 and Int. 100 as described in Example B9. MS (m / z): 529.2 (M+H).

[0463] Example B111: Preparation of 3-chloro-4-((S)-2-(dimethylamino)-3-((R)-3-(pyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluoro-N-methylbenzamide ("Compound 111")

[0464] Compound 111 (46 mg, 82%) was synthesized from Int. 99 and Int. 59 as described in Example B9. MS (m / z): 529.2 (M+H).

[0465] Example B112: Preparation of 3-chloro-4-((2S)-3-(3-(5-chloropyrimidin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide ("Compound 112")

[0466] Compound 112 (33 mg, 78%) was synthesized from Int. 99 and Int. 101 as described in Example B9. MS (m / z): 564.2 (M+H).

[0467] Example B113: Preparation of 3-chloro-4-((S)-2-(dimethylamino)-3-((R)-3-(6-methylpyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N-methylbenzamide ("Compound 113")

[0468] Compound 113 (42 mg, 74%) was synthesized from Int. 102 and Int. 10 as described in Example B9. MS (m / z): 525.2 (M+H).

[0469] Example B114: Preparation of 3-chloro-4-((S)-3-((R)-3-(5-chloropyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(dimethylamino)propyl)-N-methylbenzamide ("Compound 114")

[0470] Compound 114 (47 mg, 54%) was synthesized from Int. 102 and Int. 103 as described in Example B9. MS (m / z): 545.2 (M+H).

[0471] Example B115: Preparation of 3-chloro-4-((2S)-2-(dimethylamino)-3-(3-(6-methoxypyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N-methylbenzamide ("Compound 115")

[0472] Compound 115 (50 mg, 65%) was synthesized from Int. 102 and Int. 25 as described in Example B9. MS (m / z): 541.2 (M+H).

[0473] Example B116: Preparation of 3-chloro-4-((2S)-2-(dimethylamino)-3-(3-(6-methoxypyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N-methylbenzamide ("Compound 116")

[0474] Compound 116 (45 mg, 65%) was synthesized from Int. 102 and Int. 26 as described in Example B9. MS (m / z): 529.3 (M+H).

[0475] Example B117: Preparation of 3-chloro-4-((2S)-2-(dimethylamino)-3-(3-(5-methoxypyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N-methylbenzamide ("Compound 117")

[0476] Compound 117 (25 mg, 42%) was synthesized from Int. 102 and Int. 104 as described in Example B9. MS (m / z): 541.3 (M+H).

[0477] Example B118: Preparation of 3-chloro-4-((2S)-2-(dimethylamino)-3-(3-(4-methylpyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N-methylbenzamide ("Compound 118")

[0478] Compound 118 (25 mg, 42%) was synthesized from Int. 102 and Int. 105 as described in Example B9. MS (m / z): 525.2 (M+H).

[0479] Example B119: Preparation of 3-chloro-4-((2S)-2-(dimethylamino)-3-(3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N-methylbenzamide ("Compound 119"):

[0480] Compound 119 (36 mg, 74%) was synthesized from Int. 102 and Int. 106 as described in Example B9. MS (m / z): 511.2 (M+H).

[0481] Example B120: Preparation of 3-chloro-4-((2S)-2-(dimethylamino)-3-(3-(3-fluoropyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N-methylbenzamide ("Compound 120")

[0482] Compound 120 (36 mg, 74%) was synthesized from Int. 102 and Int. 107 as described in Example B9. MS (m / z): 529.2 (M+H).

[0483] Example B121: Preparation of 3-chloro-4-((2S)-2-(dimethylamino)-3-(3-(5-fluoropyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N-methylbenzamide ("Compound 121")

[0484] Compound 121 (16 mg, 33%) was synthesized from Int. 102 and Int. 108 as described in Example B9. MS (m / z): 529.3 (M+H).

[0485] Example B122: Preparation of 3-chloro-4-((2S)-3-(3-(5-chloropyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(dimethylamino)propyl)-N-methylbenzamide ("Compound 122")

[0486] Compound 122 (16 mg, 35%) was synthesized from Int. 102 and Int. 109 as described in Example B9. MS (m / z): 545.2 (M+H).

[0487] Example B123: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(2-methylthiazolyl-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propamido)propyl)-3-fluoro-N-methylbenzylamine ("Compound 123")

[0488] Compound 123 (33 mg, 63%) was synthesized from Int. 110 and Int. 6 as described in Example B9. MS (m / z): 515.2 (M+H).

[0489] Example B124: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluoro-N,3-dimethylbenzamide ("Compound 124")

[0490] Compound 124 (35 mg, 71%) was synthesized from Int. 111 and Int. 15 as described in Example B9. MS (m / z): 509.2 (M+H).

[0491] Example B125: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(6-methylpyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluoro-N,3-dimethylbenzylamine ("Compound 125")

[0492] Compound 125 (26 mg, 56%) was synthesized from Int. 111 and Int. 10 as described in Example B9. MS (m / z): 523.2 (M+H).

[0493] Example B126: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-5-methyl-3-(pyridin-3-yl)hexamido)propyl)-N,3-dimethylbenzamide ("Compound 126")

[0494] Compound 126 (30 mg, 59%) was synthesized from Int. 112 and Int. 113 as described in Example B9. MS (m / z): 439.3 (M+H).

[0495] Example B127: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(3-fluoropyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N,3-dimethylbenzamide ("Compound 127")

[0496] Compound 127 (10 mg, 39%) was synthesized from Int. 112 and Int. 114 as described in Example B9. MS (m / z): 509.2 (M+H).

[0497] Example B128: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(4-fluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N,3-dimethylbenzylamine ("Compound 128")

[0498] Compound 128 (32 mg, 78%) was synthesized from Int. 112 and Int. 115 as described in Example B9. MS (m / z): 508.3 (M+H).

[0499] Example B129: Preparation of 4-((S)-3-((S)-4,4-dimethyl-3-(pyridin-3-yl)pentylamino)-2-(dimethylamino)propyl)-N,3-dimethylbenzylamine ("Compound 129"):

[0500] Compound 129 (14 mg, 63%) was synthesized from Int. 112 and Int. 116 as described in Example B9. MS (m / z): 439.3 (M+H).

[0501] Example B130: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(pyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N,3-dimethylbenzamide ("Compound 130")

[0502] Compound 130 (32 mg, 78%) was synthesized from Int. 112 and Int. 59 as described in Example B9. MS (m / z): 491.3 (M+H).

[0503] Example B131: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N,3-dimethylbenzamide ("Compound 131")

[0504] Compound 131 (32 mg, 78%) was synthesized from Int. 112 and Int. 15 as described in Example B9. MS (m / z): 491.3 (M+H).

