WO2018102006A1

WO2018102006A1 - Compounds for the inhibition of indoleamine-2,3-dioxygenase activity and use thereof

Info

Publication number: WO2018102006A1
Application number: PCT/US2017/051837
Authority: WO
Inventors: Timothy F. Briggs; Tyler J. CIPRIANI; Heather Davis; Jeremy R. DUVALL; Stephen P. Hale; Jun Jiang; Maurice D. LEE; Giovanni MUNCIPINTO; Christopher J. OALMANN; Cheri SNEDEKER
Original assignee: Ensemble Therapeutics Corp
Current assignee: Ensemble Therapeutics Corp
Priority date: 2016-11-30
Filing date: 2017-09-15
Publication date: 2018-06-07
Anticipated expiration: 2019-05-30

Abstract

The present invention relates to compounds, and pharmaceutically acceptable compositions thereof, useful as antagonists of indoleamine-2,3-dioxygenase (IDO) activity, and methods of treating IDO-related disorders.

Description

COMPOUNDS FOR THE INHIBITION OF

INDOLEAMINE-2,3-DIOXYGENASE ACTIVITY AND USE THEREOF CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of and priority to U.S. Provisional Patent

Application No.62/428,048, filed November 30, 2016, which is hereby incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to compounds useful as antagonists of indoleamine-2,3- dioxygenase (IDO) activity. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using such compounds and compositions in the treatment of IDO-related disorders.

BACKGROUND OF THE INVENTION

[0003] The oxygenase indoleamine-2,3-dioxygenase (IDO, also known as IDO 1 or IDO-1), is a heme-containing cytosolic enzyme that catalyzes the extra-hepatic metabolism of the essential amino acid, tryptophan (Trp). The heme pocket of IDO 1 binds both molecular oxygen and Trp, catalyzing oxidative cleavage of the indole ring of Trp. The product of this first and rate- limiting step of Trp metabolism is N-formyl kynurenine, which is a precursor of a variety of bioactive molecules known as kynurenines that have immunomodulatory properties (Shwarcz et al. (2012) NAT. REV. NEUROSCI.13(7):465-77).

[0004] IDO is an inducible enzyme that has a primary role in immune cell modulation. Given that Trp is required for immune T cell activation, the reduction of Trp levels and/or an increase in the pool of kynurenines can prevent the activation of effector immune cells and promote adaptive immune suppression.

[0005] It has been discovered that certain cancers evade tumor-directed immune responses by over expressing IDO, thereby down regulating the anti-tumor T cell response through tryptophan depletion. Comparative studies on the levels of IDO gene expression in human cancer versus normal tissues indicate a significant role in various cancers including cervical, renal, endometrial and squamous cell carcinomas and large B cell lymphoma. Another study using patient plasma levels of kynurenine, in comparison to normal values, as an indicator of IDO disease activity implicated the following cancers: acute myeloid leukemia (AML), colorectal, prostate, head and neck cancer, and lung cancer. [0006] Exemplary IDO inhibitors are described in U.S. Patent Nos. 8,034,953, 8,088,803, 8,232,313, and 8,389,568 and International (PCT) Publication No. WO 2014/150677, and include the small molecules INCB024360, also known as Epacadostat (Incyte Corporation), Indoximod (NewLink Genetics), NLG919 (NewLink Genetics), and F001287 (Flexus

Biosciences). Certain compounds that specifically inhibit IDO activity have been shown to enhance an anti-tumor response and are undergoing clinical evaluation to assess their safety and efficacy (Moon et al. (2015) J. IMMUNOTHER. CANCER 3:51). For example, clinical trials have been testing Epacadostat, a hydroxyamidine small molecule IDO inhibitor, either alone or in combination with other agents, in the treatment of a variety of cancers including melanoma, ovarian cancer, myelodysplastic syndrome, and non-small cell lung cancer.

[0007] Despite these efforts to date, there is still a need for more inhibitors of IDO 1 for use in treating various medical disorders.

SUMMARY

[0008] The present invention provides compounds, methods of inhibiting IDO 1 activity, and methods of treating various medical conditions implicated or otherwise associated with elevated levels of IDO enzyme activity, for example, cancer, using such compounds.

[0009] In one aspect, the invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, where the variables are described in the detailed description. The invention also provides pharmaceutical compositions including a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0010] In various embodiments, the invention provides a compound of Formula (la):

(la) or a pharmaceutically acceptable salt thereof, where the variables are described in the detailed description. The invention also provides pharmaceutical compositions including a compound of Formula Ia or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the invention provides a compound of Formula (Ib):

or a pharmaceutically acceptable salt thereof, where the variables are described in the detailed description. The invention also provides pharmaceutical compositions including a compound of Formula Ib or a pharmaceutically acceptable salt thereof.

[0012] In certain embodiments, the invention provides a compound of Formula (Ic):

or a pharmaceutically acceptable salt thereof, where the variables are described in the detailed description. The invention also provides pharmaceutical compositions including a compound of Formula Ic or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, the invention provides a method of reducing IDO activity in a subject in need thereof. The method includes administering to the subject an effective amount of a compound of Formula I (including Formulae Ia, Ib, and Ic) or a pharmaceutical composition including a compound of Formula I (including Formulae Ia, Ib, and Ic).

[0014] The invention also provides methods of treating a subject suffering from or susceptible to a medical condition that is implicated or otherwise associated with elevated levels of IDO enzyme activity, for example, cancer, such as cervical, renal, endometrial, squamous cell, colorectal, prostate, head and neck, or lung cancers, large B cell lymphoma, or acute myeloid leukemia.

[0015] Accordingly, in various embodiments, the invention provides a method of treating a cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of Formula I (including Formulae Ia, Ib, and Ic), or a pharmaceutical composition including a compound of Formula I (including Formulae Ia, Ib, and Ic). The cancer may be characterized as having an elevated level of IDO activity and/or expression when compared to non-cancerous cells or tissue. Alternatively or in addition, the subject may be characterized as having an elevated concentration of kynurenine in a body fluid, such as whole blood or a blood product, when compared to similar body samples harvested from subjects without the cancer.

[0016] In some embodiments, the invention provides a method of treating a cancer in a subject in need thereof, the method including: administering to the subject an effective amount of a compound of Formula I (including Formulae Ia, Ib, and Ic), or a pharmaceutical composition including a compound of Formula I (including Formulae Ia, Ib, and Ic), where cells associated with the cancer are characterized as having an elevated level of IDO gene expression relative to average IDO gene expression levels in cells of the same cell type without the cancer.

[0017] In certain embodiments, the invention provides a method of treating a cancer in a subject in need thereof, the method including: administering to the subject an effective amount of a compound of Formula I (including Formulae Ia, Ib, and Ic), or a pharmaceutical composition including a compound of Formula I (including Formulae Ia, Ib, and Ic), where the subject has a kynurenine level in a body fluid, for example, whole blood or a blood product, that is elevated relative to the average serum kynurenine levels in similar body fluids of subjects without the cancer.

[0018] In each of the foregoing methods, it is contemplated that the method can also include the administration of an additional therapeutic agent, for example, a cancer immunotherapy agent, such as a PD-1 inhibitor.

[0019] The foregoing and other aspects and embodiments of the invention can be more fully understood by reference to the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION I. Definitions

[0020] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[0021] The terms“a” and“an” as used herein mean“one or more” and include the plural unless the context is inappropriate.

[0022] The term“alkyl” as used herein refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂ alkyl, C₁-C₁₀ alkyl, and C₁-C₆ alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,

2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

[0023] The term“heteroalkyl” as used herein refers to alkyl groups in which one or more carbon atoms are replaced with a heteroatom (e.g., oxygen, nitrogen, sulfur, or the like).

[0024] The terms“alkenyl” and“alkynyl” as used herein refer to unsaturated hydrocarbon groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

[0025] The term“cycloalkyl” as used herein refers to a monovalent fully saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-10, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as“C_4-8 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and

cyclopropane.

[0026] The term“alkylene” as used herein refers to the diradical of an alkyl group.

[0027] The term“methylene” as used herein refers to a divalent -CH₂- group present in an alkyl or alkylene moiety.

[0028] The term“C₀ alkylene” as used herein refers to a bond. Thus, a moiety defined herein as“-(C₀-C₆ alkylene)-aryl” includes both -aryl (i.e., C₀ alkylene-aryl) and -(C₁-C₆ alkylene)-aryl.

[0029] The terms“alkenylene” and“alkynylene” as used herein refer to the diradicals of an alkenyl and an alkynyl group, respectively. [0030] The term“haloalkyl” as used herein refers to an alkyl group that is substituted with at least one halogen. For example, -CH₂F, -CHF₂, -CF₃, -CH₂CF₃, -CF₂CF₃, and the like.

[0031] The term“carbocyclyl” as used herein means a monocyclic, bicyclic or polycyclic hydrocarbon ring system, where each ring is either completely saturated or contains one or more units of unsaturation, but where no ring is aromatic. Representative carbocyclyl groups include cycloalkyl groups (e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), and cycloalkenyl groups (e.g., cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like).

[0032] The term“aryl” as used herein refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system, where at least one ring is aromatic. Representative aryl groups include fully aromatic ring systems, such as phenyl, naphthyl, and anthracenyl, and ring systems where an aromatic carbon ring is fused to one or more non-aromatic carbon rings, such as indanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and the like. In certain embodiments, the aromatic ring may be substituted at one or more ring positions or may not be substituted, i.e., it is unsubstituted.

[0033] The term“aralkyl” as used herein refers to an alkyl group substituted with an aryl group.

[0034] The term“heteroaryl” as used herein refers to a monocyclic, bicyclic or polycyclic ring system where at least one ring is both aromatic and includes a heteroatom; and where no other rings are heterocyclyl (as defined below). In certain instances, a heteroaryl ring which is aromatic and includes a heteroatom can contain 1, 2, 3, or 4 ring heteroatoms in such a ring. Representative heteroaryl groups include ring systems where (i) each ring includes a heteroatom and is aromatic, e.g., imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl; (ii) each ring is aromatic or carbocyclyl, at least one aromatic ring includes a heteroatom and at least one other ring is a hydrocarbon ring or carbocyclyl, e.g., indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,

benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,

pyrido[2,3-b]-1,4-oxazin-3(4H)-one, 5,6,7,8-tetrahydroquinolinyl and

5,6,7,8-tetrahydroisoquinolinyl; and (iii) each ring is aromatic or carbocyclyl, and at least one aromatic ring shares a bridgehead heteroatom with another aromatic ring, e.g., 4H-quinolizinyl. In certain embodiments, the aromatic ring or carbocyclyl may be substituted at one or more ring positions may not be substituted, i.e., it is unsubstituted. [0035] The term“heterocyclyl” as used herein refers to a monocyclic, bicyclic and polycyclic ring system where at least one ring is saturated or partially unsaturated (but not aromatic) and includes at least one heteroatom. A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. A heterocyclic ring can be“spiro” fused, i.e., can be a twisted structure of two or more rings linked together by a common atom. Representative heterocyclyls include ring systems in which (i) every ring is non-aromatic and at least one ring includes a heteroatom, e.g., tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl; (ii) at least one ring is non-aromatic and includes a heteroatom and at least one other ring is an aromatic carbon ring, e.g.,

1,2,3,4-tetrahydroquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl; and (iii) at least one ring is non-aromatic and includes a heteroatom and at least one other ring is aromatic and includes a heteroatom, e.g., 3,4-dihydro-1H-pyrano[4,3-c]pyridine and

1,2,3,4-tetrahydro-2,6-naphthyridine. In certain embodiments, the aromatic ring may be substituted at one or more ring positions or may not be substituted, i.e., it is unsubstituted.

[0036] The term“saturated heterocyclyl” as used herein refers to a heterocyclyl where every ring is saturated, e.g., tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine and piperazine.

[0037] The terms“amine” and“amino” as used herein refer to both unsubstituted and substituted amines, e.g., a moiety represented by the general formula–N(R⁵⁰)(R⁵¹), where R⁵⁰ and R⁵¹ each independently represent hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, aralkyl, or -(CH₂)_m-R⁶¹; or R⁵⁰ and R⁵¹, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R⁶¹ represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In certain embodiments, R⁵⁰ and R⁵¹ each independently represent hydrogen, alkyl, alkenyl, or -(CH₂)_m-R⁶¹.

[0038] The terms“alkoxyl” or“alkoxy” as used herein refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, isopropyloxy, tert-butoxy, and the like. An“ether” is two hydrocarbons covalently linked by an oxygen.

[0039] The phrase“a side chain of an amino acid” as used herein generally refers to a chemical group attached to the alpha-carbon (the carbon vicinal to the amino and carboxyl groups) of a natural amino acid. For example, a side chain of an amino acid includes–CH3, - CH(CH₃)CH₂CH₃, -CH₂CH(CH₃)₂, -CH(CH₃)₂, -CH₂Ph, -CH₂-indole, -CH₂-Ph-OH, - CH₂C(O)NH₂, -CH₂-SH, -CH₂CH₂C(O)NH₂, -CH₂CH₂SCH₃, -CH₂OH, -CH(OH)CH₃, - CH₂C(O)OH, -CH₂CH₂C(O)OH, -(CH₂)₃NH-C(=NH)NH₂, -CH₂-imidazole, and–(CH₂)₄NH₂.

[0040] mbodiments, a side chain of an amino acid can refer to -CH₂-phenyl-

OMe or

.

[0041] In general, the term“substituted”, whether preceded by the term“optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an“optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned under this invention are preferably those that result in the formation of stable or chemically feasible compounds.

[0042] Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group (such as an alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene or the carbon atom of a carbocyclyl, aryl, heterocyclyl or heteroaryl) are independently, for example, halogen; -(CH₂)_0-4R°; -(CH₂)_0-4OR°; -O-(CH₂)_0-4C(O)OR°; -(CH₂)_0-4CH(OR°)₂; -(CH₂)_0-4SR°; -(CH₂)_0-4Ph, which may be substituted with R°; -(CH₂)_0-4O(CH₂)_0-1Ph, which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -NO₂; -CN; -N₃; -(CH₂)_0-4N(R°)₂; -(CH₂)_0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH₂)_0-4N(R°)C(O)NR°₂; -N(R°)C(S)NR°₂;

-(CH₂)_0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°₂; -N(R°)N(R°)C(O)OR°; -(CH₂)_0-4C(O)R°; -C(S)R°; -(CH₂)_0-4C(O)OR°; -(CH₂)_0-4C(O)SR°; -(CH₂)_0-4C(O)OSiR°₃;

-(CH₂)_0-4OC(O)R°; -OC(O)(CH₂)_0-4SR°-, SC(S)SR°; -(CH₂)_0-4SC(O)R°; -(CH₂)_0-4C(O)NR°₂; -C(S)NR°₂; -C(S)SR°; -(CH₂)_0-4OC(O)NR°₂; -C(O)N(OR°)R°; -C(O)C(O)R°;

-C(O)CH₂C(O)R°; -C(NOR°)R°; -(CH₂)_0-4SSR°; -(CH₂)_0-4S(O)₂R°; -(CH₂)_0-4S(O)₂OR°;

-(CH₂)_0-4OS(O)₂R°; -S(O)₂NR°₂; -(CH₂)_0-4S(O)R°; -N(R°)S(O)₂NR°₂; -N(R°)S(O)₂R°;

-N(OR°)R°; -C(NH)NR°₂; -P(O)₂R°; -P(O)R°₂; -OP(O)R°₂; -OP(O)(OR°)₂; -SiR°₃; -(C_1-4 straight or branched alkylene)O-N(R°)₂; or -(C_1-4 straight or branched alkylene)C(O)O-N(R°)₂, where each R° may be substituted as defined below and is independently hydrogen, C_1-6 alkyl, C_1-6 alkenyl C_1-6 alkynyl -CH₂Ph -O(CH₂)_0-1Ph or a 5-6-membered saturated partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0043] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently, for example, deuterium, halogen, -(CH₂)_0-2R^●, -(haloR^●), -(CH₂)_0-2OH, -(CH₂)_0-2OR^●, -(CH₂)_0-2CH(OR^●)₂; -O(haloR^●), -CN, -N₃, -(CH₂)_0-2C(O)R^●, -(CH₂)_0-2C(O)OH, -(CH₂)_0-2C(O)OR^●, -(CH₂)_0-2SR^●, -(CH₂)_0-2SH, -(CH₂)_0-2NH₂, -(CH₂)_0-2NHR^●, -(CH₂)_0-2NR^●

2, -NO₂, -SiR^●

3, -OSiR^●

3, -C(O)SR^●

, -(C_1-4 straight or branched alkylene)C(O)OR^●, or -SSR^●, where each R^● is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently selected from C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0044] Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: =O, =S, =NNR^*

2, =NNHC(O)R^*, =NNHC(O)OR^*, =NNHS(O)₂R^*, =NR^*, =NOR^*, -O(C(R^*

2))_2-3O-, or -S(C(R^*

2))_2-3S-, where each independent occurrence of R^* is selected from hydrogen, C_1-6 alkyl, C_1-6 alkenyl, C_1-6 alkynyl, and carbocyclyl, which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include: -O(C(R^*)₂)_2-3O-, where each independent occurrence of R^* is selected from hydrogen, C_1-6 alkyl, C_1-6 alkenyl, C_1-6 alkynyl, and carbocyclyl, which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0045] Suitable substituents on the alkyl, alkenyl, alkynyl, or carbocyclyl group of R^* include halogen, -R^●, -(haloR^●), -OH, -OR^●, -O(haloR^●), -CN, -C(O)OH, -C(O)OR^●, -NH₂, -NHR^●, -NR^●

2, or -NO₂, where each R^● is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C_1-6 alkyl, C_1-6 alkenyl, C_1-6 alkynyl, -CH₂Ph, -O(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0046] Suitable substituents on a substitutable nitrogen of an“optionally substituted” group include -R^†, -NR^†

2, -C(O)R^†, -C(O)OR^†, -C(O)C(O)R^†, -C(O)CH₂C(O)R^†, -S(O)₂R^†,

-S(O)₂NR^†

2, -C(S)NR^†

2, -C(NH)NR^†

2, or -N(R^†)S(O)₂R^†; where each R^† is independently hydrogen, C_1-6 alkyl, C_1-6 alkenyl, C_1-6 alkynyl, which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, it should be understood that a substitutable nitrogen can be substituted with four substituents (or have four bonds to less than four substituents) such that the nitrogen atom will be positively charged or its cation, i.e., N⁺. Such substitution of a substitutable nitrogen can be of a ring nitrogen, for example, a ring nitrogen of a heterocyclic group containing nitrogen as a ring atom. In particular embodiments, where one of the substituents of a cationic nitrogen atom is a hydroxyl group, the hydroxyl group can be deprotonated and represented by a negatively charged oxygen atom, i.e., O-. In such cases, a general formula for the substitution can be represented by RN⁺(O-)(R’)R’’, where R, R’ and R’’ represent carbon or other atoms, groups and/or moieties to which the nitrogen atom is bound.

[0047] Suitable substituents on the alkyl, alkenyl, alkynyl, or carbocyclyl group of R^† are independently, for example, halogen, -R^●, -(haloR^●), -OH, -OR^●, -O(haloR^●), -CN, -C(O)OH, -C(O)OR^●, -NH₂, -NHR^●, -NR^●

2, or -NO₂, where each R^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1-6 alkyl,

C_1-6 alkenyl, C_1-6 alkynyl, -CH₂Ph, -O(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0048] Any hydrogen atom present in a compound may be substituted with deuterium isotope, i.e., a deuterium atom, unless otherwise noted.

[0049] The term“oxo” as used herein refers to the group =O.

[0050] The term“moiety” as used herein refers to a portion of a compound or molecule.

[0051] The term“compound” as used herein refers to the compound itself and its

pharmaceutically acceptable salts, hydrates, and esters including its various geometric and stereoisomeric forms, unless otherwise understood from the context of the description or expressly limited to one particular form of the compound, i.e., the compound itself, or a pharmaceutically acceptable salt, hydrate, or ester thereof. A compound of the present invention can be a compound of Formula I including a compound of Formulae Ia, Ib, and Ic.

[0052] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.

Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0053] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivatizing with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0054] Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound, as well as enantiomeric mixtures thereof.

[0055] As used herein, the terms“subject” and“patient” as used herein refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and more preferably include humans.

[0056] As used herein, the term“effective amount” as used herein refers to the amount of a compound (e.g., a compound of the present invention) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term“treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. [0057] As used herein, the term“pharmaceutical composition” as used herein refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0058] As used herein, the term“pharmaceutically acceptable salt” refers to any

pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic,

naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

[0059] Examples of bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium) hydroxides, ammonia, and compounds of formula NW ⁺

4 hydroxide, where W is C1-4 alkyl, and the like.

[0060] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate,

glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na⁺, NH ⁺

4 , and NW ⁺

4 (where W is a C_1-4 alkyl group), and the like.

[0061] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are

non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0062] The term“pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0063] The term“pharmaceutically acceptable carrier” as used herein refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see, e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975].

[0064] The terms“inhibitor” and“antagonist” as used herein refer to a molecule, for example, a small molecule, that reduces or inhibits the activity of a target molecule, for example, an enzyme such as IDO. Similarly, the terms“inhibit” or“antagonize” refer to the reduction or inhibition of activity of a target molecule, for example, an enzyme such as IDO.

[0065] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0066] In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0067] Further, it should be understood that elements and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and/or in methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.

[0068] It should be understood that the expression“at least one of” includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression“and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[0069] The use of the term“include,”“includes,”“including,”“have,”“has,”“having,” “contain,”“contains,” or“containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0070] Where the use of the term“about” is before a quantitative value, the present invention also include the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term“about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred.

[0071] Where a molecular weight is provided and not an absolute value, for example, of a polymer, then the molecular weight should be understood to be an average molecule weight, unless otherwise stated or understood from the context.

[0072] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present invention remain operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0073] At various places in the present specification, substituents are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term“C_1-6 alkyl” is specifically intended to individually disclose C₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁- C₃, C₁-C₂, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆ alkyl. By way of other examples, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Additional examples include that the phrase“optionally substituted with 1-5 substituents” is specifically intended to individually disclose a chemical group that can include 0, 1, 2, 3, 4, 5, 0-5, 0-4, 0-3, 0-2, 0-1, 1-5, 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, 3-4, and 4-5 substituents.

[0001] The use of any and all examples, or exemplary language herein, for example,“such as” or“including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention. [0074] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

II. Compounds [0075] In one aspect, the invention provides a compound of Formula I:

or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, where:

“1” represents the position of ring A bound to -C(O)-N(R³)-CH(R⁶)-C(=R⁴)-R⁵ in the compound;

each of R^1a and R^1b is independently selected from hydrogen, deuterium, halogen and C₁- C₄ alkyl;

each of R^2a and R^2b is independently selected from hydrogen, deuterium, halogen, -CN, - S(O)₂-C₁-C₄ alkyl, optionally substituted phenyl, and C₁-C₄ alkyl optionally substituted with one or more of halogen; R³ is selected from hydrogen and C1-C4 alkyl;

R⁴ is O; and

R⁵ is C₃-C₆ cycloalkyl optionally substituted with one or more substituents, such as one, two, three, or four substituents, independently selected from, for example, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, heterocyclyl, halogen, hydroxyl, -N(R⁴³)₂, C₁-C₆ alkoxy, aryl, heteroaryl, benzyl, -C(O)R⁴³, -C(O)N(R⁴³)₂, and C(O)OR⁴³; or -N(R¹¹)(R¹²), where:

R¹¹ is selected from -(C₁-C₂ alkyl)-heteroaryl, -(C₁-C₂ alkyl)-heterocyclyl, -(C₁- C₂ alkyl)-aryl, and -(C₁-C₂ alkyl)-C(O)-heterocyclyl; and

R¹² is selected from hydrogen and C₁-C₄ alkyl; or

R¹¹ and R¹² are taken together to form a heterocyclyl,

where any alkyl, aryl, heterocyclyl, or heteroaryl portion of R¹¹, R¹² or R¹¹ and R¹² taken together is optionally substituted with one or more substituents selected from–halogen; -OH; C₁- C₄ alkyl; -(CH₂)_0-1-C(O)-N(R¹³)(R¹⁴); -C(O)OR¹⁴; -(CH₂)_0-1-N(R¹³)(R¹⁴); oxadiazolyl optionally substituted with a substituent selected from, for example, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl, heteroaryl, and benzyl; tetrazolyl optionally substituted with a substituent selected from, for example, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl, heteroaryl, and benzyl; and aryl optionally substituted with a substituent selected from, for example, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, heterocyclyl, halogen, hydroxyl, -N(R⁴³)₂, C₁-C₆ alkoxy, aryl, heteroaryl, benzyl, -C(O)R⁴³, -C(O)N(R⁴³)₂, and -C(O)OR⁴³; where:

R¹³ is selected from hydrogen and C₁-C₄ alkyl;

R¹⁴ is selected from C₁-C₄ alkyl, -(C₁-C₄ alkylene)-N(C₁-C₄ alkyl)₂, -(C₁-C₄ alkylene)-NH(C₁-C₄ alkyl), -(C₁-C₂ alkylene)-phenyl, -(C₁-C₂ alkylene)-heteroaryl, - CH(R’)-C(O)-O-(C₁-C₄ alkyl), -CH(R’)-C(O)-OH, -CH(R’)-C(O)-NH-(C₁-C₄ alkyl), - CH(R’)-C(O)-N(C₁-C₄ alkyl)₂, -CH(R’)-C(O)-NH-(C₁-C₄ alkylene)-phenyl, -CH(R’)- C(O)-NH-CH(R’’)-C(O)-O-(C₁-C₄ alkyl), -CH(R’)-C(O)-NH-CH(R’’)-C(O)-OH, - CH(R’)-C(O)-NH-CH(R’’)-C(O)-NH-(C₁-C₄ alkyl), -CH(R’)-C(O)-NH-CH(R’’)-C(O)- N(C₁-C₄ alkyl)₂, and -CH(R’)-C(O)-NH-CH(R’’)-C(O)-NH-(C₁-C₄ alkylene)-phenyl, where each of R’ and R’’ is a side chain of an amino acid; or

R¹³ and R¹⁴ are taken together to form a heterocyclyl; and

where any alkyl, alkylene, heteroaryl, phenyl or heterocyclyl portion of R¹³, R¹⁴ or R¹³ and R¹⁴ taken together is optionally substituted with one or more substituents, such as one, two, three, or four substituents, independently selected from, for example, C₁-C₆ alkyl, C₁-C₄ haloalkyl, (C₀-C₂ alkylene)-(C₃-C₆ cycloalkyl), heterocyclyl, halogen, hydroxyl, -N(R⁴³)2, C1-C6 alkoxy, aryl, heteroaryl, benzyl, -C(O)R⁴³, -C(O)N(R⁴³)2, and - C(O)OR⁴³; or

R⁴ is N, and R⁴ and R⁵ are taken together to form a heteroaryl or heterocyclyl optionally substituted with one or more substituents, such as one, two, three, or four substituents, independently selected from, for example, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocyclyl, halogen, hydroxyl, -N(R⁴³)₂, C₁-C₆ alkoxy, aryl, heteroaryl, benzyl, -C(O)R⁴³, -C(O)N(R⁴³)₂, and

C(O)OR⁴³;

R⁶ is a C₁-C₆ alkyl optionally substituted with one or more substituents, for example, one, two, or three substituents, independently selected from F, deuterium and C₃-C₆ cycloalkyl;

each of R^7a and R^7b is independently selected from hydrogen, halogen, and C₁- C₃ alkyl optionally substituted with halogen;

R⁸ is selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, -C(O)O-C₁-C₄ alkyl, -C(O)N(R⁹)(R¹⁰), aryl, heteroaryl, and heterocyclyl; where:

R⁹ is selected from hydrogen and C₁-C₄ alkyl; and

R¹⁰ is selected from C₁-C₆ alkyl and C₃-C₆ cycloalkyl; or

R⁹ and R¹⁰ are taken together to form a heterocyclyl, and

where any alkyl, alkenyl, cycloalkyl, heteroaryl or heterocyclyl portion of R⁸, R⁹ or R¹⁰ is optionally substituted with one or more substituents, such as one, two, three, or four substituents, independently selected from, for example, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, heterocyclyl, halogen, C₁-C₆ alkoxy, aryl, heteroaryl, benzyl, and -(C₁-C₆ alkylene)-O-phenyl; and

R⁴³ is independently hydrogen or C₁-C₆ alkyl.

[0076] Definitions of the variables in Formula I above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i)

or (ii), e.g., such as where A is

each of R^1a, R^1b, R^2a, R^2b, and R³ is hydrogen, R⁴ is O, R⁵ is–N(R¹¹)(R¹²) where R¹¹ and R¹² are taken together to form a heterocyclyl optionally substituted with–C(O)-N(R¹³)(R¹⁴), where R¹³ and R¹⁴ are taken together to form an optionally substituted heterocyclyl, R⁶ is C₁-C₆ alkyl, R^7a and R^7b are independently hydrogen or halogen, R⁸ is an optionally substituted heteroaryl or C(O)N(R⁹)(R¹⁰) where R⁹ is hydrogen and R¹⁰ is an optionally substituted C₃-C₆ cycloalkyl.

[0077] In certain embodiments, R⁸ is not methyl when A is

R¹¹ and R¹² are taken together to form an unsubstituted heterocyclyl, for example, an unsubstituted 5-membered heterocyclyl such as pyrrolidinyl, or an unsubstituted bicyclic heterocyclyl such as indolinyl.

[0078] In certain embodiments, R⁸ is not C₁-C₆ alkyl when A is

and R¹¹ and R¹² are taken together to form an unsubstituted heterocyclyl, for example, an unsubstituted 5- membered heterocyclyl such as pyrrolidinyl, or an unsubstituted bicyclic heterocyclyl such as indolinyl.

[0079] In certain embodiments, R⁸ is not methyl when R¹¹ and R¹² are taken together to form an unsubstituted heterocyclyl, for example, an unsubstituted 5-membered heterocyclyl such as pyrrolidinyl, or an unsubstituted bicyclic heterocyclyl such as indolinyl.

[0080] In certain embodiments, R⁸ is not C₁-C₆ alkyl when R¹¹ and R¹² are taken together to form an unsubstituted heterocyclyl, for example, an unsubstituted 5-membered heterocyclyl such as pyrrolidinyl, or an unsubstituted bicyclic heterocyclyl such as indolinyl.

[0081] In certain embodiments, R^1b and R^2b, or R^1a, R^1b, R^2a, and R^2b are not halogen when A

is

R¹¹ and R¹² are taken together to form an unsubstituted heterocyclyl, for example, an unsubstituted 5-membered heterocyclyl such as pyrrolidinyl. [0082] In certain embodiments, at least one of R^1a, R^1b, R^2a, and R^2b is substituted when A is

nd R¹¹ and R¹² are taken together to form an unsubstituted heterocyclyl, for example, an unsubstituted bicyclic heterocyclyl such as indolinyl.

[0083] In certain embodiments,

[0084] In certain embodiments, each of R^1a and R^1b is independently selected from hydrogen, deuterium and F.

[0085] In certain embodiments, each of R^2a and R^2b is independently selected from hydrogen, deuterium, F, Cl, -CN, -CH₃, -CF₃, -S(O)₂CH₃ and unsubstituted phenyl.

[0086] In certain embodiments, R³ is hydrogen.

[0087] In certain embodiments, R⁴ is O.

[0088] In certain embodiments, R⁴ and R⁵ are taken together to form a heteroaryl selected from thiazol-2-yl, benzo[d]oxaol-2-yl, 1,2,4-oxadiazol-5-yl, and1H-imidazol-2-yl, where the heteroaryl is optionally substituted.

[0089] In certain embodiments, R⁴ and R⁵ are taken together to form 4-((N-isopropyl-N- methyl)aminocarbonyl)thiazol-2-yl, benzo[d]oxaol-2-yl, 3-(phenylmethyl)-1,2,4-oxadiazol-5-yl, or 1-(phenylmethyl)-1H-imidazol-2-yl.

[0090] In certain embodiments, R⁶ is selected from ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropylmethyl, cyclohexylmethyl, neopentyl, and isopentyl, where R⁶ is optionally substituted with one or more deuterium or F.

[0091] In certain embodiments, R⁶ is selected from -CH₂CH(CH₃)₂,

-CH₂CF(CH₃)₂, -CD₂CD(CD₃)₂, -CH₂C(CH₃)₃, -CH₂CH(CF₃)₂ -CH₂CH₃,

-CH₂CH₂CH₃, -CH₂CH₂CH₂CH₃, -CH(CH₃)₂, -CH₂CH₂CH(CH₃)₂, -CH₂CF₃,

-CH₂CH₂CF₃, -CH₂CH₂CH₂CF₃, cyclohexylmethyl, and cyclopropylmethyl.

[0092] In certain embodiments, each of R^7a and R^7b is independently selected from hydrogen, F or -CH₃. [0093] In certain embodiments, R⁸ is selected from C1-C6 alkyl; C4-C6 alkenyl substituted with F; -C(O)O-C₁-C₄ alkyl; -C(O)N(R⁹)(R¹⁰); phenyl; oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; triazolyl; and oxetanyl, where:

R⁹ is selected from hydrogen and -CH₃; and

R¹⁰ is selected from C₁-C₆ alkyl and C₃-C₆ cycloalkyl; or

R⁹ and R¹⁰ are taken together to form a piperidinyl optionally substituted with up to 4 substituents independently selected from C₁-C₄ alkyl,

where:

any cycloalkyl portion of R¹⁰ is optionally substituted with up to 2 substituents independently selected from -CH₃, -CF₃, and -CH₂CH₃;

any alkyl portion of R¹⁰ is optionally substituted with phenyl;

any phenyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, or oxetanyl portion of R⁸ is optionally substituted with up to 2 substituents independently selected from CF₃, phenyl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenoxy-substituted C₁-C₃ alkyl, and phenyl-substituted C₁-C₃ alkyl.

[0094] In certain embodiments, R⁸ is selected from methyl, propyl, hexyl, t- butylaminocarbonyl, 5-(t-butyl)-1,2,4-oxadiazol-3-yl, 5-(t-butyl)-1,3,4-oxadiazol-2-yl, 5-(t- butyl)-oxazol-2-yl, 5-(t-butyl)-isoxazol-3-yl, 2-(t-butyl)oxazol-5-yl, 2-(t-butyl)oxazol-4-yl, 4-(t- butyl)oxazol-2-yl, 1-methylcycloprop-1-ylaminocarbonyl, dimethylaminocarbonyl,

isopropylaminocarbonyl, 1-fluoro-3,3-dimethylbut-1-enyl, 1-ethylcycloprop-1-ylaminocarbonyl, 3-(phenyl)oxetan-3-yl, 4-(t-butyl)phenyl, 2-(t-butyl)pyridin-5-yl, 2-(t-butyl)thiazol-5-yl, 2-(t- butyl)thiazol-4-yl, 5-(t-butyl)thiazol-2-yl, 4-(t-butyl)thiazol-2-yl, 4-trifluoromethylphenyl, butoxycarbonyl, t-butoxycarbonyl, 1-butyl-1,2,3-triazol-4-yl, 5-butyl-1,2,4-oxadiazol-3-yl, 1H- 1,2,3-triazol-4-yl, 1-(phenylmethyl)-1,2,3-triazol-4-yl, 1-(2-phenoxyethyl)-1,2,3-triazol-4-yl, 5- (isopropyl)oxazol-2-yl, 4-methyl-5-isopropyloxazol-2-yl, methoxycarbonyl, 2-methyl-1,3,4- oxadiazoly-2-yl, 3-ethyloxetan-3-yl, isobutoxycarbonyl, 1-fluorohex-1-enyl, 1-fluorohexyl, N- butyl-N-methylaminocarbonyl, 2-butyl-1,3,4-oxadiazol-2-yl, 5-neopentyl-1,2,4-oxadiazol-3-yl, N-(2-phenylethyl)-N-methylaminocarbonyl, bicyclo[1.1.1]pentaneaminocarbonyl, 1-cyclobut-1- ylaminocarbonyl, 1-(trifluoromethyl)cycloprop-1-ylaminocarbonyl, 2,2,6,6-tetramethylpiperidin- 1-ylcarbonyl, and N-(t-butyl)-N-methylaminocarbonyl.