[0505] Example B132: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(6-methylpyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N,3-dimethylbenzamide ("Compound 132")

[0506] Compound 132 (32 mg, 78%) was synthesized from Int. 112 and Int. 10 as described in Example B9. MS (m / z): 505.3 (M+H).

[0507] Example B133: Preparation of 4-((S)-3-((R)-4-cyclopropyl-3-(pyridin-3-yl)butyramine)-2-(dimethylamino)propyl)-N,3-dimethylbenzamide ("Compound 133"):

[0508] Compound 133 (32 mg, 78%) was synthesized from Int. 112 and Int. 49 as described in Example B9. MS (m / z): 437.3 (M+H).

[0509] Example B134: Preparation of 4-((2S)-2-(dimethylamino)-3-(3-(pyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N,3-dimethylbenzamide ("Compound 134")

[0510] Compound 134 (28 mg, 70%) was synthesized from Int. 112 and Int. 12 as described in Example B9. MS (m / z): 491.2 (M+H).

[0511] Example B135: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(2-methylpyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N,3-dimethylbenzylamine ("Compound 135")

[0512] Compound 135 (28 mg, 70%) was synthesized from Int. 112 and Int. 9 as described in Example B9. MS (m / z): 506.3 (M+H).

[0513] Example B136: Preparation of 4-((S)-3-((R)-3-(3,5-difluorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(dimethylamino)propyl)-N,3-dimethylbenzylamine ("Compound 136")

[0514] Compound 136 (18 mg, 64%) was synthesized from Int. 112 and Int. 117 as described in Example B9. MS (m / z): 526.2 (M+H).

[0515] Example B137: Preparation of 4-((S)-3-((R)-3-(5-chloropyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(dimethylamino)propyl)-N,3-dimethylbenzylamine ("Compound 137"):

[0516] Compound 137 (18 mg, 64%) was synthesized from Int. 112 and Int. 118 as described in Example B9. MS (m / z): 525.2 (M+H).

[0517] Example B138: Preparation of 4-((S)-3-((S)-3-(5-chloropyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(dimethylamino)propyl)-N,3-dimethylbenzylamine ("Compound 138")

[0518] Compound 138 (27 mg, 74%) was synthesized from Int. 112 and Int. 119 as described in Example B9. MS (m / z): 525.2 (M+H).

[0519] Example B139: Preparation of 4-((S)-3-((S)-4-cyclopropyl-3-(pyridin-2-yl)butyramine)-2-(dimethylamino)propyl)-N,3-dimethylbenzamide ("Compound 139"):

[0520] Compound 139 (10 mg, 67%) was synthesized from Int. 112 and Int. 120 as described in Example B9. MS (m / z): 437.2 (M+H).

[0521] Example B140: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-5-methyl-3-(pyridin-2-yl)hexamido)propyl)-N,3-dimethylbenzamide ("Compound 140")

[0522] Compound 140 (32 mg, 83%) was synthesized from Int. 112 and Int. 98 as described in Example B9. MS (m / z): 439.3 (M+H).

[0523] Example B141: Preparation of 4-((2S)-2-(dimethylamino)-3-(3-(pyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N,3-dimethylbenzamide ("Compound 141")

[0524] Compound 141 was synthesized from Int. 112 and Int. 121 as described in Example B9. MS (m / z): 491.3 (M+H).

[0525] Example B142: Preparation of 4-((S)-3-((R)-3-(4-chlorophenyl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)-2-(dimethylamino)propyl)-N,3-dimethylbenzylamine ("Compound 142")

[0526] Compound 142 was synthesized from Int. 112 and Int. 54 as described in Example B9. MS (m / z): 524.2 (M+H).

[0527] Example B143: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-N,3-dimethylbenzamide ("Compound 143")

[0528] Compound 143 was synthesized from Int. 112 and Int. 3 as described in Example B9. MS (m / z): 490.3 (M+H).

[0529] Example B144: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionic)propyl)-2-fluoro-N,5-dimethylbenzylamine ("Compound 144"):

[0530] Compound 144 (25 mg, 79%) was synthesized from Int. 122 and Int. 3 as described in Example B9. MS (m / z): 508.2 (M+H).

[0531] Example B145: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluoro-N,5-dimethylbenzylamine ("Compound 145")

[0532] Compound 145 (43 mg, 71%) was synthesized from Int. 112 and Int. 61 as described in Example B9. MS (m / z): 396.3 (M+H).

[0533] Example B146: Preparation of 4-((S)-3-((R)-4,4-dimethyl-3-phenylpentanylamino)-2-(dimethylamino)propyl)-2-fluoro-N,5-dimethylbenzylamine ("Compound 146"):

[0534] Compound 146 (52 mg, 76%) was synthesized from Int. 122 and Int. 69 as described in Example B9. MS (m / z): 456.3 (M+H).

[0535] Example B147: Preparation of 2-chloro-4-((S)-2-(dimethylamino)-3-((R)-5-methyl-3-phenylhexanoamino)propyl)-N-methylbenzylamine ("Compound 147")

[0536] Compound 147 (35 mg, 63%) was synthesized from Int. 123 and Int. 67 as described in Example B9. MS (m / z): 458.3 (M+H).

[0537] Example B148: Preparation of 2-chloro-4-((S)-2-(dimethylamino)-3-((S)-4-methyl-3-phenylpentaamino)propyl)-N-methylbenzylamine ("Compound 148")

[0538] Compound 148 (35 mg, 67%) was synthesized from Int. 123 and Int. 65 as described in Example B9. MS (m / z): 444.3 (M+H).

[0539] Example B149: Preparation of 2-chloro-4-((S)-2-(dimethylamino)-3-((R)-3-phenylbutyrylamino)propyl)-N-methylbenzylamine ("Compound 149"):

[0540] Compound 149 (22 mg, 81%) was synthesized from Int. 123 and Int. 61 as described in Example B9. MS (m / z): 416.2 (M+H).

[0541] Example B150: Preparation of 2-chloro-4-((S)-3-((S)-4,4-dimethyl-3-phenylpentanylamino)-2-(dimethylamino)propyl)-N-methylbenzylamine ("Compound 150"):

[0542] Compound 150 (22 mg, 81%) was synthesized from Int. 123 and Int. 70 as described in Example B9. MS (m / z): 458.3 (M+H).

[0543] Example B151: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(5-fluoropyridin-3-yl)-4,4-dimethylpentanoamino)propyl)-2-fluoro-N-methylbenzylamine ("Compound 151"):

[0544] Compound 151 (22 mg, 81%) was synthesized from Int. 97 and Int. 34 as described in Example B9. MS (m / z): 461.3 (M+H).