[0095] In certain embodiments, R⁵ is -N(R¹¹)(R¹²), where R¹¹ is selected from -(C₁-C₂ alkyl)- heteroaryl, -(C₁-C₂ alkyl)-heterocyclyl, -(C₁-C₂ alkyl)-aryl, and -(C₁-C₂ alkyl)-C(O)- heterocyclyl; and R¹² is selected from hydrogen and C₁-C₄ alkyl; where any alkyl, aryl, heterocyclyl, or heteroaryl portion of R¹¹ or R¹² is optionally substituted with one or more substituents selected from–halogen, -OH, C₁-C₄ alkyl, -(CH₂)_0-1-C(O)-N(R¹³)(R¹⁴), -C(O)OR¹⁴, -(CH₂)_0-1-N(R¹³)(R¹⁴), optionally substituted oxadiazolyl, optionally substituted tetrazolyl, and optionally substituted aryl, or

R¹¹ and R¹² are taken together to form a heterocyclyl substituted with one or more substituents selected from–halogen, -OH, C₁-C₄ alkyl, -(CH₂)_0-1-C(O)-N(R¹³)(R¹⁴), -C(O)OR¹⁴, -(CH₂)_0-1- N(R¹³)(R¹⁴), optionally substituted oxadiazolyl, optionally substituted tetrazolyl, and optionally substituted aryl.

[0096] In certain embodiments, R¹¹ is quinolin-3-ylmethyl, isoxazol-3-ylmethyl, isoxazol-4- ylmethyl, isoxazol-5-ylmethyl, 1H-pyrazol-4-yl, morpholin-2-ylmethyl, 2-(thiazol-5-yl)ethyl, 1,2,5-oxadiazol-3-ylmethyl, tetrahydrofuran-3-ylmethyl, dioxan-2-ylmethyl, pyrazin-2-ylmethyl, pyrimidin-4-ylmethyl, furan-3-ylmethyl, tetrahydropyran-4-ylmethyl, pyrrolidin-3-ylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, thiazol-4-ylmethyl, 1,2,3,4-tetrazol-5-ylmethyl, phenylmethyl, and 1-(piperazin-1-ylcarbonyl)ethyl; and where R¹¹ is optionally substituted with up to 3 substituents independently selected from C₁-C₄ alkyl and -(C₀-C₂ alkylene)-phenyl.

[0097] In certain embodiments, R¹² is selected from hydrogen and -CH₃.

[0098] In certain embodiments, R¹¹ and R¹² are taken together to form a heterocyclyl or heteroaryl ring selected from pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, morpholin-4-yl, piperidin-1-yl, azetidin-1-yl, indolin-1-yl, 5-azaspiro[2.4]heptan-5-yl, and piperazin-1-yl, where the heterocyclyl or heteroaryl ring is optionally substituted with one or more substituents independently selected from -halogen, -OH, C₁-C₄ alkyl optionally substituted with one or more substituents selected from F and deuterium, - C(O)N(R¹³)(R¹⁴), -C(O)O-(C₁-C₄ alkyl) optionally substituted with one or more substituents selected from F and deuterium), -C(O)R¹⁴, - CH₂N(R¹³)(R¹⁴), -NH-(C₁-C₄ alkyl), and a ring selected from oxadiazolyl, tetrazolyl, and optionally phenyl, where the ring substituent is optionally further substituted with one or more substituents selected from -(C₀-C₂ alkylene)-phenyl, or C₁-C₆ alkyl, where:

R¹³ is selected from hydrogen and C₁-C₄ alkyl;

R¹⁴ is selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, deuterated C₁-C₄ alkyl, -(C₁-C₄ alkylene)-N(C₁-C₄ alkyl)₂, -(C₁-C₄ alkylene)-NH(C₁-C₄ alkyl), -(C₁-C₂ alkylene)-phenyl, -(C₁-C₂ alkylene)-heteroaryl, -CH(R’)-C(O)-O-(C₁-C₄ alkyl), -CH(R’)-C(O)-OH, - CH(R’)-C(O)-NH-(C₁-C₄ alkyl), -CH(R’)-C(O)-N(C₁-C₄ alkyl)₂, -CH(R’)-C(O)-NH-(C₁- C₄ alkylene)-phenyl, -CH(R’)-C(O)-NH-CH(R’’)-C(O)-O-(C₁-C₄ alkyl), -CH(R’)-C(O)- NH-CH(R’’)-C(O)-OH, -CH(R’)-C(O)-NH-CH(R’’)-C(O)-NH-(C₁-C₄ alkyl), -CH(R’)- C(O)-NH-CH(R’’)-C(O)-N(C1-C4 alkyl)2, and -CH(R’)-C(O)-NH-CH(R’’)-C(O)-NH- (C₁-C₄ alkylene)-phenyl, or

R¹³ and R¹⁴ are taken together to form a heterocyclyl selected from piperazin-1- yl, morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-oxa-7-azaspiro[2.5]octan-7-yl, octahydropyrrolo[3,4-c]pyrrol-2-yl, 2,5-diazabicyclo[2.2.2]octan-2-yl, 3,8- diazabicyclo[3.2.1]octan-3-yl, 4,7-diazaspiro[2.5]octan-4-yl, and octahydropyrrolo[1,2- a]pyrazin-2-yl, where:

any heterocyclyl formed by taking R¹³ and R¹⁴ together is optionally substituted with up to 3 substituents independently selected from -OH, -(C₀-C₂ alkylene)-phenyl, C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, deuterated C₁-C₆ alkyl, -(C₀-C₂ alkylene)-(C₃-C₆ cycloalkyl), and -C(O)O-(C₁-C₄ alkyl); and

each of R’ and R’’ is a side chain of an amino acid.

[ In r in m im n i e chain of an amino acid is selected from–CH₃, -CH₂-Ph,

-

[001 In ri m im n h compound is represented by Formula Ia:

(Ia), or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, where:

R¹⁵ is selected from C₃-C₆ alkyl and -CH₂-(C₃-C₆ cycloalkyl);

R¹⁶ is selected from C1-C6 alkyl optionally substituted with one or more of F; C2-C6 alkenyl optionally substituted with one or more F; -C(O)OR²⁰; -C(O)N(R²¹)(R²²); triazolyl; oxazolyl; and oxadiazolyl, where

triazolyl, oxazolyl or oxadiazolyl is optionally substituted with a single substituent selected from C₁-C₆ alkyl, -(C₁-C₂ alkylene)-phenyl and -(C₁-C₂ alkylene)-O-phenyl;

R²⁰ is selected from C₃-C₆ alkyl;

R²¹ is selected from hydrogen and -CH₃; and R²² is selected from C1- C4 alkyl; C3-C6 cycloalkyl optionally substituted with C₁-C₄ alkyl; and -(C₁-C₂ alkylene)-phenyl;

each of R^17a and R^17b is independently selected from hydrogen, halogen and C₁-C₄ alkyl;

R¹⁸ is -N(R²⁴)(R²⁵), where:

R²⁴ is selected from hydrogen and -CH₃;

R²⁵ is selected from C₃-C₆ alkyl, -(C₁-C₂ alkylene)-phenyl, - CH(phenylmethyl)-C(O)-N(R²⁷)(R²⁸), where R²⁷ is selected from hydrogen and C₁-C₄ alkyl; and R²⁸ is selected from C₁-C₄ alkyl and -(C₁-C₂ alkylene)-phenyl; or

R²⁴ and R²⁵ are taken together to form morpholinyl, piperazinyl, or pyrrolidinyl, where morpholinyl, piperazinyl, or pyrrolidinyl is optionally substituted with up to three substituents independently selected from C₁-C₆ alkyl, -(C₀-C₂ alkylene)- phenyl, -(C₀-C₂ alkylene)-(C₃-C₆ cycloalkyl), and -C(O)-O-C₁-C₄ alkyl;

each of R^19a and R^19b is independently selected from hydrogen and halogen; and R²⁶ is hydrogen or -OH.

[00101] Definitions of the variables in Formula Ia above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g., such as where R¹⁵ is C₃-C₆ alkyl, R¹⁶ is oxazole optionally substituted with C₁-C₆ alkyl, or -C(O)N(R²¹)(R²²) where R²¹ is hydrogen, R²² is C₃-C₆ cycloalkyl optionally substituted with C₁-C₄ alkyl, each of R^17a and R^17b is independently hydrogen or halogen, R¹⁸ is - N(R²⁴)(R²⁵), where R²⁴ and R²⁵ are taken together to form morpholinyl or piperazinyl, optionally substituted with up to three substituents independently selected from C₁-C₆ alkyl and -(C₀-C₂ alkylene)-phenyl, each of R^19a and R^19b is hydrogen, and R²⁶ is hydrogen.

[00102] In certain embodiments, the compound is represented by Formula Ia, where:

R¹⁵ is selected from -CH₂CH(CH₃)₂, -(CH₂)₃CH₃, -(CH₂)₂CH(CH₃)₂, -(CH₂)₂CH₃, and cyclohexylmethyl;

R¹⁶ is selected from -CH₃, -CF=CH-C(CH₃)₃, -CF=CH(CH₂)₃CH₃, -CHF-(CH₂)₄CH₃, - C(O)N(CH₃)₂, -C(O)NHC(CH₃)₃, -C(O)NHCH(CH₃)₂, -C(O)OC(CH₃)₃, -C(O)OCH₂CH(CH₃)₂, -C(O)O(CH₂)₃CH₃, N-(2-(phenyl)ethyl)-N-methylaminocarbonyl, 1-ethylcycloprop-1- ylaminocarbonyl, 1-methylcycloprop-1-ylaminocarbonyl, 1-(phenylmethyl)-1,2,3-triazol-4-yl, 1- (butyl)-1,2,3-triazol-4-yl, 1-(2-phenoxy)ethyl-1,2,3-triazol-4-yl, 5-t-butyl-oxazol-2-yl, 5-butyl- 1,3,4-oxadiazol-2-yl, 5-t-butyl-1,2,4-oxadiazol-3-yl, and 5-butyl-1,2,4-oxadiazol-3-yl;

R^17a is selected from hydrogen and F;

R^17b is selected from hydrogen, F and -CH₃;

R¹⁸ is selected from -N(CH₃)CH(CH₃)₂, -N(CH₃)CH₂CH(CH₃)₂, morpholin-4-yl, 2- isopropylmorpholin-4-yl, 3-cyclopropyl-4-methylpiperazin-1-yl, 3-(butan-2-yl)-4- methylpiperazin-1-yl, 3-neopentyl-4-methylpiperazin-1-yl, 3-phenylmethyl-4-t- butoxycarbonylpiperazin-1-yl, 3-cyclobutylmethyl-4-methylpiperazin-1-yl, 3-cyclohexyl-4- methylpiperazin-1-yl, 3-cyclohexylmethyl-4-methylpiperazin-1-yl, 2-phenylmethylmorpholin-4- yl, 3-phenyl-4-methylpiperazin-1-yl, 2-phenylmethyl-4-methylpiperazin-1-yl, 3-phenylmethyl-4- methylpiperazin-1-yl, 2-phenylpyrrolidin-1-yl, N-(1-dimethylaminocarbonyl-2-(phenyl)ethyl)- N-methylamino, N-(1-(N-butyl-N-methylaminocarbonyl)-2-(phenyl)ethyl)-N-methylamino, N- 2-phenylethyl-N-methylamino, and N-(1-(2-phenylethylaminocarbonyl)-2-phenyl)ethyl-N- methylamino;

R^19a is selected from hydrogen, Cl and Br;

R^19b is hydrogen; and

R²⁶ is hydrogen or -OH.

[00103] In various embodiments, the compound is represented by the structural Formula Ib:

(Ib) or a diastereomer thereof, or a pharmaceutically acceptable salt of either of the foregoing.

[00104] It is understood that each of the variables of Formula Ib may be selected from any one or more of the embodiments noted above for Formula Ia.

[00105] In various embodiments, the compound is represented by Formula Ic:

(Ic) or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, where:

R²⁹ is selected from C₃-C₆ alkyl and -CH₂-(C₃-C₆ cycloalkyl);

R³⁰ is selected from C₁-C₆ alkyl optionally substituted with one or more F; C₂-C₆ alkenyl optionally substituted with one or more F; -C(O)OR³⁴; -C(O)N(R³⁵)(R³⁶);

triazolyl; oxazolyl; and oxadiazolyl, where

R³⁴ is selected from C₃-C₆ alkyl;

R³⁵ is selected from hydrogen and -CH₃; and

R³⁶ is selected from C₁-C₄ alkyl; C₃-C₆ cycloalkyl optionally substituted with C₁-C₄ alkyl, and -(C₁-C₂ alkylene)-phenyl;

each of R^31a and R^31b is independently selected from hydrogen, halogen and C₁-C₄ alkyl;

R³² is -N(R³⁸)(R³⁹), where:

R³⁸ is selected from hydrogen and -CH₃;

R³⁹ is selected from C₃-C₆ alkyl, -(C₁-C₂ alkylene)-phenyl, and - CH(phenylmethyl)-C(O)-N(R⁴¹)(R⁴²), where R⁴¹ is selected from hydrogen and C₁-C₄ alkyl; and R⁴² is selected from C₁-C₄ alkyl and -(C₁-C₂ alkylene)-phenyl; or

R³⁸ and R³⁹ are taken together form morpholinyl, piperazinyl, or pyrrolidinyl, where the morpholinyl, piperazinyl, or pyrrolidinyl is optionally substituted with up to three substituents independently selected from C₁-C₆ alkyl, -(C₀-C₂ alkylene)-phenyl, -(C₀-C₂ alkylene)-(C₃-C₆ cycloalkyl), and -C(O)-O-C₁-C₄ alkyl;

R³³ is selected from hydrogen, halogen, and C₁-C₄ alkyl; and

R⁴⁰ is hydrogen or–OH.

[00106] In certain embodiments, the compound is represented by Formula Ic, where:

R²⁹ is -CH₂CH(CH₃)₂, R³⁰ is selected from–C(O)NHC(CH3)(CH2)2 and -C(O)NHC(CH3)3;

R^31a is hydrogen;

R^31b is hydrogen;

R³² is selected from morpholinyl substituted with benzyl, and -N(CH₃)CH(CH₃)₂; R³³ is methyl; and

R⁴⁰ is hydrogen.

[00107] In certain embodiments, the invention provides a compound set forth in Table 1 herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including a compound set forth in Table 1 or a pharmaceutically acceptable salt thereof.

[00108] The invention also embraces pharmaceutical compositions comprising a compound of the invention as described herein; and a pharmaceutically acceptable carrier.

III. Methods of Synthesizing Compounds of the Invention

[00109] The compounds of the present invention can be prepared using an iterative peptide coupling procedure as illustrated in following synthetic schemes. Exemplary general synthetic protocols are presented in Schemes 1 through 12. The schemes and accompanying description of synthetic procedures are given for the purpose of illustrating the invention, and should not be construed as limiting the scope or spirit of the invention.

[00110] Abbreviations as used herein include

O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU);

diisopropylethylamine (DIPEA); dimethylformamide (DMF); 9-fluorenylmethoxycarbonyl (Fmoc); methanol (MeOH); methylene chloride (DCM); tert-butoxycarbonyl (Boc); tert-butyl (tBu); tetrahydrofuran (THF); trifluoroacetic acid (TFA); 1,8-diazobicyclo [5.4.0]-undec-7-ene (DBU); 1-hydroxy-7-azabenzotriazole (HOAt); phenyl (Ph); trifluoroacetic acid (TFA);

triethylamine (Et₃N); petroleum ether (PE); ethyl acetate (EA); acetic acid (AcOH); diethyl ether (Et₂O); dimethylsulfoxide (DMSO); diisopropylethylamine (DIEA); N-bromosuccinimide (NBS); triphenyl phosphine (PPh₃); diisopropyl azodicarboxylate (DIAD); methanesulfonyl chloride (MsCl); lithium hydroxide (LiOH); 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC); diisobutylaluminium hydride (DIBAL-H); hydrogen chloride (HCl); 2,4,6- trichlorobenzoylchloride (TCBC); room temperature (r.t. or RT); and thin-layer chromatography (TLC). SCHEME 1.

[00111] Scheme 1 depicts a general synthetic method for preparing a compound of Formula I (3) via coupling of a building block 1 (1) and a building block 2 (2) using HATU and DIEA.

[00112] Compounds 104-109, 112-114, 116, 117, 119-124, 126, 130, 132, 133, 135, 140, 142- 213, 216-218, 220-222, 224-230, 232-234, 236-239, 241-250, 253-263, 265-268, 270-272, 274- 286, 288-292, 294-303, 305-336, 339-345, 347-386, 388-407, and 411-498 of Table 1 were prepared by the procedure described in Scheme 1.