[0545] Example B152: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(2-methylpyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propamido)propyl)-2-fluoro-N-methylbenzylamine ("Compound 152")

[0546] Compound 152 (40 mg, 74%) was synthesized from Int. 97 and Int. 9 as described in Example B9. MS (m / z): 510.3 (M+H).

[0547] Example B153: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-3-(pyridin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl)-2-fluoro-N-methylbenzylamine ("Compound 153")

[0548] Compound 153 (19 mg, 54%) was synthesized from Int. 97 and Int. 55 as described in Example B9. MS (m / z): 495.2 (M+H).

[0549] Example B154: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionic)propyl)-2-fluoro-N-methylbenzylamine ("Compound 154")

[0550] Compound 154 (25 mg, 77%) was synthesized from Int. 97 and Int. 56 as described in Example B9. MS (m / z): 494.3 (M+H).

[0551] Example B155: Preparation of 4-((S)-3-((R)-3-(4-chlorophenyl)butyramine)-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzylamine ("Compound 155"):

[0552] Compound 155 (71 mg, 83%) was synthesized from Int. 97 and Int. 124 as described in Example B9. MS (m / z): 434.2 (M+H).

[0553] Example B156: Preparation of 4-((S)-3-((S)-3-(4-chlorophenyl)butyramine)-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzylamine ("Compound 156"):

[0554] Compound 156 (41 mg, 63%) was synthesized from Int. 97 and Int. 125 as described in Example B9. MS (m / z): 434.2 (M+H).

[0555] Example B157: Preparation of 4-((S)-3-((S)-4,4-dimethyl-3-phenylpentanylamino)-2-(pyrrolidin-1-yl)propyl)-2-fluoro-N-methylbenzylamine ("Compound 157"):

[0556] Compound 157 (41 mg, 63%) was synthesized from Int. 131 and Int. 70 as described in Example B9. MS (m / z): 468.3 (M+H).

[0557] Example B158: Preparation of 4-((S)-3-((S)-4,4-dimethyl-3-phenylpentanylamino)-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzylamine ("Compound 158"):

[0558] Compound 158 (42 mg, 77%) was synthesized from Int. 97 and Int. 70 as described in Example B9. MS (m / z): 442.3 (M+H).

[0559] Example B159: Preparation of 4-((S)-3-((R)-4,4-dimethyl-3-phenylpentanylamino)-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzylamine ("Compound 159"):

[0560] Compound 159 (600 mg, 83%) was synthesized from Int. 97 and Int. 69 as described in Example B9. MS (m / z): 442.3 (M+H).

[0561] Example B160: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-5-methyl-3-phenylhexanoamino)propyl)-2-fluoro-N-methylbenzylamine ("Compound 160"):

[0562] Compound 160 (9 mg, 43%) was synthesized from Int. 97 and Int. 67 as described in Example B9. MS (m / z): 442.3 (M+H).

[0563] Example B161: Preparation of 4,4-((S)-2-(1H-imidazol-1-yl)-3-((S)-3-phenylbutyramido)propyl)-2-fluoro-N-methylbenzamide ("Compound 161"):

[0564] Compound 161 (15 mg, 56%) was synthesized as described in Example B9. MS (m / z): 423.2 (M+H).

[0565] Example B162: Preparation of 4-((S)-2-(dimethylamino)-3-((R)-4-methyl-3-phenylpentanylamino)propyl)-2-fluoro-N-methylbenzylamine ("Compound 162"):

[0566] Compound 162 (44 mg, 69%) was synthesized from Int. 97 and Int. 66 as described in Example B9. MS (m / z): 428.3 (M+H).

[0567] Example B163: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-(pyridin-2-yl)butamido)propyl)-2-fluoro-N-methylbenzamide ("Compound 163"):

[0568] Compound 163 (44 mg, 69%) was synthesized from Int. 97 and Int. 132 as described in Example B9. MS (m / z): 401.2 (M+H).

[0569] Example B164: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-phenylbutyrylamino)propyl)-2-fluoro-N-methylbenzylamine ("Compound 164")

[0570] Compound 164 (45 mg, 82%) was synthesized from Int. 131 and Int. 62 as described in Example B9. MS (m / z): 426.3 (M+H).

[0571] Example B165: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-phenylbutyrylamino)propyl)-2-fluoro-N-methylbenzylamine ("Compound 165"):

[0572] Compound 165 (35 mg, 72%) was synthesized from Int. 97 and Int. 127 as described in Example B9. MS (m / z): 440.3 (M+H).

[0573] Example B166: Preparation of 4-((S)-2-(diethylamino)-3-((R)-4,4-dimethyl-3-phenylpentaamino)propyl)-2-fluoro-N-methylbenzylamine ("Compound 166")

[0574] Compound 166 (47 mg, 62%) was synthesized from Int. 128 and Int. 69 as described in Example B9. MS (m / z): 470.3 (M+H).

[0575] Example B167: Preparation of 4-((S)-2-(dimethylamino)-3-((S)-3-phenylbutyrylamino)propyl)-2-fluoro-N-methylbenzylamine ("Compound 167")

[0576] Compound 167 (35 mg, 62%) was synthesized from Int. 97 and Int. 62 as described in Example B9. MS (m / z): 400.3 (M+H).

[0577] Example B168: Preparation of (S)-3-(((S)-4,4-dimethyl-3-phenylpentanylamino)methyl)-N,2-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-methylamine ("Compound 168"):

[0578] Compound 168 (40 mg, 75%) was synthesized from Int. 129 and Int. 70 as described in Example B9. MS (m / z): 422.2 (M+H).

[0579] Example B169: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(7-methyl-2-sideoxy-2,3-dihydrobenzo[d]azol-6-yl)propyl)-3-(2-methylpyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionylamine ("Compound 169")

[0580] Compound 169 (9 mg, 10%) was synthesized from Int. 76 and Int. 9 as described in Example B9. MS (m / z): 506.2 (M+H).

[0581] Example B170: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(7-methyl-2-sideoxy-2,3-dihydrobenzo[d]azol-6-yl)propyl)-3-(pyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid (“Compound 170”):

[0582] Compound 170 (27.4 mg, 41%) was synthesized from Int. 76 and Int. 59 as described in Example B9. MS (m / z): 491.2 (M+H).

[0583] Example B171: Preparation of (3S)-N-[(2S)-2-(dimethylamino)-3-(7-methyl-2-sideoxy-2,3-dihydro-1,3-benzoxazo-6-yl)propyl]-3-phenylbutyramine (“Compound 171”):

[0584] Compound 171 (14.5 mg, 18%) was synthesized from Int. 76 and Int. 62 as described in Example B9. MS (m / z): 396.2 (M+H).