SCHEME 2.

[00113] Scheme 2 depicts a general synthetic method for preparing a compound of Formula Ia (6) via coupling of a building block 1a (4) and a building block 2a/b (5) using HATU and DIEA.

SCHEME 3.

[00114] Scheme 3 depicts a general synthetic method for preparing a compound of Formula Ib (8) via coupling of a building block 1b (7) and a building block 2a/b (5) using HATU and DIEA. A building block 1b is a specific stereoisomer of a building block 1a. [00115] Compounds 104-109, 112-114, 116, 117, 119-124, 126, 130, 132, 133, 135, 140, 142- 150, 153-167, 169, 171-182, 193-195, 197-200, 204-207, 210-213, 216, 217, 221, 222, 224-226, 228-230, 232, 234, 237, 239, 241-243, 245-248, 250, 253-259, 261-263, 272, 274-286, 288-290, 294-301, 308, 310-316, 318-334, 336, 339-345, 347-370, 375-377, 382-386, 388-407, 411-417, 419-459, 461-472, 475-477, 495-498 of Table 1 were synthesized by the procedure described in Schemes 2 and 3.

[00116] Scheme 4 depicts a general synthetic method for preparing a building block lb (7). A carboxylic acid 9 is treated with an amine 10 in the presence of HATU and DIEA, and the BOC group of the resulting amide is removed with TFA to provide 11. The intermediate 11 is coupled with a carboxylic acid 12, and the Fmoc group of the resulting compound is removed with DBU to form a building block lb (7).

[00117] Scheme 5 depicts a general synthetic method for preparing a building block 2a/b (5). A methyl salicylate 13 is treated with an a-bromo ester 14 in the presence of potassium carbonate to yield 15. Removal of the i-butyl group of 15 with TFA and a coupling of the resulting compound with an amine 16 in the presence of HATU and DIEA provides 17. Hydrolysis of an intermediate 17 with LiOH furnishes a building block 2a/b (5).

[00118] Compounds 159, 178, 179, 196, 200, 207, 217, 221, 222, 232, 237, 241-243, 253-258, 274, 277, 278, 294, 295, 302, 303, 308, 311, 312, 314, 315, 320-322, 324, 328, 330, 332-334, 336, 340-344, 348-350, 354-356, 358, 362, 364, 366-370, 375-377, 382, 384-386, 388-395, 398- 400, 402-404, 411, 416, 417, 420-427, 429-439, 444, 445, 448, 449, 451-456, 458, 461, 465, 466, 475, 476, and 497 of Table 1 were synthesized by the procedure described in Schemes 3-5. An exemplary synthesis of a compound of Formula Ib following the procedure of Schemes 3-5 is described in EXAMPLE 1. SCHEME 6.

[00119] Scheme 6 depicts another general synthetic method for preparing a building block 2a/b (5). A methyl salicylate 13 is treated with an alkylchloride 18 in the presence of potassium carbonate to form 17. Hydrolysis of 17 with LiOH furnishes a building block 2a/b (5).

[00120] Compounds 148, 150, 154-157, 160, 161, 163, 165, 167, 169, 171-177, 180-182, 193, 194, 198, 199, 205, 210-213, 216, 224-230, 234, 238, 239, 248, 250, 259, 261-263, 265-268, 272, 279, 280, 282-286, 288-290, 296, 301, 310, 313, 316, 318, 319, 323, 325-327, 329, 331, 339, 347, 351-353, 357, 359-361, 363, 365, 383, 396, 397, 401, 405-407, 419, and 428 of Table 1 were synthesized by the procedure described in Schemes 3, 4, and 6. An exemplary synthesis of a building block 2 a/b following the procedure of Scheme 6 is described in EXAMPLE 2.

[00121] Variations of synthetic methods of building blocks 1b and 2a/b are described in Schemes 7-10.

SCHEME 7.

[00122] Scheme 7 depicts a synthesis of an amine 10 (Scheme 4) where R²⁵ is a–

CH(phenylmethyl)-C(O)-NR²⁷R²⁸ group. An amino acid 19 is coupled with an amine 20 in the presence of EDC to form 21. Removal of the BOC group of 21 with HCl provides 22. An exemplary synthesis of 22 is described in EXAMPLE 5.

[00123] Compounds 117, 123, 132, and 144 of Table 1 were synthesized by the procedure described in Schemes 3-5, and 7. Compounds 119, 124, 126, 145, and 147 of Table 1 were synthesized by the procedure described in Schemes 3, 4, 6, and 7. SCHEME 8.

[00124] Scheme 8 depicts a variation of a synthetic method for preparing a building block 2a/b (5). An alkyne 25 is treated with an azide 26 in the presence of L-ascorbic acid, copper iodide, and DIEA to provide a building block 27.

[00125] An exemplary synthesis of 27 following the procedure of Scheme 8 is described in EXAMPLE 6. An exemplary synthesis of 26 is described in EXAMPLE 7. Compound 121 was synthesized by the procedure described in Schemes 3, 4, and 8. Compounds 104, 105, 106, 107, 108, 109, 112, 113, 114, 122 were synthesized by the procedure described in Schemes 3, 4, 7, and 8.

SCHEME 9.

[00126] Scheme 9 depicts a variation of a synthetic method for preparing a building block 2a/b (5). An aldehyde 28 is treated with 29 and NaH, and the resulting intermediate is reduced with DIBAL-H to form an alcohol 30. The intermediate 30 is treated with t-butyl 2-hydroxybenzoate (31), DIAD and triphenylphosphine to provide 32. Removal of the t-butyl group from 32 with TFA results in a building block 33.

[00127] An exemplary synthesis of 33 following the procedure of Scheme 9 is described in EXAMPLE 10. Compounds 120 and 146 of Table 1 were synthesized following the procedure described in Schemes 3, 4, 7, and 9. Compound 195 of Table 1 was synthesized following the procedure described in Schemes 3, 4, and 9. SCHEME 10.

[00128] Scheme 10 depicts a variation of a synthetic method for preparing a building block 2a/b (5). A methyl salicylate 13 is treated with a 2-bromo-2-fluoroacetate 34 and potassium carbonate to form 35. The intermediate 35 is treated with DIEA and an amine 16 to form 17. Hydrolysis of 17 with LiOH furnishes a building block 2a/b (5).

[00129] An exemplary synthesis of 5 following the procedure of Scheme 10 is described in EXAMPLE 14. Compounds 297-300, 345, 412-415, 440-443, 446-447, 450, 457, 459, 462-464, 467-472, 477, 495, 496, and 498 were synthesized by the procedure described in Scheme 3, 4, and 10. SCHEME 11.

[00130] Scheme 11 depicts a general synthetic method for preparing a compound of Formula Ic (38) via coupling of a building block 1c (36) and building block 2c (37) using HATU and DIEA. A building block 1c (36) is synthesized by the procedure described in Scheme 4. A building block 2c (37) is synthesized by the procedure described in Scheme 12. SCHEME 12.

[00131] Scheme 12 depicts a general synthetic method for preparing a building block 2c (38). A hydroxyl thiazole 39 is treated with a 2-bromoacetate 40 in the presence of potassium carbonate and potassium iodide to form 41. An intermediate 41 is treated with TFA, and the resulting acid is reacted with an amine 42 in the presence of HATU and DIEA to provide 43. Hydrolysis of 43 with LiOH furnishes 38.

[00132] Compounds 335, 473, and 474 of Table 1 were synthesized by the procedure described in Schemes 4, 11, and 12. An exemplary synthesis of 38 is described in EXAMPLE 15.

[00133] Combinations of substituents and variables contemplated by the present invention are only those that result in the formation of compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).

IV. Therapeutic Applications

[00134] The invention provides, in part, compounds for use in a method of antagonizing of inhibiting IDO activity in a subject or in a biological sample where the method includes the step of administering to the subject or contacting the biological sample with a compound of the invention, namely a compound of Formula I (including Formulae Ia, Ib, and Ic).

[00135] The compounds of the invention can be used to treat a disease, condition, or disorder where elevated IDO enzyme activity is implicated in the disease state. For example, the compounds of the invention can be used to treat a disease, condition, or disorder where a compound of the invention reduces IDO enzyme activity, for example, upon binding to IDO. The invention provides a method of inhibiting IDO activity in a subject by administering to the subject an effective amount of a compound of the invention, for example, a compound of Formula I (including Formulae Ia, Ib, and Ic). In certain embodiments, the method is used to treat or prevent a condition selected from a proliferative or hyperproliferative disease, for example, cancer.

[00136] In particular, the invention provides for the treatment of diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include a proliferative or hyperproliferative disease. Examples of proliferative and hyperproliferative diseases include cancer and myeloproliferative disorders.

[00137] The invention provides a method of treating cancer in a subject in need thereof. The method includes administering to the subject an effective amount of a compound of the invention, namely a compound of Formula I (including Formulae Ia, Ib, and Ic), or a

pharmaceutical composition including a compound of the invention, namely a compound of Formula I (including Formulae Ia, Ib, and Ic). In certain embodiments, cells associated with the cancer are characterized as having an elevated level of IDO activity and/or expression when compared to cells associated with non-cancerous tissue. Alternatively or in addition, the subject is characterized as having an elevated concentration of kynurenine in a body fluid, such as blood, serum or plasma, when compared to a similar body of a subject without the cancer.

[00138] In particular, it is contemplated that the compounds of the invention can be used to treat one or more of the following cancers: Oral: head and neck, including buccal cavity, lip, tongue, mouth pharynx; Cardiac: sarcoma (angiosarcoma fibrosarcoma rhabdomyosarcoma liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: Non-small cell lung carcinoma including adenocarcinoma, bronchioalveolar, squamous cell carcinoma

(basaloid, clear cell, papillary, small cell), large cell carcinoma, large cell neuroendocrine carcinoma (LCNEC); small cell lung cancer including small cell (oat cell) carcinoma, combined small cell; adenoid cystic carcinoma; hamartoma; lymphoma; neuroendocrine/carcinoid;

sarcoma; Gastrointestinal: esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel or small intestines (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal, rectum; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma,

osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma,

meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);

Female/Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma, hairy cell; lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis, Thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma,

undifferentiated thyroid cancer, medullary thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer,

pheochromocytoma, paraganglioma; and Adrenal glands: neuroblastoma.

[00139] In certain embodiments, the cancer is selected from head and neck, ovarian, melanoma cervical, endometrial, esophageal, and breast cancer.

[00140] In certain embodiments, the cancer is a hematopoietic disorder, for example, acute- myelogenous leukemia (AML), chronic-myelogenous leukemia (CML), acute-promyelocytic leukemia (APL), and acute lymphocytic leukemia (ALL).

[00141] In certain embodiments, the cancer is selected from cervical, renal, endometrial, squamous cell, colorectal, prostate, head and neck and lung cancers, large B cell lymphoma, and AML.

[00142] The invention provides a method of treating a cancer in a subject in need thereof. The method includes administering to the subject an effective amount of a compound of the invention, namely a compound of Formula I (including Formulae Ia, Ib, and Ic), or a

pharmaceutical composition including a compound of the invention, namely a compound of Formula I (including Formulae Ia, Ib, and Ic), where cells associated with the cancer are characterized as having an elevated level of IDO gene expression relative to average IDO gene expression in cells of the same cell type without the cancer.

[00143] In such a method, a subject suitable for treatment can be identified by obtaining a cancer cell sample from the subject; determining the level of IDO gene expression in the sample; comparing the IDO gene expression level in the sample to a threshold value typically present in normal cells, for example, a cell sample from subjects without cancer, thereby to determine if IDO gene expression is elevated in the cancer sample. Once an elevated level of IDO gene expression has been identified in the subject, the subject can then be treated by administering an effective amount of the compound of the invention, namely a compound of Formula I (including Formulae Ia, Ib, and Ic), or a pharmaceutical composition including a compound of the invention, namely a compound or Formula I (including Formulae Ia, Ib, and Ic). Exemplary gene expression assays are described, for example, in International Application No. WO

2013/095793. [00144] The expression levels of IDO can be determined using a variety of approaches known in the art. For example, a tissue or cell sample can be obtained by using conventional tumor biopsy instruments and procedures. Endoscopic biopsy, excisional biopsy, incisional biopsy, fine needle biopsy, punch biopsy, shave biopsy and skin biopsy are examples of recognized medical procedures that can be used by one of skill in the art to obtain tumor samples for use in practicing the invention. The tumor tissue sample should be large enough to provide sufficient RNA for measuring individual gene expression levels.

[00145] The tumor tissue sample can be in any form that allows quantitative analysis of gene expression or transcript abundance. In some embodiments, RNA is isolated from the tissue sample prior to quantitative analysis. Some methods of RNA analysis, however, do not require RNA extraction, e.g., the qNPA™ technology commercially available from High Throughput Genomics, Inc. (Tucson, AZ). Accordingly, the tissue sample can be fresh, preserved through suitable cryogenic techniques, or preserved through non-cryogenic techniques. Tissue samples used in the invention can be clinical biopsy specimens, which often are fixed in formalin and then embedded in paraffin. Samples in this form are commonly known as formalin-fixed, paraffin-embedded (FFPE) tissue. Techniques of tissue preparation and tissue preservation suitable for use in the present invention are well-known to those skilled in the art.

[00146] Gene expression levels (transcript abundance) can be determined by any suitable method. Exemplary methods for measuring individual gene expression levels include quantitative RT-PCR (qRT-PCR) and qNPA™.

[00147] qRT-PCR typically is performed on RNA isolated from a sample of interest, for example, a tissue sample. Methods for rapid and efficient extraction of eukaryotic mRNA (poly(a) RNA), from tissue samples are well-established and known to those of skill in the art. See, e.g., Ausubel et al., 1997, Current Protocols of Molecular Biology, John Wiley & Sons. The tissue sample can be fresh, frozen or fixed paraffin-embedded (FFPE) clinical study tumor specimens. In general, RNA isolated from fresh or frozen tissue samples tends to be less fragmented than RNA from FFPE samples. FFPE samples of tumor material, however, are more readily available, and FFPE samples are suitable sources of RNA for use in methods of the present invention. For a discussion of FFPE samples as sources of RNA for gene expression profiling by RT-PCR, see, e.g., Clark-Langone et al., 2007, BMC Genomics 8:279. Also see, De Andrés et al., 1995, Biotechniques 18:42044; and Baker et al., U.S. Patent Application

Publication No.2005/0095634. The use of commercially available kits with vendor’s instructions for RNA extraction and preparation is widespread and common. Commercial vendors of various RNA isolation products and complete kits include Qiagen (Valencia, CA), Invitrogen (Carlsbad, CA), Ambion (Austin, TX) and Exiqon (Woburn, MA).

[00148] Certain advantages of qRT-PCR include sensitivity, flexibility, quantitative accuracy, and ability to discriminate between closely related mRNAs. Guidance concerning the processing of tissue samples for quantitative PCR is available from various sources, including

manufacturers and vendors of commercial products for qRT-PCR (e.g., Qiagen (Valencia, CA) and Ambion (Austin, TX)). Instrument systems for automated performance of qRT-PCR are commercially available and used routinely in many laboratories. An example of a well-known commercial system is the Applied Biosystems 7900HT Fast Real-Time PCR System (Applied Biosystems, Foster City, CA).

[00149] Once isolated mRNA is in hand, the first step in RT-PCR is the reverse transcription of the mRNA template into cDNA, which is then exponentially amplified in a PCR reaction. Two commonly used reverse transcriptases are avilo myeloblastosis virus reverse transcriptase (AMV-RT) and Moloney murine leukemia virus reverse transcriptase (MMLV-RT). The reverse transcription reaction typically is primed with specific primers, random hexamers, or oligo(dT) primers. Suitable primers are commercially available, e.g., GeneAmp^® RNA PCR kit (Perkin Elmer, Waltham, MA). The resulting cDNA product can be used as a template in the subsequent polymerase chain reaction.

[00150] The PCR step is carried out using a thermostable DNA-dependent DNA polymerase. The polymerase most commonly used in PCR systems is a Thermus aquaticus (Taq) polymerase. The selectivity of PCR results from the use of primers that are complementary to the DNA region targeted for amplification, i.e., regions of the cDNAs reverse transcribed from the genes of the Transcription Cluster. Therefore, when qRT-PCR is employed in the present invention, primers specific to each gene in a given Transcription Cluster are based on the cDNA sequence of the gene. Commercial technologies such as SYBR^® green or TaqMan^® (Applied Biosystems, Foster City, CA) can be used in accordance with the vendor’s instructions. Messenger RNA levels can be normalized for differences in loading among samples by comparing the levels of housekeeping genes such as beta-actin or GAPDH. The level of mRNA expression can be expressed relative to any single control sample such as mRNA from normal, non-tumor tissue or cells. Alternatively, it can be expressed relative to mRNA from a pool of tumor samples, or tumor cell lines, or from a commercially available set of control mRNA.

[00151] PCR primer sets for practicing the disclosed methods can be purchased from commercial sources, e.g., Applied Biosystems. PCR primers preferably are about 17 to 25 nucleotides in length. Primers can be designed to have a particular melting temperature (Tm), using conventional algorithms for Tm estimation. Software for primer design and Tm estimation are available commercially, e.g., Primer Express™ (Applied Biosystems). By applying established principles of PCR primer design, a large number of different primers can be used to measure the expression level of any given gene.

[00152] In addition, an example of a method for determining expression levels of a gene of interest without performing an RNA extraction step is the quantitative nuclease protection assay (qNPA™), which is commercially available from High Throughput Genomics, Inc. (aka“HTG”; Tucson, AZ). In the qNPA method, samples are treated in a 96-well plate with a proprietary Lysis Buffer (HTG), which releases total RNA into solution. Gene-specific DNA

oligonucleotides, i.e., specific for each gene of interest, are added directly to the Lysis Buffer solution, and they hybridize to the RNA present in the Lysis Buffer solution. The DNA oligonucleotides are added in excess, to ensure that all RNA molecules complementary to the DNA oligonucleotides are hybridized. After the hybridization step, S1 nuclease is added to the mixture. The S1 nuclease digests the non-hybridized portion of the target RNA, all of the non- target RNA, and excess DNA oligonucleotides. Then the S1 nuclease enzyme is inactivated. The RNA::DNA heteroduplexes are treated to remove the RNA portion of the duplex, leaving only the previously protected oligonucleotide probes. The surviving DNA oligonucleotides are a stoichiometrically representative library of the original RNA sample. The qNPA oligonucleotide library can be quantified using the ArrayPlate Detection System (HTG).

[00153] It is contemplated that the expression level of IDO can be determined using a variety of accurate and reliable systems, including protocols, reagents and instrumentation that are commercially available. Selection and use of a suitable system for generating gene expression data for use in the methods described herein is a design choice, and can be accomplished by a person of skill in the art, without undue experimentation.

[00154] In addition, the invention provides a method of treating a cancer in a subject in need thereof. The method includes administering to the subject an effective amount of a compound of the invention, namely a compound of Formula I (including Formulae Ia, Ib, and Ic), or a pharmaceutical composition including a compound of the invention, namely a compound or Formula I (including Formulae Ia, Ib, and Ic), where the subject has a kynurenine level in a body fluid that is elevated relative the average serum kynurenine level in a similar body fluid harvested from subjects without the cancer. Examplary body fluids include, for example, whole blood or blood products such as plasma or serum. [00155] In such a method, a subject suitable for treatment can be identified as having an elevated concentration of kynurenine in a body fluid. This can be accomplished by obtaining a body fluid sample from the subject; determining the concentration of kynurenine in the fluid sample; and comparing the kynurenine concentration in the fluid sample against a threshold value representive of the average concentration of kynurenine present in the same type of body fluid of subjects without the cancer so as to determine if the kynurenine is elevated in the fluid sample of the subject being tested. Once an elevated concentration of kynurenine has been identified in the subject, the subject may then be treated by administering to the subject an effective amount of a compound of Formula I (including Formulae Ia, Ib, and Ic), or a pharmaceutical composition including a compound of the invention, namely a compound or Formula I (including Formulae Ia, Ib, and Ic).

[00156] It is contemplated that the kynurenine concentration (as well as tryptophan

concentration) can be determined in a sample (tissue or body fluid) of interest using standard methodologies known in the art, for example, by high pressure liquid chromatography (HPLC) (see, Widner et al. (1997) C^LINICAL C^HEM., vol.43, no.2: 2424-2426; Laich et al. (2002) CLINICAL CHEM., vol.48, no.3: 579-581), or HPLC-Tandem mass spectometry (see, de Jong et al. (2009) J. C^HEMOTHERAPY B, vol.877: 603-609), spectroscopy (see, Tokikawa et al. (1988) J. BIOL. CHEM., 263: 2041-2048; U.S. Publication No.2016/0120857).

[00157] The invention provides compounds that are useful for the treatment of other diseases, disorders, and conditions, for example, viral disease, sepsis, pneumonia, bacteremia, trauma, tuberculosis, parasitic disease, neuroinflammation, schizophrenia, depression, neurodegenerative disease, and pain. In certain embodiments, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Dementia, multiple Sclerosis, and Huntington's disease. In certain embodiments, the viral disease is selected from Human Immunodeficiency Virus (HIV), Hepatitis A-D, Human Papilloma Virus (HPV), and Herpes, including Herpes Simplex I and II, as well as the Epstein Barr Virus.

[00158] Additionally, it is contemplated that one or more compounds of the invention can be used in the manufacture of a medicament for the treatment of at least one of the aforementioned disorders. It is also contemplated that one or more compounds of the present invention or one or more pharmaceutical compositions including one or more compounds of the present invention can be used as a medicament and/or in the treatment of at least one of the aforementioned disorders. [00159] The invention also provides for combination therapies using a compound described herein and a second therapeutic agent. Combination therapy (or co-therapy) includes the administration of a compound described herein and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).

[00160] Combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, where each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. Combination therapy also can embrace the

administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.) Where the combination therapy further includes a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

[00161] Accordingly, the invention provides a method treatment, as described above, further including an additional step of administering to the subject an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an anti-viral agent, an agent for treating blood disorders, or an agent for treating immunodeficiency disorders, where the additional therapeutic agent is appropriate for the disease being treated.

[00162] In certain embodiments, the additional therapeutic agent is administered together with the compound of Formula I (including Formulae Ia, Ib, and Ic) or a composition containing the compound of Formula I (including Formulae Ia, Ib, and Ic) as a single dosage form. In certain embodiments, the additional therapeutic agent is administered separately from the

compound/composition of Formula I (including Formulae Ia, Ib, and Ic) as part of a multiple dosage form.

[00163] In certain embodiments, the invention is directed towards a method of treating cancer in a subject in need thereof, including administration of a compound of Formula I (including Formulae Ia, Ib, and Ic) and an additional therapeutic agent. In certain embodiments, the additional therapeutic agent is administered together with the compound Formula I (including Formulae Ia, Ib, and Ic) as a single dosage form. In certain embodiments, the additional therapeutic agent is administered separately from the compound of Formula I (including Formulae Ia, Ib, and Ic) as part of a multiple dosage form.

[00164] In certain embodiments, the additional therapeutic agent is an anti-cancer agent, an anti-proliferative agent, or a chemotherapeutic agent.

[00165] In certain embodiments, the additional therapeutic agent is selected from cisplatin (Platino^®), carboplatin (Paraplatin^®), oxaliplatin (Eloxatin^®), daunomycin (Daunorubicin^®, DanuoXome^®, Cerubidine^®), doxorubicin (Adriamycin^®, Rubex^®), epirubicin (Ellence^®), idarubicin (Idamycin^®), valrubicin (Valstar^®), mitoxantrone (Novantrone^®), paclitaxel (Taxol^®), docetaxel (Taxotere^®) and cyclophosphamide (Cytoxan^®).

[00166] In other embodiments, the additional therapeutic agent is selected from anti-cancer antibody or immunoglobulin therapies or agents including, but not limited to, ipilimumab (Yervoy^®), tremelimumab, antibodies or agents that target programmed death receptor 1 [PD-1] or programmed death ligand 1 [PD-L1], e.g., CT-011 (Curetech), BMS-936558 (Bristol-Myers Squibb), BMS-936559 (Bristol-Myers Squibb), AMP-224 (Amplimmune/Glaxo-Smithkline), pembrolizumab (Merck & Co.), MPDL3280A (Roche), MGA-271 (Macrogenics), dacarbazine, Lambrolizumab (MK-3475), MSB0010718C (MerckSerono), or MEDI-4736 (MedImmune). In certain embodiments, the PD-1 inhibitor is pembrolizumab. [00167] In other embodiments, the additional therapeutic agent is selected from a CTLA4 agent (e.g., ipilimumab (BMS)); GITR agent (e.g., MK-4166 (MSD)); vaccines (e.g., Nanovacc (MerckSerono), Stimuvax (MerckSerono), Sipuleucel-T (Dendron); or a SOC agent (e.g., radiation, docetaxel, Temozolomide (MSD), Gemcitibine, or Paclitaxel). In other embodiments, the additional therapeutic agent is an immune enhancer such as a vaccine, immune-stimulating antibody, immunoglobulin, agent or adjuvant including, but not limited to, sipuleucel-t

(Provenge^®), BMS-663513 (Bristol-Myers Squibb), CP-870893 (Pfizer/VLST), anti-OX40 (AgonOX), or CDX-1127 (CellDex).

[00168] In certain embodiments, the additional therapeutic agent is an anti-PD-1 or anti-PD-L1 agent and is administered together with the compound Formula I (including Formulae Ia, Ib, and Ic) as a single dosage form. In certain embodiments, the additional therapeutic agent is an anti- PD-1 or anti-PD-L1 agent and is administered separately from the compound of Formula I (including Formulae Ia, Ib, and Ic) as part of a multiple dosage form. In certain embodiments, the anti-PD-1 or anti-PD-L1 is administered as an intravenous infusion.

[00169] In certain embodiments, more than one additional therapeutic agents are used and are administered together with the compound of Formula I (including Formulae Ia, Ib, and Ic) as a single dosage form. In certain embodiments, more than one additional therapeutic agents are used and are administered separately from the compound of Formula I (including Formulae Ia, Ib, and Ic) as part of a multiple dosage form. In certain embodiments, the more than one additional therapeutic agents are anti-PD-1 or anti-PD-L1 agents. In certain embodiments, the anti-PD-1 or anti-PD-L1 agents are administered as an intravenous infusion.

[00170] Other cancer therapies or anticancer agents that may be used in combination with the inventive agents of the present invention include surgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, low- dose radiotherapy, and systemic radioactive isotopes), immune response modifiers such as chemokine receptor antagonists, chemokines and cytokines (e.g., interferons, interleukins, tumour necrosis factor (TNF), and GM-CSF)), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g. antimetics, steroids, anti-inflammatory agents), and other approved chemotherapeutic drugs.

[00171] A compound of the invention may also be useful for treating cancer in combination with or in addition to any of the following standard of care (SOC) therapeutic agents: abarelix (Plenaxis Depot^®); aldesleukin (Prokine^®); Aldesleukin (Proleukin^®); Alemtuzumab

(Campath^®); alitretinoin (Panretin^®); allopurinol (Zyloprim^®); altretamine (Hexalen^®); amifostine (Ethyol^®); anastrozole (Arimidex^®); arsenic trioxide (Trisenox^®); asparaginase (Elspar^®); azacitidine (Vidaza^®); bevacuzimab (Avastin^®); bexarotene capsules (Targretin^®); bexarotene gel (Targretin^®); bleomycin (Blenoxane^®); bortezomib (Velcade^®); busulfan intravenous (Busulfex^®); busulfan oral (Myleran^®); calusterone (Methosarb^®); capecitabine (Xeloda ^®); carboplatin (Paraplatin^®); carmustine (BCNU^®, BiCNU^®); carmustine (Gliadel^®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer^®); celecoxib (Celebrex^®); cetuximab (Erbitux^®); chlorambucil (Leukeran^®); cisplatin (Platinol^®); cladribine (Leustatin^®, 2-CdA^®); clofarabine (Clolar^®); cyclophosphamide (Cytoxan^®, Neosar^®); cyclophosphamide (Cytoxan Injection^®); cyclophosphamide (Cytoxan Tablet^®); cytarabine (Cytosar-U^®); cytarabine liposomal (DepoCyt^®); dacarbazine (DTIC-Dome^®); dactinomycin, actinomycin D

(Cosmegen^®); Darbepoetin alfa (Aranesp^®); daunorubicin liposomal (DanuoXome^®);

daunorubicin, daunomycin (Daunorubicin^®); daunorubicin, daunomycin (Cerubidine^®);

Denileukin diftitox (Ontak^®); dexrazoxane (Zinecard^®); docetaxel (Taxotere^®); doxorubicin (Adriamycin PFS^®); doxorubicin (Adriamycin^®, Rubex^®); doxorubicin (Adriamycin PFS Injection^®); doxorubicin liposomal (Doxil^®); dromostanolone propionate (Dromostanolone); dromostanolone propionate (masterone Injection^®); Elliott's B Solution (Elliott's B Solution^®); epirubicin (Ellence^®); Epoetin alfa (Epogen^®); erlotinib (Tarceva^®); estramustine (Emcyt^®); etoposide phosphate (Etopophos^®); etoposide, VP-16 (Vepesid^®); exemestane (Aromasin^®); Filgrastim (Neupogen^®); floxuridine (intraarterial) (FUDR^®); fludarabine (Fludara^®);

fluorouracil, 5-FU (Adrucil^®); fulvestrant (Faslodex^®); gefitinib (Iressa^®); gemcitabine (Gemzar^®); gemtuzumab ozogamicin (Mylotarg^®); goserelin acetate (Zoladex Implant^®);

goserelin acetate (Zoladex^®); histrelin acetate (Histrelin Implant^®); hydroxyurea (Hydrea^®); Ibritumomab Tiuxetan (Zevalin^®); idarubicin (Idamycin^®); ifosfamide (IFEX^®); imatinib mesylate (Gleevec^®); interferon alfa 2a (Roferon A^®); Interferon alfa-2b (Intron A^®); irinotecan (Camptosar^®); lenalidomide (Revlimid^®); letrozole (Femara^®); leucovorin (Wellcovorin^®, Leucovorin^®); Leuprolide Acetate (Eligard^®); levamisole (Ergamisol^®); lomustine, CCNU (CeeBU^®); meclorethamine, nitrogen mustard (Mustargen^®); megestrol acetate (Megace^®); melphalan, L-PAM (Alkeran^®); mercaptopurine, 6-MP (Purinethol^®); mesna (Mesnex^®); mesna (Mesnex Tabs^®); methotrexate (Methotrexate^®); methoxsalen (Uvadex^®); mitomycin C

(Mutamycin^®); mitotane (Lysodren^®); mitoxantrone (Novantrone^®); nandrolone phenpropionate (Durabolin-50^®); nelarabine (Arranon); Nofetumomab (Verluma^®); Oprelvekin (Neumega^®); oxaliplatin (Eloxatin^®); paclitaxel (Paxene^®); paclitaxel (Taxol^®); paclitaxel protein-bound particles (Abraxane^®); palifermin (Kepivance^®); pamidronate (Aredia^®); pegademase (Adagen (Pegademase Bovine) ^®); pegaspargase (Oncaspar^®); Pegfilgrastim (Neulasta^®); pemetrexed disodium (Alimta^®); pentostatin (Nipent^®); pipobroman (Vercyte^®); plicamycin, mithramycin (Mithracin^®); porfimer sodium (Photofrin^®); procarbazine (Matulane^®); quinacrine (Atabrine^®); Rasburicase (Elitek^®); Rituximab (Rituxan^®); sargramostim (Leukine^®); Sargramostim

(Prokine^®); sorafenib (Nexavar^®); streptozocin (Zanosar^®); sunitinib maleate (Sutent^®); talc (Sclerosol^®); tamoxifen (Nolvadex^®); temozolomide (Temodar^®); teniposide, VM-26 (Vumon^®); testolactone (Teslac^®); thioguanine, 6-TG (Thioguanine^®); thiotepa (Thioplex^®); topotecan (Hycamtin^®); toremifene (Fareston^®); Tositumomab (Bexxar^®); Tositumomab/I-131

tositumomab (Bexxar); Trastuzumab (Herceptin^®); tretinoin, ATRA (Vesanoid^®); Uracil Mustard (Uracil Mustard Capsules^®); valrubicin (Valstar^®); vinblastine (Velban^®); vincristine (Oncovin^®); vinorelbine (Navelbine^®); zoledronate (Zometa^®) and vorinostat (Zolinza^®).

[00172] In certain embodiments and dependining upon the indication to be treated, the additional therapeutic agent is selected from an antibiotic, a vasopressor, a steroid, an inotrope, an anti-thrombotic agent, a sedative, opioids, or an anesthetic.

[00173] The invention provides compounds of the invention for use as a pharmaceutical especially in the treatment or prevention of the diseases noted above. Also provided herein is the use of the present compounds in the manufacture of a medicament for the treatment or prevention of one of the diseases noted above. The present invention also provides the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease noted above.

V. Pharmaceutical Compositions and Dosing

[00174] In another aspect, the invention provides a pharmaceutical composition including a compound of the invention, namely a compound of Formula I (including Formulae Ia, Ib, and Ic), and a pharmaceutically acceptable carrier. For example, the invention also provides pharmaceutically acceptable compositions which include a therapeutically effective amount of one or more of the compounds of Formula I (including Formulae Ia, Ib, and Ic), formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally, one or more additional therapeutic agents described above.

[00175] As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.

[00176] Exemplary materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in

pharmaceutical formulations.

[00177] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[00178] Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[00179] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[00180] In certain embodiments, a formulation of the present invention includes an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.

[00181] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[00182] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.

[00183] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, troches and the like), the active ingredient is 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 starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[00184] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),

surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[00185] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the

gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[00186] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[00187] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[00188] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[00189] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[00190] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[00191] Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a

pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[00192] The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[00193] Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. [00194] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[00195] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[00196] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more

pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[00197] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention 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. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[00198] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

[00199] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[00200] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.

[00201] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[00202] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.

[00203] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[00204] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[00205] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved [00206] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day.

[00207] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain aspects of the invention, dosing is one administration per day.

[00208] While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition.

[00209] The description above describes multiple aspects and embodiments of the invention. The patent application specifically contemplates all combinations and permutations of the aspects and embodiments.

EXAMPLES

[00210] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

EXAMPLE 1– Synthesis of compound 232 (Table 1)

[00211] (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (44, 2.00 g, 8.65 mmol) was dissolved in N,N-dimethylformamide (22 mL) followed by the addition of HATU (3.62 g, 9.51 mmol). After 5 minutes, DIPEA (2.27 mL, 13.0 mmol) was added to the solution at room temperature. After 5 minutes, isopropylmethylamine (1.08 mL, 10.4 mmol) was added dropwise. The reaction was stirred for 30 minutes before being diluted with diethyl ether (50 mL). The ether layer was collected and washed with 1M HCl in water (50 mL). The aqueous phase was back extracted with diethyl ether (2 x 50 mL). The organic phases were combined, washed with saturated sodium bicarbonate in water, and saturated aqueous solution of sodium chloride. The ether layer was collected, dried over sodium sulfate, and concentrated to dryness.