[0585] Example B172: Preparation of (3S)-N-[(2S)-2-(dimethylamino)-3-(2-sideoxy-2,3-dihydro-1,3-benzoxazo-6-yl)propyl]-5-methyl-3-phenylhexylamine ("Compound 172"):

[0586] Step 1: Compound 172A was synthesized from Int. 75 and Int. 68 as described in Example B9.

[0587] Step 2: A solution of (1S,2S)-N-[(2S)-2-(dimethylamino)-3-(2-sideoxy-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzozazol-6-yl)propyl]-2-phenylcyclopropane-1-methylamine (172A, 950 mg, 1.86 mmol) in TFA (10 mL) was stirred for 1 h at room temperature. LC / MS showed conversion to product 172-A. The mixture was concentrated to dryness, dissolved in MeOH (3 mL), and potassium carbonate (99.9 mg 0.723 mmol) was added, and stirring was continued at room temperature for 16 h. The mixture was concentrated to dryness, dissolved in water, acidified to pH 6-7 with 2N HCl, and extracted with DCM (3×). The combined extracts were dried over MgSO4, concentrated, and purified by rapid chromatography (0-10% MeOH / DCM) to give (3S)-N-[(2S)-2-(dimethylamino)-3-(2-sideoxy-2,3-dihydro-1,3-benzoxazo-6-yl)propyl]-5-methyl-3-phenylhexylamine (40 mg, 63.7%). MS (m / z): 424.3 (M+H).

[0588] Example B173: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(2-sideoxy-2,3-dihydrobenzo[d]azol-6-yl)propyl)-4-methyl-3-phenylpentanylamine (“Compound 173”):

[0589] Compound 173 (23 mg, 33%) was synthesized as described in Example B172. MS (m / z): 410.2 (M+H).

[0590] Example B174: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(2-sideoxy-2,3-dihydrobenzo[d]azol-6-yl)propyl)-3-phenylheptylamine ("Compound 174")

[0591] Compound 174 was synthesized as described in Example B175. MS (m / z): 424.3 (M+H).

[0592] Example B175: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(2-sideoxy-2,3-dihydrobenzo[d]azol-6-yl)propyl)-3-phenylbutyramine (“Compound 175”):

[0593] Step 1: Preparation of 2-(benzylmethyloxy)-4-bromo-1-nitrobenzene (175A): A mixture of 5-bromo-2-nitrophenol (5 g, 22.9 mmol), benzyl bromide (3.0 mL, 25.2 mmol), and potassium carbonate (10 g, 72.3 mmol) was dissolved in DMF (36 mL) and stirred overnight at room temperature. After cooling to ambient temperature, the reaction mixture was diluted with water and ethyl acetate. The layers were then separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The crude substance was purified by rapid column chromatography (9:1 hexane / ethyl acetate) to give 2-(benzylmethyloxy)-4-bromo-1-nitrobenzene (8.25 g, 97%) as a pale yellow solid. LC-MS 332.0 (M+Na).

[0594] Step 2: Preparation of (S)-3-(3-(benzylmethyloxy)-4-nitrophenyl)-2-((tributoxycarbonyl)amino)propionate (175B): Zinc powder (1.6 g, 24.5 mmol) was added to a flame-dried round-bottom flask (100 mL), which was then purged with nitrogen. Anhydrous DMF (10 mL) was added via syringe, followed by iodine (150 mg) in a solution of anhydrous DMF (1 mL). A color change of DMF from colorless to yellow and then back to normal was observed. After 5 min, iodoalanine (2.47 g, 7.49 mmol) was added to a solution of anhydrous DMF (5 mL), followed immediately by iodine (150 mg) in a solution of anhydrous DMF (1 mL). The solution was stirred at room temperature and a significant exothermic reaction was observed. When the solution cooled (approximately 20 min), a mixture of Pd2(dba)3 (312 mg, 0.34 mmol), SPhos (279 mg, 0.68 mmol), and 2-(benzylmethyloxy)-4-bromo-1-nitrobenzene (175A, 2.1 g, 6.81 mmol) in anhydrous DMF (9 mL) was added to a flask via a syringe. The reaction mixture was heated overnight at 55 °C under positive nitrogen pressure. After cooling to room temperature, ethyl acetate (100 mL) and water (30 mL) were added. After stirring at room temperature for 30 min, the mixture was filtered through diatomaceous earth (80 g) and washed with ethyl acetate (100 mL). The yellow filtrate was then washed with water (4 × 100 mL). After drying with anhydrous MgSO4 and concentrating under vacuum, the crude reaction mixture was purified by rapid chromatography and dissolved in ethyl acetate-hexane (0 to 35%) to give a product as a white solid (2.1 g, 71%). MS (m / z): 453.2 (M+Na).

[0595] Step 3: LiBH4 (789 mg, 36.2 mmol) was slowly added to a solution of (S)-3-(3-(benzylmethyloxy)-4-nitrophenyl)-2-((tributoxycarbonyl)amino)propionate (175B, 6 g, 13.9 mmol) in anhydrous THF (60 mL) for 15 min at 0 °C, and the mixture was stirred at 0 °C for 1 h. The reaction mixture was then stirred overnight at room temperature (the reaction progress was monitored by TLC or LC-MS). The mixture was then cooled to 0 °C, and water (5 mL) and saturated NH4Cl solution (10 mL) were added dropwise (added slowly). Water (30 mL) and ethyl acetate (200 mL) were then added, the aqueous layer was separated, and further extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (40 mL) and then dried over anhydrous Na2SO4. After filtration and concentration, the crude product was lyophilized overnight and used in the next step without further purification (5.3 g). MS (m / z): 425.2 (M+Na).

[0596] Step 4: Preparation of (S)-(1-(3-(benzylmethyloxy)-4-nitrophenyl)-3-(1,3-di-dioxyisoindoline-2-yl)propyl-2-yl)aminocarbamate tributyl ester (175D): Under nitrogen atmosphere, at 0°C for 20 min, DIAD (3.3 mL, 16.7 mmol) was added dropwise to a mixture of (S)-(1-(3-(benzylmethyloxy)-4-nitrophenyl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (175C, crude product, 5.3 g), triphenylphosphine (4.4 g, 16.7 mmol), and phthalimide (2.45 g, 16.7 mmol) in anhydrous THF (60 mL). The reaction mixture was then stirred overnight from 0°C to room temperature. The crude reaction mixture was mixed with silica gel (20 g), concentrated to dryness on a rotary evaporator, purified on a 120 g silica gel column, and dissociated with EtOAc / hexane (0-50%) to give the desired product as a yellow solid (6.0 g, 81%, for both steps). MS (m / z): 554.2 (M+Na).