[00212] Fmoc-D-Leucine (46, 500 mg, 1.41 mmol) was dissolved in N,N-dimethylformamide (4 mL) followed by the addition of HATU (592 mg, 1.56 mmol) at room temperature. After 5 minutes, DIPEA (0.792 mL, 4.24 mmol) was added to the solution. After 5 minutes, compound 45 (446 mg, 1.48 mmol) dissolved in N,N-dimethyforamide (2 mL) was added dropwise. The reaction was stirred for 1 hour before being diluted with diethyl ether (20 mL). The ether layer was collected and washed twice with 1M aqueous HCl solution (20 mL). The aqueous phases were combined extracted with diethyl ether. The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated to dryness. The residue was resuspended in dimethylsulfoxide and purified by reverse phase chromatography (C18 column: 55% acetonitrile in water with 0.1% formic acid). Compound 47 was isolated as a pale yellow oil (738 mg, 100% yield).

[00213] Compound 47 (738 mg, 1.48 mmol) was dissolved in dichloromethane (5 mL) followed by the addition of DBU (0.446 mL, 2.96 mmol). The reaction was stirred at room temperature for 2 hours followed by careful addition of trifluoroacetic acid (0.341 mL, 4.43 mmol). Diethyl ether was added (10.0 mL), and the solution stirred for 30 minutes causing an oil to separate from the solution. The solution was decanted and the oil was dissolved in dichloromethane (5 mL) followed by addition of diethyl ether (5 mL). The solution was decanted and the oil was concentrated to afford a clear oil 48 (446 mg, 73% yield).

[00214] Methyl salicylate (49, 0.426 mL, 3.30 mmol) was dissolved in N,N-dimethylformamide (8 mL) followed by the addition of potassium carbonate (912 mg, 6.60 mmol) and tert-butyl bromoacetate (50, 1.07 mL, 7.26 mmol). The reaction was brought to 60°C and stirred overnight before being allowed to cool to room temperature. The reaction was diluted with diethyl ether (25 mL) and washed with 1M HCl in water (2 x 25 mL). The organic phase was collected, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated. The resultant residue was suspended in DCM and purified by silica gel column chromatography with 9:1 hexanes:ethyl acetate to afford 51 as a clear oil (786 mg, 89% yield).

[00215] Compound 51 (754 mg, 2.83 mmol) was dissolved in dichloromethane (3 mL) and trifluoracetic acid (5.00 mL, 55.9 mmol). After stirring for one hour at room temperature, the reaction mixture was concentrated. The residue was dissolved in toluene and the mixture was concentrated. This was repeated two more times to afford 52 as a white solid (553 mg, 93% yield).

[00216] Compound 52 (70.0 mg, 0.333 mmol) was dissolved in N,N-dimethylformamide (3 mL) followed by the addition of HATU (305 mg, 0.733 mmol). Once a homogenous solution was obtained, DIPEA (0.233 mL, 1.33 mmol) was added and stirred at room temperature for 5 minutes followed by dropwise addition of tert-butylamine (0.071 mL, 0.666 mmol). After stirring at room temperature for 30 minutes the reaction was diluted with diethyl ether (10 mL), and washed with 1M HCl (5 mL) in water, 1M sodium bicarbonate (5 mL) in water, and a saturated aqueous sodium chloride solution. The ether layer was collected, dried over sodium sulfate, and concentrated to afford 53 as a yellow oil. [00217] The crude product 53 was dissolved in tetrahydrofuran (2 mL) and 1M LiOH in water (1 mL, 1.00 mmol). The reaction was heated to 60°C and stirred for 16 hours. The reaction was cooled to room temperature and extracted with diethyl ether (2 mL). The aqueous phase was collected, acidified to pH 1 with 1M HCl (2 mL), and extracted with DCM (3 x 5 mL). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated to afford 54 as a white solid 36 m 43% ield over 2 ste s .

[00218] Compound 54 (10 mg, 0.040 mmol) and HATU (17 mg, 0.044 mmol) were dissolved in N,N-dimethylformamide (0.3 mL). DIPEA was added (0.021 mL, 0.119 mmol), and the mixture was stirred at room temperature for 10 minutes. Compound 48 (20 mg, 0.48 mmol) was dissolved in DMF (0.200 mL) and added dropwise to the reaction solution. The reaction mixture was stirred for 30 minutes before being diluted with dimethyl sulfoxide and loaded to a reverse phase (C8) column (acetonitrile and water, 0.1% formic acid). Compound 232 (5 mg, 26% yield) was isolated as a white powder following lyophilization.

EXAMPLE 2– Synthesis of 2-((5-(tert-butyl)-1,3,4-oxadiazol-2-yl)methoxy)benzoic acid (57)

[00219] Methyl salicylate (49, 0.085 mL, 0.66 mmol) was dissolved in N,N-dimethylformamide (3.3 mL) followed by addition of potassium carbonate (140 mg, 0.99 mmol) and 2-(tert-butyl)-5- (chloromethyl)-1,3,4-oxadiazole (55, 120 mg, 0.69 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with diethyl ether (5 mL) and washed with 1M HCl in water (2 x 5 mL). The organic phase was collected, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. Intermediate 56 was directly used in the next step without further purification. [00220] Compound 56 was dissolved in a tetrahydrofuran (2 mL) and 1M LiOH in water (1.0 mL, 1.0 mmol) and the reaction was stirred for 16 hours. The reaction was washed with diethyl ether (2 mL). The aqueous phase was collected, acidified to pH 1 with 1M HCl in water (2 mL), and extracted with DCM (3 x 5 mL). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. Compound 57 was obtained as a clear oil (90 mg, 50% yield over 2 steps).

EXAMPLE 3– Synthesis of 2-(2-(tert-butoxy)-2-oxoethoxy)benzoic acid (60)

[00221] Benzyl salicylate (58, 0.640 mL, 3.30 mmol) was dissolved in N,N-dimethylformamide (16 mL) followed by the addition of potassium carbonate (912 mg, 6.60 mmol) and tert-butyl bromoacetate (50, 1.07 mL, 7.26 mmol). The reaction was brought to 60°C and stirred overnight before being allowed to cool to room temperature. The reaction was diluted with diethyl ether (25 mL) and washed with 1M HCl in water (2 x 25 mL). The organic phase was collected, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated.

[00222] The residue 59 was dissolved in anhydrous methanol (20 mL), degassed several times and left under argon before being subjected to 10% palladium on carbon (808 mg, 0.759 mmol). The atmosphere was exchanged with hydrogen and left to stir at room temperature for 2 hours. The reaction was filtered through a celite pad before the methanol was evaporated. The crude product was purified by silica gel column with 1% methanol and 1% acetic acid in

dichloromethane to yield a colorless oil 60 (676 mg, 71% yield). MS ES- : 251.151 (expected: 251.100).

[00223] Compounds 140, 143, 149, 153, 158, 162, 164, and 166 of Table 1 were synthetized by the procedure described in Schemes 3 and 4 using intermediate 60. Compound 135 of Table 1 was synthesized by the procedure described in Schemes 3, 4, and 7 using compound 60. EXAMPLE 4– Synthesis of compound 215 (Table 1)

[00224] Compound 61 was synthesized by the procedure described in schemes 3, 4, and 6. Intermediate 61 (100 mg, 0.15 mmol) was treated with trifluoroacetic acid (1 mL) in dichloromethane (2 mL) for 30 min. The mixture was concentrated and freeze dried to give yellow powder as TFA salt of 62 (104 mg, 0.15 mmol, 100%). LC/MS (M+H) calc: 555.8; measured: 555.4

[00225] To a mixture of 62 (15 mg as TFA salt, 22 umol) and sodium triacetoxyborohydride (10 mg, 44 umol) was added DMSO (1 mL) followed by acetaldehyde (3 µL, 66 umol). The mixture was stirred for 30 min and purified by prep-HPLC to give 215 as a white powder (13 mg as TFA salt, 18 µmol, 84%). LC/MS (M+H) calc: 583.4; measured: 583.5.

[00226] Compounds 214, 219, 235, 240, 251, 252, and 287 were synthesized by a similar procedure.

EXAMPLE 5– Synthesis of (S)-N,N-dimethyl-2-(methylamino)-3-phenylpropanamide hydrochloride (65)

[00227] A suspension of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.60 g, 18.8 mmol) in 15 mL DCM was added to a 0 ^oC solution of N-(tert-butoxycarbonyl)-N- methyl-L-phenylalanine (63, 5.00 g, 17.9 mmol), 1-hydroxy-7-azabenzotriazole (2.44 g, 17.9 mmol), dimethylamine hydrochloride (2.92 g, 35.8 mmol) and N,N-diisopropylethylamine (6.25 ml, 35.8 mmol) in dichloromethane (20 mL). The cooling bath was removed and the reaction was stirred at room temperature for 30 min. The reaction mixture was washed successively with 0.1 N HCl (aq), water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the desired product 64 as a colorless solid (5.46 g, quantitative yield).

[00228] To a solution of tert-butyl (S)-(1-(dimethylamino)-1-oxo-3-phenylpropan-2- yl)(methyl)carbamate (64, 3.00 g, 9.79 mmol) in 1,4-dioxane (10 mL) was added 4M HCl in 1,4- dioxane (37.0 mL, 148 mmol). After stirring for 4 hours at room temperature, the reaction mixture was concentrated in vacuo and triturated with diethyl ether to give the desired product 65 as a colorless solid (2.38 g, quantitative yield).

EXAMPLE 6– Synthesis of 2-((1-butyl-1H-1,2,3-triazol-4-yl)methoxy)benzoic acid (67)

[00229] To a mixture of 2-(prop-2-yn-1-yloxy)benzoic acid (66, 3.65 g, 20.72 mmol), 1- azidobutane (41.4 ml, 20.72 mmol), L-ascorbic acid (10.95 g, 62.2 mmol), and N,N- diisopropylethylamine (10.86 ml, 62.2 mmol) in N,N-dimethylformamide (104 ml) was added copper (I) iodide (1.973 g, 10.36 mmol) at room temperature. After 1 h, the reaction mixture was cooled to 0^oC, quenched by the addition of saturated, aqueous ammonium chloride solution, and extracted with dichloromethane. The organic layer was washed successively with 1M HCl (aq) and brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography on silica gel (methanol in dichloromethane) afforded the desired product 67 as a colorless oil (4.80 g, 84%).

EXAMPLE 7– Synthesis of phenoxyethyl azide 69

[00230] To a solution of 2-phenoxyethanol (68, 2.00 g, 14.48 mmol, 1.0 equiv) in DCM (29 mL) and N-ethyl-N-isopropylpropan-2-amine (5.9 mL, 33.8 mmol, 2.3 equiv) at 0 ^oC was added methanesulfonyl chloride (1.34 mL, 17.37 mmol, 1.2 equiv). The reaction was stirred for one hour. The mixture was extracted with water (2 x 25 mL), and the organic layer was concentrated under reduced pressure. The crude material was then dissolved in DMF (29 ml) and sodium azide (2.82 g, 43.4 mmol, 3.0 equiv) was added. The reaction was stirred at room temperature for 3.5 hours. The reaction was concentrated under reduced pressure and the crude residue was purified by flash chromatography on silica gel (gradient 0-20% EtOAc in DCM), which provided (2-azidoethoxy)benzene (69, 1.88 g, 80% yield over 2 steps).

[00231] Compounds 104, 107, 112 were synthesized according to Schemes 3, 4, 7, and 8 using compound 69.

EXAMPLE 8– Synthesis of 2-(2-methoxy-2-oxoethoxy)benzoic acid (73)

[00232] Tert-butyl 2-hydroxybenzoate (70, 0.500 g, 2.57 mmol) and methyl 2-bromoacetate (71, 0.487 ml, 5.15 mmol) were dissolved in acetone (26 ml), then potassium carbonate (1.78 g, 12.87 mmol) was added and the reaction was stirred at room temperature overnight. Water (25 mL) was added and the solution was extracted with DCM (40 mL x3). The combined organic layers were dried over Na₂SO₄, filtrated and concentrated under vacuum. Crude tert-butyl 2-(2- methoxy-2-oxoethoxy)benzoate (72, 0.686 g, 2.58 mmol) was dissolved in DCM (26 ml) and TFA (3.97 ml, 51.5 mmol) was added. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, dissolved in toluene (3 x 10 mL) and concentrated to afford 2-(2-methoxy-2-oxoethoxy)benzoic acid (73, 0.528 g, 98% yield) as a white solid which was used in the subsequent reaction without any further purification.

[00233] Compounds 116 and 142 were synthesized according to Scheme 3, 4, and 7 using compound 73.

EXAMPLE 9– Synthesis of compound 134 (Table 1)

[00234] Compound 116 (63 mg, 0.103 mmol) was dissolved in a tetrahydrofuran (1 mL) followed by the addition of 1M LiOH in water (0.259 mL, 0.517 mmol) at room temperature. The reaction was complete after 2 hours and was quenched with 1M HCl in water until pH was 2-3. The mixture was extracted with dichloromethane (3 x 2 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to afford 74 (60 mg, 97% yield).

[00235] Compound 74 (10 mg, 0.017 mmol), dicyclohexylcarbodiimide (3.8 mg, 0.019 mmol), and 4-dimethylaminopyridine (2.3 mg, 0.019 mmol) were dissolved in dichloromethane (1 mL). Diisopropylethylamine (0.006 mL, 0.034 mmol) was added immediately afterwards followed by 2,4,6-trichlorobenzoylchloride (0.006 mL, 0.034 mmol). After 5 minutes, 2-methyl-propan-1-ol (0.005 mL, 0.051 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by a C18 column (60% acetonitrile in water with 0.1% formic acid). Compound 134 was obtained as a white solid (11 mg, 100% yield).

[00236] Compound 125 was synthesized by a similar procedure to the synthesis of 134

substituting isobutanol with butanol.

EXAMPLE 10– Synthesis of (E)-2-((2-fluorohept-2-en-1-yl)oxy)benzoic acid (79)

[00237] Under anhydrous conditions, ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (76, 1.00 ml, 4.93 mmol) was dissolved in tetrahydrofuran (5 mL) and the resulting solution was cooled to -78°C before the addition of sodium hydride, 95% (0.124 g, 4.93 mmol). In a separate flask, pentanal (75, 0.472 mL, 4.44 mmol) was dissolved in tetrahydrofuran (7 mL) and cooled to - 78°C. Once it was cooled, the solution containing 76 and NaH was added slowly to the solution of 75 and stirred for 1 hour. The reaction was slowly warmed to room temperature over 5 hours. Saturated aqueous ammonium chloride solution was added carefully and the solution was extracted with diethyl ether (3 x 50 mL). The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness.

[00238] The residue was resuspended in a minimal volume of dry dichloromethane before it was added dropwise to a stirring solution of 1M DIBAL-H in dichloromethane (8.88 mL, 8.88 mmol) at -50°C. The reaction was allowed to warm to room temperature and stir overnight. Methanol (5 mL) was carefully added followed by a saturated aqueous solution of Rochelle’s salt (30 mL). Dichloromethane was added (30 mL) and the reaction stirred for 1 hour until the mixture was clear. The aqueous layer was extracted with dichloromethane (2 x 50 mL) and the organic layers were combined, washed with brine, dried with anhydrous sodium sulfate and concentrated. Compound 77 (60 mg, 56.1% yield) was isolated after column chromatography. ¹H NMR (400MHz, CDCl₃): 5.21 (dt, 1H, J = 20), 4.23 (d, 2H, J = 20), 2.40-2.06 (br, 1H), 2.01 (dd, 2H, J = 16 Hz), 1.41-1.28 (m, 4H), 0.90 (t, 3H).

[00239] Compound 77 (56 mg, 0.424 mmol), tert-butyl 2-hydroxybenzoate (70, 165 mg, 0.847 mmol), and triphenylphosphine (445 mg, 1.695 mmol) were dissolved in anhydrous

tetrahydrofuran (4.24 mL) under argon. The solution was cooled to -40°C before the slow addition of diisopropyl azodicarboxylate (0.161 mL, 0.826 mmol). The reaction was allowed to warm to room temperature and stirred for 2 hours. Dichloromethane (20 mL) was added and washed with 1M HCl in water (2x 20 mL). The DCM layer was collected, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (5% hexanes/ethyl acetate). Compound 78 was obtained as a clear oil (60 mg, 56.1% yield). MS ES+: 253.264 (expected 253.285 m/z). ¹HNMR (400 MHz, CDCl₃): 7.70 (dd, 1H), 7.40 (td, 1H), 7.01 (td, 1H), 6.98 (d, 1H), 5.35 (m, 1H), 4.65 (d, 2H, J=20 Hz), 2.02 (q, 2H), 1.57 (s, 9H), 1.31 (m, 4H), 0.87 (t, 3H).

[00240] Compound 78 (60 mg, 0.195 mmol) was dissolved in a 1:1 mixture of dichloromethane (2 mL) and trifluoroacetic acid (2 mL, 32.4 mmol) and stirred at room temperature for 2 hours. The reaction was concentrated to dryness and resuspended in toluene (5 mL) and concentrated (3X). Compound 79 was obtained as a yellow oil (50 mg, 100% yield). MS ES+: 253.306 (expected 253.285). MS ES-: 251.290 (expected 251.285). ¹H NMR (400 MHz, CDCl₃): 8.22 (d, 1H), 7.57 (t, 1H), 7.19 (t, 1H), 7.07 (d, 1H), 5.51 (dt, 1H, J=20Hz), 4.86 (d, 2H, J=20 Hz), 2.08 (q, 2H), 1.36 (m, 4H), 0.90 (t, 3H). EXAMPLE 11 - Synthesis of Compounds 127 and 129

[00241] Compound 120 was synthesized by the procedure described in schemes 3, 4, 7, and 8, and using compound 79.

[00242] Compound 120 (0.018 g, 0.028 mmol) was dissolved in MeOH (0.553 ml), palladium on carbon (2.94 mg, 2.77 µmol, 10% weight) was added under argon, and the reaction was stirred under a hydrogen atmosphere for 90 minutes. The reaction mixture was diluted with DMSO (up to 1 mL) and purified by preparative HPLC. Compounds 127 (0.006 g, 32% yield) and 129 (0.006 g, 32% yield) were obtained as white powders. The stereochemistry at C-F was arbitrarily assigned to compounds 127 and 129.

EXMAPLE 12 - Synthesis of 2-(2-butoxy-2-oxoethoxy)benzoic acid (82)

[00243] Tert-butyl 2-(2-methoxy-2-oxoethoxy)benzoate (80, 0.300 g, 1.127 mmol) was dissolved in butan-1-ol (1.04 mL, 0.84 g, 11.27 mmol), then cesium carbonate (0.037 g, 0.113 mmol) was added and the reaction was stirred at 60°C for 48 hours. The reaction was cooled to room temperature and DCM (5 mL) was added. The solution was washed with aqueous NaHCO₃ solution (3 x 5 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated under vaccum. The crude product tert-butyl 2-(2-butoxy-2-oxoethoxy)benzoate (81, 0.244 g, 70% yield) was used for next reaction without any further purification. [00244] Tert-butyl 2-(2-butoxy-2-oxoethoxy)benzoate (81, 0.244 g, 0.791 mmol) was dissolved in DCM (4 ml), and then TFA (0.610 ml, 7.91 mmol) was added and the reaction was stirred for 1 hour. The reaction mixture was concentrated, and the residue was further dissolved in toluene (5 mL x 3) and concentrated to remove excess TFA, affording 2-(2-butoxy-2-oxoethoxy)benzoic acid (82, 0.190 g, 95% yield) as a white powder.

[00245] Compounds 136-139 were synthesized by the procedure described in Schemes 3 and 4 and using compound 82.

EXAMPLE 13 - Synthesis of methyl (R)-2-((1-(tert-butoxy)-1-oxopropan-2-yl)oxy)benzoate (84)

[00246] Tert-butyl (S)-2-hydroxypropanoate (83, 0.576 g, 3.94 mmol), methyl 2- hydroxybenzoate (49, 0.427 ml, 3.29 mmol) and triphenylphosphine (1.121 g, 4.27 mmol) were dissolved in dry THF (16 ml) and cooled to 0°C. DIAD (0.767 ml, 3.94 mmol) was added dropwise and the reaction was slowly warmed to room temperature and left overnight. The solvent was concentrated under vacuum and then crude was purified by flash column chromatography using hexanes/ethyl acetate isolating methyl (R)-2-((1-(tert-butoxy)-1- oxopropan-2-yl)oxy)benzoate (84, 0.652 g, 71% yield).

[00247] Compound 275 was synthesized by the procedure described in Schemes 3, 4, and 5 substituting the first reaction of Scheme 5 with the reaction described in EXAMPLE 13.

[00248] Compound 276 was synthesized by the same procedure as the synthesis of 275 except that tert-butyl (S)-2-hydroxypropanoate was replaced with tert-butyl (R)-2-hydroxypropanoate.

EXAMPLE 14 - Synthesis of 2-(1-fluoro-2-((1-methylcyclopropyl)amino)-2- oxoethoxy)benzoic acid (89)

8₈ ⁸⁹

[00249] Methyl salicylate (49, 3.49 mL, 27.0 mmol) was dissolved in N,N-dimethylformamide (108 mL) followed by the addition of potassium carbonate (7.47g, 54.1 mmol) and ethyl 2- bromo-2-fluoroacetate (85, 3.19 mL, 27.0 mmol). The reaction was stirred at room temperature for 5 hours before being diluted with diethyl ether (250 mL) and washed with 1M HCl in water (2 x 250 mL). The organic phase was collected, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated to afford compound 86 as a clear oil (6.90 g, 99% yield).

[00250] Compound 86 (6.90 g, 26.9 mmol) was dissolved in diisopropylethylamine (10 mL, 57.3 mmol) followed by the addition of 1-methylcyclopropan-1-amine hydrochloride (87, 3.20 g, 29.7 mmol). The reaction was heated to 50°C for 1 hour before being diluted with diethyl ether (200 mL) and washed with 1M HCl in water (2 x 200 mL). The organic phase was collected, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated. Compound 88 was isolated by column chromatography (40% ethyl acetate in hexanes) as a clear oil (3.25g, 43% yield). MS ES+: 282.247 (expected 282.106).

[00251] Compound 88 (3.25g, 11.5 mmol) was dissolved in a tetrahydrofuran (10 mL) and 2M LiOH in water (8.67 mL, 17.3 mmol) and the reaction was stirred for 2 hours. The reaction was washed with diethyl ether (50 mL). The aqueous phase was collected and 1M HCl in water (30 mL) was added until pH was 1. The aqueous phase was extracted with DCM (3 x 100 mL). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. Compound 89 was isolated by column chromatography (3:1 of 5% methanol and 5% acetic acid in dichloromethane) as a white foam (1.26g, 41% yield). MS ES+: 268.212 (expected 267.091), ES-: 266.237 (expected 266.091). EXAMPLE 15 - Synthesis of 2-methyl-4-(2-((1-methylcyclopropyl)amino)-2- oxoethoxy)thiazole-5-carboxylic acid (94)

[00252] To a solution of ethyl 4-hydroxy-2-methylthiazole-5-carboxylate (90, 201 mg, 1.07 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (223 mg, 1.61 mmol), potassium iodide 17.8 mg, 0.107 mmol) and tert-butyl 2-bromoacetate (50, 0.190 mL, 1.29 mmol). After stirring for 16 hours at room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and concentrated in vacuo. Purification by flash chromatography on silica gel with an eluent of ethyl acetate in hexanes afforded ethyl 4-(2-(tert- butoxy)-2-oxoethoxy)-2-methylthiazole-5-carboxylate (91, 212.1 mg, 66%).

[00253] Ethyl 4-(2-(tert-butoxy)-2-oxoethoxy)-2-methylthiazole-5-carboxylate (91, 212 mg, 704 mmol) was dissolved in 1:2 mixture of trifluoroacetic acid and dichloromethane (4.0 mL). After 3 hours at room temperature, the reaction mixture was concentrated in vacuo. Toluene (10 mL) was added and the solution was concentrated affording crude product (2-((5- (ethoxycarbonyl)-2-methylthiazol-4-yl)oxy)acetic acid (92)) as a light brown solid (quantitative yield).

[00254] To a solution of 2-((5-(ethoxycarbonyl)-2-methylthiazol-4-yl)oxy)acetic acid (92, 173 mg, 0.704 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.369 mL, 2.11 mmol) in N,N- dimethylformamide (4.0 mL) was added HATU (291 mg, 0.774 mmol). After stirring for 10 min, 1-methylcyclopropan-1-amine hydrochloride (87, 91 mg, 0.85 mmol) was added. After 2 hours at room temperature, the reaction mixture was concentrated and purified by flash chromatography on silica gel with an eluent of ethyl acetate in hexanes to give the desired product as an off-white solid, ethyl 2-methyl-4-(2-((1-methylcyclopropyl)amino)-2- oxoethoxy)thiazole-5-carboxylate (93, 150.3 mg, 72%). [00255] To a solution of ethyl 2-methyl-4-(2-((1-methylcyclopropyl)amino)-2- oxoethoxy)thiazole-5-carboxylate (93, 150.3 mg, 0.504 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.68 mL) was added lithium hydroxide (1.26 mL, 2.52 mmol, 2.0 M, aqueous solution). After 4 hours, the reaction mixture was concentrated under reduced pressure. The residue was acidified with 1.0 M HCl (aq) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 2-methyl-4-(2-((1- methylcyclopropyl)amino)-2-oxoethoxy)thiazole-5-carboxylic acid (94, 116.8 mg, 86%) as a yellow solid.

EXAMPLE 16– Characterization of Exemplary Compounds of Formulae I, Ia, Ib, and Ic

[00256] Other compounds of Formulae I, Ia, Ib, and Ic were synthesized by procedures similar to those described above with the appropriate substitution for one or more of the reagents. Mass spectrometry values and/or ¹H NMR data for compounds of the invention are set forth in Table 1.

TABLE 1– Characterization of Exemplary Compounds

EXAMPLE 17 - EVALUATION OF BIOLOGICAL ACTIVITY

[00257] Exemplary compounds of Formula I (including Formulae la, lb, and Ic) were tested for their ability to inhibit IDO activity in the assay described below, which used HeLa Cells. [00258] Briefly, HeLa cells were treated for 48 hours with 50 ng/mL human interferon gamma (IFNy) and 50 μΜ L-tryptophan, with and without a compound in assay media. Tryptophan conversion to N-formlkynurenine was determined by using NFKgreen reagent (Netherlands Translational Research Center, Oss, The Netherlands) added directly onto the cells. Then 8000 HeLa cells in 35 μΐ. complete medium (RPMI1640/10%FBS) were seeded into the wells (8000 cells/well) of a 384 well black clear bottom plate (Greiner). The plate was incubated overnight at 37 °C. Serial dilutions of the compounds to be tested (5 μί) were added to end of the wells of the plate and the plate was incubated at 37°C for 1 hour.

[00259] A solution containing 5X the final concentration of IFNy (250 ng/mL) and Trp (250 μΜ) was prepared in complete medium. 10 μΐ, of the IFN/Trp solution was added to each well and the plate was incubated at 37°C for 45-48 hours. Controls for background level of Trp oxidation were derived from wells receiving Trp but no IFNy.

[00260] Then, 5 μΐ, NFK green reagent was added to end well and the plate was sealed and incubated at 37°C for 4 hours. The level of fluorescence from each well of the plate was determined. The IC₅₀ value for the inhibition of the fluorescence due to the oxidation of Trp was determined from a four parameter fit of the dose response data.

[00261] A separate cell line, SW48, was used to assess the ability of compounds to inhibit TDO (tryptophan-2,3-dioxygenase) activity. SW48 cells were found to exhibit an endogenous level of TDO but no IDO is determined by Western Blotting. None of the compounds tested exhibited a significant level of inhibition of TDO over the range of concentrations tested.

[00262] The resulting IC₅₀ values of IDO inhibition are provided in Table 2, where "A" indicates an IC₅₀ value less than 100 nM; "B" indicates an IC₅₀ value in the range of 100 nM up to 1 μΜ; "C" indicates an IC₅₀ value in the range of 1 μΜ up to 10 μΜ; "D" indicates an IC₅₀ value 10 μΜ or greater, and "NT" indicates that the compound has not been tested.

TABLE 2 - Assay Results of Exemplary Compounds of Formulae I, la, lb, and Ic

INCORPORATION BY REFERENCE

[00263] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS

[00264] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

CLAIM 1. A compound having structural Formula I:

I , or a stereo somer t ereo , or a p armaceut ca y accepta e sa t of either of the foregoing, wherein:

ring A is selected from:

, wherein:

“1” represents the position of ring A bound to -C(O)-N(R³)CH(R⁶)C(=R⁴)(R⁵) in the compound;

each of R^2a and R^2b is independently selected from hydrogen, deuterium, halogen, -CN, - S(O)₂-C₁-C₄ alkyl, optionally substituted phenyl, and C₁-C₄ alkyl optionally substituted with one or more of halogen;

R³ is selected from hydrogen and C₁-C₄ alkyl;

R⁴ is O; and

R⁵ is optionally substituted C₃-C₆ cycloalkyl or -N(R¹¹)(R¹²), wherein:

R¹² is selected from hydrogen and C₁-C₄ alkyl; or

R¹¹ and R¹² are taken together to form a heterocyclyl,

wherein any alkyl, aryl, heterocyclyl, or heteroaryl portion of R¹¹, R¹² or R¹¹ and R¹² taken together is optionally substituted with one or more substituents selected from–halogen, -OH, C₁- C₄ alkyl, -(CH₂)_0-1-C(O)-N(R¹³)(R¹⁴), -C(O)OR¹⁴, -(CH₂)_0-1-N(R¹³)(R¹⁴), optionally substituted oxadiazolyl, optionally substituted tetrazolyl, and optionally substituted aryl, wherein:

R¹³ is selected from hydrogen and C₁-C₄ alkyl;

R¹⁴ is selected from C₁-C₄ alkyl, -(C₁-C₄ alkylene)-N(C₁-C₄ alkyl)₂, -(C₁-C₄ alkylene)-NH(C₁-C₄ alkyl), -(C₁-C₂ alkylene)-phenyl, -(C₁-C₂ alkylene)-heteroaryl, - CH(R’)-C(O)-O-(C₁-C₄ alkyl), -CH(R’)-C(O)-OH, -CH(R’)-C(O)-NH-(C₁-C₄ alkyl), - CH(R’)-C(O)-N(C₁-C₄ alkyl)₂, -CH(R’)-C(O)-NH-(C₁-C₄ alkylene)-phenyl, -CH(R’)- C(O)-NH-CH(R’’)-C(O)-O-(C₁-C₄ alkyl), -CH(R’)-C(O)-NH-CH(R’’)-C(O)-OH, - CH(R’)-C(O)-NH-CH(R’’)-C(O)-NH-(C₁-C₄ alkyl), -CH(R’)-C(O)-NH-CH(R’’)-C(O)- N(C₁-C₄ alkyl)₂, and -CH(R’)-C(O)-NH-CH(R’’)-C(O)-NH-(C₁-C₄ alkylene)-phenyl, wherein each of R’ and R’’ is a side chain of an amino acid; or

R¹³ and R¹⁴ are taken together to form a heterocyclyl; and

wherein any alkyl, alkylene, heteroaryl, phenyl or heterocyclyl portion of R¹³, R¹⁴ or R¹³ and R¹⁴ taken together is optionally substituted; or

R⁴ is N, and R⁴ and R⁵ are taken together to form an optionally substituted heteroaryl or heterocyclyl;

R⁶ is a C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from F, deuterium and C₃-C₆ cycloalkyl;

and

R⁸ is selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, -C(O)O-C₁-C₄ alkyl, -C(O)N(R⁹)(R¹⁰), aryl, heteroaryl, and heterocyclyl, with the proviso that R⁸ is not methyl when A is

nd R¹¹ and R¹² are taken together to form an unsubstituted heterocyclyl; wherein:

R⁹ is selected from hydrogen and C₁-C₄ alkyl; and

R¹⁰ is selected from C₁-C₆ alkyl and C₃-C₆ cycloalkyl; or

R⁹ and R¹⁰ are taken together to form a heterocyclyl, and

wherein any alkyl, alkenyl, cycloalkyl, heteroaryl or heterocyclyl portion of R⁸, R⁹ or R¹⁰ is optionally substituted.

2. The compound of claim 1, wherein ring A is

3. The compound of claim 1 or 2, wherein each of R^1a and R^1b is independently selected from hydrogen, deuterium and F.

4. The compound of any one of claims 1-3, wherein each of R^2a and R^2b is independently selected from hydrogen, deuterium, F, Cl, -CN, -CH₃, -CF₃, -S(O)₂CH₃ and unsubstituted phenyl.

5. The compound of any one of claims 1-4, wherein R³ is hydrogen.

6. The compound of any one of claims 1-5, wherein R⁴ is O.

7. The compound of any one of claims 1-5, wherein R⁴ and R⁵ are taken together to form a heteroaryl selected from thiazol-2-yl, benzo[d]oxaol-2-yl, 1,2,4-oxadiazol-5-yl, and 1H- imidazol-2-yl, wherein the heteroaryl is optionally substituted.

8. The compound of claim 7, wherein R⁴ and R⁵ are taken together to form 4-((N-isopropyl- N-methyl)aminocarbonyl)thiazol-2-yl, benzo[d]oxaol-2-yl, 3-(phenylmethyl)-1,2,4- oxadiazol-5-yl, or 1-(phenylmethyl)-1H-imidazol-2-yl.

9. The compound of any one of claims 1-8, wherein R⁶ is selected from ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropylmethyl, cyclohexylmethyl, neopentyl, and isopentyl, wherein R⁶ is optionally substituted with one or more deuterium or F.

10. The compound of claim 9, wherein R⁶ is selected from -CH₂CH(CH₃)₂,

11. The compound of any one of claims 1-10, wherein each of R^7a and R^7b is independently selected from hydrogen, F and -CH3.