[0597] Step 5: Preparation of (S)-2-(3-(3-(benzylmethyloxy)-4-nitrophenyl)-2-(dimethylamino)propyl)isoindoline-1,3-dione (175E): Add 19 mL of dialkyl solution containing 4 M HCl to a solution of (S)-(1-(3-(benzylmethyloxy)-4-nitrophenyl)-3-(1,3-di-dioxyisoindoline-2-yl)propyl-2-yl)aminocarbamate (175D, 4.5 g, 8.4 mmol) in anhydrous MeOH (60 mL). Stir the mixture overnight at room temperature. Then evaporate the solvent. The solid residue was used in the next step without further purification. To a suspension of the above solids in CH3CN (60 mL) and water (3 mL), 37% formaldehyde (3.8 mL, 50.7 mmol) and sodium cyanoborohydride (2.1 g, 33.8 mmol) were added. After stirring at room temperature for 10 min, acetic acid (1.45 mL, 25.3 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was then partitioned between ethyl acetate (200 mL) and saturated sodium bicarbonate (40 mL). The layers were separated, and the aqueous layer was extracted with more ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified on an 80 g silicone column and dissociated with 10% MeOH in DCM:DCM (0–100%) to give the desired product (3.2 g), which was impure (according to 1H-NMR and TLC) and used in the next step. MS (m / z) = 460.2 (M+H).

[0598] Step 6: Preparation of (S)-3-(3-(benzylmethyloxy)-4-nitrophenyl)-N2,N2-dimethylpropane-1,2-diamine (175F): Add hydrazine hydrate (2.3 mL, 41.8 mmol) to a solution of (S)-2-(3-(3-(benzylmethyloxy)-4-nitrophenyl)-2-(dimethylamino)propyl)isoindoline-1,3-dione (175E, 3.2 g, 6.9 mmol) in 95% ethanol (50 mL). Heat the mixture at 70 °C for 3 h. The crude reaction mixture was diluted with MeOH (50 mL) and mixed with silica gel (approximately 10 g). The mixture was concentrated to dryness using a rotary evaporator and then purified on a 40 g silica gel column. The product was dissociated with 10% MeOH in DCM (containing 1% NH4OH): DCM (0-100 / 100) to give the desired product as a white solid (1.25 g, 45%, after the last three steps). MS (m / z): 330.2 M+H).

[0599] Step 7: Preparation of (S)-N-((S)-3-(3-(benzylmethyloxy)-4-nitrophenyl)-2-(dimethylamino)propyl)-3-phenylbutyramine (175G): (S)-3-(3-(benzylmethyloxy)-4-nitrophenyl)-N2,N2-dimethylpropane-1,2-diamine (175F, 200 mg, 0.6 mmol) and acid (0.67 mmol) were dissolved in anhydrous DMF (5 mL), followed by the addition of EDCI (140 mg, 0.73 mmol), HOBT (98 mg, 0.73 mmol), and DIPEA (0.123 mL, 0.73 mmol). The reaction mixture was stirred overnight at room temperature, followed by treatment with ethyl acetate and water. The organic layer was dried over anhydrous MgSO4 and concentrated under vacuum. The crude reaction mixture was purified by rapid chromatography and dissociated with 10% MeOH in DCM (including 1% NH4OH): DCM (0-40 / 100) to give the corresponding product as a yellow solid (249 mg, 86%). MS (m / z): 476.2 (M+H).

[0600] Step 8: Preparation of (S)-N-((S)-3-(4-amino-3-hydroxyphenyl)-2-(dimethylamino)propyl)-3-phenylbutyramine (175H): MeOH (12 mL) containing (S)-N-((S)-3-(3-(benzyloxy)-4-nitrophenyl)-2-(dimethylamino)propyl)-3-phenylbutyramine (175 G, 240 mg, 0.5 mmol) and 10% palladium / carbon (55 mg, Aldrich) was stirred for 16 h under H2 atmosphere. The mixture was filtered through a Celite® filter and the filtrate was evaporated under reduced pressure to give the title compound (185 mg, 100%). MS (m / z): 356.3 (M+H).

[0601] Step 9: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(2-sideoxy-2,3-dihydrobenzo[d]azol-6-yl)propyl)-3-phenylbutyramine (compound 175). 1,1'-carbonyldiimidazole (230 mg, 1.68 mmol) was added to 7 mL of a THF solution of (S)-N-((S)-3-(4-amino-3-hydroxyphenyl)-2-(dimethylamino)propyl)-3-phenylbutyramine (175, 300 mg, 0.84 mmol), and the solution was heated at 60 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into 100 mL of water and then extracted twice with 100 mL of ethyl acetate. After removing water with sodium sulfate, the solvent was removed using a rotary flash evaporator, and the silicone column was purified by chromatography using 10% MeOH in DCM (including 1% NH4OH): DCM (0-60 / 100) to give the desired product as a white solid (94 mg, 52%, after the last 3 steps). MS (m / z): 382.2 (M+H).

[0602] Example B176: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(2-sideoxy-2,3-dihydrobenzo[d]azol-6-yl)propyl)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionylamine ("Compound 176")

[0603] Compound 176 (20 mg, 45%) was synthesized as described in Example B175 from (S)-6-(3-amino-2-(dimethylamino)propyl)benzo[d]azol-2(3H)-one (175F) and (S)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid. MS (m / z): 477.2 (M+H).

[0604] Example B177: Preparation of (S)-3-cyclopropyl-N-((S)-2-(dimethylamino)-3-(2-sideoxy-2,3-dihydrobenzo[d]azol-6-yl)propyl)-3-phenylpropionamide ("Compound 177")

[0605] Compound 177 (74 mg, 70%) was synthesized as described in Example B175. MS (m / z): 408.3 (M+H).

[0606] Example B178: Preparation of (R)-3-cyclopropyl-N-((S)-2-(dimethylamino)-3-(2-sideoxy-2,3-dihydrobenzo[d]azol-6-yl)propyl)-3-phenylpropionamide ("Compound 178")

[0607] Compound 178 (40 mg, 65%) was synthesized as described in Example B175. MS (m / z): 408.2 (M+H).