12. The compound of any one of claims 1-11, wherein R⁸ is selected from C₁-C₆ alkyl; C₄-C₆ alkenyl substituted with F; -C(O)O-C₁-C₄ alkyl; -C(O)N(R⁹)(R¹⁰); phenyl; oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; triazolyl; and oxetanyl, wherein:

R⁹ is selected from hydrogen and -CH₃; and

R¹⁰ is selected from C₁-C₆ alkyl and C₃-C₆ cycloalkyl; or

wherein:

any alkyl portion of R¹⁰ is optionally substituted with phenyl;

13. The compound of claim 12, wherein R⁸ is selected from methyl, propyl, hexyl, t- butylaminocarbonyl, 5-(t-butyl)-1,2,4-oxadiazol-3-yl, 5-(t-butyl)-1,3,4-oxadiazol-2-yl, 5- (t-butyl)-oxazol-2-yl, 5-(t-butyl)-isoxazol-3-yl, 2-(t-butyl)oxazol-5-yl, 2-(t-butyl)oxazol- 4-yl, 4-(t-butyl)oxazol-2-yl, 1-methylcycloprop-1-ylaminocarbonyl,

dimethylaminocarbonyl, isopropylaminocarbonyl, 1-fluoro-3,3-dimethylbut-1-enyl, 1- ethylcycloprop-1-ylaminocarbonyl, 3-(phenyl)oxetan-3-yl, 4-(t-butyl)phenyl, 2-(t- butyl)pyridin-5-yl, 2-(t-butyl)thiazol-5-yl, 2-(t-butyl)thiazol-4-yl, 5-(t-butyl)thiazol-2-yl, 4-(t-butyl)thiazol-2-yl, 4-trifluoromethylphenyl, butoxycarbonyl, t-butoxycarbonyl, 1- butyl-1,2,3-triazol-4-yl, 5-butyl-1,2,4-oxadiazol-3-yl, 1H-1,2,3-triazol-4-yl, 1- (phenylmethyl)-1,2,3-triazol-4-yl, 1-(2-phenoxyethyl)-1,2,3-triazol-4-yl, 5- (isopropyl)oxazol-2-yl, 4-methyl-5-isopropyloxazol-2-yl, methoxycarbonyl, 2-methyl- 1,3,4-oxadiazoly-2-yl, 3-ethyloxetan-3-yl, isobutoxycarbonyl, 1-fluorohex-1-enyl, 1- fluorohexyl, N-butyl-N-methylaminocarbonyl, 2-butyl-1,3,4-oxadiazol-2-yl, 5- neopentyl-1,2,4-oxadiazol-3-yl, N-(2-phenylethyl)-N-methylaminocarbonyl, bicyclo[1.1.1]pentaneaminocarbonyl, 1-cyclobut-1-ylaminocarbonyl, 1- (trifluoromethyl)cycloprop-1-ylaminocarbonyl, 2,2,6,6-tetramethylpiperidin-1- ylcarbonyl, and N-(t-butyl)-N-methylaminocarbonyl.

14. The compound of any one of claims 1-13, wherein R⁵ is -N(R¹¹)(R¹²), and R¹¹ is selected from -(C₁-C₂ alkyl)-heteroaryl, -(C₁-C₂ alkyl)-heterocyclyl, -(C₁-C₂ alkyl)-aryl, and -(C₁- C₂ alkyl)-C(O)-heterocyclyl; and R¹² is selected from hydrogen and C₁-C₄ alkyl; wherein any alkyl, aryl, heterocyclyl, or heteroaryl portion of R¹¹ or R¹² is optionally substituted with one or more substituents selected from–halogen, -OH, C₁-C₄ alkyl, -(CH₂)_0-1-C(O)- N(R¹³)(R¹⁴), -C(O)OR¹⁴, -(CH₂)_0-1-N(R¹³)(R¹⁴), optionally substituted oxadiazolyl, optionally substituted tetrazolyl, and optionally substituted aryl, or

R¹¹ and R¹² are taken together to form a heterocyclyl substituted with one or more substituents selected from–halogen, -OH, C₁-C₄ alkyl, -(CH₂)_0-1-C(O)-N(R¹³)(R¹⁴), - C(O)OR¹⁴, -(CH₂)_0-1-N(R¹³)(R¹⁴), optionally substituted oxadiazolyl, optionally substituted tetrazolyl, and optionally substituted aryl.

15. The compound of any one of claims 1-6 or 9-14, wherein R¹¹ is quinolin-3-ylmethyl, isoxazol-3-ylmethyl, isoxazol-4-ylmethyl, isoxazol-5-ylmethyl, 1H-pyrazol-4-yl, morpholin-2-ylmethyl, 2-(thiazol-5-yl)ethyl, 1,2,5-oxadiazol-3-ylmethyl,

tetrahydrofuran-3-ylmethyl, dioxan-2-ylmethyl, pyrazin-2-ylmethyl, pyrimidin-4- ylmethyl, furan-3-ylmethyl, tetrahydropyran-4-ylmethyl, pyrrolidin-3-ylmethyl, pyridin- 2-ylmethyl, pyridin-3-ylmethyl, thiazol-4-ylmethyl, 1,2,3,4-tetrazol-5-ylmethyl, phenylmethyl, and 1-(piperazin-1-ylcarbonyl)ethyl; and wherein R¹¹ is optionally substituted with up to 3 substituents independently selected from C₁-C₄ alkyl and -(C₀-C₂ alkylene)-phenyl.

16. The compound of any one of claims 1-6 or 9-14, wherein R¹² is selected from hydrogen and -CH₃.

17. The compound of any one of claims 1-6 or 9-14, wherein R¹¹ and R¹² are taken together to form a heterocyclyl or heteroaryl ring selected from pyrrolidin-1-yl, 3- azabicyclo[3.1.0]hexan-3-yl, morpholin-4-yl, piperidin-1-yl, azetidin-1-yl, indolin-1-yl, 5-azaspiro[2.4]heptan-5-yl, and piperazin-1-yl, wherein the heterocyclyl or heteroaryl ring is optionally substituted with one or more substituents independently selected from - halogen, -OH, C₁-C₄ alkyl optionally substituted with one or more substituents selected from F and deuterium, - C(O)-N(R¹³)(R¹⁴), -C(O)O-(C₁-C₄ alkyl) optionally substituted with one or more substituents selected from F and deuterium, -C(O)R¹⁴, - CH₂N(R¹³)(R¹⁴), -NH-(C₁-C₄ alkyl), and a ring selected from oxadiazolyl, tetrazolyl, and optionally phenyl, wherein the ring substituent is optionally further substituted with one or more substituents selected from -(C₀-C₂ alkylene)-phenyl, C₁-C₆ alkyl, wherein:

R¹³ is selected from hydrogen and C₁-C₄ alkyl;

R¹⁴ is selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, deuterated C₁-C₄ alkyl, -(C₁-C₄ alkylene)-N(C₁-C₄ alkyl)₂, -(C₁-C₄ alkylene)-NH(C₁-C₄ alkyl), -(C₁-C₂ alkylene)-phenyl, -(C₁-C₂ alkylene)-heteroaryl, -CH(R’)-C(O)-O-(C₁-C₄ alkyl), -CH(R’)-C(O)-OH, - CH(R’)-C(O)-NH-(C₁-C₄ alkyl), -CH(R’)-C(O)-N(C₁-C₄ alkyl)₂, -CH(R’)-C(O)-NH-(C₁- C₄ alkylene)-phenyl, -CH(R’)-C(O)-NH-CH(R’’)-C(O)-O-(C₁-C₄ alkyl), -CH(R’)-C(O)- NH-CH(R’’)-C(O)-OH, -CH(R’)-C(O)-NH-CH(R’’)-C(O)-NH-(C₁-C₄ alkyl), -CH(R’)- C(O)-NH-CH(R’’)-C(O)-N(C₁-C₄ alkyl)₂, and -CH(R’)-C(O)-NH-CH(R’’)-C(O)-NH- (C₁-C₄ alkylene)-phenyl, or

R¹³ and R¹⁴ are taken together to form a heterocyclyl selected from piperazin-1- yl, morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-oxa-7-azaspiro[2.5]octan-7-yl, octahydropyrrolo[3,4-c]pyrrol-2-yl, 2,5-diazabicyclo[2.2.2]octan-2-yl, 3,8- diazabicyclo[3.2.1]octan-3-yl, 4,7-diazaspiro[2.5]octan-4-yl, and octahydropyrrolo[1,2- a]pyrazin-2-yl, wherein:

each of R’ and R’’ is a side chain of an amino acid.

18. The compound of claim 1, having structural Formula Ia:

(Ia), or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

R¹⁵ is selected from C₃-C₆ alkyl and -CH₂-(C₃-C₆ cycloalkyl);

R¹⁶ is selected from C₁-C₆ alkyl optionally substituted with one or more F; C₂-C₆ alkenyl optionally substituted with one or more F; -C(O)OR²⁰; -C(O)N(R²¹)(R²²);

triazolyl; oxazolyl; and oxadiazolyl, wherein

R²⁰ is selected from C₃-C₆ alkyl;

R²¹ is selected from hydrogen and -CH₃; and

R²² is selected from C₁- C₄ alkyl; C₃-C₆ cycloalkyl optionally substituted with C₁-C₄ alkyl; and -(C₁-C₂ alkylene)-phenyl;

R¹⁸ is -N(R²⁴)(R²⁵), wherein:

R²⁴ is selected from hydrogen and -CH₃;

R²⁵ is selected from C₃-C₆ alkyl, -(C₁-C₂ alkylene)-phenyl, - CH(phenylmethyl)-C(O)-N(R²⁷)(R²⁸), wherein R²⁷ is selected from hydrogen and C₁-C₄ alkyl; and R²⁸ is selected from C₁-C₄ alkyl and -(C₁-C₂ alkylene)-phenyl; or

R²⁴ and R²⁵ are taken together to form morpholinyl, piperazinyl, or pyrrolidinyl, wherein morpholinyl, piperazinyl, or pyrrolidinyl is optionally substituted with up to three substituents independently selected from C₁-C₆ alkyl, -(C₀-C₂ alkylene)-phenyl, -(C₀-C₂ alkylene)-(C₃-C₆ cycloalkyl), and -C(O)-O-C₁- C₄ alkyl;

each of R^19a and R^19b is independently selected from hydrogen and halogen; and

R²⁶ is hydrogen or -OH.

19. The compound of claim 18, wherein:

R¹⁶ is selected from -CH₃, -CF=CH-C(CH₃)₃, -CF=CH(CH₂)₃CH₃, -CHF- (CH₂)₄CH₃, -C(O)N(CH₃)₂, -C(O)NHC(CH₃)₃, -C(O)NHCH(CH₃)₂, -C(O)OC(CH₃)₃, - C(O)OCH₂CH(CH₃)₂, -C(O)O(CH₂)₃CH₃, N-(2-(phenyl)ethyl)-N-methylaminocarbonyl, 1-ethylcycloprop-1-ylaminocarbonyl, 1-methylcycloprop-1-ylaminocarbonyl, 1- (phenylmethyl)-1,2,3-triazol-4-yl, 1-(butyl)-1,2,3-triazol-4-yl, 1-(2-phenoxy)ethyl-1,2,3- triazol-4-yl, 5-t-butyl-oxazol-2-yl, 5-butyl-1,3,4-oxadiazol-2-yl, 5-t-butyl-1,2,4- oxadiazol-3-yl, and 5-butyl-1,2,4-oxadiazol-3-yl;

R^17a is selected from hydrogen and F;

R^17b is selected from hydrogen, F and -CH₃;

R¹⁸ is selected from -N(CH₃)CH(CH₃)₂, -N(CH₃)CH₂CH(CH₃)₂, morpholin-4-yl, 2-isopropylmorpholin-4-yl, 3-cyclopropyl-4-methylpiperazin-1-yl, 3-(butan-2-yl)-4- methylpiperazin-1-yl, 3-neopentyl-4-methylpiperazin-1-yl, 3-phenylmethyl-4-t- butoxycarbonylpiperazin-1-yl, 3-cyclobutylmethyl-4-methylpiperazin-1-yl, 3- cyclohexyl-4-methylpiperazin-1-yl, 3-cyclohexylmethyl-4-methylpiperazin-1-yl, 2- phenylmethylmorpholin-4-yl, 3-phenyl-4-methylpiperazin-1-yl, 2-phenylmethyl-4- methylpiperazin-1-yl, 3-phenylmethyl-4-methylpiperazin-1-yl, 2-phenylpyrrolidin-1-yl, N-(1-dimethylaminocarbonyl-2-(phenyl)ethyl)-N-methylamino, N-(1-(N-butyl-N- methylaminocarbonyl)-2-(phenyl)ethyl)-N-methylamino, N-2-phenylethyl-N- methylamino, and N-(1-(2-phenylethylaminocarbonyl)-2-phenyl)ethyl-N-methylamino;

R^19a is selected from hydrogen, Cl and Br;

R^19b is hydrogen; and

R²⁶ is hydrogen or -OH.

20. The compound of claim 18 or 19, having the structural Formula Ib:

21. The compound of claim 1, having the structure of Formula Ic:

Ic) or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

R²⁹ is selected from C₃-C₆ alkyl and -CH₂-(C₃-C₆ cycloalkyl);

triazolyl; oxazolyl; and oxadiazolyl, wherein

R³⁴ is selected from C₃-C₆ alkyl;

R³⁵ is selected from hydrogen and -CH₃; and

R³⁶ is selected from C₁-C₄ alkyl; C₃-C₆ cycloalkyl optionally substituted with C₁-C₄ alkyl; and -(C₁-C₂ alkylene)-phenyl;

R³² is -N(R³⁸)(R³⁹), wherein:

R³⁸ is selected from hydrogen and -CH₃;

R³⁹ is selected from C₃-C₆ alkyl, -(C₁-C₂ alkylene)-phenyl, and - CH(phenylmethyl)-C(O)-N(R⁴¹)(R⁴²), wherein R⁴¹ is selected from hydrogen and C₁-C₄ alkyl; and R⁴² is selected from C₁-C₄ alkyl and -(C₁-C₂ alkylene)-phenyl; or

R³⁸ and R³⁹ are taken together form morpholinyl, piperazinyl, or pyrrolidinyl, wherein morpholinyl, piperazinyl, or pyrrolidinyl is optionally substituted with up to three substituents independently selected from C₁-C₆ alkyl, -(C₀-C₂ alkylene)-phenyl, - (C₀-C₂ alkylene)-(C₃-C₆ cycloalkyl), and -C(O)-O-C₁-C₄ alkyl;

R³³ is selected from hydrogen , halogen, and C₁-C₄ alkyl; and

R⁴⁰ is hydrogen or -OH.

22. The compound of claim 21, wherein:

R²⁹ is -CH₂CH(CH₃)₂,

R³⁰ is selected from–C(O)NHC(CH₃)(CH₂)₂ and -C(O)NHC(CH₃)₃; R^31a is hydrogen;

R^31b is hydrogen;

R⁴⁰ is hydrogen.

23. A compound in Table 1 herein, or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound of any one of claims 1-23; and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising a compound having structural Formula I:

r a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

ring A is selected from:

and

, wherein:

each of R^2a and R^2b is independently selected from hydrogen, deuterium, halogen, -CN, C₁-C₄ alkyl optionally substituted with one or more substituents selected from halogen, -S(O)₂- C1-C4 alkyl, and optionally substituted phenyl;

R³ is selected from hydrogen and C₁-C₄ alkyl;

R⁴ is O; and

R¹² is selected from hydrogen and C₁-C₄ alkyl; or

R¹¹ and R¹² are taken together to form a heterocyclyl,

R¹³ is selected from hydrogen and C₁-C₄ alkyl;

R¹³ and R¹⁴ are taken together to form a heterocyclyl; and

and

R⁸ is selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, -C(O)O-C₁-C₄ alkyl, -C(O)N(R⁹)(R¹⁰), aryl, heteroaryl, and heterocyclyl, wherein:

R⁹ is selected from hydrogen and C₁-C₄ alkyl; and

R¹⁰ is selected from C₁-C₆ alkyl and C₃-C₆ cycloalkyl; or R⁹ and R¹⁰ are taken together to form a heterocyclyl, and

wherein any alkyl, alkenyl, cycloalkyl, heteroaryl or heterocyclyl portion of R⁸, R⁹ or R¹⁰ is optionally substituted; and

a pharmaceutically acceptable carrier.

26. A method of treating a cancer in a subject in need thereof, the method comprising the step of administering to the subject an effective amount of a compound of any one of claims 1-23, or a composition of claim 24 or 25.

27. The method of claim 26, wherein cells associated with the cancer are characterized as having an elevated level of IDO activity and/or expression when compared to non- cancerous cells of the same cell type.

28. The method of claim 26 or 27, wherein the subject is characterized as having an elevated plasma concentration of kynurenine when compared to a subject without the cancer.

29. A method of treating a cancer in a subject in need thereof, the method comprising

administering to the subject an effective amount of a compound of any one of claims 1- 23 or a composition of claim 24 or 25, wherein the cancer is characterized as having an elevated level of IDO gene expression relative to average IDO gene expression in cells of the same cell type without the cancer.

30. A method of treating a cancer in a subject in need thereof, the method comprising

administering to the subject an effective amount of a compound of any one of claims 1- 23 or a composition of claim 24 or 25 wherein the subject has a kynurenine level in a body fluid that is elevated relative to the average kynurenine level in the same type of body fluid in subjects without the cancer.

31. A method of treating a cancer in a subject in need thereof, the method comprising:

a. obtaining a cancer cell sample from the subject;

b. determining the level of IDO gene expression in the sample;

c. comparing the IDO gene expression level in the sample to a threshold value in a normal cell to determine if IDO gene expression is elevated in the cancer sample; d. administering to the subject having an elevated level of IDO gene expression an effective amount of a compound of any one of claims 1-23, or a composition of claim 24 or 25.

32. A method of treating a cancer in a subject in need thereof, the method comprising:

a. obtaining a body fluid sample from the subject;

b. determining the concentration of kynurenine in the fluid sample;

c. comparing the kynurenine concentration in the fluid sample to a threshold value of kynurenine present in the same type of body fluid of subjects without the cancer thereby to determine if kynurenine is elevated in the fluid sample of the subject;

d. administering to the subject having an elevated concentration of kynurenine an effective amount of a compound of any one of claims 1-23, or a composition of claim 24 or 25.

33. The method of any one of claims 26-32, wherein the cancer is selected from cervical, renal, endometrial, squamous cell, colorectal, prostate, head and neck, lung, large B cell lymphoma, or acute myeloid leukemia.

34. The method of any one of claims 26-33, further comprising administering to the subject a cancer immunotherapy agent.

35. The method of claim 34, wherein the cancer immunotherapy agent is a PD-1 inhibitor.

36. The method of claim 35, wherein the PD-1 inhibitor is pembrolizumab.

37. A method of reducing IDO activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1- 23, or a composition of claim 24 or 25.