[0608] Example B179: Preparation of (R)-4-cyclopropyl-N-((S)-2-(dimethylamino)-3-(4-methyl-2-sideoxyindoline-5-yl)propyl)-3-(pyridin-3-yl)butyramine ("Compound 179"):

[0609] DIPEA (19.3 mg, 150 mmL) was added to a solution of 5-[(2S)-3-amino-2-(dimethylamino)propyl]-4-methyl-2,3-dihydro-1H-indol-2-one (14.8 mg, 59.8 mmol), (3R)-3-(pyridin-3-yl)-3-[1-(trifluoromethyl)cyclopropyl]propionic acid (12.3 mg, 59.8 mmol), EDC (13.8 mg, 71.8 mmol), and HOBt (4.04 mg, 29.9 mmol) in 1 mL of anhydrous DMF. The reaction mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by SiO2 chromatography (0-10% MeOH / DCM) to give the title compound (13.6 mg, 52%). MS (m / z): 435.3 (M+H).

[0610] Example B180: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(4-methyl-2-sideoxyindoline-5-yl)propyl)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 180"):

[0611] Compound 180 (20 mg, 68%) was synthesized from Int. 78 and Int. 15 as described in Example B179. MS (m / z): 489.2 (M+H).

[0612] Example B181: Preparation of (3S)-N-[(2S)-2-(dimethylamino)-3-(4-methyl-2-sideoxy-2,3-dihydro-1H-indol-5-yl)propyl]-3-phenylbutyramine (“Compound 181”):

[0613] Compound 181 (35 mg, 73%) was synthesized from Int. 78 and Int. 62 as described in Example B179. MS (m / z): 394.2 (M+H).

[0614] Example B182: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(2-sideoxyindoline-5-yl)propyl)-4-methyl-3-phenylpentanylamine ("Compound 182"):

[0615] Compound 182 (28 mg, 60%) was synthesized from Int. 79 and Int. 66 as described in Example B179. MS (m / z): 408.3 (M+H).

[0616] Example B183: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(2-sideoxyindoline-5-yl)propyl)-5-methyl-3-phenylhexylamine ("Compound 183"):

[0617] Compound 183 (22 mg, 63%) was synthesized from Int. 79 and Int. 68 as described in Example B179. MS (m / z): 422.2 (M+H).

[0618] Example B184: Preparation of (3S)-N-[(2S)-2-(dimethylamino)-3-(2-sideoxy-2,3-dihydro-1H-indol-5-yl)propyl]-3-phenylbutyramine (“Compound 184”):

[0619] Compound 184 (706 mg, 67%) was synthesized from Int. 79 and Int. 62 as described in Example B179. MS (m / z): 380.2 (M+H).

[0620] Example B185: Preparation of (3R)-N-[(2S)-2-(dimethylamino)-3-(2-sideoxy-2,3-dihydro-1H-indol-5-yl)propyl]-3-phenylbutyramine (“Compound 185”):

[0621] Compound 185 (31 mg, 62%) was synthesized from Int. 79 and Int. 61 as described in Example B179. MS (m / z): 380.2 (M+H).

[0622] Example B186: Preparation of (R)-3-cyclopropyl-N-((S)-2-(dimethylamino)-3-(2-sideoxyindoline-5-yl)propyl)-3-phenylpropionamine ("Compound 186")

[0623] Compound 186 (31.6 mg, 45%) was synthesized from Int. 79 and Int. 64 as described in Example B179. MS (m / z): 406.3 (M+H).

[0624] Example B187: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(3-sideoxy-3,4-dihydro-2H-benzo[b][1,4]chloro-7-yl)propyl)-3-phenylbutyramine (“Compound 187”):

[0625] Under nitrogen atmosphere, at 0°C for approximately 15 minutes, a solution of chloroacetyl chloride (142 mg, 1.26 mmol) in THF (2.5 mL) was added dropwise to a stirred suspension of sodium bicarbonate (189 mg, 2.25 mmol) and (S)-N-((S)-3-(4-amino-3-hydroxyphenyl)-2-(dimethylamino)propyl)-3-phenylbutyramine (175H) (320 mg, 0.9 mmol) in THF (3 mL). Vigorous bubbling and exothermic reaction were observed to approximately 25°C. The resulting yellow suspension was stirred at room temperature for 1.5 h. Potassium carbonate (311 mg, 2.25 mmol) was added, and the mixture was heated to reflux and stirred for 2 h. The mixture was cooled to 40°C and diluted with ethyl acetate and water. The layers were separated, and the aqueous solution was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by rapid column chromatography using 10% MeOH in DCM:DCM (0-50%) as a solvent to give a white solid product (140 mg, 39%). MS (m / z): 396.2.

[0626] Example B188: Preparation of N-((S)-2-(dimethylamino)-3-(2-sideoxyindoline-5-yl)propyl)-3-(pyrimidin-2-yl)-3-(1-(trifluoromethyl)cyclopropyl)acrylamide ("Compound 188"):

[0627] Compound 188 (13.1 mg, 25%) was synthesized from Int. 79 and Int. 72 as described in Example B179. MS (m / z): 476.2 (M+H).

[0628] Example B189: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(2-sideoxyindoline-5-yl)propyl)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 189"):

[0629] TSTU (24.1 mg, 0.0802 mmol) was added in a single step to a solution of acid (Int. 72, 20.7 mg, 0.0802 mmol) and DIEA (20.9 μL, 0.120 mmol) in DMF (0.3 mL). The mixture was stirred at room temperature for one hour. An amine (Int. 79, 18.7 mg, 0.0802 mmol) was then added to the reaction mixture, and stirring was continued for another hour. The reaction mixture was diluted with ethyl acetate (15 mL), saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated on a rotary evaporator. The crude material was purified by a silicone column (0-10% MeOH / DCM with 1% NH4OH) to give the title compound (21.5 mg, 57%). MS (m / z): 474.3.

[0630] Example B190: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 190"):

[0631] Step 1: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(1-toluenesulfonyl-1H-indazole-5-yl)propyl)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)propenylamine (190A). TSTU (57.2 mg, 0.190 mmol) was added to a solution of acid (Int. 4D, 49.0 mg, 0.190 mmol) and DIEA (49.7 μL, 0.286 mmol) in DMF (0.3 mL) at room temperature. The mixture was stirred at room temperature for 40 minutes. The resulting solution was injected into a suspension of (Int. 84, 70.7 mg, 0.190 mmol) and stirred for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated on a rotary evaporator. The crude material was purified on a 12 g silicone column (0-10% MeOH / DCM with 1% NH4OH) to give the title compound (38 mg, 33%). MS (m / z): 612.2 (M+H).

[0632] Step 2: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-phenyl-3-(1-(trifluoromethyl)cyclopropyl)acrylamide (compound 190): MeOH (2 mL) containing compound 190A (36.0 mg, 0.0588 mmol) was treated with K2CO3 (mg, mmol) at 70 °C for 40 min. The reaction was shown to be complete by LCMS. The reaction mixture was cooled to room temperature and concentrated to dryness. The crude substance was dissolved in DMF (1 mL) / H2O with 0.1% TFA (0.5 mL) / ACN with 0.1% TFA (0.5 mL), filtered, and purified on a C18 column (0-100% ACN with 0.1% TFA / 0.1% TFA aqueous solution). The pure fractions were combined, concentrated, and the pH was adjusted to approximately 9 with saturated NaHCO3 (aqueous solution). Extraction was performed using DCM (3×). The combined extracts were dried and concentrated to give the title compound (16 mg, 59%). MS (m / z): 459.2 (M+H).

[0633] Example B191: Preparation of (R)-N-((S)-3-(4-chloro-1H-indazol-5-yl)-2-(dimethylamino)propyl)-3-(pyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 191"):

[0634] Compound 191 was synthesized from Int. 82 and Int. 69 as described in Example B190. MS (m / z): 494.2 (M+H).

[0635] Example B192: Preparation of (R)-N-((S)-3-(4-chloro-1H-indazol-5-yl)-2-(dimethylamino)propyl)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 192"):

[0636] Compound 192 (25.8 mg, 39%) was synthesized from 192A, which was synthesized from Int. 82 and Int. 15 (59.7 mg, 68%) as described in Example B190. MS (m / z): 494.2 (M+H).

[0637] Example B193: Preparation of (R)-N-((S)-3-(4-chloro-1H-indazol-5-yl)-2-(dimethylamino)propyl)-3-phenylbutyramine ("Compound 193"):

[0638] Compound 193 (29.5 mg, 43%) was synthesized from Int. 82 and Int. 61 as described in Example B190. MS (m / z): 399.2 (M+H).

[0639] Example B194: Preparation of (S)-N-((S)-3-(4-chloro-1H-indazol-5-yl)-2-(dimethylamino)propyl)-3-phenylbutyramine ("Compound 194"):

[0640] Compound 194 (23.5 mg, 34%) was synthesized from Int. 82 and Int. 62 as described in Example B190. MS (m / z): 399.2 (M+H).

[0641] Example B195: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(4-fluoro-1H-indazol-5-yl)propyl)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 195"):

[0642] Compound 195 was synthesized from Int. 92 and Int. 15 as described in Example B190. MS (m / z): 478.2 (M+H).

[0643] Example B196: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(4-methyl-1H-indazol-5-yl)propyl)-3-(pyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 196"):

[0644] Compound 196 was synthesized from Int. 81 and Int. 59 as described in Example B190. MS (m / z): 474.3 (M+H).

[0645] Example B197: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(4-methyl-1H-indazol-5-yl)propyl)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 197"):

[0646] Compound 197 was synthesized from Int. 81 and Int. 15 as described in Example B190. MS (m / z): 474.3 (M+H).

[0647] Example B198: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(4-methyl-1H-indazol-5-yl)propyl)-3-phenylbutyramine ("Compound 198"):

[0648] Compound 198 was synthesized from Int. 81 and Int. 62 as described in Example B190. MS (m / z): 379.3 (M+H).

[0649] Example B199: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(4-methyl-1H-indazol-5-yl)propyl)-3-(1-methylcyclopropyl)-3-(pyridin-3-yl)propionic acid ("Compound 199"):

[0650] Compound 199 was synthesized from Int. 81 and Int. 77 as described in Example B190. MS (m / z): 420.3 (M+H).

[0651] Example B200: Preparation of (R)-N-((S)-3-(1H-indazol-5-yl)-2-(methylamino)propyl)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid (“Compound 200”):

[0652] (R)-N-((S)-2-(benzyl(methyl)amino)-3-(1H-indazol-5-yl)propyl)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid (200A, 120 mg, 0.224 mmol) was dissolved together with palladium(II) hydroxide (100 mg), followed by the addition of ethanol (5 ml). The flask was evacuated and then filled with hydrogen (balloon). The reaction mixture was stirred under the hydrogen balloon for 18 hours. TLC and LCMS indicated product formation. The solution was filtered through diatomaceous earth to remove palladium and the filtrate was concentrated. The residue was purified by rapid chromatography (0-15% MeOH / DCM in 1% ammonium hydroxide) to give the title compound (55 mg, 53%). MS (m / z): 446.2 (M+H).

[0653] Example B201: Preparation of (R)-N-((S)-2-amino-3-(1H-indazol-5-yl)propyl)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)acrylamide dihydrochloride ("Compound 201"):

[0654] ((S)-1-(1H-indazol-5-yl)-3-((R)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid)propyl-2-yl)carbamate tributyl ester (201A, 125 mg, 0.23 mmol) was dissolved in 1,4-dimethylethane (3 ml), and then hydrogen chloride was added dropwise to the solution in 1,4-dimethylethane (2 ml, 4 M solution). The suspension was stirred at room temperature for 18 hours. The reaction was indicated by TLC and LCMS. The solution was partially concentrated and then MTBE was added. The precipitated solid was collected by filtration. The solid was then dried under vacuum to give the title compound (110 mg, 75%) in the form of dihydrochloride. MS (m / z): 432.2 (M+H).

[0655] Example B202: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(2-methylpyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 202"):

[0656] Compound 202 was synthesized from Int. 84 and Int. 89 as described in Example B190. MS (m / z): 474.2 (M+H).

[0657] Example B203: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(5-methylpyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 203"):

[0658] Compound 203 was synthesized from Int. 84 and Int. 90 as described in Example B190. MS (m / z): 474.3 (M+H).

[0659] Example B204: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(1-methylcyclopropyl)-3-(pyridin-3-yl)propionic acid ("Compound 204"):

[0660] Compound 204 was synthesized from Int. 84 and Int. 77 as described in Example B190. MS (m / z): 406.3 (M+H).

[0661] Example B205: Preparation of (R)-3-(5-chloropyridin-3-yl)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(1-(trifluoromethyl)cyclopropyl)propionylamine ("Compound 205"):

[0662] Compound 205 was synthesized from Int. 84 and Int. 103 as described in Example B190. MS (m / z): 494.2 (M+H).

[0663] Example B206: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-4-methyl-3-(pyridin-3-yl)pentylamine ("Compound 206"):

[0664] Compound 206 was synthesized from Int. 84 and Int. 50 as described in Example B190. MS (m / z): 394.2 (M+H).

[0665] Example B207: Preparation of (S)-3-cyclopropyl-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(pyridin-3-yl)propionic acid ("Compound 207"):

[0666] Compound 207 was synthesized from Int. 84 and Int. 91 as described in Example B190. MS (m / z): 392.1 (M+H).

[0667] Example B208: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(pyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 208"):

[0668] Compound 208 was synthesized from Int. 84 and Int. 93 as described in Example B190. MS (m / z): 460.2 (M+H).

[0669] Example B209: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(pyridin-4-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 209"):

[0670] Compound 209 was synthesized from Int. 84 and Int. 59 as described in Example B190. MS (m / z): 460.2 (M+H).

[0671] Example B210: Preparation of (3S)-N-[(2S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl]-3-(pyridin-4-yl)-3-[1-(trifluoromethyl)cyclopropyl]acrylamide ("Compound 210"):

[0672] Compound 210 was synthesized from Int. 84 and Int. 12 as described in Example B190. MS (m / z): 460.2 (M+H).

[0673] Example B211: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(6-methylpyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 211"):

[0674] Compound 211 was synthesized from Int. 84 and Int. 10 as described in Example B190. MS (m / z): 474.3 (M+H).

[0675] Example B212: Preparation of (R)-4-cyclopropyl-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(pyridin-3-yl)butyramine ("Compound 212")

[0676] Compound 212 was synthesized from Int. 84 and Int. 49 as described in Example B190. MS (m / z): 406.2 (M+H).

[0677] Example B213: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(pyridin-3-yl)-3-(1-(trifluoromethyl)cyclopropyl)propionic acid ("Compound 213"):

[0678] Compound 213 was synthesized from Int. 84 and Int. 15 as described in Example B190. MS (m / z): 460.2 (M+H).

[0679] Example B214: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-5-methyl-3-phenylhexylamine ("Compound 214")

[0680] Compound 214 was synthesized from Int. 84 and Int. 68 as described in Example B190. MS (m / z): 407.3 (M+H).

[0681] Example B215: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(3-fluorophenyl)butyramine ("Compound 215"):

[0682] Compound 215 was synthesized from Int. 84 and Int. 71 as described in Example B190. MS (m / z): 383.2 (M+H).

[0683] Example B216: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(pyridin-2-yl)butyramine ("Compound 216"):

[0684] Compound 216 was synthesized from Int. 84 and Int. 132 as described in Example B190. MS (m / z): 366.3 (M+H).

[0685] Example B217: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(p-tolyl)butyramine ("Compound 217")

[0686] Compound 217 was synthesized by Int. 84 as described in Example B190. MS (m / z): 379.2 (M+H).

[0687] Example B218: Preparation of (S)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-(4-fluorophenyl)butyramine ("Compound 218")

[0688] Compound 218 was synthesized from Int. 84 as described in Example B190. MS (m / z): 383.2 (M+H).

[0689] Example B219: Preparation of (R)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-4-methyl-3-phenylpentanylamine ("Compound 219"):

[0690] Compound 219 was synthesized from Int. 84 and Int. 66 as described in Example B190. MS (m / z): 393.3 (M+H).

[0691] Example B220: Preparation of (S)-3-(4-chlorophenyl)-N-((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)butyramine ("Compound 220")

[0692] Compound 220 was synthesized from Int. 84 and Int. 125 as described in Example B190. MS (m / z): 399.2 (M+H).

[0693] Example B221: Preparation of (S)-N-(2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-3-methyl-3-phenylbutyramine ("Compound 221"):

[0694] Compound 221 was synthesized by Int. 84 as described in Example B190. MS (m / z): 379.4 (M+H).

[0695] Example B222: Preparation of (S)-N-((S)-3-(1H-...

Claims

1. A compound or its stereoisomer or a pharmaceutically acceptable salt thereof, the compound having the structure of formula (I): Formula (I); wherein: R1 is selected from C6-10 aryl and C1-9 heteroaryl, wherein the C6-10 aryl and C1-9 heteroaryl are substituted by one, two, three, four or five R7, depending on the situation; R2 is selected from C6-10 aryl and C1-9 heteroaryl, wherein the C6-10 aryl and C1-9 heteroaryl are substituted by one, two, three, four or five R8, depending on the situation; R3 is -X-R3a; X is a bond; R3a is a cyclopropyl group substituted by one R9; R4 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; R5 and R6 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; or R5 and R6 are combined to form an aza-heterocyclic butyl, pyrrolidinyl, piperidinyl or piperidine ring; Each R7 is independently selected from halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, -OR10, and -C(O)N(R10)(R11); each R8 is independently selected from halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, and -OR10; R9 is selected from C1-6 alkyl groups and C1-6 haloalkyl groups; each R10 is independently selected from hydrogen and C1-6 alkyl groups; and each R11 is independently selected from hydrogen, C1-6 alkyl groups, and C1-6 haloalkyl groups; wherein C1-9 heteroaryl groups refer to those containing 1 to 9 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur.

2. The compound of claim 1 or its stereoisomer or its pharmaceutically acceptable salt, having the structure of formula (Ia): Formula (Ia); where n is 0, 1, 2, 3 or 4.

3. The compound of claim 2 or its stereoisomer or its pharmaceutically acceptable salt, wherein R10 is independently selected from hydrogen and C1-6 alkyl, R11 is hydrogen, and n is 0, 1 or 2.

4. The compound of claim 2 or its stereoisomer or its pharmaceutically acceptable salt, wherein each R7 is independently selected from halogens and C1-6 alkyl groups.

5. The compound of claim 1 or its stereoisomer or its pharmaceutically acceptable salt, wherein R3a is a cyclopropyl group substituted with -CF3.

6. The compound of claim 1 or its stereoisomer or its pharmaceutically acceptable salt, wherein R2 is a phenyl group substituted with one, two, three, four or five R8 groups, as appropriate.

7. The compound of claim 1 or its stereoisomer or its pharmaceutically acceptable salt, wherein R2 is pyridinyl, pyrimidinyl or thiazolyl, wherein the pyridinyl, pyrimidinyl or thiazolyl is substituted by one, two or three R8s.

8. The compound of claim 1 or its stereoisomer or its pharmaceutically acceptable salt, wherein R2 is an unsubstituted phenyl group.

9. The compound of claim 1 or its stereoisomer or its pharmaceutically acceptable salt, wherein R5 and R6 are C1-C6 alkyl groups.

10. The compound of claim 1 or its stereoisomer or its pharmaceutically acceptable salt, wherein R4 is hydrogen.

11. The compound of claim 1 or its stereoisomer or an acceptable salt thereof, wherein the compound is selected from: ,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,, and.

12. A pharmaceutical composition comprising a compound or stereoisomer of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

13. Use of a compound or stereoisomer of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease or condition in an individual in need, the disease or condition being selected from neuropsychiatric disorders, depression, obsessive-compulsive disorder, alcoholism, gambling addiction, pain, opioid overdose, opioid use disorder, and addiction.